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1H and 13C n.m.r.Conformational Analysisof Adrenergic Drugs. Part2. N-Isopropyl-N- {3-[4(4-Methoxybenzoylamino)Phenoxy]-2-Hydroxypropyl} AmmoniumChloride, a New β1-BlockingAgentElena Gaggelli a , Nadia Marchettini a ,Alessandro Sega b & Gianni Valensin ca Department of Chemistry , University ofSiena , 53100, SIENA, Italyb Institute of Organic Chemistry, University ofSiena , 53100, Siena, Italyc Institute of Chemistry, University of Basilicata ,85100, Potenza, ItalyPublished online: 24 Oct 2006.

To cite this article: Elena Gaggelli , Nadia Marchettini , Alessandro Sega &Gianni Valensin (1989) 1H and 13C n.m.r. Conformational Analysis of AdrenergicDrugs. Part 2. N-Isopropyl-N- {3-[4(4-Methoxybenzoylamino)Phenoxy]-2-Hydroxypropyl} Ammonium Chloride, a New β1-Blocking Agent, SpectroscopyLetters: An International Journal for Rapid Communication, 22:8, 1045-1063, DOI:10.1080/00387018908053957

To link to this article: http://dx.doi.org/10.1080/00387018908053957

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SPECTROSCOPY LETTERS, 2 2 ( 8 ) , 1045-1063 (1989)

13 H and C n.m.r. Conformational Analysis of Adrenergic Drugs. Part 2. 1

N-Isopropyl-N- I 3- [ 4( 4-Methoxybenzoylamino) Phenoxy 3 -2-Hydroxypropyl ) Ammonium Chloride, a New B -Blocking Agent.

1

KEY WORDS H NMR 13 C NMR adrenergic drugs spin-lattice 1

relaxation rates conformation in solution

Elena Gaggelli and Nadia Marchettini Department of Chemistry,University of Siena,53100 SIENA,Italy Alessandro Sega Institute of Organic Chemistry,University of Siena.53100 Siena, Italy Gianni Valensin Institute of Chemistry,University of Basilicata,85100 Potenza, Italy _________________-__---------------------------------------------------

Dynamic and structural features of N-Isopropyl-N- I 3-[4(4-Met oxyben- zoylamino)Phenoxy] -2-Hydroxypropyl I Ammonium Chloride in [ HB]DMSO were invest'gated by measwin5 I3C and H spin-lattice relaxation rates and "C- I 'H I 'rind H- ( H I n.0.e. Correlation times for main and internal reorientational motions were interpreted in terms of internal rotation around the two planal axes. Selective and double-selective 'H spin-lattice relaxation rates were measured, wherefrom relevant proton-proton intramolecular distances were calculated. It was shown that the I3 - blocking agent assumes a preferred conformation where extensive intramolecular H-bonding prevents segmental motion along the quaternary ammonium sidechain.

9 1

1

1

1045

Copyright 8 1989 by Marcel Delrker, Inc.

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1046 GAGGELLI ET AL.

------------ INTRODUCTION

N-isopropyl-N- ( 3- [4( 4-methoxybenzoylamino)phenoxy] -2-hydroxypropyl I

ammonium chloride (1) (figure 1) is a recently synthesized drug di-

splaying strong R -blocking adrenergic activity without appreciably 1

affecting R -adrenergic receptors. A further remarkable property of

this drug is that it selectively blocks the chronotropic vs. the ino-

tropic effects. Such chronoselectivity is likely to make this drug

safer than other R-blocking agents. It is in fact possible to obtain

anti-ischemic activity at myocardial level with low risk of undesired

effects on the strength of contraction.

1

2 -

2,3

4 As a further step in our NMR investigations of adrenergic drugs,

here we present NMR delineation of motional and structural features of

1 in solution with the aim of correlating biological activity with

conformational parameters. Dynamic- and/or structure-sensitive terms

can be in fact evaluated by considering homo- and hetero-nuclear dipo-

lar interactions, as measured by C and H NMR spin-lattice relaxati-

on rates and C - I H land H-{ HI nuclear Overhauser effects.

13 1

13 1 1 1

------------ EXPERIMENTAL

The R-blocking agent was supplied by Menarini (Florence, Italy).

