AU714072B2 - Combinations of inhibitors of farnesyl-protein transferase - Google Patents
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Description
WO 97/01275 PCT/US96/11022 -1- TITLE OF THE INVENTION COMBINATIONS OF INHIBITORS OF FARNESYL-PROTEIN
TRANSFERASE
RELATED APPLICATION The present patent application is based upon copending provisional application Serial No. 60/002,251, filed June 29, 1995, priority of which is claimed hereunder.
BACKGROUND OF THE INVENTION The Ras protein is part of a signaling 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 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 farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a WO 97/01275 PCT/US96/11022 -2-
C
15 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 farnesylation. 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 famesylated proteins of unknown structure and function in addition to those listed above Inhibition of famesyl-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 famesyl-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 faresyl-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 farnesyl pyrophosphate. Farnesyl-protein transferase utilizes farnesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a famesyl 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 by inhibiting HMG-CoA reductase blocks Ras membrane localization in WO 97/01275 PCT/US96/11022 -3cultured cells. However, direct inhibition of farnesyl-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 competitive with famesyl diphosphate (FPP) and can be structural analogs of FPP or not directly analogous. The second class of inhibitors are competitive with the protein substrates Ras) for the enzyme. The protein substratecompetitive 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 farnesyl-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)). Recently, protein substrate-competitive inhibitors that lack a thiol moiety have been described (WO 95/09000; WO 95/09001; WO 95/10514; WO 95/10515; WO 95/10516; WO 95/08542; WO 95/11917; and WO 95/12612).
Inhibitors of FPTase have recently been described that incorporate characteristics of both faresyl pyrophosphate and the CAAX motif Bhide et al., Bioorg. Med. Chem. Lett., 4:2107-2112 (1994) and Manne et al., Oncogene, 10:1763-1779 (1995)). Such a bisubstrate strategy addresses the unfavorable entropic effect that might exist in bringing two molecules together at the same enzyme protein.
However, the spatial requirements for accessing two enzymatic site interactions with a single compound may result in a bisubstrate inhibitor with a molecular weight and correspondingly poor pharmacokinetic properties. Furthermore, the reported bisubstrate analogs have shown limited activity in cell-based assays.
It is, therefore, an object of this invention to develop pharmaceutical compositions which comprise two different independent faresyl protein transferase inhibitors, one inhibitor which is a WO 97/01275 PCT/US96/11022 -4competitive inhibitor with respect to the protein substrate of FPTase and the other inhibitor which is a competitive inhibitor with respect to faresyl pyrophosphate. It is a further object of this invention to develop methods of inhibiting farnesyl protein transferase and treating cancer utilizing these chemotherapeutic compositions.
SUMMARY OF THE INVENTION The present invention relates to compositions comprising amounts of at least two therapeutic agents selected from a group consisting of a faresyl protein transferase inhibitor which is an effective inhibitor of the enzyme because it is competitive with respect to the protein substrate of the enzyme (also referred to as a protein substratecompetitive inhibitor) and a farnesyl protein transferase inhibitor which is an effective inhibitor of the enzyme because it is competitive with respect to famesyl pyrophosphate (also referred to as a faresyl pyrophosphatecompetitive inhibitor). Further contained in this invention are methods of inhibiting famesyl-protein transferase and treating cancer in a mammal, which methods comprise administering to said mammal, either sequentially in any order or simultaneously, amounts of at least two therapeutic agents selected from a group consisting of a famesyl protein transferase inhibitor which is an effective inhibitor of the enzyme because it is a competitive inhibitor with respect to the protein substrate of the enzyme and a faresyl protein transferase inhibitor which is an effective inhibitor of the enzyme because it is a competitive inhibitor with respect to faresyl pyrophosphate, in amounts sufficient to achieve an additive or synergistic therapeutic effect. The additive or synergistic therapeutic effect of the instant compositions may be achieved with smaller amounts of either or both of the protein substrate-competitive inhibitor and farnesyl pyrophosphate-competitive inhibitor than would be required if such a protein substrate-competitive inhibitor or famesyl pyrophosphatecompetitive inhibitor were administered alone, thereby avoiding any nonmechanism-based adverse toxicity effects which might result from administration of an amount of the single protein substrate-competitive WO 97/01275 PCT/US96/11022 inhibitor or faresyl pyrophosphate-competitive inhibitor sufficient to achieve the same therapeutic effect.
BRIEF DESCRIPTION OF THE FIGURES FIGURES 1A, 1B and 1C: In vivo Assessment of a Combination of Compound D and Compound
E:
Figure 1A shows the partial densitometric scan of an autoradiograph of a Western blot from the SDS-PAGE gel of the method described in Example 21 wherein the FPTase inhibitory compound was Compound
D
at a concentration of 30 tM. Figure 1B shows the partial densitometric scan of an autoradiograph of a Western blot from the SDS-PAGE gel of the method described in Example 21 wherein the FPTase inhibitory compound was Compound E at a concentration of 0.3 pM. Figure 1C shows the partial densitometric scan of an autoradiograph of a Western blot from the SDS-PAGE gel of the method described in Example 21 wherein a combination of FPTase inhibitory compounds was utilized (Compound D at a concentration of 30 pM and Compound E at a concentration of 0.3 JM).
FIGURE 2A and 2B: In vivo Assessment of a Combination of Compound C and Compound
A:
Figure 2A graphically illustrates the data from a Western blot from the SDS-PAGE gel of the method described in Example 21 wherein the FPTase inhibitory compound was Compound C at various concentrations.
Figure 2B graphically illustrates the data from a Western blot from the SDS-PAGE gel of the method described in Example 21 wherein a combination of FPTase inhibitory compounds (Compound C at various concentrations and Compound A at a concentration of 0.03 tM) was utilized.
DETAILED DESCRIPTION OF THE INVENTION The term "synergistic" as used herein means that the effect achieved with the methods and compositions of this invention is greater than the sum of the effects that result from methods and compositions WO 97/01275 PCT/US96/11022 -6comprising the farnesyl-protein transferase inhibitors of this invention separately and in the amounts employed in the methods and compositions hereof.
The term "additive" as used herein means that the effect achieved with the methods and compositions of this invention is equal to the sum of the effects that result from methods and compositions comprising the famesyl-protein transferase inhibitors of this invention separately and in the amounts employed in the methods and compositions hereof.
According to one aspect of this invention, it is now possible to achieve an additive or synergistic therapeutic effect in a mammal with amounts of a protein substrate-competitive inhibitor and farnesyl pyrophosphate-competitive inhibitor which, if administered in said amounts singly, are not capable of achieving said effect. The preferred therapeutic effects achieved according to this aspect of the invention are inhibition of farnesyl-protein transferase in a mammal in need of such inhibition and treatment of cancer. The administration of the protein substrate-competitive inhibitor and farnesyl pyrophosphate-competitive inhibitor can be sequential in time or simultaneous with the simultaneous method being preferred.
Because of the additive or synergistic therapeutic effects achieved by administration of a protein substrate-competitive inhibitor and a farnesyl pyrophosphate-competitive inhibitor, this invention provides particularly advantageous methods of achieving a therapeutic inhibition of famesyl-protein transferase and treatment of cancer with less than therapeutic levels of a protein substrate-competitive inhibitor and/or a famesyl pyrophosphate-competitive inhibitor. Therefore, in practicing this invention, it is possible to minimize potential adverse effects which are not associated with inhibition of farnesyl-protein transferase and may be associated with larger, therapeutic doses of the protein substratecompetitive inhibitor and/or the farnesyl pyrophosphate-competitive inhibitor, and still achieve a farnesyl-protein transferase inhibiting or cancer treating effect.
WO 97/01275 PCT/US96/11022 -7- The present invention is not limited in any way by the specific protein substrate-competitive inhibitor and/or farnesyl pyrophosphate-competitive inhibitor but is applicable to such protein substrate-competitive inhibitors and faresyl pyrophosphate-competitive inhibitors now known or subsequently discovered or developed.
Farnesyl-protein transferase inhibitors useful in the instant invention are described hereinbelow. It is the co-administration of a protein substratecompetitive inhibitor and a famesyl pyrophosphate-competitive inhibitor as taught by this invention and not the particular protein substratecompetitive inhibitor and/or faresyl pyrophosphate-competitive inhibitor which brings about the additive or synergistic effect of this invention.
Nonetheless, the preferred protein substrate-competitive inhibitors for use in the methods an compositions of this invention and preferred farnesyl pyrophosphate-competitive inhibitors are described hereinbelow.
The composition of the instant invention may comprise a protein substrate-competitive inhibitor that incorporates a cysteinyl or sulfhydryl containing moiety at the N-terminus of the molecule. Thus the following compounds, well known in the art, are useful as protein substrate-competitive inhibitors in the instant invention: a) a peptide that comprises the amino acids CA1A2X, wherein: C cysteine; Al an aliphatic amino acid; A2 an aliphatic amino acid; and X any amino acid; b) Cys Xaa 1 Xaa 2 Xaa 3
NRR
1 wherein Cys cysteine; Xaa 1 any amino acid in the natural L-isomer form; Xaa 2 any amino acid in the natural L-isomer form; and Xaa 3
NRR
1 an amide of any amino acid in the natural Lisomer form, wherein R and R 1 are independently selected from hydrogen, C1-C12 alkyl, aralkyl, or unsubstituted or substituted aryl; WO 97/01275 PCT/US96/11022 -8c) Cys Xaal Xaa 2 Xaa 3 wherein Cys cysteine; Xaa any amino acid; Xaa 2 the amino acid phenyl alanine or a pfluorophenylalanine; and Xaa 3 any amino acid; d) Cys Xaal dXaa 2 Xaa 3 wherein Cys cysteine; Xaal any amino acid in the natural L-isomer form; dXaa 2 any amino acid in the natural L-isomer form; and Xaa 3 any amino acid in the natural L-isomer form; e) U.S. Pat. No. 5,238,922, incorporated herein by reference, X R 2 H Z R4 R'NH N
OR
HS Y
H
wherein: X, Y, and Z are independently H2 or O, provided that at least one of these is H2;
R
1 is H, an alkyl group, an acyl group, an alkylsulfonyl group or aryl sulfonyl group, wherein alkyl and acyl groups comprise straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms, or in the alternative,
R
1 NH may be absent;
R
2
R
3 and R 4 are the side chains of naturally occurring amino acids, or in the alternative may be substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or WO 97/01275 PCT/US96/11022 -9saturated chains of 2 to 8 carbon atoms, wherein the aliphatic substitutents may be substituted iwth an aromatic or heteroaromatic ring; and
R
5 is H or a straight or branched chain aliphatic group, which may be substituted with an aromatic or heteroaromatic group; f) U.S. Pat. No. 5,340,828, incorporated herein by reference, X R 2 0 ZH R'NH N n OH H
N
HS Y R 3 wherein: X and Y are independently H2 or O, provided that at least one of these is H2; R1 is H, an alkyl group, an acyl group, an alkylsulfonyl group or aryl sulfonyl group, wherein alkyl and acyl groups comprise straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms, or in the alternative,
R
1 NH may be absent;
R
2 and R 3 are the side chains of naturally occurring amino acids, or in the alternative may be substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or saturated chains of 2 to 8 carbon atoms, wherein the aliphatic substitutents may be substituted with an aromatic or heteroaromatic ring; Z is O or S; and WO 97/01275 PCT/US96/11022 n is 0, 1 or 2; g) U.S. Pat. No. 5,340,828, incorporated herein by reference, XRNH
R
2 H n Z H
N
HS Y R 3 H 0 wherein: X and Y are independently H2 or O, provided that at least one of these is H2;
R
1 is H, an alkyl group, an acyl group, an alkylsulfonyl group or aryl sulfonyl group, wherein alkyl and acyl groups comprise straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms, or in the alternative, RINH may be absent;
R
2 and R 3 are the side chains of naturally occurring amino acids, or in the alternative may be substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or saturated chains of 2 to 8 carbon atoms, wherein the aliphatic substitutents may be substituted with an aromatic or heteroaromatic ring; Z is O or S; and n is 0, 1 or 2; h) U.S.Pat. No. 5,352,705, incorporated herein by reference, 11 x
R'NH
N
H
HS"
2
H
R3
Y
wherein: X and Y are independently H2 or O; R1 is S S. *5S* 0@
I
I.
5.55
S
S
S
0 0 0**5 0505
S.
56 5.5.
S
C
R2 is an alkyl group, hydrogen, an acyl group, an alkylsulfonyl group or arylsulfonyl group, wherein alkyl and acyl groups comprise straight chain or branched chain hydrocarbons of 1 to 6 carbons atoms, which alternatively may be substituted with an aryl group; the side chains of naturally occurring amino acids, or in the alternative may be substituted or unsubstituted aliphatic, aromatic or heterocyclic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or saturated chains of 2 to 8 carbon atoms which may be branched or unbranched, wherein the aliphatic substituents may be substituted with an aromatic or heteroaromatic ring; an aromatic or heteroaromatic ring or in the alternative an alkyl group or an aryl or heteroaryl substituted alkane, wherein the aromatic ring is unsubstituted or in the alternative, substituted with one or more groups which may be alkyl, halo, alkoxy, trifluoromethyl, or sulfamoyl groups, and which may be polycyclic; 20 R 3 is i) U.S. Patent. No. 5,326,773 and PCT Publication WO 94/10137, incorporated herein by reference, WO 97/01275 PCT/US96/11022 -12-
HS
HS
OH
'N OH H 0
O
R
2
R
5 b O R'N.
N
S, s a
H
R R 3 0 wherein: R1 and R5a are independently selected from: hydrogen, a C -C6 alkyl group, a C1-C6 acyl group, an aroyl group, a C1-C6 alkylsulfonyl group, C1-C6 aralkylsulfonyl group or arylsulfonyl group wherein the alkyl group and acyl group is optionally substituted with substituted or unsubstituted aryl or heterocycle; WO 97/01275 PCT/US96/11022 -13-
R
2
R
3 and R 4 are independently selected from: a) a side chain of naturally occurring amino acids, b) an oxidized form of a side chain of naturally occurring amino acids selected from methionine sulfoxide and methionine sulfone, c) substituted or unsubstituted C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, aryl or heterocycle groups, wherein the aliphatic substituent is optionally substituted with an aryl, heterocycle or C3-C8 cycloalkyl; is a C1-C6 alkyl group, a C1-C6 acyl group, an aroyl group, a C1-C6 alkylsulfonyl group, C1-C6 aralkylsulfonyl group or arylsulfonyl group wherein the alkyl group and acyl group is optionally substituted with substituted or unsubstituted aryl or heterocycle;
R
6 is a substituted or unsubstituted aliphatic, aryl or heterocyclic group, wherein the aliphatic substituent is optionally substituted with an aryl or heterocyclic ring; and n is 0, 1 or 2; j) U.S. Pat. No. 5,504,212, incorporated herein by reference, WO 97/01275 PCT/US96/11022 -14-
R
1 NHI 0 R N N HS H
HS
HS
wherein: R I is selected from: hydrogen, a C I -C6 alkyl group, a C I -C6 acyl group, an aroyl group, a C I -C6 alkylsulfonyl group, C I -C6 aralkylsulfonyl group or arylsuifonyl group wherein the alkyl group and acyl group is optionally substituted with substituted or unsubstituted aryl. or heterocycle;
R
2
R
3 and R 4 are independently selected from: a) a side chain of naturally occurring amino acids, b) an oxidized form of a side chain of naturally occurring amino acids selected from methionine sulfoxide and methionine sulfone, c) substituted or unsubstituted C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, aryl or heterocycle groups, wherein the aliphatic substituent is optionally substituted with an aryl, heterocycle or C3-C8 cycloalkyl; X is CH2CH2 or trans CH=CH;
R
6 is a substituted or unsubstituted aliphatic, aryl or heterocyclic group, wherein the aliphatic substituent is optionally S. 15 substituted with an aryl or heterocyclic ring; and nis 0, 1 or 2; k) PCT Publication WO 94/10138 and U.S. Patent No. 5,686,472, 20 incorporated herein by reference, R 2 0 OH
R
2
O
R'NH Tn
OH
N: N N 9H 9 H
H
HS R 4
R
2
O
R'NH NR4
O
H R3 e"
O
HS R4 WO 97/01275 PCT/US96/11022 -16-
R
2 0 R R'NH N yOH S H R 3 ,1 H HS R R4 O
III
or
R
2 0 R R'NH N T N, OR 6 H 3l H HS R R 4
H
IV
wherein, R1 is hydrogen, an alkyl group, an aralkyl group, an acyl group, an aracyl group, an aroyl group, an alkylsulfonyl group, aralkylsulfonyl group or arylsulfonyl group, wherein alkyl and acyl groups comprise straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms; R2, R 3 and R5 are the side chains of naturally occurring amino acids, including their oxidized forms which may be methionine sulfoxide or methionine sulfone, or in the alternative may be substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or saturated chains of 2 to 8 carbon atoms which may be branched or unbranched, wherein the aliphatic substituents may be substituted with an aromatic or heteroaromatic ring; WO 97/01275 PCT/US96/11022 -17- R4 is hydrogen or an alkyl group, wherein the alkyl group comprises straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms; R6 is a substituted or unsubstituted aliphatic, aromatic or heteroaromatic group such as saturated chains of 1 to 8 carbon atoms, which may be branched or unbranched, wherein the aliphatic substituent may be substituted with an aromatic or heteroaromatic ring; T is O or S(O)m; m is 0, 1 or 2; and n is 0, 1 or 2; WO 97/01275 PCT/US96/11022 18 1) PCT Publication WO 95/00497, incorporated herein by reference, R 2
W
x HS N\ N- Z
F'R
4
A
B
C
wherein: X is 0Oor H2; m is Ilor 2; n is 0Oorl1; t is Ito 4; R and RI are independently selected from H, Ci.4 ailyl, oraralkyl; WO 97/01275 PCTIUS96I1 1022 -19-
R
2
R
3
R
4 and R 5 are independently selected from: Hl; C 1-8 alkyl, alkenyl, R% R 6
R
7 or6 alkynyl, aryl, heterocycle, 0 0 unsubstituted or substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) C 1-4 alkyl, b) (CH2)tOR 6 c) (CH2)tNR 6
R
7 d) halogen, 2) C3-6 cycloallcyl, 3)
OR
6 4) SR 6
S(O)R
6 S02R 6 -NR 6 R 7 6)6 0 7) 1 -N YNR R 8 0 j WO 97/01275 PCTIUS96/1 1022 8) -0O
NR
6
R
7 0 9) -0 OR 6 0
"YNR
6
R
7 0 11) -S0 2
-NR
6
R
7 12) -N-S0 2
-R
7 13) -r-R 6 ,or 0 14) r R6 0 and any two of R 2
R
3
R
4 and R 5 are optionally attached to the same carbon atom; Y is aryl, heterocycle, unsubstituted or substituted with one or more of: 1) C 1-.4 alkyl, unsubstituted or substituted with: a) C 1-4 alkoxy, b) NR 6
R
7 c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, 2) aryl or heterocycle, 3) halogen, 4) OR 6 WO 97/01275 PCTIUS96/1 1022 -21-
NR
6
R
7 6) CN, 7) N02, or 8) CF3; W is H2 orO0; Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more of the following: 1) Cl1-4 alkyl, unsubstituted or substituted with: a) C 1-.4 ailkoxy, b) NR 6
R
7 C) C3-.6 cycloalkyl, d) aryl. or heterocycle, or e) HO, 2) aryl or heterocycle, 3) halogen, 4) OR 6 5)
NR
6
R
7 6) CN, 7) N02, or 8) CF3;
R
6
R
7 and R 8 are independently selected from: H; Cl1 4 alkyl, C3-.6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) C 1 -4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, 22 e)
'YR
0 f) -S0 2 RI or g) NRRI, wherein
R
6 and R 7 may be joined in a ring, and
R
7 and R 8 may be joined in a ring; and
R
9 is C 1-4 alkyl or arailkyl; PCT Publication WO96/09821 and U.S. Patent No. 5,571,835, 10 incorporated herein by reference, 1 3
R
4 HS AV H 0 O H
R
1 HN H 2 )t Z 2 R 5a R 5 b
R
2 b R 2a R Z1
R
3 R 4 HS V H0
X..
Y
OR
6 RIHN 2 z 2 R 5 R 5 b
RH
2 R 2a R 2 WO 97/01275 PCTIUS96h11022 23 HS Z1 R 3
R
4 Y
OH
R'HN
(H
2 )t z2 R~aR 2 b HOCH 2 (0H 2 )q or HZ1 R 3
R
4
R
1 HN z2 H0 1
Z
R~b R
IV
wherein: R 1 is selected from: a) hydrogen, b) R 8
R
8
(R
8 )2NC(0)- or R 9 and c) ClI -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl,
R
8 0-,
R
8
R
8 C(O)NR8-, CN, (R 8 )2N-C(NR8)-,
R
8
R
8 N3, -N(R 8 or R 9
OC(O)NR
8 R2a and R2b are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl,
R
8
R
8
R
8 C(O)NR8-, CN, (R 8 )2N-C(NR8)-,
R
8
R
8 N3, -N(R 8 or R 9 OC(O)NR8-, c) aryl, heterocycle, cycloalkyl, alkenyl,
R
8 0-,
R
8
R
8 C(O)NR8-, CN, N02, (R 8 )2N-
C(NR
8
R
8
R
8 N3, -N(R 8 or
R
9
OC(O)NR
8 and WO 97/01275 PCT/US96/11022 -24d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3cycloalkyl; R3 and R4 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 C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R 8 N02, R 8
R
8 S(O)m-,
R
8
C(O)NR
8 CN, (R 8 )2N-C(NR8)-
R
8
R
8 N3, -N(R 8 )2,
R
9 0C(O)NR8- and Cl-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- CO1 cycloalkyl; or R3 and R 4 are combined to form (CH2)s 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 C 1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br,
N(R
8 N02, R 8
R
8
R
8
C(O)NR
8
CN,
WO 97/01275 PCTIUS96/z 1022 25
(R
8 )2N-C(NR8y..,
R
8
R
8 N3, -N(R 8 )2,
R
9 OC(O)NR8- and Cl-C20 alkyl, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- CIO 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(COR 8
R
6 is a) substituted or unsubstituted ClI -C8 ailkyl, wherein the substituent on the alkyl is selected from: 1) aryl, 2) heterocycle, 3) -N(R 9 )2, 4) -OR 8 or b)
RO
0 0'J
R".
WO 97/01275 PCT/US96/11022 -26- X-Y is R7a a) "y4 N O 0
R
7 b b)
N
c) s, (0)m d S
H
e) A or
H
f)
-CH
2
-CH
2 R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, I~i WO 97/01275 PCT/US96/11022 -27c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl;
R
8 is independently selected from hydrogen, C1-C6 alkyl and aryl;
R
9 is independently selected from C -C6 alkyl and aryl;
R
10 is independently selected from hydrogen and C1-C6 alkyl;
R
1 1 is independently selected from C1-C6 alkyl; Z1 and Z 2 are independently H2 or O, provided that Z1 is not O when X-Y is C(O)N(R 7 mis 0, 1 or 2; qis 0, 1 or 2; s is 4 or 5; and t is 3, 4 or 28 n) PCT Publication WO 96/09820 and U.S. Patent No. 5,491,164 incorporated herein by reference, HS z
XY
R
1
HN
wherein: Ri is selected from: a) hydrogen, b) R 5
R
5
(R
5 )2NC(O)- or R 6 and c) ClI-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl,
R
5 0-,
R
5
R
5
C(O)NR
5 CN, (R 5
R
5
R
5 N3, -N(R 5 or R 6
OC(O)NR
5 R2a and R2b are independently selected from: a) hydrogen, b) C I-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloallcyl, alkenyl, R 5
R
5 S(O)m-,
R
5
C(O)NR
5 CN, (R 5 )2N-C(NR 5
R
5
R
5 N3, -N(R 5 or R 6
OC(O)NR
5 and c) aryl, heterocycle, cycloalkyl, alkenyl, R 5
R
5 S(O)m-
,R
5
C(O)NR
5 CN, N02, (R 5 )2N-C(NR 5
R
5
R
5 N3, -N(R 5 or R 6
OC(O)NR
5
R
3 is selected from: a) unsubstituted or substituted aryl, b) unsubstituted or substituted heterocycle, c) unsubstituted or substituted cycloalkyl, and WO 97/01275 PCT/US96/11022 -29d) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; X-Y is R4a a) y N nr
N
0
R
4 b b) c)
O
(0)m d) s S.
H
e) ,o
H
f) -CH 2
-CH
2 R4a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R4b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and 15 g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl;
R
5 is independently selected from hydrogen, C1-C6 alkyl and aryl;
R
6 is independently selected from C1-C6 alkyl and aryl; Z is independently H2 or O; m is 0, 1 or 2, provided that m is 0 when R 5 hydrogen; nis 0, 1,2, 3 or4; and t is 3, 4 or and p) U.s. Patent No. 5,631,280, incorporated herein by reference, WO 97/01275 PCTIUS96/11022 -31- HS- mN~
A
N R R R 1 R 3 R 4 HS A A n j -V" Z R 1 PB x
Y
HS m NJ /N \R 2 R R 1 R3
P
X w HS m N n' N 2I\ wherein: X and Y are independently 0 or H2; m is Ilor 2; n is 0Oorl1; p is 1, 2or 3; q is 0,l1or 2; t is Ilto 4; R, R I and R 2 are independently selected from: H, C 1-6 alkyl, or Ci1 -6 aralkyl;
R
3 and R 4 are independently selected from: WO 97/01275 PCTfUS96/11022 32 a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by C2-C6 alkenyl,
R
6
R
5
R'
7
C(O)NR
6 CN, N3, R 6
OC(O)NR
6
R
6
R
7
N-C(NR
6
R
8
R
6
R
7
R
8 NC(O)O-, R 7
R
8
NC(O)-
R
6
R
7
-NR
6 S(O)2R5, R 6 OC(O)O-, -NR 6
R
7 or
R
7
R
8
NC(O)NR
6 c) unsubstituted or substituted cycloalkyl, alkenyl,
R
6
R
5
R
6
C(O)NR
6 CN, N02,
R
6
R
7
N-C(NR
8
R
6 N3, -NR 6
R
7 halogen or R 7
OC(O)NR
6 and d) CI -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C1O cycloalkyl; W is -CHR 9 or -R- Z is unsubstituted or substituted Cl 1-8 ailkyl, unsubstituted or substituted C2-8 alcenyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle; wherein the substituted group is substituted with one or more of: 1) C 1-4 alkyl, unsubstituted or substituted with: a) Cl1-4 alkoxy, b) NR 6
R
7 c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, 2) aryl. or heterocycle, 3) halogen, 4) OR 6 5) NR 6
R
7 6) CN, 7) N02, or 9) CF3; WO 97/01275 PCT/US96/11022 33
R
5 is C 1-4 alkyl or arailkyl;
R
6
R
7 and R 8 are independently selected from: H, Cl-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) C 1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e)
R
0 f) -S0 2
R
5 ,or g) -NR 6
R
7 or
R
6 and R 7 may be joined in a ring, and
R
7 and R 8 may be joined in a ring;
R
9 is selected from: H, C1-4 alkyl, C3-6 cycloalcyl, heterocycle and aryl, unsubstituted, monosubstituted or disubstituted with substituents independently selected from: a) C1 4 alkyl, b) C 1 4 alkoxy, c) aryl or heterocycle, d) halogen, e) HO, f)
'*YR
0 g) -S0 2
R
5 ,and h) -NR 6
R
7 -34- V is selected from: -C(R 1 -C(R 1)2- -C(OR11)R11_, -CN(R11)2R 11, -OC(R11)2-, -NR11C(R11)2-,
-C(R
1 1 )20- -C(R 1 1 )2NR 1 1 -C(O)NR11-,
-NR
1 1
C(
O
0, -NC(0)R 11, -NC(O)OR 11, -S(0)2N(R -N(R 11)S(0)2-, or S(O)m;
R
10 and R11 are independently selected from hydrogen, C1-C6 alkyl, C2-C4 alkenyl, benzyl and aryl; or the pharmaceutically acceptable salt thereof.
The composition of the instant invention may alternatively or in addition comprise a protein substrate-competitive inhibitor that does not incorporates a cysteinyl or sulfhydryl containing moiety at the N- 15 terminus of the molecule. The lack of a sulfhydryl offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. Thus the following compounds, well known in the art, 20 are also useful as protein substrate-competitive inhibitors in the instant invention: PCT Publication WO 95/09001 and U.S. Patent No. 5,576,293 incorporated herein by reference, WO 97/01275 PCTIIJS96/11022 35 z R1k R 3 R 4 0 R 5 a R 5 b N *'OR 6 H 0 R 3 R 4 Z W'-
(CH
2 )nCH 2
OH
f--fIOH 0 Z R 2 a R2b Z N QXY N 0 Rlo H R 3
R
4 0 WO 97/01275 PCT/US96/11022 -36- R is selected from: a) heterocycle, and b) C1-C10 alkyl, which is substituted with heterocycle and which is optionally substituted with one or more of C1-C4 alkyl, hydroxy or amino groups; R2a and R2b 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 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, C, Br, N02, R 8
R
9
R
8 C(O)NR8-, CN, (R 8 )2N-
C(NR
8
R
8
R
8 N3, -N(R 8 )2,
R
9 0C(O)NR8- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3cycloalkyl; or R2a and R2b are combined to form (CH2)s R3 and R4 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 C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br,
N(R
8 N02, R 8
R
9
R
8
C(O)NR
8 WO 97/01275 PCT/US96/11022 -37- CN, (R 8 )2N-C(NR 8
R
8
R
8 N3,
-N(R
8
R
9 0C(O)NR8- and C1-C20 alkyl,, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- C10 cycloalkyl; or R3 and R 4 are combined to form (CH2)s 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 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br,
N(R
8 N02, R 8
R
9
R
8
C(O)NR
8 CN, (R 8 )2N-C(NR 8
R
8
R
8 N3,
-N(R
8
R
9 0C(O)NR 8 and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3cycloalkyl; or R5a 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(COR 8
R
6 is a) substituted or unsubstituted C1-C8'alkyl, wherein the substituent on the alkyl is selected from: 1) aryl, 2) heterocycle, 3) -N(R 9 )2, WO 97/01275 PCT/US96/11022 -38- 4) -OR 8 or b)
R
10 0 O R" X-Y is R7a a) Sv N.
O 0
R
7 b b) \f N c) O (0)m d) Ss
H
e) ,or
H
f) -CH 2
-CH
2 R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, "IL.Yr~l- L WO 97/01275 PCT/US96/11022 -39d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;
R
8 is independently selected from hydrogen, C1-C6 alkyl and aryl;
R
9 is independently selected from C1-C6 alkyl and aryl; is independently selected from hydrogen and C1-C6 alkyl; R11 is independently selected from C1-C6 alkyl; Z is independently H2 or O; WO 97/01275 PCT/US96/11022 m is 0, 1 or 2; n isO0, 1 or 2; and s is 4or r) PCT Publication WO 95/09000 and incorporated herein by reference, O R 2
Z
R 3R4 U.S. Pat. No. 5,468,773, jyOH 0 0 R 2 z V NAX R 3R 4
H)CH
2
O
O R 2 z v N kX.,
N
R
3 R 4 In and O R 2
Z
R3 R 4
IV
CH2, 0, S, HN, or R 7
N;
wherein: V is
I
WO 97/01275 PCT/US96/11022 -41- R2, R3, R4 and R5 are independently the side chains of naturally occurring amino acids, including their oxidized forms which may be methionine sulfoxide or methionine sulfone, or in the alternative may be substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or saturated chains of 2 to 8 carbon atoms which may be branched or unbranched, wherein the aliphatic substituents may be substituted with an aromatic or heteroaromatic ring; X-Y is
R
a)
N
O 0
R
7 (0)m d) "iS
H
e) ,or
H
f) -CH 2
-CH
2 WO 97/01275 PCT/US96/11022 -42- R6 is a substituted or unsubstituted aliphatic, aromatic or heteroaromatic group such as saturated chains of 1 to 8 carbon atoms, which may be branched or unbranched, wherein the aliphatic substituent may be substituted with an aromatic or heteroaromatic ring; an alkyl group, wherein the alkyl group comprises straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms, which may be substituted with an aromatic or heteroaromatic group; R7 is Zis m is n is ois H2 or O; 0, 1 or 2; 0, 1 or 2; and 0, 1, 2 or 3; 43 s) PCT Publication WO 96/09836 and U.S. Patent No. 5,585,359 incorporated herein by reference, (R )tZ
R
2 a R 2 b z R5a I a lb 2 )D 1~bR 9 )r N 'x X Y O H a a a a.
a.
a.
a. a.
a a a a a.
a a a a a a a a a a a a a a a a a a.
a a a *aa a VR 8)t (~b)(ClR)
II
V (C a2,- W (CR lb 2 )p(CR lb R 9 jH R 3 R 4 0
III
and V -(CR lb 2 )p(CRlb R 9 )r I
IV
q 0 0 wherein: Ria is selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, ailkenyl, alkynyl,
(R
1 0 )2N-C(NRIO)-, RIOC(O)-, or RIOOC(O)-, and WO 97/01275 PCTIUS96IUO022 -44c) Ci1 -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 10 0-, R' 1 R I C(O)NR 10-, CN, (R 10 )2N-C(NR'10)-, RlOC(O)-, RIOOC(O)-, N3, N(R'0)2, or R I Rib is independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, cycloalkyl, alkenyl, alkynyl, (R I 0 )2N-C(NRl10)-, R IOC(O)-, or R I 0C(O)-, and c) C 1 -C6 ailkyl unsubstituted or substituted by unsubstituted or substituted aryl, cycloalcyl, ailcenyl, alkynyl, R 1 0 R I IS(O)m-, RIOC(O)NRIO-,
CN,
(RIO)2N-C(NRIO)-, RlOC(O)-, RIO0C(O)-, N3, or RI 1 1 0C(O)NRlO-; provided that Ri1b is not R IOC(O)NR 10- when R I is ailcenyl, V is hydrogen and X-Y is -C(O)NR 7 R2a and R2b 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, c) substituted or unsubstituted C I -C20 alkyl, C2-C20 alkenyl, C 3-C 10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, RIO0-, R 1 1 RIOC(O)NR10-,
CN,
(R
10 )2N-C(NR1O)-, RIOC(O)-, RIO0C(O)-, N3, -N(R 10)2, R1 1 0C(O)NR 10- and C I-C20 allcyl,and d) Ci -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3cycloalkyl; or
I
WO 97/01275 PCT/US96/11022 R2a and R2b are combined to form (CH2)s R3 and R4 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-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br,
N(R
10 N02, R 10
R
1 1
R
10 CN, (R10)2N-C(NR 1 0 R10C(O)-, R 10 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 C3cycloalkyl; or R3 and R4 are combined to form (CH2)s and R5b 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 -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 10 R11S(O)m-, R 10 C(O)NR10-, CN, (R10)2N-C(NR 1 R10C(O)-, R10OC(O)-, N3,
-N(R
10
R
1 lOC(O)NR 1 O- and C1-C20 alkyl, and WO 97/01275 PCT/US96/11022 -46d) C 1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3cycloalkyl; 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(COR10)
R
6 is a) substituted or unsubstituted C1-C8 alkyl, wherein the substituent on the alkyl is selected from: 1) aryl, 2) heterocycle, 3) -N(R11)2, 4) -OR10, or b)
R
12 0 V\ O R13
II
WO 97/01275 PCT/US96/11022 -47- X-Y is R7a
I
a) V
N
o
R
7 b b) c) ""0O (0)m d) \f
S
H
e) or
H
f) -CH 2
-CH
2 R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, f' WO 97/01275 PCT/US96/11022 -48c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10
R
1 1 S(O)m-,
R
1
OC(O)NR
1 CN, N02, R 10 R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 R11S(O)m-, RIOC(O)NH-, CN, H2N- RO1C(O)-, R 10 N3, -N(R10)2, or
R
1 1 0C(O)NH-; R9 is selected from: hydrogen, C1-C6 alkyl, R 10
R
1 1 S(O)m-,
R
1
OC(O)NRO
1 CN, N02, N3, -N(R10)2, and
R
11 WO 97/01275 PCT/US96/11022 -49provided that R 9 is not R1OC(O)NR10- when Ria is alkenyl, V is hydrogen and X-Y is -C(O)NR 7 a-;
R
10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R
11 is independently selected from C1-C6 alkyl and aryl;
R
12 is independently selected from hydrogen and C1-C6 alkyl;
R
13 is C1-C6 alkyl; V is selected from: a) aryl; b) heterocycle; or c) hydrogen; W is -NHSO2-, -SO2NH-,
-N(R
7 or -N[C(0)R7a]-; Z is independently H2 or O; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4, provided that n 0 when V is hydrogen and W is p is 0, 1, 2, 3 or 4, provided that p 0 when R 9 is not hydrogen or C1-C6 lower alkyl; q is 0, 1 or 2; ris 0orl; s is 4 or 5; and t is 0, 1 or 2, provided that t 0 when V is hydrogen; WO 97/01275 WO 9701275PCTIUS96/11022 50 t) PCT Publication WO 96/10011 and U.S. Serial No. 08/3 15,046, incorporated herein by reference, 0 Z R 2aR 2 b Z R 5 a R 5 b V NCR 2) Ci. N(
R
R 12
H
R~b R 3
R
4 R 8b R 8b H 1
R
3
R
4 0 and N 0 H 0 q R 8 b
R
3
R
4 wherein: RI is hydrogen, Cl1-C6 alkyl or aryl; WO 97/01275 PCT/US96/11022 -51- R2a and R2b 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 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N02, R 9
R
10
R
9
C(O)NR
9 CN, (R 9 )2N-
C(NR
9
R
9
R
9 N3, -N(R 9 )2, R 10C(O)NR 9 and Cl-C20 alkyl, and d) C -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; or R2a and R2b are combined to form (CH2)s R3 and R4 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-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N02, R 9
R
10
R
9
C(O)NR
9 CN, (R 9 )2N-
C(NR
9
R
9
R
9 N3, -N(R 9 )2, R10OC(O)NR 9 and Cl-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C 10 cycloalkyl; or WO 97/01275 PCT/US96/11022 -52- R3 and R4 are combined to form (CH2)s 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 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, NO2, R 9
R
10
R
9
C(O)NR
9 CN, (R 9 )2N-
C(NR
9
R
9
R
9 N3, -N(R 9 )2, R10OC(O)NR9- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3cycloalkyl; 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(COR 9
R
6 is a) substituted or unsubstituted C1-C8 alkyl, wherein the substituent on the alkyl is selected from: 1) aryl, 2) heterocycle, 3) -N(R10)2, 4) -OR 9 or b)
R
12
O
^O'K R 13 j
I
WO 97/01275 PCT/US96/11022 -53- X-Y is
R
7 a a)
N
0
R
7 b b) \V
N
c) 0 (0)m d)
S
H
e) or
H
f) -CH 2
-CH
2 R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, WO 97/01275 PCT/US96/11022 -54e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R8a and R8b are independently selected from: hydrogen, F, Cl, Br, N02, R 1 10-, R10S(O)m-, CN,
R
9 C(0)NR 9
(R
9 )2N-C(NR 9
R
9
R
9 0C(0)-, N3, -N(R 9 R10OC(0)NR 9 C1-C20 alkyl, aryl, heterocycle or C1-C20 alkyl substituted with aryl or heterocycle;
R
9 is independently selected from hydrogen, C1-C6 alkyl and aryl;
R
1 0 is independently selected from C1-C6 alkyl and aryl;
R
1 1 is independently selected from hydrogen, C -C6 alkyl and aryl, provided R 1 is C1-C6 alkyl when n is 0;
R
12 is independently hydrogen or C1-C6 alkyl;
R
13 is Cl-C6 alkyl; O is aryl or 1,2,3,4-tetrahydronaphthyl; 55 Z is independently H2 or 0; m is 0, 1 or 2; n is independently 0 to 4; p is 0 or 1; q is0, 1or 2;and s is u) PCT Publication WO 96/10034 and U.S. Patent No. 5,652,257, incorporated herein by reference, WO 97/01275 WO 9701275PCTIUS96/11022 56-
(R
8 )r R9zR 2 a R2b Z R 5 a R V -A'CR 2 )nA(C' 2 )n W -(CR' 2 N1X2 'P R' 2 R H
(R
8 )r
R
9 Z R 2 a R2b Z R 5 a
-A'(CR'
2 )nA (CR 1 2 )n W (CR' 2 )P N 12 N O R 8
HOCH
2
(CH
2 )q
R
9 Z R 2 a R 2 b Z V A' (CR' 2 )nA (CR1 2 )n W (CR' 2 )P N 12
O
SR'
R
3 4 H 0 or (R )r R9Z R 2 a R 2 b Zq V (CR' )A 2
(CR'
2 W -(CR 1 N 0
R
3 R 4 0
IV
wherein: R I is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 10 0-
TR
1 IS(O)m-, RIOC(O)NRIO-, CN, N02, (RIO)2N- C(NRIO)-, RlOC(O)-, R 1 0 N3, -N(RIO)2, or R1 1 0C(O)NR 1 0-, c) C I -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalicyl, alkenyl, alkynyl, R 10 0-, R I S R 1 I C(O)NR 1 CN, (Ri 102N-C(NR WO 97/01275 WO 9701275PCT/US96/1 1022 57 RIOC(O)-, RIO0C(O)-, N3, -N(R' 0 or RI 1 0C(O)NRIO-; R2a and R2b 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 I -C20 ailkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl. or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, Rl 0 RIIS(O)m-, RIOC(O)NRIO-, CN, (RI 0 )2N-C(NR10)-, R lOC(O)-, R 1 0 N3, -N(RIO)2, R 1 I0C(O)NRIO- and Cl-C20 alkyl, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- CIO cycloalkyl; or R2a and R2b are combined to form (CH2)s
R
3 and R4 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, c) substituted or unsubstituted ClI -C20 alkyl, C2-C20 alkenyl, C 3-Cl10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(RIO)2, N02, R 10 RI Rl 0 CN, (Rl 0 )2N-C(NRIO)-, RIOC(O)-, RIO0C(O)-, N3, -N(R 10 Rl 11OC(O)NR 10- and Cl1-C20 alkyl, and WO 97/01275 PCT/US96/11022 58d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3cycloalkyl; or R3 and R 4 are combined to form (CH2)s 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 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(R10)2, N02, R 10
R
1 1 RO1C(O)NR1O-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3,
-N(R
10 R11OC(O)NR10- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3cycloalkyl; 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
R
6 is a) substituted or unsubstituted C1-C8 alkyl, wherein the substituent on the alkyl is selected from: 1) aryl, 2) heterocycle, 3) -N(R11) 2 4) -OR10, or WO 97/01275 PTU9/12 PCTfUS96/11022 59 \Z OJ 0 R 13 X-Y is a)
>N
0
R
7 b b)N
C)
d)
H
e) o
H
f) -CH 2 -0H 2 R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C I -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; 1 WO 97/01275 PCT/US96/11022 R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 R 1 S(O)m-, R10C(O)NR 1 CN, N02, R 10 2N-C(NR10)-,
R
10 N3, -N(R10)2, or R11
O
C(O)NR
10 and c) C -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R1 0
R
1 1 S(O)m-,
R
1 OC(O)NH-, CN, H2N-C(NH)-, N3, -N(R10)2, or R 11OC(O)NH-; R9 is selected from: WO 97/01275 WO 9701275PCTIUS96/11022 61 a) hydrogen, b) alkenyl, aikynyl, peffluoroalkyl, F, Cl, Br, RIO0-, R I IS(O)m-, RIOC(O)NR10-, CN, N02, (RIO)2N- C(NRIO)-, RIOC(O)-, RIOOC(O)-, N3, -N(RIO)2, or R 1 10C(O)NR 10-, and c) C I -C6 alkyl unsubstituted or substituted by peffluoroalkyl, F, Cl, Br, R1 0 RI 1 S(O)m-,
R
1 0 C(O)NR CN, (Ri 0 )2N-C(NR
R
1
OC(O)-,
RIO0C(O)-, N3, -N(RiO)2, or RI IOC(O)NRIO-; R 10 is independently selected from hydrogen, C1I-C6 alkyl and aryl; R 1 1 is independently selected from C1I-C6 alkyl and aryl; R 12 is independently selected from hydrogen and C I-C6 ailkyl; R 1 3 is independently selected from C I-C6 alkyl;
A
1 I and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NRi10-, 0, -N(R
-NR
1 -S(0)2N(RIO0>., -N(RI 0 or S (O)m; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) ClI -C20 ailkyl wherein from 0 to 4 non-terminal 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 A 1 is a bond, n is 0 and A 2 is S (O)m or a bond; W is a heterocycle; 62 Z is independently H2 or 0; mnis 0, 1 or 2; n is 0, 1,2, 3or 4; pis 0, 1,2, 3or4; q isO0, lor 2; r is 0 to 5, provided that r is 0 when V is hydrogen; and s is 4 or v) PCT Publication WO 96/10035 and U.S. Patent Nos. 5,661,161 and 5,872,135, incorporated herein reference, M -1
M
WO 97/01275 PCT/US96/11022 63 (R )r
R
VAl(CRla 2 )nA (CRlA 2
-W
(R )r
R
A A(CRla 2 )nA (CRlA (W)u if OR 6
(R
8 )r
R
I II V -A'l(CRa 2 )nA 2 (CRla 2 )n (W/u z ~R 3 R 4 (CR1 b 2 O z R 2,_CRb HOCH 2 (0H 2 )q (R )r 7 R9 z R 3 R 4 0 V A(CR~ 2 )nA(C 2 )n NWi (CR' 2 Z IV R2aR 2 bq wherein: R Ia and R Ib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 RI IS(O)m-, RIOC(0)NRIO-, CN, N02, WO 97/01275 WO 9701275PCTIUS96/11022 -64- (Ri 0 )2N-C(NRIO0>, Ri
R
1 0 N3, -N(R 10)2, or R 11 OC(O)NR C) C I -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 R I IS(O)m-, R I C(O)NR 10-, CN, (RI 0 )2N-C(NRIO0>, RI RI 0 N3, -N(RI 0)2, or R1 R2a and R2b are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by C2-C6 alkenyl, RIO0-, RI 1 RIOC(O)NRIO-, CN, N3, (RIO)2N- RIOC(O)-, R 10
-N(R
1 0 or R1 1 OC(O)NR 1 c) aryl, heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, RIO0-,
R
1 1 Rl 0 C(O)NRIO-, CN, N02, (R' 0 )2N-C(NRIO)-, RIOC(O)-, RIO0C(O)-, N3, -N(RlO)2, or RI I0C(O)NRIO-, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C1O cycloalkyl; R3 and R 4 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 Il-C2o alkyl, C2-C20 alkenyl, C3-C 10 cycloalcyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R 10 N02, R 1 0 R 11 R IOC(O)NR CN, (RIO)2N-C(NR1O)-, RIOC(O)-, RIO0C(O)-, N3, -N(RIO)2, RI 1 OC(O)NR10- and Cl-C20 alkyl, and 1 WO 97/01275 PCT/US96/11022 d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3cycloalkyl; or R3 and R 4 are combined to form (CH2)s 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 C 1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, CF3, N(R 10 N02, R 1 0
R
1 1 S(O)m-, RlOC(O)NRO 1 CN, (R1O)2N-C(NR10)-, N3, -N(R 10
R
11
OC(O)NR
10 and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C 10 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,
R
6 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, WO 97/01275PT[S9/12 PCTIUS96/11022 66- 2) aryl, 3) heterocycle, 4) -N(R11) 2, -OR 10, or b) X-Y is a) s~Ns 0
R
7 b b)
N
C))
d)S
H
e) or
H
f) -CH 2 -0H 2 R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, WO 97/01275 PCT/US96/11022 -67c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C 10 cycloalkyl, and e) C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3- C 10 cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C 10 cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C10 cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C10 cycloalkyl and C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10
R
11 S(O)m-, R1OC(O)NR10-, CN, N02, R102N-C(NR10)-,
R
10 N3, -N(R 10 or R 1 1
OC(O)NR
10 and c) C 1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10
R
1 1 S(O)m-, WO 97/01275 WO 9701275PCTIUS96/11022 68 RIOC(O)NH-, CN, H2N-C(NH)-, RIOC(O)-, RIO0C(O)-, N3, -N(RiO)2, or RIOOC(O)NH-;
R
9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, peffluoroalkyl, F, Cl, Br, RIO0-, RI IS(O)m-, RIOC(O)NRIO-, CN, N02, (RIO)2N- C-(NR1O)-, RlOC(O)-, RIOOC(O)-, N3, -N(RlO)2, or R I I0C(O)NR 10-, and c) C1I-C6 alkyl unsubstituted or substituted by peffluoroallcyl, F, Cl, Br, R 1 0 RI IS R I C(O)NR 10-, CN, (RI 0 )2N-C(NRl R R 1 OOC(O)-, N3, -N(Rl 0)2, or R'lOC(O)NRIO-;
R
1 0 is independently selected from H, Cl-C6 alkyl, benzyl, substituted aryl and ClI-C6 alkyl substituted with substituted aryl; R 11 is independently selected from ClI-C6 alkyl and aryl; R 12 is hydrogen or ClI-C6 alkyl; R 1 3 is ClI-C6 alkyl;
A
1 I and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR10-, -NRIOC(O)-, 0, -N(RIO)-, -S(0)2N(RIO)-, -N(RIO)S(0)2-, or S(O)m; 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, WO 97/01275 PCT/US96/11022 -69 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; Z is independently H2 or O; m is n is pis q is r is s is t is uis 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 Oorl; w) U.S. Patent Nos. 5,534,537 and 5,578,629, incorporated herein by reference, Z R 3 a R4 OH N (CRib 2 )p i H Co Z R 3 a R4
OR
6 N (CRib 2 )pN Ra R 2 b
HOCH
2
(CH
2 )q z R 4
OH
H 6 R~a R 2 b ft.
ft ft ft ft ft...
ft ft ft ft Oft ft...
ft ft ft ft ft. ft.
ft ft ft ft ft ft.
ft ft ft 4* ft ft...
ft...
ft ft ft ft ft ft .4 ft.ft.
ft ft ft ft ft ft ft ft.
ft ft ft ft ft ftft ft ft ft ft. ft ft*ft ft
IN-
R R 2 b wherein: R Ia and R Ib are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, RIO0-, RI IS R I C(O)NR 10-, CN, N02, (Ri'b2N-C(NR' Oy, RI 0
R
1 OOC(O)-, N3, -N(Rl 0)2, 0 or R I I0C(O)NR 1 0-, WO 97/01275 PTU9/12 PCTfUS96/11022 71 c) C1I-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, ailkynyl, RIO0-, R I S R' 1 C(O)NR CN, (R I 0 )2N-C(NR 1 RIOC(O)-, R 10 N3, -N(RIO)2, or RI I0C(O)-
NRIO-
R2a and R2b are independently selected from: a) hydrogen, b) C1I-C6 alkyl unsubstituted or substituted by alkenyl, R 10 0-, RI IS(O)m-, RIOC(O)NRIO-, CN, N3, (Rl 0 )2N-C(NR'O)-, RIOC(O)-, RIO0C(O)-, -N(Rl 0 or RI IOC(O)NRIO-, c) aryl, heterocycle, cycloalkyl, alkenyl, RIOO-, RI IS(O)m-, RIOC(O)NRIO-, CN, N02, (RIO)2N-
C(NR
1 RIOC(O)-, RIO0C(O)-, N3, -N(RIO)2, or R 1 OC(O)NR 10-, and d) C1I-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- C 1 cycloalkyl; R3a and R3b 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 suifone, and c) substituted or unsubstituted ClI -C20 alkyl, C2-C20 ailcenyl, C3-C 10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(RIO)2, N02, RIO0-, RI IS(O)m-, Rl 0
C(O)NRIO-,
CN, (Rl 0 )2N-C(NRIO)-, RIOC(O)-, RIO0C(O)-, N3, -N(RIO)2, RI 1 0C(O)NRIO- and CI-C20 alkyl, and WO 97/01275 WO 9701275PCTIUS96/11022 72 d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from-aryl, heterocycle and C3- CIO cycloalkyl; or R3a and R3b 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)-; R4 and R5 a) b) are independently selected from: hydrogen, and (R 4 )r V Al(CRla 2 (CRla 2 (w/C1 2 )P
R
6 is a) substituted or unsubstituted ClI -C8 alkyl or substituted or unsubstituted C5-C8 cycloalkyl, wherein the substituent on the ailkyl is selected from: 1) aryl, 2) heterocycle, 3) -N(R 11)2, 4) -OR 1 0 or
R
12 0o \z 0) R 1 3
R
7 is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R1 1
R
1 OC(O)NR CN, N02, R' 0 2N-C(NR 1 RlOC(O)-, RlOOC(O)-, N3, -N(RlO)2, or RI IOC(O)NRIO-, and WO 97/01275 WO 9701275PCTfUS96/11022 73 c) C1I-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, alynyl, perfluoroalkyl,
F,
Cl, Br, RIO0-, R 1 1 RIOC(O)NH-, CN, H2N- RIOC(O)-, RIOOC(O)-, N3, -N(RIO)2, or
RIOOC(O)NH-;
R8 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 0-, RI RIOC(O)NR10-, CN, N02, -N(R'10)2, or R 1 0C(O)NR 1 and c) C1I-C6 alkyl unsubstituted. or substituted by perfluoroalkyl, F, Cl, Br, RIO0-, RI IS(O)m-, RIOC(O)NRIO-,
CN,
(R'
0 )2N-C(NRIO)-, RIOC(O)-, RIO0C(O)-, N3, -N(RIO)2, or RI OC(O)NRlO-; R 10 is independently selected from hydrogen, ClI-C6 alkyl, benzyl and aryl.; R I is independently selected from C I -C6 alkyl and aryl;
R
12 is independently selected from hydrogen and ClI-C6 alkyl; R 13 is independently selected from C1I-C6 ailkyl; Al and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR 10-, -NR IOC(O)-, 0, -N(R 1 -S(0)2N(R -N(R 1 0 or S(O)m; V is selected from: a) hydrogen, b) heterocycle, c) aryl, WO 97/01275 PCT/US96/11022 -74d) 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(0)m; W is a heterocycle; Z is independently H2 or O; m is n is p is q is ris s is u is 0, 1 or 2; 0, 1, 2, 3 or 4; 0, 1,2, 3 or4; 0, 1 or 2; 0 to 5, provided that r is 0 when V is hydrogen; 4 or 5; and 0 or 1; 75 x) U.S. Patent Nos. 5,624,936 and 5,627,202, incorporated herein by reference, 9 9 9**4 9O 9.
SW
9* 99 9 9 9.
4 9 9 9.59 9* 9*99 9* 49 S 9.
S
I 9 (R 8 )r
R
R
VAl(CRla 2 (CRla 2
(R
8 )r
R
I a(a'I V A'(CRla 2 )nA (CRla 2 )n u/ OR 12 R 4 b R 4 a, (R")r V Al(CRla 2 )nA 2 (CRia 2 )n (R9) 6 Y q R 0 lb N N C Y R2 R HQ x IV
R
4 a R 4 b wherein: R Ia and R Ib are independently selected from: WO 97/01275 WO 9701275PCT/US96/11022 76 a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, R 1 0 0-, RI IS(O)m-, RIOC(O)NRIO-, CN, N02, (RI 0 )2N-C(NRI10>, Ri R 1 OOC(O)-, N3, -N(RI 0)2, or R 1 1OC(O)NR c) C1I-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 1 0 0-, RIOC(O)-, RIO0C(O)-, N3, -N(R 1 0 or RI I0C(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 occurrng amino acid which is: i) methiomine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C I -C20 alkyl, C2-C20 alkenyl, cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(RIO)2, N02, RIO0-, RI RIOC(O)NRIO-, CN, (RIO)2N-C(NRIO)-, RIOC(O)-, RIO0C(O)-, N3, -N(RIO)2, R 1 I0C(O)NRlO- and Cl-C20 alkyl, and d) Ci -C6 alkyl 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
R
2 or R3 are combined with R 6 to form a ring such that WO 97/01275 WO 9701275PCTIUS96/11022 77 R 6 N2
HA)
R7a R 7 b R4a, ROb, R 7 a and R7b are independently selected from: a) hydrogen, b) C I -C6 alkyl unsubstituted or substituted by alkenyl, R 1 00., R 1 1 S R' 1 C(0)NR 10-, CN, N3, (R 1 I 02N-C(NR RIOC(0)-, RIO0C(0)-, -N(RlO)2, or R 1 I0C(0)NR10-, c) aryl, heterocycle, cycloalkyl, alkenyl, RIO0-,
R
1 1 RIOC(0)NR10-, CN, N02, (RIO)2N- RIOC(O)-, RIO0C(0)-, N3, -N(RIO)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; 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 occurrng amino acid which is: i) methionine sulfoxide, or ii) methiomine sulfone, c) substituted or unsubstituted ClI -C20 alkyl, C2-C20 alkenyl, C3-C1O cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(Rl 1 N02, RIO0-, RI RIOC(0)NRIO-, CN, (Ri 1 )2N-C(NR R I R 1 OOC(0)-, N3, -N(R 1 0 R 1 1 0OC(0)NR 10- and Cl1-C20 alkyl, d) Ci1 -C6 ailkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C 1 cycloalkyl; or WO 97/01275 WO 9701275PCT[US96/11022 78 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(COR 10)- R6 is independently selected from hydrogen or C I -C6 ailkyl;
R
8 is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalcyl, F, Cl, Br, R 10 R I 1 S
R
1 I C(0)NRl 10, CN, N02, R I 0 2N-C(NR 1 RI OC(0)-, R IOOC(0)-, N3, -N(R 10 or R1 1 OC(0)NR 10-, and c) Ci1 -C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RIO0-, Rl IS(0)m-, RIOC(0)NH-, CN, H2N- RlOC(0)-, RIO0C(0)-, N3, -N(RlO)2, or
R
1 OOC(0)NH-;
R
9 is selected from: a) hydrogen, b) alcenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RIO0-, R I 1 S R 1 C(0)NR 10-, CN, N02, (RI 0 )2N-C- (NRIO)-, RIOC(0)-, RIO0C(0)-, N3, -N(RIO)2, or R I IOC(0)NR 10-, and c) ClI -C6 alkyl unsubstituted or substituted by peffluoroalkyl, F, Cl, Br, RIO0-, R 1 IS(0)m-, RIOC(O)NR10-, CN, (RIO)2N-C(NR10)-, RIOC(0)-, R 10 N3, -N(RIO)2, or R I I0C(O)NR R 10 is independently selected from hydrogen, ClI-C6 alkyl, benzyl and aryl; R 1 1 is independently selected from ClI-C6 ailkyl. and aryl; WO 97/01275 PCT/US96/11022 -79-
R
12 is a) substituted or unsubstituted C 1-C8 alkyl or substituted or unsubstituted C5-C8 cycloalkyl, wherein the substituent on the alkyl or cycloalkyl is selected from: 1) aryl, 2) heterocycle, 3) -N(R11)2, 4) -OR10, or b)
R
13 0 0 R 4
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)NR1O-, -NRO1C(O)-, O, -S(0)2N(R10)-, -N(R10)S(0)2-, or S(O)m; Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C5-C7 saturated ring or a heterocycle; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C -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; WO 97/01275 WO 9701275PCTIUS96/11022 W is a heterocycle; X, Y and Z are independently H2 or 0; m is n is p is q is r is s 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; 4 3, 4 or 5; and 0 or 1; 81 y) U.S. Patent No. 5,856,936 and PCT Publication WO 96/30345, incorporated herein by reference, (R )r (R9\ R 2
R
3 V Al(CRla 2 (CR a 2 WK) (CRlb 2 )p N\4 0 R 4
R
A
:(R
8 )r (R9 R 2
JG
:V Al(O Rl 2 (C Rl 2 (CRlb 2 )PK" 7
N\
U x R B 3 R 4 **R9 2 (1( 8 N\ N- Z X G9 9*
R
wherein: R 1 a and R I b are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-Clc) cycloalkyl,.C2-C6 alkenyl, C2-C6 alkynyl, R 1 0 R I 1 R I C(O)NR 10 CN, N02, (RIO)2N-C(NR 1 RIOC(O)-, RIOOC(O)-, N3, -N(R 1 0 )2, or R I IOC(O)NR C) C1I-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 WO 97/01275 WO 9701275PCTIUS96/11022 82 alkynyl, RIO0-, RIIS(O)m-, RIOC(O)NR10-,
CN,
(RI 0 )2N-C(NRI1
R
1 0
R
1 OOC(O)-, N3, -N(Rl 0)2, or RI I0C(O)-NR10-;
R
2 and R 3 are independently selected from: H; unsubstituted or substituted Cl-8 alkyl, unsubstituted. or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or >A R 6
R
7 or substituted heterocycle, 0 0 wherein the substituted group is substituted with one or more of: 0 1) aryl or heterocycle, unsubstituted or substituted with: a) Cl1-4 alkyl, b) (CH2)pOR 6 c) (CH2)pNR 6
R
7 d) halogen, 2) C3-6 cycloalkyl, 3) OR 6 4) SR 6
S(O)R
6 S02R 6 -NR 6 R 7 -N YR 7 0 -N YNR 7 R 7 a 0 WO 97/01275 PCT/US96/11022 -83- 8) -0
NR
6
R
7 0 9) -O OR 6 0 NR6R 7 0 11) -SO 2
-NR
6
R
7
R
6 12) -N-SO2- R 7 13) -r-R 6 ,or 0 14) OR6 or 0
R
2 and R 3 are attached to the same C atom and are combined to form (CH2)u wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, S(O)m, and -N(COR
R
4 is selected from H and CH3; and any two of R 2
R
3 and R 4 are optionally attached to the same carbon atom;
R
6
R
7 and R 7 a are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) C1-4 alkoxy, WO 97/01275 WO 9701275PCT/US96/11022 84b) aryl or heterocycle, c) halogen, d) HO, e) 'Y
R
0 f) -S0 2
R
1 1 or g) N(RlO)2; or
R
6 and R 7 may be joined in a ring;
R
7 and R 7 a may be joined in a ring; R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 R I 1 S(O)m-,
RIOC(O)NR
1 CN, N02, R 10 2N-C(NRIO)-, RlOC(O)-, RlO0C(O)-, N3, -N(RIO)2, or RI I0C(O)NRIO-, and c) Cl -C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 ailkynyl, perfluoroalkyl, F, Cl, B r, R 10 RI IS R IOC(O)NH-, CN, H2N-C(NH)-, RlIOC(O)-, R I 0C(O)-, N3, -N(R 1 0 or R I 0C(O)NH-; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalcyl, F, Cl, Br, R 10 0-, Rl 1 Rl 0
C(O)NR
1 CN, N02, (Rl 0 )2N-C-(NR10)-, RIOC(O)-, RIO0C(O)-, N3, -N(IO2,or RI I0C(O)NRIO-, and c) C1I-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RIO0-, RI IS(O)m-, RIOC(O)NRIO-, CN, (R lO)2N-C(NR R 1 R lOOC(O)-, N3, -N(Rl 0)2, or RI 1
OC(O)NRIO-;
WO 97/01275 PCT/US96/11022 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R
11 is independently selected from C1-C6 alkyl and aryl;
A
1 and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR1O-, -NR1OC(O)-, 0, -S(0)2N(R10)-, -N(R10)S(0)2-, or S(O)m; G is H2 or O; 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 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 is -CH2-, or Y is aryl, heterocycle, unsubstituted or substituted with one or more of: 1) C 1-4 alkyl, unsubstituted or substituted with: a) C1-4 alkoxy, b) NR 6
R
7 c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, WO 97/01275 WO 9701275PCT/US96/11022 86f) -S(O)mR 6 or g) -C(O)NR 6
R
7 2) aryl or heterocycle, 3) halogen, 4) OR 6
NR
6
R
7 6) CN, 7) N02, 8) CF3; 9) -S(O)mR 6
-C(O)NR
6
R
7 or 11) C3-C6 cycloallcyl; Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more of the following: 1) CI-4 ailkyl, unsubstituted or substituted with: a) C 1-4 alkoxy, b) NR 6
R
7 c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O)mR 6 or g) -C(O)NR 6
R
7 2) aryl or heterocycle, 3) halogen, 4) OR 6
NR
6
R
7 6) CN, 7) N02, 8) CF3; 9) -S(O)mR 6
-C(O)NR
6
R
7 or 11) C3-C6 cycloalkyl; 87 m is 0, 1 or 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 0Oorl1; t is 0Oor1; and u is 4 z) U.S. Patent No. 5,756,528 and PCT Publication WO 96/39137, incorporated herein by reference, (R)rR Z R 2
~R
V Al(CRla 2 )nA 2 On W (C N (CR 4 2 )qA 3 5 2 )nR wherein: OV, Ria is independently selected from: 00.a) hydrogen, 15 b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C20 alkenyl, C2alkynyl, R 1 0 R I R I C(O)NR 10-, CN, .0 N02, (R' 0 RIOC(O)-, RIO0C(O)-, N3, 102,or R I IOC(O)NR 1 0-, c) C1I-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, C3-C10 cycloalkyl, C2-C20 ailkenyl, C2-C20 alkynyl, R 10 RI IS R I C(O)NR 10-, CN, (Ri 0 )2N-C(NR10).., R' R lOOC(O)-, N3, -N(Rl 0)2, or R I IOC(O)-NR Rib is independently selected from: a) hydrogen, b) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3-C 10 cycloalkyl, C2-C20 alkenyl, C2-C20 WO 97/01275 WO 9701275PCT/US96/11022 88 aikynyl, RIO0-, RI IS(O)m-, CN, N02, (RIO)2N-C(NRlO)-, R IOC(O)-, R I N3 or NR1I c) C1I-C6 alkyl unsubstituted or substituted by substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic, C3-C1O cycloalkyl, C2-C20 alkenyl, C2-C20 ailkynyl,
R
1 0 RI IS(O)m-, CN, (RIO)2N-C(NRIO)-,
RIOC(O)-,
RIO0C(O)-, N3 or -N(R'O)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, and c) substituted or unsubstituted C I-C20 alkyl, substituted or unsubstituted C2-C20 alcenyl, substituted or unsubstituted C3-C1O cycloallcyl, substituted or unsubstituted aryl or substituted or unsubstituted heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R'O)2, N02, R1 0
RI
1
RIOC(O)NRIO-,
CN, (RI 0 )2N-C(NRI10>, RI Ri OOC(O)-, N3, -N(Rl 0 RI 1 0C(O)NRIO- and CI-C20 ailkyl, and d) Cl -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- Clm cycloalkyl; or R2 and R 3 are combined to form (CH2)s or R2or R3 are combined with R 7 to form a ring such that R 2 R 3 AN 7 WO 97/01275 WO 9701275PCT/US96/11022 89
R
4 R5, Rl3a and Rl3b are independently selected from: a) hydrogen, b) C I-C6 alkyl unsubstituted or substituted by C2-C20 alkenyl, RIO0-, Rl 1 Rl 0 C(O)NRIO-, CN, N3, (RIO)2N- RIOC(O)-, or R 1 OC(O)NRlO-, c) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C 10 cycloalkyl, C2- C20 alkenyl, R 10 R' IIS(O)mv-, Rl 0
C(O)NRIO-,
CN, N02, (RIO)2N-C(NRIO)-, RIOC(O)-, N3, -N(R 1 0)2, or R IIOC(O)NR 10-, and d) C I -C6 ailkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; R6 is selected from: a) hydrogen, b) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3-C10 cycloalkyl, C2-C20 alkenyl, C2-C20 alkynyl, C 1-C20 perfluoroalkyl, allyloxy, F, Cl, Br, R 1 0 0-, RIIS(O)m-, RIOC(O)NRIO-, CN, N02, R 1 0 2N-C(NRl Rl N3, -N(RI 0)2, (Rl 2 )2NC(O)or R I I0C(O)NR 10-, and c) C1-C6 alkyl unsubstituted or substituted by substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3-C1O cycloalkyl, C2-C20 alkenyl, C2-C20 alkynyl, C2perfluoroalkyl, F, Cl, Br, R 10 R1 1 S(O)m-, RIOC(O)NH-, CN, H2N-C(NH)-, RIOC(O)-, N3, -N(RIO)2, or R 1OOC(O)NH-; R7 is independently selected from a) hydrogen, b) unsubstituted or substituted aryl, WO 97/01275 WO 9701275PCTIUS96/11022 90 c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C1O cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3- Ci10 cycloalkyl;
R
8 is selected from: a) hydrogen, b) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3-CIO cycloalkyl, C2-C20 alkenyl, C2-C20 alkynyl, CI-C20 perfluoroalkyl, allyloxy, F, Cl, Br, RIO0-, RI IS(O)m-, RIOC(O)NRIO-, -S(O)2NRI 0 2, CN, N02,
R
10 2N-C(NR10)-, RIOC(O)-, RIO0C(O)-, N3, -N(RIO)2, or R I IOC(O)NR 10-, and c) C1-C6 alkyl unsubstituted or substituted by substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3-C1O cycloalkyl, C2-C20 alkenyl, C2-C20 alkynyl, C2peffluoroalkyl, F, Cl, Br, R 10 R I IS(O)m-, RIOC(O)NH-, CN, H2N-C(NH)-, RIOC(O)-, R 1 0 0C(O)-, N3, -N(RIO)2, or R9 is selected from: a) hydrogen, b) C2-C2cj alkenyl, C2-C20 alkynyl, C2-C20 peffluoroalkyl, F, Cl, Br, RIO0-, Rl IS(O)m-, RIOC(O)NR10-, CN, N02, (Rl 0 )2N-C-(NRIO)-, RlOC(O)-, R 1 0 N3, 102,or R1 1 0C(O)NR 10-, and c) C1-C6 alkyl unsubstituted or substituted by C2-C20 perfluoroalcyl, F, Cl, Br, RIO0-, RI IS(O)m-, R' OC(O)NR 1 CN, (RI O)2N-C(NR- 1
R
1
OC(O)-,
N3, -N(RlO)2, or RI I0C(O)NR 1 0-;
R
1 0 is independently selected from hydrogen, Cl-C6 alkyl, benzyl and aryl; _I i__lilil-_i_.li-l -I Ilii- ii -II_ L WO 97/01275 PCT/US96/11022 -91- R11 is independently selected from C1-C6 alkyl and aryl;
R
12 is independently selected from hydrogen, C1-C6 alkyl and aryl, or
(R
12 )2 forms (CH2)s A1, A 2 and A 3 are independently selected from: a bond, -CH=CH-, -C(O)NR7-, -NR7C(O)-, O, -S(O)2N(R 7
-N(R
7 or S(O)m; 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; Z is independently H2 or O; mis n is p is q is r is sis t is 0, 1 or 2; 0, 1, 2, 3 or 4; 0, 1, 2, 3 or 4; 0, 1, 2, 3 or 4; 0 to 5, provided that r is 0 when V is hydrogen; 4 or 5; and 3,4 or and 92 a.
aa) U.S. Patent No. 5,710,171 and PCT Publication WO 96/37204, incorporated herein by reference, R~a
R
2 b N- (CR 2pLY~
R
5
R
wherein: R 1 a and R I b are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 8
R
9 S(O)m-,
R
8
C(O)NR
8 CN, N02, (R 8 )2N-C(NR 8
R
8
R
8 N3, -N(R 8 or R 9
OC(O)NR
8 c) C1I-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, unsubstituted or substituted C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 8
R
9
R
8
C(O)NR
8 CN, (R 8 )2N-C(NR 8
R
8
R
8 N3, -N(R 8 )2, or R 9
OC(O)-NR
8 R2a, R2b and R 3 are independently selected from: a) hydrogen, b) ClI-C6 alkyl unsubstituted or substituted by C2-C6 alkenyl,
R
8
R
9
R
8
C(O)NR
8 CN, N3, (R 8 )2N-C(NR 8
R
8
R
8
-N(R
8 or R 9
OC(O)NR
8 c) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted cycloalkyl, alkenyl, R 8 0-,
R
9
R
8
C(O)NR
8 CN, N02,
(R
8 )2N-C(NR 8
R
8
R
8 N3,
-N(R
8 halogen or R 9
OC(O)NR
8 and WO 97/01275 WO 9701275PCTIUS96/11022 93 d) C1I-C6 ailkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C1O cycloalcyl; R4 and R 5 are independently selected from: a) hydrogen, and b) (R 6 )r R7z V- Al(CRla 2 )nA (CRlA. INU (CRib R6 is independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 ailkynyl, C I -C6 perfluoroalkyl, F, Cl, Br, R 8
R
9
R
8
C(O)NR
8 CN, N02, R 8 2N-
C(NR
8
R
8
R
8 N3, -N(R 8 or
R
9
OC(O)NR
8 and c) C I -C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 ailcynyl, C I -C6 peffluoroalkyl, F, Cl, Br,
R
8
R
9
R
8 C(O)NH-, CN, H2N-C(NH)-, R 8
R
8 N3, -N(R 8 or R 8
OC(O)NH-;
R7 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C I -C6 perfluoroalkyl, F, CI, Br, R 8
R
9
R
8
C(O)NR
8 CN, N02, (R 8 )2N-C-
(NR
8
R
8
R
8 N3, -N(R 8 or
R
9
OC(O)NR
8 and C) C I -C6 alkyl unsubstituted. or substituted by C I -C6 perfluoroalkyl, F, Cl, Br, R 8
R
9
R
8
C(O)NR
8 WO 97/01275 WO 9701275PCT[US96/11022 94- CN, (R 8 )2N-C(NR 8
R
8
R
8 N3, -N(R 8 )2, or R 9
OC(O)NR
8
R
8 is independently selected from hydrogen, C I-C6 alkyl, substituted or unsubstituted C 1 -C6 arailkyl and substituted or unsubstituted aryl;
R
9 is independently selected from C1I-C6 alkyl and aryl; R 10 is independently selected from hydrogen, C1I-C6 alkyl, substituted or unsubstituted C I -C6 aralkyl and substituted or unsubstituted aryl; A'I and A 2 are independently selected from: a bond, -CH=CH-, -CR-C-,
-C(O)NR
8
-NR
8 0, -N(R 8 -S(0)2N(R 8
-N(R
8 or S(O)m; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) ClI-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 I 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; Y is selected from: a bond, -C(RIO)=C(RlO)-, -C(R 1 0 -C(ORIO)RIO-, -CN(R 1 0 2
R
10 -OC(Rl 0 -NRl 0 C(Rl 0 -C(RIO)2NRIO-, -C(0)NR10-, -NRIOC(0)-, 0, -NC(0)R 1 -NC(0)ORI -S 2N(R 1 -N(Ri or S(O)m; Z is H 2 or O; m is 0, 1 or 2; nis 0, 12, 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; and u is 0 or 1; or the pharmaceutically acceptable salts thereof.
The composition of the instant invention may alternatively or in addition comprise a protein substrate-competitive inhibitor obtained by fermentation of cultures of novel organisms. In particular, the compounds disclosed in the following patents and publications may be useful as a protein substrate-competitive inhibitor component of the instant composition: U.S. Patent Nos. 5,420,334 and 5,703,067. Those patents and publications are incorporated herein by reference.
i In addition, compounds described in the following patents and publications may also be utilised as a protein substrate-competitive inhibitor component of the instant composition: U.S. Patent No. 5,420,245; European Patent Publication 0 618 221; PCT *Patent Publications WO 94/26723; WO 95/10514; WO 95/10515; WO 95/10516; WO 95/08542; WO 95/11917; and WO 95/12612. Those patents and publications are 20 incorporated herein by reference.
Specific examples of protein substrate-competitive inhibitors useful in the compositions of the invention are: Compound A: (R:\LIBAA]07529 doc TAB WO 97/01275 WO 9701275PCT/US96/11022 96- S0 2 0
N
2
N
-H H H S A Compound B: N 00 NN N H H 0
CNB
and Compound E:
CH
3 0 HS NH 2 or the pharmaceutically acceptable salts thereof.
WO 97/01275 WO 9701275PCT/US96/1 1022 97 Other specific examples of protein substrate-competitive inhibitors useful in the compositions of the invention are: [2(R)-aniino-3-mercaptopropylaniino] -6(S)-methyl-2(R)-n-propyl- 3,4-E-octenoyl-homoserine, and the corresponding homoserine lactone, 2 (R)-amino-3-mercaptopropylamino]-6(S)-metiyl-2(R)-methy..
