AU713698B2 - Inhibitors of farnesyl-protein transferase - Google Patents

Inhibitors of farnesyl-protein transferase Download PDF

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AU713698B2
AU713698B2 AU54285/96A AU5428596A AU713698B2 AU 713698 B2 AU713698 B2 AU 713698B2 AU 54285/96 A AU54285/96 A AU 54285/96A AU 5428596 A AU5428596 A AU 5428596A AU 713698 B2 AU713698 B2 AU 713698B2
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alkyl
substituted
hydrogen
aryl
independently selected
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AU5428596A (en
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S. Jane Desolms
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Merck and Co Inc
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Merck and Co Inc
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Priority claimed from US08/600,792 external-priority patent/US5624936A/en
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Priority claimed from PCT/US1996/003974 external-priority patent/WO1996031525A2/en
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0207—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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Description

WO 96/31525 PCT/US96/03974 -1- TITLE OF THE INVENTION INHIBITORS OF FARNESYL-PROTEIN
TRANSFERASE
The present patent application is a on--part application of copendi on erial No. 08/412,626, filed March BACKGROUND OF THE INVENTION The Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) 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. In the inactive state, Ras is bound to GDP. 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 Lowy and D.M. Willumsen, Ann. Rev. Biochem. 62:851-891 (1993)). 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 transmit a growth stimulatory signal.
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-Aaal-Aaa 2 Xaa" box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 310:583-586 (1984)). Depending on the specific sequence, this motif serves as a signal sequence for the enzymes famesyl-protein transferase or geranylgeranyl-protein transferase, which WO 96/31525 PCT/US96/03974 -2catalyze the alkylation of the cysteine residue of the CAAX motif with a or C20 isoprenoid, respectively. Clarke., Ann. Rev. Biochem.
61:355-386 (1992); W.R. Schafer and J. Rine, Ann. Rev. Genetics 30:209- 237 (1992)). The Ras protein is one of several proteins that are known to undergo post-translational famesylation. Other 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 famesylated. James, et al., have also suggested that there are farnesylated proteins of unknown structure and function in addition to those listed above.
Inhibition of farnesyl-protein transferase has been shown to block the growth of Ras-transformed cells in soft agar and to modify other aspects of their transformed phenotype. It has also been demonstrated that certain inhibitors of farnesyl-protein transferase selectively block the processing of the Ras oncoprotein intracellularly Kohl et al., Science, 260:1934-1937 (1993) and G.L. James et al., Science, 260:1937-1942 (1993). Recently, it has been shown that an inhibitor of farnesyl-protein transferase blocks the growth of rasdependent tumors in nude mice Kohl et al., Proc. Natl. Acad. Sci 91:9141-9145 (1994) and induces regression of mammary and salivary carcinomas in ras transgenic mice Kohl et al., Nature Medicine, 1:792-797 (1995).
Indirect inhibition of farnesyl-protein transferase in vivo has been demonstrated with lovastatin (Merck Co., Rahway, NJ) and compactin (Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science 245:379 (1989)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids including famesyl pyrophosphate. Farnesyl-protein transferase utilizes farnesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a farnesyl group (Reiss et al., Cell, 62:81-88 (1990); Schaber et al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al., Science, 249:1133-1139 (1990); Manne et al., Proc. Natl. Acad. Sci USA, 87:7541-7545 (1990)). Inhibition of famesyl pyrophosphate biosynthesis WO 96/31525 PCT/US96/03974 -3by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells. However, direct inhibition of famesyl-protein transferase would be more specific and attended by fewer side effects than would occur with the required dose of a general inhibitor of isoprene biosynthesis.
Inhibitors of farnesyl-protein transferase (FPTase) have been described in two general classes. The first are analogs of farnesyl diphosphate (FPP), while the second class of inhibitors is related to the protein substrates Ras) for the enzyme. 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. (Schaber et al., ibid; Reiss et. al., ibid; Reiss et al., PNAS, 88:732-736 (1991)). Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the faresyl-protein transferase enzyme, or may be purely competitive inhibitors 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)). In general, deletion of the thiol from a CAAX derivative has been shown to dramatically reduce the inhibitory potency of the compound. However, 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.
It has recently been reported that faresyl-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 H7-112930).
It has recently been disclosed that certain tricyclic compounds which optionally incorporate a piperidine moiety are inhibitors of FPTase (WO 95/10514, WO 95/10515 and WO 95/10516).
Imidazole-containing inhibitors of faresyl protein transferase have also been disclosed (WO 95/09001 and EP 0 675 112 Al).
It is, therefore, an object of this invention to develop tetrapeptide-based compounds that do not have a thiol moiety, and that will inhibit farnesyl-protein transferase and thus, the post-translational WO 96/31525 PCT/US96/03974 -4farnesylation of proteins. It is a further object of this invention to develop chemotherapeutic compositions containing the compounds of this invention and methods for producing the compounds of this invention.
SUMMARY OF THE INVENTION The present invention comprises analogs of the CA 1
A
2
X
motif of the protein Ras that is modified by farnesylation in vivo. These
CA
1
A
2 X analogs inhibit the farnesylprotein transferase. Furthermore, these CA1A 2 X analogs differ from those previously described as inhibitors of farnesyl-protein transferase in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thioldependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. The compounds of the instant invention also incorporate a cyclic amine moiety in the A 2 position of the motif. Further contained in this invention are chemotherapeutic compositions containing these faresyl transferase inhibitors and methods for their production.
WO 96/31525 PCTIUS96/03974 The compounds of this invention are illustrated by the formulae: (R 8 )r V Al(CRa 2 )nA 2 (CR~a 2 )n
(R
8 )r V Al(CRa 2 )nA 2 (CR~a On IR9\
(I)U
(I
Nw/ (R )r
R
V Al(CRa 2 )nA (CR~a) Own~ (R )r (R 9 V Al(CRla 2 )nA (CR a 2
R
4 b WO 96/3 1525 PCT/US96/0 3 9 7 4 -6- DETAILED DESCRIPTION OF TME INVENTION The compounds of this invention inhibit the farnesyl-protein transferase. In a first embodiment of this invention, the farnesyl-protein transferase inhibitors are illustrated by the formula 1:
R
5 a R (R 8 )rR 96 Y ZO II
R
6 N O V Al(CRla 2 )nA 2(CR~a 2 )n-W b2 H 0 wherein: R Ia and R Ib are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, R 10 0-, RIIS(O)m-, RIOC(O)NRIO., CN, N02,
(R
1 0 )2N- C(NRlO)-, RIOC(O)-, R'OOC(O)-, N3, -N(RlO) 2 or R I'IOC(O)NR C) C I -C6 ailkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 10 0-,
R
1 1 RIOC(O)NRiO.. CN, (R'O)2N-C(NRO)., R IOC(O)-, R I N3, -N(Ri10) 2 or R I IOC(O)-
NRIO-;
R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C I -C20 alkyl, C2-C 2 O alkenyl, C3-C 10 cycloalkyl, aryl. or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(RiO) 2 N02, RiOO-,
RI
1 S(O)m- RIOC(O)NRl0-, WO 96/31525 PCT/US96/039 74 -7- CN, (R'O)2N-C(NRIO). RiOC(o)-, RIOOC(0>- N3, -N(R 1 0 2 R I IOC(O)NR 10- and CI -C20 ailkyl, and d) C1I-C6 ailkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3cycloalkyl; or R2 and R3 are combined to form (CH2)s or R2 or R3 are combined with
R
6 to form a ring such that R6K is
(HA)
R 2 R R 7 a
R
7 b R4a, R4b,
R
7 a and R7b are independently selected from: a) hydrogen, b) C I -C6 ailkyl unsubstituted. or substituted by alkenyl, R 100., R I 1 S R'IOC(O)NR 10., CN, N3, (R I )2N-C(NRl10), RIOC(0)-, RIO0C(0)-, -N(RIO)2, or RI IOC(0)NRO..
c) aryl, heterocycle, cycloalkyl, alkenyl, R 1 0 0-, RIIS(0)m-, RIOC(0)NRIO., CN, N02, (R'O)2N- C(NRI1O)-, Ri 0 RI 0 N3, -N(R 10)2, or R I IOC(0)NRi10, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-Ci10 cycloalkyl; id R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, ar WO 96/3 1525 PCTfUS96/03974 -8c) substituted or unsubstituted 'C I -C20 alkyl, C2-C20 ailkenyl, C3-ClO cycloalkyl, aryl. or heterocycle group, wherein the substituent is selected from F, Cl, Br, (R 10 N02, R 10 R I 1 S Rl 0 C(O)NRI10., CN, (Rl 0 )2N-C(NR10)..,
R
1 0 RIO0C(O)-, N3, R1 IOC(O)NR1O. and C I-C20 alkyl, d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- CIO cycloalkyl; or and R5b are combined to form (CH2)s wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, S(O)m, and R6 is independently selected from hydrogen or C I-C6 alkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R II 1 S RI 0 C(0)NRI1O-, CN, N02, Ri 0 2N-C(NR RI OC(0)-, R I N3, -N(R 10)2, or R I IOC(0)NR10-, and c) ClI-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl,
F,
Cl, Br, R 1 0 R I IS(O)m-, R IOC(O)NH-, CN, H2N- RIOC(0)-, RIO0C(0)-, N3, -N(RlO)2, or RI 0 0C(0)NH-; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RIO0-,
RI
1 RIOC(0)NRO., CN, N02, (R' 0 )2N-C- WO 96/31525 PCT/US96/03974 -9- R10C(O)-,
R
10 N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 10 R 1S(O)m-, R1OC(O)NR10-,
CN,
(R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10) 2 or R11OC(O)NR10-;
R
10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; R11 is independently selected from C1-C6 alkyl and aryl; Al and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NRIO-, -NR10C(O)-, O, -N(RO1)-, -S(0)2N(RlO)-, -N(R1O)S(0) 2 or S(O)m; Q is a substituted or unsubstituted nitrogen-containing C6-C9 bicyclic ring system, wherein the non-nitrogen containing ring is selected from an aromatic ring and a heterocycle; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl- wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; 4 X, Y and Z are independently H2 or O; m is 0,l1or 2; n is 0,1, 2, 3or 4; p is 0,1, 2 3or 4; r is 0 to 5, provided that r is 0 when V is hydrogen; s is 4 or t is 3 4 or u is 0Oorl1; or the pharmaceutically acceptable salts thereof.
In a second embodiment of this invention there is provided prodrugs of the formula 11: R R Y z R 5 a R 5 b O R 1 1R l a Ib
R
6 N
O
V- A (CRla 2 )nA (CR 2)n- W (CR' 2)p N
H,
kIu XRR
N
x R
Q
4~a Rb wherein: and R 1b are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl,
R'
0 R"
RIOC(O)NRO-,
CN, NO 2
(R'
0 2 R' 0
R'
0
-N(R'
0 2 or RlIOC(O)NR'O-; C) C 1
-C
6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl,
R'
0 0, RIOC(O)NR0-, CN, (RlO) 2 N-C(NRo)-,
R'
0
R'
0
N
3
-N(R'
0 2 or RllOC(O)NR"o-; R 2 and R 3 are independently selected from: a) a side chain of a naturally occurring amino acid, 10 ft ft.
ft ft ft ft. ft* ft.
ft ft...
ft.
ft ft *ftft ft 15 ft ft ft ft ft ft ft.
ft 5 ft *4 ft ft [RALIBA]02565. doc:TLT
I
WO 96/3 1525 PCT1US96103974 b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C I -C20 alkyl, C2-C20 alkenyl, C3-ClO cycloalkyl, aryl. or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(RIO)2, N02, RIO0-, RIIS(O)m-, RIOC(O)NRl0-, RI 'OC(O)NRl0- and Cl-C20 alkyl, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3cycloalkyl; or R2 and R 3 are combined to form (CH2)s or R2or R3are combined with R 6 to form a ring such that R6 Nis
(HA)
R 2R aO RMb R4a, R4b, R 7 a and R7b are independently selected from: a) hydrogen, b) C I -C6 alkyl unsubstituted or substituted by alkenyl, R 1 00.., RI IS(O)m-, RIOC(O)NRIO-, CN, N3, (RIO)2N-C(NRIO)-, R IOC(O)-, R I -N(R 10)2, or R I IOC(O)NR c) aryl, heterocycle, cycloalkyl, alkenyl, RIO0-, RI IS(O)m-, RIOC(O)NRlO-, CN, N02, (RIO)2Nor R I I0C(O)NR 10-, and WO 96/31525 PCTIUS96/03 9 74 -12d) C1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-CIO cycloalkyl; R5a and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Ci -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br,
(R
1 0 N02,
R
1 0
R
1 1 S(O)m-, R1 0 C(O)NR10-, CN, (R1 0 )2N-C(NR R1 0
R
10 N3, -N(R10) 2 R 10OC(O)NR10- and alkyl, d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C10 cycloalkyl; or and R5b are combined to form (CH2)s wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, S(O)m, and R6 is independently selected from hydrogen or C1-C6 alkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 RI S(O)m-, RlOC(0)NRO0-, CN, N02, R102N-C(NR10)-,
R
1 OC(0)-,
R
1 0 N3, -N(R10) 2 or RI I0C(0)NR10-, and WO 96/3 1525 PCT/US96/039 7 4 13 R9 is c) C I -C6 ailkyl unsubstituted or substituted by aryl, heterocycle, cycloallcyl, alkenyl, alkynyl, perfluoroalkyl,
F,
Cl, Br, RIO0-, RIIS(O)m-, RIOC(O)NH-, CN, H2N- C(NII)-, RIOC(O)-, R'OOC(O)-, N3, -N(RiO) 2 or
R
1 0 0C(O)NH-; selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalcyl, F, Cl, Br, R 1 0 0-, RIIS(O)m-, RlOC(O)NRO-., CN, N02, (Rl 0 )2N-C- (NRIO)-, RIOC(O)-, RIOOC(O)-, N3, -N(RlO) 2 or R I IOC(O)NR 10-, and C) C I-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 1 0 R II 1 RIOC(O)NRO-,
CN,
or Ri 11OC(O)NR R 1 0 is independently selected from hydrogen, C I-C6 alkyl, benzyl and aryl;, Ri is independently selected from ClI-C6 alkyl and aryl;
R
1 2 jis a) substituted or unsubstituted C I -C8 alkyl, substituted or unsubstituted C5-C8 cycloalkyl, or substituted or unsubstituted cyclic amine, wherein the substituted alkyl, cycloalkyl or cyclic amine is substituted with 1 or 2 substituents independently selected from: 1) C1I-C6 alkyl, 2) aryl, 3) heterocycle, 4) -N(R 11)2,
-OR
10 or WO 96/31525 PCTIUS96/0397 4
R
13
O
O R 1 4
R
13 is independently selected from hydrogen and C1-C6 alkyl; R1 4 is independently selected from C1-C6 alkyl; Al and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR1O-, -NRIOC(O)-, O, -S(0)2N(R10)-,
-N(R
10
)S(O)
2 or S(O)m; Q is a substituted or unsubstituted nitrogen-containing C6-C9 bicyclic nng system, wherein the non-nitrogen containing ring is selected from an aromatic ring and a heterocycle; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; X, Y and Z are independently H2 or O; m is 0, 1 or 2; nis 0,1, 2 3 or 4; pis 0, 1, 2, 3 or 4; r is 0 to 5, provided that r is 0 when V is hydrogen; WO 96/31525 PCTIUS96/039 7 4 s is 4 or t is 3 4 or u is 0Qori1; or the pharmaceutically acceptable sal .ts thereof.