Solutions were made in DMSO-d 99.96% (Merck) and were carefully

deoxygenated by bubbling nitrogen gas. 6

The NMR experiments were carried out on a Varian VXR-200 FT-NMR

spectrometer at probe temperature of 25+loC. Chemical shifts were

referenced to internal TSP-d 2 mmol dm . -3 A

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ADRENERGIC DRUGS. I1 1047

18 17 15 11 10

1' 18' 17' 11' 10'

Figure 1 - Molecular formula of compound 1.

1 13C and H non selective spin-lattice relaxation rates were measu-

red with the inversion recovery pulse sequence (t-180- ' t -90) . 80 and 12 FIDs were respectively collected for each experiment. The relaxati-

on rates were calculated with an exponential regression analysis of

the recovery curves of longitudinal magnetization components by u s i n g

the computer of the spectrometer. An accuracy of 4% was calculated

in almost every case.

n

Selective and double-selective proton spin-latttice relaxation

rates were measured with inversion recovery pulse sequence in which

the 180° pulse was provided by the proton decoupler switched on for

relatively long times at the selected frequencies at low power. Typi-

cal experimental settings for a 180" pulse were 20-30 ms with 12-18 db

attenuation. The 9 0 O pulse was, in contrast, the usual nonselective

90" pulse provided by the proton transmitter. Examples of selective

and double selective partially relaxed spectra are given in figure 3.

The corresponding relaxation rates were calculated in the initial rate

appoximation. 1

5

COSY 2D H NMR experiments were performed using pulse sequences

described in Ref. 6. The spectral width was 2000 Hz, and the data set

consisted of 1024 points in both the t and t dimensions. 16 FIDs

were collected for each value of t for a total accumulation time of 1

ca. 8 h. 1

1 2

H J resolved 2D spectra were obtained using the pulse sequence

described in Ref. 7. The spectral width was 2000 Hz and the data set

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1048 G A G G E L L I E T A L .

consisted of 1024 points in the t dimension and 128 points in the t 2 1

dimension. 16 FIDs were collected for each value of t for a total

accumulation time of ca. 4h. 1

------- RESULTS

------ 1 1 The 200 MHz H NMR spectrum is shown in figure 2 , while all H NMR

parameters are summarized in table 1. Assignments were performed on

the basis of COSY experiments and reference to data in the literature.

Coupling constants were measured in 2D J spectra and ratified by com-

puter simulation of spin patterns. Non selective H NMR relaxation

rates are reported in table 2 together with some selective and double-

selective spin-lattice relaxation rates to be used for delineation of

conformational features. Typical experiments for measurement of double

-selective relaxation rates are shown in figure 3 where simultaneous

excitation of the imino proton H and either H or H is conside-

red. The fact that the double-selective relaxation rates are faster

than the selective ones indicates (eqs.(4)) that W > W and, hence,

that molecular motions are within the extreme narrowing region. As

a consequence, F ratios (table 2 ) can be used to state that the dipo-

lar interaction provides the dominant relaxation mechanism. The lower

than 1.5 F ratios for methylene and methyl protons can be in fact

accounted for by considering that the relaxation mechanism is mainly

prov'ided by dipolar interactions between geminal protons that cannot

be separated by selective irradiation, such that, for this interacti-

1

13 11 17

8 2 0

8-10

5

nsel sel i i *

on, R = R 1 The temperature dependence of H NMR spectra is exemplilAcd in

figure 4 for selected regions of the spectrum. It is evident that

raising the temperature results into sharpening of linewidths, thus

improving the resolution of multiplets.

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ADRENERGIC DRUGS. I1 1049

Y

a2 Q) N

II

c

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10 50 GAGGELLI ET A L .

H 1.23 J = 6.5 1 182

1.26 H1' H

H 4

4'

HZ H

H 21

7,7'

H5 H

H

H

6

10,lO'

18,18'

H1l,ll' H

H 17,17'

3

2.95 J = 12.3 4,4' 3.11

3.31

3.85

3.96

4.19

5.90

6.94

7.04

7.68

7.95

8.56

H 8.83

H 10.05 3'

13

J = 5.6

J = 4.9 795

5,6

J = 8.8 10.11

J = 9.' 17,18

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ADRENERGIC DRUGS. I1 1051

10 9 8 7 6 5 4 3 2 1 PPm

1 Figure 3 - Partially relaxed H NMR spectra of 1 showing double-selec-

tive excitation of the imino proton H and either H or

H 13 11

17'

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1052 GAGGELLI ET AL.

