GRAPHICAL

ABSTRACTS

BioMed. Chem. L~tt. 1994,4,

653

BioMed. Chem. L&t. 1994,4,

657

Synthesis of C$5ymmetric
Inhibitors of the HIV-l Protease, with
N,N-Substituted Ethylenediamide and Ethylenediamine Linkers.
J. P. Mazalcyrat*, I. Rage, J. savrda, M. Mouna and M. Wakselman. CNRSCERCOA, 2, rue Hem Dunant, F-94320 Thiais, France.
R. Boulay and Y. L&&e. Rhdne-PoulencRarer, 13, quai Jules Guesde. F94403 Vitty-sur-Seine. France.
C2-symmetric compounds [Z-Val-Phe-N(R)CH2-12
(I: X= CO; R= H,
CH3) and [Z-V&Phe(PCH2N)-N(R)CH2-12
(I: X= CH2; R= H, CH3;
CH2-COOH;
CH2-CH2-OH)
have been synthesized.
They are
moderately active inhibitors of the HIV-l protease.

Ca2+-ATPase

INHIBITORY

ACTIVITY

OF A LOCKED

ANALOGUE
OF THAPSIGARGIN
Annette Andersen, Marek Treiman, Claus Cornet&, Peter Moldt, Jens-Christian J. Paulsen,
Carl Erik Olsen and S. Bmgger Christensen * . * PharmaBiotec, Department of Medicinal
Chemistry, Royal Danish School of Pharmacy, Universitetsparken
2,
DK-2100 Copenhagen, Denmark.
preparation of a non-ionic desoxy-analogue
of thapsigarin locked as a furane is described. The
analogue possesses a Ca2+-ATPase inhibitory
potency similar to that to that of thapsigargin.
The

BioMed. Chem. L&t. 1994,4,

661

BioMed. Chem. L&t. 1994,4,

667

STRIJCTURALLY SIMPLIFIES SQUALESTATINS:

MONOCYCLIC 1,3-DIOXANE ANALOGUES

PeterJ.Sharmtt*,JulieL.~GrahamG.A.Inglis,MichaelG.Lester,
Paaayiotis A. Roqiou aad Nigcl S. Watsoa.
Glaxo GroupResemh Ltd.,Greenm. Middlesex, LIB6OHE. UK.
Monwyclicanalo~ofthesqualestatinsbase4lona1,3dioxawringwcre
preparedandevaluatsd6wtheirebilitytoinhibit~~ir,wbo.
The
compouad 16a possehag a 4,6dime&ylockaoy~l
grmp at C4 aad a
mboxam&atC2showedpotcatinhibitcsyacti&y(lCso11aM).

5-HTq RECEPTOR

ANTAGONISTS:

OXAZOLO,

OXAZINO AND OXAZEPINO[3,2-a]INDOLE

L.M.Gaster*,

P.A.Wyman

DERIVATIVES

and E.S.Ellis, SmithKline Beecham

Pharmaceuticals, The Pinnacles, Harlow, Essex, CM19 SAD, UK.

Oxazolo, oxazino and oxazepino[3,2-alindole
classes of 5-HT4 receptor antagonists.

derivatives

are reported as new

The oxazino[3,2-alindole

(4) has a

pIC50 of 10.6 in the guinea-pig isolated distal colon model of the receptor.
I

645

BioMed. Chem. Lat. D94,4,

PERHYDROTHIOPYRANOPYRROLES
DERIVATIVES:
A NOVEL SERIES OF POTENT AND SELECTIVE
NONPEPTIDE NKl SUBSTANCE P ANTAGONISTS.
D . Achard, A . Truchon and J -F . Peyronel* Rhbne-Poulenc Rorer Central Research, Medicmal Chemrsfry
Department, Centre de Recherches de Vitty-A~ortville,
B.P. 14, 94403 VITRY sur SEINE Cedex FRANCE.
The synthesis of RP 73467, a reprwntative of
4,4diphenyI ~ydrothiopyrano[2,3c]pyrroles
l-oxides,
a new series of potent and selective nonpeptide NK 1
substance P antagonists, IS described.