In a third embodiment of this invention, the inhibitors of famnesyl transferase are illustrated by the formula
III:
HOCH
2
(CH
2 )q
(R
8 )r R9Y
Z
ACl 2 (CR~a) I b
OH
xR 4; Q R 4 b R Ia and RlIb are independently selected from: b) aryl, heterocycle, cycloalkyl, alkenyl, ailkynyl, R 1 0 0-, RI IS(O)m-, R'OC(O)NRIO0, CN, N02, (RlO)2N- C(NR 1 R IOC(0)-, R I N3, -N(R 10)2, or R' lOC(O)NRO-, c) ClI -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 100.., RI 1 R IOC(O)NR 10-, CN, (RlIO)2N-C(NR RIOC(0)-, RIOOC(O)-, N3, -N(RlO) 2 or RI IOC(O)-
NRIO-;
R
2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or WO 96/3 1525 PCTIUS96/03974 -16i) methionine sulfone, and c) substituted or unsubstitutedC CI -C20 alkYl, C2-C20 alkenyl, C3-CIO cycloalicyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R'10)2, N02, R 1 0 R I 1 IS(0)m-, RIOC(0)NRlO-, CN, (RiO)2N-C(NR1O), RIOC(0)-, RIOOC(O)-, N3, -N(RlO)2, RI IOC(0)NRO.. and CI-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- CiG cycloalkyl; or
R
2 and R3 are combined to form (CH2)s or R2or R3 are combined with R 6 to form a ring such that R 6 is
(H)A
R4a, R4b, R 7 a. and R7b are independently selected from: a) hydrogen, b) C I-C6 alkyl unsubstituted or substituted by alkenyl, R 100..,
R
1 IS(0)m-, RiOC(0)NRIO.., CN, N3, (R'O)2N-C(NRIO)-, R IOC(0)-, R I -N(R 10)2, or R I I0C(0)NR c) aryl, heterocycle, cycloalkyl, alkenyl,
R
1 0 0-, RI IS(0)m-, RIOC(O)NRlO-, CN, N02, (RIO)2N- C(NRlO)-, RIOC(O)-, RIO0C(O)-, N3, -N(R'0)2, or R1 1OC(0)NRO.., and d) C1I-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl;
R
6 is independently selected from hydrogen or C I-C6 ailkyl; WO 96/31525 PCTIUS96/03974 -17- R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalcyl, F, Cl, Br, R 1 0 R II 1 RI 0
C(O)NR
1 CN, N02, Ri 0 2N-C(NRI1O)-, RI 0 R I N3, -N(R'10)2, or R I IOC(O)NRi10-, and c) C1I-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl,
F,
Cl, Br, RIO0-, RI IS(O)m-, RIOC(O)NH-, CN, H2N- RIOC(O)-, RIO0C(O)-, N3, or
R
1 0 0C(O)NH-; R9 is selected from: a) hydrogen, b) ailkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 0-, RI IS(O)m-, R'OC(O)NRI0-, CN, N02, (RIO)2N-C- (NRIO)-, RIOC(O)-, RIO0C(O)-, N3, or Ri 11OC(O)NR 10-, and C) C I-C6 alkyl unsubstituted or substituted by perfluoroalcyl, F, Cl, Br, R 1 0 RI IS R IOC(O)NRi10-,
CN,
(RI O)2N-C(NRl Ri 0 RI 0 N3, -N(Ri 0)2, or R I IOC(O)NR R 10 is independently selected from hydrogen, C I-C6 ailkyl, benzyl and aryl; R I is independently selected from C I -C6 alkyl and aryl.; A I and A 2 are independently selected from: a bond, -CH=CH-,
-CE=C-,
-C(O)NRIO-, -NRIOC(O)-, 0, -N(RIO)-, -S (0)2N(RI -N(RI or S(O)m; 18 Q is a substituted or unsubstituted nitrogen-containing
C
6
-C
9 bicyclic ring system, wherein the non-nitrogen containing ring is selected from an aromatic ring and a heterocycle; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) Ci-C 2 0 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S and N, and 1 0 e) C 2
-C
20 alkenyl, provided that V is not hydrogen if A' is and V is not hydrogen if A' is a bond, n is 0 and A 2 is S(0),m; W is a heterocycle; X, Y and Z are independently
H
2 or 0; 1 i mis 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is O, 1, 2, 3 or 4; *q is 0, 1 or 2; r is 0 to 5, provided that r is 0 when V is hydrogen; 20 sis 4 tis 3, 4 or 5; and uis Oorl; g: or the pharmaceutically acceptable salts thereof.
In a fourth embodiment of this invention there is provide prodrugs of the formula IV: o [R:\LIBA]02565.doc:TLT WO 96/31525 PCT[US96/03974 -19- (RB)r V Al(CRa 2 )nA (CR a 2 )n
(I
Nw/ R 4b wherein: R Ia and R Ib are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalcyl, aikenyl, alkynyl, RIO0-, RIIS(O)m-, RIOC(O)NRIO., CN, N02, (RIO)2N- C(NRIO)-, RIOC(O)-, RIO0C(O)-, N3, or Ri 11OC(O)NR c) C I-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalicyl, alkenyl, alkynyl, R 1 0 0-, RIOC(O)-, RIO0C(O)-, N3, -N(RIO)2, or RlI C(O)-
R
2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methiomine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C I-C20 alkyl, C2-C20 ailcenyl, C3-C1O cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R'0)2, N02, RIO0-, R1 IS(O)m-,
RIOC(O)NRIO-,
(RI 0 )2N-C(NRI1 Rl RI 0 N3, RI IOC(O)NR10- and C1-C20 ailkyl, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C 10 cycloalkyl.; or WO 96/3 1525 PCTIUS96/03974 20
R
2 and R3 are combined to form (CH2.)s or 2or R3 are combined with R 6 to form a ring such that R 6 Nis
(HA)
R 3RiB. Rib R4a, R4b, R 7 a and R7b are independently selected from: a) hydrogen, b) C I -C6 alkyl unsubstituted or substituted by alkenyl, R 100.., RI RIOC(0)NRIO-, CN, N3, (R'O)2N-C(NR1O).,
R
1 RIO0C(0)-, or RI IOC(0)NRO.., c) aryl, heterocycle, cycloalkyl, alkenyl, RIO0-, RI IS(O)m-, RIOC(O)NR1O-, CN, N02, (R'%2N- C(NR 1 R IOC(0)-, R I N3, -N(R 10)2, or R I I0C(O)NR and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-CIO cycloalkyl;
R
6 is independently selected from hydrogen or C I -C6 alkyl;
R
8 is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Ci, Br, R1 0
R
1 IS(0)m-, RI 0 C(0)NR 1 0, CN, N02, R 1 0 2N-C(NR Ri OC(0)-, R I N3, -N(R 10)2, or R IIOC(0)NR10-, and c) C I -C6 alkyl unsubstituted or substituted by aryl, heterocycie, cycloalkyl, aikenyl, ailkynyl, perfluoroalkyl,
F,
Ci, Br, RIO0-, R 1 1S(0)m-, Rl 0 C(0)NH-, CN, 112N- WO096/31525 PCT/US96/03974 -21- RIOC(O)-,
R
1 0 N3, -N(RlO)2, or RI 0 0C(O)NH-; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 0-, RI IS R IOC(O)NRl10-, CN, N02,
(R
1 0 )2N-C-
R
1 RIOOC(O)-, N3, -N(RlO)2, or RI 'OC(O)NR10-, and ClI-C6 ailkyl unsubstituted or substituted by peffluoroalkyl, F, Cl, Br, R 1 0 R I 1 R'OC(O)NRO-,
CN,
(Ri %2N-C(NR Rl Rl 0 N3, -N(Ri 0)2, or R I R 10 is independently selected from hydrogen, C1I-C6 alkyl, benzyl and aryl; RI I is independently selected from C1I-C6 ailkyl and aryl; AlI and A 2 are independently selected from: a bond, -CH=CH-,
-C=EC-,
-C(O)NRIO-, -NRIOC(O)-, 0, -N(RIO)-, -S(O)2N(RI10>., -N(Rl 0 or S(O)m; Q is a substituted or unsubstituted nitrogen-containing C6-C9 bicyclic ring system, wherein the non-nitrogen containing ring is selected from an aromatic ring and a heterocycle; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C I -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from 0, S, and N, and e) C2-C20 alkenyl,
I
WO 96/31525 PCT/US96/03974 22provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if A is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; X, Y and Z are independently H2 or O; m is 0, 1 or 2; nis 0, 1, 2 ,3 or4; p is 0,1, 2, 3 or 4; q is 0, 1 or 2; r is 0 to 5, provided that r is 0 when V is hydrogen; s is 4 or t is 3 4 or 5; and uis Oorl; or the pharmaceutically acceptable salts thereof.
In a more preferred embodiment of this invention, the Ras famesyl transferase inhibitors are illustrated by the Formula
I:
(R)r R 5a R 5 b I R Z O V- A(CRia 2 )nA2(CR1a- 2 n W (CRib2 Hp xR2 R 3 Q X R 4 b R4a wherein: Rla is independently selected from: hydrogen or C1-C6 alkyl;
R
1 b is independently selected from: a) hydrogen, WO096/31525 PCT1US96/0397 4 23 b) aryl, heterocycle, cycloalkyl., R 10 -N(RlO) 2 or alkenyl, C) C I-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R 10 or -N(Rl1O) 2 R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occur-ring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Ci-ClO alkyl, C2-C10 alkenyl, C3-CIO cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 10 R' IIS(O)m-, R IOC(O)NR 10-, CN, (Ri O)2N-.C(p4 1 RI 0
R
1 0 N3, -N(R 10)2, R I IOC(O)NR 10- and C1I-C20 alkyl, and d) C1I-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C 10 cycloalkyl; or R2 and R3 are combined to form (CH2)s or R2or R3 are combined with R 6 to form a ring such that R 6 6-IINis
(HA)
R 2 RaR 7 b R4a and R 7 a are independently selected from: a) hydrogen, b) C I -C6 alkyl unsubstituted or substituted by alkenyl, R 100-., RI IS(0)m,, RIOC(0)NRI0-, CN, N3, (R'O)2N..C(NR10)-, RIOC(O)-, RIO0C(O)-, -N(RIO)2, or RI IOC(O)NR0-, WO 96/31525 PCTIUS96/039 74 -24c) aryl, heterocycle, cycloalkyl, alkenyl,
R
10 0-, R 1 R1OC(O)NR10-, CN, N02, (R 10 )2N- C(NRIO)-, RIOC(O)-, R100C(o)-, N3, -N(R1O) 2 or R110C(O)NR10-, and d) C1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3cycloalkyl; R4b and R7b are hydrogen; is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from methionine and glutamine, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted CI-CIO alkyl, C2-CO10 alkenyl, C3-CO10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02,
R
10 R1S(O)m-, R1OC(O)NR10, (R1 0 CN, (R10)2N-C(NR10)-,
RIOC(O)-,
RIOOC(O)-, N3, -N(R10) 2 R 11OC(O)NR10- and alkyl, and d) C1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3cycloalkyl; is selected from: a) hydrogen, and b) C1-C3 alkyl; R6 is independently selected from hydrogen or C1-C6 alkyl; R 8 is independently selected from: a) hydrogen,
C-C
6 alkyl, C 2
-C
6 alkenyl, C 2
-C
6 alkynyl, C-C 6 perfluoroalkyl, F, Cl, IR1 0 0-,
R'
0 RJOC(O)NR10- CN, N0 2 (Rlo) 2 R' 0
R'
0 -N(R 0 2 or R''OC(O)NRO-, and C) C I-C 6 alkyl substituted by C I-C6 perfluoroalkyl, R 1 0 R
R'
0 or -N(0)2; R' is selected from: a) hydrogen, iob)
C
2
-C
6 alkenyl,
C
2
-C
6 alkynyl,
CI-C
6 perfluoroalkyl, F, Cl, R' 0 R' R t OC(O)NR' CN, NO 2 2 N-C(NR10)-, R' 0
R'
0 or R' IOC(O)NR0-, and C) C,-C 6 alkyl unsubstituted or substituted by CI-C 6 perfluoroalkyl, F, Cl, R' 0 0-, R"S(Om, RIOC(O)NR0-, CN, (R"o) 2 R' 0
R'
0
-N(R'
0 2 or RIIOC(O)NR"o-; R1 0 is independently selected from hydrogen,
C,-C
6 alkyl, benzyl and aryl; R' '1is independently selected from C I-C 6 alkyl and aryl; Q is selected from: and [RALIBA]2565.doc:TLT WO 96/31525 PCT/US96/0397 4 -26- Al and A 2 are independently selected from: a bond, -CH=CH-,
-CC-,
-C(O)NR10-, O, or S(O)m; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2 -oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2 -oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; X, Y and Z are independently H2 or O; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; pis 0,1, 2 3 or4; r is 0 to 5, provided that r is 0 when V is hydrogen; t is 3, 4 or 5; and uis 0orl; or the pharmaceutically acceptable salts thereof.
In a second more preferred embodiment of this invention, the prodrugs of the preferred compounds of Formula I are illustrated by the Formula
II:
WO 96/31525 PCTIUS96/03974 27
(R
8 )r V Al(CRla 2 )nA2(CR~a 2 )n (R9\
(I)U
wherein: R Ia is independently selected from: hydrogen or ClI-C6 alkyl; R Ib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 1 0 -N(RlO) 2 or alkenyl, c) C1I-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, RIO0-, or -N(RIO)2; R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cl-Clo alkyl, C2-ClO alkenyl, C3-C1O cycloalkyl, aryl. or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, RIO0-, RIIS(O)m-, RlOC(O)NRIO-,
CN,
(Rl 0 )2N-C(NRI10>, Rl Rl 0 N3, -N(R'10)2, R1 1 OC(O)NR 10- and ClI-C20 ailkyl, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3cycloalkyl; or
R
2 and R3 are combined to form (CH2)s or WO 96/3 1525 PCTIUS96/03 9 7 4 28 R2 or R3 are combined with R 6 to form a ring such that is
(HA)
R 2 RR7 R 7 b R4a and R7a are independently selected from: a) hydrogen, b) C I -C6 alkyl unsubstituted or substituted by alkenyl, R 1 S R IOC(O)NR 10-, CN, N3, (R IO)2N-C(NR10)-, ~R IOC(O)-, R IOOC(O)-, -N(R 10) 2 or R c) aryl, heterocycle, cycloalkyl, alkenyl, RIO0-, R I IS(O)m-, R'IOC(O)NR10-, CN, N02, (R1'O)2N- C(NR 1 Ri I Ri I N3, -N(R 10)2, or R I IOC(O)NRl10-, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- C 10 cycloallcyl; R4b and R7b are hydrogen; is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from methionine and glutamnine, b) an oxidized form of a side chain of a naturally occur-ring amino acid which is: i) methiomine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C I-Ci10 alkyl, C2-C 10 alkenyl, cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02,
R
1 0 R1 IS(O)m-, RIOC(O)NRl0-,
(R'
0 2 CN, (RIo) 2 N-C(NR'Oa>
R'
0
R'
0
N
3
-N(R'
0 2 R 11OC(O)NRO- and C I-C 20 alkyl, and d) C 1
-C
6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C 3
-C
10 cycloalkyl; R 5 b is selected from: a) hydrogen, and b) C I-C 3 alkyl; R 6 is independently selected from hydrogen or C I-C 6 alkyl;
R
8 is independently selected from: 0a) hydrogen, b)
C
1
-C
6 alkyl, C 2
-C
6 alkenyl,
C
2
-C
6 alkynyl,
C
1
-C
6 pcrfluoroalkyl, F, Cl, R' 0 0-, RIOC(O)NRO, CN,
NO
2
(R'O)
2 N-CcNR")-,
R'
0 R"O0C(O)-,
-N(R'
0 2 or R" OC(O)NRO-, and C) C 1
-C
6 alkyl substituted by CI-C 6 perfluoroalkyl,
R'
0
R'
0
R'
0 or (Rs2
R
9 is selected from: a) hydrogen,
C
2
-C
6 alkenyl,
C
2
-C
6 alkynyl,
CI-C
6 perfluoroalkyl, F, Cl, R' 0 R" S(O)m-,
R
1 0 C(O)NR'Ot CN, NO 2
(R'O)
2 N-C(NRI0)-
R'
0
R'
0
-N(RI
0 or RI'OC(O)NR10, and c) C 1
-C
6 alkyl unsubstituted or substituted by C 1
-C
6 perfluoroalkyl, F, Cl, R1 0 0-,
~R
1 RIOC(O)NRO-, CN, (Rlo) 2 N-C(NRIO).,
R'
0
R'
0
-N(R'
0 2 or
R''OC(O)NR
0 [RALIBA]02565,doc:TLT WO 96/31525 PCT/US96/0397 4 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R
1 1 is independently selected from Cl-C 6 alkyl and aryl;
R
12 is a) substituted or unsubstituted C -C8 alkyl, substituted or unsubstituted C5-C8 cycloalkyl, or substituted or unsubstituted cyclic amine, wherein the substituted alkyl, cycloalkyl or cyclic amine is substituted with 1 or 2 substituents independently selected from: 1) Cl-C6 alkyl, 2) aryl, 3) heterocycle, 4) -N(R11)2, -OR10, or b)
R
13 0
R
13 is independently selected from hydrogen and C1-C6 alkyl;
R
14 is independently selected from C1-C6 alkyl; Q is selected from: and WO 96/31525 WO 96/31525 PCT/US96/03974 -31- Al and A 2 are independently selected from: a bond, -CH=CH- -C(O)NR10-, O, -N(R 10), or S(O)m; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2 -oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2 -oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; X, Y and Z are independently H2 or O; m is 0, 1 or 2; nis 0, 1, 2, 3 or 4; p is 0, 1, 2 3 or 4; r is 0 to 5, provided that r is 0 when V is hydrogen; t is 3, 4 or 5; and uis 0orl; or the pharmaceutically acceptable salts thereof.
