WO2004045611A1

WO2004045611A1 - Use of a thiazolidinedione for the reduction of side effects of chemotherapy

Info

Publication number: WO2004045611A1
Application number: PCT/IB2003/005127
Authority: WO
Inventors: Zoltán SZILVÁSSY; Péter LITERÁTI NAGY
Original assignee: N-Gene Research Laboratories Inc.
Priority date: 2002-11-18
Filing date: 2003-11-07
Publication date: 2004-06-03
Also published as: WO2004045611A8; HUP0203985A2; HUP0203985A3; HU0203985D0

Abstract

The invention refers to the use of a thiazolidinedione derivative of the formula I for the preparation of a pharmaceutical composition suitable for the reduction or elimination of the side effect(s) of an antitumor agent.

Description

DINEDIONE FOR THE REDUCTION OF SIDE EFFECTS OF CHEMOTHERAPY

The invention refers to a novel pharmaceutical use of known thiazolidinedione derivatives.

It is known that the antitumor agents (cytostatics), in addition to their primary antitumor effect, often seriously damage the healthy cells. These side effects can make impossible to continue the treatment with the cytostatics, moreover, in some cases, may lead to the death of the patient. Therefore, it would have very high significance if, during the antitumor treatment, the development of a toxic side effect could be avoided or at least reduced by the parallel administration of another pharmaceutical composition.

Thiazolidinedione derivatives suitable for the reduction of the blood sugar level and blood lipid level are known from the descriptions of US-P 4,572,912; 4,687,777 and 5,002,953.

Furthermore, it is known that certain thiazolidinedione derivatives have also antitumor effect.

It has been found that the known thiazolidinedione derivatives can be used to reduce or eliminate the toxic side effects of antitumor agents.

Thus, the invention refers to the use of thiazolidinedione derivatives of the formula

X-(NR₁)_k-V-(NR₂)_m-(C=O)_n-Y-(Ar)_p-A-C— C=O

I I I

S NH \ / C=O

wherein

X stands for a cyclohexyl group optionally susbtituted by a C-|.₃ alkyl group; a phenyl group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of halo, trifluoromethyl and C₁-5 alkoxy, or the phenyl group is fused with a further benzene ring or a 6-membered saturated ring optionally substituted by 1 to 4 methyl group(s); a 5- or 6- membered, saturated, unsaturated or aromatic heterocyclic group containing 1 or 2 heteroatom(s) selected from the group consisting of nitrogen, oxygen and sulphur and optionally substituted by 1 to 3 substituent(s) selected from the group consisting of C-|.₃ alkyl, oxygen, a further 5- or 6-membered, saturated, unsaturated or aromatic heterocyclic group containing 1 or 2 heteroatom(s) which latter can be nitrogen and/or oxygen and/or sulphur, and a phenyl group optionally substituted by 1-3 substituent(s) selected from the group consisting of C-|.₃ alkyl, hydroxy and Cι_₃ alkoxy, or the heterocyclic group is fused with a phenyl group optionally substituted by 1 to 4 substituent(s) selected from the group consisting of C-|.₃ alkyl, hydroxy and C-|.₃ alkoxy;

Ri and R₂ represent, independently, a hydrogen atom or a Cι-₃ alkyl group;

V is a valence bond or a Cι_₄ alkylene group optionally substituted by a hydroxy or a C₃.₆ cycloalkyl;

Y means a valence bond, an oxygen atom or a group of the formula -NH- or =C=O;

Ar stands for a phenylene group or a naphthylene group, wherein the phenylene group is optionally substituted by 1 to 3 substituent(s) selected from the group consisting of halo, Cι_₃ alkyl and Cι-₃ alkoxy, or the phenylene group is fused with a 5- or 6-membered, saturated, unsaturated or aromatic heterocyclic group containing 1 or 2 heteroatom(s) selected from the group consisting of nitrogen, oxygen and sulphur; A represents a valence bond or a CH group; Zi and Z₂ mean a hydrogen atom or Zi forms with Z₂ a valence bond; k, m, n and p, independently, have a value of 0 or 1 ; or pharmaceutically suitable acid addition salts thereof or salts thereof formed with pharmaceutically suitable bases for the preparation of a pharmaceutical composition suitable for the reduction or elimination of the side-effect(s) of an antitumor agent.

In the description and claims, a C-ι-₃ alkyl group is a methyl, ethyl, n-propyl or isopropyl group.

A Cι-₃ alkoxy group is a methoxy, ethoxy, n-propoxy or isopropoxy group. A C₁.₅ alkoxy group may have straight or branched chain and is, for example, a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, n-pentoxy group etc.

A halo atom is, for example, a fluoro, chloro, bromo or iodo atom.

In the heterocyclic group containing one heteroatom, the latter can be a nitrogen, oxygen or sulphur atom. If the heterocyclic group contains two heteroatoms, the heteroatoms can be two identical or different atoms selected from the group consisting of nitrogen, oxygen and sulphur.

The unsaturated heterocyclic ring contains one or more double bond, however, it does not have an aromatic structure. The unsaturated heterocyclic ring can be examplified by a dihydropyridyl or tetrahydropyridyl group.

If a substituent is substituted by two or more further substituents, such further substituents can be identical or different.

If in formula I, Zi forms with Z₂ a valence bond, then A is attached to the thiazolidine ring by a double bond i.e. A stands for a methylidene group. If A represents a valence bond, then Z₂ means a hydrogen atom.

A pharmaceutically suitable acid addition salt is a salt of the compound of the formula I formed with an inorganic acid such as hydrochloric acid or an organic acid such as acetic acid.

A salt of the compound of the formula I formed with a pharmaceutically suitable base is, in general, the alkali metal salt such as sodium or potassium salt of the compound of the formula I.