669

I3 quai Jules Guesde,

RP 73467

SYNTHESIS OF RPR 100893, PROTOTYPE OF A NEW

SERIES OF POTENT AND SELECTIVE NON PEPTIDE NKl
ANTAGONISTS: THE TRIARYLPERHYDROISOINDOLOLS
M. Tabart and J-F. Peyronel*
Recherches de Wry-Aljortville,

BioMed. Chem. Lat. 1994,4, 673

RhBne-Poulenc Rorer Central Research, Medicmal Chemrstty Department, Centre de

I3 quar Jules Guesde, B.P. I4, 94403 FTTRY sur SEINE Ceab WCE.

The synthesis ofRPR 100893, a non peptide

substance P antagonist with higher affinity
for human NKl receptor is described..
RPR 1001193

I
EMD 61756
AS A FAVOURABLE REPRESENTATIVE OF
STRUCTURALLY NOVEL ARYLACETAMIDO-TYPE
K OPIATE
RECEPTOR AGONISTS
Ft. Goltschlich, K. A. Ackemxann, A. Bad&,
G. D. BartcszykW, H. E. Greinefl
* Medicinal Chemistry Department, # Biological Research Department
E. Merck, D-64271 Darmstadt, Federal Republic of Germany

Bioh4ed. Chem. Lat. l!W,4,

611

-I

EMD 61 756 is the first representative of the ~arylacetamide-type k opiates.

Derivatives of this compound are described and structure-activity relationships
are discussed. In the formalin test in mice EMD 61 753 shows a profile similar
to that of the antiinflammatory drugs.

BioMed. Chem. Latt. lY!M,4, 683

3-SUBSTITUTED 6-BUTYL-1,2-DIHYDROPYRIDIN-2-ONRS:
A NEW SERIES
OFPOTENT NONPEF'TIDEANGIOTENSINIIRECEFTORANTAGONISTS
Mathias Osswald*, Werner W. K. R. Medersld, Michael Schwa&, Norbert Beier, Ingeborg Lues,
Klaus-Otto Minck, E. Merck, Preclinical Pharmaceutical Research and Central Pmcess
Developme&. 64271 Darmwadt, Germany.
The syntheses and biological activities of a series of novel 3-substituted 6-butyl-l&jihydropyridin-2-ones are presented. A number of these compounds are shown to be potent antagonists of
angiotensin II with in vitro potencies in the nanomolar or even subnanomolar range. They also
have proven their suitabdity as effective inhibitors of angiotensin II pressor response in viw.

646

Bio~ed. Chem. Len. 1994,4,689

SYNTEESISANDBIOLOGICALACTIYITY OF C-5 MODEM D~~A~~

OF (+)-As76AND(+)_UH232:INCREASEDDOPAMINE D3 RECEPTOR
~CO~C
PROFIT
P~CE~~RO~

A series of (i)-AJ76 and (+)4BiZ32 anaiogswith theC-5 metboxy group modified was synthesized and biologically
evaiuated. Compounds with a tridate or nitrile group were found to he behavioral stimulants with high metabolic
stability. The triflate analogs also displayed a 14 fold preference for the D3 receptor site in vitro.

Pymzolofl $-a]pyridlncts
as !iHT&ntagonkts

Bio~~d. Chem. La.

and Pyrazolo[1+b]pyridazines

1994,4,695

J. Ehdo Hansen*, J. Wels, P.D. Suzdak, and K. Eskesen

Now Nordisk A/S, Nova Nordisk Park, DK-2760 M&w,
Denmar%
3-Carboxamides and 3-carboxylatas of pyrazoio[l,5-alpyridines and pyrazorO[l,5-b]~~~n~
have been synthesized and shown to be SHTs-antagonists.

SYNTHESIS AND ANTI-TUBULIN ACTIVITY OF

~-COMB~A~A~S

X:

CH N

Y:

NH

R: H

CH,

BioMed. Chem. Z&t. 1994,4, 699

Ryuicbi Shirai, Kazuyosbi Tokuda, Yukiko Koiso and Shigeo Iwasaki*

H,CO

A series of aza-combratastatin

was synthesized and their activity against microtuble

assembly was evaluated. ~-~~l~~rne
analogs with avariety of side chains showed
moderate to excellent ~ibitory
activity while beuzanilide analogs had little activity.

