FARNESYL PROTEIN TRANSFERASE INHIBITOR COMBINATIONS WITH CAMPTOTHECIN COMPOUNDS

Abstract: The present invention is concerned with combinations of a farnesyl transferase inhibitor and a camptothecin compound for inhibiting the growth of tumor cells and useful in the treatment of cancer.

Description: FARNES YL PROTEIN TRANSFERASE INHIBITOR COMBINATIONS WITH CAMPTOTHECIN COMPOUNDS The present invention is concerned with combinations of a farnesyl transferase inhibitor and a camptothecin compound for inhibiting the growth of tumor cells, and useful in the treatment of cancer. Oncogenes frequently encode protein components of signal transduction pathways which lead to stimulation of cell growth and mitogenesis. Oncogene expression in cultured cells leads to cellular transformation, characterized by the ability of cells to grow in soft agar and the growth of cells as dense foci lacking the contact inhibition exhibited by non-transformed cells. Mutation and/or overexpression of certain oncogenes is frequently associated with human cancer. A particular group of oncogenes is known as ras which have been identified in mammals, birds, insects, mollusks, plants, fungi and yeasts. The family of mammalian ras oncogenes consists of three major members ("isoforms") : H-ras, K-ras and N-ras oncogenes. These ras oncogenes code for highly related proteins generically known as p21 ras . Once attached to plasma membranes, the mutant or oncogenic forms of p21 ras will provide a signal for the transformation and uncontrolled growth of malignant tumor cells. To acquire this transforming potential, the precursor of the p21 ras oncoprotein must undergo an enzymatically catalyzed farnesylation of the cysteine residue located in a carboxyl- terminal tetrapeptide. Therefore, inhibitors of the enzyme that catalyzes this modification, farnesyl protein transferase, will prevent the membrane attachment of p21 ras and block the aberrant growth of ras-transformed tumors. Hence, it is generally accepted in the art that farnesyl transferase inhibitors can be very useful as anticancer agents for tumors in which ras contributes to transformation. Since mutated, oncogenic forms of ras are frequently found in many human cancers, most notably in more than 50 % of colon and pancreatic carcinomas (Kohl et al., Science, vol 260, 1834 - 1837, 1993), it has been suggested that farnesyl tranferase inhibitors can be very useful against these types of cancer. Following further investigations, it has been found that a farnesyl transferase inhibitor is capable of demonstrating antiproliferative effects in vitro and antitumor effects in vivo in a variety of human tumor cell lines with and without ras gene mutations. WO-97/21701 descπbes the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting (ιmιdazoly-5-yl)methyl-2-quιnohnone deπvatives of formulas (I), (II) and (HI), as well as intermediates of formula (II) and (HI) that are metabolized in vivo to the compounds of formula (I). The compounds of formulas (I), (II) and (HI) are represented by (I) (II) (HI) the pharmaceutically acceptable acid or base addition salts and the stereochemically lsomeric forms thereof, wherein the dotted line represents an optional bond; X is oxygen or sulfur; R! IS hydrogen, Ci -i2alkyl, Ar , Ar^Ci-βalkyl, qmnolιnylCi-6alkyl, pyπdylCι_6alkyl, hydroxyCi -6alkyl, Ci-6alkyloxyCi-6alkyl, mono- or dι(C i -6alkyl)ammoC i -6alkyl, aminoC i -6alkyl , or a radical of formula -Alk!-C(=O)-R 9 , -Alk!-S(O)-R 9 or -Alk!-S(O)2-R 9 , wherein Alk^ is Ci-6alkanedιyl, R 9 is hydroxy, Ci-6alkyl, Ci-6alkyloxy, amino, Ci-Salkylamino or Ci-8alkylammo substituted with Ci-6alkyloxycarbonyl; R2, R3 and R 6 each independently are hydrogen, hydroxy, halo, cyano, Ci-6alkyl, Cι_6alkyloxy, hydroxyCi -6alkyloxy, Ci -6alkyloxyCi -6alkyloxy, amιnoCι_6alkyl- oxy, mono- or di(Ci-6alkyl)amιnoCi-6alkyloxy, Ar^, Ar^Ci -όalkyl, Ar^oxy, Ar^Ci-όalkyloxy, hydroxycarbonyl, Ci -6alkyloxycarbonyl, tπhalomethyl, trihalomethoxy, C2-6alkenyl, 4,4-dimethyloxazolyl; or when on adjacent positions R 2 and R^ taken together may form a bivalent radical of formula -O-CH2-O- (a-1), -O-CH2-CH2-O- (a-2), -O-CH=CH- (a-3), -O-CH2-CH2- (a-4), -O-CH2-CH2-CH2- (a-5), or -CH=CH-CH=CH- (a-6); R4 and R^ each independently are hydrogen, halo, Ar^, Cι -βalkyl, hydroxyCι_6alkyl, Ci-6alkyloxyCι_6alkyl, Ci-6alkyloxy, Ci -6alkylthio, amino, hydroxycarbonyl, Ci-6alkyloxycarbonyl, Ci-6alkylS(O)Cι_6alkyl or Cι_6alkylS(O)2Ci-6alkyl; R" and R^ each independently are hydrogen, halo, cyano, Ci-βalkyl, Ci-6alkyloxy, Ar oxy, trihalomethyl, C i -6alkylthio, di(Ci -6alkyl)amino, or when on adjacent positions R^ and R^ taken together may form a bivalent radical of formula -O-CH2-O- (c-1), or -CH=CH-CH=CH- (c-2); R8 is hydrogen, Ci -βalkyl, cyano, hydroxycarbonyl, Cι_6alkyloxycarbonyl, Cι_6alkylcarbonylCi-6alkyl, cyanoCi -6alkyl, Cι_6alkyloxycarbonylCi-6alkyl, carboxyCi-βalkyl, hydroxyCi-βalkyl, aminoCi-6alkyl, mono- or di(Ci -6alkyl)- aminoCi-6alkyl, imidazolyl, haloCi-6alkyl, Ci-6alkyloxyCi-6alkyl, aminocarbonylCi-6alkyl, or a radical of formula _O-Rl0 (b-1), -S-RlO (b-2), . N .R 1 1R12 (b-3), wherein RlO is hydrogen, Ci-6alkyl, Ci-6alkylcarbonyl, Arl, Ar 2 Ci-6alkyl, Ci-6alkyloxycarbonylCι_6alkyl, or a radical or formula -Alk 2 -OR*3 or -Alk -NR 14 R 15 ; R 11 is hydrogen, Ci -i2alkyl, Ar 1 or Ar 2 Ci-6alkyl; R* 2 is hydrogen, Ci- alkyl, Cι_i6alkylcarbonyl, Ci-6alkyloxycarbonyl, Ci-6alkylaminocarbonyl, Arl, Ar 2 Cι_6alkyl, Ci-6alkylcarbonyl- Cι_6alkyl, a natural amino acid, Arlcarbonyl, Ar 2 C _6alkylcarbonyl, aminocarbonylcarbonyl, Ci-όalkyloxyCi-βalkylcarbonyl, hydroxy, Ci -6alkyloxy, aminocarbonyl, di(Ci-6alkyl)aminoCi-6alkylcarbonyl, amino, Ci-6alkylamino, Ci-6alkylcarbonylamino, or a radical or formula -Alk 2 -OR 13 or -Alk 2 -NR 14 R 15 ; wherein Alk 2 is Cι_6alkanediyl; R!3 is hydrogen, Cι_6alkyl, Ci-6alkylcarbonyl, hydroxy- Cι_6alkyl, Ar 1 or Ar 2 Ci-6alkyl; R 14 is hydrogen, Ci-6alkyl, Ar 1 or Ar 2 Ci-6alkyl; Rl5 i s hydrogen, Ci -6a]kyl, Ci-6alkylcarbonyl, Ar or Ar 2 Ci-6alkyl; Rl7 is hydrogen, halo, cyano, Ci-6alkyl, Ci -βalkyloxycarbonyl, Arl; Rl8 is hydrogen, Cι_6alkyl, Ci-6alkyloxy or halo; R! is hydrogen or Ci-6alkyl; Arl i s phenyl or phenyl substituted with Ci .galkyl, hydroxy, amino, Cι _6alkyloxy or halo; and Ar 2 is phenyl or phenyl substituted with Cι_6alkyl, hydroxy, amino, Ci-6alkyloxy or halo. WO-97/16443 concerns the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting compounds of formula (IV), as well as intermediates of formula (V) and (VI) that are metabolized in vivo to the compounds of formula (IV). The compounds of formulas (IV), (V) and (VI) are represented by (IV) (V) (VI) the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein the dotted line represents an optional bond; X is oxygen or sulfur, R! IS hydrogen, Ci-i 2alkyl, Arl, Ar Ci -6alkyl, quιnohnylCi -6alkyl, pyπdyl- Cι_6alkyl, hydroxyCi-6alkyl, Ci-6alkyloxyCι_6alkyl, mono- or dι(C i -6alkyl)- ammoCi-6alkyl, amιnoCi-6alkyl, or a radical of formula -Alkl-C(=O)-R 9 , -Alk!-S(O)-R 9 or -Alkl-S(O)2-R 9 , wherein Alkl is Cι_6alkanedιyl, R 9 is hydroxy, Ci -6alkyl, Ci-6alkyloxy, amino, Ci-8alkylammo or Ci-8alkylamιno substituted with Ci -6alkyloxycarbonyl; R 2 and R 3 each independently are hydrogen, hydroxy, halo, cyano, Ci - alkyl, Ci -6alkyloxy, hydroxyCi-6alkyloxy, Ci-6alkyloxyCi-6alkyloxy, amino- Ci-6alkyloxy, mono- or dι(Cι -6alkyl)amιnoCι -βalkyloxy, Arl, Ar 2 Ci-6alkyl, Ar 2 oxy, Ar 2 Ci-6alkyloxy, hydroxycarbonyl, Ci-galkyloxycarbonyl, tπhalomethyl, tπhalomethoxy, C2-6alkenyl; or when on adjacent positions R 2 and R 3 taken together may form a bivalent radical of formula -O-CH2-O- (a-1), -O-CH2-CH2-O- (a-2), -O-CH=CH- (a-3), -O-CH2-CH2- (a-4), -O-CH2-CH2-CH2- (a-5), or -CH=CH-CH=CH- (a-6); R 4 and R 5 each independently are hydrogen, Ar 1 , Cι_ 6 alkyl, Ci 6 alkyloxyC] 6 alkyl, C^alkyloxy, Ci 6 alkylthιo, ammo, hydroxycarbonyl, Cι. 6 alkyloxycarbonyl, Cι. 6 alkylS(O)C,. 6 alkyl or Cι. 6 alkylS(O) 2 Cι. 6 alkyl; R^ and R^ each independently are hydrogen, halo, cyano, C i -6alkyl, Ci-6alkyloxy or Ar 2 oxy; R^ is hydrogen, Ci -6alkyl, cyano, hydroxycarbonyl, Ci-6alkyloxycarbonyl, Ci-6alkyl- carbonylCi-6alkyl, cyanoCι_6alkyl, Ci-6alkyloxycarbonylCi-6alkyl, hydroxy- carbonylCι_6alkyl, hydroxyCi-6alkyl, amιnoCι_6alkyl, mono- or dι(Ci-6alkyl)- ammoCi-βalkyl, haloCι_6alkyl, Ci-6alkyloxyCi-6alkyl, amιnocarbonylCi-6alkyl, Arl, Ar 2 Ci-6alkyloxyCi-6alkyl, Cι_6alkylthιoCi-6alkyl; RIO IS hydrogen, C i -6alkyl, Ci-6alkyloxy or halo; RU IS hydrogen or Ci-6alkyl; Arl 1S phenyl or phenyl substituted with Ci-6alkyl,hydroxy,amιno,Ci -6alkyloxy or halo; Ar 2 is phenyl or phenyl substituted with Ci .βalkyl, hydroxy, amino, Ci-6alkyloxy or halo. WO-98/40383 concerns the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting compounds of formula (VII) the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein the dotted line represents an optional bond; X is oxygen or sulfur; -A- is a bivalent radical of formula -CH=CH- (a-1), -CH2-S- (a-6), -CH2-CH2- (a-2), -CH2-CH2-S- (a-7), -CH2-CH2-CH2- (a-3), -CH=N- (a-8), -CH2-O- (a-4), -N=N- (a-9), or -CH2-CH2-O- (a-5), -CO-NH- (a-10); wherein optionally one hydrogen atom may be replaced by Ci -4alkyl or Arl; R! and R 2 each independently are hydrogen, hydroxy, halo, cyano, Cι_6alkyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, Ci-βalkyloxy, hydroxyCi-6alkyloxy, Ci-6alkyloxyCι_6alkyloxy, Ci-6alkyloxycarbonyl, aminoCi-6alkyloxy, mono- or di(Ci-6alkyl)aminoCi-6alkyloxy, Ar 2 , Ar 2 -Ci-6alkyl, Ar 2 -oxy, Ar 2 -Cι_6alkyloxy; or when on adjacent positions R! and R 2 taken together may form a bivalent radical of formula -O-CH2-O- (b-1), -O-CH2-CH2-O- (b-2), -O-CH=CH- (b-3), -O-CH2-CH2- (b-4), -O-CH2-CH2-CH2- (b-5), or -CH=CH-CH=CH- (b-6); R 3 and R 4 each independently are hydrogen, halo, cyano, Ci -βalkyl, Ci-6alkyloxy, Ar^-oxy, Cι_6alkylthio, di(Ci-6alkyl)amino, trihalomethyl, trihalomethoxy, or when on adjacent positions R 3 and R 4 taken together may form a bivalent radical of formula -O-CH2-O- (c-1), -O-CH2-CH2-O- (c-2), or -CH=CH-CH=CH- (c-3); R5 is a radical of formula wherein R 3 is hydrogen, halo, Ar 4 , Ci-6alkyl, hydroxyCi-βalkyl, Ci .