Dipeptide nitrile cathepsin K inhibitors

Details Dipeptide nitrile cathepsin K inhibitors Dipeptide nitrile cathepsin K inhibitors

2001-02-07

2003-11-04

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S331000, C544S393000, C546S230000

Reexamination Certificate

active

06642239

ABSTRACT:

This invention relates to inhibitors of cysteine proteases, in particular to dipeptide nitrile cathepsin K inhibitors and to their pharmaceutical use for the treatment or prophylaxis of diseases or medical conditions in which cathepsin K is implicated.
Cathepsin K is a member of the family of lysosomal cysteine cathepsin enzymes, e.g. cathepsins B, K, L and S, which are implicated in various disorders including inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis, tumors (especially tumor invasion and tumor metastasis), coronary disease, atherosclerosis (including atherosclerotic plaque rupture and destabilization), autoimmune diseases, respiratory diseases, infectious diseases and immunologically mediated diseases (including transplant rejection).
Our copending International patent application WO 99/24460 describes dipeptide nitrites which are inhibitors of cysteine cathepsins and their use for treatment of cysteine cathepsin dependent diseases or medical conditions. New dipeptide nitrile compounds have now been made which are inhibitors of cathepsin K, and which have desirable properties for pharmaceutical applications.
Accordingly the present invention provides a compound of formula I, or a pharmaceutically acceptable salt or ester thereof:
In which
R
1
and R
2
are independently H or C
1
-C
7
lower alkyl, or R
1
and R
2
together with the carbon atom to which they are attached form a C
3
-C
8
cycloalkyl ring, and
Het is an optionally substituted nitrogen-containing heterocyclic substituent, provided that Het is not 4-pyrrol-1-yl.
The Het substituent may be at the 2- or 3-position of the phenyl ring, though is preferably at the 4-position.
In the present description “nitrogen-containing heterocycle” signifies a heterocyclic ring system containing at least one nitrogen atom, from 2 to 10, preferably from 3 to 7, most preferably 4 or 5, carbon atoms and optionally one or more additional heteroatoms selected from O, S or preferably N.
Het may comprise an unsaturated, e.g. an aromatic, nitrogen-containing heterocycle; though preferably comprises a saturated nitrogen-containing heterocycle. Particularly preferred saturated nitrogen-containing heterocycles are piperazinyl, preferably piperazin-1-yl, or piperidinyl, preferably piperidin-4-yl.
Het may be substituted by one or more substituents, e.g. by up to 5 substituents independently selected from halogen, hydroxy, amino, nitro, optionally substituted C
1-4
alkyl (e.g. alkyl substituted by hydroxy, alkyloxy, amino, optionally substituted alkylamino, optionally substituted dialkylamino, aryl or heterocyclyl), C
1-4
alkoxy.
Preferably Het is substituted at a nitrogen atom, most preferably mono-substituted at a nitrogen atom.
Preferred substituents for Het are C
1
-C
7
lower alkyl, C
1
-C
7
lower alkoxy-C
1
-C
7
lower alkyl, C
5
-C
10
aryl-C
1
-C
7
lower alkyl, or C
3
-C
8
cycloalkyl.
R
1
and R
2
as C
1
-C
7
lower alkyl are preferably the same, e.g. methyl, or R
1
and R
2
together with the carbon atom to which they are attached preferably form a C
3
-C
8
cycloalkyl ring, e.g. a cyclopropyl ring. Most preferably both R
1
and R
2
are H.
Thus in particularly preferred embodiments the invention provides a compound of formula II, or a pharmaceutically acceptable salt or ester thereof:
wherein X is CH or N, and
R is H, C
1
-C
7
lower alkyl, C
1
-C
7
lower alkoxy-C
1
-C
7
lower alkyl, C
5
-C
10
aryl-C
1
-C
7
lower alkyl, or C
3
-C
8
cycloalkyl.
Thus particular examples of R as C
1
-C
7
lower alkyl are methyl, ethyl, n-propyl, or i-propyl.
A particular example of R as C
1
-C
7
lower alkoxy-C
1
-C
7
lower alkyl is methoxyethyl.
A particular example of R as C
5
-C
10
aryl-C
1
-C
7
lower alkyl is benzyl.
A particular example of R as C
3
-C
8
cycloalkyl is cyclopentyl.
Examples of particular compounds of formula II are:
N-[1-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(piperazin-1-yl)-benzamide;
