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  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
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  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

• Ras proteins are part of a signalling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation.
• Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein.
• Ras In the inactive state, Ras is bound to GDP.
• Ras Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conformational change.
• the GTP-bound form of Ras propagates the growth stimulatory signal until the signal is terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D.R. Lowy and D.M.
• Mutated ras genes (Ha-ras, Ki4a-ras, Ki4b-ras and N-ras) are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. The protein products of these genes are defective in their GTPase activity and constitutively
• Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras.
• the Ras C-terminus contains a sequence motif termed a "CAAX” or "Cys-Aaa 1 -Aaa 2 -Xaa” box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et ai. Nature 310:583-586 (1984)).
• this motif serves as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C 15 or C 20 isoprenoid, respectively.
• the Ras protein is one of several proteins that are known to undergo post-translational farnesyl- ation.
• farnesylated proteins include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also suggested that there are farnesylated proteins of unknown structure and function in addition to those listed above.
• FPTase farnesyl-protein transferase
• FPP farnesyl diphosphate
• Ras protein substrates
• Bisubstrate inhibitors and inhibitors of farnesyl-protein transferase that are non-competitive with the substrates have also been described.
• the peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation.
• Such inhibitors may inhibit protein prenylation while serving as altemate substrates for the farnesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S. Patent 5,141 ,851 , University of Texas; N.E. Kohl et al., Science, 260: 1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)).
• deletion of the thiol from a CAAX derivative has been shown to dramatically reduce the inhibitory potency of the compound.
• the thiol group potentially places limitations on the therapeutic application of FPTase inhibitors with respect to pharmacokinetics, pharmacodynamics and toxicity. Therefore, a functional replacement for the thiol is desirable.
• farnesyl-protein transferase inhibitors are inhibitors of proliferation of vascular smooth muscle cells and are therefore useful in the prevention and therapy of arteriosclerosis and diabetic disturbance of blood vessels (JP H7-1 12930).
• the present invention comprises arylheteroaryl- containing compounds which inhibit the farnesyl-protein transferase. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.
• the compounds of this invention are useful in the inhibition of farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.
• the inhibitors of farnesyl-protein transferase are illustrated by the formula A:
• R 1 and R 2 are independently selected from:
• substituent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl,
• R 3 , R 4 and R 5 are independently selected from:
• substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl,
• R 12 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, (R 10 ) 2 NC(O)-, R 10 2 N-C(NR 10 )-, CN, R 10 C(O)-, N 3 , -N(R 10 ) 2 , and R 11 OC(O)-NR 10 -;
• R 6a , R 6b , R 6c , R 6d and R 6e are independently selected from:
• substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl,
• R 7 is selected from: H; C 1 -4 alkyl, C 3-6 cycloalkyl, heterocycle, aryl aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
• R 8 is independently selected from:
• cyanophenyl heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-, R 1 1 S(O) m -, R 10 C(O)NH-, (R 10 ) 2 NC(O)-, R 10 2 N-C(NR 10 )-, CN, R 10 C(O)-, N 3 , -N(R 10 ) 2 , or R 10 OC(O)NH-; provided that when R 8 is heterocycle, attachment of R 8 to V is through a substitutable ring carbon;
• R 9 is independently selected from:
• R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl,
• R 11 is independently selected from C 1 -C 6 alkyl and aryl
• R 1 2 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6
• aralkyl C 1 -C 6 substituted aralkyl, C 1 -C 6 heteroaralkyl, C 1 -C 6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C 1 -C 6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
• V is selected from:
• aryl d) C 1 -C 20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C 2 -C 20 alkenyl,
• V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O) m ;
• V when V is heterocycle, attachment of V to R 8 and to A 1 is through a substitutable ring carbon;
• W is a heterocycle
• n is independently 0, 1 , 2, 3 or 4;
• p is independently 0, 1 , 2, 3 or 4;
• q 0, 1 , 2 or 3;
• r is 0 to 5, provided that r is 0 when V is hydrogen; and t is 0 or 1 ; or the pharmaceutically acceptable salts thereof.