In a third more preferred embodiment of this invention, the inhibitors of famesyl transferase are illustrated by the formula
III:
WO 96/31525 PCTJUS96/03974 32
HOCH
2
(CH
2 )q
(R
8 )r (R9 VAl(CRa 2 )nA 2 (CR On) la I
U
R
4 b wherein: Ri1a is independently selected from: hydrogen or ClI-C6 alkyl; Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R1 00-, -N(Ri 0)2 or alkenyl, 0 c) C I-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, RiOO-, or -N(R'O)2; ar id RJ are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine suifoxide, or ii) methionine sulfone, c) substituted or unsubstituted C I-C 10 alkyl, C2-C 1O alkenyl, C3-C10 cycloallcyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 10 R I IS(O)m-, R 11 0 C(O)NR1O-,
CN,
RIOC(O)-, RIO0C(O)-, N3, -N(R'10)2, R I I0C(O)NR 1 0- and ClI-C20 alkyl, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3cycloalkyl; or WO 96/3 1525 PCT1US96/03974 33 R2 and R 3 are combined to form (CH-2)s or R2 or R 3 are combined with R 6 to formn a ring such that is HAK R2 R3 a R 7 b R4a and R 7 a1 are independently selected from: a) hydrogen, b) C1I-C6 alkyl unsubstituted or substituted by alkenyl, R 1 0 0-, RI IS(O)m-, RIOC(O)NRIO-, CN, N3, (RlO)2N-C(NR1O)-, RlOC(O)-, RIO0C(O)-, -N(RlO)2, or R1 1
OC(O)NRIO-,
c) aryl, heterocycle, cycloalkyl, alkenyl, RIO0-, RI IS(O)m-, R'OC(O)NR1O-, CN, N02, (R 1 0 )2N- C(NRl RI 0 Rl 0 N3, -N(Rl 0)2, or R 1 0C(O)NR 10-, and d) C1I-C6 ailkyl substituted with an unsubstituted. or substituted group selected from aryl, heterocyclic and C3- C 10 cycloallcyl; R4b and R7b are hydrogen; R6 is independently selected from hydrogen or C Il-C6 alkyl;
R
8 is independently selected from: a) hydrogen, b) C I -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C I -C6 perfluoroalcyl, F, Cl, RIO0-, RIOC(O)NRlO-, CN, N02, (RI 0 )2N-C(NR RI RI 0 -N(R 10)2, or Ri 11OC(O)NR 10-, and 34 C) C I-C 6 alkyl substituted by C 1
I-C
6 perfluoroalkyl, R R' 0
R'
0 or
R
9 is selected from: a) hydrogen, b) C 2
-C
6 alkenyl,
C
2
-C
6 alkynyl,
C
1
-C
6 perfluoroalkyl, F, Cl, R' 0 R' 'S(O)II-, R'OC(O)NRO- CN, NO,,
R'
0
R'
0
N(R'
0 2 or R' 'OC(O)NRIO, and C) C 1
-C
6 alkyl unsubstituted or substituted by CI-C 6 perfluoroalkyl, F, Cl, R' 0 0-, R' RIOC(O)NR1O, CN, (R'o) 2 R 10
R'
0
N(R'
0 2 or R''OC(O)NR"o-; R 1 0 is independently selected from hydrogen, C I-C 6 alkyl, benzyl and aryl; is independently selected from CI-C 6 alkyl and aryl; Q is selected from: N*
NN~
**SL o and
S.
2.
A and A 2 are independently selected from: a bond, -CH=CH-,
-C(O)NR'
0 0, -N(R 10 orS(), V is selected from: hydrogen, [R V-IBA]02565.doc TLT [R'L18A102565docTLT WO 96/31525 PCT/US96/03 9 74 b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2 -oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from 0, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A1 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, pyridinyl, thiazolyl, pyridonyl, 2 -oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; X, Y and Z are independently H2 or O; mis 0, 1 or2; nis 0, 1, 2 3 or 4; p is 0, 1, 2 3 or 4; q is 0, 1 or 2; r is 0 to 5, provided that r is 0 when V is hydrogen; t is 3 4 or 5; and uis 0orl; or the pharmaceutically acceptable salts thereof.
In a fourth more preferred embodiment of this invention, the prodrugs of the preferred compounds of Formula III are illustrated by the Formula
IV:
WO 96/31525 PCT/US96/03974 -36- R4a V- Al(CR'a)A2(CRr), N.A
ZN
wherein: Ria is independently selected from: hydrogen or C -C6 alkyl; Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl,
R
10 -N(R10)2 or alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl,
R
10 or -N(R10)2; R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO2, R 10
R
1 1 RO1C(O)NR10-,
CN,
(R10)2N-C(NR10)_, R10C(O)-, R100C(O)-, N3, 2 R11OC(O)NR10- and C1-C20 alkyl, and d) C l-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3cycloalkyl; or
R
2 and R3 are combined to form (CH2)s or R2 or R3 are combined with R 6 to form a ring such that x N is(CH 2 )t RRk
R
7 a
R
7 b R 4 a and are independently selected from: a) hydrogen b) C 1
-C
6 alkyl unsubstituted or substituted by alkenyl, R' 0 R' 'S(Olm-,
R'
0
C(O)NR'
0 CN, N 3
(RI')
2
N-C(NR'
0
R'
0
R
10
-N(R'
0 or R''0C(O)NR' 0 c) aryl, heterocycle, cycloalkyl, alkenyl, R' 0
R'
0
C(O)NR'
0
CN,
NO
2
(R'
0 2
N-C(NR
1 0
R'
0
R'
0
N
3
-N(R'
0 2 or R' 'OC(O)NR' 0 and d) C I-C 6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C 3
-CI
0 cycloalkyl; R 4 b and R 7 b are hydrogen; R .R 6 is independently seetdfrom hyrgnor CI-C6 alkyl; R 8 is independently selected from: i a) hydrogen, b) C 1
-C
6 alkyl, C 2
-C
6 alkenyl, C 2
-C
6 alkynyl, C 1
-C
6 perfluoroalkyl, F, Cl, R' 0 0-, R C(O)NR CN, NO 2
(R'
0 2
N-C(NR'
0
R'
0
R'
0
N(R'
0 2 or
R''OC(O)NR'
0 and C) C I-C 6 alkyl substituted by C I-C 6 perfluoroalkyl, R1 R R 10 or [R \LIBA]02565.doc:TLT WO 96/3 1525 PCTIUS96/03974 38 R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, ClI-C6 perfluoroalkyl, F, Cl, RIO0-, RIIS(O)m-, RIOC(O)NRl0-, CN, N02, (R'Q)2N- C(NRIO)-, RIOC(O)-, RIOOC(O)-, -N(RlO) 2 or R I'IOC(O)NRl10, and C) C I -C6 alkyl unsubstituted or substituted by C I -C6 perfluoroalkyl, F, Cl, R 1 0 RI 1 R IOC(O)NR CN, (R I 0 )2N-C(NR R I Ri I -N(R 10)2, or RIlOC(O)NR1O.; R 1 0 is independently selected from hydrogen, C I-C6 alkyl, benzyl and aryl; R 1 1 is independently selected from C I-C6 alkyl and aryl; Q is selected from: and-
A
1 I and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR 10-, 0, -N(R or S (O)m; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2 -oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C,-C 2 o alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from 0, S, and N, and e) C 2
-C
2 o alkenyl, and s provided that V is not hydrogen if A' is and V is not hydrogen if A' is a bond, n is 0 and A 2 is S(O) 1 W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2 -oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; X, Y and Z are independently
H
2 or 0; mnis 0,l1or 2; n is 0,1, 2 3or 4; p is 0,1, 2 3or 4; q is 0,l1or 2; r is 0 to 5, provided that r is 0 when V is hydrogen; t is 3 4 or u uis 0Oorl1; a 4or the pharmaceutically acceptable salts thereof.
a~a:Another aspect of the invention provides a compound of the formula 1: 8R 5 a R 5 b (Rr
R
9 6 y z
OH
I. I a 2 a j I IlIb R N V-A (CR' 2 )nA (CR' 2)n- W (CR N
IH
R
2
R
x
Q
a a la* 4a R a 5 a 7 0 1 wherein
R
1 Rb R 2 R R 4 R~b R~ R~b R 6 ,R~a R~b R, R' 0 R' Q,
A
2 V, W, X, Y, Z, mn, n, p, r, t and u are as defined in pages 22-26 above, and R 8 is independently selected from C 1
-C
6 alkyl substituted by RiuC(O)NRO-, (R1 0) 2
N-
C(NR'
0 or R"OC(O)NRO.
Another aspect of the present invention provides a compound of the formula 11: [R:\LIBA]02565. d0c:TLT [R \LIB A] 02565 dcc TLT R I I R'6 Y zOR 1 2 I laCR' alb) R N V- 2),-W 2 A(CR 2)p
N
6
H~
II N 0 II 4 a6
R~
wherein b,R, R 3
,R
4 R~b R 5 Rsb R, R 7 R~ R 9 R1 0 ,R1 1 ,R R, R' 3
R'Q
A' 2, V, W, X, Y, Z, mn, n, p, r, t and u are as defined in pages 27-31 above, and R8is independently selected from C 1
-C
6 alkyl substituted by RiOC(O)NRiO-,
(R'
0 2
N-
C(NR'
0 orRiiOC(O)NRO.
A further aspect of the present invention provides a compound of the formula
III:
FIOCH
2
(CH
2 )q :9 )Y O H I la )a N Z N %V-A (CR
_W~A(R~
2 (CR lbp
NR
(CR N 0 x 2R 4b wherein R la R Ib, R 2 R 3 R 4 a R 4 b, R 6
R
7 a, R 7 b, R 9 Rio, R 11, Q, A 2 V WXyZ, m, n, p, q, r, t and u are as defined in pages 32-3 5 above, and o R8 is independently selected from C 1
-C
6 alkyl substituted by RiOC(O)NRio-,
(R'
0 2
N-
C(NR'
0 or RiiOC(O)NRiK- J:1 9 *9A still further aspect of the present invention provides a compound o h oml V *q 9 9 RR~ Rb
R
6 Y Z N0 I I aN ux
R
Q9 ~ivR 4 a ROb wherein R, Rib R, R 3 R R~b R R 7 R, R 9 RI,RQAAVWXyZ, mn, n, p, q, r, t and u are as defined in pages 36-39 above, and [R.ULBA02565.doc:TLT 3 9b
R
8 is independently selected from CI-C 6 alkyl substituted by R' 0 C(O)NR', 10 0)N C(N'O-,or R" OC(O)NR' 0 The preferred compounds of this invention are as follows: N- lHimidazol-4ylacetyl-2(S)-amino-3 (S)-methylpentyl] 1,2,3 4 -tetrahydro-3 isoquinolinecarbonyl-methionine methyl ester N- H-imidazol-4ylacetyp2(S)-arino-3(S)-methylpentyl] -1,2,3 ,4-tetrahydro-3 isoquinolinecarbonyl-methionine N- [L-Pyroglutamyl.2(S)-amino-3(S)-methylpentyl] 1,2,3 ,4-tetrahydro-3 isoquinolinecarbonyl-methionine methyl ester N-[L-Pyroglutamyl2(S)-amino-3(S)-methylpentyl] 1,2,3 ,4-tetrahydro-3(S)isoquinolinecarbonylrnethionine go 0 so
%:S
[R:'IBA]02565.doc:TLT WO096/31525 PCTIUS96/03974 N- iiao-4ypoiny)2S-mio3S-etypny1,2,3,4tetrahydro-3 (S)-isoquinolinecarbonylmetioin methyl ester N- H-imidazol-4-ylpropionyl)2(S)-arino-.
3 (S)-methylpentyl]- 1,2,374tetrahydro-3 (S)-isoquinolinecarbonylrnethionine N- [(1-(4-cyanobenzyl)-lHiia1l5y aeyl-()-mn-(S)methylpentyl]- 1,2,34-tetrahydro-3 (S)-isoquinolinecarbonyl methionine methyl. ester N- 4 -cyanobenzyl)- 1H-imidazol-5-yl)acetyl]y2(Sy..aflio3 methylpentyl]- 1 2 ,34-tetrahydro-3 (S)-isoquinolinecarbonyI methionine N-[N -ynbezl--yrguay 2S-mn-(S)-methylpentyl] 1,2,3 ,4-tetrahydro-3 (S)-isoquinolinecarbonylpmethiorjne methyl. ester N-[N -ynbezl--yrguay 2S-mn-(S)-methylpentyl] 1,2,3 ,4-tetrahydro-3 (S)-isoquinolinecarbonyl-methiopjne or the pharmaceutically acceptable salts or optical isomer thereof.
Specific examples of compounds of the invention are: N- [L-Pyroglutamyl-2(S)-anmjno-3(S)-methylpentyl]- 1,2,3 ,4-tetrahydro- 3 (S)-isoquinolinecarbonyl..methionine
SCH
3 0 VH OH N
N
H 0 WO 96/31525 PCTIUS96/039 7 4 -41- N- [L-Pyroglutamyl.2(S).amj 110 3 (S)-methylpentylj.. 1,2,3 ,4-tetrahydro- 3 (S)-isoquinolinecarbonyl..retfionine methyl ester
SCH
3 H H-
OCH
3 0\ HN
N
or the pharmaceutically acceptable salts or optical isomer thereof.
In the present invention, the amino acids which are disclosed are identified both by conventional 3 letter and single letter abbreviations as indicated below: Alanine Ala
A
Arginine Arg
R
Asparagmne Asn
N
Aspartic acid Asp
D
Asparagine or Aspartic acid Asx
B
Cysteine Cys
C
Glutamine Gln
Q
Glutamic acid Glu
E
Glutamine or Glutamic acid Glx
Z
Glycine Gly
G
Histidine His
H
Isoleucine Ile
I
Leucine Leu
L
WO 96/31525 PCT/US96/03 9 7 4 -42- Lysine Lys
K
Methionine Met
M
Phenylalanine Phe
F
Proline Pro p Serine Ser
S
Threonine Thr
T
Tryptophan Trp
W
Tyrosine Tyr
Y
Valine Val
V
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.
As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
As used herein, "cycloalkyl" is intended to include nonaromatic 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.
Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl, 2-butenyl, 2 -methyl-2-butenyl, isoprenyl, famesyl, geranyl, geranylgeranyl and the like.
As used herein, "aryl" is intended to include any stable monocyclic, bicyclic or tricyclic carbon ring(s) of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of aryl groups include phenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl, phenanthrenyl and the like.
1___11 WO 96/31525 PCT/US96/0397 4 -43- The term heterocycle or heterocyclic, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11membered bicyclic or stable 11-15 membered tricyclic heterocycle 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, 0, 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. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2 -oxoazepinyl, 2 -oxopiperazinyl, 2-oxopiperidinyl, 2 -oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyridyl N-oxide, pyridonyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolinyl N-oxide, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydro-quinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.
As used herein, the terms "substituted aryl", "substituted heterocycle" and "substituted cycloalkyl" are intended to include the cyclic group which is substituted with 1 or 2 substitutents selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(Cl- C6 alkyl)2, N02, CN, (C1-C6 alkyl)O-, -OH, (Cl-C6 alkyl)S(O)m-, (Cl- C6 alkyl)C(O)NH-, H2N-C(NH)-, (C1 -C6 alkyl)C(O)-, (C1 -C6 alkyl)OC(O)-, N3,(C1-C6 alkyl)OC(O)NH- and C1-C20 alkyl.
WO 96/31525 PCTIUS96/0397 4 -44- The following structure:
H
2 )t represents a cyclic amine moiety having 5 or 6 members in the ring, such a cyclic amine which may be optionally fused to a phenyl or cyclohexyl ring. Examples of such a cyclic amine moiety include, but are not limited to, the following specific structures: N c"r' It is also understood that substitution on the cyclic amine moiety by R8a and R8b may be on different carbon atoms or on the same carbon atom.
