MXPA01000161A - Farnesyl protein transferase inhibitors with in vivo - Google Patents
Farnesyl protein transferase inhibitors with in vivoInfo
- Publication number
- MXPA01000161A MXPA01000161A MXPA/A/2001/000161A MXPA01000161A MXPA01000161A MX PA01000161 A MXPA01000161 A MX PA01000161A MX PA01000161 A MXPA01000161 A MX PA01000161A MX PA01000161 A MXPA01000161 A MX PA01000161A
- Authority
- MX
- Mexico
- Prior art keywords
- alkyl
- hydrogen
- alkyloxy
- compound
- methyl
- Prior art date
Links
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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
INHIBITORS OF FARNESIL-PROTEIN TRANSFERASE WITH RADIO-SENSITIZING PROPERTIES IN VIVO
DESCRIPTIVE MEMORY
The present invention relates to the discovery that farnesyl protein transferase inhibitors have radiosensitizing properties that make them useful for preparing a pharmaceutical composition for administration before, during, or after irradiation of a tumor to treat cancer in vivo. WO97 / 21701, describes the preparation, formulation and pharmaceutical properties of (imidazol-5-yl) methyl-2-quinolinone derivatives that inhibit farnesyl protein transferase of formulas (I), (II) and (III) , as well as the intermediates of formulas (II) and (III) which are metabolized in vivo in the compounds of formula (I). The compounds of formulas (I), (II), (III) are represented by
(I) (III) the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein the dotted line represents an optional bond; X is oxygen or sulfur; R1 is hydrogen, C? -? 2 alkyl, Ar1, Ai ^ - C? -6 alkyl, quinolinyl-C1-6 alkyl, pyridyl-alkyl of d-6, hydroxy-alkyl of C? -6, C 1-6 alkyloxy-C 1-6 alkyl, mono- or di (C 1-6 alkyl) amino C 1-6 alkyl, C 1-6 amino-alkyl, or a radical of formula -Alk1-C (= O) -R9, -Alk1-S (O) -R9 or -Alk1-S (0) 2R9, where Alk1 is C1-6 alkanediyl, -R9 is hydroxy, Cvβ alkyl, alkyloxy C? -6, amino, C? -8 alkylamino or substituted alkylamino with Ci-β alkyloxycarbonyl; R2, R3 and R16 each independently are hydrogen, hydroxy, halogen, cyano, C-? 6 alkyl, Ci-β alkyloxy, d-6 hydroxy-alkyloxy, alkyloxy (Ci-βJ-C alquilo alkyloxy) 6, C-? -6-aminoalkyloxy, mono- or dKalkyloxyCi-e ^ amino-alkyloxy of d-6, Ar1, Ai ^ -alkyl of C? -6, Ar? Oxy, Ai ^ -alkyloxy of C? -6, hydroxycarbonyl, C-α-6 alkyloxycarbonyl, trihalogenomethyl, trihalogenometoxy, C 2-6 alkenyl, 4,4-dimethyloxazolyl, or when in adjacent positions, R 2 and R 3 taken together can form a bivalent radical of formula
0-CH2-O- (a-1), O-CH2-CH2-0- (a-2), 0-CH = CH- (a-3), • 0-CH2-CH2- (a-4) , 'O-CH-CH2-CH2- (a-5), or CH = CH-CH = CH- (a-6);
R4 and R5 are each independently hydrogen, halogen, Ar1, C1-6alkyl, hydroxyC1-6alkyl, C1.6alkyloxy- C1.6alkyl, C6-6alkyloxy, alkylthio C? .6, amino, hydroxycarbonyl, C1-alkyloxycarbonyl. 6, alkyl (C? .6) -S (O) -alkyl of C? .6 or alkyl (C? .6) -S (0) 2-alkyl of d.6, R6 and R7 each independently are hydrogen halogen, cyano, d-6 alkyl, d-β alkyloxy, Ai ^ oxy, trihalogenomethyl, alkylthio of C? _6, di (C? 6) -amino alkyl, or when in adjacent positions, R6 and R7 together can form a divalent radical of formula -0-CH2-O- (c-1), or -CH = CH-CH = CH- (c-2);
R8 is hydrogen, C1-6 alkyl. cyano, hydroxycarbonyl, C 1-6 alkyloxycarbonyl, alkylcarbonyl (C? -6) -alkyl of C? -6, cyano-alkyl
C? -6, alkyloxycarbonyl (C? 6) -alkyl of C 1-6, carboxy-alkyl of C 1-6, hydroxyalkyl of C? -6, amino-alkyl of d-6, mono- or C? -6, imidazolyl, halogen-d-6alkyl, (C6-6) alkyloxy-C1.6alkyl, aminocarbonyl-C-? -6alkyl, or a radical of the formula
where R10 is hydrogen, -β-alkyl, C1.6-alkylcarbonyl, Ar1, Ar2-d6 alkyl, alkyloxycarbonyl (C6-6) -Cl6-alkyl, or a radical of the formula -Alk2-OR13 or - Alk2-NR 4R15; R11 is hydrogen, C1-12 alkyl, Ar1 or Ar2 alkyl of d-β; R 12 is hydrogen, C 1-6 alkyl, C? -6 alkylcarbonyl, C? .6 alkylaminocarbonyl C1-6 alkyloxycarbonyl, Ar.sub.1, Ar.sub.2 -C.sub.6 alkyl, alkylcarbonyl (C.sub.6-6) -alkyl. -6, a natural amino acid, Ar1 carbonyl, Ar2 alkylcarbonyl of d-6, aminocarbonylcarbonyl, alkyloxy-d-ene-alkylcarbonyl of C1.6, hydroxy, alkyloxy of C6.6, aminocarbonyl, di (alkyl (C6-6) ) - C 1-6 aminoalkylcarbonyl, amino, C 1-6 alkylamino, alkylcarbonylamino of d.6, or a radical or of formula Alk2-OR13 or -Alk2-NR14R15; wherein Alk2 is C 1-6 alkanediyl; R13 is hydrogen, C1-6 alkyl, C1-6 alkylcarbonyl, C6-6 hydroxyalkyl, Ar1 or Ar2 alkyl of d-β; R 14 is hydrogen, C 1-6 alkyl, Ar 1 or Ar 2 C 1-6 alkyl; R15 is hydrogen, C1.6alkyl, C6-6 alkylcarbonyl, Ar1 or Ar2 alkyl of d.6; R17 is hydrogen, halogen, cyano, C6.6 alkyl, alkyloxycarbonyl of d-, Ar1; R18 is hydrogen, d-6 alkyl, alkyloxy or halogen;
