Posters / European Journal of Pharmaceutical Sciences 2 (1994) 117-194 145

P105 SYNTHESIS OF HOMOCHIRkL BENZOMORPHAN ANALOGUES BY iNTRAMOLECULAR OXA-I~CTET-SPENGLER REACTION B. Wnnsch, M. Zott Inslitut for Pharmazie u Lebensmittelchamle, Universit~ MQnchen, 80333 M0r ,~ , Germany

P106 A CONVERGENT AND F.XCEPT1ONALLY MILD APPROACH TO 2-ARYL- and 2-ALKENYL-2,3- BUTADIENOATES BY USE OF BORON AND Z)NC ORGANOMETALUC REAGENTS T, Weeber, T. Gillmann Inslilut f~r Pharmazeutiscbe Chemie, Phifipps-Universititt Marburg, 35032 Marburg, Germany

Bcnzonmrphans and their ring C htmmlogues, for example eptazocine (I, racemate), are well

known as strong analgesics. Therefore, we investigated the psyehopharmaeological effects of

the homoehiral benzon'torphan analogues 4 a.d cot-4 (n = 1, 2). The key step in the synthesis

of 4 ~ent-4) was an i.tramolecular Oxa-Pictet-Spengler reactkm of the aeetals 3 (ent-3), which

were obtained by aminolysis of the hydrexy ester 2 (ent-2). Mitsunobu inversion of the

(S)-configurated hydro×y ester 2, which was prepared in four steps starting from (S)-tyrosine,

led to the enantiomerlc hydroxy ester ellt-2.

OCH 3 HaCO

I~ I= aCHe (S)-Tyrosine 4 sj_ep_s Mitsunobu

~H HO/~cO2CHa H3CO2~

Ha

H 3 ~ H

CH 3

1, F_.ptazocine

2 ent-2

OCH 3 HaCO H 3 C O ' ~ ~ OCH3

H o . ~ O O H ' ~ O H

(RO)aHC-(CH2)n'NH HN-(CHa)6CH(OR)2

3 ent-3

OCH a H3CO H a C O ~ ~ ] / ° C H a

H' . . . . . . H n = 1 , 2 H~' " H

/ XR' R'

4 ent-4

Ever since the discover/ of the enediyrm antitumor ant~bk)tics such as neocarzinostatJn and the calicheamicins in the late t98Os, these natural products have been extraordinarily stimulating to researchers in bioorganic chemistry, molecular biology and pharmacology, as well as in organic synthesis.[ 1] Being able to underpo an electrcoyclization reaction to form a highly reactive diradical species upon suitable activation, these molecules exert their highly potent ¢ytotaxic activity by H-atom abstraction from the deoxyribose backbone of DNA double helices leading to strand sclsslon.

In view of the complexity of their molecular architecture, it has been a prime goal to design more simple analogues that would serve as models for the natural prototypes. As a further development, the structurally related enyneatlene family of to.systems has vet/ mceatly emergsd as an even more reactive aitemative.[ 2] Since electron-deficient alienes are known to be strong alkylating agents, we envisaged enyneallenes bearing ester substituents to show ONA-cteaving properties via a dual mechanism of action, i.e, not only by forming a reactive dlradlcal but siso by alkylatJng DNA.

Synthetic approaches to enyneallenes have been confined to just a few examples so far, cleady indicating the need to search for new pathways towards that molecular skeleton. A reasonable synthetic approach has to meet at least three requirements. Apart from an ever desirable convergence. any synthesis should be general so as to allow for a systematic veriation of substituents to delineate structure activity relationships. Finally, the process shou~ be rrdld enough to prevent the potentially thermolabile molecules from premature cyclization.

AS an initial pad of our research project aimed at gelding a deeper understanding of the cyclizat~ behavior of the enyneallenes, we report here our development of a convergent and exceptionally mild preparative method for the formation of C-C bonds between ¢(-helo silenic esters and aryl or oieflnic fragments. As starting materials, rnethyl 2-bmrno- and 2-iodo-2,3-butadlenoates were comparatively studied in Palladium-catalyzed cross-coupling reactions with boron and zinc organornetalfic reagents.

O O

, ~ X RB(OH)2 ~ , ~ R CHsO Pd-eaL CHaD

+ or

RZnCI

X - Br, I

The affinity of 4 and cnt-4 (n = 1, 2; R' = H, CH3) to the phcncyclidine binding site of the

NMDA receptor was investigated. Watching the behaviour of mice after application of the test

compounds (Irwin screen) revealed the in vivo effects of 4 and ent-4.

