P104 polymeric prodrugs of broxuridine

Posters / European Journal of Pharmaceutical Sciences 2 (1994) 117-194

144

P101 PYRIDO[3~-dJ[1]BENZAZ1EPINES. SYNTHESIS OF A NOVEL HETEROCYCLIC SYSTEM C. Kunick, A. Unk Institutfdr Pharmazie,Universil~itHamburg,20146Hamburg,Germany H

0

P102 NEW SYN'fHESIS OF NON-PROTEINOGENIC TRANS..3-ARYLPRO LINES S. Hahn, P. Pachaiy PharmazeutischesInstitul,Univers~t~tBonn,53115Bonn,Germany

In a series of fused [1]benzazepines tested in the in vitro antitumor screening program of the National Cancer Institute, the indolo[3,2-d][I]benzazepine 1 caused selective growth inhibition on distinctive tumor cell lines.

HN

To gain information about struCture activity relationships, related derivatives containing the novel heterocyclic ring system pyrido[3,2-c0il]benzazepine were synthesized.

Br

1

For a typical procedure the 1-benzazepinedione 3 was prepared starting with the anthranilic acid ester 2. The product of a Michael reaction of 3 with benzalacetophenone was cyclized with ammonia in the presence of an oxidising reagent, e.g. iron-fill), to yield the lactame 4. The cyclic amine 5 was synthesized via the corresponding thiolactame, which was S-methylated and subsequently reduced by lithium aluminohydride.

Non-proteinogenic amino acids are frequently components of B-lactam-anfibiotics and they are essential for the antibacterial activity. Because of the secondary amino group and the volunfinous side chain trans-3-arylproline derivates of 6-aminopenicillanic acid may be potent penicillines which are supposed to be resistant again 8-1actamase and amidase. To this purpose several trans-3arylprolinea were synthesized. Hitherto various methods are known to produce trans-3-at2/lprolines, but they have disadvantages relative to stereoselectivity", number of stepd~ or use of expensive reagents~L Keducfion of the trans-3-aryl-5-oxoproline-cthyl-eaters (_1), which are easily synthesized by Michael-addition '~, with LAH in THF and subsequent acylation with beazylchlorofommte leads to Z-protected trans-3-arylprolinoles (_2)~LOnthe one hand direct hydrogenolysis (Pd-C 10%) affords trans-3-arylprolinolea (2), on the other hand oxidation with Jones reagent to Z-trans-3-arylprolines (3) and hydrogenolysis gives trans-3-arylprolines (3) in good yields~<

0

4 ...

COOC2H 5

e

I. ph.d. ~ p h Ar

~ ' ~ v

5 steps

NH2

-benzyloxyma~bonyl

=

OCH3 ~ N

5

H

0

H

2. H~CI 3, LiAIH4 Ph

Ph

Ph

Ph

4

5

PI03 A CHEMOENZYMATIC ROUTE TO BOTH ENANTIOMERS OF THE MACROCYCUC LACTONE LASIODIPLODIN B. Sehulte, F. Sracher Institutfor Pharm.Chemie,Techn.Unb.8raunschweig,38106Braunsahweig,Germam/ The macrocyclic lactune lasiodiplodin, isolated from Lasiodiplodia theobromae and

Euphorbia splendens, exlfibits significant antileukemic activity. Similar macrocyclic lactones have potent estrogenic activity. In order to provide larger amounts of lasiodiplodin for

screening and to explore

structure-activity-relationships, we worked out a strategy for the preparation of both the nstural (R)-enantiomer and the unnatural (S)-enantiomer (Scheme). Both enantiomers of 1-(l,3-dithian-2-yl)propan-2-ol are available by reduction of the corresponding ketone with appropriate microorganisms. Deprotumtion and alkyladon with 5-bromo-l-petuene gives a chiral building block, which can be converted to an organoborane and coupled with an aryl triflate under Pd-candysis. Lactonization and subsequent one pot desulfurization and debenzylation gives the macrocyclic lactone.

