AU738341B2 - Asparate ester inhibitors of interleukin-1beta converting enzyme - Google Patents

Asparate ester inhibitors of interleukin-1beta converting enzyme Download PDF

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Publication number
AU738341B2
AU738341B2 AU49023/97A AU4902397A AU738341B2 AU 738341 B2 AU738341 B2 AU 738341B2 AU 49023/97 A AU49023/97 A AU 49023/97A AU 4902397 A AU4902397 A AU 4902397A AU 738341 B2 AU738341 B2 AU 738341B2
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Prior art keywords
oxo
pentanoic acid
acetoxy
phenyl
naphthalen
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AU49023/97A
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AU4902397A (en
Inventor
Hans P. Albrecht
Hamish John Allen
Kenneth Dale Brady
Bradley William Caprathe
John Lodge Gilmore
William Glen Harter
Sheryl Jeanne Hays
Catherine Rose Kostlan
Elizabeth Ann Lunney
Kimberly Suzanne Para
Anthony Jerome Thomas
Nigel Walker
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Abbott GmbH and Co KG
Warner Lambert Co LLC
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BASF SE
Warner Lambert Co LLC
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Assigned to WARNER-LAMBERT COMPANY, ABBOTT GMBH & CO. KG reassignment WARNER-LAMBERT COMPANY Alteration of Name(s) in Register under S187 Assignors: BASF AKTIENGESELLSCHAFT, WARNER-LAMBERT COMPANY
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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Description

-1- ASPARATE ESTER INHIBITORS OF INTERLEUKIN-P0 CONVERTING ENZYME FIELD OF THE INVENTION This invention relates to compounds that are inhibitors of interleukin- 13 converting enzyme. This invention also relates to a method of treatment of stroke, reperfusion injury, Alzheimer's disease, shigellosis, inflammatory diseases, and to a pharmaceutically acceptable composition that contains a compound that is an inhibitor of interleukin- 1 converting enzyme.
BACKGROUND OF THE INVENTION Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.
The compounds of the present invention are inhibitors of interleukin-lp converting enzyme (ICE; Caspase-1) and are useful in treating diseases in which interleukin-1 plays a role.
ICE acts on pro-interleukin- 1 (pro-IL- 1) to produce interleukin-1 P (IL- 1), which is an inflammatory cytokine. In addition, ICE (Caspase-1) regulates at least four cytokines. ICE activates IL-P and IL-18 and indirectly regulates the production of ILloc and IFNy. Several diseases are associated with interleukin-1 activity. Examples of diseases in which interleukin-1 is involved include, but are not limited to, inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease, neuroinflammatory disorders such as stroke. Other diseases include septic shock, reperfusion injury, Alzheimer's disease, and shigellosis.
I 1 .71n nt- -la- Agents that modulate IL-13 activity have been shown to have beneficial in vivo effects. For example, compounds that are interleukin-1 receptor antagonists have been shown to inhibit ischaemic and excitotoxic damage in rat brains. See, for example, Relton et al., Brain Research Bulletin, 1992;29:243-246. Additionally, ICE inhibitors were shown to reduce e o e 9~no-, MN\P i WO 98/16502 PCTIUS97/18514 -2inflammation and pyrexia in rats. See Elford et al., British Journal of Pharmacology, 1995;1 15:601-606.
The compounds of the present invention are also inhibitors of other cysteine proteases in the ICE family. Many of these proteases have only recently been described in the literature. While the nomenclature is still unresolved, the following proteases are representative members of this class of enzymes; Ich-2 (also called Tx or ICErel-II), ICErel-III, Ich-I (also called Nedd-2), CPP-32 (also called apopain and yama), Mch-2, Mch-3 (also called ICE-lap3, CMH-1), and Ced-3. See Henkart Immunity, 1996;4:195-201. It is recognized that members of this enzyme family play key biological roles in both inflammation and apoptosis (programmed cell death). In particular, Caspase-4 can activate IL-10 and IL-18. It has been shown that a murine homolog of Caspase-4 can activate ICE. Thus, inhibition of Caspase-4 will act to inhibit ICE. See Thornberry et al., Perspectives in Drug Discovery and Design, 1994;2:389-399.
In addition to its effects on IL-1p production, ICE has been shown to play a role in the production of the inflammatory mediator interferon-y (Ghayur, et al., Nature 1997;386(6625):619-623). ICE processes the inactive proform of interferon-y inducing factor (IGIF; Interleukin-18) to active IGIF, a protein which induces production of interferon-y by T-cells and natural killer cells. Interferon-y has been implicated in the pathogenesis of diseases such as inflammatory disorders and septic shock. Therefore, ICE inhibitors would be expected to have beneficial effects in such disease states by effects on interferon-y.
Recently, the nomenclature of those cysteine proteases in the ICE family (also known as caspases with ICE being known as Caspase-1) has been further defined. The following proteases are representative members of this class of enzymes using the nomenclature described in Alnemri, et al, Cell, 1996;87:171: Caspase-2 (also known as Ich-1); Caspase-3 (also known as CPP32, Yama, and apopain); Caspase-4 (also known as TX, Ich-2, and ICE rel-II); Caspase-5 (also known as ICE rel-III); Caspase-6 (also known as Mch2 Caspase-7 (also known WO 98/16502 PCTIUS97/18514 -3as Mch3); Caspase-8 (also known as FLICE and Mch5); Caspase-9 (also known as ICE-LAP6 and Mch6); Caspase-l10 (also known as Mch4).
SUMMARY OF THE INVENTION The present invention provides compounds of the Formula I C0 2 H 0 NR-_ O)<"R2
H
0 0 11 wherein RI is R 3
OC-,
R
3
CO-,
R
3
SO
2
R
5
NCHR
6
CO-,
each Ra is independently hydrogen, C 1
I-C
6 alkyl, or -(CH2)n aryl;
R
2 is -(CRR)n-aryl, WO 98/16502 WO 9816502PCTIUS97/18514 -4- -(CRR)n-heteroaryl, -(CRR),,-X-heteroary1, -(CRR)n-(substituted-heteroaryI), -(CRR)n-(substituted-ary1), -(CRR)n-arY1-arYl, -(CRR)n-aryl-heteroaryl,
-(CRR)
1 1 -CH(arYl) 2 -(CRR)-cycloalkyl, -(CRR)n-X-cycloalky1,
-(CRR)
11 -heterocycle, -(CRR)n-X-heterocycle, -(CRR)n substituted heterocycle, (CH2)naryl (CRR)n CH (CH2)nsubstituted aryl (CRR)n- CH 0 (CRR)
NS
(CH2)nheteroaryl (CRR) n-CH WO 98/16502 WO 9816502PCTIUS97/18514 0 0 11 N N- S- [aryl, or substituted aryl] 11 0 0 ,N-C(CH)i-[aryl, or substituted aryl] 0 NIayl aryl -(CR~nCH NH aryl
(CRR)~
WO 98/16502 PCTIUS97/18514 -6- -(CRR)n or T4 J~4 N CHr~n- o >'CHR)neach R is independently hydrogen, C I-C 6 alkyl, halogen or hydroxy; X is 0or S;
R
3 is C 1
I-C
6 alkyl, aryl, heteroaryl, -(CHR)n-aryl, -(CHR)n-heteroaryl, -(CHR)n-substituted heteroaryl, -(CHR)n-substituted aryl, 0 11 -(CRR)nCORa, -(CRR)nS(CH2)n-aryl, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, 0 11 -(CRR)nCNRaRa, WO 98/16502 WO 9816502PCTIUS97/18514 -7- 0 11 0 0 -(CRR)n-SC I -C 6 alkyl,
II
J-CH
2
CH-,
0
II
-CHR
6 C-heteroaryl, 0 -(CRR)nS(CH 2 )nCORa, 0 0 -(CRR)nS(CH 2 )nC0Ra, -(CRR)nS(CH2)n-aryl, 0 11 -(CRR)flS(CH2)fl-arYl, 11 0 0 I1 -(CRR)nSCC I -C 6 alkyl, 0 I1 -(CRR)nS(CH2)n aryl, 0 -(CRR)nS(CH 2 )nCO 2 Ra, WO 98/16502 WO 9816502PCTIUS97/18514 0 11
-(CH
2 11 NHOC I -C 6 alkyl, 0 11
-(CH
2 )nCNRbRb, 0 I (CH 2 aryl
N
aryl-N kN 0
DID
phenyl 0
II
N
R'~
(CH
2 A 0 0 aryl -S N C(R~ arl o=s=o 1 0 N 1 CD/-C(CRR)j- WO 98/16502 PCT/US97/18514 -9each R' is independently C I-C 6 alkyl,
C
1
I-C
6 alkylaryl, aryl, or hydrogen; each J is independently
-CO
2 Rb, -CONRbRb,
-SO
2 NRbRb, or
-SO
2 Rb; each Rb is independently hydrogen, C I-C 6 alkyl, aryl, substituted aryl; arylalkyl, heteroarylalkyl, substituted arylalkyl, or substituted heteroarylalkyl;
R
4 is hydrogen, C I-C 6 alkyl, 0 11
CH
3 0C-, -phenyl, or 0 11 C I-C 6 alkyl C-;
R
5 is C I-C 6 alkyl-CO-, -(CH2)n arYl, 0 11
C
1 I -C 6 -alkylOC-,,
C
1
-C
6 -alkyl-X-(CH 2 1 1 C0, 0 11
C
1
-C
6 -alky1-X-(CH 2 )n0C-, WO 98/16502 WO 9816502PCTIUS97/18514 0 11 -C(CRR)nary1, 0 11 -CNRaRa, 0 11 -SC I-C 6 alkyl, 11 o 0
-C(CH
2 )nCNRaRa, 0 11 -C0(CHr2)n aryl, 0 11 -CO(CH-r2)n substituted aryl, o 0 -C(CRR)nNHC0(CH 2 )-ary1, 0a II R k(6 -(CH2)nX(CH2)n-arYl, -C 1
-C
6 alkyl X-C I-C 6 alkyl aryl, or 0 0 0
-C-CII-NHC-CH-NHCC
1 -C~alky1; 1 1
(CH
2 )n Ut12-heteroaryl C0 2 Ra -11 R~a i 0- I I
GC-C-
6 akl, 0 -Co 1 U -C 6 alky], o 0 -C IN -NHC 1 -Ck- 6 akyl,
(CH
2 )n aryl or substituted aryl, 0 C0(CH 2 aryl, C(CH1 2 aryl, or o 0
.Y
CH
2 heteroaryl *R 6
R
6 is hydrogen,
CX-
6 alkyl, -(CH 2 aryl, -(CH 2 ).C0 2 Wa, hydroxyl substituted C 1
-C
6 ailkyl, or imidazole substituted CI-C 6 ailcyl; n is independently 0 to 3, and the pharmaceutically acceptable, salts, esters, amides, and prodrugs thereof; provided that a compound of fonmula is not:llaand further provided that: when RW is aryl, substituted aryl, cycloalkyl, phenyl-phenyl-CH 2 piperidino, heteroaryl or substituted heteroaryl; and R' is (R 5 Ra)N-CH(R 6 then W~ is not hydrogen when R' is a side chain of an amino acid; R' is aryl-C(O)-, aryl-(CH 2 where R is H or (C,-C,)alkyl or Rsa NH-CH(R 6 where R' is a side chain of an amino acid and W 5 is an amino acid 10 protecting group; when R' is R 3 where W 3 is CH 2
=CH-CH
2 then Wi is not Ph(CH 2 2 PhO(CH 2 2 trans-PhCH=CH or cyclohexyl(CH 2 2 when R' is (RsRa)N-CH(R 6 where R 6 is H, (C 1
-C
6 )alkyl, benzyl or hydroxyalcyl; R' is H, (C 1
-C
6 )alkyl, phenyl or benzyl; and
R
5 is 1
-C
6 )alkyl, 1
-C
6 )alkyl, -phenyl- O-(Cl-C 6 )alkyl or -phenyl-(CH 2 )1A-N(RaRa); then Wi is not a phenyl. or naphthyl group optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, CF 3
NO
2
(C
1
-C
6 )allcoxy, -CO-(C 1
-C
6 )alkyl, -NaC(Oy..(Cl-
C
6 )alkyl, -CON(RaWa), SO 2 N(RaWa), S0 2 (Cl-.C 6 )alkyl, COO-(C 1 lib-
C
6 )allcyl, -C 6 )alkyl, cycloalkyl and -O-(CH 2 1 -,-phenyl-O-(C-C 6 )alcyl; and when R'is R 5
-NH-CH(R
6 where W 5 is RWa-NIICH(R 6 and R5. is 1
-C
6 )allcyl or -C(O)-aryl, then W 2 is not mono-, di-,,tri- tetra- or penta- substituted phenyl or mono-, di-, tni-substituted phenyl, 1 -naphthyl, 9-anthracyl or 3- or 4-pyridyl.
In a preferred embodiment of the compounds of Formula I, R1 is 0 phenyl-CH 2
-OC-.
In another preferred embodiment of the compounds of Formula I, R' is phenyl- 10S2so:so- -12- In another preferred embodiment of the compounds of Formula I,
O
I I
R
1 is CH 3
-OC-.
In another preferred embodiment of the compounds of Formula I, R 1 is phenyl-
CH
2
CH
2
-CO-.
In another preferred embodiment of the compounds of Formula I, R' is
O
CH3
NH
0 CH3 In another preferred embodiment of the compounds of Formula I, R' is
*O
NH
CH
3
CH
3 In another preferred embodiment of the compounds of Formula I, R' is phenyl- In another preferred embodiment of the compounds of Formula I, R is phenyl.
In another preferred embodiment of the compounds of Formula I, R 2 is -(CH 2 )nnaphthyl.
In another preferred embodiment of the compounds of Formula I, R 2 is -(CH 2 )n-Ophenyl.
In another preferred embodiment of the compounds of Formula I, R 2 is -(CHyr)-Onaphthyl.
naphthyl.
-13- In another preferred embodiment. of the compounds of Formula 1,
R
2 is -(CH2)n-S-PhenYl.
In another preferred embodiment of the compounds of Formula 1,
R
2 is-(C2n-CH(phenyI) 2 In another preferred embodiment, of the compounds of formula. I.
Ra is hydrogen; R I is benzyloxycarbonyl; R 2 is azy-X(CRR)n-, aryI-(CRR)nheteroaryl-(CRR)n-, or cycloallyl-(CRR)n-; n is 1, 2, or 3; X is 0 or S; and R is hydrogen, methyl, or benzyl.
In another preferred embodiment of the compounds of Formula 1, 10 Ra is hydrogen; RI is benzyloxycarbonyl; and
R
2 is -(CH2)n-nagphthY1, -(CH2)n-cYcloal, -(CH2),n0(CH 2 )n-naphthyl, -(CH2)nO(CH 2 )n-phenyl, or {CH2)nS(CH 2 )n-phenyl.
In another preferred embodiment of the compounds of Formula I.' Ra is hydrogen; 20 Rl is benzyloxycarbonyl; and
R
2 is -CH-,-naphthyl.
In another preferred embodiment of the compounds of Formula 1, Ra is hydrogen;
R
1 is benzyloxycarbonyl, 0 WO 98/16502 PCTIS97/18514 -14- 0 0 0 0 II II II II
-C-CH-NHC-CHNHC-CHNHCC
1
-C
6 alkyl S CH 2 heteroaryl
CH
3 CH3 CH 2
CH
2
CO
2
H
0 0 0 0 O O O O II II II II -C-CH-NHC-CHNHC- CHNHCC 1
-C
6 alkyl CH2aryl
CH
3
CH
3
CH
2
CH
2
CO
2 H 2 0 11
-C-CH-CH
2 -S-aryl, or
CH
3 O 0 11
II
-C-CHCH
2 -S-aryl.
I II
CH
3
O
Also provided is a method of inhibiting interleukin-lp converting enzyme, the method comprising administering to a patient in need of inhibition of interleukin-1 converting enzyme a therapeutically effective amount of a compound of Formula I.
Also provided is a method of inhibiting Caspase-4, the method comprising administering to a patient in need of Caspase-4 inhibition a Caspase-4 inhibiting amount of a compound of Formula I.
Also provided is a method of treating stroke, the method comprising administering to a patient having a stroke or having had a stroke a therapeutically effective amount of a compound of Formula I.
Also provided is a method of treating inflammatory diseases, the method comprising administering to a patient having an inflammatory disease a therapeutically effective amount of a compound of Formula I.
In a preferred embodiment of the treatment of inflammatory diseases, the inflammatory disease is arthritis.
15 According to a seventh aspect the present invention provides a method of treating Alzheimer's disease, the method comprising administering to a patient having Alzheimer's disease a therapeutically effective amount of a compound of the first aspect.
According to an eighth aspect the present invention provides a method of treating shigellosis, the method comprising administering to a patient having shigellosis a therapeutically effective amount of a compound of the first aspect.
According to a ninth aspect the present invention p rovides a pharmaceutically acceptable composition that contains a compound of the first aspect.
~.According to a tenth aspect the present invention provides the compounds: 3-Benzenesulfonylamino-5-(naphthalen- 1-yl-acetoxy)-4-oxo-pentanoic acid; 1-yl-acetoxy)-4-oxo-pentanoic acid; 1-yl-acetoxy)-4-oxo-3-(3 -phenyl-propionylamino)-pentanoic acid; 3 -Methoxycarbonylamino-4-oxo-5-phenoxyacetoxy-pentanoic acid; and 3-(2-Methanesulfonyl-l1-methyl-ethylsulfanylamino)-5-(naphthalen- 1-yl-acetoxy)- 4-oxo-pentanoic acid.
According to an eleventh aspect the present invention provides the compounds: (S)-5-(Naphthalen- 1-yl-acetoxy)-4-oxo-3-phenylacetylamino-pentanoic acid; 1-yl-acetoxy)-4-oxo-3-(2-thiophene-2-yl-acetylamino)pentanoic acid; 3 2 -Carbamnoy1-cyclopentanecarbonyl)-amino]-5-(naphthalen-1 -yl-acetoxy)-4oxo-pentanoic acid; 3-[(3-Carbamroyl-bicyclo [2.2.1 ]heptane-2-carbonyl)-amino]-5-(naphthalen-l1-ylacetoxy)-4-oxo-pentanoic acid; 3-(3-Methanesulfony-2-methy-propionylamiio)-5-(naphthalen-1 -yl-acetoxy)-4oxo-pentanoic acid; 16 3 -Benzenesulfonyl-2-methyl-propionylamino)-5 -(naphthalene- 1 -yl-acetoxy)- 4-oxo-pentanoic acid; 3-Butyrylamino-5-(naphthalen-2-yl-acetoxy)-4-oxo-pentanoic acid; 1-yl-acetoxy)-4-oxo-pentanoic acid; 3-(3-Methanesulfonyl-2-methyl-propionylamino)-5-(naphthalen- 1-yl-acetoxy)-4oxo-pentanoic acid; 3-(3-Methyl-butyrylamino)-5-(naphthalen- 1-yl-acetoxy)-4-oxo-pentanoic acid; 3-(3-Carbamoyl-propionylamnino)-5-(naphthalen- 1-yl-acetoxy)-4-oxo-pentanoic acid; acetoxy)-4-oxo-pentanoic acid; and trans-3 -[(3-Carbamoyl-cyclopentanecarbonyl)-amino]-5-(naphthalen- l-ylacetoxy)-4-oxo-pentanoic acid.
According to a twelfth aspect the present invention provides the compounds: 3-[(2-Carboxy-cyclohexanecarbonyl)-amiino]-5-(naphthalen- 1 -yl-acetoxy)-4oxo-pentanoic acid; 3-[(2-Methoxycarbonyl-cyclohexanecarbonyl)-amino]-5-(naphthalen- l-ylacetoxy)-4-oxo-pentanoic acid; and 3 -[(2-Carbamoyl-cyclohexanecarbonyl)-aniino]-5-(naphthalen- 1-yl-acetoxy)-4oxo-pentanoic acid.
According to a thirteenth aspect the present invention provides the compounds: 3 -(3-Benzylsulfany1-2-methyl-propionylamino)-5-(naphthalen 1 -yl-acetoxy)- 4-oxo-pentanoic acid; 3 2 -Methyl-3-phenymethanesulfonyl-propionylamino)-5.(naphthalen.. -yl- 425 acetoxy)-4-oxo-pentanoic acid; 17 3 -[3-(2-Carboxy-ethanesulfanyl)-2-methyl-propionylamino]-5-(naphthalen 1 -yl-acetoxy)-4-oxo-pentanoic acid; 5-(2-Benzyl-3-phenyl-propionyloxy)-3-[3-(2-carboxy-ethanesulfonyl)2methyl propionylamino]-4-oxo-pentanoic acid; a a a.
a a a a a a a a a.
a .a -18 2 -BenzyI-3-phenyl-propionyloxy)-3-3-(3-carboxy.propane. 1 -sulfinyl)- 2-methyl-propionyiamino]-oxo-pentanoic acid; 5-(Naphthalen-1I-yl-acetoxy)-4-oxo-3-(2-phenylmethanesulfanyl.
pi-opionylamino)-pentanoic acid; 3 2 -MethyI-3-phenylsulfanyI-propionlamino)-5-<naphthalen-. -yIacetoxy)-4-oxo-pentanoic acid; 2 -Benzyl-3-phenyi-propionyloxy)-3-<2-methy1.3-phenyisulfany..
propionylaxnino)-4-oxo-pentanoic acid; 3 2 -Methyl-3-phenethylsulfanyI- propianylamihnoy..5..naphhn... 1-yIacetoxy)-4-oxo-pernanoic acid; 9: propionylamino)-4-.oxo-pentanoic acid; 3 2 -Benzy-3-3phenyi-r plfn)-propioyon3.eyl~anoyI5-naphtI.. n propicoym)-4-oxo-pentanoic acid; propionylamin)-4-oxo-pentanoic acid; l-yI-acetaxy)-4-oxo-pentanoic acid; aceoxioy-4-o-pentanoic acid; 3phnlmtanslfnipropionylanxyn)-4-oxo-pentanoic acid; 2 -Benzyl-3-phenyi-propionyloxy)-4-oxo-3effiy-pheny.hetansufoy.
propionylamrio)-pentanoic acid; 19 3-[2-Methyl-3-(3-phenyl-propane-l1-sulfonyl)-propionylandno]- I -yl-acetoxy)-4-oxo-pentanoic acid,- 5-(2-Benzyl-3-phenyI-propionyloxy)-3-[2-niethyl-3-(3-phenyI-propane- 1 -sulfonyl)-propionylamino]-4-oxo-pentanoic acid, 5-(2-Benzyl-3-phenyl-propionyloxy)-3-[3-(2-carboxy.ethylsulfanyl)- 2-methyl-propionylarrino]-4-oxo-pentanoic acid; 3-[3-(3-Carboxy-propylsulfanyl)-2-methyl-propionylamino]- I -yI-acetoxy)-4-oxo-pentanoic acid, 2 -Benzyl-3-phenyl-propionyloxy)-3-[3-(3-carboxy-propysulfanyl..
2-methyl-propionylamino]-4-oxo-pentanoic acid; 3-(3-Carboxymethylsulfanyl-2-methyl-propionylamino)-5.{naphthalen.
1 -yI-acetoxy)-4-oxo-pentanoic acid; 5-(2-Benzyl -3-phenyl-propionyloxy)-3-(3-carboxy methylsulfanyl- 2-methyl-propionylamino)-4-oxo-pentanoic acid; 3-[3-(2-Carboxy-ethaesulfonyl)-2-niethyl-propionylaniino]- 3-[3-(3-Carboxy-;propane-l1-sulfonyl)-2-rncthyl-propionylamino]- 5-(naphthalen- 1 -yI-acetoxy)-4-oxo-pentanoic acid; 1 -npae- -yI-acetoxy)-4-oxo-pentanoic acid; 25 3 3 -Carboxyethanefl-li)2-methyl-propiony In).ammo a~n I -y-acetoxy)-4-oxo-pentanoic acid n
S-(
2 -BenzyI-3-phenyI-propionyloxy)-3-[2-(3ecrbyl--3p-propane-foy- 12-suethyl-propionylamino-4-oxo-pentanoic acid 20 According to a fourteenth aspect the present invention provides the compounds: 3 -[3-Methy1-2-(phenethylcarbamoy1-methy1)-butyrylamino]-5- (naphthalen- 1-yl-acetoxy)-4-oxo-pentanoic acid; and 3-(3-Carboxy-2-methyl-propionylamino)-5-(naphthalen- 1 -yl-acetoxy)-4oxo-pentanoic acid.
According to a fifteenth aspect the present invention provides the compound: 3-(2-Methyl-3-sulfamoyl-propionylamino)-5-(naphthalen- 1-yl-acetoxy)- 4-oxo-pentanoic acid.
.0 According to a sixteenth aspect the present invention provides the compounds: 0 10 3-Benzyloxycarbonylamino-5-(naphthalen-1 lactxy--xopntni acid; aacid; 3-Benzvloxvcarbonvlamino-4-oxo-5-(phenyl-prooyl-pentanoic S3-Benzyloxycarbonylamnino-5-(3-cyctle-yl-propionyloxy)-4-oxo-pentanoic acid; (na-phaen- yl-oxy)-actoxy]-4-oxo-pentanoic acid; -21- 3-Benzyloxycarbonylamino-5-(2-naphthalen- 1-yl-propionyloxy)-4-oxo-pentanoic acid; -[(Acetyl-phenyl-amlino)-acetoxy]-3-benzyloxycarbonyl-anijno-4-oxo-pentanoic acid; 3-Benzyloxycarbonylamino-5-(2-benzy-3-pheny-propionyloxy)-4-oxo.
pentanoic acid; 3 -Benzyloxycarbonylamino-5-(hydroxy-naphthalen- 1-yl-acetoxy)-4-oxopentanoic acid; C C 3 -Benzyloxycarbonylamino-4-oxo-5-[(pheny1-amnino)-acetoxy]-pentanoic acid; 10 3 -Benzyloxycarbonylamino-5-[(6-hydroxy-naphthalen- 1-yl)-acetoxy]-4-oxopentanoic acid; 3 -Benzyloxycarbonylamino-5-[3-(4-hydroxy-phenyl)-2-naphthalen- 1-yl- **see:propionyloxy]-4-oxo-pentanoic acid; (S--ezlxcroya*n--x--hnlctx-etni acd (S)-3-Benzyloxycarbonylamino-4-oxo-5-(phenyletyry-pentanoic acid; (3-Benzyloxycarbonyla-ino-4-oxo-5-(4-iphen-yl-tyryoxy)entanoi acid 3-Benzyloxycarbonylamino4xo-5-[(4phyl-naphthalen-1-yl)-acetoxy]-- T& 2 pentanoic acid; 3-ezlxcabnlmn-5[4mtylnptae- y)aetx]4oo 22 3-Benzyloxycarbonylamino-5-[(2-fluoro-naphthalen- 1-yl)-acetoxy]-4-oxopentanoic acid; 5-[(4-Benzyl-naphthalen- 1-yI)-acetoxy]-3-benzyloxycarbonylamino-4-oxopentanoic acid; 3-Benzyloxycarbonylamino-5-[(3,4-dihydro-naphthalen- 1-yl)-acetoxy]-4-oxopentanoic acid; 3-Benzyloxycarbonylamino-5-(3,4-diphenyl-butyryloxy)-4-oxo-pentanoic acid; 3-Benzyloxycarbonylamino-4-oxo-5-(3-phenyl-3-phenylaniino-propionyloxy)- >pentanoic acid; 10 3-Benzyloxycarbonylamino-4-oxo-5-[( 1,2,3 ,4-tetrahyclro-naphthalen-2-yl)acetoxy]-pentanoic acid; 3-Benzyloxycarbonylaniino-4-oxo-5-[(2,3 ,5,6-tetramethyl-phenyl)-acetoxy]pentanoic acid; *0*t3-Benzyloxycarbonylamino-5-[(2,3-dichloro-phenyl)-acetoxy]-4-oxo-pentanoic 15 acid; 3 -B enzyloxycarbonylamino-5'-[(5-methyl-naphthalen- 1 -yl)-acetoxy] -4-oxo- :pentanoic acid; 3-Benzyloxycarbonylamino-5-[(2-iodo-phenyl)-acetoxy]-4-oxo-pentanoic acid; 3-B enzyloxycarbonylamino-5-[(5-methoxy-naphthalen- 1-yl)-acetoxy]-4-oxopentanoic acid; 3-B enzyloxycarbonylamino-5-[(8-methyl-naphthalen- 1-yl)-acetoxy]-4-oxopentanoic acid; 3-Benzyloxycarbonylarnino-5-[(9H-fluoren-9-yl)-acetoxy]-4-oxo pentanoic acid; 10,1 1-dihlydro-5H-dibenzo[a,d]-cyclohepten-5yl)-acetoxy]-4-oxo-pentanoic acid; 23 3 -Benzyloxycarbonylamino-5-(2-benzy-3-phenyl-propionyoxy)-4-oxopentanoic acid; and 3-Benzyloxycarbonylamino-5-[(5-cyano-naphthalen- 1-yl)-acetoxy]-4-oxopentanoic acid.
According to a seventeenth aspect the present invention provides the compounds: ahh l--ylacetoxy)-4-oxo-pentanoic acid; 1-yl-acetoxy)-4-oxo-3-[2-(4-phenyl-butyrylamino)-propylaniino]pentanoic acid; 10 3 2 -Methanesulfonylamnino-propionylamino)-5-(naphthalen- 1-yl-acetoxy)-4oxo-pentanoic acid; 3 2 2 -Acetylamino-4-pheny-butyrylamino)-propionyaiino]-5-(naphthaen- 1yl-acetoxy)-4-oxo-pentanoic acid; 3-(2-Acetylamino-butyrylamino)-5-(naphthialen- 1-yl-acetoxy)-4-oxo-pentanoic acid; 3 -[2-(4-Carbamoyl-butyrylamino)-propionylaxnino]-5-(naphthalenl- 1 -yl-acetoxy)- 4-oxo-pentanoic acid; 3 2 -Benzyloxycarbonylamino-propionylamino)-5-(naphthaen 1 -yl-acetoxy)-4oxo-pentanoic acid; 5-(Naphthalen- 1-yl-acetoxy)- 4 -oxo- 3 -(2-ureido-propionylaniino)-pentanoic acid; 3 2 -Acetylamino-propionylamnino)-5-(naphthalen- 1-yl-acetoxy)-4-oxo-pentanoic acid; 3-(2-Acetylamino-acetylamino)-5-(naphthalen- 1-yl-acetoxy)-4-oxo-pentanoic acid; 24 3-(2-Acetylamino-propionylamino)-5-(3 ,3-diphenyl-propionyloxy)-4-oxopentanoic acid; 3-[2-(2-Acetylamino-4-carboxy-butyrylaniino)-propionylamnino]-5-(naphthalen- 1 -yl-acetoxy)-4-oxo-pentanoic acid; 5-(Naphthalen- 1-yl-acetoxy)-4-oxo-3-[2-(3-phenyl-propionylaniino)propionylaniino]-pentanoic acid; 3-[2-(3-Methyl-butyrylamino)-propionylamnino]-5-(naphthalen- 1-yl-acetoxy)-4oxo-pentanoic acid; and 3-(4-Carbamoyl-butyrylamino)-5-(naphthalen- 1-yl-acetoxy)-4-oxo-pentanoic acid.
