UA64796C2 - Farnesyl protein transferase inhibitors with radiosensitizing properties in vivo - Google Patents

Abstract

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.

Description

This invention relates to the discovery that farnesyl protein transferase inhibitors have radiosensitizing properties that make them useful in the preparation of pharmaceutical compositions for administration before, during and after tumor irradiation in the treatment of ip mimo cancer. UUO-97/21701 describes the preparation, formulation and pharmaceutical properties of (imidazolyl-5-yl)methyl-2-quinolinone derivatives of formulas (1), (II) and (I), as well as intermediate compounds of formulas (II) and ( II), as inhibitors of farnesyl protein transferase, which are metabolized immeasurably into compounds of formula (I). Compounds of formulas (1), (II) and (1) are given as

Kk how ke zm her- Z Kv m in - tur - h yo:

E Kz. In two x zne village

I eat ME!

Ki 0)

Ben Te a ey zi

S

MBantte from packs We 2:

There is about y

Kriy di A. ke Shchy put» xx kt ZA She .

M vv and ki

GAT8)

Echo and that's it. t all eat M ovh trya MN -

Viz ih A ih yi Ti Kk yi --sh

I: A 5 - I Ж SA I

In iv- ivv ia

Skin 0

PE pharmaceutically acceptable addition salts of a base or acid and their stereochemically isomeric forms, where dashed lines indicate an optional bond;

X means oxygen or sulfur;

IN! means hydrogen, C1-alkyl, Ag, Ag?C1-alkyl, quinolinylC1-alkyl, pyridylC-alkyl, hydroxyC1-alkyl,

Si-alkyloxySi-alkyl, mono- or di(Si-alkyl)aminoSi-alkyl, aminoSi-alkyl, or a radical of the formula -АЙК!-

C(-O0)-VU, -AIK'-5(0)-B? or -AIIK!-5(0)2-8U.

AIK! means Si-valcandiyl,

IN? means hydroxy, C1-alkyl, C1-alkyloxy, amino, C1-alkylamino, or C1-alkylamino substituted by C1-alkyloxycarbonyl;

B, BZ, and B'E are each independently hydrogen, hydroxy, halo, cyano, C1-alkyl, C1-alkyloxy, hydroxyCi-alkyloxy, C1-alkyloxyCi-alkyloxy, aminoCi-alkyloxy, mono- or di(Ci-E alkyl) aminoCi-alkyloxy, Ag, Ag2Ci-alkyl, Aggoxy, AtH?Ci-alkyloxy, hydroxycarbonyl, Si-alkyloxycarbonyl, trihalomethyl, trihalomethoxy, Cg-vealkenyl, 4,4-dimethyloxazolyl; or in adjacent positions B: and VU, taken together can form a bivalent radical of the formula -0-СНо-0- (а-1), -0-Сно-Сно-о- (а-2), -0-сн-сн - (а-3), -0-Сно-Сне- (а-4), -0-снНо-СНо-СНе- (а-5) or -бн-Ссн-сСн-сн- (а-6)

IN? or B? each independently is hydrogen, a halo group, Ag", Si-alkyl, hydroxySi-alkyl, Sch-

valkyloxySi-valkyl, Si-valkyloxy, Si-valkylthio, amino group, hydroxycarbonyl, Si. alkyloxycarbonyl, C-alkyl IZ(O) C-alkyl or C-alkyl IZ(O)2 C-alkyl;

B3 and B" are each independently hydrogen, halo, cyano, C1-alkyl, C1-alkyloxy, Agoxy, trihalomethyl, C3-alkylthio, di(C1-weaalkylamino) or in adjacent positions HB? and B" taken together can form a bivalent the radical of the formula -0-Сно-о- (с-1), or -бснА:сСн-снеСсн- (с-г);

BZ means hydrogen, C1-alkyl, cyano group, hydroxycarbonyl, C:-alkyloxycarbonyl, C1-alkylcarbonyls-alkyl, cyanoCi-alkyl, C1-alkyloxycarbonylsC-alkyl, carboxysC3-alkyl, hydroxyCi-alkyl, aminoCi-alkyl, mono- or di( C-alkyl)aminoC:-alkyl, imidazolyl, haloC3-alkyl, C-alkyloxyCi-alkyl, aminocarbonyl - alkyl, or a radical of the formula -0-8'o (p-1), -5-819 (p-r), -M-B'"!B!2 (p-3), where B"? means hydrogen, C1-alkyl, C1-alkylcarbonyl, Ag, Ag2Ci-alkyl, C1-alkyloxycarbonyls-alkyl, or a radical or the formula -AIK2-OV!Z or AIK2-MA B;

B" means hydrogen, C1-alkyl, Ag! or A! C1-alkyl;

IN!? means hydrogen, C1-alkyl, C1-alkylcarbonyl, C1-alkyloxycarbonyl, C1-alkylaminocarbonyl, Ag,

Ag?Ci-alkyl, C1-alkylcarbonylCi-ealkyl, natural amino acid, Ag'carbonyl, A!Ci-alkylcarbonyl, aminocarbonylcarbonyl, C1-alkyloxyCi-alkylcarbonyl, hydroxy, C1-alkyloxy, aminocarbonyl, di(Ci-alkyl)aminoCi-alkylcarbonyl , an amino group, a C-alkylamino group, a C-alkylcarbonylamino group, or a radical, or the formula -AIK2-OV"Z or AIK2-MA B; where AIKe means C-valcanediyl;

AZZ means hydrogen, C-alkyl, C-vealalkylcarbonyl, hydroxyC-alkyl, Ag! or Ag2Si-alkyl;

A"" means hydrogen, Si-valkyl, Ag! or AgSi-valkyl;

IN! means hydrogen, C-alkyl, C-halkylcarbonyl, Ag! or Ag7Si-alkyl;

B" means hydrogen, halo group, cyano group, C-alkyl, C-alkylcarbonyl, Ag;

IN!? means hydrogen, C1-alkyl, C1-halkyloxy or halo;

B'Denotes hydrogen or C-alkyl;

Ag means phenyl or phenyl substituted with C 1 -alkyl, hydroxy, amino, C 1 -alkyloxy or halo; and

Huh? means phenyl or phenyl substituted with C1-6alkyl, hydroxy, amino, C1-6alkyloxy or halo. Ммо-97/16443 describes the preparation, formulation and pharmaceutical properties of compounds of the formula (IM), as well as intermediate compounds of the formulas (M) and (MI), as inhibitors of farnesyl protein transferase, which are metabolized ip mimo into compounds of the formula (IM). Compounds of the formulas (IM), (M) and (MI) are given as k3 Ki x V Kih 3 cho z cell KE her in ve Tv i He t KU Ko i sce s Y what Ti A ra sho How A pko

