Novel bisphosphonates and uses thereof

A compound of formula (I):

• 45
• wherein G is a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue, or G is an orthoester glycoside moiety of the Formula (II):
• 46
• wherein A′ is a glycofuranosyl or glycopyranosyl ring;
• Ra is hydrogen;
• Rb is hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue;
• each R1, which may be the same or different, is hydrogen, alkyl, aryl, benzyl or alkali metal cation, or two —OR1 groups, on the same phosphorus atom, taken together with —CH2)2—, —CH2)3—, or —CH2C(CH3)2CH2—, form a heterocyclic ring containing one phosphorus, two oxygens and two or three carbons;
• Q is selected from the group consisting of:
• (1) —CH—, —CNH2—, —COH—, —CCl—, —CF— or —C-alkyl—;
• (2) —C(R4)(R5)(CH2)m[C(R6)(R7)]n—;
• wherein n is 0 or 1 and m is an integer from 1 to 8;
• R4 and R6, which may be the same or different, are hydrogen, —SO3H, a lower aliphatic group which may optionally contain one or more heteroatoms and which contains at least one —SO3H group or a covalent bond to Y,
• R5 and R7, which may be the same or different, are hydrogen, —OH, —NH2, —NHMe, —NMe2, —SO3H, substituted alkyl or a covalent bond to Y;
• or
• R4 and R5 taken together with the atom to which they are bound form a carbonyl, thiocarbonyl, or ═NOH;
• and
• R6 and R7 taken together with the atom to which they are bound form a carbonyl, thiocarbonyl, or ═NOH;
• (3)
• 47
• wherein R8 and R9, which may be the same or different, are:
• (a) a covalent bond to Y, —NO2 or —NH2;
• (b) —SR11 wherein R11 is hydrogen, alkyl, phenyl, acyl, benzoyl, aralkyl, halogen, allyl or a covalent bond to Y;
• (c) —OR10 wherein R10 is hydrogen, alkyl, allyl, acyl, benzoyl, aralkyl or a covalent bond to Y;
• (d) —CH2)pCO2A′, wherein A′ is hydrogen, alkyl or a covalent bond to Y;
• (e) —(CH2)pCH2OR10 wherein R10 is defined as above;
• (f) —CH2NHR12 wherein R12 is hydrogen, alkyl, phenyl, acyl, benzoyl, aralkyl or a covalent bond to Y;
• (g) —CH2N(R12)(R13) wherein R12 and R13 can be the same or different and are hydrogen, alkyl, phenyl, acyl, benzoyl, aralkyl or a covalent bond to Y;
• a is 1 or 2;
• b is 1 to 4;
• Rc and Rd, which may be the same or different in each instance, are hydrogen or alkyl;
• with the proviso that when the ring containing R8 is a pyridine ring, b is 1 to 3;
• p is 1 to 5;
• with the proviso that only one of A′, R4, R5, R6, R7, R8, R9, R10, R11, R12 and R13 is a covalent bond to Y;
• Y is chosen from the group consisting of optionally substituted C1-10 alkylene, aryl, heteroaryl, heterocyclo, a steroidal hormone, a compound exhibiting oestrogenic activity or a prostaglandin;
• and
• pharmaceutically acceptable salts or esters thereof.

A compound of Formula (I′):

• 48
• wherein each OR1 is the same or different and is OH or a hydrolysable group, or two OR1 groups on the same phosphorus atom form a substituted or unsubstituted 5, 6 or 7 membered heterocyclic ring;
• R is H, alkyl or halogen or is a group —O—G, —S—G, —NH—G or —NR12—G;
• each G is the same or different and is hydrogen or a straight or branched chain glycosidic residue or glycosidic orthoester residue, or amino derivative thereof, provided that at least one group G is a glycosidic residue or glycosidic orthoester residue,
• X is O, S, NH or NR12;
• each R12 is the same or different and is hydrogen, alkyl, phenyl, acyl, benzoyl or aralkyl;
• Q is an optionally substituted alkylene or alkenylene group or is an optionally substituted alkylene containing at least one O, S or NH or is O, S or NH, or is a direct bond to Y;
• Y represents a binary or tertiary alkyl-substituted amine, C1-10 alkylene, aryl, heteroaryl, heterocyclyl, a steroidal hormone, a group exhibiting oestrogenic activity or a prostaglandin, said group Y being optionally substituted;
• provided that, in —X—Y—Q— there is no direct bond between one O, S or N atom and another O, S or N,
• and pharmaceutically acceptable salts, esters and pro-drugs thereof.