N-[1-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(4-methyl-piperazin-1-yl)-benzamide;
N-[1-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(4-ethyl-piperazin-1-yl)-benzamide;
N-[1-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-[4-(1-propyl)-piperazin-1-yl]-benzamide;
N-[1-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(4-isopropyl-piperazin-1-yl)-benzamide;
N-[1-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(4-benzyl-piperazin-1-yl)-benzamide;
N-[1-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-benzamide;
N-[1-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(1-propyl-piperidin-4-yl)-benzamide;
N-[1-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-[1-(2-methoxy-ethyl)-piperidin-4-yl]-benzamide;
N-[1-(Cyanomethyl-carbamoyl)-cyclohexyl](1-isopropyl-piperidin-4-yl)-benzamide;
N-[1-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(1-cyclopentyl-piperidin-4-yl)-benzamide;
N-[1-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(1-methyl-piperidin-4-yl)-benzamide, and
N-[1-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(piperidin-4-yl)-benzamide.
Compounds of formula I and II and the specific compounds above are hereinafter referred to as Compounds of the Invention.
Compounds of the Invention may be prepared by coupling the corresponding Het substituted benzoic acid derivative with I-amino-cyclohexanecarboxylic acid cyanomethyl amide. For example, the benzoic acid derivative, preferably in the form of its hydrochloride, is mixed with 1-amino-cyclohexanecarboxylic acid cyanomethyl amide, e.g. in the presence of HOBT (1-hydroxybenzotriazole), WSCD and trimethylamine, in solution, e.g. in DMF, and stirred, e.g. overnight at room temperature. The product may be recovered, for instance, by evaporation of the solvent, followed by washing with aqueous sodium carbonate solution, preferably under mildly basic conditions, followed by solvent extraction, e.g. with ethyl acetate, drying of the extract, e.g. over sodium sulfate, evaporation of the solvent and filtration. Alternative procedures and reagents may be used; for instance, as hereinafter described in the Examples.
Thus in a further aspect the invention provides a process for the preparation of a compound of formula I which comprises coupling the corresponding Het substituted benzoic acid derivative of formula III:
With 1-amino-cyclohexanecarboxylic acid cyanomethyl-amide.
1-Amino-cyclohexanecarboxylic acid cyanomethyl-amide may be prepared by coupling 1-amino-cyclohexane carboxylic acid, typically in appropriate amino protected form, e.g. FMOC-1-amino-cyclohexane carboxylic acid, with 2-aminoacetonitrile. For example, FMOC-1-amino-cyclohexane carboxylic acid, e.g. with HOBT and WSCD, is added to a solution of 2-aminoacetonitrile and triethylamine in DMF and the mixture stirred at 25° C. overnight. 1-Amino-cyclohexanecarboxylic acid cyanomethyl-amide may be recovered as described in the Examples. FMOC-1-aminocyclohexane carboxylic acid may be prepared as described in the Examples.
Compounds of the invention are either obtained in the free form, or as a salt thereof if salt forming groups are present.
Compounds of the Invention having basic groups can be converted into acid addition salts, especially pharmaceutically acceptable salts. These are formed, for example, with inorganic acids, such as mineral acids, for example sulfuric acid, a phosphoric or hydrohalic acid, or with organic carboxylic acids, such as (C
1
-C
4
)alkanecarboxylic acids which, for example, are unsubstituted or substituted by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, succinic, maleic or fumaric acid, such as hydroxycarboxylic acids, for example glycolic, lactic, malic, tartaric or citric acid, such as amino acids, for example aspartic or glutamic acid, or with organic sulfonic acids, such as (C
1
-C
4
)-alkylsulfonic acids (for example methanesulfonic acid) or arylsulfonic acids which are unsubstituted or substituted (for example by halogen). Preferred are salts formed with hydrochloric acid, methanesulfonic acid and maleic acid.
In view of the close relationship betwee

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