45

A Thiophene Analogue of Moprolol

Synthesis and Pharmacological Study of a Thiophene Analogue of
Moprolol and Related Compounds
M.B.El-Ashmawy and J. Lissavetzky*
Instituto de Quimica Mddica (C.S.I.C.), Juan de la Cierva 3,28006 -Madrid, Spain

V. Darias and D. Martin-Herrera
Departamentode Farmacagnosia-Farmacodinamia,Facultad de Farmacia, Universidad de la Laguna, Tenerife, Spain
Received August 4,1989

The syntheses of the thiophenic analogue of Moprolol (Id) and of its related
compound l a are described. From a preliminary pharmacological evaluation
compound Id seems worthy of further studies due to its notable P-blocking
activity and its remarkable anti-plateletaggregationaction.

Moprolol') is an interesting P-blocker commercialized in Italy as Omeral,
being of clinical

We describe in this paper the synthesis and a preliminary
pharmacological evaluation of the p-adrenergic blocking
activity of the thiophene isoster of Moprolol Id. The
pharmacological profile of this compound is completed
with the study of its in vifro antiplatelet aggregation activity.
fjO-*-L*-w-pJ

Synthese und pharmakologische Untersuchung eines Thiophen-Analogen von Moprolol und venvandter Verbindungen
Die Synthese des Thiophenisosters I d des Moprolols und der verwandten
Verbindung la wird beschrieben. Aus einer vorlaufigen phakologischen
Untersuchung geht hervor, da6 Id wegen seiner P-Rezeptoren blockierenden
Wirkung und seiner beachtenswerten antiagpgatorischen Eigenschaften
weiter untersucht werden sollte.

by a new method in our laboratory4), has been used as a
convenient starting material to obtain the oxirane derivative
5 in an acceptable global yield. Treatment of 5 with a great
excess of isopropylamineafforded Id.
The planned synthesis of the other thienyloxy propanolamine derivatives la-c has been approached by an altemative route starting from the hydroxythiophene compounds
6a-c as depicted in Scheme 2.

on

OH

YOPROLOL

Besides, we wish to report the synthesis and pharmacological evaluation of compound la, in whi; ch the presence of
a lipophilic chloro substituent at the thiophenic ring can be
interesting for the antiplatelet aggregation activity. Unfortunately compounds l b and l c could not be synthesized so
that structure-activity relationship studies could not be performed.
Compound Id has been prepared as depicted in Scheme 1.
3-Bromo-4-methoxythiophene(Z), recently synthesized

.:x=n

, YICI

b:X=H

I YrOCH3

0:xta

I

d:X=ocIIs

Y=H
Y=H

The reaction of the potassium salts of 6a-c, prepared from
K-terr-butoxide with epichlorohydrin in DMSO led to the
epoxides 7a-c, which were reacted with a great excess of
isopropylamine at room temp. The expected open chain pro-

F

Arch. Phurm. (Weinheim)324.45-48 (1991)

OVCH VerlagsgesellschaftmbH, D-6940 Weinheim, 1991

0365-6233/91/0101-0045S 3.50 + .25/0

46

Lissavetzky and coworkers

+

Schomo 2

In contrast with the lack of partial agonist activity of Moducts 8a and 8b were successfully isolated, but in the case
of 8c a lactamic neutral compound was obtained in 61% prolol*), the thiophenic isoster l d shows a moderate intrinyield which was identified by its spectral and analytical data sic sympathomimetic action in reserpinized rats higher than
that observed for Alprenolol (Table 2).
(Table 1).
These compounds decrease the responses to a nociceptive
Hydrolysis of compounds 8a-c by heating at refluxing
temp. with 1N NaOH gave only two of the desired carbox- stimulus, this effect being smaller and shorter lasting than
ylic acids 9a and 9c, corresponding to the monochlorosub- that shown by Propranolol and Alprenolol.
On the other hand compounds la and Id show a remarkstituted derivatives in good yield. On the other hand, the
acid derivative 9b could not be obtained, neither by the able "in vitro" antiplatelet aggregation activity, specially
described isolation method nor by any modification per- that referred to the inhibition of the aggregation induced by
formed. The reaction product has been assigned as 10 based collagen, having IC50 values lower than Aspirin (Table 3).
In the assays of approximate acute toxicity carried out on
on its analytical and spectral data. This compound was
probably formed via hydrolysis and subsequent demethyla- mice, these new compounds, which were administered in
tion and decarboxylation of the corresponding not isolated two different ways, proved to be much less toxic than Alprenolol and Propranolol.
derivative 9b.
In conclusion the thiophenic isoter of Moprolol Id seems
Thermal decarboxylation of the thiophene-2-carboxylic
acid 9a gave the desired final product l a in 56% yield, to be worthwile of further study. This compound has a noisolated as its HC1 salt. Unfortunately, the decarboxylation table P-blocking activity and unlike the benzenic Moprolol,
product from 9c could not be isolated. Decomposition in the shows a weak partial agonist activity. Furthermore, this
reaction medium was observed, probably due to the thermal compound has a remarkable antiplatelet aggregation activity, that improves considerably its pharmacological profile.
instability of the product.
The results of a preliminary pharmacological testing of the
thienyloxypropanolamine la and Id are presented in tables Experimental Part
2 and 3.
Melting points: Biichi 510 m.p. apparatus, Melting and boiling points are
Compound Id, a thiophenic isoster of Moprolol, displays
a level of activity in inhibiting positive chronotropic and
hypotensive responses similar to Alprenolol and about 80%
of that of Propranolol. This compound presents a greater
capacity for blocking the vascular than the myocardic receptors. This lack of cardioselectivity must, however, be confirmed in further experiments on animals capable of yielding more meaningful results.
Direct cardiovascular effects of these compounds are
weaker than those of the reference drugs (Table 2).