ON THE MECHANISM OF ENZYMATIC INACTIVATION OF BLEOMYCIN.

THE AMINOALA~~ID~
MOIETY AS AN ~NZ~R-DEP~~T
MOL k ULAR SWITCH

R = H, (cH~)&H, ( n = 0 - 5 1
f (CH~)~CO~~
= (CH&@i20H

Biohfed. Chem. Lea 1994,4,705

Tom Sugiyama,*MasajiOhno: Mmakatsu Shibasaki: Masami Otsuka,k Yukio Sugiura,bSusumu

Kobayaship Kenji Maeda Faculty
qfMammceutica1
Sciences,
The Universityof Tokyo, Hongo,
&nkyoJcu, TokyolI3, Japm. I~~t~e for ~~~c~~ Re.wmh, Kyoto U~~ersi~. Uji, Kyot~~l*
Japan. cSagand Chemical Reseurch
Cmter,
~a~a~~a-~~,
Kanagawa229,.iapt
Micro&al Ckmistry, Kamiowki, Shinagawa-ku,Tokyo141+Japan

d~nstit&

Tmatment of a Aryan
model PYML-6 with mouse liver extract resulted in the hy~iysis
of the carbamoyl group of the axial side &ii to give an inactive product deamido-PYh=fL.-k
demonsting the~-~~~i~i~
moiety tube an ~zyrne-~~~nt
switch of activity.

647

of

Me0

PYML-6 R..CONH, H
deamido-PY~-6
R = CO2H

SYNTHESIS AND BIOLOGICAL

MODIFIED

BioMed. Chem. Lat. 1994,4, 7 11

ACTIVITY OF

ENEDIYNE CHEMOTYPES

Gregory P. Roth*, Daniel R. Marshall, John F. Mow.

Stephen W. hfamber, William C. Rose, Wyk Solomon,

and Nada Zein; Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway,
Connecticut

Wallingford,

06492 and Princetctn.New Jersey 08543

A series of electronically and sterically altered enediyne cores, based on esperamicin were prepared and
evaluated as antitumor agentsin both in vitro and in viva models.

NOVEL HIV-1 PROTEASE INHIBITORS CONTAINING

A b-HYDROXY SULFIDE ISOSTERE.
S.Y. Stephen Cho, Louis N. Jungheim,* and Angela J. Baxter
Lilly Research Laboratories,
Eli Lilly and Company, Indianapolis,

SH

+ CBZ-NH&
CONH 1-B

Br

BioMed. Chem. Len. 1994,4,

715

IN 46285

CONH I-Bu

CBZNHJLS
d

Synthesis of l-(Z-Deoxy-2-C-fluoromethyi-~-D-arabinofuranosyl)cytosine As a Potential Antineoplastic

Agent
Ymchi Yoshimura,* Kazuko Saitoh.] Noriyuki Ashida,*
Shmji Sakata,
j Akira Mats&a2
lResearch and Development Diviston, Yamasa Corporation, 2-10-1,
Araotcho, Choshi, Chtba 288. Japan, 2Faculty of Pharmaceutical
Sctences. Hokkatdo University, Krta-12, Nishi-6, Kita-ku, Sapporo
060, Japan
The trtle compound 1 was synthesized from arabinofuranosyluractl
its antitumor activmes were evaluated.

m 8 steps and

BioMed. Chem. Lat. 1994,4, 721

0
ti
HO

BioMed. Chem. Lx%. 1!394,4, 725

BENZOFURAN BASED NON-PEPTIDE ANTAGONISTS
ANGIOTENSIN II RELATED TO GRl17289:
PART IV; IMIDAZOPYRIDINYLBENZOFIJRANS.

OF

D B Judd*, K S Cardwell, T A Pan&d, T.I. Jack, M Pass, T. Hubbard, A.W. Dean, AU Butt,
J E Hobson, N M. Heron, S P. Watson, G.S Curie, D tiddlemiss,
D.G Allen, N.M Aston,
J M S Paton, G M Drew, A Hilditch, D Gsllacher, M K Elayliss, and M C Donnelly

Abstract: The identification of a series of imidazopyridinylbenz.ofurans

as potent, nonpcpttde antagonists of angiotensin II is described. Several of these cotqxnmds cause marked
falls in blood pressure in the renal artery ltgated rat model of hypertension after oral
admimstration, two of which have high bioavailabihty and low plasma clearance in rats.