According to an eighteenth aspect the present invention provides the compounds: 3-(2-Methyl-3-phenethylcarbamnoyl-propionylamino)-5-(naphthalen-1 -ylacetoxy)-4-oxo-pentanoic acid; 3- [3-Methyl-2-(3-phenyl-propionylaniino)-butyrylamino]-4-oxo-5-[(l1-oxo- ::15 1,2,3 ,4-tetrahydro-naphthalen-2-yl)-acetoxy]-pentanoic acid; 5-(Naphthalen- 1-yl-acetoxy)-4-oxo-3-[2-( 1-oxo- 1,2,3 ,4-tetrahydro-naphthalen-2yl)-acetylainino]-pentanoic acid; 5-(2-Benzyl-3-phenyl-propionyloxy)-.4-oxo-3 -oxo- 1,2,3 ,4-tetrahydronaphthalen-2-yl)-acetylamino]-pentanoic acid; 4-Oxo-5-[(1 -oxo- 1,2,3 ,4-tetrahydro-naphthalen-2-yl)-acetoxy]-3-[2-(l1-oxo- 1,2,3 ,4-tetrahydro-naphthalen-2-yl)-acetylamino].-pentanoic acid; 3-(2-Acetylamino-3-methyl-butyrylamnino)-5-(naphthalen- 1-yl-acetoxy)-4-oxo pentanoic. acid; 3-(2-Acetylamino-3-methyl-butyrylainino)-5-(2-benzyl-3-phenyl-propionyloxy)- ,S-Tk 25 4-oxo-pentanoic acid; 25 3-(2-Acetylamino-3-methyl-butyrylamino)-5-(3 -benzyl-4-phenyl-butyryloxy)-4oxo-pentanoic acid; 3-(2-Acetylamino-3 -methyl-butyrylamino)-5-(4-benzy-5-pheny-pentanoyloxy..
4-oxo-pentanoic acid; 3-(2-Acetylamino-3-methyl-butyrylamino)-4-oxo-5-[(l1-oxo- 1,2,3 ,4-tetrahydronaphthalen-2-yl)-acetoxy]-pentanoic acid; and 3 -Benzy1-4-pheny1-butyryloxy)-3-[3-meth1-2-(3-phenyl-propionylamino)butyrylamino]-4-oxo-pentanoic acid.
According to a nineteenth aspect the present invention provides the compounds: 10 3-[2-(2-Benzyloxycarbonylamino-4-carboxy-butyrylamino)-3 -methyl- 1-yl-acetoxy)-4-oxo-pentanoic acid; 3 2 2 (naphthalen- 1-yl-acetoxy)-4-oxo-pentanoic acid; 3-(2-Acetylamino-3-methyl-butyrylamino)-5-(naphthalen- 1-yl-acetoxy)-4-oxo- 15 pentanoic acid; 3 2 2 (3,3-diphenyl-propionyloxy)-4-oxo-penitanoic acid; 3 2 2 (2-benzy1-3-pheny1-propionyloxy)-4-oxo-pentanoic acid; 3 2 2 (naphthalen- 1-yl-acetoxy)-4-oxo-pentanoic acid; 5-(2-Benzyl-3-phenyl-propionyloxy)-3- {2-[4-carboxy-2-(3-phenylpropionylamino)-butyrylamino]-3-methyl-butyrylaniino} -4-oxo-pentanoic acid; 3-( 2 -Benzyloxycarbonylamino-3-methyl-biitryamino..s..(3,3-.dipheny1.
propionyloxy)-4-oxo-pentanoic acid; 26 3-(2-Acetylamnino-3-hydroxy-butyrylamino)-5-(naphthalen- 1-yl-acetoxy)-4-oxopentanoic acid; 3-(2-Acetylwmino-3-hydroxy-butyrylamino)-5-(3 ,3-diphenyl-propionyloxy)-4oxo-pentanoic acid; and 5-(3,3-Diphenyl-propionyloxy)-4-oxo-3-[2-(4-phenyl-butyrylamino)propionylamino]-pentanoic acid.
According to a twentieth aspect the present invention provides the compound: {2-[2-Acetylamino-3-(4-hydroxy-phenyl)-propionylamino]-4-carboxybutyrylamino)}-3-methyl-butyrylamino)-5-(naphthalen- 1-yl-acetoxy)-4-oxo-pentanoie acid.
According to a twenty-first aspect the present invention provides the compounds: 3-(3-Carbamoyl-2-methyl-propionylamino)-5-(naphthalen- 1 -yl-acetoxy)-4-oxopentanoic acid; 3 -(2-Benzyloxycarbonylamino-3-methyl-naphthalen- 1-yl-acetoxy)-4-oxopentanoic, acid; 3-[(2-Carbamoyl-cyclopentanecarbonyl)-amino]-5-(naphthalen- 1-yl-acetoxy)-4oxo-pentanoic acid; {2-[2-Acetylamnino-3-(4-hydroxy-phenyl)-propionylamino]-4-carboxybutyrylamino} -3-methyl-butyrylamino)-5-(2-benzyl-3-phenyl-propionyloxy)-4-oxopentanoic acid; 3-(3-Carbainoyl-2-methyl-propionylamino)-5-(naphthalen- 1-yl-acetoxy)-4-oxopentanoic acid;, 3-(2-Carbamoylmethyl-3 -methyl-butyrylamino)-5-(naphthalen- 1-yl-acetoxy)-4oxo-pentanoic acid; 27 3-(3 -Benzyloxy-2-ureido-propionylamino)-5-(naphthalen- 1-yl-acetoxy)-4-oxopentanoic acid;.
3-[2-(2-Benzyloxycarbonylamnino-4-carboxy-butyrylamino)-3-methylbutyrylaniino]-5-(2-benzyl-3 -phenyl-propionyloxy)-4-oxo-pentanoic acid; 3- {2-[4-Carboxy-2-(3-phenyl-propionylamino)-butyrylamino]-3-methylbutyrylamino} -5-(naphthalen- 1-yl-acetoxy)-4-oxo-pentanoic acid; and 3-[2-(2-Acetylamino-4-carboxy-butyrylatnino)-3-methyl-butyrylaniino]-5- (naphthalen- 1-yl-acetoxy)-4-oxo-pentanoic acid.
10 According to a twenty-second aspect the present invention provides a compound the Formula I C0 2
H
1 N 0 RN O.)I 1 R2
H
0 wherein R' is 0
-COCH-
2 phenyl, 0 S-phenyl, 0 0 11
CCH
2
CH
2 phenyl, 28 o 0
CH
3 0
-(CH
2 3 phenyl 0 0 11 11 -C-CH-NHCOCH2pheny,
H
3 C CH 3 0 0I *-C-CH-NHS-CH-NH, H3 CHH2) 0 00
-C-C-NH-I{CCH
3
I
CH
3
(H)
-kl-,InH2S phenyL 0 0 -I N rlIN 2 -29 o 0
-CI-CHCH
2
-S-CH
3 0H 0 o o -C(CHrJ 2 )3kCNH 2 o 0
-CCH
2 N1 2 o 0 **,CHn 3 0 0 02SH3 **M3
CH
3
CH
3 -CCNtC-CHNHCOCH 2 pheny,
CH
3 O0 0 0 1 1 1
-C-CH-NHCOCH
2 phenyL,
H
3 C CH 3 O 0 0 11 11 11 C-CH-NHC-CHNHCCHi 3
(CIT
2 2 CCI- SCH 2 pheny, O 0 0 -C-CH-NHC-C-iHCOtCH 2 pheny,
*H
3 C CIT 3
(CIT
2 2 CO2H 0 11 1
H
3 C CTN CI 2 2
M
il -31 0 11
UC-NH~
2 0 11 C o ol 0 11 11 1 CH- NHC- CH- IN IC(CH 2 2 phenyl
H
3 C CH 3
(CH
2 2 0 2
H
o 0
H-.NHC(CH
2 2 phenyL, 0H 0 CH 3
-C-CH-NHC-CH
Cti 3 CH 2
CH
3 0 0
-C-H-NHCCH
3
H
3 C ',OH O 0 0 -UUCCHCH 2
CNH(CH
2 2 phenyL,
CIT
3 0 0 0 0 11 11111 -C-CH-NHC-CH-NHCCI4ICCH 3
H
3 C CIT 3
(CI
2 2
CH
2 C0 2
H
OH
32 0 11 -kCC- CH 2 S-phenyL, &H3 o 0
-CCHCH
2 -S-phenyL, &H3 0 0 11 C- CHCH 2
-S-(CH
2 2 phenyL,
JH
3 o 0 CH-l-CH 2
S(CH
2 2 Phenyl
CH
3 0
-C-CHCH
2
SCH
2 PheflYl Ck1 3 .0 0 %Got,
CH-I-CH
2
S(CH
2 2 Phenyl
CH
3 0 0 64
-C-CH-SCH
2 phenyl, C3b 0 0 11 11
-C-CH--NHCCH
2
CH
2 pheny,
H
3 C CH 3 33 0 11 O 0
S-GHCH
2
SCH
3 0OGH 3 0 O 0 -CGHCkH 2 SGCHt 3 0 11 :Osse
-CCHCH
2
CO
2
H,
0
HNGI
@600 0000 00 rUG 0 5 -GGHGi-H 2
S(CH
2 3 -pC02yl 0 0
'CH
00 0 1 11 0H 0 -34- Ris -CHCH, phenyl,
-CH
2 naphthyl,
-CH
2
CH
2 cyclohexyl,
-CH
2 O naphthyl,
-CH
2 O phenyl,
-CH
2 S-phenyl, -CH,-substituted naplithyl,
-CH
2 CH(pheny1) 2
-(CH
2 3 -phenyl, CH-naphthyL,
CH
3
-CH
2 N -phenyl
CH[CH
2 PhenYl] 2 -CH-naphtlyL,
-CH
2 -NH phenyL, C2substituted phenyl
CH
2
CH
namphthyl
-CH
2 -naphthyl-phenyL,
CH
2 fluoreny,
CH
2 -naphthyl-CH 2 phenyL
CH
2 substituted phenyl, phenyl
-CH
2
-CH
CH
2 phenyl phenyl
-CH
2
-CH
NHphenyl -CH2
-CH
2 -CH2 each n is independently 0 to 3, and the pharmaceutically acceptable, salts, esters, amides, and prodrugs thereof.
o 5 According to a twenty-third aspect the present invention provides use of a compound according to the first aspect for the manufacture of a medicament for inhibiting interleukin- 1 3 converting enzyme.
According to a twenty-fourth aspect the present invention provides use of a compound according to the first aspect for the manufacture of a medicament for inhibiting Caspase-4.
-36- According to a twenty-fifth aspect the present invention provides use of a compound according to first aspect for the manufacture of a medicament for treating stroke.
According to a twenty-sixth aspect the present invention provides use of a compound according to the first aspect for the manufacture of a medicament for treating inflammatory disease.
According to a twenty-seventh aspect the present invention provides use of a compound according to the first aspect for the manufacture of a medicament for treating reperfusion injury.
According to a twenty-eighth aspect the present invention provides use of a compound according to the first aspect for the manufacture of a medicament for treating Alzheimer's disease.
According to a twenty-ninth aspect the present invention provides use of a compound according to the first aspect for the manufacture of a medicament for treating shigellosis.
o DETAILED DESCRIPTION OF THE INVENTION The term "alkyl" means a straight or branched chain hydrocarbon.
S* "Representative examples of alkyl groups are methyl, ethyl, propyl, isopropyl, isobutyl, butyl, tert-butyl, sec-butyl, pentyl, and hexyl.
The term "alkoxy" means an alkyl group attached to an oxygen atom.
Representative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, propoxy, and isobutoxy.
SThe term "halogen" includes chlorine, fluorine, bromine and iodine.
-37- The term "aryl" means an aromatic hydrocarbon. Representative examples of aryl groups include phenyl and naphthyl.
C
C C
CCC.
C
C
C C C C
C
C
CCC.
C.
C C C C CC C
C.
C
THE NEXT PAGE IS PAGE WO 98/16502 WO 9816502PCTIUS97/18514 -38- -CH2-benzothienyl, -CH2-naphthy1-CH 2 phenyl,
-CH
2 -substituted phenyl,
CH
2
-CH
2 -substituted indolyl, 0 11 C-phenyl 0
II
CNC~pey phenyl
CH-CH
\CH
2 phenyl' /phenyl CH -CH ~NHpheny1
-CH
2
C
CH WO 98/16502 PCT/US97/18514 -39-
CH-
2 /pyridyl -CH -CH phenyl
-(CH
2 2 pyridyl, or each n is independently 0 to 3, and the pharmaceutically acceptable, salts, esters, amides, and prodrugs thereof.
DETAILED DESCRIPTION OF THE INVENTION The term "alkyl" means a straight or branched chain hydrocarbon.
Representative examples of alkyl groups are methyl, ethyl, propyl, isopropyl, isobutyl, butyl, tert-butyl, sec-butyl, pentyl, and hexyl.
The term "alkoxy" means an alkyl group attached to an oxygen atom.
Representative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, propoxy, and isobutoxy.
The term "halogen" includes chlorine, fluorine, bromine and iodine.
The term "aryl" means an aromatic hydrocarbon. Representative examples of aryl groups include phenyl and naphthyl.
WO 98/16502 PCT/US97/18514 The term "heteroatom" includes oxygen, nitrogen, sulfur, and phosphorus.
The term "heteroaryl" means an aryl group wherein one or more carbon atom of the aromatic hydrocarbon has been replaced with a heteroatom. Examples of heteroaryl groups include furan, thiophene, pyrrole, thiazole, pyridine, pyrimidine, pyrazine, benzofuran, indole, coumarin, quinoline, isoquinoline, and naphthyridine.
The aryl or heteroaryl groups may be substituted with one or more substituents, which can be the same or different. Examples of suitable substituents include alkyl, alkoxy, thioalkoxy, hydroxy, halogen, trifluoromethyl, amino, alkylamino, dialkylamino, -NO 2 -CN, -CO 2 H, -CO 2 alkyl, -SO 3 H, -CHO, -COalkyl, -CONH 2 -CONH-alkyl, -CONHRq, -CON(alkyl) 2 -(CH2)n-NH 2 -(CH2)nOH, -(CH2)n-NH-alkyl, -NHRq, or -NHCORq, where n is 1 to 5 and Rq is hydrogen or alkyl.
The term "cycloalkyl" means a cyclic alkyl group. Examples of cycloalkyl groups include cyclopropane, cyclobutane, cyclopentane, and cyclohexane.
The term "heterocycle" means a cycloalkyl group on which one or more carbon atom has been replaced with a heteroatom. Examples of heterocycles include piperazine, morpholino, and piperidine.
The terms aryl, heteroaryl, cycloalkyl, and heterocycle as used herein include substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycle.
The symbol means a bond.
The compounds of Formula I can be administered to a patient either alone or as part of a pharmaceutically acceptable composition. The compositions can be administered to patients such as humans and animals either orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), intracistemally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments, or drops), or as a buccal or nasal spray.
Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile WO 98/16502 PCT/US97/18514 -41injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or, fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; humectants, as for example, glycerol; disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; solution retarders, as for example paraffin; absorption accelerators, as for example, quaternary ammonium compounds; wetting agents, as for example, cetyl alcohol, and glycerol monostearate; WO 98/16502 PCT/US97/18514 -42adsorbents, as for example, kaolin and bentonite; and lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan or mixtures of these substances, and the like.
Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol WO 98/16502 PCT/US97/18514 -43and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kg, a dosage in the range of about 0.01 to about 100 mg/kg of body weight per day is preferable. The specific dosage used, however, can vary. For example, the dosage can depend on a numbers of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to those skilled in the art.
The term "pharmaceutically acceptable salts, esters, amides, and prodrugs" as used herein refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "salts" refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be WO 98/16502 PCT/US97/18514 -44prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like.
These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. (See, for example, Berge et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19, which is incorporated herein by reference).
Examples of pharmaceutically acceptable, non-toxic esters of the compounds of this invention include C 1
-C
6 alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C 5
-C
7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C 1
-C
4 alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods.
Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary
C
1
-C
6 alkyl amines and secondary C -C 6 dialkyl amines wherein the alkyl groups are straight or branched chain. In the case of secondary amines the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom.
Amides derived from ammonia, C 1
-C
3 alkyl primary amines and C1-C 2 dialkyl secondary amines are preferred. Amides of the compounds of the invention may be prepared according to conventional methods.
The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. A thorough discussion is provided in Higuchi T. and WO 98/16502 PCT/US9718514 Stella "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S.
Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B.
Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
The compounds of the present invention can exist in different stereoisomeric forms by virtue of the presence of asymmetric centers in the compounds; ie, each asymmetric carbon can have either the R or S configuration.
It is contemplated that all stereoisomeric forms of the compounds as well as mixtures thereof, including racemic mixtures, form part of this invention.
The compounds of the present invention are administered to a patient in need of ICE or Caspase-4 inhibition. In general, patients in need of ICE or Caspase-4 inhibition are those patients having a disease or condition in which ICE or Caspase-4 plays a role. Examples of such diseases include, but are not limited to, inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease, neuroinflammatory disorders such as stroke, and septic shock. Other diseases include reperfusion injury, Alzheimer's disease, and shigellosis.
A "therapeutically effective amount" is an amount of a compound of Formula I that when administered to a patient having a disease that can be treated with a compound of Formula I ameliorates a symptom of the disease. A therapeutically effective amount of a compound of Formula I is readily determined by one skilled in the art by administering a compound of Formula I to a patient and observing the results.
The following examples illustrate particular embodiments of the invention and are not intended to limit the scope of the specification and claims in any manner.
WO 98/16502 PCT/US97/18514 -46-
EXAMPLES
The following Schemes 1 through 11 show generally how compounds of the present invention can be made.
WO 98/16502 PCTIUS97/1814 -47- Scheme 1 Step A
O
O HBr RCO 2
H,
[IIv~ CO2tBu base (KF or K 2
CO
3
DMF
Step B 0
CF
3
CO
2 H Nr N 'O r
R
H 0 I 1
I
CO
2
H
3-Benzyloxycarbonylamino-5-bromo-4-oxo-pentozoic acid tert-butyl ester, also known as Z-Asp(OtBu)-bromomethyl ketone, can be purchased commercially or prepared according to the procedure of Dolle, et al., J. Med. Chem., 1994;37:563-564. This methylbromo ketone is treated with an appropriately substituted carboxylic acid and a base such as potassium fluoride. Alternately, other bases such as potassium carbonate, cesium carbonate, or potassium t-butoxide could be used. The reagents should be mixed in dimethyl formamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), acetonitrile or other appropriate solvent and stirred at room temperature for 8 to 24 hours. The t-butyl ester protecting group can be removed in acidic media ,preferably trifluoroacetic acid, to produce the carbobenzoxy aspartyl esters shown in Scheme 1.
WO 98/16502 PCT/US97/18514 -48- Scheme 2 O Step A 0 0 H QO R 2
H
2 20% Pd/C HCI H 2 N OR2 C0 2 tBu HCI (1.1 eq) CO 2 tBu Step B StepC
O
R-N=C=0 RI A O R 2 CF3CO2H I O R 2 or RSO CI orRS2C Co 2 tBu L CO 2
H
RCOCI
or
ROCOCI
A mixture of an appropriately substituted acyloxymethyl ketone of a carbobenzoxy aspartyl t-butyl ester was hydrogenated with an equivalent of hydrochloric or other acid in the presence of a catalyst such as palladium on carbon to yield the amine salt. The salt can be acylated with an appropriately substituted isocyanate, sulfonyl chloride, chloroformate or phenylpropionyl chloride to afford the N-substituted derivatives. These isocyantes, sulfonyl chlorides, or chloro formates can be purchased commercially or synthesized by methods described in the chemical literature. The t-butyl ester protecting group can be removed in the final step using acidic media, preferably trifluoroacetic acid, to produce the acyloxy methylketone derivatives shown in Scheme 2.
WO 98/16502 PCT/IJS97/18514 -49- Scheme 3 Step A
O
2 RICO H HCI *H 2 N 0 R C 2
H,
O Coupling reagent,
CO
2 tBu HOBT, base 0 1 H 2 Step B R N O R
CF
3
CO
2 H O
O
CO
2
H
In a manner similar to Example 2, the amine salt of the acyloxymethyl ketone of Z-Asp(Ot-Bu)OH was synthesized and treated with an appropriately substituted carboxylic acid and coupling reagent. The coupling agent may be, but is not limited to, such reagents as I ,3-dicyclohexylcarbodiimide
(DCC),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1,1'-carbonyldiimidazole (CDI), 1,1'-carbonylbis(3-methylimidazolium) triflate (CBMIT), isobutylchloroformate, benzotriazol- I -yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), 2-(3,4-dihydro-4-oxo-1,2,3benzotriazin-3-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TDBTU), and 2-(lIH-benzotriazol- I -yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU). 1 -Hydroxybenzotriazole hydrate should be added to the reaction to improve yield and limit isomerization and base, preferably an amine such as trimethyl amine or methyl morpholine should be added as an acid scavenger. The resulting amide product was treated with acidic media, preferably trifluoroacetic acid, to remove the t-butyl ester and produce the final products as described in Scheme 3.
WO 98/16502 PCT/US97/18514 Scheme 4 Step A HCI H2N O R,,R2 R 1 COX (X=CI,F)
CO
2 tBu Step B R1 N O R 2
CF
3
CO
2 H
S---CO
2
H
In a manner similar to Example 2, the amine salt of the acyloxymethyl ketone of Cbz-Asp(OtBu)OH was synthesized and treated with an appropriately substituted acid chloride or acid fluoride to generate an amide product. The acid chlorides were purchased commercially or were prepared by treating carboxylic acids with agents such as thionyl chloride, phosphorous tribromide, or oxalyl chloide/DMF. The acid fluorides were prepared by treating a carboxylic acid with cyanuric fluoride. The penultimate amide product was treated with acidic media preferably trifluoroacetic acid to remove the t-butyl ester and afford the final products as described in Scheme 4.
WO 98/16502 PCTIUS97/18514 -51- Scheme Step A 0 1. RIC02H, HC* H 2 N R
H
HCI" OMe Coupling reagent, R HOH
CO
2 tBu 2. NaOH
CO
2 tBu Step B Step C Formation of the
RCO
2 H, KF, bromo methyl ketone D
DMF
Step D 0
CF
3
CO
2 H R N OYR 2 O
CO
2
H
The hydrochloride salt of H-Asp(OtBu)OMe was treated with an appropriately substituted carboxylic acid and coupling reagent. The coupling agent may be but is not limited to such reagents described in Example 3.
1-Hydroxybenzotriazole hydrate should be added to the reaction to improve yield and limit isomerization and base, preferably an amine such as trimethyl amine or methyl morpholine should be added as an acid scavenger. The resulting amide product was treated with an alkaline reagent such as sodium hydroxide to hydrolyze the methyl ester to the carboxylic acid. The resulting acid was treated with a chloroformate such as isobutylchloroformate, followed by diazomethane and then hydrobromic acid to afford the methyl bromo ketone. Treatment of the methylbromo ketone with an appropriately substituted carboxylic acid and a base such as potassium fluoride (as described in Example 1) produced the desired acyloxymethyl ketones which were deprotected as described previously with trifluoroacetic acid to afford the final compounds as described in Scheme WO 98/16502 PCT/US97/18514 -52- Scheme 6 Steps A-D Step E 0 i. Coupling of Cbz-AA Formation of the bromo HCI H 2 N O ii. Removing Cbz methyl ketone 2 H1•OMe methyl iii. Coupling of Cbz-AA CO2tBu iv. etc.
Step F Step G Removal of remaining H HR
RCO
2 H, KF, DMF ester protecting groups P-AA YN O R 2 0 02H P Protecting group CO 2
H
The hydrochloride salt of H-Asp(OtBu)OMe was treated with an appropriately protected amino acid and coupling reagent. The coupling agent may be, but is not limited to, such reagents as described in Example 3.
1-Hydroxybenzotriazole hydrate should be added to the reaction to improve yield and limit isomerization and base, preferably an amine such as trimethyl amine or methyl morpholine should be added as an acid scavenger. The resulting amide product was treated with an alkaline reagent such as sodium hydroxide to hydrolyze the methyl ester to the carboxylic acid. The Cbz-amine protecting group was removed using standard catalytic hydrogenation conditions and coupling of another protected amino acid can proceed as described above. This process was repeated until the peptide was the desired length. The resulting peptide product was treated with an alkaline reagent such as sodium hydroxide to hydrolyze the methyl ester to the carboxylic acid. The resulting acid was subsequently treated with a chloroformate such as isobutylchloroformate, followed by diazomethane and then hydrobromic acid to afford the methylbromo ketone. Treatment of the methylbromo ketone with an appropriately substituted carboxylic acid and a base such as potassium fluoride (as described in Example 1) produced the desired acyloxymethyl ketones which were deprotected as described previously with trifluoroacetic acid to afford the final compounds as described in Scheme 6.
WO 98/16502 PCTIS97/18514 -53- Scheme 7 Step A H 0 Cbz-AA N. O H 2 20% Pd/C 0 t CO2tBu Step B
O
H T
RCO
2
H,
H
2 N-AA N<N O O 0 Coupling reagent
CO
2 tBu Step C 0 0
CO
2
H.
The appropriately substituted acyloxymethyl ketone of a protected amino acid was synthesized as described in Example 7. The Cbz-amine protecting group was removed using standard catalytic hydrogenation conditions, and the amine product was treated with an appropriately substituted carboxylic acid and a coupling reagent. The coupling agent may be, but is not limited to, such reagents described in Example 3. 1-Hydroxybenzotriazole hydrate should be added to the reaction to improve yield and limit isomerization and base, preferably an amine such as trimethyl amine or methyl morpholine should be added as an acid scavenger. The penultimate amide product was treated with acidic media preferably trifluoroacetic acid to remove the t-butyl ester and afford the final products as described in Scheme 7.
WO 98/16502 PCT/US97/18514 -54- Scheme 8
O
HCI H 2 N. O R2
CO
2 tBu pyridine, DMAP 1. Amide or ester formation 2. CF 3
CO
2
H
Trans-1,2-cyclohexanedicarboxylic anhydride was treated with the amine salt of an appropriately substituted acyloxymethyl ketone of aspartyl t-butyl ester in the presence of pyridine and 4-dimethylaminopyridine (DMAP) to yield the amide product. The carboxylic acid can be functionalized with appropriately substituted amines or alcohols and standard coupling reagents as described in Example 3 to afford amide and ester products. The penultimate product was treated with acidic media, preferably trifluoroacetic acid, to remove the t-butyl ester and afford the final products as described in Scheme 8.
WO 98/16502 PCTIUS97/18514 Scheme 9 Me Me 1. RSH, NaH S.
CI
CO
2 R' 2. NaOH R
CO
2 H HC H 2
N
CO
2 tBu Me 0 1. Coupling reagents R1/S N OyR 2. NaOH 0 2t
CO
2 Bu 1. Oxidation Me 0 2. CF 3
CO
2 H R1
O
CO
2
H
n 0, 1 and 2 Methyl methacrylate was treated with the anion of an appropriately substituted sulfide to afford the Michael adduct which was hydrolyzed in basic media such as sodium hydroxide to produce the carboxylic acid. This acid was combined with the amine salt of the acyloxymethyl ketone of aspartyl t-butyl ester and a coupling reagent such as those described in Example 3 to obtain the amide product. If the sulfide (where n 0) is the desired product, no oxidation step is employed, and the amide t-butyl ester is deprotected in acidic media, preferably trifluoroacetic acid, to afford the final product. Alternately, if the sulfoxide (n 1) or sulfone (n 2) is the final product, the amide intermediate is treated with an oxidizing agent which may be, but is not limited to, m-chloroperbenzoic acid, potassium monoperoxysulfate, or sodium perborate to obtain the desired oxidized product. The t-butyl ester of the penultimate intermediate was deprotected in acidic media, preferably trifluoroacetic acid, to afford the final compounds as described in Scheme 9.
WO 98/16502 WO 9816502PCT/US97/18514 -56- Scheme 0 ANH i. n-BuLi, -78'C Ri Rj RCH COCI 0 0 R C0 2 tBu o 0
R
i. NaN(SiMe 3 2 -78 0
C
ii. BrCH 2
CO
2 t Bu LiOH, H 2 0 2
R
THF, water p u2,
CO
2 H1 Coupling reagent H I R N
N
R
3 1. PhSiH 3 Pd(PPh 3 4
-,P
2. Formation of the bromo methyl ketonej 3. R2CO 2 H, KF, DMF 3 N0 R 0
O
0 0 0 0--lPh
H
2 1. CF 3
CO
2
H
2. R 3
R
2 NH or PhCH 2
ONH-
2 coupling reagent 1. PhSiH 3 Pd(PPh 3 4 2. Formation of the bromo methyl ketone 3. R 2
CO
2 H, KF, DMF -Tr R2 0 0 ,Ph 1. CF 3 CO2
H
2. Formation of ester 3. H1 2 20% Pd/C Rj N
R
2 0 0 C0 2
H
WO 98/16502 PCT/US97/18514 -57- A 4-substituted-2-oxazolidinone chiral auxiliary as described by Evans, et al., J. Org. Chem., 1985;50:1830 was mixed with a base, such as but not limited to, n-butyl lithium followed by treatment with an appropriately substituted acid chloride or other activated carboxylic acid to afford the N-acylated product. This product was subsequently treated with a base such as, but not limited to, sodium bis(trimethylsilyl)amide and t-butyl bromoacetate to produce the alkylated chiral product. The chiral auxiliary was removed using lithium hydroxide and hydrogen peroxide to obtain the chiral acid. Treatment of the acid with the amine salt of H-Asp(OBz)O-allyl and a coupling reagent as described in Example 3 afforded the succinyl amide product.
At this stage of the process, the product can be elaborated in one of two ways. First the t-butyl ester was removed in acidic media, preferably trifluoroacetic acid, and the resulting acid was coupled with an appropriately substituted amine in the presence of a coupling reagent as described in Example 3 to form a new amide product. The allyl ester was removed with phenylsilane and tetrakis(triphenyl-phosphine)palladium or other Pd(0) catalyst to obtain the carboxylic acid, and the acid was converted to the methylbromo ketone and subsequently to the acyloxymethyl ketone as described in Example 5. The penultimate intermediate was subjected to catalytic hydrogenation to remove the benzyl ester and afford the final amide products as described in Scheme Alternatively, in a second route to the final products, the allyl ester is removed using phenylsilane and tetrakistetrakis(triphenylphosphine)palladium or other Pd(0) catalyst to obtain the carboxylic acid. This acid is converted to the methylbromo ketone and subsequently to the acyloxymethyl ketone as described in Example 5. Removal of the t-butyl ester of the acyloxymethyl ketone with trifluoroacidic acid and subsequent conversion of the resulting carboxylic acid to the ester resulted in a new ester product. The esterification can be accomplished using a variety of literature techniques which includes but is not limited to treatment of the carboxylic acid with an appropriately substituted alcohol in the presence of a coupling reagent. The penultimate intermediate was subjected to catalytic hydrogenation to remove the benzyl ester and afford the final ester products as described in Scheme WO 98/16502 WO 9816502PCTIUS97/18514 -58- Scheme I1I Me Y S, ,C2 0 1. PhCH 2 Br,
DBU
0R.
0l S C2HP 2. C1 2 (gas) EtOH:CC1 4 (1:9) 1. (R) 2 NH, Et 3
N,
CH
2
CI
2 2. H 2 20% Pd/C R
RI
N CO H
R
R =MeO
CH
2 "0 HI 1.
RIN N I Nl-C0 2
H
R 0 C 2 tBu 2.
1. SOC1 2 or cyuranic fluoride 'p 2. H-Asp(OtBu)-OMeeHC1 NMM,
CH
2 Cl 2 3. NaOH, H 2 EtOH Formation of the bromo methyl fetone I1.
RCO
2 H, KF, DMF Ceric amimonium nitrate
CH
3
CN:H
2 0 (95:5)
R
2. CF 3
CO
2
H
The appropriately substituted S-acetyl mercapto carboxylic acid was treated with benzyl bromide and I ,8-diazobicyclo[5.4.0]undec-7-ene (DBU) to WO 98/16502 PCTfUS97/18514 -59produce the benzyl ester which was subsequently reacted with chlorine gas to yield the sulfonyl chloride. The sulfonyl chloride was treated with N,N-bis(pmethoxybenzyl)amine to afford the sulfonamide which was subjected to catalytic hydrogenation to obtain the intermediate carboxylic acid. The acid was activated using cyuranic fluoride which was then mixed with the amine salt of H-Asp(Ot- Bu)OMe to produce the amide product. The methyl ester was hydrolyzed with sodium hydroxide, and the carboxylic acid was elaborated to the acyloxymethyl ketone by chemistry previously described for Example 5. The p-methyoxybenzyl protecting groups of the sulfonamide were removed using oxidizing conditions preferably, but not limited to ceric ammonium nitrate, and the t-butyl ester protecting group was removed in acidic media preferably with trifluoroacetic acid to afford the desired sulfonamide products as described in Scheme 11.
