Some synthetic polymers with functional groups for biomedical applications

Synthetic polymers with functional groups for biomedical applications

2703

16. M. GUPTA and G. S. Y. YEH, J. Macromol. Sei. (Phys.) B15: 119, 1978 17. A. BJORNHAUG, O. ELLEFSEN and B. A. TONNESEN, J. Polymer Sci. 12: 621, 1954 18. G. D. WIGN),LL and G. W. LONGMAN, J. Mat. Sei. 8: 1439, 1973 19. S. M. WE(~KER, T. M. DAVIDSON a n d J. B. COHEN, J. Mat. Sci. 7: 1249, 1970 20. R. HOSEMANN, G. WlLLMANN and B. ROESSLER, Phys. Rev. 6A: 2243, 1972; B. STEFFEN a n d R. HOSEMANN, ibid, 13B: 3232, 1976 21. M. GUPTA and G. S. Y. YEH, Submitted to J. Macromol. Sci. (Phys.), accepted. 22. P. HARFGET and S. M. AHARONI, J. Macromol. Sci. (Phys.) B12: 209, 1976 23. J. R. KATZ, Z. Phys. Chem. A125: 321, 1927; Trans. F a r a d a y Soc. 32: 77, 1936 24. G. S. Y. YEH, J. Maeromol. Sci. (Phys.) B6: 465, 1972 25. G. S. Y. YEH and P. H. GEIL, J. Macromoh Sci. (Phys.) BI: 235, 1967 26. G. W. LONGMAN, R. P. SHELDON and G. D. WIGNALL, J. Mat. Sci. 11: 1339, 1976 27. C. S. WANG a n d G. S. Y. YEH, Polymer 18: 1085, 1977 28. W. J. JACKSON, Jr. a n d H. F. KUHFUSS, J. Polym. Sci. (Chem.) 14: 2043, 1976 29. T. E. BRADY a n d G. S. Y. YEH, ft. Polym. Letters 10: 731, 1972 30. E. B. BOKHYAN, Yu. K. OVCHINNIKOV, G. S. MARKOVA and V. A. KARGIN, Polymer Sci. U.S.S.R. 13: 2026, 1971 31. D. LUCH a n d G. S. Y. YEH, J. Appl. Phys. 43: 4326, 1972 32. C. S. WANG and G. S. Y. YEH, (to be published) 33. O. S. Y. YEH, Critical Reviews in Macromol. Sci. 1: 173, 1972 34. J. K. OVCHINNIKOV, G. S. MARKOVA a n d V. A. KARGIN, Polymer Sci. U.S.S.R. 11: 329, 1969 35. I. VOIGT-MARTIN a n d F. C. J. MIJLHOFF, J. Appl. Phys. 46: 1165, 1975 36. G. W. LONGMAN, C. D. WIGNALL and R. P. SHELDON, Polymer 17: 486, 1976

Polymer Science U.S.S.R. Vol. 21, pp. 2703-2714.

0032-3950/79/1101-2703507.50l~

O PergamonPress Ltd. 1980. Printed in Poland

SOME SYNTHETIC POLYMERS WITH FUNCTIONAL GROUPS FOR BIOMEDICAL APPLICATIONS* YA. KALAL Institute of Macromolecular Chemistry, Czechoslovakian Academy of Sciences Three groups of hydrophilic, soluble and biocompatible polymers (poly(hydroxyalkyl acrylates), N-substituted polyacrylamides and polyamides of the polypeptido type) are examined as carriers of various functional groups. Tests showed that polymeric derivatives formed between the original functional groups and pharmacologically active groups possess biological activity. Fluorescent tracers were used to follow * Vysokomol. soyed. A21: No. 11, 2447-2456, 1979.

YA. K ~ A L

2704

the localization of the polymers in the organism at the cell and tissue levels. The results indicates the occurrence of t u b u l a r resorption, a process that has not been described previously in pharmakinetics. The reactivity of the functional groups was studied b y kinetic methods and by E P R spectroscopy, and it is shown t h a t this depends essentially on the mobility of the side chain joining t h e reactive group to the main chain, a n d is determined to a considerable extent also b y the nature of the microenvironment, in particular the polarity of the polymeric carrier. I n production of polymeric materials for medical purposes it is essential to have complete knowledge of both the effect of the separate factors, and of these factors in combination.