I) D.A. Cox, A.W. Jolmsea, A.B. Mauger: d.Chem.Soc(1964). 5024-5029 2) IL Surges, J.IL Treaer: J.Org.Chem.39,(1974),1710-1716 3) Y.N. Bclokon, A.G Bulychcv, V.A. Parley, E.B. Fedorova, V.A.Tsyt~apkiu, V.A. Bakhmutow, V.M. Belikov: J.Chem.Soc, Pcrkin Transac|ions 1. S,(19SS),2075.2083 4) P.Pachaly, S. Daskalakis, K.S. Sin:Arch.Pharm.(lYemhemO 17,(1984),588-594 5) A. Corlea, J,N. Denis, A.E. Greene: Synth.Commun.ll,(1991), 1-9 6) J.K. Thottathil, J.LMoniol, R.H. Mucller, M.K.Y. Wens, T.P. Kissick: ~Org.Chem.51,(1986),3140-3148

P104 POLYMERIC PRODRUGS OF BROXURIDINE 8. Zorc, I. Kalcic, L Butula Facultyof Pharmacyand Bb~amistry, Universityof Zagreb,41000Zagreb,Croatia

Broxuridine (5-bromo-2'-deoxyuridine; BrdU), a well k n o w n antineoplastic drug, has b e e n covalently b o n d to cq~-poly(2-hydroxyethyl)-DL-asparta m i d e (PHEA) 1 and ~,l~-poly-[(2-aminoethyl)-DL-aspartamide]-~,13-poly[(2hydroxyethyl)-DL-aspartamide] (PAHA). PHEA is a hydrophilic, nontoxic and n o n a n t i g e n i c polymer, previously p r o p o s e d as blood plasma e x p a n d e r and d r u g carrier. PAHA is a n e w c o p o l y m e r p r e p a r e d by aminolysis o f poly(2,5-dioxo-l,3-pyrolidinediyl) (PSI) with 2 - a m i n o e t h a n o l and s u b s e q u e n t l y with ethylenediamine. BrdO has been chemically modified to 3'-O-acety|-5-bromo-2'-deoxyuridine (AcBrdU), 3'-O-acetyl-5'-Ochloroformyl-5-bromo-2'-deoxyuridin e (AcCBrdU), and 3'-O-acetyl-5'-Ophosphooxydichloride-5-bromo-2'-deoxyuridine (AcPBrdU). These comp o u n d s have b e e n b o n d to PHEA by c a r b o n a t e and p h o s p h o e s t e r linkages, respectivelly. On the o t h e r side, 5 - b r o m o . 2 ' d e o x y u r i d i n e 5'm o n o p h o s p h a t e (PBrdU) w a s linked to PAHA by an amide b o n d . In vitro evaluation of the synthetized polymer-drug conjugates are in progress.

.c.2c.2o.

o

cH3o

Pd'

Cn30

3 ) NaOH 2~ o / e l l s

or

0

2

B O

2 -H

2. Fe3"/NH4"

-COOC2H5

~

=

..... COOH

I R

2

O

0

d

~N/~'"CH20H I R

I H

i

H

Ar

~r

A~

C~CH~

SOC~

D

n

S enO

O~.N ~

CO I H" HNICH~co

OR' BrdU AcBrdU R-H, R'=Ac AcCBrdU R=COCl, R'=Ac AcPBrdU R=POCI2~ R'=Ac PBrdU R=PO3H2, R'-H

PHEA

n R=OH,

NHCH2CH2R ]

COOH

~o

l ~H2

J

HN/CH'-CH/CO f HN--~H 2 Jm COOH EAHA

F=NH 2

3) RaNi

t. P. Neri, G. Antoni, F. Benvenuti, F. Cocola. G. Gazzei, J.Med.Chem. 16 (1973) 893