Synthesis and dopaminergic activity of heterocycli analogues of 5,6-dihydroxy-2-aminotetralins

Article abstract of DOI:10.1016/S0960-894X(00)00049-4

The heterocyclic analogues of 5,6-dihydroxy-2-aminotetralins (6) were synthesized and their in vitro dopaminergic activity was compared to that of (-)-DP-5,6-ADTN and the novel potent agonist Z12571. The results show that changing the cathecol ring for a heterocycle decreases the D₁-like activity of the target molecules 6. However, the D₂-like activity of tetra-hydroquinoline (6j) was comparable to that of (-)-DP-5,6-ADTN. (C) 2000 Elsevier Science Ltd. All rights reserved.

Full text of DOI:10.1016/S0960-894X(00)00049-4

Bioorganic & Medicinal Chemistry Letters 10 (2000) 563±566
Synthesis and Dopaminergic Activity of Heterocyclic Analogues
of 5,6-Dihydroxy-2-aminotetralins
Joan Bosch, a,* Tomas Roca, a Carles G. Perez a and Stefania Montanari b
aLaboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028-Barcelona, Spain
bR&D, Zambon Group spa, Via Lillo del Duca 10, 20091 Bresso (Milano), Italy
Received 15 October 1999; accepted 21 January 2000
AbstractÐThe heterocyclic analogues of 5,6-dihydroxy-2-aminotetralins (6) were synthesized and their in vitro dopaminergic
activity was compared to that of ( )-DP-5,6-ADTN and the novel potent agonist Z12571. The results show that changing the
cathecol ring for a heterocycle decreases the D1-like activity of the target molecules 6. However, the D2-like activity of tetra-
hydroquinoline (6j) was comparable to that of ( )-DP-5,6-ADTN. # 2000 Elsevier Science Ltd. All rights reserved.
Dopaminergic system disfunction in peripheral tissues
has been related to congestive heart failure (CHF).1
Pharmacological and biochemical evidence suggests the
existence of two subtypes of peripheral dopamine
receptors,2 called DA1 and DA2. Stimulation of these
receptors induces renal and peripheral vasodilation,
diuresis, and natriuresis. In addition, these receptors are
involved in the control of aldosterone and renin secre-
tion and sympathetic tone reduction. So, activation of
DA receptors exerts a neurohormonal control which is
potentially useful in the treatment of CHF.
for biological activity. Unfortunately, most of them (e.g.
( )2-(dipropylamino)-5,6-dihydroxytetralin (DP-5,6-
ADTN)3) do not show speci®city for DA receptors since
they also activate a adrenoreceptors, which o€sets the
bene®cial e€ects of dopaminergic stimulation. However,
aminotetralins Z10464 and Z125715 have been recently
identi®ed as speci®c dopaminergic agents. Nevertheless,
the low oral bioavailability and the short duration of
the e€ect6 of DA agonists containing cathecol or phenol
rings has stimulated the development of bioisosteres, in
particular heterocyclic replacements.7 Compounds 1±5
are examples of heteroaromatic systems reported as
cathecol/phenol bioisosteres.
During the last 20 years, a number of di€erent cate-
gories of compounds2a such as arylalkylamines, amino-
tetralins, tetrahydrobenzazepines, tetrahydroisoquino-
lines, and octahydrobenzoquinolines, which embody the
dopamine moiety, have been synthesized and evaluated
This led us to study whether replacing the cathecolic
portion of Z12571 by a heterocycle would lead to
compounds with similar dopaminergic properties but a
*Corresponding author. Fax: +34-93-402-1896; e-mail: jbosch@
farmacia.far.ub.es
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00049-4

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J. Bosch et al. / Bioorg. Med. Chem. Lett. 10 (2000) 563±566
better pharmacokinetic pro®le. With this aim, we syn-
thesized the class of compounds represented by the
general formula below. All the compounds were
screened for their D1-like and D2-like activities.
carboxylic acid 10 with thionyl chloride. Treatment of
the heterocyclic amines 7 with acyl chloride 8 under
typical acylation conditions, followed by reduction of
the resulting diamides 11 with borane±dimethylsul®de
complex gave the target diamines 6a±6c and 6e±6k. In
the case of diamide 11d reduction by this procedure
brought about concomitant reduction of the pyrrole
ring. More conveniently, reduction of 11d was achieved
by using a nucleophilic reducing agent, DIBAL-H.
Finally, cleavage of the methoxy group of 6k with 48%
aqueous hydrobromic acid a€orded diamine 6l.
The target molecules 6 were synthesized by a general
and ecient route, involving the acylation of an appro-
priate heterocyclic amine 7 with a common, easily
accessible acyl chloride intermediate 8.
The key intermediate 8 was prepared in 82% overall
yield as shown in Scheme 1, by acylation of 6-amino-
hexanoic acid with (4-methylsulfonylphenyl)acetyl
chloride (9),8 followed by treatment of the resulting
The required heterocyclic amines 7 were prepared either
as described in the literature (7a,9 7d,7e 7e,7a,7f 7g,7b
.
Scheme 1. i, NaOH, H2O, CH2Cl2. ii, SOCl2, DMF, CH2Cl2. iii, TEA, DMF, CH2Cl2. iv, (CH3)2S BH3 (DIBAL-H for 11d). v, 48% HBr.

J. Bosch et al. / Bioorg. Med. Chem. Lett. 10 (2000) 563±566
565
.
Scheme 2. i, NH2OH HCl. ii, H2, Raney Ni. iii, PrNH2, NaBH(AcO)3.
.
Scheme 3. i, H2NOCH2CH=CH2, ~. ii, ~, air. iii, 10% H2SO4. iv, I2, H2NC(S)OEt. v, (CH3)2S BH3.
Table 1. E€ect of structure modi®cation on dopaminergic activity
Compound
D1-like (pD2)
D2-like (pD2)
Compound
D1-like (pD2)
D2-like (pD2)
6a
6b
6c
6e
6g
6h
<5
<5
<5
6.3
<5
5.5
Ð
<6
Ð
8.4
5.5
<6
6i
6j
6l
<5
<5
<5
8.6
5.3
6.5
6.3
8.4
Ð
10.1
7.4
9.8
Z12571
DPDA
)-DP-5,6-ADTN
(
7h,7b 7j7a and 7k7a) or as outlined in Schemes 2 and 3
(7b, 7c, 7f and 7i). Reductive amination of 4,5,6,7-tet-
rahydro-5-oxoindole (12)10 with hydroxylamine hydro-
chloride or propylamine provided the primary and
secondary amines 7b and 7c, respectively. On the other
hand, the thiazole derivative 7f was prepared by
Hantzsch11 synthesis by reaction of 4-propanamido-
cyclohexanone (13)12 with O-ethyl thiocarbamate13 in
the presence of iodine, followed by reduction of the
propanamide 14 with borane±dimethylsul®de complex.
Finally, 6-aminoquinoline (7i) was prepared by thermal
rearrangement14 of the O-allyl ether oxime of the above
cyclohexanone 13, followed by acid hydrolysis of the
resulting amide 15.
to be necessary in this series to maintain a potent D1-
like activity, both the tetrahydroquinoline and the 2-
aminothiazole rings are suitable cathecol bioisosteres as
regards the D2-like activity. In this context, it is worth
mentioning that tetrahydroquinoline 3a has been
reported to be a relatively selective DA autoreceptor
agonist.7a
Acknowledgement
C.G.P. acknowledges ®nancial support by Zambon
Group spa.
An in vitro study of the dopaminergic activity15 of the
novel compounds was carried out. The pharmacological
data are summarized in Table 1. The D1-like activity
was evaluated as pD2 (-log EC50) on a superfused rabbit
splenic artery, whereas the D2-like activity was mea-
sured as pD2 on a superfused rabbit ear artery. As
can be seen in Table 1, changing the cathecol ring of
Z12571 for a heterocycle substantially decreases the D1-
like activity of the target molecules 6. The relaxant e€ect
of the aminothiazole derivative 6e shown in the splenic
artery test is not due to a dopaminergic activity, because
it is not antagonized by SCH23390, which is the selec-
tive D1-like dopamine antagonist used. As far as the D2-
like activity is concerned, tetrahydroquinoline 6j and
2-aminothiazole 6e proved to be potent agonists (pD2
8.4).
References and Notes
1. (a) Semeraro, C.; Marchini, F.; Ferlanga, P.; Masotto, C.;
Morazzoni, G.; Pradella, L.; Pocchiari, F. Clin. Exp. Hyper-
tens. 1997, 19, 201; (b) Jose, P. A.; Felder, R. A.; Monsma, F.
J.; Sibley, D. R.; Mouradian, M. M. In Cardiovascular and
Renal Actions of Dopamine; Soares da Silva, P., Ed.; Pergamon
Press: Oxford, 1993; pp 51±61.
2. (a) For a review on peripheral DA receptors, see: Ince, F. In
Comprehensive Medicinal Chemistry; Hansch, C., Ed.; Perga-
mon Press: Oxford, 1990; Vol. 3, pp 291±398; (b) Kohli, J. D.
Am. J. Hypertens. 1990, 3, 25S; (c) Goldberg, L. I.; Kohli, J.
D. Commun. Phsychopharmacol. 1979, 3, 447; (d) Goldberg, L.
I. Pharmacol. Rev. 1972, 24, 1.
3. (a) Grol, C. J.; Jansen, L. J.; Rollema, H. J. Med. Chem.
1985, 28, 679; (b) Grol, C. J.; Rollema, H. J. Pharm. Pharmac.
1977, 29, 153.
4. Montanari, S.; Bertolini, G.; Casagrande, C.; Cavalleri, P.;
Ferlenga, P.; Marchini, F.; Pradella, L.; Pocchiari, F.; San-
tangelo, F.; Semeraro, C. Bioorg. Med. Chem. Lett. 1996, 6,
2795.
In conclusion, the preliminary data presented suggest
that, although the presence of the cathecol moiety seems

566
J. Bosch et al. / Bioorg. Med. Chem. Lett. 10 (2000) 563±566
5. Montanari, S.; Cavalleri, P.; Fraire, C.; Grancini, C.;
Napoletano, M.; Santangelo, F. WO Patent 9608228, 1996;
Chem. Abstr. 1996, 125, 86653.
6. Swart, P. J.; Jansman, F. G. A.; Drenth, B. F. H.; de Zeeuw,
R. A.; Dijkstra, D.; Horn, A. S. Pharmacol. Toxicol. 1991, 68,
215.
8. Acyl chloride 9 was prepared following the procedure
reported for the preparation of (4-methoxy-3-methylphenyl)-
acetyl chloride: Katagari, N.; Kato, N. T.; Nakano, J. Chem.
Pharm. Bull. 1982, 30, 2446.
9. Hamdan, A.; Wasley, J. W. F. Synth. Commun. 1985, 15, 71.
10. Remers, W. A.; Gibs, G. J.; Weiss, M. J. J. Heterocycl.
Chem. 1971, 8, 1083.
11. For a review on thiazole Hantzsch synthesis, see: Katritzky,
A. R.; Rees, C. W. In Comprehensive Heterocyclic Chemistry;
Potts, K. T., Ed; Pergamon: New York, 1984; Vol. 6, pp 296±300.
12. 4-Propanamidocyclohexanone (13) was prepared following
the procedure reported for the preparation of the 4-acetamido
analogue: (a) Hall, H. K. J. Am. Chem. Soc. 1958, 80, 6412;
(b) Fraser, R.; Swingle, R. Can. J. Chem. 1970, 48, 2065.
13. Davies, W.; Maclaren, J. A. J. Chem. Soc. 1951, 1434.
14. (a) Kusumi, C.; Yoneda, K.; Kakisawa, H. Synthesis 1979,
221; (b) Irie, H.; Katayama, I.; Mizuno, Y. Heterocycles 1979,
12, 771.
7. (a) Glase, S. A.; Corbin, A. E.; Pugsley, T. A.; He€ner, T.
G.; Wise, L. D. J. Med. Chem. 1995, 38, 3132; (b) Claudi, F.;
Cingolani, G. M.; Giorgioni, G.; Cardellini, M.; Amenta, F.;
Polidori, C. Eur. J. Med. Chem. 1995, 30, 415; (c) Asselin, A.
A.; Humber, L. G.; Voith, L.; Metcalf, G. J. Med. Chem.
1986, 29, 215; (d) Cannon, J. G.; Demopoulos, B. J.; Long, J.
P.; Flynn, J. P.; Sharabi, F. M. J. Med. Chem. 1981, 24, 238;
(e) Bach, N. J.; Kornfeld, E. C.; Jones, N. D.; Chaney, M. O.;
Dorman, D. E.; Paschal, J. W.; Clemens, J. A.; Smalstig, E. B.
J. Med. Chem. 1980, 23, 481; (f) Schneider, C. S.; Mierau, J. J.
Med. Chem. 1987, 30, 494; (g) Laguzza, B. C.; Turner, W. W.
Eur. Patent 207696, 1987; Chem. Abstr. 1987, 106, 131726; (h)
Doll, M. K.-H.; Nichols, D. E.; Kilts, J. D.; Prioleau, C.
Lawler, C. P.; Lewis, M. M.; Mailman, R. B. J. Med. Chem.
1999, 42, 935.
15. For in vitro pharmacological methods, see: Emerson, M.;
Paul, W.; Ferlenga, P.; Semeraro, C.; Page, C. Br. J. Pharma-
col. 1997, 122, 68.