Hydroxypropylamide peptidomimetics as inhibitors of aspartyl...

Details Hydroxypropylamide peptidomimetics as inhibitors of aspartyl... Hydroxypropylamide peptidomimetics as inhibitors of aspartyl...

1999-09-29

2001-02-20

Venkat, Jyothsna (Department: 1627)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C435S007100, C436S501000, C436S518000, C544S168000, C544S386000, C544S404000, C564S161000, C564S169000, C564S176000

Reexamination Certificate

active

06191277

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to peptidomimetic analogs (hydroxypropyl amides) that display inhibitory activity against the aspartyl proteases, plasmepsin and cathepsin D.
BACKGROUND OF THE INVENTION
The malaria parasite avidly consumes the host hemoglobin as a source of nutrients. Plasmepsin I and II are proteases from
Plasmodium falciparum
that are required for the initial stages of hemoglobin digestion. The primary site of hydrolysis is in the &agr;-chain of hemoglobin between Phe 33 and Leu 34; however other sites are substrates as well. It has been shown that a peptidomimetic inhibitor blocked plasmepsin, thus preventing hemoglobin degradation and resulting in death of the malaria parasite in culture (Francis, S. E., Gluzman, I. Y., Oksman, A., Knickerbocker, A., Mueller, R., Bryant, M. L., Sherman, D. R., Russell, D. G. and Goldberg, D. E. (1994)
EMBO J,
13, 306-317). Due to the increasing problem of resistance to known antimalarial therapies, new antimalarial therapies are desperately needed. Therefore, plasmepsin inhibition is an excellent target for antimalarial therapy.
Cathepsin D is a human protease in the endosomal-lysosomal pathway involved in lysosomal biogenesis and protein targeting. Cathepsin D may also be involved in antigen processing and presentation of peptide fragments. Therefore, cathepsin D displays broad substrate specificity but prefers hydrophobic residues on either side of the scissile bond. Cathepsin D has been implicated in a variety of diseases such as connective tissue disease, muscular dystrophy and breast cancer. Most recently, cathepsin D is believed to be &ggr;-secretase, the protease which processes the &bgr;-amyloid precursor protein to generate the C-terminus of &bgr;-amyloid (Dreyer, R. N., Bausch, K. M., Fracasso, P., Hammond, L. J., Wunderlich, D., Wirak, D. O., Davis, G., Brini, C. M., Bucholz, T. M., Konig, G., Kamark, M. E., and Tamburini, P. P. (1994)
Eur. J. Biochem.,
224, 265-271 and Ladror, U.S., Synder, S. W., Wang, G. T., Holzman, T. F., and Krafft, G. A. (1994)
J. Biol. Chem.,
269, 18422-18428). &bgr;-Amyloid is the major component of plaques in the brains of Alzheimer's patients. Therefore, inhibitors of cathepsin D could be useful in treating various human diseases.
The present invention relates to hydroxypropyl amides and their inhibiting action against aspartyl proteases. In particular, the invention relates to the identification of inhibitors that display selective inhibitory activity against plasmepsin and cathepsin D. Although statine-containing peptides are known to inhibit aspartyl proteases (Shewale, J. G.; Takahashi, R.; Tang, J.;
Aspartic Proteinases and Their Inhibitors,
Kostka, V., Ed. Walter de Gruyter: Berlin, 1986; pp 101-116), few potent and selective inhibitors are known for plasmepsin (U.S. Pat. No. 5,734,054). The invention also relates to the solid phase synthesis of such agents.
SUMMARY OF THE INVENTION
In one aspect, the invention is directed to compounds of Formula I:
wherein:
R
1
is chosen from the group consisting of alkyl, —(CH
2
)
m
-cycloalkyl and aralkyl; where n=1-3;
R
2
is H or [S]—C(O)—L—, wherein [S] is a solid support and —L— is a linker;
Y is —OC(O)NHR
3
or —NR
4
R
5
, wherein R
3
is alkyl, aralkyl, aryl or aryloxyalkyl and
R
4
and R
5
are independently selected from the group consisting of H, alkoxyalkyl, R
3
, —C(O)R
3
, —SO
2
R
3
,
wherein m=0-3; or R
4
and R
5
together with the nitrogen atom to which they attach is
where X=NR
6
or O;
R
6
is chosen from the group consisting of H, R
3
, —C(O)R
3
and —SO
2
R
3
;
Z is chosen from the group consisting of —C(O)R