3,4-E-octenoyl-homserine, and the corresponding homoserine lactone, 2 (R)-amino-3-mercaptopropyla nino]-6(S)-methyl-2(R)-ethyl-3 ,4- E-octenoyl-homserine, and the corresponding homoserine lactone, 2 (R)-aniino-3-mercaptopropylamino]-6(S)-methyl-2(R)-i-propyl- 3,4-E-octenoyl-homoserine, and the corresponding homoserine lactone, 5(S)-[2(R)-aniino-3-mercaptopropylamino]-6(S)-methyl-2(R)-n-butyl- 3,4-E-octenoyl-homoserine, and the corresponding homoserine lactone, [2(R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)-s-butyl- 3,4-E-octenoyl-homoserine, and the corresponding homoserine lactone, 5(S)-[2(R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)-t-butyl-3 ,4- E-octenoyl-homoserine, and the corresponding homoserine lactone, [2(R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)cyclohexyl-3 ,4-E-octenoyl-homoserine, and the corresponding homoserine lactone, [2(R)-amino-3-mercaptopropylamino] -6(S)-methyl-2(R)cyclopentyl-3 ,4-E-octenoyl-homoserine, and the corresponding homoserine lactone, WO 97/01275 WO 9701275PCTIUS96/11022 98 [2(R)-axino-3-mercaptopropylamino]F6(S)-methyl-2(R)-benzyl-3 ,4- E-octenoyl-homoserine, and the corresponding homoserine lactone, [2(R)-aniino-3-mercaptopropylaniino]-6-methyl-2(R)-i-propyl-3 ,4- E-octenoyl-homoserine, and the corresponding homoserine lactone, [2(R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)-i-propyl- 3,4-E-octenoyl-methionine, and the corresponding methyl ester, [2(R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)-n-butyl- 3,4-E-octenoyl-methionine, and the corresponding methyl ester, [2(R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)-benzyl-3 ,4- E-octenoyl-methionine, and the corresponding methyl ester, 5(S)-[2(R)-aniino-3-mercaptopropylamino]-6(S )-methyl-2(R)-n-propyloctanoyl-homoserine, and the corresponding homoserine lactone, 5(S)-[2(R)-amino-3-mercaptopropylamino]-6(S )-methyl-2(R)-benzyloctanoyl-homoserine, and the corresponding homoserine lactone, N-(3-phenyl-2(S)-(mercaptopropionylamino)prop- 1 -yl)isoleucylmethiomine, N-(2(R)-amino-3-mercaptopropyl)isoleucyl-phenylaanyl-methione, N-(3-mercaptopropyl)isoleucyl-phenylalanyl-methionine, N-(3-mercaptopropyl)valyl-isoleucyl-methiornne, N-(2(R)-amino-3-mercaptopropyl)valyl-isoleucyl-methionine, N-(3-methyl-2(S)-(cysteinylamino)but- 1-yl)phenylalanyl-methionine, WO 97/01275 WO 9701275PCTIUS96/1 1022 99 N-(3-methyl-2(S)-(mercaptopropionylamino)but- 1-yl)-phenylalanylmethionine, N- 2 (S)-(2(R)-amino-3-mercaptopropylamino)-3(S)methylpentyl]y phenylalanyl-methionine, N- 2 3 -mercaptopropylamino)-3(S)methylpentyl-phenylalanyl.
methionine,
N-(
2 (R)-amino-3-mercaptopropyl)isoleucyl-phenylalanylb(methionne sulfone),
N-(
2 (R)-amino-3-mercaptopropyl)isoleucyl)-(p-iodophenylaanyl..
methionine, N- [2(R)-(cysteinyl-isoleucylaxnino)-3 (S)-methylpentyl]-methionine, N-[2(R)-(N'-(2(R)-aniino-3-mercaptopropyl)-isoleucylaniino)-3-phenylpropyllmethionine, N- [2(R)-(N'-(2(R)-amino-3-mercaptopropyl)-isoleucylaniino)-3 methylpentyl]methionine, N-(3-mercaptopropyl)valyl-isoleucyl-methionine methyl ester,
N-(
2 (R)-amino-3-mercaptopropyl)isoleucyl-phenylalanyl-methionjne ethyl ester, N-(2(R)-amino-3-mercaptopropyl)isoleucyl-phenylalanyl-methionine benzyl ester, N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-phenethylamide, N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-benzylamide, WO 97/01275 WO 7/0275PCTIUS96/1122 100- N- 2 (R)-Amino- 3 -mercaptopropy]-L-.isoleucine-.3..meffybutyamde, N- 2 (R)-Amino- 3 -mercaptopropyl]-L-isoleucine-3-.phenylpropy1lamde,
N-[
2 (R)-Amino-3-mercaptopropyl]Lisoleucyl1L-.phenylalninol, N-2R-mn--ecporpl--ioecn-'mtybnyaie N- 2 (R)-Amino-3-mercaptopropyl]-L-soeucine-(4.
methoxybenzyl)amide, N- 2 (R)-Amino-3-mercaptopropyl]-Lisoleucine-(2,4-dichloro.
benzyl)amide, N- 2 (R)-Amino- 3 -mercaptopropy1]-L-isoleucine-(4-trifluoromefiyl benzyl)amide, N- 2 (R)-Amino-3-mercaptopropyl-Lisoleucine(2,4.dchlrophenethyl)ainide,
N-[
2 (R)-Amino-3-mercaptopropy]-L-isoleucine-.(2-benziida 0 1..
ylmethyl)aniide, N- 2 (R)-Aniino-3-mercaptopropyl]-L-isoleucine-(l1-indanyl)amide, N- 2 (R)-Amino-3-mercaptopropyl-L-isoleucine(2,4-dimethyl.
benzyl)amide, N- 2 (R)-Amino-3-mercaptopropyl]-L-isoleucine-(2,3.dichlorobenzyl)amide,
N-[
2 (R)-Amino-3-mercaptopropyl-L-isoleucine-(4-sulfamoyl.
benzyl)amide, WO 97/01275 WO 9701275PCTIUS96/11022 101 N- 2 (R)-Amino- 3 -mercaptopropy1]..L-.isoeucineailde, N- 2 (R)-Amino- 3 -mercaptopropyl-Lisoeucine-(2,4-dimethy..
phenyl)amide, N- 2 (R)-Amino- 3 -mercaptopropy]-Lisoeucine-(2,3-dimethyl..
phenyl)amide, L-Cysteinyl-L-isoleucine-phenethylamide, N- 2 (R)-Amino-3-mercaptopropylamio3-methype 1 tyll phenethylamide,
N-(
2 (R)-Amino-3-mercaptopropyl).L..alaninebenzylamide, N-Benzyl-[ 2 2 (R)Amino3mercaptopropy)aminobuyrnde,
N-(
2 (R)-Amino-3-mercaptopropyl)>L-.norleucinebenzyamide,
N-(
2 (R)-Aniino-3-mercaptopropy).L-.norvalinebenzylamide, N-2R-mn--ecporplioeclpeyaay-ooeie
N-(
2 (R)-Amino-3-mercaptopropyl)isoleucyl.isoleucyl-homoserine,
N-(
2 (R)-Amino- 3 -mercaptopropyl)isoleucyl.phenylalanyl.homoserine lactone,
N-(
2 (R)-Amino-3-mercaptopropyl)isoleucyl-isoleucyl.homoserine lactone,
N-(
2 (R)-Anmino- 3 -mercaptopropy)isoleucy-phenylalanyl.homocysteine lactone, WO 97/01275 WO 9701275PCTIUS96/11022 -102- N- 2 2 (R)-Amino-3-mercaptopropy)3(S..methypenty}.isoeucy..
homoserine lactone, N- 2 (R)-Amino-3-mercaptopropyl)isoleucylbphenylalanyl].3 amino-tetrahydropyran-2-one, N- 2 (R)-Amino-3-mercaptopropyl)isoleucyl-isoleucyly3 (S)-aminotetrahydropyran-2-one,
N-(
2 (R)-Amino- 3 -mercaptopropyl)isoleucyl.isoleucyl..homocysteine lactone, N- 2 (S)-(2(R)-Amino-3-mercaptopropylamino)-3 (S)-methyl pentyllisoleucyl-homoserine, N- 2 (R)-Aniino-3-mercaptopropyl)isoleucyl-phenylalanyl]y3(S..
aniino-4-hydroxypentanoic acid, N- 2 (R)-Axnino-3-mercaptopropyl)isoleucyl-isoleucyly3 (S)-amino-4hydroxypentanoic acid, N- [2(S)-(2(R)-amino-3-mercaptopropylamino)-3 (S)-methylpentyl]-Nmethyl-isoleucyl-homoserine,
N-[
2 (S)-(2(R)-amino-3-mercaptopropylamino)-3 (S)-methylpentyl]-Nmethyl-isoleucyl-homoserine lactone,
N-[
2 (S)-(2(R)-amino-3-mercaptopropylaniino)-3 (S)-methylpentyl]-Nmethyl-phenylalanyl-homoserine, N- 2 (S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl-N-.
methyl-phenylalanyl-homoserine lactone, WO 97/01275 WO 9701275PCTIUS96/11022 -103- N- 2 2 (R)-amino-3-mercaptopropylaino..3-methyl-butyl].N-.
methyl-phenylalanyl-homoserine, N- 2 2 (R)-amino-3-mercaptopropylaino..3-mefiylbutyl].Nmethyl-phenylalanyl-homoserine lactone,
N-[
2 2 (R)-anino-3-mercaptopropylamino)3(Sy..mefiyl.
pentyl]-N-methyl-isoleucylanino I-3-methyltetra-hydropyran-2-one, N- 2 2 (R)-amino-3-mercaptopropylamino).3(S)-mefiyl.
pentyl]-N-methyl-isoleucylamino }-2-methyl-5-hydroxypentanoic acid, N- 2 2 (R)-amino-3-mercaptopropylaminoy..3(S)-.methylpentyly- N-methyl-isoleucylaniino -5-methyl-5-hydroxyhexanoic acid, N- 2 2 (R)-amino-3-mercaptopropylalninoy.3(S)-methylpentyl-Nmethyl-norvalyl-homoserine, N- 2 2 (R)-amino-3-mercaptopropylamino)-3 (S)-methylpentyl]-Nmethyl-norvalyl-homoserine lactone,
N-[
2 2 (R)-amino-3-mercaptopropylamino)-3(S)methylpentyl]N-.
methyl-isoleucyl-methionine,
N-[
2 2 (R)-amino-3-mercaptopropylamino)-3 (S)-methylpentyl]-Nmethyl-isoleucyl-methionine methyl ester, N- 2 2 (R)-amino-3-mercaptopropylamino)-3 (S)-methylpentyl]-Nmethyl-phenylalanyl-methionine, N- 2 2 (R)-amino- 3 -mercaptopropylamino)-3(S)-methylpentyl].Nmethyl-phenylalanyl-methionine methyl ester, WO 97/01275 WO 9701275PCT([US96/1 1022 -104- I N-[ 2 2 (R)-amino-3-mercaptopropylanmino)-3(S)-mefiyl pentyl]-N-methyl-isoleucylanmino 6 6 -dimethyl-tetrahydropyran-2-one, N- 2 2 (R)-amino-3-mercaptopropylamno.3 (S)-methylpentyl]-Nmethyl-norvalyl-methionine, N- 2 2 (R)-alnino-3-mercaptopropylaiino)-3 (S)-methylpentyl]-Nmethyl-norvalyl-methionine methyl ester, N- 2 2 (R)-amino-3-mercaptopropylaino)-3 (S)-methylpentyl]-Nmethyl-D-norvalyl-homoserine, N- 2 2 (R)-amino-3-mercaptopropylanjno)-3(Sy.methylpentyl]N-.
methyl-D-norvalyl-homoserine lactone, [2(S)-[2(R)-Amino-3-mercaptolpropylamino-3(S)-methyl] pentyloxy-3-phenylpropionyl-homoserine lactone, 2 2 2 (R)-Amino-3-mercapto]propylanino.3 (S)-methyl] pentyloxy-3-phenylpropionyl-homoserine, 2 (R)-Amino-3-mercapto]propylaniino-3 (S)-methyl] pentyloxy- 2 -methyl-3-phenylpropionyl.homoserine lactone, 2 2 2 (R)-Amino-3-mercapto]propylamino-3 (S)-methyl] pentyloxy- 2 -methyl-3-phenylpropionyl-homoserine, 2 2 2 (R)-Amino-3-mercaptolpropylaniino-3 (S)-methyl] pentyloxy-4-pentenoyl-homoserine lactone, [2(S)-[2(R)-Ar-nino-3-mercapto]propylaniino-3 (S)-methyl] pentyloxy-4-pentenoyl-homoserine, WO 97/01275 WO 9701275PCTIIJS96/1 1022 105 [2(R)-Amino-3-mercaptolpropylamino-3 (S)-methyl] pentyloxypentanoyl-homoserine lactone, [2(R)-Amino-3-mercaptolpropylamino-3 (S)-methyl] pentyloxypentanoyl-homoserine, [2(R)-Aniino-3-mercapto]propylamino-3 (S)-methyl] pentyloxy-4-methylpentanoyl-homoserine lactone, [2(R)-Amino-3-mercapto]propylamino-3 (S)-methyl] pentyloxy-4-methylpentanoyl-homoserine, [2(R)-Amino-3-mercapto] propylamino-3 (S)-methyl] pentyloxy-3-methylbutanoyl-homoserine lactone, [2(R)-Amino-3-mercapto]propylamino-3 (S)-methyl] pentyloxy- 3-methylbutanoyl-homoserine, [2(R)-Amino-3-mercapto]propylamino-3 (S)-methyl] pentyloxy-3-phenylbutanoyl-homoserine lactone, [2(R)-Amino-3-mercaptolpropylamino-3(S)-methyl] pentyloxv- 3-phenylbutanoyl-homoserine, [2(R)-Amino-3-mercapto]propylamino-3 (5)-methyl] pentylthio-2-methyl-3-phenylpropionyl-homoserine lactone, [2(R)-Amino-3-mercaptoljpropylamino-3(S)-methyl] pentylthio-2-methyl-3 -phenyipropionyl-homoserine, [2(R)-Amino-3-mercaptollpropylamnino-3(S)-methyl] pentylsulfonyl-2-methyl-3-phenylpropionyl-homoserine lactone, WO 97/01275 WO 9701275PCTIUS96/11022 -106- 2 (R)-Amino-3-mercapto]propylamino-3 (S)-methyl] pentylsulfonyl-2-methyl-3-phenylpropionyl-homoserine, [2(R)-Amino-3-mercaptolpropylarnino-3 (5)-methyl] pentyloxy-3-phenylpropionyl-methionine methyl ester, 2 2 (R)-Amino-3-mercapto]propylaniino-3(S )-methyl] pentyloxy-3-phenylpropionyl-methionine, [2(R)-Amino-3-mercaptolpropylarnino-3 (5)-methyl] pentyloxy-3-phenylpropionyl-methionine sulfone methyl ester, [2(R)-Amino-3-mercapto]propylamino-3 (S)-methyl] pentyloxy-3-phenylpropionyl-methionine sulfone, 2-(S [2(R)-Amino-3-mercaptolpropylamino-3 (S)-methyl] pentyloxy-3-naphth-2-yl-propionyl-methionine sulfone methyl ester, 2-(S [2(R)-Amino-3-mercapto]propylamino-3 (S)-methyl]pentyloxy-3-naphth-2-yl-propionyl-methionine sulfone, [2(R)-Amino-3-mercaptolpropylamino-3(S)-methyl]pentyloxy-3-naphth- 1-yl-propionyl-methionine sulfone methyl ester, 2-(S)-[2(S)-[2(R)-Amino-3-mercaptolpropylamino-3(S)-methyl]pentyloxy-3-naphth- 1 -yl-propionyl-methionine sulfone, 2-(S [2(R)-Amino-3-mercapto] propylamino-3 (S)-methyl]pentyloxy-3-methybutanoyl-methionine methyl ester, 2-(S [2(R)-Amino-3-mercaptolpropylamino-3 (5)-methyl] pentyloxy-3-methybutanoyl-methionine, WO 97/01275 WO 9701275PCT/US96/1 1022 -107- Disuiphide of [2(R)-Amino-3-mercaptolpropylaniino-3 methyl]pentyloxy-3-phenylpropionyl-homoserine lactone, Disulphide, of [2(R)-Amino-3-mercapto]propylamino-3(S)methyllpentyloxy-3-phenylpropionyl-homoserine, Disulphide of [2(R)-Amino-3-mercaptolpropylaniino-3 methyllpentyloxy-3 -methylbutanoyl-methionine methyl ester.
1- [2-(R)-Amino-3-mercaptopropyl] 1-butyl)-4-(2,3-dimethylbenzoyl)piperazine dihydrochioride 1- [2(R)-Amino-3-mercaptopropyl]-2(S)-(n -butyl)-4-( 1naphthoyl)piperazine 1- [2(R)-Amino-3-mercaptopropyl]-2(S)-benzyl-4- dimethyl)benzoyllpiperazine 1- [2(R)-Amino-3-mercaptopropyl]-2(S )-(2-methoxy)ethyl-4- dimethyl)benzoyl]piperazine 1- [2(R)-Amino-3-mercaptopropyl]-2(S)-(2-methylthio)ethyl- 4 dimethyl)benzoyl]piperazine 1- [2(R)-Amino-3-mercaptopropyII-2(S)-(n -butyl)-4- dihydrobenzofuroyl)]piperazine 1 -(2(R)-Amino-3-mercaptopropyl)-4-(l1-naphthoyl)-2(S)pyridinylcarboxyl-4-piperazine dihydrochioride Methyl 4-(2(R)-amino-3-mercaptopropyl)-l1-(1 -naphthy1methyl)piperazine-2-carboxylate hydrochloride 1- [2(R)-Amino-3-mercaptopropy]-2(S)-(2-methoxyethyl)- 4 1naphthoyl)piperazine WO 97/01275 WO 9701275PCTfUS96/11022 -108quinolinylcarbonyl)piperazine 1- [2(R)-Amino-3-mercaptopropyl]-2(S)-(2.( 1-propoxy)ethyl)-4-( 1naphthoyl)piperazine 1- 2 (R)-Amino-3-mercaptopropyl]-2(S)-(3-methoxy 1 -propyl)-4-( 1naphthoyl)piperazine 1- [2(R)-Amino-3-mercaptopropyl]-2(S)-(2-( 1-propoxy)ethyl)-4-(8quinolinoyl)piperazine 1- [2(R)-Amino-3-mercaptopropyl]-2(S)- [(3-pyridyl)methoxyethyl)]-4-( 1naphthoyl)piperazine 1- 2 (R)-Amino- 3 -mercaptopropyl]-4-naphthoylh2(S(2phenysufonyl..
ethyl)piperazine dihydrochioride bis- 1,1 2 (R)-Amino-3-(2(S)-(2-methoxyethyl)-4-naphthoylpiperazinyl)]propyl disulfide tetrahydrochioride bis- 1,1 '-[2(R)-Amino-3-(4-naphthoyl-2(S)-(2-phenylsulfonylethyl). 1piperazinyl)]propyl disulfide tetrahydrochionide 1- [2(R)-Arnino-3-mercaptopropyl]-4-naphthoyl-2(S cyclopropyloxyethyl)piperazine dihydrochioride 1- [2(R)-Amino-3-mercaptopropyl]-4-( 1-naphthoyl)-2(S acetamidobutyl)piperazine dihydrochioride 1- [2(R)-Amino-3-mercaptopropyl]-4-naphthoyl-2(S cyclopropylmethylsulfonylethyl)piperazine dihydrochioride Pyroglutamyl-valyl-phenylalanyl-methionine WO 97/01275 WO 9701275PCT/US96/11022 109 Pyroglutamyl-valyl-phenylalanyl-methionine methyl ester; Pyroglutamyl-valyl-isoleucyl-methionine; Pyroglutamyl-valyl-isoleucyl-methionine methyl ester; Nicotinoyl-isoleucyl-phenylalanyl-methionine; Nicotinoyl-isoleucyl-phenylalanyl-methionine methyl ester; N- [2(S)-(L-Pyroglutamylamino)-3-methylbutyllphenylalanyl-methionine; N- [2(5 )-(L-Pyroglutamylamino)-3 -methylbutyl]phenylalanyl-methionine methyl ester; N- [5 (S)-(L-Pyroglutamylamino)-6(S )-methyl-2(R)-butyl-3 octenoyl]-methionine; N-[5(S)-(L-Pyroglutamylamino)-6(S)-methyl-2(R)-butyl-3,4(E)octenoyl]-methionine methyl ester; N-[5(S)-((Imidazol-4-yl)acetylamino)-6(S)-methyl-2(R)-butyl-3 octenoyl] -methionine; N- [5(S)-((Imidazol-4-yl)acetylamino)-6(S )-methyl-2(R)-butyl-3 octenoyl]-methionine methyl ester; N-[5(S)-((Imidazol-4-ylcarbonylamino)-6(S )-methyl-2(R)-butyl-3 octenoyl]-methionine; N- [5(S )-((Imidazol-4-ylcarbonylamino)-6(S )-methyl-2 (R)-butyl-3 octenoyl]-methionine methyl ester; WO 97/01275 WO 9701275PCT[US96/11022 -110- N- (S )-(Imidazol-4-yl)acetylamino)-3(S)-methylpentyloxy)-3phenylpropionyl]-methionine; N- [2(S)-(2(S)-(Imidazol-4-yl)acetylamino)-3 (S)-methylpentyloxy)-3 phenylpropionyl]-methiomine methyl ester; N- [2(5 )-Pyroglutamylamino-3 (S)-methylpentyloxy)-3phenylpropionyl]-methionine; N- (S)-Pyroglutamylamino-3 (S )-methylpentyloxy)-3phenylpropionyl]-methionine methyl ester; N- [2(S)-(2(S)-Imidazol-4-ylcarbonyl)amino)-3(S)-methylpentyloxy)-3phenyipropionyl] -methiomine; N- [2(5 )-Imidazol-4-ylcarbonyl)amino)-3 (S )-methylpentyloxy)-3 phenylpropionyl]-methionine methyl ester; N-[2(S)-(2(S)-((3-Picolinyl)amino)-3(S)-methylpentyloxy)-3phenyipropionyl] -methionine; N- (S )-((3-Picolinyl)amino)- 3(S )-methylpentyloxy)-3 phenylpropionyl]-methionine methyl ester; N-[2(S)-(2(S)-((Histidyl)amino)-3 (S)-methylpentyloxy)-3phenyipropionyl] -methiomine; N- (S )-((Histidyl)amino)-3 (S)-methylpentyloxy)-3phenyipropionyll-methionine methyl ester; N-Benzyl-N- [2(S)-((Imidazol-4-ylcarbonyl)amino)-3 (S )-methylpentyl] glycyl-methionine; WO 97/01275 WO 9701275PCT/US96/1 1022 ill N-B enzyl-N- [2(S)-((Imidazol-4-ylcarbonyl)amino)-3 (S )-methylpentyl] glycyl-methionine methyl ester; N-Benzyl-N-[2(S)-((Imidazol-4-ylacetyl)amino)-3 (S )-methylpentyl] glycyl-methionine; N-B enzyl-N- [2(S)-((Imidazol-4-ylacetyl)amino)-3 (S )-methylpentyl] glycyl-methiomine methyl ester; N-Benzyl-N- [2(S)-((Pyroglutamyl)amino)-3 (S )-methylpentyl] -glycylmethionine; N-Benzyl-N- [2(S)-((Pyroglutamyl)amino)-3 (S )-methylpentyl] -glycylmethiomine methyl ester; N-(l1-Naphthylmethyl)-N- [2(S)-((imidazol-4-ylcarbonyl)amino)-3 (S methylpentyl] -glycyl-methionine; 1-Naphthylmethyl)-N- [2(S)-((imidazol-4-ylcarbonyl)amino)-3 (S methylpentyl]-glycyl-methionine methyl ester; 1-Naphthylmethyl)-N- [2(S)-((imidazol-4-ylacetyl)amiuno)-3 (S methylpentyl] -glycyl-methionine; N-(l1-Naphthylmethyl)-N-112(S)-((imidazol-4-ylacetyl)amino)-3(S)methylpentyl]-glycyl-methionine methyl ester; N-(l1-Naphthylmethyl)-N- [2(S)-((pyroglutamyl)amino-3 (S)-methylpentyl]-glycyl-methionine; and 1-Naphthylmethyl)-N- [2(S )-((pyroglutamyl)amino-3 (S)-methylpentyl]-glycyl-methionine methyl ester; WO 97/01275 WO 9701275PCTIUS96/1 1022 -112- N-[i1 -(Pyroglutamylamino)cyclopent- 1 -ylmethyl]-N-( 1 -naphthylmethyl)glycyl-methionine methyl ester N- [1-(Pyroglutamylamino)-cyclopent- 1 -ylmethyl]-N-(l1-naphthylmethyl)-glycyl-methionine N-(2(S)-L-Histidylaniino-3 (S)-methylpentyl)-N-(benzylmethyl)glycyl.
methionine methyl ester N-(2(S)-L-Histidylaniino-3 (S )-methylpentyl)-N-(benzylmethyl)glycylmethionine N-(2(S)-L-Histidylaniino-3 (S )-methylpentyl)-N-( 1-naphthylmethyl)glycyl-methionine methyl ester N-(2(S )-L-Histidylamino-3 (S )-methylpentyl)-N-( 1 -naphthylmethyl)glycyl-methionine [2(S )-(L-Pyroglutamyl)amino-3 (S )-methylpentyloxy]-3 methylbutanoyl-methionine methyl ester 2 (S)-[2(S)-(L-Pyroglutamyl)amino-3(S)-methylpentyloxy]-3 methylbutanoyl-methionine 2 (S)-[2(S)-(Lridazol-4-ylacetyl)amino-3(S)-methylpentyloxy]-3methylbutanoyl-methionine methyl ester [2(S )-(Imidazol-4-ylacetyl)amino-3 (S )-methylpentyloxy] -3methylbutanoyl-methionine N-(Benzyl)-N- [2(S )-(2-oxopyrrolidin-5 (R,S)-ylmethyl)amino-3 methylpentyl] -glycyl-methionine methyl ester WO 97/01275 WO 9701275PCT/US96/1 1022 113 N-(Benzyl)-N- [2(S)-(2-oxopyrrolidin-5 (R,S)-ylmethyl)amino-3 methylpentylll-glycyl-methionine N-(Benzyl)-N- I [((D,L)-2-thiazolyl)alanyl)amino]-3(S)methylpentyl I -glycyl-methionine methyl ester N-(Benzyl)-N- [((D,L)-2-thiazolyl)alanyl)amino]-3 (S methylpentyl I -glycyl-methionine N-(Benzyl)-N- [2(S)-(3-pyridylmethyl)aniino-3 (S )-methylpentyl] -glycylmethionine methyl ester N-(B enzyl)-N- [2(S )-(3-pyridylmethyl)amino-3 (S)-methylpentyl]-glycylmethiomine [2(S )-(2-Oxopyrrolidin-5 (S)-ylmethyl)amino-3(S)methylpentyloxy]-3-phenylpropionyl-methionine methyl estr [2(S )-(2-Oxopyrrolidin-5(S)-ylmethyl)amino-3 (S)-methylpentyloxy]-3 -phenyipropionyl-methionine [2(S )-(L-Pyroglutamyl)amino-3 (S )-methylpentyloxy] 1naphthyl)propionyl-methionine sulfone methyl ester [2(S)-(L-Pyroglutamyl)amino-3 (S )-methylpentyloxy] 1naphthyl)propionyl-methionine sulfone [2(S )-(L-Pyroglutamyl)amino-3 (S )-methylpentyloxy]-3-(2naphthyl)propionyl-methionine sulfone methyl ester [2(S)-(L-Pyroglutamyl)amino-3 (5)-methylpentyloxy] naphthyl)propionyl-methionine sulfone [2(S)-(Imidazol-4-ylacetyl)amino-3 (S )-methylpentyloxy] 1naphthyl)propionyl-methionine sulfone methyl ester WO 97/01275 WO 9701275PCT/US96/1 1022 114- [2(S)-(Imidazol-4-ylacetyl)amino-3 (S)-methylpentyloxy]-3-( 1naphthyl)propionyl-methionine sulfone [2(S)-(Imidazol-4-ylacetyl)amino-3 (S )-methylpentyloxy] naphthyl)propionyl-methionine sulfone methyl ester [2(S )-(Imidazol-4-ylacetyl)amino-3 (S )-methylpentyloxy] naphthyl)propionyl-methionine sulfone N- [2(S)-(L-pyroglutamyl)amino-3 (S )-methylpentyl] -N-(3-quinolylmethyl)glycyl-methionine methyl ester N- [2(S )-(L-pyroglutamyl)amino-3 (S )-methylpentyl] -N-(3-quinolylmethyl)glycyl-methionine N-(Benzyl)-N- [2(S )-(tetrazol- 1 -ylacetyl)amino-3 (S)-methylpentyl] glycyl-methionine methyl ester N-(Benzyl)-N- [2(S )-(tetrazol- 1-ylacetyl)armno-3 (S)-methylpentyl]glycyl-methionine N-(Benzyl)-N- [2(S )-nicotinoylamino-3 (S )-methylpentyl] -glycylmethionine methyl ester N-(Benzyl)-N- [2(S )-nicotinoylamino-3 (S)-methylpentyl] -glycylmethiomine N-[2(S)-(L-Pyroglutamnyl)amino-3(S)-methylpentyl]-N-( 1naphthylmethyl)-glycyl-methionine sulfoxide methyl ester N-[2(S )-(L-Pyroglutamyl)amino-3 (S )-methylpentyl] 1naphthylmethyl)-glycyl-methionine sulfoxide WO 97/01275 WO 9701275PCT/US96/1 1022 115 I [2(5 ,R)-(Imidazol-4-yl)-2-aminoacetyl)amino]-3(S)methylpentyloxy }-3-phenylpropionyl-methionine sulfone methyl ester I [2(S ,R)-(Imidazol-4-yl)-2-aminoacetyl)amino]-3 methylpentyloxy -3-phenyipropionyl-methiomine sulfone 2(S)-[2(R,S)-(Imidazol-4-yl)-2-aminoacetyl)amino]-3(S)methylpentyloxy I -3-phenyipropionyl-methionine sulfone methyl ester I [2(R,S)-(Imidazol-4-yl)-2-aminoacetyl)amino]-3(S)methylpentyloxy I-3-phenyipropionyl-methionine sulfone N- I 2(S)-12(S,R)-(Imidazol-4-yl)-2-aminoacetyl]amino-3(S)-methylpentyl I -N-(l1-naphthylmethyl)-glycyl-methionine methyl ester N- I 2(S)-[2(S,R)-(Imidazol-4-yl)-2-aminoacetyl]amino-3(S)methylpentyl)I-N-(l1-naphthylmethyl)-glycyl-methionine N- I 2(S)-[2(R,S)-(Imidazol-4-yl)-2-aminoacetyl]amino-3(S)-methylpentyl }-N-(l1-naphthylmethyl)-glycyl-methionine methyl ester N- I [2(R,S)-(Imidazol-4-yl)-2-aminoacetyl]amiuno-3 methylpentyl I 1 -naphthylmethyl)-glycyl-methionine N- I [(Imidazol-4-yl)methyl] amino-3 (S )-methylpentyl 1naphthylmethyl)-glycyl-methionine methyl ester N- [(Imidazol-4-yl)methyl] amino-3 (S )-methylpentyl 1naphthylmethyl)-glycyl-methionine N- [2(S )-(L-pyroglutamyl)amino-3 (S )-methylpentyl] 1naphthylmethyl)glycyl-methionine isopropyl ester WO 97/01275 WO 9701275PCT/US96/11022 -116- N- [2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-( 1-naphthylmethyl)glycyl-methionine t-butyl ester N- [2(S)-(L-pyroglutamyl)amino-3 (S )-methylpentyl]-N-(4-quinolylmethyl)glycyl-methionine methyl ester N- [2(S)-(L-pyroglutamyl)amino-3 (S)-methylpentyl]-N-(4-quinolylmethyl)glycyl-methionine N- [3-(Imidazol-4-yl)propyl] amino-3 (S )-methylpentyl 1naphthylmethyl)glycyl-methionine methyl ester N- [3-(Imidazol-4-yl)propyllamino-3 (S )-methylpentyl I 1naphthylmethyl)glycyl-methiomne N- [2(S)-(L-pyroglutamyl)amino-3 (S )-methylpentyl] 1-naphthylmethyl)glycyl-norleucine N- [2(S)-(L-pyroglutamyl)amino-3 (S )-methylpentyl]-N-( 1 -naphthylmethyl)glycyl-norleucine methyl ester N- [2(5 )-(L-pyroglutamyl)amino-3 (S )-methylpentyl] 1-naphthylmethyl)glycyl-glutamine N- [2(S )-(L-pyroglutamyl)amino-3 (S)-methylpentyl] 1-naplithylmethyl)glycyl-glutamine t-butyl ester N- [2(S )-(L-pyroglutamyl)amino-3 (S)-methylpentyl]-N- [5 -(dimethylamino)naphthylsulfonyllglycyl-methionine methyl ester N- [2(S)-(3-pyridylmethyl)amino-3 (S)-methylpentyl] 1 -naphthylmethyl)glycyl-methionine WO 97/01275 WO 9701275PCTIUS96II 1022 117- I [2-(Imidazol-4-yl)ethyl] amino-3 (S )-methylpentyloxy -3phenyipropionyl-methionine sulfone methyl ester f [2-(Imidazol-4-yl)ethyl] amino-3 (S )-methylpentyloxy 1-3phenyipropionyl-methionine sulfone N- [2(S )-(L-pyroglutamyl)amino-3 (S)-methylpentylj-N-( 1-naphthylmethyl)glycyl-serine methyl ester N- [2(S )-(L-pyroglutamyl)amino-3 (S )-methylpentyl] 1 -naphthylmethyl)glycyl-(D,L)-serine N- [2(S )-(L-pyroglutamyl)amino-3 (S )-methylpentyl] 1-naphthylmethyl)glycyl-(L,D)-serine N- [2(S)-(L-pyroglutamyl)amino-3 (S )-methylpentyl] 1-naplithylmethyl)glycyl-homoserine lactone N- [2(S)-(L-pyrogalutamyl)amino-3 (S )-methylpentyl] 1 -naphthylmethyl)glycyl-homoserine N- [2(S )-(L-pyroglutamyl)amino-3 (S )-methylpentyl] -N-(cinnamyl)glycyl-methionine methyl ester N- (L-pyro glutamyl)amino-3 (S )-methylpentyl] -N-(cinnamyl)glycyl-methionine N- I [2-(Imidazol-4-yl)ethyl] amino-3 (S )-methylpentyl I 1naphthylmethyl)glycyl-methionine methyl ester N- [2-(Imidazol-4-yl)ethyl] amino-3 (S)-methylpentyl I 1naphthylmethyl)glycyl-methionine WO 97/01275 PCT/US96/11022 118- N- 2 (S)-(L-pyroglutamyl)amino-3 (S)-methylpentyl]-N-( 1-naphthylmethyl)glycyl-alanine methyl ester N- 2 (S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-( 1-naphthylmethyl)glycyl-alanine N- 2 (S)-(D-pyroglutamyl)amino-3 (S )-methylpentyl]-N-( 1-naplithylmethyl)glycyl-methionine methyl ester N- 2 (S)-(D-pyroglutamyl)anmino-3 (S)-methylpentyl 1-naphthylmethyl)glycyl-methionine [2(S )-(L-Pyroglutamyl)amino-3 (S )-methylpentyloxy]-3 -phenylpropionyl-methionine sulfone methyl ester [2(S )-(L-Pyroglutamyl)amino-3 (S )-methylpentyloxy]-3 -phenylpropionyl-methionine sulfone N- (L-pyroglutamyl)amino-3(S )-methylpentyl] -methylenedioxybenzyl)glycyl-methionine methyl ester N- 2 (S)-(L-pyroglutamyl)amino-3(S)-methylpenty-N(23 methylenedioxybenzyl)glycylbmethionine N- 2 (S)-(Imidazol-4-ylacetyl)amino-3(S)-methylpentylpN-(2,3dihydrobenzofuran-7-ylmethyl)glycyl.methionine methyl ester N- [2(S )-(Imidazol-4-ylacetyl)amino-3 (S )-methylpentyl]-N-(2,3dihydrobenzofuran-7-ylmethyl)glycyl.methionine [3 -(3-indolyl)propionyl] amino-3 (S)-methylpentyl 1naphthylmethyl)glycyl-methionine methyl ester WO 97/01275 WO 9701275PCTIUS96/1 1022 -119- N- I [3-(3-indolyl)propionyllamino-3 (S)-methylpentyl I 1naphthylmethyl)glycyl-methionine N- I [3-(l1-indolyl)propionyl] amino-3 (S )-methylpentyl I 1naphthylmethyl)glycyl-methionine methyl ester N-1{ 1 -indolyl)propionyllamino-3 (S)-methylpentyl 1naphthylmethyl)glycyl-methionine N- [2(5 )-(L-pyroglutamyl)amino-3 (S )-methylpentyl]-N-( 1naphthylmethyl)glycyl-histidine methyl ester N- (L-pyroglutamyl)amino-3 (S )-methylpentyl] 1-naphthylmethyl)glycyl-histidine N- [2(S)-(L-pyroglutamyl)amino-3 (S )-methylpentyl]-N-(cyclopropylmethyl)glycyl-methionine methyl ester N- [2(S)-(L-pyroglutamyl)amino-3 (S )-methylpentyl]-N- (cyclopropylmethyl)glycyl-methionine N- (Imidazol-4-ylacetyl)amino-3 (S )-methylpentyl]-N- (cyclopropylmethyl)glycyl-methionine methyl ester N- [2(S)-(Imidazol-4-ylacetyl)amino-3(S)-methylpentyl]-N- (cyclopropylmethyl)glycyl-methionine N- [2(S)-(L-pyroglutamyl)amino-3 (S )-methylpentyl]-N-(2,3 dihydrobenzofuran-7-ylmethyl)glycyl-methionine methyl ester N- [2(S )-(L-pyroglutamyl)amino-3 (S )-methylpentyl] dihydrobenzofuran-7-ylmethyl)glycyl-methionine WO 97/01275 WO 9701275PCT[US96/1 1022 -120- [2(S)-N-(L-Pyroglutamyl)-N-methylamino-3 (S)-methylpentyloxy]- 3-phenyipropionyl-methionine methyl ester [2(S)-N-(L-Pyroglutamyl)-N-methylamino-3 (S )-methylpentyloxy]- 3-phenyipropionyl-methionine N- [2(S)-(L-pyroglutamyl)armno-3 (S )-methylpentyl]-N-( 1naphthylmethyl)glycyl-O-methylserine methyl ester N- [2(S)-(L-pyroglutamyl)amino-3 (S )-methylpentyl] -N naphthylmethyl)glycyl-O-methylserine 1-Naphthylmethyl)-N- [2(S (L-pyroglutamyl)-N'-methylamino)- 3 (S)-methylpentyl]-glycyl-methionine methyl ester 1-Naphthylmethyl)-N- [2(S )-(N'-(L-pyroglutamyl)-N'-methylamino)- 3(S )-methylpentyl]-glycyl-methiomne N- [1-(Pyroglutamylamino)cyclopent- 1-ylmethyl]-N-( 1-naphthylmethyl)glycyl-methionine methyl ester N-[i -(Pyroglutamylamino)-cyclopent- 1 -ylmethyl] 1-naphthylmethyl)glycyl-methionine N- [2(5 )-(Pyridin-2-on-6-ylcarbonyl)amino-3 (S)-methylpentyl] 1naphthylmethyl)glycyl-methionine methyl ester N- [2(S )-(Pyridin-2-on-6-ylcarbonyl)amino-3 (S )-methylpentyl]-N-( 1naphthylmethyl)glycyl-methionine N- [2(S )-(L-pyroglutamyl)amino-3 (S )-methylpentyl]-N-(3-chlorobenzyl)glycyl-methionine methyl ester N- [2(S)-(L-pyroglutamyl)amino-3 (S )-methylpentyl]-N-(3-chlorobenzyl)glycyl-methionine WO 97/01275 WO 9701275PCT/US96/11022 121 N- [2(S)-(L-pyroglutamyl)amino-3 (S )-methylpentyl]-N-(l1-naphthylmethyl)glycyl-O-methylhomoserine methyl ester N- [2(S)-(L-pyroglutamyl)amino-3 (S )-methylpentyl] 1-naphthylmethyl)glycyl-O-methylhomoserine N- [2(S)-(L-pyroglutamyl)amino-3 (S )-methylpentyl] -N-(2,3-dimethylbenzyl)glycyl-methionine methyl ester N- [2(S)-(L-pyroglutamyl)amino-3 (S )-methylpentyl] -dimethylbenzyl)glycyl-methionine N- [2(S)-(L-pyroglutamyl)amino-3 (S )-methylpentyl]-N-( 1-naphthylmethyl)glycyl-(2-thienyl)alanine methyl ester N- [2(S)-(L-pyroglutamyl)amino-3 (S )-methylpentyl] 1-naphthylmethyl)glycyl-(2-thienyl)alanine N- [2(S)-(pyrrolidin-2-on- 1-yl)-3-methylbutanoyl ]-isoleucyl-methionine; N- [2(S)-(piperidin-2-on- 1-yl)-3-methylbutanoyl 1-i soleucyl-methionine; or the pharmaceutically acceptable salts or optical isomers thereof.
WO 97/01275 PCT/US96/11022 122- The composition of the instant invention also comprises a farnesyl pyrophosphate-competitive inhibitor. Thus the following compounds, well known in the art, are useful as farnesyl pyrophosphate-competitive inhibitors in the instant invention: bb) U.S.Pat. No. 5,260,465, incorporated herein by reference, RO 0
OR
2
CH
3
I
or 0 0
OO
OX-Xi CH3
H
3 C II wherein: X X is: CH CH (cis); CH CH (trans); or CH2CH2;
R
1 and R 2 are each independently selected from: a) H; b) C1-5 alkyl; c) C1-5 alkyl substituted with a member of the group consisting of: i) phenyl; ii) phenyl substituted with methyl, methoxy, halogen (Cl, Br, F, I) or hydroxy; or a pharmaceutically acceptable salt of a compound of formula in which at least one of R 1 and R 2 is hydrogen; WO 97/01275 PCT/US96/11022 123cc) U.S.Pat. No. 5, 420,157, incorporated herein by reference, RO 0"
O
R2 Oi;)zCH3
CH
3 or 0 0 O CH3
H
3 C
II
wherein:
R
1 and R 2 are each independently selected from: a) H; b) C1-5 alkyl; c) C1-5 alkyl substituted with a member of the group consisting of: i) phenyl; ii) phenyl substituted with methyl, methoxy, halogen (Cl, Br, F, I) or hydroxy; or a pharmaceutically acceptable salt of a compound of formula in which at least one of R1 and R 2 is hydrogen; dd) U.S.Pat. Nos. 5, 245,061 and 5, 350,867, incorporated herein by reference, 124-
H
3
C.
.OR
2
CO
2
R
1
S
S
S
wherein: X- X is:
R
1 and R 2 CH CH (cis); CH CH (trans); or CH2CH2; are each independently selected from: a) H; b) C1-5 alkyl; c) C1-5 alkyl substituted with a member of the group consisting of: i) phenyl; ii) phenyl substituted with methyl, methoxy, halogen (Cl, Br, F, I) or hydroxy; or a pharmaceutically acceptable salt of a compound of formula in which at least one of R 1 and R 2 is hydrogen; ee) PCT Publication WO 96/10037 and U.S. Patent No. 5,661,128, incorporated herein by reference, i II__ I L;--lii~l-ll_-i- -ii- II ilt ~-ili i- I__Xi~ WO 97/01275 PCT/US96/11022 125-
R
4 0 2 C C0 2
R
4 O R 2 H
(CH
2
H
2 N NNH 2 N N NH 2 R H 0 R 3
H
or the pharmaceutically acceptable salts, hydrates, esters or amides thereof, wherein: n is: 0 to 4,
R
1 and R 3 independently are CO-4 alkyl, substituted with substituents selected from the group consisting of: a) aryl, which is defined as phenyl or naphthyl, unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of: i) F, ii) Cl, iii) Br, iv) nitro, v) cyano, vi) C1-8 alkoxy, vii) C1-8 alkylthio, viii) C1-8 alkylsulfonyl, ix) sulfamoyl, or x) C1-8 alkyl; or b) heteroaryl, which is defined as indolyl, imidazolyl or pyridyl, unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of: i) F, ii) Cl, iii) Br, WO 97/01275 WO 9701275PCTIUS96/11022 126 iv) nitro, v) cyano, vi) Cl-8 alkoxy, vii) CI-8 allcylthio, viii) Cl-8 alkylsulfonyl, ix) sulfamoyl, or x) Cl..8 alkyl;
R
2 is: CO-6 alkyl, which is unsubstituted or substituted with a substituent selected from the group consisting of: a) unsubstituted or substituted aryl, as defined in RI(a), b) unsubstituted or substituted heteroaryl, as defined in R 1(b), c) C3-8 cycloalcyl, d) C1-8 allcylthio, e) CI-8 alkylsulfonyl, f) CI-8 alkoxy, or g) aryl CI-8 alkyl sulfonyl; and
R
4 is: H; ff) U.S. Pat. Nos. 5,298,655 and 5,362,906; incorporated herein by reference; N N (CH 2 )m-X (CH 2 )n-Y wherein: X is CH2, CH(OH), C=0, CHCOR, CH(NH2), CH(NHCOR), 0, S(O)p, NH, NHCO, o 0 -CNH-, -NH-P-; WO 97/01275 PCT/US96/11022 127p is 0, 1 or 2; Y is PO3RR1 or CO2R; R is H, lower alkyl, or CH2CH2N+Me 3
A-;
R1 is H, lower alkyl, or CH2CH2N+Me 3
A-;
A is a pharmaceutically acceptable anion; m is 0, 1, 2, or 3; and n is 0, 1, 2, or 3; S gg) PCT Publication WO 96/05169, incorporated herein by reference, R3
R
8 R Ar'-X--Y A-2-CH 2 R /Ar 4 R9
R
2 CH CH Ar H N AA-CO 2
H
R 5 H R 6 0
R
wherein each of C Ar 2 Ar 3 and Ar 4 which are the same or different, is an aryl group or a heteroaromatic ring group; A is a C2-8 saturated or unsaturated aliphatic hydrocarbon group which may have substituent(s) selected from the group consisting of a lower alkyl group, a hydroxyl group, a lower hydroxyalkyl group, a lower alkoxy group, a carboxyl group, a lower carboxyalkyl group, an aryl group and an aralkyl group; each of X and Y which are the same or different, is an oxygen atom, a sulfur atom, a carbonyl group or a group of the formula -CHRa- (wherein Ra is a hydrogen atom or a lower alkyl group) or -NRb (wherein Rb is a hydrogen atom or a lower alkyl group), or X and Y together represent WO 97/01275 PCT/US96/11022 128a vinylene group or an ethynylene group; each of R1, R 2
R
3
R
8 and
R
9 which are the same or different, is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group or a lower alkoxy group; each of R 4 and R 5 which are the same or different, is a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group, a lower alkyl group, a lower hydroxyalkyl group, a lower fluoroalkyl group or a lower alkoxy group; R 6 is a lower alkyl group; and R 7 is a hydrogen atom or a lower alkyl group, provided that when one of X and Y is an oxygen atom, a sulfur atom or a group of the formula -NRb- (wherein Rb is as defined above), the other is a carbonyl group or a group of the formula
-CHR
a (wherein Ra is as defined above); hh) PCT Publication WO 96/05168, incorporated herein by reference, R7 Ar'-Q-C--H 2 Ar 3
R
R
2 CH CH RHAr rN A-CO 2
H
R
4 wherein each of Ar- Ar 2 and A 3 which are the same or different, is an aryl group or a heteroaromatic ring group; A is a C2-8 saturated or unsaturated aliphatic hydrocarbon group which may have substituent(s) selected from the group consisting of a lower alkyl group, a hydroxyl group, a lower hydroxyalkyl group, WO 97/01275 PCT/US96/11022 129a lower alkoxy group, a carboxyl group, a lower carboxyalkyl group, an aryl group and an aralkyl group; Q is a group of the formula -(CH2)m- (wherein m is an integer of from 1 to 6) or -(CH2)n-W- (CH2)p- (wherein W is an oxygen atom, a sulfur atom, a vinylene group or an ethynylene group; and each of n and p which are the same or different, is an integer of from 0 to R 1 is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, or an aryl or heteroaromatic ring group which may have substituent(s) selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group; each of R 2
R
7 and R 8 which are the same or different, is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group or a lower alkoxy group; each of
R
3 and R 4 which are the same or different, is a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group, a lower alkyl group, a lower hydroxyalkyl group, a lower fluoroalkyl group or a lower alkoxy group; R 5 is a lower alkyl group; and R 6 is a hydrogen atom or a lower alkyl group; or the pharmaceutically acceptable salts thereof.
Specific examples of farnesyl pyrophosphate-competitive inhibitors include: 3-Hydroxy-7,11,15-trimethylhexadeca-6,10,14-trienoic acid, Oxo-6,10,14-trimethylpentadeca-5,9,13-trienyl]phosphonic acid Hydroxy-6,10,14-trimethylpentadeca-5,9,13-trienyl]phosphonic acid Acetyl-4,8,12-trimethylpentadeca-3,7,11-trienyl]phosphonic acid WO 97/01275 WO 9701275PCTIUS96/11022 130- ,7,11 -Trimethyl-2,6, 10-dodecatrienylamino] -2-oxoethyl]phosphonic acid 8,1 2-Trimethyl-3 ,7,1 1-tridecatrienyl]thiomethyl-phosphonic acid 3- 1-Trimethyl-2,6, 1 -dodecatrienylamino]-3-oxo-propionic acid ,7,11 -Trimethyl-2,6, 10-dodecatrienylamino] -2-oxoethyllphosphonic acid monomethyl ester ,7,11 -Trimethyl-2,6, 10-dodecatrienylamino]-l1-oxomethyliphosphonic: acid [1I -Hydroxy-(E,E)-3 ,7,11I -trimethyl-2,6, 1 0-dodecatrienyl]-phosphonic acid [1 -Hydroxy-(E,E)-5,9, 13-trimethyl-4,8,1 2-tetradecatrienyl]-phosphonic acid [1 -Hydroxy-(E,E)-4,8, 12-trimethyl-3 ,7,1 1-tridecatrienyl] -phosphonic acid [2-Acetamido-(E,E)-4,8, 12-trimethyl-3 ,7,1 1-tridecatrienyl] -phosphonic acid and [2-Hydroxy-(E,E)-4,8, 12-trimethyl-3 11 -tridecatrienyl]-phosphonic acid N-1{ (IRS,2RS ,4E)-2-(4-chlorophenyl)- 1-methyl-S -(2-naphthyl)-4pentenyl I (2-naphthylmethyl1)-carbamoylmethylsuccinic acid WO 97/01275 PCT/US96/1 1022 131 N-1{ (IRS,2RS ,4E)-2-(4-chlorophenyl)- 1 -methyl-5-(l1-naphthyl)-4pentenyl (2-naphthylmethyl1)-carbamoylmethylsuccinic acid N- {(iRS 2 RS)-2-(4-chioropheny1)-i-methy-5-(2-.naphthy1)pentyl naphthylmethyi)carbamoylmethylsuccinic acid N- {(iRS 2 RS)-2-(4-chlorophenyi)--methyli4.(2-naphthoxy)buty 1-N- 2 -naphthylmethyi)carbamoylmethylsuccinic acid N- {(iRS ,2RS (4-chiorophenyi)-1-methyl-4-(2-naphthyi)butyi I-(2 naphthyimethyl)carbamoylmethylsuccinjc acid N- I (IRS 2
RS)-
2 4 -chlorophenyi)-1-methyl-6-(2-naphthyl)hexyI I naphthylmethyl)carbamoyimethyisuccinic acid N- I (IRS ,2RS 2 4 -chiorophenyl)-1-methyl-5-phenyi-4-pentynyi I naphthyimethyl)carbamoylmethyisuccinic acid N- I (IRS ,2RS 4 E)-2-(4-methoxypheny)-1-methyl-5-(2-naphthyl).4.
pentenyl)}-N-(2-naphthyimethyl)carbamoylmethyisuccinic acid N- {(iRS ,2RS ,4E)-1-methyl-2-(4-methylphenyl)-5- (2-naphthyl)-4pentenyl I-N-(2-naphthyl1methyi)carbamoyimethylsuccinic acid N- I (IRS ,2RS ,4E)-i-methyi-5-(2-naphthyl)-2-(4-nitrophenyl).4 pentenyl I -N-(2-naphthylmethyi)carbamoyimethyisuccinic acid N- f (IRS ,2RS ,4E)-2-(4-fluorophenyi)-1-methyi-5-(2-naphthyi)-4pentenyl }-N-(2-naphthyimethyl)carbamoyimethyisuccinic acid N- I (IRS ,2RS ,4E)-i-methyl-5-(2-naphthyl)-2-(4-trifluoromethyphenyl).
4-pentenyi }-N-(2-naphthylmethyi)carbamoyimethylsuccinic acid WO 97/01275 WO 9701275PCTIUS96/1 1022 132 N- I (1RS,2RS,4E)-l-methyl-5-(2-naphthyl)-2-phenyl-4-pentenyl naphthylmethyl)carbamoylmethylsuccinic acid N- I (IRS ,2RS ,4E)-1-methyl-2-(6-methyl-3-pyridyl)-5-(2-naphthyl)-4pentenyl I -N-(2-naphthylmethyl)carbamoylmethylsuccinic acid N- I (IRS ,2RS ,6E)-2-(4-chlorophenyi)-1-methyl-7-phenyl-6-heptenyl (2-naphthyimethyl)carbamoylmethylsuccinic acid N- I (IRS ,2RS ,6E)-2-(4-chlorophenyl)-1-methyl-7- (2-naphthyl)-6heptenyl }-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid N- I (IRS ,2RS ,4E)-2-(4-chlorophenyl)-1-methyl-5-(2-naphthyl)-4pentenyl }-N-(3-quinolylmethyl)carbamoylmethylsuccinic acid N- I (IRS ,2RS ,4E)-2-(4-chlorophenyl)-1-methyi-5- (2-naphthyl)-4pentenyl I-N-(3 ,4-difluorobenzyl)carbamoylmethylsuccinic acid N-(2-benzoxazolyimethyi)-N- (IRS ,2RS ,4E)-2-(4-chlorophenyl)-imethyl-5-(2-naphthyi)-4-pentenyliicarbamoylmethylsuccinic acid N-(2-benzo thienylmethyi)-N- {(iRS ,2RS (4-chlorophenyl)-lmethyi-5-(2-naphthyi)-4-pentenyl Icarbamoylmethylsuccinic acid N-1{ (IRS ,2RS ,4E)-i-methyi-2-(3 ,4-methyienedioxyphenyl)-5- (2naphthyi)-4-pentenyi I -N-(2-naphthyimethyl)carbamoylmethylsuccinic acid I (I ,2S ,4E)-2-(4-chiorophenyl)-i-methyi-5-(2-naphthyi)- 4-pentenyl I-N- (2-naphthylmethyl)carbamoylmethyl] succinic acid (2R* I (iR* ,2R* ,4E)-2-(4-chiorophenyi)- 1 -methyl-5- (2naphthyi)-4- pentenyl I-N-(2-naphthyimethyi)carbamoyimethyi] succinic acid WO 97/01275 PCTIUS96/11022 133 (2S (1R* ,2R*,4)2 -hoohnl-lmty--2npty) 4-pentenyl)}-N- 2 -naphthylmethyl)carbamoylmethyl] succimic acid (2S {(iS *,2S 4
E)-
2 -(4-chlorophenyl)lmethyl15-.(2-naphthyl)- 4-pentenyl 2 -naphthylmethyl)carbamoylmeffiy1]succinic acid {(iRS ,2RS 4
E)-
2 4 -chlorophenyi)-l-methyi..5-.(2.naphthyi)-4 pentenyl I 2 -naphthyimethyi)carbamoyilpentanoic acid (iRS ,2RS 4 E)-5-(2-benzoxazoy)-l-methy..2-.(3 ,4methylenedioxyphenyi)-4-pentenyI I (2-naplithyimethyl)carbamoyimethyllsuccinic acid (iRS ,2RS 4 Z)-5-(2-benzoxazoy)-i-methy..2-.(3 ,4methyienedioxyphenyi)-4-pentenyi I-N- (2-naplithylmethyl)carbamoylmethyllsuccinjc acid [N-(2-benzo [b]furanylmethyl)-N- (1RS,2RS benzoxazolyl)-l-methy1-2(3,4-methyienedioxyphenyi-4pentenyl Icarbamoyimethyl]succinate (2R *)-.2...[N-(2-benzo[b]thienylmethyi)..N-{ (iRS ,2RS (2-benzoxazoiyi)-1-methyi-2-(3 4 -methylenedioxyphenyi-4pentenyl I carbamoylmethyl] succinic acid (2*--N[ISRE--2b{zxzll--3,4bis(methoxycarbonyi)phenyi 1-1 -methyl-4-pentenyl] naphthylmethyl)carbamoylmethyi] succinic acid [N-(2-benzo [b]thienyimethyi)-N- {(iRS ,2RS 2 -benzoxazolyi)-2-(4-methoxycarbonyiphenyiy..imethyi-4 pentenyl I carbamoylmethyl] succinic acid WO 97/01275 PCTUS96/11022 134 [N-(2-benzo[b]furanylmethyl)N-. I (IRS ,2RS benzoxazolyl)>%(4methoxycarbonylphenyl)lmethyl- 4 pentenyl I carbamoylmethyl]succinic acid [N-(2-benzo [b]thienylmethyl)-N.. (IRS ,2RS benzoxazolyl)-2-(4-cyanopheny).1..methy14pentenyl I carbamoylmethyl] succiflic acid [N-(5-benzo [b]thienylmethyl)-N-. (IRS ,2RS benzoxazolyl)-2(4methoxycarbonylphenyl)lmethy14pentenyl I carbamoylmethyl] succinic acid N- I (IRS ,2RS,4)5(-hoo4mtypenl--4clrpey)l methyl-4-pentenyl I 2 -naphthylmethyl)carbamoylmethylsuccinic acid N- I (IRS ,2RS -chloro-4-methylphenyl)y2(4-.chlorophenyl)1l methyl-4-pentenyl I 2 -naphthylmethyl)carbamoylmethylsuccinic acid N- I (IRS .2RS ,4E)-5 -(2-benzo [b]furanyl)-2- 4 -chlorophenyl)-I-methyl-4 pentenyl I 2 -naphthylmethyl)carbamoylmethylsuccinic acid (IRS .2RS 4 2 -benzo[b]furanyl)2-.(4.chorophenyl)lmethyI4pentenyl I 2 -naphthylmethyl)carbamoylmethylsuccinic acid N- I (IRS ,2RS 4 2 -benzoxazolyl)y2.(4-.chloropheny)lmethyi4pentenyl I 2 -naphthylmethyl)carbamoylmethylsuccinic acid N- f (IRS .2RS.4)5(-ezxzll -4-hoohnl--ehl4 pentenyl I 2 -naphthylmethyl)carbamoylmethylsuccinic acid N- I (IRS, 2RS ,4E)-5 2 -benzimidazolyl)-2-(4-chiorophenyl). 1 -methyl-4pentenyl I 2 -naphthylmethyl)carbamoylmethylsuccinic acid WO 97/01275 PCTJUS96/11022 135 N- I (IRS ,2RS ,4E)-2-(4-chlorophenyl)-1-methyl-5-(3 ,4methylenedioxyphenyl)-4-pentenyl)}-N-(2naphthylmethyl)carbamoylmethylsuccinic acid N- {(iRS ,2RS ,4E)-5-(2-benzothiazoiyi)-2- (4-chiorophenyl)-l1-methyl-4pentenyl I -N-(2-naphthylmethyl)carbamoylmethylsuccinjc acid N- I (IRS ,2RS 4 E)-5-(2-benzoxazoiyl)-2-(4-cyanophenyl.. 1 -methyl-4pentenyl I 2 -naphthylmethyl)carbamoyimethylsuccinic acid 4- f (IRS ,2RS ,4E)-5-(2-benzoxazolyl)- 1 -methyl-2-(3 ,4methylenedioxyphenyl)-4-.pentenyl)I-N-(2-naphthylmethyl)carbamoyl]- 1 ,2,3-butanetricarboxylic acid 3- (iRS ,2RS ,4E)-5-(2-benzoxazoiyi)-l1-methyl-2-(3 ,4methylenedioxyphenyi)-4-pentenyi }-N-(2-naphthylmethyl)carbamoyi]- 1 2 2 -propanetricarboxyiic acid (1RS,2RS,4E)-5-(2-benzoxazolyl)-1-methyl-2- (3 4 -methylenedioxyphenyl)-4-pentenyl I naphthylmethyl)carbamoylmethyl] -3-carboxy-2-hydroxybutanoic acid 4- [N-((1RS ,2RS,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4methyienedioxyphenyl)-4-pentenyi 1-N- (2-naphthyimethyl)carbamoyl] 3-carboxy-4-methoxybutanoic acid (1RS,2RS,4E)-5-(2-benzoxazolyl)-i-methyl-2-(3,4.
methylenedioxyphenyl)-4-pentenyl (2-naphthyimethyl)carbamoyi] 4-carboxy-3-carboxymethylpentanoic acid 1- {(iRS ,2RS 4 E)-5-(2-benzoxazolyl)-2-(4-methoxycarbonyphenyl).
1-methyl-4-pentenyi I -N-(2-naphthylmethyl)carbamoyl]- 1,2,3propanetricarboxylic acid WO 97/01275 PCT/US96/11022 136 (IRS ,2RS ,4E)-5-(2-benzoxazolyl)-.l-methyl-2- (3,4methylenedioxyphenyl)-4-pentenyl I -N-(2-naphthylmethyl)carbamoyl] 3-methoxybutanoic acid (3S (IRS ,2RS ,4E)-5-(2-benzoxazolyl)-i-methyi-2-(3 ,4methylenedioxyphenyi)-4-pentenyl I-N-(2-naphthyimethyi)carbamoyi] 3-methoxybutanoic acid N- I (IRS ,2RS 4 E)-5-(2-benzoxazoiyi)-2-(4-carboxyphenyl)-1-methyi-4pentenyl }-N-(2-naphthyimethyi)carbamoylmethyisuccinic acid N-I (IRS ,2RS ,4E)-5-(2-benzoxazoiyi)-1-methyl-2- methylcarbamoyl)phenyi I -4-pentenyl] naphthyimethyi)carbamoylmethylsuccinic acid {(iRS ,2RS ,4E)-5-(2-benzoxazoiyi)-2-(4-hydroxy-3 methoxyphenyi)-1-methyl-4-pentenyl I naphthylmethyl)carbamoylmethylsuccinic acid N- I (IRS ,2RS ,4E)-2-(4-hydroxymethyiphenyl)- 1 -methyl-5-(2-naphthyl)- 4-pentenyl }-N-(2-naphthyimethyl)carbamoyimethyisuccinic acid N- I (IRS ,2R5 ,4E)-2-(4-aminophenyl)-1-methyl-5-(2-naphthyl)-4pentenyl }-N-(2-naphthylmethyi)carbamoyimethylsuccinic acid disodium (3RS .4RS)-4- RS ,2R5 ,4E)-5-(2-benzoxazoiyl)-l-methyl- 2-(3,4-methyienedioxyphenyi)-4-pentenyI I naphthyimethyi)carbamoyl] -3-carboxy-4-hyroxybutanoate N-{I (iRS,2RS,4E)-5-(2-benzoxazolyi)-i-methyl-2-(3,4methylenedioxyphenyl)-4-pentenyl I oxotetrahydrofuran-2-carboxyamide WO 97/01275PCUS6102 PCTIUS96/11022 137 sodium 4- RS ,2RS ,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3 ,4methylenedioxyphenyl)-4-pentenyl I -N-(2-naphthylmethyl)]carbamoyl- 4-hyroxybutanoate 4- (1RS,2RS ,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3 ,4methylenedioxyphenyl)-4-pentenyl -N-(2-naphthylmethyl)carbamoyl] 2-oxotetrahydrofuran-3-yl-acetic acid I (1R*,2R* ,4E)-5-(2-benzoxazolyl)-2-(4methoxycarbonylphenyl)-1-methyl-4-pentenyl naphthylmethyl)carbamoylmethyllsuccinic acid {(iS *,2S *,4E)-5-(2-benzoxazolyl)-2-(4methoxycarbonylphenyl)-l-methyl-4-pentenyl I naphthylmethyl)carbamoylmethyllsuccinic acid (2*--N-2bnob heymehl (iS *,2S (2-benzoxazolyl)-1-methyl-2-(3 ,4-methylenedioxyphenyl)-4pentenyl I carbamoylmethyl] succinic acid [N-(2-benzo[b]thienylmethyl)-N- I (1R* ,2R* (2-benzoxazolyl)-1-methyl-2- (3 ,4-methylenedioxyphenyl)-4pentenyl I carbamoylmethyl]succinic acid (iRS ,2RS )-5-(2-benzoxazolyl)-1-methyl-2- (3,4methylenedioxyphenyl)pentyi I naphthyimethyl)carbamoylmethyilsuccinic acid [N-(2-benzo[bjthienyimethyl)-N- I (2-benzoxazoiyl)-1-methyl-2- (3 ,4-methylenedioxyphenyl)pentyl }carbamoylmethyl] succinic acid WO 97/01275 WO 9701275PCT/US96/1 1022 138 I (1R*,2*--2bnoxzll--4 methoxycarbonylphenyl)-1-methylpentyl I naphthylmethyl)carbamoylmethyl]succinic acid disodium (3 S,4S)-4- R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2- (3 ,4-methylenedioxyphenyl)-4-pentenyl I naphthylmethyl)carbamoyl] -3-carboxy-4-hyroxybutanoate (Compound
D)
sodium (3 S,4S R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3 ,4methylenedioxyphenyl)-4-pentenyl -N-(2-naphthylmethyl)carbamoyl] 3-ethoxycarbonyl-4-hyroxybutanoate {(1R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4methylenedioxyphenyl)-4-pentenyl (2-naphthylmethyl)carbamoyl] 3-tert-butoxycarbonyl-4-hydroxy-3-butenoic acid
OH
Yl ,C0 2
H
0 C0 2 t-Bu WO 97/01275 PCT/US96/1 1022 139 (lR, 2
R,
4 E)-5-(2-benzoxazolyl)-1methy1..2(3, 4 methylenedioxyphenyl)-4-pentenyl I-N- 2 -naphthylmethyl)carbamoyl]y 4 -hydroxy-3-methoxycarbonyl3butenoic acid (lR, 2 R,4E)-5-(2-benzoxazolyl)-lmethyl..2-.(3,4 methylenedioxyphenyl)-4-pentenyl 1-N- 2 -naphthylmethyl)carbamoyl] 4 -hydroxy-3-isopropoxycarbonyl.3-butenoic acid 4- (1 R, 2 R,4E)-5-(2-benzoxazoy)-l-methy..2-.(3 ,4methylenedioxypheny)-4-.pentenyI 2 -naphthylmethyl)carb amoyl] 3 -cyclohexyloxycarbony-4-hydroxy-3-.butenoic acid 4- R, 2 R,4E)-5-(2-benzoxazoly1)-lmethy..2-.(3 ,4methylenedioxypheny)-4-penteny1 2 -naphthylmethyl)carb amoyl]- 4 -hydroxy-3-(2-methoxyethoxy)cabonyl..3-butenoic acid 4- [N-1(1 R, 2 R,4E)-5-(2-benzoxazoyl)-l-methyl..2-.(3 ,4methylenedioxyphenyl)-4-pentenyl
I-N-(
2 -naphthylmethyl)carbamoyl] 3 -benzyloxycarbonyl-4-hydroxy-3-.butenoic acid 4- I (1 R, 2 R,4E)-5-(2-benzoxazoy>1.-methyl..2..(3,4methylenedioxyphenyl)-4-pentenyl)I-N-( 2 -naphthylmethyl)carbamoyl]y 3 -cyclopentyloxycarbonyl-4-hydroxy-3-.butenoic acid 4- (1 R, 2 R,4E)-5-(2-benzoxazolyl)-l-methyl2..(3,4methylenedioxyphenyl)-4-pentenyl I-N- 2 -naphthylmethyl)carbamoyl] 4 -hydroxy- 3 -(3-tetrahydrofuranyloxycarbonyl)-.3-butenoic acid 4- R,2R,4E)-5-(2-benzoxazolyl)-l-methyl12-(3,4methylenedioxyphenyl)-4-pentenyl I-N- (2-naphthylmethyl)carb amoyl] 4-hydroxy-3-(2-hydroxy- 1 -hydroxymethylethoxycarbonyl)..3-butenoic acid -1 WO 97/01275 PCTIUS96I11o22 140 3-allyloxycarbonyl-4-[N- (lR, 2
R,
4 E).5(2..benzoxazolyl)-lmethyl2- (3 4 -methylenedioxyphenyl)4pentenyl I 1-2 naphthylmethyl)carbamoyl-4-hydroxy-3-.butenoic acid 4- 2,E--2-ezxzll-2(,-ehlneixpey)l methyl-4-pentenyl I 2 -naphthylmethyl)carbamoyl].3.
carboxymethylcarbonyl4hydroxy3butenoic acid 5- I (lR, 2 R,4E)-5-(2-benzoxazoy)-l-.methy..2-.(3 ,4methylenedioxyphenyl)-4-pentenyl I (2-naphthylmethyl)carb amoyl]- 4 -ethoxycarbonyl-5-hydroxy4pentenoic acid {(lR, 2 R,4E)-5-(2-benzoxazolyl)-l-methyl2-(3,4methylenedioxyphenyl)-4-.pentenyI I 2 -naphthylmethyl)carbamoyl] 4 -tert-butoxycarbonyl..5.hydroxy4pentenoic acid 4-N- I (lR, 2 R,4E)-5-(2-benzoxazolyl)-lmethyl12-(3 ,4methylenedioxyphenyl)-4-.pentenyI I 2 -naphthylmethyl)carbamoyl] 4 -hydroxy-3-hydroxymethyl-3butenoic acid 4- f (IRS ,2RS ,SE)-6-(2-benzoxazoly1)-1..methy12-(3 ,4- I 2 -naphthylmethyl)carbamoyl]y3.
tert-butoxycarbonyl-4-hydroxy-3-.butenoic acid (2S {(1R,2R,4E)-5- 2 -benzoxazolyl)-l-methyl-2-.(3 ,4methylenedioxyphenyl)-4-pentenyl I-N- 2 -naphthylmethyl)carbamoyl] 1 ,2,3-butanetricarboxylic acid (2R* (lR, 2 R,4E)-5-(2.benzoxazolyl-lmethyp2(3,4 methylenedioxyphenyl)-4-pentenyl I-N-(2-naphthylmethyl)carbamoyl] 1 ,2,3-butanetricarboxylic acid WO 97/01275 PCTUS96I1 1022 141 N- [(IRS 2 RS)-l-methyl-2-(4-nitrophenyl)-3. 5-(phenylcarbamoyl).2furyl }propyl]-N-( 2 -naphthylmethyl)carbamoylmethylsuccinic acid N- [(IRS ,2RS 4 -dimethoxyphenylcarbamoyl).2-furyI I1-1-methyl- 2 4 -nitrophenyl)propyl] naphthylmethyl)carbamoylmethylsuccinic acid N- [(IRS ,2RS f 5-( 2 -hydroxyphenylcarbamoyl)2-uryl -1 -methyl-2- (4ntohnlpoylN(-ahhymty~abmymtyscii acid N- [(IRS,2RS )-1-methyi-3-1{ -(N-methyiphenylcarbamoyl).2-ffryiI J-2-(4nirpey~rpl--2nptymty~abmymtyscii acid N- [(IRS 2 RS)-1-methy1-2-(4-nitropheny).3..{ 3 -pyridyicarbamoyl)-2furyl Ipropyi]-N-( 2 -naphthylmethy1)carbamoylmethyisuccinic acid N- [(IRS 2 RS)-l-methyi-2-(4-nitrophenyl)3. pyridyicarbamoyi)-2-furyi Ipropyl]-N-(2naphthylmethyi)carbamoylmethylsuccinic acid N- [(IRS ,2RS )-i-methyl-2-(4-nitropheny).3.. pyrimidinyicarbamoy)-%..furyl Ipropyi]-N-(2naphthylmethyi)carbamoylmethylsuccinic acid N- [(IRS,2RS )-i-methyl-2-(4-nitrophenyiy-3-. 2 -thiazoiylcarbamoyly..
2-furyl Ipropyl]-N-( 2 -naphthylmethyi)carbamoylmethylsuccinic acid N- [(IRS 2RS)-2-(4-chloropheny)-l-methy..3- {5-(phenyicarbamoyi)-2furyl }propyl]-N-( 2 -naphthylmethyl)carbamoyimethyisuccinic acid N- I (IRS ,2RS )-2-(4-chloropheny)--methy.3-(3phenylcarbamoyiphenyl)propyi I naphthylmethyl)carbamoylmethyisuccinic acid WO 97/01275 PCT/US96/11022 142 N- [(IRS 2
RS)-
2 4 -chloropheny)--methy.3 J 3 isoxazolyl Ipropyl]-N-( 2 -naphthylmethyl)carbamoylmeffiy~succinic acid N- [(IRS 2 RS)-2-(4-chlorophenyl)-lmethyl..3-. 4 -(phenylcarbamoyl)-2pyridyl }propyl] 2 -naphthylmethyl)carbamoylmethylsuccinic acid [N-(2-benzo[b]thienylmethyl)-N-[(iRS ,2RS)-1-methyl-2-(3 ,4methylenedioxyphenyl).3. {5-(phenylcarbamoyl)-2furyl }propyl]carbamoylmethy]succinic acid methyi-2-(3 ,4-methylenedioxyphenyl).3 -(3-pyridylcarbamoyi)-2fuiryl )propyllcarbamoyimethyl] succinic acid monopivaioyloxymethyl [N-(2-benzo[b]thienyimethyl>N- [(IRS ,2RS )-i-methyi-2-(3 ,4-methyienedioxypheny)-3-. f (phenyicarbamoyi)-2-furyl I propyilcarbamoyimethyi] succinate (2R* (IRS 2 RS)-2-(4-methoxycarbonylpheny)-l-methy.3-.(3 phenoxymethyiphenyi)propy 11I -N-2naphthyimethyl)carbarnoylmethyllsuccinic acid (2R* RS,2RS 2 -(4-methoxycarbonyiphenyl)-l.
methyi-3 (phenoxymethyl)-5-( 1,2,4-oxadiazolyl) I propyl]-N-(2naphthyimethyl)carbamoylmethyi] succinic acid [(IRS ,2R5 2 4 -methoxycarbonylpheny)-..methyi-3-. 3-styryiphenyl propyi]-N-(2-naphthylmethyl)carbamoylmethyl] succinic acid (2R* [(IRS ,2RS)-2- (4-methoxycarbonylphenyl)-1-methyl-3. 3 phenyiethyl)phenyi I propyl]-N-(2-naphthylmethyl)carbamoylmethyl] succinic acid WO 97/01275 PCTIUS96/11022 -143- N- J (IRS 2
RS)-
2 4 -choropheny)-1-methy..3-.(4-.phenylethynylphenyl)propyl 2 -naphthylmethyl)carbamoylmethylsuccinic acid N- [(IRS 2 RS)-2-(4-chlorophenyl)- 1 -methyl-3- I styryiphenyl }propyi]-N-( 2 -naphthylmethy1)carbamoylmethylsuccinic acid N- I (lRS,2RS)-2-(4-methoxycarbonylpheny). 1 phenoxymethyi-2-furyl)propyl naphthyimethyi)carbamoylmethylsuccinic acid 4- [(IRS ,2RS)-l1-methyl-2-(4-nitrophenyl..3. (phenyicarbainoyl)-2-furyi 1propyl]-N-( 2 -naphthylmethyl)carbanmoyll- 1,2,3-butanetricarboxylic acid disodium (3RS,4RS)-3-carboxylato-4-hydroxy-4..[N- [(IRS,2RS)- 1methyl-2-(4-nitrophenyi)-3- I -(phenylcarbamoyl)-2-furyl Ipropyl] -N- 2 -naphthylmethyi)carbamoyl]butanoate disodium 3
SR,
4 SR)-3-carboxyato-4-hydroxy-4..[N- [(IRS,2RS)- 1methyl-2-(4-nitrophenyi)-3-1{ -(phenylcarbamoyi)-2-furylI propyl] -N- 2 -naphthylmethyl)carbamoyl]butanoate 3-tert-butoxycarbonyl-4-hydroxy-4..[N- [(iRS,2RS)- 1 -methyl-2-(4nitrophenyl)-3-1I5-(phenyicarbamoyl)-2-furyl }propyl] naphthyimethyl)carbamoyl]-3-butenoic acid 3-tert-butoxycarbonyl-4-hydroxy-4- [(IRS ,2RS )-l1-methyl-2-(3 ,4methylenedioxyphenyi)-3- (phenylcarbamoyl)-2-furyl }propyl] (2naphthylmethyl)carbamoyl]-3-butenoic acid 3-tert-butoxycarbonyl-4-hydroxy-4- (IRS ,2RS)-1-methyl- 2 4 -nitrophenyl)-3-(3-phenoxymethylphenyi)propyI I WO 97/01275 PCT/US96/11022 -144naphthylmethyl)carbamoyl]..3-butenoic acid 4 -hydroxy-3-methoxycarbony 1-4- [(IRS ,2RS)-1-methyl-2-(3 ,4methylenedioxyphenyl)-3-1{ -(phenylcarbamoyl)-2-furyl }propyl]-N-(2naphthyhnethyl)carbamoyl]-3-butenoic acid 3 -allyloxycarbonyl-4-hydroxy.4-.[N- [(lRS,2RS)-1-methy1-2-(3 ,4methylenedioxyphenyl)-3- f 5-(phenylcarbamoyl)-2-furyl propyl]-N- 2 -naphthylmethyl)carbamoyly3-butenoic acid 5-hydroxy-4-isopropylcarbonyls...[N- [(IRS ,2RS)-l-methyl-2-(4nitrophenyl)-3-1{ -(phenylcarbamoyl)-2-furylI propyl]-N-(2naphthylmethyl1)carbamoyl]-4-pentenoic acid 3-tert-butoxycarbonyl-4- {N-(2,3-dichlorobenzyl).N.[(IRS ,2RS)-lmethyl-2-(4-nitrophenyl)-3-f -(phenylcarbamoyl)-2furyl }propyilcarbamoyl]-4-hydroxy-.3-butenoic acid or a pharmaceutically acceptable salt or optical isomer thereof.
