WO2018134800A1 - Dialkyl complexes of gallium and indium and their use for preparation of polylactide-pharmaceutically active compound conjugates and for immortal ring-opening polymerization of heteroc clic monomers - Google Patents

Dialkyl complexes of gallium and indium and their use for preparation of polylactide-pharmaceutically active compound conjugates and for immortal ring-opening polymerization of heteroc clic monomers Download PDF

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WO2018134800A1
WO2018134800A1 PCT/IB2018/050402 IB2018050402W WO2018134800A1 WO 2018134800 A1 WO2018134800 A1 WO 2018134800A1 IB 2018050402 W IB2018050402 W IB 2018050402W WO 2018134800 A1 WO2018134800 A1 WO 2018134800A1
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pla
active compound
complexes
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pharmaceutically active
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French (fr)
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Paweł HOREGLAD
Martyna CYBULARCZYK
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Uniwersytet Warszawski
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/78—Preparation processes
    • C08G63/82—Preparation processes characterised by the catalyst used
    • C08G63/823—Preparation processes characterised by the catalyst used for the preparation of polylactones or polylactides
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29K—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2067/00—Use of polyesters or derivatives thereof, as moulding material
    • B29K2067/04—Polyesters derived from hydroxycarboxylic acids
    • B29K2067/046—PLA, i.e. polylactic acid or polylactide

Definitions

  • the object of the invention are dialkyl complexes of gallium and indium and their use for preparing polylactide-pharmaceutically active compound conjugates and for immortal ring-opening polymerisation of heterocyclic monomers, especially in the polymerisation of lactide.
  • PLA polylactide
  • PLA copolymer polylactide-O(Drug) conjugates
  • an important element is the synthesis of the said conjugates with the ending group constituting the drug (a substance with pharmaceutical activity) and the polymer part having a strictly defined microstructure, and thus - properties.
  • R and R 2 are the same or different and independently represent a hydrogen atom, C r C 2 alkyl, C 2 -C 2 alkenyl, C 2 -C 2 alkynyl, C 3 -C 2 cycloalkyl, C 3 -C 2 cycloalkenyl, C 3 -C 2 cycloalkynyl, C 5 -C 20 aryl or C 5 -C 20 heteroaryl, wherein each substituent R and R 2 may be independently substituted with at least a substituent selected from the group consisting of a halogen atom, C C 2 alkyl, C 2 -C 2 alkenyl, C 2 -C 12 alkynyl, -OR 3 ,-SR 3 , -S(0) x R 3 , -S0 2 NR 3 R 4 , -S(0) 2 OR 3 , -N0 2 , -NO, -SCN, -NR 3 R 4 , -N(R 3 )OR 4
  • each x represents independently 0, 1 or 2;
  • each y represents independently 0, 1 , 2, 3 or 4;
  • each z represents independently 1 or 2;
  • each substituent R 3 , R 4 , R 5 , R 6 represents independently a hydrogen atom, a halogen atom, C r C 2 alkyl, C 2 -C 2 alkenyl, C 2 -C 2 alkynyl, C 3 -C 2 cycloalkyl, C 5 -C 20 aryl, 5-12 membered heteroaryl;
  • X represents an atom containing a free pair of electrons or a group containing a free pair of electrons on an atom bound to atom M;
  • M represents a gallium atom or an indium atom
  • ROH represents any organic compound containing a hydroxyl group
  • L represents a neutral ligand with base properties
  • n any natural number greater than or equal to 1
  • m represents any number greater than or equal to 0,
  • k represents any number of coordinated molecules of a neutral ligand L to one coordination centre, meeting the condition 0 ⁇ k ⁇ 4;
  • R R 2 GaOR(L) wherein R and R 2 represent alkyl substituents, OR represents an alkoxy group, and L represents a neutral ligand exhibiting Lewis base properties, including N-heterocyclic carbenes.
  • m 0, and X represents -O-biologically active compound, more preferably, the -O-biologically active compound represents -O-pharmaceutically active compound, even more preferably, the -O-pharmaceutically active compound represents -O-beta-adrenolytic drug.
  • m is greater than 0, and ROH represents HO-biologically active compound, more preferably, m is greater than or equal to 1, even more preferably, the HO-biologically active compound represents HO-pharmaceutically active compound, most preferably, the HO-pharmaceutically active compound represents HO-beta-adrenolytic drug.
  • M represents a gallium atom
  • n represents 2
  • m represents any number greater than 0, more preferably, m is greater than or equal to 1.
  • M represents Ga
  • ROH represents a primary or secondary, or tertiary alcohol.
  • X represents -OR 7 group, -SR 7 group, NR 7 R 7 group or PR 7 group, wherein
  • R 7 and R 7 independently represent a hydrogen atom, C r C 2 alkyl, C 2 -C 2 alkenyl, C 2 -C 2 alkynyl,
  • R 8 group represents C C 2 alkylene, C 2 -C 2 alkenylene, C 2 -C 2 alkynylene, and R 9 group represents hydrogen, C r C 2 alkyl,
  • each q represents independently 0, 1 or 2;
  • each r represents independently 0, 1 , 2, 3 or 4;
  • each s represents independently 1 or 2; each substituent R 11 , R 2 , R 3 , R 4 represents independently a hydrogen atom, a halogen atom, C C 2 alkyl, C 2 -C 2 alkenyl, C 2 -C 2 alkynyl, C 3 -C 2 cycloalkyl, C 5 -C 20 aryl, 5-12 membered heteroaryl.
  • the object of the invention is also the use of the complexes defined above for the preparation of polylactide-pharmaceutically active compound conjugates.
  • Another object of the invention is the use of complexes defined above as catalysts for immortal ring- opening polymerisation of heterocyclic monomers, preferably the heterocyclic monomers contain an oxygen atom as the heteroatom, more preferably the heterocyclic monomers are lactones, even more preferably, the complexes are used for stereoselective polymerisation of lactide, most preferably the complexes are used for stereoselective polymerisation of racemic lactide.
  • halogen atom means an element selected from F, CI, Br, I.
  • carbene means a particle containing an inert carbon atom with a valence number of two and two unpaired valence electrons.
  • carbene also includes carbene analogues in which the carbon atom is replaced with another chemical element such as boron, silicon, germanium, tin, lead, nitrogen, phosphorus, sulfur, aluminum, gallium, selenium and tellurium.
  • neutral ligand with base properties means a ligand not having any charge and having Lewis base properties enabling its coordination to the metal.
  • alkyl refers to a saturated, linear, or branched hydrocarbon substituent with indicated number of carbon atoms.
  • alkyl substituent are methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl, and -n-decyl.
  • Representative branched alkyls include -iso-propyl, -sec-butyl, -iso-butyl, -tert-butyl, -iso-pentyl, -neopentyl, -1 -methyl-butyl, -2-methyl-butyl, -3-methyl-butyl, -1 ,1 -dimethyl-propyl, 1 ,2-dimethyl-propyl, -1 -methyl-pentyl, -2-methyl-pentyl, -3-methyl-pentyl, -4-methyl-pentyl, -1 -ethyl-butyl, -2-ethyl-butyl, -3-ethyl-butyl, -1 ,1 -dimethyl-butyl, -1 , 2-dimethyl-butyl, -1 ,3-dimethyl-butyl, -2,2-dimethyl-butyl, -2,3
  • alkoxy refers to an alkyl substituent as defined above bound via an oxygen atom.
  • perfluoroalkyl means an alkyl group as defined above in which all of the hydrogen atoms have been replaced with the same or different halogen atoms.
  • cycloalkyl refers to a saturated, mono- or polycyclic hydrocarbon substituent with indicated number of carbon atoms. Examples of the cycloalkyl substituent are -cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl, and the like.
  • alkenyl refers to a saturated, linear, or branched, non-cyclic hydrocarbon substituent with indicated number of carbon atoms and containing at least one carbon-carbon double bond.
  • alkenyl substituent examples include -vinyl, -allyl, 1 -butenyl, 2-butenyl, iso-butylenyl, -1 -pentenyl, -2-pentenyl, 3-methyl-1 -butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1 -hexenyl, 2-hexenyl, -3-hexenyl, 1 -heptenyl, -2-heptenyl, 3-heptenyl, 1 -octenyl, -2-octenyl, 3-octenyl, 1 nonenyl, -2-nonenyl, -3-nonenyl, -1 -decenyl, -2-decenyl, 3-decenyl and the like.
  • cycloalkenyl refers to a saturated, mono- or polycyclic hydrocarbon substituent with indicated number of carbon atoms and containing at least one carbon-carbon double bond.
  • examples of the cycloalkenyl substituent are cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, -cycloheptenyl, -cycloheptadienyl, cycloheptatrienyl, cyclooctenyl, -cyclooctadienyl, cyclooctatrienyl, cyclooctatetraenyl, cyclononenyl, cyclononadienyl, -cyclodecenyl, cyclodecadienyl and the like.
  • alkynyl refers to a saturated, linear, or branched, non-cyclic hydrocarbon substituent with indicated number of carbon atoms and containing at least one carbon-carbon triple bond.
  • alkynyl substituents are acetylenyl, propynyl, 1 -butynyl, 2-butynyl, -1 -pentynyl, -2-pentynyl, 3-methyl-1 -butynyl, 4-pentynyl, 1 -hexynyl, -2-hexynyl, 5-hexynyl and the like.
  • cycloalkynyl refers to a saturated, mono- or polycyclic hydrocarbon substituent with indicated number of carbon atoms and containing at least one carbon-carbon triple bond.
  • examples of the cycloalkynyl substituent are cyclopentynyl, cyclohexynyl, cycloheptynyl and the like.
  • aryl refers to an aromatic, mono- or polycyclic hydrocarbon substituent with indicated number of carbon atoms. Examples of aryl substituents are phenyl, tolyl, xylyl, naphthyl.
  • heteroaryl refers to an aromatic mono- or polycyclic hydrocarbon substituent with indicated number of carbon atoms in which at least one carbon atom has been replaced with a heteroatom selected from O, N and S.
  • heteroaryl substituent are furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidyl, triazinyl, indolyl, benzo[b]furyl, benzo[b]thienyl, indazolyl, benzimidazolyl, azaindolyl, quinolyl, isoquinolyl, carbazolyl and the like.
  • heterocycle refers to a saturated or partially unsaturated, mono- or polycyclic hydrocarbon substituent with indicated number of carbon atoms in which at least one carbon atom has been replaced with a heteroatom selected from O, N and S.
  • heterocyclic substituent are furyl, thiophenyl, -pyrrolyl, -oxazolyl, -imidazolyl, -thiazolyl, -isooxazolyl, -pyrazolyl, isothiazolyl, -triazinyl, -pyrrolidinonyl, -pyrrolidinyl, -hydantoinyl, -oxiranyl, oxetanyl, -tetrahydrofuranyl, -tetrahydrotiophenyl, quinolinyl, isoquinolinyl, chromonyl, coumarinyl, indolyl, indolizinyl, benzo[b]
  • HO-biologically active compound, HO-pharmaceutically active compound (HO-Drug) or HO-beta-adrenolytic drug (HO (fiAD)) used herein refer to the corresponding compounds which contain a hydroxyl group (OH-) in their structure.
  • HO-biologically active compound, -O-pharmaceutically active compound (-O-Drug), -O-beta-adrenolytic drug (-0(/3 ⁇ 44D)) mean groups formed as a result of proton detachment from HO-biologically active compound, HO-pharmaceutically active compound or HO-beta-aderenolytic drug, respectively.
  • the biologically active compound is any chemical compound that exerts its effects on living organisms.
  • Biologically active compounds include, among others, pharmaceutically active compounds, plant protection agents and the like.
  • pharmaceutically active compound has its usual meaning used in the art.
