ZA200100151B

ZA200100151B - Farnesyl protein transfease inhibitors with in vivo radiosensitizing properties.

Info

Publication number: ZA200100151B
Application number: ZA200100151A
Authority: ZA
Inventors: Robert Franciscus Van Ginckel; Wim Joanna Floren; David William End; Walter Boudewijn Leopo Wouters
Original assignee: Janssen Pharmaceutica Nv
Priority date: 1998-07-06
Filing date: 2001-01-05
Publication date: 2002-01-07
Also published as: UA64796C2; NZ509646A

Description

0g WO 00/01411 PCT/EP99/04545 . N -1-

Farnesyl protein transferase inhibitors with in vivo radiosensitizing properties

J —

The present invention is concerned with the finding that farnesyl protein transferase inhibitors have radiosensitizing properties which makes them useful for preparing a pharmaceutical composition for administration before, during or after irradiation of a tumor for treating cancer in vivo.

WO-97/21701 describes the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting (imidazoly-5-yl)methyl-2-quinolinone derivatives of formulas (I), (IT) and (II), as well as intermediates of formula (I) and (III) that are metabolized in vivo to the compounds of formula (I). The compounds of formulas (I), (II) and (III) are represented by

R3 Rie R4 R3 Rye Rs

Ns =| Ns =

Ry wa I+, Rol wa Ig,

ZZ ZF 7 a

RIA NS x RIN NSS N

Lod ML Soe LET

EN ke Te lke Tw

Rj) . ¢Y) Im

R3 Ris Rs 27 -|=

Rl ul | N_Rs

A A

RNS ~

AVL ea + 2 Po nN > Rig Ry & (IID) 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, C;_12alkyl, Arl, Ar2C)_galkyl, quinolinylC)-galkyl, pyridylCj-galkyl, hydroxyC;-salkyl, Ci-ealkyloxyCj.ealkyl, mono- or di(Cj-alkyl)

iP ) aminoCj_galkyl, aminoCj-galkyl, or a radical of formula -Alkl-C(=0)-R9, -Alk!-S(0)-R? or -Alk1-S(0),-RY, wherein Alkl is C;_galkanediyl,

RY is hydroxy, C)-galkyl, C;-galkyloxy, amino, C;-galkylamino or : Cj-galkylamino substituted with Cj_galkyloxycarbonyl; - RZ, R3 and R16 each independently are hydrogen, hydroxy, halo, cyano, Ci-galkyl,

Ci-ealkyloxy, hydroxyCj-salkyloxy, Ci-galkyloxyC)-galkyloxy, aminoCj_galkyl- oxy, mono- or di(C}-galkyl)aminoC;-galkyloxy, Arl, Ar2Cj_galkyl, Ar2oxy,

Ar2Cj_.galkyloxy, hydroxycarbony], Ci-ealkyloxycarbonyl, trihalomethyl, trihalomethoxy, Cy.ealkenyl, 4,4-dimethyloxazolyl; or when on adjacent positions R? and R3 taken together may form a bivalent radical of formula -O-CH3-0O- (a-1), -O-CH2-CH3-O- (a-2), -O-CH=CH- (a-3), -O-CH»-CHs- (a-4), -O-CH3-CH»-CH»- (a-5), or -CH=CH-CH=CH- (a-6);

R4 and R35 each independently are hydrogen, halo, Arl, Cj_galkyl, hydroxyCj_galkyl, :

Ci-salkyloxyCj.galkyl, C)_galkyloxy, C}_galkylthio, amino, hydroxycarbonyl, R

Ci-salkyloxycarbonyl, C;-6alkylS(O)C|_galkyl or C1-galkylS(O);C1-galkyl;

R6 and R7 each independently are hydrogen, halo, cyano, Cj.galkyl, Cj-galkyloxy,

Aroxy, trihalomethyl, Cj.galkylthio, di(Cj.galkyl)amino, or when on adjacent positions R% and R7 taken together may form a bivalent radical of formula -O-CH,-O- (c-1), or -CH=CH-CH=CH- (c-2);

R8 is hydrogen, C-galkyl, cyano, hydroxycarbonyl, C|_galkyloxycarbonyl, C)-galkyl- carbonylCj_galkyl, cyanoCj-galkyl, C}_galkyloxycarbonylCj.galkyl, carboxy-

Ci-6alkyl, hydroxyCj-galkyl, aminoCj_galkyl, mono- or di(Cj-galkyl)amino-

Ci-salkyl, imidazolyl, haloC)_galkyl, Cj.galkyloxyC)_galkyl, aminocarbonyl-

Ci-ealkyl, or a radical of formula _O-R10 (b-1), -S-R10 (b-2), -N-RURI2 (b-3), wherein R10 is hydrogen, Cy_galkyl, C;_galkylcarbonyl, Arl, Ar2Cj_galkyl,

C1-salkyloxycarbonylCj_galkyl, or a radical or formula

: © WO 00/01411 PCT/EP99/04545 ’ -Alk2-OR13 or -Alk2-NR14R 13;

R11 js hydrogen, C;.1zalkyl, Ar! or Ar2Cj_galkyl;

R12 is hydrogen, Cj-galkyl, Cj-6alkylcarbonyl, Cj.galkyloxy- carbonyl, C;-galkylaminocarbonyl, Ar!, Ar2Cj.galkyl,

C1-salkylcarbonylC;_galkyl, a natural amino acid, )

Arlcarbonyl, Ar2C;_galkylcarbonyl, aminocarbonylcarbonyl,

Ci-e6alkyloxyCj_galkylcarbonyl, hydroxy, Cj-galkyloxy, aminocarbonyl, di(C;.galkyl)aminoCj.galkylcarbonyl, amino,

Ci-ealkylamino, Cj_galkylcarbonylamino, or a radical or formula -Alk2-OR!3 or -Alk2-NRI4R15; wherein Alk? is C)_galkanediyl;

R13 is hydrogen, Cj_galkyl, Cj_galkylcarbonyi, hydroxyCj_ealkyl, Ar! or Ar2Cj_galkyl;

R14 is hydrogen, C}_galkyl, Ar! or Ar2C)_galkyl;

R15 is hydrogen, Cj.galkyl, C;_galkylcarbonyl, Ar! or Ar2Cj.galkyl;

R17 is hydrogen, halo, cyano, C;_salkyl, C}.galkyloxycarbonyl, Ar};

R!8 is hydrogen, Ci.galkyl, Cj.galkyloxy or halo;

R19 is hydrogen or C].¢alkyl;

Ar! is phenyl or phenyl substituted with Cj_ealkyl, hydroxy, amino, C}-galkyloxy or halo; and

Ar? is phenyl or phenyl substituted with C}_galkyl, hydroxy, amino, C)-ealkyloxy 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

SCN AL

Ry—r [ 2-Rs Ro— [ 2-Rs “ “

Riz Pe NN SN Rita NN NN

J Rell Re SEI x7 N I2%s 5 N The ® Xa,

Rj

Iv) -()

@ . Ras R, : R= N rr pS 7 “

Ri ~ XN NN < J] Rs | J Re

NYSE x

I Rig 18 7 (VD 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; . Rlis hydrogen, Cj_jalkyl, Ar!, Ar2C_galkyl, quinolinylC;_galkyl, pyridylCj.galkyl, hydroxyCj-ealkyl, Ci.ealkyloxyCi_galkyl, mono- or di(Cj.ealkyl)aminoCj_galkyl, aminoCj_galkyl, or a radical of formula -Alk!-C(=0)-R?, -Alk!-S(0)-R? or -Alk1-S(0O);-R9, wherein Alk! is C;_galkanediyl,

R? is hydroxy, Ci-¢alkyl, Cj-galkyloxy, amino, C;_galkylamino or

Ci-salkylamino substituted with Cj_galkyloxycarbonyl;

R2 and R3 each independently are hydrogen, hydroxy, halo, cyano, C;_galkyl, .