Table 2 Non selective, selective and double selective 1 H NMR

-3 spin-lattice relaxation rates of 1 0.02 mol dm in DMSO-d T=298 K 6'

H

H 1

1'

H4

H

H

H

2

21

7

H

H 5

6

H

H

H

10,lO'

18,18'

11,111

H 17,17'

H

H 3,3'

13

3.12

3.64

6.42 5.06

2.85

1.30

5.26 4.95

3.11

3.14 2.13

1.79 1.38

1.53 1.02

1.46 1.08

1.49 1.11

3.28

3.24 2.33

1.27

1.06

1.47

1.30

1.32

1.35

1.34

1.39

R44'7= 5.17

R 4'3= 5.10 4

784

7,6 R7 = 5.06

R7 = 5.02

6.5 = 2.45

R 6'7= 2.20 6

6 10,11

18,17 = 1.56

R = 1.25

= 1.27

= 1.26 R RL1ll, 13 11 17,13

= 1.32 17,18

R17 R = 1.34 17

R1 0

1811, 10

13'''= 2.56

= 2.64 R13~3.i7 *13

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H 6

H 3,3'

& T=85OC

A A - T=25OC

I I I I I ! I I I , , , I a , , , , , , , b S S S 10% 9.9 E .b

T=78OC

- .9 3 b

T=25OC

- 3 .s 2.b

Figure 4 - Temperature dependence of se lected regions of the spectrum

i n f igure 2.

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1054 GAGGELLI ET AL.

I3C NMR parameters are shown in table 3. Assignments were performed

on the basis of I3C spectral editing for quaternary, methine, methyle-

ne and methyl carbons (attached proton test)" and reference to data

in the literature. The spin-lattice relaxation rates (R ) and the

n.0.e. values allow to build up, together with some specific H NMR

relaxation rates, the data matrix wherefrom a dynamic picture of mole-

cular motions can be gained. The fact that I3C relaxation rates, nor-

malized to the number of attached protons (R /n ) , are characterized

by different values in different moieties is a direct proof that

molecular motions cannot be described within the framework of whole

isotropic motion.

1 1

1 H

12,13

DISCUSSION

--_------- Motional features of the benzanilide moiety were first considered

as aromatic carbons have fewer degrees of freedom than side chain car-

bons. The fact that I 3 C spin-lattice relaxation rates of protonated

carbons within any ring are similar to each other but different from

those within the other ring demonstrates that molecular motions within

the benzanilide moiety are not completely isotropic. Applying the for-

mula by Allerhand et al. (Rl/nH = 2 . 0 2 3 5 ~ 1 0 ~ ~ 1 ) would lead to

calculate T = 90 ps and 130 ps for reorientations of C - H ( o r

C -H ) and C -H (or C -H ) relaxation vectors respectively;

12

17 17

18 18 10 10 11 11 whereas consideration of 0 and 0 as calculated by the

differences R

R

17,18 se57 I l8 17 :fd ' sel 10,11 - 10 17 18

sel 14-18 11 10 C

- R18 ) and R

would lead to calculate T = 250

- R (or R 17

sel 10,11 (or R - Rll ) t

ps and 170 ps for reorientations of H -H and H -H relaxation

vectors respectively. Evaluation of such correlation times strongly

suggests that the C -C and the C -C axes provide the main rotati-

onal axes for ring A and B respectively. Relaxation rates of ring

17 18 10 11

16 19 9 12

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ADRENERGIC DRUGS. I1 1055

carbons could be therefore interpreted in terms of an anisotropic mo-

del made by internal librational motions coupled with a main reorien-

tational rotation around the two molecular axes, leading to T =

30 ps and 90 ps for rings A and B respectively, being T the cor-

relation time for internal motion. The fact that internal motions are

different in the two rings is consistent with the steric hindrance

exerted by the quaternary ammonium side chain vs. that by the methyl-

oxy group.

12,19 G

G

The obtained values of correlation times were then used to evaluate

the distances between the amide proton H and H and H by making

use of double-selective irradiation techniques, as shown in figure 3.

