Amidino compounds as cysteine protease inhibitors
The present invention is directed to compounds that are inhibitors of cysteine proteases, in particular, cathepsins B, K, L, F, and S and are therefore useful in treating diseases mediated by these proteases. The present invention is directed to pharmaceutical compositions comprising these compounds and processes for preparing them.
1 . A compound of Formula (I):
wherein:
R 1 is benzoxazol-2-yl, oxazolo-[4.5-b]-pyridin-2-yl, 2-ethyl-[1.3.4]-oxadiazol-5-yl, 2-phenyl-[1.3.4]-oxadiazol-5-yl, 3-phenyl-[1.2.4]-oxadiazol-5-yl, 3-thien-3-yl-[1.2.4]-oxadiazol-5-yl, 3-pyridin-3-yl-[1.2.4]-oxadiazol-5-yl, 3-ethyl-[1.2.4]-oxadiazol-5-yl, 5-ethyl-[1.2.4]-oxadiazol-3-yl, or 2-methoxymethyl-[1.3.4]-oxadiazol-5-yl; and
R 2 is ethyl or n-propyl;
R 3 is cylohexylmethyl, 1-methylcyclohexylmethyl, cyclopentylmethyl, 1-methylcyclopentylmethyl, cyclopropylmethylsulfinylmethyl, cyclopropylmethylsulfonylmethyl, 2-phenylsulfanylethyl, 2-phenylsulfonylethyl, pyridin2-ylmethylsulfonylmethyl, benzylsulfinylmethyl, benzylsulfonylmethyl, 2-(difluoromethoxy)-benzylsulfonylmethyl, or 2-chlorobenzyl;
R 4 is methyl, phenyl, 4-fluorophenyl, isopropylamine, cyclopentylamine, tetrahydropyran-4-yl, morpholin-4-yl, or pyrrolidin-1-yl;
R 5 is methylsulfonyl, 2,2,2-trifluoroethyl, ethoxycarbonyl, or pyridin-3-ylsulfonyl; or
R 4 and R 5 together with the atoms to which they are attached form 1,1-dioxo-benzo[d]isothiazol-3-yl or 1,1-dioxo-1,4-dihydro-λ 6 -benzo[1.2.4]thiadiazin-3-yl; or a pharmaceutically acceptable salts thereof.
2 . A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
3 . A compound formula:
4 . A pharmaceutical composition comprising a compound of any of the claims 1 - 3 in admixture with one or more suitable excipients.
5 . A method for treating a disease in an animal mediated by cysteine proteases which method comprises administering to the animal a therapeutically effective amount of a compound of any of the claims 1 - 3 .
6 . A method of treating a patient undergoing a therapy wherein the therapy causes an immune response in the patient comprising administering to the patient a compound of any of the claims 1 - 3
7 . The method of claim 6 wherein the therapy involves treatment with a biologic.
8 . The method of claim 7 wherein the biologic is a protein.
9 . The method of claim 7 wherein the biologic is an antibody.
10 . The method of claim 9 wherein the biologic is Remicade®, Refacto®, Referon-A®, Factor VIII, Factor VII, Betaseron®, Epogen®, Embrel®, Interferon beta, Botox®, Fabrazyme®, Elspar®, Cerezyme®, Mybloc®, Aldurazyme®, Verluma®, Interferon alpha, Humira®, Aranesp®, Zevalin® or OKT3.
11 . A method of treating immune response in an animal that is caused by administration of a biologic to the animal which method comprises administering to the animal in need of such treatment a therapeutically effective amount of a compound of any of the claims 1 - 3 .
12 . A method of conducting a clinical trial for a biologic comprising administering to an individual participating in the clinical trial a compound of any of the claims 1 - 3 with the biologic.
13 . A method of prophylactically treating a person undergoing treatment with a biologic with a compound of any of the claims 1 - 3 to treat the immune response caused by the biologic in the person.
14 . A method of determing the loss in the efficacy of a biologic in an animal due to the immune response caused by the biologic comprising administering the biologic to the animal in the presence and absence of a compound of any of the claims 1 - 3 .
15 . A method of improving efficacy of a biologic in an animal comprising administering the biologic to the animal with a compound of any of the claims 1 - 3 .
16 . The method of claim 5 wherein the cysteine protease is Cathepsin S.
17 . The method of claim 16 wherein the disease is psoriasis or Grave's exophthalmos.
18 . Use of a compound of any of the claims 1 - 3 for the manufacture of a medicament for combination therapy with a biologic wherein the compound treats the immune response caused by the biologic.