PHARMACEUTICAL AGENT FOR IRON CHELATING

Abstract

The invention relates to a pharmaceutical agent for the complexation of iron. The pharmaceutical agent includes an initiator group, a polymer and a terminal group R.sup.7, and has the structure: initiator group-polymer-R.sup.7. The pharmaceutical agent further includes one or more functional hydroxamic acid groups of the type (CO)NHOH or (CO)NCH.sub.3OH.

Claims

1. A process for preparing a pharmaceutical for physiological iron chelation, comprising the steps of (a) providing an initiator selected from the group comprising alcohols; compounds containing a protected hydroxamic acid group selected from ##STR00047## and lithium organyls and free-radical initiators; (b) providing at least one monomer selected from the group comprising epoxides selected from ##STR00048## or acrylics selected from ##STR00049## or styrenes selected from ##STR00050## where the initiator and/or one of the monomers contains a protected hydroxarnic acid group or at least one monomer is an epoxide including the epoxide ##STR00051## R.sup.1 is selected from aliphatic groups having a formula (CH.sub.2).sub.p with p=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; alkoxide groups; aliphatic ether groups having a formula (CH.sub.2).sub.qO(CH.sub.2).sub.s with q=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and s=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; oligoethylene glycol groups having the formula (CH.sub.2CH.sub.2O).sub.t with t=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; aromatic groups; and derivatives of the above groups; R.sup.3 is a protecting group selected from the group comprising aliphatics C.sub.kH.sub.2k+1 with k=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, vinyl, allyl, phenyl, benzyl and silyls; R.sup.4 is a protecting group selected from the group comprising aliphatics C.sub.mH.sub.2m+1 with m=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, vinyl, allyl, phenyl, benzyl and silyls; R.sup.5 is selected from the group comprising (CH.sub.2); acetonides; cyclohexanone radicals; and sodium tetraborate radical (B.sub.4O.sub.7); R.sup.6 is selected from H and CH.sub.3; (c) mixing one or more of the monomers provided in step (b) with the initiator in a defined molar ratio to form a reaction mixture; and (d) polymerizing the reaction mixture.

2. The process as claimed in claim 1, wherein the process further comprises adding, in a subsequent step (e), a further monomer listed in step (b) to the reaction mixture and continuing the polymerization.

3. The process as claimed in claim 2, wherein the process further comprises executing step (e) repeatedly.

4. The process as claimed in claim 2 wherein the process further comprises terminating the polymerizing step by consuming the at least one monomer or by addition of a terminator.

5. The process as claimed in claim 4, wherein the polymerization is ended by adding a terminator selected from the group comprising protic reagents; alcohols; alkyl halides; active esters; or activated carbonyl compounds.

6. The process as claimed in claim 4, wherein the at least one hydroxamic acid group is deprotected.

7. The process as claimed in claim 6, wherein the at least one hydroxamic acid group is deprotected by adding a deprotecting agent selected from the group comprising aqueous and nonaqueous solutions of inorganic acids; aqueous and nonaqueous solutions of organic acids; or by using acidic ion exchangers.

8. The process as claimed in claim 4, wherein said process further comprises including, in step (c) or (e), one or more of the epoxides listed in step (b) including the epoxide ##STR00052## and, after terminating the polymerization, adding a hydroxamic acid-functionalized compound having the formula ##STR00053## and conjugating the hydroxamic acid-functionalized compound with the furan groups of the polymer.

9. A pharmaceutical prepared by a process as claimed in claim 6.

10. A pharmaceutical comprising an initiator group, a polymer and an end group R.sup.7 and having an initiator group-polymer-R.sup.7 structure, which further comprises one or more functional hydroxamic acid groups having a formula (CO)NHOH or (CO)NCH.sub.3OH type, wherein the initiator group is selected from the group comprising alkoxide groups; hydroxamic acid-functionalized groups of the formula R.sup.1(CO)NHOH or R.sup.3(CO)NCH.sub.3OH; and residues of a lithium organyl or free-radical initiator; and the polymer consists of units selected from the group comprising ##STR00054## or the polymer consists of acrylic units selected from the group comprising ##STR00055## or the polymer consists of styrene units selected from the group comprising ##STR00056## where R.sup.1 is selected from aliphatic groups having a formula (CH.sub.2).sub.p with p=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; alkoxide groups; aliphatic ether groups having a formula (CH.sub.2).sub.qO(CH.sub.2).sub.s with q=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and s=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; oligoethylene glycol groups having a formula (CH.sub.2CH.sub.2O).sub.t type with t=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; aromatic groups; and derivatives of the above groups; R.sup.2 is selected from H and CH.sub.3; R.sup.6 is selected from H and CH.sub.3; R.sup.7 is selected from the group comprising H; CH.sub.3; (CH.sub.2).sub.uCH.sub.3 with u=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; esters; allyl radicals; propargyl radicals; and alcohol radicals.

11. The pharmaceutical as claimed in claim 10, wherein R.sup.1 is a pentanol group O(CH.sub.2).sub.5 or a phenol group O(C.sub.6H.sub.4).

12. The pharmaceutical as claimed in claim 10, wherein the pharmaceutical has a structure of either OHNH(CO)R.sup.1-polymer-R.sup.7 or OHNCH.sub.3(CO)R.sup.1-polymer-R.sup.7, and the polymer is a polyethylene glycol (CH.sub.2CH.sub.2O).sub.n with 3n100.

13. The pharmaceutical as claimed in claim 10 to 12, wherein the pharmaceutical has a polydispersity M.sub.w/M.sub.n2.

14. The pharmaceutical as claimed in claim 13, wherein the pharmaceutical has a polydispersity M.sub.w/M.sub.n1.6.

15. The pharmaceutical as claimed in claim 10, wherein the pharmaceutical has a molar mass MW, with 600 g.Math.mol.sup.1MW40 000 g.Math.mol.sup.1.

16. The pharmaceutical as claimed in claim 15, wherein the pharmaceutical has a molar mass MW of 800 g.Math.mol.sup.1M40 000 g.Math.mol.sup.1.