• f(s) are independently N or N->O, and the remaining f's are independently CH;
• R 1 is independently selected from: hydrogen, C 3 -C 10 cycloalkyl, R 10 O-, -N(R 10 ) 2 , F or C 1 -C 6 alkyl;
• R 2 is independently selected from:
• substituent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, R 10 O- and -N(R 10 ) 2 ;
• R 3 , R 4 and R 5 are independently selected from:
• R 6a , R 6b , R 6c , R 6d and R 6e are independently selected from:
• substituted C 1 -C 6 alkyl wherein the substituent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 12 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, (R 10 ) 2 NC(O)-, R 10 2 N-C(NR 10 )-, CN,
• R 7 is selected from: H; C 1 -4 alkyl, C 3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
• R 8 is independently selected from:
• aryl, substituted aryl, heterocycle C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 perfluoroalkyl, F, Cl, R 10 O-, R 10 C(O)NR 10 -, CN, NO 2 , (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, -N(R 10 ) 2 , or R 11 OC(O)NR 10 -, and c) C 1 -C 6 alkyl substituted by C 1 -C 6 perfluoroalkyl,
• R 10 O-, R 10 C(O)NR 10 -, (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, -N(R 10 ) 2 , or R 11 OC(O)NR 10 -; provided that when R 8 is heterocycle, attachment of R 8 to V is through a substitutable ring carbon;
• R 9 is selected from:
• R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl,
• R 11 is independently selected from C 1 -C 6 alkyl and aryl
• R 12 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 aralkyl, C 1 -C 6 substituted aralkyl, C 1 -C 6 heteroaralkyl, C 1 -C 6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C 1 -C 6 perfluoroalkyl,
• V is selected from:
• heterocycle selected from pyrrolidinyl, imidazolyl,
• V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O) m ;
• W is a heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, triazolyl or
• n is independently 0, 1 , 2, 3 or 4;
• r is 0 to 5, provided that r is 0 when V is hydrogen; and t is 0 or 1 ; or the pharmaceutically acceptable salts thereof.
• f(s) are independently N or N->O, and the remaining f's are independently CH;
• R 1 is selected from: hydrogen, C 3 -C 10 cycloalkyl, R 10 O-, -N(R 10 ) 2 , F or C 1 -C 6 alkyl;
• R 2 is independently selected from:
• substituent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, R 10 O- and -N(R 10 ) 2 ;
• R 3 and R 4 are independently selected from:
• substituted C 1 -C 6 alkyl wherein the substituent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 12 O-, R 1 1 S(O) m -, R 10 C(O)NR 10 -, (R 10 ) 2 NC(O)-, R 10 2 N-C(NR 10 )-, CN, R 10 C(O)-, N 3 , -N(R 10 ) 2 , and R 11 OC(O)-NR 10 -;
• R 6a , R 6b , R 6c , R 6d and R 6e are independently selected from:
• R 12 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, (R 10 ) 2 NC(O)-, R 10 2 N-C(NR 10 )., CN, NO 2 , R 10 C(O)-, N 3 , -N(R 10 ) 2 , or R 11 OC(O)NR 10 -,
• R 8 is independently selected from:
• R 8 when R 8 is heterocycle, attachment of R 8 to V is through a substitutable ring carbon;
• R 9a and R 9b are independently hydrogen, C 1 -C 6 alkyl, trifluoromethyl and halogen;
• R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl,
• R 1 1 is independently selected from C 1 -C 6 alkyl and aryl
• R 12 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6
• aralkyl C 1 -C 6 substituted aralkyl, C 1 -C 6 heteroaralkyl, C 1 -C 6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C 1 -C 6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
• V is selected from:
• heterocycle selected from pyrrolidinyl, imidazolyl,
• V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O) m ;
• V is heterocycle, attachment of V to R 8 and to A 1 is through a substitutable ring carbon;
• m is 0, 1 or 2;
• n is independently 0, 1 , 2, 3 or 4;
• p 0, 1 , 2, 3 or 4;
• r is 0 to 5, provided that r is 0 when V is hydrogen; or the pharmaceutically acceptable salts thereof.
