[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

EP1267871A2 - Farnesyl protein transferase inhibitor combinations with anti-tumor podophyllotoxin derivatives - Google Patents

Farnesyl protein transferase inhibitor combinations with anti-tumor podophyllotoxin derivatives

Info

Publication number
EP1267871A2
EP1267871A2 EP01913838A EP01913838A EP1267871A2 EP 1267871 A2 EP1267871 A2 EP 1267871A2 EP 01913838 A EP01913838 A EP 01913838A EP 01913838 A EP01913838 A EP 01913838A EP 1267871 A2 EP1267871 A2 EP 1267871A2
Authority
EP
European Patent Office
Prior art keywords
6alkyl
alkyl
hydrogen
6alkyloxy
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01913838A
Other languages
German (de)
French (fr)
Inventor
Mary Ellen Margaret Rybak
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Janssen Pharmaceutica NV
Original Assignee
Janssen Pharmaceutica NV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Janssen Pharmaceutica NV filed Critical Janssen Pharmaceutica NV
Priority to EP01913838A priority Critical patent/EP1267871A2/en
Publication of EP1267871A2 publication Critical patent/EP1267871A2/en
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention is concerned with combinations of a farnesyl transferase inhibitor and an anti-tumor podophyllotoxin denvative for inhibiting the growth of tumor cells and useful in the treatment of cancer
  • Oncogenes frequently encode protein components of signal transduction pathways which lead to stimulation of cell growth and mitogenesis
  • Oncogene expression in cultured cells leads to cellular transformation, charactenzed by the ability of cells to grow in soft agar and the growth of cells as dense foci lacking the contact inhibition exhibited by non-transformed cells
  • Mutation and/or overexpression of certain oncogenes is frequently associated with human cancer
  • a particular group of oncogenes is known as ras which have been identified in mammals, birds, insects, mollusks, plants, fungi and yeasts
  • the family of mammalian ras oncogenes consists of three major members ("isoforms") H-ras, K-ras and N-ras oncogenes
  • These ras oncogenes code for highly related proteins genencally known as p21 ra5 Once attached to plasma membranes, the mutant or oncogenic forms of p21 r ⁇ s will provide
  • farnesyl transferase inhibitors can be very useful as anticancer agents for tumors in which ras contnbutes to transformation
  • R 9 is hydroxy, C ⁇ _6alkyl, C ⁇ _6alkyloxy, amino, Ci-8alkylamino or C ⁇ _8alkylamino substituted with Ci -6alkyloxycarbonyl;
  • R4 and R ⁇ each independently are hydrogen, halo, Ar , C ⁇ _6alkyl, hydroxyC ⁇ _6alkyl, Ci- ⁇ alkyloxyCi-galkyl, Ci-6alkyloxy, Ci-6alkylthio, amino, hydroxycarbonyl, C ⁇ _6alkyloxycarbonyl, Ci-6alkylS(O)Ci-6alkyl or Ci-6alkylS(O)2Ci-6alkyl; R6 and R ⁇ each independently are hydrogen, halo, cyano, Ci-6alkyl, Ci- ⁇ alkyloxy, Arloxy, trihalomethyl, Ci-6alkylthio, di(C ⁇ _6alkyl)amino, or when on adjacent positions R ⁇ and R ⁇ taken together may form a bivalent radical of formula
  • R8 is hydrogen, Ci- ⁇ alkyl, cyano, hydroxycarbonyl, Ci-6alkyloxycarbonyl,
  • RlO is hydrogen, C ⁇ _6alkyl, Ci-6alkylcarbonyl, Arl, Ar ⁇ Ci- ⁇ alkyl, Ci-6alkyloxycarbonylC ⁇ _6alkyl, or a radical or formula -Alk2-ORl3 or -Alk 2 -NR 14 R 15 ;
  • R 1 1 is hydrogen, Ci-i2alkyl, Ar* or Ar ⁇ Ci- ⁇ alkyl;
  • Rl2 is hydrogen, C ⁇ _6alkyl, Ci-i6alkylcarbonyl, Ci-6alkyloxycarbonyl,
  • R!3 is hydrogen, Ci-6alkyl, Ci- ⁇ alkylcarbonyl, hydroxy-
  • Rl4 is hydrogen, Ci-6alkyl, Arl or Ar 2 C ⁇ _6alkyl
  • Rl5 is hydrogen, Ci-6alkyl, Ci- ⁇ alkylcarbonyl, Ar or Ar 2 Ci-6alkyl
  • Rl7 is hydrogen, halo, cyano, Ci-6alkyl, Ci-6alkyloxycarbonyl, Arl
  • R !8 is hydrogen, C ⁇ _6alkyl, Ci-6alkyloxy or halo
  • Rl 9 is hydrogen or Ci-6alkyl
  • Arl j s phenyl or phenyl substituted with Ci-6alkyl, hydroxy, amino, C ⁇ _6alkyloxy or halo
  • Ar 2 is phenyl or phenyl substituted with Ci-6alkyl, hydroxy, amino, Ci-6alkyloxy or halo.
  • WO-97/16443 concerns the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting compounds of formula (IV), as well as intermediates of formula (V) and (VI) that are metabolized in vivo to the compounds of formula (IV).
  • the compounds of formulas (IV), (V) and (VI) are represented by
  • R 9 is hydroxy, Ci-6alkyl, Ci-galkyloxy, amino, Ci-8alkylamino or Ci-8alkylamino substituted with C ⁇ _6alkyloxycarbonyl;
  • R 2 and R 3 each independently are hydrogen, hydroxy, halo, cyano, Ci-6alkyl, C ⁇ _6alkyloxy, hydroxyCi - ⁇ alkyloxy, Ci-6alkyloxyC ⁇ _6alkyloxy, amino- C ⁇ _6alkyloxy, mono- or di(Ci-6alkyl)aminoCi-6alkyloxy, Arl, Ar Ci-6alkyl,
  • Ar oxy, Ar 2 Ci-6alkyloxy, hydroxycarbonyl, Ci-6alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C2-6alkenyl; or when on adjacent positions R 2 and R 3 taken together may form a bivalent radical of formula - -OO--CCHH72--OO-- (a-1), -O-CH2-CH2-O- (a-2),
  • R 4 and R , 5 5 each independently are hydrogen, Ar 1 , C ⁇ _ 6 alkyl, C ⁇ _ 6 alkyloxyC]. 6 alkyl,
  • R6 and R ⁇ each independently are hydrogen, halo, cyano, Ci-6alkyl, C ⁇ _6alkyloxy or Ar 2 oxy;
  • R8 IS hydrogen, C ⁇ _6alkyl, cyano, hydroxycarbonyl, Ci-6alkyloxycarbonyl, Ci- ⁇ alkyl- carbonylCi-6alkyl, cyanoCi-6alkyl, Ci-6alkyloxycarbonylCi-6alkyl, hydroxy- carbonylCi-6alkyl, hydroxyCi -6alkyl, am ⁇ noC ⁇ _6alkyl, mono- or d ⁇ (Ci-6alkyl)- am ⁇ noCi-6alkyl, haloCi-6alkyl, C ⁇ _6alkyloxyCi-6alkyl, ammocarbonylCi-6alkyl, Arl, Ar 2 Ci-6alkyloxyCi-6alkyl, Ci-6alkylth ⁇ oCi-6alkyl;
  • RIO IS hydrogen, Ci-6alkyl, Ci- ⁇ alkyloxy or halo
  • Rl 1 is hydrogen or C ⁇ _6alkyl
  • Arl 1S phenyl or phenyl substituted with Ci-6alkyl, hydroxy, amino, Ci-6alkyloxy or halo
  • Ar 2 is phenyl or phenyl substituted with Ci-galkyl, hydroxy, ammo, -galkyloxy or halo.
  • WO-98/40383 concerns the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting compounds of formula (VII)
  • the dotted line represents an optional bond
  • X is oxygen or sulfur
  • Rl and R 2 each independently are hydrogen, hydroxy, halo, cyano, Ci- ⁇ alkyl, tnhalomethyl, tnhalomethoxy, C2-6alkenyl, C ⁇ _6alkyloxy, hydroxyC ⁇ _6alkyloxy,
  • R3 and R 4 each independently . ire hydrogen, halo, cyano, C ⁇ _6alkyl, Ci-6alkyloxy,
  • Ar- ⁇ -oxy, Ci- ⁇ alkylthio, di(C ⁇ _6alkyl)amino, trihalomethyl, trihalomethoxy, or when on adjacent positions R3 and R 4 taken together may form a bivalent radical of formula
  • R ⁇ is a radical of formula
  • R 13 R- wherein Rl3 is hydrogen, halo, Ar 4 , Ci-6alkyl, hydroxyCi -6alkyl, Ci- ⁇ alkyloxy- C ⁇ _6alkyl, C ⁇ _6alkyloxy, C ⁇ _6alkylthio, amino, Ci-6alkyloxy- carbonyl, Ci-6alkylS(O)Ci-6alkyl or Ci-6alkylS(O)2C ⁇ _6alkyl; Rl ⁇ is hydrogen, Ci-6alkyl or di(Ci-4alkyl)aminosulfonyl; R6 is hydrogen, hydroxy, halo, C - ⁇ alkyl, cyano, haloCi-6alkyl, hydroxyCi - ⁇ alkyl, cyanoCi-6alkyl, aminoC ⁇ _6alkyl, Ci-6alkyloxyC ⁇ _6alkyl, Ci-6alkylthioCi-6alkyl, aminocarbonylCi-6alkyl,
  • R 7 is hydrogen, Ci- ⁇ alkyl, C ⁇ _6alkylcarbonyl,
  • Ci-6alkyloxycarbonylC ⁇ _6alkyl or a radical of formula -Alk-OR 0 or -Alk-NRllRl 2 ;
  • R8 is hydrogen, C ⁇ _6alkyl, Ar 7 or Ar " 7-C ⁇ _6alkyl;
  • R 9 is hydrogen, Ci-6alkyl, Ci- ⁇ alkylcarbonyl, Ci-6alkyloxycarbonyl, Ci-6alkylaminocarbonyl, Ar ⁇ , Ar ⁇ -Ci- ⁇ alkyl, Ci- ⁇ alkylcarbony]- Ci-6alkyl, Ar°-carbonyl, Ar°-C ⁇ _6alkylcarbonyl, aminocarbonyl- carbonyl, Ci- ⁇ alkyloxyCi- ⁇ alkylcarbonyl, hydroxy, Ci-galkyloxy, aminocarbonyl, di(Ci-6alkyl)aminoCi-6alkylcarbonyl, amino,
  • Ci- ⁇ alkylamino Ci-galkylcarbonylamino, or a radical or formula -Alk-OR 10 or -Alk-NRURl 2 ; wherein Alk is Ci-galkanediyl;
  • RIO is hydrogen, Ci-6alkyl, Ci- ⁇ alkylcarbonyl, hydroxyCi -6alkyl, Ar 9 or Ar 9 -Ci-6alkyl;
  • RU is hydrogen, Ci- ⁇ alkyl, Ci-6alkylcarbonyl, ArlO or
  • Rl 2 is hydrogen, C ⁇ _6alkyl, ArH or Arl l-Ci-6alkyl
  • Arl t0 Aril are each independently selected from phenyl; or phenyl substituted with halo, Ci-6alkyl, Ci- ⁇ alkyloxy or trifluoromethyl.
  • WO-98/49157 concerns the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting compounds of formula (VHI)
  • Rl and R 2 each independently are hydrogen, hydroxy, halo, cyano, Ci- ⁇ alkyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, Ci-6alkyloxy, hydroxyCi -6alkyloxy,
  • R3 and R 4 each independently are hydrogen, halo, cyano, Ci_6alkyl, C ⁇ _6alkyloxy, Arloxy, C ⁇ _6alkylthio, di(Ci-6alkyl)amino, trihalomethyl or trihalomethoxy;
  • R5 IS hydrogen, halo, Ci- ⁇ alkyl, cyano, haloCi-6alkyl, hydroxyCi - ⁇ alkyl, cyanoCi-6alkyl, ammoCi- ⁇ alkyl, Ci-6alkyloxyC ⁇ _6alkyl, C i - ⁇ alkyl thioC i - ⁇ alkyl, amino
  • ArlCi-6alkyloxyC ⁇ _6alkyl or a radical of formula -O-RlO (a-1),
  • Rl° IS hydrogen, Ci-6alkyl, Ci-6alkylcarbonyl, Ar , ArlCi-6alkyl,
  • Ci-6alkyloxycarbonylCi-6alkyl or a radical of formula -Alk-ORl3 or -Alk-NRl 4 Rl 5 , RU IS hydrogen, Ci-6alkyl, Arl or ArlCi-6alkyl, Rl 2 IS hydrogen, Ci-6alkyl, Ci-6alkylcarbonyl, Ci-6alkyloxycarbonyl, Ci-6alkylammocarbonyl, Arl, ArlC ⁇ _6alkyl, Ci-6alkylcarbonyl-
  • Ci-6alkyl Arlcarbonyl, ArlCi-6alkylcarbonyl, aminocarbonyl- carbonyl, Ci- ⁇ alkyloxyCi- ⁇ alkylcarbonyl, hydroxy, Ci-6alkyloxy, aminocarbonyl, d ⁇ (Ci-6alkyl)am ⁇ noCi-6alkylcarbonyl, amino, Ci_6alkylamino, Ci-6alkylcarbonylam ⁇ no, or a radical or formula -Alk-ORl 3 or -Alk-NRl 4 Rl 5 , wherem Alk is Ci-6alkaned ⁇ yl,
  • Rl3 IS hydrogen, Ci- ⁇ alkyl, Ci-6alkylcarbonyl, hydroxy-
  • R 1 6 R I 1177 wherein Rl ⁇ s hydrogen, halo, Arl, Ci- ⁇ alkyl, hydroxyCi - ⁇ alkyl, C ⁇ _6alkyloxy- Ci-6alkyl, Ci- ⁇ alkyloxy, Ci-6alkylth ⁇ o, amino,
  • Ci-6alkyloxycarbonyl Ci-6alkylth ⁇ oCi-6alkyl, Ci-6alkylS(O)Ci-6alkyl or Ci-6alkylS(O)2Ci-6alkyl
  • R 7 is hydrogen or C ⁇ _6alkyl provided that the dotted line does not represent a bond
  • R 8 is hydrogen, Ci-6alkyl or Ar CH2 or HetlCH2
  • R 9 is hydrogen, Ci- ⁇ alkyl , Ci-6alkyloxy or halo; or
  • Arl i s phenyl; or phenyl substituted with 1 or 2 substituents each independently selected from halo, C ⁇ _6alkyl, C ⁇ _6alkyloxy or trifluoromethyl;
  • Ar 2 is phenyl; or phenyl substituted with 1 or 2 substituents each independently selected from halo, C ⁇ _6alkyl, Ci-6alkyloxy or trifluoromethyl; and
  • Hetl j s pyridinyl; pyridinyl substituted with 1 or 2 substituents each independently selected from halo, Ci-6alkyl, C ⁇ _6alkyloxy or trifluoromethyl.
  • WO-00/39082 concerns the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting compounds of formula (IX)
  • R , R and R are independently hydrogen, C ⁇ . alkyl, hydroxy, C 1- alkyloxy, aryloxy, C ⁇ _ alkyloxycarbonyl, hydroxyCi. 4 alkyl, C ⁇ _ 4 alkyloxyC ⁇ _ alkyl, mono- or di(C ⁇ . 4 alkyl)aminoC ⁇ . 4 alkyl, cyano, amino, thio, C ⁇ _ 4 alkylthio, arylthio or aryl; 1 7
  • each R independently is hydrogen, halo, halocarbonyl, aminocarbonyl, hydroxyCi_ 4 alkyl, cyano, carboxyl, C ⁇ _ alkyl, C ⁇ _ alkyloxy, C]. 4 alkyloxyC ⁇ . 4 alkyl, C ⁇ _ 4 alkyloxycarbonyl, mono- or di(C ⁇ _ alkyl)amino, mono- or di (C i .
  • alkyl)aminoC i _ 4 alkyl , aryl ; r and s are each independently 0, 1, 2, 3, 4 or 5; t is 0, 1, 2 or 3; each R 1 and R 2 are independently hydroxy, halo, cyano, Ci-galkyl, trihalomethyl, trihalomethoxy, C 2 . 6 alkenyl, C ⁇ _ 6 alkyloxy, hydroxyC ⁇ _ alkyloxy, C ⁇ _ 6 alkylthio, C ⁇ _ 6 alkyloxyC ⁇ _ 6 alkyloxy, C ⁇ _ 6 alkyloxycarbonyl, aminoC].
  • R 3 is hydrogen, halo, Cj. 6 alkyl, cyano, haloC ⁇ _ 6 alkyl, hydroxyCi _ 6 alkyl, cyanoC]. alkyl, aminoC ⁇ _ 6 alkyl, C]. 6 alkyloxyC ⁇ . 6 alkyl, C ⁇ . 6 alkylthioC]. 6 alkyl, aminocarbonylC ⁇ _ 6 alkyl , hydroxycarbonyl , hydroxycarbonylC i _ alkyl , C ⁇ . 6 alkyloxycarbonylC ⁇ . 6 alkyl, C ⁇ _ 6 alkylcarbonylC ⁇ . 6 alkyl, C ⁇ . 6 alkyloxycarbonyl, aryl, arylC ⁇ _ 6 alkyloxyCi-6alkyl, mono- or di(C]. 6 alkyl)aminoC ⁇ _ 6 alkyl; or a radical of formula
  • R 10 is hydrogen, C ⁇ _ 6 alkyl, C]. 6 alkylcarbonyl, aryl, arylC ⁇ _ 6 alkyl,
  • R 11 is hydrogen, Ci 6 alkyl, aryl or arylCi 6 alkyl;
  • R 12 is hydrogen, C ⁇ _ 6 alkyl, aryl, hydroxy, amino, Ci 6 alkyloxy,
  • alkyl 6 alkyl)am ⁇ nocarbonyl wherein the alkyl moiety may optionally be substituted by one or more substituents independently selected from aryl or 3 alkyloxycarbonyl, aminocarbonylcarbonyl, mono- or d ⁇ (C ⁇ 6 alkyl)am ⁇ noC] 6 alkylcarbonyl, or a radical or formula -Alk-OR 13 or -Alk-NR I4 R 15 ; wherein Alk is Ci 6 alkaned ⁇ yl,
  • R 13 is hydrogen, C t 6 alkyl, Ci 6 alkylcarbonyl, hydroxyCi 6 alkyl, aryl or arylCi 6 alkyl;
  • R 14 is hydrogen, Ci 6 alkyl, aryl or arylCi 6 alkyl;
  • R 15 is hydrogen, Ci 6 alkyl, d 6 alkylcarbonyl, aryl or arylCi 6 alkyl;
  • R 4 is a radical of formula R 16 (c-2),
  • R 16 is hydrogen, halo, aryl, d 6 alkyl, hydroxyCi 6 alkyl, Ci 6 alkyloxyC] 6 alkyl, Ci 6 alkyloxy, Ci 6 alkylth ⁇ o, amino, mono- or d ⁇ (C ⁇ _ 4 alkyl)am ⁇ no, hydroxycarbonyl, C_ 6 alkyloxycarbonyl, Ci ⁇ alkylthioC) 6 alkyl,
  • R 16 may also be bound to one of the nitrogen atoms in the imidazole nng of formula (c-1) or (c-2), in which case the meaning of R when bound to the nitrogen is limited to hydrogen, aryl, C ⁇ _ 6 alkyl, hydroxyCi 6 alkyl,
  • Ci alkyloxyC ⁇ 6 alkyl C ⁇ . 6 alkyloxycarbonyl, Ci 6 alkylS(O)C ⁇ . 6 alkyl or
  • R 17 is hydrogen, Q 6 alkyl, C ⁇ _ 6 alkyloxyC ⁇ 6 alkyl, arylCi 6 alkyl, tnfluoromethyl or d ⁇ (C ⁇ _ 4 alkyl)am ⁇ nosulfonyl;
  • R is Ci 6 alkyl , Ci 6 alkyloxy or halo;
  • aryl is phenyl, naphthalenyl or phenyl substituted with 1 or more substituents each independently selected from halo, C] 6 alkyl, C] 6 alkyloxy or tnfluoromethyl.
  • Podophyllotoxm which is extracted from the mandrake plant, is the parent compound from which two glycosides have been developed which show significant therapeutic activity in several human neoplasms, including pediatnc leukemia, small cell carcinomas of the lung, testicular tumors, Hodgkin's disease, and large cell lymphomas
  • etoposide VP-16
  • VM-26 teniposide
  • R 9 is hydroxy, Ci-6alkyl, Ci-6alkyloxy, amino, Ci-8alkylamino or Ci-8alkylamino substituted with Ci- ⁇ alkyloxycarbonyl;
  • R 2 , R3 and Rl6 each independently are hydrogen, hydroxy, halo, cyano, Ci- ⁇ alkyl, C ⁇ _6alkyloxy, hydroxyCi - ⁇ alkyloxy, Ci-6alkyloxyC ⁇ _6alkyloxy, aminoCi - ⁇ alkyloxy, mono- or di(Ci-6alkyl)aminoCi-6alkyloxy, Arl,
  • R4 and R ⁇ each independently are hydrogen, halo, Arl, Ci- ⁇ alkyl, hydroxyCi- ⁇ alkyl, Ci-6alkyloxyCi-6alkyl , Ci - ⁇ alkyloxy, Ci-6alkylthio, amino, hydroxycarbonyl, Ci-6alkyloxycarbonyl, Ci-6alkylS(O)Ci-6alkyl or Ci-6alkylS(O)2Ci-6alkyl; R" and R 7 each independently are hydrogen, halo, cyano, Ci-6alkyl, Ci-6alkyloxy,
  • Ar 2 oxy, trihalomethyl, Ci_6alkylthio, di(Ci-6alkyl)amino, or when on adjacent positions R" and R ' taken together may form a bivalent radical of formula -O-CH2-O- (c-1), or
  • R 8 is hydrogen, Ci- ⁇ alkyl, cyano, hydroxycarbonyl, C ⁇ _6alkyloxycarbonyl, C ⁇ _ 6 alkyl- carbonylC ⁇ _6alkyl, cyanoCi- ⁇ alkyl, Ci-6alkyloxycarbonylCi-6alkyl, carboxy- Ci-6alkyl, hydroxyCi -6alkyl, aminoC ⁇ _6alkyl, mono- or di(Ci-6alkyl)amino- Ci-6alkyl, imidazolyl, haloC ⁇ _6alkyl, Ci-6alkyloxyCi-6alkyl, aminocarbonyl-
  • Ci-6alkyl or a radical of formula
  • R ⁇ is hydrogen, Ci-6alkyl, Ci_6alkylcarbonyl, Arl, Ar 2 C ⁇ _6alkyl,
  • C ⁇ _6alkyloxycarbonylCi-6alkyl or a radical or formula -Alk 2 -ORl3 or -Alk -NRl4Rl5 ;
  • RU is hydrogen, Ci-I2alkyl, Arl or Ar 2 Ci-6alkyl;
  • Rl 2 is hydrogen, Ci-6alkyl, Ci-i6alkylcarbonyl, Ci_6alkyloxycarbonyl, C ⁇ _6alkylaminocarbonyl, Arl, Ar 2 C ⁇ _6alkyl, Ci-6alkylcarbonyl-
  • Ci-6alkyl a natural amino acid, Arlcarbonyl, Ar 2 Ci_6alkylcarbonyl, aminocarbonylcarbonyl, Ci-6alkyloxyCi-6alkylcarbonyl, hydroxy, C ⁇ _6alkyloxy, aminocarbonyl, di(Ci-6alkyl)aminoCi-6alkylcarbonyl, amino, Ci-6alkylamino, Ci-6alkylcarbonylamino, or a radical or formula - Alk 2 -OR 1 or - Alk 2 -NR 1 4 R 15 ; wherein Alk 2 is Ci-6alkanediyl;
  • Rl3 is hydrogen, Ci-6alkyl, Ci_6alkylcarbonyl, hydroxyCi - ⁇ alkyl, Arl or Ar 2 Ci-6alkyl
  • Rl4 is hydrogen, Ci-6alkyl, Arl or Ar 2 C ⁇ _ 6 alkyl
  • Rl5 is hydrogen, Ci-6alkyl, Ci-6alkylcarbonyl, Arl or
  • Ar 2 Ci-6alkyl; Rl 7 is hydrogen, halo, cyano, C ⁇ _6alkyl, C ⁇ _6alkyloxycarbonyl, Arl ; Rl ⁇ is hydrogen, Ci- ⁇ alkyl, C ⁇ _6alkyloxy or halo; Rl is hydrogen or Ci- 6 alkyl; Arl is phenyl or phenyl substituted with Ci-6alkyl, hydroxy, amino, Ci-6alkyloxy or halo; and Ar 2 is phenyl or phenyl substituted with C ⁇ _6alkyl, hydroxy, amino, Ci-6alkyloxy or halo
