JP2003525236A - Combination of a farnesyl protein transferase inhibitor with vinca alkaloids - Google Patents

Abstract

  (57) [Summary] The present invention relates to a combination of a farnesyltransferase inhibitor and a vinca alkaloid useful for inhibiting tumor cell growth and for treating cancer.

Description

Detailed Description of the Invention

[0001] The present invention relates to a combination of farnesyl transferase inhibitors and anti-tumor vinca alkaloids for inhibiting the growth of tumor cells and useful in the treatment of cancer.

[0002]   Oncogenes are signaling pathway targets that lead to the promotion of cell proliferation and mitogenesis.
Often codes for protein components. Oncogene expression in cultured cells
Leading to the ability of cells to grow in soft agar and to the untransformed cells.
Characterized by proliferation of cells as dense foci lacking more shown contact inhibition
To be Mutation and / or overexpression of certain oncogenes is often
Is associated with cancer. Specific groups of oncogenes include mammals, birds, insects,
Known as ras identified in somatic animals, plants, fungi and yeast. Feeding
The family of animal ras oncogenes consists of three major members (“isoforms”).
), Ie, H-ras, K-ras and N-ras oncogenes. this
The ras oncogene is generally p21.^ras A highly related tan known as
It encodes quality. Once bound to the plasma membrane, p21^ras Mutant of
Alternatively, the oncogenic morphology is associated with transformation and uncontrolled growth of malignant cells.
Emits a signal. To obtain this transformation ability, p21^ras Oncoprote
In precursor is a cysteine residue located within the carboxyl-terminal tetrapeptide
Must undergo enzymatic catalyzed farnesylation. Therefore, this modification is catalyzed
The inhibitor of farnesyl protein transferase, which is ^ras  Of the ras-transformed tumors. Servant
Therefore, farnesyl transferase inhibitors are ras that contributes to transformation.
It is generally known in the art that it may be significantly useful as an anticancer agent for tumors
Is recognized by.

Mutated carcinogenic forms of ras are often found in more than 50% of many human cancers, most notably colon and pancreatic cancer (Kohl et al., Science, vol 2
60, 1834 to 1837, 1993), suggesting that farnesyl transferase inhibitors may be significantly useful against these types of cancer. After further study, farnesyl transferase inhibitors could demonstrate anti-proliferative effects in vitro and in vivo in a variety of human tumor cell lines with and without ras gene mutations. It has been found to be.

WO-97 / 21701 describes farnesyl protein transferase-inhibiting (imidazoli-5-yl) methyl-2-quinolinone derivatives of formula (I), (II) and (III), and of formula (I) The preparation, formulation and pharmaceutical properties of intermediates of formula (II) and (III) that are metabolized in vivo to the compounds have been described. The compounds of formula (I), (II) and (III) are

[0005]

[Chemical 9]

[0006] Represented by their pharmaceutically acceptable acid or base addition salts and stereoisomers
, In the formula, Dotted lines represent arbitrary bonds; X is oxygen or sulfur; R¹ Is hydrogen, C_1-12Alkyl, Ar¹ , Ar² C_1-6 Alkyl, quinolinyl C_{1- 6}  Alkyl, pyridyl C_1-6 Alkyl, hydroxy C_1-6 Alkyl, C_1-6 Al
Killoxy C_1-6 Alkyl, mono- or di (C_1-6 Alkyl) amino C_1-6 
Alkyl, amino C_1-6 Alkyl, Or formula-Alk¹ -C (= O) -R⁹ , -Alk¹ -S (O) -R⁹ Or
-Alk¹ -S (O)₂ -R⁹ Is the basis of (In the formula, Alk¹ Is C_1-6 Is an alkane diyl, R⁹ Is hydroxy, C_1-6 Alkyl, C_1-6 Alkyloxy, amino, C_1-8 A
Rukiruamino or C_1-6 C substituted with alkyloxycarbonyl_1-8 A
Rukiruamino); R² , R³ And R¹⁶Are each independently hydrogen, hydroxy, halo, cyano,
C_1-6 Alkyl, C_1-6 Alkyloxy, hydroxy C_1-6 Alkyloxy, C _1-6  Alkyloxy C_1-6 Alkyloxy, amino C_1-6 Alkyloxy, mono
-Or di (C_1-6 Alkyl) amino C_1-6 Alkyloxy, Ar¹ , Ar² 
C_1-6 Alkyl, Ar² Oxy, Ar² C_1-6 Alkyloxy, hydroxycal
Bonil, C_1-6 Alkyloxycarbonyl, trihalomethyl, trihalomethoxy
, C_2-6 Alkenyl, 4,4-dimethyloxazolyl; or R in adjacent positions² And R³ Are expressions together -O-CH₂ -O- (a-1), -O-CH₂ -CH₂ -O- (a-2), -O-CH = CH- (a-3), -O-CH₂ -CH₂ -(A-4), -O-CH₂ -CH₂ -CH₂ -(A-5), or -CH = CH-CH = CH- (a-6) May form a divalent group of R^Four And R^Five Are each independently hydrogen, halo, Ar¹ , C_1-6 Alkyl, hydr
Roxy C_1-6 Alkyl, C_1-6 Alkyloxy C_1-6 Alkyl, C_1-6 Alkyl
Oxy, C_1-6 Alkylthio, amino, hydroxycarbonyl, C_1-6 Alkyl
Oxycarbonyl, C_1-6 Alkyl S (O) C_1-6 Alkyl or C_1-6 Al
Kill S (O)₂ C_1-6 Alkyl; R⁶ And R⁷ Are each independently hydrogen, halo, cyano, C_1-6 Alkyl, C_{1- 6}  Alkyloxy, Ar² Oxy, trihalomethyl, C_1-6 Alkylthio, di (
C_1-6 Alkyl) amino, or R in adjacent positions⁶ And R⁷ Are expressions together -O-CH₂ -O- (c-1), or -CH = CH-CH = CH- (c-2) May form a divalent group of R⁸ Is hydrogen, C_1-6 Alkyl, cyano, hydroxycarbonyl, C_1-6 Alkyl
Oxycarbonyl, C_1-6 Alkyl carbonyl C_1-6 Alkyl, cyano C_1-6 A
Rukiru, C_1-6 Alkyloxycarbonyl C_1-6 Alkyl, carboxy C_1-6 A
Ruquil, hydroxy C_1-6 Alkyl, amino C_1-6 Alkyl, mono- or di
(C_1-6 Alkyl) amino C_1-6 Alkyl, imidazolyl, halo C_1-6 Alkyl
, C_1-6 Alkyloxy C_1-6 Alkyl, aminocarbonyl C_1-6 Alkyl,
Or formula -OR^Ten                (B-1), -SR^Ten                (B-2), -NR¹¹R¹²            (B-3) Is the basis of (In the formula, R^TenIs hydrogen, C_1-6 Alkyl, C_1-6 Alkylcarbonyl, Ar¹ , A
r² C_1-6 Alkyl, C_1-6 Alkyloxycarbonyl C_1-6 Alkyl or formula
-Alk² -OR¹³Or-Alk² -NR¹⁴R¹⁵Is the basis of; R¹¹Is hydrogen, C_1-12Alkyl, Ar¹ Or Ar² C_1-6 Alkyl; R¹²Is hydrogen, C_1-6 Alkyl, C_1-16Alkylcarbonyl, C_1-6 Alkyl oki
Sicarbonyl, C_1-6 Alkylaminocarbonyl, Ar¹ , Ar² C_1-6 Archi
Le, C_1-6 Alkyl carbonyl C_1-6 Alkyl, natural amino acid, Ar¹ Carboni
Le, Ar² C_1-6 Alkylcarbonyl, aminocarbonylcarbonyl, C_1-6 A
Luquiloxy C_1-6 Alkylcarbonyl, hydroxy, C_1-6 Alkyloxy,
Aminocarbonyl, di (C_1-6 Alkyl) amino C_1-6 Alkylcarbonyl, a
Mino, C_1-6 Alkylamino, C_1-6 Alkylcarbonylamino, or formula-A
lk² -OR¹³Or-Alk² -NR¹⁴R¹⁵Is the basis of; Where Alk² Is C_1-6 Alkane diyl; R¹³Is hydrogen, C_1-6 Alkyl, C_1-6 Alkyl carbonyl, hydroxy C_1-6 A
Rukiru, Ar¹ Or Ar² C_1-6 Alkyl; R¹⁴Is hydrogen, C_1-6 Alkyl, Ar¹ Or Ar² C_1-6 Alkyl; R¹⁵Is hydrogen, C_1-6 Alkyl, C_1-6 Alkylcarbonyl, Ar¹ Or Ar ²  C_1-6 Alkyl); R¹⁷Is hydrogen, halo, cyano, C_1-6 Alkyl, C_1-6 Alkyloxycarbonyl
, Ar¹ And R¹⁸Is hydrogen, C_1-6 Alkyl, C_1-6 Alkyloxy or halo; R¹⁹Is hydrogen or C_1-6 Alkyl; Ar¹ Is phenyl or C_1-6 Alkyl, hydroxy, amino, C_1-6 Alkyl
Phenyl substituted with oxy or halo; and Ar² Is phenyl or C_1-6 Alkyl, hydroxy, amino, C_1-6 Alkyl
Phenyl substituted with oxy or halo.

WO-97 / 16443 describes the production of farnesyl protein transferase inhibitory compounds of formula (IV) and intermediates of formulas (V) and (VI) which are metabolized in vivo to compounds of formula (IV), Relating to formulation and pharmaceutical properties. The compounds of formulas (IV), (V) and (VI) are

[0008]

[Chemical 10]

[0009] Represented by their pharmaceutically acceptable acid or base addition salts and stereoisomers
, In the formula Dotted lines represent arbitrary bonds; X is oxygen or sulfur; R¹ Is hydrogen, C_1-12Alkyl, Ar¹ , Ar² C_1-6 Alkyl, quinolinyl C _1-6  Alkyl, pyridyl C_1-6 Alkyl, hydroxy C_1-6 Alkyl, C_1-6 A
Luquiloxy C_1-6 Alkyl, mono- or di (C_1-6 Alkyl) amino C_{1- 6}  Alkyl, amino C_1-6 Alkyl, Or formula-Alk¹ -C (= O) -R⁹ , -Alk¹ -S (O) -R⁹ Or
-Alk¹ -S (O)₂ -R⁹ Is the basis of (Alk in the formula¹ Is C_1-6 Is an alkane diyl, R⁹ Is hydroxy, C_1-6 Alkyl, C_1-6 Alkyloxy, amino, C_1-8 A
Rukiruamino or C_1-6 C substituted with alkyloxycarbonyl_1-8 A
Rukiruamino); R² And R³ Are each independently hydrogen, hydroxy, halo, cyano, C_1-6 
Alkyl, C_1-6 Alkyloxy, hydroxy C_1-6 Alkyloxy, C_1-6 A
Luquiloxy C_1-6 Alkyloxy, amino C_1-6 Alkyloxy, mono-if
Kuhaji (C_1-6 Alkyl) amino C_1-6 Alkyloxy, Ar¹ , Ar² C_1-6 
Alkyl, Ar² Oxy, Ar² C_1-6 Alkyloxy, hydroxycarbonyl
, C_1-6 Alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C_{2- 6}  Alkenyl; or R in adjacent positions² And R³ Are expressions together -O-CH₂ -O- (a-1), -O-CH₂ -CH₂ -O- (a-2), -O-CH = CH- (a-3), -O-CH₂ -CH₂ -(A-4), -O-CH₂ -CH₂ -CH₂ -(A-5), or -CH = CH-CH = CH- (a-6) May form a divalent group of R^Four And R^Five Are each independently hydrogen, Ar¹ , C_1-6 Alkyl, C_1-6 Al
Killoxy C_1-6 Alkyl, C_1-6 Alkyloxy, C_1-6 Alkylthio, Ami
No, hydroxycarbonyl, C_1-6 Alkyloxycarbonyl, C_1-6 Alkyl
S (O) C_1-6 Alkyl or C_1-6 Alkyl S (O)₂ C_1-6 In alkyl
R; R⁶ And R⁷ Are each independently hydrogen, halo, cyano, C_1-6 Alkyl, C_{1- 6}  Alkyloxy or Ar² Is oxy; R⁸ Is hydrogen, C_1-6 Alkyl, cyano, hydroxycarbonyl, C_1-6 Alkyl
Oxycarbonyl, C_1-6 Alkyl carbonyl C_1-6 Alkyl, cyano C_1-6 A
Rukiru, C_1-6 Alkyloxycarbonyl C_1-6 Alkyl, hydroxycarboni
Le C_1-6 Alkyl, hydroxy C_1-6 Alkyl, amino C_1-6 Alkyl, mono-
Or J (C_1-6 Alkyl) amino C_1-6 Alkyl, halo C_1-6 Alkyl, C _1-6  Alkyloxy C_1-6 Alkyl, aminocarbonyl C_1-6 Alkyl, Ar¹ 
, Ar² C_1-6 Alkyloxy C_1-6 Alkyl, C_1-6 Alkylthio C_1-6 Al
Is a kill; R^TenIs hydrogen, C_1-6 Alkyl, C_1-6 Alkyloxy or halo; R¹¹Is hydrogen or C_1-6 Alkyl; Ar¹ Is phenyl or C_1-6 Alkyl, hydroxy, amino, C_1-6 Alkyl
Phenyl substituted with oxy or halo; Ar² Is phenyl or C_1-6 Alkyl, hydroxy, amino, C_1-6 Alkyl
Phenyl substituted with oxy or halo.

