Biooqanic dr MedicinalChemistryL&em, Vol. 4. No. 1, pp. 69-74.1994 0960-894XJ94 $6.00 + .

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PhtE!dillGT~Bhill 0 1993 PergamonPressLtd

POTENT IMIDAZOLE ANGIOTENSIN TIANTAGONISTS: ACM, SULFONAMIDES

AND ACYL SULFAMIDES AS TETRAZOLE REPLACEMENTS1

Elizabeth M. Naylor,**t Prasun K. Chakravarty,? Colleen A. Costel1o.t Raymond S. Chang,*

Tsing-Bau Chen,S K&tie A. Faust,* Victor J. Lot&* Salah D. Kivlighn,$ Gloria J. Zingaro,$
Peter K. S. Siegl,* Pancras C. Wong,o David J. Carini,~ Ruth R. Wex1er.Q
Arthur A. Patchen,? William J. Greenlee.~
berck Research L.&oratories, Rahway, NJ 07065; SMerck Research Laboratories, West Point, PA 19486 and
4The Du Pont Merck Pharmaceutical Company, Wilmington, DE 19880.

Abstract: Acyl sulfonamides and acyl sulfamides were synthesized and their in vitro and in vivo biological
properties evaluated. AT1 binding affinities for these potent AII antagonists were similar to their tetrazole
analogs. An enhancement in AT2 potencies was observed, particularly with acyl sulfonamides or sulfamides
bearing hydrophobic substituents.

Various facets of the renin angiotensin system (RAS) have received a great deal of attention as a result of the
importance of this cascade in the regulation of blood pressure and fluid and electrolyte balance.2 Angiotensin II
(AII). the primary effector hormone of this proteolytic cascade bids to receptors that are present in several
tissues (for example, blood vessels, kidney, heart. brain). The discovery of non-peptidic AII antagonists such as
losartan, @Up 753, MK 954),3 which is presently undergoing phase III clinical trials, has stimulated significant
interest in this mode of blocking the RAS. Losarmn 1 is a potent, orally active angiotensin II antagonist. The
metabolite of losartan, 2 (EKP3174) contributes critically to the antihypertensive effect of losartan in rats and in
man. 4

1 DuP 752 R6 - C&OH 3 DMP811R6-COOH

2 EXPS174A - COOH 4 DMP581 I?-CHO

There is evidence that there are at least two subtypes of AII receptors that have been designated as AT1 and
AT2.5 Losartan is highly selective for the AT1 receptor subtype. The tetrahydroimidaxo[4,5-c]pyridine AI1
antagonist, PD- 123.3 19 binds selectively to the AT2 receptore Vasoconstriction and renal sodium reabsorption
are primarily controlled by AII binding to the AT1 receptor. The function mediated by the AT2 receptor remains
to be determined.
In looking for structurally diverse AI1 antagonists, it was noted that the medicinal chemistry of sulfonamides
and related compounds has been widely investigated for a number of therapeutic targets. For example,
sulfamethoxazole is prescribed for urinary tract infections and sulfacetamide sodium is applied topically to treat
70 E. M. NAYLORet al.

ophthalmic infections.7 More recently, the leukotriene D4 receptor antagonist, ICI 204,219, that incorporates a
substituted benzoyl sulfonamide as a carboxylic acid replacement, has been reported to be under evaluation for
the treatment of asthma.8 It was, therefore, considered reasonable to investigate acyl sulfonamides 5 and acyl
sulfamides 6 as non-tetrazole analogs of imidazole AII antagonists such as EXP3 174 and the recently disclosed
4-ethyl-2-propylimidazole based ligands 3 (DMP 811) and 4 (DMP 58l)? The syntheses and biological
properties of these novel AII antagonists are presented here.
of Acvl Sulfonarmdes
The synthesis of the acyl sulfonamides 5 is exemplified by the preparation of the 5-carboxyimidaxoles St-g
(Scheme 2). The bromide alkylating agent 10 was prepared from 2bromoaniline (see Scheme 1). Diazotization,
followed by treatment with sulfur dioxide and copper(I) chloride, afforded the sulfonyl chloride 7. *u Reaction of
sulfonyl chloride 7 with fart-butylamine provided sulfonamide 8. Biaryl coupling with p-tolyltrimethyltin in the
presence of bis(triphenylphosphine)palladium(II) chloride gave the biaryl sulfonamide 9.l’ Benzylic
bromination with N-bromosuccinimide (NBS) and a&-azoisobutyronitrile (AIBN) as catalyst afforded the
desired alkylating agent 10.