When
R
3 and R 4 are combined to form (CH2)s cyclic moieties are formed. Examples of such cyclic moieties include, but are not limited to: 0 cii When R5a and R5b are combined to form (CH2)s cyclic moieties as described hereinabove for R 3 and R 4 are formed. In addition, such cyclic moieties may optionally include a heteroatom(s). Examples of such heteroatom-containing cyclic moieties include, but are not limited to:
I
WO 96/31525 PCT/US96/039 74 0 O- 7
S
HN\
Sl
H
<'1 N As used herein, the phrase "nitrogen containing C6-C9 bicyclic ring system wherein the non-nitrogen containing ring is selected from an aromatic ring and a heterocycle" which defines moiety of the instant invention includes but is not limited to the following ring systems:
N
It is well understood by persons of ordinary skill in the art that the "side chain" of the naturally occurring amino acid glycine is a hydrogen moiety.
The pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds WO 96/31525 PCT/US96/03974 -46of this invention as formed, from non-toxic inorganic or organic acids. For example, 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.
It is intended that the definition of any substituent or variable R10, Z, n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, -N(R10)2 represents -NHH, -NHCH3, -NHC2H5, etc. It is understood that 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 readily synthesized by techniques known in the art as well as those methods set forth below.
Preferably, Rla and Rib are independently selected from: hydrogen,
-N(R
8
R
8
C(O)NR
8 or C1-C6 alkyl unsubstituted or substituted by -N(R 8
R
8 0- or R 8 C(O)NR8-.
Preferably,
R
2 is the sidechain of glycine (hydrogen).
Preferably,
R
3 is selected from: a) a side chain of a naturally occurring amino acid, b) substituted or unsubstituted C1-C20 alkyl, wherein the substituent is selected from F, Cl, Br, N(R1 0 N02, R 10 R11S(O)m-, R1OC(O)NR10., CN, (R1 0 )2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, R11OC(O)NR10-and C1-C20 alkyl, and c) C 1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3cycloalkyl; or R3 is combined with R 6 to form pyrrolidinyl ring.
Preferably, R4a, R4b, R7a and R7b are independently selected from: hydrogen, C -C6 alkyl, aryl and benzyl.
WO 96/31525 PCT/US96/039 7 4 -47- Preferably,
R
5 a and R5b are independently selected from: a side chain of a naturally occurring amino acid, methionine sulfoxide, methionine sulfone and unsubstituted or substituted C1-C6 alkyl Preferably, R6 is: hydrogen or is combined with R 3 to form pyrrolidinyl ring.
Preferably, R8 is selected from: hydrogen, perfluoroalkyl,
F,
C1, Br, R 10
R
1 1 CN, N02, R102N-C(NR10)-,
R
10
R
10 N3, -N(R10)2, or R 11C(O)NR10- and C1-C6 alkyl.
Preferably,
R
9 is hydrogen.
Preferably, R10 is selected from H, C1-C6 alkyl and benzyl.
Preferably,
R
12 is selected from C1-C6 alkyl and benzyl.
Preferably, Al and A 2 are independently selected from: a bond, -C(0)NR10-, -NRO1C(O)-, 0, -S(0)2N(RO1)- and- N(R10)S(0)2-.
Preferably, Q is a tetrahydroisoquinolinyl moiety.
Preferably, V is selected from hydrogen, heterocycle and aryl.
Preferably, n, p and r are independently 0, 1, or 2.
Preferably t is 3.
The pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety conventional chemical methods. Generally, the salts are prepared 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.
The compounds of the invention can be synthesized from their constituent amino acids by conventional peptide synthesis techniques, and the additional methods described below. Standard methods of peptide synthesis are disclosed, for example, in the following works: Schroeder et al., "The Peptides", Vol. I, Academic Press 1965, or Bodanszky et al., "Peptide Synthesis", Interscience Publishers, 1966, or McOmie "Protective Groups in Organic Chemistry", Plenum Press, 1973, or Barany et al., "The Peptides: Analysis, Synthesis, Biology" 2, WO 96/31525 PCT/US96/0397 4 -48- Chapter 1, Academic Press, 1980, or Stewart et al., "Solid Phase Peptide Synthesis", Second Edition, Pierce Chemical Company, 1984. The teachings of these works are hereby incorporated by reference.
Abbreviations used in the description of the chemistry and in the Examples that follow are: Boc
DBU
DMAP
DME
DMF
EDC
HOBT
Et3N EtOAc
FAB
HOOBT
HPLC
MCPBA
MsC1 NaHMDS Py
TFA
THF
Acetic anhydride; t-Butoxycarbonyl; 1,8-diazabicyclo[5.
4 .0]undec-7-ene; 4 -Dimethylaminopyridine; 1, 2 -Dimethoxyethane; Dimethylformamide; 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimidehydrochloride; 1-Hydroxybenzotriazole hydrate; Triethylamine; Ethyl acetate; Fast atom bombardment; 3-Hydroxy-1, 2 2 -benzotriazin-4(3H)-one; High-performance liquid chromatography; m-Chloroperoxybenzoic acid; Methanesulfonyl chloride; Sodium bis(trimethylsilyl)amide; Pyridine; Trifluoroacetic acid; Tetrahydrofuran.
Compounds of this invention are prepared by employing the reactions shown in the following Reaction Schemes A-J, 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. Some key bond-forming and peptide modifying reactions are: WO 96/31525 PCT/US96/03974 -49- Reaction A Reaction B Amide bond formation and protecting group cleavage using standard solution or solid phase methodologies.
Preparation of a reduced peptide subunit by reductive alkylation of an amine by an aldehyde using sodium cyanoborohydride or other reducing agents.
Reaction C Deprotection of the reduced peptide subunit Reaction D Reaction E Peptide bond formation and protecting group cleavage using standard solution or solid phase methodologies.
Preparation of a reduced subunit by borane reduction of the amide moiety.
Reaction Schemes A-E illustrate bond-forming and peptide modifying reactions incorporating acyclic peptide units. It is well understood that such reactions are equally useful when the NHC(RA) moiety of the reagents and compounds illustrated is replaced with the following moiety:
^-K
R
7 b R7a These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the reactions described in the Reaction Schemes.
M-
W0 96/31525 PCTIUS96/03974 50 REACTION SCHEME A Reaction A. Coupling-of residues to form an amide bond 0 RA C0 2
R
00 EDO, HOBT or HOOBT
EI
3 N, DMF HCI or
TEA
H
0 R 4 b R 4 b WO 96/3 1525 PCTfUS96/0397 4 -51- REACTION SCHEME
B
Reaction B. preparation of reduced peptide subunits by reductive alkylation 0O R A C0 2
R
0 N H H 0
(Q
Xi R 4b NaCNBH, 3 H C0 2
R
R
4 b REACTION SCHEME
C
Reaction C. Deprotection of reduced eptide subunits H C0 2
R
Y
0 R 4 a, TFA or
R
4 b HCI C0 2
R
Q
R
4 b R4a, WO 96/3 1525 PCTIUS96/039 7 4 52 REACTION SCHEME?%4
D-
Reaction D. CoupIingy of residues to orm an amide bond
H
2 N 0 0 EDC, HOBT or HOOBT Et 3 N, DMF R 4 b HOI or TEA R 4 w WO 96/31525 PCT/US96/03974 -53- REACTION SCHEME E Reaction E. Preparation of reduced dipeptides from peptides 0
BH
3
THF
R
4 b
CO
2
R
R
4 b where RA is R 2
R
3 R5a or R5b as previously defined; R4a and R4b are as previously defined; and R is an appropriate protecting group for the carboxylic acid.
Reaction Schemes F M illustrate reactions wherein the nonsulfhydryl-containing moiety at the N-terminus of the compounds of the instant invention is attached to an acyclic peptide unit which may be further elaborated to provide the instant compounds. It is well understood that such reactions are equally useful when the NHC(RA) moiety of the reagents and compounds illustrated is replaced with the following moiety:
R
7 b WO 96/31525 PCT/US96/03974 -54- These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the reactions described in Reaction Schemes A E.
The intermediates whose synthesis are illustrated in Reaction Schemes A and C can be reductively alkylated with a variety of aldehydes, such as I, as shown in Reaction Scheme F. The aldehydes can be prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses, 1988, 67, 69-75, from the appropriate amino acid (Reaction Scheme The reductive alkylation can be accomplished at pH 5-7 with a variety of reducing agents, such as sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent such as dichloroethane, methanol or dimethylformamide. The product II can be deprotected to give the final compounds III with trifluoroacetic acid in methylene chloride. The final product III is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others. The product diamine I can further be selectively protected to obtain IV, which can subsequently be reductively alkylated with a second aldehyde to obtain V. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole VII can be accomplished by literature procedures.
Alternatively, the protected dipeptidyl analog intermediate can be reductively alkylated with other aldehydes such as 1-trityl-4carboxaldehyde or 1-trityl-4-imidazolylacetaldehyde, to give products such as VIII (Reaction Scheme The trityl protecting group can be removed from VIII to give IX, or alternatively, Vm can first be treated with an alkyl halide then subsequently deprotected to give the alkylated imidazole X. Alternatively, the dipeptidyl analog intermediate can be acylated or sulfonylated by standard techniques.
The imidazole acetic acid XI can be converted to the acetate XII by standard procedures, and XIII can be first reacted with an alkyl halide, then treated with refluxing methanol to provide the regiospecifically alkylated imidazole acetic acid ester XIV. Hydrolysis and reaction with the protected dipeptidyl analog intermediate in the 1 WO 96/31525 PCT/US96/03974 55 presence of condensing reagents such as l-(3-dimethylaminopropyl)-3ethylcarbodiimide (EDC) leads to acylated products such as XV.
If the protected dipeptidyl analog intermediate is reductively alkylated with an aldehyde which also has a protected hydroxyl group, such as XVI in Reaction Scheme I, the protecting groups can be subsequently removed to unmask the hydroxyl group (Reaction Schemes I, 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 Grignard reagents, to obtain secondary alcohols such as XX. In addition, the fully deprotected amino alcohol XXI can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXII (Reaction Scheme or tertiary amines.
The Boc protected amino alcohol XVIII can also be utilized to synthesize 2 -aziridinylmethylpiperazines such as XXIII (Reaction Scheme Treating XVIII with 1,1 '-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine XXIII. The aziridine reacted in the presence of a nucleophile, such as a thiol, in the presence of base to yield the ring-opened product
XXIV.
In addition, the protected dipeptidyl analog intermediate can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as XXX, as shown in Reaction Scheme M. When R' is an aryl group, XXX can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XXXI. Alternatively, the amine protecting group in XXX can be removed, and O-alkylated phenolic amines such as XXXII produced.
Similar procedures as are illustrated in Reaction Schemes F- M may be employed using other peptidyl analog intermediates such as those whose synthesis is illustrated in Reaction Schemes B E.
Reaction Schemes N-R illustrate syntheses of suitably substituted aldehydes useful in the syntheses of the instant compounds wherein the variable W is present as a pyridyl moiety. Similar synthetic C~I_ I~~ WO 96/31525 PCTJLJS96/03974 -56strategies for preparing alkanols that incorporate other heterocyclic moieties for variable W are also well known in the art.
WO 96/31525 PCT/US96/0397 4 57 REACTION SCHEME
F
y B
H
2 N C0 2
RB
RA
Q
4 b Et 3 NHBoc H y Boc NH/- 0 2
R
RA
Q
NH
2 Ra:
R
4 b
NH
2 NC 2 RA
Q
III b T-,H C0 2
R
BocNH NA j oc NHI
I
oc NH
CHO
NaBH(OAc)3 N CICH 2
CH
2
CI
CF
3 00 2
H
CH
2
CI
2
BOC
2 0
CH
2
CI
2 cx:O
HO
NaBH(OAc)3 Et 3 N CICH 2
CH
2
CI
RA
IV
R 4 b WO 96/31525 PCT/US96/03974 58 REACTION SCHEME F (continued)
H
BocNH/
H
NH 2
N
CF
3 00 2 H, CH 2 Ci 2 NaHCO 3 R 4 b
->NC
AgON IR 4 b WO096/31525 PCTIUS96/0397 4 59 REACTION SCHEME G y
H
2
N
R
A
IC0 2
R
R 4 b H y CO
F
NR A Q N R
F
+r Vill NaBH(OAc) 3
EI
3 N CICH- 2
CHPC
(CH
2 )nCHO
N
Tr t4b 1) Ar CHAX CH 3
CN
2) CF 3 C0 2 H, 0H 2 C1 2
(C
2
H
5 3 SiH C0 2 H, C~-
(C
2
H
5 3 SiH H y
(CH
2 nJL N 4 H IxR
ICO
2
R
R 4 b N
(N
-R 4 b WO 96/3 1525 PCT/US96/039 7 4 REACTION SCHEME
H
N HC2
CH
3 0H N CH 2
CO
2
CH
3 NHCI
N
H H H01 AI X~i
(C
6
H
5 3 CBr N CH 2 0 2
CH
3 1) ArCH 2 X CHCN ____reflux
(C
2
H
5 3 N N 2) CH 3 OH, reflux DMF +r xiII Ar\NS
CH
2
CO
2
CH
3
N
2.5N HClaq 550C
XIV
CH
2 C0 2
H
'.WO 96/31525 PCTfUS96/03974 -61 REACTION SCHEME
I
NSCH
2 00 2
H
N
ROb EDO HCI HOBt
DMF
R 4 b WO096/31525 PCTIUS96/0397 4 62 REACTION SCHEME
J
y HAN C0 2
R
R A
Q
R 4a; Q R 4 b NaBH(OAc),
EI.
3 N, CICH,CH 2 Cl BnO BocNHICHO NHBoc BnO/-- C0 2 R 20% Pd(OH) 2
H
2 BOH
CH
3
O
Q
CH
3
CO
2
H
XVII 4b NHBoc HO
N
XVIRA
CICOCOCI
DMSO
CH
2
CI
2
(C
2
H
5 3
N
ROb WO096/31525 PCT1US96/03974 63 REACTION SCHEME J (C--ONTINUED) H NHBoc y C0 2
R
R Q XIX R 4;Q
R
4 b 1. R'MgX
(C
2
H
5 2 0 2. TEA, CH 2
CI
2
HO
R
4 a,
I
WO 96/31525 PCT/US96/03974 -64- REACTION SCHEME
K
NHBoc HO
N
H
XVIII
CF
3
CO
2
H
CH
2 Ci 2 R 4 b
.NH
2
HO
ROCHO
NaBH(OAc) 3
CICH
2
CH
2
CI
R 4 b
R'CH
2 NH y CO
R
HO
H;
R
Q
XXII R 4;Q R 4 b WO 96/3 1525 PCTIUS96/03974 65 REACTION SCHEME
L
NHBoc HO N
F
xviII H
H
,R N
,-N
NS
R
4 b NaH, DMFQ 0
OC
IC0 2
R
R'SH
(C
2
H
5 3
NA
CH
3 0H XXIII
XXIV
R 4 b WO 96/31525 PCTIUS96/03974 66 REACTION
SCHEMEM
HO
io
H
2 N C0 2
H
1) Boc 2 O, K 2 C0 3 TH F-H 2 0 2) CH 2
N
2 EtOAc
HO
BocNH C0 2 0H 3 xxv xxvi
LIAIH
4
THF
0-200C
R'CH
2
X
CS
2 00 3
DMF
BocNH' 'OH20 xxvi"
R'CH
2 0 BocNH
CH
2 0H xxv"'l pyridine SO
DMSO
(C
2
H
5 3
N
0
C
R'CH
2 0 BocNH CHO xxix WO 96/3 1525 PCT/US96/03974 67 REACTION SCHEME M (continued)
R'CH
2 O 0 BocNH
CHO
H
2
N
XXIX
NaBH(OAC) 3
CICH
2
CH
2
CI
R 4 a 1) 20% Pd(OH) 2
CH
3 OH, CH 3 00 2
H
HCI EtOAc 2) HO!, EtOAc R 4 b WO 96/3 1525 PCTIUS96/03974 68 REACTION SCHEME N
CH
3
H
2 N- N 1) HNO 2 ,Br 2 2) KMnO 4 3) MeOH,H+ 00 2
CH
3 Br' N I MgCI -C0 2
CH
3 ZnC1 2 NiCI 2 (Ph 3
P)
2 NaBH 4 (excess)
SO
3 'Py, Et 3
N
CHO
~I N DMS0 WO 96/31525 PCTIUS96/03974 69 REACTION SCHEME
P
R
6
N'
MgCI 00 2 0H 3
CNI
Zn, CuCN NaBH 4 (excess)
R
6
SO
3 'Py, Et 3
N
SCH
2 0H DMSO
N'
13 I' MgCI ZnCI 2 NiCI 2 (PhP) 2 NaBH 4 (excess) SOTPY, Et 3
N
DMSO
I WO096/31525 PCTIUS96/03974 REACTION SCHEME 0 qO 2
CH
3
N
R
6 C-rMgCI 1. LDA, 002 2. Me0H, H+ ZnCI 2 NiCI 2 (Ph 3
P)
2 NaBH 4 (excess) S0 3 'Py, Et 3
N
DMSO
WO 96/3 1525 PCTIUS96/03974 -71- REACTION SCHEME
R
N Br 1. LDA, C0 2 2. (CH 3 3 SiCHN 2 C0 2
CH
3 Br R. Br Zn, NiCI 2 (Ph 3
P)
2 N~ C0 2
CH
3 excess NaBH 4 N~
CH
2 0H
SO
3 'Py, Et 3
N
DMSO
CHO
WO 96/31525 PCT/US96/03974 -72- 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 formation neurofibromin (NF-1), neu, scr, ab1, Ick, fyn) or by other mechanisms.