WO 98/16502 PCTIS97/18514 EXAMPLE 1 3-Benzvloxvcarbonvlamino-5-(naphthalene-l-yl-acetoxy)-4-oxo-pentanoic acid Step A A mixture of Z-Asp(OtBu)-bromomethylketone (Z is carbobenzoxy, also known as cbz, Asp is aspartic acid and tBu is tert-butyl) (2.03 g, 5.07 mmol, purchased from BACHEM Bioscience Inc. or prepared according to the procedure of Dolle et al., Med. Chem., 1994;37:563-564]), 1-naphthylacetic acid (1.00 g, 5.37 mmol) and potassium fluoride (0.74 g, 12.74 mmol) in 10 mL of dimethylformamide (DMF) was stirred at room temperature for 12 hours. The mixture was partitioned between ethyl acetate and saturated NaHCO 3 solution.
The ethyl acetate extract was washed with saturated KH 2
PO
4 and brine solutions, dried (MgSO 4 filtered, and concentrated. Medium pressure chromatography (silica gel, 75% hexanes-25% ethyl acetate) of the crude oil afforded 3-benzyloxycarbonylamino-5-(naphthalene-1-yl-acetoxy)-4-oxo-pentanoic acid tert-butyl ester as a colorless oil.
Step B A solution of 3-benzyloxycarbonylamino-5-(naphthalene-1-yl-acetoxy)- 4-oxo-pentanoic acid tert-butyl ester (0.500 g, 0.989 mmol, Example 1, Step A) and trifluoroacetic acid (10 mL, 0.13 mol) in 20 mL of dichloromethane was stirred at room temperature for 2 hours. The solution was concentrated to give the title compound as a foamy white solid.
Analysis calculated for C 2 5
H
2 3 N0 7 .0.70H 2 0 (462.075): C, 64.98; H, 5.32; N, 3.03.
Found: C, 64.94; H, 5.01; N, 3.01.
In a process analogous to Example 1, the corresponding compounds were prepared: WO 98/16502 PCTIUS97/18514 -61- EXAMPLE Ila 3 -Benzloxvcarbonylamino-4-oxo-5-(3-phenvl-12ropionvyloxy)-yentanoic acid, as white solid.
Analysis calculated for C 2 2
H
2 3 N0 7 .0.25H 2 0 (4 17.935): C, 63.23; H, 5.67, N, 3.35.
Found: C, 63.19; H, 5.55; N, 3.27.
EXAMPLE l b 3-Benzyloxycarbonvylamino-5-(3 -cyclohexyl-propionyloxy)-4-oxo-pentanoic acid, as white foamy solid.
Analysis calculated for C 2 2
H
2 9 N0 7 .0.67H 2 0 (431.489): C, 61.24; H, 7.09; N, 3.25.
Found: C, 61.2 5; H, 6.8 5; N, 3.2 1.
EXAMPLE Ic r(naphthalene- 1 -l-oxy)-acetoxyl -4-oxo-pentanoic acid, as white foamy solid.
Analysis calculated for C 2 5
H
2 3 N0 8 .0.40H 2 0 (472.670): C, 63.53; H, 5.08; N, 2.96.
Found: C, 63.55; H, 4.87; N, 2.77.
EXAMPLE Id 3 -Benzloxycarbonylamino-4-oxo-5-phenoxvacetoxy-pentanoic acid, as foamy white solid.
Analysis calculated for C 21
H
2 1 N0 8 .0.67H 2 0 (427.414): C, 59.01; H, 5.27; N, 3.28.
Found: C, 58.99; H, 4.91; N. 3.15.
WO 98/16502 PCTIUS97/18514 -62- EXAMPLE le 3-Benzvloxvcarbonylamino-4-oxo-5-phenylsulfanylacetoxy-pentanoic acid, as white solid.
Analysis calculated for C 2 1
H
2 1 N0 7 S (431.468): C, 58.46; H, 4.91; N, 3.25.
Found: C, 58.08; H, 4.83; N, 3.14.
EXAMPLE If 3-Benzvloxycarbonylamino-5-4(6-methox-naphthalene- I -vy)-acetoxyl-4-oxopentanoic acid, as off-white solid.
Analysis calculated for C 2 6
H
2 5 N0 8
.H
2 0 (497.506): C, 62.77; H, 5.47; N, 2.82.
Found: C, 62.73; H, 5.24; N, 2.61.
EXAMPLE Ig 3 -Benvloxycarbonylamino-5-(naphthalene-2-yl-acetoxy)-4-oxo-pentanoic acid, as off-white solid.
Analysis calculated for C 2 5
H
23 N0 7 .0.80H 2 0 (463.877): C, 64.73; H, 5.34; N, 3.02.
Found: C, 64.64; H, 4.94; N, 2.88.
EXAMPLE Ih 3 -Benzvloxycarbonylamino-5-(3-naphthalene-2-vl-propionylox)-4-oxo-pentanoic acid, as white solid.
Analysis calculated for C 2 6
H
2 5 N0 7 (463.492): C, 67.38; H, 5.44; N, 3.02.
Found: C, 64.39; H, 5.10; N, 2.76.
EXAMPLE ii 3-Benzvloxvcarbonylamino-5-(3,3-diphenyl-2ropionloxv)-4-oxo.pentanoic acid, as foamy tan solid.
WO 98/16502 PCTIUS97/18514 -63- Analysis calculated for C 2 8
H
2 7 N0 7 (489.530): C, 68.70; H, 5.56; N, 2.86.
Found: C, 66.68; H, 5.72; N, 3.07.
EXAMPLE lj 3 -Benzloxycarbonvlamino-5-[(l1H-indol-3-yl')-acetoxv]l-4-oxo-pentanoic acid, as off-white solid.
Analysis calculated for C 2 3
H
2 2
N
2 0 7
.OH
2 0 (454.655): C, 60.76; H, 5.28; N, 6.16.
Found: C, 60.76; H, 4.88; N, 5.65.
EXAMPLE 1 k 3-Benzloxycarbonylamino-5-(indol-1 -yl-acetoxy)-4-oxo-pentanoic acid, as light purple solid.
Analysis calculated for C 2 3
H
2 2
N
2 0 7 .0.75H 2 0 (451.952): C, 61.12; H, 5.24; N, 6.20.
Found: C, 61.20; H, 5.11; N, 5.90.
EXAMPLE I11 3-Benzloxycarbonvylamino-5-(2-naphthalene- 1 -YI-Rropionvyloxy)-4-oxo-pentanoic acid, as white solid.
Analysis calculated for C 2 6
H
2 5 N0-pO.20H 2 0 (467.095): C, 66.86; H, 5.48; N, 3.00.
Found: C, 66.87; H, 5.61; N, 2.71.
EXAMPLE Im 3-Benzvloxycarbonylamino-4-oxo-5- r(2-oxo-pvaolidin-1I-yl)-acetoxyl-pentanoic acid, as white solid.
Analysis calculated for C I 9
H
2 2
N
2 0 8 .0.50H 2 0 (415.403): C, 54.94; H, 5.58; N, 6.74.
Found: C, 55.18; H, 5.72; N, 6.36.
WO 98/16502 PCT/US97/18514 -64- EXAMPLE In r(Acetvl-nhenyl-amnino)-acetoxyl-3-benzvloxycarbonlyl-amino-4-oxo-pentanoic acid, as off-white solid.
Analysis calculated for C 2 3
H
2 4
N
2 0 8 O.7ONaHCO 3 (5 15.264): C, 55.25; H, 4.83; N, 5.44.
Found: C, 55.03; H, 4.86; N, 5.41.
EXAMPLE Ilo 3 -Benzloxycarbonylamnino-5-(2-benzvl-3-phenyl-propionyloxy)-4-oxo-tpentanoic aci, potassium salt as hygroscopic white solid.
Analysis calculated for C 2 9
H
2 8 N0 7 .K.0.90H 2 0 (557.865): C, 62.44; H, 5.3 8; N, 2.5 1.
Found: C, 62.40; H, 5.19; N, 2.17.
EXAMPLE ip 1 -vl-acetoxv)-4-oxopentanoic acid, as white solid.
Analysis calculated for C 2 5
H
2 3 N0 8 .0.3 0H 2 0 (470.869): C, 63.77; H, 5.05; N, 2.98.
Found: C, 63.73; H, 4.87; N, 2.93.
EXAMPLE Ilq 3-Benzloxycarbonylamino-4-oxo-5-h'pheniyl-amino)-acetoxyl-pentanoic acid, trifluoroacetic acid salt, as brown solid.
Analysis calculated for C 21 I H 2 2
N
2 0 7 .0.5OCF 3
CO
2 H (471.431): C, 5 6.05; H, 4.8 1; N, 5.94.
Found: C, 55.72; H, 4.98; N, 5.78.
EXAMPLE I r 3 -Benzvloxycarbonvylamino-5-[(6--hvdroxy-naphthalene- I -yl)-acetoxyl-4-oxopentanoic acidl as white solid.
WO 98/16502 PCT/US97/18514 Analysis calculated for C 2 5
H
2 3 N0 8 .0.40H 2 0 (472.670): C, 63.53; H, 5.08; N, 2.96.
Found: C, 63.53; H, 5.25; N, 2.83.
EXAMPLE I s 3-Benzloxycarbonvylamino-5-[3-(4-hydroxv-phenvl)-2-naphthalene-l I -i propionyloxv)-4-oxo- pentanoic acid, as white solid.
Analysis calculated for C 3 2
H
2 9 N0 8 .0.50H 2 0 (564.598): C, 68.08; H, 5.36; N, 2.48.
Found: C, 67.98; H, 5.40; N, 2.34.
EXAMPLE It -Benzvloxycarbonylamino-4-oxo-5-phenvlacetoXv-Dentanoic acid I H NMR (400 MHz, d 6 DMSO) 7.31 (in, 1IOH), 5.05 2H), 4.92 (in, 2H), 4.45 (mn, lH), 3.75 2H), 2.71 (dd, 1H), 2.52 (dd, I1H) EXAMPLE lu (S)-3-Benzvloxycarbonvylainino-4-oxo-5-(4-phenyl-butvrloxy)-pentanoic acid I H NMR (400 MHz, d 6 DMSO) 7.86 (bs, I 7.27 (mn, I OH), 5.05 2H), 4.91 (in, 2H), 4.46 (mn, 1H), 2.72 (dd, 1H), 2.61 2.52 (dd, 1H), 2.36 (t, 2H), 1.83 (in, 2H) EXAMPLE Ilv 3-Benzvloxvcarbonylamino-4-oxo-5-[(4-phenyl-naphthalen-lI-vl)-acetoxylpentanoic acid, as a white solid, mp 111-1 19TC, dec.
Analysis calculated for C 3
IH
2 7 N0 7 (525.5 63): C, 70.85; H, 5.18; N, 2.67.
Found: C, 70.60; H, 5.11; N, 2.64.
WO 98/16502 PCT/US97/18514 -66- EXAMPLE 1 w 3-Benzloxycarbonvlamino-5-[(4-methvl-naphthalen- I -vl)-acetoxyl -4-oxopentanoic acid, as a white solid, mp 94- 1 O0 0 C, dec.
Analysis calculated for C 2 6
H-
2 5 N0 7 *0.15 H 2 0 (466.194): C, 66.99; H, 5.47; N, 3.00.
Found: C, 66.95; H, 5.32; N, 2.94..
EXAMPLE Ilx 3-Benzvloxvcarbonylamino-4-oxo-5-[(4-thiophen-2-vl-naphthalen- 1 -yl)-acetoxylpentanoic acid, as an off-white solid, mp 63-68'C, dec.
Analysis calculated for C 2 9
H-
2 5 N0 7 S (531.589): C, 65.52; H, 4.74; N, 2.63.
Found: C, 65.32; H, 5.08; N, 2.47.
EXAMPLE Ily 3-Benzyloxycarbonylainino-5-r(4-fluoro-nap~hthalen- I -yl)-acetoxyl-4-oxopentanoic acid, as a white solid, mp 100- 103'C, dec.
Analysis calculated for C 2 5
H
2 2 FN0 7 (467.455): C, 64.24; H, 4.74; N, 3.00.
Found: C, 63.98; H, 4.52; N, 2.89.
EXAMPLE Ilz 3-Benzloxycarbonyamino-5- r(2-methyl-naphthalen- I -yl)-acetoxyl-4-oxopentanoic acid, as a white solid, mp 139-144 0
C.
Analysis calculated for C 2 6
H
2 5 N0 7 (463.492): C, 67.38; H, 5.44; N, 3.02.
Found: C, 67.09; H, 5.44; N, 2.84.
EXAMPLE Ilaa.
3 -Benzyloxycarbonylamnino-5-[(2-fluoro-naphthalen- 1 -yl)-acetoxul-4-oxopentanoic acid, as a white solid, mp 98-102 0
C.
WO 98/16502 PCTIUS97/18514 -67- Analysis calculated for C 2 5
H
2 2 FN0 7 (467.455): C, 64.24; H, 4.74; N, 3.00.
Found: C, 63.57; H, 4.47; N, 2.85.
EXAMPLE lbb 5-(Benzofuran-4-yl-acetoxv)-3-benzvloxycarbonylamino-4-oxo-pentanoic acid, as light yellow oil.
Analysis calculated for C 2 3 H1 2 N0 8 -0.65 H 2 0 (451.136): C, 61.24; H, 4.98; N, 3.10.
Found: C, 61.22; H, 4.80; N, 2.98.
EXAMPLE I cc rblthiophen-7-yl-acetoxy)-3-benvloxvcarbonylanmino4.oxopentanoic acid, as light yellow oil.
Analysis calculated for C 2 3
H
2 IN0 7 S'l1.5 H 2 0 (482.513): C, 57.25; H, 5.01; N, 2.90.
Found: C, 57.35; H, 4.82; N, 2.76.
EXAMPLE Ildd 5-(Benzofblthiophen-4-yl-acetox)-3-benZyloxycarbonlamino4.oxopentanoic aias a foamny off-white solid.
Analysis calculated for C 2 3
H
2 1 N0 7 S (455.490): C, 60.65; H, 4.65; N, 3.08.
Found: C, 60.90; H, 4.90; N, 2.92.
EXAMPLE l ee r(4-BeMvl-naphthalen- I yl')-acetoxyl-3-benzvloxvcarbonylamino-4-oxopentanoic acid, as a white solid, mp 66-77'C, dec.
Analysis calculated for C 3 2
H
2 9 N0 7 .0.30 H 2 0 (544.995): C, 70.52; H, 5.48; N, 2.57.
Found: C, 70.55; H, 5.35; N, 2.49.
WO 98/16502 PCTfUS97/18514 -68- EXAMPLE 1ff 3-Benzvloxvcarbonvlamino-5-[(3 .4-dihydro-naphthalen- I -vl)-acetoxvl-4-oxo- Pentanoic acid, as a foamy light yellow solid.
Analysis calculated for C 2 5
H
2 5 N0 7 *0.20 H 2 0 (455.084): C, 65.98; H, 5.63; N, 3.08.
Found: C, 66.06; H, 5.74; N, 3.04.
EXAMPLE Igg 3-Benzvloxycarbonvlamino-5-[(5-bromo-I H-indol-3 -vl)-acetoxvl-4-oxoventanoic acid, as a tan solid, mp 122-129C, dec.
Analysis calculated for C 2 3
H
21 BrN 2
O
7 (517.342): C, 53.40; H, 4.09; N, 5.41.
Found: C, 53.77; H, 3.94; N, 5.25.
EXAMPLE Ihh 3 -Benzvloxvcarbonylamino-5-(3 .4-diphenvl-butvrvloxv)-4-oxo-pentanoic acid, as a hygroscopic white solid.
Analysis calculated for C 2 9
H
2 9 N0 7 *0.30 H 2 0 (508.962): C, 68.44; H, 5.86; N, 2.75.
Found: C, 68.41; H, 5.92; N, 2.56.
EXAMPLE Iii 3 -Benzvloxycarbonvlamino-4-oxo-5-(3-phenl-3phenvlaminopropionvloxv)pentanoic acid as a hygroscopic light green solid.
Analysis calculated for C 2 8
H
2 8
N
2 0 7 *0.50 H 2 0 (513.552): C, 65.49; H, 5.69; N, 5.46.
Found: C, 65.58; H, 5.62; N, 5.19.
EXAMPLE ljj 3-Benzvloxvcarbonvlamino-4-oxo-5-[( 1.2.3,4-tetrahvdro-naphthalen-2-l)acetoxyl-pentanoic acid, as a white solid, mp 75-83'C, dec.
WO 98/16502 PCTIUS97/18514 -69- Analysis calculated for C 2 5
H
2 7 N0 7 (453.496): C, 66.21; H, 6.00; N, 3.09.
Found: C, 66.02; H, 5.89; N, 2.96.
EXAMPLE Ilkk 3-Benzyloxvcarboniylamino-5-r( I -methanesulfonyl-jpiperidin-4-yl)-acetoxvl-4oxo-pentanoic acid as a yellow amorphous solid.
Analysis calculated for C 2 1
H
2 8
N
2 0 9 S*0.25 EtOAc (506.556): C, 52.16; H, 5.97; N, 5.53.
Found: C, 51.96; H, 6.09; N, 5.22.
EXAMPLE Ill 3-BenZyloxvcarbonvylamino-4-oxo-5-I (2.3.5 .6-tetramethvl-phenyl)-acetoxy]pentanoic acid,, mp 139-145'C.
Analysis calculated for C 2 5
H
2 9 N0 7 C, 65.92; H, 6.42; N, 3.07.
Found: C, 65.66; H, 6.30; N, 2.97.
EXAMPLE 1rm 5-(Benzothiazol-4-yl-acetoxy)-3-benzvloxycarbonvlamino-4-oxo-nentanoic acid, as a white solid.
Analysis calculated for C 2 2
H
2 0
N
2 0 7 S*0.15 CF 3
CO
2 H (473.582): C, 56.56; H, 4.29; N, 5.92.
Found: C, 56.52; H, 4.09; N, 6.02.
EXAMPLE Inn 5-(Benzofuran-3-yl-acetoxv')-3-benzloxvcarbonylamino-4-oxo-npentanoic acid as a foamy white solid.
Analysis calculated for C 2 3 H1 2 IN0 8 *O.14 CF 3
CO
2 H (455.389): C, 61.40; H, 4.68; N, 3.08.
Found: C, 61.49; H, 4.86; N, 3.13.
WO 98/16502 PCTIUS97/18514 EXAMPLE 100o 5-(Benzo[blthiophen-3-yl-acetoxv')-3-benzvloxycarbonylamino-4-oxo-n1entanoic acid, mplIl1- 111 0
'C.
Analysis calculated for C 2 3 H1 2 IN0 7
S:
C, 60.65; H, 4.65; N, 3.08; S, 7.04.
Found: C, 60.45; H, 4.67; N, 3.02; S, 7.07.
EXAMPLE Ipp 3 -Benzyloxycarbonylamino-4-oxo-5-(3-phenyl-3-12yidin-2-yl-1ropionloxy)pentanoic acid, as an amorphous white solid.
Analysis calculated for C 2 7
H
2 6
N
2 0 7
*CF
3
CO
2 H (604.542): C, 57.62; H, 4.50; N, 4.63.
Found: C, 57.32; H, 4.65; N, 4.46.
EXAMPLE Ilqq 3 -Benzloxycarbonylamino-5-[(2,3-dichloro-phenl)-acetoxyl.4-oxo-pentanoic acid, as awhite solid.
Analysis calculated for C 21 H 9 C1 2 N0 7 '0.18 CF 3
CO
2 H (488.818): C, 52.48; H, 3.96; N, 2.86.
Found: C, 52.46; H, 4.03; N, 2.80.
EXAMPLE Irr 3-B enzloxvcarbonylamino-5-[(5-me~thyl-nanhthalen-1I-yl)-acetoxvl-4-oxopentanoic acid, as a gray solid.
Analysis calculated for C 2 6
H
2 5 N0 7 *0.20 CF 3
CO
2 H (486.296): C, 65.2 1; H, 5.22; N, 2.8 8.
Found: C, 65.21; H, 5.30; N, 2.88.
EXAMPLE I ss 3-Benzloxycarbonylamino-5-[(2-iodo-12henvl)-acetoxvl-4-oxo-pentanoic acid, as an off-white hygroscopic solid.
WO 98/16502 PCT/US97/18514 -71- Analysis calculated for C 2 1
H
2 0 1N0 7 (525.300): C, 48.02; H, 3.84; N, 2.67.
Found: C, 48.33; H, 3.88; N, 2.66.
EXAMPLE Itt 3-Benzvloxvcarbonvlamino-4-oxo-5-(3-pvridin-3-vl-propiofLvloxv)-pentanoic acid, trifluoroacetic acid salt as an off-white solid.
Analysis calculated for C 2 1
H
2 2
N
2 0 7
-CF
3
CO
2 H (528.443): C, 52.28; H, 4.39; N, 5.30.
Found: C, 52.26; H, 4.36; N, 5.19.
EXAMPLE luu 3-Benzyloxvcarbonvlamino-5-[(5-methoxv-naphthalen- I-vl)-acetoxvl-4-oxopentanoic acid, as a white solid.
Analysis calculated for C 2 6
H
2 5 N0 8 -0.03 CF 3
CO
2 H (482.912): C, 64.82; H, 5.22; N, 2.90.
Found: C, 64.86; H, 5.22; N, 2.92.
EXAMPLE Ivv [(8-methyl-naphthalen- 1 -yl)-acetoxyl-4-oxopentanoic acid, as a tan solid.
Analysis calculated for C 2 6
H
2 5 N0 7 -0.2 CF 3
CO
2 H (486.297): C, 65.21; H, 5.22; N, 2.88.
Found: C, 65.16; H, 5.38; N, 2.73.
EXAMPLE Iww 3-Benzloxycarbonvlamino-5-[(9H-fluoren-9-yl)-acetoxyl-4-oxo-pentanoic acid MS (APCI) m/z 488.4 (M+l) EXAMPLE lxx 0311 -dihydro-51-dibenzofa,dlcvclohepten-5-vl)acetoxvl-4-oxo-Dentanoic acid WO 98/16502 PCTIUS97/18514 -72- MS (APCI) mi/z 515.8 (M+1) EXAMPLE lyy 5-Oxo-1I-(toluene-4-sulfonvl)-pyrrolidine-2-carboxylic acid 3benzvoxycarbonvylamino-4-carboxy-2-oxo-butyI ester MIS (APCI) m/z 547.3 (M+1) EXAMPLE Ilzz 5-Oxo-pyrrolidine-1I,2-dicarboxylic acid 1 -benzl ester 2-(3-benzloxycarbonvylainino-4-carboxv-2-oxo-butyl) ester MS (APCI) m/z 527.3 (M+1) EXAMPLE Ilaaa 1 -Benzoyl-pvrrolidine-2-carboxylic acid 3-benzloxvcarbonvlamino-4-carboxy-2oxo-bulyl ester MIS (APCI) m/z 483.0 (M+1) EXAMPLE lbbb Eyrrolidine-1I 2-dicarboxylic acid I -benzl ester 2-(3-benzloxycarbonylamino-4carboxv-2-oxo-bulyl) ester MIS (APCI) m/z 469.1 (M-43) EXAMPLE Iccc 3-Benzloxycarbopylamino-5-(2-benzyl-3-phenvl-propionyloxy)-4-oxo-12entanoic acid MS (ESI) ni/z 502.4 (M-H) EXAMPLE lddd 3-Benzloxvcarbonylamino-5-[(5-cvano-naphthalen- I yl)-acetoxyl-4-oxopentanoic acid, as a tan solid.
WO 98/16502 PCT/~S97/18514 -73- Analysis for C 2 6
H
22
N
2 0 7 0.07 CF 3
CO
2 H (482.456) C, 65.08; H, 4.61; N, 5.81.
Found: C, 65.03; H, 4.79; N, 5.64.
EXAMPLE 1 eee 3-Benzvloxvcarbonvlamino-4-oxo-5-(3-phenvl-3 -pvridin-3-vl-propionvloxv)pentanoic acid as an orange solid.
Analysis calculated for C 2 7
H
2 6
N
2 0 7 1.02 CF 3
CO
2 H (606.822): C, 57.48; H, 4.49; N, 4.62.
Found: C, 57.45; H, 4.69; N, 4.29.
EXAMPLE 1 fff 3-Benzyloxvcarbonylamino-4-oxo-5-(3 -phenyl-3-pvridin-4-vl-propionvloxy)pentanoic acid, as a tan solid.
Analysis calculated for C 2 7
H
2 6
N
2 0 7 -1.23 CF 3
CO
2 H (630.767): C, 56.10; H, 4.35; N, 4.44.
Found: C, 56.10; H, 4.50; N, 4.25.
EXAMPLE 1 ggg 3 -Benzvloxvcarbonylamino-4-oxo-5-r(I -oxo-3 .4-dihydro- 1 H-isoguinolin-2-yl)acetoxyl-pentanoic acid MS (ESI) m/z 469.1 (1-Oxo-3,4-dihydro- 1 H-isoquinolin-2-yl)-acetic acid was prepared according to the procedure of W. K. Anderson, et al., J. Med. Chem., 1988;31:2097.
EXAMPLE 2 I -vl-acetoxv)-4-oxo-pentanoic acid Step A A mixture of 3-benzyloxycarbonylamino-5-(naphthalen- I-yl-acetoxy)-4oxo-pentanoic acid tert-butyl ester (1.495 g, 2.956 mmol, Example 1, Step A), Pd/C (0.50 g) and concentrated hydrochloric acid (1.00 mL, 12.1 mmol) in ml of ethanol was hydrogenated under balloon pressure at room temperature for 2 hours. The mixture was filtered through a pad of Celite, and the filtrate was WO 98/16502 PCTIUS97/18514 -74concentrated to give 3-amino-5-(naphthalen-1 -yl-acetoxy)-4-oxo-pentanoic acid, tert-butyl ester hydrochloride as a foamy off-white solid.
Step B To a solution at 0°C under nitrogen of 3-amino-5 (naphthalen-1-ylacetoxy)-4-oxo-pentanoic acid, tert-butyl ester hydrochloride (0.239 g, 0.587 mmol, Example 2, Step A) in 10 mL of acetonitrile was added dropwise (via syringe) benzenesulfonyl chloride (0.075 mL, 0.588 mmol), followed by dropwise addition of 4-methylmorpholine (0.20 mL, 1.819 mmol). The solution was allowed to slowly warm to room temperature overnight. The solution was concentrated, redissolved into ethyl acetate and washed with saturated NaHCO 3 saturated KH 2
PO
4 and brine solutions. The ethyl acetate extract was dried (MgSO 4 filtered, concentrated and chromatographed (silica gel, 80% hexanesethyl acetate) to give 4-oxo-pentanoic acid, tert-butyl ester as a light yellow oil.
Step C A solution of 3-benzenesulfonylamino-5-(naphthalen- -yl acetoxy)-4-oxopentanoic acid, tert-butyl ester (0.136 g, 0.266 mmol, Example 2, Step B) and mL of trifluoroacetic acid in 20 mL of dichloromethane was stirred at room temperature for 1 hour. The solution was concentrated to give the titled compound as a foamy off-white solid.
Analysis calculated for C 2 3
H
2 1
NO
7 S.0.75H 2 0 (469.002): C, 58.90; H, 4.84; N, 2.99.
Found: C, 58.94; H, 4.73; N, 3.02.
In a process analogous to Example 2, using the appropriately substituted isocyantes, appropriately substituted sulfonyl chlorides, appropriately substituted chloroformates, or appropriately substituted acid chlorides with 3-amino- 5-(naphthalen--yl-acetoxy)-4-oxo-pentanoic acid, tert-butyl ester hydrochloride (Example 2, Step the corresponding compounds were prepared as follows: WO 98/16502 PCTIUS97/18514 EXAMPLE 2a I -yl-acetoxv)-4-oxo-ventanoic acid, as off-white solid.
Analysis calculated for ClqHlqH0 7 (373.366): C, 61.12; H, 5.13; N, 3.75.
Found: C, 60.85; H, 5.25; N, 3.58.
EXAMPLE 2b 5-(Nanhthalene-lI-yl-acetoxy)-4-oxo-3-(3-phenvl-propionylaniino)-pentanoic acid, as white solid.
Analysis calculated for C 2 6
H
2 5 N0 6 .O.25H 2 0 (451.996): C, 69.09; H, 5.69; N, 3. Found: C, 69.06; H, 5.45; N, 2.91.
EXAMPLE 2c 3-Methoxycarboniylarnino-4-oxo-5-phenoxvacetox-Dentanoic acid, as foamny offwhite solid.
Analysis calculated for C 1 I 5 H 1 7 N0 8 8ONaHCO 3 (406.5 C, 46.68; H, 4.41; N, 3.45.
Found: C, 46.89; H, 4.44; N, 3.43.
EXAMPLE 2d 3-(2-Methanesulfonyl-ethanesulfonvylamino)-5-(naphthalen- 1 -l-acetoxy)-4-oxopentanoic acid, as a solid, mp 131-135TC.
Analysis calculated for C 2 0
H
2 3 N0qS 2 (485.536): C, 49.48; H, 4.78; N, 2.88.
Found: C, 49.26; H, 4.60; N, 2.88.
WO 98/16502 PCTfUS97/18514 -76- EXAMPLE 2e 3-(2-Methanesulfonyl- 1 -methvl-ethvlsulfanylamino)-5-(naphthalen- 1 -vI-acetoxy)- 4-oxo-pentanoic acid Analysis calculated for C 2 lH 2 5 N0 9
S
2 *l .0 H 2 0 (5 17.578): C, 48.73; H, 5.26; N, 2.71.
Found: C, 48.90; H, 5.60; N, 2.78.
EXAMPLE 3 rS-(R* R)--2-ctlmnopoi hhln-v-i-acetoxy)- 4-oxo-pentanoic acid Step A To a solution at O'C under nitrogen of N-acetyl alanine 176 g, 1.34 mmol), 3 -amino-5 -(naphthalene-1I -yl-acetoxy)-4-oxo-pentanoic acid, tertbutyl ester, hydrochloride (0.500 g, 1.22 mmol, Example 2, Step 2-(1Hbenzotriazole-1 -yl)-l ,1 ,3,3-tetramethyluronium tetrafluoroborate (0.431 g, 1.34 mniol), 1-hydroxybenzotriazole (0.214 g, 1.58 mmol) in 15 ml, of dichloromethane was added dropwise (via syringe) N,N-diisopropylethylamine (0.531 mL, 3.05 mmol). The solution was allowed to slowly warm to room temperature overnight. The solution was then dissolved in ethyl acetate and washed with 2x 5% citric acid solution, 2X saturated NaHCO 3 and Ilx brine. The ethyl acetate extract was dried (MgSO 4 filtered, concentrated, and chromatographed (silica gel, 30% tetrahydrofuran-70% dichioromethane) to give -(ahhaee I -yl-acetoxy)- 4 -oxo-pentanoic acid, tert-butyl ester as a light yellow thick oil.
Step B A solution of 3 -(2-Acetylaino.propionylain) I -yl-acetoxy)-4-oxo-pentanoic acid, tert-butyl ester (0.467 g, 0.96 mmol), and 7.5 mL of trifluoroacetic acid in 7.5 mL of dichioromethane was stirred at room temperature for 2 hours. The solution was concentrated and chromatographed (silica gel, 94% dichloromethane-5% methanol-1I% acetic acid) WO 98/16502 PCT/US97/18514 -77to give the title compound as an oily foam. The title compound was then lyophilized to a solid from acetonitrile and water.