  • combinations are hereinafter refened to as combinations according to the invention. These combinations may provide a synergistic effect whereby they demonstrate an advantageous therapeutic effect which is greater than that which would have been expected from the effects of the individual components of the combinations
  • R4 or R ⁇ may also be bound to one of the nitrogen atoms in the imidazole nng In that case the hydrogen on the nitrogen is replaced by R4 or R ⁇ and the meaning of R and R-> when bound to the nitrogen is limited to hydrogen, Arl, Ci-6alkyl, hydroxyCi -6alkyl, Ci- ⁇ alkyloxyCi- ⁇ alkyl, Ci-6alkyloxycarbonyl, Ci-6alkylS(O)Ci-6alkyl, Ci-6alkylS(O)2Ci-6alkyl.
  • substituent Rl8 1S situated on the 5 or 7 position of the qumohnone moiety and substituent R IS situated on the 8 position when Rl8 IS on the 7 -position.
  • Still another group of interesting compounds are those compounds of formula (I) wherein R 3 is hydrogen or halo; and R 2 is halo, Ci-6alkyl, C2-6alkenyl, Ci_6alkyloxy, trihalomethoxy or hydroxyCi -6alkyloxy.
  • a further group of interesting compounds are those compounds of formula (I) wherem R 2 and R 3 are on adjacent positions and taken together to form a bivalent radical of formula (a-1), (a-2) or (a-3).
  • a still further group of interesting compounds are those compounds of formula (I) wherein R ⁇ IS hydrogen and R4 IS hydrogen or C -6alkyl
  • a particular group of compounds are those compounds of formula (I) wherein R° is hydrogen, hydroxy, haloCi- ⁇ alkyl, hydroxyCi - ⁇ alkyl, cyanoC ⁇ _6alkyl, Ci-6alkyloxy- carbonylCi-6alkyl, lmidazolyl, or a radical of formula -NRI R 2 wherein R is hydrogen or Ci-i2alkyl and R 2 IS hydrogen, C -galkyl, C -6alkyloxy, hydroxy,
  • Ci-6alkyloxyC -6alkylcarbonyl or a radical of formula -Alk 2 -ORl3 wherein Rl3 IS hydrogen or C -galkyl
  • Prefened compounds are those compounds wherein R IS hydrogen, Ci-galkyl, C ⁇ _6alkyloxyCi-6alkyl, d ⁇ (Ci-6alkyl)am ⁇ noCi-6alkyl, or a radical of formula
  • Alkl 1S methylene and R 9 is Ci-8alkylam ⁇ no substituted with Ci-6alkyloxycarbonyl;
  • R 2 is halo, C ⁇ _6alkyl, C2-6alkenyl, C ⁇ _6alkyloxy, tnhalomethoxy, hydroxyCi_6alkyloxy or Arl,
  • R3 1S hydrogen, R4 IS methyl bound to the nitrogen in 3-pos ⁇ t ⁇ on of the imidazole;
  • R 7 is hydrogen,
  • Ci-6alkyloxyC ⁇ _6alkylcarbonyl or a radical of formula -Alk 2 -ORl3 wherein Rl3 1S
  • X'-X 2 -X 3 is a tnvalent radical of formula (x-1), (x-2), (x-3), (x-4) or (x-9) wherein each R independently is hydrogen, C ⁇ -4 alkyl, Ci 4 alkyloxycarbonyl, amino or aryl and R 7 is hydrogen,
  • R 1 is halo, Ci 6 alkyl or two R 1 substituents ortho to one another on the phenyl nng may independently form together a bivalent radical of formula (a-1),
  • R 3 is halo or a radical of formula (b-1) or (b-3) wherem
  • R 1 is hydrogen or a radical of formula -Alk-OR .
  • R 11 is hydrogen;
  • R 12 is hydrogen, Ci 6 alkyl, C ⁇ _ alkylcarbonyl, hydroxy, Ci 6 alkyloxy or mono- or d ⁇ (C ⁇ . 6 alkyl)ammoC ⁇ . 6 alkylcarbonyl;
  • Alk is C ⁇ . 6 alkaned ⁇ yl and
  • R 13 is hydrogen;
  • R 4 is a radical of formula (c-1) or (c-2) wherein
  • R 16 is hydrogen, halo or mono- or d ⁇ (C ⁇ _ alkyl)am ⁇ no;
  • R 17 is hydrogen or Ci 6 alkyl;
  • aryl is phenyl
  • R is hydrogen or hydroxy
  • Ci- ⁇ alkyl defines straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl and the like;
  • C ⁇ _8alkyl encompasses the straight and branched chained saturated hydrocarbon radicals as defined in Ci-6alkyl as well as the higher homologues thereof containing 7 or 8 carbon atoms such as, for example heptyl or octyl;
  • Ci-i2alkyl again encompasses Ci-8alkyl and the higher homologues thereof containing 9 to 12 carbon atoms, such as, for example, nonyl, decyl, undecyl, dodecyl;
  • Ci-i6alkyl again encompasses C ⁇ _i2alkyl and the higher homologues thereof containing 13 to
  • S(O) refers to a sulfoxide
  • S(O)2 to a sulfon.
  • natural ammo acid refers to a natural ammo acid that is bound via a covalent amide linkage formed by loss of a molecule of water between the carboxyl group of the amino acid and the amino group of the remainder of the molecule.
  • Examples of natural amino acids are glycine, alanine, vahne, leucine, isoleucine, methionine, prohne, phenylana ne, tryptophan, senne, threomne, cysteine, tyrosme, asparagine, glutamine, aspartic acid, glutamic acid, lysme, arginme, histidine.
  • the pharmaceutically acceptable acid or base addition salts as mentioned hereinabove are meant to compnse the therapeutically active non-toxic acid and non-toxic base addition salt forms which the compounds of formulas (I), (H), (HI), (IV), (V), (VI), (VH), (VHI) or (IX) are able to form
  • the compounds of formulas (I), (H), (HI), (IV), (V), (VI), (VH), (VHI) or (IX) which have basic properties can be converted in their pharmaceutically acceptable acid addition salts by treating said base form with an appropnate acid Appropnate acids compnse, for example, inorganic acids such as hydrohahc acids, e.g hydrochlonc or hydrobromic acid, sulfunc, nitnc; phosphonc and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succmic (I e
  • butanedioic acid maleic, fumanc, malic, tartanc, citnc, methanesulfonic, ethanesulfomc, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicyhc, pamoic and the like acids
  • the compounds of formulae (I), (H), (HI), (IV), (V), (VI), (VH), (VHI) or (IX) which have acidic properties may be converted in their pharmaceutically acceptable base addition salts by treating said acid form with a suitable organic or inorganic base.
  • Appropnate base salt forms compnse, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamme, hydrabamme salts, and salts with amino acids such as, for example, arginme, lysme and the like.
  • acid or base addition salt also compnse the hydrates and the solvent addition forms which the compounds of formulae (I), (H), (HI), (IV), (V), (VI), (VH), (VHI) or (IX) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
  • stereochemically isomenc forms of compounds of formulae (I), (H), (HI), (IV), (V), (VI), (VH), (VEH) or (IX), as used hereinbefore, defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of formulae (I), (H), (HI), (IV), (V), (VI), (VH), (VHI) or (IX) may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomenc forms which said compound may possess.
  • Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound All stereochemically isomenc forms of the compounds of formulae (I), (H), (HI), (IV), (V), (VI), (VH), (VHI) or (IX) both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.
  • Prefened anti-tumor anti-tumor podophyllotoxin derivatives for use in accordance with the invention include etoposide and teniposide refened to above.
  • Etoposide is commercially available for example from Bristol-Myers Squibb under the trade name VePesid, and may be prepared for example as described in European patent specification No. 111058, or by processes analogous thereto.
  • Teniposide is commercially available for example from Bristol-Myers Squibb under the trade name Vumon and may be prepared for example as described in PCT patent specification No. WO 93/02094, or by processes analogous thereto.
  • Other anti-tumor podophyllotoxin derivatives may be prepared in conventional manner for example by processes analogous to those described above for etoposide and teniposide.
  • the present invention also relates to combinations according to the invention for use in medical therapy for example for inhibiting the growth of tumor cells.
  • the present invention also relates to the use of combinations according to the invention for the preparation of a pharmaceutical composition for inhibiting the growth of tumor cells.
  • the present invention also relates to a method of inhibiting the growth of tumor cells in a human subject which comprises administering to the subject an effective amount of a combination according to the invention.
  • This invention further provides a method for inhibiting the abnormal growth of cells, including transformed cells, by administering an effective amount of a combination according to the invention.
  • Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g. loss of contact inhibition) This includes the abnormal growth of .
  • tumor cells tumor cells (tumors) expressing an activated ras oncogene
  • tumor cells tumor cells in which the ras protein is activated as a result of oncogenic mutation of another gene
  • ras oncogenes not only contnbute to the growth of of tumors in vivo by a direct effect on tumor cell growth but also indirectly, i.e. by facilitating tumor-mduced angiogenesis (Rak. J. et al, Cancer Research, 55, 4575-4580, 1995).
  • pharmacologically targetting mutant ras oncogenes could conceivably suppress solid tumor growth in vivo, in part, by inhibiting tumor-mduced angiogenesis
  • This invention also provides a method for inhibiting tumor growth by admimstenng an effective amount of a combination according to the present invention, to a subject, e g a mammal (and more particularly a human) in need of such treatment.
  • this invention provides a method for inhibiting the growth of tumors expressing an activated ras oncogene by the administration of an effective amount of combination according to the present invention.
  • tumors which may be inhibited include, but are not limited to, lung cancer (e.g adenocarcinoma and including non- small cell lung cancer), pancreatic cancers (e.g. pancreatic carcinoma such as, for example exocnne pancreatic carcinoma), colon cancers (e.g.
  • colorectal carcinomas such as, for example, colon adenocarcinoma and colon adenoma), hematopoietic tumors of lymphoid lineage (e g. acute lymphocytic leukemia, B-cell lymphoma, Burkitt's lymphoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid folhcular cancer, myelodysplastic syndrome (MDS), tumors of mesenchymal ongin (e.g. fibrosarcomas and rhabdomyosarcomas), melanomas, teratocarcinomas, neuroblastomas, ghomas, benign tumor of the skin (e.g. keratoacanthomas), breast carcinoma (e.g. advanced breast cancer), kidney carninoma, ovary carcinoma, bladder carcinoma and epidermal carcinoma.
  • lymphoid lineage e g. acute lymphocytic leukemia
  • This invention also provides a method for inhibiting prohferative diseases, both benign and malignant, wherem ras proteins are abenantly activated as a result of oncogenic mutation in genes, i.e. the ras gene itself is not activated by mutation to an oncogenic mutation to an oncogenic form, with said inhibition being accomplished by the administration of an effective amount of a combination according to the invention, to a subject in need of such a treatment.
  • the benign prohferative disorder neurofibromatosis, or tumors in which ras is activated due to mutation or overexpression of tyrosine kinase oncogenes may be inhibited by the combinations according to the invention.
  • the anti-tumor podophyllotoxin derivative and the farnesyl transferase inhibitor may be administered simultaneously (e.g. in separate or unitary compositions) or sequentially in either order. In the latter case, the two compounds will be administered within a period and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is achieved.
  • the prefened method and order of administration and the respective dosage amounts and regimes for each component of the combination will depend on the particular anti-tumor podophyllotoxin derivative and farnesyl transferase inhibitor being administered, their route of administration, the particular tumor being treated and the particular host being treated.
  • the optimum method and order of administration and the dosage amounts and regime can be readily determined by those skilled in the art using conventional methods and in view of the information set out herein.
  • the farnesyl transferase inhibitor is advantageously administered in an effective amount of from 0.0001 mg/kg to 100 mg/kg body weight, and in particular from 0.001 mg/kg to 10 mg/kg body weight. More particularly, for an adult patient, the dosage is conveniently in the range of 50 to 500mg bid, advantageously 100 to 400 mg bid and particularly 300mg bid.
  • the anti-tumor podophyllotoxin derivative is advantageously administered in a dosage of 30 to 300 mg per square meter (mg/m 2 ) of body surface area, for example 50 to 250mg/m 2 , particularly for etoposide in a dosage of about 35 to 100 mg/m 2 and for teniposide in about 50 to 250 mg/m 2 per course of treatment.
  • These dosages may be administered for example once, twice or more per course of treatment, which may be repeated for example every 7,14,21 or 28 days.
  • the components of the combinations according to the invention i.e. the anti-tumor podophyllotoxin derivative and the farnesyl transferase inhibitor may be formulated into various pharmaceutical forms for administration purposes.
  • the components may formulated separately in individual pharmaceutical compositions or in a unitary pharmaceutical composition containing both components
  • Farnesyl protein transferase inhibitors can be prepared and formulated into pharmaceutical compositions by methods known in the art and in particular according to the methods descnbed in the published patent specifications mentioned herein and incorporated by reference, for the compounds of formulae (I), (H) and (HI) suitable examples can be found in WO-97/21701.
  • the present invention therefore also relates to a pharmaceutical composition compnsmg an anti-tumor podophyllotoxm denvative and a farnesyl tranferase inhibitor of formula (I) together with one or more pharmaceutical earners.
  • a pharmaceutical composition compnsmg an anti-tumor podophyllotoxm denvative and a farnesyl tranferase inhibitor of formula (I) together with one or more pharmaceutical earners.
  • an effective amount of a particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable earner, which earner may take a wide vanety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally, percutaneously, or by parenteral injection.
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid earners such as starches, sugars, kaolin, lubncants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical earners are obviously employed. For parenteral compositions, the earner will usually compnse stenle water, at least in large part, though other ingredients, to aid solubility for example, may be included.
  • Injectable solutions may be prepared in which the earner compnses saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropnate liquid earners, suspending agents and the like may be employed.
  • the earner optionally compnses a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause a significant deletenous effect to the skm. Said additives may facilitate the administration to the skin and/or may be helpful for prepanng the desired compositions.
  • These compositions may be administered in vanous ways, e.g., as a transdermal patch, as a spot-on, as an ointment
  • Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical earner.
  • dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
  • each component of the combination may be appropnate to administer the required dose of each component of the combination as two, three, four or more sub-doses at appropnate intervals throughout the course of treatment
  • Said sub-doses may be formulated as unit dosage forms, for example, in each case containing independently 0.01 to 500 mg, for example 0.1 to 200 mg and in particular 1 to lOOmg of each active ingredient per unit dosage form.
  • the combinations according to the invention may be tested for their efficacy in inhibiting tumor growth using conventional assays descnbed in the literature for example the HTB177 lung carcinoma descnbed by Liu M et al, Cancer Research, Vol 58, No.21, 1 November 1998, pages 4947-4956, and the anti-mitotic assay descnbed by Moasser M et al, Proc. Natl. Acad. Sci. USA, Vol. 95, pages 1369-1374, February 1998.
  • Other in vitro and in vivo models for determining ant-tumor effects of combinations and possible synergy of the combinations according to the invention are descnbed in WO 98/54966 and WO 98/32114.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The present invention is concerned with combinations of a farnesyl transferase inhibitor and an anti-tumor podophyllotoxin derivative for inhibiting the growth of tumor cells and useful in the treatment of cancer.