  • beta-adrenolytic drug in other words, ⁇ -blocker, ⁇ -sympatholytic drug
  • beta-adrenolytic drug is a group of drugs acting antagonistically on ⁇ 1 and ⁇ 2 adrenergic receptors, which inhibit the activity of the sympathetic system, exerting effects on almost the entire organism. It is one of the most important groups of drugs used in cardiology, and especially in ischemic heart disease and hypertension.
  • beta-adrenergic drugs examples include oxprenolol, metipranolol, pindolol, propranolol, sotalol, timolol, nadolol, alprenolol, inevitablyolol, metoprolol, atenolol, celiprolol, acebutolol, betaxolol, bisoprolol, esmolol, nebivolol, labetalol and carvedilol.
  • this method can be used to obtain PLA and PLA copolymers against [R R 2 MX] 2 /ROH, what is unprecedented in the literature in the case of gallium complexes.
  • the results which are the basis of the invention described show that immortal Ring-Opening Polymerisation (iROP) of rac-LA against [R R 2 GaX] 2 /ROH catalytic systems allows obtaining PLA-OR polymers, in a controlled and heteroselective way. In this case, the results obtained, in combination with literature reports (Polym.
  • [R" 2 GaOR'] 2 exhibits particularly advantageous properties.
  • Gallium complexes formed after isolation of the polymer do not bind permanently to polylactide, which allows an easy production of even short PLA chains ( n ⁇ 15000 Da) with Ga content lower than 20 ppm in accordance with the guidelines of The European Pharmacopeia (https://www.edqm.eu/en/european-pharmacopoeia-8th-edition-1563.html) (Molecules 2014, 19, 19460).
  • catalysts having [R" 2 MOR'] n centres could be used for synthesis of PLA-OR' or (copolymer PLA)-OR' having OR' ending groups with specific properties or having additional functional groups other than those found in the PLA chain, or model-like small groups such as O'Pr, 0(CH 2 ) 2 OCH 3 or OCH(CH 3 )CH 2 OCH 3 not containing other functional groups or substituents with significant steric hindrances.
  • PLA-camptothecin copolymers As an example of specific properties of PLA-O(Drug) conjugates, PLA-camptothecin copolymers can be mentioned, the properties of which indicate that they may be used as systems for controlled drug delivery (Molecules 2014, 19, 19460).
  • [R R 2 MO(/3/AD)] 2 centres can be obtained by reacting [R R 2 MX] n with HO(fiAD) in the temperature range of -60°C to 150°C, preferably in the range of 40°C to 70°C (conditions for conducting the polymerisation of lactide against dialkylalkoxy gallium centres), as is indicated by the formation and structure of PLA-(A), PLA-(B), PLA-(C) and PLA-(D) (PLA-atenolol) as a result of the use of [R R 2 MOR'] 2 (and/or [R R 2 M04r] 2 )/H(A), [R R 2 MOR'] 2 (and/or [R R 2 M ( _ ] 2 )/H(B), [R R 2 MOR'] 2 (and/or [R R 2 M ( _ ] 2 )/H(C) or [R R 2 MOR'] 2 (and/or [R R 2 MO/4r
  • isoselective polymerisation against [R R 2 MO(Dri/g)] 2 preferably [R R 2 MO(/3 ⁇ 44D)] 2 in the presence of organosuperbases
  • organosuperbases the following publications specify the term organosuperbase: T.
  • PLA-O(Drug) conjugates preferably PLA-0(/3/ADJ conjugates, containing a predominantly heterotactic PLA, including stereo diblock PLA
  • iROP immortal polymerisation
  • cyclic esters including lactide
  • Activated Monomer type Organic-metallics 2013, 32, 1694
  • R R 2 GaX] n /ROH catalytic systems are the only examples of alkoxygallium complexes allowing the immortal polymerisation of lactide and other cyclic esters.
  • new [R R 2 GaX] n /ROH catalytic systems are used in the process of immortal ring-opening polymerisation, preferably stereoselective polymerisation of rac-LA in the temperature range of -60°C to 150°C, preferably in the range of 40°C to 70°C. (Example VII).
  • the polymerisation of rac-LA proceeds in a controlled manner, leading to obtaining chains of similar length, as indicated by the MALDI TOF analysis of the obtained PLA, as well as by monomodal distribution of average molecular weight n with low polydispersity.
  • n moles of ROH alcohol to [R R 2 GaOR'] 2 leads to obtaining n+2 chains of PLA (nPLA-OR + 2 PLA-OR').
  • n moles of ROH alcohol to [R R 2 GaO/Ar] 2 where there is no any insertion of lactide in Ga-OAr bond, leads to obtaining n chains of PLA (nPLA-OR) (Example VII).
  • the synthesis was conducted in a protective atmosphere of argon with the use of dehydrated and deoxygenated solvents.
  • EXAMPLES II - VII include a series of rac-LA polymerisations against dialkylalkoxy gallium and dialkylalkoxy indium catalysts leading to PLA terminated with different ending groups, including conjugates of PLA-(PAD) - PLA-(A), PLA-(B), PLA-(C) and PLA-(D) types.
  • the presence of appropriate ending groups was indicated by PLA analyses with the use of H NMR spectroscopy.
  • insertion of rac-LA in Ga-O a i koxy bond was only observed .
  • lactide in Ga-O ary i oxy bond under polymerisation conditions was not confirmed.
  • the polymerisation was conducted in a protective atmosphere of argon with the use of dehydrated and deoxygenated solvents.
  • Appropriate amount of catalyst in solution (0.5 ml in toluene or CH 2 CI 2 ) was added to the lactide solution (0.9 g - 3.55 g depending on the ratio of LA/catalyst, Table 1 ) in the solvent used.
  • the obtained solution was mixed, and after the time indicated in Table 1 the polylactide was separated from the catalyst by adding 50 ml of 5% HCI solution and shaking it for 5 minutes. Then, the organic layer was separated and washed by shaking two times with the use of 50 ml of distilled water.
  • the organic phase was dried using anhydrous MgS0 4 , and the polylactide terminated with OH and alkoxy groups - HO-PLA-OR' (also referred to in a simplified manner in this disclosure as PLA-OR') was obtained by removing solvents under vacuum.
  • HO-PLA-OCH 2 CH 2 NHCH 3 (HO-PLA-OCH 2 CH 2 NHMe): d 1 .55 (m, 3H, CHCH 3 ), 5.14 (m, 1 H, CHCH 3 ) (c) ending groups: 2.62-2.80 (br s, 1 H, NHCH 3 ), 3.26-3.37 (m, 2H, CH 2 CH 2 NH), 3.47-3.58 (m, 2H, OCH 2 CH 2 )
  • HO-PLA-OCH 2 CH 2 NHCH(CH 3 ) 2 (HO-PLA-OCH 2 CH 2 NH'Pr): d 1 .55 (m, 3H, CHCH 3 ), 5.14 (m, 1 H, CH CH 3 ) (c) ending groups: 1 .18-1 .29 (m, 6H, CH(CH 3 ) 2 ), 3.21 -3.35 (m, 2H, CH 2 CH 2 ), 3.45-3.58 (m, 2H, CH 2 CH 2 )
  • HO-PLA-OCH(CH 2 OC 6 H 5 )CH 2 NHCH(CH 3 ) 2 (HO-PLA-OCH(CH 2 OPh)CH 2 NH'Pr or HO-PLA-(A)): d 1 .55 (m, 3H, CHCH 3 ), 5.14 (m, 1 H, CHCH 3 ) (c) ending groups: 1 .20-1 .34 (m, 6H, CH(CH 3 ) 2 )), 3.86 (m, 1 H, OCH), 3.95-4.09 (m, 4H, OCH(CH 2 OC 6 H 5 )CH 2 NH), 6.79-6.99 (m, 3H, ArH), 7.20-7.29 (m, 2H, ArH)
  • HO-PLA-OCH(CH 2 OC 6 H 4 CH 2 C(0)NH 2 )CH 2 NHCH(CH 3 ) 2 (HO-PLA-(D) or HO-PLA-(atenolol)): d 1 .55 (m, 3H, CHCH 3 ), 5.14 (m, 1 H, CHCH 3 ) (c) ending groups: 1 .15-1 .35 (m, 6H, CH(CH 3 ) 2 ), 3.53-3.78 (m, 2H, C(0)CH 2 Ar) OCH(CH 2 OC 6 H 5 )CH 2 NH), 3.78-3.89 (m, 1 H, OCH), 3.91 -4.12 (m, 4H, OCH(CH 2 OC 6 H 5 )CH 2 NH), 6.78-6.89 (m, 2H, ArH), 7.1 0-7.19 (m, 2H, ArH),
  • HO-PLA-OCH(CH 3 ) 2 (HO-PLA-O'Pr): d 1 .55 (m, 3H, CHCH 3 ), 5.14 (m, 1 H, CH CH 3 ) (c) ending groups: 1 .23 (dd, 6H), 3.72 (m, 1 H)
  • EXAMPLE III - shows first of all the possibility of synthesis of PLA-(BAD) - PLA-(A), PLA-(B) conjugates in the ring-opening polymerisation CROP) of rac-LA with the use of [Me 2 Ga(A)l2_and [Me z ln(A)l 2 , and [Me z Ga(B)l2_complexes, accordingly, as catalysts.
  • EXAMPLE IV - shows first of all the possibility of synthesis of PLA-(BAD) - PLA-(A).
  • PLA-(D) conjugates in immortal ring-opening polymerisation (iROP) of rac-LA with the use of Me 2 GaOR/H(BAD) and Me z lnO/Ar/H(BAD) catalytic systems.
  • HO-PLA-(A), HO-PLA-(B), HO-PLA-(D) conjugates was confirmed with the use of MALDI-TOF spectroscopy (visible in the spectrum as HO-PLA- (A)/K + , HO-PLA-(B)/K + , HO-PLA-(D)/K + .
  • EXAMPLE V - shows first of all the possibility of stereoselective synthesis of PLA-(BAD) - PLA-(A), PLA- (B) coniugates in the ring-opening polymerisation CROP) of rac-LA with the use of [Me z Ga(A)l2_and [Me z ln(A)l 2 , and [Me 2 Ga(B)l z complexes, accordingly, against Lewis bases, as catalysts.
  • PV-2 a [Me 2 GaOCH 2 CH 2 NH'Pr] 2 /DMAP 50 40 120 95 11 .0 1 .15 0.84" (dimethylamino pyridine) (1 :6) 0.88 e
  • EXAMPLE VI - shows first of all the possibility of stereoselective synthesis of PLA-(BAD) - PLA-(A), PLA- (B), PLA-(C), PLA-(D) coniugates in immortal ring-opening polymerisation (iROP) of rac-LA with the use of Me 2 GaOR/H(BAD) catalytic systems.
  • the dotted line indicates the distribution corresponding to HO-PLA-OCH(CH 2 C 6 H 5 )CH 2 NH'Pr/K + (HO-PLA-A/K + ) ( ⁇ ) formed a result of intermolecular transesterification reactions.
  • EXAMPLE VII - shows first of all the possibility of synthesis of PLA in immortal ring-opening polymerisation (iROP) of rac-LA with the use of Me?GaOR/ROH and Me 2 GaO/Ar/ROH (OAr - aryloxy group) catalytic systems. Formation of HO-PLA-O'Pr and HO-PLA-OCH(CH 3 )C0 2 CH 3 was confirmed with the use of MALDI-TOF spectroscopy (observed as HO-PLA-0'Pr/K + ( ⁇ ) and HO-PLA- OCH(CH 3 )C0 2 CH 3 /K + ( ⁇ )) - PVII-1 , PVII-2, PVII-3.