17. The process as claimed in claim 1, wherein (i) the alcohols are selected from HOCH.sub.3, HOCH.sub.2CH.sub.3, HO(CHCH.sub.3)CH.sub.3, HO(CH.sub.2).sub.2CH.sub.3, HO(CH.sub.2).sub.3CH.sub.3, and HO(CH.sub.2).sub.4CH.sub.3; (ii) the lithium organyls and free-radical initiators are selected from n-butyilithium, sec-butyllithiurn, dibenzoyl peroxide, azoisobutyronitile, potassium peroxodi-sulfate, and ammonium peroxodisulfate; (iii) the R.sup.1 alkoxide group is selected from OCH.sub.2, OCH.sub.2CH.sub.2, O(CHCH.sub.3)CH.sub.2, O(CH.sub.2).sub.3, O(CH.sub.2).sub.4, and O(CH.sub.2).sub.5; and the R.sup.1 aromatic groups are phenol or naphthyl radicals; and (iii) the R.sup.3 and R.sup.4 silyls are trimethylsilyl or triisopropylsilyl; and (iv) the R.sup.5 acetonides are (C(CH.sub.3).sub.2) or (CHPh) and the cyclohexanone radicals are (C.sub.6H.sub.10).

18. The process as claimed in claim 5, wherein the protic reagent is H.sub.2O; the alcohol is methanol, ethanol or propanol; the alkyl halide is methyl iodide, ethyl bromide, allyl chloride, allyl bromide, propargyl bromide; and the activated carbonyl compound is acid chloride, acid anhydride or N-hydroxysuccinimide ester.

19. The process as claimed in claim 7, wherein the inorganic acid is hydrochloric acid or sulfuric acid; and the organic acid is para-toluenesulfonic acid or camphor-10-sulfonic acid.

20. A pharmaceutical as claimed in claim 10, wherein (i) the alkoxide group is OCH.sub.3, OCH.sub.2CH.sub.3, O(CHCH.sub.3)CH.sub.3, O(CH.sub.2).sub.2CG.sub.3, O(CH.sub.2).sub.3CH.sub.3, or O(CH.sub.2).sub.4CH.sub.3; and (ii) the residue of the lithium organyl or free-radical initiator is CH.sub.3 (CH.sub.2).sub.3, CH.sub.3CH.sub.2(CHCH.sub.3), Ph(CO)O, CNCH.sub.3CH.sub.3C, or SO.sub.2OHO; (iii) the R.sup.1 alkoxide group is OCH.sub.2, OCH.sub.2CH.sub.2, O(CHCH.sub.3)CH.sub.2, O(CH.sub.2).sub.3, O(CH.sub.2).sub.4, or O(CH.sub.2).sub.5; the R.sup.1 aromatic groups are phenol or naphthyl radicals (iv) the R.sup.7 esters are (CO)CH.sub.3 and the R.sup.7 alcohol radicals are OCH.sub.3; OCH.sub.2CH.sub.3; OCH(CH.sub.3).sub.2; or O(CH.sub.2).sub.2CH.sub.3.

21. The pharmaceutical as claimed in claim 14, wherein the pharmaceutical has a polydispersity M.sub.w/M.sub.b1.2.

22. The pharmaceutical as claimed in claim 14, wherein the pharmaceutical has a polydispersity M.sub.w/M.sub.n1.1.

23. The pharmaceutical as claimed in claim 15, wherein the pharmaceutical has a molar mass MW of 1000 g.Math.mol.sup.1MW40 000 g.Math.mol.sup.1.

Description

EXAMPLE 1: PREPARATION OF INITIATOR AND MONOMER

(i) Synthesis of N,6-dihydroxyhexanamide

[0130] A 250 mL round-bottom flask is initially charged with 17.12 g (150 mmol, 1 eq) of epsilon-caprolactone, and a prepared solution of hydroxylamine in methanol is added. To prepare the hydroxylamine solution, 11.47 g (165 mmol, 1.1 eq) of hydroxylamine hydrochloride in 60 mL of methanol are neutralized with a solution of 12.62 g (225 mmol, 1.5 eq) of KOH in 32 mL of methanol, cooled and then filtered. After stirring at room temperature for 90 minutes, the reaction solution is acidified to pH 4 with concentrated HCl, concentrated in vacuo and recrystallized from THF. The product obtained after hot filtration and crystallization at 20 C. for h is 7.99 g (54 mmol, 36% of theory) of N,6-dihydroxyhexanamide as a colorless solid.

##STR00020##

[0131] .sup.1H NMR (300 MHz, DMSO-d6): [ppm]=10.37 (s, 0.9H, h), 9.72 (s, 0.1H, h), 9.03 (s, 0.1H, i), 8.68 (s, 0.9H, i), 4.37 (s, 1H, g), 3.35 (t, J=6.4 Hz, 2H, f), 1.93 (t, J=7.5 Hz, 2H, b), 1.52-1.42 (m, 2H, c), 1.42-1.32 (m, 2H, e), 1.30-1.16 (m, 2H, d).

[0132] .sup.13C NMR (75 MHz, DMSO-d6): [ppm]=169.25 (A), 60.67 (F), 32.42 (B), 32.30 (E), 25.23 (D), 25.16 (C).

[0133] IR-ATR [cm.sup.1]=3311 m, 3205 m, 3029 m, 2932 m, 2858 m br, 1616 vs (CO), 1544 m, 1499 m, 1466 m, 1362 m, 1346 m, 1274 m, 1116 m, 1078 m, 1055 vs, 1012 vs, 977 vs, 785 m.

(ii) Synthesis of the initiator 5-(5,5-dimethyl-1,4,2-dioxazol-3-yl)pentan-1-ol

[0134] A 500 mL flask is initially charged with 4.27 g (29 mmol, 1 eq) of N,6-dihydroxyhexanamide, which were suspended with 300 mL of dry dichloromethane. Subsequently, 8.90 g (67 mmol, 2.3 eq) of 2,2-diethoxy-propane and 6.74 g (29 mmol, 1 eq) of camphor-10-sulfonic acid are added and the mixture is stirred vigorously at room temperature. As soon as no reactant is detectable any longer (30 to 90 minutes), the reaction is admixed with 70 mL of saturated sodium hydrogencarbonate solution up to a pH of 8. The organic phase is removed and washed with 20 mL of saturated sodium hydrogencarbonate solution, dried over sodium sulfate and concentrated in vacuo. After purification by column chromatography by means of silica (petroleum ether:ethyl acetate 9:1->1:1), 1.25 g (7 mmol, 23% of theory) of 5-(5,5-dimethyl-1,4,2-dioxazol-3-yl)pentan-1-ol are obtained.