Ci-salkyloxy, hydroxyCj.galkyloxy, Ci-salkyloxyC)-galkyloxy, aminoC 1-6alkyl- oxy, mono- or di(Cj-galkyl)aminoCj.galkyloxy, Arl, Ar2C)_galkyl, Ar2oxy,

Ar2C-galkyloxy, hydroxycarbonyl, Cj-salkyloxycarbonyl, trihalomethyl, trihalomethoxy, Cj_galkenyl; or when on adjacent positions R? and R3 taken together may form a bivalent radical of formula -O-CHj-O- (a-1), -O-CHj-CH3-0O- (a-2), -O-CH=CH- (a-3), -O-CH,-CHj- (a-4), -O-CH,-CH;-CHj3- (a-5), or -CH=CH-CH=CH- (a-6);

R* and RS each independently are hydrogen, Ar!, C;_galkyl, C;_galkyloxyC}_galkyl,

Ci-ealkyloxy, C}_galkylthio, amino, hydroxycarbonyl, Ci-salkyloxycarbonyl,

C1-6alkylS(O)Cj-galkyl or Ci-6alkylS(0),C)-galkyl;

RO and R7 each independently are hydrogen, halo, cyano, C_galkyl, Cj-salkyloxy or

Ar2oxy;

oo © WO 00/01411 PCT/EP99/04545 ag i R8 is hydrogen, C}-salkyl, cyano, hydroxycarbonyl, C;-galkyloxycarbonyl, C;-galkyl- carbonylCj-galkyl, cyanoCj_galkyl, C;.ealkyloxycarbonylC;_galkyl, hydroxy- carbonylCj.galkyl, hydroxyCj.ealkyl, aminoCj-galkyl, mono- or di(C;-galkyl)- aminoCj_galkyl, haloCj.galkyl, Cj_galkyloxyCj-g¢alkyl, aminocarbonylCi_galkyl,

Arl; Ar2C) galkyloxyC.galkyl, Cy.galkylthioCy.galkyl;

R10 jg hydrogen, Cj.salkyl, Cj.galkyloxy or halo;

R!! is hydrogen or Cj.¢alkyl;

Ar! is phenyl or phenyl substituted with C\-ealkyl, hydroxy, amino, C;_salkyloxy or halo;

Ar? is phenyl or phenyl substituted with Cj_galkyl, hydroxy, amino, C}_galkyloxy or halo.

PCT/EP98/01296, filed 3 March 1998, concerns the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting compounds of formula (VII)

RZ R4

Ne Ne)

F FF

R6 : - Rr (vi), } xX - : A 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), -CHy-S- (a-6), -CH2-CHa- (a-2), -CH,-CH,-S- (a-7), -CH;-CH,-CHjy- (a-3), -CH=N- (a-8), -CHj-O- (a-4), -N=N- (a-9), or -CH,-CH;-0O- (a-5), -CO-NH- (a-10); wherein optionally one hydrogen atom may be replaced by Cj 4alkyl or Ar!;

R! and R2 each independently are hydrogen, hydroxy, halo, cyano, C;_galkyl, trihalo- methyl, trihalomethoxy, Cy-galkenyl, Cj_galkyloxy, hydroxyCj_-galkyloxy,

Ci-salkyloxyC)-galkyloxy, Cj-galkyloxycarbonyl, aminoCj_galkyloxy, mono- or vy ©. di(C}-galkyl)aminoCj_galkyloxy, Ar2, Ar2-C}_galkyl, Ar2-oxy, Ar2-Cj.galkyloxy; or when on adjacent positions R! and R? taken together may form a bivalent radical of formula - -0-CH;,-O- (b-1), - -0-CH;-CH;,-O- (b-2), -O-CH=CH- (b-3), -0-CH3-CH>- (b-4), -O-CH;-CH;,-CHj- (b-5), or -CH=CH-CH=CH- (b-6);

R3 and R4 each independently are hydrogen, halo, cyano, C}_galkyl, C.galkyloxy,

Ar3-oxy, C_galkylthio, di(Cj.galkyl)amino, trihalomethyl, trihalomethoxy, or when on adjacent positions R3 and R# taken together may form a bivalent radical of formula -O-CH»-O- (c-1), -O-CH;-CH,-O- (c-2), or -CH=CH-CH=CH- (c-3);

R> is a radical of formula —J (d-1), ~~ Fo (d-2),

R13 ! a ] wherein R13 is hydrogen, halo, Ar4, C;_galkyl, hydroxyC)_galkyl, C;-galkyloxy.

Ci-salkyl, Ci-ealkyloxy, Cj-galkylthio, amino, C}_galkyloxycarbonyl, )

C1-6alkylS(O)C|-galkyl or Cj-alkylS(O)2Cj-galkyl;

R14 is hydrogen, Cj.alkyl or di(C}_4alkyl)aminosulfonyl;

R6 is hydrogen, hydroxy, halo, C;_galkyl, cyano, haloC 1-6alkyl, hydroxyCj-ealkyl, cyanoC)_galkyl, aminoCj-galkyl, Cj.ealkyloxyCj-galkyl, C)_galkylthioCj.galkyl, aminocarbonylCj-galkyl, Cj-galkyloxycarbonylCj_galkyl, Ci-galkylcarbonyl-

Ci-salkyl, Cj.galkyloxycarbonyl, mono- or di(Cj-galkyl)aminoC;_galkyl, Ar3,

Ar3-C|_galkyloxyCj_galkyl; or a radical of formula -O-R7 (e-1), _S-R7 (e-2), -N-R8R? (e-3), wherein R7 is hydrogen, Cj-galkyl, Cj-galkylcarbonyl, Ar6, Ar6-Cj._galkyl,

C)-salkyloxycarbonylCj_ealkyl, or a radical of formula -Alk-OR 10 or -Alk-NR1IR12:

R8 is hydrogen, Cj-salkyl, Ar’ or Ar’-C_galkyl;

: © WO 00/01411 PCT/EP99/04545 ) RY is hydrogen, C-6alkyl, Ci-ealkylcarbonyl, C;_galkyloxycarbonyl,

C1-galkylaminocarbonyl, Ar, Ar8-C}_galkyl, C}.galkylcarbonyl-

Ci-6alkyl, Ar8-carbonyl, Ar8-Cj_galkylcarbonyl, aminocarbonyl- carbonyl, Cj.galkyloxyCj.galkylcarbonyl, hydroxy, Cj.g¢alkyloxy, : aminocarbonyl, di(Cj-ealkyl)aminoCj.galkylcarbonyl, amino,

C1.ealkylamino, Cj_galkylcarbonylamino, or a radical or formula -Alk-OR 10 or -Alk-NR1IR12; wherein Alk is Cj.galkanediyl;

R10 is hydrogen, C;-salkyl, C;-galkylcarbonyl, hydroxy-

C1-6alkyl, Ar9 or Ar9-C_galkyl;

R! is hydrogen, Cj.galkyl, Cy.galkylcarbonyl, Arl0 or

Arl0-C_galkyl;

R12 is hydrogen, C}-galkyl, Ar!! or Ar!l-C;_galkyl; and

Ar! to Ar!! are each independently selected from phenyl; or phenyl substituted with halo, C-galkyl, Cj_galkyloxy or trifluoromethyl.

PCT/EP98/02357, filed 17 April 1998, concerns the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting compounds of . 20 formula (VII)

R’ R* oo : o! 7 A 3 Ege

ZF Va

RL A ®

BY 6 (VID),

RVI

R R 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;

R! and RZ each independently are hydrogen, hydroxy, halo, cyano, Cj-galkyl, trihalomethyl, trihalomethoxy, C;_galkenyl, Cj.galkyloxy, hydroxyCj-galkyloxy,

Ci-salkyloxyCj-galkyloxy, C)_-galkyloxycarbonyl, aminoC;_galkyloxy, mono- or di(C|-galkyl)aminoC].galkyloxy, Arl, ArlC)_galkyl, Arloxy or ArlC)_galkyloxy; R3 and R4 each independently are hydrogen, halo, cyano, Cj.galkyl, C;-galkyloxy,

Arloxy, Cy_galkylthio, di(Cj.ealkyl)amino, trihalomethyl or trihalomethoxy;

) R35 is hydrogen, halo, Cj_galkyl, cyano, haloCj_galkyl, hydroxyCj.galkyl, cyano- : Ci-6alkyl, aminoC)_galkyl, C}-galkyloxyCj-galkyl, Ci.salkylthioC.galkyl, aminocarbonylCj.galkyl, C}-galkyloxycarbonylCj_galkyl, Cj.galkylcarbonyl-

Ci-6alkyl, Cj.galkyloxycarbonyl, mono- or di(C;-galkyl)aminoCj-galkyl, Arl,

ArlCj_galkyloxyCj.galkyl; or a radical of formula -O-R10 (a-1), _S-R10 (a-2), . -N-R11R12 (a-3), : wherein R10 js hydrogen, C;-galkyl, Cj-galkylcarbonyl, Arl, ArlC;_galkyl,

Ci-galkyloxycarbonylCj_galkyl, or a radical of formula -Alk-OR!3 or -Alk-NR14R15;

R11 is hydrogen, Cj-galkyl, Ar! or Ar!Cy_galkyl;

R12 is hydrogen, C;-galkyl, C}-galkylcarbonyl, C-salkyloxycarbonyl,

C-salkylaminocarbonyl, Arl, ArlCj_galkyl, Cj-ealkylcarbonyl-

Cj-ealkyl, Arlcarbonyl, ArlCj.galkylcarbonyl, aminocarbonyl- carbonyl, Cj.galkyloxyCj.ealkylcarbonyl, hydroxy, Cj.galkyloxy, aminocarbonyl, di(C;.galkyl)aminoC_galkylcarbonyl, amino,

Ci-¢alkylamino, Cj_galkylcarbonylamino, or a radical or formula -Alk-OR13 or -Alk-NR14R 15; wherein Alk is Cj_galkanediyl; .