βalkyloxy- Cι_6alkyl, Ci-galkyloxy, Cι_6alkylthio, amino, Cι_6alkyloxy- carbonyl, Cι_6alkylS(O)Ci-6alkyl or Ci-6alkylS(O)2Cι_6alkyl; Rl 4 is hydrogen, Cι _6alkyl or di(Ci-4alkyl)aminosulfonyl; R6 is hydrogen, hydroxy, halo, Ci-6alkyl, cyano, haloCi-6alkyl, hydroxyCi-6alkyl, cyanoCι_6alkyl, aminoCi-βalkyl, Ci -6alkyloxyCi -6alkyl, C 1 _6alkylthioC 1.βalkyl, aminocarbonylC 1 -6alkyl, C 1 _6alkyloxycarbonylC 1 -6alkyl, C 1 _6alkylcarbonyl-C 1 _6alkyl, Cι_6alkyloxycarbonyl, mono- or di(Ci-6alkyl)aminoCι _6alkyl, Ar^, Ar5-Ci-6alkyloxyCi-6alkyl; or a radical of formula -O-R7 (e-1), -S-R7 (e-2), -N-R8R 9 (e-3), wherein R^ is hydrogen, Ci -6alkyl, Ci-6alkylcarbonyl, Ar^, Ar6-Cι _6alkyl, Ci-6alkyloxycarbonylCi-6alkyl, or a radical of formula -Alk-OR O or -Alk-NRl lRl 2 ; R8 is hydrogen, Ci-6alkyl, Ar? or Ar7-Ci-6alkyl; R 9 is hydrogen, Cι _6alkyl, Ci-6alkylcarbonyl, Ci .βalkyloxycarbonyl, Ci-6alkylaminocarbonyl, Ar^, Ar^-Ci-6alkyl, Ci-6alkylcarbonyl- Ci-6alkyl, Ar^-carbonyl, Ar^-Cι_6alkylcarbonyl, aminocarbonyl- carbonyl, Ci-6alkyloxyC i -6alkylcarbonyl, hydroxy, Cι _6alkyloxy, aminocarbonyl, di(Ci-6alkyl)aminoCi-6alkylcarbonyl, amino, Ci-6alkylamino, Ci-6alkylcarbonylamino, or a radical or formula -Alk-ORl° or -Alk-NR 1 lR i2 ; wherein Alk is Ci-galkanediyl; R O is hydrogen, Ci-βalkyl, Ci -βalkylcarbonyl, hydroxyCi-βalkyl, Ar 9 or Ar 9 -Ci-6alkyl; RU is hydrogen, Ci-6alkyl, Ci-6alkylcarbonyl, Ar O or Ar 10 -Ci-6alkyl; R i2 is hydrogen, Ci-6alkyl, ArH or Ar l-Ci -6alkyl; and Arl to Arl are each independently selected from phenyl; or phenyl substituted with halo, Ci-6alkyl, Ci-6alkyloxy or trifluoromethyl. WO-98/49157 concerns the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting compounds of formula (VHI) the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein the dotted line represents an optional bond; X is oxygen or sulfur; Rl and R 2 each independently are hydrogen, hydroxy, halo, cyano, Ci -βalkyl, trihalomethyl, trihalomethoxy, C2-6 a lkenyl, Ci-6alkyloxy, hydroxyCi -όalkyloxy, Cι_6alkyloxyCi-6alkyloxy, Cι_6alkyloxycarbonyl, aminoCi-6alkyloxy, mono- or di(Ci-6alkyl)aminoCi-6alkyloxy, Arl, ArlCι_6alkyl, Arloxy or ArlCi -6alkyloxy; R 3 and R 4 each independently are hydrogen, halo, cyano, Ci -6alkyl, Ci .ζalkyloxy, Arloxy, Cι_6alkylthio, di(Ci-6alkyl)amino, trihalomethyl or trihalomethoxy; R5 is hydrogen, halo, Ci-6alkyl, cyano, haloCι _6alkyl, hydroxyCi-6alkyl, cyanoCι_6alkyl, aminoCι_6alkyl, Ci-6alkyloxyCi-6alkyl, Ci-6alkylthioCi-6alkyl, aminocarbonylCi-6alkyl, C i _6alkyloxycarbonylC i _6alkyl , C i -6alkylcarbonyl-C i _6alkyl , Ci_6alkyloxycarbonyl, mono- or di(Ci-6alkyl)aminoCi-6alkyl, Arl, ArlCi-6alkyloxyCi-6alkyl; or a radical of formula _O-Rl0 (a-1), -S-RlO ( a - 2 )- _ N _R11R12 (a-3), wherein R O is hydrogen, Ci-6alkyl, Ci-6alkylcarbonyl, Arl, ArlCi_6alkyl, Ci-6alkyloxycarbonylCi-6alkyl, or a radical of formula -Alk-ORl3 or -Alk-NRl 4 Rl 5 ; RU is hydrogen, Cι _6alkyl, Ar or ArlCi - alkyl; R 2 is hydrogen, Ci-6alkyl, Ci -6alkylcarbonyl, Ci-6alkyloxycarbonyl, Ci-galkylammocarbonyl, Ar , ArlCi-βalkyl, Ci -βalkylcarbonyl- Cι_6alkyl, Arlcarbonyl, ArlCi-βalkylcarbonyl, aminocarbonyl- carbonyl, Ci -6alkyloxyCi-6alkylcarbonyl, hydroxy, Ci-6alkyloxy, aminocarbonyl, dι(Ci-6alkyl)ammoCi-6alkylcarbonyl, amino, Ci-6alkylamιno, Ci-6alkylcarbonylamιno, or a radical or formula -Alk-ORl 3 or -Alk-NRl 4 Rl 5 , wherem Alk is Ci -6alkanedιyl, R 3 IS hydrogen, Ci -6alkyl, Ci-6alkylcarbonyl, hydroxy- Cι_6alkyl, Ar or ArlCμόalkyl, Rl 4 IS hydrogen, Ci-6alkyl, Arl or Ar Ci-6alkyl; Rl5 IS hydrogen, Ci-6alkyl, Ci-6alkylcarbonyl, Arl or Ar Ci-όalkyl; R6 IS a radical of formula wherein hydrogen, halo, Ar , Ci-galkyl, hydroxyCi-6alkyl, Ci-ζalkyloxy- Cι_6alkyl, Ci -6alkyloxy, Cι_6alkylthιo, amino, C i -6alkyloxycarbonyl , C i .galkylthioC i _6alkyl , Cι_6alkylS(O)Ci-6alkyl or Cι_6alkylS(O)2Ci-6alkyl, hydrogen, Cι_6alkyl or dι(Ci-4alkyl)ammosulfonyl, R' is hydrogen or Ci -6alkyl provided that the dotted line does not represent a bond, R 8 is hydrogen, Cι_6alkyl or Ar 2 CH2 or HetlCH2; R 9 is hydrogen, Ci-6alkyl , Ci-βalkyloxy or halo; or R 8 and R 9 taken together to form a bivalent radical of formula -CH=CH- (c-1), -CH2-CH2- (c-2), -CH2-CH2-CH2- (c-3), -CH2-O- (c-4), or -CH2-CH2-O- (c-5); Arl 1S phenyl; or phenyl substituted with 1 or 2 substituents each independently selected from halo, Ci-6alkyl, Ci -6alkyloxy or tπfluoromethyl; Ar 2 is phenyl; or phenyl substituted with 1 or 2 substituents each independently selected from halo, Ci-6alkyl, Ci -6alkyloxy or tπfluoromethyl; and Hetl 1S pyπdinyl; pyπdinyl substituted with 1 or 2 substituents each independently selected from halo, Ci-6alkyl, Ci-6alkyloxy or tπfluoromethyl WO-00/39082 concerns the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting compounds of formula (IX) or the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein =X'-X 2 -X 3 - is a trivalent radical of formula =N-CR 6 =CR 7 - ( χ -1), =CR 6 -CR 7 =CR 8 - (x-6), =N-N=CR 6 - (χ- 2 ), =CR 6 -N=CR 7 - (x-7), =N-NH-C(=O)- (x-3), =CR 6 -NH-C(=O)- (x-8), or =N-N=N- (χ- 4 ), =CR 6 -N=N- (x-9); =N-CR 6 =N- (x-5), wherein each R 6 , R 7 and R 8 are independently hydrogen, C]_ 4 alkyl, hydroxy, Cι_ 4 alkyloxy, aryloxy, Cι_ 4 alkyloxycarbonyl, hydroxyCι_ 4 alkyl, C]- 4 alkyloxyCι_ 4 alkyl, mono- or di(C). alkyl)aminoCι_ alkyl, cyano, amino, thio, Cι_ 4 alkylthio, arylthio or aryl; > γ i _γ 2 _ j s a tπva ι ent ra ical of formula >CH-CHR 9 - (y-1), >C=N- (y-2), >CH-NR 9 - (y-3),or >C=CR 9 - (y-4); wherein each R 9 independently is hydrogen, halo, halocarbonyl, aminocarbonyl, hydroxyC]. alkyl, cyano, carboxyl, Cι_ 4 alkyl, Cι_ alkyloxy, Cι_ 4 alkyloxyC]. alkyl, Cι_ alkyloxycarbonyl, mono- or di(Cι_ 4 alkyl)amino, mono- or di (C i _ alkyl )aminoC i _ 4 alkyl , aryl ; r and s are each independently 0, 1, 2, 3, 4 or 5; t is O, 1, 2 or 3; each R 1 and R 2 are independently hydroxy, halo, cyano, Ci-6alkyl, trihalomethyl, trihalomethoxy, C 2 _ 6 alkenyl, Cι_ 6 alkyloxy, hydroxyC^alkyloxy, Cι_ 6 alkylthio, C]. 6 alkyloxyCι_ 6 alkyloxy, C]. 6 alkyloxycarbonyl, aminoCι_ 6 alkyloxy, mono- or di(Cι. 6 alkyl)amino, mono- or di(Cι_ 6 alkyl)aminoCι_ alkyloxy, aryl, arylCi-βalkyl, aryloxy or arylC]. alkyloxy, hydroxycarbonyl, Cι_ 6 alkyloxycarbonyl, aminocarbonyl, aminoCι_ 6 alkyl, mono- or di(Cι_ 6 alkyl)aminocarbonyl, mono- or dι(Cι 6 alkyl)ammoCι 6 alkyl, or two R 1 or R 2 substituents adjacent to one another on the phenyl πng may independently form together a bivalent radical of formula -O-CH2-O- ( a -i)> -O-CH 2 -CH 2 -O- (a-2), -O=CH=CH- (a-3), -O-CH 2 -CH 2 - (a-4), -O-CH 2 -CH 2 - CH 2 - (a-5), or -CH=CH-CH=CH- (a-6), R 3 is hydrogen, halo, Cι_ alkyl, cyano, haloCi 6 alkyl, hydroxyCi 6 alkyl, cyanoCi 6 alkyl, amιnoCι- 6 alkyl, Ci 6 alkyloxyCι 6 alkyl, Cι_ alkylthιoCι 6 alkyl, aminocarbonylCi 6 alkyl, hydroxycarbonyl, hydroxycarbonylCι_ 6 alkyl, Ci 6 alkyloxycarbonylCι_ 6 alkyl, Ci alkylcarbonylCι 6 alkyl, Ci 6 alkyloxycarbonyl, aryl, arylCi 6 alkyloxyCι _6alkyl, mono- or dι(Cι 6 alkyl)ammoCι_ 6 alkyl, or a radical of formula -O-R 10 (b-1), -S-R 10 (b-2), -NR U R 12 (b-3), wherein R 10 is hydrogen, Ci 6 alkyl, Ci 6 alkylcarbonyl, aryl, arylC] 6 alkyl, Cι_ 6 alkyloxycarbonylCι_6alkyl, or a radical of formula -Alk-OR 13 or -Alk-NR 14 R 15 ; R n is hydrogen, Cj 6 alkyl, aryl or arylCi 6 alkyl, R !2 is hydrogen, Cj 6 alkyl, aryl, hydroxy, amino, Cι_ 6 alkyloxy, Cι_ 6 alkylcarbonylCι_ 6 alkyl, arylCi 6 alkyl, Cι_ 6 alkylcarbonylamιno, mono- or dι(Cι_ 6 alkyl)ammo, Ci 6 alkylcarbonyl, aminocarbonyl, arylcarbonyl, haloCi 6 alkylcarbonyl, arylC t 6 alkylcarbonyl, Ci 6 alkyloxycarbonyl, Ci 6 alkyloxyCi_ 6 alkylcarbonyl, mono- or dι(Cι 6 alkyl)amιnocarbonyl wherein the alkyl moiety may optionally be substituted by one or more substituents independently selected from aryl or Ci 3 alkyloxycarbonyl, aminocarbonylcarbonyl, mono- or dι(Cι 6 alkyl)ammoCι 6 alkylcarbonyl, or a radical or formula -Alk-OR 13 or -Alk-NR ,4 R 15 ; wherein Alk is Cι_ 6 alkanedιyl; R 13 is hydrogen, Cj 6 alkyl, Ci 6 alkylcarbonyl, hydroxyCi. 6 alkyl, aryl or arylCi 6 alkyl; R 14 is hydrogen, Ci 6 alkyl, aryl or arylCι_ 6 alkyl; R 15 is hydrogen, Cι_ alkyl, Ci 6 alkylcarbonyl, aryl or arylCi 6 alkyl; R 4 is a radical of formula wherein R 16 is hydrogen, halo, aryl, Cι. alkyl, hydroxyCi _ 6 alkyl, Cι_ 6 alkyloxyCι_ 6 alkyl, Cι_ 6 alkyloxy, Cι_ 6 alkylthio, amino, mono- or di(Cι_ alkyl)amino, hydroxycarbonyl, Cι_ 6 alkyloxycarbonyl, Cι-6alkylthioCι. 6 alkyl, Cι_ 6 alkylS(O)Cι_ 6 alkyl or Cι. 6 alkylS(O) 2 C,_ 6 alkyl; R 16 may also be bound to one of the nitrogen atoms in the imidazole ring of formula (c-1) or (c-2), in which case the meaning of R 1 when bound to the nitrogen is limited to hydrogen, aryl, Cι_ 6 alkyl, hydroxyCι_ alkyl, Cι_ 6 alkyloxyC]. 6 alkyl, C]_ 6 alkyloxycarbonyl, Cι_ 6 alkylS(O)Cι_ 6 alkyl or Cι. 6 alkylS(O) 2 Cι_ 6 alkyl; R 17 is hydrogen, Cι_ 6 alkyl, Cι_ 6 alkyloxyCι_ 6 alkyl, arylCι_ 6 alkyl, trifluoromethyl or di(C]. 