The invention includes a method for reducing the side effect(s) in a patient treated with an antitumor agent having side effect(s) comprising administering an effective amount of a thiazolidinedione derivative of the formula I or a pharmaceutically suitable acid addition salt thereof or a salt thereof formed with a pharmaceutically suitable base in addition to said antitumor agent.

Preferred thiazolidinedione derivatives consists of the compounds of the formula I, wherein

X stands for a cyclohexyl group optionally susbtituted by a Cι-₃ alkyl group; a phenyl group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of halo, trifluoromethyl and C₁-₅ alkoxy or the phenyl group is fused with a pyran ring; a 5- or 6-membered, saturated, unsaturated or aromatic heterocyclic group containing 1 or 2 heteroatom(s) selected from the group consisting of nitrogen and oxygen and optionally substituted by 1 to 3 substituent(s) selected from the group consisting of C-|.₃ alkyl, oxygen, and a phenyl group optionally substituted by 1-3 substituent(s) selected from the group consisting of Cι-₃ alkyl, hydroxy and C₁.₃ alkoxy, or the heterocyclic group is fused with a phenyl group optionally substituted by 1 to 4 substituent(s) selected from the group consisting of C-|.₃ alkyl, hydroxy and C-|.₃ alkoxy; R₁ and R₂ represent, independently, a hydrogen atom or a C-|.₃ alkyl group; V is a valence bond or a C-M alkylene group optionally substituted by a hydroxy or a C₃.₆ cycloalkyl;

Y means a valence bond, an oxygen atom or a group of the formula -NH- or =C=O;

Ar stands for a phenylene group or a naphthylene group, wherein the phenylene group is optionally substituted by 1 to 3 substituent(s) selected from the group consisting of halo, Cι-₃ alkyl and Cι-₃ alkoxy;

A represents a valence bond or a CH group;

Zi and Z₂ mean a hydrogen atom or

Zi forms with Z₂ a valence bond; k, m, n and p, independently, have a value of 0 or 1 ; or pharmaceutically suitable acid addition salts thereof or salts formed with pharmaceutically suitable bases.

Still preferred thiazolidinedione derivatives consists of the compounds of the formula I, wherein

X stands for a cyclohexyl group optionally susbtituted by a C-|.₃ alkyl group; a phenyl group optionally substituted by 1 to 3 Cι-₃ alkoxy group(s) or the phenyl group is fused with a pyran ring; a 5- or 6-membered, saturated, unsaturated or aromatic heterocyclic group containing 1 or 2 heteroatom(s) selected from the group consisting of nitrogen and oxygen and optionally substituted by 1 to 3 C-ι-₃ alkyl group(s), or the heterocyclic group is fused with a phenyl group optionally substituted by 1 to 4 C-|.₃ alkyl group(s); Ri and R₂ represent, independently, a hydrogen atom or a C-|.₃ alkyl group;

V is a C-ι-4 alkylene group; Y means an oxygen atom;

Ar stands for a phenylene group, wherein the phenylene group is optionally substituted by 1 to 3 substituent(s) selected from the group consisting of halo, C-|.₃ alkyl and C-|.₃ alkoxy;

A represents a CH group;

Zi and Z₂ mean a hydrogen atom; k, m, n and p, independently, have a value of 0 or 1 ; or pharmaceutically suitable acid addition salts thereof or salts thereof formed with pharmaceutically suitable bases.

Especially preferred thiazolidinedione derivatives consists of the compounds of the formula I, wherein X stands for a cyclohexyl group optionally susbtituted by a Cι-₃ alkyl group; a phenyl group optionally substituted by 1 to 3 C-|.₃ alkoxy group(s) or the phenyl group is fused with a pyran ring; a 5- or 6-membered, saturated, unsaturated or aromatic heterocyclic group containing 1 or 2 heteroatom(s) selected from the group consisting of nitrogen and oxygen and optionally substituted by 1 to 3 Cι-₃ alkyl group(s), or the heterocyclic group is fused with a phenyl group optionally substituted by 1 to 4 Cι-₃ alkyl group(s); Ri represents a C-|.₃ alkyl group;

Y is a Cι-₂ alkylene group;

Y means an oxygen atom;

Ar stands for a phenylene group; A represents a CH group; Zi and Z₂ mean a hydrogen atom; k has a value of 0 or 1 , m and n has a value of 0, and p has a value of 1; or pharmaceutically suitable acid addition salts thereof or salts thereof formed with pharmaceutically suitable bases.

Especially preferred species of the formula I are the following thiazolidinedione derivatives: pioglitazone (+)-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]- methyl]-2,4-thiazolidinedione, troglitazone: (±)-5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetra- methyl-2H-1-benzopyran-2-yl)methoxy]-phenyl]methyl]-2,4- thiazolidinedione, ciglitazone: 5-[[4-[(1 -methylcyclohexyl)methoxy]phenyl]- methyl]-2,4-thiazolidinedione, rosiglitazone: (±)-5-[4-[2-[N-methyl-N-(2-pyridyl)amino]- ethoxy]benzyl]-2,4-thiazolidinedione, englitazone: (-)-5-[(2R)-2-benzyl-6-chromanylmetil]-2,4- thiazolidinedione, balaglitazone: 5-[4-(3,4-dihydro-3-methyl-4-oxo-2- quinazolinyl)-methoxyphenylmetil]-2,4-thiazolidinedione, rivoglitazone: 5-[4-(6-methoxy-1 -methyl-1 H-benzimidazol-2- yl)-methoxyphenylmethyl]-2,4-thiazolidinedione, darglitazone: (+)-5-[4-[3-(5-methyl-2-phenyl-4-oxazolyl)- propionyl]benzyl]-2,4-thiazolidinedione, isaglitazone: (MC-555) 5-[6-(o-fluorobenzyloxy)-2-naphthyl- methyl]-2,4-thiazolidinedione,