R13 is hydrogen, C}-galkyl, Cj-galkylcarbonyl, hydroxy-

Ci.6alkyl, Ar! or ArlC;_galkyl;

R14 is hydrogen, Cj-galkyl, Ar! or Ar!C;_galkyl;

R15 is hydrogen, C}_galkyl, C,_galkylcarbonyl, Ar! or

ArlCy_galkyl;

RO is a radical of formula —J (b-1), — ris (b-2), = N

R!S RY wherein R16 is hydrogen, halo, Arl, C1-e6alkyl, hydroxyCj-galkyl, Cj-galkyloxy.

Ci-e6alkyl, Cj-galkyloxy, Cj-galkylthio, amino, C)_galkyloxy- carbonyl, C)-galkylthioCj_galkyl, Ci.galkylS(O)C;-galkyl or

C1-6alkylS(0)Cy alkyl;

R17 is hydrogen, C;_galkyl or di(Cj_salkyl)aminosulfonyl;

R7 is hydrogen or Cj_galkyl provided that the dotted line does not represent a bond;

R8 is hydrogen, C}_galkyl or Ar2CHj or Het!CHj;

\ © WO 00/01411 PCT/EP99/04545 )

RY is hydrogen, Cj.galkyl , Cj.galkyloxy or halo; or

R8 and RY taken together to form a bivalent radical of formula -CH=CH- (c-1), -CH;,-CHj- (c-2), + -CHy-CH)-CH;- (c-3), -CH,-O- (c-4), or -CH,-CHy-O- (c-5);

Ar! is phenyl; or phenyl substituted with 1 or 2 substituents each independently selected from halo, Cy-galkyl, Cj_galkyloxy or trifluoromethyl;

Ar? is phenyl; or phenyl substituted with 1 or 2 substituents each independently selected from halo, Cj-galkyl, Cj_galkyloxy or trifluoromethyl; and

Het! is pyridinyl; pyridiny! substituted with 1 or 2 substituents each independently selected from halo, Cj_galkyl, Cj-galkyloxy or trifluoromethyl.

Other useful farnesyl protein transferase inhibitors have the structure : psd

Br 0}

TJ Hom : lo)

SCH-66336 5 :

YY OY

0] 0 < he

NH

Nx/ 0)

PD-169551

These farnesyl protein transferase inhibitors decrease the growth of tumors in vivo by a direct effect on tumor cell growth but also indirectly, i.e. by inhibiting angiogenesis (Rak. J. er al, Cancer Research, 55, 4575-4580, 1995). Consequently, treatment with these inhibitors suppresses solid tumor growth in vivo at least in part by inhibiting

) angiogenesis. This being the case, one could expect that treatment with these compounds could result in hypoxic tumors, thereby inducing or causing increased radio-resistance.

Unexpectedly, we have now found that that does not happen. On the contrary, it - appears that administration of a farnesyl protein transferase inhibitor as described hereinbefore sensitizes tumor cells in vivo to irradiation or ionizing radiation and moreover, resensitizes radioresistant cells. Thus, farnesyl protein transferase inhibitors are useful as in vivo radiosensitizing (radiation-sensitizing or radiation-potentiating) agents.

The present invention is concerned with the use of at least a famesyl protein transferase inhibitor for the preparation of a pharmaceutical composition having radiosensitizing properties for administration before, during or after irradiation of a tumor for treating cancer in vivo.

In particular, the present invention is concerned with the use of at least a farnesyl protein transferase inhibitor for the preparation of a pharmaceutical composition having radiosensitizing properties for administration before, during or after irradiation of a tumor for treating cancer in vivo, wherein said famesyl protein transferase inhibitor is an (imidazoly-5-yl)methyl-2-quinolinone derivative of formula (I), or a compound of : formula (II) or (III) which is metabolized in vivo to the compound of formula (I), said compounds being represented by .

Rs Ris R Ry Ris R

Ns <5 PA 1

Ro / NR; rR, / NR

Rin EN x Ri x A x Rg | J J re « Nx Rs | J J Re x2 NT R NTN R

I Rg N18 7 Ryo N18 7

R; @ an

Ry Ry R

NGA = N

RL a EN g,

SZ Va

Rim SNS N

Rg 7 Re

Sp 2 oO Ryo Rig Ry (In

) 4 WO 00/01411 PCT/EP99/04545 ; 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; Rlis hydrogen, C1.12alkyl, Ar!, Ar2C)-galkyl, quinolinylC)-galkyl, pyridylC;_salkyl, hydroxyCj-ealkyl, Cj.galkyloxyCj.¢alkyl, mono- or di(Cj.galkyl)aminoCj_galkyl, aminoC)-galkyl, or a radical of formula -Alk!-C(=0)-R9, -Alk1-S(0)-RY or -Alk!-S(0)2-R9, wherein Alk! is C;-galkanediyl,

R® is hydroxy, C;-galkyl, Cj-alkyloxy, amino, C}.galkylamino or

C-galkylamino substituted with Cj_galkyloxycarbonyl;

RZ, R3 and R!6 each independently are hydrogen, hydroxy, halo, cyano, C;-galkyl,

Ci-salkyloxy, hydroxyCj-galkyloxy, Cj-galkyloxyCj-galkyloxy, aminoC;-galkyl- oxy, mono- or di(C}-salkyl)aminoC)-galkyloxy, Ar!, Ar2C_galkyl, Ar2oxy,

Ar?Cj_galkyloxy, hydroxycarbonyl, C}_galkyloxycarbonyl, trihalomethy], trihalomethoxy, Cy-galkenyl, 4,4-dimethyloxazolyl; or - when on adjacent positions RZ and R3 taken together may form a bivalent radical of - formula -O-CH,-0O- (a-1), -O-CH;,-CH3-O- (a-2), - -O-CH=CH- (a-3), -O-CH;-CH,- (a-4), ’ -O-CH,-CH;,-CHj- (a-5), or -CH=CH-CH=CH- (a-6); R%and RS each independently are hydrogen, halo, Ar!, C)_galkyl, hydroxyCj-galkyl,

Ci-salkyloxyCj_ealkyl , Ci-galkyloxy, C)-ealkylthio, amino, hydroxycarbonyl,

Ci-ealkyloxycarbonyl, C;-6alkylS(O)Cj-ealkyl or Cj.alkylS(O)2C;-salkyl;

RS and R7 each independently are hydrogen, halo, cyano, C;-galkyl, C}-galkyloxy,

Ar2oxy, trihalomethyl, C_galkylthio, di(C}.salkyl)amino, or when on adjacent positions R® and R” taken together may form a bivalent radical of formula -0-CHj-O- (c-1), or -CH=CH-CH=CH- (c-2);

R8 is hydrogen, C;-galkyl, cyano, hydroxycarbonyl, C;.galkyloxycarbonyl, C;-galkyl- carbonylC}_galkyl, cyanoCj_galkyl, Cj_galkyloxycarbonylC;-galkyl, carboxy-

Cji-ealkyl, hydroxyCj_galkyl, aminoCj.galkyl, mono- or di(Cj_galkyl)amino-

Ww ) C1-6alkyl, imidazolyl, haloCj.galkyl, Ci-salkyloxyCj.ealkyl, aminocarbonyl-

Ci-ealkyl, or a radical of formula -O-R10 (b-1), -S-R10 (b-2), -N-R1IR12 (b-3), wherein R10 is hydrogen, Cj-galkyl, Ci-galkylcarbonyl, Arl, Ar2C_galkyl,

Ci-salkyloxycarbonylCj.galkyl, or a radical or formula -Alk2-OR!3 or - -Alk2-NR14R 15; : R1 is hydrogen, C;-12alkyl, Ar! or Ar2Cy_galkyl;

R12 js hydrogen, C;.galkyl, C;-jgalkylcarbonyl, C 1-6alkyloxycarbonyl,

Cj-salkylaminocarbonyl, Arl, Ar2Cj_galkyl, Cj-galkylcarbonyl-

C)-ealkyl, a natural amino acid, Arlcarbonyl, Ar2C)_galkylcarbonyl, : : aminocarbonylcarbonyl, Cj_galkyloxyCj.galkylcarbonyl, hydroxy,