Description

FARNESYL PROTEIN TRANSFERASE INHIBITOR COMBINATIONS WITH ANTI-TUMOR PODOPHYLLOTOXLN DERIVATIVES
The present invention is concerned with combinations of a farnesyl transferase inhibitor and an anti-tumor podophyllotoxin denvative for inhibiting the growth of tumor cells and useful in the treatment of cancer
Oncogenes frequently encode protein components of signal transduction pathways which lead to stimulation of cell growth and mitogenesis Oncogene expression in cultured cells leads to cellular transformation, charactenzed by the ability of cells to grow in soft agar and the growth of cells as dense foci lacking the contact inhibition exhibited by non-transformed cells Mutation and/or overexpression of certain oncogenes is frequently associated with human cancer A particular group of oncogenes is known as ras which have been identified in mammals, birds, insects, mollusks, plants, fungi and yeasts The family of mammalian ras oncogenes consists of three major members ("isoforms") H-ras, K-ras and N-ras oncogenes These ras oncogenes code for highly related proteins genencally known as p21ra5 Once attached to plasma membranes, the mutant or oncogenic forms of p21r< s will provide a signal for the transformation and uncontrolled growth of malignant tumor cells To acquire this transforming potential, the precursor of the p21ra,s oncoprotem must undergo an enzymatically catalyzed farnesylation of the cysteme residue located in a carboxyl- terminal tetrapeptide Therefore, inhibitors of the enzyme that catalyzes this modification, farnesyl protein transferase. will prevent the membrane attachment of p21raι and block the abenant growth of rαs-transformed tumors Hence, it is generally accepted in the art that farnesyl transferase inhibitors can be very useful as anticancer agents for tumors in which ras contnbutes to transformation
Since mutated, oncogenic forms of ras are frequently found in many human cancers, most notably in more than 50 % of colon and pancreatic carcinomas (Kohl et al , Science, vol 260, 1834 - 1837, 1993), it has been suggested that farnesyl tranferase inhibitors can be very useful against these types of cancer Following further investigations, it has been found that a farnesyl transferase inhibitor is capable of demonstrating antiprohferative effects ... vitro and antitumor effects in vivo in a vanety of human tumor cell lines with and without ras gene mutations WO-97/21701 describes the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting (imidazoly-5-yl)methyl-2-quinolinone derivatives of formulas (I), (II) and (III), as well as intermediates of formula (II) and (HI) that are metabolized in vivo to the compounds of formula (I). The compounds of formulas (I), (II) and (HI) are represented by
(I) (II)
(in) 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;
Rl is hydrogen, Ci -i2alkyl, Ar*, Ar^Ci-όalkyl, quinolinylCi-6alkyl, pyridylCi-6alkyl, hydroxyCi -6alkyl, Ci-6alkyloxyCi-6alkyl, mono- or di (C i -6alkyl)aminoC i -6alkyl, aminoC \ -όalkyl , or a radical of formula -Alk1-C(=O)-R9, -Alk!-S(O)-R9 or -Alk!-S(O)2-R9, wherein Alk* is Ci-6alkanediyl,
R9 is hydroxy, Cι_6alkyl, Cι_6alkyloxy, amino, Ci-8alkylamino or Cι_8alkylamino substituted with Ci -6alkyloxycarbonyl; R^, R3 and Rl°" each independently are hydrogen, hydroxy, halo, cyano, Cι_6alkyl, Ci -6alkyloxy, hydroxyCi -6alkyloxy, Ci-6alkyloxyCι_6alkyloxy, aminoCi-6alkyl- oxy, mono- or di(Ci-6alkyl)aminoCi-6alkyloxy, Ar*, Ar^Ci-όalkyl, Arloxy, Ar^Ci- alkyloxy, hydroxycarbonyl, Cι_6alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, 4,4-dimethyloxazolyl; or when on adjacent positions R^ and R^ taken together may form a bivalent radical of formula
-O-CH2-O- (a-1),
-O-CH2-CH2-O- (a-2),
-O-CH=CH- (a-3),
-O-CH2-CH2- (a-4), -O-CH2-CH2-CH2- (a-5), or
-CH=CH-CH=CH- (a-6); R4 and R^ each independently are hydrogen, halo, Ar , Cι_6alkyl, hydroxyCι_6alkyl, Ci-όalkyloxyCi-galkyl, Ci-6alkyloxy, Ci-6alkylthio, amino, hydroxycarbonyl, Cι_6alkyloxycarbonyl, Ci-6alkylS(O)Ci-6alkyl or Ci-6alkylS(O)2Ci-6alkyl; R6 and R^ each independently are hydrogen, halo, cyano, Ci-6alkyl, Ci-βalkyloxy, Arloxy, trihalomethyl, Ci-6alkylthio, di(Cι_6alkyl)amino, or when on adjacent positions R^ and R^ taken together may form a bivalent radical of formula
-O-CH2-O- (c-1), or -CH=CH-CH=CH- (c-2);
R8 is hydrogen, Ci-βalkyl, cyano, hydroxycarbonyl, Ci-6alkyloxycarbonyl,
C 1 -6alkylcarbonylC 1 -6alkyl , cyanoC 1 -6alkyl, C 1 _6alkyloxycarbonylC 1 -6alkyl , carboxyCi-βalkyl, hydroxyCi -6alkyl, aminoCi-6alkyl, mono- or di(Cι_6alkyl)- aminoCi-6alkyl, imidazolyl, haloCi-6alkyl, Ci-6alkyloxyCi-6alkyl, aminocarbonylCi-βalkyl, or a radical of formula
-O-RlO (b-1),
-S-RlO (b-2),
-N-Rl lRl2 (b-3), wherein RlO is hydrogen, Cι_6alkyl, Ci-6alkylcarbonyl, Arl, Ar^Ci-όalkyl, Ci-6alkyloxycarbonylCι_6alkyl, or a radical or formula -Alk2-ORl3 or -Alk2-NR14R15; R11 is hydrogen, Ci-i2alkyl, Ar* or Ar^Ci-όalkyl; Rl2 is hydrogen, Cι_6alkyl, Ci-i6alkylcarbonyl, Ci-6alkyloxycarbonyl,
Ci-6alkylaminocarbonyl, Arl, Ar2Cι_6alkyl, Ci-βalkylcarbonyl- Cι_6alkyl, a natural amino acid, Arlcarbonyl, Ar^Ci-όalkylcarbonyl, aminocarbonylcarbonyl, Cι_6alkyloxyCι_6alkylcarbonyl, hydroxy,
Cι_6alkyloxy, aminocarbonyl, di(Ci-6alkyl)aminoCi-6alkylcarbonyl, amino, Ci-6alkylamino, Ci-6alkylcarbonylamino, or a radical or formula -Alk2-OR13 or -Alk2-NR14R15; wherein Alk2 is Ci-6alkanediyl;
R!3 is hydrogen, Ci-6alkyl, Ci-βalkylcarbonyl, hydroxy-
Cι_6alkyl, Ar or Ar2Ci-6alkyl; Rl4 is hydrogen, Ci-6alkyl, Arl or Ar2Cι_6alkyl; Rl5 is hydrogen, Ci-6alkyl, Ci-βalkylcarbonyl, Ar or Ar2Ci-6alkyl; Rl7 is hydrogen, halo, cyano, Ci-6alkyl, Ci-6alkyloxycarbonyl, Arl ; R !8 is hydrogen, Cι_6alkyl, Ci-6alkyloxy or halo; Rl9 is hydrogen or Ci-6alkyl; Arl js phenyl or phenyl substituted with Ci-6alkyl, hydroxy, amino, Cι_6alkyloxy or halo; and Ar2 is phenyl or phenyl substituted with Ci-6alkyl, hydroxy, amino, Ci-6alkyloxy or halo.
WO-97/16443 concerns the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting compounds of formula (IV), as well as intermediates of formula (V) and (VI) that are metabolized in vivo to the compounds of formula (IV). The compounds of formulas (IV), (V) and (VI) are represented by
(IV) (V)
(VI) the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein the dotted line represents an optional bond; X is oxygen or sulfur;
Rl is hydrogen, Ci-I2alkyl, Arl, Ar2Ci-6alkyl, quinolinylCi-βalkyl, pyridyl- Cι_6alkyl, hydroxyCi -όalkyl, Cι_6alkyloxyCi-6alkyl, mono- or di(Cι_6alkyl)- aminoCi-6alkyl, aminoCι_6alkyl, or a radical of formula -Alkl-C(=O)-R9, -Alkl-S(O)-R9 or -Alkl-S(O)2-R9, wherein Alkl js Cι_6alkanediyl,
R9 is hydroxy, Ci-6alkyl, Ci-galkyloxy, amino, Ci-8alkylamino or Ci-8alkylamino substituted with Cι_6alkyloxycarbonyl; R2 and R3 each independently are hydrogen, hydroxy, halo, cyano, Ci-6alkyl, Cι_6alkyloxy, hydroxyCi -βalkyloxy, Ci-6alkyloxyCι_6alkyloxy, amino- Cι_6alkyloxy, mono- or di(Ci-6alkyl)aminoCi-6alkyloxy, Arl, Ar Ci-6alkyl,
Ar oxy, Ar2Ci-6alkyloxy, hydroxycarbonyl, Ci-6alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C2-6alkenyl; or when on adjacent positions R2 and R3 taken together may form a bivalent radical of formula - -OO--CCHH72--OO-- (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 - -CCHH==CCHH--CCHH==CCHH-- (a-6);
R4 and R ,5 5 each independently are hydrogen, Ar1, Cι_6alkyl, Cι_6alkyloxyC].6alkyl,
Cι_6alkyloxy, C].6alkylthio, amino, hydroxycarbonyl, C].6alkyloxycarbonyl,
Cι.6alkylS(O)C].6alkyl or Cι_6alkylS(O)2C,.6alkyl;
R6 and R^ each independently are hydrogen, halo, cyano, Ci-6alkyl, Cι_6alkyloxy or Ar2oxy; R8 IS hydrogen, Cι_6alkyl, cyano, hydroxycarbonyl, Ci-6alkyloxycarbonyl, Ci-βalkyl- carbonylCi-6alkyl, cyanoCi-6alkyl, Ci-6alkyloxycarbonylCi-6alkyl, hydroxy- carbonylCi-6alkyl, hydroxyCi -6alkyl, amιnoCι_6alkyl, mono- or dι(Ci-6alkyl)- amιnoCi-6alkyl, haloCi-6alkyl, Cι_6alkyloxyCi-6alkyl, ammocarbonylCi-6alkyl, Arl, Ar2Ci-6alkyloxyCi-6alkyl, Ci-6alkylthιoCi-6alkyl;
RIO IS hydrogen, Ci-6alkyl, Ci-βalkyloxy or halo;
Rl 1 is hydrogen or Cι_6alkyl,
Arl 1S phenyl or phenyl substituted with Ci-6alkyl, hydroxy, amino, Ci-6alkyloxy or halo; Ar2 is phenyl or phenyl substituted with Ci-galkyl, hydroxy, ammo, -galkyloxy or halo.
WO-98/40383 concerns the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting compounds of formula (VII)
the pharmaceutically acceptable acid addition salts and the stereochemically isomenc forms thereof, wherein
the dotted line represents an optional bond;
X is oxygen or sulfur;
-A- is a bivalent radical of formula -CH=CH- (a-1), CH2-S- (a-6),
-CH2-CH2- (a-2), CH2-CH2-S- (a-7), -CH2-CH2-CH2- (a-3), CH=N- (a-8),
-CH2-O- (a-4), ■N=N- (a-9), or
-CH2-CH2-O- (a-5), CO-NH- (a-10); wherein optionally one hydrogen atom may be replaced by Ci-4alkyl or Arl; Rl and R2 each independently are hydrogen, hydroxy, halo, cyano, Ci-βalkyl, tnhalomethyl, tnhalomethoxy, C2-6alkenyl, Cι_6alkyloxy, hydroxyCι_6alkyloxy,
Ci-6alkyloxyCi-6alkyloxy, Ci-6alkyloxycarbonyl, ammoCi-6alkyloxy, mono- or di(Ci-6alkyl)aminoCι_6alkyloxy, Ar2, Ar2-Cι_6alkyl, Ar2-oxy, Ar -Ci-6alkyloxy; or when on adjacent positions Rl and R2 taken together may form a bivalent radical of formula
-O-CH2-O- (b-1),
-O-CH2-CH2-O- (b-2),
-O-CH=CH- (b-3),
-O-CH2-CH2- (b-4),
-O-CH2-CH2-CH2- (b-5), or
-CH=CH-CH=CH- (b-6);
R3 and R4 each independently . ire hydrogen, halo, cyano, Cι_6alkyl, Ci-6alkyloxy,
Ar-^-oxy, Ci-βalkylthio, di(Cι_6alkyl)amino, trihalomethyl, trihalomethoxy, or when on adjacent positions R3 and R4 taken together may form a bivalent radical of formula
-O-CH2-O- (c-1),
-O-CH2-CH2-O- (c-2), or
-CH=CH-CH=CH- (c-3);
R^ is a radical of formula
~N (d-1), j{— R13 (d-2),
R13 R- wherein Rl3 is hydrogen, halo, Ar4, Ci-6alkyl, hydroxyCi -6alkyl, Ci-^alkyloxy- Cι_6alkyl, Cι_6alkyloxy, Cι_6alkylthio, amino, Ci-6alkyloxy- carbonyl, Ci-6alkylS(O)Ci-6alkyl or Ci-6alkylS(O)2Cι_6alkyl; Rl^is hydrogen, Ci-6alkyl or di(Ci-4alkyl)aminosulfonyl; R6 is hydrogen, hydroxy, halo, C -βalkyl, cyano, haloCi-6alkyl, hydroxyCi -όalkyl, cyanoCi-6alkyl, aminoCι_6alkyl, Ci-6alkyloxyCι_6alkyl, Ci-6alkylthioCi-6alkyl, aminocarbonylCi-6alkyl,
C 1 -6alkyloxycarbonylC i-6alkyl, C 1 -6alkylcarbonyl-C 1 _6alkyl, Ci-6alkyloxycarbonyl, mono- or di(Ci-6alkyl)aminoCi-6alkyl, Ar , Ar5-Ci-6alkyloxyCι_6alkyl; or a radical of formula -O-R7 (e-1), -S-R7 (e"2),
-N-RδR9 (e-3), wherein R7 is hydrogen, Ci-βalkyl, Cι_6alkylcarbonyl,
Ci-6alkyloxycarbonylCι_6alkyl, or a radical of formula -Alk-OR 0 or -Alk-NRllRl2; R8 is hydrogen, Cι_6alkyl, Ar7 or Ar"7-Cι_6alkyl; R9 is hydrogen, Ci-6alkyl, Ci-ζalkylcarbonyl, Ci-6alkyloxycarbonyl, Ci-6alkylaminocarbonyl, Ar^, Ar^-Ci-βalkyl, Ci-βalkylcarbony]- Ci-6alkyl, Ar°-carbonyl, Ar°-Cι_6alkylcarbonyl, aminocarbonyl- carbonyl, Ci-βalkyloxyCi-βalkylcarbonyl, hydroxy, Ci-galkyloxy, aminocarbonyl, di(Ci-6alkyl)aminoCi-6alkylcarbonyl, amino,
Ci-βalkylamino, Ci-galkylcarbonylamino, or a radical or formula -Alk-OR10 or -Alk-NRURl2; wherein Alk is Ci-galkanediyl;
RIO is hydrogen, Ci-6alkyl, Ci-βalkylcarbonyl, hydroxyCi -6alkyl, Ar9 or Ar9-Ci-6alkyl;
RU is hydrogen, Ci-βalkyl, Ci-6alkylcarbonyl, ArlO or
Ar10-Cι_6alkyl;
Rl2 is hydrogen, Cι_6alkyl, ArH or Arl l-Ci-6alkyl; and
Arl t0 Aril are each independently selected from phenyl; or phenyl substituted with halo, Ci-6alkyl, Ci-βalkyloxy or trifluoromethyl.
WO-98/49157 concerns the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting compounds of formula (VHI)
the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein the dotted line represents an optional bond; X is oxygen or sulfur;
Rl and R2 each independently are hydrogen, hydroxy, halo, cyano, Ci-βalkyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, Ci-6alkyloxy, hydroxyCi -6alkyloxy,
Cι_6alkyloxyCi-6alkyloxy, Ci-6alkyloxycarbonyl, aminoCi-6alkyloxy, mono- or di(Ci-6alkyl)aminoCi-6alkyloxy, Arl, ArlCi-6alkyl, Arloxy or ArlCi-6alkyloxy; R3 and R4 each independently are hydrogen, halo, cyano, Ci_6alkyl, Cι_6alkyloxy, Arloxy, Cι_6alkylthio, di(Ci-6alkyl)amino, trihalomethyl or trihalomethoxy; R5 IS hydrogen, halo, Ci-βalkyl, cyano, haloCi-6alkyl, hydroxyCi -όalkyl, cyanoCi-6alkyl, ammoCi-βalkyl, Ci-6alkyloxyCι_6alkyl, C i -όalkyl thioC i -βalkyl, aminocarbonylC 1 -όalkyl , C i -όalkyloxycarbonylC i -βalkyl, C i -6alkylcarbonyl-C i -galkyl , Ci-6alkyloxycarbonyl, mono- or dι(Ci-6alkyl)ammoCi-6alkyl, Ar ,
ArlCi-6alkyloxyCι_6alkyl, or a radical of formula -O-RlO (a-1),
-S-RlO (a-2),
-N-Rl lRl2 (a-3), wherein Rl° IS hydrogen, Ci-6alkyl, Ci-6alkylcarbonyl, Ar , ArlCi-6alkyl,
Ci-6alkyloxycarbonylCi-6alkyl, or a radical of formula -Alk-ORl3 or -Alk-NRl4Rl5, RU IS hydrogen, Ci-6alkyl, Arl or ArlCi-6alkyl, Rl2 IS hydrogen, Ci-6alkyl, Ci-6alkylcarbonyl, Ci-6alkyloxycarbonyl, Ci-6alkylammocarbonyl, Arl, ArlCι_6alkyl, Ci-6alkylcarbonyl-
Ci-6alkyl, Arlcarbonyl, ArlCi-6alkylcarbonyl, aminocarbonyl- carbonyl, Ci-βalkyloxyCi-βalkylcarbonyl, hydroxy, Ci-6alkyloxy, aminocarbonyl, dι(Ci-6alkyl)amιnoCi-6alkylcarbonyl, amino, Ci_6alkylamino, Ci-6alkylcarbonylamιno, or a radical or formula -Alk-ORl3 or -Alk-NRl4Rl5, wherem Alk is Ci-6alkanedιyl,
Rl3 IS hydrogen, Ci-βalkyl, Ci-6alkylcarbonyl, hydroxy-
Ci-6alkyl, Arl or ArlCi-6 lkyl,
Rl4 ΪS hydrogen, Ci-6alkyl, Arl or ArlCi-β lkyl, Rl5 IS hydrogen, Ci-6alkyl, Ci-6alkylcarbonyl, Arl or
ArlCi-6alkyl,
R° ιs a radical of formula
— N \ J (b-1), { jj-R16 (b-2), \ R Λ N
R1 6 R I 1177 wherein Rl^s hydrogen, halo, Arl, Ci-βalkyl, hydroxyCi -βalkyl, Cι_6alkyloxy- Ci-6alkyl, Ci-ζalkyloxy, Ci-6alkylthιo, amino,
Ci-6alkyloxycarbonyl, Ci-6alkylthιoCi-6alkyl, Ci-6alkylS(O)Ci-6alkyl or Ci-6alkylS(O)2Ci-6alkyl, Rl ' IS hydrogen, Ci-6alkyl or dι(Ci-4alkyl)amιnosulfonyl, R7 is hydrogen or Cι_6alkyl provided that the dotted line does not represent a bond, R8 is hydrogen, Ci-6alkyl or Ar CH2 or HetlCH2; R9 is hydrogen, Ci-βalkyl , Ci-6alkyloxy or halo; or
R8 and R9 taken together to form a bivalent radical of formula -CH=CH- (c-1),
-CH2-CH2- (c-2),
-CH2-CH2-CH2- (c-3), -CH2-O- (c-4), or
-CH2-CH2-O- (c-5);
Arl is phenyl; or phenyl substituted with 1 or 2 substituents each independently selected from halo, Cι_6alkyl, Cι_6alkyloxy or trifluoromethyl;
Ar2 is phenyl; or phenyl substituted with 1 or 2 substituents each independently selected from halo, Cι_6alkyl, Ci-6alkyloxy or trifluoromethyl; and
Hetl js pyridinyl; pyridinyl substituted with 1 or 2 substituents each independently selected from halo, Ci-6alkyl, Cι_6alkyloxy or trifluoromethyl.
WO-00/39082 concerns the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting compounds of formula (IX)
or the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein
=X!-X2-X3- is a trivalent radical of formula
=N-CR6=CR7- (x-1), =CR6-CR7=CR8- (x-6),
=N-N=CR6- (χ-2), =CR6-N=CR7- (x-7),
=N-NH-C(=O)- (x-3), =CR6-NH-C(=O)- (x-8), or
=N-N=N- (x-4), =CR6-N=N- (χ-9);
=N-CR6=N- (x-5), wherein each R , R and R are independently hydrogen, Cι. alkyl, hydroxy, C1- alkyloxy, aryloxy, Cι_ alkyloxycarbonyl, hydroxyCi.4alkyl, Cι_4alkyloxyCι_ alkyl, mono- or di(Cι.4alkyl)aminoCι.4alkyl, cyano, amino, thio, Cι_4alkylthio, arylthio or aryl; 1 7
>Y -Y - is a trivalent radical of formula
>CH-CHR9- (y-i),
>C=N- (y-2),
>CH-NR9- (y-3),or
>C=CR9- (y-4); wherein each R independently is hydrogen, halo, halocarbonyl, aminocarbonyl, hydroxyCi_4alkyl, cyano, carboxyl, Cι_ alkyl, Cι_ alkyloxy, C].4alkyloxyCι.4alkyl, Cι_4alkyloxycarbonyl, mono- or di(Cι_ alkyl)amino, mono- or di (C i . alkyl)aminoC i _4alkyl , 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, Ci-galkyl, trihalomethyl, trihalomethoxy, C2.6alkenyl, Cι_6alkyloxy, hydroxyCι_ alkyloxy, Cι_6alkylthio, Cι_6alkyloxyCι_6alkyloxy, Cι_6alkyloxycarbonyl, aminoC]. alkyloxy, mono- or di(C]_6alkyl)amino, mono- or di(Cι_6alkyl)aminoCι.6alkyloxy, aryl, arylC].6alkyl, aryloxy or arylCι_6alkyloxy, hydroxycarbonyl, C].6alkyloxycarbonyl, aminocarbonyl, aminoCι_ alkyl, mono- or di(Ci.6alkyl)aminocarbonyl, mono- or di(Cι.6alkyl)aminoCι. alkyl; or two R1 or R2 substituents adjacent to one another on the phenyl ring may independently form together a bivalent radical of formula
