A total of 12 water-soluble N-substituted polyaspartamides, some of these previously reported, are synthesized from the polysuccinimide 1 by nucleophilic ring opening and are characterized microanalytically and spectroscopically. The relative hydrolytic mainchain stabilities of the product polymers are evaluated in dialysis tests (6000-8000 molecular-mass cut-off) performed over periods of 24-48 h in aqueous solution in an effort to assess their suitability as homo-or copolymeric carriers for aqueous-phase coupling to biologically active agents. In agreement with previous work, resistance to main-chain degradation is found to be very poor with the N-(2-aminoethyl)-and N-(3-aza-6-oxahexyl)-substituted derivatives 2a and 2b (10-20% recovery after 48 h), and moderately poor with the 3,6-diazahexyl-substituted 2c (45% recovery). These three representatives, hence, cannot efficaciously be subjected to aqueous-phase drugcoupling reactions save for short exposure times. Good to excellent stabilities, however, with product recoveries in the 70 -95% range, are shown by the remainder of polymers, 2d-21, all of which are characterized by the absence of primary or secondary amino groups in the side chains separated from the amide nitrogen atom by less than three carbon atoms. Polyaspartamides selected from this group for their promising drug coupling potential include the N-(3-aminopropyl)-, N-(3-aminohexyl)-, and N-(2-pipera-zinylethy1)-substituted types 2e, 2f and 2 h possessing primary or secondary amine functions as anchoring sites, and the N-(2-(dimethoxy)ethyI) derivative 2 1, of interest as the precursor to a formyl-functionalized carrier polymer. Lastly, the units of 2i and 2j, featuring 3-(dimethylamino)propyl and 3-(morpholin-4-yl)propyl substituents, lend themselves as solubilizing segments in copolymers that comprise additional repeat units equipped with drug-anchoring sites. ZUSAMMENFASSUNGZwolf wasserldsliche N-substituierte Polyaspartamide wurden aus Polysuccinimid 1 durch nucleophile Ringaffnung hergestellt und elementaranalytisch sowie spektroskopisch charakterisiert. Die relative Hydrolysebestandigkeit der Hauptketten wurde durch 24 -48 h dauernde Dialyse waSriger Ltisungen der Polymeren bestimmt, um deren Eignung als homo-oder copolymere TrLger fur biologisch aktive Substanzen zu prufen. In ubereinstimmung rnit fruheren Arbeiten zeigte sich, da13 die N-(2-Aminoethyl)-und N-(3-Aza-6-oxahexyl)-substituierten Derivate 2a und 2 b (10-20% Ruckgewinnung nach 48 h) sehr unbestandig und das 3,6-Diazahexyl-substituierte Derivat 2c (45% Ruckgewinnung) relativ unbestandig waren. Diese drei Substanzen sind daher fur eine Kupplungsreaktion mit biologisch aktiven Substanzen in wanriger Ltisung ungeeignet, es sei denn, da13 eine solche Reaktion kurzzeitig durchgefuhrt werden kann. Eine gute bis ausgezeichnete Stabilitat rnit einer Ruckgewinnung im Bereich 70-95 Yo weisen jedoch die Polymeren 2 d -21 auf, welche keine primaren oder sekundaren Aminogruppen in der Seitenkette tragen, die weniger als drei C-Atome vom Amid-St...

Poly‐D, L‐succinimide (1) is converted to copolyaspartamides of the general type 2 by sequential treatment with diamine nucleophiles R′NH2 and R″NH2, in which R′ is a group containing a tertiary amine function providing water solubility, and R″ represents a substituent comprising primary or secondary amino groups capable of interaction with suitably carboxyl‐ or carbonyl‐functionalized drug models. The reactions are performed in dimethylformamide medium under mild, yet carefully controlled conditions conducive to aminolytic imide ring opening in the educt polymer without causing crosslink formation through difunctional interaction of the R″NH2 co‐nucleophile. The perfectly water‐soluble polymeric products (ηinn, 5–30 ml/g), purified and isolated by dialysis (12,000–14,000 molecular mass cut‐off) and freeze‐drying, are of interest as macromolecular carrier species for pharmaceuticals and other biologically active agents. The drug‐binding potential of the target polymers is demonstrated by the coupling, through active ester intermediacy, of phenylacetic acid as a representative drug model to selected copolyamides.

In the light of the observed carcinostatic activity of the monoamineplatinum complexes K[PtCI, (NH,)] and K [PtCl,(t-butylamine)], it has been of interest in this laboratory to develop water-soluble, antineoplastic conjugates in which square-planar platinum complex structures of the monoamineplatinum type are linked to suitable carrier polymers possessing water solubility for improved pharmacokinetics. In the present paper the synthesis is described of conjugates in which each platinum atom is coordinated to a single, primary amine ligand provided by a water-soluble polyaspartamide-type carrier. Microanalytical data suggest the remaining three coordination sites on the metal center to be occupied on average by one aquo and two chloro ligands. The carriers, prepared by a known method from polysuccinimide by stepwise aminolytic ring-opening, are designed so as to feature randomly placed hydrosolubilizing units and metal-binding units in a ratio of 3:1, thus providing spatial insulation between the latter and minimize intramolecular interaction between the platinum complexes incorporated subsequently. Platination of the carriers is brought about by treatment with K2PtC14 in aqueous solution at 25-60 "C in the pH range 5-6, and the polymer-platinum conjugates are purified and isolated in 50-70% yield by aqueous-phase dialysis and freeze-drying. The extent of platination attained depends inter alia on the Pt/NH, feed ratio (equivalents of tetrachioroplatinate per carrier base unit); in optimal cases complete metal coordination to the carrier-attached primaryamine ligands is achieved with a feed ratio of 1.4: 1. The conjugates, initially showing complete solubility in water, tend to undergo an ageing process on storage believed to involve intermolecular solid-state interaction of the bound platinum complexes with proximate amine sites, resulting in gradual loss of solubility. In frozen aqueous solution, however, the conjugates are stable for extended periods of time.

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