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Synthesis of the Naphthalenic Bioisostere of Indorenate. Synthese des Naphthalin-Bioisosters von Indorenat

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Naphthalenic Bioisostere of Indorenate
Synthesis of the Naphthalenic Bioisostere of Indorenate
Synthese des Naphthalin-Bioisosters von Indorenat
Said Youa),Patrick Depreuxa)*,and Pierre Renardb)
Institut de Chimie Pharmaceutique, 3 Rue du Professeur Laguesse, BP 83,59006 Lille Cedex, France
Societe ADIR, 1, Rue Carle Hebert, 92415 Courbevoie Cedex, France
Received July 27, 1992
The relationships between some physiological processes and central nervous system or peripheral activity of serotonin (5-HT; A) has resulted in
extensive studies of the chemistry and biological properties of many serotoninergic (agonists or antagonists) compounds” and the existence of multiple serotoninergic receptors subtypes is supported by pharmacological
evidence2). So, central 5-HT binding sites can be classified into 5-HT1
(IA, lB, IC, ID), 5-HT2, 5-HT3 and 5-HT4 subtype^^*^! There is some
basis for considering that central serotoninergic agonists might be antihypertensives acting via 5-HT,, receptor^^.^.^). Indorenate (B), a synthetic
indole, closely related to serotonin, has antihypertensive properties resulting from agonist activity at central serotoninergic receptors with a relatively high affinity for 5-HTIAsites’).
A possible approach in the design of new serotoninergic ligands and
more generally new drug candidates may consist in the application of the
bioisosteric theory. So, the NH group is a classical bioisostere of the vinyl
increment and the naphthalene nucleus could be considered as a bioisostere of the indole ring. Few examples of the naphthalene-indole bioiso-
sterism have emerged in the lit.9s’0.”). Here we describe the synthesis of
the naphthalenic bioisostere C of B (Scheme 1)
We used 1-cyanomethyl-5-methoxy naphthalene (3) as
the key intermediate. The acid 1l0)was reacted with SOCl:!
and ammonia to produce amide 2. Dehydration of 2 with
trifluoroacetic anhydride12) gave the nitrile 3 which was
reacted with dimethylcarbonate and Na” to give the cyano
methyl ester 4. From this intermediate two procedures were
elaborated giving access to structure C. In procedure I, 4
was hydrogenated with H2 over Raney nickel in acetic
anhydride yielding the p-amino ester 5. Hydrolysis of 5
with NaOH afforded the p-amino acid 6 which was methylated to the desired naphthalenic p-amino ester 7 with an
overall yield of 30 % for 3 steps from 4. In procedure 11, 7
was obtained in 40% yield from nitrile 4 by reduction of the
cyano group using NaBH4-CoC12’3).
Serotonin ( A )
Indorenate ( B )
C H‘
Scheme 1
Arch. Pharm. (Weinheim) 326,119-120 (1993)
0VCH Verlagsgesellschaft mbH, D-6940 Weinheim, 1993 0365-6233/93/0202-0119 $3.50 + .25/0
Experimental Part
General remarks: M.p.: Biichi 5 10.- IR spectra: Perkin-Elmer 297 specirophotometer: 'H-NMR spectra: WP 80 Bruker (80 MHz) spectrometer,
6 values (ppm), internal standard (CH&Si.- Purity was checked by TLC.
- M ~ I o .-naphrhplj
ucetamide (21
To :i boiling solution of (7-methoxy-I-naphthyl) acetic acid'"' (10.8 g,
0.05 mole) in 300 ml of chloroform, SOCI, (0.2 mole) is added dropwise
and the mixture ia refluxed for 2 h. After cooling and evaporation i.vac.,
the resulting oil which crystallises by cooling is dissolved in anhydrous
ether (200 ml). To this cooled solution, aqueous conc. NH3 (200 mlj is
added in one time. After stirring for 30 min, the white precipitate is filtrated and recrystallised from 95% ethanol to give 93% of pure 2: m.p. 201202°C.- 'H-NMR (D,-DMSO)): 6 (ppm) = 3.82 (s: 3H, OCH?), 3.90 (s;
2H, CH2j. 6 3 0 (s: 2H, NH2), 7.00-7.80 (m: 6H aromatic).. Cl,H,,NOz
(215.2) Calcd. C72.5 H 6.08 N 6.5FoundC72.8 H6.03 N 6.4.
To a suspension of 2 (4.3 g, 0.02 mole) in tetrahydrofuran (80 ml),
triethylamine (0.045 mole) is added. The mixture is cooled and trifluoracetic anhydride (0.022 mole) is added dropwise. After stirring for I h at
room temp., the solvents are evaporated i.vac. and the residue is taken up
with water. The obtained solid is dried and recrystallised from hexane to
give 83% of pure 3; m.p. 83-85°C.- 'H-NMR (CDCI,): 6 (ppm) = 3.92 (s:
3H, OCH,), 4.00 (s; 2H, CH,CN), 7.00-7.80 (m; 6H aromatic): CI1H,,NO
(197.2)Cnlcd.C79.2 H5.62N7.1 FoundC79.2H5.52N7.0.