O-CH2-O- (a-1),
O-CH2-CH2-O- (a-2),
O=CH=CH- (a-3),
O-CH2-CH2- (a-4),
O-CH2-CH2- CH2- (a-5), or
CH=CH-CH=CH- (a-6);
R3 is hydrogen, halo, Cj.6alkyl, cyano, haloCι_6alkyl, hydroxyCi _6alkyl, cyanoC]. alkyl, aminoCι_6alkyl, C].6alkyloxyCι.6alkyl, Cι.6alkylthioC].6alkyl, aminocarbonylC ι _6alkyl , hydroxycarbonyl , hydroxycarbonylC i _ alkyl , Cι.6alkyloxycarbonylCι.6alkyl, Cι_6alkylcarbonylCι.6alkyl, Cι.6alkyloxycarbonyl, aryl, arylCι_6alkyloxyCi-6alkyl, mono- or di(C].6alkyl)aminoCι_6alkyl; or a radical of formula
-O-R10 (b-1),
-S-R10 (b-2), -NRnR12 (b-3), wherein R10 is hydrogen, Cι_6alkyl, C].6alkylcarbonyl, aryl, arylCι_6alkyl,
C].6alkyloxycarbonylCι-6alkyl, or a radical of formula -Alk-OR13 or -Alk-NR14R15; R11 is hydrogen, Ci 6alkyl, aryl or arylCi 6alkyl; R12 is hydrogen, Cι_6alkyl, aryl, hydroxy, amino, Ci 6alkyloxy,
Cι.6alkylcarbonylCι 6alkyl, arylCi 6alkyl, Ci 6alkylcarbonylamιno, mono- or dι(Cι 6alkyl)amιno. Ci 6alkylcarbonyl, aminocarbonyl, arylcarbonyl, haloCi 6alkylcarbonyl, arylCi 6alkylcarbonyl, Cι.6alkyloxycarbonyl, C) 6alkyloxyCι 6alkylcarbonyl, mono- or dι(Cι.6alkyl)amιnocarbonyl wherein the alkyl moiety may optionally be substituted by one or more substituents independently selected from aryl or 3alkyloxycarbonyl, aminocarbonylcarbonyl, mono- or dι(Cι 6alkyl)amιnoC] 6alkylcarbonyl, or a radical or formula -Alk-OR13 or -Alk-NRI4R15; wherein Alk is Ci 6alkanedιyl,
R13 is hydrogen, Ct 6alkyl, Ci 6alkylcarbonyl, hydroxyCi 6alkyl, aryl or arylCi 6alkyl; R14 is hydrogen, Ci 6alkyl, aryl or arylCi 6alkyl;
R15 is hydrogen, Ci 6alkyl, d 6alkylcarbonyl, aryl or arylCi 6alkyl; R4 is a radical of formula R16 (c-2),
wherein R16 is hydrogen, halo, aryl, d 6alkyl, hydroxyCi 6alkyl, Ci 6alkyloxyC] 6alkyl, Ci 6alkyloxy, Ci 6alkylthιo, amino, mono- or dι(Cι_4alkyl)amιno, hydroxycarbonyl, C_ 6alkyloxycarbonyl, Ci βalkylthioC) 6alkyl,
Ci 6alkylS(O)Cι 6alkyl or d 6alkylS(O)2C, 6alkyl;
R16 may also be bound to one of the nitrogen atoms in the imidazole nng of formula (c-1) or (c-2), in which case the meaning of R when bound to the nitrogen is limited to hydrogen, aryl, Cι_6alkyl, hydroxyCi 6alkyl,
Ci alkyloxyCι 6alkyl, Cι.6alkyloxycarbonyl, Ci 6alkylS(O)Cι.6alkyl or
Cι.6alkylS(O)2Cι 6alkyl;
R17 is hydrogen, Q 6alkyl, Cι_6alkyloxyCι 6alkyl, arylCi 6alkyl, tnfluoromethyl or dι(Cι_4alkyl)amιnosulfonyl; R is Ci 6alkyl , Ci 6alkyloxy or halo; aryl is phenyl, naphthalenyl or phenyl substituted with 1 or more substituents each independently selected from halo, C] 6alkyl, C] 6alkyloxy or tnfluoromethyl.
Podophyllotoxm, which is extracted from the mandrake plant, is the parent compound from which two glycosides have been developed which show significant therapeutic activity in several human neoplasms, including pediatnc leukemia, small cell carcinomas of the lung, testicular tumors, Hodgkin's disease, and large cell lymphomas These denvatives are refened to as etoposide (VP-16) which has the chemical name 41- demethylepιpodophyllotoxιn-9-[4,6-O-(R)-ethylιdene-beta-D-glucopyranosιde] and teniposide (VM-26) which has the chemical name 41-demethylepιpodophyllotoxιn-9-[4,6- O-(R)-thenyhdene-beta-D-glucopyranosιde] These compounds have a similar mechanism of action which involves the induction of DNA strand breaks by an interaction with DNA topoisomerase II or the formation of free radicals Both etoposide and teniposide, however, suffer from certain toxic side-effects especially myelosuppression
There is therefore a need to increase the inhibitory efficacy of anti-tumor podophyllotoxm denvatives against tumor growth and also to provide a means for the use of lower dosages of anti-tumor podophyllotoxm denvatives to reduce the potential of adverse toxic side effects to the patient
It is an object of the invention to provide a therapeutic combination of an anti-tumor podophyllotoxm denvative and a farnesyl transferase inhibitor of the type descnbed above which has an advantageous inhibitory effect against tumor cell growth, in companson with the respective effects shown by the individual components of the combination
According to the invention therefore we provide a combination of an anti-tumor podophyllotoxm denvative and a farnesyl transferase inhibitor of formula (I), (II), (III), (IV), (V), (VI), (VII), (VHI) or (IX) above, in particular a compound of formula (I), (II) or (HI)
(I) (ID
(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;
Rl is hydrogen, Ci-i2alkyl, Arl, Ar2Ci-6alkyl, quinolinylCi-βalkyl, pyridyl- Cι_6alkyl, hydroxyCi -βalkyl, Ci-6alkyloxyCi-6alkyl, mono- or di(Ci-6alkyl)- aminoCi-6alkyl, aminoCi-6alkyl, or a radical of formula -Alkl-C(=O)-R9, -Alkl-S(O)-R9 or -Alkl-S(O)2-R9, wherein Alkl js Ci-6alkanediyl,
R9 is hydroxy, Ci-6alkyl, Ci-6alkyloxy, amino, Ci-8alkylamino or Ci-8alkylamino substituted with Ci-βalkyloxycarbonyl; R2, R3 and Rl6 each independently are hydrogen, hydroxy, halo, cyano, Ci-βalkyl, Cι_6alkyloxy, hydroxyCi -όalkyloxy, Ci-6alkyloxyCι_6alkyloxy, aminoCi -όalkyloxy, mono- or di(Ci-6alkyl)aminoCi-6alkyloxy, Arl,
Ar2Ci-6alkyl, Ar2oxy, Ar2Cι_6alkyloxy, hydroxycarbonyl, Ci_6alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, 4,4- dimethyloxazolyl; or when on adjacent positions R2 and R3 taken together may form a bivalent radical of formula
-O-CH2-O- (a-1), -O-CH2-CH2-O- (a-2),
-O-CH=CH- (a-3), -O-CH2-CH2- (a-4), --OO--CCHH22--CCHH22--CCHH22-- (a-5), or -CH=CH-CH=CH- (a-6); R4 and R^ each independently are hydrogen, halo, Arl, Ci-βalkyl, hydroxyCi-βalkyl, Ci-6alkyloxyCi-6alkyl , Ci -όalkyloxy, Ci-6alkylthio, amino, hydroxycarbonyl, Ci-6alkyloxycarbonyl, Ci-6alkylS(O)Ci-6alkyl or Ci-6alkylS(O)2Ci-6alkyl; R" and R7 each independently are hydrogen, halo, cyano, Ci-6alkyl, Ci-6alkyloxy,
Ar2oxy, trihalomethyl, Ci_6alkylthio, di(Ci-6alkyl)amino, or when on adjacent positions R" and R ' taken together may form a bivalent radical of formula -O-CH2-O- (c-1), or
-CH=CH-CH=CH- (c-2);
R8 is hydrogen, Ci-βalkyl, cyano, hydroxycarbonyl, Cι_6alkyloxycarbonyl, Cι_6alkyl- carbonylCι_6alkyl, cyanoCi-βalkyl, Ci-6alkyloxycarbonylCi-6alkyl, carboxy- Ci-6alkyl, hydroxyCi -6alkyl, aminoCι_6alkyl, mono- or di(Ci-6alkyl)amino- Ci-6alkyl, imidazolyl, haloCι_6alkyl, Ci-6alkyloxyCi-6alkyl, aminocarbonyl-
Ci-6alkyl, or a radical of formula
-O-RlO (b-1),
-S-RlO (b-2),
-N-Rl lRl2 (b-3), wherein R ^is hydrogen, Ci-6alkyl, Ci_6alkylcarbonyl, Arl, Ar2Cι_6alkyl,
Cι_6alkyloxycarbonylCi-6alkyl, or a radical or formula -Alk2-ORl3 or -Alk -NRl4Rl5; RU is hydrogen, Ci-I2alkyl, Arl or Ar2Ci-6alkyl; Rl2is hydrogen, Ci-6alkyl, Ci-i6alkylcarbonyl, Ci_6alkyloxycarbonyl, Cι_6alkylaminocarbonyl, Arl, Ar2Cι_6alkyl, Ci-6alkylcarbonyl-
Ci-6alkyl, a natural amino acid, Arlcarbonyl, Ar2Ci_6alkylcarbonyl, aminocarbonylcarbonyl, Ci-6alkyloxyCi-6alkylcarbonyl, hydroxy, Cι_6alkyloxy, aminocarbonyl, di(Ci-6alkyl)aminoCi-6alkylcarbonyl, amino, Ci-6alkylamino, Ci-6alkylcarbonylamino, or a radical or formula - Alk2-OR 1 or - Alk2-NR 14R 15 ; wherein Alk2 is Ci-6alkanediyl;
Rl3 is hydrogen, Ci-6alkyl, Ci_6alkylcarbonyl, hydroxyCi -όalkyl, Arl or Ar2Ci-6alkyl; Rl4 is hydrogen, Ci-6alkyl, Arl or Ar2Cι_6alkyl; Rl5 is hydrogen, Ci-6alkyl, Ci-6alkylcarbonyl, Arl or
Ar2Ci-6alkyl; Rl7is hydrogen, halo, cyano, Cι_6alkyl, Cι_6alkyloxycarbonyl, Arl ; Rl^is hydrogen, Ci-βalkyl, Cι_6alkyloxy or halo; Rl is hydrogen or Ci-6alkyl; Arl is phenyl or phenyl substituted with Ci-6alkyl, hydroxy, amino, Ci-6alkyloxy or halo; and Ar2 is phenyl or phenyl substituted with Cι_6alkyl, hydroxy, amino, Ci-6alkyloxy or halo
The above descnbed combinations are hereinafter refened to as combinations according to the invention. These combinations may provide a synergistic effect whereby they demonstrate an advantageous therapeutic effect which is greater than that which would have been expected from the effects of the individual components of the combinations
In Formulas (I), (H) and (HI), R4 or R^ may also be bound to one of the nitrogen atoms in the imidazole nng In that case the hydrogen on the nitrogen is replaced by R4 or R^ and the meaning of R and R-> when bound to the nitrogen is limited to hydrogen, Arl, Ci-6alkyl, hydroxyCi -6alkyl, Ci-βalkyloxyCi-βalkyl, Ci-6alkyloxycarbonyl, Ci-6alkylS(O)Ci-6alkyl, Ci-6alkylS(O)2Ci-6alkyl.
Preferably the substituent Rl8 1S situated on the 5 or 7 position of the qumohnone moiety and substituent R IS situated on the 8 position when Rl8 IS on the 7 -position.
Interesting compounds are these compounds of formula (I) wherein X is oxygen.
Also interesting compounds are these compounds of formula (I) wherein the dotted line represents a bond, so as to form a double bond.
Another group of interesting compounds are those compounds of formula (I) wherein Rl IS hydrogen, Ci-6alkyl, Ci-6alkyloxyCi-6alkyl, dι(Ci-6alkyl)ammoCi-6alkyl, or a radical of formula -Alkl-C(=O)-R9, wherein Alkl 1S methylene and R9 is Ci-8alkyl- amino substituted with Ci-6alkyloxycarbonyl.
Still another group of interesting compounds are those compounds of formula (I) wherein R3 is hydrogen or halo; and R2 is halo, Ci-6alkyl, C2-6alkenyl, Ci_6alkyloxy, trihalomethoxy or hydroxyCi -6alkyloxy.
A further group of interesting compounds are those compounds of formula (I) wherem R2 and R3 are on adjacent positions and taken together to form a bivalent radical of formula (a-1), (a-2) or (a-3).
A still further group of interesting compounds are those compounds of formula (I) wherein R^ IS hydrogen and R4 IS hydrogen or C -6alkyl
Yet another group of interesting compounds are those compounds of formula (I) wherein R7 is hydrogen, and R^ IS Ci-6alkyl or halo, preferably chloro, especially 4-chloro
A particular group of compounds are those compounds of formula (I) wherein R° is hydrogen, hydroxy, haloCi-βalkyl, hydroxyCi -όalkyl, cyanoCι_6alkyl, Ci-6alkyloxy- carbonylCi-6alkyl, lmidazolyl, or a radical of formula -NRI R 2 wherein R is hydrogen or Ci-i2alkyl and R 2 IS hydrogen, C -galkyl, C -6alkyloxy, hydroxy,
Ci-6alkyloxyC -6alkylcarbonyl, or a radical of formula -Alk2-ORl3 wherein Rl3 IS hydrogen or C -galkyl
Prefened compounds are those compounds wherein R IS hydrogen, Ci-galkyl, Cι_6alkyloxyCi-6alkyl, dι(Ci-6alkyl)amιnoCi-6alkyl, or a radical of formula
-Alkl-C(=O)-R9, wherem Alkl 1S methylene and R9 is Ci-8alkylamιno substituted with Ci-6alkyloxycarbonyl; R2 is halo, Cι_6alkyl, C2-6alkenyl, Cι_6alkyloxy, tnhalomethoxy, hydroxyCi_6alkyloxy or Arl, R3 1S hydrogen, R4 IS methyl bound to the nitrogen in 3-posιtιon of the imidazole; R^ IS hydrogen, R^ IS chloro, R7 is hydrogen, R8 IS hydrogen, hydroxy, haloCμόalkyl, hydroxyCi -όalkyl, cyanoC -βalkyl,
Cι_6alkyloxycarbonylCi-6alkyl, lmidazolyl, or a radical of formula -NRI R1 wherein Rl 1 is hydrogen or Ci-i2alkyl and Rl2 IS hydrogen, Ci-6alkyl, Ci-6alkyloxy,
Ci-6alkyloxyCι_6alkylcarbonyl, or a radical of formula -Alk2-ORl3 wherein Rl3 1S
Ci-6alkyl, R 7 IS hydrogen and R!& is hydrogen
Most preferred compounds are
4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(l-methyl-lH-ιmιdazol-5-yl)methyl]-
1 -methyl-2( lH)-qumolιnone,
6-[ammo(4-chlorophenyl)-l-methyl-lH-ιmιdazol-5-ylmethyl]-4-(3-chlorophenyl)- l-methyl-2(lH)-quιnolmone,
6-[(4-chlorophenyl)hydroxy(l-methyl-lH-ιmιdazol-5-yl)methyl]-4-(3-ethoxyphenyl)-
1 -methyl-2( lH)-qumolmone,
6-[(4-chloroρhenyl)(l -methyl- lH-ιmιdazol-5-yl)me.hyl]-4-(3-ethoxyphenyl)- 1-methyl-
2(lH)-qumohnone monohydrochlonde monohydrate, 6-[ammo(4-chlorophenyl)(l-methyl-lH-ιmιdazol-5-yl)methyl]-4-(3-ethoxyphenyl)-l- methyl-2(lH)-qumolιnone, 6-amιno(4-chlorophenyl)(l-methyl-lH-ιmιdazol-5-yl)methyl]-l-methyl-4-(3- propylphenyl)-2(lH)-quιnohnone, a stereoisomenc form thereof or a pharmaceutically acceptable acid or base addition salt; and
(+)-6-[amιno(4-chlorophenyl)(l-methyl-lH-ιmιdazol-5-yl)methyl]-4-(3-chlorophenyl)- l-methyl-2(lH)-qumolιnone (Compound 75 in Table 1 of the Expenmental part of WO-97/21701) ; or a pharmaceutically acceptable acid addition salt thereof The latter compound is especially prefened
Further prefened embodiments of the present invention include compounds of formula (IX) wherein one or more of the following restnctions apply.
• =X'-X2-X3 is a tnvalent radical of formula (x-1), (x-2), (x-3), (x-4) or (x-9) wherein each R independently is hydrogen, Cι-4alkyl, Ci 4alkyloxycarbonyl, amino or aryl and R7 is hydrogen,
• >Y'-Y2- is a tnvalent radical of formula (y-1), (y-2), (y-3), or (y-4) wherein each R9 independently is hydrogen, halo, carboxyl, Ci alkyl or C\ alkyloxycarbonyl;
• t is 0;
• R1 is halo, Ci 6alkyl or two R1 substituents ortho to one another on the phenyl nng may independently form together a bivalent radical of formula (a-1),
• R2 is halo;
• R3 is halo or a radical of formula (b-1) or (b-3) wherem
R1 is hydrogen or a radical of formula -Alk-OR . R11 is hydrogen; R12 is hydrogen, Ci 6alkyl, Cι_ alkylcarbonyl, hydroxy, Ci 6alkyloxy or mono- or dι(Cι.6alkyl)ammoCι.6alkylcarbonyl; Alk is Cι.6alkanedιyl and R13 is hydrogen;
• R4 is a radical of formula (c-1) or (c-2) wherein
R16 is hydrogen, halo or mono- or dι(Cι_ alkyl)amιno; R17 is hydrogen or Ci 6alkyl;
• aryl is phenyl.
A particular group of compounds consists of those compounds of formula (IX) wherem =X'-X2-X3 is a tnvalent radical of formula (x-1), (x-2), (x-3), (x-4) or (x-9), >Y1-Y2 is a tnvalent radical of formula (y-2), (y-3) or (y-4), r is 0 or 1, s is 1, t is 0, R1 is halo, C(i_ )alkyl or forms a bivalent radical of formula (a-1), R2 is halo or C1-4alkyl, R3 is hydrogen or a radical of formula (b-1) or (b-3), R4 is a radical of formula (c-1) or (c-2), R6 is hydrogen, Cι_4alkyl or phenyl, R7 is hydrogen, R9 is hydrogen or Cι_ alkyl, R10 is hydrogen or -Alk-OR13, R11 is hydrogen and R12 is hydrogen or C].6alkylcarbonyl and R13 is hydrogen;
Prefened compounds are those compounds of formula (IX) wherein =X'-X2-X3 is a trivalent radical of formula (x-1) or (x-4), >Y1-Y2 is a trivalent radical of formula (y- 4), r is 0 or 1, s is 1, t is 0, R1 is halo, preferably chloro and most preferably 3-chloro, R2 is halo, preferably 4-chloro or 4-fluoro, R3 is hydrogen or a radical of formula (b-1) or (b-3), R4 is a radical of formula (c-1) or (c-2), R6 is hydrogen, R7 is hydrogen, R9 is hydrogen, R10 is hydrogen, R11 is hydrogen and R12 is hydrogen;
Other prefened compounds are those compounds of formula (IX) wherein =X1-X2-XJ is a trivalent radical of formula (x-2), (x-3) or (x-4), >Y1-Y2 is a trivalent radical of formula (y-2), (y-3) or (y-4), r and s are 1, t is 0, R1 is halo, preferably chloro, and most preferably 3-chloro or R1 is Cι- alkyl, preferably 3-methyl, R2 is halo, preferably chloro, and most preferably 4-chloro, R3 is a radical of formula (b-1) or (b-3), R4 is a radical of formula (c-2), R6 is Cι_4alkyl, R9 is hydrogen, R10 and R11 are hydrogen and
1 "1
R is hydrogen or hydroxy.
The most prefened compounds of formula (IX) are
7-[(4-fluorophenyl)(lH-imidazol-l-yl)methyl]-5-phenylimidazo[l,2-a]quinoline; α-(4-chlorophenyl)- -(l-methyl-lH-imidazol-5-yl)-5-phenylimidazo[l,2-a]quinoline-
7-methanol;
5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(l -methyl- lH-imidazol-5-yl)-imidazo [1,2- a]quinoline-7-methanol;
5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(l-methyl-lH-imidazol-5-yl)imidazo[l,2- a]quinoline-7-methanamine;
5-(3-chlorophenyl)- -(4-chlorophenyl)-α-(l-methyl-lH-imidazol-5-yl)tetrazolo[l,5- a] quinoline-7-methanamine ; 5-(3-chlorophenyl)-α-(4-chlorophenyl)- 1 -methyl-α-( 1 -methyl- lH-imidazol-5-yl)- 1.2,4- triazolo[4,3-a]quinoline-7-methanol;