A method of preparing a compound of Formula (XI):

• 52
• wherein each OR1 is the same or different and is OH or a hydrolysable group, or two OR1 groups on the same phosphorus atom form a substituted or unsubstituted 5, 6 or 7 membered heterocyclic ring;
• R is H, alkyl or halogen or is a group —O—G, —S—G, —NH—G or —NR12—G;
• G is hydrogen or a straight or branched chain glycosidic residue or glycosidic orthoester residue, or amino derivative thereof, provided that at least one group G is a glycosidic residue or glycosidic orthoester residue,
• R12 is hydrogen, alkyl, phenyl, acyl, benzoyl or aralkyl;
• Q is an optionally substituted alkylene or alkenylene group or is an optionally substituted alkylene containing at least one O, S or NH or is O, S or NH;
• Y represents a binary or tertiary alkyl-substituted amine, C1-10 alkylene, aryl, heteroaryl, heterocyclyl, a steroidal hormone, a group exhibiting oestrogenic activity or a prostaglandin, said group Y being optionally substituted;
• provided that, in —O—Y—Q— there is no direct bond between one O, S or N atom and another O, S or N,
• R38 is selected from the group consisting of hydrogen, acetyl, benzoyl, nicotinoyl, benzyl, methyl and phenyl;
• which method comprises:
• (a) reacting a glycoside having the Formula (XII):
• 53
• wherein R38 is other than hydrogen;
• with a group of formula Hal-Y—Q—X3, wherein Hal and X3 individually represent halogen, and is preferably a 1,3-dihaloalkane, in the presence of a strong base in an aprotic solvent to give a compound of Formula (XIII):
• 54
• wherein X3 is as defined;
• and
• (b) reacting the compound of Formula (XIII) with a compound of the Formula (XIV):
• 55
• wherein R and R1 are as defined, in the presence of a strong base in an aprotic solvent to give a compound of Formula (XI), wherein R1 and R38 are other than hydrogen.

A process for the preparation of a compound of formula (XX):

• 56
• wherein each OR1 is the same or different and is OH or a hydrolysable group, or two OR1 groups on the same phosphorus atom form a substituted or unsubstituted 5, 6 or 7 membered heterocyclic ring;
• R is H, alkyl or halogen or is a group —O—G, —S—G, —NH—G or —NR12—G;
• G is hydrogen or a straight or branched chain glycosidic residue or glycosidic orthoester residue, or amino derivative thereof, provided that at least one group G is a glycosidic residue or glycosidic orthoester residue,
• R12 is hydrogen, alkyl, phenyl, acyl, benzoyl or aralkyl;
• Q is an optionally substituted alkylene or alkenylene group or is an optionally substituted alkylene containing at least one O, S or NH or is O, S or NH;
• Y represents a binary or tertiary alkyl-substituted amine, C1-10 alkylene, aryl, heteroaryl, heterocyclyl, a steroidal hormone, a group exhibiting oestrogenic activity or a prostaglandin, said group Y being optionally substituted;
• provided that, in —N—Y—Q— there is no direct bond between one O, S or N atom and another O, S or N,
• R38 is selected from the group consisting of hydrogen, acetyl, benzoyl, nicotinoyl, benzyl, methyl and phenyl;
• said method comprising dissolving a compound of formula (XXI):
• 57
• in an aqueous medium together with sufficient of a trialkylamine compound to form a salt thereof;
• removing the water;
• dissolving the salt in a water miscible, organic solvent;
• adding a compound of formula (XII):
• 58
• and maintaining the resulting mix under such conditions as to form a trialkylamine salt of the compound of formula (XX).