  • iROP immortal ring-opening polymerisation
  • PVII-7 a [Me 2 Ga(p-OC 6 H 4 OMe)] 2 /'PrOH (1 :2) 100 70 48 92 14.2 1 .37 0.54 a
  • PVII-8 a [Me 2 Ga(p-OC 6 H 4 OMe)] 2 / PrOH (1 :6) 150 70 144 98 8.20 1 .66 0.50 a
  • GPC gel permeation chromatography

Abstract

The object of the invention are dialkyl complexes of gallium and indium having general formula I: and their use for preparing polylactide-pharmaceutically active compound conjugates and for immortal ring-opening polymerisation of heterocyclic monomers, especially in the polymerisation of lactide.

Description

Dialkyl complexes of gallium and indium and their use for preparing polylactide-pharmaceutically active compound conjugates and for immortal ring-opening polymerisation of heterocyclic monomers
The object of the invention are dialkyl complexes of gallium and indium and their use for preparing polylactide-pharmaceutically active compound conjugates and for immortal ring-opening polymerisation of heterocyclic monomers, especially in the polymerisation of lactide.
In recent years, intensive research is carried out relating to preparation of polylactide (PLA), which is associated with PLA properties, such as biodegradability and biocompatibility, which allow for many potential applications. The most important and still intensively researched possibilities of PLA applications include the use of PLA-0(Drug) or (PLA copolymer)-O(Drug) conjugates as systems for controlled drug delivery (Polyester Drug Delivery Systems, Ed. MNV Ravikumar, 2016, Taylor & Francis Group, LLC; Organometallics 2015, 34, 4871 ). In this case, an important element is the synthesis of the said conjugates with the ending group constituting the drug (a substance with pharmaceutical activity) and the polymer part having a strictly defined microstructure, and thus - properties. One of the most advantageous cases is to obtain the said conjugates as a result of the polymerisation of lactide or lactide and other heterocyclic monomers, without any necessity to additionally bind the drug to the polymer. A very interesting case in this context constitutes the possibility to obtain (PLA copolymer) -paclitaxel conjugates having the expected structure and properties (Angew. Chem. Int. Ed. 2008, 47, 4830). It should be noted that both their toxicity and their properties resulting from the structure of the polymer fragment significantly affect the applicability of PLA-0(Drug) or (PLA copolymer)-O(Drug) conjugates in medicine. In the first case, lack of PLA toxicity is highly desirable, which depends both on the catalyst used and the method of conducting the polymerisation. In turn, the PLA's structure, which includes the tacticity (stereostruture) of the PLA chain, has a key impact on PLA properties, and in particular the rate of its degradation, and thus the release rate of drugs from PLA-0(Drug) or (PLA copolymer)-O(Drug) conjugates. Research carried out by us and our colleagues has shown that dialkyl-alkoxy-galium catalysts [Me2GaOR']2 (Me = methyl group; OR' = alkoxy group) allow obtaining a PLA which does not exhibit cytotoxicity (Molecules 2014, 19, 19460). The same research has shown that these catalysts allow for easy modification of the PLA's tacticity, which is important for the release rate of drugs from PLA-0(Drug) conjugates. Although analogous dialkylalkoxy-indium complexes [Me2lnOR']2 allow for modification of the PLA's tacticity to a more limited extent compared to [Me2GaOR']2 complexes, they also represent an interesting group of catalysts (Polym. Chem. 2016, 7, 2022; Organometallics 2011 , 30, 1202). However, the research carried out so far on [Me2MOR']2 (M = Ga, In) included only model cases and did not show any possibility to introduce ending groups which constitute a drug or an ending group having an analogous structure. For this class of catalysts, it was also not possible to introduce any end ing group having specific properties, as a result of polymerisation of lactide against [Me2MOR']2 (M = Ga, In). Thus, the synthesis of PLA-0(Drug) or (PLA copolymer)-O(Drug) conjugates against catalyst of [R"2MOR']2-type (M = Ga, In; R" = alkyl group) could constitute an easy method for obtaining PLA-O(Drug) or (PLA copolymer)-O(Drug) conjugates of varied tacticity and different abilities to release the drugs. It should be noted at this point that neither [R"2MOR']2 (M = Ga, In) complexes nor any other catalysts have been demonstrated so far to allow for the synthesis of PLA or PLA copolymers with ending groups having specific properties, including ending groups being the drug or a group of analogous structure, while providing at the same time the possibility to control the PLA's tacticity to the extent allowed by [Me2MOR']2 complexes (M = Ga, In) (Appl. Organomet. Chem. 2013, 27, 328; Organometallics 2015, 34, 3480; Polym. Chem. 2016, 7, 2022) and with the lack of cytotoxicity of PLA obtained against them, as in the case of [Me2GaOR']2 complexes (Molecules 2014, 19, 19460).
It has surprisingly been found that complexes of the invention allow the production of PLA- pharmaceutically active compound conjugates.
Thus, the object of the present invention are complexes of general formula I:
[R R2MX]n (ROH)m (L)k
I
wherein:
R and R2 are the same or different and independently represent a hydrogen atom, CrC 2 alkyl, C2-C 2 alkenyl, C2-C 2 alkynyl, C3-C 2 cycloalkyl, C3-C 2 cycloalkenyl, C3-C 2 cycloalkynyl, C5-C20 aryl or C5-C20 heteroaryl, wherein each substituent R and R2 may be independently substituted with at least a substituent selected from the group consisting of a halogen atom, C C 2 alkyl, C2-C 2 alkenyl, C2-C12 alkynyl, -OR3,-SR3, -S(0)xR3, -S02NR3R4, -S(0)2OR3, -N02, -NO, -SCN, -NR3R4, -N(R3)OR4, -N(R3)NR3R4, -CN, -C(0)R3, -OC(0)R3, -0(CR3R4)yR5, -NR3C(0)R4, -(CR3R4)yC(0)OR5, -(CR3R4)yOR5, -C(=NR3)NR4R5, -NR3C(0)NR4R5, -NR3S(0)zR4, -NC(=0)R3C(=0)R4, -NR3P(=0)R4R5, -NR3As(=0)R4R5, -PR3R4, -POR3R4, -PR3OR4, -P(=0)R3R4, -P(=0)OR3R4, -P(=0)OR3OR4, -AsR3R4, -AsOR3R4, -AsOR3OR4, -As(=0)R3R4, -As(=0)OR3R4, -As(=0)OR3OR4, -NR3-C(=NR4)NR5R6, -C(=0)R3, -C(=0)OR3, -C(=S)OR3, -C(=0)SR3, -C(=S)SR3, -C(=S)NR3R4, -SiR3R4R5, -SiOR3R4R5, -SiOR3OR4R5, -SiOR3OR4OR5, -(CR3R4)y(3-12 membered heterocycle), -(CR3R4)y(C3-C12 cycloalkyl), -(CR3R4)y(C5-C20 aryl), -(CR3R4)y(5-12 membered heteroaryl), -(CR3R4)yC(0)NR5R6, or -(CR4R5)yC(0)R6;
each x represents independently 0, 1 or 2;
each y represents independently 0, 1 , 2, 3 or 4;
each z represents independently 1 or 2;
each substituent R3, R4, R5, R6 represents independently a hydrogen atom, a halogen atom, CrC 2 alkyl, C2-C 2 alkenyl, C2-C 2 alkynyl, C3-C 2 cycloalkyl, C5-C20 aryl, 5-12 membered heteroaryl;
X represents an atom containing a free pair of electrons or a group containing a free pair of electrons on an atom bound to atom M;
M represents a gallium atom or an indium atom;
ROH represents any organic compound containing a hydroxyl group,
L represents a neutral ligand with base properties,
n represents any natural number greater than or equal to 1 , m represents any number greater than or equal to 0,
k represents any number of coordinated molecules of a neutral ligand L to one coordination centre, meeting the condition 0 < k < 4;
with exclusion of monomeric complexes R R2GaOR(L), wherein R and R2 represent alkyl substituents, OR represents an alkoxy group, and L represents a neutral ligand exhibiting Lewis base properties, including N-heterocyclic carbenes.
Preferably, m represents 0, and X represents -O-biologically active compound, more preferably, the -O-biologically active compound represents -O-pharmaceutically active compound, even more preferably, the -O-pharmaceutically active compound represents -O-beta-adrenolytic drug.
In another preferred embodiment, m is greater than 0, and ROH represents HO-biologically active compound, more preferably, m is greater than or equal to 1, even more preferably, the HO-biologically active compound represents HO-pharmaceutically active compound, most preferably, the HO-pharmaceutically active compound represents HO-beta-adrenolytic drug.
In a further preferred embodiment, M represents a gallium atom, n represents 2, and m represents any number greater than 0, more preferably, m is greater than or equal to 1.
Preferably, M represents Ga, ROH represents a primary or secondary, or tertiary alcohol.
In a preferred embodiment, X represents -OR7 group, -SR7group, NR7R7 group or PR7 group, wherein
R7 and R7 independently represent a hydrogen atom, CrC 2 alkyl, C2-C 2 alkenyl, C2-C 2 alkynyl,
C3-C 2 cycloalkyl, C3-C 2 cycloalkenyl, C3-C 2 cycloalkynyl, C5-C20 aryl, 3-12 membered heterocycle,
5-12 membered heteroaryl, -R8(C=0)OR9, or -R8(C=0)R8 group, wherein R8 group represents C C 2 alkylene, C2-C 2 alkenylene, C2-C 2 alkynylene, and R9 group represents hydrogen, CrC 2 alkyl,
C3-C 2 cycloalkyl, C2-C 2alkene, C3-C 2cycloalkene, C2-C 2alkyne, C3-C 2 cycloalkyne, C C 2 alkoxy,
7 7'
C5-C20aryl, C5-C20 heteroaryl, 3-12 membered heterocycle, wherein each substituent R , R , R and
R9 may be substituted with at least one substituent R 0, wherein each substituent R 0 represents independently a halogen atom, CrC12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, -OR11, -SR , -S(0)qR11, -S02NR2R13, -S(0)2OR11, -N02, -NO, -SCN, -NR R12, -N(R )OR12, -N(R )NR 2R13, -CN, -C(0)R11, -OC(0)R11, -0(CR R2)rR13, -NR C(0)R12, -(CR R2)nC(0)OR13, -(CR R2)rOR13, -C(=NR )NR2R13, -NR C(0)NR2R13, -NR S(0)sR12, -NC(=0)R C(=0)R12, -NR P(=0)R2R13, -NR As(=0)R2R13, -PR R12, -POR R12, -PR OR12, -P(=0)R R12, -P(=0)OR R12, -P(=0)OR OR12, -AsR R12, -AsOR R12, -AsOR OR12, -As(=0)R R12, -As(=0)OR R12, -As(=0)OR OR12, -NR -C(=NR2)NR3R14, -C(=0)R11, -C(=0)OR12, -C(=S)OR11, -C(=0)SR11, -C(=S)SR11, -C(=S)NR R12, -SiR R2R13, -SiOR R 2R13, -SiOR OR2R13, -SiOR OR2OR13, -(CR R2)r(3-12 membered heterocycle), -(CR R2)r(C3-C12 cycloalkyl), -(CR R2)r(C5-C20 aryl), -(CR R2)r(5-12 membered heteroaryl), -(CR R2)rC(0)NR 3R14, or -(CR R2)rC(0)R13;
each q represents independently 0, 1 or 2;
each r represents independently 0, 1 , 2, 3 or 4;
each s represents independently 1 or 2; each substituent R11 , R 2, R 3, R 4 represents independently a hydrogen atom, a halogen atom, C C 2 alkyl, C2-C 2 alkenyl, C2-C 2 alkynyl, C3-C 2 cycloalkyl, C5-C20 aryl, 5-12 membered heteroaryl.
The object of the invention is also the use of the complexes defined above for the preparation of polylactide-pharmaceutically active compound conjugates.
The invention also relates to a method of preparing polylactide-pharmaceutically active compound conjugates characterised in that the lactide is polymerised against a complex of general formula I, wherein n = 2, X represents -O-pharmaceutically active compound and/or ROH represents HO-pharmaceutically active compound, at a temperature in the range of 0 to 150°C, preferably in solution at a temperature in the range of 40 to 100°C.
Another object of the invention is the use of complexes defined above as catalysts for immortal ring- opening polymerisation of heterocyclic monomers, preferably the heterocyclic monomers contain an oxygen atom as the heteroatom, more preferably the heterocyclic monomers are lactones, even more preferably, the complexes are used for stereoselective polymerisation of lactide, most preferably the complexes are used for stereoselective polymerisation of racemic lactide.
Terms used:
The term "halogen atom" means an element selected from F, CI, Br, I.
The term "carbene" means a particle containing an inert carbon atom with a valence number of two and two unpaired valence electrons. The term "carbene" also includes carbene analogues in which the carbon atom is replaced with another chemical element such as boron, silicon, germanium, tin, lead, nitrogen, phosphorus, sulfur, aluminum, gallium, selenium and tellurium.
The term "neutral ligand with base properties" means a ligand not having any charge and having Lewis base properties enabling its coordination to the metal.
The term "alkyl" refers to a saturated, linear, or branched hydrocarbon substituent with indicated number of carbon atoms. Examples of the alkyl substituent are methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl, and -n-decyl. Representative branched alkyls include -iso-propyl, -sec-butyl, -iso-butyl, -tert-butyl, -iso-pentyl, -neopentyl, -1 -methyl-butyl, -2-methyl-butyl, -3-methyl-butyl, -1 ,1 -dimethyl-propyl, 1 ,2-dimethyl-propyl, -1 -methyl-pentyl, -2-methyl-pentyl, -3-methyl-pentyl, -4-methyl-pentyl, -1 -ethyl-butyl, -2-ethyl-butyl, -3-ethyl-butyl, -1 ,1 -dimethyl-butyl, -1 , 2-dimethyl-butyl, -1 ,3-dimethyl-butyl, -2,2-dimethyl-butyl, -2,3-dimethyl-butyl, -3,3-dimethyl-butyl, -1 -methyl-hexyl, -2-methyl-hexyl, -3-methyl-hexyl, -4-methyl-hexyl , -5-methyl-hexyl, -1 ,2-dimethyl-pentyl, -1 ,3-dimethyl-pentyl, -1 ,2-dimethyl-hexyl, -1 ,3-dimethyl-hexyl, 3,3-dimethyl-hexyl, -1 ,2-dimethyl-heptyl, 1 ,3-dimethyl-heptyl, and -3,3-dimethyl-heptyl and the like.
The term "alkoxy" refers to an alkyl substituent as defined above bound via an oxygen atom.
The term "perfluoroalkyl" means an alkyl group as defined above in which all of the hydrogen atoms have been replaced with the same or different halogen atoms.
The term "cycloalkyl" refers to a saturated, mono- or polycyclic hydrocarbon substituent with indicated number of carbon atoms. Examples of the cycloalkyl substituent are -cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl, and the like. The term "alkenyl" refers to a saturated, linear, or branched, non-cyclic hydrocarbon substituent with indicated number of carbon atoms and containing at least one carbon-carbon double bond. Examples of the alkenyl substituent are -vinyl, -allyl, 1 -butenyl, 2-butenyl, iso-butylenyl, -1 -pentenyl, -2-pentenyl, 3-methyl-1 -butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1 -hexenyl, 2-hexenyl, -3-hexenyl, 1 -heptenyl, -2-heptenyl, 3-heptenyl, 1 -octenyl, -2-octenyl, 3-octenyl, 1 nonenyl, -2-nonenyl, -3-nonenyl, -1 -decenyl, -2-decenyl, 3-decenyl and the like.
The term "cycloalkenyl" refers to a saturated, mono- or polycyclic hydrocarbon substituent with indicated number of carbon atoms and containing at least one carbon-carbon double bond. Examples of the cycloalkenyl substituent are cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, -cycloheptenyl, -cycloheptadienyl, cycloheptatrienyl, cyclooctenyl, -cyclooctadienyl, cyclooctatrienyl, cyclooctatetraenyl, cyclononenyl, cyclononadienyl, -cyclodecenyl, cyclodecadienyl and the like.
The term "alkynyl" refers to a saturated, linear, or branched, non-cyclic hydrocarbon substituent with indicated number of carbon atoms and containing at least one carbon-carbon triple bond. Examples of the alkynyl substituents are acetylenyl, propynyl, 1 -butynyl, 2-butynyl, -1 -pentynyl, -2-pentynyl, 3-methyl-1 -butynyl, 4-pentynyl, 1 -hexynyl, -2-hexynyl, 5-hexynyl and the like.
The term "cycloalkynyl" refers to a saturated, mono- or polycyclic hydrocarbon substituent with indicated number of carbon atoms and containing at least one carbon-carbon triple bond. Examples of the cycloalkynyl substituent are cyclopentynyl, cyclohexynyl, cycloheptynyl and the like.
The term "aryl" refers to an aromatic, mono- or polycyclic hydrocarbon substituent with indicated number of carbon atoms. Examples of aryl substituents are phenyl, tolyl, xylyl, naphthyl.
The term "heteroaryl" refers to an aromatic mono- or polycyclic hydrocarbon substituent with indicated number of carbon atoms in which at least one carbon atom has been replaced with a heteroatom selected from O, N and S. Examples of the heteroaryl substituent are furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidyl, triazinyl, indolyl, benzo[b]furyl, benzo[b]thienyl, indazolyl, benzimidazolyl, azaindolyl, quinolyl, isoquinolyl, carbazolyl and the like.
The term "heterocycle" refers to a saturated or partially unsaturated, mono- or polycyclic hydrocarbon substituent with indicated number of carbon atoms in which at least one carbon atom has been replaced with a heteroatom selected from O, N and S. Examples of the heterocyclic substituent are furyl, thiophenyl, -pyrrolyl, -oxazolyl, -imidazolyl, -thiazolyl, -isooxazolyl, -pyrazolyl, isothiazolyl, -triazinyl, -pyrrolidinonyl, -pyrrolidinyl, -hydantoinyl, -oxiranyl, oxetanyl, -tetrahydrofuranyl, -tetrahydrotiophenyl, quinolinyl, isoquinolinyl, chromonyl, coumarinyl, indolyl, indolizinyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, purinyl, -4H-quinolizinyl, isoquinolyl, quinolil, phthalazine, -naphthyridinyl, carbazolyl, -β-carbolinyl and the like.
The terms HO-biologically active compound, HO-pharmaceutically active compound (HO-Drug) or HO-beta-adrenolytic drug (HO (fiAD)) used herein refer to the corresponding compounds which contain a hydroxyl group (OH-) in their structure. The terms -O-biologically active compound, -O-pharmaceutically active compound (-O-Drug), -O-beta-adrenolytic drug (-0(/¾4D)) mean groups formed as a result of proton detachment from HO-biologically active compound, HO-pharmaceutically active compound or HO-beta-aderenolytic drug, respectively. The biologically active compound is any chemical compound that exerts its effects on living organisms. Biologically active compounds include, among others, pharmaceutically active compounds, plant protection agents and the like. The term pharmaceutically active compound has its usual meaning used in the art. The term beta-adrenolytic drug (in other words, β-blocker, β-sympatholytic drug) is a group of drugs acting antagonistically on β1 and β2 adrenergic receptors, which inhibit the activity of the sympathetic system, exerting effects on almost the entire organism. It is one of the most important groups of drugs used in cardiology, and especially in ischemic heart disease and hypertension. Examples of beta-adrenergic drugs include oxprenolol, metipranolol, pindolol, propranolol, sotalol, timolol, nadolol, alprenolol, kartenolol, metoprolol, atenolol, celiprolol, acebutolol, betaxolol, bisoprolol, esmolol, nebivolol, labetalol and carvedilol.
Polymerisation of rac-LA by/with new complexes [R R2MO(/3/4D)]2 (M = Ga, In) according to the invention, wherein 0(fiAD) is an alkoxy group - derivative of beta-adrenergic drugs - HO(/ )), drugs used in cardiology, and especially in ischemic heart disease and hypertension, allows obtaining PLA-0(/¾4D) conjugates in a controlled and stereoselective way. This can be accomplished both as a result of ring- opening polymerisation (ROP) against [R R2MO(/¾4D)]2 and as a result of immortal Ring-Opening Polymerisation (iROP) with the use of catalytic system [R R2MX]2/HO(/¾4D). In the case of immortal Ring- Opening Polymerisation of rac-LA, creation of centres [R R2MO(/ ))]2 under polymerisation conditions is to be expected. In the case of using [R R2MO(/3/AD)]2 complexes (M = Ga, In) as catalysts, possibility of modifying the PLA's tacticity in the range 0.22 < P, < 0.85 (Pt - probability of racemo connections in PLA) should be also expected. Possibility of introducing the 0(βΑΩ) ending group and obtaining PLA-O (fiAD) or PLA copolymers-0(/¾AD) conjugates has not been described in the literature so far either for catalysts allowing such a wide modification of tacticity as [R"2MOR']2 catalysts (M = Ga, In), or for the [R"2MOR']2 catalysts themselves (M = Ga, In), including [R"2GaOR']2 allowing obtaining of PLA characterised by lack of toxicity. It should be noted that the results obtained indicate the possibility to use [R R2MO(Dri/g)]2 (M = Ga, In) catalytic centres instead of [R R2MO(/¾4D)]2 (M = Ga, In) to obtain PLA-0(Drug) conjugates, wherein HO(Drug) is a substance exhibiting a pharmacological activity and containing primary, secondary or tertiary hydroxyl groups.