1H NMR (400 MHz, d 6 DMSO), 12.43 (bs, 8.44 1H), 7.95 (in, 2H), 7.87 (in, lH), 7.51 (in, 4H), 4.87 (in, 2H), 4.56 (in, 4.23 2H), 4.18 (in, 1H), 2.72 (dd, 111), 2.54 (dd, lH), 1.81 3H), 1.17 3H) In a process analogous to Example 3, the corresponding compounds were prepared: EXAMPLE 3a 1 -v-acetoxy)-4-oxo-3- kthiophene-3-carbonyl')-aminol-pentanoic acid, as a foamy off-white solid.
Analysis calculated for C 2 2 HlqN0 6 S-0.45 H20 (433.571): C, 60.95; H, 4.63; N, 3.23.
Found: C, 60.98; H, 4.8 1; N, 3.29.
EXAMPLE 3b 3-[(Furan-3-carbonvl)-aminol-5-(naphthalen- 1 -v-acetoxy)-4-oxo-pentanoic acid, as a white solid.
Analysis calculated for C 2 2 H I 9 N0 7 *O.25 1120 (413.903): C, 63.84; H, 4.75; N, 3.38.
Found: C, 63.86; H, 4.50; N, 3.39.
EXAMPLE 3c I -vl-acetoxy)-4-oxo-3- [2-(4-phenyl-butvrvlamino)-pronylaminolpentanoic acid MS(CI) m/z 533 (M+l) EXAMPLE 3d.
3-(2-Methanesulfonvylainino-propionylamino)-5-(naphthalen- 1 -yl-acetoxy)-4-oxopentanoic acid MS(APCI) m/z 465 (M+1) WO 98/16502 PCTIUS97/18514 -78- EXAMPLE 3e 3-r2-(2-Acetylamino-4-phenl-butnlaino)-propionyamino-5-(naphthalen- 1yl-acetoxy)-4-oxo-pentanoic acid MS (APCI) m/z 590.4 (M+1) EXAMPLE 3f 3-(2-Acetvlamino-butvrvamino)-5-(nap~hthalen- 1 -vi-acetoxy)-4-oxo-Dentanoic acid MS (APCI) m/z 443.5 (M+1) EXAMPLE 3g 3 -[2-(4-Carbamoyl-butvrvamino)-lpropionyIlamino] -5 -(naphthalen- I -VI-acetoxy)- 4-oxo-pentanoic acid MS (APCI) ni/z 500.5 (M+1) EXAMPLE 3h 3-(2-Benzvloxycarbonylamino-propionylamino)-5-(naphthalen- I -yl-acetoxv')-4oxo-pentanoic acid MS (APCI) m/z 521.4 (M+1) EXAMPLE 3i 5-(Naphthalen-1I-yl-acetoxy)-4-oxo-3-(2-ureido-pronionylamino)-pentanoic acid MS (APCI) m/z 430.5 (M+1) EXAMPLE 3j 3-(2-Acetvlamino-propionvylamino)-5-(naphthalen- I -yl-acetoxy)-4-oxo-pentanoic acid MS (APCI) mlz 429.5 (M+1) EXAMPLE 3k 3-r( I-Acetvl-vvrrolidine-2-carbonvl)-aminol-5-(naphthalen-1I-yl-acetoxy)-4-oxopentanoic acid WO 98/16502 PCTIUS97/18514 -79- MS (APCI) m/z 455.5 (M±1) EXAMPLE 31 3-(2-Methyl-3 -oxo-3 -thiophen-2-v1-propionvaimino)-5-(naphthalen-1 -vI-acetoxy)- 4-oxo-pentanoic acid MS (APCI) mlz 482.4 (M+l) EX.AMPLE 3m 3-(2-Acetvlamino-acetvlamino)-5-(naphthalen- 1-yl-acetoxy)-4-oxo-pentanoic acid MS (APCI) m/z 415.5 (M+1) EXAMPLE 3n 3-(2-Acetvlamino-propionylamino)-5-(3.3 -diphenyl-propionyloxy)-4-oxopentanoic acid MS (APCJ) m/z 469.2 (M+1) EXAMPLE 3o 3-[2-(2-Acetvlamino-4-carboxv-butvrvlamino)-propionylaminol-5-(naphthalen-
I-
yl-acetoxy)-4-oxo-pentanoic acid MS (APCI) m/z 596.1 (M-1) Example 3p 5-(Naphthalen-1-I 1-acetoxy)-4-oxo-3-r2-(3-phenyl-Rropionvamino)propioniylaminol-pentanoic acid MS (APCI) m/z 518.8 (M+1) EXAMPLE 3q 3 -[2-(3-Methyl-butvrvamino)-propionvlaminol-5-(naphthalen- I -yl-acetoxy)-4oxo-p2entanoic acid MS (APCI) m/z 470.8 (M+l) WO 98116502 PCTIUS97/18514 EXAMPLE 3r 34-[I Carbamoyl-pvrrolidine-2-carbonv1l)-amfinl-5-(naphthalen-1I-yi-acetoxy)-4oxo-pentanoic acid EXAMPLE 3s 3-(3-Benzvoxy-2-ureido-propionvylamino)-5-(laphthalel I l-acetoxy)-4-oxopentanoic acid EXAMPLE 3t 34-[1 Acetyl-4-benzvloxy-pvrrolidine-2-cabonl)-amillfO-5-(flaphthalenl- I -v acetoxy')-4-oxo-pentanoic acid EXAMPLE 3u 3-(4-Carbamoyl-butvrlamino)-5-(naphthalel- I -YI-acetoxy)-4-oxo-pentanoic acid EXAMPLE 3v 3 -(3-Carbainoy-2-methyl-provionylamino)-5-(lahthalel-1I-yl-acetoxy)-4-oxopentanoic acid EXAMPLE 3w 1-Methyl-i H-imidazol-4-yl)-acetvlarninol -5-(naphthalen- 1 -l-acetoxy)-4oxo-p2entanoic acid EXAMPLE 4 (S)-5-(Naphthalene-1I-yl-acetox)-4-oxo-3-phenvlaceylalinfo-pentafloic acid Step A To a solution at room temperature under nitrogen of phenylacetyl chloride 160 mL, 1.22 mmol), 3-amino-5-(naphthalene- I -yl-acetoxy)-4-oxo-pentanoic acid, tert-butyl ester, hydrochloride (0.500 g, 1.22 mmol, example 2, Step A), 4-dimethylaminopyridine (catalytic) in 25 mL of acetonitrile was added dropwise (via syringe) NN-diisopropylethylamine (0.47 1 mL, 2.69 mmol). The solution was stirred overnight. The solution was then dissolved in ethyl acetate and washed WO 98/16502 PCTIUS97/18514 -81with 2x 5% citric acid solution, 2x saturated NaHCO 3 and I X brine. The'ethyl acetate extract was dried (MgSO4), filtered, concentrated, and chromatographed (silica gel, 40% ethyl acetate-60% hexanes) to give (S)-5-(naphthalene-1I-ylacetoxy)-4-oxo-3-phenylacetylamino-pentanoic acid, tert-butyl ester as a thick oil.
Step B -(Naphthalene- I -yl-acetoxy)-4-oxo-3-phenylacetylamino-pentanoic acid, tert-butyl ester (0.300 g, 0.61 mmol, Example 4, Step A) and 7.5 mL of trifluoroacetic acid in 7.5 mL of dichloromethane was stirred at room temperature for 2 hours. The solution was concentrated and chromatographed (silica gel, ethylacetate-59% hexanes- 1% acetic acid) to give the title compound as an oily foam. The title compound was then lyophilized to a solid from acetonitrile and water.
I H NMR (400 MHz, d 6 DMSO), 12.49 (bs, I 8.64 (bs, I 7.94 (in, 2H), 7.84 (in, 1H), 7.49 (in, 7.27 (mn, 5H), 4.85 (bs, 2H), 4.62 (in, 1H), 4.21 (s, 2H), 3.47 2H), 2.69 (dd, 1H), 2.59 (dd, I H) In a process analogous to Example 4, the corresponding compounds were prepared: EXAMPLE 4a I -yl-acetoxv')-4-oxo-3-(2-thiophene-2-YI-acetvlamino)pentanoic acid I H NMR (400 MHz, d 6 DMSO), 12.52 (bs, 1H), 8.67 (bs, 1H), 7.89 (in, 3H), 7.49 (mn, 4H), 7.34 (in, 114), 6.93 (mn, 2H), 4.88 (bs, 2H), 4.62 (mn, 1H), 4.22 2H), 3.71 2H), 2.69 (dd, 1H), 2.60 (dd, IlH) EXCAMPLE 4b and 4c 3-[(2-Carbainoyl-cyclopentanecarbonvl)-aminol-5-(na]phthalen- 1 -yl-acetoxy)-4oxo-pentanoic acid, diastereoiner A and B WO 98/16502 PCTIUS97/18514 -82- Step A To a solution of trans-2-carbamoyl-cyclopentanecarboxylic acid (13 0 mg, 0.83 mmol) and pyridine (65 mg, 0.83 mmol) in acetonitrile (100 mL) was added cyanuric fluoride (110 mg, 0.83 mmol) and the reaction mixture was stirred at room temperature for 3 hours. Ice water (10 mL) was added and the reaction mixture was stirred for 5 minutes. It was extracted with methylene chloride mL) and the organic layer was evaporated to give the crude intermediate acid fluoride (50 mg). A solution of the acid fluoride in 1: 1 methylene chloride:acetonitrile (20 mL) was treated with the hydrochloride salt of 3 (naphthalene- 1 -yl-acetoxy) 4-oxo-pentanoic acid tert- butyl ester (100 mg, 0.25 mmol, Example 2, Step A) and N-methylmorpholine (0.5 mmol). The reaction mixture was stirred at room temperature for 2 hours followed by evaporation of the solvent. Purification by flash chromatography (silica gel, ethyl acetate) gave two diastereomers of 3- [(2-carbamoyl-cyclopentanecarbonyl)amino] -5-(naphthalen- I -yl-acetoxy)-4-oxo-pentanoic acid tert-butyl ester [diastereomer A (high RI) MS 510.9 and diastereomer B(low RI)] MS (APCI) mlz 510.9 Step B Diastereomer A or B was reacted with trifluoroacetic acid as described for Example 4 to yield 3-[(2-carbamoyl-cyclopentanecarbonyl)-amino]-5-(naphthalen- I1-yl-acetoxy)-4-oxo-pentanoic acid 4b (diastereomer mp 171-185*C and 3-[(2-carbamoyl-cyclopentanecarbonyl)-amino]-5-(naphthalen- I -yl-acetoxy)-4oxo-pentanoic acid 4c (diastereomer mp 208-210 0
*C.
EXAMPLE 4d -Carbamoyl-bicyclo[2.2. 1 lheptane-2-carbonyl)-aminol-5 -(naphthalen- I -ylacetoxy)-4-oxo-pentanoic acid 3-[(3-Carbamoyl-bicyclo 1]heptane-2-carbonyl)-aniino]-5-(naphthalen- I -yl-acetoxy)-4-oxo-pentanoic acid tert-butyl ester was prepared by the method of Example 4b and 4c in 47% yield from (I R, 2S, 3S, 4S)-3-carbamoyl-2carboxybicyclo[2.2.I1heptane (Ohtani, et al., JOC 1991;562:122-2127).
WO 98/16502 PCT/US9~7/18514 -83- EXAMPLE 4e 3-(3-Carbamovl-2-methvl-propionvlamino)-5-(naphthalen- -vl-acetoxv)-4-oxopentanoic acid Step A To a solution of(S)-(-)-2-methylsuccinamic acid (0.160 g, 1.22 mmol, prepared according to the procedure in Chem. Pharm. Bull., 1991;39(10):2706- 2708) in 25 mL of dichloromethane and 25 mL of tetrahydrofuran at -78 0 C was added N-methylpiperidine (0.163 mL, 1.34 mmol) followed by dropwise addition of isobutyl chloroformate (0.166 mL, 1.26 mmol). The reaction mixture was stirred for 1 hour at -78 0 C. A solution of 3-amino-5-(naphthalene-1-yl-acetoxy)- 4-oxo-pentanoic acid tert-butyl ester, hydrochloride (0.500 g, 1.22 mmol, Example 2, Step A) in dichloromethane (25 mL) and tetrahydrofuran (25 mL) was added dropwise while simultaneously adding N-methylpiperidine (0.163 mL, 1.34 mmol) dropwise with a second addition funnel. The reaction mixture was allowed to slowly warm to room temperature and was stirred overnight. The reaction mixture was diluted with ethyl acetate was washed sequentially with 5% citric acid, saturated sodium bicarbonate, and finally with saturated sodium chloride.
The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was suspended in diethyl ether, collected by filtration, washed with diethyl ether and dried under reduced pressure to yield 294 mg of the intermediate 3-(3-carbamoyl-2-methyl-propionylamino)-5-(naphthalen-1 -ylacetoxy)-4-oxo-pentanoic acid tert-butyl ester.
Step B A solution of 3-(3-carbamoyl-2-methyl-propionylamino)-5-(naphthalen-1yl-acetoxy)-4-oxo-pentanoic acid tert- butyl ester (0.150 g, 0.309 mmol, Example 4e, Step A) in 10 mL of 4N hydrochloric acid/dioxane was stirred at room temperature for 2 hours. The solution was concentrated and the product purified by reverse phase HPLC. Lyophilization from acetonitrile and water gave 3-(3- -yl-acetoxy)-4-oxopentanoic acid as a solid.
WO 98/16502 PCT/US97/18514 -84- 'HNMR(400MHz, DMSO) 12.38 (bs,lH), 8.49 7.88 7.54(m,4H), 7.28 6.76 4.89 4.46 4.22 2.71 2.74 2.32 (dd, 1H), 2.08 (dd, 1H), 0.98 MS (APCI) m/z 429.1 EXAMPLE 4f 3-(3-Methanesulfonvl-2-methvl-propionvlamino)-5-(naphthalen-1-vl-acetoxy)-4oxo-pentanoic acid Part A A solution of2(S)-methyl -3-methylsulfonyl) propionic acid (250 mg, mmol, prepared according to the procedure ofVazquez, M. et al., [WO 94/10136]) in 10 mL of thionyl chloride was allowed to stirred at 55 0 C under
N
2 for 2 hours. The solvent was removed under reduced pressure, washed with benzene and reconcentrated to give an off-white solid. The resultant solid was dissolved in 40 mL THF and N-methylmorpholine (300 mg, 3.0 mmol) and 4-dimethylaminopyridine (120 mg, 1.0 mmol.) added followed by 3 (naphthalene-1 -yl-acetoxy) 4-oxo-pentanoic acid tert butyl ester, hydrochloride (Example 2, Step A) (407 mg, 1.0 mmol) in a single portion. The mixture allowed to stir at room temperature for 16 hours. The solution was diluted with ethyl acetate and washed with saturated NaHC0 3 saturated KHPO 4 and brine solution, dried (MgSO 4 filtered, and concentrated. Medium pressure chromatography (silica gel, 75% hexanes-25% ethyl acetate to 60% hexanes-40% ethyl acetate) of the crude oil afforded [S-(R*,R*)]-3-(3-methanesulfonyl-2-methyl- 1-yl-acetoxy)-4-oxo-pentanoic acid tert butyl ester.
Part B A solution of [S-(R*,R*)]-3-(3-methanesulfonyl-2-methylpropionylamino)-5-(naphthalen-1-yl-acetoxy)-4-oxo-pentanoic acid tert butyl ester (232 mg, 0.45 mmol.)and trifluoroacetic acid (5 mL, 0.065 mol) in 5 mL of dichloromethane was stirred at room temperature for 2 hours. The solution was concentrated in vacuo and suspended in water to give the title compound as a offwhite solid.
WO 98/16502 PCTIUS97/18514 Analysis calculated for C 2 2
H
2 5
NO
8
S*H
2 0 (481.51): C, 54.87; H, 5.65; N, 2.91.
Found: C, 54.78; H, 5.42; N, 2.78.
EXAMPLE 4g 3-(3-Benzenesulfonvl-2-methyl-propionvlamino)-5-(naphthalen- -vl-acetoxy)-4oxo-pentanoic acid Part A To a solution of 2-methyl-3-(thiobenzene) propionic acid methyl ester (4 g, 19 mmol., prepared according to the procedure J. Org. Chem., 1981;46:235-9) in 100 mL of acetic acid was added sodium perborate (7.33 g, 47.6 mmol) and the mixture heated to 55°C for 17 hours. The reaction was poured into water, extracted with methylene chloride, washed with aqueous sodium bicarbonate, dried (MgSO 4 and concentrated to give of 2-methyl-3-(benzenesulfonyl) propionic acid methyl ester as a colorless oil.
Part B To a solution of 2-methyl-3-(benzenesulfonyl) propionic acid methyl ester (4.47 g, 18.5 mmol) in 60 mL of THF was added a solution of lithium hydroxide (0.93 g, 22.2 mmol.) in water (30 mL). The solution was allowed to stir at room temperature for 16 hours and then acidified to pH 1 with IN KHSO 4 and the solution extracted with ethyl acetate 3 times. The combined organic solution was dried (MgSO 4 and concentrated to give a colorless oil which solidified upon standing to give 2-methyl-3-(benzenesulfonyl) propionic acid.
Part C A solution of 2-methyl-3-(benzenesulfonyl) propionic acid (300 mg, 1.3 mmol) in 10 mL of thionyl chloride was allowed to stir at 55 0 C under N 2 for 16 hours. The solvent was removed under reduced pressure washed with benzene and reconcentrated to give yellow oil. The resultant oil was dissolved in 40 mL THF and N-methylmorpholine (300 mg, 3.0 mmol) and 4-dimethylaminopyridine (120 mg, 1.0 mmol.) added followed by 3 4-oxo-pentanoic acid, tert-butyl ester, hydrochloride (407 mg, 1.0 mmol, Example WO 98/16502 PCT/US97/18514 -86- 2, Step A) in a single portion. The mixture allowed to stir at room temperature for 36 hours. The solution was diluted with ethyl acetate and washed with saturated NaHCO 3 saturated KHPO 4 and brine solution, dried (MgSO4), filtered, and concentrated. Medium pressure chromatography (silica gel, 75% ethyl acetate to 60% hexanes-40% ethyl acetate) of the crude oil afforded 3-(3benzenesulfonyl-2-methyl-propionylamino)-5-(naphthalen-1-yl-acetoxy)-4-oxopentanoic acid tert butyl ester.
Part D A solution of 3-(3-benzenesulfonyl-2-methyl-propionylamino)-5- (naphthalen-1-yl-acetoxy)-4-oxo-pentanoic acid tert butyl ester (216 mg, mmol) and trifluoroacetic acid (5 mL, 0.065 mol) in 5 mL ofdichloromethane was stirred at room temperature for 2 hours. The solution was concentrated in vacuo and suspended in ethyl ether to give the title compound as a off-white solid.
Analysis calculated for C 2 7
H
2 7
NO
8
S-C
2
HF
3 0 2 (611.10) C, 56.01; H, 4.58; N, 2.29.
Found: C, 56.12; H, 4.86; N, 2.40.
In a process analogous to Example 4, the corresponding compounds were prepared: EXAMPLE 4h 3-Butvrvlamino-5-(naphthalen-2-vl-acetoxy)-4-oxo-pentanoic acid MS (CI) m/z 386 (M+I) EXAMPLE 4i 3-Acetylamino-5-(naphthalen-1-vl-acetoxv)-4-oxo-pentanoic acid as a foamy off-white solid.
Analysis calculated for C 19
H
19 N0 6
*H
2 0 (375.382): C, 60.80; H, 5.64; N, 3.73.
Found: C, 61.07; H, 5.70; N, 3.57.
WO 98/16502 PCT/US97/18514 -87- EXAMPLE 4j 3-(3-Methanesulfonvl-2-methyl-propionylamino)-5-(nphthalen- 1 -vl-acetoxy)-4oxo-pentanoic acid Analysis calculated for C 2 2
H
2 5 N0 8 S*1 .0 H 2 0 (481.526): C, 54.88; H, 5.65; N, 2.91.
Found: C, 54.78; H, 5.42; N, 2.78.
EXAMPLE 4k 3-(3-Methyl-butvrlamino)-5-(naphthalen- 1 -l-acetoxy)-4-oxo-pentanoic acid MS (APCI) nI/z 399.8 (M+1) EXAMPLE 41 3-(3-Carbamovl-propionylaniino)-5-(naphthalen- 1 -yl-acetoxy)-4-oxo-Dentanoic acid IH NMR (400 Mhz, DMSO) 12.38 (bs,1H), 8.44 7.93 (m,3H), 7.50(m,4H), 7.28 6.75 4.92 (dd,2H), 4.56 4.23 2.68 (dd,1IH), 2.52 (dd, IH), 2.49 (in, 4H).
MS (APCI) in/z 415.5 (M+H) EXAMPLE 4m )1-3-(3-Acetylsulfanyl-2-methyl-propionylainino)-5-(naphthalen -viyacetoxy)-4-oxo-pentanoic acid Analysis calculated for C 2 3
H
2 5 N0 7 S*0.1I CF 3
CO
2 H (470.925): C, 59.17; H, 5.37; N, 2.97.
Found: C, 59.39; H, 5.59; N, 3.01.
EXAMPLE 4n trans-3-[(3 -Carbainovl-cvclopentanecarbonyl)-aminol-5-(naphthalen-1 I -i acetoxv)-4-oxo-pentanoic acid WO 98/16502 PCTIUS97/18514 -88- Analysis calculated for C 2 4
H
2 6
N
2 0 7 1.5 H 2 0: C, 59.86; H, 6.07; N, 5.82.
Found: C, 59.74; H, 5.80; N, 5.48.
EXAMPLE 3-(1,2,3,4-tetrahydro-l-oxo-isoquinoline-2-vl)-acetamino-5-(naphthalene- 1-yl acetoxv)-4-oxo-pentanoic acid Step A To a solution of (1,2,3,4-tetrahydro-1 -oxo-isoquinoline-2-yl)acetic acid (2.7 g, 13.0 mMol) prepared according to the procedure of Anderson et al., J. Med. Chem, 1988;31:2097 and H-Asp (OtBu)OMe*HCl (2.9 g, 12.0 mMol) in dimethylformamide (40 mL) was added at 0°C l-ethyl-3-(3'-dimethylaminopropyl) carbodiimide x HC1 (2.5 g, 13.0 mMol) and triethylamine (4.05 g, mMol). The mixture was stirred at room temperature for 16 hours. Most of the solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate. The organic phase was washed successively with aqueous sodium hydrogen carbonate and water, dried over sodium sulfate, and concentrated to give g of an amorphous residue.
The residue was dissolved in 40 mL of dioxane/water and hydrolyzed in the presence of thymolphthalein by dropwise addition of 1N NaOH (12.0 mL).
After evaporation of most of the dioxane and dilution with water the aqueous solution was extracted with ether, acidified with dilute HC1 to pH 2-3, and the product extracted into ethyl acetate. The organic phase was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to give 3.4 g of crystalline N-(1,2,3,4-tetrahydro- -oxo-isoquinoline-2-yl)-acetyl aspartic acid, 4-tert-butyl ester.
Step B To a solution of N-(1,2,3,4-tetrahydro-l-oxo-isoquinoline-2-yl)-acetyl aspartic acid, 4-tert-butyl ester (2.8 g, 7.4 mMol) in tetrahydrofuran (40 mL) at was added N-methylmorpholine (0.75 mL, 8 mMol) followed by dropwise WO 98/16502 PCT/US97/8514 -89addition of ethyl chloroformate (0.79 mL, 8 mMol). After 15 minutes at mL of a 0.2N solution of diazomethane in ether was added dropwise. The reaction was kept for 2 hours at room temperature then 15 mL of a solution of 48% HBr in glacial acetic acid was added dropwise at o0C. After stirring for 15 minutes the reaction mixture was poured into ethyl acetate. The organic phase was washed successively with saturated aqueous sodium hydrogen carbonate and water, dried over sodium sulfate, and concentrated under reduced pressure to give 3-(1,2,3,4-tetrahydro-l-oxo-isoquinoline-2-yl)-acetamino-5-bromo-4-oxopentanoic acid, tert-butyl ester (3.1 g).
Step C To a mixture of 3-(1,2,3,4-tetrahydro- 1-oxo-isoquinoline-2-yl)acetamino-5-bromo-4-oxo-pentanoic acid, tert-butyl ester (0.7 g, 1.5 mMol) and potassium fluoride (0.26 g, 4.5 mMol) in dimethylformamide (30 mL) was added 1-naphthylacetic acid (0.28 g, 1.5 mMol). The mixture was stirred at room temperature for 16 hours. Most of the solvent was evaporated under reduced pressure, the residue was partitioned between ethyl acetate and water. The organic phase was washed successively with aqueous sodium hydrogen carbonate and water, dried over sodium sulfate. Evaporation under reduced pressure followed by chromatography over silica (elution with dichloromethane/acetone 20:1) gave 0.31 g of 3-(1,2,3,4-tetrahydro- -oxo-isoquinoline-2-yl)-acetaminoacetoxy)-4-oxo-pentanoic acid, tert-butyl ester.
Step D 3-(1,2,3,4-tetrahydro-1 1-yl acetoxy)-4-oxo-pentanoic acid, tert-butyl ester (0.28 g, 0.5 mMol) in 20 mL of a 1:1 mixture of dichloromethane/trifluoroacetic acid was stirred at room temperature for 45 minutes. Evaporation under reduced pressure followed by crystallization from dichloromethane/ether/hexane gave 3-(1,2,3,4-tetrahydro- 1 -oxo-isoquinoline-2-yl)-acetamino-5-(naphthalene- -yl acetoxy)-4-oxo-pentanoic acid (0.19 g).
WO 98/16502 PCT/US97/18514 m. p. 117 0 C-124 0 C; NMR (d 6 -DMSO, ppm): 12.5 (bs, 1H), 8.5 1H), 8.1-7.8 4H), 7.6-7.4 5H), 7.4-7.2 2H), 5.0 2H), 4.65 (dd, 1H), 4.25 2H), 4.18 (dd, 2H), 3.6 2H), 3.0 2H), 2.75-2.5 (2m, 2H).
EXAMPLE 3-(2-Methvl-3-phenethvlcarbamovl-propionvlamino)-5-(naphthalen-l-vl-acetoxy)- 4-oxo-pentanoic acid Step A A solution of itaconic anhydride (5.00g, 44.6 mmol) and phenethylamine (5.95 g, 49.1 mmol) in 100 mL of acetonitrile was stirred at room temperature under nitrogen for 72 hours. The mixture (solid had formed) was concentrated, then partitioned between EtOAc and IN HC1. The organic extract was washed with brine, dried (MgSO 4 concentrated and the residue was crystallized from diethyl ether to give 5.24 g of 2-(phenethylcarbamoyl-methyl)-acrylic acid as a white solid: mp 133-140 0
C.
Analysis calculated for C 13
H
1 5
NO
3 (233.269): C, 66.94; H, 6.48; N, 6.00.
Found: C, 66.74; H, 6.56; N, 6.00.
Step B A solution of 2-(phenethylcarbamoyl-methyl)-acrylic acid 2.76 g, 11.8 mmol, Step A) in 100 mL of THF was treated with 5% Pd/C (0.2 g) and hydrogenated at room temperature and 52 psi of hydrogen for 2.5 hours. The mixture was filtered and concentrated to give 2.39 g of 2-(phenethylcarbamoyl-methyl)-propionic acid as an off-white solid.
Analysis calculated for C 13
H
17 N0 3 (235.285): C, 66.36; H, 7.28; N, 5.95.
Found: C, 65.31; H, 7.05; N, 5.80.
WO 98/16502 PCTIUS97/18514 -91- Step C A mixture of 2-(phenethylcarbamoyl-methyl)-propionic acid (1.63 g, 6.93 mmol, Step H-Asp(OtBu)-OMe-HCI (1.83 g, 7.64 mmol, purchased from Bachem Bioscience Inc.), 1-hydroxybenzotriazole hydrate (1.17 g, 7.64 mmol), N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (1.46 g, 7.62 mmol) and 4-methylmorpholine (0.95 mL, 8.64 mmol) in 100 mL of dichloromethane was stirred at room temperature for 24 hours. The mixture was concentrated, then partitioned between EtOAc and saturated NaHCO 3 solution.
The organic extract was washed with saturated KH 2
PO
4 and brine solutions, dried (MgSO 4 filtered, concentrated, and chromatographed (silica gel, 25% hexanes- EtOAc) to give 2.54 g of 2-(2-methyl-3-phenethylcarbamoylpropionylamino)-succinic acid, 4-tert-butyl ester 1-methyl ester as a waxy white solid.
Analysis calculated for C 2 2
H
3 2
N
2 0 6 (420.510): C, 62.84; H, 7.67; N, 6.66.
Found: C, 62.68; H, 7.69; N, 6.54.
Step D A solution of 2-(2-methyl-3-phenethylcarbamoyl-propionylamino)succinic acid, 4-tert-butyl ester 1-methyl ester (2.11 g, 5.01 mmol, Step C) and 0.1N sodium hydroxide solution (60.1 mL, 6.01 mmol) in 60 mL of ethanol was stirred at room temperature for 12 hours. The solution was concentrated, acidified with saturated KH 2
PO
4 solution to a pH -5 and extracted with chloroform (2 x 100 mL). The combined chloroform extract was dried (MgSO 4 filtered and concentrated to give 2.23 g of 2-(2-methyl-3-phenethylcarbamoylpropionylamino)-succinic acid, 4-tert-butyl ester as a colorless oil, which was used without further purification.
A solution of 2 2 -methyl-3-phenethylcarbamoyl-propionylamino)succinic acid, 4-tert-butyl ester (2.23 g, 5.49 mmol) and 4-methylmorpholine (0.61 mL, 5.73 mmol) in 50 mL of THF in a Clear-Seal joint 250-mL roundbottom flask was cooled to ca. -45 0 C (Dry Ice-acetonitrile slurry) and treated with WO 98/16502 PCT/US97/18514 -92isobutyl chloroformate (0.75 mL, 5.78 mmol). Solid immediately formed, the mixture was stirred for 15 minutes, then treated with a 0.5 M diazomethane in ether solution (55 mL, 27.5 mmol, generated from Diazald). The cooling bath was removed, the light yellow solution was stirred at room temperature for 2 hours, cooled to 0°C and treated dropwise with a solution of 48% hydrobromic acid mL, 184 mmol) in 10 mL of acetic acid. The colorless solution was stirred at room temperature for 30 minutes, then partitioned between EtOAc and water (-200 mL of each). The organic extract was washed with water, saturated NaHCO 3 and brine solutions, dried (MgSO 4 filtered, and concentrated to give 1.40 g of 2-(2-methyl-3-phenethylcarbamoyl-propionylamino)-5-bromo- 4-oxo-pentanoic acid, tert-butyl ester as a light yellow solid.
Step E A mixture of 2-(2-methyl-3-phenethylcarbamoyl-propionylamino)- 5-bromo-4-oxo-pentanoic acid, tert-butyl ester (0.70 g, 1.45 mmol, Step D), 1-naphthylacetic acid (0.34 g, 1.81 mmol) and potassium fluoride (0.21 g, 3.61 mmol) in 2.5 mL of DMF was stirred at room temperature for 12 hours. The sample was partitioned between EtOAc and saturated NaHCO 3 solution. The organic extract was washed with saturated KH 2
PO
4 and brine solutions, dried (MgSO 4 filtered, and concentrated. The residue was chromatographed (silica gel, 25% hexanes-75% EtOAc) to give 0.65 g of 3-(2-methyl- 3-phenethylcarbamoyl-propionylamino)-5-(naphthalen-l-yl-acetoxy)-4-oxopentanoic acid, tert-butyl ester.
Step F A solution of 3-(2-methyl-3-phenethylcarbamoyl-propionylamino)- 5-(naphthalen-l-yl-acetoxy)-4-oxo-pentanoic acid, tert- butyl ester (0.62 g, 1.06 mmol, Step E) and trifluoroacetic acid (5 mL) in 20 mL of dichloromethane was stirred at room temperature for 1 hour, then concentrated to a yellow oil. The sample was partitioned between EtOAc and saturated KH 2
PO
4 solution. The organic extract was washed with brine, dried (MgSO 4 filtered, and concentrated WO 98/16502 PCT/US97/18514 -93to 0.51 g of 3-(2-methyl-3-phenethylcarbamoyl-propionylamino)- 1 -yl-acetoxy)-4-oxo-pentanoic acid as a white solid.