KRP-297: 5-[4-methoxy-3-[4-(trifluoromethyl)phenylmethyl- aminocarbonyl]phenylmethyl]-2,4-thiazolidinedione, DN-108: 5-[4-(1 -phenyl-1 -ciclopropanecarbonylamino)- benzyl]-2,4-thiazolidinedione,

DRF-2189: 5-[4-[2-(1 H-indole-1 -yl)-ethoxy]phenylmethyl]-2,4- thiazolidinedione,

T-174: 5-[2-(2-naphthylmethyl)-5-benzoxazolyl]methyl]-2,4- thiazolidinedione,

BM 152054: 5-[4-[2-[5-methyl-2-(2-thienyl)-4-oxazolyl]ethoxy- benzo[b]thien-7-yl]methyl]-2,4-thiazolidinedione,

AD 5075: 5-[4-[-2-hydroxy-2-(5-methyl-2-phenyl-4-oxazolyl)- ethoxy]phenylmethyl]-2,4-thiazolidinedione,

BM 131258: 5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]- benzo[b]thien-7-yl]-methyl]-2,4-thiazolidinedione and

TZ-181 : N-[4-[(Z)-(2,4-dioxo-5-thiazolidinylidene)methyl]- phenyl]-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalene- carboxamide, or pharmaceutically acceptable acid addition salts thereof or salts thereof formed with pharmaceutically suitable bases.

The pharmaceutical composition employed according to the invention is suitable, primarily, for peroral administration, and can be solid or liquid.

The solid pharmaceutical compositions suitable for peroral administration may be powders, capsules, tablets, film-coated tablets, microcapsules etc., and can comprise binding agents such as gelatine, sorbitol, poly(vinylpyrrolidone) etc.; filling agents such as lactose, glucose, starch, calcium phosphate etc.; auxiliary substances for tabletting such as magnesium stearate, talc, poly(ethylene glycol), silica etc.; wetting agents such as sodium laurylsulfate etc. as the carrier.

The liquid pharmaceutical compositions suitable for peroral administration may be solutions, suspensions or emulsions and can comprise e.g. suspending agents such as gelatine, carboxymethylcellulose etc.; emulsifiers such as sorbitane monooleate etc.; solvents such as water, oils, glycerol, propylene glycol, ethanol etc.; preservatives such as methyl p- hydroxybenzoate etc. as the carrier.

The pharmaceutical composition contains dosage unit, in general. A typical dose for adult patients amounts to 0.1 to 1000 mg, preferably 1 to 250 mg of the thiazolidinedione derivative of the formula l or a pharmaceutically suitable acid addition salt or a pharmaceutically suitable salt thereof calculated for 1 kg body weight, daily. The daily dose can be administered in one or more portions. The actual dosage depends on many factors and is determined by the doctor.

The pharmaceutical composition is prepared by admixing the thiazolidonedione derivative of the formula I to one or more pharmaceutical carrier(s) and transforming the mixture obtained into a pharmaceutical composition in a manner known per SΘ.

Dosage forms listed above as well as other dosage forms, the manufacture thereof and pharmaceutical carriers are known from the literature, see e.g. Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co., Easton, USA (1990).

If the thiazolidinedione derivative of the formula I contains one or more chiral carbon atom(s), the pharmaceutical composition may comprise the racemic form, an enantiomer or any mixture of the optical isomers.

It is preferred to administer the thiazolidinedione derivative of the formula I in the form of a controlled release pharmaceutical composition delivering the active ingredient in the course of longer time such as 12 to 24 hours. In this way, the toxic side effect that develops in the treatment with the antitumor agent is continuously reduced.

A known antitumor agent is, from the point of view of the effect, primarily an active agent that inhibits, directly or indirectly, the DNA synthesis and/or transcription (RNA synthesis) and/or translation of the tumor cell or injures the developed DNA.

In detail, the known antitumor agent inhibits:

- adenosine deaminase,

- biosynthesis of purine nucleus,

- biosynthesis of pyrimidine nucleus,

- reduction of ribonucleotides,

- synthesis of thymidine monophosphate,

- synthesis of RNA,

- adduct of DNA,

- synthesis of DNA,

- damage of DNA,

- synthesis of purine nucleus and reduction of dihydrofolate,

- protein synthesis and deamination of asparagine,

- function of proliferation. From the point of view of chemical structure, the known antitumor agents may be:

- alkylating agents comprising nitrogen-containing mustard derivatives, ethylene imine and methylmelamine derivatives, alkyl sulfonates, nitrosoureas, aziridines, triazenes etc.,

- antimetabolites including folic acid analogues, pyrimidine analogues, purine analogues etc.,

- native substances including vinca alkaloids, antibiotics, podophyllotoxins, etc.,

- hormones including adrenocorticosteroids, estrogens, androgens, antiestrogens etc.,

- other substances such as complex forming agents. From the known antitumor agents, preferred alkylating agents are, for example, the following ones: chlormethine: 2-chloro-N-(2-chloroethyl)-N-methyl- ethaneamine hydrochloride mechlorethamine oxide: 2-chloro-N-(2-chIoroethyl)-N-methyl- ethaneamine N-oxide cyclophosphamide: N,N-bis(2-chloroethyl)tetrahydro-2H-

1 ,3,2-oxazaphosphorin-2-amine-2- oxide, iphosphamide: N,3-bis(2-chloroethyl)tetrahydro-2H-