It should be noted that while PLA-0(/¾4D) conjugates can be obtained as a result of immortal Ring- Opening Polymerisation (iROP) against [R R2MX]2/HO(/¾4D) (M = Ga, In), this method can be used to obtain PLA and PLA copolymers against [R R2MX]2/ROH, what is unprecedented in the literature in the case of gallium complexes. The results which are the basis of the invention described show that immortal Ring-Opening Polymerisation (iROP) of rac-LA against [R R2GaX]2/ROH catalytic systems allows obtaining PLA-OR polymers, in a controlled and heteroselective way. In this case, the results obtained, in combination with literature reports (Polym. Chem. 2016, 7, 2022; Organometallics 2010, 29, 3729), indicate the possibility of a smooth modification of PLA heterotacticity in the range of Pr = 0.5 - 0.85. Immortal ring-opening polymerisation of lactide is definitely different from the classic ring-opening polymerization (ROP). On the one hand, it gives the possibility to reduce the amount of metal complex and to control the average molecular weight ( n) of polylactide by properly selected ratio LA:ROH instead of LA:M (M - metal in the alkoxy complex), which allows to reduce metal content in the obtained PLA or in the PLA-O(Drug) conjugate. Furthermore, it makes it possible to obtain, e.g., branched polymers or PLA copolymers, by using macroinitiators containing alcoholate groups, including HO(Drug) or HO(/ )) as described above, through which it gives the possibility to directly obtain PLA-0(Drug) or (PLA copolymer- 0(Drug)) conjugates. Demonstration of the possibility of such polymerisation against [R R2GaX]2/ROH catalysts which allow controlled and heteroselective polymerisation of rac-LA and easy modification of PLA heterotaxicity in the above-mentioned range has no precedence in the literature. Although the possibility of introducing simple alkoxy ending groups has been demonstrated in the literature for the immortal polymerization of lactide using [R"2lnOR']2/ROH ar|d [R"2lnOR']2/RNH2 catalytic systems (Organometallics 2013, 32, 1694; Organometallics 2011 , 30, 1202), there are no literature reports regarding introduction of any alkoxy groups, including alkoxy groups with specific properties, as a result of the immortal polymerization of lactide (iROP) against [R R2GaX]2/(ROH)m (wherein m is larger than or equal to 0) catalytic systems leading to the production of PLA-OR and (PLA copolymer)-OR polymers. It should be emphasized that the use of any catalytic systems, and especially [R"2GaX]n/ROH catalytic systems leading to the creation of [R"2GaOR]2 active centres will be equivalent to the use of [R"2GaOR]2 type catalysts. It should also be emphasized that the use of [R"2GaOR']2 dimeric complexes is a completely different case from monomeric gallium complexes of R"2GaOR'(NHC) type (NHC = N-heterocyclic carbene), in the case of which we demonstrated the possibility of conducting polymerisation in an immortal way against alcohols (iROP) for simple alcohols, e.g. isopropanol (Organometallics 2015, 34, 3480). In the case of both [R"2MOR']2 dimeric catalysts and [R"2GaOR']2/B catalytic systems (wherein B = Lewis base) immortalized polymerization (iROP) of lactide or other heterocyclic monomers has no precedence in literature. It should be mentioned that the use of other metal complexes in the polymerisation of lactide against alcohols has been described in the literature, and the most important catalysts include tin octanoate which is used for the polymerisation of cyclic alcoholic esters in industrial processes (Polym. Adv. Technol. 2014, 25, 436). However, tin octanoate does not exhibit stereoselectivity in the polymerization of lactide. It should also be noted that the catalyst used has a decisive influence on the ability to separate thereof from PLA and toxicity. In this regard, [R"2GaOR']2 exhibits particularly advantageous properties. Gallium complexes formed after isolation of the polymer do not bind permanently to polylactide, which allows an easy production of even short PLA chains ( n < 15000 Da) with Ga content lower than 20 ppm in accordance with the guidelines of The European Pharmacopeia (https://www.edqm.eu/en/european-pharmacopoeia-8th-edition-1563.html) (Molecules 2014, 19, 19460).
In the literature, there are no reports on the use of [R R2MO(Dri/g)] catalysts or catalytic centres (M = Ga, In), wherein HO(Drug) is a substance with pharmacological activity having one or more hydroxyl groups for potential use as a drug or prodrug, in the polymerisation of lactide and obtaining PLA-0(Drug) or (PLA copolymer)-O(Drug) conjugates. It should be noted that it has not been demonstrated either that catalysts having [R"2MOR']n centres (n = 1 , 2 or 3) could be used for synthesis of PLA-OR' or (copolymer PLA)-OR' having OR' ending groups with specific properties or having additional functional groups other than those found in the PLA chain, or model-like small groups such as O'Pr, 0(CH2)2OCH3 or OCH(CH3)CH2OCH3 not containing other functional groups or substituents with significant steric hindrances. It should be noted that in the case of PLA-0(Drug) or (PLA copolymer)-O(Drug) conjugates, these systems definitely differ in properties from the corresponding PLA-OR or (PLA copolymer-OR), having simple OR ending groups not having specific properties the synthesis of which was presented in the literature with the use of [Me2MOR'] (M = Ga, In) (Organometallics, 2010, 29, 3729; Appl. Organomet. Chem. 2013, 27, 328; Polym. Chem. 2016, 7, 2022). As an example of specific properties of PLA-O(Drug) conjugates, PLA-camptothecin copolymers can be mentioned, the properties of which indicate that they may be used as systems for controlled drug delivery (Molecules 2014, 19, 19460). R R2MO(Dri/g)]2 catalysts and catalytic centres (M = Ga, In) being the object of the present invention (part A) can be successfully obtained in the reaction of HO(Drug) with R3Ga (Scheme 1 a) or in the reaction of [R R2MOR']n (or [R R2MO/4r]n)(n = 2 or 3) with HO(Drug) (Scheme 1 b). In the latter case, HO(Drug) group exchanges with OR' (or OAr) group, leading to the creation of [R R2MO(Dri/g)]2 catalytic centres. It should be noted that the use of any [R R2MX]n complex in the case shown in Scheme 1 a, wherein X represents a heteroatom, and lactide may be inserted into the M-X bond with the creation of [R R2MOR'] centres, should be considered equivalent to the use of [R R2MOR']n (n = 2 or 3). Similarly, the use of any [R R2MX]n complex able to react with HO(Drug) with the creation of [R R2GaO(Dri/g)]2, catalytic centres, instead of [R R2MOR']n (or [R R2MO/4r]n) (n = 2 or 3) (Scheme 1 b), should be considered equivalent to the use of [R R2MOR']n (or [R R2MO/4r]n). It should be noted that [R R2GaOR']2 dimeric catalytic centres should be expected in the case of non-selective polymerisation without the addition of a Lewis base, in heteroselective polymerisation in the presence of bases such as e.g. pyridines or other compounds with Lewis base properties, e.g. THF (Polym. Chem. 2016, 7, 2022; Organometallics, 2010, 29, 3729) and in the case of isoselective polymerisation in the presence of organosuperbases (Appl. Organomet. Chem. 2013, 27, 328). However, in the case of isoselective polymerisation in the presence of N-heterocyclic carbenes (NHC) or other strong Lewis bases, formation of R R2GaOR'(NHC)-type monomeric centres should be expected (Organometallics, 2015, 34, 3480).
Figure imgf000009_0001
Scheme 1 Methods of obtaining PLA-0(/¾4D) conjugates with the use of dialkylalkoxy gallium centres, for example PLA-(propranolol) conjugates
According to the invention, [R R2MO(Dri/g)]2 catalysts (M = Ga, In), wherein R , R2 are the same or different and represent alkyl groups (as defined above), and O(Drug) is an alkoxy group, derivative of HO(drug) which is characterised by pharmacological activity and has one or more hydroxyl groups with potential use as a drug or prodrug, preferably [R R2MO(/¾4D)]2 (M = Ga, In) (wherein H 0(fiAD) - β-adrenolytic drug), is obtained by reacting R"3M trialkylaluminum or trialkylindium complexes (wherein M = Ga, In, and groups R " are the same or different, and according to the above introduced designation, represent alkyl groups) with HO(Drug) (as in the case of obtaining [R"2MOR']2 complexes, wherein M = Ga, In (Chem. Rev. 2006, 250, 682)) in a dehydrated, deoxygenated organic solvent, preferably in CH2CI2, at the temperature from -78°C to 150°C, preferably in the range of -78°C to 25°C, within 5 minutes to 24 hours, preferably within 5-60 minutes, in the atmosphere of an inert gas, preferably argon (Example I). As examples of [R R2MO(Dri/g)]2 complexes (M = Ga, In), preferably [R R2MO(/3/4D)]2 complexes (M = Ga, In; pAD - β-adrenolytic drug), [(CH3)2M(OCH(CH2OC6H5)CH2NH(CH(CH3)2))]2 (M = Ga, In) - [(CH3)2M(A)]2 (wherein (OCH(CH2OC6H5)CH2NH(CH(CH3)2)) - A constitutes a full skeleton of β-adrenolytics (https://en.wikipedia.org/wiki/Beta_blocker)) and model complexes [(CH3)2Ga(0(CH2)NH(CH(CH3)2))]2 - [(CH3)2Ga(B)]2 and [(CH3)2Ga(0(CH2)NH(CH3))]2 - [(CH3)2Ga(C)]2, wherein the ligands (0(CH2)NH(CH(CH3)2)) - (B) and (0(CH2)NH(CH3)) - (C) mimic the interaction of β-adrenolytics with the gallium centre in the case of [R R2GaO(/¾4D)]2, were obtained and characterised.
It can be expected that [R R2MO(Dri/g)]2 catalytic centres, preferably [R R2MO(/3/AD)]2 ones (M = Ga, In), can be also obtained in the reaction of [R R2MX]2 with HO(/ )) (Scheme 2) under conditions of immortal polymerisation of lactide (iROP). This is indicated by formation of PLA-OR' and PLA-(C) chains in the polymerisation of rac-LA against [R R2MOR']2/H(C), as well as formation of only PLA-(C) conjugates in the polymerisation of rac-LA against [R R2MO/4r]2/H(C). Therefore, it should be expected that [R R2MO(/3/AD)]2 centres can be obtained by reacting [R R2MX]n with HO(fiAD) in the temperature range of -60°C to 150°C, preferably in the range of 40°C to 70°C (conditions for conducting the polymerisation of lactide against dialkylalkoxy gallium centres), as is indicated by the formation and structure of PLA-(A), PLA-(B), PLA-(C) and PLA-(D) (PLA-atenolol) as a result of the use of [R R2MOR']2(and/or [R R2M04r]2)/H(A), [R R2MOR']2(and/or [R R2M(_ ]2)/H(B), [R R2MOR']2(and/or [R R2M(_ ]2)/H(C) or [R R2MOR']2(and/or [R R2MO/4r]2)/H(D), respectively, as catalytic systems. (Examples II, IV, VI).
Figure imgf000010_0001
Scheme 2
According to the invention, new [R R2MO(Dri/g)]2 catalysts and catalytic centres (M = Ga, In) find their use in the process of ring-opening polymerisation (ROP) of lactide (rac-LA) in the temperature range of -60°C to 150°C, preferably polymerisation of rac-LA against [R R2MO(/¾4D)]2 (M = Ga, In) in the range of -20°C to 70°C. Polymerization of lactide occurs as a result of insertion of lactide in M-0(/ )) bond (M = Ga, In), which is consistent with the commonly accepted coordination and insertion mechanism of lactide polymerisation against alkoxy metal catalysts (Chem. Rev. 2004, 104, 6147) and leads to formation of PLA-0(fiAD) conjugates. Polymerisation of rac-LA in the presence of [R R2MO(Dri/g)]2 catalysts (M = Ga, In), preferably [R R2MO(/3/AD)]2 ones (M = Ga, In), at the temperature of 40°C and 70°C leads to formation of only linear conjugates PLA-(A), PLA-(B) or PLA-(C), which was confirmed primarily with the use of MALDI-TOF spectroscopy (Example I II). Similarly, linear conjugates PLA-(A), PLA-(B) or PLA-(C) and PLA-(D) (PLA-atenolol) can be obtained against [R R2MO(/ ))]2 centres (M = Ga, In) created as a result of reaction of [R R2MOR]2 or [R R2MO/4r]2 (OAr = aryloxy group) with appropriate aminoalcohols in immortal ring-opening polymerization (iROP) of rac-LA (Example IV). Heteroselective polymerisation of rac-LA against [R R2MO(Dri/g)]2, preferably [R R2MO(/ ))]2 in the presence of Lewis base, preferably pyridine derivatives, allows modification of PLA tacticality in PLA-O(Drug) conjugate, preferably PLA-0(/¾4DJ conjugate, in the range of 0.50 < Pr < 0.86 (Pr - probability of racemo connections in PLA) (Example V). In turn, isoselective polymerisation against [R R2MO(Dri/g)]2, preferably [R R2MO(/¾4D)]2 in the presence of organosuperbases (the following publications specify the term organosuperbase: T. Ishikawa (Ed.), Superbases for Organic Synthesis: Guanidines, Amidines Phosphazenes and Related Organocatalysts, WileyChichester, 2009; Chem. Eur. J. 2012, 18, 3621 ), preferably DBU (1 ,8-diazabicyclo[5.4.0]undec-7-ene), leads to formation of PLA-O(Drug) conjugates, preferably PLA-0(/¾4DJ conjugates, having isotactic (Pr = 0.22) blocks of PLA (Example V). It was also confirmed that it is possible to obtain PLA-O(Drug) conjugates, preferably PLA-0(/3/ADJ conjugates, containing a predominantly heterotactic PLA, including stereo diblock PLA, in the immortal polymerisation of rac-LA against [Me2MOR']2 and [Me2MO/4r]2 systems (Example VI). The possibility to obtain PLA-0(fiAD) containing stereo diblock PLA was confirmed as a result of obtaining the conjugate of (atactic PLA)20-Jb-(predominantly heterotactic PLA (P, = 0.86))80-atenolol (Example VI , PVI-8 (Table 5)). Formation of the latter is indicated by analyses of GPC and NMR (Example VI , PVI-8 (Table 5) and MALDI-TOF (PIV-5 (Table 3), Figure 9).