[0010]   WO-98 / 40383 has the formula (VII)

[0011]

[Chemical 11]

With respect to the preparation, formulation and pharmaceutical properties of the farnesyl protein transferase inhibitor compounds, their pharmaceutically acceptable acid addition salts and stereoisomers, wherein the dotted line represents any bond; X is is oxygen or sulfur; -A- has the formula -CH = CH- (a-1) , -CH 2 -CH 2 - (a-2), -CH 2 -CH 2 -CH 2 - (a-3) _{, -CH 2 -O- (a-4} ), -CH 2 -CH 2 -O- (a-5), -CH 2 -S- (a-6), -CH 2 -CH 2 -S- ( a-7), -CH = N- (a-8), -N = N- (a-9), or -CO-NH- (a-10) divalent group; Hydrogen atoms may be substituted by C _1-4 alkyl or Ar ¹ ; R ¹ and R ² are each independently Hydrogen, hydroxy, halo, cyano, C _1-6
Alkyl, trihalomethyl, trihalomethoxy, C _2-6 alkenyl, C _1-6 alkyloxy, hydroxy C _1-6 alkyloxy, C _1-6 alkyloxy C _1-6 alkyloxy, C _1-6 alkyloxycarbonyl, Amino C _1-6 alkyloxy, mono- or di (C _1-6 alkyl) amino C _1-6 alkyloxy, Ar ² ,
Ar ² -C _1-6 alkyl, Ar ² -oxy, Ar ² -C _1-6 alkyloxy; or when in adjacent positions, R ¹ and R ² together are of the formula —O—CH ₂ -O- (b-1), -O -CH 2 -CH 2 -O- (b-2), -O-CH = CH- (b-3), -O-CH 2 -CH 2 - (b _{-4), -O-CH 2 -CH} 2 -CH 2 - (b-5), or -CH = CH-CH = CH- ( b-6) of the may form a bivalent radical; R ³ and R ⁴ are each independently hydrogen, halo, cyano, C _1-6 alkyl, C _1-6 alkyloxy, Ar ³ - oxy, C _1-6 alkylthio, di (C _1-6 alkyl) amino, trihalomethyl a trihalomethoxy or when in adjacent positions, R ³ and R ⁴ together formula _{-O-CH 2 -O- (c-} 1),, - _{-CH 2 -CH 2 -O- (c-} 2), or -CH = CH-CH = CH- ( c-3) of the may form a bivalent radical; R ⁵ has the formula

[0013]

[Chemical 12]

[0014] (Wherein R is¹³Is hydrogen, halo, Ar^Four , C_1-6 Alkyl, hydroxy
C_1-6 Alkyl, C_1-6 Alkyloxy C_1-6 Alkyl, C_1-6 Alkyloxy
, C_1-6 Alkylthio, amino, C_1-6 Alkyloxycarbonyl, C_1-6 Al
Kill S (O) C_1-6 Alkyl or C_1-6 Alkyl S (O)₂ C_1-6 Alkyl
And R¹⁴Is hydrogen, C_1-6 Alkyl or di (C_1-4 Alkyl) aminosul
Honil); R⁶ Is hydrogen, hydroxy, halo, C_1-6 Alkyl, cyano, halo C_1-6 Alkyl
, Hydroxy C_1-6 Alkyl, cyano C_1-6 Alkyl, amino C_1-6 Alkyl,
C_1-6 Alkyloxy C_1-6 Alkyl, C_1-6 Alkylthio C_1-6 Alkyl, a
Minocarbonyl C_1-6 Alkyl, C_1-6 Alkyloxycarbonyl C_1-6 Archi
Le, C_1-6 Alkylcarbonyl-C_1-6 Alkyl, C_1-6 Alkyl oxycarbo
Nyl, mono- or di (C_1-6 Alkyl) amino C_1-6 Alkyl, Ar^Five , A
r^Five -C_1-6 Alkyloxy C_1-6 Alkyl; or formula -OR⁷               (E-1), -SR⁷               (E-2), -NR⁸ R⁹           (E-3) (Wherein R is⁷ Is hydrogen, C_1-6 Alkyl, C_1-6 Alkylcarbonyl,
Ar⁶ , Ar⁶ -C_1-6 Alkyl, C_1-6 Alkyloxycarbonyl C_1-6 Al
Kill or formula-Alk-OR^TenOr-Alk-NR¹¹R¹²Is the basis of; R⁸ Is hydrogen, C_1-6 Alkyl, Ar⁷ Or Ar⁷ -C_1-6 Alkyl;
R⁹ Is hydrogen, C_1-6 Alkyl, C_1-6 Alkylcarbonyl, C_1-6 Alkyl oki
Sicarbonyl, C_1-6 Alkylaminocarbonyl, Ar⁸ , Ar⁸ -C_1-6 Al
Kill, C_1-6 Alkyl carbonyl C_1-6 Alkyl, Ar⁸ -Carbonyl, Ar⁸ 
-C_1-6 Alkylcarbonyl, aminocarbonylcarbonyl, C_1-6 Alkylio
Kishi C_1-6 Alkylcarbonyl, hydroxy, C_1-6 Alkyloxy, Aminoca
Lubonyl, di (C_1-6 Alkyl) amino C_1-6 Alkylcarbonyl, amino, C _1-6  Alkylamino, C_1-6 Alkylcarbonylamino, Or formula-Alk-OR^TenOr-Alk-NR¹¹R¹²Is the basis of; Where Alk is C_1-6 Alkane diyl; R^TenIs hydrogen, C_1-6 Alkyl, C_1-6 Alkyl carbonyl, hydroxy C_1-6 A
Rukiru, Ar⁹ Or Ar⁹ -C_1-6 Alkyl; R¹¹Is hydrogen, C_1-6 Alkyl, C_1-6 Alkylcarbonyl, Ar^TenOr Ar ^Ten -C_1-6 Alkyl; R¹²Is hydrogen, C_1-6 Alkyl, Ar¹¹Or Ar¹¹-C_1-6 Is alkyl)
; And Ar¹ Or Ar¹¹Are each independently phenyl; or halo, C_1-6 Alkyl
, C_1-6 From phenyl substituted with alkyloxy or trifluoromethyl
To be elected.

[0015]   WO-98 / 49157 has the formula (VIII)

[0016]

[Chemical 13]

[0017] Farnesyl protein transferase inhibitory compounds, their pharmaceutical
To the production, formulation and pharmaceutical properties of acid-acceptable acid addition salts and stereoisomers
, In the formula, Dotted lines represent arbitrary bonds; X is oxygen or sulfur; R¹ And R² Are each independently hydrogen, hydroxy, halo, cyano, C_1-6 
Alkyl, trihalomethyl, trihalomethoxy, C_2-6 Alkenyl, C_1-6 Al
Kiroxy, hydroxy C_1-6 Alkyloxy, C_1-6 Alkyloxy C_1-6 A
Lucyloxy, C_1-6 Alkyloxycarbonyl, amino C_1-6 Alkyloxy
, Mono- or di (C_1-6 Alkyl) amino C_1-6 Alkyloxy, Ar¹ ,
Ar¹ C_1-6 Alkyl, Ar¹ Oxy or Ar¹ C_1-6 Is alkyloxy
; R³ And R^Four Are each independently hydrogen, halo, cyano, C_1-6 Alkyl, C_{1- 6}  Alkyloxy, Ar¹ Oxy, C_1-6 Alkylthio, di (C_1-6 Alkyl)
Amino, trihalomethyl or trihalomethoxy; R^Five Is hydrogen, halo, C_1-6 Alkyl, cyano, halo C_1-6 Alkyl, hydroxy
C_1-6 Alkyl, cyano C_1-6 Alkyl, amino C_1-6 Alkyl, C_1-6 Archi
Loxy C_1-6 Alkyl, C_1-6 Alkylthio C_1-6 Alkyl, aminocarboni
Le C_1-6 Alkyl, C_1-6 Alkyloxycarbonyl C_1-6 Alkyl, C_1-6 A
Lukyrcarbonyl-C_1-6 Alkyl, C_1-6 Alkyloxycarbonyl, mono-
Or J (C_1-6 Alkyl) amino C_1-6 Alkyl, Ar¹ , Ar¹ C_1-6 A
Luquiloxy C_1-6 Alkyl; or formula -OR^Ten              (A-1), -SR^Ten              (A-2), -NR¹¹R¹²          (A-3) Is the basis of (In the formula, R^TenIs hydrogen, C_1-6 Alkyl, C_1-6 Alkylcarbonyl, Ar¹ , A
r¹ C_1-6 Alkyl, C_1-6 Alkyloxycarbonyl C_1-6 Alkyl, or
Formula-Alk-OR¹³Or-Alk-NR¹⁴R¹⁵Is the basis of; R¹¹Is hydrogen, C_1-6 Alkyl, Ar¹ Or Ar¹ C_1-6 Alkyl; R¹²Is hydrogen, C_1-6 Alkyl, C_1-6 Alkylcarbonyl, C_1-6 Alkyl oki
Sicarbonyl, C_1-6 Alkylaminocarbonyl, Ar¹ , Ar¹ C_1-6 Archi
Le, C_1-6 Alkyl carbonyl C_1-6 Alkyl, Ar¹ Carbonyl, Ar¹ C_{1- 6}  Alkylcarbonyl, aminocarbonylcarbonyl, C_1-6 Alkyloxy C _1-6  Alkylcarbonyl, hydroxy, C_1-6 Alkyloxy, aminocarboni
Le, J (C_1-6 Alkyl) amino C_1-6 Alkylcarbonyl, amino, C_1-6 A
Rukiruamino, C_1-6 Alkylcarbonylamino, Or formula-Alk-OR¹³Or-Alk-NR¹⁴R¹⁵Is the basis of; Where Alk is C_1-6 Alkane diyl; R¹³Is hydrogen, C_1-6 Alkyl, C_1-6 Alkyl carbonyl, hydroxy C_1-6 A
Rukiru, Ar¹ Or Ar¹ C_1-6 Alkyl; R¹⁴Is hydrogen, C_1-6 Alkyl, Ar¹ Or Ar¹ C_1-6 Alkyl; R¹⁵Is hydrogen, C_1-6 Alkyl, C_1-6 Alkylcarbonyl, Ar¹ Or Ar  ¹C_1-6 Alkyl); R⁶ Is an expression

[0018]

[Chemical 14]

Wherein R ¹⁶ is hydrogen, halo, Ar ¹ , C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkyloxy C _1-6 alkyl, C _{1- 6} alkyloxy, C _1-6 alkylthio, amino, C _1-6 alkyloxycarbonyl, C _1-6 alkylthio C _1-C6 alkyl, C _1-6 alkyl S (O) C _1-6 alkyl or C _1-6 Alkyl S
(O) ₂ C _1-6 alkyl; R ¹⁷ is hydrogen, C _1-6 alkyl or di (C _1-4 alkyl) aminosulfonyl); R ⁷ is when the dotted line does not represent a bond. is hydrogen or C _1-6 alkyl; R ⁸ is hydrogen, C _1-6 alkyl or Ar ² CH ₂ or Het ¹ CH _2; R ⁹ is hydrogen, C _1-6 alkyl, C _1-6 alkyloxy Or R ⁸ and R ⁹ together are of the formula —CH═CH— (c-1), —CH ₂ —CH ₂ — (c-2), —CH ₂ —CH ₂ —CH ₂ - (c-3), -CH 2 -O- (c-4), or -CH ₂ -CH ₂ -O- to form a bivalent radical of (c-5); Ar ¹ is phenyl; or halo, C _1-6 alkyl, C _1-6 alkyloxy or selected independently from trifluoromethyl one or two Is phenyl substituted with substituent; Ar ² is phenyl; or halo, C _1-6 alkyl, one or two substituents each independently selected from C _1-6 alkyloxy or trifluoromethyl Het ¹ is pyridinyl; substituted with 1 or 2 substituents independently selected from halo, C _1-6 alkyl, C _1-6 alkyloxy or trifluoromethyl. Is pyridinyl.

