US 11,884,687 B2
Boronated multifunctional targeting drug conjugates, their uses and methods for their preparation
Pedro Gois, Lisbon (PT); and Fabio Santos, Montelavar (PT)
Assigned to Hovione Scientia Limited, Cork (IE)
Appl. No. 16/489,884
Filed by Hovione Scientia Limited, Cork (IE)
PCT Filed Mar. 1, 2018, PCT No. PCT/GB2018/050534
§ 371(c)(1), (2) Date Aug. 29, 2019,
PCT Pub. No. WO2018/158582, PCT Pub. Date Sep. 7, 2018.
Claims priority of application No. 109941 (PT), filed on Mar. 2, 2017.
Prior Publication US 2020/0010484 A1, Jan. 9, 2020
Int. Cl. C07F 5/02 (2006.01); A61K 47/64 (2017.01); A61K 47/66 (2017.01); A61K 47/55 (2017.01); A61K 47/60 (2017.01); A61K 47/69 (2017.01); A61K 49/00 (2006.01)
CPC C07F 5/025 (2013.01) [A61K 47/55 (2017.08); A61K 47/60 (2017.08); A61K 47/643 (2017.08); A61K 47/66 (2017.08); A61K 47/6951 (2017.08); A61K 49/0039 (2013.01); A61K 49/0052 (2013.01); A61K 49/0054 (2013.01); A61K 49/0056 (2013.01)] 21 Claims
 
1. A multifunctional compound comprising a tripodal boranated core, wherein the multifunctional compound further comprises:
(a) at least one therapeutically useful cargo molecule, or a residue thereof;
(b) at least one water-soluble moiety or a residue of a water-soluble molecule; and at least one of components (c) or (d), wherein
(c) is at least one functionalizing moiety capable of being post-functionalised with a targeting unit or a residue of a targeting molecule; and
(d) is at least one targeting unit or a residue of a targeting molecule;
in which any residue of a molecule is such that, on breaking at least one covalent bond of the multifunctional compound, the complete molecule is released; and
wherein the tripodal boronated core is as defined in the general formula:

OG Complex Work Unit Chemistry
wherein:
R1 represents H, Cn=1-6 alkyl, alkene or alkyne which can be straight, branched or cyclic and optionally contain one or more heteroatoms selected from nitrogen, oxygen or sulphur; formyl or Cn=2-6 alkanoyl; or Ar, CH2Ar or CH2CH2Ar, in which the Ar group may be a phenyl, a Cl-, Br- or F- substituted phenyl ring in the o-, m- or p- positions, a naphthyl, a heterocyclic ring or fused ring comprising at least one ring heteroatom selected from nitrogen, oxygen or sulphur;
R2 to R5 represents H, Cn=1-6 alkyl, alkene or alkyne which can be straight, branched or cyclic and optionally contain one or more heteroatoms selected from nitrogen, oxygen or sulphur; formyl or Cn=2-6 alkanoyl; amide; ester; Ar, CH2Ar or CH2CH2Ar in which the Ar group may be a phenyl, a Cl-, Br- or F- substituted phenyl ring in the o-, m- or p- positions, a naphthyl, a heterocyclic ring or fused ring comprising at least one ring heteroatom selected from nitrogen, oxygen or sulphur, OH, OCH3, OCH2CH3, OCHCH3CH3, OCH2CHCH3CH3, OPh, CCH, CCPh, CN, COOH, NH2, CONHR′ NHR′ or NR′R″ in which the R′ and R″ groups may be optionally a phenyl or a substituted phenyl, a 5 or 6 member azacyclic ring, Cn=1-6 alkyl which optionally may incorporate one further heteroatom selected from oxygen, sulphur or nitrogen;
R6 to R9 represents H, Cn=1-6 alkyl, alkene or alkyne which can be straight, branched or cyclic and optionally contain one or more heteroatoms selected from nitrogen, oxygen or sulphur; formyl or Cn=2-6 alkanoyl; amide; ester; Ar, CH2Ar or CH2CH2Ar in which the Ar group may be a phenyl, a Cl-, Br- or F- substituted phenyl ring in the o-, m- or p- positions, a naphthyl, a heterocyclic ring or fused ring comprising at least one ring heteroatom selected from nitrogen, oxygen or sulphur, OH, OCH3, OCH2CH3, OCHCH3CH3, OCH2CHCH3CH3, OPh, CCH, CCPh, CN, COOH, NH2, CONHR′ NHR′ or NR′R″ in which the R′ and R″ groups may be optionally a phenyl, a Cl-, Br- or F- substituted phenyl ring in the o-, m- or p- positions, a 5 or 6 member azacyclic ring, Cn=1-6 alkyl which optionally may incorporate one further heteroatom selected from oxygen, sulphur or nitrogen;
R10 represents H, Cn=1-6 alkyl, alkene or alkyne which can be straight, branched or cyclic and optionally contain one or more heteroatoms selected from nitrogen, oxygen or sulphur; a vinyl group of the general formula CH═CHR′ in which the R′ represents a H, Cn=1-6 alkyl, alkene or alkyne which can be straight, branched or cyclic and optionally contain one or more heteroatom selected from nitrogen, oxygen or sulphur, a phenyl or a Cl-, Br- or F- substituted phenyl ring in the o-, m- or p-positions, a naphthyl, a monocyclic or bicyclic heterocyclic ring comprising at least one ring heteroatom selected from nitrogen, oxygen or sulphur; a phenyl or a Cl-, Br- or F- substituted phenyl ring in the o-, m- or p- positions; a naphthyl; or a monocyclic or bicyclic heterocyclic ring comprising at least one ring heteroatom selected from nitrogen, oxygen or sulphur; and
X and Y each independently represent a heteroatom selected from oxygen or nitrogen
wherein the at least one therapeutically useful cargo molecule, or a residue thereof comprises an API selected from anti-cancer agents; anti-neurodegeneratives; or anti-inflammatories; and/or an agent selected from chalcone, adamantylamine, or peptides.