SO,NHCBu

Acyl sulfonamides Sf-g were prepared starting with imidazole 11. 12 Alkylation with bromide 10 gave a mixture
of regioisomers 12 and 13 that were separated by flash chromatography. The regiochemistry of the alkylatlon
was determined by examination of the nuclear Overhauser effect (NOE) between the benzylic protons, the
a-protons of the butyl group and the proton directly attached to the imidazole ring.

b
I

: a) K&O DMF, 10.24 h;(b) TFA 24 h:(c) RCOCI,

--i!TY
(d) I. RCOOH. C I, l-H ,50 “c, 8h, II. DBU. 50 -‘C. 12 h: (e) 2N LiOH.
 Potent imidazole AII antagonists 71

Treatment of regloisomer 13 with neat trifluoroacetic acid (TPA) cleanly removed the rerr-butyl group to give
free sulfonamlde 14. Reaction with benzoyl chloride in pyridine afforded the benzoyl sulfonamide 5a.
Acylation of free sulfonamide 14 using the imidazolyl ester of cyclopropanecarboxylic acid (prepared from the
acid and carbonyl diimidazole (CDI)) in the presence of 1,8-diazabicyclo[5.4.Olundec-7-ene (DBU) afforded the
cyclopropanecarbonyl sulfonamide Sb. The latter acylating conditions are the method of choice, generally
producing a cleaner, higher yielding reaction. Saponification of esters Sa-b gave the desired diacidic compounds
5f-g.

sofAcvlS_
The synthesis of the acyl sulfamides is outlined in Scheme 3. Alkylation of imidazole 11 with bromide13 15
provided a mixture of regioisotners 16 and 17 that were separated by flash chromatography. The minor isomer
17 was reduced to the aniline 18. then sulfamoylatecl with the required sulfamoyl chloride to give the acyl
sulfamides 6a-c. The sulfamoyl chlorides were prepared from the appropriate carboxylic acid and
chlorosulfonyl isocyanate.t4 Saponification of the imidazole esters 6a-c afforded the desired acids 6d-f.

a
-

b
I

~RsPgsm:(3KsC4~DMF.8h;@)Hp,10%WIC,MoOH.21h;(C)E~.THF.-50~to~,~h;
(d) UOH, THFMpo, a-12 h.

The in Vito binding affinities for the acyl sulfonamides and sulfamides were determined using rabbit aorta
membranes and rat midbrain as sources of ATt and AT2 receptors respectively (see Table). Tetrazole&*3 l-4,
19-21 are included for comparison purposes.
The binding data for the acyl sulfonamides indicates that this replacement for the tetrazole moiety produced
potent AII antagonists. The AT1 receptor binding affinity of the benzoyl sulfonamide analog of EXP3174,5h
was three-fold greater than that of the parent compound 2. Comparison of the cyclopropanecarbonyl
sulfonamides with their benzoyl counterparts indicated that the latter afforded the more potent AII antagonists
for both the ATt and AT2 receptors. In particular, the AT2 receptor binding affinity for the benzoyl
sulfonamide Sk (500 nM) was Cfold greater than that of the cyclopropyl analog 51 and more than 60 fold that of
the tetrazole DMP 5814. Generally, enhanced AT2 potency was observed when the substituent at the Qosition
of the imidazole ring was an aldehyde or ester, rather than the more polar carboxylic acid functionality.
72 E. M. NAYLORet al.

X -.,

5a SaNHCOPh H COOMe 21 >lOOO

5b S@NHCOc-Pr nBu H COOMe 39 8000
5c S~COPh nBu Cl CooMe 8.8 5300
5d S@NHCOPh nPr Et COOMe 0.5 1000
5e sQ$wxk-Pr nPr Et COOMe 2.6 2100
5f SmCOPh nBu H COOH 6.2 4500
5g SOgvHCoc-Pr nBu H COOH 5.8 5800
5h SO$WCOPh ?IBU Cl COOH 2.0 9500
5i SQ$IHCOPh nPr Et COOH 1.7 7ooo
5.i sO$wIcoc-Pr nPr Et CooH 4.3 >loooo
5k S~COPh nPr Et CHO 2.4 500
51 SOgHcDc-Pr nPr Et CHO 12 zoo0