The compounds of the instant invention inhibit farnesylprotein transferase and the farnesylation of the oncogene protein Ras.
The instant compounds may also inhibit tumor angiogenesis, thereby affecting the growth of tumors Rak et al. Cancer Research, 55:4575- 4580 (1995)). 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 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. For example, 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 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 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 Schaffner et al.
WO 96/31525 PCT/US96/03974 -73- American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al.FASEB Journal, 2:A3160 (1988)).
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 parepterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
For oral use of a chemotherapeutic compound according to this invention, the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When 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. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled in order to render the preparation isotonic.
The present invention also encompasses a pharmaceutical composition useful in the treatment of cancer, comprising the administration of a therapeutically effective amount of the compounds of this invention, with or without pharmaceutically acceptable carriers or diluents. Suitable compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacologically acceptable carriers, saline, at a pH level, 7.4. The solutions may be introduced into a patient's intramuscular blood-stream by local bolus injection.
WO 96131525 PCT/US96/0397 4 -74- When a compound according to this invention is administered into a human subject, 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.
In one exemplary application, 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 20 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 10 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.
Thus the composition to be tested may be divided and the two portions contacted with 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. After the assay mixtures are incubated for an sufficient period of time, well known in the art, to allow the FPTase to farnesylate the substrate, the chemical content of the assay mixtures may be determined by well known immunological, radiochemical or chromatographic techniques. Because the compounds of the instant invention are selective 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.
It would be readily apparent to one of ordinary skill in the art that such an assay as described above would be useful in identifying tissue samples which contain famesyl-protein transferase and quantitating the enzyme. Thus, 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
I
WO 96/31525 PCT/US96/03974 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. The concentration of a sufficiently potent inhibitor one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel) required to inhibit the enzymatic activity of the sample by is approximately equal to half of the concentration of the enzyme in that particular sample.
EXAMPLES
Examples provided are intended to assist in a further understanding of the invention. Particular materials employed, species and conditions are intended to be further illustrative of the invention and not limitative of the reasonable scope thereof.
The standard workup referred to in the examples refers to solvent extraction and washing the organic solution with 10% citric acid, 10% sodium bicarbonate and brine as appropriate. Solutions were dried over sodium sulfate and evaporated in vacuo on a rotary evaporator.
EXAMPLE 1 Preparation of N-[(lH-imidazol-4-ylacetyl-2(S)-amino)-3(S)methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester and N-[(1H-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]-1,2,3,4tetrahdro-3(S)-isouinolinecarbonl-methionine trifluoroacetate Step A: N-(t-Butoxvcarbonvl)-isoleucinal This compound was synthesized by applying the procedure of Goel, Krolls, Stier, and Kesten [Organic Syntheses, 67, 69 (1988)] to N-(t-butoxycarbonyl-isoleucine. The compound was obtained as a colorless oil, which was used without purification.
WO096/31525 PCTIUS96/0397 4 76 Step B: N- 2 S)-(t-Butyloxycarbonylamino)-3(S)-methylpentyy..
1,2,3,4ttayr-3S sqiolncroyi acid benzyl ester.
N-tBtlxcronl-sluia (1.5 g, 0.0070 mol) and 1,2,3,4ttay o3S-sounlncroyi acid benzyl ester (2.23 g, 0.0084 MOl) were dissolved in MeOH (30 mL) at ambient temperature under nitrogen and treated with 3A molecular sieves (3 g) and sodium cyanoborohydride (0.66 g, 0.0 105 mol) with stirring. After 18 h the mixture was filtered, concentrated, and the residue was partitioned between EtOAc (50 miL) and satd aq NaHCO3 solution (50 mL). The basic layer was washed with EtOAc (3 x 30 mL), the organics combined, washed with brine, and dried (Na2SO4). Filtration and concentration to dryness gave the title compound as a colorless oil after chromatography (SiO2, hexane: EtOAc, lH NMR (CDCl3) 67.02-7.35(in, 9H), 5.11 2H), 4.6-4.78 (in, 1H), 3.98 2H), 3.84 1H, J=5 Hz), 3.64- 3.75 (mn, I1H), 3.05-3.27 (mn, 2H), 2.84 (dd, IlH, J=5, 13 Hz), 2.59 (dd, I1H, 13 Hz), 1.70-1.82 (in, 1H), 1.40 9H), 1.26-1.37 (in, 1H), 0.97- 1. 13 (in, 1H), 0.92 3H, J=7 Hz), 0.86 3H, J= 7 Hz).
Step C: N- 2 S)-(t-Butyloxycarbonylamjino).3 (S)-inethylpentyl..
1.2.3 .4-tetrahvdro-3(S -isoguinlolinecarboxylic acid N- 2 S)-(t-Butyloxycarbonylanino).3 (S)-inethylpentyl).
1,,,-erhdo3S-iounlncroyi acid benzyl ester (1.5 9, 0.0032 mol) was dissolved in methanol (50 inL) EtOAc (50 mL), treated with 10% palladium on carbon 15 g) and hydrogenated under a balloon of hydrogen for 4 h. Filtration and concentration to dryness gave the title compound as a white solid which was used without further purification.
Step D: N- 2 (S)-(t-ButyloxycarbonylanAno-3(S)-methylpentyl] 1,2,3 ,4-tetrahydro-3 (S)-isoquinolinecarbonyl-methionine methyl ester N- 2 S)-(t-Butyloxycarbonylan-ino.3 (S)-inethylpentyl)- 1,2,3 ,4-tetrahydro-3 (S)-isoquinolinecarboxylic acid (0.67 g, 0.00178 inol) WO 96/31525 PCT/US96/03974 -77was dissolved in DMF (10 mL) with stirring at ambient temperature and treated with EDC (0.376 g, 0.00196 mol), HOBT (0.265 g, 0.00196 mol), and methionine methyl ester hydrochloride (0.427 g, 0.00214 mol). The pH was adjusted to 7 with Et3N (0.546 mL, 0.00392 mol) and stirring was continued for 18 h. The reaction mixture was concentrated, then partitioned between EtOAc (50 mL) H20 (50 mL). The aq layer was washed with EtOAc (2 x 30 mL), the organics combined, washed with aq satd NaHCO3 solution, brine, and dried (Na2SO4). Filtration and concentration gave the title compound after chromatography (Si02, CH2C12: MeOH, 99.5:0.5). IH NMR (CD30D) 87.05-7.2 4H), 4.43-4.52 1H), 3.98 1H, J=13 Hz), 3.68-3.82 2H), 4.87 (s, 3H), 3.55 1H, J=6 Hz), 2.96-3.14 2H), 2.84 (dd, 1H, J= 5, 13 Hz), 2.70 (dd, 1H, J= 5,13 Hz), 1.88-2.14 2H), 1.95 3H), 1.
3 2 -1.57(m, 2H), 1.41 9H), 1.06-1.25 1H), 0.84-0.96 6H).
Step
E
N-[2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)isoquinolinecarbonyl-methionine methyl ester HC1 gas was bubbled into a solution of butyloxycarbonylamino-3(S)-methylpentyl]- 1,2,3,4-tetrahydro-3(S)isoquinolinecarbonyl-methionine methyl ester (0.37 g, 0.71 mmol) in EtOAc (25 mL) with stirring at -20oC over 0.5 h. The solution was purged with argon for 0.5 h, then concentrated to give the title compound as a white solid which was used without further purification.
Step F: N-[(1H-imidazol-4-ylacetyl-2(S)-amino)-3(S)methylpentyl]-l,2,3, 4 -tetrahydro-3(S)-isoquinolinecarbonylmethionine methyl ester trifluoroacetate 1H-Imidazol-4-ylacetic acid (0.18 g, 1.11 mmol) was dissolved in DMF (10 mL) and treated with EDC (0.213 g, 1.11 mmol), HOBT (0.15 g, 1.11 mmol), and N-[ 2 (S)-amino-3(S)-methylpentyl]- 1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester (0.275 g, 0.556 mmol) with stirring at ambient temperature. Et3N (0.618 mL, 4.44 mol) was added to bring the pH of the solution to 8, and stirring was continued for 16 h. The reaction mixture was concentrated to WO 96/31525 PCT/US96/03974 -78remove the DMF, and the residue was partitioned between EtOAc mL) and H20 (30 mL). The aqueous layer was washed with EtOAc (3 x mL), the organics combined, washed with brine and dried (Na2SO4).
Filtration and concentration to dryness gave the title compound after preparative reverse phase chromatography (CH3CN: H20 gradient). 1H NMR (CD30D) 8.48 1H), 7.07 1H), 6.92-7.04 4H), 4.29 (d, 1H, J= 14 Hz), 4.0-4.15 3H), 3.85-3.9 1H), 3.45 (ABq, 2H), 3.35 3H), 2.9 3.2 4H), 2.05-2.2 2H), 1.72 3H), 1.55-1.7 (m, 2H), 1.2-1.35 1H), 1.1 1.20 1H), 0.8-0.9 1H), 0.55 0.6 (m, 6H). FAB MS 530 (M 1).
Step G: N-[(1H-imidazol-4-ylacetyl)-2(S)-amino-3(S)methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonylmethionine trifluoroacetate N-[(1H-imidazol-4-ylacetyl-2(S)-amino)-3(S)methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester (0.037 g, 0.049 mmol) was dissolved in CH30H (2 mL) in an ice-H20 bath and treated with In NaOH (0.195 mL, 0.195 mmol) with stirring. After 3 h the reaction mixture was neutralized with IN HCI (0.195 mL, 0.195 mmol), then chromatographed on a preparative VYDAC reverse phase column, eluting with 0.1% TFA, H20: 0.1% TFA, CH3CN 95:5 to 5:95 gradient to give the title compound. 1H NMR (CD30D) 8 8.81 1H), 7.42 1H), 7.2-7.4 4H), 4.52 1H, J= 14 Hz), 4.25-4.45 3H), 4.15-4.25 1H), 3.80 (ABq, 2H), 3.25 3.5 2H), 2.3-2.5 2H), 2.05 3H), 2.03 2.15 1H), 1.9-2.0 1H), 1.57 1.7 1H), 1.42 -1.55 1H), 1.1 1.23 1H), 0.9 6H). FAB MS 516 (M 1).
Using the methods outlined above, the following compounds are prepared: N-[(1H-imidazol-4-ylpropionyl)-2(S)-amino-3(S)-methylpentyl]-1,2,3,4tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester WO 96/31525 PCT/US96/03974 -79- H-imidazol-4-ylpropionyl)-2(S)-amino-3(S)-methylpentyl]-1,2,3,4tetrahydro-3(S)-isoquinolinecarbonyl-methionine EXAMPLE 2 Preparation of N-[(1-(4-Cyanobenzyl)-1 H-imidazol-5-yl)acetyl]-2(S)amino-3(S)-methylpentyl]- 1,2,34-tetrahydro-3(S)-isoquinolinecarbonyl methionine methyl ester and N-[(1-(4-Cyanobenzyl)-1H-imidazol-5-yl)acetyl-2(S)-amino-3(S)methylpentyll- 1 .2.34-tetrahdro-3(S)-isoquinolinecarbonvyl methionine Step A: 1H-Imidazole-4- acetic acid methyl ester hydrochloride A solution of 1H-imidazole-4-acetic acid hydrochloride (4.00g, 24.6 mmol) in methanol (100 ml) was saturated with gaseous hydrogen chloride. The resulting solution was allowed to stand at room temperature (RT) for 18hr. The solvent was evaporated in vacuo to afford the title compound as a white solid.
1 H NMR(CDCl3, 400 MHz) 8 8.85(1H, s),7.45(1H, 3.89(2H, s) and 3.75(3H, s) ppm.
Step B: 1-(Triphenylmethyl)- 1H-imidazol-4-ylacetic acid methyl ester To a solution of 1H-imidazole-4- acetic acid methyl ester hydrochloride 2 4 .85g, 0.141mol) in dimethyl formamide (DMF) (115ml) was added triethylamine (57.2 ml, 0.412mol) and triphenylmethyl bromide(55.3g, 0.171mol) and the suspension was stirred for 24hr. After this time, the reaction mixture was diluted with ethyl acetate (EtOAc) (11) and water (350 ml). The organic phase was washed with sat. aq. NaHCO3 (350 ml), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (SiO2, 0-100% ethyl acetate in hexanes; gradient elution) to provide the title compound as a white solid.
1 H NMR (CDC13, 400 MHz) 6 7.35(1H, 7.31(9H, 7.22(6H, m), 6.76(1H, 3.68(3H, s) and 3.60(2H, s) ppm.
WO 96/31525 PCT/US96/03974 Step C: 4 -Cyanobenzyl)-lH-imidazol-5-yl]acetic acid methyl ester To a solution of 1-(triphenylmethyl)-lH-imidazol-4-ylacetic acid methyl ester 8 .00g, 2 0 .9mmol) in acetonitrile (70 ml) was added bromo-p-toluonitrile (4.10g, 20.92 mmol) and heated at 55 0 C for 3 hr.
After this time, the reaction was cooled to room temperature and the resulting imidazolium salt (white precipitate) was collected by filtration.
The filtrate was heated at 55 0 C for 18hr. The reaction mixture was cooled to room temperature and evaporated in vacuo. To the residue was added EtOAc (70 ml) and the resulting white precipitate collected by filtration. The precipitated imidazolium salts were combined, suspended in methanol (100 ml) and heated to reflux for 30min. After this time, the solvent was removed in vacuo, the resulting residue was suspended in EtOAc (75ml) and the solid isolated by filtration and washed (EtOAc).
The solid was treated with sat aq NaHCO3 (300ml) and CH2C12 (300ml) and stirred at room temperature for 2 hr. The organic layer was separated, dried (MgS04) and evaporated in vacuo to afford the title compound as a white solid 1 HNMR(CDCl 3 400 MHz) 7.65(1H, d, J=8Hz), 7.53(1H, 7.15(1H, d, J=8Hz), 7.04(1H, 5.24(2H, 3.62(3H, s) and 3.45(2H, s) ppm.
Step D: 4 -Canobenzv-H-imidazol-5-v1acetic acid A solution of 4 acid methyl ester 4 .44g, 17.4mmol in THF (100ml) and 1 M lithium hydroxide (17.4 ml, 17.4 mmol) was stirred at RT for 18 hr. 1 M HCI (17.4 ml) was added and the THF was removed by evaporation in vacuo.
The aqueous solution was lyophilized to afford the title compound containing lithium chloride as a white solid.
1 H NMR(CD30D, 400 MHz) 5 8.22(1H, 7.74(1H, d, J=8.4Hz), 7.36(1H, d, J=8.4Hz), 7.15(1H, 5.43(2H, s) and 3.49(2H, s) ppm.
WO 96/31525 PCTIUS96/03974 81 Step E: N- 4 -Cyanobenzyl)-l1H-imidazol-5-yl)acetyl] amino-3 (S)-methylpentyl]. 1 ,2,34-tetrahydro-3 isoguinolinecarbon I methionine methyl ester Using the method described in Example 1, Step F, but substituting [1 4 -cyanobenzyl)- 1H-imidazol-5-yl]acetic acid for 1 Himidazol-4-ylacetic acid, the title compound is obtained.