The following equations could be in fact given by considering the

explicit forms of relaxation transition probabilities:

13 11 17'

8,lO

from which the two distances can be calculated by suhstituting the va-

lues of the correlation times for internal motion. Moreover, a com-

parison with the Dreiding model of the benzanilide moiety provides a

way o f determining the dihedral angles between the amide unit and

either ring A or ring B from the calculated distances. Angles and di-

stances are summarized in table 4 and illustrated in figure 5.

The same kind of approach, based on interpretation of spin-lattice

relaxation rates, was also considered for conformational analysis of

the quaternary nitrogen sidechain. As already stated, measuring cross-

relaxation terms allows to evaluate interproton distances provided a

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1056 GAGGELLI ET AL.

V H n.0.e. R 1 Carbon 6 -1 -1

( PPm) ( 8 ) ( 6 )

C

C

C

C

1

1'

4

2

c21

c7

c18,18'

cll, 11 1

C 5

C 10,lO'

C

C

'16 C 9

C 19

12

17,17'

17.9

18.4

46.5

49.3

55.2

65.0

69.8

113.1

114.1

121.7

126.7

127.6

132.6

154.1

161.4

164.5

5

5

1.86 2.02 2 0.11

2.07 2.03 5 0.10

1.87 5.81 2 0.41

1.88 2.48 5 0.13

2.07 0.60 L 0.02 2.05 3.27 2 0.14

1.90 6.06 5 0.25

2.02 1.81 2 0.03

1.94 2.66 2 0.07

2.01 2.60 2 0.05

1.29 0.23 2 0.01

1.91 1.79 5 0.03

1.13 0.44 2 0.03

0.29 0.30 2 0.02

0.75 0.21 2 0.02

1.32 0.19 5 0.01

0.67

0.67

2.90

2.48

0.20

3.27

3.03

1.81

2.66

2.60

---- 1.79

---- ---- ____ ----

rll, 13 @

2.30 L 0.1 A

+ 40 - r 2.20 2 0.14 A 17.13

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ADRENERGIC DRUGS. I1 105 7

Figure 5 - Projection of the benzanilide moiety: A , plane of ring A ;

A ' , plane of the amide unit; B, plane of ring B.

guess of the motional correlation tlme can be made. It is evident from

the data in table 3 that normalized 13C relaxation rates of sidechain

carbons, but those of the methyls, are very close to each other and

not very different from those of ring carbons. Such feature, if consi-

dered together with the sixth power dependence on the interproton di-

stance, decreases the error introduced by the assumption of motional

correlation time. Moreover, these findings point to absence of free

rotation of the alkyl chain, thus suggesting the occurrence of some

'preferred' conformation.

As a consequence, from the appropriate double selective and selec-

tive relaxation rates and using T = 140 ps (table 2). it was possi-

ble to estimate r = 2.7 2 0.1 A and r = 2.9

+ 0.1 A . This set of distances is consistent with only one conformati-

on, shown in figure 6. In such a spatial arrangement there are not

eclipsed bonds and hydrogen bonding can occur between: i) the alcoho-

lic oxygen 0 and anyone of the two N H+ protons; ii) the alcoholic

0

= 2.2 & 0.1 A , r 596 4,7 6,7

-

6 3

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1050

H

H

GAGGELLI ET AL.

H

H

I I I I l l 1 7 1 I l l

-3 2 Figure 6 - 'Preferred' conformation of 1 0.02 mol dm in [ H IDMSO.

6

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ADRENERGIC DRUGS. I1

Table 5

1059

Temperature dependence o f chemical s h i f t o f exchangeable p ro tons

o f 1 (0.02 mol dm-3 i n DMSO-d ) 6

Proton

oxygen 0 and uorh N H+ pro tons and i i i ) one of t h e N H+ pro tons and

6 ' t he e t h e r e a l oxygen 0

The presence of t hese H-bonds is l i k e l y t o p reven t segmental motion

a long t h e s i d e c h a i n , a t least wi th in t h e C -N segment, a f ac t t h a t

ag rees wi th I3C r e l a x a t i o n ra tes t h a t i n d i c a t e a very l i m i t e d e x t e n t

o f i n t e r n a l f l e x i b i l i t y while going from t h e benzan i l ide moiety t o t h e

quaternary n i t rogen .