IN this report some properties of polymers with functional groups attached to the main chain are discussed. Since our interest is in problems associated with the use of polymers in medicine, the polymers that we use are to a considerable extent polar substances. Polymers as carriers of functional groups. The first group consists of crosslinked gels, swollen in water. The best known representative of these is poly(hydroxyethyl methacrylate) (PHEMA)

i=0 CHr--,

--

~H.CH.OH _1.

_L'~

crosslinked by ethylene glycol dimethacrylate (EGDMA). Since in the case of P H E M ~ partial transesterification always occurs, with formation of EGDMA, it cannot be obtained in the form of a linear, water-soluble polymer. It can, however, be obtained as a polymer soluble in an alcohol (methanol), which erosslinks on drying, forming a completely insoluble hydrogel. The second group consists of N-substituted methacrylamides, which do not undergo transamidation, and consequently give linear, stable, water soluble and biocompatible eopolymers [1]. For the most part we studied polymers and copolymers of N-(2-hydroxypropyl)methacrylamide (HPMA) [2], which among other applications is used as a blood plasma substitute

1 INH I

CH2CH(OII)CHs PHPMA

The third polymer chosen for study was a polyamide of the polypeptide type based on aspartic acid polymer obtained from polysuocinimide (PSI). A poly-

Synthetic polymers with functional groups for biomedical applications

2705

aspartamide (PHEA) is prepared by reacting polysuecinimide with 2-am!noethanol, and it has been examined as a possible substitute for blood plasma [4] I!

o

o

./:

Ii

C

// \

/

CH

N--CIt

\

/

Ctt2--C ' \

N

C

\ /

"\

~/

/

NCfI2CH,,OII

O

ii/

N --

---.

--CH

I c=o

o

I

NH--CH

CH2

\

"Nlf--

/

CH~--C

rl o

I

I1

\ /

/\

C=O

I

/

\

I

C

CII2--C

%\ o

NItCH2CtI20II

41

NHCH2CH20tt NCII2Ct-I20H

I1 PSI

PHEA

We confirmed the inertness of the latter and of other polyaspartamides i~ rive and in vitro [5, 6]. As a basis for a whole group of chemical modifications we used a reactive polymer in $he form of a macroporous carrier with spherical particles. I t was obtained by suspension polymerization of glycidyl methacrylate [7], using different crosslinking agents. I n oases where a certain hydrophic character of the network does not interfere with the application ethylene glycol dimothacrylatm was used [7], otherwise more hydrophilic crosslinking agents were used, namely derivatives of polyhydric alcohols [8]. The resulting carrier, in which the size, surface area and porosity of the spherical particles can be varied over wide limits by the use of suitable technology [9], can be converted to a large number of derivatives by means of conventional reactions [10]. Funvtiortal groups with pharmacological properties. The essential purpose of our research is always the solution of general problems of the use of polymers ha medicine. For example, we prepared polymeric antidiabetic materials in order to discover whether substances of this type preserve their biological activity in the macromolecular form. We feel that formation of various types of covalent bond between the functional molecule and a polymeric carrier, and study of the biological activity of the resulting preparations, could assist in solution of this problem. We chose insulin as an example of a material with a group with high biological activity, and oranil as an example of one with low biological activity. In order to obtain the pharmacologically active polymers we used both reactions carried out on the preformed polymeric carrier, and copolymerization with derivatives of the biologically active substance. By the former type of reaction insulin was added through a covalent bond to a copolymer of N-(2-hydroxy-

2706

YA. KALAL

propyl)methaerylamide with the 2v-nitrophenyl ester of N-methaerylylglyeidylglyeine [11]