Analysis calculated for C 3 0 H1 3 2
N
2 0 7 *1/3 H 2 0 (538.604): C, 66.90; H, 6.11; N, 5.20.
Found: C, 66.90; H, 6.14; N, 5. In a process analogous to Example 5, the corresponding compounds were prepared: EXAMPLE 5-(Nahthalen-2-vl-acetoxv)-4-oxo-3-r2-(2-oxo-6-phenvl-piperidin. 1 -vl)acetylaminol-pentanoic acid (as a mixture of diastereomers): I1H NMR (d 6 -DMSO): 812.5 (1 H, 8.3 8 (1 H, 2d), 7.90-7.75 (4H, in), 7.50-7.10 (8H, in), 4.90 (2H, dd), 4.70-4.50 (211, mn), 4.40 (1 H, in), 3.90 (2H, s), (111, dd), 2.7 (IH, mn), 2.40-2.30 mn), 2.20 (111, m) 1.8-1.5 (4H1, mn). The starting acid, 6-phenyl-piperidine-2-one, was prepared according to the procedure of L.D. Desaubry, C.G. Wermuth and J.J. Bourguignon, Tetrahedron Lett., 1995;36:4249, then alkylation with ethyl bromoacetate (NaR/toluene; 1 hour at 11 I0 0 C) followed by alkaline hydrolysis.
EXAMPLE 1 -l-acetoxv)-4-oxo-3-[2-(2-oxo-6-phenyl-Dperidin-lI-vl)acetylaminoL-pentanoic acid (as a mixture of diastereomers): 11H NMR (d 6 -DMSO): 813.0-12.0 (11H, bs), 8.4 (1 H, in), 8.1-7.8 (3H, in), 7.6-7.0 (911, in), 5.05-4.8 (2H, in), 4.70-4.50 (211, in), 4.45-4.35 (JH, in), 4.25 (211, 3.0 (1H, in), 2.7 (1H, in), 2.5 (DMSO 1H1, in), 2.40 (211, in), 2. 10 (1 H, in) 1. 8-1.5 (311, in). The starting acid, 6-phenyl-piperidine-2-one, was prepared as described for Example WO 98/16502 PCTIUS97/18514 -94- EXAMPLE 3-r3 -Methyl-2-(3-phenvl-Rropionvlamino)-butvrvlaminol-4-oxo-5-r( I-o 1,2,3 .4-tetrahydro-naphthalen-2-yl')-acetoxyl-pentanoic acid MIS (ESI) m/z 565.2 (M+1) EXAMPLE 5-(Naphthalen-2-yl-acetoxy)-4-oxo-3-r2-( 1 -oxo-3 .4-dihydro- IH-isociuinolin-2-yl)acetylaminol-pentanoic acid IH NMR (d 6 -DMSO): 812.5 (114, m) 8.6 (11H, 8.0-7.8 (5H, in), 7.55-7.25 (611, 2m), 4.95 (2H1, dd), 4.65 (1 H, dd), 4.15 (211, 3.95 (2H, 3.55 (2H4, dd), 3.0 (21-1, in), 2.75 (11H, dd), 2.6 (11H, mn). The starting acid, Il-oxo-3,4-dihydro-1IHisoquinolin-2-yl)-acetic acid, was prepared as described for Example EXAMPLE 5-(2-Benzvl-3 -phenvl-propionyloxy)-4-oxo-3-[2-( I -oxo-3 .4-dihydro- 1Hisociuinolin-2-yl)-acetylaminol-pentanoic acid MIS (ESI) in/z 557.2 (M+1) The starting acid, (1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-acetic acid, was prepared as described for Example EXAMPLE 5-(2-Benzv-3-phenv1-pronionyloxv)-4-oxo-3-r2-(2-oxo-6-Rhenyl-piperidin- I -vi)acetylaminol-pentanoic acid (as a mixture of diastreomers) 111 NMR (d 6 -DMSO): 812.5 (1H, bs), 8.35 (111, 2d), 7.4-7.1 (1511, in), 4.75 (2H, dd), 4.6 (211, in), 4.40 (1 H, in), 3.1-2.5 (8H, in), 2.3 5 (211, in), 2. 10 (11H, in) 1.8-1.5 (311, in). The starting acid, 6-phenyl-piperidine-2-one, was prepared as described for Example EXAMPLE 5-(Naphthalen-1 -yI-acetoxy)-4-oxo-3-[2-( I-oxo- 1,2,3 ,4-tetrahydro-naphthalen- 2-yl)-acetylarninol-pentanoic acid WO 98/16502 PCTIUS97/18514 MS (ESI) m/z 483.5 (M-H 2 The starting acid, (l-oxo-3,4-dihydro- IHisoquinolin-2-yl)-acetic acid, was prepared as for Example EXAMPLE 5-(Naphthalen-1-I v-acetoxy)-4-oxo-3-[2-( 1-oxo-3,4-dihydro- 1H-isociuinolin-2-vl)propionylaminol-pentanoic acid MS (ESI) m/z 517.4 The starting acid, 2-(1-oxo-3,4-dihydro-1Hisoquinolin-2-yl)-propionic acid, was prepared in analogy to the literature procedure of Example 5, starting from ethyl 2-bromopropionate.
EXAMPLE .5-(Nlaphthalen-2-yl-acetoxy)-4-oxo-3- r2-( I -oxo-3,4-dihydro- 1H-isociuinolin-2-yl)propionyiaminol-rpentanoic acid MIS (ESI) ml/z 517.3 The starting acid, 2-(l-oxo-3,4-dihydro-1Hisoquinolin-2-yl)-propionic acid, was prepared as described for Example EXAMPLE I-Benzenesulfonvyl-I1H-pyrrol-2-yl)-4-oxo-bunurlaminol-5-(ngphthalen- I -yi-acetoxy)-4-oxo-pentanoic acid MS (ESI) mn/z 605.4 The starting acid, 4-(1 -benzenesulfonyl-1IH-pyrrol- 2-yl)-4-oxo-butyric acid, was prepared as described according to the procedure of M. Kakushima,et al., J. Org. Chem., 1983;48: 3214.
EXAMPLE 51 5-(2-BenZyl-3 -phenvl-propiopyloxy)-4-oxo-3 I-oxo-1I .2,4-tetrahyvdronaphthalen-2-yl')-acetylamino]-pentanoic acid MIS (ESI) m/z 556.4 The starting acid, (1-oxo-3,4-dihydro-1H-isoquinolin- 2-yl)-acetic acid, was prepared as described for Example EXAMPLE 5-(2-Benzv-3-phenvl-propionvloxy)-4-oxo-3 1-oxo-3 ,4-dihvdro- 1Hisocuinolin-2-yl)-propionylaminol-pentanoic acid (as a mixture of diastreomers): WO 98/16502 PCT/US97/18514 -96mn), 5.2 (11H, in), 4.8 (2H, in), 4.65 mn), 3.55 (2H, mn), 3.1-2.65 (9H, rn), 1. 3 (3 H, The starting acid, 2-(l -oxo-3,4-dihydro-1IH-isoquinolin-2-yl)propionic acid, was prepared as described as described for Example EXAMPLE 4-Oxo-3-[2-( I -oxo-3 .4-dihydro- 1 H-isocluinolin-2-vyl)-propionvlaminol-5r( 1 -oxo- 1 .2,3,4-tetrahydro-nap~hthalen-2-vI')-acetoxyl-pentanoic acid (as a mixture of diastreoiners): 'H NMR (d 6 -DMSO): 812.5 (1lH, 8.6-8.5 (1IH, 2d), 7.9 in), 7.6-7.2 (6H1, mn), 5.3-5.1 (1 H, in), 4.9 (2H, 4.7 (1IH, in), 3.45 (2H, mn), 3.2-2.5 (9H, in), 2.2 in), 1.95 (1 H, in), 1.3 (3H, The starting acid, 2-(1-oxo-3,4-dihydro- I1H-isoquinolin-2-yl)-propionic acid, was prepared as described for Example EXAMPLE 3-4(41 -Benzenesulfoniyl- 1H-pyrrol-2-vl')-4-oxo-butyrvlaminol-5-(2-benzvl- .3-phenyl-1propionyloxy)-4-oxo-pentanoic acid MIS (ESI) inlz 659.4 The starting acid, 4-(1 -benzenesulfonyl-1IH-pyrrol- 2-yl)-4-oxo-butyric acid, was prepared as described for Example EXAMPLE 4-Oxo-S-r( -oxo- 1.2,3 .4-tetrahvdro-naphthalen-2-vl)-acetoxyl-3-[2-( I-oxo- .1,2,3 ,4-tetrahvdro-nanhthalen-2-yl)-acetvlaminol -pentanoic acid MIS (ESI) in/z 520.2 The starting acid, (I1-oxo-3,4-dihydro-1IH-isoquinolin- 2-yl)-acetic acid, was prepared as described for Example EXAMPLE Sq 5-(Nap~hthalen-l1 yl-acetoxy)-4-oxo-3-[2-(2-oxo-3-phenyl-iinidazolidin- 1 propionylaininol-pentanoic acid MIS (ESI) ml/z 518.2 The starting acid, 2-(2-oxo-3-phenyl-imidazolidin- 1 -yl)-propionic acid, was prepared according to the procedure of Basha (see Example 5s) followed by alkylation and subsequent alkaline hydrolysis.
WO 98/16502 PCT/US97/18514 -97- EXAMPLE I-yl-acetoxy)-4-oxo-3 -[2-(2-oxo-3-phenvl-tetrahvdro-pyrimidin- I -yl)-propionylaminol-p~entanoic acid MS (ESI) m/z 546.3 The starting acid, 2 -(2-oxo-3-phenyl-tetrahydropyrimidin-1-yl)-propionic acid was prepared from 2-oxo-3-phenyl-tetrahydro pyrimidine (see Basha, Example 5s) followed by alkylation with ethyl 2-bromopropionate and subsequent alkaline hydrolysis.
EXAMPLE 1-yl-acetoxy)-4-oxo-3- r2-(2-oxo-3-phenyl-tetrahydro-pvfimidin- 1 -vl)-acetvlaminol-pentanoic acid MIS (ESI) m/z 532.3 I1-Phenyl-tetrahydropyrimidine-2-one was prepared according to the procedure of A. Basha, Tetrahedron Lett., 1988;29:2525 followed by alkylation with ethyl bromoacetate (NaHIDMF; 16 hours at room temp.) and subsequent alkaline hydrolysis.
EXAMPLE 3-(2-Acetvlamino-3-methyl-butrl amino)-5-(naphthal en- 1 -YI-acetoxy)-4-oxopentanoic acid MS (ESI)mlz 455.3 EXAMPLE 3-( 2 -Ace~ylalino-3-methyl-butyrylamino)-5-(2-benzyl-3-phenyl-pronionyloxv)- 4-oxo-pentanoic acid MS (ESI) m/z 511.3 EXAMPLE 3-(2-Acetvlamino-3-methyl-butvrvlamino)-5-(3-benzyl-4-phenyl-butvrloxv)- 4-oxo-pentanoic acid MS (ESI) In/z 525.3 1).
WO 98/16502 PCTIUS97/18514 -98- EXAMPLE 3-(2-Aceylamino-3-methyl-butyrvamino)-5-(4-benzy-5-phenvl-pentanoyloxv)- 4-oxo-pentanoic acid MS (ESI) m/z 537.3 EXAMPLE 3-(2-Acetvlamino-3-methyl-butvrvlamino)-4-oxo-5-(1-oxo-1,2,3 ,4-tetrahydronaphthalen-2-yl)-acetoxyl-pentanoic acid MS (ESI) m/z 475.3 EXAMPLE 5-(3-Benzyl-4-phenyl-butyrvloxy)-3 -r3-methyl-2-(3 -phenyl-propionylamino)butvrvlaminol-4-oxo-pentanoic acid MS (ESI) m/z 601.3 EXAMPLE 3-r2-(3-Acetwlamino-2-oxo-2H-pvridin-I -yl)-acetvlaminol-5-(3,3-diphenvlpropionyloxy)-4-oxo-pentanoic acid as a course pink powder. The starting acid was prepared as described in Bioorganic Medicinal Chemistry Letters, 1997;7:1337-1342.
Analysis calculated for C 2 9
H
2 9
N
3 0 8 0.585 CF 3
CO
2 H (614.274): C, 58.99; H, 4.86; N, 6.84.
Found: C, 59.38; H, 5.16; N, 6.20.
EXAMPLE Saa 3-[2-(3-Acetvlamino-2-oxo-2H-pyridin- I -vi)-acetYlaminol-5-(2-benzvl-3-phenylpropionloxy)-4-oxo-pentanoic acid as a fine brown powder. The starting acid was prepared as described in Bioorganic Medicinal Chemistry Letters, 1997;7: 1337- 1342.
Analysis calculated for C 3 0
H
3 1
N
3 0 8 0.468 CF 3
CO
2 H (614.960): C, 60.42; H, 5.16; N, 6.83.
Found: C, 60.82; H, 5.39; N, 6.42.
WO 98/16502 PCT/US97/18514 -99- EXAMPLE 6 3-[2-(2-Benzvloxycarbonvlamino-4-carboxy-butvrylamino)-3-methlbutvrvlaminol-5-(naphthalen-1-yl-acetoxy)-4-oxo-pentanoic acid Step A A mixture of HCl*H-Asp (OtBu)-OMe (13.1 g, 54.6 mmol), Z-Val-OH (15.1 g, 60.1 mmol), HOBT*H 2 0 (9.2 g, 60.0 mmol), 1-ethyl-3-(3'dimethylaminopropyl)carbodiimide hydrochloride (EDCI*HCl, 11.5 g, 60.0 mmol) and 4-methylmorpholine (7.5 mL, 68.2 mmol) in 500 mL of dichloromethane was stirred at room temperature under nitrogen for 12 hours. The mixture was concentrated, then partitioned between ethyl acetate and sat. NaHCO 3 solution.
The organic extract was washed with sat. KH 2
PO
4 and brine solutions, dried (MgSO 4 filtered and concentrated to give 23.9 g of 2-(2-benzyloxycarbonylamino-3-methyl-butyrylamino)-succinic acid 4-tert-butyl ester 1-methyl ester as a white solid. MS (APCI) m/z (rel intensity) 436.9 100), 380.9 (M-56, 94).
Step B A solution of 2-(2-benzyloxycarbonylamino-3-methyl-butyrylamino)succinic acid 4-tert-butyl ester 1-methyl ester (23.8 g, 54.5 mmol, Example 6, Step A) and concentrated hydrochloric acid (5.0 mL, 60.5 mmol) in 600 mL of EtOH:THF was treated with 20% Pd/C (2.0 g) and hydrogenated at room temperature, 50 psig H2 for 1.2 hours. The sample was filtered and concentrated.
The resultant oily solid was washed with diethyl ether, filtered and vacuum dried to give 16.5 g of 2-(2-amino-3-methyl-butyrylamino)-succinic acid 4-tert-butyl ester 1-methyl ester, hydrochloride as a white solid, mp 166-167 0
C.
MS(APCI) m/z (rel intensity) 302.1 20), 301.1 100).
Analysis calculated for C 14
H
2 6
N
2 0 5 *HCI (338.835): C, 49.63; H, 8.03; N, 8.27.
Found: C, 49.62; H, 8.19; N, 8.21.
WO 98/16502 PCTIS97/18514 -100- Step C A mixture of HCl-H-ValAsp (OtBu)-OMe (2-(2-amino-3-methylbutyrylamino)-succinic acid 4-tert-butyl ester 1-methyl ester, hydrochloride, 15.4 g, 45.6 mmol, Example 6, Step Z-Glu(OtBu)-OH (15.8 g, 46.9 mmol),
HOBT-H
2 0 (7.7 g, 50.1 mmol), EDCI-HC1 (9.6 g, 50.1 mmol) and 4-methylmorpholine (6.3 mL, 57.3 mmol) in 500 mL of dichloromethane was stirred at room temperature under nitrogen for 12 hours. The mixture was concentrated, then partitioned between ethyl acetate and sat. NaHCO 3 solution.
The organic extract was washed with sat. KH 2 P0 4 and brine solutions, dried (MgSO4), filtered and concentrated to give 26.3 g of Z-Glu(OtBu)ValAsp(OtBu)-OMe [2-(2-benzyloxycarbonylamino-4-tertbutoxycarbonyl-butyrylamino)-3-methyl-butyrylamino]-succinic acid 4-tert-butyl ester 1-methyl ester] as a white solid. MS(APCI) m/z (rel intensity) 622.0 100), 565.9 (M-56, 68).
Analysis calculated for C 3 1
H
4 7
N
3 0 1 0 (621.734): C, 59.89; H, 7.62; N, 6.76.
Found: C, 59.88; H, 7.63; N, 6.70.
Step D A solution of Z-Glu(OtBu)ValAsp(OtBu)-OMe (17.2 g, 27.6 mmol, Example 6, Step C) and 0.1N sodium hydroxide (330 mL, 33.0 mmol) in 300 mL of ethanol was stirred at room temperature under nitrogen for 1 hour. The slightly cloudy solution was concentrated (to remove most of the ethanol), acidified with saturated KH 2
PO
4 solution to a pH -5 and extracted twice with 500 mL of chloroform:methanol The combined organic extract was dried (MgSO 4 filtered, and concentrated to give 15.0 g of Z-Glu(OtBu)ValAsp(OtBu)-OH as a foamy white solid.
Analysis calculated for C 3 0
H
4 5
N
3 010 (607.707): C, 59.29; H, 7.46; N, 6.91.
Found: C, 59.26; H, 7.57; N, 6.54.
WO 98/16502 PCTIUS97/18514 -101- Step E A solution of Z-Glu(OtBu)ValAsp(OtBu)-OH (14.9 g, 24.6 mmol) and 4-methylmorpholine (2.7 mL, 24.6 mmol) in 200 mL of THF at ca. -40 oC (Dry Ice- CH 3 CN bath) was treated with iso-butyl chloroformate (3.2 mL, 24.6 mmol).
Solid immediately formed. The sample was stirred for 15 minutes, then treated with cold diazomethane (300 mL of an ether solution, freshly prepared for Diazald). The sample was stirred at room temperature for 2 hours, cooled to 0 C and quenched by dropwise addition of a 48% hydrobromic acid-acetic acid solution (35 mL of each). The ice-bath was removed, the sample was stirred at room temperature for 30 minutes, then extracted with ethyl acetate-water (500 mL of each). The organic extract was washed with water, sat. NaHCO 3 and brine solutions, dried (MgSO 4 filtered, and concentrated. The residue was crystallized from dichloromethane-hexanes to give 10.5 g of benzyloxycarbonylamino-4-tert-butoxycarbonyl-butyrylamino)-3-methylbutyrylamino]-5-bromo-4-oxo-pentanoic acid tert-butyl ester (Z-Glu(OtBu)ValAsp(OtBu)CH 2 Br) as a white solid.
Analysis calculated for C 3 1
H
4 6 BrN 3 0 9 (684.636): C, 54.39; H, 6.77; N, 6.14.
Found: C, 54.24; H, 6.63; N, 6.08.
Step F A mixture of Z-Glu(OtBu)ValAsp(OtBu)CH 2 Br (9.4 g, 13.8 mmol, Example 6, Step 1-naphthylacetic acid (3.2 g, 17.2 mmol) and potassium fluoride (2.0 g, 34.4 mmol) in 20 mL of DMF was stirred at room temperature for 12 hours. The mixture was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic extract was washed with sat. KH 2
PO
4 and brine solutions, dried (MgSO 4 filtered and concentrated to give 3-[2-(2-benzyloxyoxyconylamino-4-tert-butoxycarbonyl-butyrylamino)-3-methyl-butyrylamino]- 5-(naphthalen-1-yl-acetoxy)-4-oxo-pentanoic acid tert-butyl ester as a white solid, mp 92-105 0
C.
WO 98/16502 PCTIUS97/18514 -102- Analysis calculated for C 4 3
H
5 5
N
3 0 1 1 (789.93 1): C, 65.38; H, 7.02; N, 5.32.
Found: C, 65.13; H, 7.20; N, 5.36.
Step G A solution of 3-[2-(2-benzyloxycarbonylamnino-4-tert-butoxycarbonyl.
1-yI-acetoxy)-4-oxopentanoic acid tert-butyl ester (1.0 g, 1.27 mmol, Example 6, Step F) and 10 mL of trifluoroacetic acid in 20 mL of dicliloromethane was stirred at room temperature for 1 hour. The solution was concentrated to a light yellow oil. Ether (-50 mL) was added and the oil slowly solidified. The mixture was filtered and vacuum dried to give 0.81 g of 3-[2-(2-benzyloxycarbonylamino- 4-carboxy-butyrylamino)-3-methyl-butyrylamnino]-5-(naphthalen- I -yl-acetoxy)- 4-oxo-pentanoic acid as a white solid.
Analysis calculated for C 35
H
39
N
3 0 1 v' 0 70
H
2 0 (690.325): C, 60.90; H, 5.90; N, 6.09.
Found: C, 60.90; H, 5.90; N, 6.30.
In a process analogous to Example 6, the corresponding compounds were prepared: EXAMPLE 6a 3-f2-(2-Benzvloxvcarbonvylamino-3-methyl-butvrvlamino)-propionylarninol- 5-(naphthalen-1I-yl-acetoxy)-4-oxo-pentanoic acid as a white solid, mp 160-163'C.
Analysis calculated for C 3 3
H
3 7
N
3 0 9 *0.50 H 2 0 (628.685): C, 63.05; H, 6.09; N, 6.68.
Found: C, 63.13; H, 5.96; N, 6.68.
WO 98/16502 PCT/US97/18514 -103- EXAMPLE 6b 3 -(2-Acetylamino-3-methyl-butyrvlamino)-5-(naphthalen- I yI-acetoxy)-4-oxopentanoic acid MS (APCI) m/z 457.5 (M+1) EXAMPLE 6c 3-[2-(2-Benzvloxycarbonylamino-3-methyl-butyrvamino)-propionylaninol- 5-(3,3-diphenvl-propionyloxy)-4-oxo-pentanoic acid as a white solid, mp 99-104'C.
Analysis calculated for C 3 6 11 4
IN
3 0 9 (659.743): C, 65.54; H, 6.26; N, 6.37.
Found: C, 65.25; H, 6.23; N, 6.25.
EXAMPLE 6d 3-(2-Benzvloxycarbonylamnino-3-methyl-naphthalen-lI-yl-acetoxy)-4-oxopentanoic acid MS (APCI) m/z 549.0 (M+1) EXAMPLE 6e 3-[2-(2-Benzyloxvcarbonylamino-4-carboxy-butvrlamino)-3-methylbutyrvlaminol-5-(2-benzvl-3 -1henyl-propionyloxv)-4-oxo-pentanoic acid as white solid.
Analysis calculated for C 39
H
45
N
3 0 1 1- 0 50
H
2 0 (740.8 C, 63.23; H, 6.26; N, 5.67.
Found: C, 63.14; N, 6.16; N, 5.55.
WO 98/16502 PCT/US97/18514 -104- EXAMPLE 6f 3 -[2-(2-Benzyloxycarbonlamino-3 -methvl-butvrvlamino)-Pronionlamnol- 2 -benzvl-3-phenyl-propionvloxy)-4-oxo-pentanoic acid as a white solid.
Analysis calculated for C 3 7
H
43
N
3 0 9 0.13 CF 3
CO
2 H (688.593): C, 64.99; H, 6.31; N, 6.10.
Found: C, 64.98; H, 6.50; N, 6.10.
EXAMPLE 6g 3- r2-(2-Benzvloxycarbonlamino-3 -methl-butvalamino)-propionylaminol- I -vl-acetoxv)-4-oxo-Dentanoic acid as a white solid.
Analysis calculated for C 3 3
H
3 7
N
3 0 9 *0.25 CF 3
CO
2 H (648.184): C, 62.08; H, 5.79; N, 6.48.
Found: C, 62.07; H, 5.85; N, 6.68.
EXAMPLE 6h 3-(2-12-[2-Acetylamino-3-(4 -hdroxy-phenyl)-propionylamino]-4-carboxybutrylaminol 3 -methvl-butvrvamino)-5-(2-benzyl-3-phenvl-proionvloxy)- 4-oxo-pentanoic acid as a white solid, mp 156-168'C, dec.
Analysis calculated for C 4 2
H
5 0
N
4 0 1 2
-H
2 0 (820.902): C, 61.45; H, 6.38; N, 6.82.
Found: C, 61.43; H, 6.27; N, 6.76.
EXAMPLE 6i 5-(2-Benzvl-3-phenvl-propionyloxv)-3- (2-[4-carboxy-2-(3-phenylpropionlamino)-butvrvlaminol-3 -methyl-butyrylamino 4 -oxo-pentanoic acid as a white solid.
Analysis calculated for C 4 0
H
4 7
N
3 0 1 0*0. 13 CF 3
CO
2 H (744.65 8): C, 64.94; H, 6.38; N, 5.64.
Found: C, 64.93; H, 6.63; N, 5.61.
WO 98/16502 PCT/US97/18514 -105- EXAMPLE 6j 3-f 2- [4-Carboxy-2-(3-phenvl-propionvylamino)-butvrvlaminol-3-methyl= butyrylaminol~-5-(naphthalen-1I-yl-acetoxy)-4-oxo-pentanoic acid as a white solid.
Analysis calculated for C 3 6
H
4 1
N
3 0 10 *0.44 CF 3
CO
2 H (725.9 13): C, 61.02; H, 5.75; N, 5.79.
Found: C, 61.04; H, 6.04; N, 6.19.
EXAMPLE 6k 3-(2-Benzloxycarbonvylamino-3-methyl-butvrlamino)-5-(3 .3-diphenylpropionyloxy)-4-oxo-pentanoic acid MS (APCI) m/z 588.9 (M+1) EXAMPLE 61 3-(2-Acetvlamino-3-hydroxy-butyrylamino)-5-(naphthalen- I -YI-acetoxy)-4-oxopentanoic acid MS (APCI) ni/z 456.9 (M-1) EXAMPLE 6m 3-(2-Acetvlamino-3 -hydroxy-butvrlamino)-5-(3 .3 -diphenyl-propionyloxy)-4-oxop2entanoic acid MS (APCI) m/z 496.9 (M-1) EXAMPLE 6n 3-(2-1~2-[2-Acetylamino-3 H-indol-3-yl)-propionvylaminol-4-carboxybutyrylamino l-3 -methyl-butvrlamino)-5-(2-benzv-3-p~henyl-propionlyloxy)- 4-oxo-pentanoic acid as an orange solid.
Analysis calculated for C 44
H
5 lN 5 0 1 1 1 33
H
2 0 (849.944): C, 62.18; H, 6.36; N, 8.24.
Found: C, 62.16; H, 6.24; N, 8.18.
WO 98/16502 PCTfUS97/18514 -106- EXAMPLE 6o 5-(3 .3-Diphenvyl-rpropionyloxy)-4-oxo-3-[2-(4-phenvl-butyryamino)propionylaminol-pentanoic acid MS (APCI) m/z 573.2 (M+1) EXAMPLE 7 34(2-f 2-2-Acelylamino-3-( H-indol-3-yl)-propionylaminol-4-carboxybutyrlaminol -3-methvl-butvrvlamino)-5-(naphthalen- 1 -yl-acetoxy)-4-oxoventanoic acid Step A A solution of 3-[2-(2-benzyloxycarbonylamino-4-tert-butoxycarbonyl- I -yl-acetoxy)-4-oxopentanoic acid tert-butyl ester (5.3 g, 6.7 mmol, Example 6, Step F) in 300 mL of ethanol:THF 1) was treated with 0.6 g of 20% Pd/C andhydrogenated at room temperature, balloon pressure for 3 hours. The sample was filtered and concentrated to 5.0 g of 3-[2-(2-amino-4-tert-butoxycarbonyl- I -yl-acetoxy)-4-oxopentanoic acid tert-butyl ester as yellow oil.
Step B A mixture of 3-[2-(2-amino-4-tert-butoxycarbonyl-butyrylamino)- 3-methyl-butyrylamino] -5-(naphthalen-1I-yl-acetoxy)-4-oxo-pentanoic acid tertbutyl ester (1.25 g, 1.91 mmol, Example 7, Step AcTrp-OH (0.52 g, 2. 10 mmol), HOBT*H 2 0 (0.32 g, 2. 10 mmol), EDCI*HCl (0.40 g, 2. 10 mmol) and 4-methylmorpholine (0.26 mL, 2.36 mnmol) in 25 mL of dichioromethane was stirred at room temperature for 12 hours. The sample was concentrated, then partitioned between ethyl acetate and sat. NaHCO 3 solution. The organic extract was washed with sat. KH 2
PO
4 and brine solutions, dried (MgSO 4 filtered and concentrated. The residue was chromatographed (MPLC, silica gel, 25% hexanesethyl acetate) to give 0.95 g of 3-(2-{2-[2-acetylamino-3-(1H-indol- 3-yl)-propionylamnino]-4-tert-butoxycarbonyl-butyrylamino)}-3-methyl- WO 98/16502 PCTIUS97/18514 -107- I -yl-acetoxy)-4-oxo-pentanoic acid, tert-butyl ester as a white solid.
Step C A solution of {2-[2-acetylamino-3-( 1H-indol-3-yl)-propionylamino]- 4-tert-butoxycarbonyl-butyrylamino} -3-methyl-butyrylamino)-5-(naphthalen- l-yIacetoxy)-4-oxo-'pentanoic acid, tert-butyl ester (0.93 g, 1.05 mmol, Example 7, Step B) and 10 ml, of trifluoroacetic acid in 20 mL of dichloromethane was stirred at room temperature for 2 hours. The sample was concentrated to a purple oil.
Ether (-50 mL) was added and the oil slowly solidified. The sample was filtered and vacuum dried to give 0.78 g of 3-(2-{2-[2-acetylamino-3-(lH-indol- 3-yl)-propionylamino] -4-carboxy-butyryl amino)}-3-methyl-butyrylamnino)- I -yl-acetoxy)-4-oxo-pentanoic acid as a light purple solid.
Analysis calculated for C 40
H-
45
N
5 0 1 1- 0 50
H
2 0 (780.839): C, 61.53; H, 5.94; N, 8.97.
Found: C, 61.45; H, 6.12; N, 8.81.
In a process analogous to Example 7, the corresponding compounds were prepared: EXAMPLE 7a 3-[2-(2-Acetvlamino-4-carboxy-butvrlamino)-3 -methyl-butyryaminol- 5-(naphthalen-l -yl-acetoxy)-4-oxo-pentanoic acid as an off-white solid.
Analysis calculated for C 2 9
H
3 5
N
3 0 1 0
-H
2 0 (603.632): C, 57.70; H, 6.18; N, 6.96.
Found: C, 57.59; H, 6.11; N, 7.28.
EXAMPLE 7b 3 f2-[2-Acetylamino-3-( 4 -hydroxy-p~henvl)-poronionylamino1-4-carboxybutyrlamino l-3-methyl-butvrvlamino)-5-(naphthalen-1I-yl-acetoxv)-4-oxopentanoic acid as a white solid.
WO 98/16502 PCTIUS97/18514 -108- Analysis calculated for C 3 8
H
4 4
N
4 0 1 2
*H
2 0 (766.809): C, 59.52; H, 6.00; N, 7.31.
Found: C, 59.36. H, 5.79; N, 7.24.
EXAMPLE 8 3-[(2-Carboxy-cclohexanecarbonvl)-aminol-5-(naphthalen-1 -vl-acetoxy)-4-oxopentanoic acid Step A A solution of the hydrochloride salt of 3 amino-5-(naphthalene- 1-ylacetoxy)-4-oxo-pentanoic acid tert-butyl ester (1.7 g, 4.6 mmol) (Example 2, Step A) and 1,2-trans-cyclohexanedicarboxylic anhydride (0.79 g, 5.1 mmol) in mL of methylene chloride was treated with pyridine (5 mL) and a catalytic amount of dimethylaminopyridine (DMAP). The reaction mixture was stirred at room temperature overnight and the solvent was evaporated. The residue was partitioned between diethyl ether and 5% HCl, and the layers separated. The organic layer was washed with 5% HCI, dried (MgSO4), filtered, and concentrated. The crude product was purified by flash chromatography (silica gel acetone/l% formic acid/methylene chloride) to give 0.3 g of pure I -yl-acetoxy)-4-oxopentanoic acid tert-butyl ester as a mixture of two diastereomers.