##STR00021##

[0135] .sup.1H NMR (300 MHz, chloroform-d): [ppm]=3.64 (t, J=6.3 Hz, 2H, f), 2.31 (t, J=7.3 Hz, 2H, b), 1.76 (s, 1H, g), 1.69-1.56 (m, 4H, e+c), 1.55 (s, 6H, i), 1.50-1.39 (m, 2H, d).

[0136] .sup.13C NMR (75 MHz, chloroform-d): [ppm]=160.39 (A), 114.53 (H), 62.65 (F), 32.26 (E), 25.22 (D), 25.18 (C), 24.91 (I), 23.95 (B).

(iii) Synthesis of the monomer 5,5-dimethyl-3-(5-(oxiran-2-ylmethoxy)pentyl)-1,4,2-dioxazole

[0137] A 25 mL flask is initially charged with 210 mg (0.65 mmol, 0.1 eq) of tetrabutylammonium bromide, 1.217 g (6.5 mmol, 1 eq) of 5-(5,5-dimethyl-1,4,2-dioxazol-3-yl)pentan-1-ol and 6 mL of benzene, and 6 mL of 30% sodium hydroxide solution are added. Subsequently, 1.200 g (13.0 mmol, 2 eq) of epichlorohydrin are added gradually and the reaction mixture is stirred at room temperature for 48 h. The reaction solution is taken up in 100 mL of diethyl ether, and the organic phase is removed and washed twice with saturated sodium hydrogencarbonate solution, water and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. After purification by column chromatography by means of silica (petroleum ether:ethyl acetate 4:1), 306 mg (1.3 mmol, 19% of theory) of 5,5-dimethyl-3-(5-(oxiran-2-ylmethoxy)pentyl)-1,4,2-dioxazole are obtained.

##STR00022##

[0138] .sup.1H NMR (300 MHz, DMSO-d6): [ppm]=3.66 (dd, J=11.5, 2.7 Hz, 1H, g), 3.41 (td, J=6.4, 1.2 Hz, 2H, f), 3.21 (dd, J=11.5, 6.4 Hz, 1H, g), 3.13-3.01 (m, 1H, j), 2.71 (dd, J=5.2, 4.2 Hz, 1H, k), 2.53 (dd, J=5.2, 2.7 Hz, 1H, k), 2.29 (t, J=7.3 Hz, 2H, b), 1.61-1.42 (m, 4H, e+c), 1.49 (s, 6H, i), 1.43-1.24 (m, 2H, d).

[0139] .sup.13C NMR (75 MHz, DMSO-d6); d [ppm]=159.64 (A), 113.84 (H), 71.19 (G), 70.24 (F), 50.34 (J), 43.39 (K), 28.67 (E), 24.93 (D), 24.65 (C), 24.39 (I), 22.95 (B).

[0140] IR-ATR [cm.sup.1]=2990 w, 2936 m, 2865 w, 1641 m (CN), 1456 w, 1374 s, 1340 w, 1217 vs (CO), 1153 m, 1110 vs, 1000 vs, 910 m, 850 m, 814 m, 760 m

[0141] Rf (EA:PE=1:1)=0.63

[0142] ESI-MS=244.1 (M+H, 100%), 260.2 (M+Na, 73%), 282.1 (M+K, 24%), 509.3 (2M+Na, 52%).

EXAMPLE 2: SYNTHESIS OF ALPHA-1,4,2-DIOXAZOLE-FUNCTIONAL POLYETHYLENE GLYCOL

(i) Polymerization of Polyethylene Glycol with alpha-1,4,2-dioxazole

[0143] A dried flask is initially charged with the initiator 5-(5,5-dimethyl-1,4,2-dioxazol-3-yl)pentan-1-ol and stirred with 0.9 eq of cesium hydroxide monohydrate and 5 mL of benzene under static vacuum for 60 minutes. Subsequently, the initiator salt is dried under high vacuum overnight and, the next day, dissolved in 10 mL of dry THF. Subsequently, ethylene oxide is cryotransferred into the reaction vessel and the reaction solution is stirred at 40-60 C. for 24 to 48 hours. After termination by addition of 1 mL of methanol, any solvent is removed in vacuo and the polymer is obtained by precipitation in ice-cold diethyl ether.

(ii) Detachment of the Protecting Group and Deprotection of the Hydroxamic Acid

[0144] The alpha-1,4,2-dioxazole-functional polyethylene glycol is mixed with the same amount of DOWES 50WX8 ion exchange resin in isopropanol and agitated for 20 h. Subsequently, the solution is filtered, the filtrate is concentrated in vacuo and the hydroxamic acid-functional polyethylene glycol is obtained by precipitation in ice-cold diethyl ether.

EXAMPLE 3: DETECTION AND QUANTIFICATION OF COMPLEXATION

[0145] The colorless hydroxamic acids form highly colored complexes with metals. It is usually trishydroxamatometal complexes that

##STR00023##

are formed.

[0146] (HA=hydroxamic acid)

[0147] In the case of iron(III), the result is an octahedral deep blue complex having an absorption maximum around 540 nm. By titration of a polymer solution with an iron(III) solution of known concentration, it is possible to photometrically monitor and quantify the formation of the complex. Formation of the mono complex is followed by the formation of the bis- and then of the trishydroxamatoiron(III) complex with constantly increasing absorption until occurrence of an asymptotic progression on total binding of the hydroxamic acids to the iron(III) atoms. FIG. 1 shows the absorption as a function of the concentration ratio of Fe.sup.3+ to the alpha-1,4,2-dioxazole-functional polyethylene glycol, which is identified in the diagram of FIG. 1 by HA for hydroxamic acid.