648

SYNTHESIS OF B-NOR+AZA&x-ANDROSTANE
COMPOUND AS Sa-REDUCTASE INHIBITOR
Koki Ishibashi, Hitoshi Kurata, Koichi Kojima. and Hiroyoshi Horikosh?

1994,4,729

1 BioMed. Chem. tea

Medicinal Chemistry Research L&oratories and Biological Research Laboratories

Ph

N4Ph

Sankyo Co., Ltd., I-2-58 Hiromachi, Shinagawa-ku, Tokyo 140, Japan.

B-Nor4aza-Sa-andmstane

derivative 1 was synthesized, The compound 1

Ll@
N

H
1

showed potent inhibition activity against testosterone 5a-reductase.

S-S
OF CYCLOHEXYL
RESTRICTWIN

BioMed. Chem. L&t. 1994,4,733

ANALOGS OF

Takuo Tsukuda, MasamiWatanabe+Hitomi Gotsuka,

Yasuko Fujimoto, and Noboo Shimma*
Department sf Medicinal Chemistry, Nippon Roche
Research Center, 200Kajiwam. Kamakura 247, Japan

Rd)9-2056:
x=N
ROW-2127:
x=CH

Synthesisof cyclohcxyl analogsof Rest&kin (RoO!%2056,

RoO9-2127),
a novel typeof antifungalagent from(-) R-carvone

and theirin vtiro antifungalxtivity are described.

BioMed. Chem. L&t, 1!@4,4,737

The Conformation-dependent Lipophilicity of Morphine Ghxumnides

as Calculated from their Molecular Lipophilicity Potential
PatrickGailkud, Pierre-AlainCarruptand BeanardT&a*, Institutde Chimie Thkrapeutique, Ecole de Pharmacie, BEP,
Universitk de Lausanne, CH-1015 Luusanne, Switzerland
of morphine-3-GTklipopbilicityofc
wmonide (M3G) and morphine-6-Gglucuronide
&6G) wascakulatedbythemolecularl@ophikity

potfzntialmekxl(MLP)inordertoquatWythe
chruneleon? behavior(hydrophilicin water,
lipophilicin lipidicmedia)ofthex compounds.

c+,

DESIGN OF A REUSABLE ENZYMATIC SYSTEM

FOR TEE PREPARATION
OF PORPHYRINS
OF BIOLOGICAL INTEREST
Mario D. Gonzalez and A. Ian Scott*
Center for Biological NMR, Department of Chemistry,
Texus A&M University, College Station, Texas 778433255, USA
Abstract.
The immobilization of porphobilinogen deaminase, and
eogen
III synthase wae achieved by reaction
of each enzyme with BrCN activated Sepharuse.

649

BioMed.

Chem. L&t. l!W4,4,743

Substituted 1,3-Benzodioxole & 1,3-Benzodithiole

-2-Carboxylates and Their Tetrazole Analogs with Potent
Binding Affinity to the Angiotensin II AT1 Receptor.

BioMeti. Gem. Lea X994,4, 747

R.A. Rivero, W.J.Greenlee,and

RS. L Chang,Departmentof
&ploratory
Chemistry,
Merck Research
Laboratories,
RYSOG-331,
P.O.BoxZ~O,R~way,NewJer~ey 07065 USA.

cxN

NS".P,
N
x

Synthesis and angiotensin

II receptor binding affinity of
Abstract:
substituted
1,3-benzodioxole-2-carboxylates
and 1,3-benzodithiole-2carboxylates (II) and their tetrazole analogs are described.

SYNTHEXS OF

ti

II: R = CC& 0

III: R = CN.+H

I Btoh4ed
. .Chern.Lea

NOVEL RlNG CONTRACTED

ARTEMISININ DERIVATIVE.

x994,4,
751

B. Venugopalan*, C. P. Bapat and P. J. Karnik

Department of Chemistry, Research Centre,
Hoechst India Ltd, Mulund,Bombay. India.
400 080.
Bromoacetal 1 undergoes a novel ring
contracted reaction to give the product
2 in the presence of DBU.