[0020]   WO-00 / 39082 has the formula (IX)

[0021]

[Chemical 15]

[0022] Farnesyl protein transferase inhibitory compounds or their preparation
Preparation, formulation and pharmaceutical properties of pharmaceutically acceptable acid addition salts and stereoisomers
Regarding, in the formula, = X¹ -X² -X³ − Is an expression = N-CR⁶ = CR⁷ -(X-1), = N-N = CR⁶ -(X-2), = N-NH-C (= O)-(x-3), = N-N = N- (x-4), = N-CR⁶ = N- (x-5), = CR⁶ -CR⁷ = CR⁸ -(X-6), = CR⁶ -N = CR⁷ -(X-7), = CR⁶ -NH-C (= O)-(x-8), or = CR⁶ -N = N- (x-9) Is a trivalent group of (In the formula, each R⁶ , R⁷ And R⁸ Independently hydrogen, C_1-4 Alkyl, hi
Droxy, C_1-4 Alkyloxy, aryloxy, C_1-4 Alkyl oxycal
Bonyl, hydroxy C_1-4 Alkyl, C_1-4 Alkyloxy C_1-4 Alkyl, mo
No or Di (C_1-4 Alkyl) amino C_1-4 Alkyl, cyano, amino, thi
Oh, C_1-4 Alkylthio, arylthio or aryl); > Y¹ -Y² − Is an expression > CH-CHR⁹ -(Y-1), > C = N- (y-2), > CH-NR⁹ -(Y-3), or > C = CR⁹ -(Y-4) Is a trivalent group of (In the formula, each R⁹ Are independently hydrogen, halo, halocarbonyl, aminocarbo
Nyl, hydroxy C_1-4 Alkyl, cyano, carboxyl, C_1-4 Alkyl, C _1-4  Alkyloxy, C_1-4 Alkyloxy C_1-4 Alkyl, C_1-4 Alkylio
Xycarbonyl, mono- or di (C_1-4 Alkyl) amino, mono-or
The (C_1-4 Alkyl) amino C_1-4 Alkyl and aryl); r and s are each independently 0, 1, 2, 3, 4 or 5; t is 0, 1, 2 or 3; Each R¹ And R² Are independently hydroxy, halo, cyano, C_1-6 Archi
L, trihalomethyl, trihalomethoxy, C_2-6 Alkenyl, C_1-6 Alkylio
Xy, hydroxy C_1-6 Alkyloxy, C_1-6 Alkylthio, C_1-6 Alkyl
Oxy C_1-6 Alkyloxy, C_1-6 Alkyloxycarbonyl, amino C_1-6 
Alkyloxy, mono- or di (C_1-6 Alkyl) amino, mono-or
The (C_1-6 Alkyl) amino C_1-6 Alkyloxy, aryl, aryl C_1-6 
Alkyl, aryloxy or aryl C_1-6 Alkyloxy, hydroxyca
Lubonyl, C_1-6 Alkyloxycarbonyl, aminocarbonyl, amino C_1-6 
Alkyl, mono- or di (C_1-6 Alkyl) aminocarbonyl, mono-if
Kuhaji (C_1-6 Alkyl) amino C_1-6 Alkyl; or Two Rs adjacent to each other on the phenyl ring¹ Or R² Substituents taken together in formula
-O-CH₂ -O- (a-1), -O-CH₂ -CH₂ -O- (a-2), -O = CH = CH- (a-3), -O-CH₂ -CH₂ -(A-4), -O-CH₂ -CH₂ -CH₂ -(A-5), or -CH = CH-CH = CH- (a-6) May independently form a divalent group of R³ Is hydrogen, halo, C_1-6 Alkyl, cyano, halo C_1-6 Alkyl, hydroxy
C_1-6 Alkyl, cyano C_1-6 Alkyl, amino C_1-6 Alkyl, C_1-6 Archi
Loxy C_1-6 Alkyl, C_1-6 Alkylthio C_1-6 Alkyl, aminocarboni
Le C_1-6 Alkyl, hydroxycarbonyl, hydroxycarbonyl C_1-6 Archi
Le, C_1-6 Alkyloxycarbonyl C_1-6 Alkyl, C_1-6 Alkyl Carboni
Le C_1-6 Alkyl, C_1-6 Alkyloxycarbonyl, aryl, aryl C_{1- 6}  Alkyloxy C_1-6 Alkyl, mono- or di (C_1-6 Alkyl) amino
C_1-6 Alkyl; Or expression -OR^Ten                      (B-1), -SR^Ten                      (B-2), -NR¹¹R¹²                    (B-3) Is the basis of (In the formula, R^TenIs hydrogen, C_1-6 Alkyl, C_1-6 Alkylcarbonyl, aryl,
Aryl C_1-6 Alkyl, C_1-6 Alkyloxycarbonyl C_1-6 Alkyl,
Or formula-Alk-OR¹³Or-Alk-NR¹⁴R¹⁵Is the basis of; R¹¹Is hydrogen, C_1-6 Alkyl, aryl or aryl C_1-6 Is alkyl
; R¹²Is hydrogen, C_1-6 Alkyl, aryl, hydroxy, amino, C_1-6 Archi
Roxy, C_1-6 Alkyl carbonyl C_1-6 Alkyl, aryl C_1-6 Alkyl
, C_1-6 Alkylcarbonylamino, mono- or di (C_1-6 Alkyl)
No, C_1-6 Alkylcarbonyl, aminocarbonyl, arylcarbonyl, halo
C_1-6 Alkyl carbonyl, aryl C_1-6 Alkylcarbonyl, C_1-6 Archi
Luoxycarbonyl, C_1-6 Alkyloxy C_1-6 Alkylcarbonyl, mono-
Or J (C_1-6 Alkyl) aminocarbonyl (where the alkyl moiety is
Therefore aryl or C_1-3 Independently selected from alkyloxycarbonyl
Optionally substituted by one or more substituents), aminocarbonyl
Lubonyl, mono- or di (C_1-6 Alkyl) amino C_1-6 Alkyl Carboni
Or formula-Alk-OR¹³Or-Alk-NR¹⁴R¹⁵Is the basis of; Where Alk is C_1-6 Alkane diyl; R¹³Is hydrogen, C_1-6 Alkyl, C_1-6 Alkyl carbonyl, hydroxy C_1-6 A
Ruquil, aryl or aryl C_1-6 Alkyl; R¹⁴Is hydrogen, C_1-6 Alkyl, aryl or aryl C_1-6 Is alkyl
; R¹⁵Is hydrogen, C_1-6 Alkyl, C_1-6 Alkylcarbonyl, aryl or
Aryl C_1-6 Alkyl); R^Four Is an expression

[0023]

[Chemical 16]

[0024] Is the basis of (In the formula, R¹⁶Is hydrogen, halo, aryl, C_1-6 Alkyl, hydroxy C_1-6 Al
Kill, C_1-6 Alkyloxy C_1-6 Alkyl, C_1-6 Alkyloxy, C_1-6 A
Rukiruthio, amino, mono- or di (C_1-4 Alkyl) amino, hydroxy
Carbonyl, C_1-6 Alkyloxycarbonyl, C_1-6 Alkylthio C_1-6 Al
Kill, C_1-6 Alkyl S (O) C_1-6 Alkyl or C_1-6 Alkyl S (O)₂ 
C_1-6 Alkyl; R¹⁶Is one of the nitrogen atoms in the imidazole ring of formula (c-1) or (c-2)
May be bonded, in which case R when bonded to nitrogen¹⁶Means hydrogen, a
Reel, C_1-6 Alkyl, hydroxy C_1-6 Alkyl, C_1-6 Alkyloxy C _1-6  Alkyl, C_1-6 Alkyloxycarbonyl, C_1-6 Alkyl S (O) C_{1- 6}  Alkyl or C_1-6 Alkyl S (O)₂ C_1-6 Limited to alkyl; R¹⁷Is hydrogen, C_1-6 Alkyl, C_1-6 Alkyloxy C_1-6 Alkyl, aryl
C_1-6 Alkyl, trifluoromethyl or di (C_1-4 Alkyl) aminosul
Honil); R^Five Is C_1-6 Alkyl, C_1-6 Alkyloxy or halo; Aryl is phenyl, naphthalenyl or halo, C_1-6 Alkyl, C_1-6 Archi
1 or 2 independently selected from luoxy or trifluoromethyl
Is phenyl substituted with further substituents.

The anti-tumor vinca alkaloids are related to or derived from extracts of Periwinkle (Vinca rosea). Among these compounds, vinblastine and vincristine are important clinical agents for the treatment of leukemia, lymphoma and testicular cancer, and vinorelbine has activity against lung and breast cancer.
However, each of these compounds suffers from toxicological effects, for example vinblastine causes leukopenia while reaching a nadir within 7 to 10 days after drug administration and followed by recovery within 7 days. Shows some neurological toxicity such as numbness and shivering of the extremities, loss of deep tendon reflexes and weakness of the muscle tissue of the distal extremities. Vinorelbine has some toxicity in the form of granulocytopenia but with modest thrombocytopenia and less neurotoxicity than other vinca alkaloids.

Thus, for increasing the inhibitory potency of anti-tumor vinca alkaloids on tumor growth and also for the use of lower dosages of anti-tumor vinca alkaloids to reduce the potential for adverse toxic side effects to the patient. There is a need to provide the means of

For the treatment of anti-tumor vinca alkaloid and farnesyl transferase inhibitors of the type described above, which have a beneficial inhibitory effect on tumor cell growth compared to the respective effects exhibited by the individual components of the combination. It is an object of the invention to provide a combination.

Therefore, in accordance with the present invention, we have identified anti-tumor vinca alkaloids and the above formulas (I), (II), (III), (IV), (V), (VI), (VII).
, A farnesyl transferase inhibitor of (VIII) or (IX), especially a compound of formula (I), (II) or (III):

[0029]

[Chemical 17]

[0030] Combinations of their pharmaceutically acceptable acid or base addition salts and stereoisomers
Providing an agent, in the formula, Dotted lines represent arbitrary bonds; X is oxygen or sulfur; R¹ Is hydrogen, C_1-12Alkyl, Ar¹ , Ar² C_1-6 Alkyl, quinolinyl C _1-6  Alkyl, pyridyl C_1-6 Alkyl, hydroxy C_1-6 Alkyl, C_1-6 A
Luquiloxy C_1-6 Alkyl, mono- or di (C_1-6 Alkyl) amino C_{1- 6}  Alkyl, amino C_1-6 Alkyl, Or formula-Alk¹ -C (= O) -R⁹ , -Alk¹ -S (O) -R⁹ Or
-Alk¹ -S (O)₂ -R⁹ Is the basis of (Alk in the formula¹ Is C_1-6 Is an alkane diyl, R⁹ Is hydroxy, C_1-6 Alkyl, C_1-6 Alkyloxy, amino, C_1-8 A
Rukiruamino or C_1-6 C substituted with alkyloxycarbonyl_1-8 A
Rukiruamino); R² , R³ And R¹⁶Are each independently hydrogen, hydroxy, halo, cyano,
C_1-6 Alkyl, C_1-6 Alkyloxy, hydroxy C_1-6 Alkyloxy, C _1-6  Alkyloxy C_1-6 Alkyloxy, amino C_1-6 Alkyloxy, mono
-Or di (C_1-6 Alkyl) amino C_1-6 Alkyloxy, Ar¹ , Ar² 
C_1-6 Alkyl, Ar² Oxy, Ar² C_1-6 Alkyloxy, hydroxycal
Bonil, C_1-6 Alkyloxycarbonyl, trihalomethyl, trihalomethoxy
, C_2-6 Alkenyl, 4,4-dimethyloxazolyl; or R in adjacent positions² And R³ Are expressions together -O-CH₂ -O- (a-1), -O-CH₂ -CH₂ -O- (a-2), -O-CH = CH- (a-3), -O-CH₂ -CH₂ -(A-4), -O-CH₂ -CH₂ -CH₂ -(A-5), or -CH = CH-CH = CH- (a-6) May form a divalent group of R^Four And R^Five Are each independently hydrogen, halo, Ar¹ , C_1-6 Alkyl, hydr
Roxy C_1-6 Alkyl, C_1-6 Alkyloxy C_1-6 Alkyl, C_1-6 Alkyl
Oxy, C_1-6 Alkylthio, amino, hydroxycarbonyl, C_1-6 Alkyl
Oxycarbonyl, C_1-6 Alkyl S (O) C_1-6 Alkyl or C_1-6 Al
Kill S (O)₂ C_1-6 Alkyl; R⁶ And R⁷ Are each independently hydrogen, halo, cyano, C_1-6 Alkyl, C_{1- 6}  Alkyloxy, Ar² Oxy, trihalomethyl, C_1-6 Alkylthio, di (
C_1-6 Alkyl) amino, or R in adjacent positions⁶ And R⁷ Are expressions together -O-CH₂ -O- (c-1), or -CH = CH-CH = CH- (c-2) May form a divalent group of R⁸ Is hydrogen, C_1-6 Alkyl, cyano, hydroxycarbonyl, C_1-6 Alkyl
Oxycarbonyl, C_1-6 Alkyl carbonyl C_1-6 Alkyl, cyano C_1-6 A
Rukiru, C_1-6 Alkyloxycarbonyl C_1-6 Alkyl, carboxy C_1-6 A
Ruquil, hydroxy C_1-6 Alkyl, amino C_1-6 Alkyl, mono- or di
(C_1-6 Alkyl) amino C_1-6 Alkyl, imidazolyl, halo C_1-6 Alkyl
, C_1-6 Alkyloxy C_1-6 Alkyl, aminocarbonyl C_1-6 Alkyl,
Or formula -OR^Ten                (B-1), -SR^Ten                (B-2), -NR¹¹R¹²            (B-3) Is the basis of (In the formula, R^TenIs hydrogen, C_1-6 Alkyl, C_1-6 Alkylcarbonyl, Ar¹ , A
r² C_1-6 Alkyl, C_1-6 Alkyloxycarbonyl C_1-6 Alkyl, or
Formula-Alk² -OR¹³Or-Alk² -NR¹⁴R¹⁵Is the basis of; R¹¹Is hydrogen, C_1-12Alkyl, Ar¹ Or Ar² C_1-6 Alkyl; R¹²Is hydrogen, C_1-6 Alkyl, C_1-16Alkylcarbonyl, C_1-6 Alkyl oki
Sicarbonyl, C_1-6 Alkylaminocarbonyl, Ar¹ , Ar² C_1-6 Archi
Le, C_1-6 Alkyl carbonyl C_1-6 Alkyl, natural amino acid, Ar¹ Carboni
Le, Ar² C_1-6 Alkylcarbonyl, aminocarbonylcarbonyl, C_1-6 A
Luquiloxy C_1-6 Alkylcarbonyl, hydroxy, C_1-6 Alkyloxy,
Aminocarbonyl, di (C_1-6 Alkyl) amino C_1-6 Alkylcarbonyl, a
Mino, C_1-6 Alkylamino, C_1-6 Alkylcarbonylamino, Or formula-Alk² -OR¹³Or-Alk² -NR¹⁴R¹⁵Is the basis of; Where Alk² Is C_1-6 Alkane diyl; R¹³Is hydrogen, C_1-6 Alkyl, C_1-6 Alkyl carbonyl, hydroxy C_1-6 A
Rukiru, Ar¹ Or Ar² C_1-6 Alkyl; R¹⁴Is hydrogen, C_1-6 Alkyl, Ar¹ Or Ar² C_1-6 Alkyl; R¹⁵Is hydrogen, C_1-6 Alkyl, C_1-6 Alkylcarbonyl, Ar¹ Or Ar ²  C_1-6 Alkyl); R¹⁷Is hydrogen, halo, cyano, C_1-6 Alkyl, C_1-6 Alkyloxycarbonyl
, Ar¹ And R¹⁸Is hydrogen, C_1-6 Alkyl, C_1-6 Alkyloxy or halo; R¹⁹Is hydrogen or C_1-6 Alkyl; Ar¹ Is phenyl or C_1-6 Alkyl, hydroxy, amino, C_1-6 Alkyl
Phenyl substituted with oxy or halo; and Ar² Is phenyl or C_1-6 Alkyl, hydroxy, amino, C_1-6 Alkyl
Phenyl substituted with oxy or halo.