In the literature, there are no reports on the use of [R R2GaX]n/ROH catalytic systems in the immortal polymerisation of lactide against alcohols. The catalytic systems being the object of the present invention (part B) can be successfully obtained as a result of mixing [R R2GaX]n complexes, preferably [R R2GaOR]2 or [R R2GaO/Ar]2 (wherein OAr = aryloxy group with alcohols (ROH)). Although the mechanism of immortal polymerisation (iROP) of cyclic esters, including lactide, may be of Coordination- Insertion type or of Activated Monomer type (Organometallics 2013, 32, 1694), in the case described, creation of catalytic centres can be expected, analogously to the example shown in Scheme 3, which allows for the immortal polymerisation of rac-LA in accordance with the Coordination-Insertion mechanism. This is consistent with obtaining [R R2MO(/¾4D)]2 as a result of reacting [R R2MOR']2 with HO(/¾4D) under conditions of rac-lactide polymerisation against [R R2MOR']2/ HOifiAD) or [R R2MOAr]2/HO(/3/AD) conducted at the temperature of 40°C or 70°C (Examples II , IV and VI). By analogy, it can be expected that the use of a different alcohol (ROH) than HO(fiAD) to obtain [R R2GaX]n/ROH catalytic systems will lead to formation of [R R2GaOR']2 dialkylalkoxy gallium catalytic centres which are active in the polymerisation of lactide (Scheme 1 ), which was confirmed and presented in example VI I (as well as examples I I, IV, VI). It should be noted that in this case the [R R2GaX]n procatalysts used may or may not exhibit activity in the polymerisation of lactide. However, they must react with alcohols, leading to formation of [R R2GaOR']2 centres or otherwise catalyse the polymerisation of lactide, e.g. by activating the monomer in the case of the activated monomer mechanism. In turn, due to the presence of equilibrium shown in Scheme 3, leading to even growth of PLA chains, a similar effect can be expected when using both mono- and polyhydric alcohols. R R2GaX]n/ROH catalytic systems are the only examples of alkoxygallium complexes allowing the immortal polymerisation of lactide and other cyclic esters. In this case, the possibility of stereoselective polymerisation of rac-LA, even in the presence of alcohols, is extremely important and allows to expect the possibility of obtaining a polylactide having a stereoblock structure. According to the invention, new [R R2GaX]n/ROH catalytic systems are used in the process of immortal ring-opening polymerisation, preferably stereoselective polymerisation of rac-LA in the temperature range of -60°C to 150°C, preferably in the range of 40°C to 70°C. (Example VII). The polymerisation of rac-LA proceeds in a controlled manner, leading to obtaining chains of similar length, as indicated by the MALDI TOF analysis of the obtained PLA, as well as by monomodal distribution of average molecular weight n with low polydispersity. It should be noted that the addition of n moles of ROH alcohol to [R R2GaOR']2 leads to obtaining n+2 chains of PLA (nPLA-OR + 2 PLA-OR'). In turn, the addition of n moles of ROH alcohol to [R R2GaO/Ar]2, where there is no any insertion of lactide in Ga-OAr bond, leads to obtaining n chains of PLA (nPLA-OR) (Example VII). In addition, in the presence of pyridine derivatives, the polymerisation proceeds stereoselectively, leading to a heterotactic PLA with maximum heterotacticity expressed as P, = 0.86 (Example VI).
Below, embodiments of the invention are presented.
EXAMPLE I -
Figure imgf000012_0001
(M= Ga. In)
Possibility of obtaining [R R2MO(/3/AD)]2 (M = Ga, In) was confirmed with the use of both O, N ligands constituting the most important portion of the skeleton of β-adrenolytic drugs (PAD) from the point of view of PAD interaction with the catalytic centre (B and C), and the ligand constituting a typical skeleton for PAD (A), distinguished for ligands A, B, C which are presented below with a bold line and font.
Figure imgf000012_0002
H(C) H(B) H(A)
The synthesis was conducted in a protective atmosphere of argon with the use of dehydrated and deoxygenated solvents.
[MezGa(A)lz: A solution of (CH3)3Ga (0.267 g, 2.3 mmol) in CH2CI2 (5 ml) was added to the Schlenk vessel and cooled with a dry ice/acetone mixture to about -80°C. Then, a solution of HOCH(CH2OPh)CH2NH(CH(CH3)2) (0.486 g, 2.3 mmol) in CH2CI2 (1 ml) was added dropwise and the cooling bath was removed to allow the reaction mixture to spontaneously warm to room temperature. After cessation of gas evolution, the reaction was conducted for 2 hours, and then the solvents were removed under reduced pressure. Colourless crystals [Me2Ga(A)]2 (0.554 g, 82%) were obtained as a result of the crystallisation of the obtained post-reaction mixture with toluene/n-hexane. H NMR (CD2CI2, 400 MHz): -0.33 (s, 6H), 1 .19 (br, 6H), 2.72 (s, 1 H), 2.93 (m, 2H), 3.92 (m, 1 H), 4.02 (m, 1 H), 4.2 (s, 1 H), 6.90-6.96 (m, 3H), 7.26-7.30 (m, 2H); 3C NMR (CD2CI2, 100MHz): -5.5, 22.93, 50.3, 52.3, 70.5, 73.2, 115.0, 121 .3, 130.0, 159.4.
[Me?ln(A)l2: A solution of (CH3)3ln (0,263 g, 1 .7 mmol) in CH2CI2 (5 ml) was added to the Schlenk vessel and cooled with a dry ice/acetone mixture to about -80°C. Then, a solution of HOCH(CH2OPh)CH2NH(CH(CH3)2) (0.345 g, 1 .7 mmol) in CH2CI2 (2 ml) was added dropwise and the cooling bath was removed to allow the reaction mixture to spontaneously warm to room temperature. After cessation of gas evolution, the reaction was conducted for 1 hour, and then the solvent was removed under reduced pressure. Colourless crystals [Me2ln(A)]2 (0.581 g, 70%) were obtained as a result of crystallisation of the obtained post-reaction mixture with CH2CI2/n-hexane. H NMR (CD2CI2, 400 MHz): -0.46 (s, 1 H), -0.37 (s, 4H), -0.26 (s, 1 H), 1 .12 (m, 6H), 2.33-2.50 (m, 1 H), 2.72-2.84 (m, 1 H), 2.87-2.97 (m, 1 H), 3.73-3.83 (m, 1 H), 3.84-3.95 (m, 1 H), 4.00-4.09 (m, 1 H), 6.86-7.00 (m, 3H), 7.26-7.34 (m, 2H); 3C NMR (CD2CI2, 100MHz): -5.7, 22.7, 23.2, 49.6, 52.0, 69.9, 73.1 , 114.6, 120.8, 129.7, 159.3.
[MezGa(B)lz: The reaction was conducted analogously to the synthesis of [Me2Ga(A)]2, with the use of 0.197 g (1 .72 mmol) (CH3)3Ga and 0.177 g (1 .72 mmol) HO(CH2)2NH(CH(CH3)2). Colourless crystals [Me2Ga(B)]2 (0.236 g, 68%) were obtained as a result of crystallisation of the obtained post-reaction mixture with CH2CI2/n-hexane in -20°C. H NMR (CD2CI2, 400 MHz): -0.43 (s, 6H), 1 .14 (d, 3J(H,H)= 6.4 Hz, 6H), 2.69 (q, 3J(H,H)= 6.6 Hz, 2H), 2.84-2.88 (m, 1 H), 3.68 (t, 3J(H,H)= 6.0 Hz, 2H); 3C NMR (CD2CI2, 100MHz): -5.9, 23.2, 50.1 , 50.5, 62.3.
[MezGa(C)lz: The reaction was conducted analogously to the synthesis of [Me2Ga(A)]2, with the use of 0.690 g (6 mmol) (CH3)3Ga and 0.450 g (6 mmol) HO(CH2)2NH(CH3). [Me2Ga(C)]2 in the form of a white crystalline solution was obtained quantitatively after removal of solvents under reduced pressure from the post-reaction mixture. H NMR (CD2CI2, 400 MHz): -0.49 (s, 6H), 2.36 (s, 3H), 2.68 (t, 3J(H,H)= 6.0 Hz, 2H), 3.62 (t, 3J(H,H)= 6.0 Hz, 2H); 3C NMR (CD2CI2, 100MHz): -7.1 , 35.2, 53.7, 59.7.
EXAMPLES II - VII include a series of rac-LA polymerisations against dialkylalkoxy gallium and dialkylalkoxy indium catalysts leading to PLA terminated with different ending groups, including conjugates of PLA-(PAD) - PLA-(A), PLA-(B), PLA-(C) and PLA-(D) types. In each of the cases listed in Tables 1 to 6, in addition to data on the structure of PLA and PLA conjugates of PLA-(PAD) type, the presence of appropriate ending groups was indicated by PLA analyses with the use of H NMR spectroscopy. In each case, insertion of rac-LA in Ga-Oaikoxy bond was only observed . However, insertion of lactide in Ga-Oaryioxy bond under polymerisation conditions was not confirmed.
The polymerisation was conducted in a protective atmosphere of argon with the use of dehydrated and deoxygenated solvents. Appropriate amount of catalyst in solution (0.5 ml in toluene or CH2CI2) was added to the lactide solution (0.9 g - 3.55 g depending on the ratio of LA/catalyst, Table 1 ) in the solvent used. The obtained solution was mixed, and after the time indicated in Table 1 the polylactide was separated from the catalyst by adding 50 ml of 5% HCI solution and shaking it for 5 minutes. Then, the organic layer was separated and washed by shaking two times with the use of 50 ml of distilled water. Then, the organic phase was dried using anhydrous MgS04, and the polylactide terminated with OH and alkoxy groups - HO-PLA-OR' (also referred to in a simplified manner in this disclosure as PLA-OR') was obtained by removing solvents under vacuum.