T Z I | te u Tse Sh v ke giya u zny still "about nv i, Kub MV 7 What Age V

Fo IB and je Sky ki b vyh rute

Z o C, where

Zk pre dk y

Her also Ki: Ku

ZY

TC EVI pharmaceutically acceptable addition salts of a base or acid and their stereochemically isomeric forms, where dashed lines mean an optional bond;

X means oxygen or sulfur;

IN! means hydrogen, C1-alkyl, Ag, Ag?C1-alkyl, quinolinylC1-alkyl, pyridylC1-alkyl, hydroxyC1-alkyl,

C-alkyloxyCi-alkyl, mono- or di(C:-alkyl)amino group, C-alkyl, aminoCi-alkyl, or a radical of the formula -

AIK!-S(-0)-8U, -AIK!-5(0)-82 or -AIK!-5(0)2-NU, AK! means Si-valcandiyl;

IN? means hydroxy, C1-alkyl, C1-alkyloxy, amino, C1-alkylamino, or C1-alkylamino substituted by C1-alkyloxycarbonyl;

IN? and BZ are each independently hydrogen, hydroxy, halo, cyano, C-alkyl, C-alkyloxy,

hydroxyCi-valkyloxy, Ci-valkyloxyCi-ealkyloxy, aminoCi-alkyloxy, mono- or di(Ci-alkyl)aminos-valkyloxy, Ag, AggCi-valkyl, Aggoxy, AgCi-valkyloxy, hydroxycarbonyl, Ci-valkyloxycarbonyl, trihalomethyl, trihalomethoxy, Cg - valkenyl; or in adjacent positions B? and VU taken together can form a bivalent radical of the formula -0-СНо-0- (а-1), -0-Сно-Сне-о- (а-д), -0-сн-Сн- (а-3 ), -0-Сно-Сне- (а-4), -0-СНо-СНо-СНео- (а-5) or -бнесСн-СнН:Ссн- (а-6);

IN? or BZ is each independently hydrogen, Ag, C1-alkyl, C1-alkyloxy C1-alkyl, C1-alkyloxy, C1-alkylthio, amino, hydroxycarbonyl, C1-alkyloxycarbonyl, C1-alkyl3(O)2C1i-alkyl or Si. alkyl IZ(O)2 with Si-alkyl;

AND? and B" are each independently hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxy or Agoxy;

VAZ means hydrogen, C1-alkyl, cyano, hydroxycarbonyl, C1-alkyloxycarbonyl, C1-alkylcarbonyl, C1-alkyl, cyanoC1-alkyl, C1-veaalkyloxycarbonyls-alkyl, hydroxycarbonyl-alkyl, hydroxyC3-alkyl, aminoC3-alkyl, mono- or di( C3-alkyl)-aminoC3-alkyl, haloC3-alkyl, C3-alkyloxyC3-alkyl, aminocarbonylC3-alkyl,

Ah, Ah? C1-alkyloxyC3-alkyl, C1-valkylthio C1-alkyl;

IN! means hydrogen, C1-alkyl, C1-halkyloxy or halo;

B" means hydrogen or C-alkyl;

Ar means phenyl or phenyl substituted with C 1 -alkyl, hydroxy, amino, C 1 -alkyloxy or halo; and

Huh? means phenyl or phenyl substituted with C 1 -alkyl, hydroxy, amino, C 1 -alkyloxy or halo.

The application PCT/ЕРО8/01296, filed in March 1998, describes the preparation, formulation, and pharmaceutical properties of compounds of the formula (MII) as farnesyl protein transferase inhibitors. her tu v kya tt, De y , shchi " village o: 2 shchi

SA

And pharmaceutically acceptable addition salts of a base or acid and their stereochemically isomeric forms, where dashed lines mean an optional bond;

X means oxygen or sulfur; -A- means the bivalent radical of the formula -en.- (8-В, NIV. (а-8) -СНеАСН- (2-7), "СЙ СН": ев -ЕН,.- СВ» СМ" (8- 3, Not M- (8-8) -С»О» (a-, -ЩеМ. (8-93 or "СНУ СНО (а-5у; -2О-МН- я-10у; where one atom is optional hydrogen can be replaced by C-alkyl or Ag;

IN! and B? each independently is hydrogen, hydroxy, halo, cyano, C 1 -alkyl, trihalostyl, trihalomethoxy, covalkenyl, C 1 -alkyloxy hydroxyC 1 -alkyloxy, C 1 -alkyloxyC 1 -alkyloxy, /-C 1 -alkyloxycarbonyl, aminoC 1 -alkyloxy, mono- or di(C -alkyl)aminoC:-alkyloxy, Ag, AI?-Ci-alkyl,

Ag?-oxy, Al?-Ci-valkyloxy; or in adjacent positions B! and B, taken together, can form a bivalent radical of the formula -0-CH3-O- (p-1), -0-Cno-Cng-o (p-g), -0-cn-cn (p-3), -0-Сно-Сне- (р-4), -0-СНо-СНо-СНео- (6-5) or -бнесСн-СнН:Ссн- (р-б);

BZ and B" each independently with hydrogen, halo, cyano, C-alkyl, C-alkyloxy, Ag-oxy, C-alkyl, di(Ci-alkylamino), trihalomethyl, trihalomstoxy, or in adjacent positions BZ and B" taken together , can form a bivalent radical of the formula -0-СНо-0- (с-1), -0-Сно-Сне-о- (с-2), or -бнесСн-СнН:Ссн- (с-3);

IN? is a radical of the formula deya y shk Y IS - A chik (8-2u, che MO in Me where B!Z each independently is hydrogen, halogroup, Ag", C-alkyl, hydroxyC:-alkyl, C-alkyloxyCz-alkyl, Si -alkyloxy, C1-alkylthio, amino group, C1-alkyloxycarbonyl, C1-alkyl3(O)C1-alkyl or

C-alkyl IZ(O)2 C-alkyl;

B" is hydrogen, C 1 -alkyl or di(C 1 -alkyl)aminosulfonyl;

VAZ is hydrogen, hydroxy, halo, C-alkyl, cyano, haloC-alkyl, hydroxyC-alkyl, cyanoC-alkyl, aminoC-alkyl, C-alkyloxyC-alkyl, C-alkylthioC-alkyl, aminocarbonyl-alkyl, C-alkyloxycarbonyl C -alkyl, C1-alkylcarbonyl, C1-alkyl, C1-alkyloxycarbonyl, mono- or di(C1-alkyl)aminoC-alkyl, Ag", Ag"-Ci-alkyloxyC:-alkyl; or a radical of the formula -0-8"- (e-1), -8-87 (e-2),