Ci-salkyloxy, aminocarbonyl, di(Cj.galkyl)aminoC_galkylcarbonyl, amino, C}_galkylamino, Cj_galkylcarbonylamino, or a radical or formula -Alk?-OR13 or -Alk2-NR14R 15; wherein Alk2 is C|_galkanediyl; - : R13 is hydrogen, Cj.galkyl, C}-galkylcarbonyl, hydroxyCj_galkyl, Ar! or : Ar2Cj_galkyl;

R!4 is hydrogen, Cj-salkyl, Ar! or Ar2Cj_galkyl; }

R15 is hydrogen, Cy-galkyl, C}-¢alkylcarbonyl, Ar! or Ar2Cy_galkyl;

R17 is hydrogen, halo, cyano, Cj.galkyl, C).galkyloxycarbonyl, Ar;

R18 is hydrogen, Cj_galkyl, Cy.galkyloxy or halo;

R19 is hydrogen or C1_galkyl;

Ar! is phenyl or phenyl substituted with C)_galkyl, hydroxy, amino, Cj-galkyloxy or halo; and

Ar? is phenyl or phenyl substituted with Cj_galkyl, hydroxy, amino, Cj-galkyloxy or halo.

In formulas (I), (II) and (III), R4 or RS may also be bound to one of the nitrogen atoms in the imidazole ring. In that case the hydrogen on the nitrogen is replaced by R4 or RS and the meaning of R4 and R3 when bound to the nitrogen is limited to hydrogen, Ar!,

Ci-salkyl, hydroxyCj.ealkyl, Cj_salkyloxyCj_galkyl, C}-galkyloxycarbonyl,

C1-6alkylS(O)Cj.ealkyl, C;.6alkylS(O),C1-galkyl.

As used in the foregoing definitions and hereinafter halo defines fluoro, chloro, bromo and iodo; Cj_galkyl defines straight and branched chained saturated hydrocarbon

3 wo 0001411 PCT/EP99/04545

LL 13- : radicals having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl and the like; C;-galkyl encompasses the straight and branched chained saturated hydrocarbon radicals as defined in Cj.galkyl as well as the higher homologues thereof containing 7 or 8 carbon atoms such as, for example heptyl or octyl; Cy.12alkyl again encompasses Cj_galkyl and the higher homologues thereof containing 9 to 12 carbon atoms, such as, for example, nonyl, decyl, undecyl, dodecyl,

Ci-16alkyl again encompasses Cj-j2alkyl and the higher homologues thereof containing 13 to 16 carbon atoms, such as, for example, tridecyl, tetradecyl, pentadecy! and hexadecyl; Cj.galkenyl 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; Cj.galkanediyl defines bivalent straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the branched isomers thereof. The term “C(=0)” 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 amino acids are glycine, alanine, valine, leucine, isoleucine, methionine, proline, phenylanaline, tryptophan, serine, threonine, cysteine, tyrosine, asparagine, glutamine, i - aspartic acid, glutamic acid, lysine, arginine, histidine.

The pharmaceutically acceptable acid or base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and non-toxic base addition salt forms which the compounds of formulas (I), (II) and (III) are able to form.

The compounds of formulas (I), (II) and (III) which have basic properties can be converted in their pharmaceutically acceptable acid addition salts by treating said base form with an appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesuifonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.

The compounds of formulas (I), (II) and (III) 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. Appropriate base salt forms comprise,

IS

) 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 formulas (I), (IT) and (III) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.

The term stereochemically isomeric forms of compounds of formulas (I), (II) and (III), 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 formulas (I), (I) and (IIT) 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 stereo- } chemically isomeric forms of the compounds of formulas (I), (IT) and (III) 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 formulas (I), (I) and (III) 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 formulas (I), (I) and (III)" is meant to include also the pharmaceutically acceptable acid or base addition salts and all stereoisomeric forms.

Preferably the substituent R18 is situated on the 5 or 7 position of the quinolinone moiety and substituent R19 is situated on the 8 position when R!8 is on the 7-position.

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

R! is hydrogen, Cj.galkyl, Cj.alkyloxyCj_galkyl, di(C;.galkyl)aminoC)_galkyl, or a

. © WO 00/01411 PCT/EP99/04545 ; radical of formula -Alkl-C(=0)-R9, wherein Alk! is methylene and RY is C;_galkyl- amino substituted with Cj_galkyloxycarbonyl.

Still another group of interesting compounds are those compounds of formula (I) wherein R3 is hydrogen or halo; and R? is halo, Cj.6alkyl, Cz.¢alkenyl, C}_galkyloxy, trihalomethoxy or hydroxyCj.ealkyloxy.

A further group of interesting compounds are those compounds of formula (I) wherein

R2 and R3 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 R3 is hydrogen and R# is hydrogen or C;_galkyl.

Yet another group of interesting compounds are those compounds of formula (I) wherein R7 is hydrogen; and RY is C;_galkyl or halo, preferably chloro, especially ” 4-chloro. - A particular group of compounds are those compounds of formula (I) wherein R38 is hydrogen, hydroxy, haloCj_galkyl, hydroxyCj_.galkyl, cyanoCj._galkyl, Cj.galkyloxy- carbonylCj_galkyl, imidazolyl, or a radical of formula -NR11R12 wherein R}! is hydrogen or Cj.17alkyl and R12 is hydrogen, Cj_galkyl, C;_galkyloxy, hydroxy,

C1.galkyloxyCj.galkylcarbonyl, or a radical of formula -Alk2-OR!3 wherein R13 is os hydrogen or Cj_galkyl.

Prefered compounds are those compounds wherein R! is hydrogen, C).galkyl,

Ci.ealkyloxyCj.galkyl, di(Cj.galkyl)aminoC;_galkyl, or a radical of formula -Alk}-C(=0)-R9, wherein Alk! is methylene and R? is C;.galkylamino substituted with

C\-salkyloxycarbonyl; R2 is halo, C}_galkyl, Cp galkenyl, C}_galkyloxy, trihalo- methoxy, hydroxyCj.galkyloxy or Ar!; R3 is hydrogen; R# is methyl bound to the nitrogen in 3-position of the imidazole; RS is hydrogen; R6 is chloro; R7 is hydrogen;

R8 is hydrogen, hydroxy, haloCj.galkyl, hydroxyCj.galkyl, cyanoCj_galkyl, C).galkyl- oxycarbonylCj.galkyl, imidazolyl, or a radical of formula -NR1!R1? wherein R!1 is hydrogen or Cj_jpalkyl and R12 is hydrogen, Cj_galkyl, C.galkyloxy, C;_galkyloxy. Cji.palkylcarbonyl, or a radical of formula -Alk2-OR13 wherein R13 is Cj.galkyl; R17 is hydrogen and R18 is hydrogen.

Most preferred compounds are a 3 -16- ) 4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1- . methyl-2(1H)-quinolinone; : 6-[amino(4-chlorophenyl)-1-methyl- 1 H-imidazol-5-ylmethyl]-4-(3-chlorophenyl)- : - 1-methyl-2(1 H)-quinolinone; 6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)- : 1-methyl-2(1 H)-quinolinone; 6-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1 -methyl- .. 2(1H)-quinolinone monohydrochloride. monohydrate; > 6-[amino(4-chlorophenyl)(1-methyl- 1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1- methyl-2(1H)-quinolinone, 6-amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-4-(3-propyl- phenyl)-2(1H)-quinolinone; a stereoisomeric form thereof or a pharmaceutically - acceptable acid or base addition salt; and in particular (+)-(R)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl}-4-(3-chloro- phenyl)-1-methyl-2(1H)-quinolinone (Compound 75 in Table 1 of the Experimental ~ Part); or a pharmaceutically acceptable acid addition salt thereof. } Farnesyl protein transferase inhibitors can be formulated into pharmaceutical . compositions as known in the art ; for the compounds of formulas (I), (IT) and (III) suitable examples can be found in WO-97/21701. To prepare the aforementioned pharmaceutical compositions, a therapeutically effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with pharmaceutically acceptable carriers, which may take a wide ) variety of forms depending on the form of preparation desired for administration.

These pharmaceutical compositions are, desirably as unitary dosage forms, administered orally, parenterally, percutaneously, rectally or topically for systemic action, which is preferred, or for topical action. In case of oral liquid pharmaceutical preparations, comprising solutions, suspensions, syrups, elixirs and emulsions, any of the usual pharmaceutical media, such as, for example, water, glycols, oils, alcohols and the like, may be employed, whereas in case of oral solid pharmaceutical preparations, comprising powders, pills, capsules and tablets, excipients such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like may be employed.

