ZA200306404B - Combination comprising a signal transduction inhibitor and an epothilone derivative. - Google Patents

Description

] oo to WO 02/067941 PCT/EP02/02049 -q-

Combination comprising a Signal Transduction Inhibitor and an Epothilone Derivative

The invention relates to a pharmaceutical combination which comprises (a) a signal ' transduction inhibitor selected from a PDGF (platelet-derived growth factor) receptor tyrosine kinase inhibitor and an active ingredient which decreases the activity of the epidermal growth factor (EGF) and (b) an epothilone derivative of formula | and optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use, in particular, for the delay of progression or treatment of a proliferative disease, especially a solid tumor disease; a pharmaceutical composition comprising such a combination; the use of such a combination for the preparation of a medicament for the delay of progression or treatment of a proliferative disease; a commercial package or product comprising such a combination as a combined preparation for simultaneous, separate or sequential use; and to a method of treatment of a warm-blooded animal, especially a human.

The phosphorylation of proteins has long been known as an important step in the regulation of the differentiation and proliferation of cells. The phosphorylation is catalysed by protein kinases which are divided into serine/threonine kinases and tyrosine kinases. The PDGF receptor and the EGF receptor belong to the group of receptor tyrosine kinases. STI571 and STI571B decreases the activity of the PDGF receptor tyrosine kinase. PKI166 and

IRESSA™ are examples for compounds that decrease the activity of the EGF.

The microtubule-stabilizing effect of the epothilones was first described by Bollag et al.,

Cancer Research 55, 1995, 2325-33. A suitable treatment schedule of different types of tumors, especially tumors which are refractory to the treatment by other chemotherapeutics, in particular TAXOL™, is described in WO 99/43320.

Surprisingly, it has now been found that the anti-proliferative effect, i.e. especially the effect in the delay of progression or treatment of a proliferative disease, of a combination as defined herein is greater than the effect that can be achieved with either type of . combination partner alone, i.e. greater than the effect of a monotherapy using only one of the combination partners (a) and (b) as defined herein. In particular, it was found that the effect of a combination partner (b) is potentiated in the presence of a PDGF receptor tyrosine kinase inhibitor.

A ) []

Co WO 02/067941 PCT/EP02/02049 -D.

Hence, the present invention pertains to a combination such as a combined preparation or . a pharmaceutical composition which comprises (a) a signal transduction inhibitor selected from a PDGF receptor tyrosine kinase inhibitor, especially N-{5-[4-(4-methyl-piperazino- . . methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine (STI571) or the monomesylate salt thereof, and an active ingredient which decreases the activity of the epidermal growth factor (EGF), and (b) an epothilone derivative of formula

R

. LZ 3 a »—

HO M17 NY N ww { A :

O OH O ) in which compound A represents O or NRy, wherein Ry is hydrogen or lower alkyl, R is hydrogen or lower alkyl, and Z is O or a bond, in which the active ingredients (a) and (b) are present in each case in free form or in the form of a pharmaceutically acceptable salt and optionally at least one pharmaceutically acceptable carrier; for simultaneous, separate or sequential use.

A compound of formula | wherein A represents O, R is hydrogen and Z is O is known as epothilone A; a compound of formula | wherein A represents O, Ris methyland Zis O is known as epothilone B; a compound of formula 1 wherein A represents O, Ris hydrogen and Z is a bond is known as epothilone C; a compound of formula | wherein A represents 0, Ris methyl and Z is a bond is known as epothilone D.

The term “a combined preparation”, as used herein defines especially a “kit of parts” in the sense that the combination partners (a) and (b) as defined above can be dosed inde- pendently or by use of different fixed combinations with distinguished amounts of the . combination partners (a) and (b), i.e., simultaneously or at different time points. The parts of the kit can then, e.g., be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts.