A further embodiment of the specific famnesyl pyrophosphate-competitive inhibitors includes: disodiumn (3RS .4RS)-4- (1 RS,2RS 4 E)-5-(2-benzoxazolyl)lmethylp 2-(3 4 -methyienedioxyphenyl)-4-pentenyl IN(2 naphthylmethyl)carbamoyl-3-carboxyl-4-.hyroxybutanoate (Compound
D)
145 and sodium {(1R,2R,4E)-5-(2-benzoxazolyl)-1 -methyl-2-(3,4-methylenedioxyphenyl)-4pentenyl}-N-(2-naphthylmethyl)carbamoyl]-3-tert-butoxycarbonyl-4-hydroxy-3-butenoate (Compound C)
N
OH
O
NCO
2 Na O
CH
3 0 CO 2 t -Bu The composition of the instant invention may alternatively or in addition comprise a farnesyl pyrophosphate-competitive inhibitor obtained by fermentation of cultures of novel organisms. In particular, the compounds disclosed in U.S. Patent No. 5,510,371 may be useful as a farnesyl pyrophosphate-competitive inhibitor component of the instant 10 composition. U.S. Patent No. 5,510,371 is incorporated herein by reference.
In addition, compounds described in the following patents and publications may also be utilised as a farnesyl pyrophosphate-competitive inhibitor component of the instant composition: European Patent Publication 0 537 008; European Patent Publication 0 540 782; PCT Patent Publications WO 94/1935; WO 95/12572 and WO 95/08546. Those 15 patents and publications are incorporated herein by reference.
The protein substrate-competitive inhibitors and farnesyl pyrophosphate-competitive inhibitors of the present invention may have asymmetric centres and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention. Unless otherwise [R\LIBAA]07529.doc:TAB WO 97/01275 PCTIUS96/11022 -146specified, named amino acids are understood to have the natural "L" stereoconfiguration.
The following definitions apply to compounds of the general formulas a) through ff) hereinabove: 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, farnesyl, 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.
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, WO 97/01275 PCT/US96/11022 147benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isoclromanyl, 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(CI-C6 alkyl)2, N02, CN, (Cl-C6 alkyl)O-, -OH, (Cl-C6 alkyl)S(O)m-, (CI-C6 alkyl)C(O)NH-, H2N-C(NH)-, (Cl-C6 alkyl)C(O)-, (C1-C6 allyl)OC(O)-, N3,(Cl-C6 alkyl)OC(O)NH- and alkyl.
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: WO 97/01275 PCT/US96/11022 -148- N N N N N It is also understood that substitution on the cyclic amine moiety by R 2 a, R2b, R 7 a and R7b may be on different carbon atoms or on the same carbon atom.
When R 2 a and R 2 b,and 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: 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: 0 S 0 S 0NH 0 S N CO HRO CORio WO 97/01275 PCT/US96/11022 -149- As used herein, the phrase "nitrogen containing C4-C9 mono or bicyclic ring system wherein the non-nitrogen containing ring may be a C6 aromatic ring, a C5-C7 saturated ring or a heterocycle" which defines moiety of the instant invention includes but is not limited to the following ring systems: 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 protein substratecompetitive inhibitors and farnesyl pyrophosphate-competitive WO 97/01275 PCT/US96/11022 150inhibitors 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.
The pharmaceutically acceptable salts of the protein substrate-competitive inhibitors and farnesyl pyrophosphate-competitive inhibitors of this invention include the conventional non-toxic salts of the compounds of 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, phenyl-acetic, glutamic, benzoic, salicylic, sulfanilic, 2acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
The pharmaceutically acceptable salts of the protein substrate-competitive inhibitors and farnesyl pyrophosphate-competitive inhibitors of this invention can be synthesized from the corresponding inhibitor of this invention which contain a basic moiety by conventional chemical methods. Generally, the salts are prepared 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 following definitions apply to compounds of the general formulas gg) through hh) hereinabove: The aryl group means a phenyl group, a naphthyl group or an anthryl group. A phenyl group or a naphthyl group is preferred.
The heteroaromatic ring group means a 5-membered or 6-membered monocyclic aromatic heterocyclic group containing one or two heteroatoms, which are the same or different, selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, or a fused aromatic heterocyclic group having such a monocyclic WO 97/01275 PCT/US96/11022 151 aromatic heterocyclic group fused with the above-mentioned aryl group or having the same or different such monocyclic aromatic heterocyclic groups fused with each other, which may, for example, be a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, an oxazolyl group, an isoxazolyl group, a furyl group, a thienyl group, a thiazolyl group, an isothiazolyl group, an indolyl group, a benzofuranyl group, a benzothienyl group, a benzimidazolyl group, a benzoxazolyl group, a benzisoxazolyl group, a benzothiazolyl group, a benzisothiazolyl group, an indazolyl group, a purinyl group, a quinolyl group, an isoquinolyl group, a phthalazinyl group, a naphthylidinyl group, a quinoxalinyl group, a quinazolinyl group, a cinnolinyl group or a pteridinyl group. Among them, a furyl group, a thienyl group, a pyridyl group, a pyrimidinyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, a benzofuranyl group, a benzothienyl group, a benzimidazolyl group, a benzoxazolyl group, a benzothiazolyl group or a quinolyl group is preferred.
The lower alkyl group means a C1-6 linear or branched alkyl group, which may, for example, be a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, a tert-butyl group, a pentyl group or a hexyl group. Among them, a methyl group or an ethyl group is preferred.
The lower hydroxyalkyl group means the abovementioned lower alkyl group having a hydroxyl group, i.e. a C1-6 hydroxyalkyl group, such as a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group or a hydroxybutyl group. Among them, a hydroxymethyl group or a hydroxyethyl group is preferred.
The lower alkoxy group means a C1-6 alkoxy or alkylenedioxy group, which may, for example, be a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a tert-butoxy group, a methylenedioxy group, an ethylenedioxy group or a trimethylenedioxy group. Among them, a methoxy group, an ethoxy group or a methylenedioxy group is preferred.
The lower carboxyalkyl group means the above- WO 97/01275 PCT/US96/11022 152mentioned lower alkyl group having a carboxyl group, i.e. a C1-7 carboxyalkyl group, such as a carboxymethyl group, a carboxyethyl group, a carboxypropyl group or a carboxybutyl group. Among them, a carboxymethyl group or a carboxyethyl group is preferred.
The aralkyl group means the above-mentioned lower alkyl group having the above-mentioned aryl group, such as a benzyl group, a phenethyl group, a 3-phenylpropyl group, a 1-naphthylmethyl group, a 2-naphthylmethyl group or a l-(2-naphthyl)ethyl group. Among them, a benzyl group, a phenethyl group or a 2-naphthylmethyl group is preferred.
The saturated aliphatic hydrocarbon group may, for example, be an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, a hexamethylene group, a heptamethylene group or an octamethylene group. For example, a trimethylene group, a tetramethylene group or a pentamethylene group is preferred.
The unsaturated aliphatic hydrocarbon group means an unsaturated aliphatic hydrocarbon group having one or more, preferably one or two double bonds, at optional position(s) on the carbon chain, which may, for example, be a vinylene group, a propenylene group, a 1-butenylene group, a 2-butenylene group, a 1,3butadienylene group, a 1-pentenylene group, a 2-pentenylene group, a 1,3-pentadienylene group, a 1,4-pentadienylene group, a 1-hexenylene group, a 2-hexenylene group, a 3-hexenylene group, a 1,3hexadienylene group, a 1,4-hexadienylene group, a group, a 1,3,5-hexatrienylene group, a 1-heptenylene group, a 2heptenylene group, a 3-heptenylene group, a 1,3-heptadienylene group, a 1,4-heptadienylene group, a 1,5-heptadienylene group, a 1,6heptadienylene group, a 1,3,5-heptatrienylene group, a 1-octenylene group, a 2-octenylene group, a 3-octenylene group, a 4-octenylene group, a 1,3-octadienylene group, a 1,4-octadienylene group, a octadienylene group, a 1,6-octadienylene group, a 1,7-octadienylene group, a 2,4-octadienylene group, a 2,5-octadienylene group, a 2,6-
II
WO 97/01275 PCT/US96/11022 153 octadienylene group, a 3,5-octadienylene group, a 1,3,5-octatrienylene group, a 2,4,6-octatrienylene group or a 1,3,5,7-octatetraenylene group.
Among them, a propenylene group, a 1-butenylene group, a 1,3butadienylene group or a 1-pentenylene group is preferred.
The halogen atom may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. For example, a fluorine atom or a chlorine atom is preferred.
The lower alkoxycarbonyl group means a Cl-7 alkoxycarbonyl group, such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group or a tert-butoxycarbonyl group. Among them, a methoxycarbonyl group or an ethoxycarbonyl group is preferred.
The lower alkylcarbamoyl group means a carbamoyl group mono-substituted or di-substituted by the above-mentioned lower alkyl group, such as a methylcarbamoyl group, an ethylcarbamoyl group, a dimethylcarbamoyl group or a diethylcarbamoyl group.
The lower fluoroalkyl group means the above-mentioned lower alkyl group having fluorine atom(s), i.e. a C1-6 fluoroalkyl group, such as a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 1-fluoroethyl group, a 2-fluoroethyl group, a 2,2,2trifluoroethyl group or a pentafluoroethyl group.
The salt of the compound of the formula (gg) or (hh) may be a pharmaceutically acceptable common salt, which may, for example, be a base-addition salt of the terminal carboxyl group or of a carboxyl group when R 4 and/or R 5 or R 3 and/or R 4 is a carboxyl group, or when a carboxyl group or a lower carboxyalkyl group is present on a saturated or unsaturated aliphatic hydrocarbon group represented by A in the formulas (gg) and or an acid-addition salt of an amino group when R 4 and/or R 5 or R 3 and/or R 4 is an amino group, or of a basic heteroaromatic ring when such a basic heteroaromatic ring is present.
The base-addition salt may, for example, be an alkali metal salt such as a sodium salt or a potassium salt; an alkaline earth metal salt WO 97/01275 PCT/US96/11022 154such as a calcium salt or a magnesium salt; an ammonium salt; or an organic amine salt such as a trimethylamine salt, a triethylamine salt, a dicyclohexylamine salt, an ethanolamine salt, a diethanolamine salt, a triethanolamine salt, a procaine salt or an N,N'-dibenzylethylenediamine salt.
The acid-addition salt may, for example, be an inorganic acid salt such as a hydrochloride, a sulfate, a nitrate, a phosphate or a perchlorate; an organic acid salt such as a maleate, a fumarate, a tartrate, a citrate, an ascorbate or a trifluoroacetate; or a sulfonic acid salt such as a methanesulfonate, an isethionate, a benzenesulfonate or a p-toluenesulfonate.
The ester of the compound of the formula (gg) or (hh) means a pharmaceutically acceptable common ester of the terminal carboxyl group or of a carboxyl group when R 4 and/or R 5 or R3 and/or R 4 is a carboxyl group, or when a carboxyl group or a lower carboxyalkyl group is present on the saturated or unsaturated aliphatic hydrocarbon group represented by A in the formulas (gg) and It may, for example, be an ester with a lower alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, a tert-butyl group, a cyclopropyl group or a cyclopentyl group, an ester with an aralkyl group such as a benzyl group or a phenethyl group, an ester with a lower alkenyl group such as an allyl group or a 2-butenyl group, an ester with a lower alkoxyalkyl group such as a methoxymethyl group, a 2-methoxyethyl group or a 2ethoxyethyl group, an ester with a lower alkanoyloxyalkyl group such as an acetoxymethyl group, a pivaloyloxymethyl group or a 1pivaloyloxyethyl group, an ester with a lower alkoxycarbonylalkyl group such as a methoxycarbonylmethyl group or an isopropoxycarbonylmethyl group, an ester with a lower carboxyalkyl group such as a carboxymethyl group, an ester with a lower alkoxycarbonyloxyalkyl group such as a 1-(ethoxycarbonyloxy)ethyl group or a 1-(cyclohexyloxycarbonyloxy)ethyl group, an ester with a lower carbamoyloxyalkyl qroup such as a carbamoyloxymethyl group, an ester with a phthalidyl group, or an ester with a (5-substituted-2-oxo- WO 97/01275 PCT/US96/11022 155- 1,3-dioxol-4-yl)methyl group such as a (5-methyl-2-oxo-l,3-dioxol-4yl)methyl group.
Further, when a hydroxyl group is present at the yor 8-position of the terminal carboxyl group or of a carboxyl group when such a carboxyl group or a lower carboxyalkyl group is present on the saturated or unsaturated aliphatic hydrocarbon group represented by A in the formulas (gg) and such a hydroxyl group and a carboxyl group may form an intramolecular ester i.e. a 5-membered or 6-membered lactone ring.
Further, the compound of the present invention may have stereoisomers such as optical isomers, diastereomers or geometrical isomers, depending upon the form of its substituents. The compound of the present invention includes all of such stereoisomers and their mixtures.
Further, the compound of the present invention may have enol form and keto form tautomers, depending upon the form of its substituents. The compounds of the present invention includes such enol form and keto form isomers and their mixtures.
Some of the protein substrate-competitive inhibitors and farnesyl pyrophosphate-competitive inhibitors 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, Chapter 1, Academic Press, 1980, or Stewart et al., "Solid Phase Peptide Synthesis", Second Edition, Pierce Chemical Company, 1984. Also useful in exemplifying syntheses of specific unnatural amino acid residues are European Pat. Appl. No. 0 350 163 A2 (particularly page 51-52) and J. E. Baldwin et al.
Tetrahedron, 50:5049-5066 (1994). With regards to the synthesis of instant compounds containing a (P-acetylamino)alanine residue at the C- WO 97/01275 PCTIUS96/11022 156terminus, use of the commercially available Na-Z-L-2,3diaminopropionic acid (Fluka) as a starting material is preferred. 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
MsCI 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.
The protein substrate-competitive inhibitors of this invention designated hereinabove are prepared by employing the reactions shown in the following Reaction Schemes A-R, 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. Such Reaction Schemes are also useful in preparing other protein substrate-competitive inhibitors WO 97/01275 PCT/US96/11022 157and farnesyl pyrophosphate-competitive inhbitors. For example, Reaction Schemes A-E are especially useful in preparing the inhibitors designated through through and "ee)" hereinabove. Some key bond-forming and peptide modifying reactions are: Reaction A Amide bond formation and protecting group cleavage using standard solution or solid phase methodologies.
Reaction B Reaction C Preparation of a reduced peptide subunit by Ireductive alkylation of an amine by an aldehyde using sodium cyanoborohydride or other reducing agents.
Alkylation of a reduced peptide subunit with an alkyl or aralkyl halide or, alternatively, reductive alkylation of a reduced peptide subunit with an aldehyde using sodium cyanoborohydride or other reducing agents.
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 D Reaction E 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:
H
2 )t Cl Wi WO 97/01275 PCT/US96/11022 158- 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 alkylation reactions described in the Reaction Schemes.
WO 97/01275 PCT/US96/11022 159 REACTION SCHEME A Reaction A. Coupling ofresidues to formn an amide bond R A 0OJ H 0
RB
H
2 N RC 0 EDO, HOBT or HOOBT Et 3 N, DMF HCI or
TFA
0 R A 0
ORC
0 R B R A H 0
H
2 N ~ORC 0
RB
REACTION SCHEME B Reaction B. Prepar ation of reduced peptide subunits by reductive alkylation H0 NaCNBH 3
RB
H
2 N Cy RC 0 H
OR
WO 97/01275 PCT/US96/11022 160 REACTION SCHEME C Reaction C. Alkylation/reductive alkylation of reduced pentide subuinits 0 5 HN=Y13AORC H RB R 7 bXL, base or 0 11 RYCH, NaCNBH 3 0 WO 97/01275 PCT/US96/11022 161 REACTION SCHEME D Reaction D. Coupling of residues to form an amide bond O O 0 N
H
H
2 N 0
O
EDC, HOBT or HOOBT Et 3 N, DMF
RA
O 0 o H O iJ HCI or TFA
RA
H 0 N
A
H2N kN Sw 0 REACTION SCHEME E Reaction E. Preparation of reduced dipeptides from peptides 0IX RA 0 N ORc
BH
3
THF
0 R a O RA 0 0O N ORC
H
H
RB
where RA and RB are R3, R4, R5a or R5b as previously defined; RC is R6 as previously defined or a carboxylic acid protecting group; XL is a WO 97/01275 PCT/US96/11022 162leaving group, Br-, I- or MsO-; and RY is defined such that R7b is generated by the reductive alkylation process.
Certain compounds of this invention wherein X-Y is an ethenylene or ethylene unit are prepared by employing the reaction sequences shown in Reaction Schemes F and G. Reaction Scheme F outlines the preparation of the alkene isosteres utilizing standard manipulations such as Weinreb amide formation, Grignard reaction, acetylation, ozonolysis, Wittig reaction, ester hydrolysis, peptide coupling reaction, mesylation, cleavage of peptide protecting groups, reductive alkylation, etc., as may be known in the literature or exemplified in the Experimental Procedure. For simplicity, substituents
R
2 a and R 2 b on the cyclic amine moiety are not shown. It is, however, understood that the reactions illustrated are also applicable to appropriately substituted cyclic amine compounds. The key reactions are: stereoselective reduction of the Boc-amino-enone to the corresponding syn amino-alcohol (Scheme F, Step B, Part and stereospecific boron triflouride or zinc chloride activated organomagnesio, organo-lithio, or organo-zinc copper(l) cyanide SN2' displacement reaction (Scheme F, Step Through the use of optically pure N-Boc amino acids as starting material and these two key reactions, the stereo-chemistry of the final products is well defined. In Step H of Scheme F, the amino terminus sidechain, designated Rx is incorporated using coupling reaction A and RxCOOH; the alkylation reaction C using RxCHO and a reducing agent; or alkylation reaction C using RxCH2XL. Such reactions as described in Step H are described in more detail in Reaction Schemes J-X hereinbelow.
The alkane analogs are prepared in a similar manner by including an additional catalytic hydrogenation step as outlined in Reaction Scheme G.
WO 97/01275 PCT/US96/11022 163 REACTION SCHEMEF Boc O
OH
CICO
2 i-Bu MeONHMe 2 B rM g Boc 0
(HA)
Step A 1 NaBH 4 2. Ac 2 O, Py Step B 1. 03, Me 2
S
2. Ph 3
P=CHCO
2 Me Step C Boc c
HA)
BcOAc 2 Me
HA)
WO 97/01275 PCTIUS96/1 1022 -164- REACTION SCHEME F (CONT'D) Step D 1. LiCH Step E 2. EDO, HOBT amino acid (ester) OMe, EF SMe MsCI, py El StepEF Boc s0 HA) 0
R
3 MgCuCNCIBF 3 Step G Boc H 0 0K 1. HCI 2. NaCNBH 3 RxCHO Step H RxCH 2 H 0
N~)E
wherein (R9~ Rx (R )r V A'l(CRla 2 )nA (CRlaOn (CRlb) WO 97/01275 PCTIUS96/11022 165 REACTION SCHEME F (CONTD) NaOH 1. HCI Alternate Step H 0 11 2. RX-COH- EDO, HOBT 0J t NaOH 0 Rx WO 97/01275PC/S6n2 PCT/US96/11022 166- REACTION SCHEME G Bocj0
OH
(H
2 )t 1. CICO 2 i-Bu MeONHMe BrMg s Boc 0 (2) 1. NaBH 4 2. AC 2 O, py Boc Qc 1. 03, Me 2
S
2. Ph 3
P=CHCO
2 Me Boc GAc0 C0~C 2 Me 0 P9HA) 1. LIOH 2. EDO, HOBT Boc O
H
-0 MsCI, py WO 97/01275 PCT/US96/1 1022 167 REACTION SCHEME G (CONTD) Boc OMs H0
N~Q
H
2 )t 0 0 1.1 R 3 MgCuCNCI*BF 3 2. H 2 5% Pd/C 0 1. HOI 2. NaCNE RxCH RxCH 2
R
3 (DH 2 1 0
~H
3 0 H 0 0 NaOH RxCH 2
(H
2 )t WO 97/01275 PCTIUS96/11022 168- REACTION SCHEME G (CONT'D) or
O
II
1. HCI 2. RXCOH EDC, HOBT RX" R 3
O
NN
(CH
2 t 0 NaOH 0 RX R 3
O
N OH SH2)t 0 .OH The oxa isostere compounds of this invention are prepared according to the route outlined in Scheme H. An aminoalcohol 1 is acylated with alpha-chloroacetyl chloride in the presence of trialkylamines to yield amide 2. Subsequent reaction of 2 with a deprotonation reagent sodium hydride or potassium t-butoxide) in an ethereal solvent such as THF provides morpholinone 3. Alkylation of 3 with R3XL, where XL is a leaving group such as Br-, I- or Cl- in THF/DME (1,2-dimethoxyethane) in the presence of a suitable base, preferably NaHMDS [sodium bis(trimethylsilyl)amide], affords 4, which is retreated with NaHMDS followed by either protonation or the addition of an alkyl halide R4X to give a or 5b. respectively, as a enantiomeric mixture. Alternatively, 5a can be prepared from 3 via an WO 97/01275 PCT/US96/11022 169 aldol condensation approach. Namely, deprotonation of 3 with NaHMDS followed by the addition of a carbonyl compound RYRzCO gives the adduct 6. Dehydration of 6 can be effected by mesylation and subsequent elimination catalyzed by DBU (1, 8 -diazabicyclo[5.4.0]undec- 7-ene) or the direct treatment of 6 with phosphorus oxychloride in pyridine to give olefin 7. Then, catalytic hydrogenation of 7 yields (wherein -CHRYRZ constitutes
R
3 Direct hydrolysis of 5 with lithium hydrogen peroxide in aqueous THF, or aqueous HC1, produces acid 8a.
Compound 8a is then derivatized with BOC-ON or BOC anhydride to give 8b. The peptide coupling of acid 8b with either an alphaaminolactone homoserine lactone, etc.) or the ester of an amino acid is carried out under the conditions exemplified in the previously described references to yield derivative 9. Treatment of 9 with gaseous hydrogen chloride gives 10, which undergoes further elaboration as described in Reaction Schemes J- hereinbelow.
An alternative method for the preparation of the prolyl oxa isostere (compounds 21 and 24 is shown in Scheme H-1. Referring to Scheme H-1, the aminoalcohol I is protected with trifluoroacetic anhydride and the blocked compound 15 treated with diphenyl disulfide in the presence of tributylphosphine to provide the thioether 16.
Chlorination of compound 16 provides compound 17 which can be reacted with the appropriate carboxylic acid alcohol in the presence of silver perchlorate and tin (II) chloride, to afford the mixed acetal 18.
Removal of the phenylmercapto moiety with Raney nickel provides compound 19. Compound 19 is doubly deprotected, then selectively BOC protected to provide the acid 20, which undergoes the steps previously described for incorporating terminal amino acid. Still another alternative method for the preparation of the prolyl oxa isostere (compounds 23 and 24 is described in the literature [Ruth E.
TenBrink, J. Org. Chem., 52, 418-422 (1987)].
4 WO 97/01275 WO 9701275PCT/US96/1 1022 170 SCHEME H c
I
01c base 3 Base
R
3
X
Base RyRzCO
HO
Rz Base R 4 X or 5a: R 4
=H
R
4 substituent -H20 0 Rz'
H
2 Pd/C WO 97/01275 WO 9701275PCTIUS96/1 1022 171 SCHEME H (CONT'D) 1. LiOOH; or aq. HOI, 2. BOC 2 0
EDC
8 +H-A
HOBT
HCI
Rw yR
O-CO
2
H
H2) a, Rw H b, R'w=BOC Boc HOI
H
0 NH,_k 0 0 or NH 6 R Ra WO 97/01275 WO 9701275PCTIUS96/1 1022 172 SCHEME H- I 0 11
CFAC
2 0 O OH
CF
3
C
H
2 )t 0 01 SPh c
(H
2 1 Ph-S-S-Ph nBu 3
P
0 11
CF:
3
C
SPh N-chlorosuccinimide
H
2 )t
R
HO
CO
2 Me AgCIO 4 SnCI 2 4A Mol. sieves 0 11
CF
3 0
CO
2 Me Raney Ni WO 97/01275 PCT/US96/11022 173- SCHEME H-l (CONT'D)
O
II
CFaC
H
2 )t
R
3 R4 COg2Me 1. aq. HCI 2. BOC) 2 0 Boc
H-A
Boc
EDC
HOBT
H
2 )t
HCI
HCI
The thia, oxothia and dioxothia isostere compounds of this invention are prepared in accordance to the route depicted in Scheme I.
Aminoalcohol 1 is derivatized with BOC20 to give 25. Mesylation of followed by reaction with methyl alpha-mercaptoacetate in the presence of cesium carbonate gives sulfide 26. Removal of the BOC group in 26 with TFA followed by neutralization with diisopropylethylamine leads to lactam 27. Sequential alkylation of 27 with the alkyl halides R 3 X and R 4 X in THF/DME using NaHDMS as the deprotonation reagent produces 28. Hydrolysis of 28 in hydro-chloride to yield 29a, which is derivatized with Boc anhydride to yield 29b. The coupling of 29b with an alpha-aminolactone homoserine lactone, etc.) or the ester of an amino acid is carried out under conventional WO 97/01275 PCT/US96/11022 -174conditions as exemplified in the previously described references to afford 30. Sulfide 3 is readily oxidized to sulfone 31 by the use of MCPBA (m-chloroperoxybenzoic acid). The N-BOC group of either or 31 is readily removed by treatment with gaseous hydrogen chloride.
WO 97/01275 PCT/US96/11022 175 SCHEME I
BOC
2 0 1) MsCI
CS
2 00 3
HSCH
2 C0 2
CH
3 1) TFA 2) (i-Pr) 2 NEt 1) R 3
X,
Base 2) R 4
X,
Base
HCI
H
2 0 R R 3 R 4 0 0 2
H
H-A, EDO
HOBT
a, Rw=H D B0C 2 0 b, RW=BOO 0 N H 0 o r NH,,OR 6 WO 97/01275 PCT/US96u11022 176- SCHEME I (CONTD) Boc
(H
2 )t M=2.31 R 3 R 4
A
0
SMCPBA
HOI
HCI H
R
3 S (O)m
A
H2)t 0 m 0 or 2
I
WO 97/01275 PCT/US96/11022 177- Reaction Schemes J R illustrate reactions wherein the nonsulfhydryl-containing moiety at the N-terminus of the compounds of the instant invention is attached to the fully elaborated cyclic amino peptide unit, prepared as described in Reaction Schemes A-I. It is understood that the reactions illustrated may also be performed on a simple cyclic amino acid, which may then be further elaborated utilizing reactions described in Reaction Schemes A- I to provide the instant compounds.
The intermediates whose synthesis are illustrated in Reaction Schemes A-I can be reductively alkylated with a variety of aldehydes, such as V, as shown in Reaction Scheme J. 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 VI can be deprotected with trifluoroacetic acid in methylene chloride to give the final compounds VII. The final product VII is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others. The product diamine VII can further be selectively protected to obtain VIII, which can subsequently be reductively alkylated with a second aldehyde to obtain IX. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XI can be accomplished by literature procedures.
Alternatively, the protected cyclic aminopeptidyl intermediate can be reductively alkylated with other aldehydes such as 1-trityl-4-carboxaldehyde or 1-trityl-4-imidazolylacetaldehyde, to give products such as XII (Reaction Scheme The trityl protecting group can be removed from XII to give XIII, or alternatively, XII can first be treated with an alkyl halide then subsequently deprotected to give the alkylated imidazole XIV. Alternatively, the dipeptidyl analog intermediate can be acylated or sulfonylated by standard techniques.
WO 97/01275 PCT/US96/11022 178- The imidazole acetic acid XV can be converted to the protected acetate XVII by standard procedures, and XVII can be first reacted with an alkyl halide, then treated with refluxing methanol to provide the regiospecifically alkylated imidazole acetic acid ester XVIII. Hydrolysis and reaction with the protected dipeptidyl analog intermediate in the presence of condensing reagents such as 1-(3dimethylaminopropyl)-3-ethylcarbodiimide (EDC) leads to acylated products such as XIX.
If the protected dipeptidyl analog intermediate is reductively alkylated with an aldehyde which also has a protected hydroxyl group, such as XX in Reaction Scheme N, the protecting groups can be subsequently removed to unmask the hydroxyl group (Reaction Schemes N, 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 XXIV. In addition, the fully deprotected amino alcohol XXV can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXVI (Reaction Scheme or tertiary amines.
The Boc protected amino alcohol XXII can also be utilized to synthesize 2-aziridinylmethylpiperazines such as XXVII (Reaction Scheme Treating XXII with 1,1 '-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine XXVII The aziridine may be reacted in the presence of a nucleophile, such as a thiol, in the presence of base to yield the ringopened product XXVIII.
In addition, the protected dipeptidyl analog intermediate can be reacted with aldehydes derived from amino acids such as Oalkylated tyrosines, according to standard procedures, to obtain compounds such as XXXIV, as shown in Reaction Scheme R. When R' is an aryl group, XXXIV can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XXXV.
Alternatively, the amine protecting group in XXXIV can be removed, and O-alkylated phenolic amines such as XXXVI produced.
WO 97/01275 PCT/US96/1 1022 179 REACTION SCHEME J Boc NHI Boc NH CHO R 4b NaBH(OAc)3 RbEt 3 N CICH 2
CH
2
CI
NH
2 R
NH
2
Q
VII
R 4a;:-xR 4 b NHBoc Boc NH/
R
VI R4 R 4 b
CF
3
CO
2
H
CH
2
CI
2 Boc 2 0 0H 2 C1 2
NH
2 BocNH
CHO
NaBH(OAc)3 Et 3 N CICH 2
CH
2
CI
wherein
'OR
6 or WO 97/01275 PCTIUS96/11022 180 REACTION SCHEME J (continued)
NH
CF
3
CO
2 H, 0H 2 01 2 NaHCO 3 R 4 b
NC
AgCN L
NH
2 x R 4 b R 4 b WO 97/01275 PCTIUS96/1 1022 181 REACTION SCHEM
K
N-(CH2 )nCHO Q N R 4 b N Tr
CH
2 )n+l R NrR~ ROb
CF
3 C0 2 H, CH 2
CI
2
(C
2
H
5 3 SiH NaBH(OAC) 3 Et 3 N CICH 2
CH
2
CI
1) Ar CH 2 X, CH 3
CN
2) CF 3
CO
2 H, 0H 2 01 2
(C
2
H
5 3 SiH 'R 4 b R 4 b WO 97/01275 PCTIUS96/11022 182 REACTION SCHEME L
CH
2
CO
2
H
N
H
CH
3 0H
HCI
-HCI
XV'
(C
6
H
5 3 CBr
(C
2
H
5 3
N
DMF
1) ArCH 2 X CH 3
CN
reflux 2) CH 3 OH, reflux xv"l N CHqCOqCH 3
N
2.5N HClaq 5500 xv"'l Ar---\N-CH 2 00 2
H
N
WO 97/01275 PTU9/12 PCTIUS96/11022 183 REACTION SCHEME M 0H 2 00 2
H
R
R~a;,iR 4 b EDO'- HCt HOBt
DMF
N 0
R
Arl/N XIX R4a R 4 b WO 97/01275 PCTfUS96/11o22 184 REACTION
SCHEMEN
NaBH(OAC) 3 Et 3 NI CHC 2
CH
2
CI
R
4 b BnO BocNHICHO Pd(OH) 2
H
2
CH
3 0H R 4 b CH 3
CO
2 H XX' R 4 a, NHBoc
R
HO
XXII R4aR 4 b CICOCOCi DMSO
CH
2
CI
2
(C
2
H
5 3
N
WO 97/01275 PCT/US96/11022 185 REACTION SCHEME N (CONTINUED H NHBoc 0/I 1. RlMgX
(C
2
H
5 2 0 2. TFA, CH 2
CI
2 xxill R4a, R 4 b R
NH
2
R
HO
Q
xxivR4a; R 4 b WO 97/01275 PCTIUS96/11022 186 REACTION SCHEME P NHBoc
R
Q
x)1R aDR4
CF
3 00 2
H
CH
2
CI
2
NH
2 Ho',r
R
HO R4 R4
ROCHO
NaBH(OAC) 3 -m
CICH
2
CH
2
CI
R'CH
2
NH
HOT- XXVIRb R 4b WO 97/01275 PCTIUS96/11022 187 REACTION SCHEME 0 H H
N,
NaH, DMF 000 xx' R 4 b
R'SH
(PAO)
3 A
CH
3 0H xxv"l ROb
R'S
NH
2
R
Q
R 4a;QxR 4 b xxv"'l WO 97/01275 PCTIUS96/11022 188 REACTION SCHEME
R
1) Boc 2 O, K, 2 C0 3
THF-H
2 2) CH 2
N
2 EtOAc BocNH
H
2 N C0 2
H
XXIX
XXX
HO,
LiAIH 4
THF
0-200C
R'CH;
2
X
DMF
CH
2 0H
XXXI
R'CH
2 0 BocNH
CH
2 0H
XXXII
R-CH
2 0 pyridieS ,i
DMSO
(0 2
H
5 3 N BoN CH 200C0 oN
H
XXXIII
WO 97/01275 PCTIUS96/11022 189 REACTION SCEME R (continued)
R-CH
2 0
+Q
BocNH
CHO
R 4 b
XXXIII
NaBH(OAC) 3
CICH
2
CH
2
CI
R 4 b 1) 20% Pd(OH) 2
CH
3 OH, CH 3 00 2
H
HOI\EtOAc ,NH 2 2) HOI, EtOAc R 4 b
XXXVI
R 4 b WO 97/01275 PCT/US96/11022 190- Reactions used to generate the inhibitors of this invention which are designated are shown in the Reaction Schemes 1-16, 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. Substituents Ra and Rb, as shown in the Schemes, represent the substituents
R
2
R
3
R
4 and R 5 however their point of attachment to the ring is illustrative only and is not meant to be limiting.
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 alkylation reactions described in the Reaction Schemes. Reaction Schemes 1-16 are also useful in preparing inhibitors of this invention that are designated Synopsis of reaction Schemes 1-16: The requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures, for the most part. In Scheme 1, for example, the synthesis of 2-alkyl substituted piperazines is outlined, and is essentially that described by J.
S. Kiely and S. R. Priebe in Organic Preparations and Proceedings Int., 1990, 22, 761-768. Boc-protected amino acids I, available commercially or by procedures known to those skilled in the art, can be coupled to N-benzyl amino acid esters using a variety of dehydrating agents such as DCC (dicyclohexycarbodiimide) or EDC-HC1 (l-ethyl-3- (3-dimethylaminopropyl)carbodiimide hydrochloride) in a solvent such as methylene chloride chloroform, dichloroethane, or in dimethylformamide. The product II is then deprotected with acid, for example hydrogen chloride in chloroform or ethyl acetate, or trifluoroacetic acid in methylene chloride, and cyclized under weakly basic conditions to give the diketopiperazine III. Reduction of III with lithium aluminum hydride in refluxing ether gives the piperazine IV, which is protected as the Boc derivative V. The N-benzyl group can be WO 97/01275 PCT/US96/11022 191 cleaved under standard conditions of hydrogenation, palladium on carbon at 60 psi hydrogen on a Parr apparatus for 24-48 h. The product VI can be treated with an acid chloride, or a carboxylic acid under standard dehydrating conditions to furnish the carboxamides VII; a final acid deprotection as previously described gives the intermediate VIII (Scheme The intermediate VIII can be reductively alkylated with a variety of aldehydes, such as IX. 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 (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 X can be deprotected to give the final compounds XI with trifluoroacetic acid in methylene chloride.
The final product XI is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others. The product diamine XI can further be selectively protected to obtain XII, which can subsequently be reductively alkylated with a second aldehyde to obtain XIII. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XV can be accomplished by literature procedures.
Alternatively, the protected piperazine intermediate VII can be reductively alkylated with other aldehydes such as l-trityl-4carboxaldehyde or 1-trityl-4-imidazolylacetaldehyde, to give products such as XVI (Scheme IV). The trityl protecting group can be removed from XVI to give XVII, or alternatively, XVI can first be treated with an alkyl halide then subsequently deprotected to give the alkylated imidazole XVIII. Alternatively, the intermediate VIII can be acylated or sulfonylated by standard techniques. The imidazole acetic acid XIX can be converted to the acetate XXI by standard procedures, and XXI can be first reacted with an alkyl halide, then treated with refluxing methanol to provide the regiospecifically alkylated imidazole acetic acid ester XXII. Hydrolysis and reaction with piperazine VIII in the WO 97/01275 PCT/US96/11022 192 presence of condensing reagents such as l-( 3 -dimethylaminopropyl)-3ethylcarbodiimide (EDC) leads to acylated products such as XXIV.
If the piperazine VIII is reductively alkylated with an aldehyde which also has a protected hydroxyl group, such as XXV in Scheme 6, the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 6, 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 XXIX. In addition, the fully deprotected amino alcohol XXX can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXXI (Scheme or tertiary amines.
The Boc protected amino alcohol XXVII can also be utilized to synthesize 2 -aziridinylmethylpiperazines such as XXXII (Scheme Treating XXVII with 1,1'-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine XXXII. The aziridine reacted in the presence of a nucleophile, such as a thiol, in the presence of base to yield the ring-opened product
XXXIII.
In addition, the piperazine VIII can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as XXXIX.
When R' is an aryl group, XXXIX can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XL.
Alternatively, the amine protecting group in XXXIX can be removed, and O-alkylated phenolic amines such as XLI produced.
Depending on the identity of the amino acid I, various side chains can be incorporated into the piperazine. For example when I is the Boc-protected P-benzyl ester of aspartic acid, the intermediate diketopiperazine XLII where n=l and R=benzyl is obtained, as shown in Scheme 10. Subsequent lithium aluminum hydride reduction reduces the ester to the alcohol XLIII, which can then be reacted with a variety of alkylating agents such as an alkyl iodide, under basic conditions, for example, sodium hydride in dimethylformamide or tetrahydrofuran.
WO 97/01275 PCT/US96/11022 193- The resulting ether XLIV can then be carried on to final products as described in Schemes 3-9.
N-Aryl piperazines can be prepared as described in Scheme 11. An aryl amine XLV is reacted with bis -chloroethyl amine hydrochloride (XLVI) in refluxing n -butanol to furnish compounds XLVII. The resulting piperazines XLVII can then be carried on to final products as described in Schemes 3-9.
can be prepared as shown in Scheme 12.
Reductive amination of Boc-protected amino aldehydes
XLIX
(prepared from I as described previously) gives rise to compound L.
This is then reacted with bromoacetyl bromide under Schotten-Baumann conditions; ring closure is effected with a base such as sodium hydride in a polar aprotic solvent such as dimethylformamide to give LI. The carbamate protecting group is removed under acidic conditions such as trifluoroacetic acid in methylene chloride, or hydrogen chloride gas in methanol or ethyl acetate, and the resulting piperazine can then be carried on to final products as described in Schemes 3-9.
The isomeric piperazin-3-ones can be prepared as described in Scheme 13. The imine formed from arylcarboxamides LII and 2aminoglycinal diethyl acetal (LIII) can be reduced under a variety of conditions, including sodium triacetoxyborohydride in dichloroethane, to give the amine LIV. Amino acids I can be coupled to amines LIV under standard conditions, and the resulting amide LV when treated with aqueous acid in tetrahydrofuran can cyclize to the unsaturated LVI. Catalytic hydrogenation under standard conditions gives the requisite intermediate LVII, which is elaborated to final products as described in Schemes 3-9.
Access to alternatively substituted piperazines is described in Scheme 14. Following deprotection with trifluoroacetic acid, the N-benzyl piperazine V can be acylated with an aryl carboxylic acid. The resulting N-benzyl aryl carboxamide LIX can be hydrogenated in the presence of a catalyst to give the piperazine carboxamide LX which can then be carried on to final products as described in Schemes 3-9.
WO 97/01275 PCT/US96/11022 194- Reaction Scheme 15 provides an illustrative example the synthesis of compounds of the instant invention wherein the substituents
R
2 and R 3 are combined to form (CH2)u For example, 1aminocyclohexane-1-carboxylic acid LXI can be converted to the spiropiperazine LXVI essentially according to the procedures outlined in Schemes 1 and 2. The piperazine intermediate LXIX can be deprotected as before, and carried on to final products as described in Schemes 3-9. It is understood that reagents utilized to provide the substituent Y which is 2-(naphthyl) and the imidazolylalkyl substituent may be readily replaced by other reagents well known in the art and readily available to provide other N-substituents on the piperazine.
The aldehyde XLIX from Scheme 12 can also be reductively alkylated with an aniline as shown in Scheme 16. The product LXXI can be converted to a piperazinone by acylation with chloroacetyl chloride to give LXXII, followed by base-induced cyclization to LXXIII. Deprotection, followed by reductive alkylation with a protected imidazole carboxaldehyde leads to LXXV, which can be alkylation with an arylmethylhalide to give the imidazolium salt LXXVI. Final removal of protecting groups by either solvolysis with a lower alkyl alcohol, such as methanol, or treatment with triethylsilane in methylene chloride in the presence of trifluoroacetic acid gives the final product LXXVII.
WO 97/01275 WO 9701275PCTfUS96/11022 195 SCHEME 1 0 Ra N ,OH
H
0 o PhCH 2 NHCHC0 2
C
2
H
DCC, CH 2
CI
2 ro
H
1) H~t, CH 2
CI
2 2) NaHCO 3 RB 0 HN N-t 0 Rb
LAH
THE, reflux Ra HN N Rb/ Ra
BOC
2 0
CH
2
CI
2 Ra 10% Pd/C 0 -N
N
H
2
CH
3 0H
NH
-KRb WO 97/01275 WO 9701275PCT/US96/1 1022 196 SCHEME 2 Ra
EE
BocN NH vi Rb
R\/
BocN N4 Rb ViI HCIN NN N Rb Vill )C-HCI, HOBT
)MF
HOI, EtOAc WO 97/01275 WO 9701275PCT/US96/11022 197 SCHEME 3
R\/
HCI -N N4 R b Boo NH I I Boc NH CHO NaBH(OAc)3 Et 3 N CICH 2
CH
2
CI
Boc NH rN N- NHIBoc Rb
CF
3
CO
2
H
CH
2
CI
2
NH
2 N Nb0
CHCI
2
NH
2 R xi BocNH cN N-
NH
2 R b
~-~CHO
NaBH(OAc)3 Et 3 N CICH 2
CH
2
CI
WO 97/01275 PCTIUS96/11022 198 SCHEME 3 (continued) BocNH N N- NH Rb NHL N N4 NH Rb
XIV
CF
3
CO
2 H, CH 2 01 2 NaHCO 3
NC
AgCN A
R\/
N N- N N> Rb WO 97/01275 PCT/US96/11022 199 SCHEME 4
HCI
NaBH(OAC) 3 Et 3 N CICH 2
CH
2
CI
N-(CH2 )nCHO
N
Vill N (C H 2 -+lN N b- Rb N
IXVI
+r I 1) Ar CH 2 X, CH 3
CN
2) CF 3 00 2 H, CH 2
CI
2
(C
2
H
5 3 SiH
CF
3
CO
2 H, CH 2
CI
2 (0 2
H
5 3 SiH H
XVII
0 Rb
XVIII
WO 97/01275 WO 9701275PCT/US96I1 1022 200 SCHEME N-
CH
2 00 2
H
N
H
XX
CH
3 0H
HCI
N CH 2 00 2
CH
3
N
H HCI
(C
6
H
5 3 CBr (0 2
H
5 3
N
DMF
N- CH 2 00 2 0H 3 1) ArCH 2 X CH 3
CN
reflux N 2) CH 3 OH, reflux xxi Ar' N-CH 2 00 2
CH
3
N
XXII
Ar-'-\N-CH 2 00 2
H
N
XXIII
2-5N HClaq 550C WO 97/01275 WO 9701275PCTIUS96/11022 201 SCHEME 5 (continued) N CH 2 00 2
H
N
xxiII HC-HN N- R b Vill EDC -HCI HOBt
DMF
.HCI
Ar"
XXIV
WO 97/01275 PCT/US96/11022 202 SCHEME 6 NaBH(OAC) 3 Et 3 N CICH 2
CH
2
CI
HOI
BnOI BocNH CHO xxv
R\/
BnO N N- NHBoc Rb 20% Pd(OH) 2
H
CH
3 0H
CH
3
CO
2
H
xxvi HO NN NHBoc Rb xxv"l
CICOCOCI
DMSO
CH
2
CI
2
(C
2
H
5 3
N
WO 97/01275PC/19102 PCTIUS96/11022 203 SCHEME 6 (CONTINUED)
R\/
N N-- H NHBoc Rb 1. R'MgX (0 2
H
5 2 0 2. TEA,
CH
2
CI
2 xxviII HO /N N- RlHNH 2 Rb
XXIX
WO 97/01275 WO 9701275PCT[US96/1 1022 204 SCHEME 7
\CF
3 00 2
H
HO N NP DC2I NHBoc R b
XXVII
\ROCHO
N N -NaBH(OAC) 3
NH
2 R b 0 CICH 2
CH
2
CI
xxx NH R b R'0H 2
XXX'
WO 97/01275 WO 9701275PCTfUS96/11022 205 SCHEME 8 H H N, NN, 02 NaH, DMF 0 0
C
xxviI N N N Rb
H
XXXII
R'SH
(C
2
H
5 3 N
A
CH
3 0H R'S N N
NH
2 R b
XXXIII
WO 97/01275 PCT/US96/11022 206 SCHEME 9 1) Boc 2 O, 1(2003
THF-H
2 0 2) 0H 2
N
2 EtOAc BocNH'
H
2
N
XXXIV
XXXV
LIAIH
4
THE
0-200C
HO
B oc NH CH 2 0H
RCHX
DMF
XXX
VI
R-CH
2 0
DMSO
(C
2
H)
3 N BocNH CHO 200C
XXXVIII
H -CH 2 0H
XXXVII
WO 97/01275 PTU9/12 PCTfUS96/11022 207 SCHEME 9 (continued)
R-CH
2 0 BocNH CHO
XXXVI
Rb Vill NaBH(OAc) 3
CICH
2
CH
2
CI
NHBoc
XXXIX
1) 20% Pd(OH) 2
CH
3 OH, CH 3 C0 2
H
2) HOI, EtOAc
HCI
ETOAc
NH
2 R b
XLI
NH
2 R b WO 97/01275 PCT/US96/11022 208 C0 2
R
HN I N 0
XLII
1) LAH, Et 2
O
2) BOC 2 0 R 6 1 NaH, DMF 0 +-0 R 6 0 n()
XLIV
XLIII
SCHEME 11 ArNH 2 2 NH -HOI
XLV
XLVI
n butanol ref lux RaR b ArN HNH -HCI a R b
XLVII
WO 97/01275 WO 9701275PCT/US96/11022 209 SCHEME 12 0 Ra
CH~
H oHD 0 Ra H 0
XLVIII
3
NHOCH
3
-HC!
HCI, HOBT MF, Et 3 N, pH 7 LAH, E1 2 0 0 o N yH
H
0 o
XLIX
O, N),,NHCH 2 Ar
H
ArCH 2
NH
2 NaBH(0Ac) 3
CICH
2
CH
2
CI
pH 6 1) BrCH 2 00Br EIOAc, H 2 0, NaHC0 3 2) NaH, THE, DMF WO 97/01275 PCT/US96/1 1022 210 SCHEME12 SCHEE 1(CONT'D) 0 1) TEA, 0H 2
CI
2 HN
N-
Ar 0 WO 97/01275 PCT/US96/11022 -211 SCHEME 13 ArCHO
NH
2
CH
2 CH(0C 2
H
5 2 NaBH(OAc) 3 Ar CH 2
NHCH
2 CH(0C 2
H,)
2 il0 Ra o J ,OH I H 0 o EDO. HCI, HBT DMF, Et 3 N, pH 7
LIV
0 Ra r(Ar N yN -CH(C 2
H)
2 H 0 6N HOI
THE
Ra a NN4
H
2 1 O%Pd/C
CH
3 0H Ra 0 0 0;
N
LVII
WO 97/01275 WO 9701275PCTfUS96/I 1022 212 SCHEME 14 1) CF 3 00 2 H, 0H 2
C
2 2) NaHCO 3 ArCO 2
H
EDO*- HCI HOBT, DMF
LVIII
R b N
N-I(/
10% Pd C
H
2
CH
3 0H HNN N-- WO 97/01275 WO 9701275PCTIUS96/11022 213 SCHEME BocNH C0 2
H
PhCH 2
NHCH
2
CO
2
C
2
H
5 DCC, CH 2
CI
2 BocNH N N--C 0 2
C
2
H
0LXII a) TEA,
CH
2
CI
2 b) NaHCO 3
(CH
3
)AA
CHCI
3 U0 HN N
LXIV
BOC
2 0 Boci
CH
2
CI
2
LD
LiAIH 4
THE
LXV
N\ N b
~VI
H
2 Pd/C
CH
3 0H WO 97/01275 WO 9701275PCTIUS96/11022 214 SCHEME 15 (continued) Codi
-CO
NaHCO 3 EtOAc BocN NH
LXVII
U
BocN N- LX VIII 0 a) TEA, CH 2
CI
2 b) NaBH(OAc) 3 C(=0)H
N
N
6Ph 3 TEA CH 2
CI
2 (0 2
H
5 3 SiH CPh 3
LXIX
2TFA
LXX
WO 97/01275 WO 9701275PCTIUS96/1 1022 215 SCHEME 16
R
BocNH ',CHO
XLIX
ArNH 2 NaBH(OAC) 3
CICH
2
CH
2
CI
R
H
BocNHI-Nl NA
LXXI
0 C I c EtOAc
H
2 0 NaHC0 3
R
BocNH N-Ar
LXXII
NaH
DMF
R
BocN N-Ar
HOI
EtOAc
LXXIII
WO 97/01275 WO 9701275PCTIUS96/11022 216 SCHEME 16 (continued)
R
HCI-HN NA
LXXIV
CHO
N
N
C(Ph) 3 NaBH (OAc) 3
CICH
2
CH
2
CI
pH 5-6
R
N N-Ar
N
(Ph) 3
C
LXXV
ArCH 2
X
CH
3
CN
R
N N-Ar
N
(Ph),C X LXX VI
R
Ar-\ N N-Ar 0
N
LXXVII
MeOH or TEA, CH 2
CI
(C
2
H
5 3 SiH The compound of the formula (gg) of the present invention can be prepared, for example, by the following process 1, 2, 3, 4, 5 or WO 97/01275 PCT/US96/11022 -217- Process 1 The compound of the formula (gg) can be prepared by reacting a compound of the formula (II):
R
3 R8P S Ar'-XP-YP Ar 2 -CH2 Ar 4 YI R 7
R
2p CH (II) R4p/ NH rR 6 wherein each of 0 Ar 2 r 3 and Ar 4 which are the same or different, is an aryl group or a heteroaromatic ring group; each of XP and YP which are the same or different, is an oxygen atom, a sulfur atom, a carbonyl group or a group of the formula -CHRa- (wherein Ra is a hydrogen atom or a lower alkyl group) or -NRbp- (wherein Rbp is a hydrogen atom, a lower alkyl group or an imino-protecting group), or XP and YP together represent a vinylene group or an ethynylene group; each of Rip, R 2 p, R 3 p, R 8 p and R 9 p which are the same or different, is a hydrogen atom, a halogen atom, a hydroxyl group which may be protected, a lower alkyl group or a lower alkoxy group; each of R 4 p and R 5 p which are the same or different, is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a lower alkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group, a lower alkyl group, a lower fluoroalkyl group, a lower alkoxy group or a hydroxyl, amino, carboxyl or lower hydroxyalkyl group which may be protected; R 6 is a lower alkyl group; and R 7 is a WO 97/01275 PCT/US96/11022 -218hydrogen atom or a lower alkyl group, provided that when one of XP and YP is an oxygen atom, a sulfur atom or a group of the formula -NRbp- (wherein Rbp is as defined above), the other is a carbonyl group or a group of the formula -CHRa- (wherein Ra is as defined above), with a carboxylic acid of the formula (III) or its reactive derivative: HO AP-CO 2 RP 0 wherein AP is a C2-8 saturated or unsaturated aliphatic hydrocarbon group which may have substituent(s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, an aryl group, an aralkyl group, and hydroxyl, lower hydroxyalkyl, carboxyl and lower carboxyalkyl groups which may be protected; and RP is a hydrogen atom or a carboxyl-protecting group, to obtain a compound of the formula (IV):
R
p
R
8 p r -XP-YP Ar 2
-C
2 Ar 4 xp_yp r 2 RT,,,.C R2P C C H
(IV)
X/ N AP-CO 2
RP
R4pH 0 r
R
5p wherein Ar-- Ar 2 Ar 3 Ar 4 wherein AP, XP, YP, RIP, R 2 p, R 3 p, R 4 p, R 5 p, R 6
R
7
R
8 p, R 9 p and RP are as defined above, and, if necessary, removing any protecting group.
As the reactive derivative of the carboxylic acid of the formula (III), an acid halide, a mixed acid anhydride, an active ester or an active amide may, for example, be used. When the carboxylic acid of the formula (III) is used, it is preferred to conduct the reaction in the presence of a condensing agent such as N,N'- IWIT WO 97/01275 PCT/US96/11022 -219dicyclohexylcarbodiimide, 1-ethyl-3-(3dimethylaminopropyl)carbodiimide or 2-chloro-1,3-dimethylimidazolyl chloride.
The reaction of the compound of the formula (II) with the carboxylic acid of the formula (III) or its reactive derivative, is conducted usually by using 1 mol or an excess molar amount, preferably from 1 to 5 mols, of the carboxylic acid of the formula (III) or its reactive derivative, per mol of the compound of the formula (II).
The reaction is conducted usually in an inert solvent. The inert solvent may, for example, be a halogenated hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane or trichloroethylene; an ether such as ethyl ether, tetrahydrofuran or dioxane; an aromatic hydrocarbon such as benzene, toluene, chlorobenzene or xylene; an aprotic polar solvent such as dimethylformamide, acetonitrile, acetone, ethyl acetate or hexamethylphosphoric triamide, or a mixture of such solvents.
The reaction temperature is usually from -70 0 C to the boiling point of the solvent used for the reaction, preferably from -20 0
C
to 100°C.
The reaction time is usually from 5 minutes to 7 days, preferably from minutes to 24 hours.
The above readtion can be conducted in the presence of a base to facilitate the reaction.
As such a base, it is preferred to conduct the reaction in the presence of an inorganic base such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate or sodium hydrogen carbonate, or an organic base such as triethylamine, N-ethyldiisopropylamine, pyridine, 4dimethylaminopyridine or N,N-dimethylaniline.
Such a base is used usually in an amount of 1 mol or an excess molar amount, preferably from 1 to 5 mols, per mol of the reactive derivative of the carboxylic acid of the formula (III).
The acid halide of the compound of the formula (III) can be obtained by reacting the carboxylic acid of the formula (III) with a
I
WO 97/01275 PCT/US96/11022 -220halogenating agent in accordance with a conventional method. As the halogenating agent, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, oxalyl chloride or phosgene may, for example, be used.
The mixed acid anhydride of the compound of the formula (III) can be obtained by reacting the carboxylic acid of the formula (III) with an alkyl chlorocarbonate such as ethyl chlorocarbonate or with an aliphatic carboxylic acid chloride such as acetyl chloride, in accordance with a conventional method. Further, an intramolecular acid anhydride may be formed between carboxyl groups at both terminals, or when in the formula (III), a carboxyl group is present on the saturated or unsaturated aliphatic hydrocarbon group for AP, an intramolecular acid anhydride may be formed between such a carboxyl group and a carboxyl group to be involved in the reaction, to constitute a reactive derivative of the carboxylic acid.
The active ester of the compound of the formula (III) can be prepared by reacting the carboxylic acid of the formula (III) with an N-hydroxy compound such as N-hydroxysuccinimide, Nhydroxyphthalimide or 1-hydroxybenzotriazole, or a phenol compound such as a 4nitrophenol, 2,4-dinitrophenol, 2,4,5-trichlorophenol or pentachlorophenol, in the presence of a condensing agent such as N,N'dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide in accordance with a conventional method.
The active amide of the compound of the formula (III) can be prepared by reacting the carboxylic acid of the formula (III) with e.g. 1,1'carbonyldiimidazole or 1,1'-carbonylbis(2-methylimidazole) in accordance with a conventional method.
When a hydroxyl group is present on the group of the formula
R
3 p Ar- Ar 2 or r4
R
2 P R9P WO 97/01275 PCT/US96/11022 -221 when a hydroxyl group, a lower hydroxyalkyl group, a carboxyl group or a lower carboxyalkyl group is present on the saturated or unsaturated aliphatic hydrocarbon group represented by AP, and when a hydroxyl group, an amino group, a carboxyl group or a lower hydroxyalkyl group is present on the group of the formula R4p
A-
it is preferred to conduct the reaction after protecting such a hydroxyl group, a lower hydroxyalkyl group, an amino group, a carboxyl group or a lower carboxyalkyl group appropriately by a hydroxyl-protecting group, an amino-protecting group or a carboxyl-protecting gtoup and removing the protecting group after the reaction. Further, in a case where one of XP and YP is a group of the formula -NRbp- (wherein Rbp is as defined above), and the other is a group of the formula -CHRa- (wherein Ra is as defined above), Rbp is preferably a lower alkyl group or an imino-protecting group, and when Rbp is an iminoprotecting group, it is preferred to remove such a protecting group after the reaction.
The hydroxyl-protecting group may, for example, be a lower alkylsilyl group such as a trimethylsilyl group or a tertbutyldimethylsilyl group; a lower alkoxymethyl group such as a methoxymethyl group or a 2-methoxyethoxymethyl group; a tetrahydropyranyl group; an aralkyl group such as a benzyl group, a pmethoxybenzyl group, a p-nitrobenzyl group or a trityl group; or an acyl group such as a formyl group or an acetyl group. Particularly preferred is a methoxymethyl group, a tetrahydropyranyl group, a trityl group, a tert-butyldimethylsilyl group or an acetyl group.
The amino- or imino-protecting group may, for example, be an aralkyl group such as a benzyl group, a p-methoxybenzyl group, a p-nitrobenzyl group, a benzhydryl group or a trityl group; a lower alkanoyl group such as a formyl group, an acetyl group, a propionyl
I
WO 97/01275 PCT/US96/11022 -222group, a butyryl group or a pivaloyl group; a lower haloalkanoyl group such as a trifluoroacetyl group; a lower alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group or a tert-butoxycarbonyl group; a lower haloalkoxycarbonyl group such as a 2,2,2-trichloroethoxycarbonyl group; an alkenyloxycarbonyl group such as a 2-propenyloxycarbonyl group; an aralkyloxycarbonyl group such as a benzyloxycarbonyl group or a pnitrobenzyloxycarbonyl group; or a lower alkylsilyl group such as a trimethylsilyl group or-a tert-butyldimethylsilyl group. Further the amino-protecting group may, for example, be an aralkylidene group such as a benzylidene group, a p-chlorobenzylidene group or a pnitrobenzylidene group. Particularly preferred is an acetyl group, a trifluoroacetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group.
The carboxyl-protecting group may, for example, be a lower alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group or a tert-butyl group; a lower haloalkyl group such as a 2,2,2-trichloroethyl group; a lower alkenyl group such as 2-propenyl group; or an aralkyl group such as a benzyl group, a pmethoxybenzyl group, a p-nitrobenzyl group, a benzhydryl group or trityl group. Particularly preferred is a methyl group, an ethyl group, a tert-butyl group, a 2-propenyl group, a benzyl group, a pmethoxybenzyl group or a benzhydryl group.
After completion of the reaction, conventional treatment is conducted to obtain a crude product of the compound of the formula The compound of the formula (IV) may or may not be purified in accordance with a conventional method, and if necessary, reactions for removing protecting groups such as a hydroxyl group, an amino group and a carboxyl group, are appropriately conducted to obtain a compound of the formula (gg).
Removal of protecting groups may vary depending upon their types, but can be-conducted in accordance with the methods disclosed in a literature (Protective Groups in Organic Synthesis, T.W.
Greene, John Wiley Sons (1981)) or methods similar thereto, for WO 97/01275 PCT/US96/11022 -223example by solvolysis employing an acid or a base, by chemical reduction employing a metal hydride complex or by catalytic reduction employing a palladium-carbon catalyst or Raney nickel.
Process 2 A compound of the formula (gg-a): (gg-a)
CO
2
H
wherein Crl-, Ar 2 A- Ar 4 A, RI, R 2
R
3
R
4
R
5
R
6
R
7
R
8 and R 9 are as defined above, and
X
a and ya are as defined below, can be prepared by reacting a compound of the formula S Ar' a
Z
R2
(V)
wherein Xa is a carbonyl group or a group of the formula -CHRa- (wherein Ra is as defined above), Z is a leaving group; and r R 1 p and R 2 P are as defined above, with a compound of the formula (VI): I _I WO 97/01275 PCT/US96/11022 -224-
(VI)
wherein ya is an oxygen atom, a sulfur atom or a group of the formula -NRb- (wherein Rb is as defined above); and Ar 2 Ar 3 Ar 4 AP, R 3 p, R 4 p, R 5 p, R 6
R
7
R
8 p R 9 p and RP are as defined above, to obtain a compound of the formula (IV-a):
R
9 p
CH
2 CH CH N
AP-CO
2
RP
R
6 (IV-a)
R
5 p wherein Ar- r2- r3-- r 4 AP, Xa, ya,
R
1 p,
R
2 p, R 3 p, R 4 p, R 5 p, R 6
R
7
R
8 p, R 9 p and RP are as defined above, and, if necessary, removing any protecting group.
Process 2 is a process for preparing a compound of the formula (gg) wherein is a group of the formula -COO-, -COS-, WO 97/01275 PCT/US96/11022 -225- -CONRb-, -CHRaO-, -CHRaS- or -CHRaNRb- (wherein Ra and Rb are as defined above) i.e. a compound of the formula (gg-a).
The reaction of the compound of the formula with a compound of the formula (VI) is carried out usually by using 1 mol or an excess molar amount, preferably from 1 to 3 mols, of the compound of the formula per mol of the compound of the formula (VI).
The reaction is conducted usually in an inert solvent. The inert solvent may, for example, be a halogenated hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane or trichloroethylene; an ether such as ethyl ether, tetrahydrofuran or dioxane; an aromatic hydrocarbon such as benzene, toluene, chlorobenzene or xylene; an aprotic polar solvent such as dimethylformamide, acetonitrile, acetone, ethyl acetate or hexamethylphosphoric triamide, or a mixture of such solvents.
The reaction temperature is usually from -70°C to the boiling point of the solvent used for the reaction, preferably from -20 0
C
to 100 0
C.
The reaction time is usually from 5 minutes to 7 days, preferably from 10 minutes to 24 hours.
The above reaction is preferably conducted in the presence of a base to facilitate the reaction. Especially when ya in the formula (VI) is not a group of the formula -NRb- it is necessary to carry out the reaction in the presence of an inorganic base such as sodium hydride, n-butyl lithium, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate or sodium hydrogen carbonate, or an organic base such as triethylamine, Nethyldiisopropylamine, pyridine, 4 -dimethylaminopyridine or N,Ndimethylaniline.
The base is used usually in an amount of 1 mol or an excess molar amount, preferably from 1 to 5 mols, per mol of the compound of the formula The leaving group represented by Z in the formula (V) _CII__ WO 97/01275 PCT/US96/11022 -226may, for example, be a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, or an organic sulfonyloxy group such as a methanesulfonyloxy group, a p-toluenesulfonyloxy group or a benzenesulfonyloxy group.
When a hydroxyl group is present on the group of the formula R3p S Ar'- Ar 2 or r4 R2P R9P when a hydroxyl group, a lower hydroxyalkyl group, a carboxyl group or a lower carboxyalkyl group is present on the saturated or unsaturated aliphatic hydrocarbon group represented by AP, and when a hydroxyl group, an amino group, a carboxyl group or a lower hydroxyalkyl group is present on the group of the formula R4pYA- Ar 3
R
5
P
it is preferred to conduct the reaction after protecting such a hydroxyl group, a lower hydroxyalkyl group, an amino group, a carboxyl group or a lower carboxyalkyl group appropriately by a hydroxyl-protecting group, an amino-protecting group or a carboxyl-protecting group and removing any protecting group after the reaction.
The hydroxyl-protecting group, the amino-protecting group and the carboxyl-protecting group may be the protecting groups mentioned above with respect to process 1.
After completion of the reaction, a usual treatment is carried out to obtain a crude product of the compound of the formula The compound of the formula (IV-a) thus obtained may or may not be purified by a conventional method, and if necessary, reactions for removing the hydroxyl-, amino- and carboxyl-protecting groups may be WO 97/01275 PCT/US96/11022 -227carried out in a proper combination to obtain a compound of the formula (gg-a).
The method for removing a protecting group varies depending upon the type of the protecting group and the stability of the desired compound However, removal of protecting groups can be appropriately conducted in accordance with the methods disclosed in the above-mentioned literature or methods similar thereto.
Process 3 A compound of the formula (gg-b):
R
3
R
8 Sr'-xb-y b Ar 2
-CH
2 R R9 R2 I H (gg-b) 4HA NO A-CO 2
H
R
wherein r- Ar 2 Ar- A,r 4 A, R 1
R
2
R
3
R
4
R
5
R
6
R
7
R
8 and R 9 are as defined above, and Xb and yb are as defined below, can be prepared by reacting a compound of the formula (VII):
(VII)
M
-M
WO 97/01275 PCT/US96/11022 -228wherein Xb is an oxygen atom, a sulfur atom or a group of the formula Ar'- -NRb- (wherein Rb is as defined above); and Rip and
R
2 p are as defined above, with a compound of the formula (VIII):
R
3 p Z-yb Ar 2
-CH
2
IH
(VIII)
wherein yb is a carbonyl group or a group of the formula -CHR a (wherein R a is as defined above); and Ar 2 Ar 3 Ar 4 AP, Z, R 3 p, R 4 p, R 5 p, R 6
R
7
R
8 p, R 9 p and RP are as defined above, to obtain a compound of the formula (IV-b):
AP-CO
2
RP
(IV-b) WO 97/01275 PCT/US96/11022 -229wherein Ar- Ar 2 Ar 3 C r 4 wherein AP, Xb, yb, RIp, R 2 p, R 3 p, R 4 p, R 5 p, R 6
R
7 R8p, R 9 p and RP are as defined above, and, if necessary, removing any protecting group.
Process 3 is a process for preparing a compound of the formula (gg) wherein is a group of the formula -OCO-, -SCO-, -NRbCO-, -OCHRa-, -SCHRa- or -NRbCHRa- (wherein Ra and Rb are as defined above) i.e. a compound of the formula This process can be conducted usually in an inert solvent, preferably in the presence of a base, by using 1 mol or an excess molar amount, preferably from 1 to 3 mols, of the compound of the formula (VII), per mol of the compound of the formula (VIII). The types of the inert solvent and the base as well as the reaction conditions may be the same as described above with respect to process 2. Accordingly, the reaction and the post-treatment after the reaction may preferably be carried out all in accordance with process 2.
Further, in the above processes 2 and 3, when Xa or yb is a carbonyl group, a compound wherein the group corresponding to Z is a hydroxyl group i.e. a compound wherein Z and the adjacent Xa or yb together represents a carboxyl group, can be used. In such a case the reaction conditions, etc. are preferably in accordance with the reaction conditions for the reaction of the compound of the formula (II) with the compound of the formula (III) in the above process 1.
Process 4 A compound of the formula (gg-c): WO 97/01275 WO 9701275PCT/US96/11022 230 3 r Ar 2
-CH
2 Ar 4 R H 0
I
wherein rl ,C r_ r3 ,C r4 A Rl, R 2
R
3
R
4
R
5
R
6
R
7
R
8 and R 9 are as defined above, and *1a and R 2 a are as defined below, can be prepared by reacting a compound of the formula (LX): Ar-C- Ria R02 (IX) wherein Rla is a hydrogen atom or a lower alkyl group; and C ~ri RP and R 2 P are as defined above, with a compound of the formula WO 97/01275 PCTfUS96/1 1022 -231-
R
3 p Q-CH Ar2-0H 2 7 Ar 4 2a H (X R CH
R
5 P R wherein Q is a triphenyiphosphonio group, a dimethoxyphosphoryl group or a diethoxyphosphoryl. group; R 2 a is a hydrogen atom or a lower alkyl group; and r-9C r-'AP,
R
3 P, R 4 P, R 5 P, R 6
R
7
R
8 P, R 9 P and RP are as defined above, to obtain a compound of the formula (XI): Ar-C Ar2- CH 2 r I II Rk 7,
AP-CO
2
RP
P
(XI)
wherein Ar-, CAr2-, CAr3-, A 4 AP, RlP, R 2 P, R 3 P, R 4 p, R 5 P, R 6
R
7
R
8 P, R 9 P, RP, Ria and R 2 a are as defined above, and, if necessary, removing any protecting group.
WO 97/01275 PCT/US96/11022 -232- Process 4 is a process for preparing a compound of the formula (gg) wherein is -CHR aCHR 2 a- (wherein each of R a and R2a which are the same or different, is a hydrogen atom or a lower alkyl group) i.e. a compound of the formula (gg-c).
The reaction of the compound of the formula (IX) with a compound of the formula is carried out usually by employing equimolar amounts of the two reactants or using a slightly excess amount of one of them.
The reaction is carried out usually in an inert solvent. Such an inert solvent may, for example, be an ether such as ethyl ether, tetrahydrofuran or dioxane; an aromatic hydrocarbon such as benzene, toluene, chlorobenzene or xylene; an aprotic polar solvent such as dimethylformamide, acetonitrile, acetone, ethyl acetate or hexamethylphosphoric triamide; or a mixture of such solvents.
The reaction temperature is usually from -100 0 C to the boiling point of the solvent used for the reaction, preferably from to 50 0
C.
The reaction time is usually from 5 minutes to 7 days, preferably from 10 minutes to 24 hours.
Further, the above reaction can be conducted in the presence of a base to facilitate the reaction. Especially when Q in the formula is a triphenylphosphonio group, the reaction is preferably conducted in the presence of a base such as sodium hydride, n-butyl lithium, sodium methoxide, potassium tert-butoxide, sodium hydroxide or potassium hydroxide.
Such a base is used in an amount of 1 mol or an excess molar amount, preferably from 1 to 5 mols per mol of the compound wherein Q is a triphenylphosphonio group.
The reaction of reducing the compound of the formula (XI) obtained in the above step is usually preferably conducted by catalytic reduction employing a palladium carbon catalyst, a Raney nickel catalyst or a platinum catalyst in an inert solvent.
The inert solvent may, for example, be an alcohol such as methanol, ethanol or propanol, or acetic acid.
WO 97/01275 PCTIUS96/1022 233 The reaction temperature is usually from -20 0 C to 100 0 C, preferably from 0°C to room temperature.
The reaction time is usually from 5 minutes to 7 days, preferably from 10 minutes to 24 hours.
The hydrogen pressure in the catalytic reduction reaction is usually preferably from atmospheric pressure to 5 atm, and the amount of the catalyst is usually from 0.01 to 1 mol, preferably from 0.05 to 0.2 mol, per mol of the starting material compound (XI).
After completion of the reaction, the product is subjected to a usual treatment after removing any protecting group if such a protecting group is present or directly if no such protecting group is present, to obtain a compound of the formula (gg-c).
Removal of the protecting group and the post treatment may be conducted by the methods described with respect to the above process 1.
Process A compound of the formula (gg-c):
R
3
R
8
R
1 Rla R 2 a R 9 Ar- C Ar 2
-CH
2 Ar 4 H H R7 I 1 R2
CH
r; TN
AP-CO
2
H
gg-c wherei Ar- Ar 2 C r3- Ar 4 wherein WO 97/01275 WO 9701275PCTIUS96/1 1022 234 A, Rl, R 2
R
3
R
4
R
5
R
6
R
7
R
8 and R 9 Rl a and R 2 a are as defined above, can be obtained by reacting a compound of the formula (XII):
(XII)
wherein R IP, R 2 P and R 1a are as defined above, with a compound of the formula (XIII): R 2 a-C.
0
(XIII)
wherein r- ~4 AP, R 3 p, R 4 P, R 5 P, R 6
R
7
R
8 P, R 9 P, RP and R 2 a are as defined above, to obtain a compound of the formula (XI):
I
WO 97/01275 PCTIUS96/11022 -235-
R
5 p
(XI)
wherein Ar- r 2 Cr 3 Ar 4 AP, Rip, R 2 p, R 3 p, R 4 p, R 5 p, R 6
R
7
R
8 p, R 9 p, RP, Rla and R 2 a are as defined above, then reducing the compound of the formula and, if necessary, removing any protecting group.
Like process 4, process 5 is a process for producing a compound of the formula (gg) wherein is -CHRlaCHR 2 a- (wherein Rla and R 2 a are as defined above) i.e. a compound of the formula (gg-c).
Process 5 is equal to the reaction of process 4 wherein staring material compounds (IX) and are replaced by the compounds (XIII) and (XII), respectively. Accordingly, the manner and conditions of the reaction may be all in accordance with process 4.