Step F: N- -(4-Cyanobenzyl)- 1H-imidazol-5-yl)acetyl]y2(Sy..
amino-3(S)-methylpentyly- 1 ,2,34-tetrahydro-3(S)isoguinolinecarbonyl methionine Using the method described in Example 1, Step G, the title compound is obtained.
EXAMPLE 3 Preparation of N- [L-Pyroglutamy1-2(S)-.an1no.3(S)-methylpel]- 1.2.3 .4-tetrahydro-3(S -isoguino~inecrn- met-hio-ne trifluoroacetate Step A: N- [L-Pyroglutamyl-2(S)..amno-3 (S)-methylpentyl]- 1,2,3,4terhdo3S-sqioieabnlmtinn methyl ester trifluoroacetate Following the methods described in Example 1, but using Lpyroglutamic acid in place of 1H-imidazol-4-yl acetic acid, the title compound was prepared. Anal. calcd for C27H40N40 5 CF3CO2H: C, 51.20; H, 5.94; N, 7.96; Found: C, 51.01; H, 6.00; N, 8.23.
Step B: N- [L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]- 1,2,3,4tetrahydro-3 (S)-isoquinolinecarbonyl..methionine trifluoroacetate The title compound was prepared following the method dscribed in Example 1, Step G. FAB MS 519 (M I).
WO 96/31525 PCT/US96/03974 -82- EXAMPLE 4 Preparation of N-[N-(4-Cyanobenzyl)-L-Pyroglutamyl-2(S)-amino-3(S)methylpentyl]-1,2,3,4-tetrahydro3(S)-isoquinolinecarbonyl-methionine methyl ester and 4 -Cyanobenzyl)-L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]- 12.34-tetrahdro-3(S)isouinolinearbonvl-methionine Step A: L-Pvroglutamic acid methyl ester L-Pyroglutamic acid (15.17 g, 0.1175 mol) was dissolved in (100 mL), cooled to 0°C. under Ar and treated dropwise with thionyl chloride (18.9 mL, 0.259 mol) with stirring. The bath was removed and stirring was continued at ambient temperature for 3.5 h.
Water (150 mL) and solid NaHCO3 (60 g) were added, the CH30H was removed on a rotary evaporator, and the residue extracted with CH2C12 (3 x 150 mL). The organic layers were combined, washed with brine, dried (MgS04), filtered and concentrated to dryness to give the title compound.
Step B: N-( 4 -Cvanobenzl pyrolutamic acid methyl ester L-Pyroglutamic acid methyl ester (1.36 g, 0.0095 mol) was dissolved in dry THF (20 mL) under Ar, treated with NaH (60% oil dispersion) (0.58 g, 0.0145 mol) with stirring for 5 min, then the mixture was cooled to 0°C. p-Cyanobenzylbromide (1.78 g, 0.0091 mol) was added, and the mixture left to slowly warm to ambient temperature. After 48 h the reaction mixture was partitioned between EtOAc and satd NaHCO3 solution, the aqueous layer separated and washed with CH2C12, the organics combined, washed with brine and dried (MgSO4). Filtration and concentration to dryness followed by trituration with ether gave the white solid product. 1 H NMR(CDCl3, 400 MHz) 6 7.62(2H, d, J=8 Hz), 7.33(2H, d, J=8 Hz), 4.98(1H, d, J=15.4 Hz), 4.13(1H, d, J=15.4 Hz), 3.99(1H, dd, J=3, 9 Hz) and 2.5-2.6 (1H, 2.4-2.5 (1H, 2.2-2.45 (1H, 2.1-2.2 (1H, m) ppm.
1 WO 96/31525 PCTIUS96/03974 -83- Step C: N-( 4 Cvanobenzyl)-L-pyroglutamic acid N-(4-Cyanobenzyl)-L-pyroglutamic acid methyl ester (0.875 g, 0.0034 mol) was dissolved in THF:H20 (12 mL) and treated with LiOH (0.294 g, 0.007 mol) with stirring at ambient temperature. After stirring for 3 h, the solution was neutralized with 1 N HC1, and concentrated to dryness to give the title compound and 2.1 eq of LiCl which was used without further purification.
Step D: N-[N-(4-Cyanobenzyl)-L-Pyroglutamyl-2(S)-amino-3(S)methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonylmethionine methyl ester Using the method described in Example 1, Step F, but substituting
N-(
4 -Cyanobenzyl)-L-pyroglutamic acid for 1H-imidazol-4ylacetic acid, the title compound is obtained.
Step E: 4 -Cyanobenzyl)-L-Pyroglutamyl-2(S)-amino- 3 methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonylmethionine Using the method described in Example 1, Step G, the title compound is obtained.
EXAMPLE In vitro inhibition of ras farnesyl transferase Assays offarnesyl-protein transferase. Partially purified bovine FPTase and Ras peptides (Ras-CVLS, Ras-CVIM and RAS- CAIL) were prepared as described by Schaber et al., J. Biol. Chem.
265:14701-14704 (1990), Pompliano, et al., Biochemistry 31:3800 (1992) and Gibbs et al., PNAS U.S.A. 86:6630-6634 (1989), respectively.
Bovine FPTase was assayed in a volume of 100 gl containing 100 mM N- (2-hydroxy ethyl) piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 m MgCl2, 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 gg/ml FPTase at 31 0 C for 60 min. Reactions were WO 96/31525 PCT/US96/03974 -84initiated 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 Pplate counter. The assay was linear with respect to both substrates, FPTase levels and time; less than 10% of the 3 H]-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.
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% polyethylene glycol 20,000, 10 gM 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% trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.
The compounds of the instant invention described in Examples 1, Step G, and Example 3, Step B, were tested for inhibitory activity against human FPTase by the assay described above and were found to have IC50 of 10 .M.
EXAMPLE 6 In vivo ras farnesylation assay The cell line used in this assay is a v-ras line derived from either Rat 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 After 4 hours at 37 0
C,
the cells are labelled in 3 ml methionine-free DMEM supple-meted with regular DMEM, 2% fetal bovine serum and 400 mCi[ 3 5 S]methionine (1000 Ci/mmol). After an additional 20 hours, the WO 96/31525 PCT/US96/03974 cells are lysed in 1 ml lysis buffer NP40/20 mM HEPES, pH 7.5/5 mM MgCl2/1mM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml mM PMSF) and the lysates cleared by centrifugation at 100,000 x g for 45 min. Aliquots of lysates containing equal numbers of acid-precipitable counts are bought to 1 ml with IP buffer (lysis buffer lacking DTT) and immunoprecipitated with the ras-specific monoclonal antibody Y13-259 (Furth, M.E. et al., J. Virol. 43:294-304, (1982)).
Following a 2 hour antibody incubation at 4 0 C, 200 ml of a suspension of protein A-Sepharose coated with rabbit anti rat IgG is added for 45 min. 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 NaCI) 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 nonfamesylated ras proteins are compared to determine the percent inhibition of farnesyl transfer to protein.
EXAMPLE 7 In vivo growth inhibition assay To determine the biological consequences of FPTase inhibition, the effect of the compounds of the instant invention on the anchorage-independent growth of Ratl cells transformed with either a vras, v-raf, or v-mos oncogene is tested. Cells transformed by v-Raf and v-Mos maybe included in the analysis to evaluate the specificity of instant compounds for Ras-induced cell transformation.
Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x 104 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 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 WO 96/31525 WO 96/31525 PCT/US96/0397 4 -86twice 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.

Claims (5)

1. A compound which inhibits Ras farnesyl-transferase having the Formula 1: (R )r R I a In V Al(CRa 2 )nA (CR a 2 )n .OH 0 wherein: R Ia and R Ib are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloallcyl, alkenyl, alkynyl, R 10 0-, RIIS(O)m-, R'OC(O)NRlO-, CN, N02, (Ri 0 )2N-C(NR R 0 RI 0 N3, -N(Ri 0)2, or RI 0C(0)NRIO-, c) C I -C6 ailkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, RIO0-, RI IS(O)m-, RIOC(O)NR10-, CN, (RiO)2N-C(NRIO)-, RIOC(O)-, RIO0C(O)-, N3, -N(RiO)2, or Ri 1 0C(O)- R 2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C I -C20 alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, WO 96/31525 PCTIUS96/03974 88 wherein the substituent is selected from F, Cl, Br, N(R 10)2, N02, R 10 R 11S(0)mr, R IOC(0)NR CN, (R IO)2N-C(NRl10)-, R IOC(0)-, R IOOC(0)-, N3, -N(RlO)2, RI 'OC(0)NR10- and CI-C20 alkyl, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C 10 cycloallcyl; or R2 and R3 are combined to form (CH2)s or R2 or R3 are combined with R 6 to form a ring such that R 6 R2 R (HA) 0,10 R 7 b R4a, R4b, R 7 a and R7b are independently selected from: a) hydrogen, b) ClI-C6 alkyl unsubstituted or substituted by alkenyl, R 100., RI IS(0)m-, RlOC(0)NRO-, CN, N3, (RIO)2N-C(NRlO)-, R IOC(0)-, R I -N(R'10)2, or R I I0C(0)NRl10-, c) aryl, heterocycle, cycloalkyl, alkenyl, R 1 0 0-, RI IS(O)m-, RIOC(0)NRl0-, CN, N02, (RIO)2N- C(NRIO)-, RIOC(O)-, RIO0C(0)-, N3, -N(RlO)2, or R I I0C(O)NR
10-, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-CIO cycloalcyl; and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: WO 96/3 1525 PCT/US96/03974 89 I) methiomine sulfoxide, or i) methionine sulfone, c) substituted or unsubstituted ClI-C20 alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl. or heterocycle group, wherein the substituent is selected from F, Cl, iBr, (R 10 N02, R 1 0 R II 1 S(O)m-, Rl 0 C(O)NR CN, (Ri 0 )2N-C(NR RI 0 R I N3, -N(R'1O)2, R IIOC(O)NRO10- and ailkyl, d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- cycloallcyl; or and R5b are combined to form (CH2)s wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, S(O)m, and -N(CORIO)-; R6 is independently selected from hydrogen or ClI -C6 alkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, ailkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 RlI 1 S(O)m-, R IOC(O)NRO10., CN, N02, RlIO2N-C(NR10)-, RI OC(0)-, R I N3, -N(R 10) 2 or R I I0C(0)NRl10-, and c) C I-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, ailcenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RIO0-, RI IS(0)m-, RIOC(0)NFI-, CN, H2N- R IOC(0)-, R IOOC(0)-, N3, -N(R 10) 2 or RIO0C(0)NH-; R9 is selected from: a) hydrogen, WO 96/31525 PCTJUS96/03974 90 b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 0-, R 1 1 RIOC(O)NRlO-, CN, N02, (RIO)2N-C- (NRIO)7, RIOC(O)-, RIO0C(O)-, N3, or R I IOC(O)NR and c) C1-C6 alkyl. unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 1 0 R II 1 R IOC(O)NR 10-, CN, (Ri 0 )2N-C(NR 1 R I R' I N3, -N(R 10)2, or R I RIO is independently selected from hydrogen, Ci -C6 alkyl, benzyl and aryl; R I is independently selected from C I1-C6 alkyl and aryl; A I and A 2 are independently selected from: a bond, -CH=CH-, -CFC-, -C(O)NRIO-, -NRIOC(O)-, 0, -N(RIO)-, -S(0)2N(RiO)-, -N(RiO)S(0) 2 or S(O)m; Q is a substituted or unsubstituted nitrogen-containing C6-C9 bicyclic ring system, wherein the non-nitrogen containing ring is selected from an aromatic ring and a heterocycle; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C I-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from 0, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; X, Y and Z are independently H 2 or 0; m is 0,l1or 2; n is 0, 1, 2, 3 or 4; p is 0,1, 2, 3or 4; r is 0 to 5, provided that r is 0 when V is hydrogen; s is 4 t is 3, 4or u is 0Oorl1; or a pharmaceutically acceptable salt thereof.