Very preferably, the time intervals are chosen such that the effect on the treated disease in bs AR -

Co WO 02/067941 PCT/EP02/02049 the combined use of the parts is larger than the effect which would be obtained by use of . only any one of the combination partners (a) and (b) or such that the effect of a combination partner (b) is potentiated due to the presence of a combination partner (a). The ratio of the . total amounts of the combination partner (a) to the combination partner (b) to be administered in the combined preparation can be varied, e.g. in order to cope with the needs of a patient sub-population to be treated or the needs of the single patient which different needs can be due to age, sex, body weight, etc. of the patients. Preferably, there is at least one beneficial effect, e.g., a mutual enhancing of the effect of the combination partners (a) and (b), in particular a synergism, e.g. a more than additive effect, additional advantageous effects, less side effects, potentiation, i.e. a combined therapeutical effect in a non-effective dosage of one or both of the combination partners (a) and (b), and very preferably a strong synergism of the combination partners (a) and (b).

The term “delay of progression” as used herein means administration of the combination to patients being in an early phase of the proliferative disease to be treated.

The term “solid tumor disease” as used herein comprises, but is not restricted to glioma, thyroid cancer, breast cancer, ovarian cancer, cancer of the colon and generally the Gl tract, cervix cancer, lung cancer, in particular small-cell lung cancer, and non-small-cell lung cancer, head and neck cancer, bladder cancer, cancer of the prostate or Kaposi's sarcoma.

In one preferred embodiment of the invention, the tumor disease to be treated is glioma, cancer of the prostate or thyroid cancer. The present combination inhibits the growth of solid tumors, but also liquid tumors. Furthermore, depending on the tumor type and the particular combination used, a decrease of the tumor volume can be obtained. The combinations disclosed herein are also suited to prevent the metastatic spread of tumors and the growth or development of micrometastases.

It will be understood that references to the combination partners (a) and (b) are meant to : also include the pharmaceutically acceptable salts. If these combination partners (a) and (b) have, for example, at least one basic center, they can form acid addition salts. Corres- } ponding acid addition salts can also be formed having, if desired, an additionally present basic center. The combination partners (a) and (b) having an acid group (for example

COOH) can also form salts with bases. The combination partner (a) or (b) ora

! Sl .

Co WO 02067941 PCT/EP02/02049 pharmaceutically acceptable salt thereof may also be used in form of a hydrate or include . other solvents used for crystallization. . Compounds which decreases the activity of the PDGF receptor tyrosine kinase and methods for their preparation are in particular generically and specifically disclosed in the patent applications EP 0 564 409 A1 and WO 99/03854, in particular in the compound claims and the final products of the working examples, the subject-matter of the final products, the pharmaceutical preparations and the claims are hereby incorporated into the present application by reference to these publications.

Active ingredients which decrease the activity of the EGF are selected from the group consisting of compounds which inhibit the EGF receptor tyrosine kinase, compounds which inhibit the EGF receptor and compounds binding to EGF, and are in particular those compounds generically and specifically disclosed in WO 97/02266, EP 0 564 409, WO 99/03854, EP 0520722, EP 0 566 226, EP 0 787 722, EP 0 837 063, US 5,747,498, WO 98/10767, WO 97/30034, WO 97/49688, WO 97/38983 and, especially, WO 96/33980; in each case in particular in the compound claims and the final products of the working examples, the subject-matter of the final products, the pharmaceutical preparations and the claims is hereby incorporated into the present application by reference to this publications.

Comprised are likewise the corresponding stereoisomers as well as the corresponding crystal modifications, e.g. solvates and polymorphs, which are disclosed therein. The compounds used as active ingredients in the combinations disclosed herein can be prepared and administered as described in the cited documents, respectively. In one preferred embodiment of the invention, the employed active ingredient which decreases the activity of the EGF is PKI166, OSI774, C225 (cetuximab), CI-1033, ABX-EGF, EMD-72000,

IRESSA™ or MDX-447. In a more preferred embodiment of the invention, the employed active ingredient which decreases the activity of the EGF is PKI166, OS1774, C225 or

IRESSA™. Most preferably, such active ingredient is PKI166 {(R)-6-(4-hydroxy-phenyl)-4- - [(1-phenyi-ethyl)-amino}-7H-pyrrolo[2,3-d]-pyrimidine)}, which is disclosed in WO 97/02266. ’ Epothilone derivatives of formula | wherein A represents O or NRy, wherein Ry is hydrogen or lower alkyl, R is hydrogen or lower alkyl and Z is O or a bond, and methods for the preparation of such epothilone derivatives are in particular generically and specifically disclosed in the patents and patent applications WO 93/10121, US 6,194,181, WO

’ oo ;

To © WO 02/067941 PCT/EP02/02049 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO 00/31247 in each case in . particular in the compound claims and the final products of the working examples, the subject-matter of the final products, the pharmaceutical preparations and the claims is . hereby incorporated into the present application by reference to this publications.