• R 1 is selected from: hydrogen, C 3 -C 10 cycloalkyl, R 10 O-, -N(R 10 ) 2 , F or C 1 -C 6 alkyl;
• R 2 is independently selected from:
• substituent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, R 10 O- and -N(R 10 ) 2 ;
• R 3 and R 4 are independently selected from:
• R 6a , R 6b , R 6c , R 6d and R 6e are independently selected from:
• R 8 is independently selected from:
• R 8 when R 8 is heterocycle, attachment of R 8 to V is through a substitutable ring carbon;
• R 9a and R 9b are independently hydrogen, C 1 -C 6 alkyl, trifluoromethyl and halogen;
• R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl,
• R 11 is independently selected from C 1 -C 6 alkyl and aryl;
• R 12 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6
• aralkyl C 1 -C 6 substituted aralkyl, C 1 -C 6 heteroaralkyl, C 1 -C 6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C 1 -C 6 perfluoroalkyl,
• V is selected from:
• V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O) m ;
• V when V is heterocycle, attachment of V to R 8 and to A 1 is through a substitutable ring carbon;
• n is independently 0, 1 , 2, 3 or 4;
• p is 0, 1 , 2, 3 or 4, provided that p is not 0 if X is a bond or O;
• r is 0 to 5, provided that r is 0 when V is hydrogen; or the pharmaceutically acceptable salts thereof.
• R 1 is selected from: hydrogen, C 3 -C 10 cycloalkyl or C 1 -C 6 alkyl;
• R 2 is independently selected from:
• R 3 is selected from:
• substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl,
• R 12 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, (R 10 ) 2 NC(O)-, R 10 2 N-C(NR 10 )-, CN, R 10 C(O)-, N 3 , -N(R 10 ) 2 , and R 11 OC(O)-NR 10 -;
• R 4 is selected from H, halogen, C 1 -C 6 alkyl and CF 3 ;
• R 6a , R 6b , R 6c , R6d and R6e are independently selected from: a) hydrogen,
• R 8 is independently selected from:
• R 9a and R 9b are independently hydrogen, halogen, CF 3 or methyl;
• R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl,
• R 11 is independently selected from C 1 -C 6 alkyl and aryl;
• R 12 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 aralkyl, C 1 -C 6 substituted aralkyl, C 1 -C 6 heteroaralkyl, C 1 -C 6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C 1 -C 6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
• a 1 is selected from: a bond, -C(O)-, O, -N(R 10 )-, or S(O) m ;
• n 0, 1 or 2;
• p is 0, 1 , 2, 3 or 4; or the pharmaceutically acceptable salts thereof.
• the inhibitors of farnesyl-protein transferase are illustrated by the formula E: wherein: from 1 -2 of f(s) are independently N or N->O, and the remaining f's are independently CH;
• R 1 is selected from: hydrogen, C 3 -C 10 cycloalkyl, R 10 O-, -N(R 10 ) 2 , F or C 1 -C 6 alkyl;
• R 2 is independently selected from:
• R 3 is selected from:
• R 10 2 N-C(NR 10 )-, CN, R 10 C(O)-, N 3 , -N(R 10 ) 2 , and R 1 1 OC(O)-NR 10 -;
• R 4 is selected from H, halogen, C 1 -C 6 alkyl and CF 3 ;
• R 6a , R 6b , R 6c ; R 6d and R 6e are independently selected from:
• R 8 is independently selected from:
• R 8 when R 8 is heterocycle, attachment of R 8 to V is through a substitutable ring carbon;
• R 9a and R 9b are independently hydrogen, halogen, CF 3 or methyl;
• R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl,
• R 11 is independently selected from C 1 -C 6 alkyl and aryl;
• R 12 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6
• aralkyl C 1 -C 6 substituted aralkyl, C 1 -C 6 heteroaralkyl, C 1 -C 6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C 1 -C 6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifIuoroethyl;
• n 0, 1 or 2;
• p is 0, 1 , 2, 3 or 4, provided that p is not 0 if X is a bond or O; or the pharmaceutically acceptable salts thereof.
• R 1 is selected from: hydrogen, C 3 -C 10 cycloalkyl or C 1 -C 6 alkyl;
• R 2 is independently selected from:
• R 3 is selected from:
• substituted C 1 -C 6 alkyl wherein the substituent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl,
• R 4 is selected from H, halogen, CH 3 and CF 3 ;
• R 6a , R 6b , R 6c , R 6d and R 6e are independently selected from:
• R 3 , R 6a , R 6b , R 6c , R 6d or R 6e is through a substitutable heterocycle ring carbon
• R 9a and R 9b are independently hydrogen, halogen, CF 3 or methyl
• R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl,
• R 11 is independently selected from C 1 -C 6 alkyl and aryl;
• R 1 2 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6
• aralkyl C 1 -C 6 substituted aralkyl, C 1 -C 6 heteroaralkyl, C 1 -C 6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C 1 -C 6 perfluoroalkyl,
• p is 0, 1 , 2, 3 or 4; or the pharmaceutically acceptable salts thereof.
