Dipeptide derivatives

A compound of formula I, or a physiologically-acceptable and -cleavable ester or a salt thereof

• 635
• wherein:
• R is optionally substituted (aryl, lower alkyl, lower alkenyl, lower alkynyl, or heterocyclyl);
• R2 and R3 are independently hydrogen, or optionally substituted [lower alkyl, cycloalkyl, bicycloalkyl, or (aryl, biaryl, cycloalkyl or bicycloalkyl)-lower alkyl];
• or
• R2 and R3 together represent lower alkylene, optionally interrupted by O, S or NRC, so as to form a ring with the carbon atom to which they are attached
• wherein R6 is hydrogen, lower alkyl or aryl-lower alkyl;
• or
• either R2 or R3 are linked by lower alkylene to the adjacent nitrogen to form a ring;
• R4 and R5 are independently H, or optionally substituted (lower alkyl, aryl-lower alkyl), —C(O)OR7, or —C(O)NR7R8,
• wherein
• R7 is optionally substituted (lower alkyl, aryl, aryl-lower alkyl, cycloalkyl, bicycloalkyl or heterocyclyl), and
• R8 is H, or optionally substituted (lower alkyl, aryl, aryl-lower alkyl, cycloalkyl, bicycloalkyl or heterocyclyl), or
• R4 and R5 together represent lower alkylene, optionally interrupted by O, S or NR6, so as to form a ring with the carbon atom to which they are attached
• wherein R6 is hydrogen, lower alkyl or aryl-lower alkyl, or
• R4 is H or optionally substituted lower alkyl and R5 is a substituent of formula —X2—(Y1)n—(Ar)p-Q-Z
• wherein
• Y1 is O, S, SO, SO2, N(R6)SO2, N—R6, SO2NR6, CONR6 or NR6CO;
• n is zero or one;
• p is zero or one;
• X2 is lower alkylene;
• or when n is zero, X2 is also C2-C7-alkylene interrupted by O, S, SO, SO2, NR6, SO2NR6, CONR6 or NR6CO;
• wherein R6 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, Y1-lower alkylene or C2-C7-alkylene interrupted by Y1;
• X1 is —C(O)—, —C(S)—, —S(O)—, —S(O)2—, or —P(O)(OR6)—,
• wherein R6 is as defined above;
• Y is oxygen or sulphur;
• L is optionally substituted -Het-, -Het-CH2— or —CH2-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;
• provided that when R is lower alkyl not substituted by aryl,
• one of R4 or R5 is a substituent of formula —X2-(Y1)n—(Ar)p-Q-Z;
• provided that when x is one, L is —O—, or —CH2—O— and X1 is —C(O)—,
• either one of R4 or R5 is a substituent of formula —X2—(Y1)n—(Ar)p-Q-Z, or R is not unsubstituted phenyl;
• provided that when R2═R4═R5═H, x is zero and X1 is —C(O)—,
• R3 is not H, —CH3, —CH(CH3)2, —CH2—CH—(CH3)2, —CH2—COOH, or —CH2—COO—CH2—CH3, when R is unsubstituted phenyl,
• R3 is not H, —CH(CH3)2, or —CH2—CH—(CH3)2, when R is 4-aminophenyl or 4-nitrophenyl,
• R3 is not H when R is 3-aminophenyl, 3-nitrophenyl 2-chloropyridin-4-yl, or vinyl or
• R3 is not —CH2—CH2—S—CH3 when R is pyridin-3-yl or 2-chloropyridin-4-yl,
• provided that when R2═R3═R4═H, x is zero and X1 is —C(O)— and R is phenyl,
• R5 is not —CH(CH3)2,
• provided that when R3═R4═H, R5 is —CH2—CH2—COOH, x is zero and X1 is —C(O)—,
• R2 does not form a heterocyclic ring with the adjacent nitrogen atom, and
• provided that when R2═R3═R4═R5═H, x is zero and X1 is —SO2—,
• R is not 4-methylphenyl.

A cathepsin inhibiting pharmaceutical composition comprising a compound of formula III

• 638
• wherein
• R30 is an acyl group derived from an organic carboxylic, carbonic, carbamic or sulfonic acid;
• R32 and R33 are independently hydrogen, lower alkyl, cycloalkyl, bicycloalkyl, or (aryl, biaryl, cycloalkyl or bicycloalkyl)-lower alkyl;
• or R32 and R33 together represent lower alkylene so as to form a ring together with the carbon to which they are attached;
• R34 is hydrogen or lower alkyl;
• Y1 is O, S, SO, SO2, N(R6)SO2, N—R6, SO2NR6, CONR6 or NR6CO;
• n is zero or one;
• p is zero or one;
• X2 is lower alkylene;
• or when n is zero, X2 is also C2-C7-alkylene interrupted by O, S, SO, SO2, NR6, SO2NR6, CONR6 or NR6CO;
• wherein R6 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, Y1-lower alkylene or C2-C7-alkylene interrupted by Y1;
• or a pharmaceutically acceptable salt or ester thereof;
• in combination with a pharmaceutically acceptable carrier.

A compound of formula III

• 639
• wherein
• R30 is an acyl group derived from an organic carboxylic, carbamic or sulfonic acid;
• R32 and R33 are independently hydrogen, lower alkyl, cycloalkyl, bicycloalkyl, or (aryl, biaryl, cycloalkyl or bicycloalkyl)-lower alkyl;
• or R32 and R33 together represent lower alkylene so as to form a ring together with the carbon to which they are attached;
• R34 is hydrogen or lower alkyl;
• Y1 is O, S, SO, SO2, N(R6)SO2, N—R6, SO2NR6, CONR6 or NR6CO;
• n is zero or one;
• p is zero or one;
• X2 is lower alkylene;
• or when n is zero, X2 is also C2-C7-alkylene interrupted by O, S, SO, SO2, NR6, SO2NR6, CONR6 or NR6CO;
• wherein R6 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, Y1-lower alkylene or C2-C7-alkylene interrupted by Y1;
• or a pharmaceutically acceptable salt or ester thereof.