6a NHSO2NHCOPh nBu H COOMe 20 1800

6b NHsogHCOc-Pr nBu H CQOMe 32 loo00
6c NHSO$JHCOn-Hept nBu H COOMe 1.9 500
6d NHSO$I-HCOPh nBu H COOH 6.0 >lOOOO
6e NHso~COc-Pr t&l H CQOH 7.4 >lOOOO
6f NHS~NHCOn-Hept nBu H COOH 0.2 2300

19 Tetramle nBu H COOMe 15 >5oooo

20 Tetrazole nBu Cl COOMe 13 >5oooo
21 Tetrazole nBu H COOH 2.9 >5oooo
DuP753 1 Tetrazole nBu Cl CH2OH 50 >5oooo
xP3174 2 Tetramle nBu Cl COOH 7.0 >5oooo
x4P811 3 Tctrazole nPr Et COOH 6.0 >lOOO
xwJ581 4 Tetrazole nPr Et CHO 8.0 >3oooo

a The binding data is presented as IC50 values - the inhibitor coocentr&ons that give 50% displacement of
‘251-~ar’.11eg-~m that is speciftiy bound to the AT1 or AT2 recepta as rqxuprk. Tlte pmtocols for the biing
assays are as described in ref. 15 except that BSA was omitted from the binding assay buffer.
 Potent imidazole AII antagonists 13

Replacement of the tetraxole moiety by acyl sulfamides (see Table) also produced potent AII antagonists. A
significant enhancement in binding affinities at both the AT1 and AT2 receptors was observed with the
n-octanoyl sulfamides, 6c and 6f compared to the benzoyl sulfamides. 6a and 6d respectively.

Zn Viva Stud&
The acyl sulfonamides, Sf and Sh wereevaluated in conscious normotensive rats.te The pressor responses to a
submaximal dose of AII (0.1 pg/kg iv) were measured before and after intravenous administration of the test
compound. Data for AII antagonists 5f and Sh together with their tetraxole analogs 21 and 2 are presented in
Graphs 1 and 2 respectively. Both the sulfonamides exhibited good inhibition of the All pressor response at 1
rug/kg; however, the duration of action was short.

PHL
100-

80.

Mean % Mean% 60’

Inhibition Inhibition
40.

i
-1
Time (h) Time 0)
- C!pd.# 21 1.0 mgkg iv (n=2) --0- Cpd.#2 0.3 mgkgiv (n=2)
---C Cpd. # Sf 1.0 mg/kg iv (n=2) ‘-)- Cpd. # 5h 1.0 mg/kg iv (n=2)

The antihypertensive effects of acyl sulfonamides 51 and Sj, analogs of DMP 811 3 were examined in renal
hypertensive rats.17 Cumulative iv injections (3 to 300 pg&g given at 15 minute intervals) of sulfonamide 5i or
Sj produ& a dose dependent fall in mean arterial pressure (MAP). Injection of captopril(3.0 mgkg) at 1.75 h
did not reduce MAP further. ED30 values (the dose required to decrease blood pressure by 30 mmHg) for
intravenous admhiisuation of AII antagonists Si and Sjwere0.009
and0.004
mgfkg respectively. These data are
similar to the analogous m value for the tetrazole DMP 811 3 (0.005 mg/kg)? An oral dose (0.1 mg/kg) of
the cyclopropanecarbonyl sulfonamide Sj produced a modest, sustained fall in MAP (max. 38 mmI-Ig).

The acyl sulfonamides and sulfamides were found to be potent AI1 antagonists with similar AT1 binding
ilffinities to their tetraxole counterparts. Replacement of tetrazole by either an acyl sulfonamide or sulfamide led
to an enhancement in AT2 potency. This was particularly pronounced with acyl sulfonamides and sulfamides
bearing hydrophobic groups and imidazole moieties with lipophilic substituents. In normotensive rats, acyl
sulfonamides 5f and Sh displayed good inhibition of the AI1 pressor response but short duration of action
compared to their tetrazole analogs. Further in vivo studies will be required to determine whether or not this is a
general phenomenon of AII antagonists with acyl sulfonamide moieties.
74 E. M. NAYL.ORet al.

Acknowledgment: We would like to thank Dr. George A. Doss for conducting the NOE experiments and Dr.
Lawrence F. Colwell and Ms. Amy M. Bemick for FAB-mass spectrometry services.

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(Received 29 July 1993; accepted 21 September 1993)