Comprised are likewise the corresponding stereoisomers as well as the corresponding crystal modifications, e.g. solvates and polymorphs, which are disclosed therein.

The transformation of epothilone B to the corresponding lactam is disclosed in Scheme 21 (page 31, 32) and Example 3 of WO 99/02514 (pages 48 - 50). The transformation of a compound of formula | which is different from epothilone B into the corresponding lactam can be accomplished analogously. Corresponding epothilone derivatives of formula wherein Ry is lower alkyl can be prepared by methods known in the art such as a reductive alkylation reaction starting from the epothilone derivative wherein Ry is hydrogen.

The structure of the active ingredients identified by code nos., generic or trade names may be taken from the actual edition of the standard compendium “The Merck Index” or from databases, e.g. Patents International (e.g. IMS World Publications). The corresponding content thereof is hereby incorporated by reference. Any person skilled in the art is fully enabled to identify the active ingredients and, based on these references, likewise enabled to manufacture and test the pharmaceutical indications and properties in standard test models, both in vitro and in vivo.

The compounds used as combination partners (a) and (b) disclosed herein can be prepared and administered as described in the cited documents, respectively. PDGF inhibitors of formula Il can, for example, be formulated as disclosed in WO 99/03854, especially the monomesylate salt of N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}- 4-(3-pyridyl)-2-pyrimidine-amine can be formulated as described in Examples 4 and 6 of

WO 99/03854. Epothilone derivatives of formula |, especially epothilone B, can be administered as part of pharmaceutical compositions which are disclosed in WO 99/39694.

A combination which comprises (a) a signal transduction inhibitor selected from a PDGF (platelet-derived growth factor) receptor tyrosine kinase inhibitor and an active ingredient which decreases the activity of the epidermal growth factor (EGF) and (b) an epothilone derivative of formula | in which compound A represents O or NR, wherein Ry is hydrogen

1d A oo or lower alkyl, R is hydrogen or lower alkyl, and Z is O or a bond, in which the active . ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt and optionally at least one pharmaceutically acceptable carrier, will be ‘ referred to hereinafter as a COMBINATION OF THE INVENTION. - The nature of proliferative diseases like solid tumor diseases is multifactorial. Under certain circumstances, drugs with different mechanisms of action may be combined. However, just considering any combination of drugs having different mode of action does not necessarily lead to combinations with advantageous effects.

All the more surprising is the experimental finding that in vivo the administration of a

COMBINATION OF THE INVENTION results not only in a beneficial, especially a synergistic therapeutic effect, but also in further surprising beneficial effects, e.g. less than additive side-effects and a decreased mortality and morbidity, compared to a equiefficacious monotherapy applying only one of the pharmaceutically active ingredients used in the

COMBINATION OF THE INVENTION. In particular, an increased up-take of the epothilone derivative of formula | in the tumor tissue is observed, when the epothilone derivative of formula | is applied in combination with a PDGF receptor tyrosine kinase inhibitor, especially those disclosed hereinbefore and hereinafter, even if the tumor cells themselves have no

PDGF receptors.

A further benefit is that lower doses of the active ingredients of the COMBINATION OF THE

INVENTION can be used, for example, that the dosages of at least one combination partner need not only often be smaller, but are also applied less frequently, in order to diminish the incidence of side-effects. This is in accordance with the desires and requirements of the patients to be treated. it can be shown by established test models and in particular those test models described herein that a COMBINATION OF THE INVENTION results in a more effective delay of progression or treatment of a proliferative disease compared to the effects observed with the single combination partners. The person skilled in the pertinent art is fully enabled to select a relevant test mode! to prove the hereinbefore and hereinafter mentioned thera- peutic indications and beneficial effects. The pharmacological activity of a COMBINATION o \ A oT

To WO 02/067941 PCT/EP02/02049 -7-

OF THE INVENTION may, for example, be demonstrated in a clinical study or in a test . procedure as essentially described hereinafter. : Suitable clinical studies are in particular open label non-randomized, dose escalation studies in patients with advanced solid tumors. Such studies prove in particular the synergism of the active ingredients of the COMBINATIONS OF THE INVENTION. The beneficial effects on proliferative diseases can be determined directly through the results of these studies or by changes in the study design which are known as such to a person skilled in the art. Such studies are, in particular, suitable to compare the effects of a monotherapy using the active ingredients and a COMBINATION OF THE INVENTION.

