Lymphocyte function antigen-1 antagonists

A compound of formula II

• wherein
• Ra is H;
• C1-6 alkyl;
• C1-6 alkyl substituted by OH or C1-4 alkyoxy;
• C2-6 alkenyl;
• or aryl-C1-4 alkyl;
• R2 is C1-8alkyl, C3-7cycloalkyl, aryl, heteroaryl, C3-7cycloalkyl-C1-4alkyl, aryl-C1-4alkyl or heteroaryl-C1-4alkyl;
• R3 is a radical of formula (i), (ii), (iii) or (iv)
• wherein X1 and Y1 are (H,H), (H,OH) or ═O;
• X2 and Y2 are ═O or (R,R) wherein each R independently is H, C1-3 alkyl, substituted C1-3 alkyl or X2 and Y2 form together with the carbon atom to which they are bound a 4-, 5-, 6- or 7-membered carbo- or heterocyclic ring,
• R4 is ORa wherein Ra is as defined above;
• or —O—CORb wherein Rb is C1-8 alkyl optionally substituted by OH, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-4alkyl, aryl, aryl-C1-4 alkyl, heteroalkyl, heteroaryl or heteroaryl-C1-4 alkyl;
• or NRcRd wherein each of Rc and Rd, independently, is C1-6alkyl or form together with the nitrogen to which they are bound a heterocyclic ring optionally comprising an oxygen or another nitrogen atom;
• R5 is H, C1-4 alkyl, C3-9 alkenyl, C3-9 alkynyl, aryl-C1-4 alkyl or C3-7 cycloalkyl-C1-4 alkyl;
• R6 is —CHR11—CO—NR12R13 wherein R11 is R5 and each R12 and R13, independently, is H, C1-4 alkyl, or substituted C1-4 alkyl;
• R7 is ═O or (H,OH);
• R8 is ORa;
• or NReRf wherein each of Re and Rf, independently, is H, C1-6alkyl, C1-6alkyl substituted by OH or C1-4alkoxy, or a 5-membered heterocyclic ring;
• or R7 and R8, together, form a dioxy-C1-4alkylene group or —O—CO—O—;
• R9 is R5;
• R10 is COORa;
• CH2ORc wherein Rc is Ra or CORb;
• or CONR14R15 or CH2NR14R15 wherein each of R14 and R15 independently is C1-4alkyl, hydroxy substituted C1-4alkyl, carbamoyl-methyl, (C1-4alkyl)-carbamoyl-methyl or di(C 1-4alkyl)-carbamoyl-methyl, or one of R14 and R15 is hydrogen and the other is C1-6alkyl, C1-6alkyl substituted by OH and/or a group selected from carbamoyl, (C1-4alkyl)-carbamoyl, di(C1-4alkyl)-carbamoyl and heteroaryl-C1-4alkyl, C1-6alkoxy-carbonyl-methyl, adamantyl-methyl, C3-7cycloalkyl-C1-4alkyl, aryl-C1-4alkyl wherein aryl may be substituted and C1-4alkyl may be substituted by carbamoyl or C1-4alkoxy-carbonyl, or heteroaryl-C1-4alkyl wherein heteroaryl may be substituted by carbamoyl or C1-4alkoxy-carbonyl and C1-4alkyl may be substituted by carbamoyl, or R14 and R15 form together with the nitrogen to which they are attached a heterocyclic ring optionally consisting of a further nitrogen atom and optionally substituted by C1-4alkyl, (C1-4alkoxy)-carbonyl, carbamoyl, dioxy-C1-4alkylene, aryl-C1-4alkyl or heteroaryl wherein heteroaryl may be substituted by C1-4alkoxy-carbonyl;
• R16 is H;
• C1-4alkyl;
• aryl-C1-4alkyl wherein aryl may be substituted by halogen, OH, amino optionally substituted, COOH, CF3, C1-4 alkoxy or cyano;
• or C3-7cycloalkyl-C1-4aryl;
• each of a-b and α-β, independently, is either a single bond or a double bond, in free form or in a pharmaceutically acceptable salt form provided that
• 1) R4 is other than ORa when R3 is a radical of formula (i) wherein X1 and Y1 are (H,H), (H,OH) or ═O,
• 2) R8 is other than ORa when R3 is a radical of formula (iii) wherein R10 is COORa and R7 is (H,OH),
• 3) R10 is other than CH2ORa when R3 is a radical of formula (iii) wherein R7 and R8 form together a dioxy C1-4 alkylene group and R9 is H, or
• 4) One of R14 and R15 is other than aryl C1-4 alkyl wherein C1-4 alkyl is substituted by C1-4 alkoxy-carbonyl, the other of R14 and R15 being H, when R3 is a radical of formula (iii) wherein R10 is CONR14R15.