Preparation of fused polycyclic alkaloids by ring closure of azomethine ylides, novel compounds thereof and their use as chemotherapeutic agents

A method for the preparation of a compound of Formula (Ia):

• 35
• comprising the step of cycling an azomethine ylide of general formula (IIa):
• 36
• wherein R1-R8, R14 and Y may be the same or different and each are selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally protected hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkenoxy, optionally substituted alkynoxy, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, carboxy ester, carboxamido, acyl, acyloxy, mercapto, optionally substituted alkylthio, halogen, nitro, sulfate, phosphate and cyano;
• Z is a carbon or a heteroatom;
• and
• n is selected from 0, 1, 2, or 3.

A method for the preparation of a compound of Formula (Ib)

• 37
• comprising the step of cyclizing an azomethine ylide of general Formula (IIb).
• 38
• wherein R1-R4, R14 and Y may be the same or different and each are selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally protected hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkenoxy, optionally substituted alkynoxy, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, carboxy ester, carboxamido, acyl, acyloxy, mercapto, optionally substituted alkylthio, halogen, nitro, sulfate, phosphate and cyano;
• Z is a carbon or a heteroatom;
• n is selected from 0, 1, 2, or 3 and
• RA1RA2C—CRA3RA4 form a cyclic group which is an optionally substituted aryl group or an aromatic heterocyclic group;
• or
• RA1RA2C—CRA3RA4 form a cyclic group wherein RA2 and RA3, together with the carbon atoms to which they are attached form an optionally substituted saturated or unsaturated carbocyclic or heterocyclic group and RA1 and RA4 are as defined for R1-R4, R14 and Y above, or together form a bond;
• or
• RA1RA2C—CRA3RA4 is a non-cyclic group wherein RA1-RA4 are as defined for R1-R4, R14 and Y above and RA2 or RA3 may optionally together form a bond.

A compound of general Formula (I)

• 53
• wherein
• A is a cyclic group being an optionally substituted aryl group or an aromatic heterocyclic group;
• or
• A is a cyclic group RA1RA2C—CRA3RA4 wherein RA2 and RA3, together with the carbon atoms to which they are attached form an optionally substituted saturated or unsaturated carbocyclic or heterocyclic group and RA1 and RA4 are as defined below or together form a bond;
• or
• A is a non-cyclic group RA1RA2C—CRA3RA4 wherein RA1-RA4 are as defined below and RA2 and RA3 may optionally together form a bond;
• Z is a carbon or a heteroatom;
• n is selected from 0, 1, 2 or 3;
• and
• RA1-A4, W, X and Y may be the same or different and each are selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally protected hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkenoxy, optionally substituted alkynoxy, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, carboxy ester, carboxamido, acyl, acyloxy, mercapto, optionally substituted alkylthio, halogen, nitro, sulfate, phosphate and cyano, or W and X, together with the nitrogen and carbon atoms to which they are attached, form a saturated or unsaturated nitrogen containing heterocyclic group which may be optionally substituted or optionally fused to a saturated or unsaturated carbocyclic group, aryl group or heterocyclic group;
• provided that the compound is not one selected from Lamellarin A-N, S—X;
• D, L, K, M, N-triacetate;
• I-acetate;
• G-trimethyl ether;
• or T, U, V, Y-20-sulphate.

A compound of general Formula (II):

• 54
• wherein
• A is a cyclic group being an optionally substituted aryl group or an aromatic heterocyclic group;
• or
• A is a cyclic group RA1RA2C—CRA3RA4 wherein RA2 and RA3, together with the carbon atoms to which they are attached form an optionally substituted saturated or unsaturated carbocyclic or heterocyclic group and RA1 and RA4 are as defined below or together form a bond;
• or
• A is a non-cyclic group RA1RA2C—CRA3RA4 wherein RA1-RA4 are as defined below and RA2 and RA3 may optionally together form a bond;
• Z is a carbon or a heteroatom;
• n is selected from 0, 1, 2 or 3;
• and
• RA1-A4, W, X and Y may be the same or different and each are selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally protected hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkenoxy, optionally substituted alkynoxy, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, carboxy ester, carboxamido, acyl, acyloxy, mercapto, optionally substituted alkylthio, halogen, nitro, sulfate, phosphate and cyano, or W and X, together with the nitrogen and carbon atoms to which they are attached, form a saturated or unsaturated nitrogen containing heterocyclic group which may be optionally substituted or optionally fused to a saturated or unsaturated carbocyclic group, aryl group or heterocyclic group.