CIt3 HC,~ CH3 II --Ctt2--C--CH2--C--CH2--C-l

co I

NH' 1

CH2 I

I

CO

CO

NH

NH

CH~

CH2

CH--OH CO

CH--0H

CH.~

CHs

I

NH

Ai ~

polymeric

+

CH2 co o

(.) I

NO2 where At is glycine, B1 phenylalanine and B~s lycine. I t was found that the covalent bond reduees the activity, both i~ vitro and in v/vo. In comparison with crystalline insulin, however, the polymeric insulin gives a slower onset of activity and a 50% longer glyeaemi¢ action. For the ¢opolymerization method the following derivatives of N-(4-aminobenzenesulphenyl)-N'-ureas were synthesized [12]

I'--CO--NII--~--SO2--NH--CO-- NH--C4Hg, CHa CHa CHa I where R: (:He=f:--, CH_.=C--CONH--(Ctt=)5--, CH==C--COO(CH=)20__ ' CH~ I (~H,,--~ CH2=C--C{)O(CH~)~OCONII--CII-Copolymers of these with N-(2-hydroxypropyl)methacrylamide were prepared and their activity in vivo was tested. The tests showed that both the monomerie and polymeric derivatives possess biological activity. It is quite clear that the whole polymer molecule can take part in at least some reactions involved in the activity of sulphonylurea antidiabetic materials. The use of fluorescent tracers for observing the behaviour of soluble, synthetic 1~olymers in the organism. As we have previously reported [13], fluorescent tracers were chosen for observation of the distribution and accumulation of polymers in the body, in view of the versatility of this method. The • results are illustrated b y two examples. In fluorescent tracing by means

Synthetic polymers with functional groups for biomedical applications

2707

of a covalently combined derivative of fluoreseein [14], the sensitivity of detecting;: the polymer in a tissue is in the region of 10-s-10 -9 g/g, this being a level tha~ can be attained only b y the use of isotopic methods. I n study of the localization of a polymer at the cell and tissue levels the fluorescence method is much m o r e suitable, because it enables more accurate localization to be obtained than with micro-autoradiography. Figure 1 shows the elimination of two soluble polyaspartamides in the body of a rabbit. The control polymer, which contains only hydroxyethyl groups, is compared with a polyaspartamide containing 20 moles ~/o., of tyrosine residues in addition to the latter groups. Both polymers wereA~

soL =

-

!I / ' / i2Ol

_

20

I

"3

I

|

-I/!

eZ_.b .

! Time 7hr

Fro.

l

0

5

Fro.

10

I5

d

2

FxG. I. Quantity of polymer A, retained in the organism. Rabbit, 10 mg/kg (intraveneously), I, 3 and 4--PI-IEA, _M x 10 -3 = 10, 20 and 30 respectively; 5 and O--PH_EA in which 2(> ~ mole % of the IW-hydroxyethyl groups have been replaced by butyl (5) and 2-(4-hydroxyphenyl)ethyl groups (6). FIG. 2. l~ate of aminolysis of eopolymers (a, a') and m o n o m e r s (b, b') of 4-nitrophenyl ester~containing - - C O N H (CH~)nCOOC3H41WO2 (a, b) and -- C O (NHCI-12CO)xOC6H4NO, (a', b') side chains: l'-2'-- values of x; 2-7, I/--values of n. Tert.-butylamine (0.I mole/L) was used, aS 25 °. The concentration of nitrophenyl esters Co was 10 -3 mole/l. ; k==In (Co/Ct)/O'it; d ia the number of atoms between the main chain and the reactive centre.

prepared from the same precursor, which was PSI containing 0.5 mole of a fluorescent tracer. It is seen from the graphs t h a t the tyrosine residues alter the kinetics of elimination substantially, and sectioning of the whole frozen organism showed t h a t preferential retention in the kidneys occurs. Histological specimens of the kidneys after introduction of 50 mg/kg, of polymer c o n t a i n i n g tyrosine residues, showed that the polymer is present in high concentration in t h e proximal canals, this situation remaining basically unchanged in the course of two months (up to the end of the experiment). This indicates the occurrence of a.