4 alkyl)aminosulfonyl; R 5 is Cι_ 6 alkyl , Cι_ 6 alkyloxy or halo; aryl is phenyl, naphthalenyl or phenyl substituted with 1 or more substituents each independently selected from halo, Cι_ 6 alkyl, Cι_ 6 alkyloxy or trifluoromethyl. The class of camptothecin compounds are related to or derived from the parent camptothecin compound which is a water-insoluble alkaloid derived from the Chinese tree Camptothecin acuminata and the Indian tree Nothapodytes foetida. Camptothecin has a potent inhibitory activity against biosynthesis of DNA and has shown high activity against tumor cell growth in various experimental systems. Its clinical use in anti-cancer therapy is however limited significantly by its high toxicity, and various analogues have been developed in attempts to reduce the toxicity of camptothecin while retaining the potency of its anti-tumor effect. Example of such analogues include irinotecan and topotecan. These compounds have been found to be specific inhibitors of DNA topoisomerase I. Topoisomerases are enzymes that are capable of altering DNA topology in eukaryotic cells. They are critical for important cellular functions and cell proliferation. There are two classes of topoisomerases in eukaryotic cells, namely type I and type H Topoisomerase I is a monomeric enzyme of approximately 100,000 molecular weight. The enzyme binds to DNA and introduces a transient single-strand break, unwinds the double helix (or allows it to unwind) and subsequently reseals the break before dissociating from the DNA strand. Irinotecan, namely 7-ethyl-10-(4-(l-piperidino)- l-piperidino)carbonyloxy-(20S)-camptothecin, and its hydrochloride, also known as CPT 11, have been found to have improved potency and reduced toxicity and with superior water-solubility. Irinotecan has been found to have clinical efficacy in the treatment of various cancers especially colorectal cancer. Another important camptothecin compound IS topotecan, namely (S)-9-dιmethylamιnomethyl-10-hydroxy-camptothecm which, in clinical tπals has shown efficacy against several solid tumors, particularly ovaπan cancer and non-small cell lung carcinoma Although camptothecin compounds have widely used as chemotherapeutic agents in humans, they are not therapeutically effective in all patients or against all types of tumors There is therefore a need to increase the inhibitory efficacy of camptothecin compounds against tumor growth and also to provide a means for the use of lower dosages of camptothecin compounds to reduce the potential of adverse toxic side effects to the patient. It is an object of the invention to provide a therapeutic combination of a camptothecin compound and a farnesyl transferase inhibitor of the type descπbed above which has an advantageous inhibitory effect against tumor cell growth, in compaπson with the respective effects shown by the individual components of the combination. According to the invention therefore we provide a combination of a camptothecin compound and a farnesyl transferase inhibitor of formula (I), (II), (HI), (IV), (V), (VI), (VH), (VIH) or (IX) above, in particular a compound of formula (I), (H) or (HI): (D (II) (III) the pharmaceutically acceptable acid or base addition salts and the stereochemically lsomeπc forms thereof, wherein the dotted line represents an optional bond, X is oxygen or sulfur, R is hydrogen, Cj-i2alkyl, Arl, Ar Cι_6alkyl, quιnolιnylCi-6alkyl, pyπdyl- Ci-6alkyl, hydroxyCi -βalkyl, Ci-6alkyloxyCi-6alkyl, mono- or dι(Cι_6alkyl)- amιnoCi-6alkyl, aminoCi-βalkyl, or a radical of formula -Alkl-C(=O)-R 9 , -Alkl-S(O)-R 9 or -Alkl-S(O)2-R 9 , wherein Alkl is Ci-βalkanediyl, R 9 is hydroxy, Cι_6alkyl, Ci-6alkyloxy, amino, Ci-8alkylamιno or Ci-8alkylamιno substituted with Ci-6alkyloxycarbonyl; R 2 , R3 and Rl" each independently are hydrogen, hydroxy, halo, cyano. Ci-6alkyl, Ci-6alkyloxy, hydroxyCi _6alkyloxy, C ι_6alkyloxyCi-6alkyloxy, aminoCi_6alkyloxy, mono- or dι(Ci-6alkyl)amιnoCi-6alkyloxy, Arl, Ar 2 Cι_6alkyl, Ar 2 oxy, Ar 2 Cι_6alkyloxy, hydroxycarbonyl, Ci-6alkyloxycarbonyl, tπhalomethyl, tπhalomethoxy, C2-6alkenyl, 4,4- dimethyloxazolyl; or when on adjacent positions R 2 and R^ taken together may form a bivalent radical of formula -O-CH2-O- (a-1), -O-CH2-CH2-O- (a-2), -O-CH=CH- (a-3), -O-CH2-CH2- (a-4), -O-CH2-CH2-CH2- (a-5), or -CH=CH-CH=CH- (a-6), R 4 and R^ each independently are hydrogen, halo, Ar , Ci-βalkyl, hydroxyCi -6alkyl, Ci-6alkyloxyCι_6alkyl , Ci-6alkyloxy, Cι_6alkylthιo, amino, hydroxycarbonyl, Cι_6alkyloxycarbonyl, Cι_6alkylS(O)Ci-6alkyl or Cι.6alkylS(O)2Cι_6alkyl, R^ and R7 each independently are hydrogen, halo, cyano, Ci-6alkyl, Ci-βalkyloxy, Ar 2 oxy, tπhalomethyl, Cι_6alkylthιo, dι(Cι_6alkyl)amιno, or when on adjacent positions R^ and R *7 taken together may form a bivalent radical of formula -O-CH2-O- (c-1), or -CH=CH-CH=CH- (c-2), R" is hydrogen, Cι_6alkyl, cyano, hydroxycarbonyl, Cι_6alkyloxycarbonyl, Cι_ 6 alkyl- carbonylCι_6alkyl, cyanoC _6alkyl, Ci-6alkyloxycarbonylCi-6alkyl, carboxy- Ci-6alkyl, hydroxyCi -6alkyl, ammoCi-6alkyl, mono- or dι(Ci-6alkyl)amιno- Cι_6alkyl, lmidazolyl, haloCi-6alkyl, Ci-6alkyloxyCi-6alkyl, ammocarbonyl- Ci-6alkyl, or a radical of formula -O-RlO (b-1), -S-RlO (b-2), -N-Rl lRl2 (b-3), wherein hydrogen, Ci-6alkyl, Ci-6alkylcarbonyl, Arl, Ar Ci-6alkyl, Ci-6alkyloxycarbonylCi-6alkyl, or a radical or formula -Alk -ORl3 or -Alk -NRl 4 Rl 5 ; RU is hydrogen, Ci-i2alkyl, Arl or Ar 2 Cι_6alkyl, Rl 2 is hydrogen, C _6alkyl, Cι_i6alkylcarbonyl, Ci-βalkyloxycarbonyl, C _6alkylaminocarbonyl, Arl, Ar 2 Ci-6alkyl, Ci-βalkylcarbonyl- Cι_6alkyl, a natural amino acid, Arlcarbonyl, Ar 2 Ci-6alkylcarbonyl, aminocarbonylcarbonyl, Ci-6alkyloxyC _6alkylcarbonyl, hydroxy, C i -6alkyloxy, aminocarbonyl , dι(C i _6alkyl)amιnoC i -ζalkylcarbonyl , ammo, Ci-6alkylamιno, Ci-6alkylcarbonylamιno, or a radical or formula -Alk 2 -ORl 3 or -Alk 2 -NRl 4 R 15 ; wherem Alk 2 is Cι_6alkanedιyl; Rl3 IS hydrogen, Cι_6alkyl, Ci-6alkylcarbonyl, hydroxy- Cι_6alkyl, Ar or Ar 2 Cι_6alkyl; Rl 4 IS hydrogen, Ci-6alkyl, Arl or Ar 2 Ci- 6 alkyl; Rl5 IS hydrogen, Ci-6alkyl, Ci-βalkylcarbonyl, Ar or Ar 2 Ci-6alkyl; RI^ IS hydrogen, halo, cyano, Ci-6alkyl, Cι_6alkyloxycarbonyl, Arl; hydrogen, Cι_6alkyl, Ci-6alkyloxy or halo; Rl is hydrogen or Ci_ 6 alkyl; Ar 1S phenyl or phenyl substituted with Ci-6alkyl, hydroxy, amino, Ci-6alkyloxy or halo; and Ar 2 is phenyl or phenyl substituted with Ci-6alkyl, hydroxy, ammo, C _6alkyloxy or halo. The above descπbed combinations are hereinafter referred to as combinations according to the invention. These combinations may provide a synergistic effect whereby they demonstrate an advantageous therapeutic effect which is greater than that which would have been expected from the effects of the individual components of the combinations. In Formulas (I), (H) and (HI), R 4 or R^ may also be bound to one of the nitrogen atoms in the imidazole πng. In that case the hydrogen on the nitrogen is replaced by R 4 or R^ and the meaning of R 4 and R^ when bound to the nitrogen is limited to hydrogen, Arl, Ci-6alkyl, hydroxyCi _6alkyl, Ci-6alkyloxyCi-6alkyl, Ci-6alkyloxycarbonyl, Ci-6alkylS(O)Ci-6alkyl, Ci-6alkylS(O)2Cι_6alkyl Preferably the substituent R1^ is situated on the 5 or 7 position of the quinohnone moiety and substituent R 9 IS situated on the 8 position when Rl° IS on the 7-posιtιon Interesting compounds are these compounds of formula (I) wherein X is oxygen Also interesting compounds are these compounds of formula (I) wherein the dotted line represents a bond, so as to form a double bond Another group of interesting compounds are those compounds of formula (I) wherein Rl IS hydrogen, Ci-6alkyl, Ci-6alkyloxyCi-6alkyl, dι(Ci-6alkyl)amιnoCi-6alkyl, or a radical of formula -Alkl-C(=O)-R 9 , wherein Alkl is methylene and R 9 is Ci-8alkyl- armno substituted with Ci-βalkyloxycarbonyl Still another group of interesting compounds are those compounds of formula (I) where R^ is hydrogen or halo, and R 2 is halo, Ci-6alkyl, C2-6 a lkenyl, Ci-6alkyloxy, tπhalomethoxy or hydroxyCi -βalkyloxy. A further group of interesting compounds are those compounds of formula (I) wherein R 2 and R 3 are on adjacent positions and taken together to form a bivalent radical of formula (a-1), (a-2) or (a-3) A still further group of interesting compounds are those compounds of formula (I) wherein R^ is hydrogen and R 4 is hydrogen or Cι_6alkyl Yet another group of interesting compounds are those compounds of formula (I) wherein R^ is hydrogen, and R^ IS Ci-6alkyl or halo, preferably chloro, especially 4-chloro. A particular group of compounds are those compounds of formula (I) wherein R° is hydrogen, hydroxy, haloCi-βalkyl, hydroxyCi -6alkyl, cyanoCi-6alkyl, Ci-6alkyloxy- carbon ylCι_6alkyl, lmidazolyl, or a radical of formula -NRI R1 2 wherein Rl 1 is hydrogen or Ci-i2alkyl and Rl IS hydrogen, Ci-6alkyl, Cι_6alkyloxy, hydroxy, Ci_6alkyloxyCi_6alkylcarbonyl, or a radical of formula -Alk 2 -ORl3 wherein Rl3 1S hydrogen or Ci-6alkyl Preferred compounds are those compounds wherein R is hydrogen, Ci-6alkyl, Cι_6alkyloxyCi-6alkyl, di(Ci-6alkyl)aminoCι_6alkyl, or a radical of formula -Alkl-C(=O)-R 9 , wherein Alkl j s methylene and R 9 is Ci-8alkylamino substituted with Ci-6alkyloxycarbonyl; R 2 is halo, Ci-6alkyl, C2-6alkenyl, Ci-6alkyloxy, trihalomethoxy, hydroxyCi - alkyloxy or Arl; R3 i s hydrogen; R 4 is methyl bound to the nitrogen in 3-position of the imidazole; R^ is hydrogen; R^ is chloro; R^ is hydrogen; R8 is hydrogen, hydroxy, haloCι_6alkyl, hydroxyCi-βalkyl, cyanoCι_6alkyl, Ci-6alkyloxycarbonylCi-6alkyl, imidazolyl, or a radical of formula -NRI 1R1 2 wherein RU is hydrogen or Ci-i2alkyl and Rl 2 is hydrogen, Cι_6alkyl, Ci-6alkyloxy, Cι_6alkyloxyCi-6alkylcarbonyl, or a radical of formula -Alk 2 -ORl3 wherein R 3 is Ci-6alkyl; R 7 is hydrogen and Rl8 J S hydrogen. Most preferred compounds are 4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(l-methyl-lH-imidazol-5-yl)methyl]- 1 -methyl-2( lH)-quinolinone, 6-[amino(4-chlorophenyl)-l-methyl-lH-imidazol-5-ylmethyl]-4-(3-chlorophenyl)- l-methyl-2(lH)-quinolinone; 6-[(4-chlorophenyl)hydroxy(l-methyl-lH-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)- l-methyl-2(lH)-quinolinone; 6-[(4-chlorophenyl)(l-methyl-lH-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-l-methyl- 2(lH)-quinolinone monohydrochloride.monohydrate; 