Cysteine protease inhibitors

Details Cysteine protease inhibitors Cysteine protease inhibitors

2002-01-30

2003-10-21

Gerstl, Robert (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C544S168000, C544S400000, C546S233000, C548S557000, C560S032000, C560S159000, C564S153000

Reexamination Certificate

active

06635621

ABSTRACT:

This invention relates to derivatives of alpha-amino acid amides, to pharmaceutical compositions containing such compounds, and to their use in medicine as inhibitors of cysteine proteases, particularly the cathepsins.
BACKGROUND TO THE INVENTION
The cathepsin family (C1) of lysosomal cysteine (or thiol) proteases is a subset of the papain superfamily (clan CA of cysteine proteases) and includes cathepsin B, H, K, S, L and the recently discovered cathepsins O, O2/K, V, X, Z and W (lymphopain). Related enzymes also regarded as cysteine proteases are the cytoplasmic Ca
2+
dependent calpains (family C2). Cysteine proteases are classified both functionally and according to the nature of their active site, which has a thiol residue. They differ in substrate specificities and other enzymatic activities, these differences probably arising from evolutionary divergence.
The known cathepains are synthesized on membrane bound ribosomes, transferred to the endoplasmic reticulum, then to the Golgi apparatus and finally to the lysosome and endosomes. They have an important function in regulation of intracellular protein metabolism, mobilisation of tissue proteins and conversion of proenzymes, prohormones and neuropeptides into biologically active molecules. The cathepsins are believed to be involved in a number of diseases.
Cathepsin K can be secreted into the extracellular space and is involved in bone and cartilage remodelling. Cathepsin K is implicated in the pathogenesis of osteoporosis. Cathepsin K inhibitors can prevent osteoporosis in animal models (PNAS.1997. 94:14249-14254). Cathepsin L inhibitors have also been shown to inhibit osteoporosis (Bone, 1997. 20:465-471).
Cathepsin B and other cysteinyl cathepsins have also been shown to be released extracellularly by various tumour cells and are thought to play a role in tumour invasion (Journal of cellular Physiology. 1992. 150:534-544).
The cysteinyl cathepsins have also been shown to play a role in rheumatoid arthritis (Arthritis and Rheumatism 1994. 37:236-247) and neuronal and cardiac ischaemia (European Journal of Neuroscience. 1998. 10.1723-1733).
Cathepsins S and L both play a role in the generation of free MHC class II molecules capable of binding antigenic peptides in the endosomes. These class II/peptide complexes move to the cell membrane and are involved in T lymphocyte activation. Inhibitors of Cathepsin S have been shown to inhibit allergic immune responses (Journal of Clinical Investigation. 1998. 101:2351-2363).
In addition to their role in the above diseases, cysteinyl cathepsins play a major role in the pathogenesis of infectious diseases. For example, cysteinyl cathepsins are used by the protozoal parasites Plasmodium (malaria) and Trypanosoma (Chagas Disease) to invade the human host and cysteinyl cathepsin inhibitors can inhibit experimental disease in both cases (Antimicrobial agents and chemotherapy. 1998. 42:2254-2258; Journal of Experimental Medicine. 1998. 188:725-734). Cysteinyl cathepsins are also virulence factors for several pathogenic bacteria.
A recent review (Annu. Rev. Physiol. 1997. 59:63-88) describes the state of the art of cysteine proteases, including the cathepsins, and their presumed biological functions. Other reviews deal with cathepsin B inhibitors as potential anti-metastatic agents (Exp. Opin. Ther. Patents, 1998, 8: 645-672), and cathepsin K inhibitors as potential treatments for osteoporosis (Exp. Opin. Ther. Patents, 1999, 9: 683-644).
International patent applications WO 96/32408, WO 98/12176, WO 98/12210 and GB 9806287.0 describe, inter alia, classes of cysteine protease inhibitors which may be represented by formula (IA):
wherein Y, R
1
, R
2
and R
3
