Dipeptide nitriles

Details Dipeptide nitriles Dipeptide nitriles

2000-08-22

2002-03-05

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C548S561000

Reexamination Certificate

active

06353017

ABSTRACT:

This invention relates to inhibitors of cysteine proteases, in particular to dipeptide nitrile cathepsin inhibitors and to their pharmaceutical use for the treatment or prophylaxis of diseases or medical conditions in which cathepsins are implicated.
The cysteine cathepsins, e.g. cathepsins B, K, L and S, are a class of lysosomal enzymes 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).
In accordance with the invention it has been found that dipeptide nitrites are particularly useful as cysteine cathepsin inhibitors and can be used for the treatment of the above-cited cysteine cathepsin dependent conditions.
Accordingly the present invention provides an N-terminal-substituted dipeptide nitrile, i.e. a dipeptide in which the C-terminal carboxy group of the dipeptide is replaced by a nitrile group (—C≡N) and in which the N-terminal nitrogen atom is substituted via a peptide or pseudopeptide linkage which optionally additionally comprises a -methylene-hetero atom-linker or an additional hetero atom, directly by aryl, lower alkyl, lower alkenyl, lower alkynyl or heterocyclyl, or a physiologically-acceptable and -cleavable ester or a salt thereof, for use as a pharmaceutical.
The invention further provides a pharmaceutical composition comprising an N-terminal-substituted dipeptide nitrile as defined above as an active ingredient.
The invention also provides a method of treating a patient suffering from or susceptible to a disease or medical condition in which a cathepsin is implicated, comprising administering an effective amount of an N-terminal-substituted dipeptide nitrite as defined above to the patient.
The invention further includes the use of an N-terminal-substituted dipeptide nitrite as defined above for the preparation of a medicament for therapeutic or prophylactic treatment of a disease or medical condition in which a cathepsin is implicated.
The dipeptide nitrile of the invention conveniently comprises &agr;-amino acid residues, including both natural and unnatural &agr;-amino acid residues. Herein the “natural &agr;-amino acid residues” denote the 20 amino acids obtainable by translation of RNA according to the genetic code or the corresponding nitrites thereof, as appropriate. “Unnatural &agr;-amino acid residues” are &agr;-amino acids which have &agr;-substituents other than those found in “natural &agr;-amino acid residues”. Preferred &agr;-amino acid residues, as the C-terminal amino acid residue of the dipeptide nitrite, are the nitrites of tryptophan, 2-benzyloxymethyl-2-amino-acetic acid, 2,2-dimethyl-2-amino-acetic acid, 2-butyl-2-amino-acetic acid, methionine, leucine, lysine, alanine, phenylalanine, and glycine and derivatives thereof, e.g. as hereinafter described. Preferred amino acid residues as the N-terminal amino acid residue of the dipeptide nitrite are 1-amino-cyclohexanecarboxylic acid, 1-amino-cycloheptanecarboxylic acid, phenylalanine, histidine, tryptophan and leucine and derivatives thereof, e.g. as hereinafter described.
The aryl, lower alkyl, lower alkenyl, lower alkynyl or heterocyclyl substituent (hereinafter referred to as R) is attached to the the N-terminal nitrogen atom of the dipeptide via a peptide linkage, i.e. as R—C(O)—NH—, or via a pseudopeptide linkage. Suitable pseudopeptide linkages include sulphur in place of oxygen and sulphur and phosporous in place of carbon, e.g. as R—C(S)—NH—, R—S(O)—NH—, R—S(O)
2
—NH— or R—P(O)
2
—NH and analogues thereof. Additionally the peptide or pseudopeptide linkage between the R substituent and the N-terminal nitrogen atom may comprise an additional hetero atom, e.g. as R—Het—C(O)—NH—, or a -methylene-hetero atom-linker, e.g. as R—Het—CH