6 3 3

8' 3 while t h e o t h e r N H+ is hydrogen bonded t o 0

7 3

1 The temperature dependence o f H NMR chemical s h i f t s ( f i g u r e 4 )

was s u b s t a n t i a l l y r a t i f y i n g the occurrence o f t h e hydrogen-bond

between hydroxyl and ammonium groups, s i n c e t h e temperature c o e f f i c i -

e n t s of t h e corresponding p ro tons were found t o be ( t a b l e 5 ) much

sma l l e r than t h a t o f t h e amide NH proton. Moreover, when r a i s i n g t h e

temperature , some almost f e a t u r e l e s s proton resonances ( e s p e c i a l l y t h e

two H resonances, f i g u r e 5 ) were changing t o well r e s o l v e d mult i -

p l e t s , wherefrom r e l e v a n t v i c i n a l coupl ings could be measured. Confor-

mational a n a l y s i s could t h e r e f o r e be at tempted even though r a i s i n g t h e

4

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1060 CACGELLI ET AL.

12.5 12 .5

J 9.2 9 . 4

2.1 1 . 9

J 4 , 4 '

J4 ' , 5

495

J 5.5

J 5.5

. J 6.5

597

5,7'

192

temperature is expected t o enhance t h e motional averaging p rocess o f

d i f f e r e n t conformers. I n s p i t e o f t h a t , t h e h igh temperature va lues o f

v i c i n a l coupl ings between H and H p ro tons are very d i f f e r e n t from

each o t h e r (2 .1 and 9.2 Hz r e s p e c t i v e l y ) and, t h e r e f o r e , sugges t une-

qual d i s t r i b u t i o n o f popu la t ions among t h e t h r e e main conformers. If

motional averaging does n o t occur a t high temperature , t h e same must

of course hold a t room temperature .

5 4

Where i t was p o s s i b l e to compare coup l ing c o n s t a n t s a t t h e two

temperatures ( t a b l e 1 and t a b l e 6 ) . very small, i f any, changes were

observed. I n o r d e r t o poss ib ly know t h e room temperature va lues of

J and J ' 3 mg of t h e l an than ide s h i f t r e a g e n t Eu( fod) were

added t o the s o l u t i o n such t h a t t h e H and H resonances could be

separated. As r e p o r t e d i n t a b l e 6, t h e v i c i n a l coup l ing c o n s t a n t s w i th

t h e H proton, as measured af ter a d d i t i o n o f t h e s h i f t reagent, a re

very similar to those measured a t high temperature. If t h e l an than ide

had somehow a l t e r e d t h e d i s t r i b u t i o n of conformer popu la t ions one

could n o t have found t h e same va lues of J's i n t h e two cases. I t can

4,5 4 ' , 5 ' 3

4 4 '

5

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ADRENERGIC DRUGS. I1 1061

I

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GAGGELLI ET AL. 1062

be therefore stated that the observed J's reflect the actual conformer

distribution at room temperature.

The fact that the two J vicinal couplings are equal to each

other suggests that the two dihedral angles between the H -C -C plane

and the C -C -H or the C -C -H planes are very close to each other.

On the other hand, the two vicinal couplings between H and H protons

suggest that the two dihedral angles between the H -C -C plane and

the C -C -H o r the C -C -H planes are very different from each

other.

5,7

5 5 7

5 7 7 5 7 7 '

4 5

5 5 4

5 4 4 5 4 4 '

The spatial configuration of the sidechain, as obtained by consi-

dering double selective and selective relaxation rates (figure 6 ) ,

agrees with the calculated 3J values: the C -H bond almost bisects

the H -C -H angle ( - C O O ) and the angles between the C -H bond and

the C -H and C -H bonds are, respectively, - 2 5 O and -95' (figure

5 5

7 7 7 ' 5 5

4 4 4 4 '

7 ) .

It is interesting to note that the 'preferred' conformation found

for the present compound in DMSO solution on the basis of NMR relaxa-

tion data is in very good agreement with that suggested for proprano-

101, another R-adrenergic antagonist, in solution. 20

1 C.A.Maggi, S.Manzini, M.Capasso, M.Parlani, and A.Meli, Proc. 5th

Int. Catecholamine Syrnp., Goteborg (Sweden) (1983).

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ua te Received: 05/25/89 Date Accepted: 06/24/89

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