R) 1? 9a is hydrogen or C 1-5 alkyl; Ar 1 is phenyl or phenyl substituted with d-6 alkyl, hydroxy, amino, C 1-6 alkyloxy or halogen and Ar 2 is phenyl or phenyl substituted with d-6 alkyl, hydroxy, amino, d-6 alkyloxy or halogen . WO97 / 16443 relates to the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibitor compounds of formula (IV), as well as the intermediates of formulas (V) and (VI) which are metabolized in vivo into the compounds of formula (IV). The compounds of formulas (IV), (V) and (VI) are represented by
(IV) the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein the dotted line represents an optional bond; X is oxygen or sulfur; R1 is hydrogen, d.sub.2 alkyl, Ar.sub.1, Ai.sub.--d6 alkyl, quinolinyl-d-6 alkyl, pyridyl-C de.sub.6 alkyl) hydroxy-d.β.alkyl, alkyloxy ( C? -6) -alkyl of C? _6, mono- or di (alkyl (C? -6)) -aminoalkyl of d-b, aminoalkyl of d-b, or a radical of formula -Alk1-C (= O ) -R9, -Alk1-S (O) -R9 or -Alk1-S (0) 2 -R9, wherein Alk1 is d-ß-alkyndiyl, R9 is hydroxy, C6-alkyl, C?-Alkyloxy 6, amino, C? -8 alkylamino or d-β alkylamino, substituted with C? -6 alkyloxycarbonyl; R2 and R3 are each independently hydrogen, hydroxy, halogen, cyano, C6-6 alkyl, C1-6 alkyloxy, hydroxy-alkyloxy of C6-6 > (C 6) alkyloxy-d-6alkyloxy, C 1-6 -alkyloxy, mono- or di (C 1-6 alkyl) -alkyloxy alkyloxy of C? .6, Ar 1, Ai ^ -alkyl of C? -6, Ar ^ oxy, Ai ^ -alkyloxy of C? -6, hydroxycarbonyl, alkyloxycarbonyl of d-6, trihalogenomethyl, trihalogenomethoxy, C2-6 alkenyl; or when they are in adjacent positions R2 and R3 together can form a bivalent radical of formula O-CH2-O- (a-1). • O-CH2-CH2-0- (a-2). O-CH = CH- (a-3), O-CH2-CH2- (a-4), O-CH2-CH2-CH2- (a-5), or CH = CH-CH = CH- (a- 6);
R4 and R5 are each independently hydrogen, Ar1, alkyl
of C1.6, alkyloxy (C? -6) -alkyl of C? 6, alkyloxy of Ci-β, alkylthio d-6, amino, hydroxycarbonyl, alkyloxycarbonyl of d-6, alkyl (C? -6) - S (0) -alkyl of -ß or
alkyl (C? -6) -S (O) 2-C? -6 alkyl, R6 and R7 are each independently hydrogen, halogen, cyano, C-uß alkyl, C? -6 alkyloxy or Ai ^ oxy , R8 is hydrogen, C6-6alkyl, cyano, hydroxycarbonyl, C6-6alkyloxycarbonyl, alkylcarbonyl (C6.6), C6-6alkyl) cyano-C6alkyl, alkyloxycarbonyl C? -6) -alkyl of C? 6, hydroxycarbonyl-C1-6alkyl, hydroxyC? -6alkyl, amino-C-? -6alkyl, mono- or di (alkyl (C? 6)) amino-Ci-β alkyl, halogen-C?-6 alkyl, C C-6 alkyloxy-C?-6 alkyl, aminocarbonyl-C?-6 alkyl, Ar1, C1- 6, alkylthio (C? -6) -alkyl of d-6,
R 10 is hydrogen, d-6 alkyl, C 1-6 alkyloxy, or halogen; R11 is hydrogen, C-? -6 alkyl; Ar1 is phenyl or phenyl substituted with C? -6 alkyl, hydroxy, amino, d-6alkyloxy or halogen; Ar 2 is phenyl or phenyl substituted with d-6 alkyl, hydroxy, amino, d-6 alkyloxy or halogen.
PCT / EP98 / 01296, filed March 3, 1998, relates to the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibitor compounds of formula (VII)
the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein the dotted line represents an optional bond; X is oxygen or sulfur; -A- is a bivalent radical of formula
• CH = CH- (a-1), -CH2-S- (a-6), • CH2-CH2- (a-2), -CH2-CH2-S- (a-7), • CH2-CHH2 -CH2- (a-3), -CH = N- (a-8), CH2-O- (a-4), -N = N- (a-9), CH2-CH2-O- (a- 5), -CO-NH- (a-10),
wherein optionally a hydrogen atom can be replaced by C 1 .4 alkyl or Ar 1;
R1 and R2 each independently are hydrogen, hydroxy, halogen, cyano, C6-6alkyl, trihalogenomethyl, trihalogenomethoxy-C2-6alkenyl) C-? 6alkyloxy, hydroxy-alkyloxy of d-6, alkyloxy C? -6, C-? -6-alkyloxycarbonyl, d-6-aminoalkyloxy mono- or di (alkyl (C-? 6)) - amino C 1-6 alkyloxy, Ar 2, Ar 2 -alkyl of d-? 6, Ai ^ -oxi, Ai ^ -alkyloxy of Ci-β; or when they are in adjacent positions, R1 and R2 together can form a bivalent radical of formula
R3 and R4 are independently hydrogen, halogen, cyano, d-6 alkyl, d-6alkyloxy, Ar -oxi, C? -6 alkylthio, di (C? -6) alkyl amino, trihalogenomethyl, trihalogenomethoxy , or when they are in adjacent positions, R3 and R4 together can form a bivalent radical of formula
R5 is a radical of formula
wherein R 13 is hydrogen, halogen, Ar 4, C 1-6 alkyl, hydroxy C 1-6 alkyl, C? .6 alkyloxy, C 1-6 alkyl, C 1-6 alkyloxy, C? .6 alkylthio, amino C 1-6 alkyloxycarbonyl, C .6 alkyl) -S (O) C? .6 alkyl or (C? -6) -S (O) 2 alkyl of d-β; R 14 is hydrogen, d-6 alkyl or di (C 1)) -aminosulfonyl alkyl, R d is hydrogen, hydroxy, halogen, d-6 alkyl, cyano, halogen d-6 alkyl, hydroxy C 1 alkyl- 6, cyano alkyl of d-6, amino alkyl of d-6, alkyloxy of d-6, alkyl of d-6, alkylthio of C? -6, alkyl d-6, aminocarbonyl of C? -6 alkyl, alkyloxycarbonyl of C1-6, alkyl of d-6, alkyl of C-? 6, alkylcarbonyl of C 1-6, alkyl of C 1-6, alkyloxycarbonyl of C? -6, mono- or di (alkyl (C? -6)) -amino alkyl of d-6, Ar5, Ai ^ -alkyloxy of Ci-β alkyl of C-? -6 ', or a radical of formula