M-vo (e-3), where B" means hydrogen, C-alkyl, C-alkylcarbonyl, Ag?, AibC-alkyl, C-alkyloxycarbonylC: -alkyl, or a radical of the formula -AIK-OB'O, or -AIKA - MA! V",

IN? means hydrogen, Si-alkyl, Ag" or Ag"-Ci-alkyl;

AND? means hydrogen, C1-alkyl, C1-alkylcarbonyl, C1-alkyloxycarbonyl, C1-alkylaminocarbonyl, Ag?, Ag8-

C-alkyl, C-alkylcarbonylC:-alkyl, Ag-carbonyl, Al-Ci-alkylcarbonyl, aminocarbonyl-carbonyl, C-alkyloxy-Ci-alkylcarbonyl, hydroxy, C-alkyloxy, aminocarbonyl, di(Ci-alkyl)aminoCi-alkylcarbonyl, amino group , a C-alkylamino group, a C-alkyl-carbonylamino group, or a radical of the formula -AIK-OV'O, or -AIK-

МВА"В'"», where АЙИЙК means Si-valcandiyl;

IN!? means hydrogen, C-alkyl, C-alkylcarbonyl, hydroxy C-alkyl, A? or Ag2-Ci-alkyl;

BA" means hydrogen, C1-alkyl, C1-6alkylcarbonyl, Ag? or Ago-C. -alkyl;

B"2 means hydrogen, C-alkyl, Ag!!! or Ag1-C.-alkyl; and

Up - Ah! each independently selected from phenyl or phenyl substituted with halo, C 1 -alkyl, C 1 -alkyloxy or trifluoromethyl.

In the application PCT/ЕРО8/02357, submitted on April 17, 1998, the preparation, formulation and pharmaceutical properties of compounds of the formula (MIP) as inhibitors of farnesyl protein transferase are described and pharmaceutically acceptable base or acid addition salts and their stereochemically isomeric forms, where dashed lines mean an optional bond;

X means oxygen or sulfur;

IN! and B? each independently is hydrogen, hydroxy, halo, cyano, C 1 -alkyl, trihalomethyl, trihalomethoxy, C 1 -6 alkenyl, C 6 -alkyloxy, hydroxyC 6 -alkyloxy, C 1 -alkyloxyC 1 -alkyloxy, /C 1 -alkyloxycarbonyl, aminoC 1 -alkyloxy, mono- or di (Si-valkyl)aminoSi-valkyloxy, Ag, Ag! Si-valkylom,

Ag'oxy, Ah! C-valkyloxy;

VAZ and B" are each independently hydrogen, halo, cyano, C1-alkyl, C1-alkyloxy, Arg'oxy, C1-alkylthio, di(C1-alkylamino), trihalomethyl or trihalomethoxy;

VAZ is hydrogen, halo group, C-alkyl, cyano group, haloC-alkyl, hydroxyC-alkyl, cyanoC-alkyl, aminoC-alkyl, C-alkyloxyC-alkyl, C-alkylthioC:i-alkyl, aminocarbonylC-alkyl, Сch1-alkyloxycarbonyl- C-alkyl, C-alkylcarbonyl, C-alkyl, C-alkyloxycarbonyl, mono- or di(Ci-alkyl)aminoC:-alkyl, Ag", Ag!-C:i-alkyloxyC-alkyl; or a radical of the formula -0-8' o (a-t7), -5-8'o (a-2),

M-V'V: (a-3), where is V? means hydrogen C-alkyl, C-alkylcarbonyl, Ag, Ag C-alkyl, C-alkyloxycarbonyls -alkyl, or a radical of the formula -AIK-OV"U, or -AIKA-MA!"B",

B" means hydrogen, Si-alkyl, Ag! or Ag! Si-alkyl;

B!2 means hydrogen, C1-alkyl, C1-alkylcarbonyl, C1-alkyloxycarbonyl, C1-alkylaminocarbonyl, Ag,

ApSi-valkyl, Si-alkylcarbonyl. C-alkyl, Ac'carbonyl, Ag C-alkylcarbonyl, aminocarbonyl-carbonyl, C-alkyloxyCi-alkylcarbonyl, hydroxy, C-alkyloxy, aminocarbonyl, di(Ci-alkyl)aminoCi-alkylcarbonyl, amino group, C-alkylamino group, C-alkylcarbonyl an amino group or a radical of the formula -AIK-OV"Z, or -AIK-

MAV",

where AIK means Si-valcandiyl;

BZ means hydrogen, C3-alkyl, C-alkylcarbonyl, hydroxyC-alkyl, AG or Ag C-alkyl;

B" means hydrogen, Si-valkyl, Ag or Ag'Sivalkyl;

B!5 means hydrogen, C-alkyl, C-alkylcarbonyl, Ag! or Ag-Si-alkyl;

AND? is the radical of the current formula

KO, and U t. - to willow Shi CHIK! what! re dyk them | t where ВЭ is hydrogen, halo, Ar, C-alkyl, hydroxyC-alkyl, C-alkyloxyC-alkyl, C-alkyloxy, C-alkylthio, amino group, C-alkyloxycarbonyl, C-alkylthioC-alkyl, C-alkyl O) C-alkyl or C-alkyl 5(O)2 C-alkyl;

B" means hydrogen, C1-alkyl, or di(C1-alkylaminosulfonyl);

B" means hydrogen or C-alkyl, provided that dashed lines do not denote a bond;

IN? means hydrogen, Si-valkyl, or AI?gSN" or No! SnHe;

IN? means hydrogen, C1-alkyl, C1-halkyloxy or halo; or

BZ and BZ are taken together to form a bivalent radical of the formula -bsnH-Сsn- (с-1), -бСн--сн-( (с-г), -бн»-СНно-СНе- (с-3), -бно -o- (p-4), or -bSno-Sn-o- (p-5);

Ap means phenyl or phenyl substituted with 1 or 2 substituents, each of which is independently selected from halo, C 1-6 alkyl, C 1-6 alkyloxy or trifluoromethyl.

AND? means phenyl or phenyl substituted with 1 or 2 substituents each independently selected from halo, C 1 -alkyl, C 1 -alkyloxy or trifluoromethyl, and

Not! means pyridinyl; pyridinyl substituted with 1 or 2 substituents each independently selected from halo, C 1 -alkyl, C 1 -alkyloxy or trifluoromethyl.