• R 1 is selected from: hydrogen, C 3 -C 10 cycloalkyl, R 10 O-, -N(R 10 ) 2 , F or C 1 -C 6 alkyl;
• R 2 is independently selected from:
• R 3 is selected from:
• substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl,
• R 12 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, (R 10 ) 2 NC(O)-, R 10 2 N-C(NR 10 )-, CN, R 10 C(O)-, N 3 , -N(R 10 ) 2 , and
• R 1 1 OC(O)-NR 10 -;
• R 4 is selected from H, halogen, CH 3 and CF 3 ;
• R 6a , R 6b , R 6c , R 6d and R 6e are independently selected from:
• substituted C 1 -C 6 alkyl wherein the substituent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 12 O-, R 1 1 S(O) m -,
• R 9a and R 9b are independently hydrogen, halogen, CF 3 or methyl;
• R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl,
• R 11 is independently selected from C 1 -C 6 alkyl and aryl
• R 12 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 aralkyl, C 1 -C 6 substituted aralkyl, C 1 -C 6 heteroaralkyl, C 1 -C 6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C 1 -C 6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifIuoroethyl;
• a 1 is selected from: a bond, -C(O)-, O, -N(R 10 )-, or S(O) m ; m is 0, 1 or 2; and
• n O or 1; or the pharmaceutically acceptable salts thereof.
• Preferred compounds of the invention are:
• the compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention.
• any variable e.g. aryl, heterocycle, R 1 , R 2 etc.
• its definition on each occurence is independent at every other occurence.
• combinations of substituents/or variables are permissible only if such combinations result in stable compounds.
• alkyl and the alkyl portion of aralkyl and similar terms, is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; “alkoxy” represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge.
• cycloalkyl is intended to include non- aromatic cyclic hydrocarbon groups having the specified number of carbon atoms.
• examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
• Alkenyl groups include those groups having the specified number of carbon atoms and having one or several double bonds.
• alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1 -propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyl, farnesyl, geranyl, geranylgeranyl and the like.
• Alkynyl groups include those groups having the specified number of carbon atoms and having one triple bonds. Examples of alkynyl groups include acetylene, 2-butynyl, 2-pentynyl, 3-pentynyl and the like.
• Halogen or "halo” as used herein means fluoro, chloro, bromo and iodo.
• aryl and the aryl portion of aroyl and aralkyl, is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic.
• aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
• heterocycle or heterocyclic represents a stable 5- to 7-membered monocyclic or stable 8- to 1 1 -membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
• the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
• heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl,
• quinolinyl quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.
• heteroaryl is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic and wherein from one to four carbon atoms are replaced by heteroatoms selected from the group consisting of N, O, and S.
• heterocyclic elements include, but are not limited to, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl,
• the substituted group is intended to mean a substituted Cl-8 alkyl, substituted C 2-8 alkenyl, substituted C 2-8 alkynyl, substituted aryl or substituted heterocycle from which the substituent(s) R 3 , R 4 , R 5 and R 6a-e are selected.
• the substituted C 1 -8 alkyl, substituted C 3-6 cycloalkyl, substituted aroyl, substituted aryl, substituted heteroaroyl, substituted arylsulfonyl, substituted heteroarylsulfonyl and substituted heterocycle include moieties containing from 1 to 3 substituents in addition to the point of attachment to the rest of the compound.
• substituted aryl substituted heterocycle
• substituted cycloalkyl are intended to include the cyclic group which is substituted on a substitutable ring carbon atom with 1 or 2 substitutents selected from the group which includes but is not limited to F, Cl, Br, CF 3 , NH 2 , N(C 1 -C 6 alkyl) 2 , NO 2 , CN, (C 1 -C 6 alkyl)O-, -OH, (C 1 -C 6 alkyl)S(O) m -, (C 1 -C 6 alkyl)C(O)NH-, H 2 N-C(NH)-, (C 1 -C 6
• Lines drawn into the ring systems from substituents means that the indicated bond may be attached to any of the substitutable ring carbon atoms.