1 ,3,2-oxazaphosphorin-2-amine-2- oxide, melfalan: 4-[bis(2-chloroethyl)amino]-L-phenyl- alanine, chlorambucil: 4-[bis(2-chloroethyl)amino]phenyl- butanoic acid, thiotepa: triethylenethiophosphoric acid amide, busulfan: 1 ,4-butanediol dimethanesulfonate, carmustin: 1 ,3-bis(2-chloroethyl)-1 -nitrosourea, lomustin: 1 -(2-chloroethyl)-3-cyclohexyl-1 - nitrosourea, semustin: 1 -(2-chloroethyl)-3-(4-methyl- cyclohexyl)-1 -nitrosourea, improsulfan: N,N-bis(3-methylsulfonyloxypropyl)- amine, piposulfan: 1 ,4-bis[3-(methanesulfonyloxy)-1 -oxo- propyl]piperazine, benzodepa: bis(1 -aziridinyl)phosphinylcarbamic acid phenylmethyl ester, meturedepa: bis(2,2-dimethyl-1 -aziridinyl)- phosphinylcarbamic acid ethyl ester, uredepa: bis(1 -aziridinyl)-phosphinylcarbamic acid ethyl ester, carboquone: 2-[(2-aminocarbonyloxy)-1 -methoxy- ethyl]-3,6-bis(1-aziridinyl)-5-methyl-

2,5-cyclohexadiene-1 ,4-dione, altretamine: N,N,N',N',N",N"-hexamethyl-1 ,3,5- triazine-2,4,6-triamine, triethylene phosphoramide: tris(1'-aziridinyl)-phosphine oxide, trimethyloimelamine: 2,4,6-tris(methylolamino)-1 ,3,5- triazine, chlornaphazine: N,N-bis(2-chloroethyl)-2-naphthyl- amine, cyclophosphamide: N,N-bis(2-chloroethyl)-tetrahydro-2H-

1 ,3,2-oxazaphosphorin-2-amine-2- oxide, estramustine: estra-1 ,3,5(10)-triene-3,17-diol

3-[bis(2-chloroethyl)carbamate], novembichine: 2-chloro-N,N-bis(2-chloroethyl)- propaneamine hydrochloride, phenesterine: cholest-5-ene-3β-ol-4-[bis(2-chloro- ethyl)amino]phenyl acetate, prednimustine: 21-{4-[4-[bis(2-chloroethyl)amino]- phenyl]-1 -oxobutoyi}-11 ,17-dihydroxy- pregna-1 ,4-diene-3,20-dione trophosphamide: N,N,3-tris(2-chloroethyl)tetrahydro-2H-

1 ,3,2-oxazaphosphorin-2-amine-2- oxide, uracil mustard: 5-[bis(2-chloroethyl)amino]-2,4(1H,3H)- pyrimidinedione, chlorozotocin: 2-[(2-chloroethyl)nitrosoaminocarbonyl- amino]-2-deoxy-D-glucose, fotemustine: {1-[(2-chloroethyl)nitrosoaminocarbonyl- amino]ethyl}phosphonic acid diethyl ester nimustine: N'-[(4-amino-2-methyl-5-pyrimidinyl)- methyl]-N-(2-chloroethyl)-N-nitroso- urea, ranimustine: methyl 6-[(2-chloroethyl)nitrosoamino- carbonylamino]-6-deoxy-α-D-gluco- pyranoside, mannomustine: 1 ,6-bis(2-chloroethylamino)-1 ,6- dideoxy-D-mannitol dihydrochloride, mitobronitol: 1 ,6-dibromo-1 ,6-dideoxi-D-mannitol, mitolactol: 1 ,6-dibromo-1 ,6-dideoxi-galactitol, pipobroman: 1 ,4-bis(3-bromo-1 -oxopropyl)piperazine, dacarbazine: 5-(3,3-dimethyl-1-triazeno)imidazol-4- carboxamide. Preferred antimetabolites are, for example, the following ones: methotrexate: N-{4-[2,4-diamino-6-pteridinyl)-methyl- amino]benzoyl}-L-glutamic acid or sodium salt thereof, trimetrexate: 5-methyl-6-[(3,4,5-trimethoxyphenyl)- aminomethyl]-2,4-quinazolinediamine, fluoruracil: 5-fluoro-2,4(1 H,3H)-pyrimidinedione or sodium salt thereof, capecitabine N¹-pentyloxycarbonyl-5'-deoxy-5- fluorocytidine, floxuridine: 5-fluoro-2'-deoxyuridine, idoxuridine: 5-iodo-2 -deoxyuridin, doxifluridine 5^'-deoxy-5-fluorouridine, cytarabine: 4-amino-1 β-D-arabinofuranosyl-2(1 H)- pyrimidinone, azacytidine: 4-amino-1 β-D-ribofuranosyl-1 ,3,5- triazin-2(1 H)-one, gemcytabine: 2',2'-difluorodeoxycytidine, mercaptopurine: 1 ,7-dihydro-6H-purine-6-thione, thioguanine: 2-amino-1 ,7-dihydro-6H-purine-6- thione, fludarabine phosphate: 9β-D-arabinofuranosyl-2-fluoro-9H- purin-6-amine phosphate, pentostatine: (R)-3-(2-deoxy-β-D-erythropento- furanosyl)-3,6,7,8-tetrahydroimidazo- [4,5-d][1 ,3]diazepin-8-ol, cladribine: 2-chloro-2^Λ-deoxyadenosine, thiamiprine: 6-(1 -methyl-4-nitro-1 H-imidazol-5-yl- thio)-1 H-purin-2-amine, ancitabine: 2,3,3a, 9a-tetrahydro-3-hydroxy-6- imino-6H-furo[2',3':4,5]oxazolo[3,2-a]- pyrimidine-2-methanol, azacitidine: 4-amino-1 β-D-ribofuranosyl-1 ,3,5- triazin-2(1H)-one,