Further, a compound of the formula (gg-d):
R
3
R
8 R Ar 1 -C=C C Ar2-CH 2
R
7 H H H CH R2 CH
H
•r A-CO2H R H 6
R
(gg-d) WO 97/01275 PCT/US96/11022 -236- Ar
C
Ar 2 Ar 3 Ar 4 wherein, A, R 1
R
2
R
3
R
4
R
5
R
6
R
7
R
8 and R 9 are as defined above, can be obtained by removing a protecting group, as the case requires, from a compound of the formula (XI-a):
R
3p R8p R1P R 9
F
Arl-C=C Ar2-CH 2 Ar 4 I I R
R
2 P H H CH
H
r N AP-CO 2
R
p (XI-a) Ar'- Ar2- Ar 3 Ar 4 wherein AP, Rip,
R
2 p, R 3 p, R 4 p, R 5 p, R 6
R
7
R
8 p, R 9 p and RP are as defined above, i.e. a compound of the formula (XI) wherein both R la and R 2 a are hydrogen atoms, among compounds of the formula (XI) obtainable as intermediates in the above processes 4 and Process 6 A compound of the formula (gg-e): WO 97/01275 WO 9701275PCTfUS96/11022 237 Ar' Y Ar 2
OH
2
R
7
A
4 (g) C H R1 2 R 4 H-T Y I 0H 2 )q-CH(H 2 )rCO 2
H
50R60 HO
I
Ar- Ar2, r 3 wherein C ~lC r_,C r ,C
Y,
R 1
R
2
R
3
R
4
R
5
R
6
R
7
R
8
R
9 R 12 R 1 3 p, q and r are as defined above, can be prepared by oxidizing a compound of the formtla (IV-e): X p Ar 3p R 8p I OH YpAr2XH2 X O2p (H)qHC 2 rOR R pR60
OH
(IV-e) wherein R 1 2 p is a hydrogen atom or a lower hydroxyalkyl or carboxyl group which may be protected, R1 3 p is a hydrogen atom or a hydroxyl or carboxyl group which may be protected; Ar'- r- Ar3-, Ar 4 and C, XP, YP, RlP,
I
WO 97/01275 PCT/US96/11022 -238-
R
2 p, R 3 p, R 4 p, R 5 p, R 6
R
7 R8p, R 9 p, RP, p, q and r are as defined above, and, if necessary, removing any protecting group.
Process 6 is a process for preparing a compound of the formula (gg) wherein A is a group of the formula m12
-(CH
2 CC-
(CH
2 )q-CH-(CH 2 )r I
I
OH R13 (b) wherein R 12
R
13 p, q and r are as defined above, i.e. a compound of the formula (gg-e).
The reaction of oxidizing the compound of the formula (IV-e) is usually preferably carried out in an inert solvent by using socalled Dess-Martin oxidation employing 12-1-5 triacetoxyperiodinane; so-called Swern oxidation employing oxalyl chloride and dimethyl sulfoxide; a sulfur trioxide-pyridine complex; pyridinium chlorochromate; active manganese dioxide; or tetra-n-propylammonium perruthenate.
The inert solvent may, for example, be a halogenated hydrocarbon such as methylene chloride, chloroform or dichloroethane; an ether such as ethyl ether, tetrahydrofuran or dioxane; an aprotic polar solvent such as acetonitrile, acetone, ethyl acetate or dimethyl sulfoxide; or a mixture of such solvents.
The reaction temperature varies depending upon the type of the oxidizing agent, etc. However, it is usually from -100"C to the boiling point of the solvent used for the reaction, preferably from -70 0
C
to 100"C.
The reaction time is usually from 5 minutes to 7 days, preferably from 10 minutes to 24 hours.
After completion of the reaction, the product is subjected to usual treatment after removing a protecting group when such a protecting group is present, or directly when no such protecting group is present, to obtain the compound of the formula (gg-e).
WO 97/01275 PCT/US96/11022 -239- The removal of the protecting group and the post-treatment may be conducted in the same manner as described above with respect to process 1.
Further, a compound corresponding to the compound of the formula (IV-e) to be used as the starting material in the above process 6, can be prepared, for example, by hydrolyzing a compound of the formula (IV-e-1):
R
t P R3p R8P AR Y7 A' R 9 P Ar1-Xp-Ypt 2-CH2 R 2p (CAr3H 0 CIH- (CH2)q-CH-(OH2)r R4P H R6 R13p (IV-e-1) Ar-, Ar2-, Ar3-, Ar 4 wherein r- r4 XP, YP,
R
1 p, R 2 p, R 3 p, R 4 p, R 5 p, R 6
,R
7
R
8 p, R 9 p, R 1 2p, R13p, p, q and r are as defined above, in the presence of a base, to obtain a compound of the formula (IV-e-2), WO 97/01275 PCT/US96/11022 -240-
R
2 P S R1P Ar 3p YpP- CH2 R- A4 R9
R
3 P R9P Yp r 2 CH2
OH
CH I Ar 3 H N (CH 2 HCCH (CH 2 )q-CH-(CH 2 )rCO 2
M
R4pR R6 O R'2P R13p (IV-e-2) wherein M is a hydrogen atom or an alkali metal Ar 1 Ar 2 Ar3- Ar 4 atom; and
XP,
YP, Rip, R 2 p, R 3 p, R 4 p, R 5 p, R 6
,R
7
R
8 p, R 9 p, R 1 2p, R 1 3p, p, q and r are as defined above, then reacting thereto a diazo compound of the formula RPP N+ N wherein RPP is a lower alkyl group, a lower alkenyl group, an aralkyl group or a lower alkoxycarbonylalkyl group, or an alkylating agent of the formula RPP-Z 1 wherein RPP and Z1 are as defined above.
Isolation and purification of the compound of the formula (gg-d) or obtained by the above process can be conducted by a single use or a proper combination of conventional separating means such as column chromatography employing silica gel, adsorbent resin, etc., liquid chromatography, solvent extraction and recrystallization-reprecipitation.
The compound of the formula (gg-c), (gg-d) or (gg-e) can be converted to a pharmaceutically acceptable salt or ester by a conventional method. Reversely, the conversion from the I WO 97/01275 PCT/US96/11022 241 salt or ester to a free carboxylic acid can also be conducted by a conventional method.
The compounds of the formulas (III),
(VII),
(VIII), (XII) and (XIII) may be commercially available or can be prepared in accordance with the methods disclosed in literatures Med. Chem., 717 (1967); ibid., 725; J. Chem. Soc. Perkin I, 1636 (1978); Chem. Lett., 191 (1980); ibid., 375 (1984); J. Chem. Soc.
Chem. Commun., 579 (1984); J. Am. Chem. Soc., 104, 5716 (1982)) or methods similar thereto, or in accordance with the following processes or the methods disclosed in Examples.
WO 97/01275 PCTIUS96/1 1022 242 Process A R 4 p Ar 3 -0H 2
R
6 0
A
base CH R6 R WO 97/01275 PCT/US96/11022 -243-
R
8 P R 7 1) jI SAr 4
CH
2
-NH
2
R
9 p 2) reduction
R
3p 8p (.Ar l -xp-YP Ar- CH2 r I R 7 Ar
R
2 P OCH
CH
Sp HR6 In the above formulas, Q1 is a cyano group, a carboxyl group, a lower alkoxycarbonyl group, a chloroformyl group or an Nmethoxy-N-methylcarbamoyl group; Q 2 is a halogen atom; Z1 is a leaving group selected from the group consisting of a chlorine atom, a bromine atom, an iodine atom, a trifluoroacetoxy group, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group and a p-toluenesulfonyloxy group; and Ar 1 Ar 2 Ar 3 C Ar 4 XP,
YP,
RIp, R 2 p, R 3 p, R 4 p, R5p, R 6
,R
7
R
8 p, R 9 p are as defined above.
By this process, the desired compound (II) can be prepared by reacting a nitrile or a carboxylic acid derivative of the formula 1 with an alkyl lithium of the formula 2 or an alkyl Grignard reagent (or an alkyl Gilman reagent) of the formula 3 to obtain a ketone compound 4, then reacting an alkylating agent of the formula 5 to the ketone WO 97/01275 PCT/US96/11022 -244compound 4 to produce a compound of the formula 6, then reacting the compound 6 with an amine compound of the formula 7, followed by reduction.
The above reaction steps will be described in detail referring to suitable reaction conditions, etc.
The first step of preparing the ketone compound 4 is conducted usually by reacting 1 mol or an excess molar amount, preferably from 1 to 5 mols of the alkyl lithium reagent 2 or the alkyl Grignard reagent (or the alkyl Gilman reagent in the case where the substituent Ql of the compound 1 is a chloroformyl group) 3 to 1 mol of the starting material compound 1 in a solvent inert to the reaction such as tetrahydrofuran, ethyl ether or benzene, if necessary followed by hydrolysis under an acidic condition.
The reaction temperature is usually from -80°C to the boiling point of the solvent used for the reaction, preferably from to 50°C. The reaction time is usually from 5 minutes to 48 hours, preferably from 30 minutes to 24 hours.
When the substituent Ql in the formula of the starting material compound 1 is a cyano group, it may be necessary to conduct a hydrolytic reaction under an acidic condition after completion of the reaction, and such a hydrolytic reaction is conducted in e.g. methanol, ethanol, tetrahydrofuran or a solvent mixture thereof with water in the presence of an acid such as hydrochloric acid, sulfuric acid or ptoluenesulfonic acid.
The reaction temperature is usually from OC to the boiling point of the solvent used for the reaction, and the reaction time is from minutes to 24 hours.
The step of preparing the compound of the formula 6 from the ketone compound 4, can be conducted by reacting an equimolar amount or an excess molar amount, preferably from 1 to 2 mols, of the alkylating agent of the formula 5 to the ketone compound 4 in the presence of a base in an inert solvent which does not adversely affect the reaction or without using any solvent.
WO 97/01275 PCT/US96/11022 -245- The inert solvent may, for example, be an ether such as ethyl ether, tetrahydrofuran or dioxane; an aromatic hydrocarbon such as benzene, toluene or xylene; an aprotic polar solvent such as dimethylformamide, dimethyl sulfoxide or hexamethylphosphoric triamide, or a mixture of such solvents.
The base to be used for this reaction, may, for example, be an alkali metal hydride such as sodium hydride, lithium hydride or potassium hydride; a lithium amide such as lithium amide, lithium diisopropylamide or lithium bis(trimethylsilyl)amide; an alkyl lithium such as methyl lithium, butyl lithium or tert-butyl lithium; an alkali metal alkoxide such as sodium methoxide, sodium ethoxide or potassium tert-butoxide; or an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide.
The base is used usually in an amount of 1 mol or an excess molar amount, preferably from 1 to 5 mols, per mol of the starting material alkylating agent The reaction temperature is usually from -100°C to the boiling point of the solvent used for the reaction, preferably from to 100"C. The reaction time is usually from 10 minutes to 48 hours, preferably from 30 minutes to 24 hours.
The step of preparing the desired compound (II) from the compound of the formula 6 can be conducted usually in an inert solvent such as methanol, ethanol, benzene, ethyl ether or tetrahydtofuran by reacting 1 mol or an excess molar amount, preferably from 1 to 2 mols, of the amine compound of the formula 7 to 1 mol of the compound of the formula 6 to preliminarily form an imine, which is subsequently reduced.
The reaction temperature in the process for forming the above imine is usually from 0°C to the boiling point of the solvent used for the reaction, preferably from room temperature to 100°C. The reaction time is usually from 5 minutes to 48 hours, preferably from minutes to 24 hours. After the formation of the imine, the reaction solution may be used as it is to the subsequent step of the reduction reaction, or the reaction solution may be distilled or subjected to a WO 97/01275 PCT/US96/11022 -246conventional separation means to isolate the imine compound, which is then subjected to the subsequent reduction.
The reduction can be carried out by using a metal hydride complex such as sodium borohydride, sodium cyanoborohydride or lithium aluminum hydride, or by catalytic reduction employing a palladium-carbon catalyst or a Raney nickel catalyst.
When a metal hydride complex is used as a reducing agent, the reducing agent is used usually in an amount of 1 mol or an excess molar amount, preferably from 1 to 5 mols, per mol of the above imine.
For the reduction, an inert solvent, for example, an alcohol such as methanol or ethanol; an ether such as dimethyl ether, ethyl ether, diisopropyl ether, dibutyl ether, dimethoxyethane, dioxane, tetrahydrofuran or diglyme; an aliphatic hydrocarbon such as pentane, hexane, heptane or cyclohexane; or an aromatic hydrocarbon such as benzene or toluene; or a mixture of such solvents, can be used appropriately as a solvent depending upon the type of the reducing agent.
The reaction temperature is usually from 0OC to room temperature, and the reaction time is usually from 1 hour to 6 hours.
Further, in this process, it is also possible to react an alkylating agent of the formula 5 to the nitrile or carboxylic acid derivative of the formula 1 to preliminarily produce an alkyl compound and then to react an alkyl lithium of the formula 2 or an alkyl Grignard reagent (or an alkyl Gilman reagent) of the formula 3 to the alkyl compound to obtain a compound of the formula 6. Such a reaction can be conducted under the conditions similar to the above Process A.
Accordingly, the reaction conditions described for the above Process A may all be used as the reaction conditions for this reaction.
The compounds of the formulas 1,2- 3, 5 and 7 may be commercially available or can be produced by a proper combination, as the case requires, of the methods disclosed in Examples, or conventional methods or methods similar thereto.
WO 97/01275 PCT/US96/1 1022 -247- Process B reduction
-CH
2 ."CH R 6
-CH
2 OH8 1) CH 3
SO
2 CIITEA (or PBr 3 2) 1 tAr 4
CH
2
-NH
2
H
R 6 In the above formulas,
I
WO 97/01275 PCT/US96/11022 -248- Cr 2 Cr 3 (Ar 4 XP, Yp, R 1 p,
R
2 p, R 3 p, R 4 p, R 5 p, R 6
R
7
R
8 p and R 9 p are as defined above.
According to this process, the desired compound (II) can be prepared by reacting a reducing agent such as a metal hydride complex to a compound of the formula 6 to obtain an alcohol compound 8 and reacting an amine compound of the formula 7 to the alcohol compound 8.
The above reaction steps will be described in detail referring to suitable reaction conditions, etc.
The reaction for reducing the compound of the formula 6 to the alcohol compound 8 can be conducted usually by using a metal hydride complex such as sodium borohydride, diisobutyl aluminum hydride, lithium aluminum hydride or lithium tri-sec-butylborohydride (L-selectrideTM), or by catalytic reduction employing e.g. a palladiumcarbon catalyst or a Raney nickel catalyst, in an inert solvent which does not adversely affect the reaction.
When the metal hydride complex is used as the reducing agent, such a reducing agent is used usually in an amount of 1 mol or an excess molar amount, preferably from 1 to 5 mols, per mol of the starting material compound 6.
The inert solvent to be used in this reaction may be suitably selected depending upon the type of the reducing agent.
For example, when the reducing agent is sodium borohydride, an inert solvent, such as an alcohol such as methanol or ethanol; an ether such as dimethoxyethane, dioxane, tetrahydrofuran or diglyme; an aprotic polar solvent such as dimethylformamide or dimethylacetamide, or water, or a solvent mixture thereof, may be used, and particularly preferred is an alcohol such as methanol or ethanol.
For example, when the reducing agent is diisobutyl aluminum hydride, an inert solvent, such as an ether such as dimethyl ether, ethyl ether, diisopropyl ether, dibutyl ether, dimethoxyethane, I I WO 97/01275 PCT/US96/11022 -249dioxane, tetrahydrofuran or diglyme; an aliphatic hydrocarbon such as pentane, hexane, heptane or cyclohexane; an aromatic hydrocarbon such as benzene or toluene; methylene chloride, or a solvent mixture thereof may be used, and particularly preferred is toluene or methylene chloride.
For example, when the reducing agent is lithium aluminum hydride or lithium tri-sec-butylborohydride, an inert solvent, such as an ether such as dimethyl ether, ethyl ether, diisopropyl ether, dibutyl ether, dimethoxyethane, dioxane, tetrahydrofuran or diglyme; an aliphatic hydrocarbon such as pentane, hexane, heptane or cyclohexane; or an aromatic hydrocarbon such as benzene or toluene, or a solvent mixture thereof, may be used, and particularly preferred is ethyl ether or tetrahydrofuran.
For the catalytic reduction, the solvent is preferably an alcohol such as methanol or ethanol.
The reaction temperature and the reaction time vary depending upon the stability and the susceptibility to the reduction reaction of the starting material ketone compound 6, the type of the reducing agent and the type of the solvent. However, the reaction temperature is usually from -80°C to 100°C, preferably from -70C to and the reaction time is usually from 5 minutes to 2 days, preferably from 30 minutes to 24 hours.
The step of preparing the desired compound (II) from a compound of the formula 8 can be carried out by reacting a sulfonating agent such as methanesulfonyl chloride to the alcohol compound of the formula 8 in the presence of a base, or reacting a halogenating agent such as thionyl chloride or phosphorous tribromide thereto, to convert the hydroxyl group in the formula to a leaving group, followed by reacting an amine compound of the formula 7.
The reaction for introducing the leaving group can be conducted usually by reacting 1 mol or an excess molar amount, preferably from 1 to 2 mols, of a sulfonating agent and a base such as triethylamine to 1 mol of the alcohol compound 8 in an inert solvent such as methylene chloride, chloroform, benzene, tetrahydrofuran or WO 97/01275 PCT/US96/11022 -250ethyl acetate, or using 1 mol or an excess molar amount, preferably from 1 to 5 mols, of a halogenating agent.
The reaction temperature is usually from -70°C to the boiling point of the solvent used for the reaction, preferably from to 80°C, and the reaction time is usually from 5 minutes to 48 hours, preferably from 30 minutes to 24 hours.
Then, the step of reacting an amine compound 7 to the compound having the leaving group introduced, obtained by the above reaction, can be conducted usually by employing 1 mol or an excess molar amount, preferably from 1 to 50 mols, of the amine compound 7 per mol of the starting compound having the leaving group, in an inert solvent such as methylene chloride, chloroform, benzene, ethyl ether or tetrahydrofuran.
If necessary, this reaction can be conducted in the presence of a base other than the amine compound of the formula 7.
As such a base, an inorganic base such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate or sodium hydrogencarbonate, or an organic base such as triethylamine, N-ethyldiisopropylamine, pyridine or N,Ndimethylaniline may, for example, be mentioned.
Such a base is used usually in an amount of 1 mol or an excess molar amount, preferably from 1 to 5 mols, per mol of the starting material compound.
The reaction temperature is usually from -50°C to 150C, preferably from -20°C to 100°C, and the reaction time is usually from minutes to 7 days, preferably from 10 minutes to 24 hours.
WO 97/01275 WO 9701275PCTIUS96/11022 251 Process C I1)DEAD, Ph P Phthalimide (or HN 3 or DPPA) I CIPA0 2 CI, TEA orii) Phthalimide (or NaN 3 2) NH 2
NH
2 (or reduction) R 3 p '-XP-YP Ar 2
CH
2 R 4p-4?fAT3--;CH, NH;? 2) reduction R 3 p Ar'-XP-Y- SAr2-CH 2 WO 97/01275 PCT/US96/11022 -252- In the above formulas, Ar 1 Ar 2 Ar 4 XP, Yp,
R
1 p,
R
2 p, R 3 p, R 4 p, R5p, R 6
R
7
R
8 p and R 9 p are as defined above.
According to this process, the desired compound (II) can be prepared by firstly reacting diethyl azodicarboxylate, triphenylphosphine and phthalimide (or hydrogen azide or diphenylphosphoryl azide) or reacting a sulfonylation agent such as methanesulfonyl chloride in the presence of a base such as triethylamine, then reacting phthalimide (or sodium azide) in the presence of a base, to the alcohol compound of the formula 8, to obtain a phthalimideprotected form (or an azide compound) of the amine compound 9, then reacting hydrazine (or a reducing agent) to remove the phthalimide group (or reduce the azide group) to obtain an amine product of the formula 9 and finally reacting a compound of the formula 10 to the compound 9, followed by reduction.
The above reaction steps will be described in detail referring to suitable reaction conditions, etc.
For the step of producing the amine compound of the formula 9 from the alcohol compound 8, various synthetic methods and reaction conditions well known in organic synthetic chemistry for converting alcohol compounds to amines, may be employed. For example, it is preferred to employ a Mitsunobu reaction using diethyl azodicarboxylate, triphenylphosphine and phthalimide (or hydrogen azide or diphenylphosphoryl azide) or a method which comprises sulfonylation with a sulfonylation agent such as methanesulfonyl chloride in the presence of a base such as triethylamine, then reacting phthalimide (or sodium azide) in the presence of a base, and then treating the obtained phthalimide compound with hydrazine (or reducing the azide compound).
The above reactions are conducted usually in a solvent inert to the reaction. The inert solvent may,for example, preferably be tetrahydrofuran,dimethoxyethane, benzene or toluene in the case of the above-mentioned Mitsunobu reaction; methylene chloride, chloroform,
II__
WO 97/01275 PCT/US96/11022 -253tetrahydrofuran, benzene, ethyl acetate or dimethylformamide in the case of the sulfonylation followed by the reaction with phthalimide (or sodium azide); an alcohol such as methanol or ethanol in the next step of the phthalimide-removing reaction with hydrazine; an ether such as ethyl ether or tetrahydrofuran in the case where a metal hydride complex is used as the reducing agent in the reduction reaction of the azide compound; water-containing tetrahydrofuran in the case where phosphine reduction is conducted with triphenylphosphine or the like; and an alcohol such as methanol or ethanol in the reduction by catalytic reduction.
With respect to the amounts of the reagents to be used, in the above Mitsunobu reaction, each of diethyl azodicarboxylate, triphenylphosphine and phthalimide (or hydrogen azide or diphenylphosphoryl azide) is used in an amount of 1 mol or an excess molar amount, preferably from 1 to 5 mols, per mol of the starting material alcohol compound 8. In the reaction with the phthalimide (or sodium azide) after the sulfonylation, the sulfonylation agent such as methanesulfonyl chloride is used in an amount of 1 mol or an excess molar amount, preferably from 1 to 2 mols, per mol of the alcohol compound 8, and the base such as triethylamine used at that time is usually in an amount of 1 mol or an excess molar amount, preferably from 1 to 2 mols, per mol of the sulfonylation agent. In the next step of the reaction with phthalimide (or sodium azide) in the presence of a base, 1 mol or an excess molar amount, preferably from 1 to 5 mols of each of phthalimide and the base (or sodium azide) is used per mol of the starting material sulfonylation agent. Here, the base to be used together with phthalimide is preferably sodium carbonate or potassium carbonate. Otherwise, without using such a base, a sodium salt or a potassium salt of phthalimide may be used by itself. Then, in the reaction for removing the phthalimide group with hydrazine, hydrazine is used in an amount of 1 mol or an excess molar amount, preferably from 1 to 10 mols, per mol of the phthalimide compound as the starting material compound. In the reduction of the azide compound with a metal hydride complex or with triphenylphosphine, the reducing agent WO 97/01275 PCT/US96/11022 -254is used usually in an amount of 1 mol or an excess molar amount, preferably from 1 to 2 mols, per mol of the azide compound.
In the case of the above Mitsunobu reaction, the reaction temperature is usually from -70°C to 100°C, preferably from -20*C to 50°C, and the reaction time is usually from 5 minutes to 48 hours, preferably from 30 minutes to 24 hours. In the reaction for removing the phthalimide group by hydrazine, the reaction temperature is usually from 0°C to the boiling point of the solvent used for the reaction, preferably from room temperature to 100°C, and the reaction time is usually from 5 minutes to 48 hours, preferably from 30 minutes to 24 hours. In the reaction for converting the azide compound to the amine compound by reduction, when a metal hydride complex is used as the reducing agent, the reaction temperature is usually from -70'C to 150'C, preferably from -20°C to 50'C, and the reaction time is usually from 5 minutes to 48 hours, preferably from 10 minutes to 10 hours.
When triphenylphosphine is used as the reducing agent, the reaction temperature is usually from room temperature to the boiling point of the solvent used for the reaction, preferably from 30°C to 100C, and the reaction time is usually from 10 minutes to 48 hours, preferably from 30 minutes to 24 hours. Further, in the case of the reduction by catalytic reduction, the reaction temperature is usually from 0°C to 100C, preferably from room temperature to 50'C, and the reaction time is usually from 10 minutes to 48 hours, preferably from minutes to 24 hours.
The step for producing the desired compound (II) from the compound of the formula 9 is carried out usually by preliminarily forming an imine by reacting 1 mol or an excess molar amount, preferably from 1 to 2 mols of the compound of the formula 10 to 1 mol of the compound of the formula 9 in an inert solvent such as methanol, ethanol, benzene, ethyl ether or tetrahydrofuran, and then reducing it.
This step can be carried out in the same manner as the step for producing the desired compound (II) from the compound of the WO 97/01275 PCT/US96/11022 -255formula 6 in the above process A. Accordingly, with respect to the reaction conditions, etc., similar conditions may be employed.
Further, the compound of the formula 10 may be commercially available or can be produced by a proper combination, as the case requires, of the methods disclosed in Examples, or conventional methods or methods similar thereto.
WO 97/01275 WO 9701275PCTIUS96II1o22 256 Process D Ar 3
CH
2
?-R
6 R~p 0 base INrR6 0 1) reduction 2) CH 3
SO
2 CI, TEA, NaN 3 (or DEAD, Ph 3 P, DPPA) 3) reduction 7 CH
H-NH
2 WO 97/01275 PCT/US96/11022 -257-
R
8 p 0 1) II AP A-C- R R9p 2) reduction
R
3
P
NH 14 1) HO C-AP COORP [III]
II
2) selective removal of protecting groups R8P
R
3 p in the above formulas, R 14 means a hydroxylprotecting group when ya is an oxygen atom; a mercapto-protecting group when ya is a sulfur atom; or an amino- or imino-protecting group when ya is a group of the formula -NRb- (wherein Rb is as defined above); and WO 97/01275 PCT/US96/11022 -258- Ar 2 Ar3_- Ar 4 AP, ya, Z1, R 3 p, R 4 p, R 5 p, R 6
R
7
R
8 p, R 9 p and RP are as defined above.
According to this process, the desired compound (VI) can be prepared by firstly reacting an alkylating agent of the formula 11 to a ketone compound of the formula 4 to obtain a compound of the formula 12, reacting a reducing agent such as a metal hydride complex to the compound 12 to obtain an alcohol compound, then reacting diethyl azodicarboxylate, triphenylphosphine and phthalimide (or hydrogen azide or diphenylphosphoryl azide) or reacting a sulfonylation agent such as methanosulfonyl chloride in the presence of a base such as triethylamine, and then reacting phthalimide (or sodium azide) in the presence of a base, to obtain a phthalimide-protected form (or an azide compound) of the amine compound 13, then reacting hydrazine (or a reducing agent) to remove the phthalimide group (or reduce the azide group) to obtain an amine compound of the formula 13, reacting a compound of the formula 10 to the compound D, followed by reduction to obtain a compound of the formula 14, reacting a carboxylic acid of the formula (III) or its reactive derivative to the compound 14, and finally selectively removing the protecting group represented by R 1 4.
The step of producing a compound of the formula 12 from a ketone compound of the formula 4, can be carried out in the same manner as the step of producing the compound of the formula 6 from the ketone of the formula 4 in the above process A. Accordingly, with respect to the reaction conditions, etc., similar conditions may be employed.
When R 14 is a hydroxyl-protecting group, such a hydroxyl-protecting group may be the one disclosed above with respect to process 1.
When R1 4 is a mercapto-protecting group, the hydroxylprotecting group disclosed above with respect to process 1 can be used as such a mercapto-protecting group.
WO 97/01275 PCT/US96/11022 -259- When R 14 is an amino- or imino-protecting group, such an amino- or imino-protecting group may be the amino- or iminoprotecting group disclosed above with respect to process 1.
In the step of producing the amine compound of the formula 13 after reacting a reducing agent such as a metal hydride complex to the compound of the formula 12 to obtain an alcohol compound, the step of converting the compound of the formula 12 to the alcohol compound can be carried out in the same manner as the step of reducing the compound of the formula 6 to the alcohol compound 8 in the above process B. Accordingly, with respect to the reaction conditions, etc., similar conditions may be employed. Further, the step of producing an amine compound of the formula 13 from the obtained alcohol, can be carried out in the same manner as in the step of producing the amine compound 9 from the alcohol compound of the formula 8 in the above process C. Accordingly, with respect to the reaction conditions, etc., similar conditions may be employed.
The step of producing a compound of the formula 14 from the amine compound of the formula 13, can be carried out in the same manner as in the step of producing a compound of the formula (II) from the amine of the formula 9 in the above process C. Accordingly, with respect to the reaction conditions, etc., similar conditions may be employed.
In the step of producing the desired compound (VI) from the compound of the formula 14, the reaction of the compound of the formula 14 with the carboxylic acid of the formula (III) or its reactive derivative, can be carried out in the same manner as the reaction of the compound of the formula (II) with the carboxylic acid of (III) or its reactive derivative in the above process 1. Accordingly, with respect to the reaction conditions, etc., similar conditions may be employed.
For the step of selectively removing the protective group represented by R 14 from the compound obtained by the above reaction, various methods may suitably be selected depending upon the type and the characteristics of the protecting group. Namely, utilizing the difference in the stability against an acid, a base or reduction between WO 97/01275 PCT/US96/11022 -260-
R
14 and other protecting groups, the protecting group can selectively be removed by a conventional means such as an acid, a base or reduction.
With respect to specific conditions for such a reaction, the methods disclosed in known literatures, such as "Protective Groups in Organic Synthesis, T.W. Greene, John Siley Sons (1981)", may, for example, be used.
Further, the compound of the formula 11 may be commercially available, or may be produced by a proper combination, as the case requires, of the methods disclosed in Examples, or conventional methods or methods similar thereto.
WO 97/01275 PCTIUS96/11022 261 Process E Ar 3 H-TR6 R 5 p 0 1~R 3 p base R 5 Ar 2
-CH
2 I 16 0 0 1) reduction 2) CH 3
SO
2 CI, TEA, NaN 3 (or DEAD, Ph 3 P, DPPA) 3) reduction WO 97/01275 WO 9701275PCT/US96/1 1022 262 R8P 0 1)P t Ar 4 C-R7 2) reduction 1) HO -C -AP -COORP I] 2) selective removal of protecting groups R 8 p WO 97/01275 PCT/US96/11022 -263reduction
HO
HC
Ra introduction of leaving group In the above formulas, R 15 is a protected carboxyl group or a group of the formula Ra-C(ORpl)(ORP2)- (wherein each of Rpl and RP 2 which are the same or different, is a methyl group or an ethyl group, or RP 1 and RP 2 together represent an ethylene group, and Ra is as defined above); R 16 is a hydroxyl group or a group of the formula Ra (wherein Ra is as defined above); and WO 97/01275 PCT/US96/11022 -264- AP, Z, Z 1
R
3 p, R 4 p, R 5 p, R 6
R
7
R
8 p, R 9 p, Ra and RP are as defined above.
According to this process, the desired compound (VIII-a) can be prepared by firstly reacting an alkylating agent of the formula to a ketone compound of the formula 4 to obtain a compound of the formula 16, reacting a reducing agent such as a metal hydride complex to the compound 16 to obtain an alcohol compound, then reacting diethyl azodicarboxylate, triphenylphosphine and phthalimide (or hydrogen azide or diphenylphosphoryl azide), or reacting a sulfonylation agent such as methanesulfonyl chloride in the presence of a base such as triethylamine and then reacting phthalimide (or sodium azide) in the presence of a base, to obtain a phthalimide-protected form (or an azide compound) of the amine compound 17, then reacting hydrazine (or a reducing agent) to remove the phthalimide group (or reduce the azide group) to obtain an amine compound of the formula 17, reacting a compound of the formula 10 to the compound 17, followed by reduction to obtain a compound of the formula 18, reacting a carboxylic acid of the formula (III) or its reactive derivative to the compound 18, then selectively removing the protecting group at R 15 to obtain a compound of the formula 19, reacting a reducing agent to the compound 19 to obtain a compound of the formula 2Q, and finally introducing a leaving group to the compound The respective steps up to the production of the compound of the formula 19 from the ketone compound of the formula 4 can be carried out in the same manner as the respective steps for the production of the compound of the formula (VI) from the ketone compound of the formula 4 in the above process D. Accordingly, with respect to the reaction conditions, etc., the same conditions as in the corresponding respective steps can be employed.
The step of reacting a reducing agent to the compound of the formula 19 to obtain the compound of the formula 20, can be WO 97/01275 PCT/US96/11022 -265conducted in the same manner as the reduction method employing e.g.
sodium borohydride as a reducing agent in the step of reducing the compound of the formula 6 to an alcohol compound 8 in the above process B. Accordingly, with respect to the reaction conditions, etc., similar conditions can be employed.
The step of producing the desired compound (VIII-a) by introducing a leaving group to the compound of the formula 20 can be carried out in the same manner as in the method of introducing a leaving group to the compound of the formula 8 in the above process B by using, for example, a halogenating agent such as thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, oxalyl chloride or phosgene, or a sulfonating agent such as methanesulfonyl chloride, p-toluenesulfonyl chloride or benzenesulfonyl chloride. Accordingly, with respect to the reaction conditions, etc., similar conditions may be employed.
Further, the compound of the formula 15 may be commercially available, or can be produced by a proper combination, as the case requires, of the methods disclosed in Examples, or conventional methods or methods similar thereto.
Process F WO 97/01275 PCT/US96/11022 -266-
R
3 R8P H0 2 C Ar 2 -CH2 R A R9 CH CH A/r N AP-COORP
R
5 p introduction of leaving group In the above formulas, Ar- ,C r3- ~r 4 ,I AP, Z, R 3 p, R 4 p, R 5 p, R 6
R
7
R
8 p, R 9 p and RP are as defined above.
According to this process, the desired compound (VIII-b) can be prepared by introducing a leaving group to the compound of the formula 19-a in the same manner and conditions as the method of introducing a leaving group to the compound of the formula 20 in the above process E.
Process G WO 97/01275 PTU9I12 PCTfUS96/11022 267 PPh 3 or P(OMe) 3 or P(OEt) 3 In the above formulas, Ar 2 ,Ar 3 CAr 4 AP, Q, Z, R 3 p, R 4 p, R 5 P, R 6
R
7
R
8 P, R 9 P, Ra and RP are as defined above.
According to this process, the desired compound (X) can be prepared by reacting triphenyiphosphine, trimethyl phosphite or triethyl phosphite, to the compound of the formula (VIII-a).
WO 97/01275 PCT/US96/11022 -268- When a triphenylphosphine is reacted, the above reaction is carried out usually in an inert solvent which does not affect the reaction.
As such an inert solvent, toluene or xylene is, for example, preferred.
The triphenylphosphine is used usually in an amount of 1 mol or an excess molar amount, preferably from 1 to 5 mols, per mol of the compound (VIII-a).
The reaction temperature is usually from room temperature to the boiling point of the solvent used for the reaction, preferably from to 150'C. The reaction time is usually from 5 minutes to 7 days, preferably from 1 hour to 24 hours.
Likewise, when trimethyl phosphite or triethyl phosphite is reacted to the compound (VIII-a), the above reaction is conducted usually in an inert solvent which does not affect the reaction, or more preferably, an excess trimethyl phosphite or triethyl phosphite is used as both the solvent and the reactant.
The reaction temperature is usually from room temperature to the boiling point of the solvent for the reaction, preferably from to 150°C, and the reaction time is usually from 5 minutes to 7 days, preferably from 1 hour to 24 hours.
A compound of the formula (XII): R1P Ar'-CH-Q (XII)
R
2 p a ^r 1 wherein r Q, R 1 p, R 2 p and Rla are as defined above, can be prepared from a compound of the formula (XIV): WO 97/01275 PCT/US96/11022 -269- R1P t Ar'-CH-Z (XIV) R2p
R
1 wherein r wherein Z, R 1 p, R 2 p and Rla are as defined above, in accordance with process G.
Further, the compound of the formula (XIV) may be commercially available, or can be prepared by a proper combination, as the case requires, of the methods disclosed in Examples, or conventional methods or methods similar thereto.
Further, the formula (XIII):
R
3 RsP Ar 2
CH
2 Ar 4
R
2 a"
R
7 CH C H (XIII) CHO R4p, HrN N
AP-COORP
R
5
P
Ar-, Ar 3 A Ar 4 wherein AP, R 3 p, R 4 p,
R
5 p, R 6
R
7
R
8 p, R 9 p, RP and R 2 a are as defined above, is substantially the same as the formula 19 in the above process E, wherein
R
16 is a group of the formula Ra. Accordingly, the compound of the formula (XIII) can be prepared by the above process E.
1 WO 97/01275 PCT/US96/11022 -270- Process H R'9 ,COOR 20 R'9C base
R
17
CH
2
COOR'
8
II
21 HC'COOR21 22
R
17 R19 I I deprotection R1'-OOC-CH-CH-C-COOR 2 0
IH
23 COOR 21 R17
R
19
H-OOC-CH-CH-C-COOR
20 [Ill-a] I H
COOR
21 In the above formulas, each of R 17 and R 19 which are the same or different, is a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group; each of R 2 0 and R 2 1 which are the same or different, is a carboxyl-protecting group; and R 18 is a tert-butyl group, a benzyl group, a benzhydryl group or a trityl group.
Process H is a process for preparing a carboxylic acid derivative of the formula (III-a) among the compounds of the above formula (III).
According to this process, the desired carboxylic acid derivative (III-a) can be prepared by conducting a so-called Michael addition reaction which comprises reacting a maleic acid derivative or a fumaric acid derivative of the formula 22 to an ester derivative having a readily removable carboxyl-protecting group R 1 8, represented by the formula 21, in the presence of a base, and then removing the carboxylprotecting group R1 8 from the obtained Michael addition product 23 under a mild condition.
As the carboxyl-protecting group for R 2 0 and R 2 1, a WO 97/01275 PCT/US96/11022 -271 lower alkyl group such as a tert-butyl group, or a benzhydryl group, is preferred.
The protecting group R 18 is preferably the one which can readily be removed under a mild condition of catalytic reduction or weakly acidic condition and which is stable under the Michael addition reaction condition, such as a tert-butyl group, a benzyl group, a benzhydrylgroup or a trityl group.
The above Michael addition reaction can be conducted by reacting the compound of the formula 22 in an amount of 1 mol or an excess molar amount, preferably from 1 to 2 mols, to 1 mol of the compound of the formula 21 in the presence of a base such as sodium hydride, butyl lithium, lithium diisopropylamide or lithium bis(trimethylsilyl)amide usually in an inert solvent such as benzene, ethyl ether or tetrahydrofuran.
Such a base is used-usually in an amount of 1 mol or a slightly excess molar amount, preferably from 1 to 1.5 mols, per mol of the compound of the formula 22.
The reaction temperature is usually from -100°C to 100°C, preferably from -80°C to room temperature, and the reaction time is usually from 5 minutes to 24 hours, preferably from 10 minutes to hours.
The reaction conditions for the reaction for removing the protecting group from the compound of the formula 23 to form the desired carboxylic acid derivative (III-a), vary depending upon the type of the protecting group, etc. For example, when the protecting group is a tert-butyl group, a benzhydryl group or a trityl group, a method may be employed wherein the compound is treated with an acid such as acetic acid, formic acid, trifluoroacetic acid or hydrochloric acid, preferably within a temperature range of from -20'C to 50°C for from 10 minutes to 24 hours in the absence of a solvent or usually in an inert solvent such as methylene chloride, anisole, tetrahydrofuran, methanol or ethanol or a solvent mixture thereof with water.
For example, when the protecting group is a benzyl group, a benzhydryl group or a trityl group, a method may be employed WO 97/01275 PCT/US96/11022 -272wherein the compound is catalytically reduced with a catalyst such as a palladium-carboincatalyst or a Raney nickel catalyst preferably under a hydrogen pressure of from 1 to 20 kg/cm2 preferably within a temperature range of from 0°C to 40*C for from 10 minutes to 24 hours usually in an inert solvent such as methanol, ethanol, dioxane, water or acetic acid, or a solvent mixture thereof.
Among compounds of the formula (III-a), an optically active compound of the formula (III-bl):
H-OOC-CH
2 -C-CH2-COOR 1 9 (Ill-b1) H COOR 18 or the formula (III-b 2
H-OOC-CH
2
-C-CH
2
-COOR
19 (ll-b 2 H COOR 18 wherein each of R 18 and R 19 which are the same or different, is a carboxyl-protecting group, can be obtained by reacting a racemic mixture of the compound of the formula (III-b): H-OOC-CH2" -HCH 2
-COOR'
9 (lll-b)
COOR
18 wherein R 18 and R 19 are as defined above, with cinchonidine or quinine to obtain a mixture of two diastereomers, then separating and collecting either one of the diastereomers by utilizing the difference in the solubility as between the two diastereomers, followed by recovering the free carboxylic acid by treating with an acid.
Separation of the diastereomer mixture may be conducted in an organic solvent such as carbon tetrachloride or isopropyl ether.
Usually, the mixture of the diastereomers is dissolved in a solvent in a WO 97/01275 PCT/US96/11022 -273hot state, and the solution is gradually cooled to utilize the solubility difference for separation of the diastereomers.
Further, either one of the diastereomers thus obtained is treated with an acid such as hydrochloric acid to obtain an optically active compound of the formula (III-bl) or (III-b 2 The compounds of the formula 21 and 22 may be commercially available or can be produced by a proper combination, as the case requires, of the methods disclosed in Examples, or conventional methods or methods similar thereto.
WO 97/01275 WO 9701275PCT/US96/11022 274 Process I Rsk OCORt
R
3 p w N Wt Ar 2
-OH
2
(S
R p-_(Ar xCH-C IH-OCORt
R"
w O tr H2 I2(R) H- hyd rolysis WO 97/01275 PCT/US96/11022 -275-
RIP
R2p Ar-XP- YP- In the above formulas, W is (wherein Ar- XP, YP, R 1 p and R 2 p are as defined above), RI4-Ya- (wherein ya and R 14 are as defined above) or R 15 (wherein R 15 is as defined above); Rs is a hydrogen atom or a methyl group; Rt is a lower alkyl group, an aryl group or a lower alkenyl group; and CAr 2 Ar-,
R
3 p, R 4 p, R 5 p and R 6 are as defined above.
Process I is a process for preparing an optically active substance 27 or 28 of an alcohol compound 24 obtainable as the above formula 8 or a reduction product of the formula 12 or 16.
According to this process, the desired optically active alcohol compounds 27 and 28 can be prepared by reacting a vinyl ester derivative of the formula 25 to a racemic alcohol derivative of the formula 24 in the presence of a lipase, separating the obtained optically active ester derivative 26 and the optically active alcohol derivative, and then hydrolyzing the ester group with respect to the optically active ester derivative 26.
Rt of the vinyl ester derivative of the formula 25 is preferably a lower alkyl group such as a methyl group or an ethyl group; an aryl group such as a phenyl group or a naphthyl group; or an aralkyl group such as a benzyl group or a 2-phenylethyl group.
Particularly preferred is a methyl group, i.e. a case wherein the compound of the formula 25 is vinyl acetate or isopropenyl acetate.
The above optical resolution reaction by lipase can be conducted usually in an inert solvent such as methylene chloride, chloroform, ethyl ether, tetrahydrofuran, benzene, toluene, hexane, heptane or acetonitrile, or by using the starting material vinyl ester derivative of the formula 25 itself as the solvent.
WO 97/01275 PCT/US96/11022 -276- The vinyl ester derivative 25 is used usually in an amount of 1 mol or in a large excess molar amount, preferably from 1 to 100 mols, per mol of the starting material compound 24, and the amount of the lipase as the catalyst is from 0.01 to 100%, preferably from 0.1 to 20%, by weight, relative to the compound 24.
The type of the lipase is preferably a lipase derivative from Pseudomonas sp. such as Toyothium LIPTM (manufactured by Toyobo).
Further, the above enzymatic reaction tends to be accelerated, when the reaction is carried out in the presence of a base.
As a base to be used for this purpose, an organic base such as triethylamine or diisopropylethylamine, is preferred.
The base is used usually in an amount of 0.01 mol or slightly excess molar amount, preferably from 0.1 to 1.5 mols, relative to the starting material compound 24.
The reaction temperature is usually from 0°C to 50 0
C,
preferably from room temperature to 40 0 C. The reaction time is usually from 30 minutes to 7 days, preferably from 1 hour to 48 hours.
The hydrolytic reaction of the ester of the formula 26 can be conducted by a common method well known in the organic synthetic chemistry under an acidic or basic condition.
WO 97/01275 PCT/US96/11022 -277- The compound of the formula (hh) of the present invention can be prepared, for example, by the following process 1, 2, 3, 4, 5, 6 or 7.
Process 1 The compound of the formula (hh) can be prepared by reacting a compound of the formula (II): R RR 7 p RLpt Ar -Q-CH2 6, A r p CH CH
(II)
Ar2 C
NH
R
3
H'R
R
R
4p Ar- Ar 2 and Ar 3 wherein each of which are the same or different, is an aryl group or a heteroaromatic ring group; Q is a group of the formula -(CH2)m- (wherein m is an integer of from 1 to 6) or-(CH2)n-W-(CH2)p- (wherein W is an oxygen atom, a sulfur atom, a vinylene group or an ethynylene group; and each of n and p which are the same or different, is an integer of from 0 to RIp is a hydrogen atom, a halogen atom, a hydroxyl group which may be protected, a lower alkyl group, a lower alkoxy group, or an aryl or heteroaromatic ring group which may have substituent(s) selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group; each of R 2 p, R 7 p and R 8 p which are the same or different, is a hydrogen atom, a halogen atom, a hydroxyl group which may be protected, a lower alkyl group or a lower alkoxy group; each of
R
3 p and R 4 P which are the same or different, is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a lower alkoxycarbonyl
II
WO 97/01275 PCT/US96/11022 278 group, a carbamoyl group, a lower alkylcarbamoyl group, a lower alkyl group, a lower fluoroalkyl group, a lower alkoxy group or a hydroxyl, amino, carboxyl or lower hydroxyalkyl group which may be protected;
R
5 is a lower alkyl group; and R 6 is a hydrogen atom or a lower alkyl group, with a carboxylic acid of the formula (III) or its reactive derivative: HO AP-CO 2
R
P
O
wherein AP is a C2-8 saturated or unsaturated aliphatic hydrocarbon group which may have substituent(s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, an aryl group, an aralkyl group, and hydroxyl, lower hydroxyalkyl, carboxyl and lower carboxyalkyl groups which may be protected; and RP is a hydrogen atom or a carboxyl-protecting group, to obtain a compound of the formula (IV):
R
8
P
R2pL Ar'-Q-CH2 6 A CH CH
(IV)
AP COORP Wpop^ H R R4p Ar-, Ar 2 Ar 3 wherein AP, Q, Rip, R 2 p,
R
3 p, R 4 p, R 5
R
6
R
7 p, R 8 p and RP are as defined above, and, if necessary, removing any protecting group.
As the reactive derivative of the carboxylic acid of the formula (III), an acid halide, a mixed acid anhydride, an active ester or an active amide may, for example, be used.
WO 97/01275 PCT/US96/11022 -279- When the carboxylic acid of the formula (III) is used, it is preferred to conduct the reaction in the presence of a condensing agent such as N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3dimethylaminopropyl)carbodiimide or 2-chloro-1,3-dimethylimidazolyl chloride.
The reaction of the compound of the formula (II) with the carboxylic acid of the formula (III) or its reactive derivative, is conducted usually by using 1 mol or an excess molar amount, preferably from 1 to 5 mols, of the carboxylic acid of the formula (III) or its reactive derivative, per mol of the compound of the formula (II).
The reaction is conducted usually in an inert solvent. The inert solvent may, for example, be a halogenated hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane or trichloroethylene; an ether such as ethyl ether, tetrahydrofuran or dioxane; an aromatic hydrocarbon such as benzene, toluene, chlorobenzene or xylene; an aprotic polar solvent such as dimethylformamide, acetonitrile, acetone, ethyl acetate or hexamethylphosphoric triamide, or a mixture of such solvents.
The reaction temperature is usually from -70 0 C to the boiling point of the solvent used for the reaction, preferably from to 100 0
C.
The reaction time is usually from 5 minutes to 7 days, preferably from 10 minutes to 24 hours.
The above reaction can be conducted in the presence of a base to facilitate the reaction. As such a base, it is preferred to conduct the reaction in the presence of an inorganic base such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate or sodium hydrogen carbonate, or an organic base such as triethylamine, N-ethyldiisopropylamine, pyridine, 4dimethylaminopyridine or N,N-dimethylaniline.
Such a base is used usually in an amount of 1 mol or an excess molar amount, preferably from 1 to 5 mols, per mol of the reactive derivative of the carboxylic acid of the formula (III).
WO 97/01275 PCT/US96/11022 -280- The acid halide of the compound of the formula (III) can be obtained by reacting the carboxylic acid of the formula (III) with a halogenating agent in accordance with a conventional method. As the halogenating agent, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, oxalyl chloride or phosgene may, for example, be used.
The mixed acid anhydride of the compound of the formula (III) can be obtained by reacting the carboxylic acid of the formula (III) with an alkyl chlorocarbonate such as ethyl chlorocarbonate or with an aliphatic carboxylic acid chloride such as acetyl chloride, in accordance with a conventional method. Further, an intramolecular acid anhydride may be formed between carboxyl groups at both terminals, or when in the formula (III), a carboxyl group is present on the saturated or unsaturated aliphatic hydrocarbon group for AP, an intramolecular acid anhydride may be formed between such a carboxyl group and a carboxyl group to be involved in the reaction, to constitute a reactive derivative of the carboxylic acid.
The active ester of the compound of the formula (III) can be prepared by reacting the carboxylic acid of the formula (III) with an N-hydroxy compound such as N-hydroxysuccinimide, Nhydroxyphthalimide or 1-hydroxybenzotriazole, or a phenol compound such as a 4-nitrophenol, 2,4-dinitrophenol, 2,4,5-trichlorophenol or pentachlorophenol, in the presence of a condensing agent such as N,N'dicyclohexylcarbodiimide or 1-ethyl-3-(3dimethylaminopropyl)carbodiimide in accordance with a conventional method.
The active amide of the compound of the formula (III) can be prepared by reacting the carboxylic acid of the formula (III) with e.g. 1,1'-carbonyldiimidazole or 1,1'-carbonylbis(2-methylimidazole) in accordance with a conventional method.
When a hydroxyl group is present on the group of the formula WO 97/01275 PCT/US96/11022 -281- R'P R7P_ r3 P r- or R R2P R8P when a hydroxyl group, a lower hydroxyalkyl group, a carboxyl group or a lower carboxyalkyl group is present on the saturated or unsaturated aliphatic hydrocarbon group represented by AP, and when a hydroxyl group, an amino group, a carboxyl group or a lower hydroxyalkyl group is present on the group of the formula
R
3
P
Ar 2 R4P it is preferred to conduct the reaction after protecting such a hydroxyl group, a lower hydroxyalkyl group, an amino group, a carboxyl group or a lower carboxyalkyl group appropriately by a hydroxyl-protecting group, an amino-protecting group or a carboxyl-protecting group and removing the protecting group after the reaction.
The hydroxyl-protecting group may, for example, be a lower alkylsilyl group such as a trimethylsilyl group or a tertbutyldimethylsilyl group; a lower alkoxymethyl group such as a methoxymethyl group or a 2-methoxyethoxymethyl group; a tetrahydropyranyl group; an aralkyl group such as a benzyl group, a pmethoxybenzyl group, a p-nitrobenzyl group or a trityl group; or an acyl group such as a formyl group or an acetyl group. Particularly preferred is a methoxymethyl group, a tetrahydropyranyl group, a trityl group, a tert- butyldimethylsilyl group or an acetyl group.
The amino-protecting group may, for example, be an aralkylidene group such as a benzylidene group, a p-chlorobenzylidene group or a p-nitrobenzylidene group; an aralkyl group such as a benzyl group, a p-methoxybenzyl group, a p-nitrobenzyl group, a benzhydryl group or a trityl group; a lower alkanoyl group such as a formyl group, an acetyl group, a propionyl group, a butyryl group or a pivaloyl WO 97/01275 PCT/US96/11022 -282group; a lower haloalkanoyl group such as a trifluoroacetyl group; a lower alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group or a tertbutoxycarbonyl group; a lower haloalkoxycarbonyl group such as a 2,2,2-trichloroethoxycarbonyl group; an alkenyloxycarbonyl group such as a 2-propenyloxycarbonyl group; an aralkyloxycarbonyl group such as a benzyloxycarbonyl group or a p-nitrobenzyloxycarbonyl group; or a lower alkylsilyl group such as a trimethylsilyl group or a tertbutyldimethylsilyl group. Particularly preferred is an acetyl group, a trifluoroacetyl group, a tertbutoxycarbonyl group or a benzyloxycarbonyl group.
The carboxyl-protecting group may, for example, be a lower alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group or a tert-butyl group; a lower haloalkyl group such as a 2,2,2-trichloroethyl group; a lower alkenyl group such as 2-propenyl group; or an aralkyl group such as a benzyl group, a pmethoxybenzyl group, a p-nitrobenzyl group, a benzhydryl group or trityl group. Particularly preferred is a methyl group, an ethyl group, a tert-butyl group, a 2-propenyl group, a benzyl group, a pmethoxybenzyl group or a benzhydryl group.
After completion of the reaction, conventional treatment is conducted to obtain a crude product of the compound of the formula The compound of the formula (IV) may or may not be purified in accordance with a conventional method, and if necessary, reactions for removing protecting groups such as a hydroxyl group, an amino group and a carboxyl group, are appropriately conducted to obtain a compound of the formula (hh).
Removal of protecting groups may vary depending upon their types, but can be conducted in accordance with the methods disclosed in a literature (Protective Groups in Organic Synthesis, T.W.
Greene, John Wiley Sons (1981)) or methods similar thereto, for example by solvolysis employing an acid or a base, by chemical reduction employing a metal hydride complex or by catalytic reduction employing a palladium-carbon catalyst or Raney nickel.
WO 97/01275 WO 9701275PCTfUS96/11022 283 Process 2 A compound of the formula (hh-1): (hh-I) wherein Ql is -(CH2)n-CH=CH-(CH2)P- (wherein n and p are as defined above); and C ~l ~2 ,C r_ R I, R 2
R
3
R
4
R
5
R
6
R
7 and R 8 are as defined above, can be prepared by reacting a compound of the formula R1P'-- A r
(CH
2 )n -C
-H
-9n 0 wherein C ~l IR IP, R 2 P and n are as defined above, with a compound of the formula (VI): I WO 97/01275 PCT/US96/11022 -284-
R
7 p
R
8 p T CH 2
(CH
2 )p-CH2 R A
R
6 Ar I "CH (VI) R NAP COORP
R
3 P H" R4P wherein T is a triphenylphosphonio group, a dimethoxyphosphoryl Ar-, Ar_ group or a diethoxyphosphoryl group; and AP, p, R 3 P, R 4 p, R 5
R
6
R
7 P, R 8 p and RP are as defined above, to obtain a compound of the formula (IV-1):
R
7
P
RArl-(CH 2 )i CH CH (CH 2 )p-CH 2 R6 Ar 3 R2P c ROH R 6 CH (IV-1) Rp HR 5 O R-7 RN AP-
COORP
R4P Ar-, Ar-,wherein r- I r2 AP, n, p, R 1 P, R 2 p,
R
3 p, R 4 p, R 5
R
6
R
7 p, R 8 p and RP are as defined above, and, if necessary, removing any protecting group.
Process 2 is a process for preparing a'compound of the formula (hh) wherein Q is -(CH2)n-CH=CH-(CH2)p- (wherein n and p are as defined above) i.e. a compound of the formula (hh-1).
The reaction of the compound of the formula with a compound of the formula (VI) is carried out usually by employing
I
WO 97/01275 PCTIUS96/11022 -285equimolar amounts of the two reactants or using a slightly excess amount of one of them.
The reaction is carried out usually in an inert solvent. Such an inert solvent may, for example, be an ether such as ethyl ether, tetrahydrofuran or dioxane; an aromatic hydrocarbon such as benzene, toluene, chlorobenzene or xylene; an apratic polar solvent such as dimethylformamide, acetonitrile, acetone, ethyl acetate or hexamethylphosphoric triamide; or a mixture of such solvents.
The reaction temperature is usually from -100°C to the boiling point of the solvent used for the reaction, preferably from -70 0
C
to 50 0
C.
The reaction time is usually from 5 minutes to 7 days, preferably from 10 minutes to 24 hours. Further, the above reaction can be conducted in the presence of a base to facilitate the reaction.
Especially when T in the formula (VI) is a triphenylphosphonio group, the reaction is preferably conducted in the presence of a base such as sodium hydride, n-butyl lithium, sodium methoxide, potassium tertbutoxide, sodium hydroxide or potassium hydroxide.
Such a base is used in an amount of one mol or an excess molar amount, preferably from 1 to 5 mols per mol of the compound wherein T is a triphenylphosphonio group. When a hydroxyl group is present on the group of the formula R1P- R7P_ r r or R- R2p
RBP
when a hydroxyl group, a lower hydroxyalkyl group, a carboxyl group or a lower carboxyalkyl group is present on the saturated or unsaturated aliphatic hydrocarbon group represented by AP, and when a hydroxyl group, an amino group, a carboxyl group or a lower hydroxyalkyl group is present on the group of the formula WO 97/01275 PCT/US96/11022 -286-
R
3 R 3 Ar 2 R4P it is preferred to carry out the reaction after protecting such a hydroxyl group, a lower hydroxyalkyl group, an amino group, a carboxyl group or a lower carboxyalkyl group appropriately by a hydroxyl-protecting group, an amino-protecting group or a carboxyl-protecting group, and removing any protecting group after the reaction.
The hydroxyl-protecting group, the amino-protecting group and the carboxyl-protecting group may be the protecting groups mentioned above with respect to process 1.
After completion of the reaction, a conventional treatment may be carried out to obtain a crude product of the compound of the formula The compound of the formula (IV-1) thus obtained may or may not be purified by a conventional method, and if necessary, reactions for removing hydroxyl-, amino- and carboxyl-protecting groups may be carried out in a proper combination to obtain a compound of the formula (hh-1).
The method for removing a protecting group varies depending upon the type of the protecting group and the stability of the desired compound However, removal of protecting groups can be suitably conducted in accordance with the methods disclosed in the above-mentioned literature or methods similar thereto.
Process 3 A compound of the formula (hh-1): WO 97/01275 PCT/1JS96/11022 287 R 8 R 2 Arl -Q'-CH 2 6 ,Ar 3 h1 I RCH hhI Ar2"' NyW A -COOH wherein C ~l ~2 ,C r_ Q1, R I, R 2
R
3
R
4
R
5
R
6
R
7 and R 8 are as defined above, can be obtained by reacting a compound of the formula (VII): Ar 1
(CH
2 )n -CH 2 -T (VII)
A
1 wherein C r n, R IP and R 2 P are as defined above, with a compound of the formula (VIII): H C-(CH2 )p-CH 2 6 Ar 8 Ii R CH (Vill) 0 OH OH WO 97/01275 PCT/US96/11022 -288wherein AP, p, R 3 p, R 4 p, R 5
R
6 R7p, R8p and RP are as defined above, to obtain a compound of the formula (IV- 1): R7p
R
1 P
R
8P SAr (CH)a CH CH (CH2)p-CH 2 A r R2p C CH (IV-I) p Ar ,N AP
COORP
R4p wherein-, Ar'- Ar2wherein AP, n, p, Rip, R 2 p,
R
3 p, R 4 p, R 5
R
6
R
7 p, R 8 p and RP are as defined above, and, if necessary, removing any protecting group.
Like process 2, process 3 is a process for producing a compound of the formula (hh) wherein Q is -(CH2)n-CH=CH-(CH2)p- (wherein n and p are as defined above) i.e. a compound of the formula (hh-1).
Process 3 is equal to the reaction of process 2 wherein starting material compounds and (VI) are replaced by the compounds (VIII) and (VII), respectively. Accordingly, the manner and conditions of the reaction may be all in accordance with process 2.
Process 4 A compound of the formula (hh-2): WO 97/01275 PCT/US96/11022 -289-
R
2 Ar -Q 2
CH
2 Ar 3 I R6 (hh-2) CH CH
R
4 wherein Q 2 is -(CH2)m- (wherein m is as defined above); CAr-, Ar 2
A
and C A, R 1
R
2
R
3
R
4
R
5
R
6
R
7 and R 8 are as defined above, can be obtained by reducing a compound of the formula R Ar'-(CH 2 }H CH (CH, 2
H
2 R6 R2P
CH
.N AP COORP
R
3 p r
H
R4p wherein each of n1 and pi which are the same or different, is an integer Ar2- of from 0 to 3; and AP, R 1 P, R 2 p, R 3 p, R 4 p, R 5
R
6
R
7 p, R 8 p and RP are as defined above (provided that the sum of nl and pl does not exceed and, if necessary, removing any protecting group.
Process 4 is a process for producing a compound of the formula (hh) wherein Q is -(CH2)m- (wherein m is as defined above) i.e. a compound of the formula (hh-2).
WO 97/01275 PCT/US96/11022 -290- The reaction of reducing the compound of the formula (IVis usually preferably conducted by catalytic reduction employing a palladium-carbon catalyst, a Raney nickel catalyst or a platinum catalyst in an inert solvent.
The inert solvent may, for example, be an alcohol such as methanol, ethanol or propanol, or acetic acid.
The reaction temperature is usually from -20 0 C to 100 0
C,
preferably from 0°C to room temperature.
The reaction time is usually from 5 minutes to 7 days, preferably from 10 minutes to 24 hours.
The hydrogen pressure in the catalytic reduction reaction is usually preferably from atmospheric pressure to 5 atm, and the amount of the catalyst is usually from 0.01 to 1 mol, preferably from 0.05 to 0.2 mol, per mol of the starting material compound After completion of the reaction, the product is subjected to a usual treatment after removing any protecting group if such a protecting group is present or directly if no such protecting group is present, to obtain a compound of the formula (hh-2).
Removal of the protecting group and the post treatment may be conducted by the methods described with respect to the above process 1.
Process A compound of the formula (hh-3);
R
R Ar 1
-Q
3 CH2 Ar 3 R (hh-3)
CH
CH H Ar 2 N A COOH
R
3
H
WO 97101275 PCTIUS96/11022 291 wherein Q 3 is -(CH2)n-Wl-(CH2)p- (wherein n, p and Wi are as defined above); and C ~i ~2 ,C r_ Rl, R 2
R
3
R
4
R
5
R
6
R
7 and R 8 are as defined above, can be prepared by reacting a compound of the formula (IX): Ar'- (CH 2 Wi H (IX)
R
2
P
wherein Wl is an oxygen atom or a sulfur atom; and Cr n, R IP and R 2 P are as defined above, with a compound of the formula
WX:
R
8 p
(CH
2
)-CH
2 6 Ar 3 OH H
(X
3p NAP
-COORP
R~R
wherein ZI is a leaving group, and C r-r3 AP, p,
R
3 P, R 4 P, R 5
R
6
R
7 P, R 8 P and RP are as defined above, to obtain a compound of the formula (IV-3); WO 97/01275 PCT/US96/11022 -292- R7p r'-(CH 2 )n W -(CH 2 )p-CH 2 R /A r 3 R2p CH CH (IV-3) S Ar2 N AP COORP R4p Ar- Arwherein -AP, n, p, Wl, R 1 p,
R
2 p, R 3 p, R 4 p, R 5
R
6
R
7 p, R 8 p and RP are as defined above, and, if necessary, removing any protecting group.
Process 5 is a process for preparing a compound of the formula (hh) wherein Q is -(CH2)n-Wl-(CH2)p- (wherein n, p and W are as defined above) i.e. a compound of the formula (hh-3).
The reaction of the compound of the formula (IX) with a compound of the formula is carried out usually by using 1 mol or an excess molar amount, preferably from 1 to 3 mols, of the compound of the formula per mol of the compound of the formula The reaction is conducted usually in an inert solvent. The inert solvent may, for example, be a halogenated hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane or trichloroethylene; an ether such as ethyl ether, tetrahydrofuran or dioxane; an aromatic hydrocarbon such as benzene, toluene, chlorobenzene or xylene; an aprotic polar solvent such as dimethylformamide, acetonitrile, acetone, ethyl acetate or hexamethylphosphoric triamide, or a mixture of such solvents.
The reaction temperature is usually from -70 0 C to the boiling point of the solvent used for the reaction, preferably from to 100 0
C.
The reaction time is usually from 5 minutes to 7 days, preferably from 10 minutes to 24 hours.
WO 97/01275 PCT/US96/11022 -293- The above reaction is preferably conducted in the presence of a base to facilitate the reaction. Such a base may, for example, be an inorganic base such as sodium hydride, n-butyl lithium, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate or sodium hydrogencarbonate, or an organic base such as triethylamine, N- ethyldiisopropylamine, pyridine, 4dimethylaminopyridine or N,N-dimethylaniline.
The base is used usually in an amount of 1 mol or an excess molar amount, preferably from 1 to 5 mols, per mol of the compound of the formula (IX).
The leaving group represented by Z 1 may, for example, be a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, or an organic sulfonyloxy group such as a methanesulfonyloxy group, a p-toluenesulfonyloxy group or a benzenesulfonyloxy group.
When a hydroxyl group is present on the group of the formula R1S o R 7 P r or R r R2P R8p when a hydroxyl group, a lower hydroxyalkyl group, a carboxyl group or a lower carboxyalkyl group is present on the saturated or unsaturated aliphatic hydrocarbon group represented by AP, and when a hydroxyl group, an amino group, a carboxyl group or a lower hydroxyalkyl group is present on the group of the formula
RP
Ar 2
R
4p it is preferred to conduct the reaction after protecting such a hydroxyl group, a lower hydroxyalkyl group, an amino group, a carboxyl group or a lower alkoxyalkyl group appropriately by a hydroxyl-protecting group, an amino-protecting group or a carboxyl-protecting group and WO 97/01275 PCTIUS96/11022 -294removing any protecting group after the reaction.
The hydroxyl-protecting group, the amino-protecting group and the carboxyl-protecting group may be the protecting groups mentioned above with respect to process 1.
After completion of the reaction, a usual treatment is carried out to obtain a crude product of the compound of the formula The compound of the formula (IV-3) thus obtained may or may not be purified by a conventional method, and reactions for removing the hydroxyl-, amino- and carboxyl-protecting groups may be carried out in a proper combination, to obtain a compound of the formula (hh- The method for removing a protecting group varies depending upon the type of the protecting group and the stability of the desired compound However, removal of protecting groups can be appropriately conducted in accordance with the methods disclosed in the above-mentioned literature or methods similar thereto.
Process 6 A compound of the formula (hh-3):
R
1 R7 R Ar 1
-Q
3
-CH
2 6 Ar 3 I R C (hh-3) H OH
R
4 Ar 1 Ar 3 wherein r
Q
3
R
1
R
2
R
3
R
4
R
5
R
6
R
7 and R 8 are as defined above, can be prepared by reacting a compound of the formula (Xl): WO 97/01275 PCT/US96/11022 295-
(CH
2 )n -Z1
(XI)
Ar-, wherein C r ZI, RIP and R 2 P are as defined above, with a compound of the formula (XII): R 8 p H W1 (CH 2
)-CH
2
(XII)
COORP
wherein C ~2 Ar-,AP, p, Wl, R 3 P, R 4 p, R 5
R
6
R
7 p, R 8 P and RP are as defined above, to obtain a compound of the formula (IV-3): R 7p W1 (CH 2
OH
2 6 Ar 3
P
I IOH (IV-3) 7
CH
3p H 'Ny A- COORP R R H WO 97/01275 PCT/US96/11022 -296wherein -AP, n, p, W1, Rip,
R
2 p, R 3 p, R 4 p, R 5
R
6 R7p, R 8 p and RP are as defined above, and, if necessary, removing any protecting group.
Like the above process 5, process 6 is a process for preparing a compound of the formula (hh) wherein Q is -(CH2)n-Wl- (CH2)p- (wherein n, p and W1 are as defined above) i.e. a compound of the formula (hh-3).
This process can be conducted usually in an inert solvent, preferably in the presence of a base, by using 1 mol or an excess molar amount, preferably from 1 to 3 mols, of the compound of the formula per mol of the compound of the formula (XII). The types of the inert solvent and the base as well as the reaction conditions may be the same as described above with respect to process 5. Accordingly, the reaction and the post-treatment after the reaction may preferably be carried out all in accordance with process Process 7 A compound of the formula (hh-4):
R
1
R
8 R IAr-Q-CH 2
R
6 11 (hh-4) I CH
R"
CH N (CH 2 )v-C C -(CH 2
),-CH-(CH
2 )xCO 2
H
H Ar I II
I
R
3 R H HO R
R
4 Ar'- Ar2wherein Q, R 1
R
2
R
3
R
4
R
5
R
6
R
7
R
8
R
1 1
R
12 v, w and x are as defined above, can be prepared by oxidizing a compound of the formula (IV-4): WO 97/01275 PCT/US96/11022 -297-
R
1 p R R p R2p Ar'-Q-CH2 R6 (IV-4) I CH R 11 p CH
I
H N (CH 2 CH C (CH 2 )w-CH-(CH 2 )xCO 2
RP
A
r Y Y I H
I
R
3 Py s O HO
R
R4P wherein R1 p is a hydrogen atom or a lower hydroxyalkyl or carboxyl group which may be protected, R12p is a hydrogen atom or a hydroxyl or carboxyl group which may be protected; and r 1 Ar 2 A SQ, R 1 p, R 2 p, R 3 p, R 4 p, R 5
R
6
R
7 p, R 8 p, RP, v, w and x are as defined above, and, if necessary, removing any protecting group.
Process 7 is a process for preparing a compound of the formula (hh) wherein A is a group of the formula
-(CH
2 CL
(CH
2 )w-CH-(CH 2 x I
I
OH
R
12 (b) wherein R 1 1, R 12 v, w and x are as defined above, i.e. a compound of the formula (hh-4).
The reaction of oxidizing the compound of the formula (IV-4) is usually preferably carried out in an inert solvent by using socalled Dess-Martin oxidation employing 12-1-5 triacetoxyperiodinane; so-called Swern oxidation employing oxalyl chloride and dimethyl sulfoxide; a sulfur trioxide-pyridine complex; pyridinium chlorochromate; active manganese dioxide; or tetra-n-propylammonium perruthenate.
WO 97/01275 PCT/US96/11022 -298- The inert solvent may, for example, be a halogenated hydrocarbon such as methylene chloride, chloroform or dichloroethane; an ether such as ethyl ether, tetrahydrofuran or dioxane; an aprotic polar solvent such as acetonitrile, acetone, ethyl acetate or dimethyl sulfoxide; or a mixture of such solvents.
The reaction temperature varies depending upon the type of the oxidizing agent, etc. However, it is usually from -100 0 C to the boiling point of the solvent used for the reaction, preferably from to 100 0
C.
The reaction time is usually from 5 minutes to 7 days, preferably from 10 minutes to 24 hours.
After completion of the reaction, the product is subjected to usuai treatment after removing a protecting group when such a protecting group is present, or directly when no such protecting group is present, to obtain the compound of the formula (hh-4).
The removal of the protecting group and the post-treatment may be conducted in the same manner as described above with respect to process 1.
Further, a compound corresponding to the compound of the formula (IV-4) to be used as the starting material in the above process 7, can be prepared, for example, by hydrolyzing a compound of the formula (IV-4a): R R 8 (V-4a) R2p Ar-Q-CH 2 6 Ar3 O I CH H
I
/C N (CH 2 )v C H-(CH 2
),-CH-(CH
2 x SAr 2 I I R3P 0O R11p R12p WO 97/01275 PCT/US96/11022 -299wherein Q, R 1 p, R 2 p, R 3 p,
R
4 p, R 5
R
6
R
7 p, R 8 p, R 1 1 p, R 1 2p, v, w and x are as defined above, in the presence of a base, to obtain a compound of the formula (IV-4b): RP
R
7p
R!P
R Ar'-Q-H 2 R A HO (IV-4b) CH I ,CH N (CH2)(CH 2 CH 2 )Cw-CH-(H 2 )xCO 2
M
H Ar2HT Y H I|I R3p R5 0 R 11 P
R
12 p
R
4 p wherein M is a hydrogen atom or an alkali metal atom; and Ar'- Ar2- Q, RIP,
R
2 p, R 3 p, R 4 p, R 5
R
6
R
7 p, R 8 p, R 1 lp, R 1 2p, v, w and x are as defined, then reacting thereto a diazo compound of the formula RPP N+ N wherein RPP is a lower alkyl group, a lower alkenyl group, an aralkyl group or a lower alkoxycarbonylalkyl group, or an alkylating agent of the formula RPP-Z wherein RPP and Z are as defined above.
Isolation and purification of the compound of the formula (hh-3) or obtained by the above process can be conducted by a single use or a proper combination of conventional separating means such as column chromatography employing silica gel, adsorbent resin, etc., liquid chromatography, solvent extraction and recrystallization-reprecipitation.
The compound of the formula (hh-3) or (hh-4) can be converted to a pharmaceutically acceptable salt or ester WO 97/01275 PCT/US96/11022 -300by a conventional method. Reversely, the conversion from the salt or ester to a free carboxylic acid can also be conducted by a conventional method.
Further, compounds of the present invention can all be prepared by a process similar to the above processes by using the starting materials corresponding to the desired compounds.
The compounds of the formulas (III), (VI), (VII), (VIII), (XI) and (XII) may be commercially available or can be prepared in accordance with the methods disclosed in literatures Med. Chem., 10, 717 (1967); ibid., 725; J. Chem. Soc.
Perkin 1, 1636 (1978); Chem. Lett., 191 (1980); ibid., 375 (1984); J.
Chem. Soc. Chem. Commun., 579 (1984); J. Am. Chem. Soc., 104, 5716 (1982)) or methods similar thereto, or in accordance with the following processes or the methods disclosed in Examples.
Process A
R
5 Li 2 R3p (or RsMgX, R 5 2 CuLi 3)R 9 Ar 2
CH
2 -Y Ar2-CH 2
-C-R
R
4p 1 R4p 4 Ar'-Q- CH 2 -Z R base Ar'-Q -CH 2 RR2p 5CH
RI
R3p
O
R4p 6 WO 97/01275 PCT/US96/11022 -301- R7P R 6 1)
I
1 Ar 3
CH-NH
2
R
8 p 7 2) reduction
RP
RV
R
8 p Ar-Q--CH2 R6 HA R2PC
CH
/r NH [II]
R
3 p.
H"|
R4P C^Ar Ar 2 r3 In the above formulas, r- r2 A Q, R 1 p, R 2 p, R 3 p, R 4 p, R 5
R
6
R
7 p and R 8 p are as defined above; X is a halogen atom; Y is a cyano group, a carboxyl group, a lower alkoxycarbonyl group, a chloroformyl group or an N-methoxy-Nmethylcarbamoyl group; Z is a leaving group selected from the group consisting of a chlorine atom, a bromine atom, an iodine atom, a trifluoroacetoxy group, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group and a p-toluenesulfonyloxy group.
By this process, the desired compound (II) can be prepared by reacting a nitrile or a carboxylic acid derivative of the formula 1 with an alkyl lithium of the formula 2 or an alkyl Grignard reagent (or an alkyl Gilman reagent) of the formula 3 to obtain a ketone compound 4, then reacting an alkylating agent of the formula 5 to the ketone compound 4 to produce a compound of the formula 6, then reacting the compound 6 with an amine compound of the formula 7, followed by reduction.
The above reaction steps will be described in detail WO 97/01275 PCT/US96/11022 -302referring to suitable reaction conditions, etc.
The first step of preparing the ketone compound 4 is conducted usually by reacting 1 mol or an excess molar amount, preferably from 1 to 5 mols of the alkyl lithium reagent 2 or the alkyl Grignard reagent 3 (or the alkyl Gilman reagent in the case where the substituent Y of the compound 1 is a chloroformyl group) to 1 mol of the starting material compound 1 in a solvent inert to the reaction such as tetrahydrofuran, ethyl ether or benzene, if necessary followed by hydrolysis under an acidic condition.
The reaction temperature is usually from -80 0 C to the boiling point of the solvent used for the reaction, preferably from to 50 0 C. The reaction time is usually from 5 minutes to 48 hours, preferably from 30 minutes to 24 hours.
When the substituent Y in the formula of the starting material compound 1 is a cyano group, it may be necessary to conduct a hydrolytic reaction under an acidic condition after completion of the reaction, and such a hydrolytic reaction is conducted in e.g. methanol, ethanol, tetrahydrofuran or a solvent mixture thereof with water in the presence of an acid such as hydrochloric acid, sulfuric acid or ptoluenesulfonic acid.