::2708

YA.

t~rocess not previously described in the pharmacokineties of soluble polymers, i.e. of their tubular resorption. I t is evident t h a t not a single chemical structure in the synthetic polymers, is completely and without exception inert with respect to all the variety of processes taking place in the organism. This is particularly true of macromolecular c o m p o u n d s where some part is played not only by their chemical properties, but also b y the physicochemical and physical properties of the macromolecules o r of the surface systems that t h e y form. The reactivity of the side chains. The reactivity of functional groups in polymeric systems is depen.dent on a large number of factors. Two of these must be considered in the first place, namely the effect of the nature of the bond between the functional group and the macromolecule, and the so-called "microenvironment" of the functional group. Physiologically active groups are often introduced into side chains of watersoluble polymers. The activity of these groups on the organism, just like their chemical reactivity, can depend to a considerable extent on the chemical structure •of the side chain, on its rigidity and on cooperative effects of a catalytic nature. T h i s problem is of general interest. Of the number of different possible approaches, we studied the activity of functional groups attached to chemically different side chains of different length. FOr this work we used soluble derivatives of methacrylamide. The monomers were either 4-nitrophenyl esters or N-hydroxyphthalimide esters of methacrylyl •derivatives of o~-aminoacids, which were copolymerized with 2-hydroxypropyl~methacrylamide. Soluble copolymers of the following composition were obtained CHa

--

CIt:~

C=O

r

I

(CH2)n

C~O I NH I CI-I~

C=O

CH--OH

C=O

c=o ~-~

+ NH

NIt

I

Ctt2--C

-- --CHz--C

C=CH~

CH~=C

CII3

CH3

I

NIt

I

(CIl2)n

cIt2

C=O

CH--OH

A

•

1

CH:~ where A: F 0

or

I

I

NO~ ~

A ]

O

I i

-

1

=

; n=t--7,

CH:~

~30

tt.

I

N

/ \ CO CO \ / /=N

The rate of aminolysis of the monomers and copolymers was measured. This r a t e was expressed as the time, t~, required for conversion of half of the ester Quilt into the polymer• By way of illustration, Fig. 2 shows the course of amino-

Synthetic polymers with functional groups for biomedicalapplications

2709

lysis of the above 4-nitrophenyl esters (both monomeric and polymeric), using tert.-butytamine. The reaction was carried out in DMSO. We propose the following explanation of the high rate of aminolysis of tile 4-nitrophenyl esters of glycine and fl-alanine: OI(--+C

\

/

O~ Cff~

R--E=N--CIt2

,\

\

N

C+

I

l\

]l

J "'0

.--, O--NP

It \/

C~ ",

o

O--NP

-H

+

\

/

N--R'

H

0 R--C

/

CII2 / \

\ Nil

R--+C \ C

.f\ 0

Ntt--R'

/ N l

II

CII~ O--NP \,/ C /\ -0 N+--R ' /\. It H

where N p = - - / ~ N O ~ . Hydrogen bonding, detectable in the IR spectra, occurs between the amide group and the carbonyl of the ester group, with formation of a ring structure, and this causes the high rate of aminolysis. Consequently it must fall sharply when the ring contains more than six atoms, because the effect displayed by the 'hydrogen bond becomes increasingly weaker, and as the number of carbon atoms continues to increase the rate then changes very little. The slower rate of aminolysis of the polymers in comparison with the monomers is explained by steric hindrance caused by the polymer chain, i.e. possible ¢onformational effects or even reduction in the mobility of the functional groups. The mechanism of acceleration of aminolysis proposed for the case of glycine aide chains can be applied also to explanation of aminolysis of the nitrophenyl esters attached to diglycinyl and triglycinyl side groups, which is more rapid than when the side branches are aliphatic chains of the same length (Fig. 2) [15]. In the aminolysis reactions a molecule of the amine reacts with the end of the side chain. I f this molecule is replaced by a macromolecule, which apart from its low mobility, needs to be in very selective contact (and an enzyme is such a reagent), different results are obtained. In study of the splitting of the nitroanilide of phenylalanine at the end of side chains of similar polymers by ehymotripsin [16], the oligopeptide chains caused retardation of the action of the

YA. KALAL

2710

e n z y m e , a n d t h e best s u b s t r a t e was a n a]iphatic chain. W e feel t h a t f r o m t h e p o i n t o f view of t h e suitability of a p o l y m e r as a s u b s t r a t e for a n enzyme, t h e m o b i l i t y of the side chain is a v e r y i m p o r t a n t factor. The mobility of the side chains. I n order to m a k e possible direct c o m p a r i s o n o f t h e results, for m e a s u r e m e n t o f m o b i l i t y we used t h e same c0polymcrs as in t h e e x p e r i m e n t s on amino]ysis, the n i t r o p h e n y l ester being r e a c t e d w i t h 4-amino2,2,6, 6 - t c t r a m e t h y l p i p e r i d i n e N-oxime. Analysis of t h e E P R spectra showed t h a t t h e correlation t i m e v, which characterizes the m o t i o n o f t h e spin tracer, varies u n i f o r m l y w i t h the l e n g t h o f t h e side chain, w h e t h e r it be aliphatie or a polyglycine chain. This m e a n s t h a t a s t h e l e n g t h of the side chain increases, t h e m o b i l i t y of the spin t r a c e r increases s t e a d i l y [17].

~-x10 -9

1

Uo, fOa,mole/sec

5 "

0

X

I5

~Z

7o 60

q5

10

a 1

I

/

b q

2

3

5

2

t

5

I

~Sd

FIG. 3

:.

u

Ii .2,//b ? i II I

i

'-8 -1 I 3

I

5

l

1o l I 7

l

9

I

I, I 11 n

FIG. 4

FIG. 3. Dependence of the correlation time ~ on the lingth of the side chains -- CONH (CHs)n. ~ O N H R (a} and --CO (NHCHsCO)xNHR (b), where R represents 2,2,6,6-tetramethylpipe= ridine-N-oxyl; d is the number of atoms between ~he main chain and R, and the figures on the curves denote the values of n and x. FIG. 4. Dependence of the initial rate of scission of the nitroanilide of phenylalanine on the length and nature of the side chain: a--CONH(CH=)n CO--PhA--NHCeH4NOa, b---CO(iN-HCHxCO)--PhA--NHC6H~NO2 (the figures on curve b are the values of x). I n Fig. 3 a comparison is m a d e of the d e p e n d e n c e of the correlation t i m e on t h e l e n g t h of side chains of different s t r u c t u r e [18]. I t is seen t h a t t h e ends o f side chains f o r m e d o f aliphatic units h a v e m u c h g r e a t e r m o b i l i t y t h a n in t h e case o f polyglycine side groups o f the same length.

Synthetic polymers with functional groups for biomedical applications

2711

Side chains as a substrate for an enzyme. The results seemed to support our :proposition concerning t h e role of mobility in enzymatic scission of the side chains. I n order to confirm t.his, using the same series of copolymers as was used for measurement of mobility and reactivity, we subjected them to amonolysis by nitrophenyl esters, L-phenylalanile-4-nitroanilide and diglycinyl-L-phenylalanile-4-nitroanilide, obtaining macromolecular substrates for chymotrypsin, similar t o those used in the previously cited reference [16]. The initial rate, re, of elimination of 4-nitroaniline from these polymers was determined under identical conditions. Although we did not determine km and Vmaxfrom these measurements, t h e conclusion could nevertheless be reached (Fig. 4) that the highest reaction rate is obtained in the case of the aliphatic side chain formed from co-aminoheptanoic (oenanthic) acid. The fact that a polyglycinyl side chain retards enzymatic hydrolysis of the substrate is once again confirmed. This is obviously explained by the rigidity of the chain and the consequent hindrance to reaction between the active site in the enzyme and the substrate. The effect of the environment on the reactivity of the functional group. From the point of view of reaction rate, the behaviour of a functional group attached to a polymer chain can differ considerably from a chemically identical functional group attached to a small molecule. This was mentioned in the previous section, in connection with the retardation of aminolysis, Caused in all probability b y screening by the polymer chain. Selective sorption of the reactants or other components of the medium, caused b y high affinity with the polymer chain can, however, also affect the reactivity of the functional groups. The effect of the polarity of the microenvironment is seen particularly clearly in the case of crosslinked copolymers, where reaction of the functional groups Cakes place on the surface. It is known from the literature that a rhodium chelate [19] has a catalytic effect on symmetrical hydrogenation, giving a high optical and chemical yield.

H M

.

.O-~ll<,"

/CI

"P.

Me\ /

O/ ~ P

+H2- solvent +Clt2=CtlR • M e / / X , , , X O A

H

Ph Ph H Me

v

O'

Ph Ph ~p!H

Ph Ph

X/

i~

" ~ _ , , / " Cl

pith-

- -tt

c./c.R

Ph

Ph

l Cl

Ph Ph

I f this functional group is attached to a Merifield carrier, which has low polarity, it exerts a catalytic effect on hydrogenation of non-polar substances !

2712

YA. K~r.A~

such as hydrocarbons, but not on aminoacids, for example ~-acetaminocinnamic acid, though the complex on its own readily catalyses the same reaction [20] H

Ph Ph

H

Ph Ph

Ph Ph

Ph

A

Ph

B

Since there was at our disposal a large number of crosslinked, comparatively l~olar polymers containing an aldehyde functional group, by means of which we were able to obtain the catalytic group that we have just mentioned (product B above), we can verify experimentally (Fig. 5) that the polarity of the carrier of the functional group does in fact affect the possibility of catalysis [21].

10 I

I

I

lO

20

JO

Time, hp

Fro. 5. Kinetics of formation of lff-acetylphenylalanlneby the reaction $

NHCOCH s

H,

PhCH,CH~C00H

The arrow denotes the time when the ratio of the L:D isomers in the reaction mixture is 65.5: 34.5 I n reaction of insoluble polymers with biological media (whether the l~olymers macroporous or homogeneous is immaterial), the fact mentioned above is clearly evident, namely that the "non-functional" component of the polymer is not important. The combination of all the components has a decisive effect on, for example, the sorptive properties of the polymers, la'rom the point of view of the compatibility of protective materials with the blood, we investigated these problems by means of I R spectroscopy and fluorescence labelled plasma proteins [21]. Figure 6 shows the heat of wetting of polymeric carriers of different cornare

Synthetic polymers with functional groups for biomedical applications

271

position. I t is seen from this diagram t h a t it is quite hopeless to look for a n y group in the polymer t h a t is completely devoid of function. I t all reduces o n l y to the fact t h a t it is necessary to have full knowledge of these functions, b o t h Heal'of weffin~ , O/rn z 0 1 2

I

m='

l

I

I

in

' '

inn I

l

l

I

I

I

I

I

I

I

I

0 3"0 /00 Mo/ap ratio of fhe unif~ in fhe copolumer~,°/,

Fig. 6. Heat of wetting (b]sek scale) of eopo]ymers at various eornpositionR (GMA is gly¢idy] metha~ry]at~, lVl~--methy] methaerylate. EGDMA~othy]ene g]yoo] dimethacrylate and HEMA--p-hydroxyethyl methacrylate). separately and in combination, and to use the information so o b t ~ n e d for designing and synthesizing polymers for the most humanitarian purpose, n a m e l y for the preservation and betterment of the health of ma~lclud. Translated by E. O. prrtT.z.,ps

REFERENCES

1. J. KOPE~EK and H. BA~ILOV~, European Polymer J. 9: 7, 1973 2. L. ~PRINCL, J. EXNER, O. ~T~RBA and J. KOPE~EK, J. Biomed. Mat. Res. 1O: 953,

1976 3. J. VLASIkK, F. RYP.~CEK, J. DROBNIZKand V. SAUDEK, J. Polymer Sci., Polymer Symp. (in the press) 4. P. NERI, G. ANTONI, F. BENVENUTI, F. COCOLA and G. GAZZEI, J. Med. Chem. 16: 893. 1973 5. J. DROBNflg, V. SAUDEK, J, VLASJ~K and J. ~ , J. Polymer Sci., Polymer Symp. (in the press) 6. J. DROBNtK, L. DABROVSKA,M. VACHOVA,J. ~ , J. PRAUS and J. ELIS, ibid. 7. F. ~VEC, J. HRADIL, J. COUPEK and J. IL/LLAL,Angew. Makromolek. Chemie 48: 135, 1975 8. J. ~0UPEK, M. KI~IV~KOVA,J. LABSK~, J. EXNER, J. ILEAL and F. ~VEC, Czecl~ Pat. (Authors' Certificate). 177655, 1977 9. F. ~VEC, H. HUDRKOV~, D. HOR~.K and J. ~ , Angew. Makromolek. Chemio 68: 23, 1977 10. J. DROBN~K, V. SAUDEK, F. ~VEC, J. K~LAL, V. V0JTI~EK and M. Bz~RTA, Biotechnol. Bioeng. 21: 1317, 1979

=2714

P . A. KIRPICHlqIlrOV

11. V. CHYTRY, A. VR~NA and J. KOPE~EK, J. Polymer Sci. Polymer Symp. (in the press) 12. B. OBEREIGNER, M. BURESOVA, A. VRANA and J. KOPECEK, J. Polymer Sci., Polymer Syrup. (in the press) 1 3 . J. Kt~LAL, J. DROBNIK, J. KOPE~EK and J. EXNER, Brit. Polymer J. 10: 111, 1978 14. F. R Y P ~ E K , J. DROBNIK, J. KREJ~IVES and J. KALAL, J. Polymer Sci., Polymer Syrup. (in the press) 15. P. REJMANOV_~, J. LABSKY and J. KOPE~EK, Makromolek. Chem. 178: 2159, 1977 16. J. DROBNIK, J. KOPE~EK, J. LABSKY, P. REJMANOVI, J. EXNER, V. SAUDEK and J. K y ~ A L , Makromolek. Chem. 177: 2833, 1976 17. J. K ~ L A L , J. DROBNIK, J. KOPE~EK and J. EXNER, In: Polymeric I)ruggs (g. Guy a n d O. Vogl eds.), p. 131, New York, 1978 1 8 . J. LABSK~, J. PILAI~ and J. Y~LAL, J. Polymer Sei. Polymer Syrup. (in the press) 19. T. P. DANG a n d H. B. KAGAN, J. Chem. Soc., Chem. Commun., 481, 1971 :20. J. C. POULIN, W. DUMONT, T. P. DANG and H. B. KAGAN, C. r. Acad. Sci. 13277: 41, 1973 2 1 . H. B. KAGAN, Pure Appl. Chem. 43: 401, 1975 22. E. BRYNDA, J. DROBNIK, J. VACIK and J. KiLLAL, Biomed. Mat. Res. 12: 55, 1978

~Polymer Science U.S.S.R. Vol. 21, pp. 2714-2726. - ~ Pergamon Press Ltd. 1980. Printed in Poland

0032-3950179/1101-2714$07.50/0

THE SYNTHESES AND CHEMICAL REACTIONS OF SOME REACTIVE OLIGOMERS* P . A . KIRPICH~IKOV S. M. Kirov I n s t i t u t e Of Chemical Technology, K a z a n Studies in which controlled degradation of high polymers is used to produce -oligomers with reactive end groups are reviewed. The synthesis conditions, the struc. .ture and the molecular characteristics of the oligo-isobutylenes produced b y ozonolysis of the isobutylene-diene copolymers, and of oligo-sulphides with terminal HSgroups synthesized b y a reductive cleavage of dienic hydrocarbon copolymers with sulphur, sodium sulphite or linear oligo-sulphides, have been investigated. Chemical modffication takes place in the l a t t e r case simultaneously with the cleavage. Oligomers with various hetero-atoms in the terminal groups have been synthesized from oligo-isobutylenes with carboxyl end groups; these have been tested as lubrication additives and the oligo-sulphides have been used to produce sealants.

~ra~ attention given in recent years to the reactive oligomers with functional end groups, especially those capable of participating in the propagation and crosslinking of maeromolecules, has increased. Less attention was given in their .synthesis methods to an aimed degradation of compounds with a large melee* Vysokomol. soyed. A21: No. 11, 2457-2468, 1979.