6-azauridine: 2β-D-ribofuranosyl-1 ,2,4-triazine-3,5- (2H,4H)-dione, carmofur: 5-fluoro-N-hexyl-3,4-dihydro-2,4-dioxo- 1(2H)-pyrimidine carboxamide, enocitabine: N-(1 β-D-arabinofuranosyl-1 ,2-dihydro- 2-oxo-4-pyrimidinyl)docosanamide, tegafur: 5-fluoro-1-(tetrahydro-2-furanyl)-2,4- (1 H,3H)pyrimidinedione. From the known antitumor agents, preferred native substances are, for example, the following ones: vinblastine sulfate: vincaleucoblastine sulfate, vincristine sulfate: 22-oxo-vincaleucoblastine sulfate, vindesine: 3-(aminocarbonyl)-O-4-deacetyl-3- de(methoxycarbonyl)vinca- leucoblastine sulfate, irinotecan [1 ,4^x-bipiperidine]-1"-carboxylic acid (S)-4,11-diethyl-3,4,12,14-tetra- hydro-4-hydroxy-3,14-dioxo-1 H- pyrano[3\4^':6,7]indolizino[1 ,2-b]- quinolin-9-yl ester paclitaxel: [2aR-[2aα,4β,4aβ,6β,9α(αR*,βS*)- 11 α, 12α, 12aα, 12bα]]-β-(benzoyl- amino)-α-hydroxybenzenepropanoic acid [6,12b-bis(acetyloxy)-12-benzoyl- oxy-2a,3,4,4a,5,6,9,10,11 ,12,12a,12b- dodecahydro-4,11-dihydroxy-4a,8,13- 13-tetramethyl-5-oxo-7 , 11 -methano- 1 H-cyclodeca[3,4]benz[1 ,2-b]oxet-9- yl] ester, docetaxel: [2aR-[2aα,4β,4aβ,6β,9α(αR*,βS^*)- 11α,12α,12aα,12bα]]-β-[[(1 ,1- dimethylethoxy)carbonyl]amino]-α- hydroxybenzenepropanoic acid 12b-(acetyloxy)-12-(benzoyloxy)- 2a,3,4,4a,5,6,9,10,11 ,12,12a,12b- dodecahydro-4,6,11 -trihydroxy-4a,8- 13,13-tetramethyl-5-oxo-7,11- methano-1 H-cyclodeca[3,4]benz-

[1 ,2-b]oxet-9-yl] ester, etoposide: {5R-[5α, 5αβ, 8aα, 9β(R)]}-9-(4,6-O- ethylidene-β-D-glucopyranosyloxy)-5,8-

8a,9-tetrahydro-5-(4-hydroxy-3,5- dimethoxyphenyl)-furo[3',4':6,7]- naphtho[2,3-d]-1 ,3-dioxol-6-(5aH)-one, teniposide: {5R-[5α, 5αβ, 8aα, 9β(R)]}-5,8,8a,9- tetrahydro-5-(4-hydroxy-3,5-dimethoxy- phenyl)-9-[4,6-O-(2-thienylmethylene)- β-D-glucopyranosyloxy]-furo[3',4':6,7]- naphtho[2,3-d]-1 ,3-dioxol-6-(5aH)-one, dactinomycin: actinomycin D, daunorubicin: (8S-cis)-8-acetyl-10-(3-amino-2,3,6- trideoxy-α-L-lyxo-hexopyranosyloxy)-

7,8,9, 10-tetrahydro-6,8,11-trihydroxy-

1 -methoxy-5, 12-naphthacenedione, doxorubicin: (8S-cis)-8-(hydroxyacetyl)-10-(3- amino-2,3,6-trideoxy-α-L-lyxo-hexo- pyranosyloxy)-7,8,9,10-tetrahydro-6,8-

11 -trihydroxy-1 -methoxy-5, 12- naphthacenedione, epirubicin: (8S-cis)-10-(3-amino-2,3,6-trideoxy-α-

L-arabino-hexopyranosyloxy)-7,8,9-

10-tetrahydro-6,8,11-trihydroxy-8-

(hydroxyacetyl)-l -methoxy-5, 12- naphthacenedione, idarubicin: (7S-cis)-9-acetyl-7-(3-amino-2,3,6-tri- deoxy-α-L-lyxo-hexopyranosyloxy)-7,8- 9, 10-tetrahydro-6,9, 11 -trihydroxy- 5, 12-naphthacenedione, mitoxantrone: 1 ,4-dihydroxy-5,8-bis[2-(2-hydroxy- ethyl)aminoethylamino]-9,10- anthracenedione or dihddrochloride thereof, bleomycin (A₂, B₂): mixture of glycopeptide antibiotics isolated from Streptomyces verticillus species, mostly in the form of sulfate or hydrochloride, plicamycin: an antibiotic produced by