The reaction temperature is usually from OC to the boiling point of the solvent used for the reaction, and the reaction time is from 30 minutes to 24 hours.
The step of preparing the compound of the formula 6 from the ketone compound 4, can be conducted by reacting an equimolar amount or an excess molar amount, preferably from 1 to 2 mols, of the alkylating agent of the formula 5 to the ketone compound 4 in the presence of a base in an inert solvent which does not adversely affect the reaction or without using any solvent.
The inert solvent may, for example,'be an ether such as ethyl ether, tetrahydrofuran or dioxane; an aromatic hydrocarbon such as benzene, toluene or xylene; an aprotic polar solvent such as dimethylformamide, dimethyl sulfoxide or hexamethylphosphoric triamide, or a mixtute of such solvents.
WO 97/01275 PCTIUS96/11022 -303- The base to be used for this reaction, may, for example, be an alkali metal hydride such as sodium hydride, lithium hydride or potassium hydride; a lithium amide such as lithium amide, lithium diisopropylamide or lithium bis(trimethylsilyl)amide; an alkyl lithium such as methyl lithium, butyl lithium or tert-butyl lithium; an alkali metal alkoxide such as sodium methoxide, sodium ethoxide or potassium tert-butoxide; or an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide.
The base is used usually in an amount of 1 mol or an excess molar amount, preferably from 1 to 5 mols, per mol of the starting material alkylating agent The reaction temperature is usually from -100 0 C to the boiling point of the solvent used for the reaction, preferably from to 100 0 C. The reaction time is usually from 10 minutes to 48 hours, preferably from 30 minutes to 24 hours.
The step of preparing the desired compound (II) from the compound of the formula 6 can be conducted usually in an inert solvent such as methanol, ethanol, benzene, ethyl ether or tetrahydrofuran by reacting 1 mol or an excess molar amount, preferably from 1 to 2 mols, of the amine compound of the formula 7 to 1 mol of the compound of the formula 6 to preliminarily form an imine, which is subsequently reduced.
The reaction temperature in the process for forming the above imine is usually from 0°C to the boiling point of the solvent used for the reaction, preferably from room temperature to 100 0 C. The reaction time is usually from 5 minutes to 48 hours, preferably from minutes to 24 hours. After the formation of the imine, the reaction solution may be used as it is to the subsequent step of the reduction reaction, or the reaction solution may be distilled or subjected to a conventional separation means to isolate the imine compound, which is then subjected to the subsequent reduction.
The reduction can be carried out by using a metal hydride complex such as sodium borohydride, sodium cyanoborohydride or WO 97/01275 PCT/US96/11022 -304lithium aluminum hydride, or by catalytic reduction employing a palladium-carbon catalyst or a Raney nickel catalyst.
When a metal hydride complex is used as a reducing agent, the reducing agent is used usually in an amount of 1 mol or an excess molar amount, preferably from 1 to 5 mols, per mol of the above imine.
For the reduction, an inert solvent, for example, an alcohol such as methanol or ethanol; an ether such as dimethyl ether, ethyl ether, diisopropyl ether, dibutyl ether, dimethoxyethane, dioxane, tetrahydrofuran or diglyme; an aliphatic hydrocarbon such as pentane, hexane, heptane or cyclohexane; or an aromatic hydrocarbon such as benzene or toluene; or a mixture of such solvents, can be used appropriately as a solvent depending upon the type of the reducing agent.
The reaction temperature is usually from 0°C to room temperature, and the reaction time is usually from 1 hour to 6 hours.
Further, in this process, it is also possible to react an alkylating agent of the formula 5 to the nitrile or carboxylic acid derivative of the formula 1 to preliminarily produce an alkyl compound and then to react an alkyl lithium of the formula 2 or an alkyl Grignard reagent (or an alkyl Gilman reagent) of the formula 3 to the alkyl compound to obtain a compound of the formula 6. Such a reaction can be conducted under the conditions similar to the above Process A.
Accordingly, the reaction conditions described for the above Process A may all be used as the reaction conditions for this reaction.
The compounds of the formulas 1, 2, 3, 5 and 7 may be commercially available or can be produced by a proper combination, as the case requires, of the methods disclosed in Examples, or conventional methods or methods similar thereto.
WO 97/01275 PCTIUS96/11022 305 Process B Ar'-Q-OH, R 3p fE 2 CH IR reduction 1) CH 3
SO
2 CIITEA (or PBr 3
,OH
R 6
C;H
2
-NH
2 7 R 2 p.
R
8
P
[I I]
,H
In the above formulas, ri IC r2 C r_,Q RlP, R 2 p, R 3 p, R 4 p, R 5
R
6
R
7 P and R 8 p are as defined above.
According to this process, the desired compound (1I) can be prepared by reacting a reducing agent such as a metal hydride complex to a compound of the formula 6 to obtain an alcohol compound 8 and WO 97/01275 PCT/US96/11022 -306reacting an amine compound of the formula 7 to the alcohol compound 8.
The above reaction steps will be described in detail referring to suitable reaction conditions, etc.
The reaction for reducing the compound of the formula 6 to the alcohol compound 8 can be conducted usually by using a metal hydride complex such as sodium borohydride, diisobutyl aluminum hydride, lithium aluminum hydride or lithium tri-sec-butylborohydride (L-selectrideTM), or by catalytic reduction employing e.g. a palladiumcarbon catalyst or a Raney nickel catalyst, in an inert solvent which does not adversely affect the reaction.
When the metal hydride complex is used as the reducing agent, such a reducing agent is used usually in an amount of 1 mol or an excess molar amount, preferably from 1 to 5 mols, per mol of the starting material compound 6.
The inert solvent to be used in this reaction may be suitably selected depending upon the type of the reducing agent.
For example, when the reducing agent is sodium borohydride, an inert solvent, such as an alcohol such as methanol or ethanol; an ether such as dimethoxyethane, dioxane, tetrahydrofuran or diglyme; an aprotic polar solvent such as dimethylformamide or dimethylacetamide, or water, or a solvent mixture thereof, may be used, and particularly preferred is an alcohol such as methanol or ethanol.
For example, when the reducing agent is diisobutyl aluminum hydride, an inert solvent, such as an ether such as dimethyl ether, ethyl ether, diisopropyl ether, dibutyl ether, dimethoxyethane, dioxane, tetrahydrofuran or diglyme; an aliphatic hydrocarbon such as pentane, hexane, heptane or cyclohexane; an aromatic hydrocarbon such as benzene or toluene; methylene chloride, or a solvent mixture thereof, may be used, and particularly preferred is toluene or methylene chloride.
For example, when the reducing agent is lithium aluminum hydride or lithium tri-sec-butylborohydride, an inert solvent, such as an ether such as dimethyl ether, ethyl ether, diisopropyl ether, dibutyl WO 97/01275 PCT/US96/11022 -307ether, dimethoxyethane, dioxane, tetrahydrofuran or diglyme; an aliphatic hydrocarbon such as pentane, hexane, heptane or cyclohexane; or an aromatic hydrocarbon such as benzene or toluene, or a solvent mixture thereof, may be used, and particularly preferred is ethyl ether or tetrahydrofuran.
For the catalytic reduction, the solvent is preferably an alcohol such as methanol or ethanol.
The reaction temperature and the reaction time vary depending upon the stability and the susceptibility to the reduction reaction of the starting material ketone compound 6, the type of the reducing agent and the type of the solvent. However, the reaction temperature is usually from -80 0 C to 100 0 C, preferably from -70 0 C to 0 C, and the reaction time is usually from 5 minutes to 2 days, preferably from 30 minutes to 24 hours.
The step of preparing the desired compound (II) from a compound of the formula 8 can be carried out by reacting a sulfonating agent such as methanesulfonyl chloride to the alcohol compound of the formula 8 in the presence of a base, or reacting a halogenating agent such as thionyl chloride or phosphorus tribromide thereto, to convert the hydroxyl group in the formula to a leaving group, followed by reacting an amine compound of the formula 7.
The reaction for introducing the leaving group can be conducted usually by reacting 1 mol or an excess molar amount, preferably from 1 to 2 mols, of a sulfonating agent and a base such as triethylamine to 1 mol of the alcohol compound 8 in an inert solvent such as methylene chloride, chloroform, benzene, tetrahydrofuran or ethyl acetate, or using 1 mol or an excess molar amount, preferably from 1 to 5 mols, of a halogenating agent.
The reaction temperature is usually from -70 0 C to the boiling point of the solvent used for the reaction, preferably from to 80 0 C, and the reaction time is usually from 5 minutes to 48 hours, preferably from 30 minutes to 24 hours.
Then, the step of reacting an amine compound 7 to the WO 97/01275 PCT/US96/11022 -308compound having the leaving group introduced, obtained by the above reaction, can be conducted usually by employing 1 mol or an excess molar amount, preferably from 1 to 50 mols, of the amine compound 7 per mol of the starting compound having the leaving group, in an inert solvent such as methylene chloride, chloroform, benzene, ethyl ether or tetrahydrofuran.
If necessary, this reaction can be conducted in the presence of a base other than the amine compound of the formula 7.
As such a base, an inorganic base such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate or sodium hydrogencarbonate, or an organic base such as triethylamine, N-ethyldiisopropylamine, pyridine or N,Ndimethylaniline may, for example, be mentioned.
Such a base is used usually in an amount of 1 mol or an excess molar amount, preferably from 1 to 5 mols, per mol of the starting material compound.
The reaction temperature is usually from -50 0 C to 150 0 C, preferably from -20 0 C to 100 0 C, and the reaction time is usually from 5 minutes to 7 days, preferably from 10 minutes to 24 hours.
WO 97/01275 PCTIUS96/11022 309 Process C R Ar 1 -Q
H
2
R
2 P I R~p7 A72 CH OH R 2pAr'-Q -OH 2 J7~ H -Hy 1)DEAD, Ph 3
P,
Phthalimide (or HN 3 or DPPA) i) CH 3
SO
2 C1, TEA or(ii) Phthalimide (or NaN 3 2) NH 2
NH
2 (or reduction) 0 11 2) reduction
R
8
P
[11] In the above formulas, Ar- I CAr 2 CAr 3 WO 97/01275 PCT/US96/11022 -310- Q, R 1 P, R 2 p, R 3 p, R 4 p, R 5
R
6
R
7 p and R 8 p are as defined above.
According to this process, the desired compound
(II)
can be prepared by firstly reacting diethyl azodicarboxylate, triphenylphosphihe and phthalimide (or hydrogen azide or diphenylphosphoryl azide) or reacting a sulfonylation agent such as methanesulfonyl chloride in the presence of a base such as triethylamine, then reacting phthalimide (or sodium azide) in the presence of a base, to the alcohol compound of the formula 8, to obtain a phthalimideprotected form (or an azide compound) of the amine compound 9, then reacting hydrazine (or a reducing agent) to remove the phthalimide group (or reduce the azide group) to obtain an amine product of the formula 9, and finally reacting a compound of the formula 10 to the compound 9, followed by reduction.
The above reaction steps will be described in detail referring to suitable reaction conditions, etc.
For the step of producing the amine compound of the formula 9 from the alcohol compound 8, various synthetic methods and reaction conditions well known in organic synthetic chemistry for converting alcohol compounds to amines, may be employed. For example, it is preferred to employ a Mitsunobu reaction using diethyl azodicarboxylate, triphenylphosphine and phthalimide (or hydrogen azide or diphenylphosphoryl azide) or a method which comprises sulfonylation with a sulfonylation agent such as methanesulfonyl chloride in the presence of a base such as triethylamine, then reacting phthalimide (or sodium azide) in the presence of a base, and then treating the obtained phthalimide compound with hydrazine (or reducing the azide compound).
The above reactions are conducted usually in a solvent inert to the reaction. The inert solvent may, for example, preferably be tetrahydrofuran, dimethoxyethane, benzene or toluene in the case of the above-mentioned Mitsunobu reaction; methylene chloride, chloroform, tetrahydrofuran, benzene, ethyl acetate or dimethylformamide in the case of the sulfonylation followed by the WO 97/01275 PCT/US96/11022 -311 reaction with phthalimide (or sodium azide); an alcohol such as methanol or ethanol in the next step of the phthalimide-removing reaction with hydrazine; an ether such as ethyl ether or tetrahydrofuran in the case where a metal hydride complex is used as the reducing agent in the reduction reaction of the azide compound; water-containing tetrahydrofuran in the case where phosphine reduction is conducted with triphenylphosphine or the like; and an alcohol such as methanol or ethanol in the reduction by catalytic reduction.
With respect to the amounts of the reagents to be used, in the above Mitsunobu reaction, each of diethyl azodicarboxylate, triphenylphosphine and phthalimide (or hydrogen azide or diphenylphosphoryl azide) is used in an amount of 1 mol or an excess molar amount, preferably from 1 to 5 mols, per mol of the starting material alcohol compound 8. In the reaction with the phthalimide (or sodium azide) after the sulfonylation, the sulfonylation agent such as methanesulfonyl chloride is used in an amount of 1 mol or an excess molar amount, preferably from 1 to 2 mols, per mol of the alcohol compound 8, and the base such as triethylamine used at that time is usually in an amount of 1 mol or an excess molar amount, preferably from 1 to 2 mols, per mol of the sulfonylation agent. In the next step of the reaction with phthalimide (or sodium azide) in the presence of a base, 1 mol or an excess molar amount, preferably from 1 to 5 mols of each of phthalimide and the base (or sodium azide) is used per mol of the starting material sulfonylation agent. Here, the base to be used together with phthalimide is preferably sodium carbonate or potassium carbonate. Otherwise, without using such a base, a sodium salt or a potassium salt of phthalimide may be used by itself. Then, in the reaction for removing the phthalimide group with hydrazine, hydrazine is used in an amount of 1 mol or an excess molar amount, preferably from 1 to 10 mols, per mol of the phthalimide compound as the starting material compound. In the reduction of the azide compound with a metal hydride complex or with triphenylphosphine, the reducing agent is used usually in an amount of 1 mol or an excess molar amount, preferably from 1 to 2 mols, per mol of the azide compound.
WO 97/01275 PCT/US96/1122 -312- In the case of the above Mitsunobu reaction, the reaction temperature is usually from -70°C to 100 0 C, preferably from -20 0 C to 501C, and the reaction time is usually from 5 minutes to 48 hours, preferably from 30 minutes to 24 hours. In the reaction for removing the phthalimide group by hydrazine, the reaction temperature is usually from 0°C to the boiling point of the solvent used for the reaction, preferably from room temperature to 100°C, and the reaction time is usually from 5 minutes to 48 hours, preferably from 30 minutes to 24 hours. In the reaction for converting the azide compound to the amine compound by reduction, when a metal hydride complex is used as the reducing agent, the reaction temperature is usually from -70'C to 150'C, preferably from -20'C to 50'C, and the reaction time is usually from 5 minutes to 48 hours, preferably from 10 minutes to 10 hours.
When triphenylphosphine is used as the reducing agent, the reaction temperature is usually from room temperature to the boiling point of the solvent used for the reaction, preferably from 30 0 C to 100 0 C, and the reaction time is usually from 10 minutes to 48 hours, preferably from 30 minutes to 24 hours. Further, in the case of the reduction by catalytic reduction, the reaction temperature is usually from 0°C to 100'C, preferably from room temperature to 50C, and the reaction time is usually from 10 minutes to 48 hours, preferably from minutes to 24 hours.
The step for producing the desired compound (II) from the compound of the formula 9 is carried out usually by preliminarily forming an imine by reacting 1 mol or an excess molar amount, preferably from 1 to 2 mols of the compound of the formula to 1 mol of the compound of the formula 9 in an inert solvent such as methanol, ethanol, benzene, ethyl ether or tetrahydrofuran, and then reducing it.
This step can be carried out in the same manner as the step for producing the desired compound (II) from the compound of the formula 6 in the above process A. Accordingly, with respect to the reaction conditions, etc., similar modes may be employed.
Further, the compound of the formula 10 may be WO 97/01275 PCT/US96/11022 -313commercially available or can be produced by a proper combination, as the case requires, of the methods disclosed in Examples, or conventional methods or methods similar thereto.
WO 97/01275 PTU9/12 PCT/US96/11022 314 Process D Ar 2 O H 4 R RP OCH(OH)CHZ base
RP
1 0CH 2
(OH
2
PIOH
2 R 3p Ar2 7
CH'
-0 0 R 4pz12
RP
1
OCH
2
(CH
2 )pCH 2 OH-
OH-NH
2 R p 13 1) reduction 2) 0H 3 S0 2 01, TEA, NaN 3 (or DEAD, Ph 3 P, DPPA) 3) reduction 2) reduction .R 8
P
1) HO0-OC-AP O0RP 11 2) selective removal of protecting groups WO 97/01275 PCT/US96/11022 -315-
HOCH
2
(CH
2 )pCH 2 Introduction of a leaving group PPh 3 or P(OMe) 3 or P(OEt) 3
RP
Ar
T-CH
2
(CH
2 )pCH 2
I
R4p In the above formulas, RIP means a hydroxyl-protecting group; and AP, p, T, Z, ZI, R 3 p, R 4 p, R 5
R
6
R
7 p,
R
8 p and RP are as defined above.
According to this process, the desired compound (VI) can be prepared by firstly reacting an alkylating agent of the formula 11 to a ketone compound of the formula 4 to obtain a compound of the formula 12, reacting a reducing agent such as a metal hydride complex to the compound 12 to obtain an alcohol compound, then reacting diethyl azodicarboxylate, triphenylphosphine and phthalimide (or WO 97/01275 PCT/US96/11022 -316hydrogen azide or diphenylphosphoryl azide) or reacting a sulfonylation agent such as methanesulfonyl chloride in the presence of a base such as triethylamine, and then reacting phthalimide (or sodium azide) in the presence of a base, to obtain a phthalimide-protected form (or an azide compound) of the amine compound 13, then reacting hydrazine (or a reducing agent) to remove the phthalimide group (or reduce the azide group) to obtain an amine compound of the formula 13, reacting a compound of the formula 10 to the compound 13, followed by reduction to obtain a compound of the formula 14, reacting a carboxylic acid of the formula (III) or its reactive derivative to the compound 14, then selectively removing the protecting group represented by Rpl to obtain a compound of the formula 15, then introducing a leaving group to the compound 15 to obtain a compound of the 16, and finally reacting triphenylphosphine, trimethyl phosphite or triethyl phosphite to the compound 16.
The hydroxyl-protecting group of RPI may be the hydroxyl-protecting groups mentioned above with respect to process 1.
The step of producing a compound of the formula 12 from a ketone compound of the formula 4, can be carried out in the same manner as the step of producing the compound of the formula 6 from the ketone of the formula 4 in the above process A. Accordingly, with respect to the reaction conditions, etc., similar conditions may be employed.
In the step of producing the amine compound of the formula 13 after reacting a reducing agent such as a metal hydride complex to the compound of the formula 12 to obtain an alcohol compound, the step of converting the compound of the formula 12 to the alcohol compound can be carried out in the same manner as the step of reducing the compound of the formula 6 to the alcohol compound 8 in the above process B. Accordingly, with respect to the reaction conditions, etc., similar conditions may be employed. Further, the step of producing an amine compound of the formula 13 from the obtained alcohol, can be carried out in the same manner as in the step of producing the amine compound 9 from the alcohol compound of the WO 97/01275 PCT/US96/11022 -317formula 8 in the above process C. Accordingly, with respect to the reaction conditions, etc., similar conditions may be employed.
The step of producing a compound of the formula 14 from the amine compound of the formula 13, can be carried out in the same manner as in the step of producing a compound of the formula (II) from the amine of the formula 9 in the above process C. Accordingly, with respect to the reaction conditions, etc., similar conditions may be employed.
In the step of producing a compound of the formula from the compound of the formula 14, the reaction of the compound of the formula 14 with the carboxylic acid of the formula (III) or its reactive derivative, can be carried out in the same manner as the reaction of the compound of the formula (II) with the carboxylic acid of the formula (III) or its reactive derivative in the above process 1. Accordingly, with respect to the reaction conditions, etc., similar conditions may be employed.
For the step of selectively removing the protective group represented by RP 1 from the compound obtained by the above reaction, various methods may suitably be selected depending upon the type and the characteristics of the protecting group. Namely, utilizing the difference in the stability against an acid, a base or reduction between
RP
1 and other protecting groups, the protecting group can selectively be removed by a conventional means such as an acid, a base or reduction.
With respect to specific conditions for such a reaction, the methods disclosed in known literatures, such as "Protective Groups in Organic Synthesis, T.W. Greene, John Siley Sons (1981)", may, for example, be used.
The step of producing a compound of the formula l6 by introducing a leaving group to the compound of the formula 15 can be carried out in the same manner as in the method of introducing a leaving group to the compound of the formula 8 in the above process B by using, for example, a halogenating agent such as thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, oxalyl chloride or phosgene, or a WO 97/01275 PCT/US96/11022 -318sulfonating agent such as methanesulfonyl chloride, p-toluenesulfonyl chloride or benzenesulfonyl chloride. Accordingly, with respect to the reaction conditions, etc., similar conditions may be employed.
The step of producing the desired compound (VI) from the compound of the formula 16, can be carried out by reacting triphenylphosphine, trimethyl phosphite or triethyl phosphite, to the compound of the formula 16.
When a triphenylphosphine is reacted, the above reaction is carried out usually in an inert solvent which does not affect the reaction.
As such an inert solvent, toluene or xylene is, for example, preferred.
The triphenylphosphine is used usually in an amount of 1 mol or an excess molar amount, preferably from 1 to 5 mols, per mol of the compound 16.
The reaction temperature is usually from room temperature to the boiling point of the solvent used for the reaction, preferably from 80 0 C to 150 0 C. The reaction time is usually from minutes to 7 days, preferably from 1 hour to 24 hours.
Likewise, when trimethyl phosphite or triethyl phosphite is reacted to the compound 16, the above reaction is conducted usually in an inert solvent which does not affect the reaction, or more preferably, an excess trimethyl phosphite or triethyl phosphite is used as both the solvent and the reactant.
The reaction temperature is usually from room temperature to the boiling point of the solvent for the reaction, preferably from 80 0 C to 150 0 C, and the reaction time is usually from 5 minutes to 7 days, preferably from 1 hour to 24 hours.
Further, the compound of the formula 11 may be commercially available, or may be produced by a proper combination, as the case requires, of the methods disclosed in Examples, or conventional methods or methods similar thereto.
WO 97/01275 WO 9701275PCTIUS96/11022 319 Process E Ar 2
CH
2 jF-R! 0 Rp 2 0N R3CH(CH2 )pCH 2
-Z
17 base
RP
2 0, Rp 0'CH(CH2 )pCH 2
R~
3
I
R
3
P-
1) reduction 2) CH 3
SO
2 CI, TEA, NaN 3 (or DEAD, Ph 3 P, DPPA) 3) reduction Rp 2
OX
Rp 0'CH(CH2 )pCH 2
R~
3 0 I CH -CH-NH 2 R p 19 2) reduction Rp 2 0\ 2 )pCH 2 R 7p R8P R76 F
NH
R 1) H0- C -AP CORP 11 2) selective removal of protecting groups WO 97/01275 PCT/US96/11022 -320- R7p R8 p
H-C-(CH
2 )pCH 2 II 6 "1,Ar3 CH CH CH
H
N ~AP-COORP R H 5 0 [Vill] R4P In the above formulas, each of RP 2 and RP 3 which are the same or different, is a methyl group or an ethyl group, or RP 2 and RP 3 together represent an ethylene group; and AP, p, Z, R 3 p, R 4 p, R 5
R
6
R
7 p,
R
8 p and RP are as defined above.
According to this process, the desired compound (VIII) can be prepared by firstly reacting an alkylating agent of the formula 17 to a ketone compound of the formula 4 to obtain a compound of the formula 18, reacting a reducing agent such as a metal hydride complex to the compound 18 to obtain an alcohol compound, then reacting diethyl azodicarboxylate, triphenylphosphine and phthalimide (or hydrogen azide or diphenylphosphoryl azide), or reacting a sulfonylation agent such as methanesulfonyl chloride in the presence of a base such as triethylamine and then reacting phthalimide (or sodium azide) in the presence of a base, to obtain a phthalimide-protected form (or an azide compound) of the amine compound 19, then reacting hydrazine (or a reducing agent) to remove the phthalimide group (or reduce the azide group) to obtain an amine compound of the formula 19, reacting a compound of the formula 10 to the compound 19, followed by reduction to obtain a compound of the formula 20, reacting a carboxylic acid of the formula (III) or its reactive derivative to the compound 20, and then selectively removing the protecting groups represented by RP 2 and RP 3 WO 97/01275 PCT/US96/11022 -321 Removal of such protecting groups is usually preferably conducted in the presence of an acid such as hydrochloric acid, sulfuric acid or p-toluenesulfonic acid in a solvent such as water-containing methanol, water-containing ethanol or water-containing tetrahydrofuran.
The reaction temperature is usually from -20 0 C to 100 0
C,
preferably from 0°C to 50'C, and the reaction time is usually from minutes to 48 hours, preferably from 10 minutes to 24 hours.
The respective steps up to the production of the desired compound (VIII) from the ketone compound of the formula 4 can be carried out in the same manner as the respective steps for the production of the compound of the formula 15 from the ketone compound of the formula 4 in the above process D. Accordingly, with respect to the reaction conditions, etc., the same conditions as in the corresponding respective steps can be employed.
Further, the compound of the formula 17 may be commercially available, or can be produced by a proper combination, as the case requires, of the methods disclosed in Examples, or conventional methods or methods similar thereto.
WO 97/01275 PCTIUS96/11022 322 ProcessF R 3 p Ar 2
OH
2
T-R
5 0
RP
4 -(OH,)pCH 2 -7 21 base
RP-W
1
-(OH
2
PIOH
2 W~f' Af22
RP
4
-W
1
-(OH
2 )pOH 2
OH-OH-NH
2 R 3 p 1) reduction 2) 0H 3 S0 2 01, TEA, NaN 3 (or DEAD, Ph 3 P, DPPA) 3) reduction 2) reduction
RP
4 -Wl-(CH 2 )pOH 2 OH
OH
NN~ ~NH 1) HO -OC-AP -OOORP 2) selective removal of protecting groups WO 97/01275 PCTIUS96/11022 -323-
H-W'-(CH
2 )pCH 2 c A 3
CH
R -"Ar N
AP-COORP
Rna p- H" R 50 [XlI] R4P In the above formulas, RP 4 represents a hydroxyl-protecting group when Wl is an oxygen atom; or a mercapto-protecting group when Wl Ar- Aris a sulfur atom; and AP, p, W1, Z, R 3 p,
R
4 p, R 5
R
6
R
7 p, R 8 p and RP are as defined above.
According to this process, the desired compound (XII) can be prepared by firstly reacting an alkylating agent of the formula 21 to a ketone compound of the formula 4 to obtain a compound of the formula 22, reacting a reducing agent such as a metal hydride complex to the compound 22 to obtain an alcohol compound, then reacting diethyl azodicarboxylate, triphenylphosphine and phthalimide (or hydrogen azide or diphenylphosphoryl azide), or reacting a sulfonylation agent such as methanesulfonyl chloride in the presence of a base such as triethylamine and then reacting phthalimide (or sodium azide) in the presence of a base, to obtain a phthalimide-protected form (or an azide compound) of the amine compound 23, then reacting hydrazine (or a reducing agent) to remove the phthalimide group (or reduce the azide group) to obtain an amine of the formula 23, reacting a compound of the formula 10 to the compound 23, followed by reduction to obtain a compound of the formula 24, reacting a carboxylic acid of the formula (III) or its reactive derivative to the compound 24, and then selectively removing the protecting group represented by Rp 4
M
WO 97/01275 PCT/US96/11022 -324- When Rp 4 is a hydroxyl-protecting group, as such a hydroxyl-protecting group, the hydroxyl-protecting groups disclosed above with respect to process 1 may be employed.
When Rp 4 is a mercapto-protecting group, as such a mercapto-protecting group, the hydroxyl-protecting groups disclosed above with respect to process 1 can be employed.
The respective steps up to the production of the desired compound (XII) from the ketone compound of the formula 4 can be carried out in the same manner as the respective steps for the production of the compound of the formula 15 from the ketone compound of the formula 4 in the above process D. Accordingly, with respect to the reaction conditions, etc., the same conditions as in the corresponding respective steps can be employed.
Further, the compound of the formula 21 may be commercially available, or can be produced by a proper combination, as the case requires, of the methods disclosed in Examples, or conventional methods or methods similar thereto.
WO 97/01275 PCT/US96/11022 -325- Process G
R
8
P
Introduction of a leaving group [XII a]
R
6
CH
I
AC-
Ar-
I
In the above formulas, AP, p, Zl, R 3 p, R 4 p, R 5
R
6
R
7 p, R 8 p and RP are as defined above.
According to this process, the desired compound can be prepared by introducing a leaving group to the compound of the formula (XII-a).
This step can be carried out in the same manner as the method of introducing a leaving group to the compound of the formula in the above process D. Accordingly, with respect to the reaction conditions, etc., similar conditions may be employed.
A compound of the formula (VII):
(CH
2 )n -CH T (VII)
R
2
P
WO 97/01275 PCT/US96/11022 326wherein n, T, RIp and R 2 p are as defined above, can be prepared from a compound of the formula (XIII): Ar- (CH 2 )n -CH 2
Z
1
(XIII)
R
2 p Arwherein n, ZI, Rip and R 2 p are as defined above, in accordance with the method for producing a compound of the formula (VI) from the compound of the formula 1. in process D.
Further, the compound of the formula (XIII) may be commercially available, or can be prepared by a proper combination, as the case requires, of the methods disclosed in Examples, or conventional methods or methods similar thereto.
WO 97/01275 PCTfUS96/11022 327 ProcessH Wx-~CH 2 Rs-' OCORt ,HCHOH 29 W-
OH
2 I (R) Vx-OH 2
(S)
O H-HO
WX-OH
2 I (R) c J hydrolysis R~ 1H 2
(R)
O H-OHOH /Ar2 I In the above formulas, Wx is R i -,(wherein C AP 9 Q, R IP and
R
2 P are as defined above), Rp 4 -Wl-(CH2)p'- (wherein p' is an integer of from 0 to 4;and Rp 4 and W1 are as defined above) or WO 97/01275 PCT/US96/11022 -328- CH(CH2)P Rp C (wherein Rp 2 Rp 3 and p are as defined above); RS is a hydrogen atom or a methyl group; Rt is a lower alkyl group, an aryl group or a lower alkenyl group; and
R
3 p, R4p and R 5 are as defined above.
Process H is a process for preparing an optically active substance 31 or 32 of an alcohol compound 28 obtainable as the above formula 8 or a reduction product of the formula 12, 18 or 22.
According to this process, the desired optically active alcohol compounds 31 and 32 can be prepared by reacting a vinyl ester derivative of the formula 29 to a racemic alcohol derivative of the formula 28 in the presence of a lipase, separating the obtained optically active ester derivative 30 and the optically active alcohol derivative, and then hydrolyzing the ester group with respect to the optically active ester derivative Rt of the vinyl ester derivative of the formula 29 is preferably a lower alkyl group such as a methyl group or an ethyl group; an aryl group such as a phenyl group or a naphthyl group; or an aralkyl group such as a benzyl group or a 2-phenylethyl group.
Particularly preferred is a methyl group, i.e. a case wherein the compound of the formula 29 is vinyl acetate or isopropenyl acetate.
The above optical resolution reaction by lipase can be conducted usually in an inert solvent such as methylene chloride, chloroform, ethyl ether, tetrahydrofuran, benzene, toluene, hexane, heptane or acetonitrile, or by using the starting material vinyl ester derivative of the formula 29 itself as the solvent.
The vinyl ester derivative 29 is used usually in an amount of 1 mol or in a large excess molar amount, preferably from 1 to 100 mols, per mol of the starting material compound 28, and the amount of the lipase as the catalyst is from 0.01 to 100% preferably from 0.1 to 20%, by weight, relative to the compound 28.
ii_ WO 97/01275 PCT/US96/11022 -329- The type of the lipase is preferably a lipase derivative from Pseudomonas sp. such as Toyothium LIPTM (manufactured by Toyobo).
Further, the above enzymatic reaction tends to be accelerated, when the reaction is carried out in the presence of a base.
As a base to be used for this purpose, an organic base such as triethylamine or diisopropylethylamine, is preferred.
The base is used usually in an amount of 0.01 mol or slightly excess molar amount, preferably from 0.1 tol1.5 mols, relative to the starting material compound 28.
The reaction temperature is usually from 0 0 C to preferably from room temperature to 40 0 C. The reaction time is usually from 30 minutes to 7 days, preferably from 1 hour to 48 hours.
The hydrolytic reaction of the ester of the formula can be conducted by a common method well known in the organic synthetic chemistry under an acidic or basic condition.
The compositions of this invention inhibit Ras farnesyl transferase which catalyzes the first step in the post-translational processing of Ras and the biosynthesis of functional Ras protein. These compositions are useful as pharmaceutical agents for mammals, especially for humans. These compositions may be administered to patients for use in the treatment of cancer. Examples of the type of cancer which may be treated with the compositions of this invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias.
The compositions of this invention are also useful for inhibiting 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 compositions of the invention to a mammal in need of such treatment. For example, the benign proliferative disorder neurofibromatosis, or tumors in which the WO 97/01275 PCT/US96/11022 -330- Ras is activated due to mutation or overexpression of tyrosine kinase oncogenes neu, src, abl, ick, and fyn) may be inhibited by the compositions of this invention.
In practicing the methods of this invention, which comprise administering, simultaneously or sequentially or in any order, two or more of a protein substrate-competitive inhibitor and a farnesyl pyrophosphate-competitive inhibitor, such administration can be orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration. It is preferred that such administration be orally. It is more preferred that such administration be orally and simultaneously.
When the protein substrate-competitive inhibitor and famrnesyl pyrophosphate-competitive inhibitor are administered sequentially, the administration of each can be by the same method or by different methods.
The compositions 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.
For oral use of a chemotherapeutic composition according to this invention, the selected composition 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 WO 97/01275 PCT/US96/11022 331 intravenous use, the total concentration of solutes should be controlled in order to render the preparation isotonic.
Suitable compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacologically acceptable carriers, saline, at a pH level, e.g., 7.4. The solutions may be introduced into a patient's intramuscular blood-stream by local bolus injection.
When a composition 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 composition is administered to a mammal undergoing treatment for cancer. Administration occurs in an amount of a composition that comprises between about 0.1 mg/kg of body weight to about 40 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 20 mg/kg of body weight per day of a protein substratecompetitive inhibitor and an amount between about 0.1 mg/kg of body weight to about 40 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 20 mg/kg of body weight per day of a farnesyl pyrophosphate-competitive inhibitor.
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.
EXAMPLE 1 Preparation of (1RS,2RS,4E)-2-(4-chlorophenyl)-l-methyl-5-(2naphthyl)-4-pentenvl 2 -naphthylmethvlamine
I
WO 97/01275 PCT/US96/11022 -332- Preparation of (E)-3-(4-chlorophenyl)-6-(2-naphthyl)-5hexen-2-one 2.56 g of p-chlorophenylacetone was dissolved in a mixed solution of 5 ml of dimethylformamide and 5 ml of benzene, and a dimethylformamide 8 ml/benzene 8 ml solution containing 0.62 g of oily sodium hydride and 3.50 g of 3 -(2-naphthyl)-2-propenyl bromide, was added under cooling with ice with stirring, followed by stirring at room temperature for 2 hours. The reaction solution was acidified by an addition of IN hydrochloric acid and extracted by an addition of water and ethyl ether. Then, the organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 5/1) to obtain the above-identified compound.
Preparation of (2RS,3SR,5E)-3-(4-chlorophenyl)-6-(2naphthyl)-5-hexen-2-ol 4.78 g of 3 4 -chlorophenyl)-6-(2-naphthyl)-5-hexen- 2-one was dissolved in 30 ml of tetrahydrofuran, and 14.3 ml of a 1M tetrahydrofuran solution of lithium tri-sec-butyl borohydride was added at -78°C under cooling with stirring, followed by stirring at the same temperature for 2 hours. To the reaction solution, 10 ml of a 2N sodium hydroxide aqueous solution was added under cooling with ice with stirring, and then, 15 ml of a 30% hydrogen peroxide aqueous solution was gradually dropwise added, followed by stirring at room temperature for one hour. The reaction solution was extracted by an addition of ethyl ether and water. The organic layer was washed with a saturated sodium thiosulfate aqueous solution and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 15/1 to 5/1) to obtain the above-identified WO 97/01275 PCT/US96/11022 -333compound.
Preparation of (IRS,2RS, 4 E)-2-(4-chlorophenyl)-l-methyl- 5-(2-naphthyl)-4-pentenvlamine 4.06 g of (2RS,3SR,5E)-3-(4-chlorophenyl)-6-(2-naphthyl)- 5-hexen-2-ol was dissolved in 30 ml of tetrahydrofuran, and 4.77 g of triphenylphosphine, 2.89 ml of diethyl azodicarboxylate and 4.77 g of diphenylphosphoryl azide were added under cooling with ice with stirring, followed by stirring at room temperature for 30 minutes. The reaction solution was evaporated to dryness under reduced pressure.
Then, the residue was purified by silica gel column chromatography (hexane/ethyl acetate 50/1 to 30/1). The obtained azide product was heated and refluxed together with 3.2 g of triphenylphosphine in 100 ml of 10% water-containing tetrahydrofuran. The reaction solution was evaporated to dryness under reduced pressure. Then, the residue was purified by silica gel column chromatography (methylene chloride/methanol 50/1 to 20/1) to obtain the above-identified compound.
Preparation of (IRS,2RS,4E)-2-(4-chlorophenyl)-lmethyl-5-(2-naphthyl)-4-ententenl -2-naphthylmethvlamine 0.75 g of (lRS,2RS, 4
E)-
2 -(4-chlorophenyl)-l-methyl-5-(2naphthyl)-4-pentenylamine was dissolved in 10 ml of methanol, and 0.34 g of 2-naphthoaldehyde was added thereto, followed by stirring at room temperature overnight. To the reaction solution, 10 mg of tetrahydrofuran was added to dissolve the formed precipitate, and 84 mg of sodium borohydride was added thereto, followed by stirring at room temperature for 2 hours. The reaction solution was extracted by an addition of ethyl ether and water. The organic layer was washed with a saturated sodium chloride aqueous solution-and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 7/1 to 3/1) to obtain the above-identified compound.
WO 97/01275 PTU9/12 PCTIUS96/11022 334 The reaction was carried out in the same manner as in Example 1 except that instead of the p-chlorophenylacetone and/or 3-(2-naphthyl)-2-propenylbromide and/or 2-naphthoaldehyde, used as the starting material in the above reaction, the corresponding arylacetone derivative and/or halide and/or arylaldehyde derivative, was used to obtain N{ (lRS,2RS,4E)-2-(4-chlorophenyl)-l-methyl-5-(lnaphthyl)-4-pentenyl I-2-na-phthylmethylamine, N- {(lRS ,2RS)-2-(4chlorophenyl)-l-methyl-5-(2-naphthyl)-4-pentyl }1-2naphthylmethylamine, N- {(lRS ,2RS)-2-(4-chlorophenyl)-l-methyl-4- (2naphthoxy)butyl }-2-naphthylmethylamine, N-[{(iRS ,2RS)-2-(4chlorophenyl)-l-methyl-4-(2-naphthyl)butyl -2-naphthylmethylamine, N- I (IRS ,2RS)-2-(4-chlorophenyl)-l-methyl-6- (2-naphthyl)hexyI 1-2naphthylmethylamine, N- {(iRS ,2RS )-2-(4-chiorophenyl)-1-methyl-5phenyi-4-pentynyl I-2-naphthylmethylamine, N- I (IRS ,2RS methoxyphenyl)-l-methyl-5-(2-naphthyl)-4-pentenyl naphthylmethylamine, N- (lRS ,2RS ,4E)-2-(4-methyiphenyl)-l-methyl-5- (2-naphthyl)-4-pentenyl -2-naphthylmethylamine, N- I (I RS ,2RS ,4E)-1- (2-naphthyl)-2-(4-nitrophenyl)-4-pentenyl 1-2naphthylmethylamine, N- I (lRS,2RS,4E)-2-(4-fluorophenyI) I (2-naphthyl)-4-pentenyl 1 -2-naphthylmethylamine, N- f (IRS ,2RS ,4E)-1methyl-5-(2-naphthyl)-2-(4-trifluoromethylphenyl)-4-pentenyl 1-2naphthylmethylamine, N-1{ (IRS ,2RS ,4E)-l-methyl-5 -(2-naphthyl)-2phenyl-4-pentenyl 1-2-naphthylmethyiamine, N- I (IRS ,2RS ,4E)-l-methyl- 2- (6-methyl-3 -pyridyl)-5- (2-naphthyl)-4-pentenyl) -2naphthylmethylamine, N- (IRS ,2RS ,6E)-2-(4-chlorophenyl)-l-methyl-7phenyl-6-heptenyl)-2-naphthylmethylamine, IRS ,2RS chlorophenyl)-l-methyl-7-(2-naphthyl)-6-heptenyl)-2naphthylmethylamine, N-f (IRS ,2RS (4-chiorophenyl)- 1-methyl- 5-(2-naphthyl)-4-pentenyl 1-3-quinolylmethylamine, N-I{(lRS,2RS,4E)- 2-(4-chlorophenyl)-l1-methyl-5- (2-naphthyl)-4-pentenyl 1-3,4difluorobenzylamine, N-(2-benzoxazolylmethyl)- I(iRS ,2RS chlorophenyl)-l-methyi-5-(2-naphthyl)-4-pentenyl 1 amine, N-(2benzo[b]thienylmethyi)- I (IRS ,2RS ,4E)-2-(4-chiorophenyl)-l-methyl-5- WO 97/01275 PCT/US96/11022 335 (2-naphthyl)-4-pentenyl }amine, N- I (iRS ,2RS ,4E)-1-methyl-2-(3 ,4methylenedioxyphenyl)-5-(2-naphthyl)4pentenyl)}-2naphthylmethylamine, N- {(iRS ,2RS)-4,4-diethoxy-l-methyl-2-(3 ,4methylenedioxyphenyl)butyl I -2-naplithylmethylamine, N-(2benzo[b]furanylmethyi)- I (IRS ,2RS)-4,4-diethoxy-l-methyl-2-(3 ,4methylenedioxyphenyl)butyi Iamine, N-(2-benzo[b]thienylmethyy..
I (IRS ,2RS)-4,4-diethoxy-l-methyl-2-.(3 ,4methylenedioxyphenyl)butyllIamine, N- [(IRS ,2RS)-4,4-diethoxy-imethyi-2- ,4-bis(methoxycarbonyl)phenyl I butyl] -2naphthylmethyiamine, N-(2-benzo[b]thienylmethyl.. {(1RS,2RS)-4,4diethoxy-2-(4-methoxycarbonylphenyl)4...methylbutylamine, N-(2benzo[b]furanylmethyly.. I (IRS ,2RS )-4,4-diethoxy-2-(4methoxycarbonyiphenyl)- 1 -methylbutyl I amine, N-(2benzo[b]thienylmethyl)- I (IRS 2 RS)-2-(4-cyanophenyl)-4,4-diethoxy4...
methylbutyl I amine, N-(5-benzo[b]thienylmethyl).f (lRS,2RS)-4,4diethoxy-2-(4-methoxycarbonylphenyl)-l-methyibutyl Iamine, N- J (IRS 2
RS)-
2 -(4-chlorophenyl)-4,4-diethoxy-l-methylbutyl 1-2naplithylmethylamine, N- I (IRS 2 RS)-2-(4-cyanopheny)-4,4-diethoxy-l-.
methylbutyl }-2-naphthylmethylamine, N- I (lRS,2RS)-2-(4cyanophenyl)-4,4-diethoxy-l-methylbutyl I-2-naphthylmethylamine,
N-
J(IRS ,2RS 4 4 -diethoxy- 2 4 -methoxycarbonylphenyl)-.l-methylbutylI- 2-naphthylmethylamine, N- I (iRS ,2RS methoxycarbonylpheny1)-1-methyI-5-(2-naphthy1-4-pentenyl) -2naphthylmethylamine and N- [(IRS ,2RS)-5- (1 ,3-dioxolan-2-yi)-l-methyl- 2-(3 ,4-methyienedioxyphenyl)butyl] -2-naphthylmethylamine.
EXAMPLE 2 Preparation of 1 ,2-di-tert-butyl 1, 2, 3-propanetricarboxylate and its optical resolution 13.1 ml of a 1.5M cyclohexane solution of lithium diisopropylamide was dissolved in 10 ml of tetrahydrofuran, and a tetrahydrofuran solution (10 ml) containing 2.96 g of benzyl acetate was added under cooling to -70 0 C with stirring, followed by stirring at the WO 97/01275 PCT/US96/11022 -336same temperature for 30 minutes. Then, a tetrahydrofuran solution ml) containing 2.96 g of di-tert-butyl maleate, was dropwise added thereto, followed by stirring at the same temperature for 30 minutes.
The reaction solution was extracted by an addition of 20 ml of water and 50 ml of ethyl ether. The organic layer was separated, then washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was dissolved in 50 ml of dioxane, and 0.4 g of a 10% palladium carbon catalyst was added thereto, followed by catalytic reduction for 20 hours at room temperature under hydrogen atmospheric pressure. The catalyst was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was treated with hexane, whereupon the precipitate thereby obtained was collected by filtration and then dried to obtain the above-identified compound as colorless crystalline powder, mp 55-57C.
12.97 g of the di-tert-butyl ester thus obtained and 13.24 g of cinchonidine was dissolved under heating in 1 liter of carbon tetrachloride. Then, seed crystals were added thereto, and the mixture was left to stand at room temperature for 24 hours. The crystals were collected by filtration and then again dissolved under heating in 1 liter of carbon tetrachloride, and seed crystals were added thereto, and the mixture was left to stand for 24 hours. This operation was further repeated twice to obtain a cinchonidine salt of the above-identified compound, which is named as the (S*)-isomer for the sake of convenience, [cx] 2 0 D -62.7 0 (c 1.0, chloroform).
The cinchonidine salt thus obtained was dissolved in a mixed solution of ethyl ether and 1N hydrochloric acid under cooling with ice, and the organic layer was separated and then post-treated in accordance with a conventional method to obtain the (S )-isomer of the above-identified compound as colorless oily substance, 2 0
D
+4.44°(c 0.92, chloroform).
The fraction containing a large amount of the other mirror image isomer obtained in the above optical resolution operation, was converted to a free acid, and then, the same operation was carried out in WO 97/01275 PCT/US96/11022 -337isopropyl ether using quinine, whereby the mirror image isomer named as the (R*)-isomer for the sake of convenience, was obtained.
EXAMPLE 3 Preparation of (2RS,3RS)-3-tert-butoxycarbonyl-5oxotetrahvdrofuran-2-carboxvlic acid Preparation of (2RS,3SR)-2-diphenylmethoxycarbonyl-5oxotetrahvdrofuran-3-carboxvlic acid 262 mg of (2RS,3SR)-5-oxotetrahydrofuran-2,3dicarboxylic acid was dissolved in 5 ml of acetone, and 291 mg of diphenyldiazomethane was added thereto, followed by stirring at room temperature for 20 minutes. The reaction solution was evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol 100/1 to 10/1) to obtain the above-identified compound as white powder.
Preparation of 3-tert-butyl 2-diphenylmethyl (2RS,3RS)-5oxotetrahydrofuran-2.3-dicarboxvlate 163 mg of (2RS,3SR)-2-diphenylmethoxycarbonyl-5oxotetrahydrofuran-3-carboxylic acid, 59 mg of 4dimethylaminopyridine and 36 mg of tert-butanol, were dissolved in 4 ml of methylene chloride, and 110 mg of 1-ethyl-3-(3dimethylaminopropyl)carbodiimide hydrochloride was added thereto, followed by stirring at room temperature for 13 hours. The reaction solution was diluted with methylene chloride, then sequentially washed with a 10% citric acid aqueous solution, a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica WO 97/01275 PCT/US96/11022 -338gel column chromatography (hexane/ethyl acetate 10/1) to obtain the above-identified compound as colorless oily substance.
Preparation of (2RS,3RS)-3-tert-butoxycarbonyl-5oxotetrahydrofuran-2-carboxylic acid 148 mg of 3-tert-butyl 2-diphenylmethyl (2RS,3RS)-5oxotetrahydrofuran-2,3-dicarboxylate was dissolved in 4 ml of ethyl acetate, and 15 mg of a 10% palladium-carbon catalyst was added thereto, followed by catalytic reduction for 15 hours at room temperature under hydrogen atmospheric pressure. The catalyst was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was washed with benzene to obtain the aboveidentified compound as white crystalline powder.
EXAMPLE 4 Preparation of (lRS,2RS,4E)-5-(2benzoxazolyl)-l-methyl-2-(3,4-methylenedioxyphenyl)-4pentenyl }-N-(2-naphthylmethyl)carbamoylmethyl]succinic acid and (lRS,2RS,4Z)-5-(2-benzoxazolyl)- 1-methyl-2- (3,4-methylenedioxyphenyl)-4-pentenyl naphthlmethl)carbamovlmethllsuccinic acid Preparation of di-tert-butyl (iRS,2RS)-4,4diethoxy-l-methyl-2-(3,4-methylenedioxyphenyl)butyl (2-naphthlmethyl)carbamovlmethyllsuccinate 436 mg of N- (lRS,2RS)-4,4-diethoxy-1-methyl-2-(3,4methylenedioxyphenyl)butyl -2-naphthylmethylamine obtained in a manner similar to Example 1, 346 mg of 1,2-di-tert-butyl (R*)-1,2,3-propanetricarboxylate obtained in Example 2 and 122 mg of 4-dimethylaminopyridine, were dissolved in 5 ml of methylene chloride, and 249 mg of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added thereto, followed by stirring at room temperature for 14 hours. The reaction solution was diluted with ethyl WO 97/01275 PCT/US96/11022 -339acetate, then, sequentially washed with 1N hydrochloric acid, saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate.
The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 10/1 to 5/1) to obtain the above-identified compound as a colorless foam.
Preparation of di-tert-butyl (RS,2RS)-3formyl-l-methyl-2-(3,4-methylenedioxyphenyl)propyl (2-naphthylmethyl)carbamovlmethyllsuccinate 636 mg of di-tert-butyl (1RS,2RS)-4,4diethoxy-l-methyl-2-(3,4-methylenedioxyphenyl)butyl naphthylmethyl)carbamoylmethyl]succinate was dissolved in 12 ml of tetrahydrofuran, and 3 ml of 2N hydrochloric acid was added thereto, followed by stirring at room temperature for 3 hours. To the reaction solution, a saturated sodium hydrogencarbonate aqueous solution was added, and the mixture was extracted with ethyl acetate. Then, the organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure to obtain the above-identified compound as colorless oily substance.
Preparation of di-tert-butyl (RS,2RS,4E)-5- (2-benzoxazolyl)-l-methyl-2-(3,4-methylenedioxyphenyl)- 4-pentenyl -N-(2-naphthylmethyl)carbamoylmethyl]succinate 53 mg of 60% oily sodium hydride was suspended in 5 ml of tetrahydrofuran, and 634 mg of 2-benzoxazolylmethyl triphenyl)phosphonium bromide was added thereto, followed by stirring at room temperature for 30 minutes. 5 ml of a tetrahydrofuran solution containing 563 mg of di-tert-butyl (lRS,2RS)-3-formyl-lmethyl-2-(3,4-methylenedioxyphenyl)propyl} WO 97/01275 PCT/US96/11022 -340naphthylmethyl)carbamoylmethyl]succinate was added thereto, followed by stirring at room temperature for 12 hours. Then, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate.
The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate 10/1 to 5/1) to obtain the above-identified E isomer compound and Z-isomer of the aboveidentified compound, respectively, as a colorless foam.
Preparation of (RS,2RS,4E)-5-(2benzoxazolyl)-l-methyl-2-(3, 4 -methylenedioxyphenyl)-4pentenyl 2 -naphthylmethyl)carbamoylmethyl] succinic acid 486 mg of di-tert-butyl benzoxazolyl)-l-methyl-2-(3, 4 -methylenedioxyphenyl)-4-pentenyl 2 -naphthylmethyl)carbamoylmethyl]succinate was dissolved in 10 ml of formic acid, followed by stirring at room temperature for 12 hours.
Then, formic acid was distilled off under reduced pressure to obtain the above-identified compound as white solid.
1 H-NMR(CDC13) 6;0.91-1.00(3H, 2.30-3.70(8H, m), 4.20-5.30(3H, 5.90-5.94(2H, 6.43(1H, d, J=15.7Hz), 6.57- 6.76(4H, 7.26-7.84(11H, m) FAB-MS:635(M+H) By the same treatment as above except that di-tert-butyl (lRS,2RS, 4 Z)-5-(2-benzoxazolyl)-l-methyl-2-(3,4methylenedioxyphenyl)-4-pentenyl naphthylmethyl)carbamoylmethyl]succinate was used, Z-isomer of the above-identified compound was obtained.
WO 97/01275 PCTfUS96/11022 341 EXAMPLE Preparation of disodium (3RS ,4RS)-4- {(iRS ,2RS benzoxazolyl)-l-methyl-2-(3 4 -methylenedioxyphenyl)-4-pentenyl
I}-N-
2 -naphthylmethyl)carbamoll-3-carboxy-4-.hydroxybutanoate Preparation of (2RS ,3RS)-2- I (IRS ,2RS,4E)-5-(2benzoxazolyl)-l-methyl-2-(3 4 -methylenedioxyphenyl)-4pentenyl)I-N-( 2 -naphthylmethyl)carbamoylys...
oxotetrahydrofuran-3-carboxylic acid.
47 mng of tert-butyl (2RS,3RS)-2-[N- f (lRS,2RS,4E)-5-(2benzoxazolyl)-l-methyl-2-(3 4 -methylenedioxyphenyl)-4-pentenyl I -N- (2-naphthylmethyl) carbamoyl] -5-oxotetrahydrofuran-3-carboxylate prepared in a manner similar to Example 4 except that (2RS,3RS)-3tertbutoxycarbonyl-5-oxotetrahydrofuran-2-carboxylic acid obtained in Example 3 was used, instead of the 1 ,2-di-tert-butyl 1,2,3,propanetricarboxylate in Example 4, was dissolved in 1 ml of formic acid, and the solution was left to stand at room temperature overnight.
The reaction solution was distilled under reduced pressure. Then, toluene was added to the residue, followed by distillation again. The product was purified by silica gel column chromatography (hexane/ethyl acetate 2/1 to chloroform/methanol 50/1) to obtain the aboveidentified compound as white solid.
IH-NMR(CDC13)5:0.99 and l.l0(total 3H, each d, 1=6.2Hz, 6.3Hz), 2.50-3.10(5H, in), 4.15-4.25 and 4 .37-4.47(total IR, each in), 4.50- 5.35(4H, in), 5.73, 5.75, 5.88 and 5.94(total 2H, each 6.07 and 6.36(total 1H, each d, each J=15.8Hz), 6.60-6.75(4H, in), 7.25- 7.820(1H, mn) FAB-MS:633(M+H) Disodium (3RS ,4RS)-4- I (IRS ,2RS ,4E)-5-(2-benzoxazolyl)-lmethyl-2-(3 ,4-methylenedioxyphenyl }-4-pentenyl)-N-(2naphthvlmethyl)carbamoyl]-3-carboxy-4- hydroxybutanoate WO 97/01275 PCT/US96/11022 342 8 mg of the lactone thus obtained was dissolved in a mixed solution of 1 ml of methanol and 1 ml of tetrahydrofuran, and 26 tl of a IN sodium hydroxide aqueous solution was added under cooling with ice with stirring, followed by stirring at room temperature for minutes. The reaction solution was evaporated to dryness under reduced pressure to obtain the above-identified compound as white solid.
1 H-NMR(CDC13)5:0.91 and 1.03(total 3H, each d, and 6.7Hz), 2.35-3.40(6H, 4.60-5.10(4H, 5.86 and 5.90(total 2H, each 5.90-6.95(5H, 7.28-8.01(11H,m) FAN-MS:695(M+H) EXAMPLE 6 Preparation of disodium (3S, 1R,2R,4E)-5-(2-benzoxazolyl)- 1-methyl-2-(3,4-methylenedioxyphenyl)-4-pentenyl }-N-(2-naphthylmethyl)carbamoyll-3-carboxv-4-hvdroxvbutanoate (Compound D) Preparation of N-[(1R,2R)-4,4-diethoxy-1-methyl-2-(3,4methvlenedioxyphenyl)butyl
I-
2 -naphtylmethylamine Preparation of 5,5-diethoxy-3-(3,4methylenedioxyphenvl)pentan-2-one 11.7 g of 3 4 -methylenedioxyphenyl)acetone was dissolved in 100 ml of dimethylformamide, and 2.76 g of 60% oily sodium hydride and 20.9 g of 2,2-diethoxyethyliodide was added under cooling with ice with stirring, followed by stirring at room temperature for 2 hours. The reaction solution was poured into 100 ml of water and extracted with diethyl ether. Then, the organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then the solvent was distilled off under reduced pressure. The residue WO 97/01275 PCT/US96/1022 -343was purified by silica gel column chromatography (hexane/ethyl acetate 15/1 to 10/1) to obtain the above-identified compound.
Preparation of (2RS,3SR)-5,5-diethoxy-3-(3,4methylenedioxyphenvl)pentan-2-ol 18.3 g of (3,4-methylenedioxyphenyl)acetone was dissolved in 200 ml of tetrahydrofuran, and 65 ml of a 1.0 M tetrahydrofuran solution of lithium tri-sec-butyl borohydride was added at -78 0 C under cooling with stirring, followed by stirring at the same temperature for 2 hours. To the reaction solution, 130 ml of a IN sodium hydroxide aqueous solution was added under cooling with stirring, and then 150 ml of a 30% hydrogen eroxide aqueous solution was gradually dropwise added, followed by stirring at room temperature of one hour. The reaction solution was extracted by an addition of ethyl ether and water.
The organic layer was washed with a saturated sodium chloride aqueous solution and a saturated sodium thiosulfate aqueous solution and water then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 15/1 to 10/1 to 3/1) to obtain the above-identified compound.
Preparation of (2S,3R)-5,5-diethoxy-3-(3,4methylenedioxyphenyl)pentan-2-ol 31.98 g of (2RS,3SR)-5,5-diethoxy-3-(3,4-methylenedioxyphenyl)pentan-2-ol was dissolved in 320 ml of vinyl acetate, and 15.1 ml of triethylamine was added thereto. Then 1.0 g of immobilized lipase (Toyothium LIP) was added thereto, followed by stirring at 30 0 C for 16 hours. Further, 0.9 g of immobilized lipase was added thereto, followed by stirring at the same temperature for 46 hours. Then, insoluble matters were filtered off. The filtrate was diluted with ethyl acetate, then sequentially washed with 1N hydrochloric acid, a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium solfate.
1 WO 97/01275 PCT/US96/11022 -344- The drying agent was filtered off, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 5/1 to 1/1) to obtain the aboveidentified compound, []D20-31.80 (c 1.0, methanol) as colorless oily substance and (2R,3S)-2-acetoxy-5,5-diethoxy-3-(3,4methylenedioxyphenyl)pentane as colorless oily substance. Further, the absolute configuration of the above-identified compound was detered by Mosher method Am. Chem. Soc., Vol. 113, p. 4092 (1991)).
Preparation of (1R,2R)-4,4-diethoxy-1-methyl-2-(3,4methvlenedioxyphenyl)butvlamine 4.19 g of (2S,3R)-5,5-diethyl-3-(3,4methylenedioxyphenyl)pentan-2-ol was dissolved in 45 ml of ethyl acetate, and 1.64 ml of methanesulfonylchloride and 3.93 ml of triethylamine were added under cooling with ice thereto, followed by stirring under cooling with ice for 30 minutes. To the reaction solution, ml of a saturated sodium hydrogen carbonate solution was added, followed by stirring at room temperature for 45 minutes. The reaction solution was extracted by an addition of ethyl acetate and water. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. the drying agent was filtered off, and then the solvent was distilled off under reduced pressure. The residue was dissolved in 40 ml of dimethylformamide, and 4.58 g of sodium azide was added thereto, followed by stirring at 120 0 C for 30 minutes. The reaction solution was a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate.
The drying agent was filtered off, and then the solvent was distilled off under reduced pressure. The residue was dissolved in a mixed solution of 40 ml of tetrahydrofuran, and 4 ml of water was added, followed by stirring at 90 0 C for 4.5 hours. The reaction solution was distilled under reduced pressure. Then, the residue was purified by silica gel column chromatography (ethyl acetate/methanol 9/1) to obtain the aboveidentified compound.
WO 97/01275 PCT/US96/11022 -345- Preparation of N- (R,2R)-4,4-diethoxy- 1-methyl-2-(3,4methvlene-dioxyphenyl)butvl }-2-naphtvlmethylamine 150 mg of (lR,2R)-4,4-diethoxy-1-methyl-2-(3,4methylene-dioxyphenyl)butyl }-2-naphtylmethylamine was dissolved in 2 ml of methanol, and 79 mg of naphthoaldehyde was added thereto, followed by stirring at 60 0 C for 2 hours. To the reaction solution, 28 mg of sodium borohydride was added under cooling with ice thereto, followed by stirring under cooling with ice for 2 hours. The reaction solution was extracted by an addition of ethyl ether and water. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 5/1 to 3/1) to obtain the above-identified compound.
Preparation of (2S,3S)-3-tert-butoxycarbonyl-5oxotetrahydrofuran-2-carboxylic acid Preparation of 3-tert-butyl 1,2-diethyl(1S,2R)- -hydroxy- 1.2.3-propanetricarboxylate 31 ml of a 1.69 M hexane solution of n-butyl lithium was dissolved in 30 ml of tetrahydrofuran, and 7.1 ml of diisopropylamine was added under cooling with ice, followed by stirring at the same temperature for 30 minutes. Then the mixture was cooled to -78 0 C. 20 ml of a tetrahydrofuran solution containing 4.94 g of diethyl (S)-malate was dropwise added at a temperature of not higher than -50 0 C, followed by stirring at -20 0 C for 1.5 hours.
The reaction solution was cooled to -78 C, and 20 ml of a tetrahydrofuran solution containing 5.58 g of tert-butyl promoacetate and 4.66 g of hexamethylphosphoric triamide was dropwise added thereto at a temperature of not higher than -50 0 C, followed by stirring at room temperature for one hour. The reaction solution was poured into 150 ml of 0.5 N hydrochloric acid and extracted with diethyl ether. Then the organic layer was washed with a WO 97/01275 PCT/US96/11022 -346saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution and then dried over anhydrous maghnesium sulfate. The drying agent was filtered off, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 5/1 to 4/1) to obtain the above-identified compound as yellow oily substance.
Preparation of (2S,3R)-5-oxotetrahydrofuran-2,3dicarboxvlic acid 16.49 g of 3-tert-butyl 1,2-diethyl (lS,2R)-l-hydroxy- 1,2,3-propanetricarboxylate, 100 ml of acetic acid and 50 ml of concentrated hydrochloric acid were mixed and stirred at 70 0 C for 12 hours. Acetic acid and hydrochloric acid were distilled off under reduced pressure. Then the residue was again dissolved in 100 ml of acetic acid and 50 ml of concentrated hydrochloric acid and stirred at 0 C for 12 hours. Acetic acid and hydrochloric acid were distilled off under reduced pressure. Then 100 ml of trifluoroacetic acid was added to the residue, followed by stirring at 60 0 C for 5 hours. Trifluoroacetic acid was distilled off under reduced pressure, and the residue was distilled off under reduced pressure, and the residue was crystallized from hexane-ethyl acetate to obtain the above-identified compound as white powder.
Preparation of (2S,3R)-2-benzyloxycarbonyl-5oxotetrahvdrofuran-3-carboxylic acid 5.2 of (2S,3R)-5-oxotetrahydrofuran-2,3-dicarboxylic acid was dissolved in 88 ml of acetone, and 6.5 g of 1,1'dicyclohexylcarbodiimide was added thereto, followed by stirring at room temperature for 2 hours. 3.26 ml of benzyl alcohol was added to the reaction solution, and stirred at the same temperature for 12 hours. Insoluble mattes were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 4/1 to WO 97/01275 PCT/US96/11022 347 chloroform.methanol 50/1) to obtain the above-identified compound as yellow solid.
Preparation of 2-benzyl 3-tert-butyl (2S,3S)-5oxotetrahvdrofuran-2.3-dicarboxvlate 7.93 g of 2 S-3R)-2-benzyloxycarbonyl-5oxotetrahydrofuran-3-carboxylic acid was dissolved in 75 ml of chloroform,, and 5.5 g of 4 -dimethylaminopyridine, 8.6 g of 1ethyl- 3 3 -dimethylaminopropyl)carbodiimide hydrochloride and 5.7 ml of tert-butyl alcohol were sequentially added thereto, followed by stirring at room temperature for 60 hours. The reaction solution was poured into 1N hydrochloric acid cooled with ice, and extracted with ehtyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 5/1) to obtain the above-identified compound as white solid.
Preparation of 2 S,3S)-3-tert-butoxycarbonyl-5oxotetrahydrofuran-2-carboxvlic acid 6.4 g of 2 benzyl 3-tert-butyl (2S,3S)-5oxotetrahydrofuran-2,3-dicarboxylate was dissolved in 80 ml of ethyl acetate, and 640 mg of a 10% palladium-carbon catalyst was added thereto, followed by catalytic reduction for 3 hours at room temperature under hydrogen atmospheric pressure. The catalyst was filtered off, and the filtrate was evaporated to dryness under reduced pressure to obtain the above-identified compound as white solid.
Preparation of ter-butyl 1R,2R)-4,4diethoxy- -methyl- 2 -(3,4-methylenedioxyphenyl)butyl 2 -naphtylmethyl)carbamoyl]-5-oxotetrahydrofuran-3carboxylate 61 mg of N- (R,2R)-4,4-diethoxy-1-methyl-2-(3,4methylenedioxyphenyl)butyl}-2-naphtylmethylamine, 35 mg of WO 97/01275 PCT/US96/11022 348 (2S,3S)- 3 -tert-buthoxycarbonyl-5-oxotetrahydrofuran-2-carboxylic acid and 83 ll of triethylamine, were dissolved in 2 ml of chloroform, and 0.5 ml of a chloroform solution containing 34 mg of 2-chloro-l,3-dimethylimidazolinium chloride was added thereto under cooling with ice followed by stirring at the same temperature of 30 minutes. The reaction solution was poured into water and extracted with ethyl acetate. The extract solution was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 1/3) to obtain of the above-identified compound as colorless oily substance.
Preparation of tert-butyl (1R,2R)-3-formyl- 1-methyl-2-(3,4-methylenedioxyphenyl)propyl}-N-(2naphtylmethyl)carbamoyl]-5-oxotetrahydrofuran-3carboxylate 490 mg of tert-butyl 1R,2R)-4,4diethoxy- 1 -methyl-2-(3,4-methylenedioxyphenyl)butyl}-N-(2naphtylmethyl)carbamoyl]-5-oxotetrahydrofuran-3-carboxylate was dissolved in 15 ml of tetrahydrofuran, and 5 ml of 1 N hydrochloric acid was added thereto, followed by stirring at room temperature for 24 hours. To the reaction solution, a saturated sodium hydrogencarbonate aqueous solution was added, and the mixture was extracted with ethyl acetate. Then the organic layer was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Hexane/ethyl acetate 5/1) to obtain the above-identified compound as colorless oily substance.
Preparation of tert-butyl (1R,2R4E)-5-(2benzoxazolyl)- 1-methyl-2-(3,4-methylenedioxyphenyl)-4-
I
WO 97/01275 PCT/US96/11022 -349pentenyl oxotetrahvdrofuran-3-carboxvlate.
29 mg of 60% oily sodium hydride was suspended in ml of tetrahydrofuran, and 389 mg of 2benzoxazolylmethyl(triphenyl)phosphonium bromide was added thereto, followed by stirring at room temperature for 2 hours. 5 ml of a tetrahydrofuran solution containing 319 mg of tert-butyl (1R,2R)-3-formyl-l-methyl-2-(3,4methylenedioxyphenyl)propyl oxotetrahydrofuran-3-carboxylate was added thereto, followed by stirring at room temperature overnight. Then water was added to the solution, and the mixture was extracted with diethyl ether. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate 3/1) to obtain the aboveidentified compound as a colorless foam.
Preparation of (2S,3S)-2-[N-{(1R,2R,4E)-5-(2-benzoxazolyl)-1methyl-2-(3,4-methylenedioxyphenyl)-4-pentenyl naphtylmethyl)carbamoyl]-5-oxotetrahydrofuran-3-carboxylic acid.
295 mg of tert-butyl benzoxazolyl)-1 -methyl-2-(3,4-methylenedioxyphenyl)-4-pentenyl (2-naphthylmethyl)carbamoyl]-5-oxotetrahydrofuran-3-carboxylate was dissolved in 5 ml of formic acid, and the solution was left to stand at room temperature overnight. The reaction solution was distilled under reduced pressure. The product was purified by silica gel column chromatography (chloroform/methanol 50/1) to obtain the aboveidentified compound as white solid.
1 H-NMR(CDCl3)8:0:99 and 1.10 (total 3H, each d, J=6.2 Hz, 6.3 Hz), 2.50-3.10 (5H, 4.15-4.25 and 4.37-4.47 (total 1H, each 4.50- 5.35 (4H, m) 5.73, 5.75, 5.88 and 5.94 (total 2H, each 6.07 and 6.36 WO 97/01275 WO 9701275PCTfUS96/1 1022 350 (total I1H, each d, each J- 15.8Hz), 6.60-6.75 (4H, in), 7.25-7.82 (11 H, m) FAB-MS:633 (MI+H) Preparation of disodium. R,2R,4E)-5-(2benzoxazolyl)-l1-methyl-2-(3 4 -methylenedioxyphenyl)>4 pentenyl 2 -naphthylmethyl)carbamoyl] -3-carboxy-4hydroxybutanoate 262 mg of the lactone thus obtained was dissolved in a mixed solution of 10 of methanol and 5 ml of water, and 0.91 ml of a IN sodium hydroxide aquous solution was added under cooling with ice with stirring, followed by stirring at room temperature overnight. The reaction solution was evaporated to dryness under reduced pressure. The residue was crystalized from 2 ml of methanol and 10 ml of diethyl ether to obtain the above-identified compound as white solid.
IH-NMR(CD3OD)8:0.83-1.08 (3H, in), 2.30-3.20 (6H, in), 4.53- 5.10(4H, in), 5.85 and 5.89 (total 2H, each 5.80-6.95 (4H, in), 7.20-8.06 (12H, in) FAB -MS :695(M+H) EXAMPLE 7 Preparation of sodium 4- 1(1R,2R,4E)-5-(2-benzoxazolyl)- 1-methyl- 2-(3 ,4-methylenedioxyphenyl)-4-pentenyl I -N-(2-naphthylmethyl)carbamoyl] -3 -tert-butoxycarbonyl-4-hydroxy-3-.butenoate (Compound Preparation of methyl (1R,2R,4E)-5-(2benzoxazolyl)- 1 -methyl-2-(3 ,4-methylenedioxyphenyl)-4pentenyl I 2 -naphthylmethyl)carbomoyly3-tertbutoxvcarbonyl-4-hydroxybutanoate 193 mg of tert-butyl (1R,2R,4E)-5-(2benzoxazolyl)- 1 -methyl-2-(3 4 -methylenedioxyphenyl)-4-pentenyl)
-N-
2 -naphthylmethyl)carbamoyl]-5-oxotetrahydrofuran-3.carboxylate was WO 97/01275 PCT/US96/11022 -351 dissolved in a mixed solution of 5 ml of tetrahydrofuran and 2 ml of water, and 0.31 ml of a 1N sodium hydroxide aqueous solution was added thereto, followed by stirring at room temperature for 15 hours.
The reaction solution was acidified (about pH4) by an addition of IN hydrochloric acid and then extracted with ethy acetate. The extract solution was dried over anhydrous magnesium solfate. The drying agent was filtered off, and then the solvent was distilled off under reuced pressure. The obtained carboxylic acid was dissolved in ethyl acetate, and a slightly excess amount of diazomethane was added at room temperature. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 2/1) to obtain the above-identified compound as colorless oily substance.
Preparation of methyl benzoxazolyl)-1 -methyl-2-(3,4-methylenedioxyphenyl)-4pentenyl }-N-(2-naphthylmethyl)carbamoyl }-3-tertbutoxvcarbonyl-4-hydroxy-3-butenoate 36 mg of methyl (3S,4S)-4-[N-{(1lR,2R,4E)-5-(2benzoxazolyl)-l-methyl-2-(3, 4 -methylenedioxyphenyl)-4-pentenyl (2-naphthylmethyl)carbamoyl]-3-tert-butoxycarbonyl-4hyudroxybutanoate was dissolved in 2 ml of chloroform, and 42 mg of a Dess-Martin reagent (periodenane) was added thereto, followed by stirring at room temperature for 1 hour. The reaction solution was poured into a mixed solution of a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium thiosulfate aqueous solution and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel thin layer chromatography (KieselgelTM 60F254' ArtTM 5744; hexane/ethyl acetate 3/2) to obtain the above-identified compound as colorless oily substance.
WO 97/01275 PCT/US96/11022 -352- Preparation of (1R,2R,4E)-5-(2-benzoxazolyl)1methyl-2-(3, 4 -methylenedioxyphenyl)-4-penteny naphthylmethyl)carbamoyl]- 3 -tert-butoxycarbonyl-4 hvdroxv-3-butenoic acid 9.9 mg of methyl (1R,2R,4E)-5-(2-benzoxazolyl)- 1-methyl-2-(3, 4 -methylenedioxyphenyl)-4-pentenyl naphthylmethyl)carbamoyl]-3-tert-butoxycarbonyl-4-hydroxy-3butenoate was dissolved in a mixed solution of 3 ml of tetrahydrofuran and 1 ml of water, and 140 gl of a 1N sodium hydroxide aqueous solution was added thereto, followed by stirring at room temperature for 4 hours. The reaction solution was acidified by an addition of IN hydrochloric acid and extracted with ethyl acetate. The extract solution was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel thin layer chromatography (Kieselgel TM 60F254' ArtTM 5744; chloroform/methanol 10/1) to obtain the above-identified compound as a colorless foam.
1 H-NMR(CDCl3) 6:0.96-1.06 (3H, 1.41-1.51 (9H, min), 2.30-3.29 (5H, min), 4.15-4.98 (4H, min), 5.88-6.34 (3H, 6.41-6.74 (4H, min), 7.21-7.88 (11H, m) FAB-MS:705(M+H) Preparation of sodium (1 R,2R,4E)-5-(2benzoxazolyl)- 1-methyl- 2 -(3,4-methylenedioxyphenyl)-4pentenyl }-N-(2-naphthylmethyl)carbamoyl]-3-tertbutoxvcarbonvl-4-hydroxv-3-butenoate 850 mg of (1 R,2R,4E)-5-(2-benzoxazolyl)- 1methyl-2-(3,4-methylenedioxyphenyl)-4-pentenyl naphthylmethyl)carbamoyl]- 3 -tert-butoxycarbonyl-4-hydroxy-3butenoic acid, prepared as described in Step was dissolved in ml of methanol, and sodium methoxide was added thereto. The solvent was distilled off under reduced pressure. The residue was WO 97/01275 PCT/US96/11022 -353solidified from ether and hexane to obtain the above-identified compound as a white powder.
1 H-NMR(CD30D) 6:0.99-1.10 (3H, 1.45-1.53 (9H, 2.16- 3.53 (5H, 4.19-5.22 (4H, 5.50-6.33 (3H, 6.37-6.86 (4H, 7.22-8.15 (11H, m) FAB-MS:727(M+Na) EXAMPLE 8 Preparation of 2 (R)-Amino-3-mercapto]-propylamino- 3(S)-methyl]pentyloxy-3-phenylpropionyl-homoserine lactone and 2 (R)-Amino-3-mercapto]-propylamino-3(S)methvllpentvloxy-3-phenyl-propionyl-homoserine Step A: Preparation of N-(a-chloroacetyl)-L-isoleucinol To a stirred solution of L-isoleucinol (20 g, 0.17 mol) and triethylamine (28.56 ml, 0.204 mol) in CH2C12 (500 ml) at -78 0
C
was added chloroacetyl chloride (16.3 ml, 0.204 mol) over 5 minutes.