represent the groups found in corresponding positions of the compounds disclosed in those publications. These known compounds are azetidin-2-ones which are monosubstituted at positions 3 and 4.
BRIEF DESCRIPTION OF THE INVENTION
The present invention makes available a new class of cysteine protease inhibitors which differ in structure from those disclosed in WO 96/32408, WO 98/12176, WO 98/12210 and GB 9806287.0 principally in that the azetidin-2-one ring is replaced by a substituted carbonylmethyl moeity, as more fully explained below. These compounds are useful for the treatment of diseases mediated by cysteine protease activity, for example muscular dystrophy, osteoporosis, tumour metastasis, rheumatoid arthritis, neuronal or cardiac ischaemia, allergic immune response, and protozoal or bacterial disease.
DETAILED DESCRIPTION OF THE INVENTION
According to the present invention, there is provided a compound of formula (I)
wherein:
Y represents —C(O)— or —S(O
2
)—;
R
1
represents a radical of formula R
6
—(ALK)
p
—(Z)
n
—(ALK)
q
— wherein Z represents —O— or —S—, ALK represents a divalent C
1
-C
3
alkyl or halogen-substituted C
1
-C
3
alkyl radical, p and q are independently 0 or 1, n is 0 or 1 when q is 1 and n is 0 when q is 0, and R
6
is hydrogen or an optionally substituted C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclic group; or R
1
together with the carbon atom to which it is attached forms a cycloalkyl ring;
R
2
represents —OR
5
or —R
5
;
R
5
represents a radical of formula R
7
—(A)
t
— wherein t is 0 or 1; A represents (i) an optionally substituted divalent C
1
-C
6
alkyl, radical which may be interrupted by one or more non-adjacent —O—, —S— or —NH— linkages, or (ii) a divalent C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclic radical, or (iii) a —NH— link; and R
7
represents hydrogen or an optionally substituted C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclic group;
R
3
represents (i) an optionally substituted C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclic group or (ii) NHR
8
or N(R
8
)
2
or (iii) OR
8
wherein R
8
represents hydrogen or an optionally substituted C
2
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, cycloalkyl, cycloalkenyl or aryl;
A and B taken together represent a bond and R
4
represents a hydroxy or substituted hydroxy group or an amino or primary or secondary amino group, or A represents hydrogen and B and R
4
each independently represents a hydroxy or substituted hydroxy group;
or a pharmaceutically acceptable salt, hydrate or solvate thereof.
Pharmaceutically acceptable salts of the compounds of this invention include the sodium, potassium, magnesium, calcium, hydrogen chloride, tartaric acid, succinic acid, fumaric acid and p-toluenesulfonic acid salts.
As used herein the term (C
1
-C
6
)alkyl or lower alkyl means a straight or branched chain alkyl moiety having from 1 to 6 carbon atoms, including for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylprop-1-yl, 2-methylprop-2-yl, pentyl, 3-methylbutyl, and hexyl. Similar terms such as “(C
1
-C
3
)alkyl” are to be interpreted similarly.
As used herein the term C
2
-C
6
alkenyl” means a straight or branched chain alkenyl moiety having from 2 to 6 carbon atoms having at least one double bond of either E or Z stereochemistry where applicable. The term includes, for example, vinyl, allyl, 1- and 2-butenyl and 2-methyl-2-propenyl. Similar terms such as “(C
2
-C
3
)alkenyl” are to be interpreted similarly.
As used herein the term “C
2
-C
6
alkynyl” means a straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one triple bond. This term would include for example, ethynyl, 1-propynyl, 1- and 2-butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl. Similar terms such as “(C
2
-C
3
)alkynyl” are to be interpreted similarly.
As used herein the term cycloalkyl means a saturated alicyclic moiety having from 3-7 carbon atoms and includes, for example, cyclohexyl, cycloheptyl, cyclopentyl, cyclobutyl and cyclopropyl.
As used herein the term “halogen” means fluoro, chloro, bromo or iodo.
As used herein the term “aryl” refer

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