wherein R7 is hydrogen, d-6 alkyl, Ci-β alkylcarbonyl, Ar6, Ar6-C6-6alkyl, C1-6alkyloxycarbonyl (C6-6) -alkyl, or a radical of the formula -Alk- OR10 or -Alk-NR11R12. R8 is hydrogen, C? 6 alkyl) Ar7 or Ar7 C1.6 alkyl; R9 is hydrogen, d-6 alkyl, d-6 alkylcarbonyl, d-β alkyloxycarbonyl, C? -6 alkylaminocarbonyl, Ar8, Ar8-d-6 alkyl, alkylcarbonyl (C-? -6) -alkyl C -6) Ar 8 -carbonyl, Ar 8 C 1-6 alkylcarbonyl, aminocarbonylcarbonyl, C 1-6 alkyloxy-C 1-6 alkylcarbonyl, hydroxy, C? -6alkyloxy, aminocarbonyl, di (alkyl) C? 6)) - amino-alkylcarbonyl of Ci-β, amino, alkylamino of d-6, alkylcarbonylamino of d-6, or a radical or formula -Alk-OR10 or -Alk-NR11R12; wherein Alk is d-6 alkanediyl; R10 is hydrogen, C1.6alkyl, C1-6alkylcarbonyl, C6-6 hydroxyalkyl, Ar9 or Ar9-Ci-βalkyl; R 11 is hydrogen, C 1 -C 6 alkyl, C 1 6 alkylcarbonyl, Ar 10 or Ar 10 -C 6 alkyl; R12 is hydrogen, alkyl of d-6, Ar11 or Ar11-C6-alkyl, and Ar1 to Ar11 are independently selected from phenyl; or phenyl substituted by halogen, C? -6 alkyl, C?? 6 alkyloxy or trifluoromethyl. PCT / EP98 / 02357, filed April 17, 1998, relates to the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibitor compounds of formula (VIII)
the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein the dotted line represents an optional bond;
X is oxygen or sulfur; R1 and R2 each independently are hydrogen, hydroxy, halogen, cyano, C6-6 alkyl, trihalogenomethyl, trihalogenomethoxy, C2.6 alkenyl, C1-6 alkyloxy, hydroxy-C1-6alkyloxy, alkyloxy (C? _6) -C 1-6 -alkyloxy, Ci-β-alkyloxy, C 1-6 -alkyloxy, mono- or di (C 1 -6 alkyl) -amino C 1-6 alkyloxy, Ar 1, C 1 C 1 alkyl -6, Ar1 or Ar1 C1-6alkyloxy, R3 and R4 are each independently hydrogen, halogen, cyano, C1-6alkyl, d-6alkyloxy, Ar1-oxi, C6-6alkylthio) di (alkyl (d.6)) amino, trihalogenomethyl or trihalogenomethoxy; R5 is hydrogen, halogen, C1.6alkyl, cyano, halogen C1-6alkyl, hydroxyC1.6alkyl) cyano-C1.6alkyl, amino -6alkyl, alkyloxy (C1-6alkyl) ) -C1-6alkyl, alkylthio (C? -6) -alkyl of C1.6, aminocarbonyl-alkyl of C-? -6, alkyloxycarbonyl (C? -6) -alkyl of C? -6, alkylcarbonyl (C ? -6) -alkyl of d-6, alkyloxycarbonyl of C? -6, mono- or di (alkyl (C? -6) -aminoalkyl of C? -6, Ar1, Ar1alkyloxy (C? -6) -alkyl of C1-6, or a radical of formula
wherein R10 is hydrogen, C1-6alkyl, C1-ealkylcarbonyl, Ar1, Ar1C6-6alkyl, alkyloxycarbonyl (C6-6) -C1-6alkyl, or a radical of the formula -Alk- OR13 or -Alk-NR14R15; R 1 is hydrogen, C 1-6 alkyl, Ar 1 or C 1-6 alkyl;
R 12 is hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, d6 alkyloxycarbonyl, C 1-6 alkylaminocarbonyl, Ar 1, C 1-6 alkyl, C 1-6 alkylcarbonyl-C 1-6 alkyl, C 1-6 alkylcarbonyl. , C1.6alkylcarbonyl, aminocarbonylcarbonyl, (C6.6) alkyloxy-C1-6alkylcarbonyl, hydroxy, C1.6alkyloxy, aminocarbonyl di (C1-6alkyl) -alkylcarbonyl , amino, C1.6 alkylamino, C1.6 alkylcarbonylamino, or a radical of formula -Alk-OR13 or Alk-NR14R15; wherein Alk is d-β alkanediyl; R 13 is hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, d-6 hydroxy alkyl, Ar 1 or Ar.sub.1 alkyl of d.6; R 14 is hydrogen, d 6 alkyl, Ar 1 or Ar 1 alkyl of d-β; R15 is hydrogen, C-? 6 alkyl, C? -6 alkylcarbonyl, Ar.sub.1 or Ar.sub.1 -d "alkyl, R6 is a radical of formula
wherein R 16 is hydrogen, halogen, Ar 1, C 1-6 alkyl, hydroxy alkyl of 6, alkyloxy (C 6) -alkyl of C? -6, alkyloxy of C? .6 > C.sub.1.6 alkyl, amino, C.sub.6.6 alkyloxycarbonyl, C.sub.12 alkylthio- C.sub.6-6 alkyl, C.sub.1-6 alkyl (C.sub.6) -S (0) C.sub.1-6 alkyl or alkyl- S (0) alkyl of d.6; R 17 is hydrogen, C 1 .6 alkyl or di (alkyl (d 2)) aminosulfonyl;
R7 is hydrogen or C? _6 alkyl since the dotted line does not represent a bond; R8 is hydrogen, d-6 alkyl or Ar2CH2 or Het1CH2; R9 is hydrogen, C? -6 alkyl, C? -6 alkyloxy or halogen; or R8 and R9 together to form a bivalent radical of formula
Ar1 is phenyl; or phenyl substituted with 1 or 2 substituents, each independently selected from halogen, d-6 alkyl, dyalkyloxy. 6 or trifluoromethyl; Ar2 is phenyl; or phenyl substituted with 1 or 2 substituents, each independently selected from halogen, C? -6 alkyl, dyalkyloxy. 6 or trifluoromethyl; and Het1 is pyridinyl; pyridinyl substituted with 1 or 2 substituents, each independently selected from halogen, Ci-β alkyl, C 1-6 alkyloxy or trifluoromethyl. Other useful farnesyl-protein transferase inhibitors have the structure: SCH-66336 PD-169551 these farnesyl-protein transferase inhibitors reduce tumor growth in vivo by a direct effect on tumor cell growth but also indirectly, i.e. inhibiting angiogenesis (Rak, J. et al., Cancer Research, 55, 4575-4580, 1995). Consequently, treatment with these inhibitors suppresses solid tumor growth in vivo at least in part by inhibiting angiogenesis. This being the case, it could be expected that treatment with these compounds could cause hypoxic tumors, thereby inducing or causing increased radio resistance.