A compound of general Formula (IIa):

• 55
• wherein
• R1-R8, R14 and Y may be the same or different and each are selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally protected hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkenoxy, optionally substituted alkynoxy, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, carboxy ester, carboxamido, acyl, acyloxy, mercapto, optionally substituted alkylthio, halogen, nitro, sulfate, phosphate and cyano;
• Z is a carbon or a heteroatom;
• and
• n is selected from 0, 1, 2, or 3.

A compound of general Formula (IIb):

• 56
• wherein
• R1-R4, R14 and Y may be the same or different and each are selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally protected hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkenoxy, optionally substituted alkynoxy, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, carboxy ester, carboxamido, acyl, acyloxy, mercapto, optionally substituted alkylthio, halogen, nitro, sulfate, phosphate and cyano;
• Z is a carbon or a heteroatom;
• n is selected from 0, 1, 2, or 3;
• RA1RA2C—CRA3RA4 form a cyclic group which is an optionally substituted aryl group or an aromatic heterocyclic group;
• or
• RA1RA2C—CRA3RA4 form a cyclic group wherein RA2 and RA3 together with the carbon atoms to which they are attached form an optionally substituted saturated or unsaturated carbocyclic or heterocyclic group and RA1 and RA4 are as defined for R1-R4, R14 and Y above, or together form a bond;
• or
• RA1RA2C—CRA3RA4 is a non-cyclic group wherein RA1-RA4 are as defined for R1-R4, R14 and
• Y above and RA2 or RA3 may optionally together form a bond.

A compound of general Formula (III)

• 57
• wherein
• A is a cyclic group being an optionally substituted aryl group or an aromatic heterocyclic group;
• or
• A is a cyclic group RA1RA2C—CRA3RA4 wherein RA2 and RA3, together with the carbon atoms to which they are attached form an optionally substituted saturated or unsaturated carbocyclic or heterocyclic group and RA1 and RA4 are as defined below or together form a bond;
• or
• A is a non-cyclic group RA1RA2C—CRA3RA4 wherein RA1-RA4 are as defined below and RA2 and RA3 may optionally together form a bond;
• Z is a carbon or heteroatom;
• n is 0, 1, 2 or 3;
• and
• W, X and Y may be the same or different and each are selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally protected hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkenoxy, optionally substituted alkynoxy, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, carboxy ester, carboxamido, acyl, acyloxy, mercapto, optionally substituted alkylthio, halogen, nitro, sulfate, phosphate and cyano, or W and X, together with the nitrogen and carbon atoms to which they are attached, form a saturated or unsaturated nitrogen containing heterocyclic group which may be optionally substituted or optionally fused to a saturated or unsaturated carbocyclic group, aryl group or heterocyclic group;
• and the counter ion L⊖ is a stable, weakly basic anion.

A compound of general Formula (IIIa):

• 58
• wherein
• R1-R8, R14 and Y may be the same or different and each are selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally protected hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkenoxy, optionally substituted alkynoxy, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, carboxy ester, carboxamido, acyl, acyloxy, mercapto, optionally substituted alkylthio, halogen, nitro, sulfate, phosphate and cyano;
• Z is a carbon or a heteroatom;
• n is selected from 0, 1, 2, or 3;
• and
• the counter ion L⊖ is a stable basic anion.

A compound of general Formula (IIIb):

• 59
• wherein
• R1-R4, R14 and Y may be the same or different and each are selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally protected hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkenoxy, optionally substituted alkynoxy, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, carboxy ester, carboxamido, acyl, acyloxy, mercapto, optionally substituted alkylthio, halogen, nitro, sulfate, phosphate and cyano;
• Z is a carbon or a heteroatom;
• n is selected from 0, 1, 2, or 3;
• RA1RA2C—CRA3RA4 form a cyclic group which is an optionally substituted aryl group or an aromatic heterocyclic group;
• or
• RA1RA2C—CRA3RA4 form a cyclic group wherein RA2 and RA3, together with the carbon atoms to which they are attached form an optionally substituted saturated or unsaturated carbocyclic or heterocyclic group and RA1 and RA4 are as defined for R1-R4, R14 and Y above, or together form a bond;
• or
• RA1RA2C—CRA3RA4 is a non-cyclic group wherein RA1-RA4 are as defined for R1-R4, R14 and Y above and RA2 or RA3 may optionally together form a bond;
• and
• the counter ion L⊖ is a stable, weakly basic anion.