Preferably, the signal transduction inhibitor is administered with a fixed dose and the dose of the epothilone derivative of formula |, e.g. epothilone B, is escalated until the Maximum

Tolerated Dosage is reached.

In a preferred embodiment of the study, each patient receives daily doses of a PDGF receptor tyrosine kinase inhibitor, whereas the epothilone derivative of formula | is administered once weekly i.v. for three weeks, followed by one week off. Each four week interval will be considered one cycle. Day 1 of each cycle is defined as the day of administration of epothilone derivative of formula | and the PDGF receptor tyrosine kinase inhibitor. The efficacy of the treatment can be determined in these studies, e.g., after 18 or 24 weeks by radiologic evaluation of the tumors every 6 weeks. In an alternative embodiment of such a clinical study, the PDGF inhibitor is given as a pretreatment, i.e. before the treatment with the COMBINATION OF THE INVENTION is started, the PDGF . inhibitor alone is administered to the patient for a defined period of time, e.g. daily administration of the PDGF inhibitor alone for two or three days. it is one objective of this invention to provide a pharmaceutical composition comprising a quantity, which is jointly therapeutically effective against a proliferative disease comprising the COMBINATION OF THE INVENTION. In this composition, the combination partners (a) and (b) can be administered together, one after the other or separately in one combined unit dosage form or in two separate unit dosage forms. The unit dosage form may also be a fixed combination.

F o -8-

The pharmaceutical compositions according to the invention can be prepared in a manner . known per se and are those suitable for enteral, such as oral or rectal, and parenteral administration to mammals (warm-blooded animals), including man, comprising a thera- . peutically effective amount of at least one pharmacologically active combination partner alone or in combination with one or more pharmaceutically acceptable carries, especially suitable for enteral or parenteral application.

The novel pharmaceutical composition contain, for example, from about 10 % to about 100 %, preferably from about 20 % to about 60 %, of the active ingredients. Pharmaceutical preparations for the combination therapy for enteral or parenteral administration are, for example, those in unit dosage forms, such as sugar-coated tablets, tablets, capsules or suppositories, and furthermore ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example by means of conventional mixing, granulating, sugar- coating, dissolving or lyophilizing processes. It will be appreciated that the unit content of a combination partner contained in an individual dose of each dosage form need not in itself constitute an effective amount since the necessary effective amount can be reached by administration of a plurality of dosage units.

In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents; or carriers such as starches, sugars, microcristalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed.

In particular, a therapeutically effective amount of each of the combination partner of the ‘ COMBINATION OF THE INVENTION may be administered simultaneously or sequentially and in any order, and the components may be administered separately or as a fixed combination. For example, the method of delay of progression or treatment of a proliferative disease according to the invention may comprise (i) administration of the first combination partner in free or pharmaceutically acceptable salt form and (ii) adminstration of the second combination partner in free or pharmaceutically acceptable salt form, simultaneously or sequentially in any order, in jointly therapeutically effective amounts, preferably in . synergistically effective amounts, e.g. in daily or weekly dosages corresponding to the amounts described herein. The individual combination partners of the COMBINATION OF . THE INVENTION can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. Furthermore, the term administering also encompasses the use of a pro-drug of a combination partner that convert in vivo to the combination partner as such. The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.

The effective dosage of each of the combination partners employed in the COMBINATION

OF THE INVENTION may vary depending on the particular compound or pharmaceutical composition employed, the mode of administration, the condition being treated, the severity of the condition being treated. Thus, the dosage regimen for the COMBINATION OF THE

INVENTION is selected in accordance with a variety of factors including the route of administration and the renal and hepatic function of the patient. A physician, clinician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the single active ingredients required to prevent, counter or arrest the progress of the condition.

Optimal precision in achieving concentration of the active ingredients within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the active ingredients’ availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of the active ingredients.