Unexpectedly, it has been found that this does not happen. On the contrary, it appears that the administration of a farnesyl protein tdansferase inhibitor as described hereinbefore sensitizes the tumor cells in vivo to irradiation or ionizing radiation and further re-sensitizes the radioresistant cells. Therefore, farnesyl protein transferase inhibitors are useful as radiosensitizing agents in vivo (sensitization to radiation or enhancement to variation). The present invention relates to the use of at least one farnesyl protein transferase inhibitor for the preparation of a pharmaceutical composition having radiosensitizing properties for administration before, during or after irradiation of a tumor to treat cancer in vivo. In particular, the present invention relates to the use of at least one farnesyl protein transferase inhibitor for the preparation of a pharmaceutical composition having radiosensitizing properties for administration before, during or after irradiation of a tumor to treat cancer in vivo, wherein said farnesyl protein transferase inhibitor is a derivative of (imidazol-5-yl) methyl-2-quinoline of formula (I), or a compound of formulas (II) or (III) which is metabolized in vivo in the compound of formula (I), said compounds are represented by (i) (ii)
the pharmaceutically acceptable base or acid addition salts and the stereochemically isomeric forms thereof, wherein the dotted line represents an optional bond; X is oxygen or sulfur; alkyl of Cp2, Ar1, Ai ^ -alkyl of Cr6, quinolinyl-C1-6alkyl, pyridyl-C1-6alkyl, hydroxy-alkyl of d-β, alkyloxy (d-6) -alkyl of C1-6 , mono- or di (alkyl (C? -6)) -amino alkyl of d-6, amino-alkyl of C?, or a radical of formula -Alk1-C (= 0) -R9, -Alk1-S (0 ) -R9 or -Alk1- S (0) 2 -R9, wherein Alk1 is C alca alkanoid, R9 is hydroxy, d-6 alkyl, C1-6 alkyloxy, amino, ds alkylamino or C 8 alkylamino substituted with alkyloxycarbonyl
R2 R3 and R16 each independently are hydrogen,
hydroxy, halogen, cyano, C ß alkyl, C 1-6 alkyloxy, hydroxy-C 1-6 alkyloxy, alkyloxy (C? -6) -alkyloxy of d-6, amino-alkyloxy of C? , mono- or di (alkyl (C? -6)) - amino-alkyloxy of d-6, Ar1, Ai ^ -alkyl of d-β, Ai ^ oxy, Ar2-alkyloxy of d-β, hydroxycarbonyl, alkyloxycarbonyl Cr6, trihalogenomethyl, trihalogenomethoxy, C6-6 alkenyl, 4,4-dimethyloxazolyl; or when it is in adjacent positions R2 and R3 together can form a bivalent radical of formula
O-CH2-O- (a-1), • 0-CH2-CH2-O- (a-2), O-CH = CH- (a-3), • O-CH2-CH2- (a-4) ), 0-CH2-CH2-CH2- (a-5), or CH = CH-CH = CH- (a-6),
R 4 and R 5 are independently hydrogen, halogen, Ar 1, d 6 alkyl, hydroxy-d 6 alkyl, C 1-6 alkyloxy C 1-6 alkyl, d 6 alkyloxy, C ß alkylthio, amino, hydroxycarbonyl, C?-6alkyloxycarbonyl, alkyl (d-6 -) -S (O) -C 1-6 alkyl or alkyl (d-6) -S (0) 2 -alkyl of C e; R6 and R7 are each independently hydrogen, halogen, cyano, C1-6alkyl, d-6alkyloxy, Ai ^ oxy, trihalogenomethyl, C12-alkylthio, d1 (alkyl (Cr6)) -amino , or when they are in adjacent positions R6 and R7 together can form a bivalent radical of formula
R8 is hydrogen, d-6alkyl, cyano, hydroxycarbonyl, C6-6alkyloxycarbonyl, alkylcarbonyl (C-? 6) -Cr- alkyl, cyano-C1-6alkyl, alkyloxycarbonyl (C6-6) alkyl of C ß, carboxyC 1-6 alkyl. hydroxyalkyl of C?-C4, amino-C de-6-alkyl, mono- (alkyl (C? -6)) -amino-C 1-6 -alkyl, midazole, halogen-C alquilo-alkyl 6, C 1 -C 6 alkyloxy Cr 2 alkyl, aminocarbonyl 6 alkyl, or a radical of formula:
Wherein R10 is hydrogen, C6-6alkyl, d-6alkylcarbonyl, Ar1, Ai ^ C1-6alkyl, alkyloxycarbonyl (C6-6) -alkyl of C-? -6, or a radical or formula -Alk2-OR13 or -Alk2-NR1 R15; R11 is hydrogen, C1-12 alkyl, Ar1 or Ai ^ -alkyl of d-β; R12 is hydrogen; Crß alkyl. Cr6 alkylcarbonyl, d-6alkyloxycarbonyl, d-βalkylaminocarbonyl, Ar1, Ar ^ -d-βalkyl, alkylcarbonyl (Crß) -alkyl of d-β. a natural amino acid, Ar 1 -carbonyl, Ar 2 -alkylcarbonyl of Cr 6, aminocarbonylcarbonyl, alkyloxy (Cr 6) -alkylcarbonyl of C 1-6, hydroxy, alkyloxy of C 1-6, aminocarbonyl, di (alkyl (C-6)) -aminoalkylcarbonyl de-β, amino, Crι alkylamino, d-6-alkylcarbonylamino or a radical of the formula -Alk 2 -OR 13 or -Alk 2 -NR 14 R 15; wherein Alk2 is C1-6 alkanediyl; wherein R 13 is hydrogen, d-β alkyl, C β alkylcarbonyl, d-6 hydroxy alkyl, Ar 1 or Ai ^-d-β alkyl; R 14 is hydrogen, Cr 6 alkyl, Ar 1 or Ai ^ -Crß alkyl; R 15 is hydrogen, d-β alkyl, Cr 1 alkylcarbonyl, Ar 1 or R 17 is hydrogen, halogen, cyano, d-β alkyl, Cr 1 alkyloxycarbonyl, Ar 1; R18 is hydrogen, Cr, alkyl, Cr, alkyloxy, or halogen; R19 is hydrogen or Cr-alkyl; Ar 1 is phenyl or phenyl substituted with alkyl of d-β, hydroxy, amino, alkyloxy or halogen; and Ar 2 is phenyl or phenyl substituted with C 1-6 alkyl, hydroxy, amino, alkyloxy or halogen. In formulas (I), (II) and (III), R4 or R5 may also be linked to one of the nitrogen atoms in the imidazole ring. In this case the hydrogen in the nitrogen is replaced by R4 or R5 and the meaning of R4 and R5 when bound to the nitrogen is limited to hydrogen, Ar1, Cr3 alkyl, hydroxyC1 alkyl, alkyloxy (Cr3) -alkyl Crß.