EXAMPLE 4: STYRENE MONOMER WITH PROTECTED HYDROXAMIC ACID

1st Stage N-hydroxy-p-methylbenzamide

[0148] ##STR00024##

[0149] 24.00 g (0.16 mol, 1 eq) of methyl 4-methylbenzoate and 33.32 g (0.48 mol, 3 eq) of hydroxylamine hydrochloride are dissolved in 500 mL of methanol. To this solution are added 53.86 g (0.96 mol, 6 eq) of powdered KOH in multiple portions. After 12 to 24 h, the precipitate is filtered off and washed with 200 mL of methanol, and the mother liquor is acidified to pH 4.0 with concentrated HCl. The solution is fully concentrated under reduced pressure. The residue is extracted 4 times with 150 mL each time of boiling THF, and the combined organic phase is dried over Na.sub.2SO.sub.4 and completely freed of solvents under reduced pressure. The residue is recrystallized from 250 mL of ethyl acetate. After 48 h at 20 C., 19.2 g (0.127 mol, 79% of theory) of N-hydroxy-p-methylbenzamide were obtained in the form of colorless platelets.

[0150] .sup.1H NMR (400 MHz, DMSO-d.sub.6) =10.95 (s, 1H), 9.23 (s, 1H), 7.72-7.51 (m, 2H), 7.31-7.15 (m, 2H), 2.33 (s, 3H).

2nd Stage 5,5-dimethyl-3-(p-tolyl)-1,4,2-dioxazole

[0151] ##STR00025##

[0152] 10.00 g (66.2 mmol, 1 eq) of N-hydroxy-p-methylbenz-amide are suspended in 1350 mL of dichloromethane, and 24.3 mL (20.67 g, 198.6 mmol, 3 eq) of 2,2-dimethoxy-propane (DMP) are added. Added to this suspension are 15.36 g (66.02 mmol, 1 eq) of DL-camphor-10-sulfonic acid (CSA) in one addition, and the resultant solution is stirred at room temperature for 3 hours. Subsequently, the reaction is ended by adding 200 mL of saturated NaHCO.sub.3 solution. The organic phase is removed and the aqueous phase is extracted twice with 100 mL each time of dichloromethane. The combined organic phases are washed with 100 mL of saturated NaHCO.sub.3 solution and 100 mL of saturated NaCl solution and dried over CaCl.sub.2. After the solvent had been removed under reduced pressure, 11.34 g (59.3 mmol, 90% of theory) of 5,5-dimethyl-3-(p-tolyl)-1,4,2-dioxazole were obtained as a colorless liquid, which crystallizes gradually at 20 C. to give a colorless solid.

[0153] .sup.1H NMR (400 MHz, chloroform-d) =7.69-7.64 (m, 2H), 7.25-7.18 (m, 2H), 2.39 (s, 3H), 1.67 (s, 6H).

3rd Stage 3-(4-(bromomethyl)phenyl)-5,5-dimethyl-1,4,2-dioxazole

[0154] ##STR00026##

[0155] 11.34 g (59.3 mmol, 1 eq) of 5,5-dimethyl-3-(p-tolyl)-1,4,2-dioxazole, 10.57 g (59.3 mmol, 1 eq) of N-bromosuccinimide (NBS) and 0.39 g (2.38 mmol, 0.04 eq) of azobisisobutyronitrile (AIBN) are suspended in 200 mL of dried and degassed (distilled over sodium) cyclohexane. The suspension is boiled under reflux under protective gas (argon) in an oil bath at 120 C. until the solution clarifies, and succinimide is separated out as a precipitate. Subsequently, the solution is refluxed for a further hour and cooled to room temperature. The precipitate is filtered off and washed with cyclohexane, and the organic phase is concentrated on a rotary evaporator under reduced pressure. 14.67 g (54.3 mmol, 92% of theory, 75% purity by NMR) of 3-(4-(bromomethyl)phenyl)-5,5-dimethyl-1,4,2-dioxazole were obtained as crude product, which can be converted further without further purification.

[0156] .sup.1H NMR (400 MHz, chloroform-d) =7.95-7.90 (m, 2H), 7.20-7.14 (m, 2H), 4.12 (s, 2H), 1.67 (s, 6H).

[0157] 4th Stage (4-(5,5-dimethyl-1,4,2-dioxazol-3-yl)benzyl)-triphenylphosphonium bromide

##STR00027##

[0158] 14.67 g (54.3 mmol, 1 eq) of 3-(4-(bromomethyl)-phenyl)-5,5-dimethyl-1,4,2-dioxazole are dissolved in 200 mL of dried acetone (3A molecular sieve). To this solution are added 14.24 g (54.3 mmol, 1 eq) of triphenylphosphine, and the solution is refluxed for 4 hours. Subsequently, the solution is concentrated to about of its total volume under reduced pressure, and 200 mL of diethyl ether are slowly added dropwise over a period of 2 hours. After cooling at 20 C., the precipitate is filtered off with suction, and 18.7 g (35.1 mmol, 65% of theory) of (4-(5,5-dimethyl-1,4,2-dioxazol-3-yl)benzyl)triphenylphosphonium bromide are obtained as a colorless solid.

[0159] .sup.1H NMR (300 MHz, chloroform-d) 7.82-7.72 (m, 9H), 7.68-7.58 (m, 6H), 7.53-7.47 (m, 2H), 7.24-7.18 (m, 2H), 5.62 (d, J=15.0 Hz, 2H), 1.65 (s, 6H).

5th Stage 5,5-dimethyl-3-(4-vinylphenyl)-1,4,2-dioxazole

[0160] ##STR00028##

[0161] 8.55 g (16.6 mmol, 1 eq) of (4-(5,5-dimethyl-1,4,2-dioxazol-3-yl)benzyl)triphenylphosphonium bromide are dissolved in 80 mL of aqueous formaldehyde solution (30%). Added dropwise to this solution are 5.31 g of NaOH in 24 mL of water within 20 minutes. The solution is stirred for 12 hours and extracted three times with 100 mL each time of dichloromethane. The combined organic phases are washed with 30 mL of saturated NaCl solution, dried over MgSO.sub.4 and concentrated under reduced pressure. After purification by means of column chromatography (SiO.sub.2, dichloromethane, R.sub.f=1), 940 mg (4.6 mmol, 28% of theory) of 5,5-dimethyl-3-(4-vinylphenyl)-1,4,2-dioxazole were obtained as a colorless liquid.