Streptomyces argillaceus, Streptomyces tanashiensis and Streptomyces plicatus, mitomycins: a group of antitumor antibiotics produced by Streptomyces caespitosus (griseovinaceseus), aclacinomycin (A and B): an anthracyclin antibiotic produced by Streptomyces galileus, anthramycin: 3-(5,10,11 ,11 a-tetrahydro-9,11 - dihydroxy-8-methyl-5-oxo-1 H-pyrrolo- [2,1-c][1 ,4]benzodiazepin-2-il)-2- propeneamide, azaserine: O-diazoacetyl-L-serine, carubicin: 8-acetyl-10-(3-amino-2,3,6-trideoxy- α-L-lyxo-hexopyranosyloxy)-7,8,9,10- tetrahydro-1 ,6,8,11 -tetrahydroxy- 5, 12-naphthacenedione, cacti nomycin: actinomycin C, an antibiotic produced by Streptomyces chrysomallus, carzinophilin: an antibiotic produced by Streptomyces sahachiroi, chromomycins: an antibiotic complex produced by Streptomyces griseus, olivomycin: an antibiotic produced by Streptomyces olivoreticuli, nogalamycin: [2R-(2 ,3β,4α,5β,6α,11 β,13α,14α)]- 11 -(6-deoxy-3-C-methyl-2,3,4-tri-O- methyl-α-L-mannopiranosyloxy)-4- (dimethylamino)-3,4,5,6,9,11 ,12,13- 14,16-decahydro-3,5,8, 10,13-penta- hydroxy-6,13-dimethyl-9,16-dioxo- 2,6-epoxy-2H-naphthacenol[1 ,2-b]- oxocin-14-carboxylic acid methyl ester, peplomycin: N'-[3-(1-phenylethyl)-aminopropyl]- bleomycin amide, porfiromycin: 6-amino-8-(aminocarbonyloxy- methyl)-1 ,1a,2,8,8a,8b-hexahydro- 8a-methoxy-1 ,5-dimethyl-azirino- [2',3':3,4]pyrrolo[1 ,2-a]indole-4,7- dione, streptonigrin: 5-amino-6-(7-amino-5,8-dihydro-6- methoxy-5,8-dioxo-2-quinolinyl)-4- (2-hydroxy-3,4-dimethoxyphenyl)-3- methyl-2-pyridinecarboxylic acid, streptozocin: 2-deoxy-2-(methylnitrosoamino- carbonylamino)-D-glucopiranose, tubercidin: 7β-D-ribofuranosyl-7H-pyrrolo[2,3-d]- pyrimidine-4-amine, ubenimex: [(2S, 3R)-3-amino-2-hydroxy-4- phenylbutanoyl]-L-leucine, zorubicin: benzoic acid {1-[4-(3-amino-2,3,6- trideoxy-α-L-lyxo-hexopiranosyl- oxy)-1 ,2,3,4,6, 11 -hexahydro-2,5,12- trihydroxy-7-methoxy-6,11 -dioxo- 2-naphthacenyl]-ethylidene}- hydrazide, From the known antitumor agents, preferred hormones are, for example, the following ones: prednisolone: (11 β)-11 , 17,21 -trihydroxypregna- 1 ,4-diene-3,20-dione, hydroxyprogesterone: 17-hydroxypregn-4-ene-3,20-dione or the caproate thereof, medroxyprogesterone: (6α)-17-hydroxy-6-methylpregn-4- ene-3,20-dione or the acetate thereof, megestrol: 17-hydroxy-6-methylpregna-1 ,4- diene-3,20-dione or the acetate thereof, d i ethy I sti I be stro 1 : (E)-4,4'-(1 ,2-diethyH ,2-ethenediyl)- bis(phenol), ethynylestradiol: (17α)-19-norpregna-1 ,3,5(10)- triene-20-yne-3,17-diol, tamoxifen: (Z)-2-[4-(1 ,2-diphenyl-1 -butenyl)- phenoxy]-N,N-dimethylethanamine or the citrate thereof, testosterone: (17β)-17-(1 -oxopropoxy)-androst-4- ene-3-one or the propionate thereof, fluoximesterone: (11 β, 17β)-9-f luoro-11 , 17-di- hydroxy-17-methylandrost-4-ene-3- one.

Preferred other antitumor agents are, for example, the following ones: cisplatin: cis-diammine-dichloroplatinum, carboplatin: cis-diammin-[1 , 1 -cyclobutane- dicarboxylato(2)]-platinum, oxaliplatin: SP-4-2-(1 R-trans)]-(1 ,2-cyclo- hexanediamine-N,N')[ethane- dioato(2-)-O,O']platinum

L-asparaginase: an enzyme produced by e.g.

Escherichia coli, procarbazine: N-( 1 -methylethyl )-4-(2-hyd razi no- methyl)-benzamide, mitotane: 1 -chloro-2-(2,2-dichloro-1 -(4-chloro- phenyl)ethylbenzene, flutamide: 2-methyl-N-[4-nitro-3-(trifluoro- methyl)phenyl]propaneamide, leuproreline: 5-oxo-L-prolyl-L-hisztidyl-L- tryptophyl-L-seryl-L-tyrosyl-D- leucyl-L-leucyl-L-arginyl-N-ethyl-L- proline amide or the acetate thereof. The activity of the thiazolidinediones of the formula I was shown by means of the following tests.

Since myelosuppression is the most common dose-limiting toxicity of antitumor agents, it was investigated if the thiazolidinediones could confer protection against myelotoxicity produced by fluoruracil and cisplatin in mice, both used as a model experiment.

The common progenitor cell of granulocytes and macro- phages i.e. GM-CFU (Granulocyte Macrophage Colony- Forming Units) is considered as one of the main -target of myelotoxic agents. The name GM-CFU indicates that a cell colony consisting of granulocytes and/or monocytes is formed under suitable conditions during blood formation. Several antitumor agents (cytostatics) including fluoruracil and cisplatin reduce, significantly, the amount of GM-CFU in the therapeutical dose range used in the clinical practice. This fact is frequently a dose limiting toxicity resulting in the reduction of the therapeutical index, and the neutropenia that develops enhances the risk of serious infections that may even lead to the death of the patient.

Our tests were carried out on ten- to eleven-week old BDFi female mice obtained from the National Institute of Oncology, Budapest, Hungary. The experiments conformed to the European Community guiding principles for the care and use of laboratory animals. The mice were housed in an animal room, fed commercial laboratory chow and water ad libitum.

Soft agar cultures were prepared as described by Benkό et al. [J. Antimicrob. Chemother., 43, 675-681]. The animals were exterminated by cervical dislocation, the femoral bones were aseptically removed. Bone marrow cells were washed out, the single cell suspensions were prepared by suspending them in McCoy's 5A medium (GIBCO, Grand Island, NY, USA) through a thin needle syringe. Inocula of 10⁵/ml bone marrow cells were used in petri dishes (Greiner, Nϋrtingen, Germany) and the murine bone marrow cells were grown on McCoy's 5A modified medium supplemented with amino acids, sodium pyruvate, sodium hydrogen carbonate, antibiotics (streptomycin, penicillin), 0.3 % agar (Oxoid, London, United Kingdom), and 25 % horse serum. A conditioned medium of WEHI-3B cells containing colony stimulating factors was also added. Cultures were grown in triplicates for 7 days in a carbon dioxide incubator (Jouan Co., France) containing humidified atmosphere with 5 % of carbon dioxide. Then, the colonies were counted under a dissecting microscope (Olympus, Hamburg, Germany). Colonies were defined as groups of at least 50 cells, consisting of granulocytes and/or monocytes, verified by smears or cytospin preparations.