The combinations described above are hereinafter referred to as the combinations of the invention. These combinations may provide a synergistic effect whereby they demonstrate a beneficial therapeutic effect greater than might be expected from the effect of the individual components of the combination.

In formulas (I), (II) and (III), R ⁴ or R ⁵ 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 R ⁴ or R ⁵ and R ⁴ and R ⁵ when bound to the nitrogen
Means hydrogen, Ar ¹ , C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6
Limited to alkyloxy C _1-6 alkyl, C _1-6 alkyloxycarbonyl, C _1-6 alkyl S (O) C _1-6 alkyl, C _1-6 alkyl S (O) ₂ C _1-6 alkyl .

Preferably the substituent R ¹⁸ is located in the 5 or 7 position of the quinolinone moiety and the substituent R ¹⁹ is located in the 8 position when R ¹⁸ is in the 7 position.

[0034]   Important compounds are those compounds of formula (I) in which X is oxygen.

Another important compound is those compounds of formula (I) in which the dotted line indicates a bond so as to form a double bond.

[0036]   Another group of important compounds is R¹ Is hydrogen, C_1-6 Alkyl, C_1-6 Alkyl oki
C_1-6 Alkyl, di (C_1-6 Alkyl) amino C_1-6 Alkyl, or formula-
Alk¹ -C (= O) -R⁹ Group [in the formula, Alk¹ Is methylene, and R ⁹  Is C_1-6 C substituted with alkyloxycarbonyl_1-8 Is alkylamino
] A compound of formula (I)

Yet another group of important compounds is R ³ is hydrogen or halo; and R ²
Is a compound of formula (I) wherein is halo, C _1-6 alkyl, C _2-6 alkenyl, C _1-6 alkyloxy, trihalomethoxy or hydroxy C _1-6 alkyloxy.

Yet another group of compounds of interest are divalent compounds of formula (a-1), (a-2) or (a-3) wherein R ² and R ³ are in adjacent positions and taken together. A compound of formula (I) which forms a group.

Yet another group of compounds of interest are those compounds of formula (I) in which R ⁵ is hydrogen and R ⁴ is hydrogen or C _1-6 alkyl.

Yet another group of compounds of interest are those compounds of (I) in which R ⁷ is hydrogen; and R ⁶ is C _1-6 alkyl or halo, preferably chloro, especially 4-chloro.

A particular group of compounds is that R ⁸ is hydrogen, hydroxy, haloC _1-6 alkyl, hydroxy C _1-6 alkyl, cyano C _1-6 alkyl, C _1-6 alkyloxycarbonyl C _1-6 alkyl. , Imidazolyl, or a group of the formula --NR ¹¹ R ¹² wherein R ¹¹ is hydrogen or C _1-12 alkyl and R ¹² is hydrogen, C _1-6 alkyl, C _1-6 alkyloxy, hydroxy, C _1-6 alkyloxy C _1-6 alkylcarbonyl,
Or a compound of formula (I) which is a group of formula —Alk ² —OR ¹³ where R ¹³ is hydrogen or C _1-6 alkyl.

[0042]   Preferred compounds are R¹ Is hydrogen, C_1-6 Alkyl, C_1-6 Alkyloxy C_{1- 6}  Alkyl, di (C_1-6 Alkyl) amino C_1-6 Alkyl, or formula-Alk ¹  -C (= O) -R⁹ Group [in the formula, Alk¹ Is methylene and R⁹ Is C_{1- 6}  C substituted with alkyloxycarbonyl_1-8 Is alkylamino]
; R² Is Haro, C_1-6 Alkyl, C_2-6 Alkenyl, C_1-6 Alkyloxy,
Rihalomethoxy, hydroxy C_1-6 Alkyloxy or Ar¹ And R³ 
Is hydrogen; R^Four Is methyl bonded to the nitrogen at the 3-position of imidazole;
R^Five Is hydrogen; R⁶ Is chloro; R⁷ Is hydrogen; R⁸ Hydrogen and hydr
Roxy, halo C_1-6 Alkyl, hydroxy C_1-6 Alkyl, cyano C_1-6 Archi
Le, C_1-6 Alkyloxycarbonyl C_1-6 Alkyl, imidazolyl, or formula
-NR¹¹R¹²Of the group [wherein R¹¹Is hydrogen or C_1-12Alkyl and R¹² Is hydrogen, C_1-6 Alkyl, C_1-6 Alkyloxy, C_1-6 Alkyloxy C_1-6 
Alkylcarbonyl, or formula-Alk² -OR¹³Group (in the formula, R¹³Is C_1-6 
Is alkyl)]; and R¹⁷Is hydrogen and R¹⁸Is hydrogen
It is a combination.

The most preferred compound is 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-1H-imidazol-5-ylmethyl] -4- ( 3-chlorophenyl) -1-methyl-2 (1H) -quinolinone; 6-[(4-chlorophenyl) hydroxy (1-methyl-1H-imidazole-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, 6- Amino (4-chlorophenyl) (1-methyl-1H-imidazol-5-yl) methyl] -1-methyl-4- (3-propylphenyl) -2 (1H) -quinolinone; stereoisomers thereof or pharmaceuticals Acceptable acid or base addition salt;
And (+)-6- [amino (4-chlorophenyl) (1-methyl-1H-imidazol-5-yl) methyl] -4- (3-chlorophenyl) -1-methyl-2 (1H)
-Quinolinone (compound 75 in Table 1 of the experimental part of WO-97 / 21701);
Alternatively, it is a pharmaceutically acceptable acid addition salt thereof. The latter compound is especially preferred.

[0044] Further preferred embodiments of the present invention, item 1 or more of the following restrictions include compounds of the applied formula ^{(IX): · = X 1} -X 2 -X 3 is represented by the formula (x -1), (x-2), (x-3), (x-4)
Or (x-9) [wherein each R ⁶ is independently hydrogen, C _1-4 alkyl,
C _1-4 alkyloxycarbonyl, amino or aryl and R ⁷ is hydrogen];> Y ¹ -Y ² -is the formula (y-1), (y-2), (Y-3) or (y-4)
[Wherein each R ⁹ is independently hydrogen, halo, carboxyl, C _1-4 alkyl or C _1-4 alkyloxycarbonyl]; and r is 0, 1 or 2. Yes; s is 0 or 1; t is 0; R ¹ is halo, C _1-6 alkyl, or two R ¹ substituents that are ortho to each other on the phenyl ring. May together form a divalent group of formula (a-1); R ² is halo; R ³ is halo or formula (b-1) or (b-3) [Wherein R ¹⁰ is hydrogen or a group of the formula —Alk-OR ¹³ and R ¹¹ is hydrogen; R ¹² is hydrogen, C _1-6 alkyl, C _1-6 alkylcarbonyl, Hydroxy, C _1-6
Alkyloxy or mono- or di (C _1-6 alkyl) amino C _1-6 alkylcarbonyl; Alk is C _1-6 alkanediyl and R ¹³ is hydrogen]; R ⁴ is of the formula (c -1) or (c-2), wherein R ¹⁶ is hydrogen, halo or mono- or di (C _1-4 alkyl) amino; R ¹⁷ is hydrogen or C _1-6 alkyl. There is;]-Aryl is phenyl.

A particular group of compounds is the compounds of formula (x-1), (x-2), where = X ¹ -X ² -X ³
(X-3), (x-4) or (x-9) is a trivalent group, and> Y ¹ -Y ² is represented by the formula (y-2), (y-3) or (y-4). It is a trivalent group and r is 0 or 1.
And s is 1, t is 0, R ¹ is halo, C _(1-4) alkyl or forms a divalent group of formula (a-1) and R ² is halo or C _1-4 alkyl, R ³ is hydrogen or a group of formula (b-1) or (b-3), R ⁴ is a group of formula (c-1) or (c-2), R ⁶ is hydrogen, C _1-4 alkyl or phenyl, R ⁷ is hydrogen, R ⁹ is hydrogen or C _1-4 alkyl, R ¹⁰ is hydrogen or —Alk-OR ¹³ , and R ¹¹ Is hydrogen and R ¹² is hydrogen or C _1-6 alkylcarbonyl and R ¹³ is hydrogen, the formula (
IX).

Preferred compounds are those where = X ¹ -X ² -X ³ is a trivalent group of formula (x-1) or (x-4) and> Y ¹ -Y ² is of formula (y-4). It is a trivalent group and r is 0 or 1.
And s is 1, t is 0, R ¹ is halo, preferably chloro, and most preferably 3-chloro, and R ² is halo, preferably 4-chloro or 4-fluoro. , R ³ is hydrogen or a group of formula (b-1) or (b-3), R ⁴ is a group of formula (c-1) or (c-2), R ⁶ is hydrogen,
A compound of formula (IX) wherein R ⁷ is hydrogen, R ⁹ is hydrogen, R ¹⁰ is hydrogen, R ¹¹ is hydrogen and R ¹² is hydrogen.

Other preferred compounds are> Y ¹ -Y ² where = X ¹ -X ² -X ³ is a trivalent group of formula (x-2), (x-3) or (x-4). Is a trivalent group of formula (y-2), (y-3) or (y-4), r and s are 1, t is 0, R ¹ is halo, preferably chloro, and Most preferably 3-chloro, or R ¹ is C _1-4 alkyl, preferably 3-methyl, R ² is halo, preferably chloro, and most preferably 4-chloro, and R ³ is Is a group of formula (b-1) or (b-3), R ⁴ is a group of formula (c-2), R ⁶ is C _1-4 alkyl, R ⁹ is hydrogen, R A compound of formula (IX) wherein ¹⁰ and R ¹¹ are hydrogen and R ¹² is hydrogen or hydroxy.