• the substituent illustrated by the structure is a simplified representation of a phenyl ring having five (5)
• fused ring moieties may be further substituted by the remaining R 6a , R 6b , R 6c , R 6d and/or R 6e as defined
• the moiety designated by the following structure represents an aromatic 6-membered heterocyclic ring and includes the following ring systems:
• the aromatic 6-membered heterocyclic ring is a pyridyl ring.
• R 1 and R 2 are independently selected from: hydrogen, R 11 C(O)O-, -N(R 10 ) 2 , R 10 C(O)NR 10 -, R 10 O- or unsubstituted or substituted C 1 -C 6 alkyl wherein the substituent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted phenyl, -N(R 10 ) 2 , R 10 O- and R 10 C(O)NR 10 -.
• R 3 is selected from:
• substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl,
• R 12 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, (R 10 ) 2 NC(O)-, R 10 2 N-C(NR 10 )-, CN, R 10 C(O)-, N 3 , -N(R 10 ) 2 , and R 11 OC(O)-NR 10 -.
• R 4 is selected from: hydrogen, halogen, trifluoromethyl, trifluoromethoxy and C 1 -C 6 alkyl.
• R 5 is hydrogen
• R 6a , R 6b , R 6c , R 6d and R 6e are independently selected from:
• -CH CH-CH 2 -, -(CH 2 ) 4 - and -(CH 2 ) 3 -.
• R 8 is independently selected from: a) hydrogen, and
• R 9 is hydrogen, halogen, CF 3 or methyl.
• R 10 is selected from H, C 1 -C 6 alkyl and benzyl.
• a 1 and A 2 are independently .selected from: a bond, -C(O)NR 10 -, -NR 10 C(O)-, O, -N(R 10 )-, -S(O) 2 N(R 10 )- and-
• V is selected from hydrogen, heterocycle and aryl. More preferably, V is phenyl.
• W is selected from imidazolinyl, imidazolyl, oxazolyl, pyrazolyl, pyyrohdinyl, thiazolyl and pyridyl. More preferably, W is selected from imidazolyl and pyridyl.
• n and r are independently 0, 1 , or 2.
• s is 0.
• t is 1.
• any substituent or variable e.g., R 1 , R 2 , R 9 , n, etc.
• -N(R 10 ) 2 represents -NHH, -NHCH 3 , -NHC 2 H 5 , etc.
• substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials.
• the pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inorganic or organic acids.
• such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
• the pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods.
• the salts are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
• Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the Schemes 1 -21 , in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures.
• Schemes 1 -12 illustrate synthesis of the instant aryl- heteroaryl compound which incorporate a preferred benzylimidazolyl sidechain.
• a arylheteroaryl intermediate that is not commercially available may be synthesized by methods known in the art.
• a suitably substituted phenyl boronic acid I may be reacted under Suzuki coupling conditions (Pure Appl.
• a suitably substituted halogenated nicotinic acid such as 4-bromonicotinic acid
• the acid may be reduced and the triflate of the intermediate alcohol III may be formed in situ and coupled to a suitably substituted benzylimidazolyl IV to provide, after deprotection, the instant compound V.
• Schemes 2-4 illustrate other methods of synthesizing the key alcohol intermediates, which can then be processed as described in Scheme 1.
• Scheme 2 illustrates the analogous series of arylheteroaryl alcohol forming reactions starting with the methyl nicotinate boronic acid and the "terminal" phenyl moiety employed in the Suzuki coupling as the halogenated reactant.
• Such a coupling reaction is also compatible when one of the reactants incorporates a suitably protected hydroxyl functionality as illustrated in Scheme 3.
• Negishi chemistry (Org. Synth., 66:67 (1988)) may also be employed to form the arylheteroaryl component of the instant compounds, as shown in Scheme 4.
• a suitably substituted zinc bromide adduct may be coupled to a suitably substituted heteroaryl halide in the presence of nickel (II) to provide the arylheteroaryl VII.
• the heteroaryl halide and the zinc bromide adduct may be selected based on the availability of the starting reagents.
• Scheme 5 illustrates the preparation of a suitably substituted biphenylmethyl bromide which could also be utilized in the reaction with the protected imidazole as described in Scheme 1.
• a suitably substituted imidazole may first be alkylated with a suitably substituted benzyl halide to provide intermediate VIII.
• Scheme 7 illustrates synthesis of an instant compound wherein a non-hydrogen R 9b is incorporated in the instant compound.