5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(l-methyl-lH-imidazol-5-yl)tetrazolo[l,5- a]quinoline-7-methanamine;
5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(l-methyl-lH-imidazol-5-yl)tetrazolo[l,5- a]quinazoline-7-methanol;
5-(3-chlorophenyl)-α-(4-chlorophenyl)-4,5-dihydro-α-(l-methyl-lH-imidazol-5- yl)tetrazolo[l,5-a]quinazoline-7-methanol; 5-(3-chlorophenyl)-α-(4-chlorophenyl)- -(l-methyl-lH-ιmιdazol-5-yl)tetrazolo[l,5- a]qumazolιne-7-methanamιne;
5-(3-chlorophenyl)-α-(4-chlorophenyl)-N-hydroxy-α-(l -methyl- lH-ιmιdazol-5- yl)tetrahydro[l,5-a]quιnolme-7-methanamιne; α-(4-chlorophenyl)-α-(l -methyl- lH-ιmιdazol-5-yl)-5-(3-methylphenyl)tetrazolo[ 1,5- a]quιnolιne-7-methanamιne; the pharmaceutically acceptable acid addition salts and the stereochemically isomenc forms thereof.
5-(3-chlorophenyl)- -(4-chlorophenyl)-α-(l -methyl- lH-ιmιdazol-5-yl)tetrazolo[ 1,5- a]qumazolιne-7-methanamιne, especially the (-) enantiomer, and its pharmaceutically acceptable acid addition salts are especially prefened
As used in the foregoing definitions and hereinafter halo defines fluoro, chloro, bromo and lodo; Ci-βalkyl defines straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl and the like; Cι_8alkyl encompasses the straight and branched chained saturated hydrocarbon radicals as defined in Ci-6alkyl as well as the higher homologues thereof containing 7 or 8 carbon atoms such as, for example heptyl or octyl; Ci-i2alkyl again encompasses Ci-8alkyl and the higher homologues thereof containing 9 to 12 carbon atoms, such as, for example, nonyl, decyl, undecyl, dodecyl; Ci-i6alkyl again encompasses Cι_i2alkyl and the higher homologues thereof containing 13 to 16 carbon atoms, such as, for example, tndecyl, tetradecyl, pentedecyl and hexadecyl; C2-6alkenyl defines straight and branched chain hydrocarbon radicals containing one double bond and having from 2 to 6 carbon atoms such as, for example, ethenyl, 2-propenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, and the like; Ci-6alkanedιyl defines bivalent straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, for example, methylene, 1,2-ethanedιyl, 1,3-propanedιyl, 1,4-butanedιyl, 1,5-pentanedιyl, 1,6-hexanedιyl and the branched isomers thereof. The term "C(=O)" refers to a carbonyl group, "S(O)" refers to a sulfoxide and "S(O)2" to a sulfon. The term "natural ammo acid" refers to a natural ammo acid that is bound via a covalent amide linkage formed by loss of a molecule of water between the carboxyl group of the amino acid and the amino group of the remainder of the molecule. Examples of natural amino acids are glycine, alanine, vahne, leucine, isoleucine, methionine, prohne, phenylana ne, tryptophan, senne, threomne, cysteine, tyrosme, asparagine, glutamine, aspartic acid, glutamic acid, lysme, arginme, histidine. The pharmaceutically acceptable acid or base addition salts as mentioned hereinabove are meant to compnse the therapeutically active non-toxic acid and non-toxic base addition salt forms which the compounds of formulas (I), (H), (HI), (IV), (V), (VI), (VH), (VHI) or (IX) are able to form The compounds of formulas (I), (H), (HI), (IV), (V), (VI), (VH), (VHI) or (IX) which have basic properties can be converted in their pharmaceutically acceptable acid addition salts by treating said base form with an appropnate acid Appropnate acids compnse, for example, inorganic acids such as hydrohahc acids, e.g hydrochlonc or hydrobromic acid, sulfunc, nitnc; phosphonc and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succmic (I e. butanedioic acid), maleic, fumanc, malic, tartanc, citnc, methanesulfonic, ethanesulfomc, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicyhc, pamoic and the like acids
The compounds of formulae (I), (H), (HI), (IV), (V), (VI), (VH), (VHI) or (IX) which have acidic properties may be converted in their pharmaceutically acceptable base addition salts by treating said acid form with a suitable organic or inorganic base. Appropnate base salt forms compnse, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamme, hydrabamme salts, and salts with amino acids such as, for example, arginme, lysme and the like.
The terms acid or base addition salt also compnse the hydrates and the solvent addition forms which the compounds of formulae (I), (H), (HI), (IV), (V), (VI), (VH), (VHI) or (IX) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
The term stereochemically isomenc forms of compounds of formulae (I), (H), (HI), (IV), (V), (VI), (VH), (VEH) or (IX), as used hereinbefore, defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of formulae (I), (H), (HI), (IV), (V), (VI), (VH), (VHI) or (IX) may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomenc forms which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound All stereochemically isomenc forms of the compounds of formulae (I), (H), (HI), (IV), (V), (VI), (VH), (VHI) or (IX) both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.
Some of the compounds of formulae (I), (H), (HI), (IV), (V), (VI), (VH), (VHI) or (IX) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
Whenever used hereinafter, the term "compounds of formulae (I), (H), (HI), (IV), (V), (VI), (VH), (VHI) or (IX)" is meant to include also the pharmaceutically acceptable acid or base addition salts and all stereoisomeric forms.
Prefened anti-tumor anti-tumor podophyllotoxin derivatives for use in accordance with the invention include etoposide and teniposide refened to above. Etoposide is commercially available for example from Bristol-Myers Squibb under the trade name VePesid, and may be prepared for example as described in European patent specification No. 111058, or by processes analogous thereto. Teniposide is commercially available for example from Bristol-Myers Squibb under the trade name Vumon and may be prepared for example as described in PCT patent specification No. WO 93/02094, or by processes analogous thereto. Other anti-tumor podophyllotoxin derivatives may be prepared in conventional manner for example by processes analogous to those described above for etoposide and teniposide.
The present invention also relates to combinations according to the invention for use in medical therapy for example for inhibiting the growth of tumor cells.
The present invention also relates to the use of combinations according to the invention for the preparation of a pharmaceutical composition for inhibiting the growth of tumor cells.
The present invention also relates to a method of inhibiting the growth of tumor cells in a human subject which comprises administering to the subject an effective amount of a combination according to the invention.
This invention further provides a method for inhibiting the abnormal growth of cells, including transformed cells, by administering an effective amount of a combination according to the invention. Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g. loss of contact inhibition) This includes the abnormal growth of . (1) tumor cells (tumors) expressing an activated ras oncogene, (2) tumor cells in which the ras protein is activated as a result of oncogenic mutation of another gene; (3) benign and malignant cells of other prohferative diseases in which abenant ras activation occurs Furthermore, it has been suggested in literature that ras oncogenes not only contnbute to the growth of of tumors in vivo by a direct effect on tumor cell growth but also indirectly, i.e. by facilitating tumor-mduced angiogenesis (Rak. J. et al, Cancer Research, 55, 4575-4580, 1995). Hence, pharmacologically targetting mutant ras oncogenes could conceivably suppress solid tumor growth in vivo, in part, by inhibiting tumor-mduced angiogenesis
This invention also provides a method for inhibiting tumor growth by admimstenng an effective amount of a combination according to the present invention, to a subject, e g a mammal (and more particularly a human) in need of such treatment. In particular, this invention provides a method for inhibiting the growth of tumors expressing an activated ras oncogene by the administration of an effective amount of combination according to the present invention. Examples of tumors which may be inhibited include, but are not limited to, lung cancer (e.g adenocarcinoma and including non- small cell lung cancer), pancreatic cancers (e.g. pancreatic carcinoma such as, for example exocnne pancreatic carcinoma), colon cancers (e.g. colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), hematopoietic tumors of lymphoid lineage (e g. acute lymphocytic leukemia, B-cell lymphoma, Burkitt's lymphoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid folhcular cancer, myelodysplastic syndrome (MDS), tumors of mesenchymal ongin (e.g. fibrosarcomas and rhabdomyosarcomas), melanomas, teratocarcinomas, neuroblastomas, ghomas, benign tumor of the skin (e.g. keratoacanthomas), breast carcinoma (e.g. advanced breast cancer), kidney carninoma, ovary carcinoma, bladder carcinoma and epidermal carcinoma.
This invention also provides a method for inhibiting prohferative diseases, both benign and malignant, wherem ras proteins are abenantly activated as a result of oncogenic mutation in genes, i.e. the ras gene itself is not activated by mutation to an oncogenic mutation to an oncogenic form, with said inhibition being accomplished by the administration of an effective amount of a combination according to the invention, to a subject in need of such a treatment. For example, the benign prohferative disorder neurofibromatosis, or tumors in which ras is activated due to mutation or overexpression of tyrosine kinase oncogenes may be inhibited by the combinations according to the invention.
The anti-tumor podophyllotoxin derivative and the farnesyl transferase inhibitor may be administered simultaneously (e.g. in separate or unitary compositions) or sequentially in either order. In the latter case, the two compounds will be administered within a period and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is achieved. It will be appreciated that the prefened method and order of administration and the respective dosage amounts and regimes for each component of the combination will depend on the particular anti-tumor podophyllotoxin derivative and farnesyl transferase inhibitor being administered, their route of administration, the particular tumor being treated and the particular host being treated. The optimum method and order of administration and the dosage amounts and regime can be readily determined by those skilled in the art using conventional methods and in view of the information set out herein.
The farnesyl transferase inhibitor is advantageously administered in an effective amount of from 0.0001 mg/kg to 100 mg/kg body weight, and in particular from 0.001 mg/kg to 10 mg/kg body weight. More particularly, for an adult patient, the dosage is conveniently in the range of 50 to 500mg bid, advantageously 100 to 400 mg bid and particularly 300mg bid.
The anti-tumor podophyllotoxin derivative is advantageously administered in a dosage of 30 to 300 mg per square meter (mg/m2) of body surface area, for example 50 to 250mg/m2, particularly for etoposide in a dosage of about 35 to 100 mg/m2 and for teniposide in about 50 to 250 mg/m2 per course of treatment. These dosages may be administered for example once, twice or more per course of treatment, which may be repeated for example every 7,14,21 or 28 days.
It is especially prefened to administer the farnesyl tranferase inhibitor at a dosage of 100 or 200mg bid for 7, 14, 21 or 28 days with a dosage of the anti-tumor podophyllotoxin derivative in the ranges indicated above.
In view of their useful pharmacological properties, the components of the combinations according to the invention, i.e. the anti-tumor podophyllotoxin derivative and the farnesyl transferase inhibitor may be formulated into various pharmaceutical forms for administration purposes. The components may formulated separately in individual pharmaceutical compositions or in a unitary pharmaceutical composition containing both components Farnesyl protein transferase inhibitors can be prepared and formulated into pharmaceutical compositions by methods known in the art and in particular according to the methods descnbed in the published patent specifications mentioned herein and incorporated by reference, for the compounds of formulae (I), (H) and (HI) suitable examples can be found in WO-97/21701. Compounds of formulae (IV), (V), and (VI) can be prepared and formulated using methods descnbed in WO 97/16443, compounds of formulae (VH) and (VHI) according to methods descnbed in WO 98/40383 and WO 98/49157 and compounds of formula (IX) according to methods descnbed in WO 00/39082 respectively.
The present invention therefore also relates to a pharmaceutical composition compnsmg an anti-tumor podophyllotoxm denvative and a farnesyl tranferase inhibitor of formula (I) together with one or more pharmaceutical earners. To prepare pharmaceutical compositions for use in accordance with the invention, an effective amount of a particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable earner, which earner may take a wide vanety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in prepanng the compositions m oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid earners such as starches, sugars, kaolin, lubncants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical earners are obviously employed. For parenteral compositions, the earner will usually compnse stenle water, at least in large part, though other ingredients, to aid solubility for example, may be included. Injectable solutions, for example, may be prepared in which the earner compnses saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropnate liquid earners, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the earner optionally compnses a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause a significant deletenous effect to the skm. Said additives may facilitate the administration to the skin and/or may be helpful for prepanng the desired compositions. These compositions may be administered in vanous ways, e.g., as a transdermal patch, as a spot-on, as an ointment
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical earner. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
It may be appropnate to administer the required dose of each component of the combination as two, three, four or more sub-doses at appropnate intervals throughout the course of treatment Said sub-doses may be formulated as unit dosage forms, for example, in each case containing independently 0.01 to 500 mg, for example 0.1 to 200 mg and in particular 1 to lOOmg of each active ingredient per unit dosage form.
Expenmental Testing of Combinations for Inhibition of Tumor Growth
The combinations according to the invention may be tested for their efficacy in inhibiting tumor growth using conventional assays descnbed in the literature for example the HTB177 lung carcinoma descnbed by Liu M et al, Cancer Research, Vol 58, No.21, 1 November 1998, pages 4947-4956, and the anti-mitotic assay descnbed by Moasser M et al, Proc. Natl. Acad. Sci. USA, Vol. 95, pages 1369-1374, February 1998. Other in vitro and in vivo models for determining ant-tumor effects of combinations and possible synergy of the combinations according to the invention are descnbed in WO 98/54966 and WO 98/32114. Clinical models for determining the efficacy and possible synergism for combination therapy in the clinic are generally descnbed in Cancer: Pnnciples and Practice of Oncology, Fifth Edition, edited by Vincent T DeVita, Jr., Samuel Hellman, Steven A. Rosenberg, Lippincott-Raven, Philadelphia, 1997, especially Chapter 17, pages 342-346.