102. A prodrug of the formnula 11: R 5 a R 5 b RRr 6 y H OR'1 2 V-A (CR a 2 (CR 2),n (R R x R Q t RO R* and R Rbaeidpnetyslce rm a) hyroe b a r l h e e o y l,0c o l y a k n l l y y R 0 R *N N O 2-0R*- C O C O N o C O N C) CaC l y n u siue r s b tt td b r l ee o y lc y l ak l al en l al y n l Ra- R N R N C N R 0C O bL %2 Ny, hetrocyc, cyokl alenlalynlR'0 RS(Nm R 0 CO)R'- CN9O,(q 2 R'),R 0 ),R 0 0 2 rR 1 CO N [R:\LIBA]02565 .d0C tLT WO096/31525 PCTUS96/03974 92 R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: 1) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C I -C20 alkyl, C2-C20 alkenyl, C3-C1O cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, CI, Br, N(R 1O) 2 N02, R 1 0 R' IIS(O)m-, R CN, (RI O)2N-C(NRl RI RI 0 N3, -N(RlO)2, RI 'OC(O)NRIO- and Cl-C20 alkyl, and d) C I-C6 ailkyl substituted with an unsubstituted. or substituted group selected from aryl, heterocycle and C3- CIO cycloallcyl; or R 2 and R3 are combined to form (CH2)s or R2or R3 are combined with R 6 to form a ring such that Nis (HA) RA 2 R aO 7 b R4a, R4b, R 7 a and R7b are independently selected from: a) hydrogen, b) C1I-C6 alkyl unsubstituted or substituted by alkenyl, R 100-., R IOC(O)-, R I -N(R'1O)2, or R I IOC(O)NR c) aryl, heterocycle, cycloalkyl, alkenyl, R 1 0 0-, RIIS(O)m-, RIOC(O)NR10-, CN, N02, (R' 0 )2N- C(NRIO)-, RIOC(O)-, RIO0C(O)-, N3, -N(RiO)2, or R I I0C(O)NR 1 and WO 96/31525 PCTIUS96/03974 -93- d) C1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; R5a and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1 -C20 alkyl, C2-C20 alenyl, C3-C1O cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, (R 10 N02, R 1 0 R 1 1 R 10 C(0)NRl0-, CN, (R10)2N-C(NR10)-, R 10 R 10 N3, -N(R 1 0 R 11 OC(O)NR10- and C1-C20 alkyl, d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C10 cycloalkyl; or and R5b are combined to form (CH2)s wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, S(O)m, R6 is independently selected from hydrogen or C1 -C6 alkyl; R 8 is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 R 1 1 S(0)m-, R1OC(O)NRIO-, CN, N02, R1 0 2N-C(NR 1 0 R1 0 R 10 N3, -N(R 1 0 or R 1 10 C()NR10-, and WO 96/31525 PCTIUS96/03974 94 c) C I -C6 alkyl unsubstituted or sub stituted by aryl, heterocycle, cycloalcyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 RI IS(O)m-, RI OC(O)NH-, CN, H2N- RIOC(O)-, RIO0C(O)-, N3, -N(RlO) 2 or R 1 0 0C(O)NH-; R9 is selected from: a) hydrogen, b) alcenyl, alkynyl, perfluoroalcyl, F, Cl, Br, RIO0-, R I IS(O)m,, R IOC(O)NRl10-, CN, N02, (RI' 0 )2N-C- (NRIO)-, RIOC(O)-, RIO0C(O)-, N3, -N(RiO)2, Or R I I0C(O)NR 10-, and C) C1I-C6 ailkyl. unsubstituted or substituted by perfluoroalcyl, F, Cl, Br, RIO0-, RI IS(O)m-, RIOC(O)NRO-, CN, (R'0)2N-C(NRlO)-, RIOC(O)-, RIOOC(O)-, N3, -N(R'O)2, or RlIOC(O)NRIO-; R 10 is independently selected from hydrogen, C1I-C6 alkyl, benzyl and aryl; R I is independently selected from C I-C6 alkyl and aryl; R 1 2 is a) substituted or unsubstituted C I -C8 alkyl, substituted or unsubstituted C5-C8 cycloalkyl, or substituted or unsubstituted cyclic amine, wherein the substituted alkyl, cycloalkyl. or cyclic amine is substituted with 1 or 2 substituents independently selected from: 1) C I-C6 alkyl, 2) aryl, 3) heterocycle, 4) -N(R 1 1 )2, -ORI 0 or WO 96/31525 PCT/US96/03974 R 13 O R 13 is independently selected from hydrogen and C1-C6 alkyl; R 14 is independently selected from C1-C6 alkyl; Al and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NRIO-, -NR 1 O, -S(0)2N(R10)-, -N(Rl 0 )S(0) 2 or S(O)m; Q is a substituted or unsubstituted nitrogen-containing C6-C 9 bicyclic ring system, wherein the non-nitrogen containing ring is selected from an aromatic ring and a heterocycle; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; X, Y and Z are independently H2 or O; mis 0, 1 or 2; nis 0,1, 2 3 or 4; pis 0, 1, 2 3 or 4; r is 0 to 5, provided that r is 0 when V is hydrogen; WO 96/31525 PCTIUS96/03974 96- s is 4 or t is 3, 4or u is 0Oorl1; or a pharmaceutically acceptable salt thereof. 3. A compound which inhibits Ras famesyl-transferase having the Formula III: HOCH 2 (0H 2 )q (R 8 )r R(9~ R 6 Y~ N V 'C 2n C 2nW-(CRlb 2 )p NH RR 3 Q X 2 34 R 4 b wherein: R Ia and R Ib are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, ailkenyl, alkynyl, R 10 0-, RI IS(O)m-, RIOC(O)NRlO-, CN, N02, (R' 0 )2N- C(NRIO)-, RIOC(O)-, R10OC(O)-, N3, -N(RlO)2, or Ri 1 0C(O)NRl0-, C) C1I-C6 ailkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 1 0 0-, RI IS(O)m-, RIOC(O)NRIO-, CN, (R'O)2N-C(NR10)-, RIOC(O)-, RIO0C(O)-, N3, -N(RiO)2, or RI OC(O)- R 2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or WO 96/31525 PCTfUS96103974 97 ii) methionine sulfone, and c) substituted or unsubstituted CI -C20 alkyl, C2-C20 alkenyl, C3-Cl10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R 10)2, N02, R 10 R1 1 R IOC(O)NR CN, (RlO)2N-C(NRO).. RIOC(O)-, RIO0C(o)-, N3, -N(RlO)2, RI IOC(O)NRlO- and C1-C20 alkyl, and d) Ci -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- CIO cycloalkyl; or R2 and R3 are combined to form (CH2)s or R2or R3 are combined with R 6 to form a ring such that R 6 R~az;R 7 b R4a, R4b, R' 7 a and R7b are independently selected from: a) hydrogen, b) C1I-C6 alkyl unsubstituted or substituted by aikenyl, R 100-., R 1 1 R'OC(0)NRO-, CN, N3, (Rl 0 )2N-C(NRiO)-, RIOC(0)-, RIO0C(O)-, -N(RIO)2, or R1 I0C(0)NRIO-, c) aryl, heterocycle, cycloalkyl, alkenyl, R 10 0-, RI IS(0)m-, RIOC(O)NRIO-, CN, N02, (R'O)2N- C(NRIO)-, RlOC(O)-, RlO0C(O)-, N3, -N(RlO)2, or R II0C(0)NR 10-, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C1O cycloalkyl; R6 is independently selected from hydrogen or C I -C6 alkyl; WO 96/31525 PCT/US96/03974 98 R 8 is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, ailkenyl, alkynyl, peffluoroalkyl, F, Cl, Br, R 10 R II 1 S(O)m-, R IOC(O)NR10-, CN, N02, RlIO2N-C(NR 10), RI OC(O)-, RIO0C(O)-, N3, or RI I0C(O)NRIO-, and C) C I -C6 alkyl. unsubstituted or substituted by aryl, heterocycle, cycloallcyl, alkenyl, alkynyl, perfluoroaikyl, F, Cl, Br, R 10 R I IS(O)m-, R 1 OC(O)NH-, CN, H2N- RIOC(O)-, RIO0C(O)-, N3, -N(RiO)2, or RIO0C(O)NH-; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalcyl, F, Cl, Br, R 1 0 0-, RI IS(O)m-, RIOC(O)NR 1 CN, N02, (R' 0 )2N-C- (NRIO)-, RIOC(O)-, RIO0C(O)-, N3, -N(RIO)2, or R I IOC(O)NR 1 and c) C I -C6 ailkyl unsubstituted or substituted by perfluoroalcyl., F, Ci, Br, RIO0-, RI 1 RIOC(O)NRIO-, CN, or R 11OC(O)NR R 1 0 is independently selected from hydrogen, C I-C6 ailkyl, benzyl and aryl; R I is independently selected from C1I-C6 alkyl and aryl; A 1 I and A 2 are independently selected from: a bond, -CH=CH-, -C=EC-, -C(O)NRIO-, -NRlOC(O)-, 0, -N(RiO)., -S(0)2N(R -N(R 10 or S(O)m; 99 Q is a substituted or unsubstituted nitrogen-containing C 6 -C 9 bicyclic ring system, wherein the non-nitrogen containing ring is selected from an aromatic ring and a heterocycle; V is selected from: s a) hydrogen, b) heterocycle, c) aryl, d) Ci-C 20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and t0 e) C 2 -C 20 alkenyl, provided that V is not hydrogen if A' is S(0)m and V is not hydrogen if A' is a bond, n is 0 and A 2 is S(O),m; W is a heterocycle; X, Y and Z are independently H 2 or 0; s1 m is 0, 1 or 2; nis 0, 1, 2, 3 or 4; pis O, 1, 2, 3 or 4; qis 0 1 or2; r is 0 to 5, provided that r is 0 when V is hydrogen; 20 s is 4 or t is 3, 4 or 5; and uis 0 or 1; or a pharmaceutically acceptable salt thereof. A prodrug of the formula IV: [R\LIBA]02565.docTLT WO 96/3 1525 PCT/US96/03974 -100- (R 8 )r V A t (CRla 2 )nA 2 (CRla 2 )n (R9 (I R 4 b wherein: R Ia and R Ib are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, R 1 0 0-, RI IS(O)m-, R'OC(O)NR10-, CN, N02, (R 1 %)2N- C(NRIO)-, RIOC(O)-, RIOOC(O)-, N3, or R I I0C(O)NR C) C I-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, aikenyl, alkynyl, RIO0-, RI IS(O)m-, RI OC(O)NR1 CN, (Ri 0 )2N-C(NR10).., RIOC(O)-, RIO0C(O)-, N3, -N(RlO)2, or RI I0C(O)- R 2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methiomine sulfone, and c) substituted or unsubstituted C I -C20 alkyl, C2-C20 alkenyl., C3-CIO cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Ci, Br, N(RIO)2, N02, R100-., R 1 1 R IOC(O)NR -N(RlO)2, RI I0C(O)NRIO.. and Cl-C20 alkyl, and i WO 96/31525 PCTJUS96/03974 101 d) C I -C6 ailkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- CIO cycloalkyl; or R 2 and R3 are combined to form (CH2) s or R2 or R3 are combined with R 6 to form a ring such that R 6 Nis (HA) R4a, R4b, R 7 a and R7b are independently selected from: a) hydrogen, b) Ci1 -C6 alkyl unsubstituted or substituted by alkenyl, R 100-., R 1 1 RIOC(0)NRO-, CN, N3, (RlO)2N-C(NR10)-, R IOC(O)-, R I -N(R 10)2, or R I0 c) aryl, heterocycle, cycloalicyl, alcenyl, RIO0-, Rl 1 RIOC(O)NRlO-, CN, N02, (RIO)2N- C(NRIO)-, RIOC(O)-, RIO0C(O)-, N3, -N(R'O)2, or R I IOC(0)NRl10-, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C1 0 cycloalkyl; R6 is independently selected from hydrogen or ClI -C6 alkyl; R 8 is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 R I 1 R 1 I C(0)NR 10-, CN, N02, R 1 0 2N-C(NR 1 R 1 OC(0)-, R I N3, -N(R 10)2, or R I IOC(0)NR 10-, and WO 96/3 1525 PCTIUS96/0397 4 -102- C) C I -C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, peffluoroaicyl, F, Cl, Br, RIO0-, RI IS(O)m-, RIOC(0)NH-, CN, H2N- RIOC(0)-, RIOOC(O)-, N3, -N(R'O)2,.or RI 0 0C(0)NH-; R9 is selected from: a) hydrogen, b) alkenyl, aikynyl, perfluoroalkyl, F, Cl, Br, R 100., R' IIS(0)m-, RlIOC(0)NR 10-, CN, N02, (R1' 0 )2N-C- RIOC(0)-, RIO0C(0)-, N3, -N(RlO)2, or RI IOC(0)NRO.., and c) C I -C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 1 0 R1 1 S R IOC(0)NRl10-, CN, (R 1 0 )2N-C(NRI1O)-, RI 0 RI 0 N3, -N(Rl 0)2, or RI I0C(O)NRO-; R 1 0 is independently selected from hydrogen, C I -C6 alkyl, benzyl and aryl; Rl is independently selected from C I-C6 alkyl and aryl; Al and A 2 are independently selected from: a bond, -CH=CH-, -C=EC-, -C(0)NR10-, -NRIOC(O)-, 0, -N(RIO)-, -S(0)2N(RIO)-, -N(RIO)S(0) 2 or S(O)m; Q is a substituted or unsubstituted nitrogen-containing C6-C9 bicyclic ring system, wherein the non-nitrogen containing ring is selected from an aromatic ring and a heterocycle; V is selected from: a) hydrogen, b) heterocycle, c) aryl, WO 96/31525 PCT/US96/03974 -103- d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; X, Y and Z are independently H2 or O; m is n is p is q is ris s is t is u is 0, 1 or 2; 0, 1,2, 3 or 4; 0, 1, 2, 3 or 4; 0, 1 or 2; 0 to 5, provided that r is 0 when V is hydrogen; 4 or 3, 4 or 5; and 0or 1; or a pharmaceutically acceptable salt thereof. The compound according to Claim 1 of the formula I: (Rr R V A'(CRa2)nA 2 (CR1a 2 )n UR~ 1 5a R 5 b VI-1 R4b wherein: Ra is independently selected from: hydrogen or C1-C6 alkyl; WO 96/31525 PCT/US96/0397 4 -104- Rlb is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 10 -N(RO0) 2 or alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R 10 or -N(Rl10) 2 R 2 and R 3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted CI-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO2, R 10 R 1 1 RO1C(O)NR1O-, CN, (R10)2N-C(NRO1)-, R10C(O)-, R100C(O)-, N3, -N(R10)2, R11OC(O)NR10- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- cycloalkyl; or R 2 and R3 are combined to form (CH2)s or R2 or R3 are combined with R 6 to form a ring such that R 6 SN is H 2 )t R 2 R 3 R7R 7 b R4a and R 7 a are independently selected from: a) hydrogen, WO 96/31525 PCTIUS96/039 7 4 -105- b) C I -C6 alkyl unsubstituted or 'substituted by alkenyl, R R I 1 R IOC(O)NR 10-, CN, N3, (R'1O)2N-C(NR R 1 RIO0C(O)-, -N(RIO)2, or RI 'OC(O)NRO-., c) aryl, heterocycle, cycloallcyl, alkenyl, R 10 0-, RI 1 RIOC(O)NRO.. CN, N02, (R'O)2N- C(NR R 1OC(O)-, R 1OOC(O)-, N3, -N(R'1O)2, or R I'IOC(o)NR 10-, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- 10 cycloalkyl; R4b and R7b are hydrogen; is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from methionine and glutamine, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C I-Ci1O alkyl, C2-C 10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 1 0 R I IS(O)m-, R'IOC(O)NR (Ri 0 CN, (RI 0 )2N-C(NR 1 RI 0 R I N3, -N(R 10)2, R IIOC(O)NR 10. and C1I-C20 alkyl, and d) C I -C6 alkyl. substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C 10 cycloalkyl; is selected from: a) hydrogen, and b) C I-C3 alkyl; 106 *R 6 is independently selected from hydrogen or C I-C 6 alkyl; *R 8 is independently selected from: a) hydrogen, b) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 perfluoroalkyl, F, Cl, R' 0 0-, RIOC(O)NRO-, CN, NO 2 (RIO) 2 R' 0 R' 0 N(R' 0 2 or R' OC(O)NRO-, and C) C I-C 6 alkyl substituted by C I-C 6 perfluoroalkyl, R 1 0 R 1 0 R' 0 0C(O>, or 0)2; R 9 isselected from: 0 a) hydrogen; b) C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, CI-C 6 perfluoroalkyl, F, CI, R' 0 R 1 1 R' 0 C(O)NR' 0 CN, NO 2 (Rlo) 2 N-C(NR'O>- R' 0 R' 0 -N(R' 0 2 or R' 'OC(O)NR' 0 C) C 1 -C 6 alkyl unsubstituted or substituted by CI-C 6 perfluoroalkyl, F, Cl, R' 0 0-, R' 0 C(O)NR' 0 CN, (RIO) 2 N-C(NR R' 0 R' 0 -N(R' 0 2 or R lOC(O)NRO-; R1 0 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl; R' is independently selected from C 1 -C 6 alkyl and aryl; *0 Q is selected from: 0 *0 d* A* [RALIBA]02565. doc:TLT I WO 96/31525 PCTIUS96/03974 -107- VVI and A 1 and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR10-, O, or S(O)m; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2 -oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if Al 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, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; X, Y and Z are independently H2 or O; mis n is p is r is t is u is 0, 1 or 2; 0, 1,2, 3 or 4; 0, 1, 2, 3 or 4; 0 to 5, provided that r is 0 when V is hydrogen; 3, 4 or 5; and 0or 1; WO 96/31525 PCT/US96/03974 -108- or a pharmaceutically acceptable salt thereof. 