Indole derivatives with vascular damaging activity

A compound selected from

• 2-phenoxycarbonylamino-5-phenylsulphanyl-1H-indole-3-carbonitrile;
• 5-(4-hydroxyphenylsulphanyl)-2-amino-1H-indole-3-carbonitrile;
• 5-(3,6-dimethoxyphenylsulphanyl)-2-amino-1H-indole-3-carbonitrile;
• 5-phenylsulphanyl-2-(4-methylpiperazin-1-ylpropoxycarbonylamino)-1H-indole-3-carbonitrile;
• 5-phenylsulphanyl-1-(4-methylpiperazin-1-ylpropoxycarbonyl)-2-amino-1H-indole-3-carbonitrile;
• 6-benzyloxy-2-amino-1H-indole-3-carbonitrile;
• 5-[4-(4-methylpiperazin-1-yl-4-oxobutanoyloxy)phenoxy]-2-amino-1H-indole-3-carbonitrile;
• 5-(4-glycylaminophenoxy)-2-amino-1H-indole-3-carbonitrile;
• 5-(4-alanylaminophenoxy)-2-amino-1H-indole-3-carbonitrile;
• 5-(4-glutamylaminophenoxy)-2-amino-1H-indole-3-carbonitrile;
• 5-(3-glycylbenzyloxy)-2-amino-1H-indole-3-carbonitrile;
• 5-(4-hydroxyphenoxy)-2-amino-1H-indole-3-carbonitrile;
• 5-(4-phosponooxyphenoxy)-2-amino-1H-indole-3-carbonitrile;
• 5-(3-serylbenzyloxy)-2-amino-1H-indole-3-carbonitrile;
• 5-(4-acetylaminophenoxy)-2-amino-1H-indole-3-carbonitrile;
• and
• 5-(4-serylaminophenoxy)-2-amino-1H-indole-3-carbonitrile;
• or salt or solvate thereof.

A compound selected from:

• 5-(4-aminophenoxy)-2-amino-1H-indole-3-carbonitrile;
• 5-(3,4,5-trimethoxyphenoxy)-2-amino-1H-indole-3-carbonitrile;
• 5-(3,4-dimethoxyphenylsulphanyl)-2-amino-1H-indole-3-carbonitrile;
• and
• 5-(3,4,5-trimethoxyphenoxy)-2-amino-1H-indole-3-carbonitrile;
• or salt or solvate thereof.

The use of a compound of Formula (Ib) as a medicament:

• 80
• wherein R1b and R2b are independently selected from hydrogen, halogen, —CN, a hydrocarbyl group or a group of Formula (IIb);
• 81
• wherein Wb is aryl or a heterocyclic group,
• R4b is independently selected from hydrogen, halogen, —OH, amino, alkanoylamino, —OPO3H2, or a hydrocarbyl group, wherein the amino group is optionally substituted by an amino acid residue and the hydroxy group is optionally esterified or two R4b groups together form an optionally substituted cyclic or heterocyclic group;
• Xb is selected from —S—, —O—, —S(O)—, —S(O2)— and —NH—;
• pb is an integer from 0 to 4;
• and
• qb is an integer from 1 to 4;
• R3b and R10b are independently selected from hydrogen, lower alkyl or a group of Formula (IVb):
• 82
• wherein Yb is selected from —NH—, —O— or a bond;
• Zb is selected from —NH—, —O—, —C(O)— or a bond;
• rb is an integer from 0 to 4;
• tb is an integer from 0 to 1;
• R6b is hydrogen, a hydrocarbyl group or a group of Formula (Vb):
• 83
• wherein nb is an integer of from 1 to 6, and;
• R7b and R8b are independently selected from hydrogen or a hydrocarbyl group;
• and
• R11b is hydrogen or lower alkyl;
• or a salt or solvate thereof;
• provided that:
• ii) when R1 is an unsubstituted phenylthio group (Ph—S—), R2 is H, R10 is H and R11 is H then R3 is neither H nor —C(O)—O—CH2CH3.

The use of a compound of Formula (Ic) or a pharmaceutically-acceptable salt or solvate thereof, for the manufacture of a medicament to inhibit and/or reverse and/or alleviate symptoms of angiogenesis and/or any disease state associated with angiogenesis:

• 84
• wherein R1c and R2c are independently selected from hydrogen, halogen, —CN, a hydrocarbyl group or a group of Formula (IIc);
• 85
• wherein Wc is aryl or a heterocyclic group,
• R4c is independently selected from hydrogen, halogen, —OH, amino, alkanoylamino, —OPO3H2, or a hydrocarbyl group, wherein the amino group is optionally substituted by an amino acid residue and the hydroxy group is optionally esterified or two R4c groups together form an optionally substituted cyclic or heterocyclic group;
• Xc is selected from —S—, —O—, —S(O)—, —S(O2)— and —NH—;
• pc is an integer from 0 to 4;
• and
• qc is an integer from 1 to 4;
• R3c and R10c are independently selected from hydrogen, lower alkyl or a group of Formula (IVc):
• 86
• wherein Yc is selected from —NH—, —O— or a bond;
• Zc is selected from —NH—, —O—, —C(O)— or a bond;
• rc is an integer from 0 to 4;
• tc is an integer from 0 to 1;
• R6c is hydrogen, a hydrocarbyl group or a group of Formula (Vc):
• 87
• wherein nc is an integer of from 1 to 6, and;
• R7c and R8c are independently selected from hydrogen or a hydrocarbyl group;
• and
• R11c is hydrogen or lower alkyl;

A process for preparing a compound of Formula (I), or salt, or solvate thereof, which process (wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, m, n, p, q, r, t, W, X, Y and Z are unless otherwise specified as defined in Formula (I)) comprises:

• a) for compounds of Formula (I) wherein R1 is of the Formula (II) and X is —O—, —S— or —NH—, reacting a compound of Formula (A) with a compound of Formula (B),
• 88
• wherein L1 is a leaving group;
• b) for compounds of Formula (I) in which R3 is hydrogen and R11 is hydrogen may be prepared by reduction followed by ring closure of compounds of Formula (C):
• 89
• c) for compounds of Formula (I) wherein R10 is lower alkyl, reacting a compound of Formula (I) wherein R10 is hydrogen with a suitable alkylhalide,
• d) for compounds of Formula (I) wherein R1 is of the Formula (II) and X is —S(O)—, —S(O2)—, oxidising a compound of Formula (D),
• 90
• e) for compounds of Formula (I) in which R3 is a group of Formula (IV) may be prepared by the reaction of compounds of Formula (I) in which R3 is hydrogen with compounds of Formula (F) below, in which L2 is a leaving group.:
• 91
• and thereafter if necessary:
• i) converting a compound of Formula (I) into another compound of Formula (I);
• ii) removing any protecting groups;
• iii) forming a salt, or solvate.