The cooling bath was removed and the solution allowed to warm to -20°C. The mixture was diluted with EtOAc and washed sequentially with 1 M HC1, and brine and dried (Na2SO4). Evaporation in vacuo afforded the amide title compound (35 g, 100%).
Rf 0.3 CH2C12: MeOH (95:5); 1H NMR (CDC13) 5 6.80 (1H, brd, J 5 Hz), 4.10 (2H, 3.84 (1H, 3.79 (2H, 2.65 (1H, brs), 1.72 (1H, 1.55 (1H, 1.17 (1H, 0.96 (3H, d, J 6Hz) 0.90 (3H,t, J=6 Hz).
Step B: Preparation of 5(S)-[1(S)-methyl]propyl-2,3,5,6-tetrahydro-4H- 1.4-oxazin-3-one To a stirred solution of N-(a-chloroacetyl)-L-isoleucinol (7.4 g, 0.038 mol) in THF (125 ml) under argon at 0 C was slowly added sodium hydride (2.2 g of a 60% dispersion in mineral oil, 0.055 mol) with concomitant gas evolution. After completing the addition, the mixture was warmed to room temperature and WO 97/01275 PCT/US96/11022 -354stirred for 16 hr. Water (2.8 ml) was added and the solvents evaporated in vacuo. The residue was dissolved in CHC13 (70 ml) and washed with water saturated NaCl solution. The organic layer was dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed using silica gel eluting with CH2Cl2:MeOH (96:4) to afford the lactam title compound (4.35 g, 72%) as a white solid.
Rf 0.35 CH2C12:MeOH (95:5); 1H NMR 8 (CDC13) 6.72 (1H, brs), 4.20 (1H, d, J 14.5 Hz), 4.10 (1H, d, J 14.5 Hz), 3.88 (1H, dd, J 9 and 3.5 Hz), 3.58 (1H, dd, J 9 and 6.5 Hz), 3.45 (1H, brqt, J 3.5 Hz), 1.70-1.45 (2H, 1.34 1.15 (1H, 0.96 (3H, t, J 6.5 Hz), 0.94 (3H, d, J 6.5 Hz).
Step C: Preparation of methvllpropyl-2.3.5.6-tetrahydro-4H-1,4-oxazin-3-one (S)-Methyl]propyl-2,3,5,6-tetrahydro 4H-1,4oxazin-3-one (12.2 g, 0.0776 mol) and DMAP (18.9 g, 0.155 mol) were dissolved in methylene chloride (120 ml) under argon at R.T.
Boc anhydride (33.9 g, 0.155 mol) was added to the stirred solution in one portion, with concomitant gas evolution and the mixture was stirred at R.T. for 16 hr. The solvent was evaporated in vacuo and the residue was taken up in ethyl acetate and washed sequentially with citric acid, 50% NaHCO3 and finally brine. The organic extract was dried (Na2SO4) and evaporated in vacuo. Chromatography of the residue over silica gel eluting with 20% EtOAc in hexanes afforded the title compound as a white solid.
Rf 0.75 EtOAc:hexanes (20:80); mp 59-60°C Anal. Calc'd. for C13H2304N C, 60.68; H,9.01; N, 5.44. Found: C, 60.75; H, 9.01; N, 5.58.
1H NMR (CDC13) 8 4.25 (1H, d, J 15 Hz), 4.15 (1H, d, J 15 Hz), 4.15 4.00 (2H, 3.73 (1H, dd, J 10 and 2 Hz), 1.88 (1H, qt, J 6 Hz), 1.55 (9H, 1.50 1.36 (1H, 1.35 1.19 (1H, m) 1.00 (3H, d, J 6 Hz) 0.95 (3H, d, J 6.5 Hz).
WO 97/01275 PCT/US96/11022 -355- Step D: Preparation of N-(tert-Butoxycarbonyl)-2(S)-benzyl- (S)-methyl]propyl-2,3,5,6-tetrahydro-4H-1,4oxazin-3-one A solution of N-(tert-butoxycarbonyl)-5(S)-[1(S)methyl]propyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-3-one (5.75 g, 22.34 mmol) in DME (100 ml) under argon was cooled to -60°C. The cold solution was transferred via canula to a second flask containing sodium bis(trimethylsilyl)amide (24.58 ml of a IM solution in THF, 24.58 mmol) at -78 0 C under argon. After stirring for 10 minutes, benzyl bromide (2.25 ml, 18.99 mmol) was added over 5 minutes and the resulting mixture was stirred at -78 0 C for 3 hours. After this time, the reaction mixture was transferred via cannula to another flask containing sodium bis(trimethylsilyl)amide (24.58 ml of a 1M solution in THF, 24.58 mmol) at -78 0 C, under argon. After stirring for a further 5 minutes, the reaction was quenched by the addition of saturated aqueous ammonium chloride solution (24.6 ml) and allowed to warm to room temperature. This mixture was diluted with brine ml) and water (20 ml) and then extracted with ethyl acetate (2 x 100 ml). The organic extracts were washed with brine (50 ml) and evaporated in vacuo to afford an oil. Chromatography of the residue over silica gel (230-400 mesh, 300 g) eluting with 10-20% ethyl acetate in hexanes afforded the title compound as a clear oil.
Rf 0.25 EtOAc:Hexanes (20:80); 1H NMR (CDC13) 8 7.35 7.15 (5H, 4.31 (1H, dd, J 6 and 2 Hz), 4.03 (1H, d, J 12 Hz), 3.88 (1H, dd, J 6 and 1 Hz), 3.66 (1H, dd, J 12 and 2 Hz), 3.29 (1H, dd, J 12 and 3 Hz), 1.54 (9H, s), 3.12 (1H, dd, J 12 and 7 Hz), 1.47 (1H, 1.25 (1H, 1.10 (1H, 0.83 (3H, d, J 6 Hz), 0.80 (3H, t, J 6 Hz).
Step E: Preparation of N-(tert-butoxycarbonyl)-2(S)-[2(S)amino-3(S)-methyl]pentvloxv-3-phenvl-propionic acid To a stirred solution of N-(tert-butoxycarbonyl)-2(S)benzyl-5(S)-[1(S)-methyl]-propyl-2,3,5,6-tetrahydro-4H-1,4-oxazin- 3-one (5.1 g, 14.7 mmol) in THF (150 ml) and water (50 ml) at 0 C WO 97/01275 PCT/US96n1o022 -356was added hydrogen peroxide (15 ml of a 30% aqueous solution, 132 mmol) and lithium hydroxide (3.0 g, 63.9 mmol). After stirring for minutes, the reaction was quenched with a solution of sodium sulfite (28.25 g, 0.224 mol) in water (70 ml). The THF was evaporated in vacuo and the aqueous phase was acidified to pH 3-4 by addition of 10% citric acid solution and extracted with EtOAc. The organic extracts were dried (Na2SO4), evaporated in vacuo and the residue purified by chromatography over silica gel eluting with 4% MeOH in CH2C12 to give the lactam methyl]propyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-3-one and then with MeOH in CH2C12 to afford the title compound (4.03 g, 75%) as a viscous oil.
Rf 0.4 MeOH:CH2Cl2 (5:95) 0.3% AcOH; 1H NMR (d6 DMSO) 8 7.35 7.10 (5H, 6.68 (1H, br, 3.75 (1H, dd, J 7.5 and 2.5 Hz) 3.54 (1H, 3.5 3.2 (2H, m) 2.99 (1H, dd, J 12.5 and 2.5 Hz), 2.75 (1H, dd, J 12.5 and 7.5 Hz), 1.50 1.35 (11H, 0.98 (1H, sept, J 6 Hz), 0.78 (3H, t, J 6 Hz), 0.65 (3H, d, J 6 Hz); FAB MS 366 266 (MH2+ CO2tBu).
Step F: Preparation of N-(tert-butoxycarbonyl)-2(S)-[2(S)amino-3(S)-methyl]-pentyloxy-3-phenyl-propionylhomoserine lactone To a stirred solution of N-(tert-butoxycarbonyl)-2(S)- [2(S)-amino-3(S)-methyl]-pentyloxy-3-phenylpropionic acid (0.53 g, 1.45 mmol) and 3-hydroxy-1,2,3,-benzotriazin-4(3H)-one
(HOOBT)
(0.26 g, 1.6 mmol) in DMF (15 ml) at room temperature was added EDC (0.307 g, 1.6 mmol) and L-homoserine lactone hydrochloride (0.219 g, 6.0 mmol). The pH was adjusted to pH= 6.5 by addition of NEt3 (the pH was monitored by application of an aliquot of the reaction mixture to a moist strip of pH paper). After stirring at room temperature for 16 hr, the reaction was diluted with EtOAc and washed with saturated NaHCO3 and then brine and dried (NaSO4).
Evaporation in vacuo (sufficient to remove DMF) and
I
WO 97/01275 PCT/US96/11022 -357chromatography over silica gel eluting with 5% acetone in CH2C12 afforded the title compound as a white solid, mp 115-117°C.
Rf 0.3 Acetone: CH2C12 (5:95).
1H NMR (CDC13) 5 7.73 (1H, brd, J=5 Hz), 7.40-7.15 (5H, 4.68 (1H, dt, J=9 and 7.5 Hz), 4.65-4.35 (2H, 4.33-4.18 (1H, 4.20 (1H, dd, J=7 and 3 Hz), 3.78 (1H, 3.49 (1H, dd, J=7.5 and Hz), 3.37 (1H, dd, J=7.5 and 6.5 Hz), 3.15 (1H, dd, J=11.5 and 2 Hz), 2.86 (1H, dd, J=11.5 and 7.5 Hz), 2.68 (1H, m) 2.11 (1H, q, J=9 Hz), 1.55-1.30 (11H, 1.07 (1H, 0.87 (3H, t, J=6.3 Hz), 0.79 (3H, d, J=6 Hz).
Step G: Preparation of 2(S)-[2(S)-amino-3(S)-methyl]-pentyloxy- 3-phenylpropionyl-homoserine lactone hydrochloride Anhydrous HC1 gas was bubbled through a cold (0°C) solution of N-(tert-butoxycarbonyl)-2(S)-[2(S)-amino-3(S)methyl]pentyloxy-3-phenylpropionyl-homoserine lactone (3.0 g, 6.7 mmol) in ethyl acetate (120 ml) until a saturated solution was obtained. The resulting mixture was stirred at 0°C for 1 hr. The solution was purged with nitrogen and the mixture concentrated in vacuo to afford the title compound as a sticky foam which was used without further purification.
1H NMR (d6 DMSO) 6 8.60 (1H, d, J=7 Hz), 8.08 (3H, brs), 7.35- 7.15 (5H, 4.60 (1H, qt, J=8 Hz), 4.36 (1H, t J=7.5 Hz), 4.22 (1H, q, J=7.5 Hz), 4.15-3.95 (2H, 3.64 (1H, dd, J=9 and 2.5 Hz), 3.15- 3.00 (2H, 2.92 (1H, dd, J=12.5 and 5.0 Hz), 2.40-2.15 (2H, m), 1.65 (1H, 1.43 (1H, 1.07 (1H, 0.82 (3H, t, J=6 Hz), 0.72 (3H, d, J=6.0 Hz).
Step H: Preparation of 2(S)-[2(S)-[2(R)-(tert-butoxycarbonyl)amino-3-triphenylmethylmercap-to]propylamino-3(S)methyl]-pentyloxy-3-phenylpropionyl-homoserine lactone 2(S)-[2(S)-Amino-3(S)-methyl]pentyloxy-3-phenylpropionyl-homoserine hydrochloride (6.7 mmol) and N-(tert-butoxy-
I_
WO 97/01275 PCT/US96/11022 -358carbonyl)-S-triphenylmethylcysteine aldehyde (0.74 g, 7.5 mmol) (prepared from N-(tert-butoxycarbonyl)-S-triphenylmethylcysteine by the procedure of Goel, Krolls, Stier, Keston, S. Org.
Syn. 1988, 67, 69.) and potassium acetate (3.66 g, 8.2 mmol) were dissolved in methanol (48 ml). Activated 4A molecular sieves (6g) and then Na(CN)BH3 (0.70 g, 10.7 mmol) were added and the resulting slurry was stirred under argon at room temperature for 16 hr. The solids were removed by filtration and the filtrate evaporated in vacuo. The residue was dissolved in EtOAc and washed sequentially with saturated aqueous NaHCO3 and brine and then dried (Na2SO4). Evaporation in vacuo afforded an oil which was purified by chromatography over silica gel eluting with a gradient of 30-50% EtOAc in hexane to afford the title compound contaminated with a small amount of the corresponding methyl ester.
1H NMR (CD30D) 8 7.60-7.05(20H, 4.64 (1H, d, J=9.0Hz), 4.39 (1H, br t, J=9Hz), 4.25(1H, 3.93 (1H, 3.75-3.60(1H, 3.55 (1H, dd, J=9.0 and 2Hz), 3.20 (1H, dd, J=9.0 and 6.0 Hz), 3.04 (1H, dd, J=15.0 and 5.0 Hz), 2.85 (1H, dd, J=15.0 and 9.0 Hz), 2.60 (1H, dd, J=12.0 and 5.0 Hz), 2.50-2.15 (7H, 1.45 (9H, 1.40-1.20 (1H, 1.07 (1H, 0.87 (3H, t, J=6 Hz), 0.67 (3H, d, J=6.0 Hz).
Step I: Preparation of 2 2 (S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-phenylpropionylhomoserine lactone To a stirred solution of 2 (S)-[2(S)-[2(R)-(tert-butoxycarbonyl)amino-3-triphenylmethylmercapto]-propylamino-3(S)methyl]pentyloxy-3-phenylpropionyl-homoserine lactone (2.72 g, 3.49 mmol) in CH2C12 (90 ml) was added HSiEt3 (2.16 ml, 13.5 mmol) and TFA (43.2 ml, 0.56 mol) and the solution was stirred at R.T. under argon for 2 hrs. The solvent was evaporated in vacuo and the residue partitioned between 0.1% aqueous TFA (200 ml) and hexanes (100 ml). The aqueous layer was separated and washed with hexanes (20 ml) and then lyophilised. The resulting white lyophilate was chromatographed in 5 equal portions over a Waters Prepak WO 97/01275 PCT/US96/11022 -359cartridge (C-18, 15-20 mM 100 A) eluting with a gradient of 95:5 to 5:95 0.1% TFA in H20 0.1% TFA in CH3CN at 100 ml/min over min. The desired compound eluted after 19 min. The CH3CN was evaporated in vacuo and the aqueous solution lyophilised to afford the title compound (1.95 g, 77%) as the TFA salt.
The salt is hygroscopic and is prone to disulphide formation if left in solution and exposed to air.
1H NMR 6 (CD30D) 7.40-7.15 4.55-5.40 (2H, 4.33 (1H, 4.18 (1H, 3.90-3.62 (3H, 3.53 (1H, dd, J=10.5 and Hz), 3.37 (1H, dd, J=10.5 and 6.0 Hz), 3.23 (1H, 3.15-2.95 (2H, 2.88 (1H, dd, J=12.5 and 5.0 Hz), 2.55-2.25 (2H, 1.92 (1H, 1.49 (1H, 1.23 (1H, 0.94 (3H, t, J=6 Hz), 0.90 (3H, d, J=6Hz).
FAB MS 873 438 361 (MH±Ph) Anal. calc'd for C22H3604N3S 2.6 TFA:C, 43.58; H, 5.25; N, 5,82.
Found: C, 43.62; H, 5.07; N, 5.80.
Step J: Preparation of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-phenylpropionylhomoserine 2 (R)-Amino-3-mercapto]propyl-amino-3(S)methyl]pentyloxy-3-phenylpropionyl-homoserine lactone (0.00326 mmol) was dissolved in methanol (0.0506 ml) and 1N sodium hydroxide (0.0134 ml) was added followed by methanol (0.262 ml).
The conversion of the lactone to the hydroxy-acid was confirmed by HPLC analysis and NMR.
I
WO 97/01275 PCT/US96/11022 -360- EXAMPLE 9 Preparation of 2 (R)-Amino-3-mercapto]-propylamino- 3(S)-methyl]pentyloxy-3-phenylpropionyl-methionine sulfone methyl ester (Compound Step A: Preparation of Methionine sulfone methyl ester Thionyl chloride (2.63 ml, 36 mmol) was added dropwise to a stirred solution of N-Boc-Met sulfone (5 g, 18 mmol) in methanol (40 ml) cooled at 0°C. After the completion of the addition, the resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was recooled to 0°C and slowly treated with solid sodium bicarbonate to adjust the pH to 7.
The mixture was concentrated in vacuo to remove methanol and the residue was dissolved in a minimum amount of water (solution pH ca.
and extracted with ethyl acetate four times. The combined extracts were dried (Na2S04) and concentrated to give the title compound (1.5 NMR (CD30D) 8 2.04 2.21 2.98 (3H, 3.23 (2H, t, J=7Hz), 3.63 d of d, J=8.6Hz), 3.77 (3H, s).
Step B: Preparation of N-(tert-Butoxycarbonyl)-2(S)-[2(S)amino-3(S)-methyl]-pentyloxy-3-phenyl-propionylmethionine sulfone methyl ester The title compound was prepared in the same fashion as that described in Example 8, Step F, but using methionine sulfone methyl ester in place of homoserine lactone hydrochloride. NMR 8 0.80 (3H, d, J=6Hz), 0.88 (3H, t, J=6Hz), 1.12 m), 1.47 (9H, 2.10 2.32 2.93 (3H, 3.5-3.7 (2H, m), 3.74 (3H, 4.01 d of d, J=7.4Hz), 4.60 d of d, 6.60 d, J=8Hz), 7.25 (5H, m).
Step C: Preparation of 2 2 (S)-Amino-3(S)-methyl]pentyloxy-3-phenylpropionyl-methionine sulfone methyl ester hydrochloride WO 97/01275 PCTIUS96/11022 361 The title compound was prepared in the same fashion as that described in Example 8, Step G, but using N-(tertbutoxycarbony1)-2(S)-[2(S).arino.3 (S)-methyl]pentyloxy-.3phenylpropionyl-methionine sulfone methyl ester in place of N-(tertbutoxycarbonyl)-2(S)- [2(S)-amino-3 (S)-methyljpentyloxy-3phenylpropionyl-homoserine lactone. NMR (CD3OD) 6 0.85 (3H, d, J=6Hz), 0.94 (3H, t, J=6Hz), 1.20 in), 1.52 mn), 1.72 in), 2.14 in), 2.38 mn), 2.98 (3H, 3.57 d of d, J=12, 6Hz), 3.73 d of d, J=12, 9Hz), 3.78 (3H, 4.15 d of d, J=8.6Hz), 4.63 d of d, J=8.5Hz), 7.30 (5H, in).
Step D: Preparation of 2 (R)-(tert-Butoxy-carbonyl)y amino-3-triphenylinethylinercapto] -propylainino-3 mehlpnyoy3peylpoinlmtinn sulfone methyl ester The title compound was prepared in a similar fashion as that described in Example 8, Step H, but using 2 (S)-[2(S)-ainino-3(S)methyljpentyloxy-3-phenyppropionylinethionine sulfone methyl ester hydrochloride in place of 2 (S)-[2(S)-amino-3(S)methyllpentyloxy-3-phenylpropionyl..homoserine lactone hydrochloride. NMR (CD3OD) 8 0.70 (3H, d, J=6Hz), 0.88 (3H, t, J=6Hz), 1. 10 mn), 1.47 (9H, 2.15 in), 2.67 in), 2.92 (3H, 3.67 in), 4.68 d of d, J=10, 6Hz), 7.15-7.45 in).
Step E: Preparation of 2 (R)-Amino-3-mercapto]propylainino-3 (S )-iethyllpentyloxy-3 -phenylpropionylmethionine sulfone methyl ester The title compound was prepared in a similar fashion as that described in Example 8, Step I, but using 2 (S)-1 2 butoxycarbonyl)anino-.3 -triphenylinethylinercaptolpropylanino.3 inethyl]-pentyloxy-3-phenylpropionyl..iethionine sulfone methyl *ester in place of 2 (R)-(tert-butoxy-carbonyl)-anjno-3 triphenyl-inethylinercaptolpropylainino-3(S )-iethyl]pentyloxy-3- WO 97/01275 PCTIUS96/1 1022 362 phenyl-propionyl-homoserine lactone. NMR (CD3OD) 5 0.83 (3H, d, J=6Hz), 0.93 (3H, t, J=6Hz), 1.20 in), 1.51 in), 1.80 in), 2.22 in), 2.43 in), 3.00 (3H, 3.78 (3H, 4.20 d of d, J=8.4Hz), 4.72 d of d, J=10, 6Hz), 7.30 (5H, in).
FABMS m/z 532 EXAMPLE Preparation of 2 (R)-Amino-3-mercapto]-propylamino-.
3 (S)-methyl]-pentyloxy-3-phenylpropionyl..iethionine sulfone isop~ropyl ester (Compound
A)
HS
HH 0
H
2 N N%-N N 0k.
0 0 2
S\
OH
3 The title compound was prepared using methods A-B from Example 9, except for Method A. Methionine sulfone isopropyl ester was prepared by coupling t-butyloxycarbonyl-methionine sulfone with isopropyl alcohol using dicyclohexylcarbodijinide
(DCC)
and 4 -dimethylaminopyridine (DMAP) followed by deprotection with HCl in EtOAc. NMR (CD3OD) 8 0.83 (3H, d, J 6 Hz), 0.94 (3H, t, J 6 Hz), 1. 11- 1.56 (2H, in), 1.28 (6H, d, J 6 Hz), 1.8-1.96 (lH, mn), 2.12-2.27 (1H, in), 2.89-3.0 (2H, mn), 3.01 (3H, 3.06-3.3 (4H, mn), 3.42 (1H, dd, J 6, 13 Hz), 3.65 (1H, dd, J 6,13 Hz), 3.68-3.91 (3H, in), 4.2-4.27 (1H, in), 4.61-4.7 (1H, mn), 4.96-5.12 (2H, in), 7.19-7.44 (5H, in). Anal. Calc'd. for C26H45N306S 2 -2 CF3CO2H: C, 44.07; H, 5.67; N, 4.97; Found C, 44.35; H, 5.68; N, 5.23 I WO 97/01275 PCT/US96/11022 -363- EXAMPLE 11 1-( 2 (R)-Amino- 3 -mercaptopropyl)-4-(2,3-dimethylbenzoyl)piperazine dihydrochloride Step A: tert -Butyl 4 2 3 -dimethylbenzoyl)piperazine-1carboxylate tert -Butyl piperazine-1-carboxylate (0.50 g, 2.6 mmol), 2,3-dimethylbenzoic acid (0.44 g, 2.9 mmol), 1-hydroxybenzotriazole (HOBT) (0.45 g, 2.9 mmol) and l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC HC1) (0.56 g, 2.9 mmol) were added to dry, degassed dimethylformamide (7 mL). The pH of the reaction was adjusted to 7 with triethylamine, and the reaction stirred for 2 h. The dimethylformamide (DMF) was distilled in vacuo, and the residue partitioned between ethyl acetate and water. The organic phase was washed with 2% aqueous potassium hydrogen sulfate, saturated sodium bicarbonate solution, saturated sodium chloride solution, and dried over magnesium sulfate. The crude product was chromatographed on silica gel using 30% ethyl acetate in hexane as eluant. The title compound was obtained as a white solid, NMR (CDC13, 300 MHz) 6 7.17 (1H, d, J=7 Hz), 7.13 (1H, t, J=7 Hz), 6.98 (1H, d, J=7 Hz), 3.77 (2H, 3.51 (2H, 3.32 (2H, t, J=5 Hz), 3.19 (2H, 2.28 (3H, 2.18 (3H, 1.45 (9H, s).
Step B: N-Methoxy-N-methyl 2(R)-tert -butoxycarbonylamino-3triphenvlmethylthiopropionamide The title compound was synthesized essentially according to the procedure described by O. P. Goel, U. Krolls, M. Stier, and S.
Kesten in Organic Syntheses, 1988, 67, 69-75. Thus N,O-dimethylhydroxylamine hydrochloride (1.05 g, 10.82 mmol) and N-methylmorpholine (1.22 mL, 11.14 mmol) were stirred in dichloromethane (6 mL) under nitrogen at 0°C for 30 min. In a separate flask, 2(R)-tert butoxycarbonylamino-3-triphenylmethyl-thiopropionic acid (5.02 g, 10.82 mmol) in tetrahydrofuran (11.5 mL, dry) and methylene chloride
I
WO 97/01275 PCT/US96/11022 -364mL) were cooled to -20°C, and N-methylmorpholine (1.22 mL, 11.14 mmol) and isopropylchloroformate (10.82 mL of 1M solution in toluene) were added via syringe, maintaining the temperature less than 0 C. The reaction was stirred at -30°C, and the suspension of N,Odimethylhydroxylamine hydrochloride and N-methylmorpholine in methylene chloride added all at once. The cooling bath was removed and the reaction allowed to warm to room temperature over 4 h. The reaction was cooled to 0°C and quickly washed with two portions of 0.2 N hydrochloric acid, two portions of 0.5 N sodium hydroxide, and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and reduced in vacuo to obtain the title compound as a clear gum. NMR (300 MHz, DMSO-d6) 8 7.30 4.43 (1H, br 3.56 (3H, 2.99 (3H, 2.30 (2H, 1.36 (9H, s).
Step C: 2(R)-tert -Butoxycarbonylamino-3-triphenylmethylthiopropanal The title compound was synthesized essentially according to the procedure described by O. P. Goel, U. Krolls, M. Stier, and S.
Kesten in Organic Syntheses, 1988, 67, 69-75. Thus lithium aluminum hydride (0.451 g, 11.90 mmol) and diethyl ether (40 mL) were stirred at 20 0 C under nitrogen for 1 h, then cooled to -45 0 C. N-Methoxy-Nmethyl 2(R)-tert -butoxycarbonylamino-3-triphenylmethylthiopropionamide (5.50 g, 10.82 mmol) in diethyl ether (20 mL) was added in a steady stream, maintaining the temperature less than -35°C. The cooling bath was removed and the reaction warmed to 5 0 C, then cooled to -35°C. A solution of potassium hydrogen sulfate (2.94 g, 21.64 mmol) in water (50 mL) was added slowly, maintaining the temperature less than 0°C. The reaction was warmed to 20 0 C over 1 h, and filtered through Celite. The filtrate was washed with 10% citric acid, saturated sodium chloride solution, and dried over magnesium sulfate. After filtration, the solvents were removed in vacuo and the title compound obtained as a foam.
WO 97/01275 PCT/US96/11022 -365- Step D: 1-(2(R)-tert -Butoxycarbonylamino-3-triphenylmethylthiopropyl)-4-(2.3-dimethylbenzovl)piperazine The product from step A (0.480 g, 0.860 mmol) was dissolved in methylene chloride (4 mL) and trifluoroacetic acid was added (2 mL). The reaction was stirred for 30 min. at 20 0 C, then evaporated to dryness. The crude trifluoroacetate salt was taken up in dimethylformamide and the pH adjusted to 6 by the addition of triethylamine. To this solution was added sodium triacetoxyborohydride (0.331 g, 1.56 mmol), and crushed molecular sieves (0.5 g), and the reaction cooled to 0°C under nitrogen. 2(R)-N-tert -butoxycarbonylamino-3-triphenylmethylthiopropanal (0.350 g, 0.782 mmol) in dimethylformamide was added slowly dropwise. The reaction was stirred at 20 0 C under nitrogen for 2 h. The dimethylformamide was removed in vacuo and the residue partitioned between saturated sodium bicarbonate and ethyl acetate. The organic phase was washed with saturated sodium chloride and dried over magnesium sulfate. Filtration and evaporation gave the title compound as a white foam. NMR (CDC13, 300 MHz) 6 7.0-7.6 (18H, 5.60 (1H, br 4.4-4.9 (1H, 2.1-3.9 (12H, 2.25 (3H, 2.15 (3H, br 1.40 (9H, s).
Step E: 1-(2(R)-Amino-3-mercaptopropyl)-4-(2,3-dimethylbenzoyl)piperazine dihydrochloride The product from step D and triethylsilane (0.54 mL, 3.4 mmol) were dissolved in methylene chloride (6 mL). To this solution was added trifluoroacetic acid (3 mL) and the reaction stirred at 20 0
C
for 30 min. The reaction was evaporated to dryness and partitioned between hexane and water. The aqueous phase was injected onto a 40 X 100 mm Waters PrepPak® reverse phase HPLC column (Delta-PakTM C18 15 pim, 100 and pure product isolated by gradient elution using 100% Solvent A trifluoroacetic acid in water) to 50% Solvent Solvent B (0.1 trifluoroacetic acid in acetonitrile) over min at a flow rate of 40 mL/min. Combined fractions were. evaporated, dissolved in water and passed through a Biorad AG® 3X4 ion exchange WO 97/01275 PCT/US96/11022 366 resin column (100-200 mesh, Cl- form). The column eluant was lyophilized to give the title compound as a white powder.
Analysis calculated for C16H25N30S 2.4 HCI 1.4 C, 45.76; H, 7.25; N; 10.01.
Found: C, 45.73, H; 7.25; N, 10.01.
EXAMPLE 12 1-[2(R)-Amino-3-mercaptopropyl]-4(S)-(2,3-dimethylbenzoyl)-2methylpiperazine dihydrochloride Step A: 1- Benzvl-3(S)-methylpiperazine-2.5-dione The title compound was prepared according to the procedure described by John S. Kiely and Stephen R. Priebe in Organic Preparations and Procedures Int., 22 761-768 (1990). Thus 100 mL of a stock solution of dicyclohexylcarbodiimide in methylene chloride (0.5 M) was added to methylene chloride (250 mL). This solution was cooled to 0°C under nitrogen and Boc-L-alanine (9.46 g, 50.00 mmol) was added. The resulting slurry was stirred for 5 min, and then ethyl N-benzylglycinate (9.37 mL, 50.00 mmol) was added.
The reaction was stirred for 2 h at 0°C, then at 20°C overnight. The precipitate was removed by filtration, and hydrogen chloride gas bubbled through the methylene chloride solution for 2-4 h, until the reaction was shown to be complete by tic. The solvent was removed in vacuo, and the residue partitioned between ethyl acetate (150 mL) and saturated sodium bicarbonate solution (42 mL). The organic phase was washed with saturated sodium chloride, dryed over magnesium sulfate, filtered and evaporated. The crude product was recrystallized from toluene to give the title compound as white crystals. NMR (300 MHz, CDC13) 8 7.30-7.38 (3H, 7.22-7.30 (2H, 6.94 (1H, br 4.59 (2H, 4.14 (1H, q, J=7 Hz), 3.84 (2H, 1.52 (3H, d, J=7 Hz).
Step B: 4-Benzvl-1-tert -butoxycarbonyl-2(S)-methylpiperazine The product from Step A (5.88 g, 27.00 mmol) was dissolved in THF (200 mL) and cooled under nitrogen to 0°C with WO 97/01275 PCT/US96/11022 -367mechanical stirring. Lithium aluminum hydride (3.69 g, 0.097 mol) was added slowly. The reaction was refluxed for 18 h, cooled to 0°C, and quenched by the sequential slow addition of 5 mL H20, 5 mL sodium hydroxide solution and 5 mL H20. The reaction was stirred for 30 min and filtered. The solvent was removed in vacuo, the crude product taken up in methylene chloride and dried over magnesium sulfate. The drying agent was removed by filtration, and the filtrate treated with di-tert -butyl dicarbonate (6.03 g, 27.6 mmol). After 2 h at 0 C, saturated sodium bicarbonate was added. The layers were separated, and the organic phase washed with saturated sodium chloride solution, then dried over magnesium sulfate. Filtration and evaporation gave the crude product which was purified by column chromatography on silica gel, eluting with 5% ethyl acetate in hexane. The title compound was obtained as a foam. NMR (300 MHz, CDC13) 6 7.25 (5H, 4.18 (1H, br 3.80 (1H, d, J=12 Hz), 3.46 (2H, AB q, J=14 Hz), 3.11 (1H, dt, J=4, 12 Hz), 2.75 (1H, d, J=10 Hz), 2.58 (1H, d, Hz), 2.12 (1H, dd, J=4, 12 Hz), 2.00 (1H, dt, J=4, 12 Hz), 1.45 (9H, s), 1.23 (3H, d, J=7 Hz).
Step C: 1-tert -Butoxvcarbonvl-2(S)-methvlpiperazine The product from Step B (5.28 g, 18.2 mmol) was dissolved in methanol (75 mL) in a Parr bottle, and the vessel purged with argon. To this was added 10 palladium on carbon (1.0 g) and the reaction hydrogenated under 60 psi hydrogen for 24 h. The catalyst was removed by filtration through Celite, and the filtrate evaporated in vacuo to give the title compound as an oil. NMR (300 MHz, CDC13) 4.15 (1H, 3.77 (1H, d, J=12 Hz), 2.85-3.06 (3H, 2.75 (1H, d, J=12 Hz), 2.64 (1H, dt, J=4, 12 Hz), 2.13 (1H, 1.45 (9H, 1.40 (3H, d, J=7 Hz).
Step D: 1-tert -Butoxycarbonyl-4-(2,3-dimethylbenzoyl)-2(S)methylpiperazine The product from Step C (1.00 g, 5.00 mmol) was converted to the title compound according to the procedure described in iii WO 97/01275 PCTIUS96/11022 -368- Example 11, Step A using 2,3-dimethylbenzoic acid (0.750 g, 5.00 mmol), HOBT (0.765 g, 5.00 mmol), EDC HCI (0.958 g, 5.00 mmol) and triethylamine to adjust the pH to 7. The title compound was obtained as a pale yellow solid.
Step E: 1-[2(R)-N-tert -Butoxycarbonylamino-3-triphenylmethylthiopropyl]-4-(2,3-dimethylbenzoyl)-2(S)-methylpiperazine The title compound was obtained from the product of Step D (0.390 g, 1.17 mmol) according to the procedure described in Example 11, Step D. Thus, l-tert -butoxycarbonyl-4-(2,3-dimethylbenzoyl)-2(S)-methylpiperazine (0.390 g, 1.17 mmol) was first treated with trifluoroacetic acid (3 mL) in methylene chloride (6 mL) for min. The reaction was evaporated to dryness, and the crude product reacted with sodium triacetoxyborohydride (0.331 g, 1.56 mmol) and 2(R)-N-tert -butoxycarbonylamino-3-triphenylmethylthiopropanal (0.350 g, 0.782 mmol) in the presence of crushed molecular sieves g) in DMF at pH 6 and 0-20 0 C overnight. The title compound was obtained as a foam.
Step F: 1 -[2(R)-Amino-3-mercaptopropyl]-4-(2,3-dimethylbenzoyl)-2(S)-methylpiperazine dihvdrochloride The product from Step E (0.370 g, 0.55 mmol) was converted to the title compound according to the procedure described for Step E, Example 11 using triethylsilane (0.350 mL, 2.20 mmol) and trifluoroacetic acid (4.5 mL) in methylene chloride (9 mL).
Purification by preparative HPLC (gradient elution: 100% Solvent A to Solvent A/50% Solvent B, 50 min) and ion exchange provided the title compound as a white powder.
Analysis calculated for C17H27N30S 2.7 HCI 1.1 C, 46.47; H, 7.32; N; 9.56.
Found: C, 46.40, H, 7.31, N, 9.39.
WO 97/01275 PCT/US96/11022 369 EXAMPLE 13 1 2 (R)-Amino-3-mercaptopropyl]-4-(2,3-dimethylbenzoyl>2(S)-(2methoxyethyl)p2iperazine dihydrochioride Step A: 1 -Benzyl-3 (S)-cyclohexoxycarbonylmethylpiperazine.2, The title compound was prepared according to the procedure described in Example 12, Step A, except using Boc-Laspartic acid, f3-cyclohexyl ester (6.15 g, 19.5 nmmol), ethyl Nbenzylglycinate (3.76 g, 19.5 mmol) and dicyclohexylcarbodiimide (39 mL, 0.5 M in dichioromethane, 19.5 mmol). The title compound was obtained as a white powder. NMR (CD3OD, 300 MHz) 5 7.3 (5H, in), 4.77 (1H, d, J=15 Hz), 4.73 (1H, in), 4.48 (1H, d, J=15 Hz), 4.35 (1H, t, J=5 Hz), 3.96 (1H, dd, J=l, 17 Hz), 3.87 (lH, dd, J=1, 17 Hz), 3.06 (1H, dd, J=4, 17 Hz), 2.81 (1H, dd, J=5, 17 Hz), 1.78 (4H, in), 1.54 (lH, in), 1.35 (5H, in).
Step B: 4-Benzyl- 1 -tert -butoxycarbonyl-2(S )-(2-hydroxyethyl)p2iperazine The title compound was prepared according to the procedure described in Example 12, Step B, except using l-benzyl-3(S)- (1.5 g, 4.36 inmol) and lithium aluminum hydride (0.76 g, 20.1 mmol), followed by ditert -butyl dicarbonate (1.04 g, 4.77 iniol). The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate in hexane. The title compound was obtained as a clear oil.
NMR (CD3OD, 300 MHz) 8 7.3 (5H, in), 4.20 (1H, in), 3.86 (1H, din, J=13 Hz), 3.55 (1H, d, J=13 Hz), 3.46 (2H, in), 3.39 (lH, d, J=13 Hz), 3.08 (OH, t, J=12 Hz), 2.80 (1H, d, J=12 Hz), 2.73 (lH, d, J=12 Hz), 2.04 (3H, in), 1.84 (1 H, sextet, J=7 Hz), 1.45 (9H, s).
Step C: 4- Benzyl-1-tert -butoxycarbonyl-2(S)-(2-methoxyethyl)piperazine WO 97/01275 PCT/US96/11022 -370- A solution of 4-benzyl-l-tert -butoxycarbonyl-2(S)-(2hydroxyethyl)piperazine (0.322 g, 1.00 mmol) in dry, degassed dimethylformamide (4 mL) was cooled under nitrogen to 0°C. Sodium hydride was added (0.052 g, 60% dispersion in oil, 1.30 mmol) followed by methyl iodide (0.88 mL, 1.41 mmol). After 3 h, the reaction was quenched with saturated ammonium chloride. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and saturated sodium bicarbonate. The ethyl acetate was washed with water, saturated sodium chloride solution, and dried over magnesium sulfate. The crude product was chromatographed on silica gel with ethyl acetate in hexane to obtain the title compound as a clear oil. NMR 300 MHz) 5 7.3 (5H, 4.19 (1H, 3.85 (1H, dm, J=13 Hz), 3.56 (1H, d, J=13 Hz), 3.16 (1H, d, J=13 Hz), 3.28 (2H, m, partially obscured by solvent), 3.23 (3H, 3.08 1H, t, J=13 Hz), 2.80 (1H, d, J=l 1 Hz), 2.70 (1H, d, J=l 1 Hz), 2.03 (3H, 1.86, (1H, sextet, J=6 Hz), 1.45 (9H, s).
Step D: 1-tert -Butoxycarbonyl-2(S)-(2-methoxvethyl)piperazine The title compound was prepared according to the procedure described in Example 12, Step C, except using 4-benzyl-1tert -butoxycarbonyl-2(S)-(2-methoxyethyl)piperazine (0.280 g, 0.83 mmol) and 10% palladium on carbon (80 mg). The title compound was obtained as an oil. NMR (CD30D, 300 MHz) 5 4.17 (1H, 3.81 (1H, dd, J=3, 13 Hz), 3.38 (2H, t, J=6 Hz), 2.82-3.02 (2H, 2.77 (2H, ABq, J=4, 13 Hz), 2.59 (1H, dt, J=4, 7 Hz), 2.04 (1H, 1.84 (1H, m), 1.46 (9H, s).
Step E: 1-tert -Butoxycarbonyl-4-(2,3-dimethylbenzoyl)-2(S)-(2methoxvethvl)piperazine The title compound was prepared according to the procedure described for Example 11, Step A except using 1-tert butoxycarbonyl-2(S)-(2-methoxyethyl)piperazine (0.179 g, 0.73 mmol), 2,3-dimethylbenzoic acid (0.115 g, 0.75 mmol), HOBT (0.098 g, 0.73 mmol), EDC*HC1 (0.153 g, 0.80 mmol) in methylene chloride (5 mL).
WO 97/01275 PCT/US96/11022 -371 Triethylamine was added to adjust the pH to 7. Chromatography on silica gel with 40% ethyl acetate in hexane afforded the title compound as a clear oil. NMR (CDCl3, 300 MHz) 5 6.9-7.2 (5H, 4.70 (1H, 3.8-4.5 (9H, mm), 2.0-2.3 (6H, mm), 1.9 (2H, 1.59 (9H, s).
Step F: 1-[2(R)-N-tert -Butoxycarbonylamino-3-triphenylmethylthiopropyl]-4-(2,3-dimethylbenzoyl)-2(S)-(2methoxyethyl)piperazine The title compound was prepared according to the procedure described in Example 11, Step D, except using 1-tert butoxycarbonyl-4-(2,3-dimethylbenzoyl)-2(S)-(2-methoxyethyl)piperazine (0.222 g, 0.590 mmol) and trifluoroacetic acid (3 mL) in methylene chloride (7 mL). The trifluoroacetate salt was reacted with 2(R)-N-tert -butoxycarbonylamino-3-triphenylmethylthiopropanal (0.316 g, 0.710 mmol), sodium triacetoxyborohydride (0.565 g, 2.65 mmol) in the presence of crushed molecular sieves in dichloroethane.
The title compound was isolated after chromatography on silica gel with ethyl acetate in hexane.
Step G: 1-[2(R)-Amino-3-mercaptopropyl]-4-(2,3-dimethylbenzovl)-2(S)-(2-methoxvethvl)piperazine dihydrochloride The title compound was obtained according to the procedure described for Step E, Example 11 except using tert -butoxycarbonylamino-3-triphenylmethylthiopropyl]-4-(2,3dimethylbenzoyl)-2(S)-(2-methoxyethyl)piperazine (0.247 g, 0.349 mmol), triethylsilane (0.22 mL, 1.39 mmol) and trifluoroacetic acid mL) in methylene chloride (7 mL). Purification by preparative HPLC (gradient elution: 95% Solvent A to 30% Solvent A/70% Solvent B, 60 min) and ion exchange provided the title compound as a white powder.
Analysis calculated for C19H31N30S 3.80 HCI 0.6 C, 44.39; H, 7.06; N, 8.17.
Found: C, 44.46; H, 7.07; N, 8.00.
WO 97/01275 PCT/US96/11022 -372- EXAMPLE 14 1-[2(R)-Amino-3-mercaptopropyl]-4-(2,3-dimethylbenzoyl)-2(S)-(2methvlthioethvl)piperazine dihydrochloride Step A: 1-Benzyl-3(S)-( 2 The title compound was prepared according to the procedure described in Example 12, Step A, except using Boc-Lmethionine (10.0 g, 40.0 mmol), ethyl N-benzylglycinate (7.75 g, 40.0 mmol), HOBT (5.41 g, 40.0 mmol) and EDC HCI (7.68 g, 40.00 mmol) in dimethylformamide. Upon completion of the reaction, the dimethylformamide was removed in vacuo and the crude product partitioned between ethyl acetate and water. The organic phase was washed with water and saturated sodium chloride solution, then dried over sodium sulfate. The solvent was removed in vacuo and the residue taken up in methylene chloride (200 mL). Trifluoroacetic acid (100 mL) was added and the reaction stirred at 20 0 C for 2 h. The volatiles were removed in vacuo and the residue partitioned between ethyl acetate and saturated sodium bicarbonate solution.. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate. The title compound was obtained as a white solid. NMR (CHC13, 300 MHz) 5 7.4-7.2 (6H, 4.60 (2H, AB q, J= 13 Hz); 4.24 (1H, 3.85 (2H, AB q, J= 18 Hz); 2.63 (2H, t, J= 7Hz); 2.3-2.1 (2H, 2.1 (3H, s).
Step B: 4- Benzyl-l-tert -butoxycarbonyl-2(S)-(2-methylthioethyl)piperazine The title compound was prepared according to the procedure described in Example 12, Step B, except using 1-benzyl-3(S)- (2-methylthioethyl)piperazine-2,5-dione (9.08 g, 32.6 mmol) and lithium aluminum hydride (4.40 g, 0.115 mmol), followed by di-tert butyl dicarbonate (7.64 g, 35.0 mmol). The crude product was purified by column chromatography on silica gel, eluting with 5% ethyl acetate I I WO 97/01275 PCT/US96/11022 -373in hexane. The title compound was obtained as a clear oil. NMR (CHC13, 300 MHz) 8 7.35-7.25 (5H, 4.18 (1H, br 3.90 (1H, br 3.55 (1H, d, J= 13Hz); 3.40 (1H, d, J= 13Hz); 3.07 (1H, t, J= 12 Hz); 2.72 (2H, 2.40 (2H, 2.10 (3H, 1.48 (9H, s).
Step C: 1-tert Butoxycarbonyl-2(S)-(2-methylthioethyl)piperazine To a solution of the product from Step B (6.63 g, 18.9 mmol) in 20 mL methylene chloride was added 2.15 mL (20 mmol) of 1-chloroethyl chloroformate (ACE-C1) dropwise with stirring. The temperature rose from 25 OC to 32 After 90 min was added another 0.20 mL of ACE-Cl and 2.4 g of solid potassium carbonate. After min the mixture was diluted with ethyl acetate and washed successively with 10% sodium bicarbonate and brine. The solution was dried (sodium sulfate) and evaporated to afford 8.4 g of an oil. The oil was dissolved in 500 mL methanol. The mixture was stirred at room temperature for 3 h and placed in the refrigerator overnight. The solution was treated with 100 mL of water and the methanol was evaporated. The solution was washed with ethyl acetate to remove nonbasic impurities. The aqueous phase was neutralized with sodium bicarbonate and extracted with methylene chloride. The extract was dried (potassium carbonate) and evaporated to give 4.0 g of 1-tert butoxycarbonyl-2(S)-( 2 -methylthioethyl)piperazine. NMR (CHC13, 300 MHz) 8 4.17 (1H, br 3.89 (1H, br 2.92 (4H, 2.70 (1H, dt, J= 4,12 Hz); 2.6-2.4 (2H, 2.10 (3H, 1.88 (1H, 1.48 (9H,s).
Step D: 1-tert -Butoxycarbonyl-4-(2,3-dimethylbenzoyl)-2(S)-(2methvlthioethyl)piperazine The title compound was prepared according to the procedure described for Example 11, Step A except using 1-tert butoxycarbonyl-2(S)-(2-methylthioethyl)piperazine (1.87 g, 7.19 mmol), 2,3-dimethylbenzoic acid (1.08 g, 7.19 mmol), HOBT (0.970 g, 7.19 mmol), EDC*HCl (1.64 g, 8.62 mmol) in methylene chloride mL). Triethylamine was added to adjust the pH to 7. Chromatography WO 97/01275 PCT/US96/11022 -374on silica gel with 30% ethyl acetate in hexane afforded the title compound as a clear oil. NMR (DMSO-d6, 300 MHz) 8 6.9-7.3 (3H, 4.22-4.50 (2H, mm), 3.62-4.06 (2H, mm), 2.66-3.24 (4H, mm), 2.4 (1H, 2.24 (3H, 1.92-2.18 (6H, ms),l.4-1.8 (2H, 1.39 (9H, s).
Step E: 1-[2(R)-N-tert -Butoxycarbonylamino-3-triphenylmethylthiopropyl]-4-(2,3-dimethylbenzoyl)-2(S)-(2-methylthioethvl)piperazine The title compound was prepared according to the procedure described in Example 11, Step D, except using 1-tert butoxycarbonyl-4-(2,3-dimethylbenzoyl)-2(S)-(2-methylthioethyl)piperazine (0.465 g, 1.18 mmol) and trifluoroacetic acid (3 mL) in methylene chloride (7 mL). The trifluoroacetate salt was reacted with 2(R)-N-tert -butoxycarbonylamino-3-triphenylmethylthiopropanal (0.400 g, 0.890 mmol), sodium triacetoxyborohydride (0.302 g, 1.42 mmol) in the presence of crushed molecular sieves in dichloroethane.
The title compound was isolated as a foam after chromatography on silica gel with 50% ethyl acetate in hexane.
Step F: 4-[2(R)-Amino-3-mercaptopropyl]-1-(2,3-dimethylbenzoyl)-2(S)-(2-methylthioethyl)piperazine dihydrochloride The title compound was obtained according to the procedure described for Step E, Example 11 except using tert -butoxycarbonylamino-3-triphenylmethylthiopropyl]-4-(2,3dimethylbenzoyl)-2(S)-(2-methylthioethyl)piperazine (0.465 g, 0.656 mmol), triethylsilane (0.420 mL, 2.63 mmol) and trifluoroacetic acid mL) in methylene chloride (7 mL). Purification by preparative HPLC (gradient elution: 95% Solvent A to 20% Solvent A/80% Solvent B, 60 min) and ion exchange provided the title compound as a white powder.
Analysis calculated for C19H31N30S2 2.80 HCI 0.8 C, 45.85; H, 7.17; N, 8.44.
Found: C, 45.85; H, 7.14; N, 8.32.
WO 97/01275 PCT/US96/11022 -375- EXAMPLE 1-[2(R)-Amino-3-mercaptopropyl]-4-(1-naphthoyl)-2(S)-(2methoxyethyl)piperazine dihydrochloride (Compound E) Step A: 4-Benzyl-1-[2(R)-tert -butoxycarbonylamino-3-triphenylmethvlthiopropyll-2(S)-(2-methoxvethyl)piperazine 4-Benzyl- 1-tert -butoxycarbonyl-2(S)-(2-methoxyethyl)piperazine from Example 13, step C (1.17 g, 3.50 mmol) was dissolved in methylene chloride (20 mL). To this solution was added trifluoroacetic acid (10 mL) and the reaction stirred at 20 0 C for 1 h.
The volatiles were removed in vacuo and the residue taken up in dichloroethane (40 mL). Triethylamine was added to attain pH 7. To this solution was added crushed molecular seives (1 sodium triacetoxyborohydride (1.2 g, 5.3 mmol) and the reaction cooled to 0 C with ice-methanol. A solution of 2(R)-tert-butoxycarbonylamino-3-triphenylmethylthiopropanal (1.72 g, 3.85 mmol) in dichloroethane (15 mL) was added slowly dropwise. The reaction was stirred at 20 0 C overnight then quenched with saturated sodium bicarbonate. The organic phase was washed with saturated sodium chloride solution, and dried over magnesium sulfate. The crude product (2.52 g) was chromatographed on silica gel with 30% ethyl acetate in hexane using medium pressure liquid chromatography (MPLC). The title compound (Rf 0.21) was isolated as a gum. NMR (CHC13, 300 MHz) 5 7.2-7.4 (20 H, 4.70 (1H, d, J=8 Hz), 3.63 (1H, br 3.50 (1H, d, J= 13 Hz), 3.36 (1H, d, J=13 Hz), 3.2-3.35 (5H, 2.75 (1H, 2.0-2.6 (10 H, 1.75 (2H, 1.42 (9H, A diastereomeric minor product (Rf 0.14) was also isolated.
Step B: 1-[2(R)-tert -Butoxycarbonylamino-3-ttiphenylmethylthiopropvll-2(S)-(2-methoxvethvl)piperazine The title compound was obtained by treating the product of step A (0.884 g, 1.33 mmol) with 1-chloroethyl chloroformate (0.151 mL, 1.39 mL) and potassium carbonate (0.200 g, 1.45 mmol) in WO 97/01275 PCT/US96/11022 -376dichloromethane (15 mL) according to the procedure described in Example 14, step C. The crude product was chromatographed on silica gel with 5-10% methanol in chloroform. The title compound was isolated as a foam. NMR (CHC13, 300 MHz) 5 7.2-7.45 (15H, 4.66 (1H, d, J=8 Hz), 3.65 (1H, 3.35 (2H, 3.28 (3H, 2.94 (1H, dd, J=12, 3 Hz), 1.7-2.9 (13H, 1.42 (9H, s).
Step C: 1-[2(R)-tert -Butoxycarbonylamino-3-triphenylmethylthiopropyl]-2(S)-(2-methoxyethyl)-4-(1-naphthoyl)piperazine The title compound was prepared from the product of Step B (0.422 g, 0.733 mmol), 1-naphthoic acid (0.120 mg, 0.698 mmol), EDC HC1 (0.154 mg, 0.806 mmol), HOBT (0.099 g, 0.733 mmol) in DMF at pH 7 according to the procedure described in Example 11, Step A. The crude product was chromatographed on silica gel with 30-40% ethyl acetate in hexane (Rf 0.50, 40% ethyl acetate/hexane). The title compound was isolated as a gum.
Step D: 1-[ 2 (R)-Amino-3-mercaptopropyl]-2(S)-(2-methoxyethyl)- 4-(1-naphthovl)piperazine dihydrochloride The title compound was prepared from the product of Step C (0.438 g, 0.600 mmol), triethylsilane (0.383 mL, 2.4 mmol), trifluoroacetic acid (10 mL) in dichloromethane (20 mL) according to the procedure described in Example 11, Step E. The crude product was purified by preparative HPLC (gradient: 85% Solvent A/15% Solvent B to 65% Solvent A/35% Solvent After ion exchange and lyophilization, the title compound was obtained as a white powder.
Analysis calculated for C21H29N302S 2.95 HCI 0.05 C, 50.85; H, 6.51; N, 8.47.
Found: C, 50.86; H, 6.12; N, 8.31.
WO 97/01275 PCT/US96/11022 -377- EXAMPLE 16 Preparation of -(4-Nitrophenylmethyl)- 1H-imidazol-4ylacetyl)amino-3(S)-methylpentyl]-N- 1 -naphthylmethyl-glycylmethionine bis trifluoroacetate and Nitrophenylmethyl)- 1H-imidazol-5-ylacetyl)amino-3(S)-methylpentyl]- N-1-naphthylmethyl-glyyl-methionine bis trifluoroacetate Step A: Preparation of 1-(4-Nitrophenylmethyl)- 1H-imidazol-4ylacetic acid methyl ester and 1-(4-Nitrophenylmethyl)- 1 Hacid methyl ester (3:1mixture) To a solution of sodium hydride (60% in mineral oil, 99 mg, 2.5 mmol) in dimethylformamide (2 ml) cooled to 0 0 C was added, via cannula, a solution of 1H-imidazole-4-acetic acid methyl ester hydrochloride (200 mg, 1.13 mmol) in dimethylformamide (3 ml).
This suspension was allowed to stir at 0 0 C for 15 min. To this suspension was added 4-nitrobenzyl bromide (244 mg, 1.13 mmol) and stirred at room temperature for 2 h. After this time, the mixture was quenched with sat. aq. sodium bicarbonate (15 ml) and water (20 ml) and extracted with methylene chloride (2 x 50 ml). The combined organic extracts were washed with brine (20 ml), dried (MgS04), filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography using acetonitrile as eluent to give the title compounds as a yellow oil.
1 H NMR (CDC13, 400 MHz) 8 8.20 (2H, d, J=8.5 Hz), 7.49 (1H, s), 7.27 (2H, d, J=8.5 Hz), 7.03 (0.25H, 6.87 (0.75H, 5.28 (0.5H, s), 5.18 (1.5H, 3.70 (2.25H, 3.65 (1.5H, 3.61 (0.75H, s) and 3.44 s) ppm.
Step B: Preparation of 1-( 4 -Nitrophenylmethyl)-1H-imidazol-4ylacetic acid hydrochloride and 1-(4-Nitrophenyl-methyl)acid (3:1mixture) To a solution of a mixture of 1-(4-Nitrophenylmethyl)-1Himidazol-4-ylacetic acid methyl ester and 1-(4-Nitrophenylmethyl)-1H- WO 97/01275 PCT/US96/11022 -378acid methyl ester (3:1mixture, 216 mg, 0.785 mmol) in methanol (3 ml) and tetrahydrofuran (3 ml) under argon was added M sodium hydroxide (1.18 ml, 1.18 mmol) and stirred for 18 h.
After this time, 1.0 N hydrochloric acid (2.36 ml, 2.36 mmol) was added and the mixture evaporated in vacuo to give the title compounds.
1H NMR (CDCl3, 400 MHz) 8 9.04 (0.75H, 8.83 (0.25H, 8.28 (2H, d, J=8.8 Hz), 7.61 (2H, d, J=8.8 Hz), 7.54 (0.75H, 7.43 (0.25H, 5.61 (0.5H, 5.58 (1.5H, 3.84 (0.5H, s) and 3.82 (1.5H, s) ppm.
Step C: Preparation of 2 S)-N'-(1-(4-Nitrophenylmethyl)-1Himidazol-4-ylacetyl)amino-3(S)-methylpentyl]-N-1naphthylmethyl-glycyl-methionine methyl ester bis trifluoroacetate and N-[2(S)-N'-(1-(4-Nitrophenyl-methyl)- 1H-imidazol-5-ylacetyl)amino-3(S)-methylpentyl]-N-1naphthylmethyl-glycyl-methionine methyl ester bis trifluoroacetate To a solution of 1-(4-nitrophenylmethyl)-1H-imidazol-4ylacetic acid hydrochloride and 1-(4-nitrophenylmethyl)-1H-imidazolacid hydrochloride (3:1 mixture, 153 mg, 0.392 mmol), N- 2 (S)-amino-3(S)-methylpentyl]-N-naphthylmethyl-glycyl-methionine methyl ester bis hydrochloride (209 mg, 0.392 mmol) and 3-hydroxy- 1,2,3-benzotriazin-4(3H)-one (HOOBT, 64 mg, 0.39 mmol) in methylene chloride (10 ml) was added 1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (EDC, 75.2 mg, 0.392 mmol) and triethylamine (219 g1, 1.57 mmol) and the mixture stirred overnight at room temperature. After this time, sat. aq. sodium bicarbonate (10 ml) was added and the mixture was extracted with methylene chloride. The combined extracts were washed with sat. aq. sodium bicarbonate (10 ml) and the solvent evaporated in vacuo. The regioisomers were separated by Prep HPLC using a Nova Prep 5000 Semi preparative HPLC system and a Waters PrepPak cartridge (47 X 300mm, C18, 15 gm, 100A) eluting with 5 95% acetonitrile/water TFA) at 100 ml/min (chromatography method A to give after lyophilization Compounds F and G.
WO 97/01275 WO 9701275PCT/US96/11022 379
F:
IH NMR (CD3OD, 400 MHz) 8 8.96 (1H, 8.17 (1H, in), 8.23 (2H, d, J=8.7 Hz), 7.92 (2H, d, J=8.9 Hz), 7.61 (1H, d, J=6.9 Hz), 7.56 (2H, d, J=8.9 Hz), 7.50 (2H, in), 7.44 (2H, in), 5.52 (2H, 4.70 (1H, d, J=9.4 Hz), 4.49 (1H, d, J=11.9 Hz), 4.38 (1H, dd, J=4.7 and 8.9 Hz), 4.13 (OH, in), 3.67 (3H, 3.65 (4H, in), 3.30 (1H, in), 3.06 (1H, in), 2.31 (OH, in), 2.23 (1H, in), 1.97 (3H, 1.94 (1H, in), 1.71 (1H, in), 1.57 (OH, in), 1.42 (1H, in), 1.17 (1H, in), 0.90 (3H, d, J=6.9 Hz) and 0.87 (3H, t, J=7.4 Hz) ppm.
Anal. Calcd for C37H46N606S.2.40 TFA*0.25 H20: C, 51.18; H,5.02; N, 8.57. Found: C, 51.17; H, 5.03; N, 8.80.
FAB MS calcd for C37H47N606S 703 found 703.
G:
1 H NMR (CD3OD, 400 MHz) 8 8.91 (1H, 8.26 (1H, d, J=12.8 Hz), 8.21 (2H, d, J=10.7 Hz), 7.91 (2H, in), 7.65-7.36 (7H, in), 5.51 (2H, s), 4.72-,3.99 (4H, in), 3.66 (3H, 3.66-3.24 (4H, in), 3.20-2.85 (2H, in), 2.29 (1H, in), 2.20 (1H, in), 1.96 (3H, 1.91 (1H, br 1.70 (1H, d, J=16 Hz), 1.56 (1H, in), 1.38 (1H, in), 1.13 (1H, m) and 0.88 (6H, m) ppm.
FAB HRMS exact mass calcd for C37H47N606S 703.32778 found 703.32852.
Step D: Preparation of N- -(4-Nitrophenylmethyl)- 1Himidazol-4-ylacetyl)amino-3 (S )-methylpentyl] -N-inaphthylmethyl- glycyl-methionine bis trifluoroacetate To a solution of N- 1-(4-nitrophenylmethyl)- 1Hiinidazol-4-ylacetyl)amino-3 (S)-methylpentyl]-N- 1-naphthylmethylglycyl-methionine methyl ester his trifluoroacetate 21 ing, 0.023 inmol) in methanol (1 ml at room temperature was added 1LON lithium hydroxide (135 p.1, 0.135 minol). This solution was stirred for 4 h and treated with trifluoroacetic acid (100 This mixture was purified by WO 97/01275 WO 9701275PCTfUS96/11022 380 preparative HPLC using chromatography method A to give the title compound.
1 H NMR (CD3OD, 400 MHz) 8 8.86 (lH, 8.23 (2H, d, J= 8.8Hz), 8.22 (1H, in), 7.90 (2H, dd, J=7.3 Hz), 7.55 (2H, d, J=8.4 Hz), 7.44- 7.28 (5H, in), 5.50 (2H, 4.53 (1H, in), 4.35 (2H, in), 4.12 (1H, in), 3.79-3.25 (4H, in), 3.26-2.86 (2H, in), 2.27 (1H, in), 2.18 (lH, in), 1.96 (3H, 1.9 (1H, in), 1.67 (1H, in), 1.57 (1H, in), 1.42 (1H, in), 1.15 (1H, mn), 0.90 (3H, d, J=6.9 Hz) and 0.86 (3H, t, J=7.3 Hz) ppm.
FAB HRMS exact mass calcd for C36H45N606S 689.3 1213 found 689.3 1262.
Step E: Preparation of N- 1-(4-Nitrophenylinethyl)- 1Hiinidazol-5-ylacetyl)amino-3(S)-methylpentyl]N.1naphthylmethyl-glycyl-methionine bis trifluoroacetate To a solution of N-[ 2 (S)-N'-(1-(4-nitrophenylnethyl)-1H.
imidazol-5-ylacetyl)amino-3 (S)-methylpentyl]-N- 1-naphthylmethylglycyl-methionine methyl ester his trifluoroacetate, (29 ing, 0.031 inmol) in methanol (1 ml was added 1LON lithium hydroxide (187 RIU, 0. 187 mmol). This solution was stirred for 4 h and treated with trifluoroacetic acid (100 This mixture was purified by preparative HPLC using chromatography method A to give the title compound.
1 H NMR (CD3OD, 400 MHz) 6 8.89 (lH, 8.25 (1H, in), 8.21 (2H, d, J= 9.0Hz), 7.89 (2H, in), 7.64-7.34 (7H, in), 5.52 (2H, 4.59-3.88 (4H, in), 3.77-3.38 (4H, in), 3.18-2.75 (2H, in), 2.27 (1H, in), 2.18 (lH, in), 1.96 (3H, 1.9 (1H, in), 1.67 (1H, in), 1.57 (1H, in), 1.42 (1H, in), 1.15 (1H, in), 0.89 (6H, in) ppm.
FAB HRMS exact mass calcd for C36H45N606S 689.3 1213 found 689.31135.
EXAMPLE 17 Regioselective preparation of N- [2(S)-N t 1-(4-Nitrophenylinethyl)-l1Hiinidazol-5-ylacetyl)ainiino-3 (S)-inethylpentyl] -N-i -naphthylinethylglycvl-methionine methyl ester his trifluoroacetate, WO 97/01275 PCT/US96/11022 -381 Step A: Preparation of 1-(Triphenylmethyl)-1H-imidazol-4-ylacetic acid methyl ester To a suspension of 1H-imidazole-4-acetic acid methyl ester hydrochloride (7.48, 42.4 mmol) in methylene chloride (200 ml) was added triethylamine (17.7 ml, 127 mmol) and triphenylmethyl bromide (16.4 g, 50.8 mmol) and stirred for 72 h. After this time, reaction mixture was washed with sat. aq. sodium bicarbonate (100 ml) and water (100 ml). The organic layer was evaporated in vacuo and purified by flash chromatography (30-100% ethyl acetate/hexanes gradient elution) to provide the title compound as a white solid.
1 H NMR (CDC13, 400 MHz) 5 7.35 (1H, 7.31 (9H, 7.22 (6H, 6.76 (1H, 3.68 (3H, s) and 3.60 (2H, s) ppm.
Step B: Preparation of 1-(4-Nitrophenylmethyl)-lH-imidazol-5ylacetic acid methyl ester To a solution of 1-(triphenylmethyl)-1H-imidazol-4-ylacetic acid methyl ester from Step A (274 mg, 0.736 mmol) in acetonitrile ml) was added 4-nitrobenzylbromide (159 mg, 0.736 mmol) and heated to 55°C for 16 h. After this time, the reaction was cooled to room temperature, treated with ethyl acetate (20 ml) and the resulting precipitate was filtered. The filtrate was concentrated to dryness in vacuo and the residue was redissolved in acetonitrile (4 ml) and heated to 65C for 3 h. After this time, the reaction mixture was evaporated to dryness and combined with initial precipitate. This residue was dissolved in methanol (5 ml and heated to reflux for 30 min. The resulting solution was evaporated in vacuo and the residue was purified by flash chromatography methanol/methylene chloride gradient elution to provide the title compound.
1 H NMR (CDC13, 400 MHz) 8 8.20 (2H, d, J=8.8 Hz), 7.53 (1H, s), 7.19 (2H, d, J=8.8 Hz), 7.03 (1H, 5.28 (2H, 3.61 (3H, s) and 3.44 (2H, s) ppm.
WO 97/01275 PCT/US96/11022 -382- Step C: Preparation of 1-(4-Nitrophenylmethyl)-1H-imidazol-5ylacetic acid hydrochloride 1-(4-Nitrophenylmethyl)- 1 H-imidazol-5-ylacetic acid methyl ester (0.115 g, 0.42 mmol was dissolved in 1.ON hydrochloric acid (10 ml and heated at 55 0 C for 3 h. The solution was evaporated in vacuo to give the title compound as a white solid.
1 H NMR (CD30D, 400 MHz) 8 9.06 (1H, 8.27 (2H, d, J=8.8 Hz), 7.61 (1H, 7.55 (2H, d, J=8.8 Hz), 5.63 (2H, s) and 3.81 (2H, s) ppm.
Step D: Preparation of N-[2(S)-N'-(1-(4-Nitrophenylmethyl)-1Himidazol-5-ylacetyl)amino-3(S)-methylpentyl]-N-1naphthylmethyl-glycyl-methionine methyl ester bis trifluoroacetate Following the procedure described in Example 16, Step C, but using the 1-(4-nitrophenylmethyl)- 1 H-imidazol-5-ylacetic acid hydrochloride, prepared as described in Step C provided the title compound.
EXAMPLE 18 Preparation of N-[2(S)-N'-(1-(4-Cyanophenylmethyl)- ylacetyl)amino-3(S)-methylpentyl]-N- 1 -naphthylmethyl-glycylmethionine bis trifluoroacetate (Compound B) Step A: Preparation of N-[2(S)-N'-(1-(4-Cyanophenylmethyl)- 1Himidazol-5-ylacetyl)amino-3(S)-methylpentyl]-N-1naphthylmethyl-glycyl-methionine methyl ester bis trifluoroacetate Following the procedure described in Example 17, Steps B- D, but using o-bromo-p-tolunitrile in place of 4-nitrobenzylbromide provided the title compound.
1 H NMR (CD30D, 400 MHz) 6 8.92 (1H, 8.31 (1H, 8.01 (1H, d, J=8 Hz), 7.96 (1H, 7.75 (2H, d, J=8 Hz), 7.62 (1H, 7.58-7.48 (3H, 7.45 (1H, 7.41 (2H, d, J=8 Hz), 5.51 (2H, 4.97 (1H, m), WO 97/01275 PCT/US96/11022 -383- 4.76 (1H, 4.41 (1H, 4.10 (1H, m) 3.92 (2H, 3.75-3.47 (3H, 3.69-(3H, 3.25 (1H, 2.37 (1H, 2.30 (1H, 2.00 (3H, 1.97 1.79 (1H, 1.58 (1H, 1.43 (1H, 1.19 (1H, m) and 0.91 (6H, m) ppm.
Anal. Calcd for C38H46N604S*2.40 TFA*1.90 H20: C, 51.89; H, 5.31; N, 8.48. Found: C, 51.88; H, 5.29; N, 8.72.
FAB HRMS exact mass calcd for C38H47N604S 683.337951 found 683.338437.
EXAMPLE 19 In vitro inhibition of ras faresyl transferase Assays offaresyl-protein transferase. Partially purified bovine FPTase and Ras peptides (Ras-CVLS, Ras-CVIM and RAS-CAIL) is 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 is assayed in a volume of 100 ll containing 100 mM N-(2-hydroxy ethyl) piperazine- N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl2, 5 mM dithiothreitol (DTT), 100 mM 3 H]-famesyl diphosphate 3 H]-FPP; 740 CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 gg/ml FPTase at 31°C for 60 min. Reactions are initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol. Precipitates are collected onto filter-mats using a TomTec Mach II cell harvestor, washed with 100% ethanol, dried and counted in an LKB 3-plate counter. The assay is linear with respect to both substrates, FPTase levels and time; less than 10% of the 3 H]-FPP is utilized during the reaction period.
Individual purified protein substrate-competitive inhibitor and/or faresyl pyrophosphate-competitive inhibitor and compositions of the invention that comprise at least one of a protein substrate-competitive inhibitor and a farnesyl pyrophosphate-competitive inhibitor are dissolved in 100% dimethyl sulfoxide (DMSO) and are diluted into the assay. Percentage inhibition is measured by the amount of incorporation of radioactivity in the presence of the test compound
I
WO 97/01275 PCT/US96/11022 -384when compared to the amount of incorporation in the absence of the test compound.
Human FPTase is prepared as described by Omer et al., Biochemistry 32:5167-5176 (1993). Human FPTase activity is assayed as described above with the exception that 0.1% polyethylene glycol 20,000, 10 gIM ZnCl 2 and 100 nM Ras-CVIM are added to the reaction mixture. Reactions are performed for 30 min., stopped with 100 l of 30% trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.
Comparison is made between the inhibitory activity of a composition of the instant invention and the inhibitory activities of individual compounds that make up the composition in the assay.
EXAMPLE In vivo ras farnesvlation assay The cell line used in this assay is a v-ras line derived from either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21. The assay is performed essentially as described in DeClue, J.E. et al., Cancer Research 51:712-717, (1991). Cells in 10 cm dishes at 50-75% confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, is After 4 hours at 37 0 C, the cells are labelled in 3 ml methionine-free
DMEM
supplemented with 10% regular DMEM, 2% fetal bovine serum and 400 mCi[ 3 5 S]methionine (1000 Ci/mmol). After an additional 20 hours, the cells are lysed in 1 ml lysis buffer NP40/20 mM HEPES, pH 7.5/5 mM MgCl2/lmM DTT/10 gg/ml aprotinen/2 gg/ml leupeptin/2 gg/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 WO 97/01275 PCT/US96/11022 -385is 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 NaC1) boiled in SDS-PAGE sample buffer and loaded on 13% acrylamide gels. When the dye front reached the bottom, the gel is fixed, soaked in Enlightening, dried and autoradiographed. The intensities of the bands corresponding to farnesylated and nonfarnesylated ras proteins are compared to determine the percent inhibition of farnesyl transfer to protein.
Comparison is made between the inhibitory activity of a composition of the instant invention and the inhibitory activities of individual compounds that make up the composition in the assay.
EXAMPLE 21 In vivo ras faresvlation assay The cell line used in this assay is a H-ras line derived from a NIH3T3 cells, which expressed cellular Ha-ras p21. The assay is performed essentially as described in Ana Maria Garcia et al., The Journal of Biological Chemistry 268:18415-18418, (1993). Cells in 3.3 cm dishes at 50-75% confluency are treated with the test compound (final concentration of solvent, dimethyl sulfoxide, is After 24 hours the cells are lysed in lysis buffer NP40/20mM HEPES, pH 7.5/5mM MgC12/1 jgg/ml aprotinin/2 gig/ml leupeptin/2 gig/ml PMSF). The lysate was separated by centrifugation at 13000rpm for 5 min and the supernatant used as cell extract. Total protein was separated by SDS-polyacrylamide gel electrophoresis in 12% acrylamide gels. After transfer to nitrocellose, the blots were probed with NCC-RAS-004 mouse monoclonal antibody to H-ras (Nihonkayaku). All Western blots were developed using enhanced chemiluminescence reagents (Amersham Corp.). The intensities of the bands corresponding to farnesylated and nonfarnesylated ras proteins are compared to determine the percent inhibition of farnesyl transfer to protein.
I
WO 97/01275 PCTIUS96/11022 -386- Comparison is made between the inhibitory activity of a composition of instant of instant invention and the inhibitory activities of individual compounds that make up the composition in the assay.
EXAMPLE 22 In vivo growth inhibition assay To determine the biological consequences of FPTase inhibition, the effect of examples of compositions of the instant invention on the anchorage-independent growth of Ratl cells transformed with either a v-ras, v-raf, or v-mos oncogene in comparison with the effect of the individual components of such compositions on the same growth was tested. Cells transformed by v- Raf were included in the analysis to evaluate the specificity of instant compounds for Ras-induced cell transformation. Cells transformed by v-Mos may also be included in an analysis.
Rat 1 cells transformed with either v-ras or v-raf were 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 contained 0.1% methanol or an appropriate concentration of the instant composition or the individual component compounds (dissolved in methanol at 1000 times the final concentration used in the assay). The cells were fed twice weekly with ml of medium A containing 0. 1% methanol or the concentration of the instant compound. Photomicrographs were taken 9 days after the cultures are seeded and comparisons are made between treated and untreated plates.
The results of the assay are shown in Table 1. The extent of inhibition of the cell growth was inferred from the subjective quantitization of the colony growth. Wild type (vehicle only) colony growth is designated less than wild type growth is designated much less than wild type growth is designated and no visually WO 97/01275 PCT/US96/11022 -387detectable colonies is designated The assay was run against individual protein substrate-competitive FPTase inhibitors (Compounds A and B) and a farnesyl pyrophosphate-competitive FPTase inhibitor (Compound C) to establish minimum concentrations where wild type or less than wild type growth was observed. The compositions containing both the protein substrate-competitive and farnesyl pyrophosphatecompetitive inhibitors were then tested in the assay at those concentrations of the FPTase inhibitors that showed such non-inhibitory or minimally inhibitory effects for the individual compounds.
WO 97/01275 WO 9701275PCTIUS96/1 1022 388 TABLE 1 Cninnnntln rCnnr-lI M Poe 11-af MeOH Compound A 1 0.25 1 0.25 +1- Compound B Compound C Compound C Compound A Compound C Compound B 1 to+ 2.5 0.25 2.5 0.25 and and to
Claims (8)
1. A method for achieving an additive or synergistic therapeutic effect in a mammal in need thereof which comprises administering to said mammal amounts of at least two therapeutic agents selected from a group consisting of: a) a farnesyl protein transferase inhibitor which is an effective inhibitor of the enzyme because it is competitive with respect to the protein substrate of the enzyme and b) a famesyl protein transferase inhibitor which is an effective inhibitor of the enzyme because it is competitive with respect to farnesyl pyrophosphate; wherein the amount of a) alone and the amount of b) alone is insufficient to achieve said therapeutic effect.
2. The method according to Claim 1 wherein an amount of a protein substrate-competitive inhibitor and an amount of a famesyl pyrophosphate-competitive inhibitor are administered simultaneously.
