Substituted 2-aminobenzamide caspase inhibitors and the use...

Details Substituted 2-aminobenzamide caspase inhibitors and the use... Substituted 2-aminobenzamide caspase inhibitors and the use...

2000-03-16

2003-09-16

Low, Christopher S. F. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S002600, C514S009100, C514S011400, C514S538000, C514S561000, C514S560000, C514S038000, C514S041000, C514S435000, C514S254100, C514S325000, C514S410000

Reexamination Certificate

active

06620782

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention is in the field of medicinal chemistry. In particular, the invention relates to substituted 2-aminobenzamides and analogs that are inhibitors of caspases. The invention also relates to the use of these 2-aminobenzamides and analogs for reducing or treating apoptotic cell death and/or reducing interleukin 1-&bgr; production.
2. Description of Background Art
Organisms eliminate unwanted cells by a process variously known as regulated cell death, programmed cell death or apoptosis. Such cell death occurs as a normal aspect of animal development as well as in tissue homeostasis and aging (Glucksmann, A.,
Biol. Rev. Cambridge Philos. Soc
. 26:59-86 (1951); Glucksmann, A.,
Archives de Biologie
76:419-437 (1965); Ellis et al.,
Dev
. 112:591-603 (1991); Vaux et al.,
Cell
76:777-779 (1994)). Apoptosis regulates cell number, facilitates morphogenesis, removes harmful or otherwise abnormal cells and eliminates cells that have already performed their function. Additionally, apoptosis occurs in response to various physiological stresses, such as hypoxia or ischemia (PCT published application WO 96/20721).
There are a number of morphological changes shared by cells experiencing regulated cell death, including plasma and nuclear membrane blebbing, cell shrinkage (condensation of nucleoplasm and cytoplasm), organelle relocalization and compaction, chromatin condensation and production of apoptotic bodies (membrane enclosed particles containing intracellular material) (Orrenius, S.,
J. Internal Medicine
237:529-536 (1995)).
Apoptosis is achieved through an endogenous mechanism of cellular suicide (Wyllie, A. H., in
Cell Death in Biology and Pathology
, Bowen and Lockshin, eds., Chapman and Hall (1981), pp. 9-34). A cell activates its internally encoded suicide program as a result of either internal or external signals. The suicide program is executed through the activation of a carefully regulated genetic program (Wylie et al.,
Int. Rev. Cyt
. 68:251 (1980); Ellis et al.,
Ann. Rev. Cell Bio
. 7:663 (1991)). Apoptotic cells and bodies are usually recognized and cleared by neighboring cells or macrophages before lysis. Because of this clearance mechanism, inflammation is not induced despite the clearance of great numbers of cells (Orrenius, S.,
J. Internal Medicine
237:529-536 (1995)).
Mammalian interleukin-1&bgr; (IL-1&bgr;) plays an important role in various pathologic processes, including chronic and acute inflammation and autoimmune diseases (Oppenheim, J. H. et. al.
Immunology Today
, 7, 45-56 (1986)). IL-1&bgr; is synthesized as a cell associated precursor polypeptide (pro-IL-1&bgr;) that is unable to bind IL-1 receptors and is biologically inactive (Mosley et al.,
J. Biol. Chem
. 262:2941-2944 (1987)). By inhibiting conversion of precursor IL-1&bgr; to mature IL-1&bgr;, the activity of interleukin-1 can be inhibited. Interleukin-1&bgr; converting enzyme (ICE) is a protease responsible for the activation of interleukin-1&bgr; (IL-1&bgr;) (Thornberry, N. A., et al.,
Nature
356:768 (1992); Yuan, J., et al.,
Cell
75:641 (1993)). ICE is a substrate-specific cysteine protease that cleaves the inactive prointerleukin-1 to produce the mature IL-1. The genes that encode for ICE and CPP32 are members of the mammalian ICE/Ced-3 family of genes which presently includes at least twelve members: ICE, CPP32/Yama/Apopain, mICE2, ICE4, ICH1, TX/ICH-2, MCH2, MCH3, MCH4, FLICE/MACH/MCH5, ICE-LAP6 and ICE
re1
III. The proteolytic activity of this family of cysteine proteases, whose active site (a cysteine residue) is essential for ICE-mediated apoptosis, appears critical in mediating cell death (Miura et al.,
Cell
75:653-660 (1993)). This gene family has recently been named caspases (Alnernri, E. S. et. al.
Cell