7
, —C(O)CH(R
8
)OC(O)NH
3
and —C(O)CH(R
8
)NHC(O)R
3
; wherein R
7
is chosen from the group consisting of alkyl, aralkyl, aryl, —(CH
2
)
m
-cycloalkyl, heteroaryl,
and R
8
is chosen from the group consisting of H, alkyl, aralkyl and —(CH
2
)
m
-cycloalkyl.
In another aspect, the invention is directed to a method for treating a condition by inhibiting the action of plasmepsin. Particularly, the invention is directed to a method for conducting antimalarial therapy in a human suffering from malaria, comprising administering a therapeutically effective amount of a compound of Formula I.
In an additional aspect, the invention is directed to a method for treating a condition by inhibiting the action of cathepsin D. The particular invention is directed to a method for treating Alzheimer's disease in a human, which comprises administering a therapeutically effective amount of a compound of Formula I.
Another aspect of the invention is the use of divinylbenzene-cross-linked, polyethyleneglycol-grafted polystyrene beads optionally functionalized with amino groups (e.g., TentaGel™ S NH
2
, Rapp Polymere) as the solid supports for constructing compounds of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
Abbreviations and Definitions
The following abbreviations and terms have the indicated meanings throughout:
Ac
= Acetyl
BNB
= 4-bromomethyl-3-nitrobenzoic acid
BOC
= t-butoxycarbonyl
BSA
= bovine serum albumin
Bu
= butyl
c-
= cyclo
DABCYL
= 4-(4-dimethylaminophenylazo)benzoic acid
DBU
= 1,8-Diazabicyclo[5.4.0]undec-7-ene
DCM
= Dichloromethane = methylene chloride = CH
2
Cl
2
DIC
= diisopropylcarbodiimide
DIEA
= N,N-diisopropylethylamine
DMAP
= 4-(N,N-dimethylamino)pyridine
DMF
= N,N-dimethylformamide
DMSO
= Dimethyl sulfoxide
DVB
= 1,4-divinylbenzene
EDANS
= 5-[(2-aminoethyl)amino]naphthalene-1-sulfonic acid
EI
= eletron impact ionization
fab
= fast atom bombardment
Fmoc
= 9-fluorenylmethoxycarbonyl
HOAc
= acetic acid
HOBt
= 1-hydroxybenzotriazole
IBX
= iodoxybenzoic acid
in vacuo
= under vacuum
m-
= meta
Me
= methyl
NMO
= N-methylmorpholine oxide = 4-methylmorpholine N-oxide
PEG
= polyethylene glycol
Ph
= phenyl
PfP
= pentafluorophenol
r.t.
= room temperature
sat'd
= saturated
s-
= secondary
t-
= tertiary
TBS
= tert-butyldimethylsilyl
TFA
= trifluoroacetic acid
THF
= tetrahydrofuran
TMOF
= trimethyl orthoformate
TMS
= trimethylsilyl
Tf
= trifluoromethanesulfonyl
Tris
= tris(hydroxymethyl)aminomethane
Tween 20
= polyoxyethylenesorbitan monolaurate
UV
= ultraviolet light
“Alkoxy” means alkoxy groups of from 1 to 8 carbon atoms of a straight, branched or cyclic configuration and combinations thereof. Examples of alkoxy groups include: methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.
“Alkyl” is intended to include linear or branched hydrocarbon structures and combinations thereof.
“Alkoxyalkyl” means an alkyl substituted with an alkoxy group. For example: methoxyethyl, isopropoxyethyl, ethoxymethyl and the like.
“Aralkyl” means an alkyl containing an aryl ring. For example: benzyl, phenethyl, 4-chlorobenzyl, diphenylethyl and the like.
“Aryl” is a 6-membered or 10-membered aromatic ring system where each of the rings is optionally substituted with 1-3 substituents selected from alkyl, halogen, hydroxy, alkoxy, aryloxy, haloalkyl, phenyl or heteroaryl; and wherein the phenyl is optionally substituted with 1-3 substituents selected from alkyl, halogen or alkoxy. Examples of aryl groups are phenyl and naphthyl.
“Aryloxy” means a phenoxy group where the phenyl ring is optionally substituted with 1 to 2 groups selected from halo, alkoxy or alkyl.
“Cycloalkyl” includes cycloalkyl groups of from 3 to 12 carbon atoms. Examples of “cycloalkyl” groups include: c-propyl, c-butyl, c-pentyl, c-hexyl, 2-methylcyclopropyl, norbornyl, adamantyl and the like.
“Haloalkyl” means one or more hydrogen atoms present in an alkyl group are replaced with a halogen atom, except for the methylene hydrogens adjacent to the oxygen atom. For example: 2-chloroethyl and 2,2,2-trifluoroethyl.
“Halogen” includes

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