Because of their ease in administration, tablets and capsules represent the most advantageous oral unit dosage forms, in which case solid pharmaceutical carriers are obviously employed. In case of injectable pharmaceutical compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, such as semipolair solvents, may be included, for example, to aid solubility. Examples of

©. WoO 0001411 PCT/EP99/04545 ; carriers for injectable solutions comprise saline solution, glucose solution or a mixture of saline and glucose solution. Injectable solutions containing compounds of the aforementioned formulas may also be formulated in an oil for prolonged action.

Appropriate oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soy bean oil, synthetic glycerol esters of long chain fatty acids and mixtures of these and other oils. For the preparation of injectable suspensions, appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.

These compositions may be administered in various ways, €.g., as a transdermal patch, as a spot-on, as an ointment or as a gel. In case of pharmaceutical compositions for rectal administration, any of the usual excipients may be employed, comprising fat ] based and water soluble excipients, optionally combined with suitable additives, such as suspending or wetting agents. As appropriate compositions for topical application - there may be cited all compositions usually employed for topically administering drugs e.g. creams, gellies, dressings, lotions, shampoos, tinctures, pastes, ointments, salves, } 20 ovules, powders, inhalations, nose sprays, eye drops and the like. Semisolid ) compositions such as salves, creams, gellies, ointments and the like will conveniently : : be used, but application of said compositions may be, for example, also by aerosol, e.g. with a propellent such as nitrogen, carbon dioxide, a freon, or without a propellent such as a pump spray or drops.

It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage.

Unit dosage 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 carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, suppositories, ovules, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.

Preferably, a therapeutically effective amount of the pharmaceutical composition comprising a farnesyl protein transferase inhibitor is administered orally or parenterally. Said therapeutically effective amount is the amount that effectively o : sensitizes a tumor in a host to irradiation. On the basis of the current data, it appears . that the pharmaceutical composition comprising (+)-(R)-6-[amino(4-chlorophenyl) (1-methyl-1H-imidazol-5-yl)methyl}-4-(3-chlorophenyl)-1-methyl-2(1 H)-quinolinone (compound 75) as the active ingredient can be administered orally in an amount of from up to 1500 mg/m’ daily, either as a single dose or subdivided into more than one dose, or more particularly in an amount of from 100 to 1000 mg/m’ daily.

Irradiation means ionizing radiation and in particular gamma radiation, especially that emitted by linear accelerators or by radionuclides that are in common use today. The 10 irradiation of the tumor by radionuclides can be external or internal.

Preferably, the administration of the pharmaceutical composition commences up to one month, in particular up to 10 days or a week, before the irradiation of the tumor.

Additionally, it is advantageous to fractionate the irradiation of the tumor and maintain the administration of the pharmaceutical composition in the interval between the first and the last irradiation session. i ~The amount of famesyl protein transferase inhibitor, the dose of irradiation and the intermittence of the irradiation doses will depend on a series of parameters such as the type of tumor, its location, the patients’ reaction to chemo- or radiotherapy and ultimately is for the physician and radiologists to determine in each individual case. .

The present invention also concerns a method of cancer therapy for a host harboring a tumor comprising the steps of - administering a radiation-sensitizing effective amount of a farnesyl protein transferase inhibitor before, during or after - administering radiation to said host in the proximity to the tumor.

Examples of tumors which may be inhibited, but are not limited to, lung cancer (e.g. adenocarcinoma), pancreatic cancers (e.g. pancreatic carcinoma such as, for example exocrine 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 follicular cancer, myelodysplastic syndrome (MDS), tumors of mesenchymal origin (e.g. fibrosarcomas and rhabdomyosarcomas), melanomas, teratocarcinomas, neuroblastomas, gliomas, benign tumor of the skin (e. g. keratoacanthomas), breast carcinoma, kidney carninoma, ovary carcinoma, bladder carcinoma and epidermal

: carcinoma.

Experimental part

The following tables show the formulas of the compounds of formula (I), their physical data, and references to the examples in WO-97/21701 according to which the compounds in question may be prepared. In the pharmacological example, the radiation sensitizing effect of the compounds of formula (I) is illustrated.

Table 1 : cl

N=\ ® NNR

RS

ITC

0 3 al

R!

SE[ = [ow [ vm

No. | No. |B.3 CH3 CH3 O(CH2)30H mp. 135°C mp. 180°C; 16 |B.3 CH3 CHj3 O(CH»),CH3 COS 1205,0) mp. 144°C; 17 B.3 CHs CH; O(CH3),0-CgHs 3 9 CLO 18 [B.2 H CH(CHz)2 OH - 19 [B.4 CH3 CH(CHa)2 OH mp. 254°C |B.2 H (CH2)20CH3 OH mp. 112°C 21 |B.4 CH3 (CH2)20CH3 OH mp. 192°C 22 |B.3 CH3 CHj O(CHz),0H mp. 198°C mp. 150-200°C; 23 |B.8a CHj CH3 OH to Pry mp. 150-200°C; 24 |B.8a CH3 CH; OH en ply |B.11 CH; CH3 CH2-CN mp. 154°C 27 [B.2 H (CH3)30CH3 OH - 28 |IB.4 CH» (CH»)30CHj3 OH mp. 196°C; HO 29 [B.3 CHj CH O(CH2);0CH,CHj HO) 31 [B.2 H CH3 OH > 260°C 32 [B.6 CH; (CH2),0CH3 H ACEO 33 [B.6 CH3 (CH2)30CH3 H mp. 180°C; .HCI 56 |IB.12 CH3 CH; -NHCOCH;3 .CoHyO4 58 [B.11 CHa CH; -CH,COOCH,CH3 |.CoH204.3/2(H,0) 60 [B.11 CH3 CH3 1-imidazolyl - 61 |B.21 CH3 CHj -NH-CH3 mp. 164°C 65 |B.2 H (CH3)3SOCH3 OH HO 66 |B.13 CH3 CH3 -N(CH3), .2C;H704.H0O mp. 160°C 67 [B.13 CH3 CH3 -NH-(CH;),0CHj3 mp. 216°C 68 [B.13 CH3 CH; -NH-(CHy),-OH - 69 [B.7 CH; CHs -CH,Cl 2C,H04 mp. 220°C 70 |B.7 CHj3; CH; -CH,Br - 711 = CH3 CHj -CH,OH 2CH704 76 |B.4 | -(CH2),OCH3 CH3 OH mp. 150°C

VA oo - 21- ) Co. | Ex. .

TT * CH3 CH3 -CH,OCH; 2C2H704 mp.166°C 78 [B.13 CHj CH3 -NH-OCH3 mp. 170°C 79 |B.20 CHs CH3 -NH-CONH; 2H70 80 | ** CHj CHj -CH,CONH» - 81 [B.13 CH3 CHj3 -NH-OH - 82 |B.13 CH3 CHj3 -NH(CH2)2N(CH3)2 - 83 |B.4 |(CH2)2N(CH CH -32C2H204 3 |B.4 | (CH2)2N(CH3)2 3 OH 3/2H,0 mp. 200 °C 84 | * CHj CHj -CH,N(CH3), C2H204 mp. 210°C 85 [B.4 CH3 CH3 -N(CHz3)2 - 86 |IB4 CH3 CH3 NHCOCH;N(CH3)2 - 87 |B.4 CH3 CH3 -NH(CH2)9CHj3 - 88 |B.4 CH3 CHj3 -NH(CHz)2NH; - 89 |B.20 CH; CH3 NHCOCH,OCH3 HC mp. 220°C 90 [B.6 CH3 CH3 H - : 91 |B.20 CHs CH3 NHCOCH,CgHs | -C2H204.H20 mp. 170°C 92 |B.20 CHj3 CH3 -NHCOCgHs mp. 242°C 93 [B.20 CHj CH3 _NHCOCONH, | -C2H204.H20 mp. 186°C 94 |B.13 CHj3 CH3 -NHC¢Hs mp. 165°C * . prepared by functional-group transformation of compound 70 ** : prepared by functional-group transformation of compound 25

Table 2:

RS

RC no / N—R42

SF

RS

SOAS

(0) tf Cl

R!