MS (APCI) m/z 524 Step B A solution of 3-[(2-carboxy-cyclohexanecarbonyl)-amino]-5-(naphthalen- I -yl-acetoxy)-4-oxo-pentanoic acid tert-butyl ester (0.181 g, 0.3444 mmol) in 6 mL methylene chloride was treated with 4 mL of 50% trifluoroacetic acid (in methylene chloride). The reaction mixture was stirred at room temperature for 4 hours, diluted with toluene (50 mL), and concentrated under reduced pressure to give 3-[(2-carboxy-cyclohexanecarbonyl)-amino]-5-(naphthalen-1 -yl-acetoxy)- 4-oxo-pentanoic acid as a colorless solid (mixture of two diastereomers).
MS (APCI m/z 470 (M+1) WO 98/16502 PCTIUS97/18514 -109- EXAMPLE 8a 3- r(2-Methoxvcarbonyl-cyclohexanecarbonvl)-aminol-5-(naphthalen-1I-viacetoxy)-4-oxo-pentanoic acid Step A A solution of 3-[(2-carboxy-cyclohexanecarbonyl)-amino]-5-(naphthalen- I-yl-acetoxy)-4-oxo-pentanoic acid tert-butyl ester (2.3 mmol) (Example 8, Step A) in 5 mL methylene chloride was treated with excess of diazo methane in ether. The reaction mixture was stirred for 3 hours at room temperature and then quenched by the dropwise addition of glacial acetic. The solvent was evaporated under reduced pressure to give 3-[(2-methoxycarbonyI-cyclohexanecarbonyl)amino] -5-(naphthalen- 1 -yl-acetoxy)-4-oxo-pentanoic acid tert-butyl ester.
MS (APCI) mlz 540 (M+1) Step B The targeted compound was prepared from the corresponding tert-butyl ester as described for Example 8, Step B to yield 3-[2-methoxycarbonyl- I -yl-acetoxy)-4-oxo-pentanoic acid.
MS (APCI) m/z 484 (M+1) EXAMPLE 8b 3-[(2-Carbamoyl-cyclohexanecarbonl)-amino]-5-(naphthalen- 1 -yl-acetoxy)- 4-oxo-pentanoic acid Step A A solution of DCC (0.18 g, 0.88 mmol) and HOBT (0.12 g, 0.88 mmol) in ml, methylene chloride was added dropwise to a solution of 3-[2-carboxycyclohexanecarbonyl)-amino]-5-(naphthalen-1I-yl-acetoxy)-4-oxo-pentanoic acid tert-butyl ester (0.45 g, 0.85 mmol) (from Example 2, Step A) and triethylamine (0.099 g, 0.98 mmol) in 25 mL methylene chloride and the reaction mixture was stirred for 30 minutes at room temperature. Hexamethyldisilazane (0.80 g, 4.9 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 100 ml, ether and extracted three times with 5% HC1, then washed with saturated NaCi. The organic layer was dried WO 98/16502 PCT/U~S97/18514 -110- (MgSO 4 filtered and concentrated under reduced pressure. The residue was taken up in ether/hexane, filtered, and concentrated to give a sticky foam. After purification by flash chromatography, 3[(2-carbamoyl-cyclohexanecarbonyl)amino]-5-(naphthalen-1-yl-acetoxy)-4-oxo-pentanoic acid tert-butyl ester (0.086 g) was obtained as a mixture of two diastereomers.
MS (APCI) m/z 525 (M+1) Step B The targeted compound was prepared from the corresponding tert-butyl ester as described for Example 8, Step B to yield 3-[(2-carbamoylcyclohexanecarbonyl)-amino]-5-(naphthalen-1 -yl-acetoxy)-4-oxo-pentanoic acid.
MS (APCI) m/z 467 EXAMPLE 9 3-(3-Benzvlsulfanvl-2-methvl-propionylamino)-5-(naphthalen- -vl-acetoxy)- 4-oxo-pentanoic acid Step A To a solution of 3-benzylsulfanyl-2-methyl-propionic acid (3.3 g, 15.8 mmol) and H-Asp(OtBu)OMe*HCI (3.7 g, 15.8 mmol) in dimethylformamide mL) was added at 0°C 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide*HCl (3.25 g, 17.0 mmol) and triethylamine (4.4 g, 43.8 mmol). The mixture was stirred at room temperature for 16 hours. Most of the solvent was removed under reduced pressure, the residue was partitioned between ethyl acetate and 5% citric acid. The ethyl acetate extract was washed with sodium hydrogen carbonate and water, dried over sodium sulfate, and concentrated to give 6.3 g of an amorphous residue. The residue was dissolved in 100 mL of dioxane/water and hydrolyzed in the presence of thymolphthalein by dropwise addition of IN NaOH (15.0 mL). After evaporation of most of the dioxane and dilution with water, the aqueous solution was extracted with ether, acidified with dilute HCI to pH 2-3, and the product extracted into ethyl acetate. The ethyl acetate extract was washed with water, dried over sodium sulfate, and concentrated to give 6.3 g of crude product.
WO 98/16502 PCTIS9718514 -111- Chromatography over silica gel (dichloromethane/methanol 30:1) afforded 5.5 g of N-(3-benzylsulfanyl-2-methyl-propionyl)-aspartic acid 4-tert-butyl ester.
Step B To a solution of N-(3-benzylsulfanyl-2-methyl-propionyl)-aspartic acid 4-tert-butyl ester (5.4 g, 14.2 mmol) in tetrahydrofuran (670 mL) at -15 0 C was added N-methylmorpholine (1.5 mL, 16.0 mmol) followed by dropwise addition of ethyl chloroformate (1.6 mL, 16.0 mmol). After 15 minutes at -10 0 C, 110 mL of a 0.2N solution of diazomethane in ether was added dropwise. The reaction was kept for 2 hours at room temperature, then 40 mL of a solution of 48% HBr in glacial acetic acid was added dropwise at 0°C. After stirring for 15 minutes, the reaction mixture was poured into ethyl acetate. The organic phase was washed 3x with saturated aqueous sodium hydrogencarbonate then with water, dried over sodium sulfate, and concentrated under reduced pressure to give 3-(3benzylsulfanyl-2-methyl-propion-1 -yl)amino-5-bromo-4-oxo-pentanoic acid tert-butyl ester (4.2 g).
Step C To a mixture of 3-(3-benzylsulfanyl-2-methyl-propionyl)amino-5-bromo- 4-oxo-pentanoic acid tert-butyl ester (0.92 g, 2.0 mmol) and potassium fluoride (0.35 g, 6.0 mmol) in dimethylformamide (40 mL) was added 1-naphthalenelacetic acid (0.37 g, 2.0 mmol). The mixture was stirred at room temperature for 16 hours. Most of the solvent was evaporated under reduced pressure, the residue was partitioned between ethyl acetate and water. The organic phase was washed successively with aqueous sodium hydrogen carbonate and water, dried over sodium sulfate, and evaporated under reduced pressure.
Chromatography over silica (dichloromethane/acetone 40:1) gave 0.46 g 3-(3- 1-yl-acetoxy)-4-oxopentanoic acid tert-butyl ester.
WO 98/16502 PCTIUS97/18514 -112- Step D 3 -(3-Benzylsulfanyl-2-methyl-propionyl)amino-5-(naphthalene- 1yl)acetoxy-4-oxo-pentanoic acid tert-butyl ester 12 g, 0.21 mmol) in 10 ml, of a 1: 1 mixture of dichioromethane/trifluoroacetic acid containing 0. 1 mL of anisol was stirred at room temperature for 45 minutes. Evaporation under reduced pressure followed by chromatography over silica (dichioromethane/methanol 40:1 to 20: 1) gave 3-(3-benzylsulfanyl-2-methyl-propionylamino)-5-(naphthalene- 1 -yb.
acetoxy)-4-oxo-pentanoic acid 11 g).
MS (ESI) m/z 508.4 (M+1) EXAMPLE 9a 3-(2-Methvl-3-phenylmethanesulfon-yl-propionvlamino)-5-(naphthalen-1I-ylacetoxy)-4-oxo-p~entanoic acid Step A To 3-(3 (naphthalene-1I-yl-acetoxy)-4-oxo-pentanoic acid tert-butyl ester (0.33 g, 0. 58 mmol) in ethanol (10 mL) from Example 9, Step C in 10 ml, of ethanol was added at 0 0 C under stirring potassium monoperoxysulfate (1.74 mmol as a solution of 0.54 g oxone in 2 mL of water). The resulting slurry was stirred for 4 hours at room temperature. The reaction mixture was partitioned between dichioromethane and water. The organic phase was washed with aqueous sodium hydrogen carbonate and water, dried over sodium sulfate, and evaporated under reduced pressure. Chromatography over silica (dichloromethane/acetone 40: 1) gave 0.25 g of 3-(3-phenylmethanesulfanyl-2-methyl-propionyl)amino-5- (naphthalene- I -yl-acetoxy)-4-oxo-pentanoic acid tert-butyl ester.
Step B 3-(3 -Phenylmethanesulfanyl-2-methyl-propionyl)amino-5-(naphthalene- 1yl-acetoxy)-4-oxo-pentanoic acid tert-butyl ester (0.21 g, 0.3 5 mmol) in 20 ml, of a 1: 1 mixture of dichioromethane/trifluoroacetic acid containing 0.2 ml, of anisol was stirred at room temperature for 45 minutes. Evaporation under reduced pressure followed crystallization from dichioromethane/ether/hexane gave WO 98/16502 PCTI~S97/18514 -113- 3-(2-methyl-3-phenylmethanesulfonyl-propionylamino)-5-(naphthalene- 1-ylacetoxy)-4-oxo-pentanoic acid (0.16 g).
MS (ESI) m/z 540.2 (M+1) EXAMPLE 9b 3-[3-(2-Carboxy-ethanesulfanl)-2-methyl-propionylamino-5-(naphthalen- -vlacetoxy)-4-oxo-Dentanoic acid Step A To a solution of 3-(2-tert-butyloxycarbonyl)ethanesulfanyl-2-methylpropionic acid (5.0 g, 20.0 mrnmol) and H-Asp(OtBu)OMe*HCI (4.8 g, 20.0 mmol) in dimethylformamide (60 mL) was added at 0 0 C 1 -ethyl-3-(3'dimethylaminopropyl)carbodiimide*HCI (3.85 g, 20.0 mmol) and triethylamine g, 60 mmol). The mixture was stirred at room temperature for 16 hours. Most of the solvent was removed under reduced pressure, the residue was partitioned between ethyl acetate and 5% citric acid. The ethyl acetate extract was washed with sodium hydrogen carbonate and water, dried over sodium sulfate, and concentrated to give after silica gel chromatography (dichloromethane/acetone 15:1) 5.5 g of an amorphous residue. The residue was dissolved in 50 mL of dioxane/water and hydrolyzed in the presence of thymolphthalein by dropwise addition of IN NaOH (12.5 mL). After evaporation of most of the dioxane and dilution with water, the aqueous solution was extracted with ether, acidified with dilute HCI to pH 2-3, and the product extracted into ethyl acetate.
The ethyl acetate extract was washed with water, dried over sodium sulfate, and concentrated to give 5.2 g of N-(3-(2-tert-butyloxycarbonyl)ethanesulfanyl-2methyl-propionyl))-aspartic acid 4-tert-butyl ester.
Step B To a solution of N-(3-(2-tert-butyloxycarbonyl)ethanesulfanyl-2-methylpropionyl)-aspartic acid 4-tert-butyl ester (4.5 g, 10.7 mmol) in tetrahydrofuran mL) at -15 0 C was added N-methylmorpholine (1.65 mL, 15.0 mmol) followed by dropwise addition of ethyl chloroformate (1.35 mL, 13.5 mmol). After 15 minutes at -10 0 C, 105 mL of a ca 0.2N solution of diazomethane in ether was WO 98/16502 PCT/US97/18514 -114added dropwise. The reaction was kept for 2 hours at room temperature, then mL of a solution of 48% HBr in glacial acetic acid was added dropwise at 0 0 C. After stirring for 15 minutes, the reaction mixture was poured into ethyl acetate. The organic phase was washed 3x with saturated aqueous sodium hydrogencarbonate then with water, dried over sodium sulfate, and concentrated under reduced pressure to give 3-(3-(2-tert-butyloxycarbonyl)ethanesulfanyl-2methyl-propion- 1 -yl)amino-5-bromo-4-oxo-pentanoic acid tert-butyl ester (4.2 g).
Step C To a mixture of 3-(3-(2-tert-butyloxycarbonyl)ethanesulfanyl-2-methylpropionyl)amino-5-bromo-4-oxo-pentanoic acid tert-butyl ester (1.65 g, 3.3 mmol) and potassium fluoride (0.58 g, 10.0 mmol) in dimethylformamide (50 mL) was added 1-naphthalenelacetic acid (0.75 g, 4.0 mmol). The mixture was stirred at room temperature for 16 hours. Most of the solvent was evaporated under reduced pressure, the residue was partitioned between ethyl acetate and water. The organic phase was washed with aqueous sodium hydrogen carbonate and water, dried over sodium sulfate, and evaporated under reduced pressure. Chromatography over silica (dichloromethane/acetone 40:1) gave 0.89 g 3-(3-(2-tert-butyloxycarbonyl)- 1 -yl-acetoxy)-4-oxopentanoic acid tert-butyl ester.
Step D 3-(3-(2-tert-Butyloxycarbonyl)ethanesulfanyl-2-methyl-propionyl)amino- 5-(naphthalene-1-yl)acetoxy-4-oxo-pentanoic acid tert-butyl ester (0.21 g, 0.33 mmol) in 10 mL of a 1:1 mixture of dichloromethane/trifluoroacetic acid containing 0.1 mL of anisol was stirred at room temperature for 45 minutes.
Evaporation under reduced pressure and treatment of the residue with dichloromethane/ether/hexane gave 0.08 g of 3-[(3-(2-carbethoxy-ethanesulfanyl)- 1 -yl-acetoxy)-4-oxo-pentanoic acid (0.11 g).
MS (ESI) m/z 490.3 (M+1) WO 98/16502 PCT/US97/18514 -115- EXAMPLE 9c 5-(2-Benzyl-3-phenyl-propionlox)-3 43-(2-carboxv-ethanesulfonvl)-2-methvlpropionlaminol-4-oxo-pentanoic acid Step A To 5-(2-benzyl-3-phenyl-propionyloxy)-3-[3-(2-carboxy-ethanesulfanyl).
2-methyl-propionylamino]-4-oxo-pentanoic acid, tert-butyl ester (0.59 g, 0.9 mmol) prepared as described in Example 3 in 15 ml of ethanol was added at 0 0 C under stirring potassium monoperoxysulfate (2.8 mmol as a solution of 0.86 g Oxone in 3 mL of water). The resulting slurry was stirred for 3 hours at room temperature. The reaction mixture was partitioned between dichioromethane and water. The organic phase was washed with aqueous sodium hydrogen carbonate and water, dried over sodium sulfate, and evaporated under reduced pressure.
Chromatography over silica (dichioromethane/acetone 30:1) gave 0.39 g of 5-(2benzyl-3-phenyl-propionyloxy)-3-[3 -(2-carboxy-ethanesulfonyl)-2 -methylpropionylamino]-4-oxo-pentanoic acid, tert-butyl ester.
Step B 5-(2-Benzyl-3-phenyl-propionyloxy)-3-[3-(2-carboxy-ethanesulfonyl)-2methyl-propionylamino]-4-oxo-pentanoic acid, tert-butyl ester (0.33g, 0.48 mmol) in 20 mL of a 1:1 mixture of dichioromethane/trifluoroacetic acid containing 0.1 mL of anisol was stirred at room temperature for 45 minutes. Evaporation under reduced pressure followed crystallization from ether/hexane gave 5-(2benzyl-3-phenyl-propionyloxy)-3-[3-(2-carboxy-ethanesulfonyl)-2-methylpropionylamino]-4-oxo-pentanoic acid, tert-butyl ester (0.12 g).
MS (ESI) m/z 576.3 (M+1) EXAMPLE 9d 5-(2-Benzvl-3 -phenvl-proionvoxy)-3-r3-(3-carboxy-propane-l -sulfinvl)- 2-methyl-propionvlaminol-4-oxo-pentanoic acid Step A To 5-(2-benzyl-3-phenyl-propionyloxy)-3-[3-(3-carboxy-propanesulfanyl)- 2-methyl-propionylamino]-4-oxo-pentanoic acid, tert-butyl ester (0.28 g, WO 98/16502 PCTIUS97/18514 -116- 0.42 mniol) prepared as described in Example 3 in 4 mL of dichioromethane was added at -50'C under stirring 0.13 of 70% 3-chloroperbenzoic acid (0.53 mmol).
The reaction mixture kept for 1 hour at -30'C then partitioned between dichioromethane and water. The organic phase was washed with aqueous sodium hydrogen carbonate (2x) and water, dried over sodium sulfate, and evaporated under reduced pressure. Chromatography over silica (dichloromethane/acetone 1) gave 0. 15 g of 5-(2-benzyl-3-pheny1-propionyloxy)-3-[3-(3-carboxypropane-i -sulfinyl)-2-methyl-propionylamino]-4-oxo-pentanoic acid, tert-butyl ester.
Step B 5-(2-Benzyl-3-phenyl-propionyloxy)-3-[3-(3 -carboxy-propane-lI-sulfinyl)- 2-methyl-propionylamnino]-4-oxo-pentanoic acid, tert-butyl ester (0.40 g, 0. 57 mmol) in 3 0 ml, of a 1: 1 mixture of dicliloromethane/trifluoroacetic acid containing 0. 1 ml of anisol was stirred at room temperature for 45 minutes.
Evaporation under reduced pressure followed crystallization from ether/hexane gave the title compound 14 g).
MS (ESI) m/z 574.3 (M+1) In a process analogous to Example 9, using appropriately substituted sulfanyl carboxylic acids, the corresponding compounds were prepared: EXAMPLE 9e 5-(Naphthalen-1I-vl-acetoxy)-4-oxo-3-(2-phenvilmethanesulfanvl-p2ropionvlamino)pentanoic acid MS (ESI) m/z 494.3 (M+1) EXAMPLE 9f .3-(2-Methyl-3-phenvlsulfanvl-propioplamino)-5-(nahthalen- 1 -yl-acetoxv)- 4-oxo-pentanoic acid MS (El) m/z 493 WO 98/16502 PCTIUS97/18514 -117- EXAMPLE 9g 5-(2-Benzvl-3-phenyl-Ipropionvloxy)-3-(2-methyl-3-pheniylsulfanlpropionylwnino)-4-oxo-pentanoic acid MS (ESI) ni/z 548.3 (M+1) EXAMPLE 9h 3-(2-Methyl-3 -phenethylsulfanvl-propionvlamino)-5-(naphthalen- I -vi-acetoxy)- 4-oxo-12entanoic acid MS (ESI) m/z 522.2 (M+1) EXAMPLE 9i 5-(2-BeM]y-3 -pheniyl-propionyloxy)-3-(2-methyl-3-]2henethYlsulfanyl-, propionylamino)-4-oxo-pentanoic acid MS (ESI) m./z 576.3 (M+1) EXAMPLE 9j 5-(2-Benzvl-3-phe!2yl-propiopyloxy)-3-(3-benzlsulfanvl-2-methylprovionylamino)-4-oxo-pentanoic acid MS (ESI) m/z 562.3 (M+1) EXAMPLE 9k 2 -Benzvl-3-phenvl-prOoinloxy)-3-(2-benzlsulfanyl-propionylamino)-4-oxo pentanoic acid M S (ESI) m/z 546.3 (M+1) EXAMPLE 91 3-r2-Methyl-3-(3-nhenvyl-propylsulfanl)-propionylaminol.5.(naphthalen- 1 -ylacetoxy)-4-oxo-pentanoic acid MS (ESI) mlz 536.4 (M+1) In a process analogous to Example 9a, using appropriately substituted sulfone carboxylic acids, the corresponding compounds were prepared: WO 98/16502 PCTIUS97/18514 -118- EXAMPLE 9m 3 -(3-Benzenesulfonvyl-2-methyl-propionylamino)-5-(naphthalen-1 -vi-acetoxy)- 4-oxo-pentanoic acid (ESI) MS m/z 526.4 (M+1) EXAMPLE 9n 3-(3-Benzenesulfonv1l-2-methyl-provionvylanino)-5-(2-benz1-3-phenvi..
propionyloxv)-4-oxo-pentanoic acid MS (ESI) m/z 580.2 (M+1) EXAMPLE 9o 5-(2-Benzvl-3-pheniyl-propionyloxy)-3- [2-methyl-3-(2-phenyl-ethanesulfonyl)propionylaminol-4-oxo-pentanoic acid MS (ESI) m/z 608.2 (M+1) EXAMPLE 9p 3-[2-Methvl-3-(2-phenvyl-ethanesulfonvyl)-propionlaminol-5-(nanhthalen. 1-vlacetoxv)-4-oxo-pentanoic acid MS (ESI) m/z 554.2 (M+1) EXAMPLE 9q 5-(Naphthalen-1I-yl-acetoxy)-4-oxo-3 -phenylmethanesulfonyl-propionlylarnino)pentanoic acid MS (ESI) m/z 526.2 (M+1) EXAMPLE 9r 5-(2-Benzvi-3-p2henyl-propionyloxy)-3-(2-methyl-3-phenylmethanesulfonvlpropionylamino)-4-oxo-pentanoic acid MS (ESI) m/z 594.2 (M+1) WO 98/16502 PCTIUS97/18514 -119- EXAMPLE 9s 5-(2-Benzv-3-phenvl-prOpionlyloxy)-4-oxo-3-(2-phenlmethanesulfonl.
propionylamino)-pentanoic acid MS (ESI) m/z 580.1 (M+1) EXAMPLE 9t 3- [2-Methyl-3 -phenyl-propane- I I -Yl-acetoxy)-4-oxo-pentanoic acid MS (ESI) m/z 568.2 (M+1) EXAMPLE 9u 5-(2-Benzv-3-phenvyl-propioniyloxv)-3-r2-methyl-3-(3-phenyl-propane- 1 -sulfonyl)-provionylaminol-4-oxo-pentanoic acid MS (ESI) m/z 622.3 (M+1) In a process analogous to Example 9b, using appropriately substituted sulfanyl.
carboxylic acids, the corresponding compounds were prepared: EXAMPLE 9v 5-(2-Benzyl-3-phenyl-propionylox)-3-3-(2-carboxy-ethlsulfanl)2.methyl.
propionvlaminol-4-oxo-pentanoic acid MS (ESI) m/z 544.4 (M+1) EXAMPLE 9w 3-[3-(3-Carboxv-propvlsulfanl)-2-methvl-propionvylaminol-5-(naphthalen- 1 -viacetoxy)-4-oxo-pentanoic acid MIS (ESI) nilz 504.2 (M+l) EXAMPLE 9x 5-(2-Benzvl-3-phenyl-propionyloxy)-3-r3 -(3-carbox-propylsulfanyl)-2-meibylpropionvylaniinol-4-OXO-Dentanoic acid MIS (ESI) m/z 558.2 (M+1) WO 98/16502 PCT/US97/18514 -120- EXAMPLE 9y 3-(3-Carboxymethylsulfanyl-2-methyl-pronionvlamino)-5-(naphthalen- I -viacetoxy)-4-oxo-pentanoic acid MIS (ESI) m/z 476.1 (M+1) EXAMPLE 9z 5-(2-Benzvl-3-phenvyl-propionvlox)-3-(3-carboxvmethylsulfanv-2-methvl.
provionylamino)-4-oxo-12entanoic acid MS (ESI) m/z 530.1 (M+1) In a process analogous to Example 9c, using appropriately substituted sulfonyl carboxylic acids, the corresponding compounds were prepared: EXAMPLE 9aa 3-[3-(2-Carboxv-ethanesulfonvl)-2-methyl-propioniylaminol-5-(naphthalen-l I acetoxy)-4-oxo-12entanoic acid MS (ESI) nI/z 522.3 (M+1) EXAMPLE 9bb 3-[3-3-Carboxv-prorpane- I -sulfonvi)-2-methvl-propioniylaminol I -vl-acetoxy)-4-oxo-pentanoic acid MS (ESI) m/z 536.3 (M+1) EXAMPLE 9cc 3-(3-CarboxyMethanesulfonvyl-2-methvl-proioniamino)-5-(naphthalen1 -viacetoxy)-4-oxo-pentanoic acid MS (ESI) mlz 508.3 (M+1) EXAMPLE 9dd 5-(2-Benzv-3-phenyl-propionvyloxcy)-3-[3-(3-carboxy-propane- 1 -sulfonlyl)- 2-methyl-n~ropionvylaminol-4-oxo-pentanoic acid MS (ESI) m/z 588.3 (M-H) WO 98/16502 PCTIUS97/18514 -121- EXAMPLE 9ee 2 -Benzvl-3-phenl-propionyloxy)-3-(3-carboxvmethanesufov1i-2-methl.
propionylamino)-4-oxo-pentanoic acid MIS (ESI) m/z 560.2 (M-H) In a process analogous to Example 9d, using appropriately substituted sulfinyl carboxylic acids, the corresponding compounds were prepared: EXAMPLE 9ff 3-[34-3-Carboxy-provane- 1 I -yI-acetoxy)-4-oxo-pentanoic acid MS (ESI) m/z 520.4 (M+1) EXAMPLE 9gg 3 -r2-Methyl-3 -(3-pheniyl-propane-lI-sulfinyl)-rrOpionylaminol-5-(naphthalen- 1-vlacetoxy)-4-oxo-12entanoic acid MS (ESI) m/z 552.2 (M+1) EXAMPLE 9hh 5-(2-Benzvl-3-phenyl-propionvloxy)-3- r2-methvl-3-(3-phenl-roane-l I-sulfinl).
p~ropionylaminol-4-oxo-pentanoic acid MS (ESI) m/z 606.3 (M+1) EXAMPLE 3-(2-Carbamovlmethyl-3-methvl-butyilamnino)-5-(naphthalen- I -yl-acetoxy)-4oxo-pentanoic acid Step A A solution of (4S)-(-)-4-isopropyl-2-oxazolidinone (19.85 g, 0.154 mol) in 400 mL of THIF at -78'C under N 2 was treated dropwise with n-butyl lithium (64.5 mL, 0. 161 mol, 2.5 M solution in hexanes). Solid formed. The mixture was stirred at -78'C for 30 minutes, then treated with dropwise addition of iso-valeryl WO 98/16502 PCTIUS97/18514 -122chloride (20.6 mL, 0.169 mol). The reaction was allowed to warm to room temperature slowly overnight. The sample was concentrated then partitioned between EtOAc and saturated KH 2 0 4 solution. The organic extract was washed with brine, dried (MgSO 4 and the resultant yellow oil was chromatographed (MPLC, silica gel, 10% EtOAc in hexanes) to give 29.8 g of N-acyloxazolidone as a light yellow oil.
Step B A solution of N-acyloxazolidone (20.8 g, 97.5 mmol, Example 10, Step A) in 500 mL of THF at -78°C under N 2 was treated dropwise with sodium bis(trimethylsilyl)amide (107 mL, 107 mmol, 1.0 M solution in THF). The solution was stirred at -78 0 C for 30 minutes, then treated dropwise with a solution of tert-butyl bromoacetate (18.0 mL, 121.9 mmol) in 100 mL of THF. The sample was stirred at -78°C for 1 hour, then quenched by dropwise addition of saturated
KH
2
PO
4 solution (-125 mL). The mixture was warmed to room temperature, concentrated (to remove most of the THF), then extracted with ether. The organic extract was washed with saturated NaHCO 3 and brine solutions, dried (MgSO 4 concentrated and crystallized from ether-pet ether to give 21.1 g of [(S-(R*,R*)]-3-(4-isopropyl-2-oxo-oxazolidine-3-carbonyl)-4-methyl-pentanoic acid, tert-butyl ester, as a white solid.
Analysis calculated for C 17
H
2 9 N0 5 (327.424): C, 62.36; H, 8.93; N, 4.28.
Found: C, 62.30; H, 9.07; N, 4.09.
Step C The hydrolysis of the N-acyloxazolidone was achieved using lithium hydroperoxide following the procedure of Evans et al., Tet. Lett., 1987;28:6141-6144. To a stirring solution at 0°C of [(S-(R*,R*)]-3-(4-isopropyl- 2-oxo-oxazolidine-3-carbonyl)-4-methyl-pentanoic acid, tert-butyl ester (9.05 g, 27.64 mmol, Example 10, Step B) in 250 mL of THF was added dropwise hydrogen peroxide (14.1 mL, 138 mmol, 30 wt% solution in water) followed by WO 98/16502 PCTIS97/18514 -123- M lithium hydroxide solution (55.3 mL, 55.3 mmol). The reaction was allowed to warm to room temperature slowly overnight. The reaction was concentrated (to remove most of the THF), then the basic solution was washed with CH 2 Cl 2 (2 x 100 mL). The aqueous phase was cooled, acidified with saturated KH 2
PO
4 solution to a pH -5 and extracted into EtOAc. The organic extract was washed with brine solution, dried (MgSO 4 and concentrated to give 5.66 g of (S)-2-isopropyl succinic acid 4-tert-butyl ester as a colorless oil, which was used without further purification.
Step D A mixture of (S)-2-isopropyl succinic acid 4-tert-butyl ester (10.77 g, 49.80 mmol), (S)-2-amino-succinic acid 1-allyl ester 4-benzyl ester hydrochloride (14.93 g, 49.81 mmol), HOBT*H 2 0 (8.4 g, 54.8 mmol), EDCI*HCI (10.5 g, 54.8 mmol), and 4-methylmorpholine (8.2 mL, 74.6 mmol) in 250 mL of CH 2 C12 was stirred at room temperature for 12 hours. The mixture was concentrated, then partitioned between EtOAc and saturated NaHCO 3 solution. The EtOAc extract was washed with saturated KH 2 P0 4 and brine solutions, dried (MgSO 4 filtered, concentrated, and chromatographed (MPLC, silica gel, 20% EtOAc in hexanes) to give 19.21 g of [S-(R*,R*)]-2-(2-tert-butoxycarbonylmethyl-3-methylbutyrylamino)-succinic acid 1-allyl ester 4-benzyl ester as light yellow oil.
Step E A solution of [S-(R*,R*)]-2-(2-tert-butoxycarbonylmethyl-3-methylbutyrylamino)-succinic acid 1-allyl ester 4-benzyl ester (9.3 g, 23.0 mmol, Example 10, Step D) and trifluoroacetic acid (35 mL) in 35 mL ofCH 2 Cl 2 was stirred at room temperature under N 2 for 2 hours. The sample was concentrated, redissolved into CH 2 C1 2 then treated with EDCI-HCI (8.8 g, 46.0 mmol),
HOBT*H
2 0 (6.2 g, 46.0 mmol), and O-benzylhydroxylamine hydrochloride (7.3 g, 46.0 mmol). 4-Methylmorpholine (11.6 g, 115 mmol) was added dropwise, and the reaction mixture was stirred at room temperature overnight. The sample WO 98/16502 PCT/US97/18514 -124was diluted with CH2Cl 2 and washed successively with 5% HC1 and sat. nacho 3 solutions. The organic extract was dried (Na 2
SO
4 and concentrated to afford 10.25 g of the O-benzyl hydroxamate as a white solid which was carried on to the next step without further purification.