uncorrected. - IR spectra: Perkin-Elmer 257 spectrophotometer. - 'HNMR-spectra: Varian EM 390 (90 MHz) spectrometer in the solvent indicated, using TMS as int. stand.; chemical shifts in Gppm. - Analysis of
C.H.N. are within M.3%of the theoretical values and were done at the
Microanalysis Department at C.N.Q.O. (Madrid).
Zj-Epoxy-l-(4-methoxy-3-rhienyloxy)propand) (5).
S-chloro-J-hydro.~y-2-metho~~carb"11~lthiophe11~~
(6aA
3 - h ~ d r o , ~ - S - n r e t h o , ~ - 2 - n 1 ~ t h ~ . , ~ c ~ r b o ~ ~ y(6b).
lthiopheii~'
4-chloro-3-hyd~o.~~-2-n1eiho~carbo11yhhi~~phe~1~'
(6~)

These compounds were prepared according to the lit. cited.

Arch. Pharni. (Weiiiheinl) 324.45-48 (1991)

A Thiophene Analogue of Moprolol

47

Table 1: Physical and spectroscopicdata of the thiophenic compounds 1and 7 - 10.
a D20; Cmb.

-

--

Comp .

M.p.
OC

Yield

la

121-2

56

%

Mol. Formula
(M. Wt.)

Analysis
Calc./Found
%C
%H
%S
12.1 5.65
12.4 5.57

IR
(Nujol)
cm-'
3 180f OH)

'H-NM

11.2
11.0

2520(NH)

53.9 7.81 13.1
53.7 7.92 13.3

3280(0H)
3120(NH)

1.10 ( d , 6H, (CH,),C);
1.85-2.05
(m, 2H, NH, OH); 2.75-2.95 ( m , 3H,
CHz-NH-CH-); 3.95 ( s , 3H, OCH,);
4.00-4.41 ( m , 3H, -OCH,-CH-); 6.25
( d . l H , J2,,=3.9Hz, H-2 thiophenic);
6.35 ( d , lH, J2,,=3.9Hz, H-5
thiophenic)".

43.5
43.2

12.9
13.1

1680(C=O)

2.85 ( m , 2H, -CH,-epoxy); 3.30 ( m , 1H
-CH, -epoxy); 3.80 ( s , 3H, COOCH,);
4.30 ( m , 2H, -OCH,-); 6.75 ( s , lH,
H-4 thiophenic).

49.2 4.95 13.1
49.0 4.66 12.8

167@(C=O)

2.80 (m, 2H, -CH,-epoxy); 3.30 (m, 1H
-CH-epoxy); 3.80 ( s , 3H, -OCH,); 3.90
( s , 3H, COOCH,); 4.25 ( m , 2H, -OCH,);
6.10 ( s , lH, H-4 thiophenic)b.

M.S.
(Rel.
Int.)

1.40 ( d , 6H.(CH,),C);
3.30 (m, 2H,
CH7-N); 3.55 ( m , 1H. N-CH); 4.05-4.45
( m , 3H, -OCH,-CH); 6.40 ( d , lH,
J,,,=ZHz, H-4 thiophenic); 6.85
( d , lH, J,,,=2Hz, H2 thiophenic)".