oo : 22

B.6 CH3 3-Cl CH; (2-CH3| H 4 yr Soy OOO 34 B.1 |[CH3| 3-O-CH-CH3 | CH; H OH mp. 190°C mp. 160-180°C; |IB.6 | CH; 3-0-CH;-CHj3 CHj3 H H tian 36 |B.1 | CHj 3-O-CH3 CH3 H OH mp. 210°C 37 |B.1 |CH3| 3-O-(CH2)2-CH3 | CHj H OH mp. 150-160°C 38 |B.1 |CH3| 3-O-(CH2)3-CH3 | CHj H OH mp. 150-160°C 49 |B.1 |CH3| 4-O-CH2-CH3 | CHj H OH mp. 184.2°C 50 {B.1 |CH3{ 3-O-CH-(CH3); | CHj H OH mp. 147.1°C - ~| 51 |[B.6 |CH3| 3-O-(CH)3-CH3 | CHj H H mp. 164.2°C; , 3/2(CoH204) } 52 |B.6 |CH3| 3-O-(CH2)2-CH3 | CHj H H .3/2(C72H304) 53 |B.6 | CH3| 3-O-CH-(CH3); | CH; H H mp. 133.9°C; .Co2H704.H,0 54 |B.14| CH3 3-OH CH3 H OH - 64 |B.10| CH3 3-OH CH; | H OH HCLH20 55 |B.6 | CH3 3-OH CH3 H H mp. >250°C 57 {B.1 |CH;3 2-OCH,CH3 CH; H OH - : 59 |B.13| CH3z 3-OCH>CH3 CHj3 H NH» . 95 |B.8a| CH3 3-OCH,CH3 CHj H NH; (A) 96 |B.8a| CHj 3-OCH,CH3 CH3 H NH, (B) 62 [B.15| CH3 | 3-O(CH2),N(CH3),| CH3 H OH - 63 [B.11|CH3| 3-O(CH2)2-OH | CHj3 H OH - 97 |B.1 |CHj 3-CH,CH3 CH3 H OH - 98 |B.13| CHj 3-CH2CH3 CH3 H NH; mp. 240°C 99 |B.1 | CHj 3-(CH3),CH3 CH;3 H OH - 100 |[B.13 | CH3 3-(CH2)2CH3 CHj3 H NH; - 101 | * |CHs| 3-O-(CH2),0CH; | CHs H OH -3/2(C2.H204) mp. 193°C 102 |B.1 |CH3 3-CHs CHj H OH mp. >250°C 103 {B.13 | CH3 3-CH3 CH; H NH; - 104 |B.1 | CH3 3-Br CHj H OH - 105 |B.13 | CH3 3-Br CH3 H NH -

o WO 00/01411 PCT/EP99/04545 w

EHNHEIEE EEE ET

106 [B.1 | CH3 3-O-CF3 CHj3 H OH - 107 |B.13| CH3 3-O-CF3 CH; H NH; mp. 168°C 108 [B.1 | CH3 3-CeHs CHs | H OH . 109 [B.13 | CH3 3-CeHs CH3 H NH; - 110 |B.1 | CH3 3-F CH3 H OH - 111 {B.13| CH3 3-F CH3 H NH; mp. >250°C 112 B.1 | CH3 | 3-(E)-CH=CH-CH3| CH3 H OH mp. >250°C 113(B2 | H 3-Cl CH3 | 3-CI OH - 114 |B4 | CH3 3-Cl CH3 3-Cl OH - 115 {B.1 | CH3 3-Cl H |3-CH3| OH - 116 |B.4 | CH3 3-Cl CH3 |3-CH3| OH - 117 | ** | CH3 3-CN CHj H OH - 160 | B.1 | CH3 3-CF3 CHj3 H OH - *: prepared by functional-group transformation of compound 54 ** . prepared by functional-group transformation of compound 104

Table 3 : ) cl

JO x _N—CH; i RE 0 N Cl

Ri

) Table 4 : ~ KX i”

R®

A NN re 0 N F

Li

EN 4 FA I I I Ed

No. | No. mp. 170°C; 42 | B6 H H H 4-C1 | H Cots ZH 43 |B.10| H H H 4-C1 | OH mp. 180°C; .H>0O 44 | B.5 H H CH3 4-Cl | H mp. 152°C 45 | B6 | 3-Cl H H 4-Cl | H mp. 175°C; .CoH04 46 | B5 | 3-Cl H CH,CH3 | 4-C} H mp. 132°C; .CoH704 oo "| 47 | BS | 3-Cl H CH3 4-Cl H | mp. 115°C; .3/2 CoH04 48 | B9 | 3-Cl H CHs | 4-C1 | OH mp. 230°C 118 | B4 | 3-Cl1 | 3-CH3; | CHs 4-Cl | OH mp. 222°C

Table S : - rR? sls \ N—CHj

RS

F EN

25. (0) N FZ

Cu,

Co.No. [ExNo.| RMR: | Re | Rs 119 B.1 -O-CH;-0O- 4-Cl OH 120 B.13 -0-CH;-O- 4-Cl NH, 121 B.1 -O-CHj-CH»-O- 4-Cl OH 122 B.13 -0-CH,-CH3-O- 4-Cl NH 123 B.1 -O-CH=CH- 4-Cl OH x | WO 00/01411 PCT/EP99/04545 ) Table 6 : . R3 R16

XN oe ¥ N= (lz x NCH; . RS

X \ @® Cl

CH3

No. | No. 124 {B.1 | O | double | 3-OCH3 | 4-OCH3 | 5-OCH3 | OH mp. 230°C 125 |B.13| O | double | 3-OCH3 | 4-OCHj3 | 5-OCH3 | NH; mp. 218°C ) .CoHyO4 -Cl 126 {B.1 | O | single 3-C H H OH mp. 160°C 127 |B.1 | O | single | 3-Cl H H OH - 128 |B.16] S | double | 3-CI H H H -

Table 7 : cl N==\ ~~ N—CHjs

RY R®

CTF

O N R19 Cl

R!

No. | No. 129 |B.17{ H CN H H H - 130 {B.4 | CH3 CN H H H mp. 202°C 131 |B.17{ H CN H H OH - 132 |B.4 | CH3 CN H H OH - 133 |B.17| H CN H H | -CHCN . 134 |B.4 | CH3 CN H H | -CHCN | mp. 138°C 135 |B.18| H CH3 H H OH - 136 |B.4 | CH3 CH3 H H OH - 137 |B.13| CH3 CHj H H NH mp. >250°C 138 |B.18| H CeHs H H H -

k 4

No. | No. 139 |B.4 | CH3 CeHs H H gH | Y2ACH00 mp. 180°C 140 |B.18| H CeHs H H OH .- 141 |B.4 | CH3 CeHs H H OH ; 142 {B.13| CH3 CeHs H H NH; . 143 |B.13 | CHj3 Cl H H NH; - 144 |B.17| H | -COOCH,;CH3 H H OH . 145 |B.4 | CH3 | -COOCH,CH3 H H OH - 146 {B.1 | CH3 H 8-CH3 H OH - 147 |B.13 | CH3 H 8-CH3 H NH; HO 148 |B.1 | CH3 H 7-Cl H OH - 149 |B.1 | CH3 H 7-CH3 H OH - 150 |B.1 | CHs H 5-CH3 H OH - 151 {B.1 | CH3 H 8-OCH3 H OH -

Pp 1161 |B.1 | CH; H 7-CH3 | 8-CHj3 OH mp. 255°C : Table 8 : rR3

INN N= ) eA — 2) N—CH,

R® } (IJ (3

CH;

No. | No. 152 | B.1 | 3-OCH,CHj3 H |4-OCH;CH3| H OH | .3/2(C2H,04) 153 | B.1 3-Cl H H H OH - 154 | B.1 3-Cl H 4-CH3 H OH - 155 | B.1 3-Cl H 4-OCH3 H OH - 156 | B.1 3-Cl H 4-CF3 H OH - 157 | B.1 3-Cl H 2-Cl 4-Cl | OH - 158 | B.1 3-Cl 5-Cl 4-Cl H OH -

SE] = [vo] = [#]x [mmm : No. | No.

Pharmacological example 1

Male athymic nude mice weighing approximately 22 to 25 g were inoculated subcutaneously in the inguinal region with 1 x 10° of LoVo human colon tumor cells (LoVo cells) on day 0. After three weeks to allow tumors to become established (diameter approximately 0.5 to 1 cm), treatment was started with solvent or compound 75 via the oral route, and either with or without a single shot irradiation on day 32.

Parameters for activity were tumor growth rate and weight of the tumors at day 42.

Compound 75 was dissolved in water and acidified with 1 N HCl solution to pH 2.5 and administered orally (po) as 0.1 ml of compound solution per 10 g mouse body weight twice daily (bid). The dose administered was either 50 or 100 mg compound per kg bodyweight ; treatment either preceded irradiation (days 22-32), followed irradiation (days 32-42) or continued throughout the duration of the experiment (days 22-42).

Irradiation treatment consisted of a single dose of radiation on day 32 with a dose of 7

Gy that stabilized tumor growth in untreated animals, i.e. a dose that stopped the increase in tumor volume, but did not cause any reduction in its size either.

The following table (Table 9) shows each of the arms that were evaluated in the experiment. In each arm of the experiment 16 animals were included. The column ‘tumor (g)’ contains the median of the tumor weight of the animals sacrificed at day 42 of the experiment. Figures 1 and 2 represent the observed data in graphical form.

Figure 1 shows the distribution of the tumor weights (g) of the test animals receiving 50 mpk of test compound (po, bid).

v

Figure 2 shows the distribution of the tumor weights (g) of the test animals receiving 100 mpk of test compound (po, bid).

The gray box in the figures depicts the 25-75 percentiles, the solid black line therein represents the median, the lines extending from the gray box depict the 10-90

E 5 percentiles and the black dots represent the outliers. The Roman mumbers correspond to the groups of test animals as identified in Table 9.

From a statistical analysis of the data it follows that treatment with compound 75 (both 50 and 100 mpk) potentiates the effect of irradiation, more in particular that pretreatment with compound 75 (both 50 and 100 mpk) and irradiation reduces tumor weight in a statistically significant manner (when compared to irradiation alone).

Table 9

I solvent day 22-42 none 0.475

II 50 mpk day 22-42 none 0.255

III 50 mpk day 22-32 none 0.273 1% 50 mpk day 32-42 none 0.295

Vv 100 mpk day 22-42 none 0.205

Vi 100 mpk day 22-32 none 0.234

VIL 100 mpk day 32-42 none 0.277

VIII SO mpk day 22-42 7 Gy 0.207

IX 50 mpk day 22-32 7 Gy 0.156 (p =0.03)*

X S50 mpk - day 32-42 7 Gy 0.259

XI 100 mpk day 22-42 7 Gy 0.164 (p=0.0317)*

XI 100 mpk day 22-32 7 Gy 0.141 (p = 0.0022)*

XIII 100 mpk day 32-42 7 Gy 0.214

XIV Solvent day 22-42 7G 0.256 * Mann-Whitney U test vs Group XIV (radiotherapy only)

Example 2

Radioresistant human glioma cell lines (SF763, U87, U251) were treated with compound 75, 48 h prior to irradiation (2 Gy). The dose administered was 0.4 nM for

U251 and 2 nM for SF763 and U87.

CL © WO 00/01411 PCT/EP99/04545 w ) Applying compound 75 to the cells dramatically reduced the surviving of the cells after . irradiation : for SF763 and U87, a decrease of surviving fraction of about 55 % was demonstrated, whereas for U251, the decrease was 25 %.

These results demonstrate that treatment with compound 75 resensitizes radioresistant cells to irradiation.

Claims

. Q WO 00/01411 PCT/EP99/04545

:

1. Use of at least a farnesyl protein transferase inhibitor for the manufacture of a preparation having radiosensitizing properties for administration before, during or 3 after irradiation of a tumor for treating cancer in vivo. 2 The use of claim 1 wherein said farnesy! protein transferase inhibitor is a compound of formula (I), or a compound of formula (II) or (I) which is metabolized in vivo to a compound of formula (I), said compounds being represent by R3_ Ris Rs Rs __ Ris Ra N/a =|- Na =|. R= : wa | Nors —- /> +N gs ~~ NZ Rin SN SN Rs ps x NN PAS PRRS NN PN XX XX x N I Rig Ry N 0 Rig Ry Ry MD (I) R3__ Ris Rs N/a = Ry # wa | N_Rs ZF JF Rin ~~ NN XN : I VR Ge NT [ AX & R19 Rig Ry (In) a stereoisomeric form thereof, a pharmaceutically acceptable acid or base addition salt thereof, wherein the dotted line represents an optional bond; ) X is oxygen or sulfur; R' is hydrogen, C1.12alkyl, Arl, Ar2Cjgalkyl. quinolinylCi-galkyl, pyridyl- Ci-salkyl, hydroxyC-ealkyl, C,.salkyloxyCj.galkyl, mono- or di(C.ealkyl)- aminoC.ealkyl, aminoC).ealkyl, or a radical of formula -Alk!-C(=0)-R9, -Alk!-S(O)-R? or -Alk!-S(O)2-RY, wherein Alk! is Ci-¢alkanediyl, RY is hydroxy. C.ealkyl, Cj-galkyloxy, amino, Ci-galkylamino or C.galkylamino substituted with C.ealkyloxycarbonyl; AMENDED SHEET

© WO 00/01411 PCT/EP99/04545 v } R2, R3 and R16 each independently are hydrogen, hydroxy, halo, cyano, C_galkyl, : C-galkyloxy, hydroxyC;-galkyloxy, Ci-¢alkyloxyCj-galkyloxy, amino-

C1-.alkyloxy, mono- or di(Cj-salkyl)aminoC;.galkyloxy, Arl, Ar2C)_galkyl, Ar2oxy, Ar2C.galkyloxy, hydroxycarbonyl, Cj-galkyloxycarbonyl, trihalomethyl, trihalomethoxy, Cj_ealkenyl, 4,4-dimethyloxazolyl; or when on adjacent positions R2 and R3 taken together may form a bivalent radical of formula -0-CHy-O- (a-1), -O-CH,-CHj-O- (a-2), -O-CH=CH- (a-3), -O-CH»-CH»- (a-4), -0O-CH3-CH,-CHj3- (a-5), or -CH=CH-CH=CH- (a-6); R# and R> each independently are hydrogen, halo, Ar!, Cj_galkyl, hydroxy- Ci-ealkyl, Cj_galkyloxyCj.-galkyl , C;_galkyloxy, Cj-galkylthio, amino, hydroxycarbonyl, Cj-salkyloxycarbonyl, C)_alkylS(O)C)_galkyl or C1-62alkylS(0O)2C}-6alkyl; R6 and R7 each independently are hydrogen, halo, cyano, C|_galkyl, C).galkyloxy, Ar2oxy, trihalomethyl, Cj_galkylthio, di(C;.galkyl)amino, or . 20 when on adjacent positions R® and R7 taken together may form a bivalent radical of formula -O-CH3-O- (c-1), or CH=CH-CH=CH- (c-2); R8 is hydrogen, Cj-galkyl, cyano, hydroxycarbonyl, C-salkyloxycarbonyl, Ci-ealkylcarbonylCj.galkyl, cyanoCj_galkyl, Cj_galkyloxycarbonylCj_galkyl, carboxyCj_galkyl, hydroxyCj_ealkyl, aminoC|_galkyl, mono- or di(Cj.galkyl)- aminoCj.galkyl, imidazolyl, haloC;_galkyl, Cj_galkyloxyCj.ealkyl, amino- carbonylCj.galkyl, or a radical of formula -O-R10 (b-1), -S-R10 (b-2), _N-R11R12 (b-3), wherein R10 is hydrogen, C)-galkyl, C].ealkylcarbonyl, Ar!, Ar2C;_galkyl, Ci-ealkyloxycarbonylCj-galkyl, a radical or formula -Alk2-OR 13 or -Alk2-NRI4R 15; R!1 is hydrogen, C}-12alky!, Ar! or Ar2C|_galkyl; R12 is hydrogen, C;-alkyl, C}-16alkylcarbonyl, Cj-ealkyloxycarbonyl, C1-ealkylaminocarbonyl, Ar!, Ar2Cj_galkyl, C}.galkylcarbonyl-

) C1-salkyl, a natural amino acid, Arlcarbonyl, : Ar2Cj.galkylcarbonyl, aminocarbonylcarbonyl, Cy _galkyloxy-

Ci.salkylcarbonyl, hydroxy, Cj.ealkyloxy, aminocarbonyl, di(C)-¢alkyl)aminoCj.galkylcarbonyl, amino, Cj.galkylamino, : Ci-salkylcarbonylamino, or a radical of formula -Alk?-OR13 or -Alk2-NRI4R 15; wherein Alk? is Cj_galkanediyl; : R13 is hydrogen, C}-galkyl, C1-galkylcarbonyl, hydroxyCj_ealkyl, Ar! or Ar2C_galkyl; R14 is hydrogen, Cj-galkyl, Ar! or Ar2C)_galkyl; R15 is hydrogen, C-galkyl, Cj-galkylcarbonyl, Ar! or Ar?C)_galkyl; R17 is hydrogen, halo, cyano, C}_galkyl, C}_galkyloxycarbonyl, Arl; R18 is hydrogen, Cj.galkyl, C;.galkyloxy or halo; R19 is hydrogen or C}_galkyl; Ar! is phenyl or phenyl substituted with Cj_galkyl, hydroxy, amino, C|_galkyloxy or halo; and Ar? is phenyl or phenyl substituted with C}_galkyl, hydroxy, amino, Cj-galkyloxy or halo.