• a readily available 4-substituted imidazole IX may be selectively iodinated to provide the 5-iodoimidazole X. That imidazole may then be protected and coupled to a suitably substituted benzyl moiety to provide intermediate XI. Intermediate XI can then undergo the alkylation reactions that were described hereinabove.
• Scheme 8 illustrates synthesis of instant compounds that incorporate a preferred imidazolyl moiety connected to the biaryl via an alkyl amino, sulfonamide or amide linker.
• the 4-aminoalkyl- imidazole XII wherein the primary amine is protected as the phthali- mide, is selectively alkylated then deprotected to provide the amine XIII.
• the amine XIII may then react under conditions well known in the art with various activated arylheteroaryl moieties to provide the instant compounds shown.
• the suitably substituted phenol XIV may be reacted with methyl N-(cyano)methanimidate to provide the 4-phenoxyimidazole XV.
• the intermediate XVI can undergo alkylation reactions as described for the benzylimidazoles hereinabove.
• Scheme 10 illustrates an analogous series of reactions wherein the (CR 2 2 ) ⁇ X(CR 2 2 ) p linker of the instant compounds is oxygen.
• a suitably substituted halopyridinol such as 3-chloro- 2-pyridinol
• Intermediate XVI is then protected and, if desired to form a compound of a preferred embodiment, alkylated with a suitably protected benzyl.
• the intermediate XVII can then be coupled to a aryl moiety by Suzuki chemistry to provide the instant compound.
• a 1 (CR 1 2 ) n A 2 (CR 1 2 ) n linker is a substituted methylene may be synthesized by the methods shown in Scheme 1 1.
• the N-protected imidazolyl iodide XVIII is reacted, under Grignard conditions with a suitably protected benzaldehyde to provide the alcohol XIX.
• Acylation, followed by the alkylation procedure illustrated in the Schemes above (in particular, Scheme 1) provides the instant compound XX. If other R 1 substituents are desired, the acetyl moiety can be manipulated as illustrated in the Scheme.
• the final product XXII may be isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others.
• the product diamine XXII can further be selectively protected to obtain XXIII, which can subsequently be reductively alkylated with a second aldehyde to obtain XXIV. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XXV can be accomplished by literature procedures.
• the arylheteroaryl subunit reagent is reacted with an aldehyde which also has a protected hydroxyl group, such as XXVI in Scheme 14, the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 14, 15).
• the alcohol can be oxidized under standard conditions to e.g. an aldehyde, which can then be reacted with a variety of organometallic reagents such as alkyl lithium reagents, to obtain secondary alcohols such as XXX.
• the Boc protected amino alcohol XXVIII can also be utilized to synthesize 2-aziridinylmethylarylheteroaryl such as XXXIII (Scheme 16). Treating XXVIII with 1 ,1 '-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine XXXIII . The aziridine is reacted with a nucleophile, such as a thiol, in the presence of base to yield the ring- opened product XXXIV .
• a nucleophile such as a thiol
• arylheteroaryl subunit reagent can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as XL, as shown in Scheme 17.
• R' is an aryl group
• XL can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XLI.
• the amine protecting group in XL can be removed, and O-alkylated phenolic amines such as XLII produced.
• the instant compounds are useful as pharmaceutical agents for mammals, especially for humans. These compounds may be administered to patients for use in the treatment of cancer. Examples of the type of cancer which may be treated with the compounds of this invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloid leukemias and neurological tumors.
• Such tumors may arise by mutations in the ras genes themselves, mutations in the proteins that can regulate Ras activity (i.e.,
• NF- 1 neurofibromin
• the compounds of the instant invention inhibit farnesyl- protein transferase and the farnesylation of the oncogene protein Ras.
• the instant compounds may also inhibit tumor angiogenesis, thereby affecting the growth of tumors (J. Rak et al. Cancer Research,
• Such anti -angiogenesis properties of the instant compounds may also be useful in the treatment of certain forms of blindness related to retinal vascularization.
• the compounds of this invention are also useful for inhibiting other proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes (i.e., the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomplished by the administration of an effective amount of the compounds of the invention to a mammal in need of such treatment.
• a component of NF- 1 is a benign proliferative disorder.
• the instant compounds may also be useful in the treatment of certain viral infections, in particular in the treatment of hepatitis delta and related viruses (J.S. Glenn et al. Science, 256: 1331 - 1333 (1992).