Id

65-6

57

la

83-4

63

7b

68-9

77

lc

50-1

52

C,H,ClO,S
(248.7)

43.5 3.65
43.2 3.73

12.9
12.7

1710(C=O)

2.80 ( m , 2H, -CH,-epoxy); 3.40 ( m ,
lH, -CH-epoxy); 3.90 ( s , 3H, COOCH,);
4.35 ( m , 2H, -OCH,); 7.45 ( s , lH,
H-5 thiophenic)".

aa

128-9

63

C,,H,,Cl,NO,S
(344.3)

41.9 5.56
41.8 5.82

9.3
9.6

340@(OH)
2450(NH)
1680( C=O)

3.30-3.60 ( m ,
1.45 ( d , 6H, (CH,),-C);
3H, CH,-NH-CH); 3.85 ( s , 3H, COOC&);
4.25-4.35 (m, 3H, -OCH,CH-); 7.05 ( S ,
lH, H-4 thiophenic)".

308( 3)
72(100)

8b

103-4

72

C,,H,,ClNO,S
( 339.8)

45.9
45.7

6.52
6.37

9.4
9.3

3480(0H)
2470(NH)
1670(C-0)

3.20-3.60 (m,
1.55 ( d , 6H, (CH,),C),
3H, CH,-NH-CH); 3.80 ( s , 3H, -OCH,);
4.00 ( s , 3H, -COOCH,); 4.20-4.50 (m,
( m , 3H, OCH,-CH-); 6.25 (s, lH, H-4
thiophenic)".

304(2)
72(100)

8c

142-3

61

C, .H,,ClNO,S
( 275.7)

47.9 5.12
47.7 5.33

11.6
11.4

3440(0H)
1590( C=O)

2.45 (bs, lH,
1.20 ( d , 6H, (CH,),C);
HO-C); 3,50 (d,2H, CH,N); 3.95 ( m ,
lH, N-CH); 4.40 ( d , 2H, -OCH,); 4.65
(In, lH, -CH-0); 7.25 (s, lH, H-5
thiophenic)".

275( 56)
160(100)

9a

196-7

82

40.0
39.9

5.19
5.07

9.7
9.6

3390(0H)
2470(NH)
1660(C=O)

1.35 ( d , 6H,(CH,),C);
3.30 ( m , 2H,
CH2-H); 3.50 (In, 1H. N-CH); 4.15-4.45
(m, 3H, OCHz-CH): 6.95 ( s , 1H. H-4
thiophenic)".

295( 1)
72( 100)

9c

170-1

81

40.0 5.19
40.2 5.12

9.7
9.6

3290(0H)
2440(NH)
1690( C=O)

1.25 ( d , 6H, (CH,),C);
3.15-3.55 (m,
3H. CH,-N-CH); 4.10-4.30 ( m , 3H,
-OCH,CH); 7.30 ( s , lH, H-5
thiophenic)".

295(2)

12.0
12.3

3270(0H)
2400( NH)
1670(C=O)
1610(C=C)

1.35 ( d , 6H, (CH,),C);
3.20 ( m , 2H.
-CH,-N); 3.50 ( m , 1H. N-CH); 4.204.40 ( m , 4H, OCH,-CH, H-5 thiophenic),
( s , IH, H-3 thiophenic).

10

188-9

55

C,H,ClO,S
(248.7)

C,,H,,ClNO,S
(267.8)

44.9
44.9

3.65
3.39

6.77
6.65

-3-Isopropylantino-1-(4-ntethoxy-3-thienyloxy)-2-propanol
(Id)

24S(3,
72( 130)

7 2 ( 100)

vacuo (0.1 mm Hg) to dryness. The residue was thoroughly extracted with
lsopropylamine (10 ml) was added to 2,3-epoxy-1-(4-methoxy-3-thieny1- boiling n-hexane. The extract was concentrated and the solid so formed
was filtered and recrystallized from isopropanol (Table 1).
0xy)propane 5 (2.04 g; 0.01 mole). The mixture was left at room temp. for
Reactions
of rhe epoxy compounds 7a-c wirh isopropylantine
4 days and then evaporated to dryness. The residue was crystallized from
n-hexane to give I d as a colourless solid in 57% yield.
This reaction was canied out similarly to that for Id. After distilling off
the excess mine, the different products 8 were obtained as follows:
1-(2-Methoxycarbonyl-3-thienyloxy)-23-epoxypropane
7a-c
a) l-~5-Chloro-2-ntetho.rycarbonyl-3-rhien~lo.~)-3-isoprop~lan1i1ioEpichlorohydrin (14g; 0.15 mole) was added dropwise to a stirred mix2-propano1,HCl &
()I
ture of the respective 3-hydroxy-2-methoxycarbnyl-thiophene6a-c (0.1
mole) and K-tert.butoxide (12.3 g; 0.11 mole) in 170 ml of DMSO.The
8a-HCI was precipitated upon treating the ethereal solution of the base
with HC1-gas in ether and recrystallized from ethanol/ether.
mixture was heated at 9WC for 3 h, left to cool and then evaporated in

Arch. Pharm. (Weinheint)324-4548(1991)

48

Lissavetzky and coworkers

Table 2: Pharmacological data
~-

Compound

% Inhibition
of i s o p r o t e r e n o l e f f e c t s
in rats

a

Hypotension

64.5

25

20.05

-l

d

19.5

08

21

Alprenolol

82.5

73

38

0

’artial

,gonist
Heart
rate

Tachycardia

-l

Direct e f f e c t s i n ratsa
Blood
pressure

ictivityb

1

Local a n e s t h e s i a
% inhibition
of response‘
10 min. 45 min.