References: [~] Nicolaou, K. C.; Dai, W.-M. Angew. Chem. 1991, 103,1453. [2] Myers, A.G.;Oragovich, P.S.;Kuo, E.Y.J. Am. Chem..Soc. 1992, 114,9369.

P107 SYNTHESIS OF A SERIES OF NEW POTENT SUBSTANCE P ANTAGONISTS K. GrSger 1, A. $isto2, E. Poller2, C.L Fincham2, C. Gsell 1, A. Giolitfi3, A. Giachettil,2 p. Lombardi2, F. Arcarnone 3 1 8mf~.Checr~AG, 12489 Befit, Gen'nany 2 MENARINI Ricerd~ Sud, 00040 Pomezia, Italy 3A. MENARINI Farmaceutid, 50131 Rrenze, Italy

The substance P is a member of a class of structurally related peptides collectively referred to tachykinins. This neurotransmitter, stimulates NKI receptors, and may be involved in the pathogenesis of different disease procesess (inflammation, pain, etc.).

Relating to the extant literature, the substance P peptide SAR data led to the hypothesis that the Phe7-Phe 8 dipeptide subunit of substance P is important for receptor binding. As a lead compound for our study, we selected the non-peptide Fujisawa antagonist FK888 (N2-[(4R)-4-hydroxy- 1-( 1 methyl- 1 H-indol-3-yl)carbonyl-L-prolyl]-N-methyl-N-phenylmethyl-3 - (2-naphthyl)-L-aianinamide) containing three aromatic 'systems. We hypothesized that the presence of aromatic rings is crucial for the biological activity, the rest of the molecule behaving predominantly as a template in order to arrange the key aromatic groups in the right position in space. According to that hypothesis we replaced the 4-hydroxyproline by a series of several stereochemicai isomers of aminocycloalkane carboxylic acids. Another key structural feature has been derived from computer modelling studies The low energy structures of the most active compounds showed a distinct facing of two aromatic rings that could be related to the biological activities. For this reason we replaced the naphthylalanine with other aromatic amino acids.

The compounds in this study has been prepared by condensation of the fragments with EDAC/HOBt. The final compounds have been separated by HPLC. Many of the synthesized structures showed antagonism of substance P binding in the nanomolar rang~ Our results suggest, that cyclohexane is an effective scaffold for the rational design of substance P antagonists producing a high and selective affinity for NK 1 receptor.

P108 SYNTHESIS, PURIRCATION AND BIOLOGICAL ACTIVITY OF THE NOVEL POTENT NEUROKININ A ANTAGONIST MEN 10627 A. H~nsicke 1 , V. Caciagli2, F. CardinaLi2, T. Liotins 2, G. Tuchalskil, C.A. Maggi3, A. Giachetti1,2 1 Berlin.Chemic AG, 12489 Bedin, Germany 2 MENARINI Ricerche Sud, 00040 Pomezia, Italy 3 A MENARINI Induslrie Farmaceutiche Riunite, 50131 Rrenze, Italy

MEN I0627 c-(IVIet-Asp-Trp-Phe-Dap-Leu) is a novel potent selective and competitive antagonist of Neurokinin A with long lasting "in vivo" activity, particularly toward the spasmogenic action exerted by tachykinins in gastrointestinal and genitourinary tracts.

A large scale synthesis of MEN 10627 was achieved by continuos- flow methodology, using an in-house designed synthesiser capable of working up to 0,2 mol, by exploiting Fmoc-/Boc-OtBu chemistr 7 and a base labile linker between the growing peptide and the resin. The first cydization between the Asp and Dap residues was performed on the resin al~er cleavage of the side chain protecting Boc- and -OtBu-groups by TFA. The crude cleaved monocydic intermediate afforded, aRer the second cyclization in solution, the bicyclic title hexapeptide. Final purification was carried out by a Sephadex LH-20 chromatography in methanol and crystagisation of the pure MEN 10627 from methanol/water with an overall yield of 42 % calculated on the basis of the starting lencin.

Antagonist potencies of MEN 10627 at various NK 2 tachykinin receptors were estimated using Neurokinin A as an agonist yielding pA 2 values ranging from 8,17 to 9,43. In vivo MEN 10627 (3 - 30 nmol/kg i.v.) inhibited urinary bludder contraction elicited by activation of NK 2 receptor in a dose dependent manner with significant inhibition being observed up to 3 hours from i.v. administration of 30 nmol/kg