M e t k d -?-quno-2-(7-meth0,~yI-nuphthyl) acetatc (4)
To ii hot ( I 10°C) solution of 3 (19.7 g, 0.1 mole) in dimethylcarbonate
( 1 20 ml), sodium (2.3 g, 0. I atg) is added slowly during 30 min. The mix-
ture is then maintained at this temp. for 1 h and evaporated i.vac.. The residue is taken up with 100 in1 of 18% acetic acid in water. After extraction
with ethyl acetate, the org. phase is dried and evaporated. The solid residue
is recrystallised from toluene-hexane (2: I ) to give 88% of pure 4: m.p. 8283°C:- 'H-NMR (CDCI,): 6 (pprn) = 3.75 (s; 3H, COOCH,), 3.96 (s; 3H,
OCH?),5.30 (s: IH, CH), 7.10-7.90 (m: 6H aromatic).. C15Hl,N03(255.3)
Calcd. C 70.6 H 5.13 N 5.5 Found C 70.3 H 5.20 N 5.2.
Methpl3-ucetamido-2-( (51
A solution of 4 (10.2 g, 0.04 mole) in acetic anhydride (150 mi) is
hydrogenated over Raney nickel (5 g) under pressure (500 kPa) for 30 h at
60°C. After filtration and evaporation, the oil is dissolved in ethyl acetate
(250 mi). The org. layer is washed with aqueous saturated Na,C03 solution and then with water. After drying ethyl acetate is evaporated and the
solid residue is recrystallized from toluene-hexane (2:l) to give 73% of
pure 5: m.p. 118-120°C.- 'H-NMR (CDCI,): 6 (ppm) = 2.00 (s; 3H,
COCHJ. 3.25-3.90 (m; 2H, CH2). 3.70 (s; 3H, COOCH3j, 4.00 (s; 3H,
OCH ,), 4.35 (s: IH, CHj, 6.00 (s: 1H, NH), 7.00-7.80 (m; 6H aromatic):
C,,H,,NO, (301.3) Calcd. C 67.8 H 6.35 N 4.6 Found C 67.7 H 6.45 N
Yous, Depreux, and Renard
acid (6)
5 (6.02 g, 0.02 mole) is refluxed for 6 h with 1 M aqueous NaOH. After
cooling, water (50 ml) is added and the pH adjusted to 6.2 with acetic acid.
The precipitated solid is recrystallised from water to give 71% yield of
pure 6; m.p. 195-196°C.- 'H-NMR (CDCI,): 6 (ppm) = 2.90-3.60 (m: 2H,
CH,)), 3.96 ( s ; 3H, OCH,), 4.20 (dd; J , = 4.6 Hz, J Z = 10.7 Hz, IH, CH),
7.10-7.90 (m, 6H aromatic).
Methyl 3-amino-2-(7-mcthoxy-I-izaphthyl)~~r0pionu~e~HCl
Procedure I
A suspension of the acid 6 (2.45 g, 0.01 mole) in methanol (20 ml) is
cooled to -10OC. Under stimng, SOCI, (1 ml) is added and the mixture is
stirred for 36 h at room temp.. After evaporation, the residue is dissolved
in ethyl acetate and the solution is washed with saturated aqueous K2C0,
and then with water. After drying, the org. layer is evaporated and the
obtained residue dissolved in ethanol. Gazeous HC1 is bubbled into the
solution and the hydrochlond 7 precipitates. It is recrystallised from acetonitrile (66% yield): m.p. 168-170°C.- 'H-NMR (CDCI,): 6 (ppm) = 3.003.60 (m: 2H, CH,), 3.70 (s: 3H. COOCH,), 3.96 (s; 3H, OCH,), 5.00 (dd;
J , = 5 Hz, J, = 10 Hz, IH, CH), 7.10-7.80 (ni: 6H aromatic), 8.50 (s; 3H,
NH,+).- C,,H,,NO,CI . HzO (313.8) Calcd. C 57.4 H 6.37 N 4.5 Found C
57.4 H 6.54 N 4.4.
Procedure I1
To a solution of the nitrile 4 (5.10 g, 0.02 mole) in methanol (250 ml),
CoC1, (9.5 g, 0.04 mole) is added, followed by slow addition of NaBH,
(5.29 g, 0.14 mole) at room temp.. The mixture is stirred at this temp. for 2
h and then made acidic with 3 M HCI. Methanol is evaporated and the
solution is extracted with ethyl acetate. The aqueous solution is made basic
with aqueous ammonia and extracted several times with ethyl acetate. The
org. phases are evaporated and the residue is dissolved in ethanol. Gazeous
HCI is bubbled into the solution and the hydrochloride 7 precipitates. It is
recrystallized (40% yield).
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(KPh 5891
Arch. Pharm. (Weinheim) 326, 119-/20 (1993)
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synthesis, naphthalic, naphthalene, synthese, bioisosteres, indorenat, indorenate, des, von
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