• the compounds of the instant invention are also useful in the prevention of restenosis after percutaneous transluminal coronary angioplasty by inhibiting neointimal formation (C. Indolfi et al. Nature medicine, 1 :541 -545(1995).
• the instant compounds may also be useful in the treatment and prevention of polycystic kidney disease (D.L. Schafmer et al. American Journal of Pathology, 142: 1051-1060 (1993) and B. Cowley, Jr. et al.FASEB Journal, 2:A3160 (1988)).
• the instant compounds may also be useful for the treatment of fungal infections.
• the compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice.
• the compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
• the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension.
• carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added.
• useful diluents include lactose and dried com starch.
• aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added.
• sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered.
• the total concentration of solutes should be controlled in order to render the preparation isotonic.
• the compounds of the instant invention may also be co-administered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated.
• the instant compounds may be useful in combination with known anti-cancer and cytotoxic agents.
• the instant compounds may be useful in combination with agents that are effective in the treatment and prevention of NF-1 , restinosis, polycystic kidney disease, infections of hepatitis delta and related viruses and fungal infections.
• Such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent(s) within its approved dosage range.
• Compounds of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.
• the present invention also encompasses a pharmaceutical composition useful in the treatment of cancer, comprising the
• compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacolo- gically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4.
• pharmacolo- gically acceptable carriers e.g., saline
• the solutions may be introduced into a patient's blood-stream by local bolus injection.
• composition is intended to encompass a product comprising the specified ingredients in the specific amounts, as well as any product which results, directly or indirectly, from combination of the specific ingredients in the specified amounts.
• the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.
• a suitable amount of compound is administered to a mammal undergoing treatment for cancer.
• Administration occurs in an amount between about 0.1 mg/kg of body weight to about 60 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 40 mg/kg of body weight per day.
• the compounds of the instant invention are also useful as a component in an assay to rapidly determine the presence and quantity of farnesyl-protein transferase (FPTase) in a composition.
• FPTase farnesyl-protein transferase
• mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention.
• FPTase for example a tetrapeptide having a cysteine at the amine terminus
• farnesyl pyrophosphate for example a tetrapeptide having a cysteine at the amine terminus
• the chemical content of the assay mixtures may be determined by well known
• inhibitors of FPTase absence or quantitative reduction of the amount of substrate in the assay mixture without the compound of the instant invention relative to the presence of the unchanged substrate in the assay containing the instant compound is indicative of the presence of FPTase in the composition to be tested.
• potent inhibitor compounds of the instant invention may be used in an active site titration assay to determine the quantity of enzyme in the sample.
• a series of samples composed of aliquots of a tissue extract containing an unknown amount of farnesyl- protein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate are incubated for an appropriate period of time in the presence of varying concentrations of a compound of the instant invention.
• concentration of a sufficiently potent inhibitor i.e., one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel
• concentration of a sufficiently potent inhibitor i.e., one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel
• Step A 1 -Trityl-4-(4-cyanobenzyl)-imidazole
• Step E 1 -(2-Phenylpyrid-5-ylmethyl)-5-(4-cyanobenzyI)
• Step B 3-Phenyl-6-hydroxymethylpyridine
• 3-phenyl-6-carboxypyridine 1.05g, 5.27 mmol
• tetrahydrofuran 25 mL
• 1.0 M lithium aluminum hydride in tetrahydrofuran
• the reaction was allowed to stir at ambient temperature for 6 hours, cooled to 0°C, and quenched by dropwise addition of water (0.50 mL), 4 N aq. NaOH (0.50 mL), and water (1.5 mL).
• Step C 1 -(3-Phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl)
• Step B 2-(3-Trifluoromethoxyphenyl)-5-carboxy pyridine
• Step D 1 -(2-(3-Trifluoromethoxyphenyl)-pyrid-5-ylmethyl)-
• Step D 1 -(2-(2-Trifluoromethylphenyl)-pyrid-5-ylmethyI)-
• Step B 3-Phenyl-2-chloro-6-methylpyridine and 3-phenyI-4- chloro-6-methylpyridine
• Step D 1 -(3-Phenyl-2-chloropyrid-6-ylmethyl)-5-(4- cyanobenzyl)imidazole hydrochloride salt
• Step B N-bis t-Butoxycarbonyl-2-Amino-3-Phenyl-6- methylpyridine
• Step C 2-(bis t-butoxycarbonylamino)-3-phenyl-6- methylpyridine-N-oxide
• Step D N-bis t-Butoxycarbonyl-2-amino-3-phenyl-6- acetoxymethylpyridine
• Step F 1-(2-Amino-3-phenylpyrid-6-ylmethyl)-5-(4- cyanobenzyl)imidazole hydrochloride salt
• the title compound was prepared using the procedure described for Example 3 step C using N-bis t-butoxycarbonyl-2-amino-3-phenyl- 6-hydroxymethylpyridine in place of 3-phenyl-6-hydroxymethyl- pyridine.
