Substituted azetidin-2-ones as cysteine protease inhibitors

Details Substituted azetidin-2-ones as cysteine protease inhibitors Substituted azetidin-2-ones as cysteine protease inhibitors

2001-10-05

2003-05-27

Berch, Mark L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S357000, C540S359000, C540S360000

Reexamination Certificate

active

06569847

ABSTRACT:

CROSS-REFERENCE TO RELATED APPLICATION
This application is National Stage entry of International Application No. PCT/GB00/01261, filed Apr. 3, 2000, the entire specification claims and drawings of which are incorporated herewith by reference.
This invention relates to substituted azetidin-2-ones, to pharmaceutical compositions containing such compounds, and to their use in medicine as inhibitors of cysteine proteases, particularly the cathepsins.
BACKGROUND OF 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 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 cathepsins 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 others 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 cathepsins have also been shown to play a role in rheumatoid arthotis (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, cathepsins play a major role in the pathogenesis of infectious diseases. For example, cathepsins are used by the protozoal parasites Plasmodium (malaria) and Trypanosoma (Chagas Disease) to invade the human host and 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). 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. Another review (Exp. Opin. Ther. Patents, 1998, 8(6), pp645-672) deals with cathepsin B inhibitors as potential anti-metastatic agents.
International patent applications WO 96132408, 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 they are disubstituted at the 3-position. 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)
Y represents —C(O)— or —S(O
2
)—;
R represents an allyl (ie CH
2
═CHCH
2
—) group or a radical of formula R
4
-(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, R
4
represents hydrogen or halogen, or an optionally substituted phenyl group, and n, p and q are independently 0 or 1, PROVIDED THAT (i) when R
4
is hydrogen and both p and n are 0 then q is 1; and (ii) when R
4
is halogen and n is 1 then p is 1; and (iii) when R
4
is halogen then p, n and q are not all 0;
R
1
represents —OCOR
5
, —OR
5
, —SR
5
, —S(O)R
5
, or —S(O)
2
R
5
;
R
2
represents a radical of formula R
6
-(ALK)
p
-(Z)
n
-(ALK)
q
- wherein p, Z and ALK are as defined in relation to R, q is 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
2
together with the carbon atom to which it is attached forms a cycloalkyl ring;
R
3
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;
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.
Preferably, the R and R
1
groups are cis to each other.
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, 4pentynyl, 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” refers to a mono-, bi- or tri-cyclic, substituted o

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