Claims

Claims
1. A combination of an anti-tumor podophyllotoxin denvative and a farnesyl transferase inhibitor selected from compounds of formulae (I), (H), (HI), (IV), (V), (VI), (VH), (Vm) and (IX) below:
(i) (II)
(in) the pharmaceutically acceptable acid or base addition salts and the stereochemically isomenc forms thereof, wherein the dotted line represents an optional bond, X is oxygen or sulfur;
Rl IS hydrogen, Cι_i2alkyl, Arl, Ar2Cι_6alkyl, qumohnylCi-6alkyl, pyndylCi-6alkyl, hydroxyCi -6alkyl, Ci-6alkyloxyCi-6alkyl, mono- or di (C i -6alkyl)amιnoC i -6alkyl , aminoC i .βalkyl , or a radical of formula -Alkl-C(=O)-R9, -Alkl-S(O)-R9 or -Alkl-S(O)2-R9, wherem Alkl 1S Ci-6alkanedιyl,
R9 is hydroxy, Cι_6alkyl, Ci-βalkyloxy, amino, Ci-8alkylammo or Cι_8alkylamιno substituted with Ci-6alkyloxycarbonyl, R2, R3 and Rl°" each independently are hydrogen, hydroxy, halo, cyano, Ci-βalkyl, Ci-6alkyloxy, hydroxyCi -6alkyloxy, Ci-6alkyloxyCi-6alkyloxy, amιnoCi-6alkyl- oxy, mono- or dι(Ci-6alkyl)amιnoCi-6alkyloxy, Arl, Ar Cι_6alkyl, Ar2oxy, Ar2Ci-6alkyloxy, hydroxycarbonyl, Ci-6alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, 4,4-dimethyloxazolyl; or when on adjacent positions R2 and R3 taken together may form a bivalent radical of formula -O-CH2-O- (a-1),
-O-CH2-CH2-O- (a-2),
-O-CH=CH- (a-3),
-O-CH2-CH2- (a-4),
-O-CH2-CH2-CH2- (a-5), or -CH=CH-CH=CH- (a-6);
R4 and R^ each independently are hydrogen, halo, Arl, Cι_6alkyl, hydroxyCι_6alkyl, Ci-6alkyloxyCι_6alkyl, Ci-6alkyloxy, Ci-6alkylthio, amino, hydroxycarbonyl, Cι_6alkyloxycarbonyl, Ci-6alkylS(O)Ci-6alkyl or Ci-6alkylS(O)2Ci-6alkyl; R6 and R7 each independently are hydrogen, halo, cyano, C i-βalkyl, Ci-6alkyloxy, Ar2oxy, trihalomethyl, Ci-6alkylthio, di(Ci-6alkyl)amino, or when on adjacent positions R^ and R7 taken together may form a bivalent radical of formula
-O-CH2-O- (c-1), or
-CH=CH-CH=CH- (c-2); R8 is hydrogen, Ci-βalkyl, cyano, hydroxycarbonyl, Ci-6alkyloxycarbonyl,
Cι_6alkylcarbonylCi-6alkyl, cyanoCι_6alkyl, Cι_6alkyloxycarbonylCi-6alkyl, carboxyCi-6alkyl, hydroxyCi -βalkyl, aminoCi-6alkyl, mono- or di(Ci-6alkyl)- aminoCι_6alkyl, imidazolyl, haloCi- alkyl, Ci-6alkyloxyCi-6alkyl, aminocarbonylCi-6alkyl, or a radical of formula -O-RlO (b-1),
-S-RlO (b-2),
-N-RllRl2 (b-3), wherein RlO is hydrogen, Cι_6alkyl, Ci-6alkylcarbonyl, Arl, Ar2Ci-6alkyl,
Ci-6alkyloxycarbonylCi-6alkyl, or a radical or formula -Alk -ORl3 or -Alk2-NRl4Rl5;
RU is hydrogen, Cι_i2alkyl, Arl or Ar cι_6alkyl; Rl2 is hydrogen, Ci-6alkyl, Ci-i^alkylcarbonyl, Ci-6alkyloxycarbonyl, Ci-6alkylaminocarbonyl, Arl, Ar2Cι_6alkyl, Ci-6alkylcarbonyl- Ci-βalkyl, a natural amino acid, Arlcarbonyl, Ar2Cι_6alkylcarbonyl, aminocarbonylcarbonyl, Ci-6alkyloxyCi-6alkylcarbonyl, hydroxy,
Ci-6alkyloxy, aminocarbonyl, di(Ci-6alkyl)aminoCi-6alkylcarbonyl, amino, Ci-6alkylamino, Ci-6alkylcarbonylamino, or a radical or formula -Alk2-ORl3 or -Alk2-NRl Rl5; wherein Alk is Ci-6alkanediyl;
R 3 is hydrogen, Ci-βalkyl, Cι_6alkylcarbonyl, hydroxy-
Ci-6alkyl, Arl or Ar2Cι_6alkyl; Rl4 is hydrogen, Ci_6alkyl, Arl or Ar2Ci-6alkyl; R1^ is hydrogen, Ci-6alkyl, Ci-6alkylcarbonyl, Arl or Ar2Ci-6alkyl; Rl7 is hydrogen, halo, cyano, Ci-6alkyl, Ci-βalkyloxycarbonyl, Arl; Rl8 is hydrogen, Ci-βalkyl, Ci-6alkyloxy or halo; Rl9 is hydrogen or C _6alkyl; Arl is phenyl or phenyl substituted with Ci-6alkyl, hydroxy, ammo, Ci-6alkyloxy or halo; and Ar2 is phenyl or phenyl substituted with Ci-6alkyl, hydroxy, amino, Ci-6alkyloxy or halo.
(IV) (V)
(VI) the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein the dotted line represents an optional bond; X is oxygen or sulfur; R! IS hydrogen, Ci-i2alkyl, Arl, Ar2Ci-6alkyl, quιnohnylCι_6alkyl, pyndyl- Ci-6alkyl, hydroxyCi -βalkyl, Ci-6alkyloxyCi-6alkyl, mono- or dι(Cι_6alkyl)- amιnoCi-6alkyl, amιnoCi-6alkyl, or a radical of formula -Alkl-C(=O)-R9, -Alkl-S(O)-R9 or -Alkl-S(O)2-R9, wherein Alkl is Cι_6alkanedιyl,
R9 is hydroxy, Ci-ζalkyl, Cι_6alkyloxy, amino, Ci-8alkylammo or Cι_8alkylammo substituted with Ci-βalkyloxycarbonyl, R2 and R3 each independently are hydrogen, hydroxy, halo, cyano, Ci-6alkyl, Ci-6alkyloxy, hydroxyCi -6alkyloxy, Cι_6alkyloxyCi-6alkyloxy, amino- Cι_6alkyloxy, mono- or dι(Cι_6alkyl)amιnoCi-6alkyloxy, Arl, Ar2Cι_6alkyl,
Ar2oxy, Ar2Ci-6alkyloxy, hydroxycarbonyl, Ci-βalkyloxycarbonyl, tnhalomethyl, tnhalomethoxy, C2-6alkenyl, or when on adjacent positions R2 and R3 taken together may form a bivalent radical of formula -O-CH2-O- (a-1),
-O-CH2-CH2-O- (a-2),
-O-CH=CH- (a-3),
-O-CH2-CH2- (a-4),
-O-CH2-CH2-CH2- (a-5), or -CH=CH-CH=CH- (a-6),
R4 and R5 each independently are hydrogen, Ar1, Q 6alkyl, Ci 6alkyloxyCι 6alkyl, Ci 6alkyloxy, Ci 6alkylthιo, amino, hydroxycarbonyl, Ci 6alkyloxycarbonyl, Ci 6alkylS(O)Cι 6alkyl or Ci 6alkylS(O)2Cι 6alkyl, R" and R7 each independently are hydrogen, halo, cyano, Ci- alkyl, Cι_6alkyloxy or Ar2oxy,
R8 IS hydrogen, Ci-6alkyl, cyano, hydroxycarbonyl, Ci-βalkyloxycarbonyl, Cι_6alkyl- carbonylCι_6alkyl, cyanoCi-όalkyl, Cι_6alkyloxycarbonylCι_6alkyl, hydroxy- carbonylCι_6alkyl, hydroxyCi-βalkyl, ammoCi-6alkyl, mono- or dι(Cι_6alkyl)- aminoCi-galkyl, haloCi-6alkyl, Ci-6alkyloxyCι_6alkyl, amιnocarbonylCi-6alkyl, Arl, Ar2Cι_6alkyloxyCi-6alkyl, Ci-6alkylthιoCι_6alkyl,
RIO !S hydrogen, Cι_6alkyl, Ci-6alkyloxy or halo, RU is hydrogen or Cι_6alkyl, Arl 1S phenyl or phenyl substituted with Ci-6alkyl, hydroxy, amino, Ci-6alkyloxy or halo, Ar2 is phenyl or phenyl substituted with Ci-6alkyl,hydroxy,amιno,Ci-6alkyloxy or halo the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein the dotted line represents an optional bond;
X is oxygen or sulfur;
-A- is a bivalent radical of formula -CH=CH- (a-1), -CH2-S- (a-6),
-CH2-CH2- (a-2), -CH2-CH2-S- (a-7), -CH2-CH2-CH2- (a-3), -CH=N- (a-8),
-CH2-O- (a-4), -N=N- (a-9), or
-CH2-CH2-O- (a-5), -CO-NH- (a-10); wherein optionally one hydrogen atom may be replaced by Ci-4alkyl or Arl; Rl and R2 each independently are hydrogen, hydroxy, halo, cyano, C ι_6alkyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, Ci-βalkyloxy, hydroxyCi -βalkyloxy,
Ci-6alkyloxyCi-6alkyloxy, Ci-βalkyloxycarbonyl, aminoCi-όalkyloxy, mono- or di(Cι_6alkyl)aminoCi-6alkyloxy, Ar2, Ar2-Ci-6alkyl, Ar2-oxy,
Ar2-Ci-6alkyloxy; or when on adjacent positions Rl and R2 taken together may form a bivalent radical of formula -O-CH2-O- (b-1),
-O-CH2-CH2-O- (b-2),
-O-CH=CH- (b-3),
-O-CH2-CH2- (b-4),
-O-CH2-CH2-CH2- (b-5), or -CH=CH-CH=CH- (b-6);
R^ and R4 each independently are hydrogen, halo, cyano, Cι_6alkyl, Ci-6alkyloxy,
Ar^-oxy, Cι,6alkylthio, di(Cι_6alkyl)amino, trihalomethyl, trihalomethoxy, or when on adjacent positions R^ and R taken together may form a bivalent radical of formula -O-CH2-O- (c-1),
-O-CH2-CH2-O- (c-2), or
-CH=CH-CH=CH- (c-3);
R^ is a radical of formula /^N ■ N
— N \ J (d-1), — R , 1133 (d-2),
N'
R A τ.114 wherein R 3 IS hydrogen, halo, Ar4, Cι_6alkyl, hydroxyCi -6 alkyl, Ci-6alkyloxy- Cι_6alkyl, Cι_6alkyloxy, Cι_6alkylthio, amino, Ci-βalkyloxy- carbonyl, Ci-6alkylS(O)Ci-6alkyl or Ci-6alkylS(O)2Ci-6alkyl; Rl4is hydrogen, Ci-6alkyl or di(Ci-4alkyl)aminosulfonyl; is hydrogen, hydroxy, halo, Chalky], cyano, haloCi-6alkyl, hydroxyCi -6alkyl, cyanoCi-6alkyl, aminoCi-6alkyl, Ci-6alkyloxyCi-6alkyl, C i -6alkylthιoC i _6alkyl, aminocarbonylC i _6alkyl, C i -galkyloxycarbonylC i -6alkyl , C i -βalkylcarbonyl-C i _6alkyl , Ci-βalkyloxycarbonyl, mono- or di(Ci-6alkyl)aminoCi-6alkyl, Ar^,
Ar5-Ci-6alkyloxyCi_6alkyl; or a radical of formula -O-R7 (e-1), -S-R7 (e-2), -N-RδR9 (e-3), wherein
Ci-6alkyloxycarbonylCι_6alkyl, or a radical of formula -Alk-OR 10 or -Alk-NRHRl2; R8 is hydrogen, Cι_6alkyl, Ar7 or Ar^-Ci-βalkyl; R9 is hydrogen, Cι_6alkyl, Ci-6alkylcarbonyl, Ci-6alkyloxycarbonyl, Ci-6alkylaminocarbonyl, Ar^, Ar^-Ci-6alkyl, Cι_6alkylcarbonyl-
Ci-6alkyl, aminocarbonyl- carbonyl, Ci-6alkyloxyCi-6alkylcarbonyl, hydroxy, Ci-galkyloxy, aminocarbonyl, di(Ci-6alkyl)aminoCi-6alkylcarbonyl, amino. Ci_6alkylamino, Ci-6alkylcarbonylamino, or a radical or formula -Alk-ORl° or -Alk-NR1 !R12; wherein Alk is Ci-6alkanediyl;
RIO is hydrogen, Ci-6alkyl, Cι_6alkylcarbonyl, hydroxyCi-6alkyl,
Ar9 or Ar9-Cι_6alkyl;
RU is hydrogen, Cι_6alkyl, Cι_6alkylcarbonyl, ArlO or Ar10-Cι_6alkyl;
Rl2 is hydrogen, Ci-6alkyl, ArH or Arl l-Ci-6alkyl; and
Arl to Arl 1 are each independently selected from phenyl; or phenyl substituted with halo, Ci-βalkyl, Ci-6alkyloxy or trifluoromethyl. the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein the dotted line represents an optional bond; X is oxygen or sulfur;
Rl and R2 each independently are hydrogen, hydroxy, halo, cyano, Ci-βalkyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, Ci-6alkyloxy, hydroxyCi -6alkyloxy, Ci-6alkyloxyCi-6alkyloxy, Cι_6alkyloxycarbonyl, aminoCi-6alkyloxy, mono- or di(Ci-6alkyl)aminoCi-6alkyloxy, Arl, ArlCi-6alkyl, Arloxy or ArlCi-6alkyloxy;
R3 and R each independently are hydrogen, halo, cyano, Ci-βalkyl, Ci-6alkyloxy,
Arloxy, Ci-βalkylthio, di(Ci-6alkyl)amino, trihalomethyl or trihalomethoxy; R^ is hydrogen, halo, Cι_6alkyl, cyano, haloCι_6alkyl, hydroxyCi -6alkyl, cyanoCi-6alkyl, aminoCi-βalkyl, Cι_6alkyloxyCi-6alkyl, Ci-6alkylthioCi-6alkyl, aminocarbonylCi-βalkyl,
C 1 -6alkyloxycarbonylC i -6alkyl, C i _6alkylcarbonyl-C l -6alkyl, Ci-6alkyloxycarbonyl, mono- or di(Ci-6alkyl)aminoCi-6alkyl, Arl, ArlCi-6alkyloxyCi-6alkyl; or a radical of formula .O-RlO (a-1), -S-R1° (a"2),
-N-Rl lRl2 (a-3), wherein R O is hydrogen, Ci-6alkyl, Ci-6alkylcarbonyl, Arl, ArlCi-6alkyl,
Ci-6alkyloxycarbonylCi-6alkyl, or a radical of formula -Alk-OR 13 or -Alk-NRl4Rl5; R 1 is hydrogen, Ci-6alkyl, Ar or ArlCι_6alkyl;
Rl2 is hydrogen, Ci-6alkyl, Cι_6alkylcarbonyl, Ci-6alkyloxycarbonyl, Ci_6alkylaminocarbonyl, Arl, ArlCi-6alkyl, Ci-βalkylcarbonyl- Ci_6alkyl, Ar carbonyl, ArlCι_6alkylcarbonyl, aminocarbonyl- carbonyl, Cι_6alkyloxyCι_6alkylcarbonyl, hydroxy, Cι_6alkyloxy, aminocarbonyl, di(Ci-6alkyl)aminoCi-6alkylcarbonyl, amino, C i -όalkylamino, C i -6alkylcarbonylamino, or a radical or formula -Alk-ORl3 or -Alk-NRl4Rl5; wherein Alk is Cι_6alkanediyl;