3. A method for achieving a synergistic therapeutic effect in a mammal in need thereof which comprises administering to said mammal amounts of at least two therapeutic agents selected from a group consisting of: a) a farnesyl protein transferase inhibitor which is an effective inhibitor of the enzyme because it is competitive with respect to the protein substrate of the enzyme and b) a farnesyl protein transferase inhibitor Which is an effective inhibitor of the enzyme because it is competitive with respect to faresyl pyrophosphate; -390- wherein the amount of a) alone and the amount of b) alone is insufficient to achieve said therapeutic effect; and wherein said therapeutic effect of the amounts of the therapeutic agents administered is greater than the sum of the theraneutic effects of the S amounts of the individual therapeutic agents administered.
4. The method according to Claim 3 wherein an amount of a protein substrate-competitive inhibitor and an amount of a farnesyl pyrophosphate-competitive inhibitor are administered simultaneously.
5. The method according to Claim 1 wherein the protein substrate-competitive inhibitor is selected from: 15 a) a peptide that comprises the amino acids CA1A2X, wherein: C cysteine; Al an aliphatic amino acid; A2 an aliphatic amino acid; and X any amino acid; b) Cys Xaal Xaa 2 Xaa 3 NRR 1 wherein Cys cysteine; Xaal any amino acid in the natural L-isomer form; Xaa 2 any amino acid in the natural L-isomer form; and Xaa 3 NRR 1 an amide of any amino acid in the natural L-isomer form, wherein R and R 1 are independently selected from hydrogen, C1-C12 alkyl, aralkyl, or unsubstituted or substituted aryl; c) Cys Xaal Xaa 2 Xaa 3 wherein Cys cysteine; Xaal any amino acid; Xaa 2 the amino acid phenyl alanine or a p- fluorophenylalanine; and 1 WO 97/01275 PCT/US96/11022 -391 Xaa 3 any amino acid; d) Cys Xaal dXaa 2 Xaa 3 wherein Cys cysteine; Xaal any amino acid in the natural L-isomer form; dXaa 2 any amino acid in the natural L-isomer form; and Xaa 3 any amino acid in the natural L-isomer form; e) X R2 H Z R 4 R'NH- N OR N- N H Y H HSY 0 wherein: X, Y, and Z are independently H2 or O, provided that at least one of these is H2; R1 is H, an alkyl group, an acyl group, an alkylsulfonyl group or aryl sulfonyl group, wherein alkyl and acyl groups comprise straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms, or in the alternative, RINH may be absent; R 2 R 3 and R 4 are the side chains of naturally occurring amino acids, or in the alternative may be substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or saturated chains of 2 to 8 carbon atoms, wherein the aliphatic substitutents may be substituted with an aromatic or heteroaromatic ring; and WO 97/01275 PCT/US96/11022 -392- R 5 is H or a straight or branched chain aliphatic group, which may be substituted with an aromatic or heteroaromatic group; f) X R H 0 ZH R 1 NH N N H H Y H HS Y wherein: X and Y are independently H2 or O, provided that at least one of these is H2; R 1 is H, an alkyl group, an acyl group, an alkylsulfonyl group or aryl sulfonyl group, wherein alkyl and acyl groups comprise straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms, or in the alternative, RINH may be absent; R 2 and R 3 are the side chains of naturally occurring amino acids, or in the alternative may be substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or saturated chains of 2 to 8 carbon atoms, wherein the aliphatic substitutents may be substituted with an aromatic or heteroaromatic ring; Z is O or S; and n is 0, 1 or 2; WO 97/01275 PCT/US96/11022 -393- X R 2 H 0 R'NH zN Z S H Y R 3 H HS0 wherein: X and Y are independently H2 or O, provided that at least one of these is H2; R 1 is H, an alkyl group, an acyl group, an alkylsulfonyl group or aryl sulfonyl group, wherein alkyl and acyl groups comprise straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms, or in the alternative, R 1 NH may be absent; R 2 and R 3 are the side chains of naturally occurring amino acids, or in the alternative may be substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or saturated chains of 2 to 8 carbon atoms, wherein the aliphatic substitutents may be substituted with an aromatic or heteroaromatic ring; Z is O or S; and n is 0, 1 or 2; h) X R 2 R 1 NH H NR3 Y H2 H HS wherein: I WO 97/01275 PCT/US96/11022 -394- X and Y are independently H2 or O; R1 is R 2 is an alkyl group, hydrogen, an acyl group, an alkylsulfonyl group or arylsulfonyl group, wherein alkyl and acyl groups comprise straight chain or branched chain hydrocarbons of 1 to 6 carbons atoms, which alternatively may be substituted with an aryl group; the side chains of naturally occurring amino acids, or in the alternative may be substituted or unsubstituted aliphatic, aromatic or heterocyclic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or saturated chains of 2 to 8 carbon atoms which may be branched or unbranched, wherein the aliphatic substituents may be substituted with an aromatic or heteroaromatic ring; an aromatic or heteroaromatic ring or in the alternative an alkyl group or an aryl or heteroaryl substituted alkane, wherein the aromatic ring is unsubstituted or in the alternative, substituted with one or more groups which may be alkyl, halo, alkoxy, trifluoromethyl, or sulfamoyl groups, and which may be polycyclic; R3 is WO 97/01275 PTU9/12 PCTfUS96/11022 395 R 2 R 5 bO R 4 R'NH NINyOH S 5 a R 3 H R 2 R 5 bO0 R'NHN R: R 5 N yOR 6 H 0 R 2 R 5 b o OH R'NH N 'J 'N OH 7 R 5 R 3 0 R 2 R5b o R'NH 3 0 wherein: R 1 and R5a are independently selected from: hydrogen, a ClI-C6 alkyl group, a ClI-C6 acyl group, an aroyl group, a Cl-C6 alkylsulfonyl group, C1-C6 0 aralkylsulfonyl group or arylsulfonyl group r WO 97/01275 PCT/US96/11022 -396- wherein the alkyl group and acyl group is optionally substituted with substituted or unsubstituted aryl or heterocycle; R 2 R 3 and R 4 are independently selected from: a) a side chain of naturally occurring amino acids, b) an oxidized form of a side chain of naturally occurring amino acids selected from methionine sulfoxide and methionine sulfone, c) substituted or unsubstituted C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, aryl or heterocycle groups, wherein the aliphatic substituent is optionally substituted with an aryl, heterocycle or C3-C8 cycloalkyl; R 5 b is a C1-C6 alkyl group, a C1-C6 acyl group, an aroyl group, a C1-C6 alkylsulfonyl group, C1-C6 aralkylsulfonyl group or arylsulfonyl group wherein the alkyl group and acyl group is optionally substituted with substituted or unsubstituted aryl or heterocycle; a substituted or unsubstituted aliphatic, aryl or heterocyclic group, wherein the aliphatic substituent is optionally substituted with an aryl or heterocyclic ring; and R 6 is n is 0, 1 or 2; I WO 97/01275 WO 9701275PCT/US96/11022 397 R 2 0 R'NH HS R, OR4 H 0 R 2 0 R'NH H 3 oe H H 0 HS IV wherein: R I is selected from: hydrogen, a C 1-C6 alkyl group, a C 1-C6 acyl. group, an aroyl group, a C1-C6 alkylsulfonyl group, C1-C6 aralkylsulfonyl group or arylsulfonyl group I WO 97/01275 PCT/US96/11022 -398- wherein the alkyl group and acyl group is optionally substituted with substituted or unsubstituted aryl or heterocycle; R 2 R 3 and R 4 are independently selected from: a) a side chain of naturally occurring amino acids, b) an oxidized form of a side chain of naturally occurring amino acids selected from methionine sulfoxide and methionine sulfone, c) substituted or unsubstituted C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, aryl or heterocycle groups, wherein the aliphatic substituent is optionally substituted with an aryl, heterocycle or C3-C8 cycloalkyl; X is CH2CH2 or trans CH=CH; R 6 is a substituted or unsubstituted aliphatic, aryl or heterocyclic group, wherein the aliphatic substituent is optionally substituted with an aryl or heterocyclic ring; and n is 0, 1 or 2; WO 97/01275 WO 9701275PCT/US96/11022 399 ,OH H HS R 2 0 R 1 NHj H R HS R R 2 0 R'N H jl N 1 H R" H H S R III or R O H 0 HS R 2. N JT H R3 R -1YOR 6 0 wherein, RI is hydrogen, an alkyl group, an aralkyl group, an acyl group, an aracyl group, an aroyl group, an alkylsulfonyl group, I WO 97/01275 PCT/US96/11022 -400- aralkylsulfonyl group or arylsulfonyl group, wherein alkyl and acyl groups comprise straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms; R 2 R3 and R5 are the side chains of naturally occurring amino acids, including their oxidized forms which may be methionine sulfoxide or methionine sulfone, or in the alternative may be substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or saturated chains of 2 to 8 carbon atoms which may be branched or unbranched, wherein the aliphatic substituents may be substituted with an aromatic or heteroaromatic ring; R 4 is hydrogen or an alkyl group, wherein the alkyl group comprises straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms; R 6 is a substituted or unsubstituted aliphatic, aromatic or heteroaromatic group such as saturated chains of 1 to 8 carbon atoms, which may be branched or unbranched, wherein the aliphatic substituent may be substituted with an aromatic or heteroaromatic ring; T is O or S(O)m; m is 0, 1 or 2; and n is 0, 1 or 2; WO 97/01275 WO 9701275PCTIUS96/1 1022 401 X 0 HS N\/ U \j Y R R 4 R N R\R HS N\ 7N-Z m R R n R1 wherein: X is m is n is t is R and R1 0Oor H2; 1 or 2; 0 or 1; 1 to 4; are independently selected from H, Cl-4 alkyl, or aralkyl; WO 97/01275 WO 9701275PCTIUS96/1 1022 402 R 2 R 3 R 4 and R 5 are independently selected from: H; Cl-8. alkyl, N<NRor 1<OR 6 alkenyl, alkynyl, aryl, heterocycle, 0 0 unsubstituted or substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) C 1-4 alkyl, b) (CH2)tOR 6 c) (CH2)tNR 6 R 7 d) halogen, 2) C3-6 cycloalkyl, 3) OR 6 4) SR 6 S(O)R 6 S02R 6 -NR 6 R 7 6) -N R 7 0 R 6 7) 1 N 7 R 0 WO 97/01275 WO 9701275PCT/US96/11022 8) 9) 11) 12) 13) 403 -0O NR 6 R 7 0 -0O OR 6 0 "YNR 6 R 7 0 SO 2 -NR 6 R 7 RT7 0 I or Y is 14) O 0 and any two of R 2 R 3 R 4 and R 5 are optionally attached to the same carbon atom; aryl, heterocycle, unsubstituted or substituted with one or more of: 1) CI -4 alkyl, unsubstituted or substituted with: a) C1-4 aikoxy, b) NR 6 R 7 C) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, 2) aryl or heterocycle, 3) halogen, 4) OR 6 WO 97/01275 PTU9/12 PCTIUS96/11022 NR 6 R 7 6) CN, 7) N02, or 8) CF3; W is H2 orO0; Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more of the following: 1) C1-4 alkyl, unsubstituted or substituted with: a) C1-4 alkoxy, b) NR 6 R 7 c) C3-6 cycloallcyl, d) aryl or heterocycle, or e) HO, 2) aryl or heterocycle, 3) halogen, 4) OR 6 5) NR 6 R 7 6) CN, 7) N02, or 8) CF3; R 6 R 7 and R 8 are independently selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, WO 97/01275 WO 9701275PCT/US96/1 1022 405 e) 1 R9 0 f) S0 2 R 9 ,or g) NRR I, wherein R 6 and R 7 may be joined in a ring, and R 7 and R 8 may be joined in a ring; and R 9 is C1-4 alkyl or arailkyl; m) Z17~ R 3 R 4 R'HN z H2Z 2 R R2a R 2 b Z1 R 3 R H -H WO 97/01275 WO 9701275PCTIUS96/1 1022 406 R 3 R 4 OH R'HN 2 Z2 R 2 a Rb HOCH 2 (CH 2 )q III or HS-- Z R R H R 1 HN O (H Z2 H2)t 2 R 2aRb IV wherein: R1 is selected from: a) hydrogen, b) R 8 R 8 (R 8 )2NC(O)- or R 9 OC(O)-, and c) Ci -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 8 0-, R 8 R 8 C(O)NR 8 CN, (R 8 )2N-C(NR 8 R 8 R 8 N3, -N(R 8 or R 9 OC(O)NR 8 R2a and R2b are independently selected from: a) hydrogen, b) C I -C6 alkyl unsubstituted or substituted by alkenyl, R 8 R 8 R 8 C(O)NR 8 CN, (R 8 )2N-C(NR 8 R 8 R 8 N3, -N(R 8 or R 9 OC(O)NR 8 c) aryl, heterocycle, cycloalkyl, alkenyl, R 8 0-, R 8 R 8 C(O)NR 8 CN, N02, (R 8 )2N- C(NR 8 R 8 R 8 N3, -N(R 8 or R 9 OC(O)NR 8 and WO 97/01275 PCT/US96/11022 -407- d) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; R3 and R4 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 C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, C1, Br, N(R 8 N02, R 8 R 8 S(O)m-, R 8 C(O)NR8-, CN, (R 8 )2N-C(NR 8 R 8 R 8 N3, -N(R 8 )2, R 9 0C(O)NR 8 and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; or R3 and R 4 are combined to form (CH2)s 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 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(R 8 N02, R 8 R 8 R 8 C(O)NR 8 CN, WO 97/01275 PCT/US96/11022 -408- (R 8 )2N-C(NR 8 R 8 R 8 N3, -N(R 8 R 9 0C(O)NR 8 and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic 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 -N(COR 8 R 6 is a) substituted or unsubstituted Cl-C8 alkyl, wherein the substituent on the alkyl is selected from: 1) aryl, 2) heterocycle, 3) -N(R 9 )2, 4) -OR 8 or b) R 10 0 'O0 R 1 WO 97/01275 PCT/US96/11022 -409- X-Y is RI7a a) N O 0 R 7 b b) N c VO (0)m d) S s H e) ,or H f) -CH2-CH 2 R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, I WO 97/01275 PCTIUS96/11022 -410- c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R 8 is independently selected from hydrogen, Cl-C6 alkyl and aryl; R 9 is independently selected from C1-C6 alkyl and aryl; R 10 is independently selected from hydrogen and C1-C6 alkyl; R 1 1 is independently selected from Cl-C6 alkyl; Zl and Z 2 are independently H2 or O, provided that Z 1 is not O when X-Y is C(0)N(R 7 m is 0, 1 or 2; q is 0, 1 or 2; s is 4 or 5; and t is 3, 4 or WO 97/01275 WO 9701275PCTIUS96/11022 -411- n) HS-> z Xr 2a H, 2 )t 2 R Rb wherein: RI is selected from: a) hydrogen, b) R 5 R 5 (R 5 )2NC(O)- or R 6 OC(O)-, and C) CI -C6 ailkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, ailkenyl, alkynyl, R 5 0-, R 5 R 5 C(O)NR 5 CN, (R 5 )2N-C(NR 5 R 5 R 5 N3, -N(R 5 or R 6 OC(O)NR 5 R2a and R2b are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloallcyl, alkenyl, R 5 R 5 S(O)m-, R 5 C(O)NR 5 CN, (R 5 )2N-C(NR 5 R 5 R 5 N3, -N(R 5 or R 6 OC(O)NR 5 and c) aryl, heterocycle, cycloalkyl, alkenyl, R 5 0-, R 5 R 5 C(O)NR 5 CN, N02, (R 5 )2N-C(NR 5 R 5 R 5 N3, -N(R 5 or R 6 OC(O)NR 5 R3 is selected from: a) unsubstituted or substituted aryl, b) unsubstituted or substituted heterocycle, c) unsubstituted or substituted cycloalkyl, and I WO 97/01275 PCT/US96/11022 -412- d) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; X-Y is R 4a a) N 0 R 4 b b) N c) (O (0)m d) S H e) ,or H f) -CH 2 -CH 2 R4a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; WO 97/01275 PCT/US96/11022 -413- R4b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R 5 is independently selected from hydrogen, C -C6 alkyl and aryl; R 6 is independently selected from C1-C6 alkyl and aryl; Z is independently H2 or O; m is 0, 1 or 2, provided that m is 0 when R 5 hydrogen nis 0, 1,2, 3 or4; and t is 3, 4 or WO 97/01275 WO 9701275PCTIUS96/11022 -414- p) H S /Om n V N i 2 f R' R' R 3 R 4 HJnj -v B1 /N\ x Y HS' m N nw /N R 2 P P HS/( A No"" 'n' NRI wherein: X and Y are independently 0 or H2; m is 1lor 2; n is 0Oorl1; p is 1, 2or 3; q is 0,l1or 2; t is 1lto 4; R, R1 and R 2 are independently selected from: H, Cl.6 alkyl, or C1-6 aralkyl; WO 97/01275 WO 9701275PCT/US96/1 1022 415 R3ar id R 4 are independently selected from: a) hydrogen, b) C Il-C6 alkyl unsubstituted or substituted by C2-C6 alkenyl, R 6 R 5 R 7 C(O)NR 6 CN, N3, R 6 OC(O)NR 6 R 6 R 7 N-C(NR 6 R 8 R 6 R 7 R 8 NC(O)O-, R 7 R 8 R 6 R 7 -NR 6 S(O)2R 5 R 6 OC(O)O-, -NR 6 R 7 or R 7 R 8 NC(O)NR 6 c) unsubstituted or substituted cycloalkyl, ailkenyl, R 6 R 5 R 6 C(O)NR 6 CN, N02, R 6 R 7 N-C(NR 8 R 6 N3, -NR 6 R 7 halogen or R 7 OC(O)NR 6 and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C1O cycloalkyl; -CHR 9 or N9; W is Z is unsubstituted or substituted CI-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle; wherein the substituted group is substituted with one or more of: 1) Ci -4i alkyl, unsubstituted or substituted with: a) C1-4 alkoxy, b) NR 6 R 7 C) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, 2) aryl or heterocycle, 3) halogen, 4) OR 6 N4R 6 R 7 6) CN, 7) N02, or 9) CF3; WO 97/01275 WO 9701275PCT/US96/11022 -416- R 5 is C 1-4 alkyl or aralkyl; R 6 R 7 and R 8 are independently selected from: H, C 1 -4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) 0 f) -S0 2 R 5 ,or g) -NR 6 R 7 or R 6 and R 7 may be joined in a ring, and R 7 and R 8 may be joined in a ring; R 9 is selected from: H, CIl-4 alkyl, C3-6 cycloalkyl, heterocycle and aryl, unsubstituted, monosubstituted or disubstituted with substituents independently selected from: a) Cl1-4 alkyl, b) Cl-4 alkoxy, c) aryl or heterocycle, d) halogen, e) HO, f) 0 g) -S0 2 R 5 ,and h) -NR 6 R 7 WO 97/01275 WO 9701275PCTIUS96/11022 417 V is selected from: -C(Ri -C(Rl -C(ORI I)R1 -CN(R1l )2R 1 -OC(R1 -NRI lC(R 1 -C(R -C(R 1 1 )2NR1 1 -C(0)NR 11 -NR1 1 0, -NC(0)Rl 1L, -NC(O)0RI -S(0)2N(RI -N(R1 or S(O)m; R 10 and R 1 1 are independently selected from hydrogen, C I -C6 alkyl, C2-C4 alkenyl, benzyl and aryl; WO 97/01275 WO 9701275PCT/US96/11022 418 R 5 a 5 b OH *0 (CH 2 )nCH 2 0H f OH 0 Rl 0 0 WO 97/01275 PCT/US96/11022 -419- R1 is selected from: a) heterocycle, and b) CI-C10 alkyl, which is substituted with heterocycle and which is optionally substituted with one or more of C1-C4 alkyl, hydroxy or amino groups; R2a and R2b 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 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 8 R 9 R 8 C(O)NR 8 CN, (R 8 )2N- C(NR 8 R 8 R 8 N3, -N(R 8 )2, R 9 0C(O)NR 8 and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; or R2a and R2b are combined to form (CH2)s R3 and R 4 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 C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, WO 97/01275 PCT/US96/11022
420- wherein the substituent is selected from F, Cl, Br, N(R 8 N02, R 8 R 9 R 8 C(O)NR 8 CN, (R 8 )2N-C(NR 8 R 8 R 8 N3, -N(R 8 R 9 0C(O)NR 8 and C1-C20 alkyl,, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- cycloalkyl; or R3 and R4 are combined to form (CH2)s 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 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(R 8 N02, R 8 R 9 R 8 C(O)NR 8 CN, (R 8 )2N-C(NR 8 R 8 R 8 N3, -N(R 8 R 9 0C(O)NR 8 and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic 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 -N(COR 8 R 6 is a) substituted or unsubstituted C1-C8 alkyl, wherein the substituent on the alkyl is selected from: 1) aryl, WO 97/01275 PCTIUS96/1 1022 421 2) heterocycle, 3) -N(R 9 )2, 4) -OR 8 or x-Y is a) 5 N~ 0 R 7 b b) c) d) (9)m H e) ,o H f) -CH 2 -CH 2 R7a is selected from a) hydrogen, WO 97/01275 PCT/US96/11022 -422- b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R 8 is independently selected from hydrogen, C1-C6 alkyl and aryl; R 9 is independently selected from C1-C6 alkyl and aryl; is independently selected from hydrogen and C1-C6 alkyl; R 1 1 is independently selected from C1-C6 alkyl; P: WO 97/01275 PCT/US96/11022 -423- Z is independently H2 or 0; m is 0, 1 or 2; n is 0, 1 or 2; and s is 4 or r) o R 2 Z R N O R3 R 4 I O R 2 Z R V) NJX N yOR6 )0 R 3 R4 H III (CH 2 )CH 2 OH 0 R 2 Z N O L )0 R3 R 4 0 III and O R 2 Zn V N N N R 3 R 4 H IV wherein: WO 97/01275 PCT/US96/11022 -424- V is CH2, O, S, HN, or R 7 N; R 2 R 3 R 4 and R5 are independently the side chains of naturally occurring amino acids, including their oxidized forms which may be methionine sulfoxide or methionine sulfone, or in the alternative may be substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or saturated chains of 2 to 8 carbon atoms which may be branched or unbranched, wherein the aliphatic substituents may be substituted with an aromatic or heteroaromatic ring; X-Y is a) N. 0 IR7 b) NNY c) (9)m d) Sf S H e) ,or H f) -CH 2 -CH 2 WO 97/01275 PCT/US96/11022 -425- R 6 is a substituted or unsubstituted aliphatic, aromatic or heteroaromatic group such as saturated chains of 1 to 8 carbon atoms, which may be branched or unbranched, wherein the aliphatic substituent may be substituted with an aromatic or heteroaromatic ring; an alkyl group, wherein the alkyl group comprises straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms, which may be substituted with an aromatic or heteroaromatic group; R 7 is Z is m is n is o is H2 or O; 0, 1 or 2; 0, 1 or 2; and 0, 1, 2 or 3; WO 97/01275 WO 9701275PCT/US96/11022 -426- (R8)t I V (CR la W V (C a2,- W (CR1b 2 )p(CR'bR 9 )rA R OR 6 )r1~ 0 (R 8 )t V (Ra2n- W (CR' lb 2 )p(CR b R 9 r R 3 R 4 III and (R 8 )t H 11 R; R 4 0 wherein: Ria is selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, (RlO)2N-C(NRIO)-, RlOC(O)-, or R10OC(O)-, and WO 97/01275 PCT/US96/11022 427 C) Ci -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, Ri 100., R 1 R 1 0 N3, or R 1 I 1 I0C(0)NR Rib is independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, cycloalkyl, alkenyl, alkynyl, (R I 0 )2N-C(NR R IOC(0)-, or R I 0C(0)-, and c) C I -C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, cycloalkyl, alkenyl, alkynyl, Ri100-, RI IS R I C(0)NR 10-, CN, (R 1 0 )2N-C(NR10)-, RIOC(O)-, RIO0C(0)-, N3, -N(R 10)2, or R I I0C(0)NR provided that Rilb is not R IOC(0)NR 10- when R Ia is alkenyl, V is hydrogen and X-Y is -C(O)NR 7 a-; R2a and R2b 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 ClI -C20 alkyl, C2-C20 alkenyl, C3-ClO cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 1 0 R I 1 S R I C(0)NR 10-, CN, (R 10 )2N-C(NRIO)-, Rl RIO0C(0)-, N3, -N(R 10)2, R1 1 0C(0)NR 1 0- and C I-C20 alkyl,and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-CiO cycloallcyl; or WO 97/01275 PCT/US96/11022 -428- R2a and R2b are combined to form (CH2)s R3 and R 4 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 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R 10 N02, R 1 0 R 1 1 R1C(O)NR 1 O-, CN, (R10)2N-C(NR10)-, R10C(O)-, R 10 0C(O)-, N3, -N(R 10 R 1 1 OC(O)NR 10 and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; or R3 and R 4 are combined to form (CH2)s and R5b 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 -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 10 R11S(O)m-, R 10 C(O)NR10-, CN, (R10)2N-C(NR 1 0 R10C(O)-, R10OC(O)-, N3, -N(R 10 R 1 1 OC(O)NR 10 and C1-C20 alkyl, and WO 97/01275 PCTIUS96/11022 -429- 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 -N(CORO1)-; R 6 is a) substituted or unsubstituted C1-C8 alkyl, wherein the substituent on the alkyl is selected from: 1) aryl, 2) heterocycle, 3) -N(R 1 1 )2, 4) -OR 10 or b) R 12 0 Z O' R 13 I WO 97/01275 PCT/US96/11022 430 X-Y is R7a a) N o R 7 b b) v (0)m d) Y S S H e) ,or H f) -CH 2 -CH 2 R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, -:I WO 97/01275 PCT/US96/11022 -431- c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R 8 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R1 0 R11S(O)m-, R1OC(O)NR 10 CN, N02, R102N-C(NR10)-, RlOC(O)-, RIOOC(O)-, N3, -N(RO1)2, or R 1 1 OC(O)NR 10 and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 R 1 1 S(O)m-, R1OC(O)NH-, CN, H2N-C(NH)-, N3, -N(R 10 or R11OC(O)NH-; R 9 is selected from: hydrogen, C1-C6 alkyl R 10 R 1 1 S(O)m-, R 1 OC(O)NRO 0 CN, N02, N3, -N(R 10 and R 1 1OC(O)NR 10 WO 97/01275 PCT/US96/11022 -432- provided that R 9 is not RO1C(O)NR1O- when Rla is alkenyl, V is hydrogen and X-Y is -C(O)NR 7 a-; R 10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; R 11 is independently selected from C1-C6 alkyl and aryl; R 12 is independently selected from hydrogen and C1-C6 alkyl; R 13 is C1-C6 alkyl; V is selected from: a) aryl; b) heterocycle; or c) hydrogen; W is -NHSO2-, -SO2NH-, -N(R 7 or -N[C(O)R7a]-; Z is independently H2 or O; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4, provided that n 0 when V is hydrogen and W is p is 0, 1, 2, 3 or 4, provided that p 0 when R 9 is not hydrogen or C1-C6 lower alkyl; q is 0, 1 or 2; r is 0 or 1; s is 4 or 5; and t is 0, 1 or 2, provided that t 0 when V is hydrogen; WO 97/01275 PCT/US96/11022 433 '0Z R 2aR 2 b z (CR1 2 )n Cp(CR1 2n N R 3 R 4 R 8b 1 2 )qCH 2 OH R 8b and R 2aR 2b z A N Y 3 -1 q 0 0 R 8b wherein: RIis hydrogen, Cl-C6 alkyl or aryl; R2a and R2b are independently selected from: WO 97/01275 PCT/US96/11022 -434- 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 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N02, R 9 R 10 R 9 C(O)NR 9 CN, (R 9 )2N- C(NR 9 R 9 R 9 N3, -N(R 9 )2, R 10 0C(O)NR 9 and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; or R2a and R2b are combined to form (CH2)s R 3 and R 4 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 alkenyl, C3-C1 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N02, R 9 R 10 R 9 C(O)NR 9 CN, (R 9 )2N- C(NR 9 R 9 R 9 N3, -N(R 9 )2, R 10 0C(O)NR 9 and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; or R3 and R 4 are combined to form (CH2)s WO 97/01275 PCT/US96/11022 -435- 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 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N02, R 9 R 10 R 9 C(O)NR 9 CN, (R 9 )2N- C(NR 9 R 9 R 9 N3, -N(R 9 )2, R 10 0C(O)NR 9 and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- 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 -N(COR 9 R 6 is a) substituted or unsubstituted C1-C8 alkyl, wherein the substituent on the alkyl is selected from: 1) aryl, 2) heterocycle, 3) -N(R 1 0 )2, 4) -OR 9 or b) R 12 O n 0 O R 13 I WO 97/01275 PCT/US96/11022
436- X-Y is R7a a) N 0 R 7 b b) N c) Y (0)m d) S H e) ,or H f) -CH 2 -CH 2 R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, WO 97/01275 PCT/US96/11022 -437- e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R8a and R8b are independently selected from: hydrogen, F, Cl, Br, N02, R 1 10-, R1OS(O)m-, CN, R 9 C(O)NR 9 (R 9 )2N-C(NR 9 R 9 R 9 0C(O)-, N3, -N(R 9 R 10 0C(O)NR 9 C1-C20 alkyl, aryl, heterocycle or C1-C20 alkyl substituted with aryl or heterocycle; R 9 is independently selected from hydrogen, C1-C6 alkyl and aryl; R 10 is independently selected from CI-C6 alkyl and aryl; R 1 l is independently selected from hydrogen, C1-C6 alkyl and aryl, provided R 1 1 is C1-C6 alkyl when n is 0; R 12 is independently hydrogen or C1-C6 alkyl; R 13 is C1-C6 alkyl; O is aryl or 1,2,3,4-tetrahydronaphthyl; WO 97/01275 WO 9701275PCTIUS96/11022 -438- Z is independently H2 or 0; m is 0, 1 or 2; n is independently 0 to 4; p is 0 or 1; q is 0, 1 or 2; and s is 4 or u) (R 8 )r Rj 9 V A' (CR' 2 (CR 1 2 W (R) (R 8 )r Rj 9 V A' (CR 1 2 (CR 1 2 W (CR' 2 )p V A' (CR' 2 ),A 2 (CR 1 2 W (CR2 1 v F or (R 8 )r R 9 V A 1 (CR 1 2 (C R 1 2 W (CR' 2 )p R 3 R 4 WO 97/01275 PCTIUS96/11022 439 wherein: R I is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 10 RI IS(O)m-, RIOC(O)NRIO-, CN, N02, (RI 0 )2N-C(NR 1 R 1 0 R 1 OOC(O)-, N3, -N(RIO)2, or RI 1 c) Cl -C6 alkyl. unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, RIO0-, R 1 1 RIOC(O)NRIO-, CN, (R 10 )2N-C(NR10)-, RIOC(O)-, RIO0C(O)-, N3, -N(RIO)2, or R I IOC(O)NR R2a and R2b 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 ClI -C20 alkyl, C2-C20 alkenyl, C3-C 10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, RIO0-, RI IS(O)m-, RIOC(O)NRIO-, CN, (Rl 0 )2N-C(NRl R 1 R 1 0 N3, -N(R'10)2, R1 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-Cl10 cycloalkyl; or R2a and R2b are combined to form (CH2)s R3 and R4 are independently selected from: a) a side chain of a naturally occurring amino acid, WO 97/01275 PCT/US96/11022 -440- 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 -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R 1 0 NO2, R1 0 Rl lS(O)m-, R 1 0 CN, (R 1 0 )2N-C(NR10)-, RO1C(O)-, R 1 0 0C(O)-, N3, -N(R10)2, R 1 1 OC(O)NR 10 and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; or R3 and R4 are combined to form (CH2)s 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 Cl-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(R 10 N02, R 10 R 1 1 R 10 CN, (R 1 0 )2N-C(NR10)-, R10C(O)-, R 1 0 0C(O)-, N3, -N(R 10 R 1 1 OC(O)NR 10 and Cl-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; or WO 97/01275 PCT/US96/11022 -441- 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 R 6 is a) substituted or unsubstituted C1-C8 alkyl, wherein the substituent on the alkyl is selected from: 1) aryl, 2) heterocycle, 3)-N(R11)2, 4) -OR10, or b) R 12 0 O R13. WO 97/01275 PCT/US96/11022 -442- X-Y is )7a a H R 7 b b) Ni c) (0)m d) (9S H e) ,or H f) -CH 2 -CH 2 R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, WO 97/01275 PCTIUS96/11022 -443- c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 R 1 1 S(O)m-, R1OC(O)NR 1 CN, N02, R 10 2N-C(NR10)-, RlOC(O)-, R10OC(O)-, N3, -N(R10)2, or R 1 1 OC(O)NR 10 and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R 1 1 S(O)m-, R1OC(O)NH-, CN, H2N-C(NH)-, R 10 N3, -N(R 10 or R11OC(O)NH-; R 9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 0-, R 1 1 R 10 C(O)NR 10 CN, N02, (R 10 )2N- WO 97/01275 WO 9701275PCT/US96/11022 -444- C(NRIO)-, RIOC(0)-, RIOOC(O)-, N3, -N(R 1 0 or RIIOC(0)NRIO-, and C) C1I-C6 alkyl unsubstituted or substituted by peffluoroalcyl, F, Cl, Br, R 1 0 R I 1 S RIOC(0)NRIO-, CN, (R 1 0 )2N-C(NRIO)-, RIOC(0)-, R I N3, -N(R 10)2, or R' 11OC(0)NR R 10 is independently selected from hydrogen, ClI -C6 alkyl and aryl; R 1 1 is independently selected from C I-C6 alkyl and aryl; R 12 is independently selected from hydrogen and ClI-C6 alkyl; R 13 is independently selected from C 1-C6 alkyl; A I and A 2 are independently selected from: a bond, -CH=CH-, -C(0)NRIO-, 0, -N(RlO)-, -NRI -S(0)2N(Rl -N(Rl O)S or S(O)m; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) Cl -C20 alkyl wherein from 0 to 4 non-terminal 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 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 or a bond; W is a heterocycle; Z is independently H2 or 0; WO 97/01275 PCT/US96/11022 445 m is 0, 1 or 2; n is 0, 1,2, 3or 4; pis 0, 1,2,3or4; q is0,l1or 2; r is 0 to 5, provided that r is 0 when V is hydrogen; and s is 4 or WO 97/01275 WO 9701275PCT/US96/1 1022 446 V) (R 8 )r R.9z V Al(CRla 2 (CRla 2 (CR 1 2b (R )r R9z V -Al(CRla 2 )nA 2 CRla 2 )nAW/. -(CRb 2 )p (R )r R V- Al(' C R C~a) 2(On W 2 )p (R )r R V-A A(CRla 2 )nA (CRla 2 )n (CRb) 4 IV R2 wherein: Ri1a and Ri1b are independently selected from: a) hydrogen, 0 p6 Z R 5 a R 5 b WO 97/01275 PCT/US96/11022 447 b) aryl, heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, R 100-, R1 1 R IOC(O)NRl10-, CN, N02, (RIO)2N-C(NRIO)-, RIOC(O)-, R 1 OOC(O)-, N3, -N(R'10)2, or R1 1 0C(O)NR 1 0-, c) C I -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, C3-C 10 cycloalkyl, C2-C6 atkenyl, C2-C6 alkynyl, R 10 RI IS(O)m-, RIOC(O)NRIO-, CN, (RIO)2N-C(NRIO)-, RIOC(O)-, R 1 0 N3, -N(R 10 or R1 1 0C(O)-NR R2a. and R2b are independently selected from: a) hydrogen, b) C1I-C6 alkyl unsubstituted or substituted by C2-C6 alkenyl, RIO0-, RI IS(O)m-, RIOC(O)NRIO-, CN, N3, (RIO)2N- C(NRIO)-, RIOC(O)-, RIOOC(O)-, or R I I0C(O)NR 1 0-, c) aryl, heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, R 1 0 0- R1 1 R I C(O)NR 10-, CN, N02, (R 10 )2N-C(NR RIOC(O)-, RIO0C(O)-, N3, -N(RIO)2, or R I I0C(O)NR 1 and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C 10 cycloalkyl; R3 and R4 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 heterocyclic group, WO 97/01275 PCT/US96/11022 -448- wherein the substituent is selected from F, Cl, Br, N(RO)2, N02, R 10 R 1 1 R 10 CN, (R1 0 )2N-C(NR10)-, R 10 R 1 0 0C(O)-, N3, -N(R10)2, R 1 1 OC(O)NRIO- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- CO1 cycloalkyl; or R3 and R4 are combined to form (CH2)s 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 C 1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, CF3, N(R 10 N02, R 10 R 1 1 S(O)m-, CN, (R 10 )2N-C(NR10)-, N3, -N(R 10 R 11 OC(O)NR1O- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- CO1 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 -N(COR1O)- WO 97/01275 PCT/US96/1 1022 449 R 6 is a) substituted or unsubstituted Ci -C8 alkyl, substituted or unsubstituted C5-C8 cycloalcyl, 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) CI-C6 alkyl, 2) aryl, 3) heterocycle, 4) -N(Rl11)2, -OR 1 0 or b) R 1 2 0o 0 R 13 X-Y is a) N;S 0 R 7 b b) N 5 N s C) s WO 97/01275 PCTIUS96/11022 -450- d) S H e or H f) -CH 2 -CH 2 R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C10 cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C 10 cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C10 cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C10 WO 97/01275 WO 9701275PCTIUS96/11022 -451- cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstitutectnor substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; R 8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 R I 1 S(O)m-, RI OC(O)NRI CN, N02, R 1 0 2N-C(NR 1 R 1 OC(O)-, R10OC(O)-, N3, -N(RlO)2, or R 1 1OC(O)NRIO-, and C) C1I-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, peffluoroalkyl, F, Cl, Br, RIO0-, R 1 I S(O)m-, RIOC(O)NH-, CN, H2N-C(NH)-, RlOC(O)-, RIOOC(O)-, N3, -N(R 1 0 or R 10 0C(O)NH-; R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RIO0-, RI IS(O)m-, Rl 0 C(O)NR1 0 CN, N02, (R'0%2N- C-(NRIO)-, RlOC(O)-, RIO0C(O)-, N3, -N(Rl 0 or R 1 IOC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R1 0 Rl 1 RIOC(O)NRIO-, CN, (RIO)2N-C(NR 1 0 RIOC(O)-, RIOOC(O)-, N3, 102,or R1 1 0C(O)NR10-;1 R 10 is independently selected from H, C1I-C6 alkyl, benzyl, substituted aryl and C1-C6 ailkyl substituted with substituted aryl; R 1 is independently selected from C1I-C6 alkyl and aryl; R 12 is hydrogen or C1I-C6 alkyl; I WO 97/01275 PCTIUS96/11022 -452- R 13 is C1-C6 alkyl; Al and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR1O-, -NRO1C(O)-, O, -S(O)2N(R 10 -N(R 10 or S(O)m; 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 A 1 is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; Z is independently H2 or O; m is n is p is qis r is 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; WO 97/01275 WO 9701275PCT/US96/11022 453 N ,OH N (CR'b 2 N (CR1bs R VI -01 6 IN- R 2 b wherein: R Ia and R Ib are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloallcyl, alkenyl, alkynyl, R1 0 0-, R 1 RIOC(O)NRIO-, CN, N02, (RI 0 )2N-C(NR 1 R 1 R10OC(O)-, N3, 102,or R I IOC(O)NR WO 97/01275 PCT/US96/11022 454 c) C I -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalcyl, alkenyl, alkynyl, RIO00., R I R I OC(O)NR CN, (R 1 %2N-C(NR RlOC(O)-, RIOOC(O)-, N3, -N(RIO)2, or RI IOC(O)- NR 1 0-; R2a and R2b are independently selected from: a) hydrogen, b) ClI-C6 alkyl unsubstituted or substituted by alkenyl, R 10 0-, RI IS(O)m-, RIOC(O)NRIO-, CN, N3, (RIO)2N-C(NR Rl 0 R10OC(O)-, -N(RiO)2, or RI I0C(O)NRIO-, c) aryl, heterocycle, cycloalkyl, alkenyl, R 10 0-, Rl 1 RIOC(O)NRIO-, CN, N02, (RIO)2N- RI R 1 OOC(O)-, N3, -N(R 10 or R 1 OC(O)NR 1 and d) ClI -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- CG1 cycloalkyl; R3a and R3b 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 CI-C20 alkyl, C2-C20 alkenyl, C3-C1O cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R 10 N02, R 1 0 R I IS RlIOC(O)NR CN, (Rl 0 )2N-C(NRl Rl R 1 OOC(O)-, N3, -N(R 10 R I I0C(O)NR 10- and ClI-C20 alkyl, and WO 97/01275 PCT/US96/11022 455 d) C I -C6 ailkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- CIO cycloallcyl; or R3a and R3b 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)-; R4 and R5 are independently selected from: a) hydrogen, and b) (R )r R VAl(CRa 2 )A N-(CRa) Rb) R 6 is a) substituted or unsubstituted ClI-C8 ailkyl or substituted or unsubstituted C5-C8 cycloalkyl, wherein the substituent on the alkyl is selected from: 1 aryl, 2) heterocycle, 3) -N(R 11)2, 4) -OR 10 or b) R 1 2 0o 0 R 13 R7 is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloallcyl, alkenyl, ailcynyl, perfluoroalcyl, F, Cl, Br, R 10 R 1 S R 1 OC(O)NRl CN, N02, Ri 0 2N-C(NR Ri OC(O)-, R I N3, -N(R'10)2, or R I I0C(O)NR 1 and WO 97/01275 PCT/US96/11022 456 C) C I -C6 ailkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 RI IS(O)m-, RIOC(O)NH-, CN, H2N- RIOC(O)-, RIOOC(O)-, N3, -N(RlO)2, or R 10 0C(O)NH-; R8 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RIO0-, Rl 1 RIOC(O)NRlO-, CN, N02, R 1 RI 0 N3, -N(R 10)2, or R I IOC(O)NR 1 and c) C I -C6 alkyl unsubstituted or substituted by perfluoroalcyl, F, Cl, Br, RIO0-, RlS(O)m-, RIOC(O)NRIO-, CN, (RIO)2N-C(NRIO)-, RIOC(O)-, RIOOC(O)-, N3, -N(R 10)2, or Ri 11OC(O)NR10-;1 R 10 is independently selected from hydrogen, C I-C6 alkyl, benzyl and aryl; R I is independently selected from ClI-C6 alkyl. and aryl; R 12 is independently selected from hydrogen and ClI-C6 alkyl; R 1 3 is independently selected from ClI -C6 alkyl; A 1 I and A 2 are independently selected from: a bond, -CH=CH-, -CZ-C-, -C(O)NRIO-, -NRlOC(O)-, 0, -N(RIO)-, -S(0)2N(RIO0>, -N(RI 0 )S(O) 2 or S(O)m; is selected from: a) hydrogen, b) heterocycle, c) aryl, WO 97/01275 PCT/US96/11022 -457- 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 A 1 is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; Z is independently H2 or O; mis n is p is qis r is s 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 5; and 0 or 1; WO 97/01275 WO 9701275PCT/US96/11022 -458- X) (R )r (R9\Y Z R 5 a R 5 b V- Al(CRla 2 2 (CRla 2 )W (C b NY~0 x R 4aR 4 b (R 8 )r RR6Y Z R 5 a "R 5 b V Al(CRla 2 2 (CRla 2 (CR lb 2 )p N NyR Y R 2R H x 4 R 4 b 8 HOCH 2 (0H 2 )q R9 8 r R6 Y OH a 2R a b NN4 O VAl(C Rl 2 (C Rl 2 1 (CR' 2 )p u ~H 0 xR R 4 b IR R 4 a (R 8 )r (R9 R6 Y zq laI la (Clb) N N V A'l(CRla 2 )nA (CRla 2 )n W2- R2R H) IVx R i R 4 b wherein: Ri1a and Ri1b are independently selected from: a) hydrogen, WO 97/01275 PTU9/12 PCTIUS96/11022 459 b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, RIO0-, R' 1 RIOC(0)NR1 0 CN, N02, (Ri 0 )2N-C(NRl R 1 R 1 OOC(O)-, N3, 102,or R1 1 OC(0)NR c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, RIO00., R 11 R' OC(0)NR 1 CN, (Ri (b2N-C(NRl RlOC(0)-, R10OC(0)-, N3, -N(RIO)2, or RI 1 0C(0)- 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-C20 alkenyl, C3-CIO cycloalcyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(Rl%2, N02, RIO0-, RI IS(0)m-, RIOC(0)NR 1 0 CN, (RIO)2N-C(NRIO)-, RlOC(0)-, R' OOC(0)-, N3, -N(RIO)2, R 1 I0C(0)NRIO- and CI-C20 alkyl, and d) Ci -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- Clo 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 WO 97/01275 WO 9701275PCTIUS96/11022 460 R 6 N2 HA 7a 7 R4a, ROb, R 7 a and R7b are independently selected from: a) hydrogen, b) C 1-C6 ailkyl unsubstituted or substituted by alkenyl, R 10 0-, R' 1 RIOC(O)NRIO-, CN, N3, (Rl'%2N-C(NRIO)-, RIOC(O)-, RIO0C(O)-, -N(RIO)2, or RI I0C(O)NRIO-, c) aryl, heterocycle, cycloalkyl, alkenyl, RIO0-, R' RIOC(O)NRIO-, CN, N02, (RIO)2N- C(NRl R 1 R 1 OOC(O)-, N3, -N(RO)2,or RI 1 OC(O)NRIO-, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-ClO cycloalicyl; 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 alkenyl, C3-C1O cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(R 1 N02, R100O, R' 1 R 1 0 C(O)NR 1 0 CN, (RI 0 )2N-C(NRi R 1 R 1 OOC(O)-, N3, -N(Ri10)2, Ri 11OC(O)NRi10- and C I-C20 alkyl, d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- Clo cycloallcyl; or WO 97/01275 PCTIIUS96/1 1022 461 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 R I 1 S RIOC(0)NRIO-, CN, N02, R 1 0 2N-C(NRIO)-, RIOC(0)-, R 1 N3, -N(R'10)2, or R I IOC(0)NR 10-, and c) Ci -C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RIO0-, RI IS(0)m-, RIOC(0)NH-, CN, N2N- RIOC(0)-, RIO0C(O)-, N3, -N(R' 0 or R 1 0 0C(0)NH-; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RIO0-, RIIS(0)m-, RIOC(0)NRIO-, CN, N02, (R 1 0 )2N-C- (NRIO)-, RIOC(0)-, R 1 0 N3, -N(R 1 0 or R1 1 OC(0)NR 10-, and c) C I -C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RIO0-, RI 1 RIOC(0)NRlO-, CN, (Rl 0 )2N-C(NRl R 1 R 1 OOC(0)-, N3, 102,or R I I0C(0)NR RIO is independently selected from hydrogen, Cl -C6 alkyl, benzyl and aryl; R 1 1 is independently selected from C1I-C6 alkyl. and aryl; WO 97/01275 PCT/US96/11022 -462- R 12 is a) substituted or unsubstituted C1-C8 alkyl or substituted or unsubstituted C5-C8 cycloalkyl, wherein the substituent on the alkyl or cycloalkyl is selected from: 1) aryl, 2) heterocycle, 3) -N(R 1 1 )2, 4) -OR10, or b) R' 3 0 R R1 3 is independently selected from hydrogen and C1-C6 alkyl; R1 4 is independently selected from C1-C6 alkyl; A1 and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR10-, -NRO1C(O)-, O, -S(0)2N(R10)-, -N(R10)S(0)2-, or S(O)m; Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C5-C7 saturated ring or 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, I WO 97/01275 PCT/US96/11022
463- provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; X, Y and Z are independently H2 or O; m is n is pis q is r is s is t is uis 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; WO 97/01275 WO 9701275PCTIUS96/11022 -464- y) (R8)r (R9 R R 3 V Al(CRla 2 )nA (CRlaOn (CR b 2 N0N R 4 R A (R 8 r R la 2(a I lb VAl(CRla 2 )nA (CRlOn) (CRlb 2 7 N\ NZ R 3 R 4 B (R )r (R9 R 2 R3 V Al(CRla 2 )nA (CRla) On W (CR b 2 )pN x N- N -Z wherein: R Ia and R Ib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, R 1 0 RI RIOC(O)NRIO-, CN, N02, (RIO)2N-C(NRIO)-, RIOC(0)-, RIO0C(O)-, N3, -N(R 10 or R1 1 0C(O)NR 1 0-, c) C I -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 R 1 1 RIOC(O)NRIO-, CN, WO 97/01275 PCT/US96/11022 465 -N(R 10)2, or RI 'OG(O)-NR R 2 and R 3 are independently selected from: H; unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted C2-.8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, <NR6R 7 or >A R6 unsubstituted or substituted heterocycle, 0 0 wherein the substituted group is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: 0 a) C 1-4 alkcyl, b) (CH2)pOR 6 c) (CH2)pNR 6 R 7 d) halogen, 2) C3-6 cycloallcyl, 3) OR 6 4) SR 6 S(O)R 6 S02R 6 NR 6 R 7 6) N Y ~R 7 0 -N YNR 7 R 7 a 0 WO 97/01275 PCT/US96/11022 -466- 8) NR 6 R 7 0 9) -O OR 6 NR 6 R 7 0 11) -S0 2 -NR 6 R 7 R 6 12) -N-SO 2 -R 7 13) R 6 or 0 14) OR 6 or 0 R 2 and R 3 are attached to the same C atom and are combined to form (CH2)u wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, S(O)m, and -N(COR1O)-; R 4 is selected from H and CH3; and any two of R 2 R 3 and R 4 are optionally attached to the same carbon atom; R 6 R 7 and R7a are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) C1-4 alkoxy, WO 97/01275 PCT/US96/11022 467 b) aryl or heterocycle, c) halogen, d) HO, e) YR 0 f) -S0 2 R 11 g) N(RlO)2; or ,or R 6 and R 7 may be joined in a ring; R 7 and R7a may be joined in a ring; R 8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 R1 1 S(O)M-, R 1 0 C(O)NR 1 CN, N02, Ri 0 2N-C(NRIO0y, RI OC(O)-, RIO0C(O)-, N3, -N(RlO)2, or RI I0C(O)NRIO-, and C) CI -C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalcyl, F, Cl, Br, RIO0-, RI 1 S(O)m-, RIOC(O)NH-, CN, H2N-C(NH)-, RlOC(O)-, RIO0C(O)-, N3, -N(RiO)2, or R 10 0C(O)NH-; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RIO0-, R I IS(O)m-, R 1 C(O)NR 10-, CN, N02, (RI 0 )2N-C-(NRi R 1 0 RI OOC(O)-, N3, 102,or R I I0C(O)NR 10-, and c) C I -C6 ailkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 10 Rl 1 RiOC(O)NRiO-, CN, O)2N-C(NRi RI R 1 OOC(O)-, N3, -N(Ri10)2, or Ri11OC(O)NR WO 97/01275 PCT/US96/11022 -468- 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)NR10-, -NRO1C(O)-, O, -S(0)2N(R10)-, -N(R10)S(0)2-, or S(O)m; G is H2 or O; 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 A 1 is S(O)m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; X is -CH2-, or Y is aryl, heterocycle, unsubstituted or substituted with one or more of: 1) C1-4 alkyl, unsubstituted or substituted with: a) C1-4 alkoxy, b) NR 6 R 7 c) C3-6 cycloalkyl, d) aryl or heterocycle, WO 97/01275 PCT/US96/11022 469 2) 3) 4) 6) 7) 8) 9) 11) e) HO, -S(O)mR 6 or g) -C(O)NR 6 R 7 aryl or heterocycle, halogen, OR 6 NR 6 R 7 CN, N02, CF3; -S (O)mR 6 -C(O)NR 6 R 7 or C3-C6 cycloalkyl; Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more of the following: 1) Ci -4 alkyl, unsubstituted or substituted with: a) C1-4 alkoxy, b) NR 6 R 7 c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O)mR 6 or g) -C(O)NR 6 R 7 2) aryl or heterocycle, 3) halogen, 4) OR 6 NR 6 R 7 6) CN, 7) N02, 8) CF3; 9) -S(O)mR 6 -C(O)NR 6 R 7 or WO 97/01275 PCTIUS96/11022 470 11) C3-C6 cycloallcyl; m is 0, 1 or 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 0Oorl1; t is 0Oor1; and u is 4 or Z) (R 8 )r R 2R la~ R R,14 3 (RR V -A(la)A 2 (CRla) W (CRlb 2 'A N (0R 2 )qA 3 (C 5 2 )nR R 7 wherein: Ria is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-CI0 cycloalcyl, C2-C20 ailkenyl, C2- alkynyl, R 10 R1 1 R I 0 C(O)NR 10-, CN, N02, (R 1 0 )2N-C(NRI Rl R 1 0 N3, 102,or R I I0C(O)NRl10-, c) C I -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, C3-C1O cycloalkyl, C2-C20 alkenyl, C2-C20 alkynyl, R 10 RI IS R I C(O)NR 10-, CN, R 1 RI OOC(O)-, N3, -N(R 1 0 or R1 1 0C (O)-NR R Ib is independently selected from: a) hydrogen, WO 97/01275 WO 9701275PCT/US96/1 1022 471 b) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3-C1O cycloalicyl, CQ2-C20 alkenyl, C2-C20 alkynyl, R 10 RI IS(O)m-, CN, N02, (RIO)2N-C(NR10)- ,RIOC(O)-, R 1 0 N3 or -N(RIO)2, C) Ci1 -C6 ailkyl unsubstituted or substituted by substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic, C3-C1O cycloalcyl, C2-C20 alcenyl, C2-C20 alkynyl, R 1 0 R' 1 CN, (RIO)2N-C(NRIO)-, RIOC(O)-, N3 or -N(R 1 0 )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, and c) substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alcenyl, substituted or unsubstituted C3-ClO cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R 1 0 N02, R 1 0 RI IS(O)m-, Rl 0 C(O)NRIO-, CN, (RI (b2N-C(NRI R 1 R 1 0 0C(O)-, N3, -N(RIO)2, R 1 I0C(O)NR10- and C1-C20 alkyl, and d) ClI -C6 alkyl 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 R2or R3are combined with R 7 to form a ring such that WO 97/01275 WO 9701275PCT/US96/11022 -472- R 2 R 3 AN\ is (H 2 )t. R 4 R5, Rl3a and Rl3b are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by C2-C20 alkenyl, RIO0-, R 1 1 RIOC(O)NRIO-, CN, N3, (R 1 0 )2N- C(NRIO)-, RIOC(O)-, -N(RIO)2, or R 1 1 C(O)NRIO-, c) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Cl10 cycloallcyl, C2- alkenyl, R 1 0 RI IS R IOC(O)NR ,CN, N02, (RIO)2N-C(NRIO)-, RIOC(O)-, N3, 102,or R1 1 OC(O)NR 1 and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C1O cycloallcyl; R 6 is selected from: a) hydrogen, b) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3-C 10 cycloalkyl, C2-C20 alkenyl, C2-C20 alkynyl, Ci -C20 perfluoroalkyl, allyloxy, F, Cl, Br, R1 0 RI IS(O)m-, RIOC(O)NRIO-, CN, N02, R 1 0 2N-C(NRIO)-, RIOC(O)-, N3, -N(Rl 0 )2, (R 12 )2NC(O)- or Ri 11OC (O)NR 10-, and c) C I -C6 alkyl unsubstituted or substituted by substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3-ClO cycloalkyl, C2-C20 alkenyl, C2-C20 alkynyl, C2- perfluoroalkyl, F, Cl, Br, R 1 0 R I RlOC(O)NH-, CN, H2N-C(NH)-, RlOC(O)-, N3, -N(IO2,or WO 97/01275 WO 9701275PCTIUS96/11022 473 R7 is independently selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C 10 cycloallcyl, and e) Ci1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-Cl10 cycloalkyl; R 8 is selected from: a) hydrogen, b) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3-C 10 cycloalkyl, C2-C20 alkenyl, C2-C20 alkynyl, C1-C20 perfluoroalkyl, allyloxy, F, Cl, Br, R 100-, RI IS R 1 C(O)NR -S(O)2NR 1 02, CN, N02, Ri 0 2N-C(NRI10>, R' 0 R I N3, -N(Rl10)2, or Ri 11OC(O)NR 10-, and C) C I -C6 alkyl unsubstituted or substituted by substituted or unsubstituted. aryl, substituted or unsubstituted heterocycle, C3-C 10 cycloalkyl, C2-C20 alkenyl, C2-C20 alkynyl, C2- perfluoroalkyl, F, Cl, Br, R 10 R 1 I 1 S(O)m-, RIOC(O)NH-, CN, H2N-C(NH)-, RIOC(O)-, RIO0C(O)-, N3, -N(RIO)2, or RIOOC(O)NH-; R9 is selected from: a) hydrogen, b) C2-C20 alkenyl, C2-C20 alkynyl, C2-C20 perfluoroalkyl, F, Cl, Br, R 1 0 RI 1 R 10 C(O)NRI0-, CN, N02, (Rl 0 )2N-C-(NRlO)-, R 1 R 1 0 N3, 102,or R1 1 0C(O)NR 10-, and c) C I -C6 alkyl unsubstituted or substituted by C2-C20 periluoroalkyl, F, Cl, Br, R 1 0 R1 1 S(O)m-, WO 97/01275 WO 9701275PCTIUS96/11022 -474- RIOC(O)NRIO-, CN, (RIO)2N-C(NR10)-, RlOC(O)-, N3, -N(R 1 0 or RI R 1 0 is independently selected from hydrogen, C 1-C6 alkyl, benzyl and aryl; R 1 1 is independently selected from ClI-C6 alkyl and aryl; R 12 is independently selected from hydrogen, C1I-C6 alkyl and aryl, or (R 12 )2 forms (CH2)s *A 1 A 2 and A 3 are independently selected from: a bond, -CH=CH-, -C(O)NR 7 -NR 7 0, -N(R 7 -S(O)2N(R 7 -N(R 7 or S(O)m; 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 Al 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; Z is independently H2 or 0; m is 0, 1 or 2; n is 0, 1, 2, 3or 4; p is 0,1, 2, 3or 4; q is 0, 1, 2, 3or 4; WO 97/01275 WO 9701275PCT/US96/1 1022 475 r is s is t is o to 5, provided that r is 0 when V is hydrogen; 4 or 5; and 3, 4 or lb~ NR-(CR wherein: Ria and Rib are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3 -C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 8 0-, R 9 R 8 C(O)NR 8 CN, N02, (R 8 )2N-C(NR8)-, R 8 R 8 N3, -N(R 8 or R 9 OC(O)NR 8 c) C I -C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, unsubstituted or substituted C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 8 R 9 R 8 C(O)NR 8 CN, (R 8 )2N-C(NR 8 R 8 R 8 N3, -N(R 8 )2, or R 9 OC(O)-NR 8 R2a, R2b and R 3 are independently selected from: a) hydrogen, b) C 1-C6 alkyl. unsubstituted or substituted by C2-C6 alkenyl, R 8 R 9 R 8 C(O)NR 8 CN, N3, (R 8 )2N-C(NR 8 IR 8 R 8 -N(R 8 or R 9 OC(O)NR 8 WO 97/01275 WO 9701275PCT/US96/11022 -476- c) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted cycloallcyl, aikenyl, R 8 0-, R 9 R 8 C(O)NR 8 CN, N02, (R 8 )2N-C(NR 8 R 8 R 8 N3, -N(R 8 halogen or R 9 OC(O)NR 8 and d) Ci -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C 10 cycloalkyl; R 4 and R 5 are independently selected from: a) hydrogen, and b) (R 6 )r R7z V -A A(CRla 2 (CRla 2 (1,V (CRb) R6 is independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3 -C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C I -C6 perfluoroalkyl, F, Cl, Br, R 8 R 9 R 8 C(O)NR 8 CN, N02, R 8 2N-C(NR 8 R 8 R 8 N3, -N(R)2,or R 9 OC(O)NR 8 and c) C I -C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 peffluoroalkyl, F, Cl, Br, R 8 R 9 R 8 C(O)NH-, CN, H2N-C(NH)-, R 8 C(O)- R 8 N3, -N(R 8 or R 8 OC(O)NH-; R7 is selected from: a) hydrogen, WO 97/01275 WO 9701275PCT[US96/11022 477 b) C2-C6 alkenyl, C2-C6 alkynyl, C I-C6 peffluoroalcyl, F, Cl, Br, R 8 R 9 R 8 C(0)NR 8 CN, N02, (R 8 )2N-C-(NR 8 R 8 R 8 N3, -N(R 8 or R 9 OC(0)NR 8 and c) C1I-C6 alkyl unsubstituted or substituted by C I-C6 perfluoroalkyl, F, Cl, Br, R 8 R 9 R 8 C(0)NR 8 CN, (R 8 )2N-C(NR 8 R 8 R 8 N3, -N(R 8 )2, or R 9 OC(0)NR 8 R 8 is independently selected from hydrogen, C I -C6 alkyl, substituted or unsubstituted C I -C6 aralkyl and substituted or unsubstituted aryl; R 9 is independently selected from ClI -C6 ailkyl and aryl; RIO is independently selected from hydrogen, Cl-C6 ailkyl, substituted or unsubstituted C I -C6 aralkyl and substituted or unsubstituted aryl; Al and A 2 are independently selected from: a bond, -CH=CH-, -C(0)NR 8 -NR 8 0, -N(R 8 -S(0)2N(R 8 -N(R 8 )S or S(O)m; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) ClI -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 Al is S(O)m and V is not hydrogen if A 1 I is a bond, n is 0 and A 2 is S(O)m; WO 97/01275 WO 9701275PCT[US96/11022 478 W is a heterocycle; Y is selected from: a bond, -C(R I -C(R -C(RI 0)20., -C(Rl 0 2 NRIO0., -C(0)NRI -NR 1 0, -NC(0)Rl -NC(0)ORi -S(0)2N(RI -N(Rl 0 )S or S(O)m; Z is H2 or 0; m is 0, 1 or 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; and u is 0Oorl1; or a pharmaceutically acceptable salt thereof. 6. The method according to Claim 5 wherein the protein substrate competitive inhibitor is selected from: [2(R)-amnino-3 -mercaptopropylamino]-6(S )-methyl-2(R)-n-propyl- 3,4-E-octenoyl-homoserine, and the corresponding homoserine lactone, [2(R)-amino-3-mercaptopropylamino] -6(S )-methyl-2(R)-methyl- 3,4-E-octenoyl-homserine, and the corresponding homoserine lactone, [2(R)-amino-3-mercaptopropylamino] -6(5 )-methyl-2(R)-ethyl-3 ,4- E-octenoyl-homserine, and the corresponding homoserine lactone, [2(R)-amino-3-mercaptopropylamino] -6(5 )-methyl-2(R)-i-propyl- 3 ,4-E-octenoyl-homoserine, and the corresponding homoserine lactone, WO 97/01275 WO 9701275PCT/US96/11022 479 2 (R)-amino-3-mercaptopropylaniino]-6(S )-methyl-2(R)-n-butyl- 3,4-E-octenoyl-homoserine, and the corresponding homoserine lactone, 2 (R)-amino-3-mercaptopropyamino]-6(S)-methyl-2(R)s.butyl.. 3,4-E-octenoyl-homoserine, and the corresponding homoserine lactone, [2(R)-amino-3-mercaptopropylamino] -6(S)-methyl-2(R)-t-butyl- 3 ,4-E-octenoyl-homoserine,, and the corresponding homoserine lactone, 2 (R)-alnino-3-mercaptopropylamino] -6(S)-methyl-2(R)- cyclohexyl-3 ,4-E-octenoyl-hiomoserine, and the corresponding homoserine lactone, 2 (R)-amino-3-mercaptopropylamino]-6(S)-methyl-2(R)- cyclopentyl-3,4-E-octenoyl-homoserine, and the corresponding homoserine lactone, 2 (R)-aino-3-mercaptopropylamino]-6(S)-methyl-2(R)benzyl. 3 ,4-E-octenoyl-homoserine, and the corresponding homoserine lac tone, 2 (R)-amino-3-mercaptopropylamino]-6-methyb2(R)-ipropyl.3 ,4- E-octenoyl-homoserine, and the corresponding homoserine lactone, 2 (R)-amino- 3 -mercaptopropylamino]-6(S)-methylb2(R)-i.propylp 3 ,4-E-octenoyl-methionine, and the corresponding methyl ester, [2(R)-amino-3-mercaptopropylamino] -6(S)-methyl-2(R)-n-butyl- 3 ,4-E-octenoyl-methionine, and the corresponding methyl ester, [2(R)-amino-3-mercaptopropylamino] -6(S)-methyl-2(R)-benzyl- 3,4-E-octenoyl-methionine, and the corresponding methyl ester, [2(R)-amino-3-mercaptopropylamino] -6(S)-methyl-2(R)-n-propyl- octanoyl-homoserine, and the corresponding homoserine lactone, WO 97/01275 PCTIUS96/11022 480 2 (R)-amino- 3 -mercaptopropylaminoy-6(S)-methyl..2(R)-benzyl- octanoyl-homoserine, and the corresponding homoserine lactone, N-( 3 -phenyl-2(S)-(mercaptopropionylamino)prop-.1 -yl)isoleucyl- methiomine, N-( 2 (R)-amino- 3 -mercaptopropyl)isoleucyl.phenylalanyl.methionine, N-( 3 -mercaptopropy)isoeucy-phenylalany1..methionine, N-( 3 -mercaptopropyl)valyl-isoleucylbmethionine, N-( 2 (R)-amino- 3 -mercaptopropyl)valyl-isoleucyl.methionine, N-( 3 -methyl-2(S)-(cysteinylamino)but- 1 -yl)phenylalanyl-methionine, N-( 3 -methyl-2(S)-(mercaptopropionylamino)but-1 -yl)-phenylalanyl- methionine, N- 2 (R)-amino-3-mercaptopropylamino-3 (S )methylpentyl]- phenylalanyl-methionine, N- 2 (S)-(3-mercaptopropylamino)-3 (S)methylpentyl]-phenylalanylp methionine, N-( 2 (R)-amino- 3 -mercaptopropyl)isoleucyl-phenylalanyl.