2
—C(O)—NH— or R—CH
2
—Het—C(O)—NH—, wherein Het is a hetero atom selected from O, N or S, and pseudopeptide containing alternatives thereof, e.g. as defined above. When the linkage between the aryl substituent and the N-terminal nitrogen atom comprises a -methylene-hetero atom-linker, the methylene group and the hetero atom may be optionally further substituted, e.g. as hereinafter described.
The R substituent may be further substituted, e.g. by up to 3 substituents 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, C
2-6
alkenyl, CN, trifluoromethyl, trifluoromethoxy, aryl, (e.g. phenyl or phenyl substituted by CN, CF
3
, halogen, OCH
3
), aryloxy, (e.g. phenoxy or phenoxy substituted by CN, CF
3
, halogen, OCH
3
), benzyloxy or a heterocyclic residue.
Accordingly in preferred embodiments the invention provides a compound of formula I, or a physiologically-acceptable and -cleavable ester or a salt thereof
wherein:
R is optionally substituted (aryl, lower alkyl, lower alkenyl, lower alkynyl, or heterocyclyl);
R
2
and R
3
are independently hydrogen, or optionally substitued [lower alkyl, cycloalkyl, bicycloalkyl, or (aryl, biaryl, cycloalkyl or bicycloalkyl)-lower alkyl]; or
R
2
and R
3
together represent lower alkylene, optionally interrupted by O, S or NR
6
, so as to form a ring with the carbon atom to which they are attached wherein R
6
is hydrogen, lower alkyl or aryl-lower alkyl; or
either R
2
or R
3
are linked by lower alkylene to the adjacent nitrogen to form a ring;
R
4
and R
5
are independently H, or optionally substituted (lower alkyl, aryl-lower alkyl), —C(O)OR
7
, or —C(O)NR
7
R
8
,
 wherein
R
7
is optionally substituted (lower alkyl, aryl, aryl-lower alkyl, cycloalkyl, bicycloalkyl or heterocyclyl), and
R
8
is H, or optionally substituted (lower alkyl, aryl, aryl-lower alkyl, cycloalkyl, bicycloalkyl or heterocyclyl), or
R
4
and R
5
together represent lower alkylene, optionally interrupted by O, S or NR
6
, so as to form a ring with the carbon atom to which they are attached wherein R
6
is hydrogen, lower alkyl or aryl-lower alkyl, or
R
4
is H or optionally substituted lower alkyl and R
5
is a substituent of formula —X
2
—(Y
1
)
n
—(Ar)
p
—Q—Z
 wherein
Y
1
is O, S, SO, SO
2
, N(R
6
)SO
2
, N—R
6
, SO
2
NR
6
, CONR
6
or NR
6
CO;
n is zero or one;
p is zero or one;
X
2
is lower alkylene; or when n is zero, X
2
is also C
2
-C
7
-alkylene interrupted by O, S, SO, SO
2
, NR
6
, SO
2
NR
6
, CONR
6
or NR
6
CO;
wherein R
6
is hydrogen, lower alkyl or aryl-lower alkyl;
Ar is arylene;
Z is hydroxy, acyloxy, carboxyl, esterified carboxyl, amidated carboxyl, aminosulfonyl, (lower alkyl or aryl-lower alkyl)aminosulfonyl, or (lower alkyl or aryl-lower alkyl)sulfonylaminocarbonyl; or Z is tetrazolyl, triazolyl or imidazolyl;
Q is a direct bond, lower alkylene, Y
1
-lower alkylene or C
2
-C
7
-alkylene interrupted by Y
1
;
X
1
is —C(O)—, —C(S)—, —S(O)—, —S(O)
2
—, —P(O)(OR
6
)—
wherein R
6
is as defined above;
Y is oxygen or sulphur;
L is optionally substituted —Het—, —Het—CH
2
— or —CH
2
—Het—,
wherein Het is a hetero atom selected from O, N or S, and
x is zero or one;
and aryl in the above definitions represents carbocyclic or heterocyclic aryl, for use as a pharmaceutical;
a pharmaceutical composition comprising a compound of formula I as defined above as an active ingredient;
a method of treating a patient suffering from or susceptible to a disease or medical condition in which a cathepsin is implicated, comprising administering an effective amount of a compound of formula I as defined above to the patient; and
use of a compound of formula I as defined above for the preparation of a medicament for therapeutic or prophylactic treatment of a disease or medical condition in which a cathepsin is implicated.
The invention also provides novel dipeptide nitriles.
Accordingly the

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