Rl3 is hydrogen, Ci-6alkyl, Ci-βalkylcarbonyl, hydroxy-
Ci-6alkyl, Ar1 or ArlCi-6alkyl; Rl is hydrogen, Ci-6alkyl, Arl or ArlCι_6alkyl; R1^ is hydrogen, Ci-βalkyl, Ci-6alkylcarbonyl, Arl or ArlCi-6alkyl; R6 is a radical of formula
wherein Rl^is hydrogen, halo, Arl, Ci-βalkyl, hydroxyCi -6alkyl, Cι_6alkyloxy-
Cι_6alkyl, Ci-6alkyloxy, Ci-βalkylthio, amino, C i _6alkyloxycarbonyl, C i _6alkylthioC i -6alkyl , Ci-6alkylS(O)Cι_6alkyl or Cι_6alkylS(O)2Ci-6alkyl; Rl^is hydrogen, Ci-6alkyl or di(Ci-4alkyl)aminosulfonyl;
R7 is hydrogen or Cι_6alkyl provided that the dotted line does not represent a bond; R8 is hydrogen, Ci-6alkyl or Ar2CH2 or HetlCH2; R9 is hydrogen, Ci-6alkyl , Ci-6alkyloxy or halo; or R° and R9 taken together to form a bivalent radical of formula -CH=CH- (c-1),
-CH2-CH2- (c-2),
-CH2-CH2-CH2- (c-3), -CH2-O- (c-4), or
-CH2-CH2-O- (c-5); Arl is phenyl; or phenyl substituted with 1 or 2 substituents each independently selected from halo, Ci-6alkyl, Ci-6alkyloxy or trifluoromethyl;
Ar2 is phenyl; or phenyl substituted with 1 or 2 substituents each independently selected from halo, Ci-6alkyl, Ci-6alkyloxy or trifluoromethyl; and
Hetl is pyridinyl; pyridinyl substituted with 1 or 2 substituents each independently selected from halo, Ci-6alkyl, Ci-ζalkyloxy or trifluoromethyl
and or the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein
=X1-X2-X3- is a trivalent radical of formula
=N-CR6=CR7- (χ-i), =CR6-CR7=CR8- (x-6),
=N-N=CR6- (χ-2), =CR6-N=CR7- (x-7),
=N-NH-C(=O)- (x-3), =CR6-NH-C(=O)- (x-8), or
=N-N=N- (x-4), =CR6-N=N- (x-9);
=N-CR6=N- (x-5), wherein each R6, R7 and R8 are independently hydrogen, Cι_4alkyl, hydroxy,
C]. alkyloxy, aryloxy, Cι.4alkyloxycarbonyl, hydroxyC].4alkyl, Ci_4alkyloxyCi- alkyl, mono- or di(Cι_4alkyl)aminoCι. alkyl, cyano, amino, thio, C]. alkylthio, arylthio or aryl;
>Y1-Y2- is a trivalent radical of formula
>CH-CHR9- (y-i),
>C=N- (y-2),
>CH-NR9- (y-3),or
>C=CR9- (y-4); wherein each R9 independently is hydrogen, halo, halocarbonyl, aminocarbonyl, hydroxyCi.4alkyl, cyano, carboxyl, C].4alkyl, Cι. alkyloxy, Cι_4alkyloxyCι.4alkyl,
Cι_4alkyloxycarbonyl, mono- or di(Ci_4alkyl)amino, mono- or di(Cι_ alkyl)aminoCι_4alkyl, aryl; r and s are each independently 0, 1, 2, 3, 4 or 5; t is O, 1, 2 or 3; each R1 and R2 are independently hydroxy, halo, cyano, Ci-6alkyl, trihalomethyl, trihalomethoxy, C2.6alkenyl, Cι.6alkyloxy, hydroxyCi.6alkyloxy, C].6alkylthio, Cι_6alkyloxyC].6alkyloxy, C]_6alkyloxycarbonyl, aminoCι.6alkyloxy, mono- or di(Ci_6alkyl)amino, mono- or di(Cι.6alkyl)aminoCι_6alkyloxy, aryl, arylCι_6alkyl, aryloxy or arylCι_6alkyloxy, hydroxycarbonyl, Cι_ alkyloxycarbonyl, aminocarbonyl, aminoCι_6alkyl, mono- or di(C].6alkyl)aminocarbonyl, mono- or di(Cι-6alkyl)aminoCι.6alkyl; or two R1 or R2 substituents adjacent to one another on the phenyl ring may independently form together a bivalent radical of formula
-O-CH2-O- (a"l),
-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); R3 is hydrogen, halo, Cι_6alkyl, cyano, haloCι_6alkyl, hydroxyCi _ alkyl, cyanoC].6alkyl, aminoCι_6alkyl, Cι_6alkyloxyCι.6alkyl, Cι.6alkylthioC]_6alkyl, aminocarbonylCj.6alkyl, hydroxycarbonyl, hydroxycarbonylCι_6alkyl, C i . alkyloxycarbonylC i _6alkyl, C i .6alkylcarbonylC i . alkyl , C i .6alkyloxycarbonyl , aryl, arylCι_6alkyloxyCι_6alkyl, mono- or di(Cι.6alkyl)aminoC].6alkyl; or a radical of formula
-O-R10 (b-1),
-S-R10 (b-2),
-NRnR12 (b-3), wherein R10 is hydrogen, Cι_6alkyl, Cι.6alkylcarbonyl, aryl, arylCι_6alkyl,
Cι.6alkyloxycarbonylCι_6alkyl, or a radical of formula -Alk-OR 13 or -Alk-NR14R15;
R1 1 is hydrogen, C].6alkyl, aryl or arylCι_ alkyl;
R12 is hydrogen, Cι_6alkyl, aryl, hydroxy, amino, Cι_ alkyloxy,
Cι_6alkylcarbonylCι.6alkyl, arylCι_6alkyl, Cι_6alkylcarbonylamino, mono- or di(Cι_6alkyl)amino, Cι.6alkylcarbonyl, aminocarbonyl, arylcarbonyl, haloCι_6alkylcarbonyl, arylCι_6alkylcarbonyl, Cι_6alkyloxycarbonyl,
C]. alkyloxyCι- alkylcarbonyl, mono- or di(Cι.6alkyl)aminocarbonyl wherein the alkyl moiety may optionally be substituted by one or more substituents independently selected from aryl or C].3alkyloxycarbonyl, aminocarbonylcarbonyl, mono- or di(Cι_6alkyl)aminoCι.6alkylcarbonyl, or a radical or formula -Alk-OR13 or -Alk-NR14R15; wherein Alk is Cι.6alkanediyl;
R13 is hydrogen, Cι_6alkyl, Cι-6alkylcarbonyl, hydroxyCi. alkyl, aryl or arylCι- alkyl;
R14 is hydrogen, Cι_6alkyl, aryl or arylCι.6alkyl; R15 is hydrogen, Cι. alkyl, C].6alkylcarbonyl, aryl or arylCι_6alkyl;
R4 is a radical of formula wherein R16 is hydrogen, halo, aryl, C). alkyl, hydroxyCi 6alkyl, C].6alkyloxyCι.6alkyl, Ci 6alkyloxy, C).6alkylthιo, amino, mono- or dι(Cι 4alkyl)amιno, hydroxycarbonyl, Ci 6alkyloxycarbonyl, C].6alkylthιoCι 6alkyl, C).6alkylS(O)C1 6alkyl or C. 6alkylS(O)2C].6alkyl;
R may also be bound to one of the nitrogen atoms in the imidazole nng of formula (c-1) or (c-2), in which case the meaning of R1 when bound to the nitrogen is limited to hydrogen, aryl, C\ 6alkyl, hydroxyCi 6alkyl, Ci 6alkyloxyC] 6alkyl, Ci alkyloxycarbonyl, Ci 6alkylS(O)Cι.6alkyl or C, 6alkylS(O)2Cι.6alkyl;
R17 is hydrogen, Cj.6alkyl, Ci alkyloxyCι 6alkyl, arylCi 6alkyl, tnfluoromethyl or dι(C] 4alkyl)amιnosulfonyl, R5 is Ci 6alkyl , Cι_6alkyloxy or halo; aryl is phenyl, naphthalenyl or phenyl substituted with 1 or more substituents each independently selected from halo, C\ 6alkyl, C].6alkyloxy or tnfluoromethyl .
2. A combination as claimed in claim 1 wherein the farnesyl protein transferase inhibitor is a compound of formula (I) wherein X is oxygen and the dotted line represents a bond.
3. A combination as claimed in claim 1 or claim 2 wherein the farnesyl protein transferase inhibitor is a compound of formula (I) wherein Rl IS hydrogen, Cι_6alkyl, Ci-6alkyloxyCi-6alkyl or mono- or dι(Ci-6alkyl)amιnoCi-6alkyl and wherein R3 IS hydrogen and R IS halo, Ci-6alkyl, C2-6alkenyl, Ci-6alkyloxy, tnhalomethoxy or hydroxyCi -όalkyloxy
4. A combination as claimed in any of the preceding claims wherein the farnesyl protein transferase inhibitor is a compound of formula (I) wherein R° is hydrogen, hydroxy, haloCι_6alkyl, hydroxyCi .βalkyl, cyanoCi-βalkyl, Ci-6alkyloxycarbonylCι_6alkyl, lmidazolyl, or a radical of formula -NRI 1R 2 wherem Rl 1 is hydrogen or Ci-i2alkyl and Rl IS hydrogen, Ci-6alkyl, Ci-6alkyloxy, Ci-6alkyloxyCι_6alkylcarbonyl, hydroxy, or a radical of formula -Alk2-ORl wherein R IS hydrogen or Ci-6alkyl.
5. A combination as claimed in claim 1 wherem the farnesyl transferase inhibitor is selected from:
4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(l-methyl-lH-ιmιdazol-5-yl)- methyl]-l-methyl-2(lH)-qumolιnone,
6-[amιno(4-chlorophenyl)-l-methyl-lH-ιmιdazol-5-ylmethyl]-4-(3-chlorophenyl)- l-methyl-2(lH)-quιnohnone;
6-[(4-chlorophenyl)hydroxy(l-methyl-lH-ιmιdazol-5-yl)methyl]-4-(3-ethoxy- phenyl)-l-methyl-2(lH)-qumohnone;
6-[(4-chlorophenyl)(l-methyl-lH-ιmιdazol-5-yl)methyl]-4-(3-ethoxyphenyl)-l- methyl-2(lH)-quιnohnone monohydrochlonde.monohydrate, 6-[amιno(4-chlorophenyl)(l-methyl-lH-ιmιdazol-5-yl)methyl]-4-(3-ethoxyphenyl)- l-methyl-2(lH)-quιnohnone, and
6-amιno(4-chlorophenyl)(l-methyl-lH-ιmιdazol-5-yl)methyl]-l-methyl-4-(3- propylphenyl)-2(lH)-qumohnone; a stereoisomenc form thereof or a pharmaceutically acceptable acid or base addition salts thereof.
6. A combination as claimed in claim 1 wherein the farnesyl transferase inhibitor is (+)-6-[amιno(4-chlorophenyl)(l-methyl-lH-ιmιdazol-5-yl)methyl]-4-(3-chloro- phenyl)-l-methyl-2(lH)-quιnolιnone; or a pharmaceutically acceptable acid addition salt thereof.
7. A combination as claimed in claim 1 wherein the farnesyl protein transferase inhibitor is a compound of formula (IX) wherein =X]-X2-X3 is a tnvalent radical of formula (x-2), (x-3) or (x-4), >Y1-Y2 is a tnvalent radical of formula (y-2), (y-3) or (y-4), r and s are 1, t is 0, R1 is halo, preferably chloro, and most preferably 3-
1 7 chloro or R is Ci 4alkyl, preferably 3-methyl, R is halo, preferably chloro, and most preferably 4-chloro, R3 is a radical of formula (b-1) or (b-3), R4 is a radical of formula (c-2), R6 is Cι_4alkyl, R9 is hydrogen, R10 and R1 1 are hydrogen and R12 is hydrogen or hydroxy.
8. A combination as claimed in claim 1 wherein the farnesyl protein transferase inhibitor is 5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(l-methyl-lH-ιmιdazol-5- yl)tetrazolo[l,5-a]qumazolιne-7-methanamιne or a pharmaceutically acceptable acid addition salt thereof.
9. A combination as claimed in any of the preceding claims in which the anti-tumor podophyllotoxin denvative is etoposide or teniposide.
10. A combination as claimed in any of the preceding claims in the form of a pharmaceutical composition comprising an anti-tumor podophyllotoxin derivative and a farnesyl transferase inhibitor selected from compounds of formulae (I), (H), (HI), (IV), (V), (VI), (VH), (VHI) and (IX) (as defined in claim 1) together with one or more pharmaceutical carriers.
11. A combination as claimed in any of the preceding claims for use in medical therapy.
12. A combination as claimed in claim 11 for inhibiting the growth of tumor cells.
13. Use of a combination as claimed in any of claims 1 to 12 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 which comprises administering to the subject an effective amount of a combination as claimed in any of claims 1 to 12.
EP01913838A 2000-02-29 2001-02-26 Farnesyl protein transferase inhibitor combinations with anti-tumor podophyllotoxin derivatives Withdrawn EP1267871A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP01913838A EP1267871A2 (en) 2000-02-29 2001-02-26 Farnesyl protein transferase inhibitor combinations with anti-tumor podophyllotoxin derivatives