(methionine sulfone), N- 2 (R)-amino- 3 -mercaptopropyl)isoleucyl)>(p-iodophenylalanyl). methionine, N- 2 (R)-(cysteinyl-isoleucylamino)-3 (S)-methylpentyl]-methionine, WO 97/01275 WO 9701275PCT[US96/11022 481 N- [2(R)-(N'-(2(R)-amino-3-mercaptopropyl)-isoleucylamino)-3-phenyl- propyl]methionine, N- [2(R)-(N'-(2(R)-amino-3-mercaptopropyl)-isoleucylamino)-3 methylpentyl]methionine, N-(3-mercaptopropyl)valyl-isoleucyl-methionine methyl ester, N-(2(R)-amino-3-mercaptopropyl)isoleucyl-phenylalanyl-methionine ethyl ester, N-(2(R)-amino-3-mercaptopropyl)isoleucyl-phenylalanyl-methionine benzyl ester, N- [2(R)-Amino-3-mercaptopropyl]-L-isoleucine-phenethylamide, N- [2(R)-Amino-3-mercaptopropyl]-L-isoleucine-benzylamide, N- [2(R)-Amino-3-mercaptopropyl] -L-isoleucine-3-methylbutylamide, N- [2(R)-Amino-3-mercaptopropyl]-L-isoleucine-3-phenylpropylamide, N- [2(R)-Amino-3-mercaptopropyl] -L-isoleucyl-L-phenylalaninol, N- [2(R)-Amino-3-mercaptopropyl]-L-isoleucine-N-methylbenzylamide, N- [2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(4- methoxybenzyl)amide, N- [2(R)-Amino-3-mercaptopropyl] -L-isoleucine- (2 ,4-dichloro- benzyl)amide, N- [2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(4-trifluoromethyl- benzyl)amide, WO 97/01275 WO 9701275PCTIUS96/11022 482 N- [2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(2,4-dichloro- phenethyl)amide, N- [2(R)-Amino-3-mercaptopropyl] -L-isoleucine-(2-benzimidazol- ylmethyl)amide, N-[2(R)-Amino-3-mercaptopropyl]-L-isoleucine-( 1-indanyl)amide, N- [2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(2,4-dimethyl- benzyl)amide, N- [2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(2,3-dichloro- benzyl)amide, N- [2(R)-Amino-3-mercaptopropyl] -L-isoleucine-(4-sulfamoyl- benzyl)amide, N- [2(R)-Amino-3-mercaptopropyl]-L-isoleucineanilide, N- [2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(2,4-dimethyl- phenyl)amide, N- [2(R)-Amino-3-mercaptopropyl]-L-isoleucine-(2,3-dimethyl- phenyl)am-ide, L-Cysteinyl-L-isoleucine-phenethylamide, N- [2(R)-Amino-3 -mercaptopropylamino]-3-methylpentyl]- phenethylamide, N-(2(R)-Amino-3-mercaptopropyl)-L-alaninebenzylamide, N-Benzyl- [2(S)-2(R)-Amino-3-mercaptopropyl)-aminolbutyramide, WO 97/01275 WO 9701275PCTIUS96/11022 483 N- (2(R)-Amino-3-mercaptopropyl)-L-norleucinebenzylamide, N- (2(R)-Amino-3-mercaptopropyl)-L-norvalinebenzylamide, N- (2(R)-Amino-3-mercaptopropyl)isolleucyl-phenylalanyl-homoserine, N-(2(R)-Amino-3-mercaptopropyl)isoleucyl-isoleucyl-homoserine, N-(2(R)-Amino-3-mercaptopropyl)isoleucyl-phenylalanyl-homoserine lactone, N- (2(R)-Amino-3-mercaptopropyl)isoleucyl-isoleucyl-homoserine lactone, N-(2(R)-Amino-3-mercaptopropyl)isoleucyl-phenylalanyl-homocysteine lactone, N- [2(S)-(2(R)-Amino-3-mercaptopropyl)- 3(S)-methylpentyl]-isoleucyl- homoserine lactone, N- [N'-(2(R)-Amino-3-mercaptopropyl)i soleucyl-phenylalanyl]-3 (S amino-tetrahydropyran-2-one, N-[N'-(2(R)-Amino-3-mercaptopropyl)isoleucyl-isoleucyl]-3(S)-amino- tetrahydropyran-2-one, N-(2(R)-Amino-3-mercaptopropyl)isoleucyl-isoleucyl-homocysteine lactone, N- [2(S )-(2(R)-Amino-3-mercaptopropylamino)-3 (S)-methyl pentyllisoleucyl-homoserine, WO 97/01275 PCTIUS96/11022 -484- N-[N'-(2(R)-Amino-3-mercaptopropyl)isoleucyl-phenylalanyl]-3 amino-4-hydroxypentanoic acid, N- [N'-(2(R)-Amino-3-mercaptopropyl)isoleucyl-isoleucyl]-3 (S)-amino- 4-hydroxypentanoic acid, N- [2(S)-(2(R)-amino-3-mercaptopropylamino)-3 (S)-methylpentyl] -N- methyl-isoleucyl-homoserine, N- [2(S)-(2(R)-amino-3-mercaptopropylamino)- 3(S )-methylpentyl] -N- methyl-isoleucyl-homoserine lactone, N- [2(S)-(2(R)-amino-3-mercaptopropylamino)-3 (S )-methylpentyl]-N- methyl-phenylalanyl-homoserine, N- [2(S)-(2(R)-amino-3-mercaptopropylamino)-3 (S )-methylpentyl] -N- methyl-phenylalanyl-homoserine lactone, N- [2(S)-(2(R)-amino-3-mercaptopropylamino)- 3-methyl-butyl]-N- methyl-phenylalanyl-homoserine, N- (2(R)-amino-3-mercaptopropylamino)-3 -methyl-butyl]-N- methyl-phenylalanyl-homoserine lactone, {N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3 (S)-methyl- pentyl]-N-methyl-isoleucylamino -3-methyltetra-hydropyran-2-one, I N- (2(R)-amino-3 -mercaptopropylamino)-3 (S)-methyl- acid, N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)- methylpentyl]-N-methyl-isoleucylamino I acid, WO 97/01275PTU96112 PCT/US96/11022 -485- N- 2 2 (R)-amino-3-mercaptopropylamino)-3 (S)-methylpentyl] -N- methyl-norvalyl-homoserine, N- 2 (R)-amino-3-mercaptopropylamino)-3 (S )-methylpentyl]-N- methyl-norvalyl-homoserine lactone, N- 2 (R)-amino-3-mercaptopropylamino)-3 (S)-methylpentyl]-N- methyl-isoleucyl-methiomne, N- 2 2 (R)-amino-3-mercaptopropylamino)-3 (S )-methylpentyl] -N- methyl-isoleucyl-methionine methyl ester, N- 2 2 (R)-amino-3-mercaptopropylamjno)-3 (S)-methylpentyl]-N- methyl-phenylalanyl-methionine, N- 2 2 (R)-amino-3-mercaptopropylamino)-3 (S)-methylpentyl] -N- methyl-phenylalanyl-methionine methyl ester, 2 2 (R)-amino-3-mercaptopropylamino.3 (S)-methyl- pentyl]-N-methyl-isoleucylamino 6 6 -dimethyl-tetrahydropyran-2-one, N- 2 (R)-amino-3-mercaptopropylamino)-3 (S)-methylpentyl]-N- methyl-norvalyl-methionine, N- 2 2 (R)-amino-3-mercaptopropylamino)-3 (S )-methylpentyl] -N- methyl-norvalyl-methionine methyl ester, N- 2 2 (R)-amino-3-mercaptopropylamino)-3 (S )-methylpentyl]-N- methyl-D-norvalyl-homoserine, N- [2(S)-(2(R)-amino-3-mercaptopropylamino)-3 (S )-methylpentyl]-N- methyl-D-norvalyl-homoserine lactone, WO 97/01275 PCT/US96/11022 -486- 2 (R)-Amino-3-mercapto]propylamino3(S)-methyl] pentyloxy- 3 -phenylpropionylbhomoserine lactone, 2 (R)-Amino-3-mercaptolpropylamino-3 (S)-methyl] pentyloxy-3-phenylpropionylbhomoserine, 2 (R)-Amino-3-mercapto]propylamino-3 (S)-methyl] pentyloxy- 2 -methyl-3-phenylpropionylbhomoserine lactone, 2 (R)-Amino-3-mercapto]propylamino-3 (S)-methyl] pentyloxy-2-methyl-3 -phenyipropionyl-homoserine, 2 (R)-Amino-3-mercapto]propylamino-3 (S)-methyl] pentyloxy-4-pentenoyl-homoserine lactone, 2 (R)-Amino-3-mercaptolpropylamino-3 (S)-methyl] pentyloxy-4-pentenoyl-homoserine, 2 (R)-Amino-3-mercapto]propylamino-3 (S)-methyl]- pentyloxypentanoyl-homoserine lactone, 2 (R)-Amino-3-mercapto]propyl amino-..3 pentyloxypentanoyl-homoserine, 2 (R)-Amino-3-mercaptolpropylamino-3 (5)-methyl] pentyloxy-4-methylpentanoyl-homoserine lactone, 2 (R)-Amino-3-mercapto]propylamino-3 (5)-methyl] pentyloxy-4-methylpentanoyl-homoserine, 2 (R)-Amino-3-mercapto]propylamino-3 (5)-methyl] pentyloxy-3-methylbutanoyl-homoserine lactone, WO 97/01275 WO 9701275PCTIUS96/11022 -487- 2 (R)-Anlino-3-mercaptolpropylamino-.3(S)..methyl]y pentyloxy-3-methylbutanoyl-homoserjne, 2 (R)-Amino-3-mercapto]propylamino-3 (5)-methyl] pentyloxy-3-phenylbutanoyl-homoserine lactone, 2 (R)-Amino-3-mercapto]propylamino.3 (S)-methyl] pentyloxy-3-phenylbutanoyl-homoserine, 2 (R)-Amino-3-mercapto]propylamino-3 (5)-methyl] pentylthio- 2 -methyl-3-phenylpropionylbhomoserine lactone, 2 (R)-Amino-3-mercapto]propylamino-3 (S)-methyl] pentylthio- 2 -methyl-3-phenylpropionylphomoseine, 2 (R)-Amino-3-mercaptojpropylamino-3(S)-methyl]- pentylsulfonyl-2-methyl-3-phenylpropionyl-homoserine lactone, 2 (R)-Amino-3-mercapto]propylamino-3 (S)-methyl] pentylsulfonyl- 2 -methyl-3-phenylpropionyl.homoserjne, 2 (R)-Alnino-3-mercapto]propylamino-3 pentyloxy-3-phenylpropionyl-methionine methyl ester, 2 (R)-Amino-3-mercapto]propylamino-3 (S)-methyl] pentyloxy-3-phenylpropionyl-methionine, 2 (R)-Amino-3-mercapto]propylamino-3 (S)-methyl] pentyloxy-3-phenylpropionyl-methionine sulfone methyl ester, 2 (R)-Amnino-3-mercapto]propylamino-3 (S)-methyl] pentyloxy-3-phenylpropionyl-methionine sulfone, WO 97/01275 WO 9701275PCT/US96/11022 -488- [2(R)-Amino-3-mercapto]propylamino-3 (S)-methyl]- pentyloxy-3-naphth-2-yl-propionyl-methionine- sulfone methyl ester, [2(R)-Aniino-3-mercapto]propylamino-3 (S)-methyl]- pentyloxy-3-naphth-2-yl-propionyl-methionine sulfone, [2(R)-Amino-3-mercapto]propylamino-3 (S)-methyl]- pentyloxy-3-naphth- 1-yl-propionyl-methionine sulfone methyl ester, 2-(S [2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]- pentyloxy-3-naphth- 1-yl-propionyl-methionine sulfone, [2(S)-[2(R)-Amino-3-mercapto]propylamino-3 (S)-methyl] pentyloxy-3-methybutanoyl-methionine methyl ester, [2(R)-Amino-3-mercapto]propylamino-3 (S)-methyl]- pentyloxy-3-methybutanoyl-methionine, Disulphide of [2(R)-Amino-3-mercapto]propylamino-3(S)- methyllpentyloxy-3-phenylpropionyl-homoserine lactone, Disulphide of [2(R)-Amino-3-mercaptolpropylamino-3 (S methyllpentyloxy-3-phenylpropionyl-homoserine, Disulphide of [2(R)-Amino-3-mercaptolpropylamino-3 methyllpentyloxy-3-methylbutanoyl-methionine methyl ester. 1- [2-(R)-Amino-3-mercaptopropyl] 1-butyl)-4-(2,3-dimethyl- benzoyl)piperazine dihydrochloride 1- [2(R)-Amino-3-mercaptopropyl] -2(S -butyl)-4-( 1- naphthoyl)piperazine WO 97/01275 WO 9701275PCTIUS96111022 489 1- [2(R)-Amino-3-mercaptopropyl]-2(S)-benzyl-4-[ 1-(2,3- dimethyl)benzoyl]piperazine 1- [2(R)-Amino-3-mercaptopropyl]-2(S)-(2-methoxy)ethyl-4- dimethyl)benzoyllpiperazine 1- [2(R)-Amino-3-mercaptopropyl] -2(S )-(2-methylthio)ethyl-4- dimethyl)benzoyllpiperazine 1- [2(R)-Amino-3-mercaptopropyl] -2(S -butyl)-4- dihydrobenzofuroyl)]piperazine 1 -(2(R)-Amino-3-mercaptopropyl)-4-(l1-naphthoyl)-2(S pyridinylcarboxyl-4-piperazine dihydrochioride Methyl 4-(2(R)-amino-3-mercaptopropyl)- 1-(1 -naphthyl- methyl)piperazine-2-carboxylate hydrochloride 1- [2(R)-Amino-3 -mercaptopropyl] -2(S )-(2-methoxyethyl)-4-( 1- naphthoyl)piperazine 1- [2(R)-Amino-3-mercaptopropyl] -butyl-4-(8- quinolinylcarbonyl)piperazine 1- [2(R)-Amino-3-mercaptopropyl]-2(S 1-propoxy)ethyl)-4-( 1- naphthoyl)piperazine 1- [2(R)-Amino-3-mercaptopropyl] -2(S )-(3-methoxy-l1-propyl)-4-( 1- naphthoyl)piperazine 1- [2(R)-Amino-3-mercaptopropyl] (2-(l1 propoxy)ethyl)-4-(8- quinolinoyl)piperazine 1- [2(R)-Amino-3-mercaptopropyl]- 2 -pyridyl)methoxyethyl)] -4- (1 -naphthoyl)piperazine WO 97/01275 WO 9701275PCT/US96/11022 490 1- [2(R)-Amino-3-mercaptopropyl]-4-naphthoyl-2(S)-(2-phenylsulfonyl- ethyl)piperazine dihydrochioride bis- [2(R)-Amino-3-(2(S)-(2-methoxyethyl)-4-naphthoyl- 1- piperazinyl)]propyl disulfide tetrahydrochioride bis- [2(R)-Amino-3-(4-naphthoyl-2(S)-(2-phenylsulfonylethyl)- 1- piperazinyl)]propyl disulfide tetrahydrochioride 1- [2(R)-Amino-3-mercaptopropyl]-4-naphthoyl-2(S)-(2- cyclopropyloxyethyl)piperazine dihydrochioride 1- [2(R)-Amino-3-mercaptopropyl]-4-(l1-naphthoyl)-2(S)-(4- acetam-idobutyl)piperazine dihydrochioride 1- [2(R)-Amino-3-mercaptopropyl]-4-naphthoyl-2(S)-(2- cyclopropylmethylsulfonylethyl)piperazine dihydrochioride Pyroglutamyl-valyl-phenylalanyl-methionine Pyroglutamyl-valyl-phenylalanyl-methionine methyl ester; Pyroglutamyl-valyl-isoleucyl-methionine; Pyroglutamyl-valyl-isoleucyl-methionine methyl ester; Nicotinoyl-isoleucyl-phenylalanyl-methionine; Nicotinoyl-isoleucyl-phenylalanyl-methionine methyl ester; N- [2(S)-(L-Pyroglutamylamino)-3-methylbutyllphenylalanyl- methionine; WO 97/01275 WO 9701275PCTIUS96/11022 491 N- [2(S)-(L-Pyroglutamylamino)-3-methylbutyllphenylalanyl-methionine methyl ester; N- [5 (S)-(L-Pyroglutamylamino)-6(S)-methyl-2(R)-butyl-3 octenoyl]-methionine; N- [5(S)-(L-Pyroglutamylamino)-6(S)-methyl-2(R)-butyl-3 octenoyl]-methionine methyl ester; N- ((Imidazol-4-yl)acetylamino)-6(S)-methyl-2(R)-butyl-3 octenoyl]-methionine; N- [5(S)-((Lmidazol-4-yl)acetylamino)-6(S)-methyl-2(R)-butyl-3 octenoyl]-methionine methyl ester; N- [5(S)-((Imidazol-4-ylcarbonylamino)-6(S )-methyl-2(R)-butyl-3 octenoyl]-methionine; N- [5(S)-((Imidazol-4-ylcarbonylamino)-6(S)-methyl-2(R)-butyl-3 octenoyl]-methiomine methyl ester; N- [2(S)-(2(S)-(Lmidazol-4-yl)acetylamino)-3 (S)-methylpentyloxy)-3- phenylpropionyl] -methionine; N- [2(S)-(2(S)-(Imidazol-4-yl)acetylamino)-3 (S )-methylpentyloxy)-3- phenylpropionyl] -methionine methyl ester; N- [2(5 )-Pyroglutamylamino-3 (S )-methylpentyloxy)-3- phenylpropionyl]-methionine; N- [2(5 )-Pyroglutamylamino-3 (S)-methylpentyloxy)-3- phenylpropionyl] -methionine methyl ester; WO 97/01275 WO 9701275PCTIUS96/1 1022 -492- N- [2(S)-(2(S)-Imidazol-4-ylcarbonyl)amino)-3 (S )-methylpentyloxy)-3 phenylpropionyl]-methionine; N- [2(5 )-Imidazol-4-ylcarbonyl)amino)-3 (S)-methylpentyloxy)-3 phenylpropionyl]-methionine methyl ester; N- [2(S )-((3-Picolinyl)amino)-3 (S)-methylpentyloxy)-3- phenylpropionyl]-methionine; N- [2(S)-(2(S)-((3-Picolinyl)amino)-3 (S )-methylpentyloxy)-3- phenyipropionyl] -methionine methyl ester; N- [2(S)-(2(S)-((Histidyl)amino)-3 (S)-methylpentyloxy)-3- phenyipropionyl]-methionine; N- )-((Histidyl)amino)-3 (S)-methylpentyloxy)-3 phenylpropionyl]-methionine methyl ester; N-Benzyl-N- [2(S)-((Imidazol-4-ylcarbonyl)amino)-3 (S )-methylpentyl] glycyl-methionine; N-B enzyl-N- [2(S )-((Lmidazol-4-ylcarbonyl)amino)-3 (S )-methylpentyl] glycyl-methionine methyl ester; N-Benzyl-N- [2(S )-((Imidazol-4-ylacetyl)amino)-3 (S)-methylpentyl] glycyl-methionine; N-Benzyl-N- [2(S )-((Imidazol-4-ylacetyl)amino)-3 (S )-methylpentyl] glycyl-methionine methyl ester; N-Benzyl-N- [2(S)-((Pyroglutamyl)amino)-3 (S)-methylpentyl] -glycyl- methionine; WO 97/01275 WO 9701275PCTIUS96/1 1022 -493- N-Benzyl-N- [2(S )-((Pyroglutamyl)amino)-3 (S)-methylpentyl]-glycyl- methionine methyl ester; 1-Naphthylmethyl)-N- [2(8 )-((imidazol-4-ylcarbonyl)amino)-3 methylpentyl]-glycyl-methionine; N-(l1-Naphthylmethyl)-N- [2(S )-((imidazol-4-ylcarbonyl)amino)-3 methylpentyl] -glycyl-methionine methyl ester; N-(l1-Naphthylmethyl)-N- [2(S)-((imidazol-4-ylacetyl)amino)-3 methylpentylll-glycyl-methionine; N-(l1-Naphthylmethyl)-N- [2(8 )-((imidazol-4-ylacetyl)amino)-3 methylpentyl]-glycyl-methionine methyl ester; N-(l1-Naphthylmethyl)-N- [2(S)-((pyroglutamyl)amino-3 (S )-methyl- pentyl]-glycyl-methionine; and 1-Naphthylmethyl)-N- [2(8 )-((pyroglutamyl)amino-3 (S)-methyl- pentyl]-glycyl-methionine methyl ester; N- [1-(Pyroglutamylamino)cyclopent- 1 -ylmethyl 1-naphthylmethyl glycyl-methionine methyl ester N- [1-(Pyroglutamylamino)-cyclopent- 1-ylmethyl] 1-naphthyl- methyl)-glycyl-methionine N-(2(S)-L-Histidylamino-3 (S )-methylpentyl)-N-(benzylmethyl)glycyl- methionine methyl ester N-(2(S)-L-Histidylamino-3(S )-methylpentyl)-N-(benzylmethyl)glycyl- methionine WO 97/01275 WO 9701275PCTfUS96/1 1022 494 N-(2(S)-L-Histidylamino-3 (S)-methylpentyl)-N-(l1-naphthylmethyl)- glycyl-methionine methyl ester N-(2(S )-L-Histidylamino-3 (S)-methylpentyl)-N-( 1-naphthylmethyl)- glycyl-methionine [2(S)-(L-Pyroglutamyl)amino-3 (S)-methylpentyloxy] -3- methylbutanoyl-methionine methyl ester [2(S )-(L-Pyroglutamyl)amino-3 (S)-methylpentyloxy] -3- methylbutanoyl-methionine [2(S)-(Lmidazol-4-ylacetyl)amino-3 (S)-methylpentyloxy] -3- methylbutanoyl-methionine methyl ester [2(S)-(Imidazol-4-ylacetyl)amino-3 (S)-methylpentyloxy]-3- methylbutanoyl-methionine N-(B enzyl)-N- [2(S)-(2-oxopyrrolidin-5 (R,S )-ylmethyl)amino-3 (S methylpentyl]-glycyl-methionine methyl ester N-(Benzyl)-N-[2(S)-(2-oxopyrrolidin-5 (R,S)-ylmethyl)amino-3 (S methylpentyl]-glycyl-methionine N-(Benzyl)-N- I 2(S)-[((D,L)-2-thiazolyl)alanyl)amino]-3(S)- methylpentyl }-glycyl-methionine methyl ester N-(Benzyl)-N- 2(S)-[((D,L)-2-thiazolyl)alanyl)amino]-3(S)- methylpentyl -glycyl-methionine N-(B enzyl)-N- [2(S)-(3-pyridylmethyl)amino- 3 (S)-methylpentyl] -glycyl- methionine methyl ester N-(B enzyl)-N- [2(S)-(3-pyridylmethyl)amino-3 (S)-methylpentyl] -glycyl- methionine WO 97/01275 WO 9701275PCTIUS96/11022 495 [2(S )-k42-Oxopyrrolidin-5(S)-yl'mehyl)amlio-3(S)- methylpentyloxy]-3-phenyli'ropionyl-methionile methyl estr [2(S)-(2-Oxopyrrolidin-5 (S)-ylmethyl)amino-3 (S)-methyl- pentyloxy] -3-phenyipropionyl-methionine [2(S)-(L-Pyroglutamyl)amino-3 (S)-methylpentyloxy] 1- naphthyl)propionyl-methionine sulfone methyl ester [2(S)-(L-Pyroglutamyl)amino-3 (S )-methylpentyloxy] 1- naphthyl)propionyl-methiomne sulfone [2(S)-(L-Pyroglutamyl)amino-3(S )-methylpentyloxy]-3-(2- naphthyl)propionyl-methionine sulfone methyl ester [2(S)-(L-Pyroglutamyl)amino-3(S)-methylpentyloxy] naphthyl)propionyl-methionine sulfone [2(S)-(Imidazol-4-ylacetyl)amino-3 (S)-methylpentyloxy]-3-( 1- naphthyl)propionyl-methionine sulfone methyl ester [2(S)-(Imidazol-4-ylacetyl)amino-3 (S )-methylpentyloxy]-3-( 1- naphthyl)propionyl-methionine sulfone [2(S)-(Imidazol-4-ylacetyl)amino-3 (S)-methylpentyloxy] naphthyl)propionyl-methionine sulfone methyl ester [2(S )-(Imidazol-4-ylacetyl)amino-3 (S )-methylpentyloxy] naphthyl)propionyl-methionine sulfone N- (L-pyroglutamyl)amino-3 (S)-methylpentyl]-N-(3-quinolyl- methyl)glycyl-methionine methyl ester WO 97/01275 WO 9701275PCT/US96/1 1022 -496- N-[2(S )-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(3-quinoly- lmethyl)glycyl-methionine N-(Benzyl)-N- [2(S)-(tetrazol- 1-ylacetyl)amino-3 (S)-methylpentyl] glycyl-methionine methyl ester N-(Benzyl)-N- [2(S)-(tetrazol- 1-ylacetyl)amino-3 (S )-methylpentyl] glycyl-methionine N-(Benzyl)-N- [2(S)-nicotinoylamino-3 (S)-methylpentyl]-glycyl- methionine methyl ester N-(Benzyl)-N- [2(S)-nicotinoylamino-3 (S )-methylpentyl] -glycyl- methionine N- [2(S)-(L-Pyroglutamyl)amino-3 (S )-methylpentyl]-N-( 1- naphthylmethyl)-glycyl-methionine sulfoxide methyl ester N- [2(S)-(L-Pyroglutamyl)amino-3 (S )-methylpentyl] 1- naphthylmethyl)-glycyl-methionine sulfoxide [2(5 ,R)-(Imidazol-4-yl)-2-aminoacetyl)amino] methylpentyloxy 1-3 -phenyipropionyl-methionine sulfone methyl ester [2(S,R)-(Imidazol-4-yl)-2-aminoacetyl)amino]-3(S)- methylpentyloxy }-3-phenyipropionyl-methionine sulfone [2(R,S)-(Imidazol-4-yl)-2-aminoacetyl)amino] methylpentyloxy }-3-phenyipropionyl-methionine sulfone methyl ester [2(R,S)-(Imidazol-4-yl)-2-aminoacetyl)amino]-3 methylpentyloxy }-3-phenylpropionyl-methionine sulfone. WO 97/01275 WO 9701275PCTIIUS96/1 1022 -497- [2(S,R)-(Imidazol-4-yl)-2-aminoacetyl]amino-3 (S)-methyl- pentyl 1-naphthylmethyl)-glycyl-methionine methyl ester N- [2(S ,R)-(Imidazol-4-yl)-2-aminoacetyl]amino-3(S)- methylpentyl I 1 -naphthylmethyl)-glycyl-methionine N- I [2(R,S)-(Imidazol-4-yl)-2-aminoacetyl] amino-3 (S)-methyl- pentyl 1-naphthylmethyl)-glycyl-methionine methyl ester N- I [2(R,S)-(Imidazol-4-yl)-2-aminoacetyllamino-3 methylpentyl I 1 -naphthylmethyl)-glycyl-methionine N-{I [(Imidazol-4-yl)methyl]amino-3 (S)-methylpentyl 1- naphthylmethyl)-glycyl-methionine methyl ester N- I [(Imidazol-4-yl)methyl] amino- 3(S)-methylpentyl I 1- naphthylmethyl)-glycyl-methionine N- [2(S)-(L-pyroglutamyl)amino-3 (S)-methyl pentyl] 1- naphthylmethyl)glycyl-methionine isopropyl ester N-[2(S)-(L-pyroglutamyl)amino-3 (S )-methylpentyl]-N-( I -naphthyl- methyl)glycyl-methionine t-butyl ester N-[2(S)-(L-pyroglutamyl)amino-3(S)-methylpentyl]-N-(4-quinolyl- methyl)glycyl-methionine methyl ester N- [2(S )-(L-pyroglutamyl)amino-3 (S)-methylpentyl] -N-(4-quinolyl- methyl)glycyl-methionine N- I [3 -(Imidazol-4-yl)propyl] amino-3 (S )-methylpentyl (1- naphthylmethyl)glycyl-methionine methyl ester WO 97/01275 WO 9701275PCTfUS96/11022 498 N-1{ [3-(Imidazol-4-yl)propyl] amino-3 (S)-methylpentyl I 1- naphthylmethyl)glycyl-methionine N- [2(S)-(L-pyroglutamyl)amino-3 (S )-methylpentyl]-N-(l1-naphthyl- methyl)glycyl-norleucine N- [2(S)-(L-pyroglutamyl)amino-3 (S )-methylpentyl]-N-(l1-naphthyl- methyl)glycyl-norleucine methyl ester N- [2(S )-(L-pyroglutamyl)amino-3 (S )-methylpentyl]-N-( 1-naphthyl- methyl)glycyl-glutamine N- [2(5 )-(L-pyroglutamyl)amino-3 (S )-methylpentyl]-N-( 1-naphthyl- methyl)glycyl-glutamine t-butyl ester N- [2(S)-(L-pyroglutamyl)amino-3 (S )-methylpentyl] amino)naphthylsulfonyl]glycyl-methionine methyl ester N- [2(S )-(3-pyridylmethyl)amino-3 (S )-methylpentyl]-N-(l1-naphthyl- methyl)glycyl-methionine I [2-(Imidazol-4-yl)ethyl]amino-3(S )-methylpentyloxy phenyipropionyl-methionine sulfone methyl ester I 2(S)-[2-(Imidazol-4-yl)ethyl] amino-3(S )-methylpentyloxy phenyipropionyl-methionine sulfone N- [2(S )-(L-pyroglutamyl)amino- 3(S )-methylpentyl] 1-naphthyl- methyl)glycyl-serine methyl ester N- [2(S )-(L-pyroglutamyl)amino-3 (S )-methylpentyl]-N-(l1-naplithyl- methyl)glycyl- (D,L)-serine WO 97/01275 WO 9701275PCT[US96/1 1022 499 N- [2(S)-(L-pyroglutamyl)amino-3 (S)-methylpentyl]-N-(l1-naphthyl- methyl)glycyil-(L,D)-serine N- [2(S)-(L-pyroglutamyl)amino-3 (S)-methylpentyl]-N-(l1-naplithyl- methyl)glycyl-homoserine lactone N- [2(S)-(L-pyroglutamyl)amino-3 (S)-methylpentyl]-N-(l1-naphthyl- methyl)glycyl-homoserine N- [2(S)-(L-pyroglutamyl)amfino-3(S)-methylpentyl] (cinnamyl)- glycyl-methionine methyl ester N- [2(S)-(L-pyroglutamyl)amino-3 (S)-methylpentyl] -N-(cinnamyl)- glycyl-methionine N-1{2(S)-[2-(Imidazol-4-yl)ethyllamino-3 (S)-methylpentyl)I-N-( 1- naphthylmethyl)glycyl-methionine methyl ester [2-(Imidazol-4-yl)ethyl] amino-3 (S)-methylpentyl (1- naphthylmethyl)glycyl-methionine N- [2(S)-(L-pyroglutamyl)amino-3 (S )-methylpentyl]-N-( 1-naphthyl- methyl)glycyl-alanine methyl ester N- [2(S )-(L-pyroglutamyl)amino-3 (S)-methylpentyl]-N-(l1-naphthyl- methyl)glycyl-alanine N- [2(S)-(D-pyroglutamyl)amino-3 (S )-methylpentyl]-N-( 1-naphthyl- methyl)glycyl-methionine methyl ester N- [2(S)-(D-pyroglutamyl)amino-3 (S)-methylpentyl]-N-( 1-naphthyl- methyl)glycyl-methionine WO 97/01275 WO 9701275PCT/US96/11022 500 [2(S)-(L-Pyroglutamyl)amino-3(S)-methylpentyloxy]-3-phenyl- propionyl-methionine sulfone methyl ester [2(S)-(L-Pyroglutamyl)amino-3(S)-methylpentyloxy]-3 -phenyl- propionyl-methionine sulfone N- [2(S)-(L-pyroglutamyl)amino-3 (S)-methylpentyl]-N-(2,3 -methyl- enedioxybenzyl)glycyl-methionine methyl ester N- [2(S)-(L-pyroglutamyl)amino-3 (S)-methylpentyl]-N-(2, 3- methylenedioxybenzyl)glycyl-methionine N- [2(S)-(Imidazol-4-ylacetyl)amino-3 (S )-methylpentyl]-N-(2,3- dihydrobenzofuran-7-ylmethyl)glycyl-methionine methyl ester N- [2(S)-(Imidazol-4-ylacetyl)amino-3 (S )-methylpentyl]-N-(2,3- dihydrobenzofuran-7-ylmethyl)glycyl-methionine N- I [3-(3-indolyl)propionyll amino- 3 (S)-methylpentyl I 1- naphthylmethyl)glycyl-methionine methyl ester N- I -indolyl)propionyll amino- 3 (S )-methylpentyl 1- naphthylmethyl)glycyl-methionine 1-indolyl)propionyl] amino-3 (S )-methylpentyl 1- naphthylmethyl)glycyl-methionine methyl ester 1-indolyl)propionyllamino-3 (S)-methylpentyl 1- naphthylmethyl)glycyl-methionine N- (L-pyroglutamyl)amino-3 (S )-methylpentyl]-N-( 1- naphthylmethyl)glycyl-histidine methyl ester WO 97/01275 WO 9701275PCTIUS96/11022 501 N- [2(S)-(L-pyroglutamyl)amino-3 (S)-methylpentyl]-N-( 1-naphthyl- methyl)glycyl-histidine N-[2(S)-(L-pyroglutamyl)amino-3 (S)-methylpentyl]-N-(cyclo- propylmethyl)glycyl-methionine methyl ester N- [2(S)-(L-pyroglutamyl)amino-3 (S)-methylpentyl]-N- (cyclopropylmethyl)glycyl-methionine N-[2(S)-(Imidazol-4-ylacetyl)amino-3(S)-methylpentyl]-N- (cyclopropylmethyl)glycyl-methionine methyl ester N- [2(S )-(Imidazol-4-ylacetyl)amino-3 (S)-methylpentyl]-N- (cyclopropylmethyl)glycyl-methionine N- [2(S )-(L-pyroglutamyl)amino-3 (S)-methylpentyl]-N-(2,3- dihydrobenzofuran-7-ylmethyl)glycyl-methionine methyl ester N- [2(S)-(L-pyroglutamyl)amino-3 (S)-methylpentyl]-N-(2,3- dihydrobenzofuran-7-ylmethyl)glycyl-methionine (L-Pyroglutamyl)-N-methylamino-3 (S )-methylpentyloxy] 3-phenyipropionyl-methionine methyl ester (L-Pyroglutamyl)-N-methylamino-3 (S )-methylpentyloxy] 3 -phenyipropionyl-methionine N- [2(S )-(L-pyroglutamyl)amino-3 (S )-methylpentyl]-N-( 1- naphthylmethyl)glycyl-O-methylserine methyl ester N- [2(S )-(L-pyroglutamyl)amino-3 (S )-methylpentyl] 1- naphthylmethyl)glycyl-O-methylserine N-(l1-Naphthylmethyl)-N- [2(S )-(N'-(L-pyroglutamyl)-N'-methylamino)- 3 (S)-methylpentyl]-glycyl-methionine methyl ester WO 97/01275 WO 9701275PCTIUS96/11022 502 N- (1-Naphthylmethyl)-N- [2(S)-(N'-(L-pyroglutamyl)-N'-methylamino)- 3(S)-methylpentyl]-glycyl-methionine [1 -(Pyroglutamylamino)cyclopent- 1 -ylmethyl]-N-( 1 -naphthylmethyl)- glycyl-methionine methyl ester N- [1-(Pyroglutamylamino)-cyclopent- 1-ylmethyl]-N-( 1- naphthylmethyl)-glycyl-methionine N- [2(S)-(Pyridin-2-on-6-ylcarbonyl)amino-3 (S)-methylpentyl]-N-( 1- naphthylmethyl)glycyl-methionine methyl ester N- [2(S)-(Pyridin-2-on-6-ylcarbonyl)amino-3 (S)-methylpentyl]-N-( 1- naphthylmethyl)glycyl-methionine N- [2(S)-(L-pyroglutamyl)amino-3 (S)-methylpentyl]-N-(3 -chioro- benzyl)glycyl-methionine methyl ester N- [2(S)-(L-pyroglutamyl)amino-3 (S)-methylpentyl]-N-(3-chloro- benzyl)glycyl-methionine N- [2(S)-(L-pyroglutamyl)amino-3 (S )-methylpentyl]-N-( 1-naphthyl- methyl)glycyl-O-methylhomoserine methyl ester N- [2(S)-(L-pyroglutamyl)amino-3 (S )-methylpentyl]-N-( 1-naphthyl- methyl)glycyl-O-methylhomoserine N- [2(S)-(L-pyroglutamyl)amino-3 (S)-methylpentyl] -N-(2,3-dimethyl- benzyl)glycyl-methionine methyl ester N- [2(S)-(L-pyroglutamyl)amino-3 (S)-methylpentyl]-N- (2,3-dimethyl- benzyl)glycyl-methionine WO 97/01275 WO 9701275PCTIUS96/11022 503 N- [2(S)-(L-pyroglutamnyl)amino-3 (S)-methylpentyl]-N-(l1-naphthyl- methyl)glycyl-(2-thienyl)alanine methyl, ester N- [2(S)-(L-pyroglutamyl)amino-3 (S)-methylpentyl]-N-(l1-naphthyl- methyl)glycyl-(2-thienyl)alanine N- [2(S)-(pyrrolidin-2-on- 1-yl)-3-methylbutanoyl] -isoleucyl-methionine; or N-[2(S)-(piperidin-2-on- 1-yl)-3-methylbutanoyl] -isoleucyl-methionine; or a pharmaceutically acceptable salt or optical isomer thereof. 7. The method according to Claim 5 wherein the protein substrate competitive inhibitor is selected from: Compound A: SO 2 CH 3 0 HN01, Oi-Pr N N H H 0 HS U A Compound B: WO 97/01275 PCT/US96/11022 -504- S0 2 CH 3 N NOMe H H Q B CN and Compound E: CH 3 0 N N O HS NH 2 or a pharmaceutically acceptable salt or optical isomer thereof. 8. The method according to Claim 1 wherein the famesyl pyrophosphate-competitive inhibitor is selected from: bb) SiX-iil--~-~--lil- I__^II tll^--Cl-- i^ -i WO 97/01275 PCT/US96/11022 -505- CH 3 I or 0 0 OH 3 C CH H3C II wherein: X X is: CH CH (cis); CH CH (trans); or CH2CH2; R 1 and R 2 are each independently selected from: a) H; b) C1-5 alkyl; c) C1-5 alkyl substituted with a member of the group consisting of: i) phenyl; ii) phenyl substituted with methyl, methoxy, halogen (Cl, Br, F, I) or hydroxy; or a pharmaceutically acceptable salt of a compound of formula in which at least one of R 1 and R 2 is hydrogen; cc) WO 97/01275 PCT/US96/11022 506 RO 0 O R 2 Oi) CH 3 CH 3 I or O0 O= CH3 H 3 C II wherein: R 1 and R 2 are each independently selected from: a) H; b) C1-5 alkyl; c) C1-5 alkyl substituted with a member of the group consisting of: i) phenyl; ii) phenyl substituted with methyl, methoxy, halogen (Cl, Br, F, I) or hydroxy; or a pharmaceutically acceptable salt of a compound of formula in which at least one of R 1 and R 2 is hydrogen; dd) WO 97/01275 PCT/US96/11022 -507- H 3 C wherein: X X is: C0 2 R 1 II CH CH (cis); CH CH (trans); or CH2CH2; R 1 and R 2 are each independently selected from: a) H; b) C1-5 alkyl; c) C1-5 alkyl substituted with a member of the group consisting of: i) phenyl; ii) phenyl substituted with methyl, methoxy, halogen (Cl, Br, F, I) or hydroxy; or a pharmaceutically acceptable salt of a compound of formula in which at least one of R1 and R 2 is hydrogen; i -ii-l WO 97/01275 PCT/US96/11022 -508- R 4 0 2 C C0 2 R 4 0 R 2 (CH 2 n HN N NH 2 R' H R3 H or the pharmaceutically acceptable salts, hydrates, esters or amides thereof, wherein: n is: 0 to 4, R 1 and R 3 independently are CO-4 alkyl, substituted with substituents selected from the group consisting of: a) aryl, which is defined as phenyl or naphthyl, unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of: i) F, ii) Cl, iii) Br, iv) nitro, v) cyano, vi) C1-8 alkoxy, vii) C1-8 alkylthio, viii) C1-8 alkylsulfonyl, ix) sulfamoyl, or x) C1-8 alkyl; or b) heteroaryl, which is defined as indolyl, imidazolyl or pyridyl, unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of: i) F, ii) Cl, iii) Br, WO 97/01275 WO 9701275PCTILJS96/l 1022 509 iv) nitro, v) cyano, vi) C1-8 alkoxy, vii) C1-8 alkylthio, viii) C1-8 alkylsulfonyl, ix) sulfamoyl, or x) C 1-8 alkyl; R 2 is: CO-6 alkyl, which is unsubstituted or substituted with a substituent selected from the group consisting of: a) unsubstituted or substituted aryl, as defined in Rl(a), b) unsubstituted or substituted heteroaryl, as defined in R 1(b), c) C3-8 cycloatkyl, d) C1-8 alkylthio, e) C1-8 alkylsulfonyl, f) C1-8 alkoxy, or g) aryl C1-8 alkyl sulfonyl; and R 4 is: H; ff) S(CH 2 (CH 2 wherein: X is CH2, CH(OH), C=0, CHCOR, CH(NH2), CH(NHCOR), 0, S(0)p, NH-, NHCO, o 0 11 11 -CNH-, -NH-P-; p isO0, 1 or 2; Y is P03RRI or CO2R; WO 97/01275 PCT/US96/11022 -510- R is H, lower alkyl, or CH2CH2N+Me3A-; R 1 is H, lower alkyl, or CH2CH2N+Me3A-; A is a pharmaceutically acceptable anion; m is 0, 1, 2, or 3; and n is 0, 1, 2, or 3; gg) S Ar' Ar-CH2 R A r 4 CH R 2 CH I X >N A-CO 2 H R4 HR6 R wherein each of Ar 1 Ar 3 and Ar 4 which are the same or different, is an aryl group or a heteroaromatic ring group; A is a C2-8 saturated or unsaturated aliphatic hydrocarbon group which may have substituent(s) selected from the group consisting of a lower alkyl group, a hydroxyl group, a lower hydroxyalkyl group, a lower alkoxy group, a carboxyl group, a lower carboxyalkyl group, an aryl group and an aralkyl group; each of X and Y which are the same or different, is an oxygen atom, a sulfur atom, a carbonyl group or a group of the formula -CHRa- (wherein Ra is a hydrogen atom or a lower alkyl group) or -NRb (wherein Rb is a hydrogen atom or a lower alkyl group), or X and Y together represent a vinylene group or an ethynylene group; each of R 1 R 2 R 3 R 8 and R 9 which are the same or different, is a hydrogen atom, a halogen atom, a I_ iX~ WO 97/01275 PCT/US96/11022 -511 hydroxyl group, a lower alkyl group or a lower alkoxy group; each of R 4 and-R 5 which are the same or different, is a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group, a lower alkyl group, a lower hydroxyalkyl group, a lower fluoroalkyl group or a lower alkoxy group; R 6 is a lower alkyl group; and R 7 is a hydrogen atom or a lower alkyl group, provided that when one of X and Y is an oxygen atom, a sulfur atom or a group of the formula -NRb- (wherein Rb is as defined above), the other is a carbonyl group or a group of the formula -CHRa- (wherein R a is as defined above); or hh) R' R ZZCH N A-C02H R 4 wherein each of Ar- Ar 2 and CA3_ which are the same or different, is an aryl group or a heteroaromatic ring group; A is a C2-8 saturated or unsaturated aliphatic hydrocarbon group which may have substituent(s) selected from the group consisting of a lower alkyl group, a hydroxyl group, a lower hydroxyalkyl group, _I I 1_1-1 WO 97/01275 PCT/US96/11022 -512- a lower alkoxy group, a carboxyl group, a lower carboxyalkyl group, an aryl group and an aralkyl group; Q is a group of the formula -(Cl- 12)m- (wherein m is an integer of from 1 to 6) or -(CH2)n-W-(CH2)p- (wherein W is an oxygen atom, a sulfur atom, a vinylene group or an ethynylene group; and each of n and p which are the same or differentf is an integer of from 0 to R 1 is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, or an aryl or heteroaromatic ring group which may have substituent(s) selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group; each of R 2 R 7 and R 8 which are the same or different, is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group or a lower alkoxy group; each of R 3 and R 4 which are the same or different, is a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group, a lower alkyl group, a lower hydroxyalkyl group, a lower fluoroalkyl group or a lower alkoxy group; R 5 is a lower alkyl group; and R 6 is a hydrogen atom or a lower alkyl group; or a pharmaceutically acceptable salt thereof. 9. The method according to Claim 8 wherein the farnesyl pyrophosphate-competitive inhibitor is selected from: 3-Hydroxy-7,11,15-trimethylhexadeca-6,10,14-trienoic acid, Oxo-6,10,14-trimethylpentadeca-5,9,13-trienyl]phosphonic acid Hydroxy-6,10,14-trimethylpentadeca-5,9,13-trienyl]phosphonic acid Acetyl-4,8,12-trimethylpentadeca-3,7,11-trienyl]phosphonic acid WO 97/01275 WO 9701275PCTIUS96/l 1022 513 ,7,11 -Trimethyl-2,6, 10-dodecatrienylamino]-2-oxo- ethyllphosphonic acid 12-Trimethyl-3 1-tridecatrienyl]thiomethyl-phosphonic acid 3- ,7,1 1 -Trimethyl-2,6, 1 0-dodecatrienylamino] -3-oxo-propionic acid ,7,1 1 -Trimethyl-2,6, 1 0-dodecatrienylamino] -2-oxo- ethyllphosphonic acid monomethyl ester 1-Trimethyl-2,6, 10-dodecatrienylamino]-l1-oxo- methyllphosphonic acid [1 -Hydroxy-(E,E)-3 ,7,1 1-trimethyl-2,6, 10-dodecatrienyl] -phosphonic acid [1 -Hydroxy-(E,E)-5 13-trimethyl-4, 8,1 2-tetradecatrienyl] -phosphonic acid [1 -Hydroxy-(E,E)-4,8, 12-trimethyl-3 ,7,1 1-tridecatrienyl]-phosphonic acid [2-Acetamido- 12-trimethyl- 3,7,1 1 -tridecatrienyl] -phosphonic acid, [2-Hydroxy-(E,E)-4,8, 12-trimethyl-3 11 -tridecatrienyl] -phosphonic acid N-1{ (IRS,2RS ,4E)-2-(4-chlorophenyl)- 1-methyl-S -(2-naphthyl)-4- pentenyl I-N-(2-naphthylmethyl1)-carbamoylmethylsucciflic acid WO 97/01275 WO 9701275PCTfUS96/11022 514 N- {(iRS ,2RS ,4E)-2-(4-chlorophenYl)- 1-methyl-5-(l1-naphthyl)-4- pentenyllI-N-(2-naphthylmethyl1)-carbamoylmethylsucciflic acid N- I (IR2R S)2(-hoohnl--ehl5(-ahhlpny I naphthylmethyl)carbamoylmethYlsuccilic acid N- I (IRS,2S--4choohnl)lmty }(-ahhoybtl -N- (2-naphthymethy)carbamoylmethyIsucciflic acid N- I (IRS ,2RS)-2-(4-chiorophenyl)-1-methYl-4- (2-naphthyl)butyl I naphthymethy)carbamoyimethYisuccilic acid N- {(iRS ,2RS)-2-(4-chlorophenyl)-1-methyl-6-(2-naphthyl)hexyl (2- naphthylmethy)carbaolmethylsuccilic acid N- I (IR2R S)2(-hoohnl--ehl5pey--etnl naphthymethy)carbamoylmethYlsucciflic acid N- I (IRS ,2RS ,4E)-2-(4-methoxyphenyl)-1-methYb5 (2-naphthyl)-4- pentenyl I N-(2-naphthymethY1)carbamoylmethy1succinic acid N-I (IRS ,2RS,4)lmty -4mtyphnl--2npty)4 pentenyl I-N-(2-naphthyl1methyl)carbamoylmethYlsuccilic acid N- I (IRS ,2RS ,4E)-1-methyi-5-(2-naphthyl)-2(4flitrophenyl> 4 pentenyl I N-(2-naphthymethy1)carbamoylmethYlsucciflic acid N- I (IRS ,2RS (4-fluoropheny1)-1-methy-5-(2-flaphthyl) 4 pentenyl I -N-(2-naphthylmethy1)carbamoylmethYlsuccinic acid N- I (IRS ,2RS,4)lmty -2nahhl--4tilurmtypey) 4-pentenyl I N-(2-naphthylmethyi)carbamoyimethylsuccinic acid WO 97/01275 WO 9701275PCT/US96/11022 515 N- I (IRS ,2RS ,4E)-1-methy1-5-(2-naphthy1)-2-phel-b4-petel) naphthylmethyl)carbanoylmethylsuccilic acid N- I (IRS ,2RS ,4E)-1-methy1-2(6-methy-3-pyridy1-5(2flaphthyl)- 4 pentenyl N-(2-naphthylmethy)carbamlOYmethy1succiflic acid N-I (IRS ,2RS ,6E)-2-(4-chloropheny1)-1-methy1-7-phel-6-heptelyI} -N- (2-naphthylmethy)carbamoylmethysuccilic acid N- I (IRS ,2RS ,6E)-2-(4-chorophenyl)--methYl-7- (2-naphthyl)-6- heptenyl)I N-(2-naphthyimethy)carbamoyhlmethylsucciflic acid N- I (IRS ,2RS ,4E)-2-(4-chiorophenyl)-1-methyl-5- (2-naphthyi)-4- pentenyl N-(3-quinolylmethy1)carbamoylmethylsucciflic acid N- I (IRS ,2RS ,4E)-2-(4-chiorophenyi)-1-methyi-5 -(2-naphthyl)-4- pentenyl ,4-difluorobenzy)carbamoylmethysucciflic acid N- (2-benzoxazolylmethyi)-N- I (IRS ,2RS ,4E)-2-(4-chlorophenyl)-1- methyl-5-(2-naphthyl)-4-peltelYI 11carbamoylmethyisuccinic acid N- (2-benzo [b]thienyimethyi)-N- I (IRS ,2RS (4-chioropheny)-1- methyl-5-(2-naphthy)-4-penteli}carbamoylmethylsuccinic acid N- I (iRS ,2RS ,4E)-i-methyi-2-(3 ,4-methylenedioxyphenyl)-5-(2- naphthyi)-4-pentenyi I -N-(2-naphthylmethy1)carbamoyimethy1succiliC acid 4(1 ,2S *,4E)-2-(4-chloropheny1)-i-methyi-5-(2-flaphthyiY- 4-pentenyl I N-(2-naphthyimethyl)carbamoyimethyl] succinic acid (2R* I (iR* ,2R* ,4E)-2-(4-chiorophenyi)- 1 -methyl-S naphthyi)-4- pentenyl I N-(2-naphthylmethyl)carbamoyimethyl] succinic acid WO 97/01275 WO 9701275PCTIUS96/11022 -516- (I *2R*,E)2-(4-chlorophenyl)-1-methyl-5-(2-naphthyl)- 4-pentenyl }-N-(2-naphthylmethyl)carbamoylmethyl]succinic acid (2S {(iS *,2S *,4E)-2-(4-chlorophenyl)-1-methyl-5-(2-naphthyl)- 4-pentenyl (2-naphthylmethyl)carbamoylmethyl] succinic acid (iRS ,2R5 ,4E)-2-(4-chlorophenyi)-1-methyl-5-(2-naphthyi)-4- pentenyl I -N-(2-naphthyimethyl)carbamoyl]pentanoic acid (2R* I (iRS ,2R5 ,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3 ,4- methylenedioxyphenyl)-4-pentenyl I -N-(2-naphthyimethyl)- carbamoyimethyllsuccinic acid (IRS,2RS ,4Z)-5-(2-benzoxazoiyl)-1-methyl-2-(3 ,4- methylenedioxyphenyl)-4-pentenyl (2-naphthylmethyl)- carbamoylmethyllsuccimc acid (2R* [N-(2-benzo[b]furanylmethyi)-N- (iRS ,2RS benzoxazolyi)-i-methyl-2-(3 ,4-methylenedioxyphenyl)-4- pentenyl IcarbamoylmethylIsuccinate [N-(2-benzo[b]thienyimethyl)-N- (IRS ,2RS (2-benzoxazoiyl)-1-methyi-2-(3 ,4-methyienedioxyphenyi)-4- pentenyl I}carbamoyimethyi] succinic acid (2R* [N-[(iRS,2RS ,4E)-5-(2-benzoxazoiyl)-2-1{3,4- bis(methoxycarbonyl)phenyl 1-1-methyl-4-pentenyl]-N-(2- naphthylmethyl)carbamoymethysuccilic acid (2R* [N-(2-benzo[b]thienyimethYi)-N- (IRS ,2RS (2-benzoxazoly1)-2-(4-methoxycarboflphel)-1-methy1-4- pentenyl I}carbamoylmethyl]succiflic acid WO 97/01275 WO 9701275PCT(US96/11022 517 [N-(2-benzo [b]furanylmethyl)-N- I (IRS ,2RS benzoxazolyl)-2-(4-methoxycarbonylphenyl)--mfethyb 4 pentenyl I carbamoylmethyl] succinic acid (2R* [N-(2-benzo[b]thienylmethyl)-N- I (IRS ,2RS benzoxazolyl)-2-(4-cyanophenyl)-1-methyl- 4 pentenyl I carbamoylmethyl] succinic acid [N-(5-benzollb]thienylmethyl)-N- I (IRS ,2RS benzoxazolyl)-2-(4-methoxycarbonylphelyl)--methYl- 4 pentenyl I carbamoylmethyl] succinic acid N- I (IRS ,2RS (3-chloro-4-methylphenyl)-2-(4-chlorophenyl)-1- methyl-4-pentenyl }-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid N- I (IRS ,2RS (3-chloro-4-methylphenyl)-2-(4-chlorophenyl)-1- methyl-4-pentenyl }-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid N- I (IRS ,2RS (2-benzo furanyl)-2-(4-chlorophenyl)-l-methyl-4- pentenyl }-N-(2-naphthyimethyl)carbamoylmethylsuccinic acid N- I (IRS ,2RS,4Z)-5-(2-benzo[b]furanyl)-2-(4-chlorophenyl)--methYl-4- pentenyl }-N-(2-naphthylmethyl)carbamoylmethyisucciflic acid N- (IRS ,2RS (2-benzoxazolyl)-2- (4-chlorophenyl)-1-methyl-4- pentenyl I-N-(2-naphthylmethyl)carbamoylmethylsucciflic acid N- I (IRS ,2RS ,4Z)-5 -(2-benzoxazolyl)-2- (4-chiorophenyi)-1-methyl-4- pentenyl N-(2-naphthylmethy)carbamoylmethy1succilic acid N- {(iRS ,2RS ,4E)-5 -(2-benzimidazoiyl)-2-(4-chloropheflyl)-l1-methyl-4- pentenyl I -N-(2-naphthylmethy1)carbamoYlmethy1succiflic acid WO 97/01275 WO 9701275PCTIUS96/11022 518 N- I (IRS ,2RS ,4E)-2-(4-chlorophenyl)-1-methyl-5-(3 ,4- methylenedioxyphenyl)-4-pentenyl I naphthylmethyl)carbamoylmethylsuccinic acid N- I (iRS ,2RS ,4E)-5-(2-benzothiazolyl)-2-(4-chlorophenyl)- 1 -methyl-4- pentenyl I -N-(2-naphthylmethyi)carbamoylmethylsuccinic acid N- I (IRS ,2RS ,4E)-5-(2-benzoxazoiyl)-2-(4-cyanophenyl)- 1-methyl-4- pentenyl I -N-(2-naphthyimethyl)carbamoylmethylsuccinic acid 4- (IRS ,2RS ,4E)-5 -(2-benzoxazolyl)-l1-methyl-2-(3 ,4- methylenedioxyphenyi)-4-pentenyl (2-naphthyimethyi)carbamoyl] 1 ,2,3-butanetricarboxylic acid {(iRS ,2RS,4E)-5-(2-benzoxazolyl)-l1-methyl-2-(3,4- methylenedioxyphenyl)-4-pentenyl (2-naphthylmethyl)carbamoyi] 1 ,2,2-propanetricarboxylic acid (2S I (1 RS ,2RS,4E)-5-(2-benzoxazolyl)-1-methyl-2- (3 ,4-methylenedioxyphenyl)-4-pentenyl)}-N-(2- naphthylmethyi)carbamoylmethyl] -3 -carboxy-2-hydroxybutanoic acid 4- [N-((1RS,2RS,4E)-5-(2-benzoxazolyl)-l-methyl-2-(3,4- methylenedioxyphenyl)-4-pentenyl }-N-(2-naphthylmethyl)carbamoyl] 3-carboxy-4-methoxybutanoic acid I (IRS,2RS,4E)-5-(2-benzoxazolyl)-l-methyl-2-(3 ,4- methyienedioxyphenyi)-4-pentenyl I-N-(2-naphthylmethyi)carbamoyl] 4-carboxy-3-carboxymethylpentanoic acid 1- {(iRS ,2RS ,4E)-5-(2-benzoxazolyl)-2-(4-methoxycarbonylphelyl)- i-methyl-4-pentenyi (2-naphthylmethyl)carbamoyl]- 1,2,3- propanetricarboxylic acid WO 97/01275 WO 9701275PCT[US96/1 1022 519 (IRS ,2RS ,4E)-5-(2-benzoxazolyl)-1-methyl-2- (3,4- methylenedioxyphenyl)-4-pentenyl I -N-(2-naphthylmethyl)carbamoyl] 3-methoxybutanoic acid (3 (IRS ,2RS ,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3 ,4- methylenedioxyphenyl)-4-pentenyl }-N-(2-naphthylmethyl)carbamoyl] 3-methoxybutanoic acid N- I (iRS ,2RS ,4E)-5-(2-benzoxazolyl)-2- (4-carboxyphenyl)-1-methyl-4- pentenyl }-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid N- I (IRS ,2RS ,4E)-5-(2-benzoxazolyl)-l-methyl-2- f 4-(N- methyicarbamoyl)phenyl I -4-pentenyl]-N-(2- naphthylmethyl)carbamoylmethylsuccinic acid I (lRS,2RS,4E)-5-(2-benzoxazolyl)-2-(4-hydroxy-3- methoxyphenyl)-l-methyi-4-pentenyl I naphthylmethyl)carbamoylmethylsuccinic acid N- {(iRS ,2RS ,4E)-2-(4-hydroxymethylphenyl)- 1-methyl-S -(2-naphthyl)- 4-pentenyl I -N-(2-naphthylmethyl)carbamoylmethylsuccinic acid N-{j (1RS,2RS ,4E)-2-(4-aminophenyl)-1-methyl-5-(2-naphthyl)-4- pentenyl I-N- (2-naphthylmethyl)carbamoylmethylsuccinic acid disodium (3RS .4RS 1 (1 RS ,2RS ,4E)-5-(2-benzoxazoiyl)-l-methyl- 2-(3 ,4-methylenedioxyphenyl)-4-pentenyl I 2 naphthylmethyl)carbamoyl] -3-carboxy-4-hyroxybutanoate N- I (IRS ,2RS,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3 ,4- methylenedioxyphenyl)-4-pentenyi (2-naphthylmethyi)-5 oxotetrahydrofuran-2-carboxyamide WO 97/01275 WO 9701275PCT/US96/1 1022 520 sodium 4- RS,2RS ,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3 ,4- methylenedioxyphenyl)-4-pentenyl)}-N-(2-naphthylmethyl)]carbamoyl- 4-hyroxybutanoate 4- (IRS ,2RS,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3 ,4- methylenedioxyphenyl)-4-pentenyl I -N-(2-naphthylmethyl)carbamoyl] 2-oxotetrahydrofuran-3-yl-acetic acid (2R* I (1R* ,2R* ,4E)-5-(2-benzoxazolyl)-2-(4- methoxycarbonylphenyl)-1-methyl-4-pentel)- I naphthylmethyl)carbamoylmethyl] succinic acid (2R* {(iS *,2S *,4E)-5-(2-benzoxazoiyl)-2-(4- methoxycarbonylpheny)-1-methyi-4-pelteflyl I naphthyimethyl)carbamoylmethyl] succinic acid (2R* [N-(2-benzo [b]thienyimethyl)-N- {(iS *,2S (2-benzoxazolyl)-1-methyl-2-(3 ,4-methylenedioxyphenyl)-4- pentenyl Icarbamoylmethyl] succinic acid [N-(2-benzo[b]thienyimethyl)-N- (2-benzoxazolyi)-1-methyl-2-(3 ,4-methylenedioxyphenyl)-4- pentenyl }carbamoyimethyijsuccinic acid (IRS,2RS)-5-(2-benzoxazolyl)-i-methyi-2-(3,4- methyienedioxyphenyi)pentyl)I-N-(2- naphthyimethyi)carbamoymethyi] succinic acid (2R* [N-(2-benzo[b]thienylmethyi)-N- I (iRS (2-benzoxazolyi)-i-methyi- 2 (3 ,4-methyienedioxyphenyi)- pentyl I carbamoylmethyl] succinic acid WO 97/01275 WO 9701275PCT[US96/11022 521 (1R*,2*--2bnoxzll--4 methoxycarbonylphenyl)-l-methylpentyl I 2 naphthylmethyl)carbamoylmethyllsuccinic acid disodium (3 S,4S)-4- R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2- (3 ,4-methylenedioxyphenyl)-4-pentenyl I naphthylmethyl)carbamoyl]-3-carboxy-4-hyroxybutanoate (Compound D) 0OH 0 N K' CO 2 Na 0CH 3 0 CO 2 Na sodium (3S,4S)-4- R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2- (3,4- methylenedioxyphenyl)-4-pentenyl (2-naphthylmethyl)carbamoyl] 3-ethoxycarbonyl-4-hyroxybutanoate 4- R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2- (3,4- methylenedioxyphenyl)-4-pelteflyl I-N- (2-naphthylmethyl)carbamoyl]- 3-tert-butoxycarbonyl-4-hydroxy-3-butenoic acid WO 97/01275 WO 9701275PCT/US96/11022 522 4- I (1 R,2R,4E)-5-(2-benzoxazolYl)-1-methYl-2-(3 ,4- methylenedioxyphelYl)- 4 -peltelYl I -N-(2-naphthylmethyl)carbamoyl] 4-hydroxy-3-methoxycarbol-3-buteloic acid 4- I (1 R,2R,4E)-5-(2-benzoxazolyl)-1-methYl-2-(3 ,4- methylenedioxyphelYl)-4-Peltel)-N- (2-naphthylmethyl)carbamoyl] 4-hydroxy-3-isopropoxycarbofl-3-buteloic acid 4- I (1 R,2R,4E)-5-(2-benzoxazolyl)--methYl-2-(3 ,4- methylenedioxyphenyl)-4-peltelYl I -N-(2-naphthylmethyl)carbamoyl] 3-cyclohexyloxycarbofl-4-hydroxy-3-buteoic acid 4- I (1 R,2R,4E)-5-(2-benzoxazolyl)-l-methyl-2-(3 ,4- methylenedioxyphenyl)-4-peltell}-N- (2-naphthylmethyl)carbamoyl]- 4-hydroxy-3-(2-methoxyethoxy)carboflb3-buteloic acid 4- I (1 R,2R,4E)-5-(2-benzoxazolyl)--methYl-2-(3 ,4- methylenedioxyphelYl)-4-petelYl I -N-(2-naphthylmethyl)carbamll 3-benzyloxycarbofl-4-hydroxy-3buteloic acid 4- R,2R,4E)-5-(2-belzoxazolYl)--methYk2-(3 ,4- methylenedioxypheflYl) 4 -Peltel) -N-(2-naphthylmethyl)carbamoyl]- 3-cyclopentyloxycarbofl-4-hydroxy-3buteloic acid {(1R,2R,4E)-5-(2-benzoxazolYl)-1-mfethyl-2-(3, 4 methylenedioxyphenYl)- 4 -peltell -N-(2-naphthylmethyl)carbamoyl]- 4-hydroxy- 3-(3-tetrahydrofuranyloxycarbofl>3-buteloic acid 4- R,2R,4E)-5- (2-benzoxazolyl)-1-methyl-2-(3 ,4- methylenedioxyphelyl)- 4 -Petell (2-naphthylmethyl)carbamoyl] 4-hydroxy-3-(2-hydroxy 1 -hydroxymethylethoxycarbofl)3-buteloic acid WO 97/01275 WO 9701275PCT/US96/11022 523 3-allyloxcarbonyl-4- I (1 R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2- (3 ,4-methylenedioxyphenyl)-4-peltelYl I naphthylmethyl)carbamoyl-4-hydroxy-3buteloic acid 4- (LR,2R,4E)-5-(2-belzoxazolyl)-2-(3 ,4-methylenedioxyphenyl)-1- methyl-4-pentenyl I-N-(2-naphthylmethyl)carbamoyl] -3- carboxymethylcarbonyl-4-hYdroxy-3-buteloic acid 5- t(1R,2R,4E)-5- (2-benzoxazolyl)-1-methyl-2-(3 ,4- methylenedioxyphenyl)-4-peltell}-N- (2-naphthylmethyl)carbamoyl] 4-ethoxycarbony-5-hydroxy-4-Peltelic acid I (LR,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3 ,4- methylenedioxyphenyl)-4-peltell -N-(2-naphthylmethyl)carbamoyl] 4-tert-butoxycarbol-5-hydroxy-4-pelteloic acid 4-N- I (1R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3 ,4- methylenedioxyphenyl)-4-PeltelL -N-(2-naphthylmethyl)carbamnoyl] 4-hydroxy-3-hydroxymethy1-3-buteloic acid 4- I (1RS,2RS ,5E)-6-(2-benzoxazolyl)-1-methyl-2-(3 ,4- I -N-(2-naphthylmethyl)carbamoyl]-3- tert-butoxycarbony1-4-hydroxy3-buteloic acid (2S (1R,2R,4E)-5- (2-benzoxazolyl)-1-methyl-2-(3 ,4- methylenedioxypheflYl) 4 -PeltelY I -N-(2-naphthylmethyl)carbamoyl] 1 ,2,3-butanetricarboxylic acid (2R* ,3 S* {(1R,2R,4E)-5- (2-benzoxazolyl)-1-methyl-2-(3 ,4- methylenedioxyphelYl)- 4 -Peltell -N-(2-naphthylmethyl)carbamylOl- 1 ,2,3-butanetricarboxylic acid WO 97/012'75 WO 9701275PCTfUS96/11022 -524- N- [(IRS,2RS)-l-methyl-2-(4-nitrophenyl)-3- {5-(phenylcarbamoyl)-2- furyl Ipropyl] -N-(2-naphthylmethyl)carbamoylmethylsuccinic acid N- [(IRS,2RS)-3-1{5- (3 ,4-dimethoxyphenylcarbamoyl)-2-furyl I-i-methyl- 2-(4-nitrophenyi)propyl]-N-(2- naphthylmethyl)carbamoylmethylsuccinic acid N- [(iRS,2RS)-3-1{5-(2-hydroxyphenylcarbamoyl)-2-furyI -1 -methyl-2- (4-nitrophenyl)propyl] -N-(2-naphthylmethyl)carbamoylmethylsuccinic acid N- [(iRS,2RS)-1-methyl-3- {5-(N-methylphenylcarbamoyl)-2-furyl nitrophenyl)propyl]-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid N- [(iRS ,2RS)-i-methyi-2-(4-nitrophenyi)-3- {5-(3-pyridyicarbamoyi)-2- furyl Ipropyl] (2-naphthyimethyi)carbamoyimethyisuccinic acid N- [(IRS,2RS)-i-methyi-2-(4-nitrophenyi)-3- I(4 pyridyicarbamoyi)-2-furyi Ipropyl] (2- naphthyimethyi)carbamoylmethyisuccinic acid N- [(iRS,2RS)-1-methyl-2-(4-nitrophenyi)-3-1{5-(5- pyrimidinyicarbamoyl)-2-furyi }propyi]-N-(2- naphthyimethyl)carbamoylmethyisuccinic acid N- [(iRS,2RS )-i-methyi-2-(4-nitrophenyi)-3- {5-(2-thiazoiylcarbamoyi)- 2-furyl Ipropyi]-N-(2-naphthyimethy)carbamoymethySUcciflic acid N- [(iRS,2RS)-2-(4-chlorophenyi)-l-methyi-3- {5-(phenylcarbamoyl)-2- furyl Ipropyl] (2-naphthyimethy)carbamoylmethySUccilic acid N-I (iRS ,2RS )-2-(4-chlorophenyl)-i-methyi-3-(3- phenyicarbamoyiphenyi)propyi I naphthyimethy)carbamoymethysucciflic acid WO 97/01275 WO 9701275PCT/US96/11022 525 N- [(IRS,2RS )-2-(4-chlorophenyl)-1-methyl-3-1{3-(phenylcarbamoyl)-5 isoxazolyl Ipropyl]-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid N- [(IRS ,2RS)-2-(4-chlorophenyl)-1-methyl-3-1{4-(phenylcarbamoyl)-2- pyridyl Ipropyl]-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid (2R* [N-(2-benzo [b]thienylmethyi)-N- [(IRS ,2RS)-l-methyl-2-(3 ,4- methylenedioxyphenyl)-3- {5-(phenylcarbamoyl)-2- furyl Ipropyl] carbamoylmethyl] succinic acid [N-(2-benzo[b]thienyimethyl)-N- [(IRS ,2RS methyl-2- (3 ,4-methylenedioxyphenyl)-3 (3-pyridylcarbamoyl)-2- furyl }propyl] carbamoylmethyl] succinic acid monopivaloyloxymethyl (2R* (2-benzo thienylmethyl)-N- [(IRS ,2RS )-i-methyl-2-(3 ,4-methylenedioxyphenyl)-3- (phenylcarbamoyl)-2-furyi I propyl] carbamoylmethyl] succinate (IRS ,2RS)-2-(4-methoxycarbonylphenyl)-1-methyl-3-(3- phenoxymethyiphenyl)propy I naphthylmethyi)carbamoyimethyl] succinic acid (2R* [(1RS ,2RS)-2-(4-methoxycarbonylphenyl)-1- methyl-3- {3-(phenoxymethyl)-5-( 1,2 ,4-oxadiazolyl) I propyl]-N- (2- naphthyimethyl)carbamoylmethyllsuccinic acid [(1RS,2RS)-2-(4-methoxycarbonylphenyl)-l-methyi-3- 3-styryiphenyl propyl] -N-(2-naphthylmethyl)carbamoyimethyl] succinic acid (2R* [(IRS ,2RS)-2-(4-methoxycarbonylphenyi)-1-methyi-3- phenylethyl)phenyi }propyl]-N-(2-naphthylmethyl)- carbamoylmethyl] succinic acid WO 97/01275 WO 9701275PCTIUS96/11022 526 N- I (IRS ,2RS)-2-(4-chlorophenyl)-1-methyl-3-(4-pheflylethyflylpheflyl)- propyl I-N-(2-naphthylmethyl)carbamoylmethylsuccinic acid N- [(IRS ,2RS)-2-(4-chiorophenyl)-l1-methyl-3- styryiphenyl propyl]-N-(2-naphthylmethyl)carbamoylmethYisuccilic acid N- I (IRS ,2RS)-2-(4-methoxycarbonylphenyl)- 1 -methyl-3-(5 phenoxymethyi-2-furyl)propyl I naphthylmethyl)carbamoylmethyisuccinic acid 4- [(IRS ,2RS)-l1-methyl-2-(4-nitrophenyl)-3- (phenylcarbamoyi)-2-furyl }propyl]-N-(2-naphthyimethyi)carbamoyl] 1,2,3-butanetricarboxylic acid disodium (3RS,4RS)-3-carboxyiato-4-hydroxy-4- [(IRS ,2RS 1- methyl-2-(4-nitrophenyl)-3- (phenyicarbamoyl)-2-furyi Ipropyl] -N- (2-naphthyimethyi)carbamoyilbutanoate disodium (3SR,4SR)-3-carboxylato-4-hydroxy-4- [(IRS ,2RS 1- methyl-2-(4-nitrophenyl)-3- 5-(phenyicarbamoyl)-2-furyi Ipropyl] -N- (2-naphthyimethyi)carbamoyl]butaloate 3-tert-butoxycarbonyl-4-hydroxy- 4 [(IRS ,2RS)-l1-methyi-2-(4- nitrophenyl)- 3- (phenylcarbamoyl)-2-furyl Ipropyl] (2- naphthyimethyi)carbamoyi] -3-butenoic acid 3-tert-butoxycarbonyl-4-hydroxy- 4 [(IRS ,2RS)-l1-methyi-2-(3 ,4- methylenedioxyphenyl)-3- {5-(phenylcarbamoyl)-2-furyl Ipropyl]-N- (2- naphthyimethyi)carbamoy]-3-buteloic acid 3-tert-butoxycarbonyl-4-hydroxy-4- I (IRS,2RS)-i-methyi- 2-(4-nitrophenyi)-3-(3 -phenoxymethypheny)propyi WO 97/01275 PTU9/12 PCTIUS96/11022 527 naphthylmethyl)carbamoyl]-3-butenoic acid 4-hydroxy-3-methoxycarbony 1-4- [(IRS ,2RS)-l-methyl-2-(3 ,4- methylenedioxyphenyl)-3-1{5-(phenylcarbamoyl)-2-furyl }propyl] naphthylmethyl)carbamoyl] -3-butenoic acid 3-allyloxycarbonyl-4-hydroxy-4- [(IRS ,2RS)-l-methyl-2-(3 ,4- methylenedioxyphenyl)-3-1{5-(phenylcarbamoyl)-2-furyl }propyl]-N- (2-naphthylmethyl)carbamoyl]-3-butenoic acid 5-hydroxy-4-isopropylcarbonyl-5- [(IRS ,2RS)-l-methyl-2-(4- nitrophenyl)-3- {5-(phenylcarbamoyl)-2-furyl Ipropyl]-N- (2- naphthylmethyl1)carbamoyl]-4-pentenoic acid or 3-tert-butoxycarbonyl-4- N-(2,3-dichlorobenzyl)-N- [(IRS ,2RS)-l- methyl-2-(4-nitrophenyl)-3- 5- (phenylcarbamoyl)-2- furyl }propyllcarbamoyl]-4-hydroxy-3-butenoic acid or a pharmaceutically acceptable salt or optical isomer thereof. The method according to Claim 8 wherein the famnesyl pyrophosphate-competitive inhibitor is selected from: sodium 4- R,2R,4E)-5-(2-benzoxazolyl)-l-methyl-2-(3 ,4- methylenedioxyphenyl)-4-pentenyl (2-naphthylmethyl)carbamoyl]- 3-tert-butoxycarbonyl-4-hydroxy-3-butenoate (Compound C) \N 0 O9H O N CO 2 Na (I CH 3 0 CO 2 t-Bu WO 97/01275 WO 9701275PCTJUS96/11022 528 or disodium (3RS RS ,2RS ,4E)-5-(2-benzoxazolyl)-l-methyl- 2-(3 ,4-methylenedioxypheflyl)-4-pelteflyl)}-N-(2- naphthylmethyl)carbamoyl-3-carboxyl-4-hYroxybutaloate (Compound D) NN CO 2 Na K 0 CH 3 0 CO 2 Na or a pharmaceutically acceptable salt or optical isomer thereof. 11. The method according to Claim 1 wherein the protein substrate-competitive inhibitor is: Compound E: CH 3 0 HS NH 2 or a pharmnaceutically acceptable salt or optical isomer thereof and the farnesyl pyrophosphate-competitive inhibitor is: 529 disodium (3RS.4RS)-4-[N- {(RS,2RS,4E)-5-(2-benzoxazolyl)-l-methyl-2-(3,4- methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-3-carboxyl-4- hyroxybutanoate (Compound D) N 0 OH OcO N 0 'N C 0 2 Na 0- CH 3 0 CO 2 Na 12. A pharmaceutical composition for achieving a synergistic therapeutic effect in a mammal in need thereof which comprises amounts of at least two therapeutic agents selected from a group consisting of: a famesyl protein transferase inhibitor which is an effective inhibitor of the enzyme because it is competitive with respect to the protein substrate of the enzyme and to a farnesyl protein transferase inhibitor which is an effective inhibitor of 0 0 the enzyme because it is competitive with respect to farnesyl pyrophosphate; •wherein the amount of alone and the amount of alone is insufficient to achieve said therapeutic effect; and 0* wherein said therapeutic effect of the pharmaceutical composition is greater than the S 15 sum of the therapeutic effects of the amounts of the individual therapeutic agents administered. 13. The pharmaceutical composition according to claim 12 comprising an amount of S* a protein substrate-competitive inhibitor and an amount of a famesyl pyrophosphate- competitive inhibitor. 14. A method of preparing a pharmaceutical composition for achieving a synergistic therapeutic effect in a mammal in need thereof which comprises mixing amounts of at least two therapeutic agents selected from a group consisting of: a farnesyl protein transferase inhibitor which is an effective inhibitor of the enzyme because it is competitive with respect to the protein substrate of the enzyme and a famesyl protein transferase inhibitor which is an effective inhibitor of the enzyme because it is competitive with respect to faresyl pyrophosphate. wherein the amount of alone and the amount of alone is insufficient to achieve said therapeutic effect; and [R:\LIBAA)07529 doc TAB 530 wherein said therapeutic effect of the pharmaceutical composition is greater than the sum of the therapeutic effects of the amounts of the individual therapeutic agents administered. The method of preparing a pharmaceutical composition according to claim 14 comprising mixing an amount of a protein substrate-competitive inhibitor and an amount of a faresyl pyrophosphate-competitive inhibitor. 16. An embodiment which is at least two therapeutic agents selected from a group consisting of: a farnesyl protein transferase inhibitor which is an effective inhibitor of the enzyme because it is competitive with respect to the protein substrate of the enzyme and a famesyl protein transferase inhibitor which is an effective inhibitor of the enzyme because it is competitive with respect to farnesyl pyrophosphate: when used for achieving an additive of synergistic effect in a mammal, wherein the amount of alone and the amount of alone is insufficient to achieve said therapeutic S 15 effect. 17. The embodiment according to claim 16 wherein an amount of a protein substrate-competitive inhibitor and an amount of a famesyl pyrophosphate-competitive inhibitor are administered simultaneously. 18. The embodiment according to claim 16 or claim 17 wherein the protein- 20 substrate competitive inhibitor is as defined in the method according to any one of claims to 7 or 11. 19. The embodiment according to any one of claims 16 to 18 wherein the farnesyl pyrophosphate-competitive inhibitor is as defined in the method according to any one of claims 8 to 20. The use of at least two therapeutic agents selected from a group consisting of: a farnesyl protein transferase inhibitor which is an effective inhibitor of the enzyme because it is competitive with respect to the protein substrate of the enzyme and a farnesyl protein transferase inhibitor which is an effective inhibitor of the enzyme because it is competitive with respect to famesyl pyrophosphate: in the manufacture of a medicament for achieving an additive of synergistic effect in a mammal, wherein the amount of alone and the amount of alone is insufficient to achieve said therapeutic effect. 21. The use according to claim 16 wherein an amount of a protein substrate- competitive inhibitor and an amount of a farnesyl pyrophosphate-competitive inhibitor are S administered simultaneously. IR:\LIBAA]07529.doc:TAB 531 22. The use according to claim 16 or claim 17 wherein the protein-substrate competitive inhibitor is as defined in the method according to any one of claims 5 to 7 or 11. 23. The use according to any one of claims 15 to 18 wherein the farnesyl pyrophosphate-competitive inhibitor is as defined in the method according to any one of claims 8 to Dated 3 August, 1999 Banyu Pharmaceutical Co., Ltd. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON .o99 *0 Se 9* S* 9 9 o* [R:\LIBAA]07529.doc:TAB
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US225195P | 1995-06-29 | 1995-06-29 | |
| US60/002251 | 1995-06-29 | ||
| GBGB9603091.1A GB9603091D0 (en) | 1996-02-14 | 1996-02-14 | Combinations of inhibitors of farnesyl-protein transferase |
| GB9603091 | 1996-02-14 | ||
| PCT/US1996/011022 WO1997001275A1 (en) | 1995-06-29 | 1996-06-26 | Combinations of inhibitors of farnesyl-protein transferase |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU6399696A AU6399696A (en) | 1997-01-30 |
| AU714072B2 true AU714072B2 (en) | 1999-12-16 |
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| Application Number | Title | Priority Date | Filing Date |
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| AU63996/96A Ceased AU714072B2 (en) | 1995-06-29 | 1996-06-26 | Combinations of inhibitors of farnesyl-protein transferase |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0836383A1 (en) |
| JP (1) | JP2000501063A (en) |
| AU (1) | AU714072B2 (en) |
| CA (1) | CA2225255A1 (en) |
| WO (1) | WO1997001275A1 (en) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0805154A1 (en) * | 1994-08-12 | 1997-11-05 | Banyu Pharmaceutical Co., Ltd. | N,n-disubstituted amic acid derivative |
| EP0856315B1 (en) * | 1995-08-09 | 2005-08-24 | Banyu Pharmaceutical Co., Ltd. | Protein-farnesyltransferase inhibitors in combination with hmgcoa-reductase-inhibitors for the treatment of aids |
| ATE222234T1 (en) * | 1996-02-07 | 2002-08-15 | Banyu Pharma Co Ltd | CYCLIC AMIC ACID DERIVATIVES |
| EP0989114B1 (en) * | 1996-02-07 | 2002-07-24 | Banyu Pharmaceutical Co., Ltd. | N,n-disubstituted amic acid derivatives |
| WO1997029075A1 (en) * | 1996-02-07 | 1997-08-14 | Banyu Pharmaceutical Co., Ltd. | Substituted amide derivatives |
| EP0882701B1 (en) * | 1996-02-07 | 2002-07-24 | Banyu Pharmaceutical Co., Ltd. | Substituted amide derivatives |
| GB9801231D0 (en) | 1997-06-05 | 1998-03-18 | Merck & Co Inc | A method of treating cancer |
| AU7552098A (en) * | 1997-06-09 | 1998-12-30 | Takara Shuzo Co., Ltd. | Physiologically active substances tkr2449, process for producing the same, and microorganism |
| US6395897B1 (en) | 1999-03-02 | 2002-05-28 | Boehringer Ingelheim Pharmaceuticals, Inc. | Nitrile compounds useful as reversible inhibitors of #9 cathepsin 5 |
| US6420364B1 (en) | 1999-09-13 | 2002-07-16 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compound useful as reversible inhibitors of cysteine proteases |
| CA2397694A1 (en) * | 2000-02-29 | 2001-09-07 | Janssen Pharmaceutica Inc. | Farnesyl protein transferase inhibitor combinations |
| DK2124562T3 (en) | 2007-03-09 | 2016-08-01 | Second Genome Inc | BICYCLOHETEROARYLFORBINDELSER AS P2X7 modulators and uses thereof |
| US20100227811A1 (en) * | 2007-05-14 | 2010-09-09 | University Of South Florida | Farnesylamine derivatives and methods of use |
| ES2968371T3 (en) | 2013-10-10 | 2024-05-09 | Eastern Virginia Medical School | 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives as 12-lipoxygenase inhibitors |
| JO3637B1 (en) | 2015-04-28 | 2020-08-27 | Janssen Sciences Ireland Uc | Rsv antiviral pyrazolo- and triazolo-pyrimidine compounds |
| TW201932470A (en) | 2017-11-29 | 2019-08-16 | 愛爾蘭商健生科學愛爾蘭無限公司 | Pyrazolopyrimidines having activity against RSV |
| EA202091835A1 (en) | 2018-01-31 | 2020-10-20 | Янссен Сайенсиз Айрлэнд Анлимитед Компани | CYCLOALKYL SUBSTITUTED PYRAZOLOPYRIMIDINES WITH AN ACTIVITY AGAINST RSV |
| ES2957316T3 (en) | 2018-04-23 | 2024-01-17 | Janssen Sciences Ireland Unlimited Co | Heteroaromatic compounds that have activity against RSV |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5340828A (en) * | 1991-09-30 | 1994-08-23 | Merck & Co., Inc. | Inhibitors of farnesyl protein transferase |
| US5352705A (en) * | 1992-06-26 | 1994-10-04 | Merck & Co., Inc. | Inhibitors of farnesyl protein transferase |
| US5362906A (en) * | 1991-09-27 | 1994-11-08 | Merck & Co., Inc. | Farnesyl pyrophosphate analogs |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5245061A (en) * | 1991-12-16 | 1993-09-14 | Merck & Co., Inc. | Inhibitors of farnesyl protein transferase |
| WO1995000497A1 (en) * | 1993-06-18 | 1995-01-05 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
| EP0776884B1 (en) * | 1994-08-11 | 2000-01-05 | Banyu Pharmaceutical Co., Ltd. | Substituted amide derivative |
-
1996
- 1996-06-26 EP EP96923503A patent/EP0836383A1/en not_active Withdrawn
- 1996-06-26 JP JP9504573A patent/JP2000501063A/en active Pending
- 1996-06-26 CA CA002225255A patent/CA2225255A1/en not_active Abandoned
- 1996-06-26 WO PCT/US1996/011022 patent/WO1997001275A1/en not_active Application Discontinuation
- 1996-06-26 AU AU63996/96A patent/AU714072B2/en not_active Ceased
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5362906A (en) * | 1991-09-27 | 1994-11-08 | Merck & Co., Inc. | Farnesyl pyrophosphate analogs |
| US5340828A (en) * | 1991-09-30 | 1994-08-23 | Merck & Co., Inc. | Inhibitors of farnesyl protein transferase |
| US5352705A (en) * | 1992-06-26 | 1994-10-04 | Merck & Co., Inc. | Inhibitors of farnesyl protein transferase |
Also Published As
| Publication number | Publication date |
|---|---|
| AU6399696A (en) | 1997-01-30 |
| JP2000501063A (en) | 2000-02-02 |
| WO1997001275A1 (en) | 1997-01-16 |
| EP0836383A1 (en) | 1998-04-22 |
| CA2225255A1 (en) | 1997-01-16 |
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| FGA | Letters patent sealed or granted (standard patent) | ||
| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |