Die Makromolekulare Chemie 169 (1973) 55-58

Department of Chemistry, University of Reading, Berkshire, England

Water-Soluble Polymers containing Adamantylamino- and other Amino Residues

PAUL HOLT and CHANDRU THADANI

(Eingegangen am 27. November 1972)

SUMMARY: Water-soluble polymers have been prepared as potential antiviral agents (a) by the

copolymerisation of N-vinylpyrrolidone and N-allylarninoadamantane, and (b) by the copolymerisation of N-vinylpyrrolidone and crotonaldehyde followed by the formation of SCHIFF bases with 1-aminoadamantane, 2-aminopyridine, cyclohexylamine, p-toluidine or tert-butylamine.

ZUSAMMENFASSUNG: Wasserlosliche Polymere wurden (a) durch Copolymerisation von N-Vinylpyrrolidon

und N-Allylaminoadamantan und (b) durch Copolymerisation van N-Vinylpyrrolidon und Crotonaldehyd mit nachfolgender Reaktion zu SCHIFFsChen Basen mit 1-Aminoadaman- tan, 2-Aminopyridin, Cyclohexylamin, p-Toluidin oder tert-Butylarnin als mogliche Anti- virus-Substanzen dargestellt.

Introduction

BECK, BRUCK, and BROCKHAUS 1) found that poly[ (2-pyridy1)ethylene N-oxide] would prevent the cytotoxic effects normally produced when fine quartz particles are ingested by macrophages. The activity of the polymer appears to depend on its large molecular size which results in its being actively taken up by the cell, and on the presence of a biologically active group in the structure which probably affects the cell membrane or the membrane of the lysosome. The active group may be the N-oxide group.

Aminoadamantane is active against some viruses. Polymers contain- ing aminoadamantane residues and some other control structures have been synthesised to determine whether incorporation of the structure in a macromolecule would enhance its antiviral action. Other amines were incorporated in similar polymers as controls.

The polymers must be water-soluble. It was desirable tha t the anti- viral structure should be attached in two ways, (a) by a grouping un- likely to be degradable in vivo, the amino group being free in the polymer, and (b) by condensation of the amino group with a group on a polymer, giving a grouping likely to be hydrolysed in a cell there to liberate free aminoadamantane.

55

P. HOLT and C. THADANI

Results

Synthesis of water-soluble homopolymers containing the aminoada- mantane group proved difficult and it was found preferable t o copoly- merise a monomer carrying a group to which an amine could readily be attached with a vinylpyrrolidone or pyridine oxide monomer which usually confer water-solubility. This method was adopted by RINGSDORF et al. 2) for the production of water-soluble antiradiation polymers.

(a) The polymer poly[l-(2’-oxo-l’-pyrrolidinyl)-4-(N-l’-adamantyl- aminomethyl)butylen] (I) or poly[ l-(2’-oxo-l’-pyrrolidinyl)-3-(N-l”-ada- mantylaminomethyl)butylen] (11) was produced by the copolymeriza- tion of N-allylaminoadamantane and N-vinylpyrrolidone. A second poly- mer was prepared by the copolymerisation of N,N-diallylaminoadaman- tane with N-vinylpyrrolidone. They were white, readily soluble solids. The composition could not be determined because the polymers were highly hygroscopic. The C, H, and N values for the two monomer resi- dues were similar, and there were no characteristic peaks in the I R or UV spectra. The NMR spectra of the copolymers were complex and differed from that of poly[ (2-oxo-l-pyrrolidinyl)ethylene] (poly(vinylpyrro1idone)).

FH-CH2-CH2- H .. . . . - CH-CH2- CH-CH2- I I

FH2 N F -.

CH2-CH, I I1

(b) The’second method used to produce a polymer carrying an amino- adamantane group involved the copolymerisation of crotonaldehyde and N-vinylpyrrolidone to give a polymer with aldehydic groups which would react with aminoadamantane or other amines to give SCHIFF bases. The copolymerisation of crotonaldehyde and N-vinylpyrrolidone was first studied by USHAKOV, TRUKHMANOVA, MARKELOVA, and KROPACHEV~), who found tha t the yield of polymer was increased as the proportion of vinylpyrrolidone in the monomer mixture was increased. We confirmed this variation, obtaining yields varying between 60 and 20 yo of polymer from vinylpyrrolidone : crotonaldehyde ratios between 4 : 1 and 10 : 1. The products were white, very hygroscopic solids, soluble in water, chloro- form and ethanol, that decomposed a t about 360°C without melting.

USHAKOV et al. (1967) reported on the composition of the polymers formed from crotonaldehyde and N-vinylpyrrolidone using several meth-

56

Water-Soluble Polymers containing Adamantylamino- and other Amino Residues

ods, but experimental details were not given. We found difficulty in determining the composition. No reliable composition could be calculated from ultimate analyses as the polymers were extremely hygroscopic and adsorbed appreciable amounts of water even whilst being weighed.