When the combination partners employed in the COMBINATION OF THE INVENTION are applied in the form as marketed as single drugs, their dosage and mode of administration can take place in accordance with the information provided on the packet leaflet of the respective marketed drug in order to result in the beneficial effect described herein, if not mentioned herein otherwise.

If the the warm-blooded animal is a human, the dosage of a compound of formula 1 is preferably in the range of about 0.25 to 75, preferably 0.5 to 50, e.g. 2.5, mg/m? once weekly for two to four, e.g. three, weeks, followed by 6 to 8 days off in the case of an adult patient. In one embodiment of the invention, epothilone B is administered in accordance

To © WO 02/067941 PCT/EP02/02049 with the treatment schedule described in US 6,302,838 which disclosure is enclosed herein : by reference. : Unless stated otherwise herein, the PDGF receptor tyrosine kinase inhibitors are preferably administered from one to four times per day. Furthermore, the PDGF receptor tyrosine kinase inhibitors, especially N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2- methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine monomesylate, are preferably administered to the warm-blooded animal in a dosage in the range of about 2.5 to 1000 mg/day, more preferably 5 to 750 mg/day and most preferably 25 to 300 mg/day, e.g. 100 mg or 200 mg/day, when the warm-blooded animal is a human.

The dosage of PKI166, if employed, is preferably in the range of about 50 to 700, more preferably about 100 to 500, and most preferably about 150 to 300, mg/day. In one embodiment the present invention PKI166 is administered to the human subject less frequently than on a daily basis. In particular, a treatment regimen is employed wherein over at least a three week period PKI166 is administered on only about 40% to about 71% of the days.

Unless stated otherwise, in the present disclosure organic radicals and compounds designated “lower” contain not more than 7, preferably not more than 4, carbon atoms.

In a preferred embodiment of the invention, the COMBINATION OF THE INVENTION comprises (a) a PDGF receptor tyrosine kinase inhibitor which is a N-phenyl-2-pyrimidine- amine derivative of formula Il,

R, Rs

R R Rs

NEVE ( _ : a,

R; / No N, R, —N H

Ry wherein R, is 4-pyrazinyl; 1-methyl-1H-pyrrolyl; amino- or amino-lower alkyl-substituted phenyl, wherein the amino group in each case is free, alkylated or acylated; 1H-indolyl or

1H-imidazolyl bonded at a five-membered ring carbon atom; or unsubstituted or lower alkyl- substituted pyridyl bonded at a ring carbon atom and unsubstituted or substituted at the nitrogen atom by oxygen; R. and R; are each independently of the other hydrogen or lower - alkyl; one or two of the radicals Rs, Rs, Rs, R; and Rs are each nitro, fluoro-substituted lower alkoxy or a radical of formula lll . -N(Rs)-C(=X)-(Y)n-R1o (ny, wherein Rg is hydrogen or lower alkyl, X is oxo, thio, imino, N-lower alkyl-imino, hydroximino or O-lower alkyl-hydroximino, Y is oxygen or the group NH, n is 0 or 1 and Ry is an aliphatic radical having at least 5 carbon atoms, or an aromatic, aromatic-aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, heterocyclic or heterocydlic-aliphatic radical, and the remaining radicals Ry, Rs, Re, Ry and Rg are each independently of the others hydrogen, lower alkyl that is unsubstituted or substituted by free or alkylated amino, piperazinyl, piperidinyl, pyrrolidinyl or by morpholinyl, or lower alkanoyl, trifluoromethyl, free, etherified or esterifed hydroxy, free, alkylated or acylated amino or free or esterified carboxy, and (b) an epothilone derivative of formula | in which compound A represents O or NRy, wherein Ry is hydrogen or lower alkyl, R is hydrogen or lower alkyl, and Z is O or a bond, in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt and optionally at least one pharmaceutically acceptable carrier. 1-Methyl-1H-pyrrolyl is preferably 1-methyl-1H-pyrrol-2-yl or 1-methyl-1H-pyrrol-3-yl.

Amino- or amino-lower alkyl-substituted phenyl R, wherein the amino group in each case is free, alkylated or acylated is phenyl substituted in any desired position (ortho, meta or para) wherein an alkylated amino group is preferably mono- or di-lower alkylamino, for example dimethylamino, and the lower alkyl moiety of amino-lower alkyl! is preferably linear C;-

Casalkyl, such as especially methyl or ethyl. 1H-Indolyl bonded at a carbon atom of the five-membered ring is 1H-indol-2-yl or 1H-indol- 3-yl.