CrCalkyloxycarbonyl, alkyl (Crß) -S (0) -Cr, alkyl (d-β) -S (0) 2-Cr- alkyl- As used in the above definitions and hereinafter halogen defines fluorine, chlorine, bromine and iodine; d-β alkyl defines straight or 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; d-β alkyl embraces the straight and branched chain saturated hydrocarbon radicals as defined in β-alkyl as well as the more superior homologues thereof containing 7 or 8 carbon atoms such as, for example, heptyl or octyl; C 1-12 alkyl, again embraces Crs alkyl and the more superior homologs thereof containing from 9 to 12 carbon atoms, such as for example, nonyl, decyl, undecyl, dodecyl; d-iß alkyl again embraces C 1-12 alkyl and the more superior homologs thereof containing from 13 to 16 carbon atoms, such as, for example, tridecyl, tetradecyl, pentedecyl and hexadecyl; C2-6 alkyl, defines straight and branched chain hydrocarbon radicals containing a double bond and having from 2 to 6 carbon atoms, such as for example, ethenyl, 2-propenyl, 3-butenyl, 2-pentenyl, 3-methyl-2-butenyl, and the like; d-β-alkylene defines straight and branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butadin , 1,5-pentadiyl, 1,6-hexanediyl and the branched isomers thereof. The term "C (= O)" refers to a carbonyl group, "S (0)" refers to a sulfoxide and "S (O) 2" to a sulfone. The term "natural amino acid" refers to a natural amino acid that is linked by 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 rest 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. The pharmaceutically acceptable acid or base addition salts as mentioned hereinabove means comprising the non-toxic base addition salt forms and therapeutically active non-toxic acids whose compounds of formulas (I), (II) and (III) They have the ability to form them. The compounds of formulas (I), (II) and (III) having basic properties can be converted into their pharmaceutically acceptable addition salts and acids by treating said base form with an appropriate acid. Suitable acids comprise, for example, inorganic acids such as hydrohalic acids, for example hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, succinic malonic (ie, butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic , cyclamic, salicylic, p-aminosalicylic, pamoic and similar acids.
The compounds of formulas (I), (II) and (III) having acidic properties can be converted into their pharmaceutically acceptable base addition salts by treating said acid form with a suitable organic or inorganic base. Suitable base salt forms include, for example, the ammonium salts, the alkaline earth metal and alkali salts, for example the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, for example, salts of benzathine, N-methyl-D-glucamine, hydrabamine, and salts with amino acids, such as, for example, arginine, lysine and the like. The terms "base addition salt" or "acid salt" further comprise hydrates and solvent addition forms whose compounds of formulas (I), (II) and (III) have the ability to form them.
Examples of such forms are, for example, hydrates, alcoholates and the like. The term stereochemically isomeric forms of compounds of formulas (I), (II) and (III), which were used hereinbefore, define all possible compounds made from the same atoms linked by the same sequence of bonds but having different three-dimensional structures that are not interchangeable, whose compounds of formulas (I), (II) and (III) may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms that said compound may possess. Said mixture may contain all the diastereomers and / or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of formulas (I), (II) and (III) both in pure form or in a mixture with each other are intended to be included within the scope of the present invention. Some of the compounds of formulas (I), (II) and (III) may also exist in their tautomeric forms. Said forms, although not explicitly indicated in the above formula, are intended to be included within the scope of the present invention. Each time they are used in the following, the term "compounds of formulas (I), (II) and (III)" means that they also include pharmaceutically acceptable base or acid addition salts and all stereoisomeric forms. Preferably, the substituent R18 is located at the 5 or 7 position of the quinolinone portion and the R19 substituent is located at the 8 position when R18 is at the 7 position. The compounds of interest are those compounds of formula (I) wherein X it's oxygen In addition, the compounds of interest are those compounds of formula (I) wherein the dotted line represents a bond, to form a double bond. Another group of compounds of interest are those compounds of the formula (I) wherein R 1 is hydrogen, C?-6 alkyl, C?-6 alkyloxy, di (C (-6 alkyl) -amino -6, or a radical of formula -Alk1-C (= 0) -R9 wherein Alk1 is methylene and R9 is alkyl of amino ds substituted with C6-6 alkyloxycarbonyl. Still another group of compounds of interest are those compounds of formula (I) wherein R3 is hydrogen or halogen; and R 2 is halogen, C 1-6 alkyl, C 2 - alkenyl, d - β alkyloxy, d - β alkyloxy, trihalogenomethoxy or hydroxy - alkyloxy of C i - β. An additional group of compounds of interest are those compounds of formula (I) wherein R2 and R3 are in adjacent positions and together form a bivalent radical of formula (a-1), (a-2) or (a-3). Yet another additional group of compounds of interest are those compounds of formula (I) wherein R5 is hydrogen and R4 is hydrogen or d-β alkyl. Still further, another group of compounds of interest are those compounds of formula (I) wherein R7 is hydrogen; and R6 is Ci-β alkyl or halogen, preferably chlorine, especially 4-chloro. A particular group of compounds are those compounds of formula (I) wherein R8 is hydrogen, hydroxy, halo-alkyl of d-β, hydroxy-alkyl of C6-6, cyano-C6-6 alkyl, alkyloxycarbonyl of C? -6 C? -6 alkyl, imidazole, or a radical of formula -NR11R12 wherein R11 is hydrogen or C1-12 alkyl and R12 is hydrogen, d-β alkyl, d-β alkyloxy, hydroxy , C? -6 alkyloxy, C? -6 alkylcarbonyl, or a radical of formula -Alk2-OR13 wherein R13 is hydrogen or C? -6 alkyl.