Other useful farnesyl protein transferase inhibitors have the following structure

Still ri g s Ge, sho

A. t ( | o -sh7 sha r vSN-B6336 y and her; NI tre o 7 o re

I M i a i |; Lust in U - vr.ibo55i

These inhibitors of farnesyl protein transferase weaken the growth of tumors in a living organism by direct action on the growth of tumor cells and indirectly, i.e. by inhibiting angiogenesis (Vak u. Yei aI., Sapseg Vezeagsy, 55, 4575 - 4580, 1995). Therefore, treatment with these inhibitors at least partially delays the growth of solid tumors in a living organism, inhibiting angiogenesis. One would expect that treatment with these compounds would lead to a hypoxic tumor, thereby causing an increase in radioresistance.

Unexpectedly, as we have already discovered, this did not happen. On the contrary, administration of farnesyl protein transferase inhibitors, as described above, has been shown to sensitize tumor cells to radiation or ionizing radiation and, moreover, to resensitize radioresistant cells. Thus, inhibitors of farnesyl protein transferase can be used as radiosensitizing IP mimo agents (radiosensitizing or radiopotentiating).

This invention relates to the use of farnesyl protein transferase inhibitors to obtain pharmaceutical compositions having radiosensitizing properties when administered before, during, and after tumor irradiation in the treatment of ip mimo cancer.

In particular, this invention relates to the use of at least a farnesyl protein transferase inhibitor to obtain a pharmaceutical composition having radiosensitizing properties when administered before, during, and after tumor irradiation in the treatment of ip mimo cancer, in which said farnesyl protein transferase inhibitor is a derivative (imidazolyl-5 -yl)methyl-2-quinolinone of formula (I), or a compound of formulas (II) or (1), which is metabolized in a living organism into a compound of formula (I), and the indicated compounds are given as:

I m i t i I G A

Id y ik nas Kit yur sy Zh

Shshch her in) secret vk r or" ' i

Kutya mit Ho pev;

Shchi fo ych She:

Vo (B) pharmaceutically acceptable addition salts of a base or acid and their stereochemically isomeric forms, where dashed lines indicate an optional bond;

X means oxygen or sulfur;

IN! means hydrogen, C1-alkyl, Ag, Ag?C1-alkyl, quinolinylC1-alkyl, pyridylC1-alkyl, hydroxyC1-alkyl,

C-alkyloxyC-alkyl, mono- or di(Ci-alkyl)aminoC-alkyl, aminoC:-alkyl, or a radical of the formula -АЙК!-

C(-0)-88, -AIKI-5(0)-8? or -AIK'-5(0)2-VU, where AK! means Si-valcandiyl,

AV? means hydroxy, C1-alkyl, C1-alkyloxy, amino, C1-alkylamino, or C1-alkylamino substituted by C1-alkyloxycarbonyl;

B, BZ and B'E are each independently hydrogen, hydroxy, halo, cyano, C1-alkyl, C1-alkyloxy, hydroxyCi-alkyloxy, C1-alkyloxyCi-alkyloxy, aminoCi-alkyloxy, mono- or di(C1-alkyl)aminoSi -valkyloxy, Ag, Ag?Sialkyl, Agoxy, Al?Ci-valkyloxy, hydroxycarbonyl, /C-valkyloxycarbonyl, trihalomethyl, trihalomethoxy, C6-6-alkenyl, 4,4-dimethyloxazolyl; or in adjacent positions B: and VU, taken together can form a bivalent radical of the formula -0-Сно-о- (а-1), -0-Сно-Сне-0 (а-2), -0-сн-Сн- (а-3), -0-СНе-СНе- (а-4), -0-СНо-СНо-СНг (а-5) or -бснеЕСнН-СнН:Сн (а-6);

IN? or B? each independently is hydrogen, halo, Ag", C-alkyl, hydroxyC-alkyl, C-alkyloxyC-alkyl, C-alkyloxy, C-alkylthio, amino, hydroxycarbonyl, C-alkyloxycarbonyl, C-alkyl, C-alkyl, and (O)C-alkyl, or Si-alkyl IZ(O)2 Si-alkyl;

VAZ and B' are each independently hydrogen, halo, cyano, C1-alkyl, C1-alkyloxy, Agoxy, trihalomethyl, C1-alkylthio, di(C1-alkyl)amino, or in adjacent positions BZ and B" taken together can form a bivalent the radical of the formula -0-Сно-о- (с-1), or -бн-Сн-Ссн:Сн- (с-г);

BZ means hydrogen, C1-alkyl, cyano group, hydroxycarbonyl, C:-alkyloxycarbonyl, C1-alkylcarbonyls-alkyl, cyanoCi-alkyl, C1-alkyloxycarbonylsC-alkyl, carboxysC3-alkyl, hydroxyCi-alkyl, aminoCi-alkyl, mono- or di( C-alkyl)aminoC3-alkyl, imidazolyl, halo C-alkyl, C-6 alkyloxyC-alkyl, aminocarbonyl - alkyl, or a radical of the formula -0-8o (p-1), -5-8'o (p-g), -M-V'TV!: (p-3), where is V!? means hydrogen, C1-alkyl, C1-6 alkylcarbonyl, Ag, Ag?C1-alkyl, C1-alkyloxycarbonyl and -alkyl, or a radical or the formula -AIK2 -OV"Z or AIK2 -MA'YAV";

B" means hydrogen, Si-alkyl, Ag! or AggSi alkyl;

IN!? means hydrogen, C1-alkyl, C1-alkylcarbonyl, C1-alkyloxycarbonyl, C1-alkylaminocarbonyl, Ag,

Ag?Ci-alkyl, C1-alkylcarbonylCi-ealkyl, natural amino acid, Ag'carbonyl, A!Ci-alkylcarbonyl, aminocarbonylcarbonyl, C1-alkyloxyCi-alkylcarbonyl, hydroxy, C1-alkyloxy, aminocarbonyl, di(Ci-alkyl)aminoCi-alkylcarbonyl , an amino group, a C-alkylamino group, a C-alkylcarbonylamino group, or a radical of the formula -AIK2-OV'Zabo AIK2-MA B; where AIKe means Si-valcandiyl;

VAZ means hydrogen, C-alkyl, C-alkylcarbonyl, hydroxyC-alkyl, Ag, AIS-alkyl;

A"" means hydrogen, C-valkyl, A! or AgSi-valkyl;

IN! means hydrogen, C-alkyl, C-halkylcarbonyl, Ag! or Ag7Si-alkyl;

B" means hydrogen, halo group, cyano group, C-alkyl, C-alkyloxycarbonyl, Ag;

B!Z means hydrogen, C1-alkyl, C1-alkyloxy or halo;

B!Z means hydrogen or C.valkyl;

Ar means phenyl or phenyl substituted with C 1 -alkyl, hydroxy, amino, C 1 -alkyloxy or halo; and

Huh? means phenyl or phenyl substituted with C 1 -alkyl, hydroxy, amino, C 1 -alkyloxy or halo.