[0162] .sup.1H NMR (300 MHz, chloroform-d) =7.78-7.71 (m, 2H), 7.48-7.43 (m, 2H), 6.73 (dd, J=17.6, 10.9 Hz, 1H), 5.84 (dd, J=17.6, 0.7 Hz, 1H), 5.35 (dd, J=10.9, 0.7 Hz, 1H), 1.68 (s, 6H).

EXAMPLE 5: METHACRYLATE DERIVATIVE WITH PROTECTED HYDROXAMIC ACID

2-(4-(5,5-dimethyl-1,4,2-dioxazol-3-yl)phenoxy)ethyl methacrylate

[0163] ##STR00029##

[0164] In a 5 mL Schlenk flask, 237 mg (1 mmol, 1 eq) of 2-(4-(5,5-dimethyl-1,4,2-dioxazol-3-yl)phenoxy)ethan-1-ol are dissolved in 2 mL of dichloromethane, and 97 L (95 mg, 1.2 mmol, 1.2 eq) of pyridine are added. While cooling with ice, 107 L (115 mg, 1.1 mmol, 1.1 eq) of methacryloyl chloride are added and the solution is stirred at room temperature for 1 h. After the solvent has been removed under reduced pressure, the residue is purified by column chromatography (SiO.sub.2, PE/EA=4/1, Rf=0.5). 114 mg (0.37 mmol, 37% of theory) of 2-(4-(5,5-dimethyl-1,4,2-dioxazol-3-yl)phenoxy)ethyl methacrylate were obtained as a colorless liquid.

[0165] .sup.1H NMR (300 MHz, chloroform-d) =7.76-7.66 (m, 2H), 6.99-6.88 (m, 2H), 6.15-6.12 (m, 1H), 5.62-5.57 (m, 1H), 4.54-4.46 (m, 2H), 4.29-4.22 (m, 2H), 1.96-1.93 (m, 3H), 1.66 (s, 6H).

EXAMPLE 6: INITIATOR WITH PROTECTED HYDROXAMIC ACID FOR ANIONIC RING-OPENING POLYMERIZATION

1st Stage ethyl 4-(2-hydroxyethoxy)benzoate

[0166] ##STR00030##

[0167] A 250 mL flask with reflux condenser and bubble counter is initially charged with 83.09 g (0.5 mol, 1 eq) of ethyl 4-hydroxybenzoate, 46.25 g (0.525 mol, 1.05 eq) of ethylene carbonate, 7.5 g (0.05 mol, 0.1 eq) of sodium iodide, and 100 mL of diglyme are added. The solution is boiled at 140 C. for 16 hours and then refluxed for 2 hours. After cooling to room temperature, the solution is completely freed of solvents under reduced pressure and the residue is dissolved in 300 mL of ethyl acetate. The organic phase is washed with 50 mL of water, 50 mL of saturated NaHCO.sub.3 solution and 50 mL of saturated NaCl solution, dried over Na.sub.2SO.sub.4 and freed of the solvent under reduced pressure. The residue obtained is 100.2 g (0.477 mol, 95% of theory) of ethyl 4-(2-hydroxyethoxy)benzoate as a colorless solid.

[0168] .sup.1H NMR (300 MHz, chloroform-d) =7.97-7.91 (m, 2H), 6.91-6.84 (m, 2H), 4.30 (q, J=7.1 Hz, 2H), 4.10-4.05 (m, 2H), 3.98-3.90 (m, 2H), 1.34 (t, J=7.1 Hz, 3H).

2nd Stage N-hydroxy-4-(2-hydroxyethoxy)benzamide

[0169] ##STR00031##

[0170] To a solution of 20.85 g (0.3 mol, 3 eq) of hydroxylamine hydrochloride in 300 mL of methanol are added, in multiple portions, 33.60 g (0.6 mol, 6 eq) of KOH, in such a way that the temperature remains below 45 C. Subsequently, 19.62 g (0.1 mol, 1 eq) of ethyl 4-(2-hydroxyethoxy)benzoate are added and the solution is stirred at room temperature overnight. The reaction mixture is subsequently acidified to pH 4 with concentrated hydrochloric acid and concentrated to dryness under reduced pressure. The residue is subjected to hot extraction under reflux in a Soxhlet apparatus with 500 mL of THF overnight. After cooling at 20 C., the product crystallizes out in the THF solution, and is filtered off with suction and washed with a little cold THF. 19.62 g (0.093 mol, 93% of theory) of N-hydroxy-4-(2-hydroxyethoxy)benzamide were obtained as colorless platelets.

[0171] .sup.1H NMR (300 MHz, DMSO-d.sub.6) =11.06 (s, 1H), 8.90 (s, 1H), 7.74-7.68 (m, 2H), 7.01-6.96 (m, 2H), 4.89 (t, J=5.5 Hz, 1H), 4.03 (t, J=4.9 Hz, 2H), 3.72 (dt, J=5.5, 4.9 Hz, 2H)

[0172] .sup.13C NMR (75 MHz, DMSO-d.sub.6) =164.02, 160.95, 128.62, 124.82, 114.09, 67.70, 59.48.

3rd Stage 2- (4-(5,5-dimethyl-1,4,2-dioxazol-3-yl)-phenoxy) ethanol

[0173] ##STR00032##

[0174] A dried 2 L round-bottom flask that has been repeatedly evacuated and filled with inert gas is initially charged with 5.0 g (25.35 mmol, 1 eq) of AT-hydroxy-4-(2-hydroxyethoxy)benzamide in 260 mL of dichloro-methane, and 9.35 mL (7.95 g, 76.31 mmol, 3 eq) of 2,2-dimethoxypropane (DMP) are added. Subsequently, 5.92 g (25.48 mmol, 1.05 eq) of DL-camphor-10-sulfonic acid (CSA) are added in one addition and the reaction mixture is stirred at room temperature for 5 h. Subsequently, the reaction is terminated by adding 850 mL of 2 molar aqueous NaOH solution and stirred at room temperature for 48 h. The organic phase is removed and the aqueous phase is extracted with 200 mL of dichloromethane. The combined organic phases are washed twice with 150 mL each time of 2 molar aqueous NaOH solution and once with 200 mL of saturated NaCl solution and dried over MgSO.sub.4, and the solvent is removed completely under reduced pressure. The residue obtained was 2.45 g (10.33 mmol, 40% of theory) of 2-(4-(5,5-dimethyl-1,4,2-dioxazol-3-yl)phenoxy)ethanol as a colorless solid.