6-[amino(4-chlorophenyl)(l-methyl-lH-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-l- methyl-2(lH)-quinolinone, 6-amino(4-chlorophenyl)(l-methyl-lH-imidazol-5-yl)methyl]-l-methyl-4-(3- propylphenyl)-2(lH)-quinolinone; a stereoisomeric form thereof or a pharmaceutically acceptable acid or base addition salt; and (+)-6-[amino(4-chlorophenyl)(l-methyl-lH-imidazol-5-yl)methyl]-4-(3-chlorophenyl)- l-methyl-2(lH)-quinolinone (Compound 75 in Table 1 of the Experimental part of WO-97/21701) ; or a pharmaceutically acceptable acid addition salt thereof. The latter compound is especially preferred. Further preferred embodiments of the present invention include compounds of formula (IX) wherein one or more of the following restrictions apply: • =X ! -X 2 -X 3 is a trivalent radical of formula (x-1), (x-2), (x-3), (x-4) or (x-9) wherein each R 6 independently is hydrogen, Cι_ 4 alkyl, Cι_ alkyloxycarbonyl, amino or aryl and R 7 is hydrogen; • >Y 1 -Y 2 - is a trivalent radical of formula (y-1), (y-2), (y-3), or (y-4) wherein each R 9 independently is hydrogen, halo, carboxyl, Cι_ alkyl or C]_ alkyloxycarbonyl; • r is 0, 1 or 2; • s is 0 or 1; • t is O; • R 1 is halo, Cι_ 6 alkyl or two R 1 substituents ortho to one another on the phenyl ring may independently form together a bivalent radical of formula (a-1); • R 2 is halo; • R 3 is halo or a radical of formula (b-1) or (b-3) wherein R 10 is hydrogen or a radical of formula -Alk-OR 13 . R 11 is hydrogen; 1 9 R is hydrogen, Cι_ alkyl, Cι_ 6 alkylcarbonyl, hydroxy, C]. 6 alkyloxy or mono- or di (C i _ 6 alkyl)aminoC i _ 6 alkylcarbonyl ; Alk is Cι_ 6 alkanediyl and R 13 is hydrogen; • R 4 is a radical of formula (c-1) or (c-2) wherein R 16 is hydrogen, halo or mono- or di(Cι_ alkyl)amino; R 17 is hydrogen or Cι_ 6 alkyl; • aryl is phenyl. A particular group of compounds consists of those compounds of formula (IX) wherein =X ! -X 2 -X 3 is a trivalent radical of formula (x-1), (x-2), (x-3) (x-4) or (x-9), >Y1-Y2 is a trivalent radical of formula (y-2), (y-3) or (y-4), r is 0 or 1, s is 1, t is 0, R 1 is halo, C ( i_ 4 )alkyl or forms a bivalent radical of formula (a-1), R 2 is halo or Cι_ alkyl, R 3 is hydrogen or a radical of formula (b-1) or (b-3), R 4 is a radical of formula (c-1) or (c-2). R 6 is hydrogen, Cι_ alkyl or phenyl, R 7 is hydrogen, R 9 is hydrogen or Cι_ 4 alkyl, R 10 is ι ι ι n hydrogen or -Alk-OR , R is hydrogen and R is hydrogen or Cι_ 6 alkylcarbonyl and R 13 is hydrogen; Preferred compounds are those compounds of formula (IX) wherein =X -X -X is a trivalent radical of formula (x-1) or (x-4), >Y1-Y2 is a trivalent radical of formula (y- 4), r is 0 or 1, s is 1, t is 0, R 1 is halo, preferably chloro and most preferably 3-chloro, R 2 is halo, preferably 4-chloro or 4-fluoro, R 3 is hydrogen or a radical of formula (b-1) or (b-3), R 4 is a radical of formula (c-1) or (c-2), R 6 is hydrogen, R 7 is hydrogen, R 9 is hydrogen, R 10 is hydrogen, R 11 is hydrogen and R 12 is hydrogen; Other preferred compounds are those compounds of formula (IX) wherein =X ! -X 2 -X 3 is a trivalent radical of formula (x-2), (x-3) or (x-4) >Y1-Y2 is a trivalent radical of formula (y-2), (y-3) or (y-4), r and s are 1, t is 0, R 1 is halo, preferably chloro, and m preferably 3-chloro or R 1 is Cj_ alkyl, preferably 3-methyl, R 2 is halo, preferably chloro, and most preferably 4-chloro, R 3 is a radical of formula (b-1) or (b-3), R 4 is a radical of formula (c-2), R 6 is C]_ alkyl, R 9 is hydrogen, R 10 and R 1 1 are hydrogen and R 1 ") is hydrogen or hydroxy. The most preferred compounds of formula (IX) are 7-[(4-fluorophenyl)(lH-imidazol-l-y])methyl]-5-phenylimidazo[l,2-a]quinoline; α-(4-chlorophenyl)-α-(l-methyl-lH-imidazol-5-yl)-5-phenylimidazo[1.2-a]quinoline- 7-methanol; 5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(l-methyl-lH-imidazol-5-yl)-imidazo[l,2- a]quinoline-7-methanol; 5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(l-methyl-lH-imidazol-5-yl)imidazo[l,2- a]quinoline-7-methanamine; 5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(l-methyl-lH-imidazol-5-yl)tetrazolo[l,5- a]quinoline-7-methanamine; 5-(3-chlorophenyl)-α-(4-chlorophenyl)-l-methyl-α-(l -methyl- lH-imidazol-5-yl)-l, 2,4- triazolo[4,3-a]quinoline-7-methanol; 5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(l-methyl-lH-imidazol-5-yl)tetrazolo[l,5- a]quinoline-7-methanamine; 5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(l-methyl-lH-imidazol-5-yl)tetrazolo[l,5- a]quinazoline-7-methanol; 5-(3-chlorophenyl)-α-(4-chlorophenyl)-4,5-dihydro-α-(l-methyl-lH-imidazol-5- yl)tetrazolo[l,5-a]quinazoline-7-methanol; 5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(l-methyl-lH-imidazol-5-yl)tetrazolo[l,5- a]quinazoline-7-methanamine; 5-(3-chlorophenyl)-α-(4-chlorophenyl)-N-hydroxy-α-(l-methyl-lH-imidazol-5- yl)tetrahydro[l,5-a]quinoline-7-methanamine; α-(4-chlorophenyl)-α-(l-methyl-lH-imidazol-5-yl)-5-(3-methylphenyl)tetrazolo[l,5- a]quinoline-7-methanamine; the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof. 5-(3-chlorophenyl)- -(4-chlorophenyl)- -(l -methyl- lH-imidazol-5-yl)tetrazolo[ 1,5- a]quinazoline-7-methanamine, especially the (-) enantiomer, and its pharmaceutically acceptable acid addition salts are especially preferred. As used in the foregoing definitions and hereinafter halo defines fluoro, chloro, bromo and iodo; Ci-βalkyl defines straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl and the like; Ci-8alkyl encompasses the straight and branched chained saturated hydrocarbon radicals as defined in Ci-βalkyl as well as the higher homologues thereof containing 7 or 8 carbon atoms such as, for example heptyl or octyl; Ci-I2alkyl again encompasses Ci-8alkyl and the higher homologues thereof containing 9 to 12 carbon atoms, such as, for example, nonyl, decyl, undecyl, dodecyl, Cι_i6alkyl again encompasses Cι_i2alkyl and the higher homologues thereof containing 13 to 16 carbon atoms, such as, for example, tπdecyl, tetradecyl, pentedecyl and hexadecyl; C2-6 a lkenyl defines straight and branched chain hydrocarbon radicals containing one double bond and having from 2 to 6 carbon atoms such as, for example, ethenyl, 2-propenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, and the like, Ci-6alkanedιyl defines bivalent straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, for example, methylene, 1,2-ethanedιyl, 1,3-propanedιyl, 1,4-butanedιyl, 1,5-pentanedιyl, 1,6-hexanedιyl and the branched isomers thereof The term "C(=O)" refers to a carbonyl group, "S(O)" refers to a sulfoxide and "S(O)2" to a sulfon. The term "natural amino acid" refers to a natural amino acid that is bound via a covalent amide linkage formed by loss of a molecule of water between the carboxyl group of the amino acid and the amino group of the remainder of the molecule. Examples of natural ammo acids are glyc e, alanine, valine, leucine, isoleucine, methionme, proline, phenylanahne, tryptophan, seπne, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine The pharmaceutically acceptable acid or base addition salts as mentioned hereinabove are meant to compπse the therapeutically active non-toxic acid and non-toxic base addition salt forms which the compounds of formulas (I), (H), (HI), (IV), (V), (VI), (VH), (VHI) or (IX) are able to form The compounds of formulas (I), (H), (HI), (IV), (V), (VI), (VH), (VHI) or (IX) which have basic properties can be converted in their pharmaceutically acceptable acid addition salts by treating said base form with an appropπate acid. Appropπate acids compπse, for example, inorganic acids such as hydroha c acids, e.g. hydrochloπc or hydrobromic acid; sulfuπc; nitπc; phosphoπc and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e. butanedioic acid), maleic, fumaπc, malic, tartaπc, citπc, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicyhc, pamoic and the like acids The compounds of formulae (I), (H), (HI), (IV), (V), (VI), (VH), (VHI) or (IX) which have acidic properties may be converted in their pharmaceutically acceptable base addition salts by treating said acid form with a suitable organic or inorganic base. Appropπate base salt forms compπse, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. The terms acid or base addition salt also comprise the hydrates and the solvent addition forms which the compounds of formulae (I), (II), (HI), (IV), (V), (VI), (VH), (VHI) or (IX) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like. The term stereochemically isomeric forms of compounds of formulae (I), (LI), (HI), (IV), (V), (VI), (VH), (Vm) or (DC), as used hereinbefore, defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of formulae (I), (H), (HI), (IV), (V), (VI), (VH), (VHI) or (IX) may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of formulae (I), (H), (HI), (IV), (V), (VI), (VH), (VTfl) or (IX) both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention. Some of the compounds of formulae (I), (II), (HI), (IV), (V), (VI), (VH), (VHI) or (IX) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention. Whenever used hereinafter, the term "compounds of formulae (I), (H), (HI), (IV), (V), (VI), (VH), (VHI) or (IX)" is meant to include also the pharmaceutically acceptable acid or base addition salts and all stereoisomeric forms. Preferred camptothecin compounds for use in accordance with the invention include irinotecan and topotecan referred to above. Irinotecan is commercially available for example from Rhone-Poulenc Rorer under the trade name Campto and may be prepared for example as descibed in European patent specification No. 137145 or by processes analogous thereto. Topotecan is commercially available for example from SmithKline Beecham under the trade name Hycamtin and and may be prepared for example as descibed in European patent specification No. 321122 or by processes analogous thereto Other camptothecin compounds may be prepared in conventional manner for example by processes analogous to those descπbed above for lπnotecan and topotecan. The present invention also relates to combinations according to the invention for use in medical therapy for example for inhibiting the growth of tumor cells. The present invention also relates to the use of combinations according to the invention for the preparation of a pharmaceutical composition for inhibiting the growth of tumor cells. The present invention also relates to a method of inhibiting the growth of tumor cells in a human subject which compπses administeπng to the subject an effective amount of a combination according to the invention. This invention further provides a method for inhibiting the abnormal growth of cells, including transformed cells, by administeπng an effective amount of a combination according to the invention. Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g. loss of contact inhibition). This includes the abnormal growth of : (1) tumor cells (tumors) expressing an activated ras oncogene; (2) tumor cells in which the ras protein is activated as a result of oncogenic mutation of another gene; (3) benign and malignant cells of other prohferative diseases in which aberrant ras activation occurs. Furthermore, it has been suggested in literature that ras oncogenes not only contπbute to the growth of of tumors in vivo by a direct effect on tumor cell growth but also indirectly, I e by facilitating tumor-induced angiogenesis (Rak. J. et al, Cancer Research, 55, 4575-4580, 1995). Hence, pharmacologically targetting mutant ras oncogenes could conceivably suppress solid tumor growth in vivo, in part, by inhibiting tumor-mduced angiogenesis. This invention also provides a method for inhibiting tumor growth by administeπng an effective amount of a combination according to the present invention, to a subject, e g. a mammal (and more particularly a human) in need of such treatment. In particular, this invention provides a method for inhibiting the growth of tumors expressing an activated ras oncogene by the administration of an effective amount of combination according to the present invention. Examples of tumors which may be inhibited include, but are not limited to, lung cancer (e.g. adenocarcmoma and including non- small cell lung cancer), pancreatic cancers (e.g. pancreatic carcinoma such as, for example exocπne pancreatic carcinoma), colon cancers (e.g colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), hematopoietic tumors of lymphoid lineage (e.g. acute lymphocytic leukemia, B-cell lymphoma, Burkitt's lymphoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid folhcular cancer, myelodysplastic syndrome (MDS), tumors of mesenchymal oπgin (e.g. fibrosarcomas and rhabdomyosarcomas), melanomas, teratocarcmomas, neuroblastomas, g omas, benign tumor of the skin (e g keratoacanthomas), breast carcinoma (e.g. advanced breast cancer), kidney carninoma, ovary carcinoma, bladder carcinoma and epidermal carcinoma. This invention also provides a method for inhibiting prohferative diseases, both benign and malignant, wherein ras proteins are aberrantly activated as a result of oncogenic mutation in genes, i.e. the ras gene itself is not activated by mutation to an oncogenic mutation to an oncogenic form, with said inhibition being accomplished by the administration of an effective amount of a combination according to the invention, to a subject in need of such a treatment. For example, the benign prohferative disorder neurofibromatosis, or tumors in which ras is activated due to mutation or overexpression of tyrosine kinase oncogenes may be inhibited by the combinations according to the invention. The camptothecin compound and the farnesyl transferase inhibitor may be administered simultaneously (e.g. in separate or unitary compositions) or sequentially m either order. In the latter case, the two compounds will be administered within a peπod and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is achieved. It will be appreciated that the preferred method and order of administration and the respective dosage amounts and regimes for each component of the combination will depend on the particular camptothecin compound and farnesyl transferase inhibitor being administered, their route of administration, the particular tumor being treated and the particular host being treated. The optimum method and order of administration and the dosage amounts and regime can be readily determined by those skilled in the art using conventional methods and in view of the information set out herein. The farnesyl transferase inhibitor is advantageously administered in an effective amount of from 0.0001 mg/kg to 100 mg/kg body weight, and in particular from 0.001 mg/kg to 10 mg/kg body weight. More particularly, for an adult patient, the dosage is conveniently in the range of 50 to 500mg bid, advantageously 100 to 400 mg bid and particularly 300mg bid. The camptothecin compound is advantageously administered in a dosage of 0.1 to 400 mg per square meter (mg/m 2 ) of body surface area, for example 1 to 300 mg/m 2 , particularly for irinotecan in a dosage of about 100 to 350 mg/m 2 and for topotecan in about 1 to 2 mg/m 2 per course of treatment. These dosages may be administered for example once, twice or more per course of treatment, which may be repeated for example every 7, 14, 21 or 28 days. It is especially preferred to administer the farnesyl tranferase inhibitor at a dosage of 100 or 200mg bid for 7, 14, 21 or 28 days with a dosage of the camptothecin compound in the ranges indicated above. In view of their useful pharmacological properties, the components of the combinations according to the invention, i.e. the camptothecin compound and the farnesyl transferase inhibitor may be formulated into various pharmaceutical forms for administration purposes. The components may formulated separately in individual pharmaceutical compositions or in a unitary pharmaceutical composition containing both components. Farnesyl protein transferase inhibitors can be prepared and formulated into pharmaceutical compositions by methods known in the art and in particular according to the methods described in the published patent specifications mentioned herein and incorporated by reference; for the compounds of formulae (I), (H) and (HI) suitable examples can be found in WO-97/21701. Compounds of formulae (IV), (V), and (VI) can be prepared and formulated using methods described in WO 97/16443, compounds of formulae (VH) and (VHI) according to methods described in WO 98/40383 and WO 98/49157 and compounds of formula (IX) according to methods described in WO 00/39082 respectively. The present invention therefore also relates to a pharmaceutical composition comprising a camptothecin compound and a farnesyl tranferase inhibitor of formula (I) together with one or more pharmaceutical carriers. To prepare pharmaceutical compositions for use in accordance with the invention, an effective amount of a particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions, or solid earners such as starches, sugars, kaolin, lubπcants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets Because of their ease administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical earners are obviously employed For parenteral compositions, the earner will usually compnse steπle water, at least in large part, though other ingredients, to aid solubility for example, may be included Injectable solutions, for example, may be prepared in which the earner compπses saline solution, glucose solution or a mixture of saline and glucose solution Injectable suspensions may also be prepared in which case appropπate liquid earners, suspending agents and the like may be employed In the compositions suitable for percutaneous administration, the earner optionally compnses a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause a significant deleteπous effect to the skin Said additives may facilitate the administration to the skin and or may be helpful for prepaπng the desired compositions These compositions may be administered in vaπous ways, e g , as a transdermal patch, as a spot-on, as an ointment It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical earner Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof It may be appropπate to administer the required dose of each component of the combination as two, three, four or more sub-doses at appropπate intervals throughout the course of treatment Said sub-doses may be formulated as unit dosage forms, for example, in each case containing independently 0 01 to 500 mg, for example 0 1 to 200 mg and in particular 1 to lOOmg of each active ingredient per unit dosage form Experimental Testing of Combinations for Inhibition of Tumor Growth The combinations according to the invention may be tested for their efficacy in inhibiting tumor growth using conventional assays described in the literature for example the HTB177 lung carcinoma described by Liu M et al, Cancer Research, Vol. 58, No.21, 1 November 1998, pages 4947-4956, and the anti-mitotic assay described by Moasser M et al, Proc. Natl. Acad. Sci. USA, Vol. 95, pages 1369-1374, February 1998. Other in vitro and in vivo models for determining ant-tumor effects of combinations and possible synergy of the combinations according to the invention are described in WO 98/54966 and WO 98/32114. Clinical models for determining the efficacy and possible synergism for combination therapy in the clinic are generally described in Cancer: Principles and Practice of Oncology, Fifth Edition, edited by Vincent T DeVita, Jr., Samuel Hellman, Steven A. Rosenberg, Lippincott-Raven, Philadelphia, 1997, especially Chapter 17, pages 342-346.