In formulas (1), (II) and (I) B" or B? can also be connected to one of the nitrogen atoms in the imidazole ring. In this case, the hydrogen on the nitrogen atom is replaced by B" or B? and the value of B" and B: in the state of connection with nitrogen is limited to hydrogen, Ag", C-alkyl, hydroxyC-alkyl, C-alkyloxyC-alkyl, C-alkyloxycarbonyl, C-alkyl, and (O)C-alkyl or C- valkyl IZ(O)2 with Si-valkyl.

As used in the preceding definitions and in the following description, halo means fluorine, chlorine, bromine and iodine atoms; C 1 -alkyl means straight and branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl and the like; Ci-alkyl means straight or branched chain saturated hydrocarbon radicals, as defined by Ci-alkyl, as well as their higher homologues containing 7 or 8 carbon atoms, such as, for example, heptyl or octyl; Ci-alkyl includes Ci-alkyl and their higher homologues containing from 9 to 12 carbon atoms, such as, for example, nonyl, decyl, undecyl, dodecyl; Ci-alkyl again includes Ci-1 alkyl and their higher homologues containing from 13 to 16 carbon atoms, such as, for example, tridecyl, tetradecyl, pentadecyl and hexadecyl; S-valkenyl means straight or branched chain saturated hydrocarbon radicals having one double bond and from 2 to b carbon atoms, such as, for example, ethenyl, 2-propenyl, 33-butenyl, 2-pentenyl, 3-pentenyl, 3- methyl-2-butenyl and the like; cSc-alkanediyl means a bivalent straight or branched chain saturated hydrocarbon radical having from 1 to b carbon atoms, such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5 -pentanediyl, 1,6-hexanediyl and their branched isomers. The term "C(xO)" means a carbonyl group, "C(O)" means a sulfoxide and "5(O)2" means a sulfone. The term "natural amino acid" means a natural amino acid linked through a covalent amide bond formed by the loss of a water molecule 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, phenylalanine, tryptophan, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine.

Pharmaceutically acceptable acid or base addition salts, as mentioned above, are believed to include therapeutically active addition salt forms of non-toxic bases or non-toxic acids capable of forming compounds of formulas (I), (II) and (I). Compounds of formulas (I), (I) and (II) having the properties of a base can be converted into their pharmaceutically acceptable acid addition salts by treatment of the indicated form of the base with an appropriate acid. Suitable acids can be, for example, inorganic acids, such as hydrohalic acids, for example hydrochloric or hydrobromic acid; sulfuric, nitric, phosphoric and other acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, succinic (or butanedioic) acid, maleic, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p - aminosalicylic, pamoic and other acids.

Compounds of formulas (I), (II) and (I) having the properties of acids can be converted into their pharmaceutically acceptable base addition salts by treating the indicated acid forms with a suitable organic or inorganic base. Suitable base salt forms include, for example, ammonium salts, earth and alkaline earth metals, such as lithium, sodium, potassium, calcium, magnesium and the like, salts with organic bases, for example benzathine salts, M-methyl-O- glucamine, hydrobamine, and salts with amino acids such as, for example, arginine, lysine and the like.

The terms "acid or base addition salts" also include hydrates and additives in the form of solvents capable of forming compounds of formulas (I), (II) and (PI). Examples of such forms can be, for example, hydrates, alcoholates and the like.

The term "stereochemically isomeric forms" of the compounds of the formulas (1), (I!) and (PP), as used previously, means all possible compounds built from the same atoms connected by the same sequence of bonds, but they have different three-dimensional structures that are not interchangeable and that can be part of the compounds of formulas (), (PP) and (PP). Unless otherwise specified, the chemical designation of compounds includes a mixture of all possible stereochemically isomeric forms that are part of the specified compound. The specified mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of the specified compound. All stereochemically isomeric forms of compounds of formulas (1), (II) and (PI) in pure form or in a mixture with each other are included in the scope of this invention. Some of the compounds of formulas (I), (II) and (PI) may also exist in their tautomeric forms. Such forms, although not specifically specified in this specification, are contemplated within the scope of the present invention.

As used throughout the specification, the term "compounds of formulas (1), (II) and (P)" means also pharmaceutically acceptable acid or base addition salts and all stereoisomeric forms.

Preferably, the substituent B'Z is located in positions 5 or 7 of the quinoline moiety, and the substituent B" is located in position 8, if B" is in position 7. Compounds of formula (I) where X is oxygen are interesting.

Also interesting are those compounds of formula (I), where the bond is indicated by a dotted line, as if to form a double bond.

Another interesting group are those compounds of the formula (I), where B' means hydrogen, C1-alkyl, C1-alkyloxyC3-alkyl, di(C1-alkyl)aminoC:i-weaalkyl, or a radical of the formula -AIK!-C(-0 )-VU, where AIK' means methylene, and B is a C. alkylamino group substituted by C-alkyloxycarbonyl.

Another interesting group of these compounds of formula (I), where VZ means hydrogen or a halo group, and B? means halo, C 1 -alkyl, C 6 -alkenyl, C 1 -alkyloxy, trihalomethoxy or hydroxyC 3 -alkyloxy.

Another interesting group of these compounds of formula (I), where B? and VZ are located in adjacent positions and taken together to form a bivalent radical of formula (a-1), (a-2) or (a-3).

Another interesting group are the compounds of formula (I), where B? is hydrogen and B" is hydrogen or C-alkyl.

Another interesting group are compounds of formula (I), where B' is hydrogen, and B? is a Sivalkyl or halo group, preferably a chlorine atom, in particular 4-chloro. Of particular interest is the group of compounds of the formula (I), where BZ is hydrogen, hydroxy, haloCi-alkyl, hydroxyCi-alkyl, cyanoCi-alkyl, Ci-alkyloxycarbonylC-alkyl, imidazolylyl or a radical of the formula MAV", where B!! is hydrogen or Si -i-alkyl and B1:2 means hydrogen, C1-alkyl, C1-alkyloxy, hydroxy, C1-alkyloxyC1-6-alkylcarbonyl or a radical of the formula -AIK-OB"3, where B3 means hydrogen or C3-alkyl.