Total white blood cell count was determined in haemocyto- meter, the frequency of neutrophil granuloxytes was determined by differential count of 200 cells from blood smears stained with Wright-Giemsa.

Mice were randomly assigned into 18 groups. Groups 1-4 served as different controls. Vehicles of rosiglitazone and fluoruracil, 6 mg/kg of rosiglitazone (the same vehicle was used for troglitazone), 100 mg/kg of fluoruracil or 13 mg/kg of cisplatin were administered to mice in groups 1 , 2, 3, and 4, respectively. Animals in groups 5-7 received 1.5 or 3 or 6 mg/kg of rosiglitazone (Avandia^(R), GlaxoSmithKline, Brentford, United Kingdom) followed by a single dose of fluoruracil. Rosiglitazone diluted in distilled water was delivered by oral gavage for five days i.e. 96, 72, 48, 24, and 1 hour before the single ip. dose of 100 mg/kg of fluoruracil (Fluoruracil-TEVA, Pharmachemie, Haarlem, Netherlands) dissolved in 0.9 % aqueous sodium chloride solution. The mice in groups 8-10 were treated with oral doses (10, 30 and 100 mg/kg, respectively) of troglitazone preceding the administration of fluoruracil. To the animals of group 11 , a single oral dose of 13 mg/kg of cisplatin (TEVA-Biogal Pharmaceuticals, Debrecen, Hungary) was administered. The animals in groups 12-15 received the daily doses of 1.5, 3 and mg/kg of rosiglitazone, respectively, preceding the administration of cisplatin. The mice of the groups 16-18 received the 5-days' treatment schedule with troglitazone at daily doses of 10, 30 and 100 mg/kg of troglitazone, respectively, preceding the single dose of cisplatin (13 mg/kg).

Bone marrow function was evaluated on the second day following the administration of fluoruracil or cisplatin in separate sets of animals. The peripheral leukocyte count and absolute neutrophil count (ANC) were determined from samples of retro-orbital sinus blood. Cellularity of femoral bone marrow was calculated from bone marrow cell counts and volumes of the samples, the frequency of CFU-GM progenitors was established from the soft agar cultures. Total CFU-GM content of the femur was calculated (cellularity x frequency of CFU-GM).

Data obtained from individual mouse were used for statistical analysis. Each haematologic variable was evaluated using one way analysis of variance, followed by Bonferroni's post test for multiple comparisons. Differences were regarded as statistically significant at p<0.05.

The results obtained are shown in Tables 1-3 as means + standard deviation obtained with 12 animals per group.

Table 1

Effect of treatments with rosiglitazone on myelosuppression induced by a single dose of cisplatin in mice. The effects are characterized by bone marrow cellularity (cell number x 10⁹/l)

Table 2

Effect of treatments with troglitazone or rosiglitazone on myelosuppression induced by a single dose of fluoruracil or cisplatin in mice. The effects are characterized by bone marrow CFU-GM colonies/10⁵ bone marrow cells

Table 3

Effect of treatments with troglitazone or rosiglitazone on myelosuppression induced by a single dose of fluoruracil or cisplatin in mice. The effects are characterized by bone marrow CFU-GM number/femur

It can be seen from Table 1 that cisplatin reduced cellularity of the bone marrow to 38.5 % of the control value, however, in groups pretreated with 6.0 mg/kg of rosiglitazone for 5 days the cellularity was reduced only to 47.5 % of the control value. From Tables 2 it is evident that the frequency of CFU-GM progenitors, indicated by the colony numbers grown from 10⁵ bone marrow cell inoculates, was much higher in samples obtained from mice pretreated with rosiglitazone or troglitazone before the administration of a single dose of fluoruracil or cisplatin than in mice treated with any of the latter antitumor agents alone. However, the effect of rosiglitazone and troglitazone was dose-dependent, and the higher doses used gave the better result.

The same favourable effect of rosiglitazone and troglitazone can be read from Table 3. The femoral bone marrow CFU-GM number was reduced to 10-18 % of the control value due to a single treatment with fluoruracil or cisplatin. However, in case of pretreatment with 100 mg/kg of troglitazone or 6.0 mg/kg of rosiglitazone for 5 days, treatment with fluoruracil or cisplatin reduced the femoral bone marrow CFU-GM number only to 51- 67 % of the control value indicating a remarkable protecting effect.

Thus, the toxic side effect of antitumor agents can be significantly reduced by the administration of thiazolidinedione derivatives.

In most cases, the patient suffering in a tumorous illness is treated for a shorter time e.g. one week or some weeks or at intervals e.g. once or twice a week with the antitumor agent because of the toxic side effect(s) thereof. In order to reduce the side effect(s) of the antitumor agent employed, the thiazolidinedione derivative of the formula I can be administered to the patient both parallel with the administration of the antitumor agent and on the days when no antitumor agent is employed.