Claims: Claims 1. A combination of a camptothecin compound and a farnesyl transferase inhibitor selected from compounds of formulae (I), (II), (IH), (IV), (V), (VI), (VH), (VHI) and (IX) below (I) (ID (in) the pharmaceutically acceptable acid or base addition salts and the stereochemically isomenc forms thereof, wherem the dotted line represents an optional bond; X is oxygen or sulfur; Rl IS hydrogen, Ci-I2alkyl, Arl, Ar 2 Ci-6alkyl, qumohnylCi-6alkyl, pyndylCι_6alkyl, hydroxyCi -όalkyl, Ci-6alkyloxyCi-6alkyl, mono- or dι(C i -6alkyl)ammoC i -6alkyl , ammoC i -6alkyl , or a radical of formula -Alkl-C(=O)-R 9 , -Alkl-S(O)-R 9 or -Alkl-S(O)2-R 9 , wherein Alkl is Ci-6alkanedιyl, R 9 is hydroxy, Cι_6alkyl, Ci-6alkyloxy, ammo, Ci-8alkylamιno or Ci_8alkylamino substituted with Cι_6alkyloxycarbonyl, R 2 , R3 and Rl° " each independently are hydrogen, hydroxy, halo, cyano, Ci-6alkyl, Cι_6alkyloxy, hydroxyCi .βalkyloxy, Ci-6alkyloxyCi-6alkyloxy, amιnoCi-6alkyl- oxy, mono- or dι(Ci-6alkyl)amιnoCi-6alkyloxy, Arl, Ar 2 Ci_6alkyl, Ar 2 oxy, Ar 2 Cι_6alkyloxy, hydroxycarbonyl, Ci-6alkyloxycarbonyl, tnhalomethyl, trihalomethoxy, C2-6alkenyl, 4,4-dimethyloxazolyl; or when on adjacent positions R 2 and R3 taken together may form a bivalent radical of formula -O-CH2-O- (a-1), -O-CH2-CH2-O- (a-2), -O-CH=CH- (a-3), -O-CH2-CH2- (a-4), -O-CH2-CH2-CH2- (a-5), or -CH=CH-CH=CH- (a-6); R 4 and R^ each independently are hydrogen, halo, Arl, Ci-βalkyl, hydroxyCi -6 a lkyl, Ci-6alkyloxyCι_6alkyl, Cι_6alkyloxy, Cι_6alkylthio, amino, hydroxycarbonyl, Cι_6alkyloxycarbonyl, Cι_6alkylS(O)Ci-6alkyl or Cι_6alkylS(O)2Ci-6alkyl; R" and R^ each independently are hydrogen, halo, cyano, Ci-6alkyl, Ci-βalkyloxy, Ar 2 oxy, trihalomethyl, Ci-6alkylthio, di(Ci-6alkyl)amino, or when on adjacent positions R° and R^ taken together may form a bivalent radical of formula -O-CH2-O- (c-1), or -CH=CH-CH=CH- (c-2); R° is hydrogen, Ci-6alkyl, cyano, hydroxycarbonyl, Cι_6alkyloxycarbonyl, Ci-6alkylcarbonylCi-6alkyl, cyanoCi-6alkyl, Ci-6alkyloxycarbonylCi-6alkyl, carboxyCi-6alkyl, hydroxyCi-6alkyl, aminoCi-6alkyl, mono- or di(Ci-6alkyl)- aminoCi-6alkyl, imidazolyl, haloCι_6alkyl, Ci-6alkyloxyCi-6alkyl, aminocarbonylCi-6alkyl, or a radical of formula -O-RlO (b-1), -S-RlO (b- 2 ), -N-RllRl 2 (b-3), wherein RlO is hydrogen, Cι_6alkyl, Ci-6alkylcarbonyl, Arl, Ar 2 Ci-6alkyl, Ci-6alkyloxycarbonylCι_6alkyl, or a radical or formula -Alk 2 -ORl3 or -Alk 2 -NRl 4 Rl 5 ; RU is hydrogen, Cι_i2alkyl, Arl or Ar 2 Ci-6alkyl; Rl 2 is hydrogen, Ci-6alkyl, Ci-i6alkylcarbonyl, Ci-6alkyloxycarbonyl, Ci-6alkylaminocarbonyl, Ar , Ar 2 Cι_6alkyl, Cι_6alkylcarbonyl- Cι_6alkyl, a natural amino acid, Arlcarbonyl, Ar 2 Ci_6alkylcarbonyl, aminocarbonylcarbonyl, Ci-6alkyloxyCi-6alkylcarbonyl, hydroxy, Ci-6alkyloxy, aminocarbonyl, di(Cι_6alkyl)aminoCι_6alkylcarbonyl, amino, Ci-6alkylamino, Ci-6alkylcarbonylamino, or a radical or formula -Alk 2 -ORl3 or -Alk 2 -NRl 4 Rl 5 ; wherein Alk 2 is Cι_6alkanediyl; Rl IS hydrogen, Ci-6alkyl, Cι_6alkylcarbonyl, hydroxy- Ci-6alkyl, Arl or Ar 2 Ci-6alkyl, Rl 4 IS hydrogen, Ci-6alkyl, Arl or Ar 2 Cι_6alkyl, Rl5 IS hydrogen, Ci-6alkyl, Cι_6alkylcarbonyl, Arl or Ar 2 Ci-6alkyl, Rl7 IS hydrogen, halo, cyano, Cι_6alkyl, Ci-6alkyloxycarbonyl, Arl, R! ^ IS hydrogen, Cι_6alkyl, Ci-βalkyloxy or halo, Rl 9 IS hydrogen or Ci-6alkyl, Arl 1S phenyl or phenyl substituted with Ci-6alkyl, hydroxy, amino, Ci-6alkyloxy or halo, and Ar 2 is phenyl or phenyl substituted with Cι_6alkyl, hydroxy, amino, Ci-6alkyloxy or (VI) the pharmaceutically acceptable acid or base addition salts and the stereochemically isomenc forms thereof, wherein the dotted line represents an optional bond, X is oxygen or sulfur, Rl is hydrogen, Ci-I2alkyl, Arl, Ar 2 Ci-6alkyl, quιnolιnylCi-6alkyl, pyndyl- Cι_6alkyl, hydroxyCi -6alkyl, Ci-6alkyloxyCi-6alkyl, mono- or dι(Cι_6alkyl)- ammoCi-όalkyl, amιnoCι_6alkyl, or a radical of formula -Alkl-C(=O)-R 9 , -Alkl-S(O)-R 9 or -Alkl-S(O)2-R 9 , wherem Alkl 1S Cι_6alkanedιyl, R 9 is hydroxy, Ci-6alkyl, Cι_6alkyloxy, amino, Ci-8alkylamino or Ci-8alkylamino substituted with C _6alkyloxycarbonyl; R 2 and R3 each independently are hydrogen, hydroxy, halo, cyano, Ci-6alkyl, Ci-6alkyloxy, hydroxyCi -6alkyloxy, Ci-6alkyloxyCι_6alkyloxy, amino- Ci-6alkyloxy, mono- or di(Ci-6alkyl)aminoCi-6alkyloxy, Ar , Ar 2 Cι_6alkyl, Ar oxy, Ar Ci-6alkyloxy, hydroxycarbonyl, Cι_6alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C2-6alkenyl; or when on adjacent positions R 2 and R3 taken together may form a bivalent radical of formula -O-CH2-O- (a-1), -O-CH2-CH2-O- (a-2), -O-CH=CH- (a-3), -O-CH2-CH2- (a-4), -O-CH2-CH2-CH2- (a-5), or -CH=CH-CH=CH- (a-6); R 4 and R 5 each independently are hydrogen, Ar 1 , Cι_ 6 alkyl, C]- 6 alkyloxyCι_ 6 alkyl, Cι_ 6 alkyloxy, Cι_ 6 alkylthio, amino, hydroxycarbonyl, Cι_ 6 alkyloxycarbonyl, Cι_ 6 alkylS(O)C 1 . 6 alkyl or Cι_ 6 alkylS(O) 2 Cι_ 6 alkyl; R6 and R^ each independently are hydrogen, halo, cyano, Cι_6alkyl, Ci-6alkyloxy or Ar 2 oxy; R° is hydrogen, Cι_6alkyl, cyano, hydroxycarbonyl, Cι_6alkyloxycarbonyl, Ci-6alkyl- carbonylCi-6alkyl, cyanoCι_6alkyl, Ci-6alkyloxycarbonylCι_6alkyl, hydroxy- carbonylCι_6alkyl, hydroxyC _6alkyl, aminoCi-6alkyl, mono- or di(Cι_6alkyl)- aminoCi-6alkyl, haloCi-6alkyl, Ci-6alkyloxyCi-6alkyl, aminocarbonylCi_6alkyl, Arl, Ar 2 Ci-6alkyloxyCi-6alkyl, Ci-6alkylthioCι_6alkyl; RIO is hydrogen, Cι_6alkyl, Ci-6alkyloxy or halo; R 1 is hydrogen or Cι_6alkyl; Arl is phenyl or phenyl substituted with Ci-ζalkyl, hydroxy, amino, Ci-6alkyloxy or halo; Ar 2 is phenyl or phenyl substituted with Ci-6alkyl,hydroxy,amino,Ci-6 a lkyloxy or halo. the pharmaceutically acceptable acid addition salts and the stereochemically isomeπc forms thereof, wherein the dotted line represents an optional bond; X is oxygen or sulfur; -A- is a bivalent radical of formula -CH=CH- (a-1), -CH2-S- (a-6), -CH2-CH2- (a-2), -CH2-CH2-S- (a-7), -CH2-CH2-CH2- (a-3), -CH=N- (a-8), -CH2-O- (a-4), -N=N- (a-9), or -CH2-CH2-O- (a-5), -CO-NH- (a-10); wherein optionally one hydrogen atom may be replaced by Cι_4alkyl or Arl, Rl and R 2 each independently are hydrogen, hydroxy, halo, cyano, Ci-6alkyl, tnhalomethyl, tnhalomethoxy, C2-6 a lkenyl, Ci-6alkyloxy, hydroxyCi -6alkyloxy, Ci-6alkyloxyCi-6alkyloxy, Ci-6alkyloxycarbonyl, ammoCi-βalkyloxy, mono- or di(Ci_6alkyl)aminoCi-6alkyloxy, Ar 2 , Ar 2 -Cι_6alkyl, Ar 2 -oxy. Ar -C -6alkyloxy; or when on adjacent positions Rl and R 2 taken together may form a bivalent radical of formula -O-CH2-O- (b-1), -O-CH2-CH2-O- (b-2), -O-CH=CH- (b-3), -O-CH2-CH2- (b-4), -O-CH2-CH2-CH2- (b-5), or -CH=CH-CH=CH- (b-6); R and R 4 each independently ; ire hydrogen, halo, cyano, Cι_6alkyl, Ci-6alkyloxy, Ar3-oxy, Ci-βalkylthio, dι(Ci-6alkyl)amιno, tπhalomethyl, tnhalomethoxy, or when on adjacent positions R and R 4 taken together may form a bivalent radical of formula -O-CH2-O- (c-1), -O-CH2-CH2-O- (c-2), or -CH=CH-CH=CH- (c-3); R^ is a radical of formula wherein Rl3 IS hydrogen, halo, Ar 4 , Ci-6alkyl, hydroxyCi -6alkyl, Ci-6alkyloxy- Cι_6alkyl, Ci-6alkyloxy, Ci-6alkylthιo, am o, Ci-6alkyloxy- carbonyl, Ci-6alkylS(O)Ci-6alkyl or Cι_6alkylS(O)2Cι_6alkyl, R! 4 IS hydrogen, Cι.6alkyl or dι(Ci-4alkyl)amιnosulfonyl; R" is hydrogen, hydroxy, halo, Cι_6alkyl, cyano, haloCi-6alkyl, hydroxyCi-βalkyl, cyanoCι_6alkyl, amιnoCi-6alkyl, Ci-6alkyloxyCi-6alkyl, Ci-6alkylthιoCi-6alkyl, amιnocarbonylCι_6alkyl, C i -6alkyloxycarbonylC i .