Preferred compounds are those compounds where B! means hydrogen, C1-alkyl, C1-alkyloxyC1-alkyl, di(C1-alkyl)aminoC1-alkyl, or a radical of the formula -АЙК'-С(-0)-ВУ, where AK! means methylene and VU is p. alkylamino group substituted by C-alkyloxycarbonyl; IN? is halo, C1-alkyl, C1-alkyloxy, C1-alkyloxy, trihalomethoxy, hydroxyC1-alkyloxy, or Ag; VZ is hydrogen; B" is methyl bonded to the nitrogen in the third position of imidazole; B? is hydrogen; B? is chlorine; B" is hydrogen; BZ is hydrogen, hydroxy, haloCi-alkyl, hydroxyCi-alkyl, cyanoCi-alkyl, Ci-alkyloxycarbonylC:-alkyl, imidazolyl, or a radical of the formula -MV!!B"", where B!! is hydrogen or Ci-alkyl and B ! means hydrogen, C1-alkyl, C1-alkyloxy, C1-alkyloxyC1-alkylcarbonyl, or a radical of the formula -АЙК2-ОВЗ, where ВЗ means C1-alkyl; B!" means hydrogen;

IN! means hydrogen. The most preferred compounds are 4-(33-chlorophenyl)-6-((4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl|-1-methyl-2(1H)-quinolinone, 6- (amino(4-chlorophenyl)-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-ethoxyphenyl)-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; b-amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl|-1- methyl-4-(3-propylphenyl)-2(1H)-quinolinone; its stereochemical form or a pharmaceutically acceptable acid or base addition salt; and (4)-6-(amino(4-chlorophenyl)(1-methyl-1H) -imidazol-5-yl)methyl|-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (compound 75 in Table 1 in the experimental part of the description); or its pharmaceutically acceptable acid addition salt. Farnesyl inhibitors protein transferases can enter in the composition of compositions known from the state of the art; as for the compounds of formulas (1), (II) and (II), you can find relevant examples in M/O-97/21701. To obtain the above-mentioned pharmaceutical compositions, a therapeutically effective amount of a defined compound, optionally in the form of a salt, as an active ingredient, is thoroughly mixed with pharmaceutically acceptable carriers, which can take many forms depending on the form of preparation, according to the purpose.

These pharmaceutical compositions are preferably prepared in unit dosage forms intended for oral, subcutaneous, parenteral, or targeted systemic administration or preferably for targeted action. In the case of preparation of oral liquid pharmaceutical compositions, in the form of solutions, suspensions, syrups, elixirs and emulsions, any pharmaceutical medium can be used, for example, water, glycols, oils, alcohols, etc., and in the case of oral solid pharmaceutical compositions in in the form of powders, pills, capsules or tablets, such fillers as starches, sugars, kaolin, lubricants, binding agents, disintegrating agents, etc. can be used. The most preferred oral dosage form, in which solid pharmaceutical carriers are obviously used, are tablets and capsules due to the ease of their administration. In the case of pharmaceutical compositions in the form of injections, the carrier usually contains distilled water in larger quantities, although it may also contain other ingredients, such as semipolar solvents, for example, to facilitate solubility. Examples of carriers for injection solutions can be saline solutions, glucose solutions or their mixture. Injection solutions containing compounds of the above formulas can be prepared in oil for longer action. In this case, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long-chain fatty acids and their mixtures, and other types of oils are good. It is also possible to make injectable suspensions using appropriate liquid carriers, suspending agents, etc. In compositions suitable for subcutaneous administration, the carrier may contain an agent to facilitate penetration and/or a suitable humectant, optionally combined with suitable additives of any origin in a minor proportion, provided that the additives do not constitute any significant deleterious effect on the skin These additives can facilitate the introduction of the tal" into the skin or help to obtain the desired compositions. These compositions can be administered in various ways, for example, in the form of a transdermal patch, for example, an overlay on the affected site, or an ointment or gel. In the case of pharmaceutical compositions for rectal administration, any of the usual fat-based, water-soluble excipients may be used, which may, if necessary, be combined with suitable additives such as suspending or wetting agents. are used for targeted preparations, for example, creams, gels, dressings, lotions, shampoos, infusions, pastes, ointments, buds with seeds, powders, inhalations, nasal aerosols, eye drops, etc. It is convenient to use semi-solid compositions such as creams, ointments, gels, etc. The use of the specified compositions can be in the form of aerosols,

for example, with activators such as nitrogen, carbon dioxide, freon, or without activators, for example in the form of pressurized aerosols or droplets. It is especially preferred to produce the above-mentioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Dosage unit form, as used in the description and formula of the present invention, means physically discrete units suitable for unit doses, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect, mixed with the necessary pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, sachets of powders, wafers, injectable solutions or suspensions, doses in teaspoons and tablespoons, etc., or their individual compositions.

Preferably, a therapeutically effective amount of a pharmaceutical composition containing a farnesyl protein transferase inhibitor is administered orally or parenterally. The indicated therapeutically effective amount is the amount that effectively sensitizes the tumor in the host cells to radiation. Based on current data, it was found that pharmaceutical compositions containing (g)-6-(amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl|-4-(3-chlorophenyl)-1 -methyl-2(1H)-quinolinone (compound 75) as an active ingredient can be administered orally in an amount from 10 to 1500 mg/m2 per day, both in a single dose and divided into sub-doses several times a day. the dose of this composition ranges from 100 to 100 Ω/m per day.

Irradiation means ionizing radiation, particularly gamma radiation, especially emitted by linear accelerators or radionuclides commonly used today.

Irradiation of the tumor with radionuclides can be external or internal.

Preferably, the introduction of the pharmaceutical composition begins one month, in particular, 10 days or a week before the tumor is irradiated. In addition, it is preferable to fractionate the radiation of the tumor and to observe the reception of the pharmaceutical composition in the interval between the first and last radiation sessions.

The amount of farnesyl protein transferase inhibitor, the radiation dose and the interval between radiation doses will depend on a number of parameters, such as the type of tumor, its location, the patient's response to chemotherapy and radiotherapy, and completely on the determinations of the doctor and radiologists in each individual case. The present invention also relates to a method of treating cancer in a patient in the area of a tumor, comprising the steps of: administering a radiation-sensitive effective amount of a farnesyl protein transferase inhibitor before, during, and after irradiation of the tumor; appointment of the indicated patient for irradiation in the area of tumor location.