The most preferred compound of formula (IX) is 7-[(4-fluorophenyl) (1H-imidazol-1-yl) methyl] -5.
-Phenylimidazo [1,2-a] quinoline; α- (4-chlorophenyl) -α- (1-methyl-1H-imidazol-5-yl) -5-phenylimidazo [1,2-a] quinoline-7 -Methanol; 5- (3-chlorophenyl) -α- (4-chlorophenyl) -α- (1-methyl-1H-imidazol-5-yl) -imidazo [1,2-a] quinoline-7-methanol; 5 5- (3-chlorophenyl)-(3-chlorophenyl) -α- (4-chlorophenyl) -α- (1-methyl-1H-imidazol-5-yl) imidazo [1,2-a] quinolin-7-methanamine; ) -Α- (4-Chlorophenyl) -α- (1-methyl-1H-imidazol-5-yl) tetrazolo [1,5-a] quinolin-7-methanamine; 5- (3-chlorophenyl) -α- 4-chlorophenyl) -1-methyl -α-
(1-Methyl-1H-imidazol-5-yl) -1,2,4-triazolo [4,4
3- (a) quinoline-7-methanol; 5- (3-chlorophenyl) -α- (4-chlorophenyl) -α- (1-methyl-1H-imidazol-5-yl) tetrazolo [1,5-a] quinoline -7-methanamine; 5- (3-chlorophenyl) -α- (4-chlorophenyl) -α- (1-methyl-1H-imidazol-5-yl) tetrazolo [1,5-a] quinazoline-7-methanol; 5- (3-chlorophenyl) -α- (4-chlorophenyl) -4,5-dihydro-α- (1-methyl-1H-imidazol-5-yl) tetrazolo [1,5-a]
Quinazoline-7-methanol; 5- (3-chlorophenyl) -α- (4-chlorophenyl) -α- (1-methyl-1H-imidazol-5-yl) tetrazolo [1,5-a] quinazoline-7-methanamine 5- (3-chlorophenyl) -α- (4-chlorophenyl) -N-hydroxy-
α- (1-Methyl-1H-imidazol-5-yl) tetrahydro [1,5-a]
Quinoline-7-methanamine; α- (4-chlorophenyl) -α- (1-methyl-1H-imidazol-5-yl) -5- (3-methylphenyl) tetrazolo [1,5-a] quinoline-7- Methanamine; pharmaceutically acceptable acid addition salts and stereoisomers thereof.

5- (3-chlorophenyl) -α- (4-chlorophenyl) -α- (1-methyl-1H-imidazol-5-yl) tetrazolo [1,5-a] quinazoline-7-
Methanamine, especially the (-) enantiomer, and its pharmaceutically acceptable acid addition salts are especially preferred.

Halo, as used above and below, defines fluoro, chloro, bromo and iodo. C _1-6 alkyl defines straight and branched chain saturated hydrocarbon groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl and the like. C _1-8 alkyl includes straight chain and branched saturated hydrocarbon groups defined by C _1-6 alkyl and their higher homologs containing 7 or 8 carbon atoms, such as heptyl or octyl. .
C _1-12 alkyl again includes C _1-8 alkyl and their higher homologues containing 9 to 12 carbon atoms, such as nonyl, decyl, undecyl, dodecyl. C _1-16 alkyl is again C _1-12 alkyl and carbon atoms 13 to 16
And their higher homologues, including tridecyl, tetradecyl, pentadecyl and hexadecyl. C _2-6 alkenyl is a straight-chain and branched hydrocarbon radical containing one double bond and having 2 to 6 carbon atoms, such as ethenyl, 2-propenyl, 3-butenyl, 2- Define pentenyl, 3-pentenyl, 3-methyl-2-butenyl and the like. C _1-6 alkanediyl is a divalent straight-chain and branched saturated hydrocarbon radical having 1 to 6 carbon atoms, for example methylene, 1,2-ethanediyl, 1,3-propanediyl, 1, 4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and their branched isomers are defined. The term "C (= O)" refers to a carbonyl group, "S (O)" refers to sulfoxide and "S (O) ₂ " refers to sulfone. The term "natural amino acid"
Refers to a naturally occurring amino acid linked via a covalent amide bond formed by the loss of a water molecule between the carboxyl group of an amino acid and the rest of the amino groups 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.

As used herein, the pharmaceutically acceptable acid or base addition salts are of formula (I)
, (II), (III), (IV), (V), (VI), (VII), (VII
It is meant that the compounds of I) or (IX) comprise the form of therapeutically active non-toxic acid and non-toxic base addition salts which can be formed. Formula (I) having basic properties, (
II), (III), (IV), (V), (VI), (VII), (VIII)
Alternatively, the compounds of (IX) can be converted to their pharmaceutically acceptable acid addition salts by treating the base form with a suitable acid. Suitable acids are, for example, inorganic acids, such as hydrohalic acids, such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or organic acids, such as acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid. , Oxalic acid, malonic acid, succinic acid (ie butanedioic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid , Salicylic acid, p-aminosalicylic acid, pamoic acid and the like.

Formulas (I), (II), (III), (IV), (V), (having acidic properties
The compounds of VI), (VII), (VIII) or (IX) may be converted into their pharmaceutically acceptable base addition salts by treating the acid form with a suitable organic or inorganic base. Suitable base salt forms are, for example, ammonium salts, alkali and alkaline earth metal salts, for example lithium, sodium, potassium, magnesium, calcium salts, salts with organic bases, for example benzathine, N-methyl-D.
-Comprising glucamine, hydrabamine salts, as well as salts with amino acids such as arginine, lysine and the like.

The term acid or base addition salt refers to the compounds of formula (I), (II), (III), (I
V), (V), (VI), (VII), (VIII) or (IX) can also form hydrates and solvent addition forms. An example of such a form is
For example, hydrates, alcohol solvates and the like.

As used herein above, formulas (I), (II), (III), (
The term stereoisomer of a compound of IV), (V), (VI), (VII), (VIII) or (IX) consists of the same atoms connected by the same chain of bonds. , But formulas (I), (II), (III), (IV), (V
), (VI), (VII), (VIII) or (IX) define all possible compounds with different non-exchangeable tertiary structures that the compound may have.
Unless otherwise mentioned or indicated, the chemical designation of a compound includes the mixture of all possible stereoisomers that the compound may have. The mixture may contain all diastereomers and / or enantiomers of the basic molecular structure of the compound. Formula (I), both in pure form and mixed with each other, (
II), (III), (IV), (V), (VI), (VII), (VIII)
Alternatively, all stereoisomers of the compound of (IX) are intended to be included within the scope of the present invention.

Formulas (I), (II), (III), (IV), (V), (VI), (VII)
, (VIII) or some of the compounds of (IX) may exist in their tautomeric form. Such forms, although not explicitly indicated in the above formula, are intended to be included within the scope of the present invention.

Whenever used hereafter, the terms “formula (I), (II), (II
I), (IV), (V), (VI), (VII), (VIII) or (IX)
The compound of “)” is also intended to include pharmaceutically acceptable acid or base addition salts and all stereoisomers.

Preferred anti-tumor vinca alkaloids for use in the present invention include vinblastine, vincristine and vinorelbine, referred to above. Vinblastine is commercially available, for example, from Eli Lilly and Co as the sulfate for injection under the tradename Velban, and is described, for example, in DE 21204023 or similar thereto. It may be produced by a method. Vincristine is commercially available, for example, under the tradename Oncovin from Eli Lilly and Co as a sulphate for injection, and is for example the above mentioned German patent specification 21.
It may be prepared as described in 24023 or by a method similar thereto. Vinorelbine is commercially available, for example, under the tradename Navelbine from Glaxo Wellcome as the tartrate salt for injection, and is prepared, for example, as described in US Pat. No. 4,307,100, or by a method analogous thereto. You may Other anti-tumor vinca alkaloids may be prepared in a conventional manner, for example by methods similar to those described above for vinoblastine, vincristine and vinorelbine.

The present invention also relates to the combinations of the invention for use in medical therapy, eg for inhibiting the growth of tumor cells.

The present invention also relates to the use of the combination according to the invention for the manufacture of a pharmaceutical composition for inhibiting the growth of tumor cells.

The present invention also relates to a method of inhibiting the growth of tumor cells in a subject, comprising administering to a human subject an effective amount of a combination of the invention.

The present invention further provides a method for inhibiting abnormal growth of cells, including transformed cells, by administering an effective amount of the combination agent of the present invention. Cell overgrowth refers to cell growth that is independent of normal regulatory mechanisms (eg loss of contact inhibition). this is:
(1) Tumor cells expressing an activated ras oncogene (tumor); (2) Tumor cells in which the ras protein is activated as a result of oncogenic mutation of another gene; (3) Abnormal ras It includes the abnormal proliferation of benign and malignant cells of other proliferative disorders in which activation occurs. Furthermore, the ras oncogene contributes to tumor growth in vivo by not only direct effects on tumor cell growth but also indirectly, ie by promoting tumor-induced angiogenesis. It has been suggested (Rak. J. et al, Cancer Research, 55 , 4575-4580, 1995). Thus, a pharmacologically targeted mutant ras oncogene could partially suppress solid tumor growth in vivo by inhibiting tumor-induced angiogenesis.

The present invention also provides a method of inhibiting tumor growth by administering to a subject, eg, a mammal (and more specifically a human) in need of such treatment, an effective amount of a combination of the present invention. provide. In particular, the invention provides a method of inhibiting the growth of a tumor expressing an activated ras oncogene by administration of an effective amount of a combination of the invention. Examples of tumors that can be inhibited include, but are not limited to, lung cancer (eg, including adenocarcinoma, and non-small cell lung cancer), pancreatic cancer (eg, pancreatic cancer).
atic carcinoma), eg exocrine pancreatic cancer), colon cancer (eg colorectal cancer, eg colon adenocarcinoma and colon adenoma), hematopoietic tumors of the lymphoid lineage (eg acute lymphocytic leukemia, B-cell lymphoma, Burkitt lymphoma), myeloid Leukemia (eg acute myeloid leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), tumors of mesenchymal origin (eg fibrosarcoma and rhabdomyosarcoma), melanoma, teratocarcinoma, neuroblastoma , Glioma, benign tumors of the skin (eg keratoacanthoma), breast cancer (eg advanced breast cancer), renal cancer,
Mention may be made of ovarian cancer, bladder cancer and epithelial cancer.

The present invention contemplates that the ras protein is aberrantly activated as a result of oncogenic mutations in the gene (ie the ras gene itself is not activated by mutation to the oncogenic form), benign and Also provided are methods of inhibiting both malignant proliferative disorders, which inhibition is achieved by administration of an effective amount of a combination of the invention to a subject in need of such treatment. For example, tumors in which ras is activated by benign proliferative disorders, neurofibromatosis, or mutations or overexpression of the tyrosine kinase oncogene may be inhibited by the combinations of the invention.

The anti-tumor vinca alkaloids and farnesyl transferase inhibitors are
It may be administered simultaneously (eg separately or in a single composition) or sequentially in either order. In the latter case, the two compounds may be administered within a period and in an amount and manner sufficient to ensure that a beneficial or synergistic effect is achieved. The preferred method and sequence of administration for each component of the combination, as well as the respective dosage and regimen, are specific antitumor vinca alkaloid and farnesyl transferase inhibitors being administered,
It will be appreciated that they may depend on their route of administration, the particular tumor being treated and the particular host being treated. Optimal methods and sequences of administration, as well as dosages and regimens, can be readily determined by one of ordinary skill in the art using conventional methods and with reference to the information provided herein.

Farnesyl transferase inhibitors are from 0.0001 mg / kg to 10
Up to 0 mg / kg (body weight), and especially from 0.001 mg / kg to 10 mg
Advantageously, an effective amount up to / kg (body weight) is administered. More specifically, for adult patients, the dosage is conveniently in the range 50 to 500 mg twice daily, preferably 10
0 to 400 mg twice daily, and especially 300 mg twice daily.

Antitumor vinca alkaloids are 2 to 30 m / m 2 of body surface area
g (mg / m ² ) dosage, especially about 3 to 12 mg / m ² per course of treatment for vinblastine, about 1 to 2 m for vincristine
Advantageously, a dosage of g / m ^{2 and} a dosage of about 10 to 30 mg / m ² of vinorelbine are administered. These dosages may be, for example, once per course of treatment, 2
It may be administered once or more times, and may be repeated, for example, every 7, 14, 21 or 28 days.

It is especially preferred to administer the farnesyl transferase inhibitor at a dose of 100 or 200 mg twice a day for 7, 14, 21 or 28 days, with the doses of anti-tumor vinca alkaloids in the ranges indicated above. .

With reference to their useful pharmacological properties, the components of the combination of the invention, ie the antitumor vinca alkaloids and the farnesyl transferase inhibitors, may be formulated into various pharmaceutical forms for administration purposes. . The components may be formulated separately in separate pharmaceutical compositions, or in a unitary pharmaceutical composition containing both components. Farnesyl protein transferase inhibitors are prepared by methods known in the art and in particular according to the methods described in the published patent specifications incorporated herein by reference and incorporated into pharmaceutical compositions. Can be prescribed. Suitable examples of compounds of formulas (I), (II) and (III) can be found in WO-97 / 21701. formula(
Compounds of IV), (V) and (VI) are prepared using the method described in WO 97/16443, compounds of formulas (VII) and (VIII) are disclosed in WO 98/4.
According to the method described in WO 03/49157 and also
The compounds of formula (IX) can each be prepared and formulated according to the methods described in WO 00/39082.