βalkyl , C i -6alkylcarbonyl-C i _6alkyl , Ci-6alkyloxycarbonyl, mono- or dι(Ci-6alkyl)ammoCi-6alkyl, Ar\ Ar5-Ci-6alkyloxyCi-6alkyl; or a radical of formula -O-R7 (e-1), _S_R7 (e-2), -N-R8R 9 (e-3), wherein R IS hydrogen, Cι_6alkyl, Cι_6alkylcarbonyl, Ar^, Ar^-Cι_6alkyl, Ci-6alkyloxycarbonylCi-6alkyl, or a radical of formula -Alk-OR 10 or -Alk-NR u Rl 2 ; R8 IS hydrogen, Cι_6alkyl, Ar7 or Ar7-Cι_6alkyl; R 9 is hydrogen, Ci-βalkyl, Cι_6alkylcarbonyl, Cι_6alkyloxycarbonyl, Ci-6alkylamιnocarbonyl, Ar^, Ar^-Ci-6alkyl, Ci-6alkylcarbonyl- Ci-6alkyl, Ar^-carbonyl, Ar^-Ci-όalkylcarbonyl, aminocarbonyl- carbonyl, Ci-6alkyloxyCi_6alkylcarbonyl, hydroxy, Cι_6alkyloxy, aminocarbonyl, dι(Ci-6alkyl)amιnoCi-6alkylcarbonyl, amino, C i -6alkylamιno, C i _6alkylcarbonylamιno, or a radical or formula -Alk-OR 10 or -Alk-NR 1 1R1 2 ; wherein Alk is Cι_6alkanedιyl; RIO IS hydrogen, Ci-6alkyl, Ci-6alkylcarbonyl, hydroxyCi -6 a lkyl, Ar 9 or Ar 9 -Ci-6alkyl; RU IS hydrogen, Ci-βalkyl, Ci-6alkylcarbonyl, Arl° or Ar 10 -Ci-6alkyl; Rl 2 IS hydrogen, Ci-6alkyl, ArH or ArH-Cι_6alkyl; and Arl to Ari l are each independently selected from phenyl; or phenyl substituted with halo, Ci-6alkyl, Ci-βalkyloxy or tπfluoromethyl. the pharmaceutically acceptable acid addition salts and the stereochemically isomeπc forms thereof, wherein the dotted line represents an optional bond; X is oxygen or sulfur; Rl and R 2 each independently are hydrogen, hydroxy, halo, cyano, Ci-6alkyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, Ci-6alkyloxy, hydroxyCi -ζalkyloxy, Cι_6alkyloxyCi-6alkyloxy, Ci_6alkyloxycarbonyl, aminoCi-6alkyloxy, mono- or di(Ci-6alkyl)aminoCi-6alkyloxy, Arl, ArlCj-όalkyl, Arloxy or ArlCi-6alkyloxy; R3 and R 4 each independently are hydrogen, halo, cyano, Ci-βalkyl, Cι_6alkyloxy, Arloxy, Ci-βalkylthio, di(Ci-6alkyl)amino, trihalomethyl or trihalomethoxy; R5 is hydrogen, halo, Ci-6alkyl, cyano, haloCi-6alkyl, hydroxyCi -6alkyl, cyanoCι_6alkyl, aminoCι_6alkyl, Cι_6alkyloxyCi-6alkyl, C i _6alkylthioC i .βalkyl, aminocarbonylC i -βalkyl , C i _6alkyloxycarbonylC i -6alkyl, C i -6alkylcarbonyl-C l -6alkyl , Cι_6alkyloxycarbonyl, mono- or di(Ci-6alkyl)aminoCi-6alkyl, Arl, ArlCi-6alkyloxyCi-6alkyl; or a radical of formula _O-Rl0 (a-1), .S.RlO (a-2), -N-Rl lRl 2 ( a - ), wherein RlO is hydrogen, Cι_6alkyl, Ci-βalkylcarbonyl, Arl, Ar Ci-6alkyl, Cι_6alkyloxycarbonylCi-6alkyl, or a radical of formula -Alk-OR 13 or -Alk-NRl 4 Rl 5 ; R 11 is hydrogen , C i -6alkyl , Ar 1 or Ar C i -6alkyl ; R 2 is hydrogen, Cι_6alkyl, Cι_6alkylcarbonyl, Ci-6alkyloxycarbonyl, Ci-6alkylaminocarbonyl, Arl, ArlCi-6 lkyl, Cι_6alkylcarbonyl- Cι_6alkyl, Arlcarbonyl, ArlCι_6alkylcarbonyl, aminocarbonyl- carbonyl, Cι_6alkyloxyCi-6alkylcarbonyl, hydroxy, Ci-βalkyloxy, aminocarbonyl, di(Ci-6alkyl)aminoCι_6alkylcarbonyl, amino, C l _6alkylamino, C _6alkylcarbonylamino, or a radical or formula -Alk-OR i 3 or -Alk-NR 14 R 15 ; wherein Alk is Ci-βalkanediyl; Rl is hydrogen, Ci_6alkyl, Ci-galkylcarbonyl, hydroxy- Cι_6alkyl, Arl or ArlCi-6alkyl; Rl 4 is hydrogen, Cι_6alkyl, Arl or ArlCι_6alkyl; Rl5 is hydrogen, Ci-6alkyl, Ci-6alkylcarbonyl, Ar or ArlCi-6alkyl; R" is a radical of formula wherein Rl"is hydrogen, halo, Arl, Ci-6alkyl, hydroxyCi -6alkyl, Ci-βalkyloxy- Ci-6alkyl, Ci-6alkyloxy, Ci-6alkylthio, amino, C i -6alkyloxycarbonyl, C i _6alkylthioC 1 -6alkyl, Ci-6alkylS(O)Ci-6alkyl or Cι_6alkylS(O)2Ci-6alkyl; Rl7is hydrogen, Ci-6alkyl or di(Cι_4alkyl)aminosulfonyl; R7 is hydrogen or Ci-βalkyl provided that the dotted line does not represent a bond; R 8 is hydrogen, Ci-6alkyl or Ar 2 CH2 or Het CH2; R 9 is hydrogen, Cι_6alkyl , Cι_6alkyloxy or halo; or R8 and R 9 taken together to form a bivalent radical of formula -CH=CH- (c-1), -CH2-CH2- (c-2), -CH2-CH2-CH2- (c-3), -CH2-O- (c-4), or -CH2-CH2-O- (c-5); Arl i s phenyl; or phenyl substituted with 1 or 2 substituents each independently selected from halo, Ci-6alkyl, Ci-6alkyloxy or trifluoromethyl; Ar 2 is phenyl; or phenyl substituted with 1 or 2 substituents each independently selected from halo, Ci-6alkyl, C -6alkyloxy or trifluoromethyl; and Hetl is pyridinyl; pyridinyl substituted with 1 or 2 substituents each independently selected from halo, Ci-6alkyl, Ci-6alkyloxy or trifluoromethyl and or the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein =X'-X 2 -X 3 - is a trivalent radical of formula =N-CR 6 =CR 7 - (x-1), =CR 6 -CR 7 =CR 8 - (x-6), =N-N=CR 6 - (χ- 2 ), =CR 6 -N=CR 7 - (x-7), =N-NH-C(=O)- (x-3), =CR 6 -NΗ-C(=O)- (x-8), or =N-N=N- (χ- 4 ), =CR 6 -N=N- (x-9); =N-CR 6 =N- (x-5), wherein each R 6 , R 7 and R 8 are independently hydrogen, Cι -4 alkyl, hydroxy, Cι_ 4 alkyloxy, aryloxy, Cμ 4 alkyloxycarbonyl, hydroxyCi _ 4 alkyl, Cι_ alkyloxyCι_ 4 alkyl, mono- or di(Cι- alkyl)aminoCι_ 4 alkyl, cyano, amino, thio, Cι_ 4 alkylthio, arylthio or aryl; >Y*-Y 2 - is a trivalent radical of formula >CH-CHR 9 - (y-i), >C=N- (y- 2 ), >CH-NR 9 - (y-3),or >C=CR 9 - (y- 4 ); wherein each R 9 independently is hydrogen, halo, halocarbonyl, aminocarbonyl, hydroxyCι_ alkyl, cyano, carboxyl, Cι_ alkyl, Cι_ alkyloxy, Cι_ 4 alkyloxyCι_ alkyl, Cι_ 4 alkyloxycarbonyl, mono- or di(Cι_ alkyl)amino, mono- or di(Ci_ 4 alkyl)aminoCi- alkyl, aryl; r and s are each independently 0, 1, 2, 3, 4 or 5; t is 0, 1, 2 or 3; each R 1 and R 2 are independently hydroxy, halo, cyano, Ci-6alkyl, trihalomethyl, trihalomethoxy, C 2 _ 6 alkenyl, Cι_ 6 alkyloxy, hydroxyCi. 6 alkyloxy, Cι_ 6 alkylthio, Cι_ 6 alkyloxyCι_ 6 alkyloxy, Cι_ 6 alkyloxycarbonyl, aminoCι_ 6 alkyloxy, mono- or di(Cι. 6 alkyl)amino, mono- or di(Cι_ 6 alkyl)aminoCι_ 6 alkyloxy, aryl, arylCι_ 6 alkyl, aryloxy or arylCι_ alkyloxy, hydroxycarbonyl, Cι_ 6 alkyloxycarbonyl, aminocarbonyl, aminoCι_ 6 alkyl, mono- or di(Cι_ 6 alkyl)aminocarbonyl, mono- or di(Cι_ 6 alkyl)aminoCι_ 6 alkyl; or two R 1 or R 2 substituents adjacent to one another on the phenyl ring may independently form together a bivalent radical of formula -O-CH 2 -O- ( a" l) ' -O-CH 2 -CH 2 -O- (a-2), -O=CH=CH- (a-3), -O-CH 2 -CH 2 - (a-4), -O-CH 2 -CH 2 - CH 2 - (a-5), or -CH=CH-CH=CH- (a-6); R 3 is hydrogen, halo, Cι_ alkyl, cyano, haloCι_ 6 alkyl, hydroxyCi. alkyl, cyanoCι. 6 alkyl, aminoCι_ 6 alkyl, C]. alkyloxyCι. 