Examples of tumors that may be inhibited include, without limitation, lung cancer (adenocarcinoma), pancreatic cancer (pancreatic carcinoma, such as exocrine carcinoma), colon cancer (e.g., colorectal carcinoma, such as colon adenocarcinoma or adenoma). , hematopoietic tumors of lymphoid nodes (for example, acute lymphocytic leukemia (ACL), B-cell lymphoma, Burkitt's lymphoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid cancer, myelodysplastic syndrome (MDO), tumors of mesenchymal origin (eg, fibrosarcoma and rhabdomyosarcoma), melanomas, teratocarcinomas, neuroblastomas, gliomas, benign skin tumors (eg, keratoacanthomas), respiratory tract carcinoma, pediatric carcinoma, ovarian carcinoma, bladder carcinoma, and epidermal carcinoma.

Experimental part

The tables below show the formulas of the compounds of formula (I), their physical data and references to the examples in UUO-97/21701, by which the studied compounds can be prepared. Pharmacological examples illustrate the radiation-sensitizing effect of compounds of formula (1).

Table and:

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Pharmacological example 1

Male hairless mice weighing approximately 22 to 25 g were inoculated subcutaneously in the groin with human colon cancer cells in the amount of 1 x 1096 GoMo on day 0. After three weeks of tumor development to the established level (diameter approximately 0.5 to 1 cm) were treated with a solution or compound 75 orally with or without a single short-term irradiation on day 32. Activity parameters were the growth rate and weight of tumors on day 42. Compound 75 was dissolved in water and oxidized with a 1M HCl solution to pH 2.5 and administered orally (ro) in the form of 0.1 ml of a solution of the compound per 10 g of mouse body twice a day (Bria). The prescribed dose was either 50 mg or 100 mg of the compound per kg of body weight; treatment was carried out before irradiation (days 22 - 32), during irradiation (days 32 - 42) or continued throughout the experiment (days 22 - 42).

Radiation treatment included a single dose of radiation on day 32 of 7(hu), which stabilizes the growth of tumors in untreated animals, that is, a dose that stops the growth of the tumor in volume, but does not cause any reduction in its size.

The following table (Table 9) shows each site that was evaluated during the experiment. 16 experimental animals participated in each part of the experiment. The column "tumor (g)" contains the average tumor weight of animals that were left without treatment on the 42nd day of the experiment. Figures 1 and 2 provide the observed data in graphical form.

Figure 1 shows the distribution of tumor weight (g) in experimental animals receiving 50 mpec of the test compound (ro, Bia).

Figure 2 shows the distribution of tumor weight (g) in experimental animals receiving 100 mpec of the test compound (ro, Bia).

The gray blocks in the figures represent the 25th - 75th percentiles, the straight lines in the blocks represent the median values, the lines extending from the blocks represent the 10th - 90th percentiles and the black dots represent the uncertainty.

Roman numerals indicate groups of experimental animals, as shown in Table 9.

Statistical analysis of the data shows that treatment with compound 75 (both doses of 5Ompek and 100mpek) and irradiation significantly reduces tumor weight from a statistical point of view (compared to treatment with only irradiation).

Table 9 77171771 Solution | -Money22-42 0.475 17111117 bompek// | Day 22-42 0.255 "77111111 1771 B5ompek// | Day 22-32 0.273

Day 32 - 42 0.295

Day 22 - 42 0.205

Day 22 - 32 0.234

Day 32 - 42 0.277

MI Day 22 - 42 0.207 0.156

Day 32 - 42 0.259 0.164

HII 100mpek Day 22 - 32 75 la

In the year - 0.00223"

ХИЙ Day 32 - 42 0.214

Day 22 - 42 0.256 x mean Mann-Whitney O test (Mappo-ZhM/niipeu I) compared to the HMI group (irradiation only)

Example 2

Radioresistant lines of human glioma cells (5E763, 087, 0251) were treated with compound 75 for 48 hours before irradiation (2su). The prescribed dose was 0.4 nM for 251 and 2 nM for 5E763 and 087.

The introduction of compound 75 into cells significantly reduced the survival of cells after irradiation: for 5E763 and 087, the decrease in surviving fraction was approximately 55905, and for 0251 - 25965.

These results show that treatment with compound 75 resensitizes radioresistant cells to radiation.

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Claims (15)