, 87, 171 (1996), and Thomberry, N. A. et. al.
J. Biol. Chem
. 272, 17907-17911 (1997)) and divided into three groups according to its known functions. Table 1 summarizes these known caspases.
TABLE 1
Enzyme*
Group I: mediators of inflammation
Caspase-1 (ICE)
Caspase-4 (ICE
rel
-II, TX, ICH-2)
Caspase-5 (ICE
rel
-III, TY)
Group II: effectors of apoptosis
Caspase-2 (ICH-1, mNEDD2)
Caspase-3 (apopain, CPP-32, YAMA)
Caspase-7 (Mch-3, ICE-LAP3, CMH-1)
Group III: activators of apoptosis
Caspase-6 (Mch2)
Caspase-8 (MACH, FLICE, Mch5)
Caspase-9 (ICE-LAP6, Mch6)
Caspase-10
IL-1 is also a cytokine involved in mediating a wide range of biological responses including inflammation, septic shock, wound healing, hematopoiesis and growth of certain leukemias (Dinarello, C. A.,
Blood
77:1627-1652 (1991); diGiovine et al.,
Immunology Today
11:13 (1990)).
Many potent caspase inhibitors have been prepared based on the peptide substrate structures of caspases. However, in contrast to their potency in vitro, no inhibitors with good efficacy (IC
50
<1 &mgr;M) in whole-cell models of apoptosis have been reported (Thomberry, N. A.
Chem. Biol
. 5:R97-103 (1998)). Therefore the need exists for cell death inhibitors that are efficacy in whole-cell models of apoptosis and active in animal model of apoptosis. These inhibitors thus can be employed as therapeutic agents to treat disease states in which regulated cell death and the cytokine activity of IL-1 play a role.
WO 93/05071 discloses peptide ICE inhibitors with the formula:
Z—Q
2
-
Asp
-
Q
1
wherein Z is an N-terminal protecting group; Q
2
is 0 to 4 amino acids such that the sequence Q
2
-Asp corresponds to at least a portion of the sequence Ala-Tyr-Val-His-Asp; Q
1
comprises an electronegative leaving group.
WO 96/03982 discloses aspartic acid analogs as ICE inhibitors with the formula:
wherein R
2
is H or alkyl; R
3
is a leaving group such as halogen; R
1
is heteroaryl-CO or an amino acid residue.
U.S. Pat. No. 5,585,357 discloses peptidic ketones as ICE inhibitors with the formula:
wherein n is 0-2; each AA is independently L-valine or L-alanine; R
1
is selected from the group consisting of N-benzyloxycarbonyl and other groups; R
8
, R
9
, R
10
are each independently hydrogen, lower alkyl and other groups.
Mjalli et al. (
Bioorg. Med. Chem. Lett
., 3, 2689-2692, 1993) report the preparation of peptide phenylalkyl ketones as reversible inhibitors of ICE, such as:
Thornberry et al. (
Biochemistry
, 33, 3934-3940, 1994) report the irreversible inactivation of ICE by peptide acyloxymethyl ketones:
wherein Ar is COPh-2,6-(CF
3
)
2
, COPh-2,6-(CH
3
)
2
, Ph-F
5
and other groups.
Dolle et al. (
J. Med. Chem
. 37, 563-564, 1994) report the preparation of P
1
aspartate-based peptide &agr;-((2,6-dichlorobenzoyl)oxy)methyl ketones as potent time-dependent inhibitors of ICE, such as:
Mjalli et al. (
Bioorg. Med Chem. Lett
., 4, 1965-1968, 1994) report the preparation of activated ketones as potent reversible inhibitors of ICE:
wherein X is NH(CH
2
)
2
, OCO(CH
2
)
2
, S(CH
2
)
3
and other groups.
Dolle et al. (
J. Med. Chem
. 37, 3863-3866, 1994) report the preparation of &agr;-((1-phenyl-3-(trifluoromethyl)-pyrazol-5-yl)oxy)methyl ketones as irreversible inhibitor of ICE, such as:
Mjalli et al. (
Bioorg Med. Chem. Lett
., 5, 1405-1408, 1995) report inhibition of ICE by N-acyl-Aspartic acid ketones:
wherein XR
2
is NH(CH
2
)
2
Ph, OCO(CH
2
)
2
cyclohexyl and other groups.
Mjalli et al. (
Bioorg Med Chem. Lett
., 5, 1409-1414, 1995) report inhibition of ICE by N-acyl-aspartyl aryloxymethyl ketones, such as:
Dolle et al. (
J. Med. Chem
. 38, 220-222, 1995) report the preparation of aspartyl &agr;-((diphenylphosphinyl)oxy)methyl ketones as irreversible inhibitors of ICE, such as:
Graybill et al. (
Bioorg. Med. Chem. Lett
., 7, 41-46, 1997) report the preparation of &agr;-((tetronoyl)oxy)- and &agr;-((tetramoyl)oxy)methyl ketones as inhibitors of ICE, such as:
Semple et al. (
Bioorg. Med. Chem. Lett
., 8, 959-964, 1998) report the preparation of peptidomimetic aminomethylene ketones as inhibitors of ICE, such as:
SUMMARY OF THE INVENTION
The invention relates to compound of Formulae I, II and III:
wherein
R
1
is an optionally substituted alkyl or hydrogen;
R
3
i

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