6 alkyl, Cι_ 6 alkylthioCι_ 6 alkyl, aminocarbonylCi_ alkyl, hydroxycarbonyl, hydroxycarbonylCι. alkyl, Cι. 6 alkyloxycarbonylCι. 6 alkyl, Cι- 6 alkylcarbonylC]. 6 alkyl, Cι_ 6 alkyloxycarbonyl, aryl, arylCι_ 6 alkyloxyCi-6alkyl, mono- or di(Cι_ 6 alkyl)aminoCι. 6 alkyl; or a radical of formula -O-R 10 (b-1), -S-R 10 (b- 2 ), -NR n R 12 (b-3), wherein R , 10 is hydrogen, C]_ 6 alkyl, Cι_ 6 alkylcarbonyl, aryl, arylCι_ 6 alkyl, Cι_ 6 alkyloxycarbonylCι-6alkyl, or a radical of formula -Alk-OR 13 or -Alk-NR 14 R 15 ; R 1 1 is hydrogen, C]_ 6 alkyl, aryl or arylCι_ 6 alkyl; R is hydrogen, C]_ 6 alkyl, aryl, hydroxy, amino, Cι_ 6 alkyloxy, Cι_ 6 alkylcarbonylC]_ 6 alkyl, arylCι_ 6 alkyl, Cι_ 6 alkylcarbonylamino, mono- or di(Cμ alkyl)amino, Cι_ 6 alkylcarbonyl, aminocarbonyl, arylcarbonyl, haloCι. alkylcarbonyl, arylC]. 6 alkylcarbonyl, Cι_ 6 alkyloxycarbonyl, C]- alkyloxyCi_ 6 alkylcarbonyl, mono- or di(Cι_ 6 alkyl)aminocarbonyl wherein the alkyl moiety may optionally be substituted by one or more substituents independently selected from aryl or Cι_ 3 alkyloxycarbonyl, aminocarbonylcarbonyl, mono- or di(Cι_ 6 alkyl)aminoC]_ 6 alkylcarbonyl, or a radical or formula -Alk-OR 13 or -Alk-NR 14 R 15 ; wherein Alk is Cι_ 6 alkanediyl; R 13 is hydrogen, C]. 6 alkyl, C]. alkylcarbonyl, hydroxyCi _ 6 alkyl, aryl or arylCι_ 6 alkyl; R 14 is hydrogen, Cι_ alkyl, aryl or arylCι_ 6 alkyl; R 15 is hydrogen, Cι_ 6 alkyl, C]_ 6 alkylcarbonyl, aryl or arylC]_ 6 alkyl; R 4 is a radical of formula — N v J (c-1), — — R 16 (c-2), wherein R 16 is hydrogen, halo, aryl, Cι_ 6 alkyl, hydroxyCι_ 6 alkyl, Cι_ 6 alkyloxyCι_ 6 alkyl, C]_ 6 alkyloxy, Cι_ 6 alkylthio, amino, mono- or di(Cι_ alkyl)amino, hydroxycarbonyl, Cι_ 6 alkyloxycarbonyl, Cι_6alkylthioCι. 6 alkyl, Cι_ 6 alkylS(O)Cι_ 6 alkyl or Cι_ 6 alkylS(O) 2 C,. 6 alkyl; R 16 may also be bound to one of the nitrogen atoms in the imidazole ring of formula (c-1) or (c-2), in which case the meaning of R 16 when bound to the nitrogen is limited to hydrogen, aryl, Cι_ 6 alkyl, hydroxyCι_ 6 alkyl, Cι_ 6 alkyloxyC]_ 6 alkyl, Cι_ 6 alkyloxycarbonyl, Cι_ 6 alkylS(O)Cι_ 6 alkyl or Cι. 6 alkylS(O) 2 Cι_ 6 alkyl; R 17 is hydrogen, Cι_ 6 alkyl, Cι_ 6 alkyloxyCι. 6 alkyl, arylC]. 6 alkyl, trifluoromethyl or di(Cι_ 4 alkyl)aminosulfonyl; R 5 is Cι_ alkyl , Cι_ 6 alkyloxy or halo; aryl is phenyl, naphthalenyl or phenyl substituted with 1 or more substituents each independently selected from halo, Cι_ 6 alkyl, Cι_ 6 alkyloxy or trifluoromethyl . 2. A combination as claimed in claim 1 wherein the farnesyl protein transferase inhibitor is a compound of formula (I) wherein X is oxygen and the dotted line represents a bond. 3. A combination as claimed in claim 1 or claim 2 wherein the farnesyl protein transferase inhibitor is a compound of formula (I) wherein Rl is hydrogen, Ci-6alkyl, Ci-6alkyloxyCι_6alkyl or mono- or di(Ci-6alkyl)aminoCι_6alkyl and wherein R3 is hydrogen and R 2 is halo, C -6alkyl, C2-6 a lkenyl, Ci-βalkyloxy, trihalomethoxy or hydroxyCi -6alkyloxy. 4. A combination as claimed in any of the preceding claims wherein the farnesyl protein transferase inhibitor is a compound of formula (I) wherein R 8 is hydrogen, hydroxy, haloCi-6alkyl, hydroxyCi-6alkyl, cyanoCi-6alkyl, Ci-6alkyloxycarbonylCi-6alkyl, imidazolyl, or a radical of formula -MR! 1R1 2 wherein RU is hydrogen or Cι_i2alkyl and Rl 2 is hydrogen, Ci-βalkyl, Ci-6alkyloxy, Ci-6alkyloxyCi-6alkylcarbonyl, hydroxy, or a radical of formula -Alk 2 -ORl wherein Rl3 is hydrogen or Ci-6alkyl. 5. A combination as claimed in claim 1 wherein the farnesyl transferase inhibitor is selected from: 4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(l-methyl-lH-imidazol-5-yl)- methyl]-l-methyl-2(lH)-quinolinone, 6-[amino(4-chlorophenyl)-l-methyl-lH-imidazol-5-ylmethyl]-4-(3-chlorophenyl)- l-methyl-2(lH)-quinolinone; 6-[(4-chlorophenyl)hydroxy(l-methyl-lH-imidazol-5-yl)methyl]-4-(3-ethoxy- phenyl)-l-methyl-2(lH)-quinolinone; 6-[(4-chlorophenyl)(l-methyl-lH-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-l- methyl-2(lH)-quinolinone monohydrochloride.monohydrate; 6-[amino(4-chlorophenyl)(l-methyl-lH-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)- l-methyl-2(lH)-quinolinone, and 6-amino(4-chlorophenyl)(l-methyl-lH-imidazol-5-yl)methyl]-l-methyl-4-(3- propylphenyl)-2(lH)-quinolinone; a stereoisomeric form thereof or a pharmaceutically acceptable acid or base addition salts thereof. 6. A combination as claimed in claim 1 wherein the farnesyl transferase inhibitor is (+)-6-[amino(4-chlorophenyl)(l-methyl-lH-imidazol-5-yl)methyl]-4-(3-chloro- phenyl)-l-methyl-2(lH)-quinolinone; or a pharmaceutically acceptable acid addition salt thereof. 7 A combination as claimed in claim 1 wherem the farnesyl protein transferase inhibitor is a compound of formula (IX) wherein =X 1 -X 2 -X " is a tnvalent radical of formula (x-2), (x-3) or (x-4), >Y1-Y2 is a tnvalent radical of formula (y-2), (y-3) or (y-4), r and s are 1, t is 0, R 1 is halo, preferably chloro, and most preferably 3- chloro or R 1 is Ci alkyl, preferably 3-methyl, R 2 is halo, preferably chloro, and most preferably 4-chloro, R 3 is a radical of formula (b-1) or (b-3), R 4 is a radical of ffoorrmmuullaa ((cc--22)),, RR 66 iiss CCj alkyl, R 9 is hydrogen, R 10 and R 11 are hydrogen and R 12 is hydrogen or hydroxy 8 A combination as claimed in claim 1 wherein the farnesyl protein transferase inhibitor is 5-(3-chlorophenyl)-cc-(4-chlorophenyl)- α-(l -methyl- lH-ιmιdazol-5- yl)tetrazolo[l,5-a]quιnazohne-7-methanamιne or a pharmaceutically acceptable acid addition salt thereof 9. A combination as claimed in any of the preceding claims in which the camptothecin compound is topotecan or mnotecan. 10 A combination as claimed in any of the preceding claims in the form of a pharmaceutical composition compπsmg a camptothecin compound and a farnesyl transferase inhibitor selected from compounds of formulae (I), (H). (HI), (IV), (V), (VI), (VH), (VHI) and (IX) (as defined in claim 1) together with one or more pharmaceutical earners. 11. A combination as claimed in any of the preceding claims for use in medical therapy 12. A combination as claimed in claim 11 for inhibiting the growth of tumor cells. 13. Use of a combination as claimed in any of claims 1 to 12 m the manufacture of a pharmaceutical composition for inhibiting the growth of tumor cells. 14. A method of inhibiting the growth of tumor cells in a human subject which compnses admmisteπng to the subject an effective amount of a combination as claimed m any of claims 1 to 12.

Inventors: HORAK IVAN DAVID, PALMER PETER ALBERT, HORAK, IVAN, DAVID, PALMER, PETER, ALBERT
Applicants: HORAK IVAN DAVID, JANSSEN PHARMACEUTICA NV, PALMER PETER ALBERT, HORAK, IVAN, DAVID, JANSSEN PHARMACEUTICA N.V., PALMER, PETER, ALBERT
Application year: 2001
Main classification: A61K31
IPC codes: A61K31, A61P35, A61P43