6. The compound according to Claim 2 of the formula II: (R 8 )r RR 5 a R 5 b I 6 I b ROR 1 U N V- AI(CRla 2 )nA 2 (CR1a 2 n u-(CRlb 2 )pR N H R R2 R Q II aR 4 b wherein: Rl1a is independently selected from: hydrogen or C1-C6 alkyl; Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 10 -N(R 10 )2 or alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R 10 or -N(R10)2; R 2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO2, R 10 R11S(O)m-, R10C(O)NR10-, CN, (R 10 )2N-C(NR10)-, R10C(O)-, R 10 N3, -N(R 10 R11OC(O)NR10- and C1-C20 alkyl, and WO 96/31525 PCT/US96/03974 -109- d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- cycloalkyl; or R 2 and R 3 are combined to form (CH2)s or R2 or R3 are combined with R 6 to form a ring such that is H)t; R4a and R7a are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, R 1 0 0-, R 1 RIOC(O)NRO10-, CN, N3, (R 10 )2N-C(NR10)-, R 1 R 1 0 0C(O)-,-N(RIO)2, or R1 1 0C(O)NR10-, c) aryl, heterocycle, cycloalkyl, alkenyl, R 1 0 0-, R 1 1S(O)m-, R 1 OC(O)NRIO-, CN, N02, (R 1 0 )2N- RIOC(O)-, R 1 0 N3, -N(R10)2, or R 1 1 0C(O)NR10-, and d) C1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- cycloalkyl; R4b and R7b are hydrogen; is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from methionine and glutamine, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or 110 ii) methionine sulfone, and c) substituted or unsubstituted Ci-C 10 alkyl, C 2 -Cl 0 alkenyl, C 3 -CI 0 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO 2 R 1 0 RIIS(O)m-, RIIOC(O)NRO- and C 1 -C 2 o alkyl, and d) CI-C 6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C 3 -C 10 cycloalkyl; R 5bis selected from: 0 a) hydrogen, and b) C I-C 3 alkyl; *R is independently selected from hydrogen or C I-C 6 alkyl; *R 8 is independently selected from: a) hydrogen b) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 perfluoroalkyl, F, Cl, R' 0 0-, R' 0 C(O)NR' 0 CN, NO 2 2 N-C(NR' 0 R' 0 R' 0 N(R' 0 2 or R'IOC(O)NRO., and C) CI-C 6 alkyl substituted by C 1 -C 6 perfluoroalkyl, R' 0 R 1 0 R' 0 or R 9 is selected from: a) hydrogen, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 perfluoroalkyl, F, Cl, R 10 R' 'S(O)ni-3 RIOC(O)NR0-, CN, NO,, R' 0 R' 0 -N(R 1 0 2 or R 1 OC(O)NR' 0 and o.. [R:\LIBA]02565.doc:TLT WO 96/31525 PCT/US96/039 7 4 111 c) C1-C6 alkyl unsubstituted or substituted by C1-C 6 perfluoroalkyl, F, C1, R 10 R 1 1 R10C(O)NR10O CN, (R10)2N-C(NR10)-, R1OC(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-; R 1 0 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; R 1 1 is independently selected from C1-C6 alkyl and aryl; R12 is a) substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C5-C8 cycloalkyl, or substituted or unsubstituted cyclic amine, wherein the substituted alkyl, cycloalkyl or cyclic amine is substituted with 1 or 2 substituents independently selected from: 1) C1-C6 alkyl, 2) aryl, 3) heterocycle, 4) -N(R11)2, -OR 10 or b) R 13 0 0 R' 14 R 13 is independently selected from hydrogen and C1-C6 alkyl; R1 4 is independently selected from C1-C6 alkyl; Q is selected from: WO 96/31525 PCT/US96/03974 -112- and Al and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR10-, O, or S(O)m; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2 -oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2 -oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; X, Y and Z are independently H2 or O; mis n is p is r is t is uis 0, 1 or 2; 0, 1, 2, 3 or 4; 0, 1, 2, 3 or 4; 0 to 5, provided that r is 0 when V is hydrogen; 3, 4 or 5; and 0or 1; jllll WO 96/31525 PCTIUS96/03974
113- or the pharmaceutically acceptable salts thereof. 7. The compound according to Claim 3 of the formula III: HOCH 2 (CH 2 )q (R 8 r R9 Z R 6 Y V Al(CRla 2 n A 2 (CR la 2 n W (CR) N N X R2 R3 Q X III R 4b R4a wherein: Ria is independently selected from: hydrogen or C1-C6 alkyl; R 1 b is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 10 -N(R10)2 or alkenyl, c) C 1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R 10 or -N(R10)2; R 2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO2, R 10 R11S(O)m-, RO1C(O)NR10-, CN, WO 96/3 1525 PCT/US96/03974 -114- -N(R 1 0 R 1 0C(O)NR 10- and ClI-C20 alkyl, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- Ci10 cycloalkyl; or R 2 and R3 are combined to form (CH2)s or R2or R3 are combined with R 6 to form a ring such that R 6 Nj is HA) R2R W 'R 7 b R4a and R 7 a' are independently selected from: a) hydrogen, b) C 1-C6 alkyl unsubstituted or substituted by ailkenyl, Ri100-, R 1 1 Rl 0 C(O)NRIO-, CN, N3, (RiO)2N-C(NRIO)-, RIOC(O)-, RIO0C(O)-, or RI I0C(O)NRIO-, c) aryl, heterocycle, cycloalkyl, alkenyl, R1 0 0-, R II R IOC(O)NR 10-, CN, N02, (RI O2N- C(NRiO)-, R 1 R 1 0 N3, -N(R'0)2, or R I IOC(O)NR 1 and d) C1I-C6 ailkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- CIO cycloalkyl; R4b and R7b are hydrogen; R6 is independently selected from hydrogen or C I -C6 alkyl; R8 is independently selected from: a) hydrogen, 115 b) CI-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, CI-C 6 perfluoroalkyl, F, Cl, R' 0 0-, R' 0 C(O)NR' 0 CN, NO 2 (R' 0 2 N-C(NR' 0 R' 0 R' 0 -N(R' 0 2 or R ''OC(O)NR' 0 and C) C 1 -C 6 alkyl substituted by CI-C 6 perfluoroalkyl, R' 0 R' 0 R' 0 or NR02 R 9 isselected from: a) hydrogen, b) C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, CI-C 6 perfluoroalkyl, F, Cl, R' R"'C(O)NR' 0 CN, NO 2 (R' 0 2 N-C(NR' 0 R' 0 R' 0 -N(R' 0 2 or o R I IOC(O)NR' 0 and C) CI-C 6 alkyl unsubstituted or substituted by C 1 -C 6 perfluoroalkyl, F, Cl, R1 0 0-, R' 0 C(O)NR' 0 CN, (R' 0 2 N-C(NR' 0 R' 0 R' 0 -N(R' 0 2 or R"OC(O)NR' 0 R1 0 is independently selected from hydrogen, C,-C 6 alkyl, benzyl and aryl; R' '1is independently selected from C I-C 6 alkyl and aryl; Q is selected from: N N. ~:LO and b and A 2 are independently selected from: a bond, -C(O)NR' 0 0, -N(R' 0 or S(O),m; o** [R:\LIBA]02S65 doc:TLT WO 96/31525 PCT/US96/03974
116- V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from 0, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; X, Y and Z are independently H2 or O; mis n is p is q is r is tis u is 0, 1 or 2; 0, 1, 2, 3 or 4; 0, 1, 2, 3 or 4; 0, 1 or 2; 0 to 5, provided that r is 0 when V is hydrogen; 3, 4 or 5; and 0or 1; or a pharmaceutically acceptable salt thereof. 8. The compound according to Claim 4 of the formula Formula IV: WO 96/31525 PCTIUS96/03974 -117- (R 8 )r R9Y Z q R R0 V Al(CRa 2 )nA 2 (CR On)W (CRlb 2 pNy N U H 0 X R2 R 3 Q IV R 4 b wherein: Ri1a is independently selected from: hydrogen or ClI-C6 alkyl; Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloallcyl, R 1 0 -N(RlO)2 or alkenyl, c) ClI-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalicyl, alkenyl, RlO0-, or -N(Rlo)2; R 2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C 1-C 10 alkyl, C2-C 10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, RlO0-, Rl IS(O)m-, RIOC(O)NRIO-, CN, (Ri 0 )2N-C(NRl RI R 1 0 N3, -N(R'10)2, R I IOC(0)NR 1 0- and C1I-C20 ailkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- Ci1Q cycloalcyl; or R 2 and R3 are combined to form (CH2)s or 118 R2or R3are combined with R 6 to form a ring such that Nis (H 2 )t RR3 R 7 a R 7 b R 4 and R 7 are independently selected from: a) hydrogen, b) CI-C 6 alkyl unsubstituted or substituted by alkenyl, R' 0 R 10 C(O)NR 10 CN, N 3 (RlO) 2 R' 0 R' 0 -N(R' 0 2 or R' 'OC(O)NR' 0 c) aryl, heterocycle, cycloalkyl, alkenyl, R' 0 R' 1 RIOC(O)NR"o-, CN, NO,, (RlO) 2 R' 0 R' 0 N 3 -N(R' 0 or R' OC(O)NRO-, and d) C 1 -C 6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C 3 -C 10 cycloalkyl; R 4 b and R 7 b are hydrogen; R6 is independently selected from hydrogen or C I-C 6 alkyl; R8 is independently selected from: a) hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 perfluoroalkyl, F, Cl, R' 0 0-, R' 0 C(O)NR CN, NO 2 (RlO) 2 R 10 R' 0 -N(R' 0 2 or R''OC(O)NR' 0 and C) C 1 -C 6 alkyl substituted by C 1 -C 6 perfluoroalkyl, R' 0 R' 0 R' 0 0C(O)- or NR0)2 [RALIBA102565.doc:TLT WO096/31525 PCTIUS96/03974 -119- R 9 is selected from: a) hydrogen, b) C2-C6 ailkenyl, C2-C6 alkynyl, C I -C6 peffluoroalcyl, F, Cl, RIO0-, Rl IS(O)m-, RIOC(O)NRl0-, CN, N02, (RIO)2N- C(NRIO)-, RIOC(O)-, RIO0C(O)-, or and c) ClI-C6 alkyl unsubstituted or substituted by C1I-C6 perfluoroalkyl, F, Cl, R 10 R II 1 CN, (Ri 0 )2N-C(NRI1O)-, R' 0 RI 0 -N(R 10)2, orRilOC(O)NRlO-; R 1 0 is independently selected from hydrogen, C1I-C6 alkyl, benzyl and aryl; R I is independently selected from ClI-C6 alkyl and aryl; Q is selected from: AN IN and- *AI and A 2 are independently selected from: a bond, -CFI=CH-, -C7zC-, -C(O)NRlO-, 0, or S(O)m; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2 -oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, WO 96/31525 PCT/US96/03974 -120- c) aryl, d) C I -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom. selected from 0, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A I is S (O)m and V is not hydrogen if A 1 l is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2 -oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; X, Y and Z are independently H2 or 0; m is n is P is q is r is t is u is 0, 1 or 2; 0, 1, 2, 3or 4; 0, 1, 2, 3or 4; 0, 1 or 2; 0 to 5, provided that r is 0 when V is hydrogen; 3, 4or 5; and 0 or 1; or a pharmaceutically acceptable salt thereof. 9. A compound which inhibits farnesyl-protein transferase which is: N- [(1H-imidazol-4-ylacetyl-2(Sy..amino).3 (S)-methylpentyl]- 1,2,3,4- tetrahydro-3 (S)-isoquinolinecarbonyl-methionine methyl ester N- H-imidazol-4-ylacetyl-2(S)-amino.3 (S)-methylpentyl]- 1,2,3,4- tetrahydro-3 (S)-isoqumnolnecarbonyl-methionine N- [L-Pyroglutamyl-2(S )-amino-3 (S)-methylpentyl]- 1 ,2,3,4-tetrahydro- 3 (S)-isoquinolinecarbonyl-methionine methyl ester WO 96/31525 PCT1US96/03974 121 N- [L-Pyroglutamyl-2(S)-amno-3(S)-methylpentyl]- 1,2,3 ,4-tetrahydro- 3 (S)-isoquinolinecarbonylpmethiopjne N- H-imidazol4ypropiony)2(S..ainino-.3 (S)-methylpentyl]- 1,2,3,4- tetrahydro-3 (S)-isoquinolinecarbonyl-metjhjonine methyl ester lH-imidazol- 4 -ylpropionyl)y2(S)-aio..3(S)-methylpentyl] 1,2,3,4- tetrahydro-3 (S)-isoquinolinecarbonyl-methijonne N- -(4-cyanobenzyl)-l1H-imidazo-5-yl)acetyly2(S)-amin-3 methylpentyl]- 1, 2 ,34-tetrahydro-3 (S)-isoquinolinecarbonyl methionine methyl ester N- [(1-(4-cyanobenzyl)- 1H-imidazol-5-y)acetyly2(Sy..aj 1 o-3 methylpentyl]- 1,2,34-tetrahydro-3 (S)-isoquinolinecarbonyl methionine, N- 4 -cyanobenzyl)-L-pyroglutamyl.2(Sy..amno-3 (S)-methylpentyl] 1,2,3,4ttayr-(S-sqioncrbnlmtinn methyl. ester or N- 4 -cyanobenzyl)-L-pyroglutamyl..2(S)-a.nno-3 (S)-methylpentyl] 1,2,3,4ttayr-()iounoieabnlmtinn or a pharmaceutically acceptable salt or optical isomer thereof. 10. The compound according to Claim 9 which inhibits farnesyl-protein transferase which is: N- [L-Pyroglutamyl-2(S)-amno-3 (S)-methylpentyl]- 1,2,3 ,4-tetrahydro- 3 (S)-isoquinolinecarbonyl-methionine 1 22 SCH 3 0\-H OH H: N N N H 0 or a pharmaceutically acceptable salt or optical isomer thereof. 11. The compound according to claim 9 which inhibits farnesyl-protein transferase which is: [L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl] -1,2,3 ,4-tetrahydro-3 isoquinolinecarbonyl-methionine methyl ester SCH 3 0 H OH N OH H N 0 :N N H 13. A*opudo tefrua1 u 0 .3 WR R 8h r i b 2 ,R 1 a 1,R6 R7,R b 9 1 ,R ,Q 9V (RX ,Z nn ,r aduaea efndi [bN:ib]29:L 123 R' is independently selected from C 1 -C 6 alkyl substituted by RlOC(O)NRIO-, (R' 0 2 N- C(N'O-,or R"OC(O)NR' 0 14. A compound of the formula 11: 8 Rla Rlb 12 R'6 Y Z OR I a 2 a1 lb R N V A (CR 2 (CR'2nW C 2)p N IH N x R 4b II b~ 3Ra5 a b1 3 1 wherein Rib R 2 R R 4 R 4 b, R 5 a, Rb R 6 R 7 R b, R 9 R1 0 R 2 R 3 R 4 Q, A 2 V, W, X, Y, Z, mn, n, p, r, t and u are as defined in claim 6 above, and R' is independently selected from CX- 6 alkyl substituted by R' 0 C(O)NR' 0 (R' 0 2 N- u (NR' 0 or R"OC(O)NR' 0 A compound of the formula III: too. .000 HOCH 2 (CH 2 )q (Ro 6 y Z OH R N VA(CR XR Q 4~b RWaR 10 wherein R~ R",b R, R, R~ ROb R 6 R, R~b R 9 R1 0 R' Q, A1, A 2 V, W5, X, Y, Z, mn, n, p, q, r, t and u are as defined in claim 7 above, and R' is independently selected from CX- 6 alkyl substituted by R' 0 C(O)NR' 0 (R' 0 2 N- C(NR' 0 or R"OC(O)NR' 0 16. A compound of the formula IV: q .(R INa2 l I H V-A(R2)A(R2n-W -(R2)p No R9 9999 4b IV wherein R 'a Rlb, R 2 R 4 R 4 1, R 6 R 7 a, R 7 b, R 9 R1 0 Q, A 2 V, WV, X, y, Z, mn, n, p, q, r, t and u are as defined in claim 8 above, and [n:\1ibc]02695 :TLT 124 R 8 is independently selected from C 1 -C 6 alkyl substituted by R 1 (R 1 0 2 N- C(NR'O) or R 1 "OC(O)NR'O-. 17. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of any one of claims 1 to 16. 18. A method for inhibiting farnesylation of Ras protein which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 16 or of a composition of claim 17. 19. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 16 or of a composition of claim 17. A method for treating neurofibromin benign proliferative disorder which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 16 or of a composition of claim 17. 21. A method for treating blindness related to retinal vascularization which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 16 or of a composition of claim 17. 22. A method for treating infections from hepatitis delta and related viruses which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 16 or of a composition of claim 17. o 23. A method for preventing restenosis which comprises administering to a o° mammal in need thereof a therapeutically effective amount of a compound of any one of S° claims 1 to 16 or of a composition of claim 17. 24. A method for treating polycystic kidney disease which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 16 or of a composition of claim 17. 25. Use of a compound of any one of claims 1 to 16 for the manufacture of a medicament for inhibiting franesylation of Ras protein. 26. Use of a compound of any one of claims 1 to 16 for the manufacture of a medicament for the treatment of cancer. 27. Use of a compound of any one of claims 1 to 16 for the manufacture of a *o medicament for the treatment of neurofibromin benign proliferative disorder. 28. Use of a compound of any one of claims 1 to 16 for the manufacture of a medicament for the treatment of blindness related to retinal vascularization. 29. Use of a compound of any one of claims 1 to 16 for the manufacture of a medicament for the treatment of infections from hepatitis delta and related viruses. Use of a compound of any one of claims 1 to 16 for the manufacture of a medicament for the prevention of restenosis. 31. Use of a compound of any one of claims 1 to 16 for the manufacture of a 40 medicament for the treatment of polycystic kidney disease. [n:\libc]02695:TLT -_li i liii- Ci~_ll~-LIC- 125 32. A compound of any one of claims 1 to 16 or a composition of claim 17 when used in inhibiting farnesylation of Ras protein. 33. A compound of any one of claims 1 to 16 or a composition of claim 17 when used in the treatment of cancer. 34. A compound of any one of claims 1 to 16 or a composition of claim 17 when used in the treatment of benign proliferative disorder. A compound of any one of claims 1 to 16 or a composition of claim 17 when used in the treatment of blindness related to retinal vascularization. 36. A compound of any one of claims 1 to 16 or a composition of claim 17 when used in the treatment of infections from hepatitis delta and related viruses. 37. A compound of any one of claims 1 to 16 or a composition of claim 17 when used in the prevention of restenosis. 38. A compound of any one of claims 1 to 16 or a composition of claim 17 when used in the treatment of polycystic kidney disease. Dated 25 May, 1999 Merck Co., Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON i [n:\libc]02695:TLT
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US08/600,792 US5624936A (en) 1995-03-29 1996-02-13 Inhibitors of farnesyl-protein transferase
US08/600792 1996-02-13
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