[0175] .sup.1H NMR (300 MHz, DMSO-d.sub.6) =7.74-7.68 (m, 2H), 6.99-6.94 (m, 2H), 4.12 (t, J=5.2 Hz, 2H), 3.98 (t, J=5.3 Hz, 2H), 1.66 (s, 6H)

[0176] .sup.13C NMR (75 MHz, DMSO-d.sub.6) =161.12, 158.21, 128.58, 116.50, 115.34, 114.71, 61.43, 24.97.

EXAMPLE 7: EPOXIDE MONOMER WITH PROTECTED HYDROXAMIC ACID GROUP

5,5-dimethyl-3-(4-(2-(oxiran-2-ylmethoxy)ethoxy)-phenyl)-1,4,2-dioxazole

[0177] ##STR00033##

[0178] A 3-neck sulfonation flask with precision glass stirrer, septum and thermometer with ground-glass joint was initially charged with 7 mL of 50% (w/w) aqueous NaOH. While cooling with ice, 146.7 mg (0.432 mmol, 0.04 eq) of tetrabutylammonium hydrogensulfate (TBAHS) and 4.3 mL (5.07 g, 54.83 mmol, 5.3 eq) of epichloro-hydrin are added. Subsequently added dropwise to this solution are 2.45 g (10.32 mmol, 1 eq) of 2-(4-(5,5-dimethyl-1,4,2-dioxazol-3-yl)phenoxy)ethanol in 10 mL of benzene within 25 minutes. After stirring at 10-15 C. overnight, the reaction mixture is added to 35 mL of ice/water mixture, and 25 mL of diethyl ether are added. The organic phase is removed and the aqueous phase is extracted twice with 50 mL each time of diethyl ether. The combined organic phases are washed with saturated NaCl solution to pH 7.0 (5 with about 100 mL of solution) and dried over Na.sub.2SO.sub.4. After the solvent has been removed under reduced pressure, the product is obtained by column chromatography purification (SiO.sub.2, EA/PE=1/5). 2.02 g (6.9 mmol, 67% of theory) of 5,5-dimethyl-3-(4-(2-(oxiran-2-yl-methoxy)ethoxy)phenyl)-1,4,2-dioxazole were obtained as a colorless liquid.

[0179] .sup.1H NMR (300 MHz, chloroform-d) =7.76-7.65 (m, 2H), 7.00-6.88 (m, 2H), 4.17 (dd, J=5.3, 4.4 Hz, 2H), 3.99-3.82 (m, 3H), 3.48 (dd, J=11.7, 6.0 Hz, 1H), 3.23-3.15 (m, 1H), 2.81 (dd, J=5.0, 4.1 Hz, 1H), 2.63 (dd, J=5.0, 2.7 Hz, 1H), 1.66 (s, 6H).

EXAMPLE 8: BENZYL ALCOHOL-BASED INITIATOR

1st Stage N-hydroxy-4-(hydroxymethyl)benzamide

[0180] ##STR00034##

Synthesis analogous to N-hydroxy-4-(2-hydroxyethoxy)-benzamide

[0181] Yield: 52% of theory.

[0182] .sup.1H NMR (400 MHz, DMSO-d.sub.6) =11.16 (s, 1H), 8.97 (s, 1H), 7.75-7.66 (m, 2H), 7.43-7.33 (m, 2H), 4.53 (s, 2H).

2nd (4-(5,5-dimethyl-1,4,2-dioxazol-3-yl)phenyl)methanol

[0183] ##STR00035##

Synthesis analogous to 2-(4-(5,5-dimethyl-1,4,2-dioxazol-3-yl)phenoxy)ethanol

[0184] Yield: 55% of theory.

[0185] .sup.1H NMR (300 MHz, chloroform-d) =7.79-7.73 (m, 2H), 7.45-7.38 (m, 2H), 4.74 (s, 2H), 1.68 (s, 6H).

EXAMPLE 9: EPOXIDE MONOMER FROM BENZYL ALCOHOL INITIATOR

5,5-dimethyl-3-(4-((oxiran-2-ylmethoxy)methyl)phenyl)-1,4,2-dioxazole

[0186] ##STR00036##

Synthesis analogous to 5,5-dimethyl-3-(4-(2-(oxiran-2-ylmethoxy)ethoxy)phenyl)-1,4,2-dioxazole

[0187] Yield: 66% of theory.

[0188] .sup.1H NMR (400 MHz, chloroform-d) =7.78-7.73 (m, 2H), 7.42-7.37 (m, 2H), 4.71-4.52 (m, 2H), 3.81 (dd, J=11.5, 2.8 Hz, 1H), 3.42 (dd, J=11.5, 5.9 Hz, 1H), 3.24-3.15 (m, 1H), 2.81 (dd, J=5.0, 4.1 Hz, 1H), 2.62 (dd, J=5.0, 2.7 Hz, 1H), 1.67 (s, 6H).

EXAMPLE 10: ANIONIC POLYMERIZATION OF 5,5-DIMETHYL-3-(4-VINYLPHENYL)-1,4,2-DIOXAZOLE

[0189] ##STR00037##

[0190] A 100 mL Schlenk flask is initially charged with 1.0 g (4.9 mmol, 10 eq) of 5,5-dimethyl-3-(4-vinylphenyl)-1,4,2-dioxazole dried azeotropically with 5 mL of benzene under high vacuum (1E-3 mbar) for 24 h. Subsequently, 10 mL of sodium-dried THF are distilled into the flask under protective gas and the solution is cooled to 78 C. by means of an acetone/dry ice bath. Initiation is effected by adding 1.0 mL (0.49 mmol, 1 eq) of a 0.5 molar diphenylmethylpotassium solution. After a reaction time of 2 h, the polymerization is terminated by adding 1 mL of methanol and freed of solvents under reduced pressure.