The present invention therefore also relates to a pharmaceutical composition comprising an antitumor vinca alkaloid and a farnesyl transferase inhibitor of formula (I) together with one or more pharmaceutical carriers. To prepare a pharmaceutical composition for use in accordance with the present invention, an effective amount of a specific compound in the form of a base or acid addition salt as an active ingredient is combined with a pharmaceutically acceptable carrier in intimate admixture. The carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are preferably in unit dosage form, preferably for oral, rectal, transdermal, or parenteral injection. For example, in preparing compositions in oral dosage form, any conventional pharmaceutical vehicle, such as oral solutions, such as suspensions, syrups, elixirs and in the case of solutions water, glycols, oils, alcohols. Or in the case of powders, pills, capsules and tablets, solid carriers such as starch, sugars, kaolin, lubricants, binders, disintegrants and the like may be used. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously used. For parenteral compositions, the carrier will usually comprise sterile water, although at least in large part it may contain other ingredients, for example to aid solubility. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In compositions suitable for transdermal administration, the carrier optionally comprises a penetration enhancer and / or a suitable wetting agent, optionally in small proportions in combination with a suitable additive of any nature. The object does not cause any significant detrimental effects on the skin. The additive may facilitate administration to the skin and / or may serve to produce a desired composition. These compositions may be administered in various ways, eg as transdermal patches, spot-ons, ointments.

It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unit dosages, each unit in association with the required pharmaceutical carrier. It contains a predetermined amount of the active ingredient calculated to produce the desired therapeutic effect. Examples of such dosage unit forms are tablets, including scored or coated tablets
, Capsules, pills, powder sachets, cachets, injectable solutions or suspensions, teaspoons, tablespoons, and the like, and their composites separated.

It may be appropriate to administer the required dose of each component of the combination as sub doses of 2, 3, 4 or more at appropriate intervals throughout the course of treatment. The sub-dose is, for example, formulated as a unit dosage form, which in each case independently contains 0.01 to 500 mg, for example 0.1 to 200 mg, and especially 1 to 100 mg of each active ingredient per unit dosage form. You can do it. Experimental Testing of Combinations for Inhibition of Tumor Growth The combinations of the invention are tested using conventional assays described in the literature, eg Liu M et.
al., Cancer Research, Vol.58, No. 21, 1 November 1998, 4949-4956, HTB177 lung cancer, and Moasser M et al, Proc. Natl. Acad. Sci.
USA, Vol. 95, pp. 1369-1374, February 1998, may be tested for their effectiveness in inhibiting tumor growth using the anti-mitotic assay. Other in vitro and in vivo models for determining the antitumor effect of combinations and the possible synergistic effects of the combinations of the invention are described in WO 98/54966 and WO 98/32114. Clinical models to determine efficacy and possible synergies for combination therapy in the clinic are generally Cancer
: Principles and Practice of Oncology, Fifth Edition, edited by Vincent
T DeVita, Jr., Samuel Hellman, Steven A. Rosenberg, Lippincott-Raven, Ph
iladelphia, 1997, inter alia Chapter 17, pages 342-346.

─────────────────────────────────────────────────── ─── Continued front page    (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE, TR), OA (BF , BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, G M, KE, LS, MW, MZ, SD, SL, SZ, TZ , UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, B Z, CA, CH, CN, CR, CU, CZ, DE, DK , DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, J P, KE, KG, KP, KR, KZ, LC, LK, LR , LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, R O, RU, SD, SE, SG, SI, SK, SL, TJ , TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Borden, Christopher Theei             United States New Jersey State 08551             Lingus Linvale Road 115 F-term (reference) 4C084 AA19 AA20 MA02 MA52 MA55                       NA05 ZB261 ZC201                 4C086 AA01 AA02 BC29 BC46 CB05                       MA02 MA52 MA55 NA05 ZB26                       ZC20

Claims (14)