• the free base was treated with TFA and triethylsilane to effect cleavage of the t-butoxycarbonyl groups which was followed by its conversion to the hydrochloride salt.
• Bovine FPTase was assayed in a volume of 100 ⁇ l containing 100 mM N-(2-hydroxy ethyl) piperazine-N '-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl 2 , 5 mM dithiothreitol (DTT), 100 mM [ 3 H]-farnesyl diphosphate ([ 3 H]-FPP; 740 CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 ⁇ g/ml FPTase at 31 °C for 60 min. Reactions were initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol.
• Precipitates were collected onto filter-mats using a TomTec Mach II cell harvestor, washed with 100% ethanol, dried and counted in an LKB ⁇ -plate counter.
• the assay was linear with respect to both substrates, FPTase levels and time; less than 10% of the [3H]-FPP was utilized during the reaction period.
• Purified compounds were dissolved in 100% dimethyl sulfoxide (DMSO) and were diluted 20-fold into the assay. Percentage inhibition is measured by the amount of incorporation of radioactivity in the presence of the test compound when compared to the amount of incorporation in the absence of the test compound.
• DMSO dimethyl sulfoxide
• Human FPTase was prepared as described by Omer et al., Biochemistry 32:5167-5176 (1993). Human FPTase activity was assayed as described above with the exception that 0.1 % (w/v) polyethylene glycol 20,000, 10 ⁇ M ZnCl 2 and 100 nM Ras-CVIM were added to the reaction mixture. Reactions were performed for 30 min., stopped with 100 ⁇ l of 30% (v/v) trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.
• TCA trichloroacetic acid
• the cell line used in this assay is a v-ras line derived from either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21.
• the assay is performed essentially as described in DeClue, J.E. et al., Cancer Research 51 :712-717. (1991 ). Cells in 10 cm dishes at 50-75% confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, is 0.1 %).
• the cells After 4 hours at 37°C, the cells are labelled in 3 ml methionine-free DMEM supple- meted with 10% regular DMEM, 2% fetal bovine serum and 400 mCi[ 35 Sjmethionine (1000 Ci/mmol). After an additional 20 hours, the cells are lysed in 1 ml lysis buffer (1 % NP40/20 mM HEPES, pH 7.5/5 mM MgCl 2 /1mM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and the lysates cleared by centrifugation at 100,000 x g for 45 min.
• 1 ml lysis buffer (1 % NP40/20 mM HEPES, pH 7.5/5 mM MgCl 2 /1mM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PM
• the immunoprecipitates are washed four times with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1 % Triton X- 100.0.5% deoxycholate/0.1 %/SDS/0.1 M NaCl) boiled in SDS-PAGE sample buffer and loaded on 13% acrylamide gels. When the dye front reached the bottom, the gel is fixed, soaked in Enlightening, dried and autoradiographed. The intensities of the bands corresponding to farnesylated and nonfarnesylated ras proteins are compared to IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1 % Triton X- 100.0.5% deoxycholate/0.1 %/SDS/0.1 M NaCl) boiled in SDS-PAGE sample buffer and loaded on 13% acrylamide gels. When the dye front reached the bottom, the gel is fixed, soaked in Enlightening, dried and autoradiographed. The intensities of the bands corresponding to
• Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x 10 4 cells per plate (35 mm in diameter) in a 0.3% top agarose layer in medium A (Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum) over a bottom agarose layer (0.6%). Both layers contain 0.1 % methanol or an appropriate concentration of the instant compound (dissolved in methanol at 1000 times the final concentration used in the assay).
• the cells are fed twice weekly with 0.5 ml of medium A containing 0.1 % methanol or the concentration of the instant compound. Photomicrographs are taken 16 days after the cultures are seeded and comparisons are made.

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