HO-PLA-OCH(CH3)02CH3 (HO-PLA-OCH(Me)02Me): d 1 .55 (m, 3H, CHCH3), 5.14 (m, 1 H, CHCH3) (c) ending groups: 1 .25 (m, CHCH3) 3.72, 3.73 (s, OCH3), 4.34 (q, J = 6.8 Hz, CHCH3)
HO-PLA-OCH2CH2NHCH3 (HO-PLA-OCH2CH2NHMe): d 1 .55 (m, 3H, CHCH3), 5.14 (m, 1 H, CHCH3) (c) ending groups: 2.62-2.80 (br s, 1 H, NHCH3), 3.26-3.37 (m, 2H, CH2CH2NH), 3.47-3.58 (m, 2H, OCH2CH2)
HO-PLA-OCH2CH2NHCH(CH3)2 (HO-PLA-OCH2CH2NH'Pr): d 1 .55 (m, 3H, CHCH3), 5.14 (m, 1 H, CH CH3) (c) ending groups: 1 .18-1 .29 (m, 6H, CH(CH3)2), 3.21 -3.35 (m, 2H, CH2CH2), 3.45-3.58 (m, 2H, CH2CH2)
HO-PLA-OCH(CH2OC6H5)CH2NHCH(CH3)2 (HO-PLA-OCH(CH2OPh)CH2NH'Pr or HO-PLA-(A)): d 1 .55 (m, 3H, CHCH3), 5.14 (m, 1 H, CHCH3) (c) ending groups: 1 .20-1 .34 (m, 6H, CH(CH3)2)), 3.86 (m, 1 H, OCH), 3.95-4.09 (m, 4H, OCH(CH2OC6H5)CH2NH), 6.79-6.99 (m, 3H, ArH), 7.20-7.29 (m, 2H, ArH)
HO-PLA-OCH(CH2OC6H4CH2C(0)NH2)CH2NHCH(CH3)2 (HO-PLA-(D) or HO-PLA-(atenolol)): d 1 .55 (m, 3H, CHCH3), 5.14 (m, 1 H, CHCH3) (c) ending groups: 1 .15-1 .35 (m, 6H, CH(CH3)2), 3.53-3.78 (m, 2H, C(0)CH2Ar) OCH(CH2OC6H5)CH2NH), 3.78-3.89 (m, 1 H, OCH), 3.91 -4.12 (m, 4H, OCH(CH2OC6H5)CH2NH), 6.78-6.89 (m, 2H, ArH), 7.1 0-7.19 (m, 2H, ArH),
HO-PLA-OCH(CH3)2 (HO-PLA-O'Pr): d 1 .55 (m, 3H, CHCH3), 5.14 (m, 1 H, CH CH3) (c) ending groups: 1 .23 (dd, 6H), 3.72 (m, 1 H)
EXAMPLE II - shows first of all the possibility of creating both [Me2GaOCH(CH3)CQ2CH3l2 and [MezGaOCH2CH2NHCH3l2 catalytic centres, in accordance with Scheme 2 shown above in Me2GaOCH(CH3)CQ2CH3lz/ROH catalytic system, wherein ROH = HOCHzCHzNHCH3). This is indicated by formation of chains HO-PLA-OCH(CH3)C02CH3 (observed in MALDI-TOF as HO-PLA-OCH(CH3)C02CH3/K+ (·)) and HO-PLA-OCH2CH2NHCH3 (observed in MALDI-TOF as HO-PLA-OCH2CH2NHCH3/K+ (■)) both at 40°C and at 70°C. In addition, creation of [Me2GaOCH(CH3)C02CH3]2 and [Me2GaOCH2CH2NHCH3]2 catalytic centres having similar activities confirms the presence of PLA chains having similar average molecular weights ( n) and low polydispersity (demonstrated as a result of PLA analysis with the use of gel permeation chromatography - GPC (Table 1 )).
Table 1
Figure imgf000014_0001
a - in toluene, b - in CH2CI2, 0 - based on gel permeation chromatography (GPC) with calibration performed with polystyrene as a standard , d - based on H NMR methine protons of PLA after decoupling, based on J. Am. Chem. Soc. 2001 , 123, 3229. e - based on 3C NMR PLA (Macromolecules 1995, 28, 3937), PDI values were determined on the basis of GPC. EXAMPLE III - shows first of all the possibility of synthesis of PLA-(BAD) - PLA-(A), PLA-(B) conjugates in the ring-opening polymerisation CROP) of rac-LA with the use of [Me2Ga(A)l2_and [Mezln(A)l2, and [MezGa(B)l2_complexes, accordingly, as catalysts. In the case of [Me2Ga(B)]2, formation of [Me2Ga(B)]2 conjugates was demonstrated with the use of MALDI-TOF spectroscopy (observed as HO-PLA-OCH2CH2NH'Pr/K+ (HO-PLA-B/K+).
Table 2
Figure imgf000015_0001
a - in toluene, b - in CH2CI2, 0 - based on gel permeation chromatography (GPC) with calibration performed with polystyrene as a standard, d - based on H NMR methine protons of PLA after decoupling, based on J. Am. Chem. Soc. 2001 , 123, 3229. e - based on 3C NMR PLA (Macromolecules 1995, 28, 3937), PDI values were determined on the basis of GPC.
EXAMPLE IV - shows first of all the possibility of synthesis of PLA-(BAD) - PLA-(A). PLA-(B). PLA-(D) conjugates in immortal ring-opening polymerisation (iROP) of rac-LA with the use of Me2GaOR/H(BAD) and MezlnO/Ar/H(BAD) catalytic systems. Formation of HO-PLA-(A), HO-PLA-(B), HO-PLA-(D) conjugates was confirmed with the use of MALDI-TOF spectroscopy (visible in the spectrum as HO-PLA- (A)/K+, HO-PLA-(B)/K+, HO-PLA-(D)/K+. MALDI-TOF spectra: PIV-1 , PIV-2 - two almost overlapping distributions were indicated, corresponding to HO-PLA-OCH2CH2NH'Pr/K+ (HO-PLA-(B)) (·) and HO- PLA-OCH(CH3)C02CH3/K+ (■); PIV-3 - the main distribution corresponds to HO-PLA-OCH2CH2NH'Pr/K+ (HO-PLA-(B)/K+) (·), formation of HO-PLA-(p-OC6H4OMe)/K+ (■) is limited by very poor activity of [Me2Ga(p-OC6H4OMe)]2 in the polymerisation of lactide, but cannot be excluded under polymerisation conditions; PIV-4 - the indicated distributions correspond to HO-PLA-OCH(CH2C6H5)CH2NH'Pr/K+ (HO- PLA-(A)/K+) (·) and HO-PLA-OCH(CH2C6H5)CH2NH'Pr/H+ (HO-PLA-(A)/H+) (■), the dotted line indicates the distribution corresponding to HO-PLA-OCH(CH2C6H5)CH2NH'Pr/K+ (HO-PLA-(A)/K+) (·) formed a result of intermolecular transesterification reactions; PIV-5 - the indicated distribution corresponds to HO- PLA-OCH(CH2C6H4CH2C(0)NH2)CH2NH'Pr/K+ (HO-PLA-(D)/K+) (·), the dotted line indicates the distribution corresponding to HO-PLA-OCH(CH2C6H4CH2C(0)NH2)CH2NH'Pr/K+ (HO-PLA-(D)/K+) (·) formed a result of intermolecular transesterification reactions; PIV-6 - the figure shows two almost overlapping distributions corresponding to HO-PLA-OCH2CH2NH'Pr/K+ (HO-PLA-(B)/K+) (·) and HO-PLA- OCH(CH3)C02CH3/K+ (■), the dotted line indicates the distribution corresponding to HO-PLA- OCH2CH2NH'Pr/K+ (HO-PLA-(B)) (·) and HO-PLA-OCH(CH3)C02CH3/K+ (■) formed a result of intermolecular transesterification reactions; PIV-7, PIV-8 - the main distribution corresponds to HO-PLA- OCH2CH2NH'Pr/K+ (HO-PLA-(B)/K+) (·)
Table 3
Figure imgf000016_0001
a - in toluene, b - in CH2CI2, 0 - based on gel permeation chromatography (GPC) with calibration performed with polystyrene as a standard, d - based on H NMR methine protons of PLA after decoupling, based on J. Am. Chem. Soc. 2001 , 123, 3229. e - based on 3C NMR PLA (Macromolecules 1995, 28, 3937), PDI values were determined on the basis of GPC.
EXAMPLE V - shows first of all the possibility of stereoselective synthesis of PLA-(BAD) - PLA-(A), PLA- (B) coniugates in the ring-opening polymerisation CROP) of rac-LA with the use of [MezGa(A)l2_and [Mezln(A)l2, and [Me2Ga(B)lz complexes, accordingly, against Lewis bases, as catalysts. Formation of conjugates HO-PLA-OCH2CH2NH'Pr/K+ (HO-PLA-(B)/K+) (·) was confirmed with the use of MALDI-TOF spectroscopy both for the heteroselective polymerisation of rac-LA in the presence of pyridine, and for the isoselective polymerisation in the presence of DBU (PV-3)
Table 4
Figure imgf000016_0002
Catalyst LA/M Temp. Time Conversion Mn*10"3 PDI Pr
(°C) ( ) (%) (Da)c
PV-2a [Me2GaOCH2CH2NH'Pr]2/DMAP 50 40 120 95 11 .0 1 .15 0.84" (dimethylamino pyridine) (1 :6) 0.88e
PV-3° [Me2GaOCH2CH2NH'Pr]2/DBU (1 :2) 50 -20°C 18 94 7.30 1 .38 0.22a
0.22e
PV-4° [Me2Ga(A)]2/pyridine (1 :6) 50 40 96 81 8.01 1 .42 0.56a
0.62d
PV-5a [Me2Ga(A)]2/DMAP (1 :6) 50 40 96 93 6.51 1 .77 0.82"
0.85d
PV-6 ° [Me2ln(A)]2/pyridine (1 :6) 50 40 96 96 6.72 2.80 0.62a
0.62e a - in toluene, b - in CH2CI2, 0 - based on gel permeation chromatography (GPC) with calibration performed with polystyrene as a standard, d - based on H NMR methine protons of PLA after decoupling, based on J. Am. Chem. Soc. 2001 , 123, 3229. e - based on 3C NMR PLA (Macromolecules 1995, 28, 3937), PDI values were determined on the basis of GPC. DBU = (1,8-diazabicyclo[5.4.0]undec-7-ene)
EXAMPLE VI - shows first of all the possibility of stereoselective synthesis of PLA-(BAD) - PLA-(A), PLA- (B), PLA-(C), PLA-(D) coniugates in immortal ring-opening polymerisation (iROP) of rac-LA with the use of Me2GaOR/H(BAD) catalytic systems. Formation of conjugates HO-PLA-OCH2CH2NH'Pr (HO-PLA-B), HO-PLA-OCH2CH2NHMe (HO-PLA-C) and HO-PLA-OCH(CH2C6H5)CH2NH'Pr (HO-PLA-C) was shown with the use of MALDI-TOF spectroscopy. MALDI-TOF: PVI-1 , PVI-2 - in the figure, two almost overlapping distributions are indicated corresponding to HO-PLA-OCH2CH2NH'Pr/K+ (HO-PLA-B/K+) (·) and HO-PLA-OCH(CH3)C02CH3/K+ (■); PVI-3 - the indicated distributions correspond to HO-PLA- OCH2CH2NHMe/K+ (HO-PLA-C/K+) (■) and HO-PLA-OCH(CH3)C02CH3/K+ (·); PVI-4 - the indicated distributions correspond HO-PLA-OCH(CH2C6H5)CH2NH'Pr/K+ (HO-PLA-A/K+) (·) and HO-PLA- OCH(CH2C6H5)CH2NH'Pr/H+ (HO-PLA-A/H+) (■). The dotted line indicates the distribution corresponding to HO-PLA-OCH(CH2C6H5)CH2NH'Pr/K+ (HO-PLA-A/K+) (·) formed a result of intermolecular transesterification reactions.
Table 5
Figure imgf000017_0001
Catalyst LA/M Temp. Time Conversion Mn*10"3 PDI Pr
(°C) ( ) (%) (Da)c
PVI-3a [Me2GaOCH(Me)COOMe]2/ 25 40 168 88 2.58 1 .33 0.65e HOCH2CH2NHMe/pyridine (1 :2:2)
PVI-4a [Me2Ga(p-OC6H4OMe)]2/H(A) 25 40 240 93 4.08 1 .46 0.61 a /pyridine (1 :2:6) 0.68e
PVI-5a [Me2Ga(p-OC6H4OMe)]2/ 25 40 144 85 3.15 1 .53 0.70a
HOCH2CH2NH'Pr/4-methylpyridine 0.75e
(1 :2:6)
PVI-6a [Me2Ga(p-OC6H4OMe)]2/ 25 40 144 92 3.55 1 .46 0.83" HOCH2CH2NH'Pr/4-methylpyridine 0.87e (1 :2:60)
PVI-7a [Me2Ga(p-OC6H4OMe)]2/ 25 40 144 96 3.89 1 .43 0.78a HOCH2CH2NH'Pr/pyridine (1 :2:60) 0.85e
PVI-8a 1) [Me2Ga(p-OC6H4OMe)]2/H(D) 1) 20 1) 70 1) 24 87 19.23 1 .67 0.67" (1 :2) 0.71 e
2) [Me2Ga(p-OC6H4OMe)]2/ 2) 80 2) 40 2) 288
H(D)/DMAP (1 :2:6) a - in toluene, b - in CH2CI2, 0 - based on gel permeation chromatography (GPC) with calibration performed with polystyrene as a standard, d - based on H NMR methine protons of PLA after decoupling, based on J. Am. Chem. Soc. 2001 , 123, 3229. e - based on 3C NMR PLA (Macromolecules 1995, 28, 3937), PDI values were determined on the basis of GPC.