[Claims] 1. An antitumor vinca alkaloid, and the following formulas (I) and (
II), (III), (IV), (V), (VI), (VII), (VIII)
And compounds of (IX): [Chemical 1] Pharmaceutically acceptable acid or base addition salts and stereoisomers thereof (wherein
Dotted lines represent arbitrary bonds; X is oxygen or sulfur; R¹ Is hydrogen, C_1-12Alkyl, Ar¹ , Ar² C_1-6 Alkyl, quinolinyl C _1-6  Alkyl, pyridyl C_1-6 Alkyl, hydroxy C_1-6 Alkyl, C_1-6 A
Luquiloxy C_1-6 Alkyl, mono- or di (C_1-6 Alkyl) amino C_{1- 6}  Alkyl, amino C_1-6 Alkyl, Or formula-Alk¹ -C (= O) -R⁹ , -Alk¹ -S (O) -R⁹ Or
-Alk¹ -S (O)₂ -R⁹ Is the basis of (Alk in the formula¹ Is C_1-6 Is an alkane diyl, R⁹ Is hydroxy, C_1-6 Alkyl, C_1-6 Alkyloxy, amino, C_1-8 A
Rukiruamino or C_1-6 C substituted with alkyloxycarbonyl_1-8 A
Rukiruamino); R² , R³ And R¹⁶Are each independently hydrogen, hydroxy, halo, cyano,
C_1-6 Alkyl, C_1-6 Alkyloxy, hydroxy C_1-6 Alkyloxy, C _1-6  Alkyloxy C_1-6 Alkyloxy, amino C_1-6 Alkyloxy, mono
-Or di (C_1-6 Alkyl) amino C_1-6 Alkyloxy, Ar¹ , Ar² 
C_1-6 Alkyl, Ar² Oxy, Ar² C_1-6 Alkyloxy, hydroxycal
Bonil, C_1-6 Alkyloxycarbonyl, trihalomethyl, trihalomethoxy
, C_2-6 Alkenyl, 4,4-dimethyloxazolyl; or R in adjacent positions² And R³ Are expressions together -O-CH₂ -O- (a-1), -O-CH₂ -CH₂ -O- (a-2), -O-CH = CH- (a-3), -O-CH₂ -CH₂ -(A-4), -O-CH₂ -CH₂ -CH₂ -(A-5), or -CH = CH-CH = CH- (a-6) May form a divalent group of R^Four And R^Five Are each independently hydrogen, halo, Ar¹ , C_1-6 Alkyl, hydr
Roxy C_1-6 Alkyl, C_1-6 Alkyloxy C_1-6 Alkyl, C_1-6 Alkyl
Oxy, C_1-6 Alkylthio, amino, hydroxycarbonyl, C_1-6 Alkyl
Oxycarbonyl, C_1-6 Alkyl S (O) C_1-6 Alkyl or C_1-6 Al
Kill S (O)₂ C_1-6 Alkyl; R⁶ And R⁷ Are each independently hydrogen, halo, cyano, C_1-6 Alkyl, C_{1- 6}  Alkyloxy, Ar² Oxy, trihalomethyl, C_1-6 Alkylthio, di (
C_1-6 Alkyl) amino, or R in adjacent positions⁶ And R⁷ Are expressions together -O-CH₂ -O- (c-1), or -CH = CH-CH = CH- (c-2) May form a divalent group of R⁸ Is hydrogen, C_1-6 Alkyl, cyano, hydroxycarbonyl, C_1-6 Alkyl
Oxycarbonyl, C_1-6 Alkyl carbonyl C_1-6 Alkyl, cyano C_1-6 A
Rukiru, C_1-6 Alkyloxycarbonyl C_1-6 Alkyl, carboxy C_1-6 A
Ruquil, hydroxy C_1-6 Alkyl, amino C_1-6 Alkyl, mono- or di
(C_1-6 Alkyl) amino C_1-6 Alkyl, imidazolyl, halo C_1-6 Alkyl
, C_1-6 Alkyloxy C_1-6 Alkyl, aminocarbonyl C_1-6 Alkyl,
Or formula -OR^Ten                (B-1), -SR^Ten                (B-2), -NR¹¹R¹²            (B-3) Is the basis of (In the formula, R^TenIs hydrogen, C_1-6 Alkyl, C_1-6 Alkylcarbonyl, Ar¹ , A
r² C_1-6 Alkyl, C_1-6 Alkyloxycarbonyl C_1-6 Alkyl, or
Formula-Alk² -OR¹³Or-Alk² -NR¹⁴R¹⁵Is the basis of; R¹¹Is hydrogen, C_1-12Alkyl, Ar¹ Or Ar² C_1-6 Alkyl; R¹²Is hydrogen, C_1-6 Alkyl, C_1-16Alkylcarbonyl, C_1-6 Alkyl oki
Sicarbonyl, C_1-6 Alkylaminocarbonyl, Ar¹ , Ar² C_1-6 Archi
Le, C_1-6 Alkyl carbonyl C_1-6 Alkyl, natural amino acid, Ar¹ Carboni
Le, Ar² C_1-6 Alkylcarbonyl, aminocarbonylcarbonyl, C_1-6 A
Luquiloxy C_1-6 Alkylcarbonyl, hydroxy, C_1-6 Alkyloxy,
Aminocarbonyl, di (C_1-6 Alkyl) amino C_1-6 Alkylcarbonyl, a
Mino, C_1-6 Alkylamino, C_1-6 Alkylcarbonylamino, or formula-A
lk² -OR¹³Or-Alk² -NR¹⁴R¹⁵Is the basis of; Where Alk² Is C_1-6 Alkane diyl; R¹³Is hydrogen, C_1-6 Alkyl, C_1-6 Alkyl carbonyl, hydroxy C_1-6 A
Rukiru, Ar¹ Or Ar² C_1-6 Alkyl; R¹⁴Is hydrogen, C_1-6 Alkyl, Ar¹ Or Ar² C_1-6 Alkyl; R¹⁵Is hydrogen, C_1-6 Alkyl, C_1-6 Alkylcarbonyl, Ar¹ Or Ar ²  C_1-6 Alkyl); R¹⁷Is hydrogen, halo, cyano, C_1-6 Alkyl, C_1-6 Alkyloxycarbonyl
, Ar¹ And R¹⁸Is hydrogen, C_1-6 Alkyl, C_1-6 Alkyloxy or halo; R¹⁹Is hydrogen or C_1-6 Alkyl; Ar¹ Is phenyl or C_1-6 Alkyl, hydroxy, amino, C_1-6 Alkyl
Phenyl substituted with oxy or halo; and Ar² Is phenyl or C_1-6 Alkyl, hydroxy, amino, C_1-6 Alkyl
Phenyl substituted with oxy or halo] [Chemical 2] Pharmaceutically acceptable acid or base addition salts and stereoisomers thereof (wherein
Dotted lines represent arbitrary bonds; X is oxygen or sulfur; R¹ Is hydrogen, C_1-12Alkyl, Ar¹ , Ar² C_1-6 Alkyl, quinolinyl C _1-6  Alkyl, pyridyl C_1-6 Alkyl, hydroxy C_1-6 Alkyl, C_1-6 A
Luquiloxy C_1-6 Alkyl, mono- or di (C_1-6 Alkyl) amino C_{1- 6}  Alkyl, amino C_1-6 Alkyl, Or formula-Alk¹ -C (= O) -R⁹ , -Alk¹ -S (O) -R⁹ Or
-Alk¹ -S (O)₂ -R⁹ Is the basis of (Alk in the formula¹ Is C_1-6 Is an alkane diyl, R⁹ Is hydroxy, C_1-6 Alkyl, C_1-6 Alkyloxy, amino, C_1-8 A
Rukiruamino or C_1-6 C substituted with alkyloxycarbonyl_1-8 A
Rukiruamino); R² And R³ Are each independently hydrogen, hydroxy, halo, cyano, C_1-6 
Alkyl, C_1-6 Alkyloxy, hydroxy C_1-6 Alkyloxy, C_1-6 A
Luquiloxy C_1-6 Alkyloxy, amino C_1-6 Alkyloxy, mono-if
Kuhaji (C_1-6 Alkyl) amino C_1-6 Alkyloxy, Ar¹ , Ar² C_1-6 
Alkyl, Ar² Oxy, Ar² C_1-6 Alkyloxy, hydroxycarbonyl
, C_1-6 Alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C_{2- 6}  Alkenyl; or R in adjacent positions² And R³ Are expressions together -O-CH₂ -O- (a-1), -O-CH₂ -CH₂ -O- (a-2), -O-CH = CH- (a-3), -O-CH₂ -CH₂ -(A-4), -O-CH₂ -CH₂ -CH₂ -(A-5), or -CH = CH-CH = CH- (a-6) May form a divalent group of R^Four And R^Five Are each independently hydrogen, Ar¹ , C_1-6 Alkyl, C_1-6 Al
Killoxy C_1-6 Alkyl, C_1-6 Alkyloxy, C_1-6 Alkylthio, Ami
No, hydroxycarbonyl, C_1-6 Alkyloxycarbonyl, C_1-6 Alkyl
S (O) C_1-6 Alkyl or C_1-6 Alkyl S (O)₂ C_1-6 In alkyl
R; R⁶ And R⁷ Are each independently hydrogen, halo, cyano, C_1-6 Alkyl, C_{1- 6}  Alkyloxy or Ar² Is oxy; R⁸ Is hydrogen, C_1-6 Alkyl, cyano, hydroxycarbonyl, C_1-6 Alkyl
Oxycarbonyl, C_1-6 Alkyl carbonyl C_1-6 Alkyl, cyano C_1-6 A
Rukiru, C_1-6 Alkyloxycarbonyl C_1-6 Alkyl, hydroxycarboni
Le C_1-6 Alkyl, hydroxy C_1-6 Alkyl, amino C_1-6 Alkyl, mono-
Or J (C_1-6 Alkyl) amino C_1-6 Alkyl, halo C_1-6 Alkyl, C _1-6  Alkyloxy C_1-6 Alkyl, aminocarbonyl C_1-6 Alkyl, Ar¹ 
, Ar² C_1-6 Alkyloxy C_1-6 Alkyl, C_1-6 Alkylthio C_1-6 Al
Is a kill; R^TenIs hydrogen, C_1-6 Alkyl, C_1-6 Alkyloxy or halo; R¹¹Is hydrogen or C_1-6 Alkyl; Ar¹ Is phenyl or C_1-6 Alkyl, hydroxy, amino, C_1-6 Alkyl
Phenyl substituted with oxy or halo; Ar² Is phenyl or C_1-6 Alkyl, hydroxy, amino, C_1-6 Alkyl
Phenyl substituted with oxy or halo] [Chemical 3] The pharmaceutically acceptable acid addition salts and stereoisomers thereof (wherein Dotted lines represent arbitrary bonds; X is oxygen or sulfur; -A- is the formula -CH = CH- (a-1), -CH₂ -CH₂ -(A-2), -CH₂ -CH₂ -CH₂ -(A-3), -CH₂ -O- (a-4), -CH₂ -CH₂ -O- (a-5), -CH₂ -S- (a-6), -CH₂ -CH₂ -S- (a-7), -CH = N- (a-8), -N = N- (a-9), or -CO-NH- (a-10) Is a divalent group of, where one hydrogen atom may be C_1-4 Alkyl
Is Ar¹ May be replaced by R¹ And R² Are each independently hydrogen, hydroxy, halo, cyano, C_1-6 
Alkyl, trihalomethyl, trihalomethoxy, C_2-6 Alkenyl, C_1-6 Al
Kiroxy, hydroxy C_1-6 Alkyloxy, C_1-6 Alkyloxy C_1-6 A
Lucyloxy, C_1-6 Alkyloxycarbonyl, amino C_1-6 Alkyloxy
, Mono- or di (C_1-6 Alkyl) amino C_1-6 Alkyloxy, Ar² ,
Ar² -C_1-6 Alkyl, Ar² -Oxy, Ar² -C_1-6 Alkyloxy
R; or R in adjacent positions¹ And R² Are expressions together -O-CH₂ -O- (b-1), -O-CH₂ -CH₂ -O- (b-2), -O-CH = CH- (b-3), -O-CH₂ -CH₂ -(B-4), -O-CH₂ -CH₂ -CH₂ -(B-5), or -CH = CH-CH = CH- (b-6) May form a divalent group of R³ And R^Four Are each independently hydrogen, halo, cyano, C_1-6 Alkyl, C_{1- 6}  Alkyloxy, Ar³ -Oxy, C_1-6 Alkylthio, di (C_1-6 Alkyl
) Amino, trihalomethyl, trihalomethoxy, or at adjacent positions.
R³ And R^Four Are expressions together -O-CH₂ -O- (c-1), -O-CH₂ -CH₂ -O- (c-2), or -CH = CH-CH = CH- (c-3) May form a divalent group of R^Five Is an expression [Chemical 4] (Wherein R is¹³Is hydrogen, halo, Ar^Four , C_1-6 Alkyl, hydroxy
C_1-6 Alkyl, C_1-6 Alkyloxy C_1-6 Alkyl, C_1-6 Alkyloxy
, C_1-6 Alkylthio, amino, C_1-6 Alkyloxycarbonyl, C_1-6 Al
Kill S (O) C_1-6 Alkyl or C_1-6 Alkyl S (O)₂ C_1-6 Alkyl
And R¹⁴Is hydrogen, C_1-6 Alkyl or di (C_1-4 Alkyl) aminosulfonyl
is there); R⁶ Is hydrogen, hydroxy, halo, C_1-6 Alkyl, cyano, halo C_1-6 Alkyl
, Hydroxy C_1-6 Alkyl, cyano C_1-6 Alkyl, amino C_1-6 Alkyl,
C_1-6 Alkyloxy C_1-6 Alkyl, C_1-6 Alkylthio C_1-6 Alkyl, a
Minocarbonyl C_1-6 Alkyl, C_1-6 Alkyloxycarbonyl C_1-6 Archi
Le, C_1-6 Alkylcarbonyl-C_1-6 Alkyl, C_1-6 Alkyl oxycarbo
Nyl, mono- or di (C_1-6 Alkyl) amino C_1-6 Alkyl, Ar^Five , A
r^Five -C_1-6 Alkyloxy C_1-6 Alkyl; or formula -OR⁷               (E-1), -SR⁷               (E-2), -NR⁸ R⁹           (E-3) Is the basis of (In the formula, R⁷ Is hydrogen, C_1-6 Alkyl, C_1-6 Alkylcarbonyl, Ar⁶ , A
r⁶ -C_1-6 Alkyl, C_1-6 Alkyloxycarbonyl C_1-6 Alkyl again
Is the formula -Alk-OR^TenOr-Alk-NR¹¹R¹²Is the basis of; R⁸ Is hydrogen, C_1-6 Alkyl, Ar⁷ Or Ar⁷ -C_1-6 Alkyl;
R⁹ Is hydrogen, C_1-6 Alkyl, C_1-6 Alkylcarbonyl, C_1-6 Alkyl oki
Sicarbonyl, C_1-6 Alkylaminocarbonyl, Ar⁸ , Ar⁸ -C_1-6 Al
Kill, C_1-6 Alkyl carbonyl C_1-6 Alkyl, Ar⁸ -Carbonyl, Ar⁸ 
-C_1-6 Alkylcarbonyl, aminocarbonylcarbonyl, C_1-6 Alkylio
Kishi C_1-6 Alkylcarbonyl, hydroxy, C_1-6 Alkyloxy, Aminoca
Lubonyl, di (C_1-6 Alkyl) amino C_1-6 Alkylcarbonyl, amino, C _1-6  Alkylamino, C_1-6 Alkylcarbonylamino, Or formula-Alk-OR^TenOr-Alk-NR¹¹R¹²Is the basis of; Where Alk is C_1-6 Alkane diyl; R^TenIs hydrogen, C_1-6 Alkyl, C_1-6 Alkyl carbonyl, hydroxy C_1-6 A
Rukiru, Ar⁹ Or Ar⁹ -C_1-6 Alkyl; R¹¹Is hydrogen, C_1-6 Alkyl, C_1-6 Alkylcarbonyl, Ar^TenOr Ar ^Ten -C_1-6 Alkyl; R¹²Is hydrogen, C_1-6 Alkyl, Ar¹¹Or Ar¹¹-C_1-6 Is alkyl)
; And Ar¹ Or Ar¹¹Are each independently phenyl; or halo, C_1-6 Alkyl
, C_1-6 From phenyl substituted with alkyloxy or trifluoromethyl
To be elected〕 [Chemical 5] The pharmaceutically acceptable acid addition salts and stereoisomers thereof (wherein Dotted lines represent arbitrary bonds; X is oxygen or sulfur; R¹ And R² Are each independently hydrogen, hydroxy, halo, cyano, C_1-6 
Alkyl, trihalomethyl, trihalomethoxy, C_2-6 Alkenyl, C_1-6 Al
Kiroxy, hydroxy C_1-6 Alkyloxy, C_1-6 Alkyloxy C_1-6 A
Lucyloxy, C_1-6 Alkyloxycarbonyl, amino C_1-6 Alkyloxy
, Mono- or di (C_1-6 Alkyl) amino C_1-6 Alkyloxy, Ar¹ ,
Ar¹ C_1-6 Alkyl, Ar¹ Oxy or Ar¹ C_1-6 Is alkyloxy
; R³ And R^Four Are each independently hydrogen, halo, cyano, C_1-6 Alkyl, C_{1- 6}  Alkyloxy, Ar¹ Oxy, C_1-6 Alkylthio, di (C_1-6 Alkyl)
Amino, trihalomethyl or trihalomethoxy; R^Five Is hydrogen, halo, C_1-6 Alkyl, cyano, halo C_1-6 Alkyl, hydroxy
C_1-6 Alkyl, cyano C_1-6 Alkyl, amino C_1-6 Alkyl, C_1-6 Archi
Loxy C_1-6 Alkyl, C_1-6 Alkylthio C_1-6 Alkyl, aminocarboni
Le C_1-6 Alkyl, C_1-6 Alkyloxycarbonyl C_1-6 Alkyl, C_1-6 A
Lukyrcarbonyl-C_1-6 Alkyl, C_1-6 Alkyloxycarbonyl, mono-
Or J (C_1-6 Alkyl) amino C_1-6 Alkyl, Ar¹ , Ar¹ C_1-6 A
Luquiloxy C_1-6 Alkyl; or formula -OR^Ten              (A-1), -SR^Ten              (A-2), -NR¹¹R¹²          (A-3) Is the basis of (In the formula, R^TenIs hydrogen, C_1-6 Alkyl, C_1-6 Alkylcarbonyl, Ar¹ , A