Preferred compounds are those compounds wherein R 1 is hydrogen, C 1-6 alkyl, C 1-6 alkyloxy-d-, D (alkyl (C? -β)) -amino-alkyl d-β, or a radical of formula -Alk1-C (= 0) -R9, wherein Alk1 is methylene and R9 is C1-8 alkylamino substituted with Ci-6alkyloxycarbonyl wherein: R2 is halogen, -β, C2-β alkenyl, d-β alkyloxy, trihalogenomethoxy, hydroxy-C-6 alkoxy or Ar1; R3 is hydrogen; R 4 is methyl bonded to the nitrogen at the 3-position of the imidazole; R5 is hydrogen; R6 is chlorine; R7 is hydrogen; R8 is hydrogen, hydroxy, halogen-Ci-βalkyl, hydroxyC de-6alkyl, cyano-d-βalkyl, alkyl (C? -6) -oxocarbonyl, C?-6alkyl , imidazolyl, or a radical of formula -NR 11 R 12 wherein it is hydrogen or C 1 - 2 alkyl and R 12 is hydrogen, C 1-6 alkyl, C 1-6 alkyloxy, C 1-6 alkyloxy-C 1-6 alkyloxycarbonyl. β-β, or a radical of formula -Alk 2 -OR 13 wherein R 13 is d 6 alkyl, R 17 is hydrogen and R 18 is hydrogen. The most preferred compounds are: 4- (3-chlorophenyl) -6- [4-chlorophenyl) hydroxy (1-methyl-1 H-imidazol-5-yl) methyl] -1-methyl-2 (1 H) -quinolinone , 6- [amino (4-chlorophenyl) -1-methyl-1 / - / - imidazol-5-yl-ylmethyl] -4- (3-chlorophenyl) -1-methyl-2 (1 H) -quinolinone; 6 - [(4-chlorophenyl) hydroxy (1-methyl-1 H-imidazol-5-yl) methyl] -4- (3-ethoxyphenyl) -1-methyl-2- (1 H -quinolinone; monohydrochloride of 6 - [(4-chlorophenyl) (1-methyl-1 / - / - imidazol-5-yl) methyl] -4- (3-ethoxyphenyl) -1-methyl-2- (1 H) -quinolinone monohydrate;
6- [amino (4-chlorophenyl) (1-methyl-1 H -amidazol-5-yl) methyl] -4- (3-ethoxyphenyl) -1-methyl-2- (1 H) -quinolinone; 6-amino (4-chlorophenyl) (1-methyl-1 V-imidazol-5-yl) methyl] -1-methyl-4- (3-propy-phenyl) -2- (1H) -quinolinone; a stereoisomeric form thereof or a pharmaceutically acceptable base or acid addition salt; and (+) - (R) 6- [amino (4-chlorophenyl) (1-methyl-1H-imidazol-5-yl) methyl] -4- (3-chlorophenyl) -1-methyl-2- (1H- quinolonone (compound 75 in Table 1 of the experimental part), or a pharmaceutically acceptable acid addition salt thereof The farnesyl protein transferase inhibitors can be formulated into pharmaceutical compositions known in the art; formulas (I), (II) and (III) suitable examples can be found in WO-97 / 21701. To prepare the aforementioned pharmaceutical compositions, a therapeutically effective amount of the particular compound is combined, optionally in the form of addition salt, as the active ingredient in a close mixture with pharmaceutically acceptable carriers, which can take a wide variety of forms depending on the form of preparation desired for administration.These pharmaceutical compositions are, desirably as unit dosage forms, which are administered by oral, parenteral, percutaneous, rectal or topical for systemic action, which is preferred, or for topical action. In the case of oral liquid pharmaceutical preparations such as solutions, suspensions, syrups, elixirs and emulsions, any of the usual pharmaceutical means, such as, for example, water, glycols, oils, alcohols and the like, can be used, either in case of solid pharmaceutical preparations, comprising powders, pills, capsules and tablets, excipients such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which solid pharmaceutical carriers are obviously employed. In case of injectable pharmaceutical compositions, the carrier will generally comprise sterilized water, at least for the most part, although other ingredients, such as semipolar solvents, may be included, for example to aid in solubility. Examples of vehicles for injectable solutions comprise saline solution, glucose solution or a mixture of saline and glucose. Injectable solutions containing compounds of the aforementioned formulas can also be formulated in a long-acting oil. Suitable oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long chain fatty acids and mixtures of these and other oils. Injectable suspensions may also be prepared in which case suitable liquid carriers, suspending agents and the like may be employed. In compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and / or an appropriate wettable agent, optionally combined with suitable additives of any nature in minor proportions, whose additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the application to the skin and / or may be useful for preparing the desired compositions. These compositions can be administered in various forms, for example, as a transdermal patch, as a local application in the affected area, or as an ointment or as a gel. In case of pharmaceutical compositions for rectal administration, any of the usual excipients comprising fat-based and water-soluble excipients, optionally combined with suitable additives, such as suspending or wetting agents may be employed. Suitable compositions for topical application are all the compositions that are generally used to topically administer drugs, for example., creams, jellies, conditioners, lotions, shampoos, dyes, pastes, ointments, balms, ovules, powders, inhalations, nose sprays, eye drops and the like. Semi-solid compositions such as balms, creams, jellies, ointments and the like will be conveniently used, but the application of said compositions can be, for example, also with aerosol, for example with a propellant such as nitrogen, carbon dioxide, freon, or with a propellant such as pump spray or drops. In particular, it is of great advantage to formulate the aforementioned pharmaceutical compositions in unit dosage form to facilitate administration and uniformity of dosage. The unit dosage forms as used in the specification and in the claims herein, refer to physically discrete units suitable as unit dosages, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in association with the pharmaceutical vehicle required. Examples of such dosage unit forms are tablets (including labeled or coated tablets), capsules, pills, powder packets, suppositories, ovules, wafers, injectable solutions or suspensions, teaspoons, tablespoons and the like, as well as segregated multiples thereof. Preferably, a therapeutically effective amount of the pharmaceutical composition comprising a farnesyl protein transferase inhibitor is administered orally or parenterally. Said therapeutically effective amount is the amount that effectively sensitizes a tumor in a host to irradiation. On the basis of the present data, it appears that the pharmaceutical composition comprising (+) - (R) -6- [amino (4-chlorophenyl) (1-methyl-1 / - / - imidazol-5-yl) methyl] -4- (3-chlorophenyl) -1-methyl-2- (1 H) -quinolinone (compound 75) as the active ingredient can be administered orally in an amount from 10 to 1500 milligrams / m2 daily, either as a single dose or subdivided in more than one dose, or very particularly in an amount of 100 to 1, 000 milligrams / m2 daily.
Irradiation means ionizing radiation and in particular gamma radiation, especially that emitted by linear accelerators or by radionuclides that are in common use today. The irradiation of the tumor by means of radionuclides can be external or internal. Preferably, the administration of the pharmaceutical composition begins for up to one month, particularly up to 10 days or a week, before irradiation of the tumor. Additionally, it is convenient to fractionate the irradiation of the tumor and maintain the administration of the pharmaceutical composition in the interval between the first and last irradiation session. The amount of the farmesyl-protein transferase inhibitor, the irradiation dose and the intermittent capacity of the irradiation will depend on a series of parameters such as the type of tumor, its location, the reaction of the patient to chemo- or radiotherapy and finally the doctor and radiologists will determine each individual case. The present invention also relates to a method of cancer therapy for a host harboring a tumor, comprising the following steps: administering an effective radiation sensitizing amount of a farmesyl protein transferase inhibitor, before, during or then -administer the radiation to said host in proximity to the tumor. Examples of tumors that may be inhibitory, but not limited to, lung cancer (e.g., adenocarcinoma), pancreatic cancer (e.g., pancreatic carcinoma such as, for example, execrine pancreatic carcinoma), colon cancer (e.g. example, colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma) lymphoid line hematopoietic tumors (e.g., acute lymphocytic leukemia, B-cell lymphoma, Burkitt's lymphoma), myeloid leukemias (e.g., acute myelogenous leukemia) ) (AML)), follicular thyroid cancer, myelodysplastic syndrome (MDS), tumors of mesenchymal origin (eg, fibrosarcomas and rhabdomyosarcones), melanomas, teratocarcinomas, neuroblastomas, gliomas, benign skin tumor (eg, keratoacanthomas), carcinoma of breast, kidney carcinoma, ovarian carcinoma, bladder carcinoma and epidermal carcinoma.