[0191] Mn (GPC, THF, PEG)=1280 g/mol PDI=1.4

EXAMPLE 11: ANIONIC POLYMERIZATION OF EPOXY DERIVATIVES PROCEEDING FROM PROTECTED HYDROXAMIC ACIDS AS INITIATOR

[0192] A 100 mL Schlenk flask is initially charged with 0.043 mmol (1 eq) of initiator, and provided with 0.035 mmol (0.8 eq) of potassium Cert-butoxide and 0.070 mmol (1.6 eq) of 18-crown-6. Subsequently, for deprotonation, 1 mL of THF and 4 mL of benzene are added and the solution is stirred under static vacuum (about 500 mbar) at 40 C. for 30 minutes. The solvent is removed completely under high vacuum (10.sup.3 mbar) and the initiator is dried for 24 h. Subsequently, the initiator is dissolved in 10 mL of dry THF (over sodium), provided with 23 mmol (40 eq) of dried monomer and polymerized at 40-60 C. for 24-48 h. Subsequently, the reaction is terminated by adding 1 mL of methanol, the solvents are removed under high vacuum and the polymer is purified by partitioning between dichloromethane and water. For this purpose, the residue is dissolved in dichloromethane and extracted by shaking with aqueous NaCl solution. The organic phase is removed and dried over Na.sub.2SO.sub.4 and freed completely of solvents under reduced pressure. Typical yields 80-95% of theory.

[0193] Reaction Conditions:

[0194] EO: no drying of the monomer, reaction time of 48 h at 60 C. under static vacuum (10.sup.3 mbar)

[0195] PO: drying of the monomer over 3 A molecular sieve for 30 minutes, polymerization without solvent at 40 C. for 24 h under an argon atmosphere (1 atm).

EXAMPLE 12: (4-(5,5-DIMETHYL-1,4,2-DIOXAZOL-3-YL)-PHENYL)METHANOL-INITIATED POLYPROPYLENE OXIDE

[0196] ##STR00038##

[0197] Batch: 1 eq of initiator, 20 eq of propylene oxide

[0198] .sup.1H NMR (300 MHz, chloroform-d) =7.78-7.70 (m, 2H), 7.42-7.34 (m, 2H), 4.58 (s, 2H), 3.72-3.28 (m, 66H), 1.67 (s, 6H), 1.23-0.99 (m, 66H).

[0199] Mn (GPC, DMF, PEG)=1310 g/mol PDI=1.07

EXAMPLE 13: 2-(4-(5,5-DIMETHYL-1,4,2-DIOXAZOL-3-YL)-PHENOXY)ETHANOL-INITIATED POLYPROPYLENE OXIDE

[0200] ##STR00039##

[0201] Batch: 1 eq of initiator, 20 eq of propylene oxide

[0202] .sup.1H NMR (300 MHz, chloroform-d) =7.74-7.65 (m, 2H), 6.98-6.89 (m, 2H), 4.19-4.11 (m, 2H), 3.89-3.78 (m, 2H), 3.78-3.24 (m, 63H), 1.66 (s, 6H), 1.17-1.09 (m, 63H).

[0203] Mn (GPC, DMF, PEG)=1340 g/mol PDI=1.06

EXAMPLE 14: (4-(5,5-DIMETHYL-1,4,2-DIOXAZOL-3-YL)-PHENYL)METHANOL-INITIATED POLYETHYLENE GLYCOL

[0204] ##STR00040##

[0205] Batch: 1 eq of initiator, 50 eq of ethylene oxide .sup.1H NMR (300 MHz, chloroform-d) =7.84-7.71 (m, 2H), 7.47-7.37 (m, 2H), 4.62 (s, 2H), 3.82-3.52 (m, 203H), 1.70 (s, 6H).

[0206] Mn (GPC, DMF, PEG)=1340 g/mol PDI=1.06

EXAMPLE 15: 2-(4-(5,5-DIMETHYL-1,4,2-DIOXAZOL-3-YL)-PHENOXY)ETHANOL-INITIATED POLYETHYLENE GLYCOL

[0207] ##STR00041##

[0208] Batch: 1 eq of initiator, 50 eq of ethylene oxide

[0209] .sup.1H NMR (300 MHz, chloroform-d) =7.72-7.65 (m, 2H), 6.97-6.88 (m, 2H), 4.19-4.11 (m, 2H), 3.91-3.81 (m, 3H), 3.75-3.54 (m, 284H), 1.66 (s, 6H).

[0210] Mn (GPC, DMF, PEG)=2050 g/mol PDI=1.07

EXAMPLE 16: ANIONIC COPOLYMERIZATION OF EPOXY DERIVATIVES WITH EPOXIDE MONOMERS HAVING A PROTECTED HYDROXAMIC ACID GROUP

[0211] A 100 mL Schlenk flask is initially charged with 39.75 mg (0.165 mmol, 1 eq) of N,N-dibenzylaminoethanol (or benzyloxyethanol), 14.8 mg (0.14 mmol, 0.8 eq) of potassium tert-butoxide and 71.1 mg (0.269 mmol, 1.6 eq) of 18-crown-6, 1 mL of THF and 4 mL of benzene are added and the mixture is stirred under static vacuum (about 500 mbar) at 40 C. for 30 minutes. Subsequently, the initiator is freed of solvents without residue under high vacuum (10.sup.3 mbar) and dried at 40 C. for 24 h. 10 mL of THF (dried over Na) are distilled into the flask and the dried monomers are added. After a reaction time of 48 h at 40-60 C., the polymerization is terminated by adding 1 mL of methanol and the solvent is removed without residue. The residue is taken up in dichloromethane and washed repeatedly with saturated sodium chloride solution. The organic phase is dried over Na.sub.2SO.sub.4, filtered and then freed of the solvent without residue under reduced pressure. The residue obtained is the polymer with typical yields of 80-95% of theory.

EXAMPLE 17: RANDOM COPOLYMER OF PROPYLENE OXIDE AND 5,5-DIMETHYL-3-(4-((OXIRAN-2-YLMETHOXY)METHYL)PHENYL)-1,4,2-DIOXAZOLE

[0212] ##STR00042##

[0213] Conditions: initiator 1 eq (benzyloxyethanol), comonomer dried azeotropically using benzene under high vacuum (10.sup.3 mbar) for h, PO dried over 3 A molecular sieve (30 minutes, RT), polymerization under argon atmosphere for 24 h.

[0214] .sup.1H NMR (300 MHz, chloroform-d) =7.78-7.65 (m, 6H), 7.42-7.26 (m, 11H), 4.60-4.45 (m, 8H), 3.65-3.40 (m, 43H), 1.67 (s, 21H), 1.21-1.00 (m, 21H).

[0215] Comonomer content: 33 mol %

[0216] Mn (GPC, DMF, PEG)=918 g/mol PDI=1.25

EXAMPLE 18: RANDOM COPOLYMER OF PROPYLENE OXIDE AND 5,5-DIMETHYL-3-(4-(2-(OXIRAN-2-YLMETHOXY)ETHOXY)-PHENYL)-1,4,2-DIOXAZOLE

[0217] Conditions: initiator 1 eq (N,N-dibenzylaminoethanol), comonomer dried azeotropically using benzene under high vacuum (10.sup.3 mbar) for 24 h, PO dried over 3 A molecular sieve (30 minutes, RT), polymerization under argon atmosphere for 24 h.

##STR00043##

[0218] .sup.1H NMR (400 MHz, chloroform-d) =7.73-7.64 (m, 4H), 7.39-7.33 (m, 4H), 7.32-7.27 (m, 2H), 7.24-7.16 (m, 2H), 6.97-6.80 (m, 5H), 4.14-3.94 (m, 2H), 3.79 (s, 4H), 3.71-3.27 (m, 58H), 1.66 (s, 12H), 1.18-1.05 (m, 47H).

[0219] Comonomer content: 15 mol %

[0220] Mn (GPC, DMF, PEG)=960 g/mol PDI=1.15

EXAMPLE 19: RANDOM COPOLYMER OF ETHYLENE OXIDE AND 5,5-DIMETHYL-3-(4-((OXIRAN-2-YLMETHOXY)METHYL)PHENYL)-1,4,2-DIOXAZOLE

[0221] ##STR00044##

[0222] Conditions: 1 eq of initiator (N,N-dibenzylamino-ethanol), 50 eq of ethylene oxide, 5 eq of comonomer dried azeotropically using benzene under high vacuum (10.sup.3 mbar) for 24 h, polymerization under reduced pressure at 60 C. for 48 h.

[0223] .sup.1H NMR (400 MHz, chloroform-d) =7.80-7.62 (m, 10H), 7.43-7.31 (m, 18H), 4.62-4.38 (m, 3H), 3.92-3.26 (m, 287H), 2.72-2.59 (m, 2H), 1.74-1.63 (m, 28H).

[0224] Comonomer content: 7 mol %

[0225] Mn (GPC, DMF, PEG)=1920 g/mol PDI=1.08

EXAMPLE 20: RANDOM COPOLYMER OF ETHYLENE OXIDE AND 5,5-DIMETHYL-3-(4-(2-(OXIRAN-2-YLMETHOXY)ETHOXY)PHENYL)-1,4,2-DIOXAZOLE

[0226] ##STR00045##

[0227] Conditions: 1 eq of initiator (N,N-dibenzylamino-ethanol), 50 eq of ethylene oxide, 10 eq of comonomer dried azeotropically using benzene under high vacuum (10.sup.3 mbar) for 24 h, polymerization under reduced pressure at 60 C. for 48 h.

[0228] .sup.1H NMR (400 MHz, chloroform-d) 7.76-7.62 (m, 10H), 7.40-7.32 (m, 4H), 7.00-6.85 (m, 10H), 4.21-4.11 (m, 10H), 3.89-3.79 (m, 10H), 3.78-3.49 (m, 202H), 2.71-2.60 (m, 2H), 1.67 (s, 26H).

[0229] Comonomer content: 10 mol %

[0230] Mn (GPC, DMF, PEG)=1830 g/mol PDI=1.13

EXAMPLE 21: PREPARATION OF BLOCK COPOLYMERS FROM MPEG AND A PROTECTED HYDROXAMIC ACID BLOCK

[0231] ##STR00046##

[0232] In a 50 mL Schlenk flask, 327.6 mg (0.1638 mmol, 1 eq) of polyethylene glycol monomethyl ether having an average molecular weight of 1600 g/mol (GPC, DMF, PEG, PDI=1.05), 14.5 mg (0.1292, 0.8 eq) of potassium Cert-butoxide and 70.2 mg (0.26 mmol, 1.6 eq) of 18-crown-6 are provided together with 1 mL of THF and 4 mL of benzene and stirred under static vacuum (about 50 mbar) at 60 C. for 60 minutes. Subsequently, any solvent is removed under high vacuum (10.sup.3 mbar) and the initiator is dried at 80 C. for 24 h. The macroinitiator is dissolved in 5 mL of dry THF and provided with 200 mg (0.76 mmol, 4.6 eq) of 5,5-dimethyl-3-(4-((oxiran-2-yl-methoxy)methyl)phenyl)-1,4,2-dioxazole (dried azeotropically with benzene under high vacuum for 24 h) and stirred at 60 C. for 48 h. Subsequently, the reaction is terminated by adding 1 mL of methanol, the solvent is almost completely removed and the residue is precipitated in ice-cold diethyl ether. After centrifugation, the residue is taken up in dichloromethane and washed with saturated NaCl solution, and the organic phase is removed and dried over Na.sub.2SO.sub.4. After the solvent has been removed under reduced pressure, the product is obtained in a yield of 95% of theory.

[0233] .sup.1H NMR (300 MHz, chloroform-d) =7.81-7.71 (m, 8H), 7.43-7.35 (m, 8H), 4.68-4.57 (m, 8H), 3.66-3.60 (m, 145H), 3.48 (s, 3H), 1.68 (s, 24H).

[0234] Comonomer content: 10 mol %

[0235] Mn (GPC, DMF, PEG)=2040 g/mol PDI=1.06