4cute toxicity
rprox. LD

50

iv

ip

)ZOO

)200

30

>zoo

>zoo

40

32

100

22

75

4

20

0

20

17

60

31.5

13

85

Propranolol
Procaine

a

Single i.v. doses of 4 mg/Kg. a l l standard errors of the mean fell within the range of 6 - 1 3 of the man

b

Maxinun per cent increase i n the heart rate reached i n the 0.01-4 q / K g i v dose range. Standard error of
the mean fell within the range of 510%of the mean.

c

X inhibition of response t o 0.5% solution of test cmpayd

b) 3-lsopropylamino-1-(5-methoxy-2-methoxycarbonyl-3-thienylo~)- I-(2-Chloro-4-thienyloxy)-3-isopropylan1i1io
2-propan01,HCI (la)
2-propanol.HC1 (8b)
Compound 9a (Ig) was heated, under reduced pressure (0.1 mm Hg), at
Sb-HCl was obtained as 8a-HCI.
270’C for 30 min until1 C02 evolution had ceased. The residue was puric) 9-Chloro-3-hydroxy-5-isopropyl-3,45.6-tetrahydro-2H-thieno[3,2-b] fied by crystallization from an ethanol/ether to give 0.5 g (56%) of l a as a
I5-oxnzocin-6-one(&)
colourless solid of m.p. 121 ‘C
This product was isolated as shiny crystals upon triturating the reaction
Pharmacology
residue with diethyl ether.

Hydrolysisof 8

Direct effects of P-adrenergic blocking activity”, partial agonist activity”’, local anaesthesia”, inhibition of in vitro platelet aggregation” and
acute toxicity’) were determined as described.

0.01 Mole of the appropriate compound 8a-c was refluxed with 30 ml of
N NaOH for 1 h. The mixture was left to cool, treated with N HCI until
slightly acidic pH and then evaporated in vacuo to dryness. The residue
was triturated with absol. ethanol: inorganic salts were filtered off and the
References
filtrate was diluted with ether. The desired acid I-(2-carboxy-S-chloro-3thienyloxy)-3-isopropylamino-2-propanol
.HCI (9a) was obtained as col- 1 D.J. Crowther, D.J.Gilman, B.J. McLoughlin. L.H. Smith, R.W. Turourless crystals, while compound 10 (1-(25-dihydro-2-0~0-4-thienyloxy)- ner, and T.M. Wood, J. Med. Chem. 12,638 (1969).
2 R. Ferrini, G. Miragoli, and G. Groce, Arzneim.-Forsch. 20, 1974
isopropy1amino-2-propanol~HCO was obtained from 8b.
(1970).
Table 3: Inhibition of platelet aggregation
3 M. Radice, G. Folli, A. Tavecchia, G. Mariotti, and E. Cameroni,
Arzneim.-Forsch. 28,2160 (1978).
4 C. Corral, M.B. El-Ashmawy, J. Lissavetzky. A. Basilio, and A. Giraldez, Eur. J. Med. Chem. - Chim. Ther. 22,251 (1987).
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and D. Martin,I1 Farmaco-Ed. Sci. 42,268 (1987).
50
< 15
< 15
1.
6 C. Corral and J. Lissavetzky, Synthesis 1984,847.
7 C. Corral and J. Lissavetzky, J. Chem. SOC. Perkin Trans. I, 2711
> 250
100
4 15
l d
(1984).
8 J. Buendia, J. Nierat, and R. Deroy. Ger. Pat. 2719244 (1977). RousPropranolol
80
< 15
24
sel-UCLAF; C.A. 88,67047 (1978).
9 S. Conde, C. Corral and J. Lissavetzky, Arch. Pharm. (Weinheim)316,
#250
60
1s
Aspirin
537 (1983).
10 C. Corral, M.B. El-Ashmawy, J. Lissavetzky, R. Madronero, V. Dari110
115
>>250
Ticlopidin.
as, D. Martin, and E. Estevez, Eur. J. Med. Chem. - Chim. Ther. 20,
133 (1985).
[Ph726]

-

Arch. Pharm. (Weinheim)324.4548 (1991)