Experimental part The following tables show the formulas of the compounds of formula (I), their physical data and references to the examples in WO-97/21701 according to which the compounds in question can be prepared.
In the pharmacological example, the radiation sensitizing effect of the compounds of formula (I) is shown
TABLE 1
Prepared by functional transformation-group of compound 70.: Prepared by functional transformation-group of compound 25.
TABLE 2
prepared by functional transformation-group of compound 54 prepared by functional transformation-group of compound 104
TABLE 3
TABLE 4 TABLE 5 TABLE 6
TABLE 8
1
phenyl portion.
Pharmacological example 1 Male athymic skinless mice weighing approximately 23 to 25 g were inoculated subcutaneously in the inguinal region with 1 × 10 6 human colon tumor cells L0V0 (L0V0 cells) on day 0. After three weeks they were left tumors were established (diameter approximately 0.5 to 1 cm), treatment with solvent or compound 75 was initiated by the oral route, and with or without irradiation of a single shot on day 32. The parameters for the activity were the growth rate of the tumor and the weight of the tumors on day 42.
Compound 75 was dissolved in water and acidified with 1 NHCl solution with pH 2.5 and orally administered as 0.1 ml of the compound solution for every 10 g of the mouse body weight, twice a day (bid) . The dose administered was both 50 and 100 mg of compound per kilo of body weight; treatment both before irradiation (days 22, 32), followed by irradiation (32, 42) or continued throughout the duration of the experiment (days 22, 42). The irradiation treatment consisted of a simple dose of radiation at day 32 with a dose of 7 Gy that stabilized the growth of the tumor in the animals without treatment, that is, a dose that stopped the increase in the volume of the tumor, but that did not It caused no reduction in its size either. The following table (table 9) shows each of the stages that were evaluated in the experiment. At each stage of the experiment, 16 animals were included. The column "tumor (g)" contains the median tumor weight of the animals sacrificed at day 42 of the experiment. Figures 1 and 2 represent the data observed in graphic form. Figure 1 shows the distribution of tumor weights (g) of the test animals that received 50 mpk of the test compound (po, bid). Figure 2 shows the distribution of tumor weights (g) of the test animals that received 10 mpk of the test compound (po, bid). The gray box in the figures describes the 25-75 percentiles, the thick white line in said chart represents the mean, the lines that are understood from the gray box describe the 10-90 percentiles and the black dots represent the absentees. The Roman numerals correspond to the groups of test animals as identified in Table 9. From a statistical analysis of the data it can be seen that the treatment with compound 75 (both with 50 and 100 mpk) raises the potential of the effect of the irradiation, very particularly that pretreatment with compound 75 (both, with 50 and 100 mpk) and irradiation reduces the tumor weight in a statistically significant manner (compared only to irradiation).
TABLE 9
* U Mann-Whitney test vs group XIV (radiotherapy only).
EXAMPLE 2
Human glioma cell lines (SF763, U87, U251) were treated with compound 75, 48 hours prior to irradiation (2 Gy). The administered dose was 0.4 nM for U251 and 2 nM for SF763 and U87. By applying compound 75 to the cells, the survival of the cells after d irradiation was dramatically reduced: for SF763 and U87, a reduction of the surviving faction of approximately 55% was demonstrated, whereas for U251, the reduction was 25%. %. These results show that the treatment with compound 75 makes the radioresistant cells more sensitive to radiation.
Claims (15)
1. - The use as claimed in at least one farnesyl protein transferase inhibitor for the preparation of a pharmaceutical composition having radiosensitizing properties for administration before, during or after irradiation of a tumor to treat cancer.
2. The use of the compound as claimed in claim 1, wherein a farnesyl protein transferase inhibitor is a compound of formula (I), or a compound of formula (II) or (III) that is metabolized in vivo to a compound of formula (I), said compounds are represented by ( (III) a stereoisomeric form thereof, a pharmaceutically acceptable acid or base addition salt, wherein the dotted line represents an optional bond; X is oxygen or sulfur; R1 is hydrogen, C- | alkyl. 2, Ar1, Ai ^ -alkyl Ci-β, quinolinyl-d-β alkyl, pyridyl-C 1-6 alkyl, hydroxy-C 1-6 alkyl, C 1-6 alkyloxy-C? -β alkyl, mono - or dialkylamino-d-aminoalkyl of d-6, aminoalkyl of C? .6, or a radical of formula -Alk1-C (= 0) -R9, - Alk1-S (0) -R9 or - Alk1-S (0) 2R9, wherein Alk1 is C6.6 alkynediyl, R9 is hydroxy, Ci-β alkyl, Ci-β alkyloxy, amino, d-β alkylamino or alkylamino substituted with d-β-alkyloxycarbonyl; R2, R3 and R16 each ? 10 independently are hydrogen, hydroxy, halogen, cyano, C?. Beta alkyl, Ci-β alkyloxy, d-6-hydroxy-alkyloxy, C1.6 alkyloxy (C? -β) -alkyloxy, * C 1-6 amino-alkyloxy, mono- or di (C 1.) alkyl) amino-alkyloxy of C? .6 > Ar1, Ai ^ -alkyl of d-β, Ai ^ oxy, Ar ^ -alkyloxy of C? -β, hydroxycarbonyl, alkyloxycarbonyl of C? -6, trihalogenomethyl, trihalogenometoxy, alkenyl of C2-?, 4,4-dimethyloxazolyl; or when they are in adjacent positions, R2 and R3 taken together can form a bivalent radical of formula -0-CH2-0- (a-1), -0-CH2-CH2-0- (a-2), -0-CH = CH- (a-3), -0-CH2-CH2- (a -4), 20 -0-CH2-CH2-CH2- (a-5), or -CH = CH-CH = CH- (a-6); R4 and R5 are each independently hydrogen, halogen, Ar1, C? -β alkyl, hydroxyC? -6 alkyl, (C? -6) alkyloxyC? -6 alkyl, C? -6 alkyloxy , alkylthio Ci-β, amino, hydroxycarbonyl, alkyloxycarbonyl of d-β, alkyl (C?-β) -S (0) -alkyl of C?-6 or alkyl (C?