Unsubstituted or lower alkyl-substituted pyridyl bonded at a ring carbon atom is lower alkyl- substituted or preferably unsubstituted 2-, 4- or preferably 3-pyridyl, for example 3-pyridyl,

Claims (21)

What is claimed is:

1. A combination which comprises (a) a signal transduction inhibitor selected from a PDGF (platelet-derived growth factor) receptor tyrosine kinase inhibitor and an active ingredient which decreases the activity of the epidermal growth factor (EGF) and (b) an epothilone derivative of formula R 2 pL > Ss >— 1) / HO fry x | N Ww S A EO O OH O in which compound A represents O or NRy, wherein Ry is hydrogen or lower alkyl, R is hydrogen or lower alkyl, and Z is O or a bond, in which the active ingredients (a) and (b) are present in each case in free form or in the form of a pharmaceutically acceptable salt and optionally at least one pharmaceutically acceptable carrier; for simultaneous, separate or sequential use. :

2. Combination according to claim 1 which comprises (a) a PDGF receptor tyrosine kinase inhibitor which is a N-phenyi-2-pyrimidine-amine derivative of formula Ii, R, Rg R, R; R, _ H R, wherein

R, is 4-pyrazinyl; 1-methyl-1H-pyrrolyl; amino- or amino-lower alkyl-substituted phenyl, R wherein the amino group in each case is free, alkylated or acylated; 1H-indolyl or 1H- imidazolyl bonded at a five-membered ring carbon atom; or unsubstituted or lower alkyl-- . substituted pyridyl bonded at a ring carbon atom and unsubstituted or substituted at the nitrogen atom by oxygen; R; and Rj are each independently of the other hydrogen or lower alkyl, one or two of the radicals Rs, Rs, Rs, Ry and Rg are each nitro, fluoro-substituted lower alkoxy or a radical of formula Ill “N(Ro)-C(=X)-(Y)n-R1o (in), wherein Rs is hydrogen or lower alkyl, X is oxo, thio, imino, N-lower alkyl-imino, hydroximino or O-lower alkyl-hydroximino, Y is oxygen or the group NH, nisOor1and Ryo is an aliphatic radical having at least 5 carbon atoms, or an aromatic, aromatic-- aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, heterocyclic or heterocyclic-aliphatic radical, ‘and the remaining radicals Rs, Rs, Rs, R; and Rg are each independently of the others hydrogen, lower alkyl that is unsubstituted or substituted by free or alkylated amino, piperazinyl, piperidinyl, pyrrolidinyl or by morpholinyl, or lower alkanoyl, trifluoromethyl, free, etherified or esterifed hydroxy, free, alkylated or acylated amino or free or esterified carboxy, and (b) an epothilone derivative of formula 1 in which compound A represents O or NRy, wherein Ry is hydrogen or lower alkyl, R is hydrogen or lower alkyl, and Z is O or a bond, in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt and optionally at least one pharmaceutically acceptable carrier. :

3. Combination according to claim 1 or 2 which comprises (a) a PDGF receptor tyrosine kinase inhibitor of formula Il, wherein R; is pyridyl or N-oxido-pyridyl each of which is bonded at a carbon atom,

R. and R; are each hydrogen,

Rs is hydrogen or lower alkyl, . | Rs is hydrogen, lower alkyl or trifluoromethyl, Rs is hydrogen, Ry is nitro, fluoro-substituted lower alkoxy or a radical of formula Il wherein R; is hydrogen, X is oxo, nis 0 and Ryo is pyridyl bonded at a carbon atom, phenyl that is unsubstituted or substituted by halogen, cyano, lower alkoxy, carboxy, lower alkyl or by 4-methyl-piperazinyl-methyl, or Cs-Cralkyl, thienyl, 2-naphthyl or cyclohexyl, and : Rs is hydrogen; and (b) an epothilone derivative of formula | in which compound A represents O or NRy, wherein Ry is hydrogen or lower alkyl, R is hydrogen or lower alkyl, and Z is O or a bond, in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt and optionally at least one pharmaceutically acceptable carrier.