1. The use of at least an inhibitor of farnesyl protein transferase to obtain a pharmaceutical composition having radiosensitizing properties for administration ip before, during and after irradiation of a tumor in the treatment of cancer. 2. Use according to claim 1, according to which the indicated farnesyl protein transferase inhibitor is a compound of the formula (Y) or a compound of the formulas (I) or (II), which are metabolized directly into a compound of the formula (I), and the indicated compounds are provided as: Kk KA 16 (more vaki su ЖЖ ra K 1 ih s xx Kv | de - ra Xx M /-x zhk Kyu 8 ! KI n) Kz in U» y (more Ka g d- 5 Ki? o I) vv | ze pl, zm /-x Kk Vio VIV in (1) Kk x bows and 4 and t: M voi. M y 2-5 -k-x Eh V ih kh kh kh, Kv || where Z le 2K Y Vo Ki K7 s (1) their stereochemically isomeric forms, pharmaceutically acceptable addition salts of a base or acid, where dashed lines mean an optional bond; X means oxygen or sulfur; IN! means hydrogen, C1-alkyl, Ag, Ag?C1-alkyl, quinolinylC-alkyl, pyridylC:-alkyl, hydroxyC:-alkyl, C1-alkyloxyC1-alkyl, mono- or di(C1-alkyl)aminoC1-alkyl, aminoC1- valkyl, or a radical of the formula -АИК!-С(-0)-AU, -АИК!-5(0)-82 or -АИК!-5(0)2-ВУ, where AK! means Si -valkandiyl, V? means hydroxy, C 1 -alkyl, C 1 -alkyloxy, amino, C 1 -alkylamino, or C 1 -alkylamino substituted by C 1 -alkyloxycarbonyl; B, BZ and B!Z are each independently hydrogen, hydroxy, halo, cyano, C1-alkyl, C1-alkyloxy, hydroxyC1-alkyloxy, C1-alkyloxyC1-alkyloxy, aminoC1-alkyloxy, mono- or di(C1-alkyl )aminoCi-valkyloxy, Ag, Al?Sialkyl, Agoxy, AgCi-valkyloxy, hydroxycarbonyl, C1-valkyloxycarbonyl, trihalomethyl, trihalomethoxy, Cg-valkenyl, 4,4-dimethyloxazolyl; or in adjacent positions E:2 and P, taken together, can form a bivalent radical of the formula -0-Сне-О- (а-1), -0-Сно- СНо-О (а-г), -0-СНАСН- (а-3), -0- СнНе- СНе- (а-4), -0- Сно- СНо- СнНе- (а-5) or -бнНАСн-СнН-СсНн- (а-6); B" or B? is each independently hydrogen, halo, Ag'Ci-alkyl, hydroxyCi-alkyl, C-alkyloxySi- alkyl, C1-alkyloxy, C1-alkylthio, amino group, hydroxycarbonyl, C1-alkyloxycarbonyl, C1-alkyl3(O)Ci-alkyl or C1-alkyl!5(O)2Ci-alkyl; VAZ and B" are each independently hydrogen, halo, cyano, C1-alkyl, C1-alkyloxy, Agoxy, trihalomethyl, C1-alkylthio, di(C1-6alkyl)amino, or in adjacent positions Re and B" taken together can form bivalent radical of the formula -O-Sneo-O- (c-1) or -СнНАСнН-СнН-СН- (с-г); VAZ means hydrogen, C1-alkyl, cyano, hydroxycarbonyl, C1-alkyloxycarbonyl, C:-alkylcarbonyl - alkyl, cyanoCi-alkyl, C1-alkyloxycarbonylC:i-alkyl, carboxyCi-alkyl, hydroxyCi-alkyl, amino-alkyl, mono- or di(Ci-ealkylaminoCi-vealkyl, imidazolyl, haloCi-alkyl, Ci-valkyloxyCi-alkyl, aminocarbonylC-alkyl or a radical of the formula -0- Vo (p-1), -5- VO (p-g), -M-B 82 (p-3), where B? means hydrogen, C3-alkyl, C1-alkylcarbonyl, Ag, Ar?Ci-alkyl, C1-alkyloxycarbonyls and -alkyl or a radical, or the formula -AIK2-OV!Z or ADIKAMV' B""; B" means hydrogen, C1-alkyl, Ag! or AggC|i-alkyl; B! means hydrogen, C1-alkyl, C1-ialkylcarbonyl, C1-6alkyloxycarbonyl, C1-alkylaminocarbonyl, Ag, Ag?C1-alkyl , Si-alkylcarbonylC -alkyl, natural amino acid, Ag! carbonyl, AgSi-alkylcarbonyl, aminocarbonylcarbonyl, Si-valkyloxyC:i-alkylcarbonyl, hydroxy, Si-alkyloxy, aminocarbonyl, di(Si1-alkyl)aminoSi-alkylcarbonyl, amino group, Si- valkylamino group, C-valkylcarbonylaminogr upu or radical, or the formula -AIK2-OV'Zabo AIK2-MA B"; where AIK2 means C-valcanediyl; VAZ means hydrogen, C-alkyl, C-alkylcarbonyl, hydroxyC-alkyl, Ag, AIS-alkyl; B": means hydrogen, C1-alkyl, Ag! or AggCi-alkyl; B15 means hydrogen, C1-alkyl, C1-ealkylcarbonyl, Ag'or AggCi-alkyl; B" means hydrogen, halo group, cyano group, C1-alkyl , C-halkyloxycarbonyl, Ag!; IN!? means hydrogen, C1-alkyl, C1-alkyloxy or halo; B" means hydrogen or C1-alkyl; Ag means phenyl or phenyl substituted with C1-alkyl, hydroxy, amino, C1-6alkyloxy or halo; and A? means phenyl or phenyl substituted with C1-alkyl, hydroxy, amino, C- alkyloxy or halo group. 3. Use according to claim 2, according to which the indicated farnesyl protein transferase inhibitor is a compound of formula (I) and in which X is oxygen. 4. Use according to claim 2, according to which the specified farnesyl protein transferase inhibitor is a compound of formula (I) and in which the dotted lines mean a bond. 5. Use according to claim 2, according to which the specified farnesyl protein transferase inhibitor is a compound of formula (I), in which E! means hydrogen, C1-alkyl, C1-alkyloxyC1-alkyl or mono- or di(C1-alkyl)aminoC: -alkyl. 6. Use according to claim 2, according to which the specified inhibitor of farnesyl protein transferase is a compound of formula (I), in which ВZ means hydrogen, and B? means halo, C1-6alkyl, subalkenyl, C1-6alkyloxy, trimethoxy or hydroxyC1-6alkyloxy. 7. Use according to claim 2, according to which the specified farnesyl protein transferase inhibitor is a compound of the formula (), in which BU means hydrogen, hydroxy, haloCi-alkyl, hydroxyCi-alkyl, cyanoCi-alkyl, C-alkyloxycarbonyl-Ci-alkyl, imidazolyl or a radical of the formula -MV'"'B"2, where B"! means hydrogen or C1-alkylalkyl and B! means hydrogen, C1-alkyl, C1-alkyloxy, C1-alkyloxyC1-alkylcarbonyl, hydroxy or a radical of the formula -АИК2-ОВ Z , where E!Z means hydrogen or C-alkyl. 8. Use according to claim 2, according to which the compound is 4-(3-chlorophenyl)-6-(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)umethyl|-methyl-2(1H) -quinolinone, 6-(amino(4-chlorophenyl)-1-methyl-1H-imidazol-5-ylmethyl)|-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone, 6-( 4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)umethyl|-4-(3-ethoxyphenyl)-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)umethyl|-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinone and b-amino(4 -chlorophenyl)(1-methyl-1H-imidazol-5-yl)umethyl/|-1-methyl-4-(3-propylphenyl)-2(1H)-quinolinone; its stereochemical form or a pharmaceutically acceptable acid addition salt or foundations. 9. Use according to claim 2, according to which the compound is (43-6-(amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)umethyl/|-4-(3-chlorophenyl)-1 -methyl-2(1H)-quinolinone, or its pharmaceutically acceptable acid addition salt. 10. Use according to any one of the preceding clauses, according to which a therapeutically effective amount of the pharmaceutical composition is administered orally, parenterally, rectally or topically. 11. Use according to claim 9, in which the pharmaceutical composition is prescribed in an amount from 100 to 1500 mg/m: per day, or in a single dose or in divided subdoses more than one several times. 12. Use according to claim 1, according to which the irradiation is ionizing. 13. Use according to claim 1, according to which the irradiation is external or internal. 14. Use according to claim 1, according to which the administration of the pharmaceutical composition is started one month before the irradiation of the tumor. 15. Use according to claim 1, according to which the irradiation of the tumor is fractionated and the administration of the pharmaceutical composition is followed during the interval between the first and last irradiation sessions.