r¹ C_1-6 Alkyl, C_1-6 Alkyloxycarbonyl C_1-6 Alkyl, or
Formula-Alk-OR¹³Or-Alk-NR¹⁴R¹⁵Is the basis of; R¹¹Is hydrogen, C_1-6 Alkyl, Ar¹ Or Ar¹ C_1-6 Alkyl; R¹²Is hydrogen, C_1-6 Alkyl, C_1-6 Alkylcarbonyl, C_1-6 Alkyl oki
Sicarbonyl, C_1-6 Alkylaminocarbonyl, Ar¹ , Ar¹ C_1-6 Archi
Le, C_1-6 Alkyl carbonyl C_1-6 Alkyl, Ar¹ Carbonyl, Ar¹ C_{1- 6}  Alkylcarbonyl, aminocarbonylcarbonyl, C_1-6 Alkyloxy C _1-6  Alkylcarbonyl, hydroxy, C_1-6 Alkyloxy, aminocarboni
Le, J (C_1-6 Alkyl) amino C_1-6 Alkylcarbonyl, amino, C_1-6 A
Rukiruamino, C_1-6 Alkylcarbonylamino, Or formula-Alk-OR¹³Or-Alk-NR¹⁴R¹⁵Is the basis of; Where Alk is C_1-6 Alkane diyl; R¹³Is hydrogen, C_1-6 Alkyl, C_1-6 Alkyl carbonyl, hydroxy C_1-6 A
Rukiru, Ar¹ Or Ar¹ C_1-6 Alkyl; R¹⁴Is hydrogen, C_1-6 Alkyl, Ar¹ Or Ar¹ C_1-6 Alkyl; R¹⁵Is hydrogen, C_1-6 Alkyl, C_1-6 Alkylcarbonyl, Ar¹ Or Ar  ¹C_1-6 Alkyl); R⁶ Is an expression [Chemical 6] Is the basis of (In the formula, R¹⁶Is hydrogen, halo, Ar¹ , C_1-6 Alkyl, hydroxy C_1-6 Archi
Le, C_1-6 Alkyloxy C_1-6 Alkyl, C_1-6 Alkyloxy, C_1-6 Al
Kirthio, Amino, C_1-6 Alkyloxycarbonyl, C_1-6 Alkylthio C_{1- 6}  Alkyl, C_1-6 Alkyl S (O) C_1-6 Alkyl or C_1-6 Alkyl S
(O)₂ C_1-6 Alkyl; R¹⁷Is hydrogen, C_1-6 Alkyl or di (C_1-4 Alkyl) aminosulfonyl
is there); R⁷ Is hydrogen or C if the dotted line does not represent a bond_1-6 Alkyl; R⁸ Is hydrogen, C_1-6 Alkyl or Ar² CH₂ Or Het¹ CH₂ And
R; R⁹ Is hydrogen, C_1-6 Alkyl, C_1-6 Alkyloxy or halo; and
Is R⁸ And R⁹ Are expressions together -CH = CH- (c-1), -CH₂ -CH₂ -(C-2), -CH₂ -CH₂ -CH₂ -(C-3), -CH₂ -O- (c-4), or -CH₂ -CH₂ -O- (c-5) To form a divalent group of Ar¹ Is phenyl; or each independently halo, C_1-6 Alkyl, C_1-6 Al
1 or 2 substituents selected from killoxy or trifluoromethyl
Phenyl substituted with Ar² Is phenyl; or each independently halo, C_1-6 Alkyl, C_1-6 Al
1 or 2 substituents selected from killoxy or trifluoromethyl
Phenyl substituted with; and Het¹ Is pyridinyl; each independently halo, C_1-6 Alkyl, C_1-6 Archi
With 1 or 2 substituents selected from luoxy or trifluoromethyl
It is a substituted pyridinyl] And [Chemical 7] Or their pharmaceutically acceptable acid addition salts and stereoisomers [wherein = X¹ -X² -X³ − Is an expression = N-CR⁶ = CR⁷ -(X-1), = N-N = CR⁶ -(X-2), = N-NH-C (= O)-(x-3), = N-N = N- (x-4), = N-CR⁶ = N- (x-5), = CR⁶ -CR⁷ = CR⁸ -(X-6), = CR⁶ -N = CR⁷ -(X-7), = CR⁶ -NH-C (= O)-(x-8), or = CR⁶ -N = N- (x-9) Is a trivalent group of (In the formula, each R⁶ , R⁷ And R⁸ Independently hydrogen, C_1-4 Alkyl, hi
Droxy, C_1-4 Alkyloxy, aryloxy, C_1-4 Alkyl oxycal
Bonyl, hydroxy C_1-4 Alkyl, C_1-4 Alkyloxy C_1-4 Alkyl, mo
No or Di (C_1-4 Alkyl) amino C_1-4 Alkyl, cyano, amino, thi
Oh, C_1-4 Alkylthio, arylthio or aryl); > Y¹ -Y² − Is an expression > CH-CHR⁹ -(Y-1), > C = N- (y-2), > CH-NR⁹ -(Y-3), or > C = CR⁹ -(Y-4) Is a trivalent group of (In the formula, each R⁹ Are independently hydrogen, halo, halocarbonyl, aminocarbo
Nyl, hydroxy C_1-4 Alkyl, cyano, carboxyl, C_1-4 Alkyl, C _1-4  Alkyloxy, C_1-4 Alkyloxy C_1-4 Alkyl, C_1-4 Alkylio
Xycarbonyl, mono- or di (C_1-4 Alkyl) amino, mono-or
The (C_1-4 Alkyl) amino C_1-4 Alkyl and aryl); r and s are each independently 0, 1, 2, 3, 4 or 5; t is 0, 1, 2 or 3; Each R¹ And R² Are independently hydroxy, halo, cyano, C_1-6 Archi
L, trihalomethyl, trihalomethoxy, C_2-6 Alkenyl, C_1-6 Alkylio
Xy, hydroxy C_1-6 Alkyloxy, C_1-6 Alkylthio, C_1-6 Alkyl
Oxy C_1-6 Alkyloxy, C_1-6 Alkyloxycarbonyl, amino C_1-6 
Alkyloxy, mono- or di (C_1-6 Alkyl) amino, mono-or
The (C_1-6 Alkyl) amino C_1-6 Alkyloxy, aryl, aryl C_1-6 
Alkyl, aryloxy or aryl C_1-6 Alkyloxy, hydroxyca
Lubonyl, C_1-6 Alkyloxycarbonyl, aminocarbonyl, amino C_1-6 
Alkyl, mono- or di (C_1-6 Alkyl) aminocarbonyl, mono-if
Kuhaji (C_1-6 Alkyl) amino C_1-6 Alkyl; or Two Rs adjacent to each other on the phenyl ring¹ Or R² Substituents taken together in formula
-O-CH₂ -O- (a-1), -O-CH₂ -CH₂ -O- (a-2), -O = CH = CH- (a-3), -O-CH₂ -CH₂ -(A-4), -O-CH₂ -CH₂ -CH₂ -(A-5), or -CH = CH-CH = CH- (a-6) May independently form a divalent group of R³ Is hydrogen, halo, C_1-6 Alkyl, cyano, halo C_1-6 Alkyl, hydroxy
C_1-6 Alkyl, cyano C_1-6 Alkyl, amino C_1-6 Alkyl, C_1-6 Archi
Loxy C_1-6 Alkyl, C_1-6 Alkylthio C_1-6 Alkyl, aminocarboni
Le C_1-6 Alkyl, hydroxycarbonyl, hydroxycarbonyl C_1-6 Archi
Le, C_1-6 Alkyloxycarbonyl C_1-6 Alkyl, C_1-6 Alkyl Carboni
Le C_1-6 Alkyl, C_1-6 Alkyloxycarbonyl, aryl, aryl C_{1- 6}  Alkyloxy C_1-6 Alkyl, mono- or di (C_1-6 Alkyl) amino
C_1-6 Alkyl; Or expression -OR^Ten                      (B-1), -SR^Ten                      (B-2), -NR¹¹R¹²                    (B-3) Is the basis of (In the formula, R^TenIs hydrogen, C_1-6 Alkyl, C_1-6 Alkylcarbonyl, aryl,
Aryl C_1-6 Alkyl, C_1-6 Alkyloxycarbonyl C_1-6 Alkyl,
Or formula-Alk-OR¹³Or-Alk-NR¹⁴R¹⁵Is the basis of; R¹¹Is hydrogen, C_1-6 Alkyl, aryl or aryl C_1-6 Is alkyl
; R¹²Is hydrogen, C_1-6 Alkyl, aryl, hydroxy, amino, C_1-6 Alkyl
Oxy, C_1-6 Alkyl carbonyl C_1-6 Alkyl, aryl C_1-6 Alkyl,
C_1-6 Alkylcarbonylamino, mono- or di (C_1-6 Alkyl) amino
, C_1-6 Alkyl carbonyl, amino carbonyl, aryl carbonyl, halo C _1-6  Alkyl carbonyl, aryl C_1-6 Alkylcarbonyl, C_1-6 Alkyl
Oxycarbonyl, C_1-6 Alkyloxy C_1-6 Alkylcarbonyl, mono-
Shiji (C_1-6 Alkyl) aminocarbonyl (where the alkyl moiety is optionally
Aryl or C_1-3 1 independently selected from alkyloxycarbonyl
May be substituted with one or more substituents), aminocarbonylcarb
Bonyl, mono- or di (C_1-6 Alkyl) amino C_1-6 Alkyl carbonyl
Or formula-Alk-OR¹³Or-Alk-NR¹⁴R¹⁵Is the basis of; Where Alk is C_1-6 Alkane diyl; R¹³Is hydrogen, C_1-6 Alkyl, C_1-6 Alkyl carbonyl, hydroxy C_1-6 A
Ruquil, aryl or aryl C_1-6 Alkyl; R¹⁴Is hydrogen, C_1-6 Alkyl, aryl or aryl C_1-6 Is alkyl
; R¹⁵Is hydrogen, C_1-6 Alkyl, C_1-6 Alkylcarbonyl, aryl or a
Reel C_1-6 Alkyl); R^Four Is an expression [Chemical 8] Is the basis of (In the formula, R¹⁶Is hydrogen, halo, aryl, C_1-6 Alkyl, hydroxy C_1-6 Al
Kill, C_1-6 Alkyloxy C_1-6 Alkyl, C_1-6 Alkyloxy, C_1-6 A
Rukiruthio, amino, mono- or di (C_1-4 Alkyl) amino, hydroxy
Carbonyl, C_1-6 Alkyloxycarbonyl, C_1-6 Alkylthio C_1-6 Al
Kill, C_1-6 Alkyl S (O) C_1-6 Alkyl or C_1-6 Alkyl S (O)₂ 
C_1-6 Alkyl; R¹⁶Is one of the nitrogen atoms in the imidazole ring of formula (c-1) or (c-2)
May be bonded, in which case R when bonded to nitrogen¹⁶Means hydrogen, a
Reel, C_1-6 Alkyl, hydroxy C_1-6 Alkyl, C_1-6 Alkyloxy C _1-6  Alkyl, C_1-6 Alkyloxycarbonyl, C_1-6 Alkyl S (O) C_{1- 6}  Alkyl or C_1-6 Alkyl S (O)₂ C_1-6 Limited to alkyl; R¹⁷Is hydrogen, C_1-6 Alkyl, C_1-6 Alkyloxy C_1-6 Alkyl, aryl
C_1-6 Alkyl, trifluoromethyl or di (C_1-4 Alkyl) aminosul
Honil); R^Five Is C_1-6 Alkyl, C_1-6 Alkyloxy or halo; Aryl is phenyl, naphthalenyl, or each independently halo, C_1-6 Al
Kill, C_1-6 1 if selected from alkyloxy or trifluoromethyl
Is phenyl substituted with more substituents] A farnesyl transferase inhibitor selected from the following: 2. The combination according to claim 1, wherein the farnesyl protein transferase inhibitor is a compound of formula (I) in which X is oxygen and the dotted line represents a bond. 3. A farnesyl protein transferase inhibitor is R ¹
Is hydrogen, C _1-6 alkyl, C _1-6 alkyloxy C _1-6 alkyl or mono- or di (C _1-6 alkyl) amino C _1-6 alkyl, and R ³ is hydrogen and A formula (wherein R ² is halo, C _1-6 alkyl, C _2-6 alkenyl, C _1-6 alkyloxy, trihalomethoxy or hydroxy C _1-6 alkyloxy)
The combination according to claim 1 or 2, which is the compound of I). 4. The farnesyl protein transferase inhibitor is R ⁸
Is hydrogen, hydroxy, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, cyano C _1-6 alkyl, C _1-6 alkyloxycarbonyl C _1-6 alkyl, imidazolyl, or a group of the formula —NR ¹¹ R ¹² Wherein R ¹¹ is hydrogen or C _1-12 alkyl and R ¹² is hydrogen, C _1-6 alkyl, C _1-6 alkyloxy, C _1-6 alkyloxy C _1-6 alkylcarbonyl, hydroxy or formula a group of the Alk ² -OR ^13, wherein R ¹³ is a compound of formula (I) is hydrogen or C _1-6 alkyl), combination according any one of the preceding claims. 5. A farnesyl transferase inhibitor is 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-1H-imidazol-5-ylmethyl] -4- (3-chlorophenyl) -1-methyl-2 (1H) -quinolinone; 6-[(4- Chlorophenyl) hydroxy (1-methyl-1H-imidazole-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; -Amino (4-chlorophenyl) (1-methyl-1H-imidazol-5-yl) methyl] -1-methyl-4- (3-propylphenyl) -2 (1H) -quinolinone; stereoisomers thereof or them The combination according to claim 1, which is selected from the pharmaceutically acceptable acid or base addition salts of. 6. A farnesyl transferase inhibitor is (+)-6- [
Amino (4-chlorophenyl) (1-methyl-1H-imidazol-5-yl) methyl] -4- (3-chlorophenyl) -1-methyl-2 (1H) -quinolinone;
Alternatively, the combination according to claim 1, which is a pharmaceutically acceptable acid addition salt thereof. 7. The farnesyl protein transferase inhibitor is = X ¹  -X² -X³ Is a trivalent group of formula (x-2), (x-3) or (x-4)
,> Y¹ -Y² Is a trivalent group of formula (y-2), (y-3) or (y-4)
, R and s are 1 and t is 0, R¹ Is halo, preferably chloro,
Most preferably 3-chloro or R¹ Is C_1-4 Alkyl, preferably
Is 3-methyl, R² Is halo, preferably chloro, and most preferably 4
-Chloro, R³ Is a group of formula (b-1) or (b-3), and R^Four Is the expression
A group of (c-2), R⁶ Is C_1-4 Alkyl and R⁹ Is hydrogen and R^Ten And R¹¹Is hydrogen and R¹²Formula (IX) wherein is hydrogen or hydroxy
The combination according to claim 1, which is a compound of 1. 8. A farnesyl protein transferase inhibitor comprises 5-
(3-chlorophenyl) -α- (4-chlorophenyl) -α- (1-methyl-1
The combination according to claim 1, which is H-imidazol-5-yl) tetrazolo [1,5-a] quinazoline-7-methanamine or a pharmaceutically acceptable acid addition salt thereof. 9. A combination according to any of the preceding claims, wherein the anti-tumor vinca alkaloid is vinblastine, vincristine or vinorelbine. 10. An anti-tumor vinca alkaloid, together with one or more pharmaceutical carriers, as well as formula (I) (as defined in claim 1).
, (II), (III), (IV), (V), (VI), (VII), (VII
A combination according to any of the preceding claims in the form of a pharmaceutical composition comprising a farnesyl transferase inhibitor selected from compounds I) and (IX). 11. A combination according to any of the preceding claims for use in medical treatment. 12. The combination according to claim 11, for inhibiting the growth of tumor cells. 13. Use of a combination according to any of claims 1 to 12 in the manufacture of a pharmaceutical composition for inhibiting the growth of tumor cells. 14. A method of inhibiting the growth of tumor cells in a human subject, comprising administering to the subject an effective amount of the combination of any of claims 1-12.