4. Combination according to any one of claims 1 to 3 which comprises (a) a PDGF receptor tyrosine kinase inhibitor of formula Il, wherein R, is pyridyl bonded at a carbon atom, R2, Rs, Rs, Rs and Rg are each hydrogen, R, is lower alkyl, Ry; a radical of formula Il wherein R;, is hydrogen, X is oxo, nis 0 and Ryo is 4-methyl-piperazinyl-methyl, and (b) an epothilone derivative of formula | in which compound A represents O or NRy, wherein Ry is hydrogen or lower alkyl, R is hydrogen or lower alkyl, and Z is O or a bond, in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt and optionally at least one pharmaceutically acceptable carrier.

0 1 OOM

5. Combination according to any one of claims 1 to 4 which comprises (a) a PDGF receptor tyrosine kinase inhibitor of formula Il, which is N-{5-{4-(4-methyl-piperazino-methyi)- benzoylamido]-2-methylphenyi}-4-(3-pyridyi)-2-pyrimidine-amine, and (b) an epothilone derivative of formula I in which compound A represents O or NRy, wherein Ry, is hydrogen or lower alkyl, R is hydrogen or lower alkyl, and Z is O or a bond, in which the active ingredients are present in each case in free form or in the form of a phama- ceutically acceptable salt and optionally at least one pharmaceutically acceptable carrier.

6. Combination according to any one of claims 1 to 5 comprising (a) a PDGF receptor tyrosine kinase inhibitor of formula Il, which is N-{5-{4-(4-methyl-piperazino-methyi)- benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine, wherein the compound is used in the form of its monomesylate salt, and (b) an epothilone derivative of formula in which compound A represents O or NRy, wherein Ry is hydrogen or lower alkyl, Ris hydrogen or lower alkyl, and Z is O or a bond, in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt and optionally at least one pharmaceutically acceptable carrier.

7. Combination according to claim 1 which comprises an active ingredient which decreases the activity of the epidermal growth factor (EGF).

8. Combination according to claim 7 which comprises PKI166.

9. Combination according to any one of claims 1 to 8 wherein in the compound of formula A represents O, R is lower alkyl and Z is O.

10. Combination according to any one of claims 1 to 9 which is a combined preparation or a pharmaceutical composition.

11. Combination according to any one of claims 1 to 10, for use in treating a warm- blooded animal having a proliferative disease, by administration to the animal in a quantity which is jointly therapeutically effective against a proliferative disease and in which the compounds can also be present in the form of their pharmaceutically acceptable salts. AMENDED SHEET

4-31884A

12. A pharmaceutical composition comprising a quantity which is jointly therapeutically effective against a proliferative disease of a pharmaceutical combination according to any one of claims 1 to 10 and at least one pharmaceutically acceptable canier.

13. Use of a combination according to any one of claims 1 to 10 for the delay of progression or treatment of a proliferative disease.

14. Use of a combination according to any one of claims 1 to 10 for the preparation of a medicament for the delay of progression or treatment of a proliferative disease. oo

15. Use of a compound which decreases the activity of the PDGF receptor tyrosine kinase in combination with an epothilone derivative of formula | in which compound A represents O or NRy, wherein Ry, is hydrogen or lower alkyl, R is hydrogen or lower alkyl, and Z is O or a bond for the preparation of a medicament for the delay of progression or treatment of a proliferative disease.

16. Use according to claim 13, 14 or 15 wherein the proliferative disease is a solid tumor disease.

17. A commercial package comprising (a) a signal transduction inhibitor selected from a PDGF receptor tyrosine kinase inhibitor and an active ingredient which decreases the activity of the EGF and (b) an epothilone derivative of formula I in which compound A represents O or NRy, wherein Ry is hydrogen or lower alkyl, R is hydrogen or lower alkyl, and Z is O or a bond, together with instructions for simultaneous, separate or sequential use thereof in the delay of progression or treatment of a proliferative disease.

18. Combination according to claim 1, substantially as herein described and exemplified.

19. A pharmaceutical composition according to claim 12, substantially as herein described and exemplified.

20. Use according to any one of claims 13 — 15, substantially as herein described and exemplified.

21. A commercial package according to claim 17, substantially as herein described and exemplified. AMENDED SHEET