Step F The allyl ester was cleaved employing the procedure ofDessolin et al., Tet. Lett, 1995;36:5741-5744. A solution at 0°C under N 2 of allyl ester (10.25 g, 19.7 mmol, Example 10, Step E) and tetrakis(triphenylphosphine)palladium (0) (0.462 g, 0.40 mmol) in CH 2 Cl 2 was treated dropwise with phenylsilane (4.26 g, 39.4 mmol). The reaction mixture was allowed to warm to room temperature over a period of 1 hour, then washed with saturated KH 2
PO
4 solution. The organic layer was extracted with 0.5N NaOH. The basic aqueous phase was acidified with concentrated HCI and extracted with EtOAc. The organic extract was dried (Na 2
SO
4 filtered, and concentrated to afford 6.2 g of the substituted succinic acid 4-benzyl ester as foamy white solid.
To a solution of above acid (6.0 g, 12.8 mmol) and 4-methylmorpholine (1.3 g, 12.8 mmol) in THF (50 mL) at -42 0 C was added isobutyl chloroformate (1.8 g, 12.8 mmol) dropwise. After stirring 30 minutes, the reaction mixture was added to a solution of diazomethane in diethyl ether M, 200 mL) at 0°C. The reaction mixture was stirred for 2 hours at room temperature then cooled to 0 C. A solution of 48% HBr (20 mL) and HOAc (20 mL was added dropwise, and the reaction was stirred for 30 minutes at o0C. The sample was diluted with diethyl ether and washed with water (2x) and saturated NaHCO 3 solution The organic layer was dried (Na 2
SO
4 and concentrated. The residue was dissolved in
CH
2 Cl 2 and the product was precipitated with hexanes. The solid was collected by filtration, washed well with hexanes, and dried to afford 1.5 g of the bromomethyl ketone as a white solid.
A mixture of the bromomethyl ketone (0.440 g, 0.82 mmol), 1-naphthylacetic acid (0.300 g, 1.61 mmol), and potassium fluoride (0.116 g, WO 98/16502 PCT/US97/18514 -125mmol) in 2.0 mL of DMF was stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc and washed successively with water (2x) and saturated NaHCO 3 solution. The organic layer was dried (Na 2
SO
4 and concentrated. The residue was crystallized from CH 2 Cl 2 -hexanes to afford 0.430 g of napthyl acetic acid ester methyl ketone as a white solid.
Step G To a solution of substituted succinic acid 4-benzyl ester (0.43 g, Example 10, Step F) in 75 mL of THF was treated with Pd/C (0.050 and the mixture was hydrogenated at 50 psi H 2 room temperature for 2 hours. The reaction mixture was filtered and Raney Nickel (0.10 g) was added. The reaction mixture was again hydrogenated at 50 psi for 17 hours. The sample was filtered.
The filtrate was concentrated, and the residue was crystallized from acetonehexanes to afford 0.111 g of 3-(2-carbamoylmethyl-3-methyl- 1-yl-acetoxy)-4-oxo-pentanoic acid as a white solid.
Analysis calculated for C 24
H
2 8
N
2 0 7 *0.74 H 2 0: C, 61.30; H, 6.32; N, 5.96.
Found: C, 61.30; H, 6.37; N, 5.94.
In a process analogous to Example 10, the corresponding compounds were prepared: EXAMPLE 3 3 -Methvl-2-(phenethylcarbamovl-methyl)-butvrylaminol-5-(naphthalen -v-lacetoxy)-4-oxo-pentanoic acid as a white solid.
Analysis calculated for C 3 2
H
3 6
N
2 0 7 1.5 H 2 0 (587.676): C, 65.40; H, 6.69; N, 4.77.
Found: C, 65.23; H, 6.69; N, 4.74.
EXAMPLE 3-(3-Carboxv-2-methvl-propionvlamino)-5-(naphthalen-1-vl-acetoxy)-4-oxopentanoic acid WO 98/16502 PCTIUlS9718514 -126- EXAMPLE 11 3-(2-Methvl-3-sulfamovl-propionvlamino)-5-(naphthalen-l-vl-acetoxy)-4-oxopentanoic acid To solution of D-(-)-S-acetyl-p-mercaptoisobutyric acid (14.0 g, 86.4 mmol) in 125 mL of toluene at 0 C under N 2 was added dropwise 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 13.6 g, 89.5 mmol), and then benzyl bromide (15.3 g, 89.5 mmol) was added dropwise over a 5-minute period. The reaction was allowed to warm to room temperature overnight. The reaction was concentrated, diluted with saturated NaHCO 3 solution, and extracted with EtOAc The combined organic extract was washed with brine, dried (MgSO 4 filtered, and concentrated to give D-(-)-S-acetyl-p-mercaptoisobutyric acid, benzyl ester, which was carried on without further purification.
Chlorine gas was bubbled through a 0°C solution of D-(-)-S-acetyl-Pmercaptoisobutyric acid, benzyl ester (7.1 g, 20.5 mmol) in 80 mL of carbon tetrachloride:ethanol for 90 minutes. The solution was concentrated. The resultant sulfonyl chloride was dissolved into 70 mL of CH 2 C12, cooled to 0 C and treated with dropwise addition of a solution of triethylamine (2.4 g, 24.6 mmol) and bis(p-methoxy-benzyl)amine (5.5 g, 21.5 mmol, J. Org. Chem., 1992;57:7065) in 10 mL of CH 2 Cl 2 The solution was stirred at 0°C for 3 hours, concentrated, diluted with water, and extracted into EtOAc The combined organic extract was washed with brine, dried (MgSO 4 filtered, and concentrated.
The resultant brown oil was chromatographed (MPLC, silica gel, 30% EtOAc in hexanes) to give the sulfonamide as a light yellow oil.
A solution of the sulfonamide (8.45g, 17 mmol) in THF was treated with 20% palladium on carbon and hydrogenated at 50 psig H 2 and room temperature for 4 hours. The sample was filtered through a pad of Celite and concentrated to give the sulfonamide acid as a colorless oil, which solidified upon standing.
To a solution of the sulfonamide acid (4.1 g, 10 mmol) and pyridine (0.8 g, mmol) in 100 mL ofCH 2 Cl 2 at 0°C was added dropwise cyanuric fluoride (2.76 g, 20 mmol). The sample was stirred at 0°C for 2 hours, diluted with water, WO 98/16502 PCT/US97/18514 -127and extracted into CH 2 Cl 2 The combined CH 2 C1 2 extract was dried (MgSO 4 filtered, and concentrated. The resultant oil was dissolved into 100 mL of CH 2 Cl 2 then treated with H-Asp(OtBu)OMe.HCl (4.08 g, 17 mmol) followed by dropwise addition of 4-methyl-morpholine (2.0 g, 20 mmol). The solution was stirred at room temperature for 12 hours, then partitioned between EtOAc and saturated NaHCO 3 solution. The organic extract was washed with saturated NaH 2
PO
4 and brine solutions, dried (MgSO 4 and concentrated to give an oil which solidified upon standing.
The methyl ester (4.58 g, 7.73 mmol) was stirred in methanol (50 mL) and 0.5N aqueous NaOH (20 mL) overnight at room temperature. Methanol was removed in vacuo, and the residue was diluted with water (100 mL), then acidified with concentrated HCI and extracted with EtOAc. The organic layer was dried (Na 2
SO
4 and concentrated to afford 3.7 g of the free acid as a foamy yellow solid.
To a solution of the acid (3.7 g, 6.4 mmol) and 4-methylmorpholine (0.65 g, 6.4 mmol) in 50 mL of THF at -42 0 C was added isobutyl chloroformate (0.89 g, 6.4 mmol) dropwise. After stirring 30 minutes, the reaction mixture was added to a solution ofdiazomethane in diethyl ether M, 100 mL) at 0°C. The reaction mixture was stirred for 2 hours at room temperature, then cooled to 0°C.
A solution of 48% HBr (15 mL) and HOAc (15 mL) was added dropwise, and the reaction was stirred for 30 minutes at 0°C. The sample was diluted with diethyl ether and washed with water (2x) and saturated NaHCO 3 solution The organic layer was dried (Na 2
SO
4 and concentrated to afford 3.88 g of the bromomethyl ketone as a yellow solid.
A mixture of bromomethyl ketone (0.624 g, 1.0 mmol), 1-naphthylacetic acid (0.372 g, 2.0 mmol), and potassium fluoride (0.145 g, 2.5 mmol) in 2.0 mL of anhydrous DMF was stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc and washed successively with water (2x) and saturated NaHCO3 solution. The organic layer was dried (Na 2
SO
4 concentrated, WO 98/16502 PCTIS97/18514 -128and the residue was chromatographed (MPLC, silica gel, hexanes-EtOAc to afford 0.470 g of di-p-methoxybenzyl sulfonamide as a white solid.
A mixture of di-p-methoxybenzyl sulfonamide (0.760 g, 1.0 mmol) and ammonium cerium (IV) nitrate (CAN, 4.39 g, 8.0 mmol) was stirred in
CH
3 CN and 5% H 2 0 (20 mL) for 18 hours. The CH 3 CN was removed in vacuo, the sample was diluted with EtOAc, and washed with saturated NaHCO 3 solution The organic layer was dried (Na 2
SO
4 concentrated, and the residue was chromatographed (MPLC, silica gel, 50% EtOAc-50% hexanes) to afford 0.280 g of the desired primary sulfonamide tert-butyl ester.
The primary sulfonamide tert-butyl ester (0.375 g, 0.72 mmol) was treated with trifluoroacetic acid (5 mL) and CH 2 Cl 2 (5 mL) for 1 hour at room temperature. The solvents were removed in vacuo to afford a yellow solid. The residue was recrystallized from CH 2 Cl 2 -hexanes to afford 0.090 g of 3-(2methyl-3-sulfamoyl-propionylamino)-5-(naphthalen-l-yl-acetoxy)-4-oxopentanoic acid as an off-white solid.
Analysis calculated for C 2 1
H
2 4
N
2 0 8 S 10.27 CF 3
CO
2
H:
C, 52.23; H, 4.94; N, 5.66.
Found: C, 52.23; H, 5.07; N, 5.54.
INHIBITION STUDIES Compounds of Formula I are inhibitors of ICE as demonstrated by measurement ofK i (piM) and IC 5 0 using the protocol described herein. ICE (0.24 nM final concentration) is added to 400 gIL of HGDE buffer (100 mM HEPES, 20% glycerol, 5 mM DTT, 0.5 mM EDTA) containing 15 RiM substrate (Ac-Tyr-Val-Ala-Asp-AMC; KM 15 g.M) plus vehicle (DMSO) or inhibitor at concentrations bracketing the K i Substrate hydrolysis is monitored for 300 seconds by observing the fluorescence of released AMC using excitation at 380 nm and emission at 460 nm. Mean rates of substrate hydrolysis are evaluated WO 98/16502 PCTIS97/8514 -129by linear-regression analysis of the fluorescence vs time traces. To evaluate Ki, plots of percent inhibition vs inhibitor concentration are fit by non-linear regression to a reversible, competitive model: 100*[I] %Inhibition 100* 1+ is]
KM
where the competition factor (1 2.
PBMC Cellular Assay IC 5 0 Determinations Further evidence that compounds of Formula I are inhibitors of ICE is provided by their ability to inhibit IL-1I production in human peripheral blood mononuclear cells (PBMCs) as described herein. PBMCs are isolated from heparinized blood by centrifugation over a Ficoll cushion, then washed three times with phosphate-buffered saline. PBMCs are suspended in a medium containing RPMI 1640 with glutamine, penicillin, streptomycin, and 2% human AB serum, then plated at 106 cells per well in 96-well flat bottom plates. PBMCs are stimulated overnight with 10 ng/mL of lipopolysaccharide (LPS, E. coli strain 0111 :B4; Calbiochem) in the presence or absence of a compound of Formula I.
Medium is harvested and the level of mature IL- IP was determined using an ELISA kit from R D Systems. Compound inhibition (IC 5 0 is assessed by determining the concentration of agent which reduced IL-1 P levels by 50%. Cells were cultured for an additional 4 hours in the presence of 3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide (MTT) to determine viability. Compound toxicity can, therefore, be assessed by determining the concentration of agent which kills 50% of the cells (TC 5 0 ICE Colorimetric Dose-Response (IC 5 0 Assay Diluted inhibitor stocks are prepared by two-fold serial dilution from a primary stock whose concentration is selected (based on screening results or on WO 98/16502 PCT/US97/18514 -130prior attempts at IC 5 0 evaluation) to achieve approximately 95% inhibition in the most concentrated well. Aliquots of each dilution are transferred to a microtitre plate in triplicate.
ICE enzyme is diluted to approximately 24 nM in HGE buffer (100 mM Hepes pH 7.5, 0.5 mM EDTA, 20% glycerol, 0.1% Bovine Serum Albumin (BSA), and activated by adding dithiothreitol (DTT) to a final concentration of mM. The activated enzyme is then aliquoted into wells containing inhibitor or vehicle, and the plate is preincubated for 60 minutes at ambient temperature.
Substrate (Ac-Tyr-Val-Ala-Asp-pNA) is added to each well to a final concentration of 50 g.M, and plates are placed in the microtitre plate-reader thermostated to 25 0 C. Beginning 5 minutes after addition of substrate, absorbance (405 nm) of wells is monitored for 1 hour, and activity is calculated as the mean rate of change in absorbance during this interval.
Ich-2 (Caspase-4) Colorimetric Dose-Response (IC 50 Assay Inhibition of Ich-2 enzyme is assayed as described above for ICE, except that enzyme is used at 64 nM, and 60 g.M of the Ich-2-specific substrate Ac-Leu- Glu-Val-Asp-pNA is used instead of the ICE substrate Ac-Tyr-Val-Ala-Asp-pNA.
The results of these tests are shown below in Table 1.
WO 98/16502 WO 9816502PCT/US97/18514 -131- TABLE 1 Example ICE ICE PBMC PBMC Ich-2 Number KiqgM) IC 5 0 (4iM) IC 5 0 (pM) TC 50 (Caspase-4)
IC
5 0 (9iM)
I
la lb lc id le if ig lh Ii lj 1k 11 Im In lo Ip lq Ir Is it lu
IV
1w Ix ly lz laa, I bb Ice 1 dd lee 1ff 1 gg Ihh Iii ijj Ikk 111 1mnM Inn 0.460 4.500 4.100 0.990 1.700 1.100 1.300 1.300 6.000 0.760 0.600 1.900 0.970 14.00 76.00 6.40 2.80 5.60 3.90 8.10 8.300 16.00 6.2 1.3 9.1 5.6 4.4 1.7 7 4.3 2.1 5 7.62 5 4.1 9 2.015 6.9 21 7.5 2.64 0.82 3.100 32.000 30.000 3.600 0.686 1.170 8.100 9.200 35.000 7.600 6.500 8.500 8.200 3.000 6.000 35.00 1.100 29.000 9.70 66.60 24.000 50.00 15.8 5.8 32.2 12 12.5 19.5 6.7 12 24 14 19 38 20.7 16.6 0.92 15 3.9 6.0 24.0 >100 >100 >100 40.0 47.5 >100 57.5 47.5 >100 47.5 >100 >100 50.0 >100 >100 >100 >100 >100 >100 >100 95.0 >100 >100 >100 >100 >100 >100 3.60 73.00 25.00 3.00 2.00 0.93 26.00 26.00 38.00 23.00 8.60 13.00 7.00 48.00 3.90 23.00 6.80 53.00 52.00 >100 27.5 >100 42.5 >100 WO 98/16502 WO 9816502PCTIUS97/18514 -132- TABLE I (cont) Example ICE ICE PBMC PBMC Ich-2 Number Ki(giM) IC 50 (9iM) IC 5 0 (jiM) TC 5 0 (01M) (Caspase-4)
IC
5 0 (Wi) 100 1 pp I qq Inr 1 ss itt I uu Ivy lww lxx 1 yy lzz 1 ccc 1 ddd I eee 1 fff 1 ggg 2 2a 2b 2c 2d 2e 3 3a 3b 3c 3d 3e 3f 3g Ah 3i 3j 3k 31 3m 3n 3o 3 p 3c1 1.2 1.1 3.1 2 5.6 8.75 3.3 8.5 20 1.7 7.7 37 6.2 2.2 1.6 2.4 3.1 0.272 0.850 1.700 20.000 3.15 2.90 0.066 5.2 7.4 0.084 0.077 0.0815 0.5 0.16 0.068 0.129 17 0.79 0.92 1.8 0.283 0.0024 0.041 0.092 9.5 13 1.2 4.6 4.78 43 3.1 3.1 1.6 11.3 1.06 3.3 54.2 7 3.2 23 9.5 0.846 5.50 4.100 2.800 6.70 3.80 0.082 1.05 1.6 0.043 0.078 0.01 0.108 0.065 0.029 0.08 1 2 0.2 0.3 3.8 1.33 0.004 8 0.0575 0.0825 >100 >100 >100 >100 37.5 >100 >100 >100 67.5 >100 35.0 65.0 35.0 >100 >100 >100 7.0 >100 >100 9 19 1.2 14.5 8 16 >100 29 >100 32.5 0.65 >100 >100 >100 >100 >100 >100 >100 1.15 3.1 1.20 6.9 16.7 0.065 WO 98/16502 PTU9/81 PCTfUS97/18514 -133- TABLE 1 (cont) Example ICE ICE PBMC PBMC Ich-2 Number Ki(g.M) IC 5 0 (AiM) IC 5 0 (Wi) TC 50 (jiM) (Caspase-4)
IC
5 0 (pM) 3r 0.048 0.10 7 0 74.
3s 0.053 3t 0.17 3u 3.2 3v 0.10 3w 3.8 4 0.680 4a 0.500 4b 0.74 4c 0.14 4d 0.11 4e 0.17 4f 0.21 4g 0.6 4h 1.7 4i 0.17 4j 0.189 4k 1.6 41 0.48 1.4 0.072 Sb 5.55 Sc 0.78 0.49 6.1 Sf 4.5 3.7 3.9 Si 0.535 6.5 1.3 51 6.1 Sm 0.66 3.4 So 2.4 p 0.42 Sq 0.815 Sr 1.8 1.2 St 0.11 0.7 0.070 0.54 5.1 0.11 7.7 1.800 1.450 0.23 0.0 18 0.012 0.068 0.107 0.15 2.38 0.068 0.096 1.4 0.96 0.835 0.102 1 1.65 0.037 1.2 13.1 7.2 1.35 0.082 0.178 3.35 7.8 12 >100 12 >100 32.5 35.0 57.5 >100 0.02 1 0.05 1.9 0.05 4.1 17.00 1.20 >100 >100 16.5 44 7 >100 47.5 23 >100 42.5 39 46.5 11 52.5 26.8 3.37 0.196 17.9 0.563 1.62 1.14 3.5 0.043 4.3 27.5 72.5 52.5 100 14 WO 98/16502 WO 9816502PCTIUS97/18514 -134- TABLE 1 (cont) Example ICE ICE PBMC PBMC lch-2 Number Ki(pgM) IC 5 0 (ILM) IC 5 0 (riM TC 50 (Wi) (Caspase-4)
IC
5 0 (Wi) 1.1 4.5 1.2 6.9 52.5 0.11 0.06 0.44 2.6 32.5 6 0.000055 0.0019 1.6 6a 0.0019 0.55 6b 0.098 0.0215 6c 0.00091 0.0051 4.3 6d 0.0535 0.0075 6.8 6e 0.001 0.0029 2.9 6f 0.0015 0.0113 1.4 6g 0.0027 0.0015 6h 0.00012 0.0013 0.6 6i 0.00016 0.00343 2.8 6j 0.00005 0.0023 1 6k 0.082 0.27 61 0.42 0.058 9.3 6m 0.49 1.1 27.5 6n 0.0002 0.0035 6o 0.15 0.497 7 0.000056 0.0025 0.43 7a 0.0032 1.3 7b 0.077 0.0023 0.93 8 3.9 0.44 8a 4 0.127 8b 1.4 0.092 27.5 9 0.48 0.33 9a 0.11 0.095 9b 0.1465 0.021636 24 9c 0.1735 0.42797 22.7 9d 0.067 0.40277 23.3 9e 1.1 0.658 57.5 9f 0.37 0.27 11 9g 4.6 19 47.5 9h 0.49 0.32 9i 2.9 10 23.5 9j 6.8 22 37.5 9k 5 21.1 42.5 91 1.86 0.70227 26.7 9m 0.8 0.23 22.5 9n 2 12 52.5 WO 98/16502 WO 9816502PCT/US97/18514 -135- TABLE I (cont) Example ICE ICE PBMC PBMC Ich-2 Number Ki(g~M) IC 5 0 Wp~) IC 5 0 (pM) TC 5 0 (RM) (Caspase-4)
IC
5 0
(M
0.56 4 13 9P0.107 0.047 9q 1.1 1 9r 0.16 3.3 32.5 9s 4.8 27.786 9t 1.2 0.13825 24 9u 1.6 7.3799 28.3 9v 0.297 0.74924 27.7 9w 0.1485 0.024696 37.5 9x 0.342 0.75009 32.7 9y 0.4575 0.05863 1 41.5 9z 0.7105 4.5923 47.5 9aa 0.0515 0.012147 9bb 0.0565 0.0124 21.7 9cc 0.0915 0.0248 33.5 9dd 0.358 0.81376 9ee 0.1845 1.2318 9ff 0.06 0.0235595 24.7 9gg 0.69 0.15775 24.3 9hh 0.48 4.343 1 27
HEPES=
DTT EDTA Ac Glu Leu= Tyr= Val= Ala= Asp= AMC pNA HOBT
,AA
Me Et DMF EDCI 4-(2-hyd Dithioth Ethylene Acetyl Glutani Leucine Iroxymethyl)- I -piperazine ethane sulfonic acid reitol diamine tetra acetic acid c acid Tyrosine Valine Alanine Aspartic Acid 7-amino-4-methyl coumarin Para nitroaniline I -hydroxy benzotriazole An amino acid Methyl Ethyl Dimethyl formamide N-ethyl-N'-dimethyl aminopropyl carbodiimide

Claims (3)

1. A compound of the Formula I C0 2 H 0 N 0 KR2 H 0 0 11 wherein RI is R 3 OC-, R 3 CO-, R 3
502-, 1 R 5 NCHR 6 CO-, 0 0 NH 2 00 00 RIa 0 0 CNRaRa R I Ra 0 N "C\NC I I Ra/N I'll or Ra/ 0 01 each Ra is independently hydrogen, C 1 I-C 6 alkyl, or -(CH2)n aryl; R 2 is -(CRR),I-aryl, -(CRR)n-X-aryl, -(CRR)n-heteroaryl, -(CRR)-X-heteroaryl, WO 98/16502 WO 9816502PCTIUS97/18514 -137- -(CRR)n-(substituted-heteroary1), -(CRR)n-arY1-arY1, -(CRR)n-ary1-heteroaryl, -(CRR)n-CH(arY1) 2 -(CRR)n-cYcloalkyI, -(CRR)n-X-cYcloalkyl, -(CRR)n-heterocycle, -(CRR)n-X-heterocycle, -(CRR)n substituted heterocycle, (CH2)naryl (CRR)n- CH (CH2)n substituted ar (CRR)n-CH 0 (CRRnN\ (CH2)nheteroaryl (CRR)n-CH 0 0 ,N S- [aryl, or substituted aryl] WO 98/16502 PCTIUS97/18514 -138- Z9N -OCH11 ar or substituted aryl] 0 0 -(CRR)n 0 (CH2)naryl 0 -(CRR) 1 j-N armyl -(CRR)n CH NH aryl, -(CRR) -(CRR)n WO 98/16502 PCT/US97/18514 -139- ***(CRR)n or T4 4 '>CHR)n- or CR 1 each R is independently hydrogen, C 1 I-C 6 alkyl, halogen or hydroxy; X is 0or S; R 3 is C 1 I-C 6 alkyl, aryl, heteroaryl, -(CHR) 11 -aryl, -(CHR)n-heteroaryl, -(CHR)n-substituted heteroaryl, -(CHR)n-substituted aryl, 0 11 -(CRR)nCORa, -(CRR)nS(CH2)n-arYl, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, 0 11 -(CRR) 11 CNRaRa, WO 98/16502 WO 9816502PCTIUS97/18514 -140- 0 11 0 -(CRR) 11 -SC 1 -C 6 alkyl, J-CH 2 CH-, 0 1I -CHR 6 C-heteroaryl, 0 11 -(CRR) 1 S(CH 2 )nC0Ra, 0 0 -(CRR)nS(CH 2 )nC0Ra, 0 -(CRR)nS(CH 2 )-arY1, 11 -(CRR)nSCC I-C 6 alkyl, 0 11 -(CRR) 11 S(CH 2 )n aryl, 0 11 -(CRR)nS(CH 2 )nCO 2 Ra, WO 98/16502 WO 9816502PCT/US97/18514 -141- -C 6 alkyl 0 11 -(CH 2 )nNHOC 1 -U 6 alkyl, 0 11 -(CH 2 )nCNRbRb, cNRbRb N >2o, J-(CH 2 )naryI phenyl 0 II N Caly 0 II (CH 2 )n 0 0 I I I 0 arI 1 0 CD/-C(CRR),T- WO 98/16502 PCT/US97/18514 -142- each R' is independently C I-C 6 alkyl, C 1 I-C 6 alkylaryl, aryl, or hydrogen; each J is independently -CO 2 Rb, -CONRbRb, -SO 2 NRbRb, or -SO 2 Rb; each Rb is independently hydrogen, C 1 I-C 6 alkyl, aryl, substituted aryl; arylalkyl, heteroarylalkyl, substituted arylalkyl, or substituted heteroarylalkyl; R4~ is hydrogen, C 1 -C 6 alkyl, 0 CH 3 OC-, -phenyl, or 0 11 C I-C 6 alkyl C-; R 5 is C 1 I-C 6 alkyl-CO-, -(CH2)n aryl, 0 11 C 1 -C 6 -alkylOC-, C 1 -C6-alkyl-X-(CH 2 )nC0, 0 C 1 -C6-alkyl-X-(CH2)n0C- WO 98/16502 WO 9816502PCTIUS97/18514 -143- 0 11 -C(CRR-)naryl, 0 11 -CNRaRa, 0 11 -6uCI-L; 6 alkyl, 100 0 0 -C(CH 2 )nCNRaRa, 0 -CO(H2)narYl, 0 -(C2nsubstituted aryl, o 0 -C(CRR,-)nNHCO(CH 2 )-arY1, 0a -C-CH-N 'a RR~ -(CH2)nX(CH2)n-arYl, -C 1 I-C 6 alkyl X-C I -C 6 alkyl aryl, or 0 0 0 11 11 11 -C-CH-NHC-CH-lNHCC 1 -C 6 alkyl; 1 1 (CHr2)n CH2-heteroaryl C0 2 Ra -144- R~ais 0 I I t-C 6 alkyl, 0 -%COC 1 -C 6 ailyl, o 0 -C-C-NHC 1 -C 6 alkyl, (CHR 2 )n aryl or substituted aryl, 0 C0(CH 2 aryl, 0 C(CH 2 aryl, or .0 0 CCHNHCC-C-- 6 alKYl; CIT 2 heteroaryl R 6 is hydrogen, CI-C 6 alkyl, -(CH 2 )n aryl, -(CH 2 )nC0 2 Ra, hydroxyl. substituted CI-C 6 alkyl, or imidazole substituted C 1 -C 6 alkyl; 5 each n is independently 0 to 3, and the pharmaceutically acceptable, salts, esters, amides, and prodrugs thereof; provided that a compound of formula is not: 145 H 0 CH 3 0 P eNN N 0 H 0 0 COOH and fuirther provided that: when R' is aryl, substituted aryl, cycloalkyl, phenyl-phenyl-CH 2 piperidino, heteroaryl or substituted heteroaryl; and R' is (RSW)N-CH(R 6 then W~ is not hydrogen when R' is a side chain of an amino acid; R' is aryl-C(0)-, aryl-(CH 2 where R is H or (C 1 -C 6 )alkyl or R 5 "-NH-CH(R 6 where R' is a side chain of an amino acid and WS' is an amino acid protecting group; when R' is R 3 where Wi is CH 2 =CH-CH 2 then R 2 is not Ph(CH,) 2 Ph0(CH 2 2 trans-PhCH=CH or cyclohexyl(CH 2 2 when R' is (RsRa)N-CH(R 6 where R 6 is H, (Cl-C 6 )alkyl, benzyl. or hydroxyalkyl; Ra is H, (C,-C 6 )alkyl, phenyl or benzyl; and R' is 6 )alcyl, -C(O)-N(RaRa), -C(0)-(CI-C 6 )alkyl, -phenyl- 0-(Cl-C 6 )alkyl or -phenyl-(CH 2 )14-N(RRa); then W2 is not a phenyl or naphthyl group optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, CF 3 NOD, (Cl-C 6 )atkoxy, -CO-(C 1 -C 6 )alkyl, C 6 )alkyl, -CON(RaWa), SO 2 N(Ra-a), -S0 2 -(Cl-C 6 )alkYl, COO-(C 1 145a C 6 )alkyl, (CI-C 6 )alkyl, cycloalkyl and -O-(CH 2 1 6 -phenyl-O-(Cl-C 6 )alkyl; and when R 1 is R 5 -NIH-CH(R 6 where Wiis RlaNI1-CH(R 6 and R l is -C(O)-(CI-C 6 )alkyl or -C(O)-aryl, then R2 is not mono-, di-, tri- tetra- or penta- substituted phenyl or mono-, di-, tri-substituted phenyl, 1 naphthyl, 9-anthracyl or 3- or 4-pyridyl. 0 2. Acomoundaccrdig toClam 1 herin 1 isphe~l-%1120kI 2. A compound according to Claim 1 wherein R is phenyl- 2 -OC- 0 4. A compound according to Claim 1 wherein R' is CH 3 -OC-. A compound according to Claim 1 wherein R' is phenyl-CH 2 CH 2 -CO-. 0 CH 3 NH 6. A compound according to Claim 1 wherein R' is 0CH 3 00 .00 o.:..*CH3CH3 oo7. A compound according to Claim 1 wherein R' is C 3 CT 8. A compound according to Claim 1 wherein R' is phenyl-CH 2 -C0-. S9. A compound according to Claim 1 wherein each R' is. hydrogen. A compound according to Claim 1 wherein RW is -(CHI)-pheny1. 11. A compound according to Claim 1 wherein W 2 is -(CH 2 ).-naphthyl. 12. A compound according to Claim 1 wherein Wi is -(CH 2 ).-0-phenyl.,. 13. A compound according to Claim 1 wherein W 2 is -(CH 2 ).-0-naphthyl. 