Farnesyl-protein transferase inhibitors

• US 6,268,394 B1
• Filed: 07/26/1999
• Issued: 07/31/2001
• Est. Priority Date: 04/26/1997
• Status: Expired due to Fees

• Current Assignee: International Phytochemistry Research Labs Limited
• Original Assignee: International Phytochemistry Research Labs Limited
• Inventors: Adekenov, Sergazy M., Shaikenov, Tattym E.
• Primary Examiner(s): McKane, Joseph K.
• Assistant Examiner(s): Solola, Taofiq A.
• Application Number:
  US09/360,832
• Time in Patent Office: 736 Days
• Field of Search: 514/468, 514/469, 549/297, 549/298, 549/299, 549/304, 549/305
• US Class Current: 514/469
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/34 having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
• CPC Class Codes: A61K 31/343 condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
• CPC Class Codes: A61K 31/365 Lactones
• CPC Class Codes: A61K 31/475 having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine vincamine A61K31/4375
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/66 Phosphorus compounds
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 33/24 Heavy metals; Compounds thereof
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 303/38 with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 307/93 condensed with a ring other than six-membered
• CPC Class Codes: C07D 307/935 Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
• CPC Class Codes: C07D 493/04 Ortho-condensed systems
• CPC Class Codes: C07D 493/10 Spiro-condensed systems
• CPC Class Codes: C07F 9/098 Esters of polyphosphoric acids or anhydrides

Abstract

Substantially pure preparations of phosphosesquiterpenes are described. The compounds inhibit farnesyl-protein transferase activity and are useful for the treatment of cancer. Methods for inhibiting farnesyl-protein transferase activity are also described.

Claims

1. A method for inhibiting farnesyl-protein transferase activity, comprising contacting a cell with an amount of a sesquiterpene lactone effective to inhibit farnesyl-protein transferase activity of said cell, said sesquiterpene lactone having formula C,

wherein:

C1 further bonded to hydrogen, hydroxy, oxo, short chain alkyl, short chain alkanoyloxy, together with C5 form a single bond, together with C2 form a double bond, and altogether with C10 form an epoxide or a double bond;

C2 is further bonded to at least one of hydrogen, oxo, hydroxy, short chain alkanoyloxy, and together with C1 or C3 form a double bond;

C3 is further bonded to at least one of hydrogen, hydroxy, short chain alkanoyloxy, oxo, together with C4 form an epoxide, and together with C2 or C4 form a double bond;

C4 is further bonded to hydrogen, short chain alkanoyloxy, hydroxy, or together with C3, C5 or C15 form an epoxide of a double bond;

C5 is further bonded to at least one of hydrogen, hydroxy, short chain alkanoyloxy, together with C10 or C1 form a single bond, and together with C4 form an epoxide or a double bond;

C6 is further bonded to hydrogen;

C7 is further bonded to hydrogen, together with C8 form a double bond or together with C11 form a double bond;

C8 is further bonded to at least one of hydrogen, hydroxy, short chain alkanoyloxy, and together with C7 form a double bond;

C9 is further bonded to at least one of hydrogen, short chain alkanoyloxy, and together with C10 form a double bond;

C10 is further bonded to hydrogen, together with C1 to C14 form an epoxide, together with C5 form a single bond, or together with C1, C9, or C14 form a double bond;

C11 is further bonded to hydrogen, hydroxy, hydroxymethyl, or together with C7 or C13 form a double bond;

C13 is further bonded to at least one hydrogen, an optionally substituted alklyamino salt, and together with C11 form a double bond;

C14 is further bonded to at least one of hydrogen and together with C10 form an epoxide or a double bond; and

C15 is further bonded to at least one hydrogen and together with C4 form an epoxide or a double bond.

2. A method for inhibiting farnesyl-protein transferase activity, comprising contacting a cell with an amount of a sesquiterpene lactone effective to inhibit farnesyl-protein transferase activity of said cell, said sesquiterpene lactone having formula D,

wherein:

C1 further bonded to at least one of hydrogen, hydroxyl, together with C10 or C5 form an epoxide, and together with C10 or C2 form a double bond;

C2 is further bonded to at least one of hydrogen, and together with C1 form a double bond;

C3 is further bonded to at least one of hydrogen, hydroxy, short chain alkanoyloxy, and oxo;

C4 is further bonded to hydrogen, hydroxy, short chain alkanoyloxy, or together with C5 or C15 form an epoxide of a double bond;

C5 is further bonded to at least one of hydrogen, short chain alkanoic acid, together with C1 or C4 form an epoxide, together with C10 form a single bond, and together with C4 or C6 form a double bond;

C6 is further bonded to at least one of hydrogen, hydroxy, short chain alkanoyloxy, and together with C5 form a double bond;

C7 is further bonded to hydrogen, together with C11 form a double bond;

C8 is further bonded to hydrogen;

C9 is further bonded to two hydrogens;

C10 is further bonded to hydrogen, together with C5 form an single bond, together with C1 or C14 form an epoxide or together with C1 or C14 form a double bond;

C11 is further bonded to hydrogen, hydroxy, hydroxymethyl, or together with C7 or C13 form a double bond;

C13 is further bonded to at least one hydrogen, an optionally substituted alklyamino salt, and together with C11 form a double bond;

C14 is further bonded to at least one of hydrogen and together with C10 form an epoxide or a double bond; and

C15 is further bonded to at least one hydrogen and together with C4 form an epoxide or a double bond.