Nova Patents
EP0618221A2

Heterocyclic inhibitors of farnesyl protein transferase.

Abstract

Inhibition of farnesyl protein transferase is effected by compounds of the formula its enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs or solvates thereof, wherein:    A₁ and A₂ are each independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, phenyl or substituted phenyl;    G₁ is S or O;    G₂ is H, -C(O)OH, -C(O)NH₂, 5-tetrazolyl, -C(O)N(R₇)OH or -CH₂OH;    X is O or R₈N;    Y and Z are each independently -CH₂- or -C(O)-;    R₁, R₂, R₃, R₄, R₅, R₆ and R₇ are each independently H or alkyl;    R₁ may also be alkanoyl,    R₁ and A₁ taken together may be -(CH₂)m;    R₈ is H, alkyl, phenyl, phenylalkyl, substituted phenyl, (substituted phenyl)alkyl or -C(O)R₉;    R₉ is H, alkyl, phenyl, phenylalkyl, substituted phenyl or (substituted phenyl)alkyl;    m is 3 or 4;    n is 0, 1 or 2;    p is 0, 1 or 2; and    q is 0 or 1, with the proviso that when p is 0, then q is also 0.

EP0618221A2, drawing sheet 1
Sheet 1 of 138

Term

Term ended

Projected expiry passed 29 March 2014, 12.5 years ago.

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19 claims: 11 independent, 8 dependent

  1. 1
    A compound of the formula or an enantiomer, diastereomer, pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:A₁ and A₂ are each independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, phenyl or substituted phenyl;G₁ is S or O;G₂ is H, -C(O)OH, -C(O)NH₂, 5-tetrazolyl, -C(O)N(R₇)OH or -CH₂OH;X is O or R₈N;Y and Z are each independently -CH₂- or -C(O)-;R₁, R₂, R₃, R₄, R₅, R₆ and R₇ are each independently H or alkyl;R₁ may also be alkanoyl;R₁ and A₁ taken together may be -(CH₂) m ;R₈ is H, alkyl, phenyl, phenylalkyl, substituted phenyl, (substituted phenyl)alkyl or -C(O)R₉;R₉ is H, alkyl, phenyl, phenylalkyl, substituted phenyl or (substituted phenyl)alkyl;m is 3 or 4;n is 0, 1 or 2;p is 0, 1 or 2;and q is 0 or 1, with the proviso that when p is 0, then q is also 0.
  2. 6
    A compound of any preceding claim, wherein n is 1.
  3. 7
    A compound of any preceding claim, wherein R₈ is H.
  4. 12
    A compound of any preceding claim for use as an active pharmaceutical substance.
  5. 13
    Use of a compound of any one of claims 1-11 for the manufacture of a medicament for treatment of conditions requiring inhibition of farnesyl protein transferase in a mammalian subject.
  6. 14
    Use of a compound of any one of claims 1-11 for the manufacture of a medicament for treatment of conditions requiring inhibition of prenyl transferases in a mammalian subject.
  7. 15
    Use of a compound of any one of claims 1-11 for the manufacture of a medicament for treatment of conditions requiring inhibition of tumors in a mammalian subject.
  8. 16
    Use of a compound of any one of claims 1-11 for the manufacture of a medicament for treatment of diseases associated with signal transduction pathways operating through Ras in a mammalian subject.
  9. 17
    Use of a compound of any one of claims 1-11 for the manufacture of a medicament for treatment of diseases associated with proteins that are post-translationally modified by the enzyme farnesyl protein transferase, in a mammalian subject.
  10. 18
    A compound of the formula its enantiomers and diastereomers, and pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein:A₁ and A₂ are each independently H or any of the natural D-, L- or DL-amino acid side chains;W is CH-R₄;X is O or R₅N;Y is S or O;Z is H, C(O)OH, tetrazolyl, C(O)N(R₇)OH or C(O)CH₂OH;R₁, R₂, R₃, R₄ and R₇ are each independently H or alkyl;R₁ and A₁ taken together may be (CH₂) m ;R₅ is H, alkyl, phenyl, phenylalkyl, or C(O)R₆, where the phenyl and phenylalkyl may be optionally substituted on the phenyl ring;R₆ is H, alkyl, phenyl or phenylalkyl, where the phenyl and phenylalkyl may be optionally substituted on the phenyl ring;m is 3 or 4;n is 0, 1 or 2;p is 1 or 2;and q is 0 or 1.
  11. 19
    A compound of the formula or its enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs or solvates thereof, wherein:A₁ and A₂ are each independently H, alkyl, substituted alkyl, phenyl or substituted phenyl;G₁ is S or O;G₂ is H, -C(O)OH, -C(O)NH₂, 5-tetrazolyl, -C(O)N(R₇)OH or -CH₂OH;X is O or R₈N;Y and Z are each independently -CH₂- or -C(O)-;R₁, R₂, R₃, R₄, R₅, R₆ and R₇ are each independently H or alkyl;R₁ and A₁ taken together may be -(CH₂) m ;R₈ is H, alkyl, phenyl, phenylalkyl, substituted phenyl, (substituted phenyl)alkyl or -C(O)R₉;R₉ is H, alkyl, phenyl, phenylalkyl, substituted phenyl or (substituted phenyl)alkyl;m is 3 or 4;n is 0, 1 or 2;p is 0, 1 or 2;and    q is 0 or 1, with the proviso that when p is 0, q is also 0.
Independent claims11