EXAMPLE VII - shows first of all the possibility of synthesis of PLA in immortal ring-opening polymerisation (iROP) of rac-LA with the use of Me?GaOR/ROH and Me2GaO/Ar/ROH (OAr - aryloxy group) catalytic systems. Formation of HO-PLA-O'Pr and HO-PLA-OCH(CH3)C02CH3 was confirmed with the use of MALDI-TOF spectroscopy (observed as HO-PLA-0'Pr/K+ (·) and HO-PLA- OCH(CH3)C02CH3/K+ (■)) - PVII-1 , PVII-2, PVII-3.
Table 6
Figure imgf000018_0001
catalyst LA/M Temp. Time Conversion Mn*10"3 PDI Pr
(°C) ( ) (%) (Da)c
PVII-3a [Me2GaOCH(Me)COOMe]2/ 'PrOH 25 40 168 76 2.28 1 .20 0.50" (1 :2) 0.50e
PVII-4a [Me2GaOCH(Me)COOMe]2/ 'PrOH 200 70 60 95 16.6 1 .38 0.50a (1 :2)
PVII-5a [Me2GaOCH(Me)COOMe]2/ 'PrOH 500 70 120 99 7.03 1 .62 0.50a (1 :20)
PVII-6a [Me2Ga(p-OC6H4OMe)]2/'PrOH (1 :2) 50 70 24 73 7.2 1 .21 0.51 "
PVII-7a [Me2Ga(p-OC6H4OMe)]2/'PrOH (1 :2) 100 70 48 92 14.2 1 .37 0.54a
PVII-8a [Me2Ga(p-OC6H4OMe)]2/ PrOH (1 :6) 150 70 144 98 8.20 1 .66 0.50a
PVII-9a [Me2Ga(p-OC6H4OMe)]2/ PrOH 500 70 144 99 9.28 1 .50 0.51 " (1 :20) 0.53e a - in toluene, b - in CH2CI2, 0 - based on gel permeation chromatography (GPC) with calibration performed with polystyrene as a standard, d - based on H NMR methine protons of PLA after decoupling, based on J. Am. Chem. Soc. 2001 , 123, 3229. e - based on 3C NMR PLA (Macromolecules 1995, 28, 3937), PDI values were determined on the basis of GPC.

Claims

Claims
1. Complexes having general formula I:
[R R2MX]n (ROH)m (L)k
I
wherein:
R and R2 are the same or different and independently represent a hydrogen atom, CrC 2 alkyl, C2-C 2 alkenyl, C2-C 2 alkynyl, C3-C 2 cycloalkyl, C3-C 2 cycloalkenyl, C3-C 2 cycloalkynyl, C5-C20 arylor C5-C20 heteroaryl, wherein each substituent R and R2 may be independently substituted with at least a substituent selected from the group consisting of a halogen atom, C C 2 alkyl, C2-C 2 alkenyl, C2-C12 alkynyl, -OR3,-SR3, -S(0)xR3, -S02NR3R4, -S(0)2OR3, -N02, -NO, -SCN, -NR3R4, -N(R3)OR4, -N(R3)NR3R4, -CN, -C(0)R3, -OC(0)R3, -0(CR3R4)yR5, -NR3C(0)R4, -(CR3R4)yC(0)OR5, -(CR3R4)yOR5, -C(=NR3)NR4R5, -NR3C(0)NR4R5, -NR3S(0)zR4, -NC(=0)R3C(=0)R4, -NR3P(=0)R4R5, -NR3As(=0)R4R5, -PR3R4, -POR3R4, -PR3OR4, -P(=0)R3R4, -P(=0)OR3R4, -P(=0)OR3OR4, -AsR3R4, -AsOR3R4, -AsOR3OR4, -As(=0)R3R4, -As(=0)OR3R4, -As(=0)OR3OR4, -NR3-C(=NR4)NR5R6, -C(=0)R3, -C(=0)OR3, -C(=S)OR3, -C(=0)SR3, -C(=S)SR3, -C(=S)NR3R4, -SiR3R4R5, -SiOR3R4R5, -SiOR3OR4R5, -SiOR3OR4OR5, -(CR3R4)y(3-12 membered heterocycle), -(CR3R4)y(C3-C12 cycloalkyl), (CR3R4)y(C5-C20 aryl), -(CR3R4)y(5-12 membered heteroaryl), -(CR3R4)yC(0)NR5R6, or -(CR4R5)yC(0)R6;
each x represents independently 0, 1 or 2;
each y represents independently 0, 1 , 2, 3 or 4;
each z represents independently 1 or 2;
each substituent R3, R4, R5, R6 represents independently a hydrogen atom, a halogen atom, C C 2 alkyl, C2-C 2 alkenyl, C2-C 2 alkynyl, C3-C 2 cycloalkyl, C5-C20 aryl, 5-12 membered heteroaryl;
X represents an atom containing a free pair of electrons or a group containing a free pair of electrons on an atom bound to atom M;
M represents a gallium atom or an indium atom;
ROH represents any organic compound containing a hydroxyl group,
L represents a neutral ligand with base properties,
n represents any natural number greater than or equal to 1 ,
m represents any number greater than or equal to 0,
k represents any number of coordinated molecules of a neutral ligand L to one coordination centre, meeting the condition 0 < k < 4;
with exclusion of monomeric complexes R R2GaOR(L), wherein R and R2 represent alkyl substituents, OR represents an alkoxy group, and L represents a neutral ligand exhibiting Lewis base properties, including N-heterocyclic carbenes.
2. The complexes according to claim 1 , characterised in that m represents 0, and X represents -O- biologically active compound.
3. The complexes according to claim 2, characterised in that the -O-biologically active compound represents -O-pharmaceutically active compound.
4. The complexes according to claim 3, characterised in that the -O-pharmaceutically active compound represents -O-beta-adrenolytic drug.
5. The complexes according to claim 1 , characterised in that m is larger than 0, and ROH represents HO-biologically active compound.
6. The complexes according to claim 5, characterised in that m is larger than or equal to 1 .
7. The complexes according to claim 5 or 6, characterised in that the HO-biologically active compound represents HO-pharmaceutically active compound.
8. The complexes according to claim 7, characterised in that the HO-pharmaceutically active compound represents HO-beta-adrenolytic drug.
9. The complexes according to claim 1 , characterised in that M represents a gallium atom, n represents 2, and m represents any number greater than 0.
10. The complexes according to claim 9, characterised in that m is larger than or equal to 1 .
11. The complexes according to one of the preceding claims, characterised in that M represents Ga, ROH represents a primary or secondary, or tertiary alcohol.
12. The complexes according to one of the preceding claims, characterised in that X represents -OR7 group, -SR7 group, NR7R7 group or PR7 group,
wherein R7 and R7 independently represent a hydrogen atom, C C 2 alkyl, C2-C 2 alkenyl, C2-C 2 alkynyl, C3-C 2 cycloalkyl, C3-C 2 cycloalkenyl, C3-C 2 cycloalkynyl, C5-C20 aryl, 3-12 membered heterocycle, 5-12 membered heteroaryl, -R8(C=0)OR9, or -R8(C=0)R8 group, wherein R8 group represents C C 2 alkylene, C2-C 2 alkenylene, C2-C 2 alkynylene, and R9 group represents hydrogen, C C 2 alkyl, C3-C 2 cycloalkyl, C2-C 2 alkene, C3-C 2 cycloalkene, C2-C 2 alkyne, C3-C 2 cycloalkyne, CrC 2 alkoxy, C5-C20 aryl, C5-C20 heteroaryl, 3-12 membered heterocycle, wherein each substituent
R7, R7 , R8 and R9 may be substituted with at least one substituent R 0, wherein each substituent R 0 represents independently a halogen atom, C C 2 alkyl, C2-C 2 alkenyl, C2-C 2 alkynyl, -OR11 , SR11 , -S(0)qR11 , S02NR 2R13, S(0)2OR11 , -N02, -NO, -SCN, -NR R12, -N(R )OR12, -N(R )NR 2R13, -CN, -C(0)R11 , -OC(0)R11 , -0(CR R 2)rR13, -NR C(0)R12, -(CR R 2)nC(0)OR13, -(CR R 2)rOR13, -C(=NR )NR 2R13, -NR C(0)NR 2R13, -NR S(0)sR12, -NC(=0)R C(=0)R12, -NR P(=0)R 2R13, -NR As(=0)R 2R13, -PR R12, -POR R12, -PR OR12, -P(=0)R R12, -P(=0)OR R12, -P(=0)OR OR12, -AsR R12, -AsOR R12, -AsOR OR12, -As(=0)R R12, -As(=0)OR R12, -As(=0)OR OR12, -NR -C(=NR2)NR3R14, -C(=0)R11, -C(=0)OR12, -C(=S)OR11, -C(=0)SR11, -C(=S)SR11, -C(=S)NR R12, -SiR R2R13, -SiOR R 2R13, -SiOR OR2R13, -SiOR OR2OR13, -(CR R2)r(3-12 membered heterocycle), -(CR R2)r(C3-C12 cycloalkyl), -(CR R2)r(C5-C20 aryl), -(CR R2)r(5-12 membered heteroaryl), -(CR R2)rC(0)NR 3R14, or -(CR R2)rC(0)R13;
each q represents independently 0, 1 or 2;
each r represents independently 0, 1 , 2, 3 or 4;
each s represents independently 1 or 2;
each substituent R11, R2, R3, R4 represents independently a hydrogen atom, a halogen atom, CrC 2 alkyl, C2-C 2 alkenyl, C2-C 2 alkynyl, C3-C 2 cycloalkyl, C5-C20 aryl, 5-12 membered heteroaryl.
13. The use of the complexes defined in any of claims 1-12 for preparing polylactide-pharmaceutically active compound conjugates.
14. A method of preparing polylactide-pharmaceutically active compound conjugates characterised in that the lactide is polymerised against a complex of general formula I, wherein n = 2, X represents -O-pharmaceutically active compound and/or ROH represents HO-pharmaceutically active compound, at a temperature in the range of 0 to 150°C, preferably in solution at a temperature in the range of 40 to 100°C.
15. The use of the complexes defined in any of claims 9-12 as catalysts for immortal ring-opening polymerisation of heterocyclic monomers.
16. The use according to claim 15, characterised in that the heterocyclic monomers contain an oxygen atom as the heteroatom.
17. The use according to claim 16, characterised in that the heterocyclic monomers are lactones.
18. The use according to claim 17, characterised in that the complexes are used for stereoselective polymerisation of lactide.
19. The use according to claim 18, characterised in that the complexes are used for stereoselective polymerisation of racemic lactide.
PCT/IB2018/050402 2017-01-23 2018-01-23 Dialkyl complexes of gallium and indium and their use for preparation of polylactide-pharmaceutically active compound conjugates and for immortal ring-opening polymerization of heteroc clic monomers WO2018134800A1 (en)

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