-6) -S (0) 2-Ci-β alkyl, R6 and R7 each independently are hydrogen, halogen, cyano, d-β alkyl, Ci-β alkyloxy, Ai ^ oxy, trihalogenomethyl, Ci-β alkylthio, di (alkyl (C ? -6) -amino, or when they are in adjacent positions, R6 and R7 together can form a divalent radical of formula; -O-CH2-O- (c-1), or -CH = CH-CH = CH- (c-2); R8 is hydrogen, Ci-β alkyl, cyano, hydroxycarbonyl, β-alkyloxycarbonyl, C 1 -C 6 alkylalkyl- C 1-6 alkyl, cyanoC 1-7 alkyl, alkyloxycarbonyl (C 1 - 6) -alkyl of C? 6) carboxy-alkyl of d-β, hydroxy-alkyl of C? -6, amino-alkyl of d-6, mono- or di (aIqu¡l (C? -6)) -amino-d-β alkyl, imidazolyl, halogen-d-β alkyl, (C-? 6) alkyloxy-Ci-β alkyl, aminocarbonyl-C?-6 alkyl, or a radical of the formula where R10 is hydrogen, C? -6 alkyl, C? -6 alkylcarbonyl, Ar1, Ar2 C? .6 alkyl, alkyloxycarbonyl (C? 6) -alkyl of d-6, or a radical of formula -Alk2-OR13 or -Alk2-NR14R15; R11 is hydrogen, alkyl of d.12, Ar1 or Ar2 alkyl of Ci-ß; R 12 is hydrogen, C 1 -β alkyl, Ci-β alkylcarbonyl, Ci-β alkyloxycarbonyl, C 1 -C 6 alkylaminocarbonyl, Ar 1, Ar 2 Ci-β alkyl, C 1 -C 6 alkylcarbonyl-Ci alkyl -β, a natural amino acid, Ar1carbonyl, Ar2 alkylcarbonyl of d-β, aminocarbonylcarbonyl, alkyloxy (C? -β) -alkylcarbonyl of C? -β, hydroxy, d-βalkyloxy, aminocarbonyl, d; (alkyl (d-6)) - aminoalkylcarbonyl of Ci-β, amino, alkylamino of d-β, alkylcarbonylamino of C 1-6, or a radical or of formula Alk2-OR13 or -Alk2-NR1 R15; wherein Alk2 is C1.6 alkylene; R 13 is hydrogen, C 1-6 alkyl, d-β alkylcarbonyl, Ci-β hydroxy-alkyl, Ar 1 or Ar 2 alkyl of d-β; R14 is hydrogen, C1-6 alkyl, Ar1 or Ar2 Ci-β alkyl; R 15 is hydrogen, C 1 .6 alkyl, C 1 -β alkylcarbonyl, Ar 1 or Ar 2 alkyl of dβ; R 17 is hydrogen, halogen, cyano, C 1-6 alkyl, alkyloxycarbonyl of d-β, Ar 1; R18 is hydrogen, d-β alkyl, alkyloxy or halogen; R19 is hydrogen or d-β alkyl; Ar 1 is phenyl or phenyl substituted with d-β, hydroxy, amino, C alquilo. 6 alkyloxy or halogen and Ar 2 is phenyl or phenyl substituted with d-β, hydroxy, amino, C?-6 alkyloxy or halogen
3. The use of the compound as claimed in claim 2, wherein said farnesyl protein transferase inhibitor is a compound of formula (I) and wherein X is oxygen.
4. The use of the compound as claimed in claim 2, wherein said protein transferase inhibitor is a compound of formula (I) and wherein the dotted line represents a bond.
5. The use of the compound as claimed in claim 2, wherein said protein transferase inhibitor is a compound of formula (I) and wherein R 1 is hydrogen, C 1-6 alkyl, alkyloxy (C 1-6) ) -alkyl of d-ß or mono- or di (alkyl (C? -6)) -amino C? -6 alkyl.
6. The use of the compound as claimed in claim 2, wherein said protein transferase inhibitor is a compound of formula (I) and wherein R 3 is hydrogen and R 2 is halogen, d-β alkyl, C 2 alkenyl -β, d-β alkyloxy, trihalogenomethoxy or hydroxy-alkyloxy of d-β.
7. The use of the compound as claimed in claim 2, wherein said protein transferase inhibitor is a compound of formula (I) and wherein R8 is hydrogen, hydroxy, haloalkyl of C? -6, hydroxy- d-β alkyl, d-β cyanoalkyl, C 1-6 alkyloxycarbonyl-C-6 alkyl, imidazolyl, or a radical of formula -NR 11 R 12 where R 11 is hydrogen or C 12 alkyl and R 12 is hydrogen, Ci-βalkyloxy, C6-6alkyloxyalkyloxy (C?. β) -acylcarbonyl of d.6, hydroxy or a radical of formula -Alk2-OR13 wherein R13 is hydrogen or C-alkyl? -H.H.
8. The use of the compound as claimed in claim 2, wherein the compound is 4- (3-chlorophenyl) -6- [4-chlorophenyl) hydroxy (1-methyl-1 H-imidazole). 5-yl) methyl] -1-methyl-2 (1 H) -quinolinone; 6- [amino (4-chlorophenyl) -1-methyl-1 / - / - imidazol-5-yl-ylmethyl] -4- (3-chlorophenyl) -1-methyl-2 (1 - /) -quinolinone; 6 - [(4-chlorophenyl) hydroxy (1-methyl-1 H-imidazol-5-yl) methyl] -4- (3-ethoxyphenyl) -1-methyl-2- (1 HJ-quinolinone; monohydrochloride of 6-) [(4-chlorophenyl) (1-methyl-1 H-imidazol-5-yl) methyl] -4- (3-ethoxyphenyl) -1-methyl-2- (1 HJ-quinolinone monohydrate; 6- [amino (4 chlorophenyl) (1-methyl-1 / - / - imidazol-5-yl) methyl] -4- (3-ethoxyphenyl) -1-methyl-2- (1 - / J-quinolinone; and 6-amino (4 chlorophenyl) (1-methyl-1 / -imidazol-5-yl) methyl] -1-methyl-4- (3-propylphenyl) -2- (1 H-quinolinone; a stereoisomeric form thereof or a salt of base or pharmaceutically acceptable acid addition. -
9. The use of the compound as claimed in claim 2, wherein the compound is (+) - (R) -6- [amino (4-chlorophenyl)) 1-5-methyl-1 - / - imidazol-5-yl) methyl] -4- (3-chloro-phenyl) -1-methyl-2 (1H) -quinolinone, or a pharmaceutically acceptable acid addition salt thereof
10. The use of the compound as claimed in any of the preceding claims wherein it is administered orally, parenterally, rectally. or topical a therapeutically effective amount of? 10 pharmaceutical composition. *
11. The use of the compound as claimed in claim 9, wherein the pharmaceutical composition is administered orally in an amount of 100 to 1,500 mg / m2 daily, either as a single dose or subdivided into more than one dose
12. The use of the compound as claimed in claim 1, wherein the irradiation is ionizing irradiation.
13. The use of the compound as claimed in claim 1, wherein the irradiation of the tumor is external or internal.
14. The use of the compound as claimed in claim 1, wherein the administration of the pharmaceutical composition begins up to one month before irradiation of the tumor.
15. The use of the compound as claimed in claim 1, wherein the irradiation of the tumor is fractionated and the administration of the pharmaceutical composition is maintained in the interval between the first and the last irradiation session.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP98202257.6 | 1998-12-18 | ||
| EP98204330.9 | 1998-12-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA01000161A true MXPA01000161A (en) | 2001-09-07 |
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