Claims

Claims:

1. Use of a thiazolidinedione derivative of the formula

Zi Z₂

I I

X-(NR₁)_k-V-(NR₂)_m-(C=O)„-Y-(Ar)p-A-C-C=O

I I i

S NH \ / C=O

wherein

X stands for a cyclohexyl group optionally susbtituted by a Cι-₃ alkyl group; a phenyl group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of halo, trifluoromethyl and C₁-₅ alkoxy, or the phenyl group is fused with a further benzene ring or a 6-membered saturated ring optionally substituted by 1 to 4 methyl group(s); a 5- or 6- membered, saturated, unsaturated or aromatic heterocyclic group containing 1 or 2 heteroatom(s) selected from the group consisting of nitrogen, oxygen and sulphur and optionally substituted by 1 to 3 substituent(s) selected from the group consisting of Cι-₃ alkyl, oxygen, a further 5- or 6-membered, saturated, unsaturated or aromatic heterocyclic group containing 1 or 2 heteroatom(s) which latter can be nitrogen and/or oxygen and/or sulphur, and a phenyl group optionally substituted by 1-3 substituent(s) selected from the group consisting of C-|.₃ alkyl, hydroxy and Cι-₃ alkoxy, or the heterocyclic group is fused with a phenyl group optionally substituted by 1 to 4 substituent(s) selected from the group consisting of C-|.₃ alkyl, hydroxy and Cι-₃ alkoxy; Ri and R₂ represent, independently, a hydrogen atom or a C-_t-₃ alkyl group;

V is a valence bond or a C-|.₄ alkylene group optionally substituted by a hydroxy or a C₃.₆ cycloalkyl;

Y means a valence bond, an oxygen atom or a group of the formula -NH- or =C=O;

Ar stands for a phenylene group or a naphthylene group, wherein the phenylene group is optionally substituted by 1 to 3 substituent(s) selected from the group consisting of halo, Cι.₃ alkyl and Cι-₃ alkoxy, or the phenylene group is fused with a 5- or 6-membered, saturated, unsaturated or aromatic heterocyclic group containing 1 or 2 heteroatom(s) selected from the group consisting of nitrogen, oxygen and sulphur; A represents a valence bond or a CH group; Zi and Z₂ mean a hydrogen atom or Zi forms with Z₂ a valence bond; k, m, n and p, independently, have a value of 0 or 1 ; or a pharmaceutically suitable acid addition salt thereof or a salt formed with a pharmaceutically suitable base for the preparation of a pharmaceutical composition suitable for the reduction or elimination of the side effect(s) of an antitumor agent.

2. A use of Claim 1 in which the thiazolidinedione derivative of the formula I is pioglitazone or a pharmaceutically suitable acid addition salt thereof.

3. A use of Claim 1 in which the thiazolidinedione derivative of the formula I is troglitazone or a pharmaceutically suitable acid addition salt thereof.

4. A use of Claim 1 in which the thiazolidinedione derivative of the formula I is ciglitazone or a pharmaceutically suitable acid addition salt thereof.

5. A use of Claim 1 in which the thiazolidinedione derivative of the formula I is rosiglitazone or a pharmaceutically suitable acid addition salt thereof.

6. A use of Claim 1 in which the thiazolidinedione derivative of the formula I is englitazone or a salt thereof formed with a pharmaceutically suitable base.

7. A use of Claim 1 in which the thiazolidinedione derivative of the formula I is balaglitazone or a pharmaceutically suitable acid addition salt thereof.

8. A use of Claim 1 in which the thiazolidinedione derivative of the formula I is rivoglitazone or a pharmaceutically suitable acid addition salt thereof.

9. A use of Claim 1 in which the thiazolidinedione derivative of the formula I is darglitazone or a pharmaceutically suitable acid addition salt thereof.

10. A method for reducing the side effect(s) in a patient treated with an antitumor agent having side effect(s) comprising administering an effective amount of a thiazolidinedione derivative of the formula I Zi z₂

I I

X-(NR₁)_k-V-(NR₂)_m-(C=O)_n-Y-(Ar)_p-A-C-C=O

I I I

S NH \ / C=O

wherein

X stands for a cyclohexyl group optionally susbtituted by a C-|.₃ alkyl group; a phenyl group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of halo, trifluoromethyl and Cι-₅ alkoxy, or the phenyl group is fused with a further benzene ring or a 6-membered saturated ring optionally substituted by 1 to 4 methyl group(s); a 5- or 6- membered, saturated, unsaturated or aromatic heterocyclic group containing 1 or 2 heteroatom(s) selected from the group consisting of nitrogen, oxygen and sulphur and optionally substituted by 1 to 3 substituent(s) selected from the group consisting of C-|.₃ alkyl, oxygen, a further 5- or 6-membered, saturated, unsaturated or aromatic heterocyclic group containing 1 or 2 heteroatom(s) which latter can be nitrogen and/or oxygen and/or sulphur, and a phenyl group optionally substituted by 1-3 substituent(s) selected from the group consisting of C-|.₃ alkyl, hydroxy and Cι_₃ alkoxy, or the heterocyclic group is fused with a phenyl group optionally substituted by 1 to 4 substituent(s) selected from the group consisting of Cι-₃ alkyl, hydroxy and C-_t-₃ alkoxy; Ri and R₂ represent, independently, a hydrogen atom or a C-|.₃ alkyl group;

V is a valence bond or a Cι- alkylene group optionally substituted by a hydroxy or a C₃-6 cycloalkyl;

Y means a valence bond, an oxygen atom or a group of the formula -NH- or =C=O;

Ar stands for a phenylene group or a naphthylene group, wherein the phenylene group is optionally substituted by 1 to 3 substituent(s) selected from the group consisting of halo, Cι_₃ alkyl and C-|.₃ alkoxy, or the phenylene group is fused with a 5- or 6-membered, saturated, unsaturated or aromatic heterocyclic group containing 1 or 2 heteroatom(s) selected from the group consisting of nitrogen, oxygen and sulphur;

A represents a valence bond or a CH group;

Zi and Z₂ mean a hydrogen atom or

Zi forms with Z₂ a valence bond; k, m, n and p, independently, have a value of 0 or 1 ; or a pharmaceutically suitable acid addition salt thereof or a salt thereof formed with a pharmaceutically suitable base in addition to said antitumor agent.