14. A compound according to Claim 1 wherein Wi is -(CH 2 ).-S-pheny1. -146- A compound according to Claim I wherein R 2 is-(CH2-CH(phenyl) 2 16. A compound according to Claim 1 wherein each Ra is hydrogen; R 1 is benzyloxycarbonyl; R 2 is aryl-X(CRR)n-, aryI-(CRR)n-, heteroaiyl- (CRR)n-, or cycloalkyl-(CRR)n-; ais 1, 2, or 3; X is 0 or S; and R is hydrogen, methyl, or benzyl. 17. A compound according to Claim 1 wherein each Ra is hydrogen; R 1 is benzyloxycarbonyl; and R 2 is -(CH2)n-naphthy1, -(CH2)n-phenyl, -(CH 2 )n-cycloaIkyl, -(CH2)n0(CH 2 )n-naPhthYI, -(CH 2 )O(CH2n-phenyl, or -(CH2n(CH 2 )nphenyl. 18. A compound according to Claim 1 wherein each Ra is hydrogen; RI is benzyloxycarbonyl; and R2 is -CH2-naphthyl. 19. A compound in accordance with Claim I wherein each Ra is hydrogen; R 1 is benzyloxycarbonyl, CO 0 II 0 -147- 0 0 0 0 -C-CH- NHC-CHNHC_-CHNHCC-C 6 dakYl, ~A CH~htray CE 3 CE 3 CH 2 CH 2 CO 2 H o 0 0 0 -~NC-CHNHC-CE,-_NHCC-C 6 akyl, I-CC\ CHIaryH CH 3 CH 3 CH 2 CH 2 CO 2 H ay 0 I -C_-CH-CH-)-S-aryl, or CE 3 -C-CHCH 2 -S-aryl. *CH. 3 0 A method of inhibiting interleukin- 1If converting enzyme, the method 15 comprising administering to a patient in need of inhibition -of .interleukin- 1If converting enzyme a therapeutically effective amount of a compo-undof any one of Claims 1 to 19. :21. A method of inhibiting Caspase-4, the method comprising Administering to *a patient in need of inhibition of Caspase-4 inhibition a Caspase-4 inhibiting aount of acompound of cAny one of Claims. 1 to 19. 22. A method of treating stroke, the method comprising administering to a patient having a stroke or having had a stroke a therapeutically effective amountofacompoundof any one of Claims 1 to 19.. -148- 23. A method of treating inflammatory diseases, the method comprising administering to a patient having an inflammatory disease a therapeutically effective amount of a compound of any one of Claims 1 to 19. 24. The method of claim 23 wherein the inflammatory disease is arthritis. 25. The method of claim 23 wherein the inflammatory disease is inflammatory bowel disease. 26. A method of treating reperfusion injury, the method comprising administering to a patient having reperfusion injury a therapeutically effective amount of a compound of any one of Claims 1 to 19. 27. A method of treating Alzheimer's disease, the method comprising administering to a patient having Alzheimer's disease a therapeutically effective amount of a compound of any one of Claims 1 to 19. 28. A method of treating shigellosis, the method comprising administering to a patient having shigellosis therapeutically effective amount of a compound of any one of Claims 1 to 19. 29. A pharmaceutically acceptable composition that contains a compound of any one of Claims 1 to 19. 30. The compounds: 3-Benzenesulfonylamino-5-(naphthalen-1-yl-acetoxy)-4-oxo-pentanoic acid; 3-Methoxycarbonylamino-5-(naphthalen-1-yl-acetoxy)-4-oxo-pentanoic acid; 5-(Naphthalen-l-yl-acetoxy)-4-oxo-3-(3-phenyl-propionylamino)-pentanoic acid; 3-Methoxycarbonylamino-4-oxo-5-phenoxyacetoxy-pentanoic acid; and -7 9 9 9 9. 9 0* 9999 9*9* 9 9 9 .999 9* 9 9 9 9 99.9 9 9 9 0* 99 9 9. .9 9 -149- 3-(2-Methanesulfonyl-l1-methyl-ethylsulfanylamino)-5-(naphthalen- 1-yl- acetoxy)-4-oxo-pentanoic acid. 31. The compounds: 1-yl-acetoxy)-4-oxo-3-phenylacetylamino-pentanoic acid; (S)-5-(Naphthalen- 1-yl-acetoxy)-4-oxo-3-(2-thiophene-2-yl-acetylamino)- pentanoic acid; 3-[(2-Carbainoyl-cyclopentanecarbonyl)-amino]-5-(naphthalen-l1-yl-acetoxy)-4- oxo-pentanoic acid; 3-[(3-Carbamoyl-bicyclo[2.2. 1]heptane-2-carbonyl)-amino]-5-(naphthalen- l-yl- acetoxy)-4-oxo-pentanoic acid; 3-(3-Methanesulfonyl-2-methyl-propionylamino)-5-(naphthalen- 1-yl-acetoxy)-4- oxo-pentanoic acid; 3-(3-Benzenesulfonyl-2-methyl-propionylamnino)-5-(naphthalen- 1-yl-acetoxy)-4- oxo-pentanoic acid; 15 3-Butyrylamiino-5-(naphthalen-2-yl-acetoxy)-4-oxo-pentanoic acid; 3-Acetylaniino-5-(naphthalen- 1-yl-acetoxy)-4-oxo-pentanoic acid; 3-(3-Methanesulfonyl-2-methyl-propionylamino)-5-(naphthalen- 1-yl-acetoxy)-4- oxo-pentanoic acid; 3-(3-Methyl-butyrylamnino)-5-(naphthalen- 1-yl-acetoxy)-4-oxo-pentanoic acid; 3-(3-Carbamoyl-propionylammno)-5-(naphthalen- 1-yl-acetoxy)-4-oxo-pentanoic acid; [S-(R*,R)--3Aeylufnl2mthlpoinlmio--nph l--yl- acetoxy)-4-oxo-pentanoic acid; and trans-3-[(3-Carbamoyl-cyclopentanecarbonyl)-amino]-5-(naphthalen- l-yl- acetoxy)-4-oxo-pentanoic acid. -150- 32. The compounds: 3-[(2-Carboxy-cyclohexanecarbonyl)-amnino]-5-(naphthalen- 1 -yl-acetoxy)-4- oxo-pentanoic acid; 3 -[(2-.Methoxyc arbonyl-cyclohexanecarbonyl)-amino]-5-(naphthalen- l-yl- acetoxy)-4-oxo-pentanoic acid; and 3-[(2-Carbamoyl-cyclohexanecarbonyl)-amino]-5-(naphthalen- 1-yl-acetoxy)- 4-oxo-pentanoic acid. 33. The compounds: 3 -(3-Benzylsulfanyl-2-methyl-propionylamino)-5-(naphthalen- 1-yl-acetoxy)- 4-oxo-pentanoic acid; 3-(2-Methyl-3-phenylmethanesulfonyl-propionylamino)-5-(naphthalen- l-yl- acetoxy)-4-oxo-pentanoic acid; 3-[3-(2-Carboxy-ethanesulfanyl)-2-methyl-propionylamnino]-5-(naphthalen- 1 -yl-acetoxy)-4-oxo-pentanoic acid; 5-(2-Benzyl-3-phenyl-propionyloxy)-3-[3 -(2-carboxy-ethianesulfonyl)-2- methyl-propionylamino]-4-oxo-pentanoic acid; 5-(2-Benzyl-3-phenyl-propionyloxy)-3-[3-(3-carboxy-propane- 1 -sulfinyl)-2- methyl-propionylamino]-4-oxo-pentanoic acid; 1-yl-acetoxy)-4-oxo-3-(2-phenyhnethanesulfanyl- propionylamino)-pentanoic acid; 3-(2-Methyl-3-phenylsulfanyl-propionylaimino)-5-(naphthalen- 1-yl-acetoxy)-4- oxo-pentanoic acid; -151- 5-(2-Benzyl-3-phenyl-propioriyloxy)-3-(2-methyl-3-phenylsulfandyl- propionylamino)A4-oxo-pentanoic acid; 3-(2-Methyl-3-phenethylsulfanyl-propionylamino)-5-(naphthalen- I -yI-acetoxy)-4-oxo-pentanoic acid- 5-(2-Benzyl-3-phenyl-propionyloxy)-3-(2-niethyl- 3-phenethylsullbnyl-propionylamino)-4-oxo-pentanoic acid; 5-(2-Benzyl-3-phenyl-propionyloxy)-3-(3-benzylsulfanyl-.2-methyl- propionylamino)-4-oxo-pentanoic acid; 5-(2-Benzy1.-3-phenyI-propionyloxy)-3-(2-benzylsiifanyl- propionylaniino)-4-oxo-pentanoic acid; 3-[2-Methyl-3-(3-pkienyl-propylsulfanyl)-propionylaniino]- I -yl-acetoxy)-4-oxo-pentanoic acid; 3-(3-Benzenesulfonyl-2-methyl-propionylamino)-5-(naphthalen- I -yi-acetoxy)-4-oxo-pentanoic acid; 15 3-(3-Benzenesulfonyl-2-methyl-propionylamino).5-(2-benzyl- ,too:%3-phenyl-propionyloxy)4-oxo-pentanoic acid; C...5-(2-Benzyl-3-phecnyl-propionyloxy)-3-[2- methyl-3-(2-phenyl- ethanesulfonyl)-propionylamino]-4-oxo-pentanoic acid; 3 -(2-Methyl-3-(2-phenyl-ethanesulfonyl)-propionylaniino]- 20 5-(naphthalen-1-yI-acetoxy)-4-oxo-pentanoic acid; C C5-(Naphthalen- I -yl-acetoxy)-4-oxo-3-(2-phenylmethanesulfonyl- :propionylamino)-entanoic acid; t C C 5 -(2-Benzyl-3-phenyl-propionylaxy)-3-(2-Methyl- SC 3 -phenylniethanesulfonyI-propionylarnino)4..oxo-pentanoic acid;, 5-(2-Benzyl-3-phenyi-propionyoxy).4-o~xo. 3-(2-phenylmethanesulfonyl-propionylanino)-pentanoic acid; 3-[ 2 -Methyl-3-(3-phenyl-propane I -sulfonyl)-propionylarnino]- 1-yi-acetoxy}4-oxo-pentanoic acid; 3 -phenyl-propionyloxy)-3.{2methyl.3-{3phenyl. propane-I -suifonyI)-propionylamino]-4-~,o..opentanoic acid, IIST 2 -Benzyl-3-pheny1-propionyoxy)3-(3-2..oy- ethys-ulfanyl) 2 -methyIpropionyamino]ox-panoic acid;, 152 3-[3-(3-Carboxy-propylsulfanyl)-2-methyl-propionylamino]- 1 -yi-acetoxy)-4-oxo-pentanoic acid, 5-(2-Benzyl-3-phenyl-propionyloxy)-3-[3-(3-carboxy- propylsulfayl)-2-methyl-propionylan~o]-4-oxo-pentanoic acid;~ 3-(3-Carboxymethylsulfanyl-2-methyl-propionyanino)- I -yI-acetoxy)4-oxo-pentanoic acid; 5-(2-Benzyl-3-phenyl-propionyloxy)-3-(3-carboxymethylsufani- 2-methYl-proPionyiamino)-4-oxo-pentanoic acid,- 3-[3-(2-Carboxy-ethanesulfonyl)-2-methy-propionylaniino]- 5-(naphthalen-1I -yI-acetoxy)-4-oxo-pentanoic acid; 3-[3-(3-Carboxy-propane- I-sulfonyl)-2- methyl-propionylaniino]- I -YI-acetoxY)-4-oxo-pentanoic. acid; :0 -(3-Carboxymethanesulfonyl-2-methyl-propionylaniino) :0 5-(naphthalen- I -yi-acetoxy)-4-oxo-pentanoic acid; 15 5-(2-Benzyl-3-phen;yl-propionyloxy)-3-[3-(3-carboxy-propane- I -sulfonyl)-2-methyl-propionylaniino]-4-oxo-pentanoic acid; sO. 5-(2-Benzyl-3-phenyl-propionyloxy}-3-(3-carboxyniehaesulfonyl- 2-rnethyl-propionylamino)-4-oxo-p .entanoic acid; 3-L3-(3-Carboxy-propane- I -sulfinyl)-2-methyl-propionyiarmno] 5-(naphthaen- 1--yI-acetoxy)-4-o'xo-pentanoic acid; 0,01 32Mehl3(phylpoane-l1-sulfinyl)-propionylamino]- 5-(naphtbalen- 1 -yl-acetoxy)-4-oxo-pentanoic acid; and 5-(2-Benzyl-3-phenyl-propionyoxy)-3-2-methyl-3.-(3-phenyl- S.0*propane- I -sulfinyl)-propionylamino]--xo-pentanoic acid. 34. The compounds: 3 3 -Methyl-. 2 -,phenethylcarbamoyi-metl1>butyry (naphthalen- I -yl-acetoxy)-4-oxo-pentanoic acid; and 3-(3-Carboxy-2-methy-propionyam1no>5(phthale-1 -yl- acetoxY)-4-oxo-pentanoic acid. 153 The compound: 3-(2-Methyl-3-sulfamnoyl-propionylaniino)-5-(naphthalen- 1-yl-acetoxy)-4-oxo- pentanoic acid. 3. The compounds: 1-yl-acetoxy)-4-oxo-pentanoic acid; 3-Benzyloxycarbonylamino-4-oxo-5-(3-phenyl-propionyloxy)-pentanoic acid; 3-Benzyloxycarbonylamnino-5-(3-cyclohexyl-propionyloxy)-4-oxo-pentanoic acid; 1-yl-oxy)-.acetoxy]-4-oxo-pentanoic acid; 0 00* 0:0. .0.00* 0 0 00% :000. 3-Benzyloxycarbonylamino-4-oxo-5-phenoxyacetoxy-pentanoic acid; 3-Benzyloxycarbonylamino-4-oxo-5-phenylsulfanylacetoxy-pentanoic acid; 3-Benzyloxycarbonylamino-5-[(6-methoxy-naphthalen- 1-yl)-acetoxy]-4-oxo- pentanoic acid; 3 -Benzyloxycarbonylamino-5-(naphthalen-2-yl-acetoxy)-4-oxo-pentanoic acid; 3-Benzyloxycarbonylamino-5-.(3-naphthalen-2-yl-propionyloxy)-4-oxo-pentanoic acid; 3-Benzyloxycarbonylamino-5-(3,3-diphenyl-propionyloxy)-4-oxo-pentanoic acid; 3-B enzyloxycarbonylainino-5-(2-naphthalen- 1-yl-propionyloxy)-4-oxo-pentanoic acid; 5-[(Acetyl-phenyl-amino)-acetoxy]-3-benzyloxycarbonyl-amino-4-oxo-pentanoic acid; 3 -Benzyloxycarbonylaniino-5-(2-benzyl-3-phenyl-propionyloxy)-4-oxo- pentanoic acid; Csr 154- 1-yl-acetoxy)-4-oxo- pentanoic acid; 3-Benzyloxycarbonylamnino-4-oxo-5-[(phenyl-amino)-acetoxy]-pentanoic acid; 3-Benzyloxycarbonylamino-5-[(6-hydroxy-naphthalen- 1-yl)-acetoxy]-4-oxo- pentanoic acid; 3-Benzyloxycarbonylamino-5-[3-(4-hydroxy-phenyl)-2-naphthalen- l-yl- propionyloxy]-4-oxo-pentanoic acid; (S)-3-Benzyloxycarbonylainino-4-oxo-5-phenylacetoxy-pentanoic acid; (S)-3-Benzyloxycarbonylatmino-4-oxo-5-(4-phenyl-butyryloxy)-pentanoic acid; 3-B enzyloxycarbonylamino-4-oxo-5-[(4-phenyl-naphthalen- 1-yl)-acetoxy]- pentanoic acid; 3-B enzyloxycarbonylamnino-5-[(4-methyl-naphthalen- 1-yl)-acetoxy]-4-oxo- pentanoic acid; 3-B enzyloxycarbonylamnino-4-oxo-5-[(4-thiophen-2-yl-naphthalen- l-yl)- 000: 15 acetoxy]-pentanoic acid; 0 3-Benzyloxycarbonylaniino-5-[(4-fluoro-naphthalen- 1-yl)-acetoxy]-4-oxo- pentanoic acid; 0 ooooos3-Benzyloxycarbonylamino-5-[(2-methyl-naphthalen- 1-yl)-.acetoxy]-4-oxo- oo.o 0 0 00 pentanoic acid; 0, 0:52[4-Benzylxcroyaio5[2fur-naphthalen-1-yl)-acetoxy]-3-ezlxcroyain-4-oxo- pentanoic acid; 3-ezlxcroyaio5-[(3 ,4-nhydr-naphthalen-1-yl)-acetoxy]-3bnyoyabnlmn-4-oxo- 5pentanoic acid; 155 3-B enzyloxycarbonylamino-5-(3 ,4-diphenyl-butyryloxy)-4-oxo-pentanoic acid; 3-Benzyloxycarbonylaniino-4-oxo-5-(3-phenyl-3-phenylamino-propionyloxy)- pentanoic acid; 3-Benzyloxycarbonylamino-4-oxo-5-[( 1,2,3,4-tetrahydro-naphthalen-2-yl)- acetoxy]-pentanoic acid; 3 -Benzyloxycarbonylamino-4-oxo-5- ,5,6-tetramethyl-phenyl)-acetoxy]- pentanoic acid; 3-Benzyloxycarbonylamino-5-[(2,3-dichloro-phenyl)-acetoxy]-4-oxo-pentanoic acid; 3-Benzyloxycarbonylamino-5-[(5-methyl-naphthalen- 1-yl)-acetoxy]-4-oxo- pentanoic acid; 3-Benzyloxycarbonylamino-5-[(2-iodo-phenyl)-acetoxy]-4-oxo-pentanoic acid; 3-Benzyloxycarbonylamino-5-[(5-methoxy-naphthalen- 1-yl)-acetoxy]-4-oxo- :pentanoic acid; 3-Benzyloxycarbonylamino-5-[(8-methyl-naphthalen- 1-yl)-acetoxy]-4-oxo- pentanoic acid; 3-Benzyloxycarbonylamnino-5-[(9H-fluoren-9-yl)-acetoxy]-4-oxo pentanoic acid; 10,1 1-dihydro-5H-dibenzo[a,d]cyclohepten-5- yl)-acetoxy]-4-oxo-pentanoic acid; 3-B enzyloxycarbonylamino-5-(2-benzyl-3-phenyl-propionyloxy)-4-oxo- pentanoic acid; and 3-Benzyloxycarbonylamino-5-[(5-cyano-naphthalen- 1-yl)-acetoxy]-4-oxo- pentanoic acid. 37. The compounds: 156- 1 -yl-acetoxy)-4- oxo-pentanoic acid; 1-yl-acetoxy)-4-oxo-3-[2-(4-phenyl-butyrylaniino)-propylamino]- pentanoic acid; 3-(2-Methanesulfonylamino-propionylamino)-5-(naphthalen- 1-yl-acetoxy)74- oxo-pentanoic acid; 3-[2-(2-Acetylamnino-4-phenyl-butyrylamino)-propionylamino]-5-(naphthalen- 1- yl-acetoxy)-4-oxo-pentanoic acid; 3 -(2-Acetylamino-butyrylamino)-5-(naphthalen- 1-yl-acetoxy)-4-oxo-pentanoic acid; 3-[2-(4-Carbamoyl-butyrylaniino)-propionylamino]-5-(naphthalen- 1-yl-acetoxy)- 4-oxo-pentanoic acid; 3-(2-Benzyloxycarbonylamino-propionylamino)-5-(naphthalen- 1-yl-acetoxy)-4- oxo-pentanoic acid; 5-(Naphthalen- 1-yl-acetoxy)-4-oxo-3-(2-ureido-propionylamino)-pentanoic acid; 3-(2-Acetylaniino-propionylamino)-5-(naphthalen- 1-yl-acetoxy)-4-oxo-pentanoic acid; 3-(2-Acetylamino-acetylaxnino)-5-(naphthalen- 1-yl-acetoxy)-4-oxo-pentanoic acid; 20 3-(2-Acetylanino-propionylamino)-5-(3 ,3-diphenyl-propionyloxy)-4-oxo- pentanoic acid; I3-[2-(2-Acetylamino-4-carboxy-butyrylamino)-propionylaxnino]-5-(naphthalen- 1 -yl-acetoxy)-4-oxo-pentanoic acid; 1-yl-acetoxy)-4-oxo-3-[2-(3-phenyl-propionylamino)- Spropionylamino]-pentanoic acid; A -157- 3 -[2-(3-Methyl-butyrylamino)-propionylamino]-5-(naphthalen- 1-yl-acetoxy)-4- oxo-pentanoic acid; and 3-(4-Carbamoyl-butyrylamino)-5-(naphthalen- 1-yl-acetoxy)-4-oxo-pentanoic acid. 38. The compounds: 3 -(2-Methyl-3-phenethylcarbamoyl-propionylamino)-5-(naphthalen- 1-yl- acetoxy)-4-oxo-pentanoic acid; 3-[3-Methyl-2-(3 -phenyl-propionylamino)-butyrylaxnino]-4-oxo-5-[( 1-oxo- 1 ,2,3,4-tetrahydro-naphthalen-2-yl)-acetoxy]-pentanoic acid; 5-(Naphthalen- 1-yl-acetoxy)-4-oxo-3-[2-(1 -oxo- 1,2,3 ,4-tetrahydro-naphthalen-2- yl)-acetylamino]-pentanoic acid; 5-(2-Benzyl-3-phenyl-propionyloxy)-4-oxo-3-[2-(1 -oxo- 1,2,3 ,4-tetrahydro- naphthalen-2-yl)-acetylamino]-pentanoic acid; 4-Oxo-5-[(l1-oxo- 1,2,3,4-tetrahydro-naphthalen-2-yl)-acetoxy]-3-[2-(1 -oxo- 1,2,3 ,4-tetrahydro-naphthalen-2-yl)-acetylainino]-pentanoic acid; 3-(2-Acetylamino-3-methyl-butyrylamino)-5-(naphthalen- 1-yl-acetoxy)-4-oxo pentanoic acid; 3-(2-Acetylamino-3-methyl-butyrylamino)-5-(2-benzyl-3-phenyl-propionyloxy)- 4-oxo-pentanoic acid; 3-(2-Acetylamino-3-methyl-butyrylam-ino)-5-(3-benzyl-4-phenyl-butyryloxy)-4- oxo-pentanoic acid; 3 -(2-Acetylamino-3-methyl-butyrylamino)-5-(4-benzyl-5-phenyl-pentanoyloxy)- 4-oxo-pentanoic acid; 3-(2-Acetylamino-3-methyl-butyrylaniino)-4-oxo-5-[(1 -oxo- 1,2,3 ,4-tetrahydro- naphthalen-2-yl)-acetoxy]-pentanoic acid; and 158 5-(3-Benzyl-4-phenyl-butyryloxy)-3-[3 -methyl-2-(3-phenyl-propionylamino)- butyrylamino]-4-oxo-pentanoic acid. 39. The compounds: 3-[2-(2-Benzyloxycarbonylamino-4-carboxy-butyrylaniino)-3 -methyl- butyrylamnino]-5-(naphthalen- 1-yl-acetoxy)-4-oxo-pentanoic acid; 3-[2-(2-Benzyloxycarbonylamnino-3-methyl-butyrylamino)-propionylamino]-5- (naplithalen- 1-yl-acetoxy)-4-oxo-pentanoic acid; 3-(2-Acetylamnino-3-methyl-butyrylamino)-5-(naphthalen- 1-yl-acetoxy)-4-oxo- pentanoic acid; 3-[2-(2-Benzyloxycarbonylamnino-3-methyl-butyrylainino)-propionylaniino]-5- (3,3 -diphenyl-propionyloxy)-4-oxo-pentanoic acid; 3-[2-(2-Benzyloxycarbonylamino-3-methyl-butyrylamnino)-propionylamnino]-5- (2-benzyl-3-phenyl-propionyloxy)-4-oxo-pentanoic acid; 3-[2-(2-Benzyloxycarbonylamino-3-methyl-butyrylaanino)-propionylamino]-5- (naphthalen- 1-yl-acetoxy)-4-oxo-pentanoic acid; *:5-(2-Benzyl-3-phenyl-propionyloxy)-3- f{2-[4-carboxy-2-(3-phenyl- propionylamnino)-butyrylamino]-3-methyl-butyrylamino} -4-oxo-pentanoic acid; 3-(2-Benzyloxycarbonylaniino-3-methyl-butyrylamino)-5-(3 ,3-diphenyl- :propionyloxy)-4-oxo-pentanoic acid; 20 3-(2-Acetylamino-3-hydroxy-butyrylamino)-5-(naphthalen- 1-yl-acetoxy)-4-oxo- pentanoic acid; 3-(2-Acetylaniino-3-hydroxy-butyrylamnino)-5-(3,3-diphenyl-propionyloxy)-4- oxo-pentanoic acid; and 5-(3 ,3-Diphenyl-propionyloxy)-4-oxo-3-[2-(4-phenyl-butyrylamino)- propionylamino]-pentanoic acid. 159- The compound: {2-[2-Acetylamino-3-(4-hydroxy-phenyl)-propionylamino]-4-carboxy- butyrylamino -methyl-butyrylamino)-5-(naphthalen- 1-yl-acetoxy)-4-oxo-pentanoic acid. 41. The compounds: 3-(3-Carbamoyl-2-methyl-.propionylaminmo)-5-(naphthalen- 1-yl-acetoxy)-4-oxo- pentanoic acid; 3 enzyloxycarbonylamino-3-methyl-naphthalen-1 -yl-acetoxy)-4-oxo- pentanoic acid; 3-[(2-Carbamoyl-cyclopentanecarbonyl)-amino]-5-(naphthalen- 1-yl-acetoxy)-4- oxo-pentanoic acid; {2-[2-Acetylamino-3-(4-hydroxy-phenyl)-propionylamino]-4-carboxy- butyrylamnino} -3-methyl-butyrylamino)-5-(2-benzyl-3-phenyl-propionyloxy)-4-oxo- acid; 153 -Carbamoyl-2-methyl-propionylamino)-5-(naphthalen- 1-yl-acetoxy)-4-oxo- pentanoic acid; 3-(2-Carbamoylmethyl-3-methyl-butyrylamino)-5-(naphthalen- 1-yl-acetoxy)-4- oxo-pentanoic acid; 3-(3-Benzyloxy-2-ureido-propionylaxnino)-5-(naphthalen- 1-yl-acetoxy)-4-oxo- 20 pentanoic acid; 3-[2-(2-Benzyloxycarbonylamino-4-carboxy-butyrylamino)-3-methyl- butyrylamino]-5-(2-benzyl-3-phenyl-propionyloxy)-4-oxo-pentanoic acid; 3- {2-[4-Carboxy-2-(3-pheny1-propionylamino)-butyrylamino]-3-methy- butyrylamino} -5-(naphthalen- 1-yl-acetoxy)-4-oxo-pentanoic acid; and -160- 3-[2-(2-Acetylamino-4-carboxy-butyrylamino)-3-methyl-butyrylamino]-5- (naphthalen- 1-yl-acetoxy)-4-oxo-pentanoic acid. 42. A compound of the Formula I C0 2 H 00 R' is 0 -COCH 2 phenyL, 0 -S-phenyL, 0 -CCHC2 ey 0 0 C-HHCCH 3 CH 3 161 0 -kC 1 -C 6 alkyl -(CH 2 3 phenyl 0 0 11 11 -C-C-NHCOCH 2 phenyL, H 3 C CH 3 o 0 -CH-NHS-CH 3 o 0 0 C11 3 (CH 2 2 phenyl 0. 0 0 0 CH2-phnHCH 3 0 0 3 162 o 0 0 0i 0H 0 o 0 1C(H 2 2 C11, ofi 0 -CCH 2 CH, 0H 3 0:0 CCH 2 nC3 0 00 0* 0 H 3* 90 0 0 0 CCH-NSCH 3 phn 9 9 CH 3 CH 163 o o 0 11 11 11 C-CH-NHC-CHNHCCH 3 3 (CH 2 2 -CCHt-S-CH 2 pheny, o o 0 -C-CH- NC-C- NCOCH 2 phenyL, H 3 C CH 3 (CH 2 2 C0 2 H o 0 0 0 11 11 11 11 -C-CH- NHC-CH-NHCCHNHCCH 3 B 00*H 3 C CH 3 (CIT 2 C0 2 H OH 00 S 0 00 C-NOH 0 0 II 11 164 O 0 0 -C-CH-NHC-CHt- NHC(CtH 2 2 phenyl H 3 C CH 3 (Gil 2 2 o o CHt-NHC(CH 2 2 phenyL, -C-CH-Ni{C-CH CH 3 CH 2 CH 3 0 0 -C-CH-NHC 3 H 3 C OH 0* 0 -CCHCH 2 CNH(CH 2 2 phenyL Gil 3 O 0 0 0 11 11 11 11 -C-CH-NHC--CH-NHCCHNHCCH 3 H 3 C CH 3 (CH 2 2 S.H 0 0 2 -CCH.r-CH 2 -S-phenyL, Gil 3 165 o 0 -CCHClt.H 2 S-pheny, &H 3 0 0 11 -CCHC%-H 2 S-(CH 2 2 Phenyl o o -C -CH-CH 2 S(CH 2 2 Phenyl, 1 11 CH 3 0 0 11 CHCrlH 2 SCH 2 phenyL, o 0 -CC-H 2 -S(CH 2 2 phenyl 0 0 I1 11 -C-CH-SCH 2 phenyL, CH 3 0 0 0 C-CH--NHCCH 2 CH 2 pheny, H 3 C CH 3 C0 2 H -166- o 0 -S-CHCH 2 SCH 3 11 1 11 0OCH 3 0 o 0 -CCjIICH 2 SCCH 3 &H3 0 -CCHCH 2 C0 2 H, &H3 0 -CCHCH 2 CO 2 Ll 9* *3 I 2 NC 0 -CCHCH 2 S-(C1 2 3 -PhenYl, CH 3 o 0 -C-CH-CH 2 S-(CH 2 3 -Phenyl 0 11 -C-CH-CH 2 S(CH 2 2 C021L CHi 3 o 0 -C-CHCH 2 S(CH 2 2 G0 2 1l or III -CCHCH 2 S-(CH 2 2 C0 2 H; and L~t"Gil 3 167- R 2 iS -CHCH 2 phenyl, -CH 2 naphthyl, -CH 2 CH 2 cyclohexyl, -CH 2 O naphthyl, -CH 2 O phenyl, -CH 2 S-phenyl, -CH 2 -substituted naphthyl, -CH 2 CH(phenyl) 2 -(CH 2 3 -phenyl, -CH-naphthy, CH 3 CH 3 0 -CH 2 -I--PhenYl CH[CH 2 PhenYl] 2 -CH-napbthyL, -CH 2 -NR phenyl, CH 2 substituted phenyl CH 2 -CH naplthyl -CH 2 -naPhthYl-PhenAl -CE 2 flUOrenyl, -CH 2 -naphthyl-CH 2 phenyl, -CH 2 -substitued phenyl, 168- phenyl -CH 2 -CH CH 2 phenyl phenyl -CH 2 -CH NHphenyl -CH2 0 0* a a. a. each n is independently 0 to 3, and the pharmaceutically acceptable, salts, esters, amides and prodrugs thereof. 43. Use of a compound according to any one of claims 1 to 19 for the manufacture of a medicament for inhibiting interleukin-1 3 converting enzyme. 44. Use of a compound according to any one of claims 1 to 19 for the manufacture of a medicament for inhibiting Caspase-4. Use of a compound according to any one of claims 1 to 19 for the manufacture of a medicament for treating stroke. 46. Use of a compound according to any one of claims 1 to 19 for the manufacture of a medicament for treating inflammatory disease. 47. Use according to claim 46, wherein the inflammatory disease is arthritis. 169- 48. Use according to claim 46, wherein the inflammatory disease is inflammatory bowel disease. 49. Use of a compound according to any one of claims 1 to 19 for the manufacture of a medicament for treating reperfusion injury. 50. Use of a compound according to any one of claims 1 to 19 for the manufacture of a medicament for treating Alzheimer's disease. 51. Use of a compound according to any one of claims 1 to 19 for the manufacture of a medicament for treating shigellosis. 52. A compound of Formula I or a pharmaceutically acceptable salt thereof, substantially as herein described with reference to any one of the examples. 53. A method of inhibiting interleukin-11 converting enzyme, substantially as herein described with reference to any one of the examples. 54. A method of inhibiting Caspase-4, substantially as herein described with reference to any one of the examples. 15 55. A method of treating stroke, substantially as herein described with reference to any one of the examples. 56. A method of treating inflammatory disease, substantially as herein described with reference to any one of the examples. 57. A method of treating reperfusion injury, substantially as herein described with reference to any one of the examples. 58. A method of treating Alzheimer's disease, substantially as herein described with reference to any one of the examples. 59. A method of treating shigellosis, substantially as herein described with reference to any one of the examples. -170- A pharmaceutically acceptable composition containing a compound of Formula I, substantially as herein described with reference to any one of the examples. 61. Use of a compound of Formula I in the manufacture of a medicament, substantially as herein described with reference to any one of the examples. DATED this 28h day of June 2001. WARNER-LAMBERT COMPANY AND BASF AKTIIENGESELLSCHAFT Attorney: IVAN A. RAJKOVIC Fellow Institute of Patent Attorneys of Australia of BALDWIN SHELSTON WATERS b e be be. be
21937-OO.DOC
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AU4902397A (en) 1998-05-11
KR20000049048A (en) 2000-07-25
JP2001506974A (en) 2001-05-29
NO991677D0 (en) 1999-04-09
NO991677L (en) 1999-06-09

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