The IR peaks due to carbonyl groups in the copolymer are merged and the ratio of the monomers cannot be calculated by this method. The peaks due to carbonyl in both monomers are a t 1700 cm-1. Polymerisation eliminates conjugation of the carbonyl groups and shifts the peak to 1675 cm-1. There is no definite peak in the UV spectrum.

The composition was most easily deduced from the content of croton- aldehyde carbonyl ; the carbonyl group of the pyrrolidone is unreactive. This value was obtained by adding an excess of ethanolic 2,4-dinitro- phenylhydrazine to the polymer in ethanolic solution, removing the dinitrophenylhydrazone of the polymer by filtration and estimating the excess reagent by spectrophotometry using the peak a t 353 nm. From monomers in the ratio, crotonaldehyde : N-vinyl-2-pyrrolidone = 1 : 10 and 1 % 2,2'-azoisobutyronitrile the polymer isolated after 24 h a t 70 "C con- tained monomer residues in the ratio 1 :4.

The poly(viny1-2-pyrrolidone-co-crotonaldehyde) in acid solution was converted into SCHIFF bases with 1-aminoadamantane, p-toluidine, 2-aminopyridine and cyclohexylamine ; tha t with aminoadamantane, for example, containing the structure I11

'iH3 ..-CH-CH2-CH- H c

CH I

I N

CH2-CH2

The SCHIFF bases were white, very hygroscopic solids, soluble in water, chloroform, and ethanol.

The antivirial activity of these polymers will be reported.

Experimental

Copolymerisation of N-allylaminoadamantane with N-vinylpyrrolidone, ratio 1 :10

N-vinylpyrrolidone (11,l g), N-allylaminoadamantane (1,91 g) and azobisisobutyro- nitrile (0,065 g) were sealed in a tube under nitrogen then heated for 30 days at 70°C.

57

P. HOLT and C. THADANI

The contents of the tube were dissolved in chloroform and precipitated with a mixture of diethyl ether and petroleum ether (bp 40-60°C). The precipitate was filtered off and dried i.vac. The poly(N-vinylpyrrolidone-co-N-ally1aminoadamantane) was purified by precipitation from chloroform solution by an ether/petroleum ether mixture. Yield 7,3 g.

By a similar method poly(N-vinylpyrrolidone-co-N,N-diallylaminoadamantane) (8,6 g) was prepared.

SCHIFF bases of poly(N-vinylpyrrolidone-cc-crotonaldehyde) N-vinylpyrrolidone (44,4 g), crotonaldehyde (2,8 g), and azobisisobutyronitrile (0,47 g)

were sealed in a tube that had been previously dried, flushed with nitrogen and evacuated. The tube was heated at 7OoC for 24 h. The contents of the tube were dissolved in chloro- form then precipitated with a mixture of diethyl ether and petroleum ether (bp 40-60°C). The precipitate was removed by filtration and dried i.vac. The polymer was purified by precipitation from chloroform solution by an ether/petroleum ether mixture. The poly- (vinylpyrrolidone-co-crotonaldehyde) (33 g) was a white, very hygroscopic powder that decomposed without melting at 360°C.

[8(CsHgN05) + (C4HsO) + 3 H20)* (1477,3), Calcd. C 62,lO H 8,32 N 10,35 Found C 62,32 H 8,30 N 10,82

Other preparations were similarly made using N-vinylpyrrolidone : crotonaldehyde mono- mer ratios varying from 2 : 1 to 10 : 1.

Poly( N-vinylpyrrolidone-co-crotonaldehyde) (6 g) and 1-aminoadamantane hydro- chloride (1,s g) were heated under reflux in ethanol (60 cm3) for 6 h. The solution was reduced to half its volume and the polymer was precipitated in dry diethyl ether. The precipitate was filtered off, washed with dry ether and dried i.vac. The SCHIFF base from adamantamine and poly(N-vinylpyrrolidone-co-crotonaldehyde) (7,3 g) was a white, ex- tremely hygroscopic solid. Assuming the complete reaction of all aminoadamantane, the SCHIFF base contains 23% of aminoadamantane. A solution in water passed through a column of Sephadex G10 gave a single peak, indicating that monomers and unreacted aminoadamantane were absent.

SCHIFF bases of the' copolymer similarly prepared from cyclohexylamine, 2-amino- pyridine, p-toluidine, and tert-butylamine had similar properties.

The authors acknowledge a grant from the WELLCOME TRUST.

1) E. G. BECK, J. BRUCH, and A. BROCKHAUS, Z. Zellforsch. 59 (1963) 568. 2) H. RINGSDORF, A. G. HEISLER, F. H. MULLER, E. H. GRANT, and W. R ~ T H E R , in:

Biological Aspects of Radiation Protection, ed. by T. SUGAHARA and 0. HUG, Igaku Shoin Ltd., Tokyo 1970.

3) S. N. USHAKOV, L. B. TRUKHMANOVA, T. M. MARKELOVA, and V. A. KROPACHEV, Vyso- komol. Soedin. A 9 (1967) 999.

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