20 .

3. The use of claim 2 wherein said farnesyl protein transferase inhibitor is a compound of formula (I) and wherein X is oxygen.

4. The use of claim 2 wherein said farnesyl protein transferase inhibitor is a compound of formula (I) and wherein the dotted line represents a bond.

5. The use of claim 2 wherein said farnesyl protein transferase inhibitor is a compound of formula (I) and wherein R! is hydrogen, C_galkyl, C;.¢alkyloxy- C1-salkyl or mono- or di(Cj.galkyl)aminoCj_galkyl.

6. The use of claim 2 wherein said farnesyl protein transferase inhibitor is a compound of formula (I) and wherein R3 is hydrogen and R2 is halo, C}_galkyl,

Cy.salkenyl, Cj.galkyloxy, trihalomethoxy or hydroxyCj_galkyloxy.

7. The use of claim 2 wherein said farnesyl protein transferase inhibitor is a compound of formula (I) and wherein R® is hydrogen, hydroxy, haloC.galkyl, hydroxyCj_galkyl, cyanoCj_galkyl, Ci_galkyloxycarbonylC.galkyl, imidazolyl, or a radical of formula -NR1!IRI2 wherein R!! is hydrogen or C|.}zalkyl and R12 is a -33- hydrogen, C1-62alkyl, Ci-alkyloxy, Ci-6alkyloxyC-galkylcarbonyl, hydroxy, or a radical of formula -Alk2-OR13 wherein R13 is hydrogen or Cjgalkyl.

8. The use of claim 2 wherein the compound is 4-(3-chiorophenyl)-6-[(4-chlorophenylhydroxy(1-methyl- 1H-imidazol-5-yl)- methyl]-1-methyl-2(1H)-quinolinone, : 6-[amino(4-chlorophenyl)-1-methyl-1H-imidazol-5-yimethyl}-4-(3-chlorophenyl)- 1-methyl-2(1H)-quinolinone; ~ 10 6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxy- phenyl)-1-methyl-2(1H)-quinolinone; 6-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl}-4-(3-ethoxyphenyl)-1- methyl-2(1H)-quinolinone monohydrochloride.monohydrate; 6-[amino(4-chlorophenyl)(1-methyl- 1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)- 1-methyl-2(1H)-quinolinone, and 6-amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl}-1-methyl-4-(3- propylphenyl)-2(1H)-quinolinone; a stereoisomeric form thereof or a pharmaceutically acceptable acid or base addition salts thereof.

9. The use of claim 2 wherein the compound is (+)-(R)-6-[amino(4-chlorophenyl)(1 -methyl-1H-imidazol-5-yl)methyl]-4- (3-chloropheny!l)- 1-methyl-2(1H)-quinolinone; or 2 pharmaceutically acceptable acid addition salt thereof. Co

25. 10. The use of any one of the preceding claims wherein a therapeutically effective amount of the preparation is administered orally, parenterally, rectally or topically.

‘11. The use of claim 9 wherein the preparation is administered orally in an amount of from 10 to 1500 mg/m? daily, either as a single dose or subdivided into more than one dose. :

12. The use of claim 1 wherein the irradiation is ionizing irradiation.

13. The use of claim 1 wherein the irradiation of the tumor is external or internal.

14. The use of claim 1 wherein the administration of the preparation commences up "to one month before the irradiation of the tumor. AMENDED SHEET j * §WO 00/01411 -34- PCT/EP99/04545

15. The use of claim 1 wherein the irradiation of the tumor is fractionated and the administration of the preparation is maintained in the interval between the first and the last irradiation session.

16. A substance or composition for use in a method of cancer therapy for a host harboring a tumor, said substance or composition comprising a farnesyl protein transferase inhibitor, and said method comprising the steps of - administering a radiation-sensitizing effective amount of said substance or composition before, during or after - administering radiation to said host in the proximity to the tumor.

17. A substance or composition for use in a method of treatment according to claim 16 wherein the farnesyl protein transferase inhibitor is a compound of formula (I), or a compound of formula (II) or (III) which is metabolized in vivo to a compound of formula (I), according to claim 2.

18. A substance or composition for use in a method of treatment according to claim 17 wherein said farnesyl protein transferase inhibitor is a compound of formula (I) and wherein X is oxygen.

19. A substance or composition for use in a method of treatment according to claim 17 wherein said farnesyl protein transferase inhibitor is a compound of formula (I) and wherein the dotted line represents a bond.

20. A substance or composition for use in a method of treatment according to claim 17 wherein said farnesyl protein transferase inhibitor is a compound formula (I) and wherein R! is hydrogen, C,¢alkyl, C,salkyloxy-C alkyl or mono- or di(C,. calkyl)aminoC, _¢alkyl.

21. A substance or composition for use in a method of treatment according to claim 17 wherein said farnesy! protein transferase inhibitor is a compound of formula (I) and wherein R? is hydrogen and R? is halo, C, qalkyl, C,.calkenyl, C,. calkyloxy, trihalomethoxy or hydroxyC, ecalkyloxy. AMENDED SHEET

) ] ¢wo 00/01411 -35- PCT/EP99/04545

22. A substance or composition for use in a method of treatment according to claim 17 wherein said farnesyl protein transferase inhibitor is a compound of formula (I) and wherein R? is hydrogen, hydroxy, haloC, alkyl, hydroxyC, salkyl, cyanoC, alkyl, C, salkyloxycarbonylC, salkyl, imidazolyl, or a radical of formula -NR!'R!2 wherein R!! is hydrogen or C, ,alkyl and R' is hydrogen, C, «alkyl, C, qalkyloxy, C, qalkyloxyC, salkylcarbonyl, hydroxy, or a radical of formula -Alk2.-OR!? wherein R!? is hydrogen or C, alkyl. © 23. A substance or composition for use in a method of treatment according to claim 17 wherein the compound is " 4-(3-chlorophenyl)-6-[(4chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)- methyl}-1-methyl-2(1H)-quinolinone, 6-[amino(4-chloropheny!)-1-methyl-1H-imidazol-5-ylmethyl}-4-(3-chlorophenyl)- 1-methyl-2(1H)-quinolinone; 6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxy- phenyl)-1-methyl-2(1H)-quinolinone; 6-[(4-chlorophenyl)(1-methyl- 1 H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1- methyl-2(1H)-quinolinone monohydrochloride.monohydrate; 6-{amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)- 1-methyl-2(1H)-quinolinone, and 6-amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-4-(3- propylphenyl)-2(1H)-quinolinone; a stereoisomeric form thereof or a pharmaceutically acceptable acid or base addition salts thereof.

24. A substance or composition for use in a method of treatment according to claim 17 wherein the compound is (+)-(R)-6-[amino(4-chloropheny!)(1-methyl-1H -imidazol-5-yl)methyl]-4- (3-chlorophenyl)-1-methyl-2(1H)-quinolinone; or a pharmaceutically acceptable acid addition salt thereof.

25. A substance or composition for use in a method of treatment according to any one of claims 16 to 24 wherein a therapeutically effective amount of the substance or composition is administered orally, parenterally, rectally or topicaily. AMENDED SHEET

“ N° 00/01411 -36- PCT/EP99/04545

26. A substance or composition for use in a method of treatment according to claim 24 wherein the substance or composition is administered orally in an amount of from 10 to 1500 mg/m? daily, either as a single dose or subdivided into more than one dose.

27. A substance or composition for use in a method of treatment according to claim 16 wherein the irradiation is ionizing irradiation.

»8. A substance or composition for use in a method of treatment according to claim 16 wherein the irradiation of the tumor is external or internal.

29. A substance or composition for use in a method of treatment according to claim 16 wherein the administration of the substance or composition commences up to one month before the irradiation of the tumor.

30. A substance or composition for use in a method of treatment according to claim 16 wherein the irradiation of the tumor is fractionated and the administration of the substance or composition is maintained in the interval between the first and the last irradiation session.

31. Use according to claim 1, substantially as herein described and illustrated.

32. A substance or composition for use in a method of treatment according to claim 16, substantially as herein described and illustrated.

33. New use of at least a farnesyl protein transferase inhibitor, or a substance OF composition for a new use in a method of treatment, substantially as herein described. : AMENDED SHEET