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP00200695 2000-02-29
EP00200695 2000-02-29
PCT/EP2001/002167 WO2001064198A2 (en) 2000-02-29 2001-02-26 Farnesyl protein transferase inhibitor combinations with anti-tumor podophyllotoxin derivatives
EP01913838A EP1267871A2 (en) 2000-02-29 2001-02-26 Farnesyl protein transferase inhibitor combinations with anti-tumor podophyllotoxin derivatives

Publications (1)

Publication Number Publication Date
EP1267871A2 true EP1267871A2 (en) 2003-01-02

Family

ID=8171114

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01913838A Withdrawn EP1267871A2 (en) 2000-02-29 2001-02-26 Farnesyl protein transferase inhibitor combinations with anti-tumor podophyllotoxin derivatives

Country Status (5)

Country Link
EP (1) EP1267871A2 (en)
JP (1) JP2003525238A (en)
AU (1) AU2001239275A1 (en)
CA (1) CA2397256A1 (en)
WO (1) WO2001064198A2 (en)

Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2581125C (en) 2004-09-22 2013-04-23 Nippon Kayaku Kabushiki Kaisha Modified poly(ethylene oxide-amino acid) copolymer, micelle preparation, and anticancer agent containing the same
EP2545919A1 (en) 2005-12-23 2013-01-16 Link Medicine Corporation Treatment of synucleinopathies
JP5249016B2 (en) 2006-03-28 2013-07-31 日本化薬株式会社 Taxane polymer conjugates
CA2652656A1 (en) * 2006-05-18 2007-11-29 Nippon Kayaku Kabushiki Kaisha High-molecular weight conjugate of podophyllotoxins
US8334364B2 (en) 2006-11-06 2012-12-18 Nipon Kayaku Kabushiki Kaisha High-molecular weight derivative of nucleic acid antimetabolite
JP5548365B2 (en) 2006-11-08 2014-07-16 日本化薬株式会社 Polymer derivatives of nucleic acid antimetabolites
WO2009041570A1 (en) 2007-09-28 2009-04-02 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of steroid
CN101977631A (en) 2008-03-18 2011-02-16 日本化药株式会社 Polymer conjugate of physiologically active substance
JP5366940B2 (en) 2008-05-08 2013-12-11 日本化薬株式会社 Polymer conjugate of folic acid or folic acid derivative
US8808749B2 (en) 2009-05-15 2014-08-19 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of bioactive substance having hydroxy group
WO2012067138A1 (en) 2010-11-17 2012-05-24 日本化薬株式会社 Novel polymer derivative of cytidine metabolism antagonist
KR101849142B1 (en) 2011-09-11 2018-04-16 니폰 가야꾸 가부시끼가이샤 Method for manufacturing block copolymer
WO2014062667A1 (en) 2012-10-16 2014-04-24 Janssen Pharmaceutica Nv Phenyl linked quinolinyl modulators of ror-gamma-t
BR112015008515A2 (en) 2012-10-16 2017-07-04 Janssen Pharmaceutica Nv heteroaryl-linked quinolinyl ror t modulators
UY35084A (en) 2012-10-16 2014-04-30 Janssen Pharmaceutica Nv MODULATORS OF RORYT OF QUINOLINILO UNITED BY METHYLENE
US10555941B2 (en) 2013-10-15 2020-02-11 Janssen Pharmaceutica Nv Alkyl linked quinolinyl modulators of RORγt
US9328095B2 (en) 2013-10-15 2016-05-03 Janssen Pharmaceutica Nv Heteroaryl linked quinolinyl modulators of RORgammat
US9221804B2 (en) 2013-10-15 2015-12-29 Janssen Pharmaceutica Nv Secondary alcohol quinolinyl modulators of RORγt
EP3057422B1 (en) 2013-10-15 2019-05-15 Janssen Pharmaceutica NV Quinolinyl modulators of ror(gamma)t
US9403816B2 (en) 2013-10-15 2016-08-02 Janssen Pharmaceutica Nv Phenyl linked quinolinyl modulators of RORγt
US9284308B2 (en) 2013-10-15 2016-03-15 Janssen Pharmaceutica Nv Methylene linked quinolinyl modulators of RORγt
US9346782B2 (en) 2013-10-15 2016-05-24 Janssen Pharmaceutica Nv Alkyl linked quinolinyl modulators of RORγt

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW349948B (en) * 1995-10-31 1999-01-11 Janssen Pharmaceutica Nv Farnesyl transferase inhibiting 2-quinolone derivatives
PT865440E (en) * 1995-12-08 2002-09-30 Janssen Pharmaceutica Nv (IMIDAZOL-5-IL) METHYL-2-KINOLINONE DERIVATIVES AS FARNESIL PROTEIN INHIBITORS TRANSFERASE
TW591030B (en) * 1997-03-10 2004-06-11 Janssen Pharmaceutica Nv Farnesyl transferase inhibiting 1,8-annelated quinolinone derivatives substituted with N- or C-linked imidazoles
RU2205831C2 (en) * 1997-04-25 2003-06-10 Янссен Фармацевтика Н.В. Quinazolinones inhibiting farnesyltransferase activity
WO1999032114A1 (en) * 1997-12-22 1999-07-01 Schering Corporation Combination of benzocycloheptapyridine compounds and antineoplastic drugs for treating proliferative diseases
EP1087770A4 (en) * 1998-06-15 2001-11-14 Merck & Co Inc Inhibitors of prenyl-protein transferase
EP1091736A4 (en) * 1998-07-02 2001-10-24 Merck & Co Inc Inhibitors of prenyl-protein transferase
WO2000039082A2 (en) * 1998-12-23 2000-07-06 Janssen Pharmaceutica N.V. 1,2-annelated quinoline derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0164198A2 *

Also Published As

Publication number Publication date
CA2397256A1 (en) 2001-09-07
WO2001064198A2 (en) 2001-09-07
WO2001064198A3 (en) 2002-03-21
JP2003525238A (en) 2003-08-26
AU2001239275A1 (en) 2001-09-12

Similar Documents

Publication Publication Date Title
WO2001064198A2 (en) Farnesyl protein transferase inhibitor combinations with anti-tumor podophyllotoxin derivatives
US20030022918A1 (en) Farnesyl protein transferase inhibitor combinations with an her2 antibody
US20090018164A1 (en) Farnesyl protein transferase inhibitors for treating breast cancer
US20030027808A1 (en) Farnesyl protein transferase inhibitor combinations with platinum compounds
EP1261341A2 (en) Farnesyl protein transferase inhibitor combinations with camptothecin compounds
EP1267848A1 (en) Dosing regimen comprising a farnesyl protein transferase inhibitor for the treatment of cancer
US20030078281A1 (en) Farnesyl protein transferase inhibitor combinations with anti-tumor alkylating agents
US20030186925A1 (en) Farnesyl protein transferase inhibitor combinations with anti-tumor nucleoside derivatives
US20030125326A1 (en) Farnesyl protein transferase inhibitor combinations
US20030181473A1 (en) Farnesyl protein transferase inhibitor combinations with taxane compounds
EP1261374A2 (en) Farnesyl protein transferase inhibitor combinations with further anti-cancer agents
WO2001064197A2 (en) Farnesyl protein transferase inhibitor combinations with anti-tumor anthracycline derivatives
US20030050323A1 (en) Farnesyl protein transferase inhibitor combinations with anti-tumor podophyllotoxin derivatives
US20030060480A1 (en) Farnesyl protein transferase inhibitor combinations with vinca alkaloids
EP1263437A2 (en) Farnesyl protein transferase inhibitor combinations with vinca alkaloids
US20030125268A1 (en) Farnesyl protein transferase inhibitor combinations with anti-tumor anthracycline derivatives

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20020930

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Free format text: AL PAYMENT 20020930;LT PAYMENT 20020930;LV PAYMENT 20020930;MK PAYMENT 20020930;RO PAYMENT 20020930;SI PAYMENT 20020930

17Q First examination report despatched

Effective date: 20040204

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20040615