BioMed. Chem. Left. 1994,4, 753

SYNTHESISOFFOSTULATEDMETABOLlTESOF
la,25DIHYDROXY-22-OXAVITAMIN
D3
Noboru Kubodera* and Hiroyoshl Watanabe
Fuji Gotemba Research Laboratories,
Chugai Pharmaceutical
Co., Ltd
I-135 Komakado, Gotemba, Shizuoka 412, Japan
Susumt Hatakeyama,
Kazukl Tazuml and Senchi Takano*
Pharmaceutical
Instrtute. Tohoku University.
Aobayama,
Sendal 980, Japan
Abstract:
As the postulated metabolites of la,25-dihydroxy-22-oxavltamln
D3
(OCT), 24-hydroxylated
OCT, 26.hydroxylated
OCT and pentanorOCT
wele
synthesized
In the prehminary
metabolic studies of OCT, the metabolites
possessing
the same retention time in high-performance
liqwd chromatography
analysis as petanorOCT
and 24(R)-hydroxylated
OCT were observed

Stereoselectivity in the Hydrolysis of Synthetic Esters by

Cultured Cancer Cells and Normal Tissue Extracts of Rat

BitMed. Chem. Left. 1994,4, 757

Y.Ogawa,Y.Yamazaki,*
and H. Okuno
NationalInstituteofBioscience and Human Technology,AIST, Tsukuba,ibaraki 305, Japan
The stereoseie~tivi~
ofcancercefls
forester
hydrolysis
isdifferent
fromthatofn~alcelIs
ofrat.
rat normal pancreas
*
34.1 %e.e.

(S) - 5
83.9%e.e.

650

SYNTHESIS AND CRYSTAL STRUCTURE OF 3-FLlJORO-J-METHYL23.DIDEOXYTHYMIDINE. INHIBITORY PROPERTIES OF 3-FLIJORO3-METHYL-23-DIDEOXYTHYMIDINE-S-TRIPHOSPHATE

IN THE
SYNTHESJS OF DNA IN CELL-FREE MEDIA

Bioh4ed. Chem. Lat. 1994,4,

761

A.D. Shutalev. I.E. Mikerin,B M Arshava. A.A. Nikilenko. Y.E. Raifeld.G.Y. VidZ, V.J. Lee* , GV Gunkaya. L.S. Viktomva~
M.V. Jasko, D.G. Semizar&. V.E Zavodnik
Laboratoryof Carbohydralesand Nucleoside Synlhesis Moscow Insr~tuteof Pine Chemical Technology and JVAngarex
Moscow 117571, Russia
Medical Research Division, American Cyanamid Company. Pearl River. New York IO965
Instituteof Molecular Biology RAS and lnstiluteof Physical Chemistry.Moscow, I 17915. Russia

The synthesis, physicochemical

properties and chain-lermination

properties of 3methyLFLT am described.

BioiWed, Chem. L&t. 1994,4, 769

N-Sulfonamides of Benzopyran-Related Potassium Channel
Openers: Conversion of Glyburide Insensitive Smooth Muscle Relaxants
to Potent Smooth Muscle Contractors.
R. M. Soll,q* P. J. Doilings~ R. J. McCaul1y.q T. M. Argentieri,i N. Lodge,8 G. Oshiro$ T.
Fls
Colatsky,~ N. W. Norton,5 D. Zebick,s C. Havens,s and N. Halakd
Ha
60,
%epaument of Medicinal Chemistry and Division of ~Cardiovascular and Metabolic
N
Diseases, Wyeth-Ayerst Research, CN-8000, Princeton, NJ 08543-8ooO
FsC 0
N-sulfonamides of the benzopyran-related class of potassium channel openers were found to
inhibit KCI-induced contractions of smooth muscle preparations (rat aorta or bladder
preparations) in a glyburide insensitive manner or to augment contractions. These activities
were found to be a function of the nature of the sulfonamide substituents.

651