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Dibenz[bf]azepines Part 7[1]Synthesis of New Potentially CNS Active Dibenz[bf]azepine Derivatives.

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Dibenz[b,flazepines, Part 7"':
Synthesis of New, Potentially CNS Active Dibenz[bflazepine Derivatives
Ferenc HaBsz*, ZoltBn T6th, and Vilmos Galamb
Alkaloida Chemical Company Ltd , H 4440 Tiazavasvan, POB 1, Hungary
Key Words: dibenz[b,f]azepines; anticonvulsant; antidepressant
Summary
Reactions of 5-carboxamido-5H-dibenz[bflazepines
(la-ld) with
glyoxylic acid methylester methyl hemiacetal (GMHA) led to
5-(carboxamido-N-a-hydroxy-aceticacid methyl ester)-5Hdibenz[b,Aazepines (2a-2d). The reactions with glycols yielded
the oligoethylene glycol derivatives (3,4). The new compounds
were screened as anticonvulsants andor antidepressants (AD).
serpine induced decrease of spontaneous motility in mice)17]
properties. The known anticonvulsant effect of the compounds la-ldl8I changed after derivatization with GMHA.
Introduction
la-Id
Compounds bearing dibenz[b,fJazepinering system are of
considerable pharmacological interest both as anticonvulsant
and as antidepressant drugsL2'. The 5-carboxamido derivatives are important members of the group of anticonvulsant
drugs including carbamazepine[21and o x ~ a r b a z e p i n e ~
On
~~~].
the other hand, most of the tricyclic antidepressants with
dibenz[b,flazepine ring (e.g. imipramine, desipramine, trimi- Scheme 1
pramine, opipramol) have a basic side chain coupled to the
azepine nitrogen. We were interested in the derivatisation of
the carboxam i d e function of 5 -c arboxamido-5Hdibenz[b,flazepines with non-basic groups and thus in studying changes in their biological effects.
I
It is known that glyoxylic acid derivatives react readily with
amides to give the corresponding carbamoyl acetic acid type
compounds[5]. We thus report here the synthesis of 5-(carboxamido-N-a- h y drox y - ace t i c aci d me thy1 ester)- 5Hdibenz[b,fiazepines and their ethylene glycol derivatives. The
new compounds were tested as promising candidates for
anticonvulsant and antidepressant drugs.
1
C(l0)
C(1,)
a =
b c
-.Ao
d / o \
3a
3b
3c
3d
4a
4b
4c
4d
,
394
Scheme 2
Results and Discussion
The synthesis of compounds (2a-d) was performed by
condensation of the corresponding 5-carboxamidodibenz[b,flazepine with glyoxylic acid methyl ester methyl
hemiacetal (GMHA). (Scheme 1)
The reactions were carried out in refluxing chloroform,
1,2-dichloroethane or toluene with an excess of GMHA. The
best yields were observed in chloroform. Treatment of 2a and
2b with glycols in the presence of p-TsOH led to compounds
3 (Scheme 2).
The efficacy of compounds 2 , 3 , and 4 were screened for
their anticonvulsant (Maximal Electroshock Seizure, MES on
mice)[61and antidepressant (AD) (protection against the re-
Arch. Phasrn. Phasrn. Med. Chein.
Thus 2a was found to have antidepressant (69 % protection
at 0.308 mmol/kg i.p.) and anticonvulsant properties (70%
protection at 0.308 mmol/kg ip). 2c showed an anticonvulsant
effect (70% protection at 0.147 mmol/kg i.p.) and antidepressant properties while 2b produced 100 % protection at
0.306 mmolkg ip in an antidepressant test. The di- and tetraethylene-glycol derivatives (3b) and (3d) showed 88% and
100%protection on reserpine induced decrease of spontaneous motility in mice, respectively. These two compounds
were found to be inactive in the MES-test (Table). In spite of
our expectations, compounds 4 were found to be inactive.
0VCH Verlagsgesellschaft mbH, D-69451 Weinheim, 1996
0365-6233/96/12 12.0551 $5.00 + .25/0
552
3c
3d
Hazisz. T6th, and Galamh
0.174
0. I 5 I
0.2 I6
carbamazepine ( l a)
imiprrimine 0. I78
~--
~~
100, (0.024) 10.013-0.0801
I00
100. (0.038) [0.032-0.058]
The highest dose level was indicated for the inactive compounds.
Ten (for MES test) or six (for AD t a t ) CFI,P mice per group received
\ingle ip injections of the tcst compounds.
c) The EDso values and the 95 '1confidence limits were determincd by
lea\t-square regression Analysi5 with Hill-equation.
")
h'
In summary, the modification of the carboxamide group of
the parent anticonvulsive molecules oxcarbazepine (lc) and
10.1 1-epoxy-carbamazepine (Id) resulted in the decreasing
or loss of the biological activity, while in the case of carbamazepine (la) an antidepressive effect appeared (2a). The
pharmacological effect of 10,l 1 -dihydro-5-carboxamidoSH-dibenz[b,fjazepines ( l b ) which also has anticonvulsive
turned to purely antidepressive after derivatization with GMHA (2b).The di- and tetraethylene-glycol derivatisation of 2a led to the amplification of this feature parallel
with the ceasing of anticonvulsive property (3b, 3d). The
efficiency of the later cornpound (3d) is similar to that of
imipramine's activity.
With these findings the present study demonstrates a new
class of antidepressive compounds with dibenz[b,flazepine
ring without basic side chain. A detailed biological study will
be published elsewhere.
Experimental
Chemical Methods
Melting points are uncorrected. The htarting S-carboxamidodihen~[h,f]ar.epine\were prepared by published routes "O'lll. The structure
of each new compound was confirmed by means of 'H-NMR- and MS
apectroccopic methods. ' H - N M K spectra were recorded on a VARlAN
GEMINI-200 instrument (Chemical shifts ( 6 )are i n ppm. coupling constant5
(J)i n HL, the spectra were recorded in CDCli unless a different solvent
indicated, TMS wa\ uhed as internal standard). MS spectra were determined
with a VG TRIO-2 quadrupole inass spectrometer instrument. The dctcrmined elemental analytical data (C, H. N j werc within the range 10.4% of
the thcoi-etical values.
Rerrctioiz,\ of5-C ~ i r l ~ ~ ~ . i - ~ i ~ ih,,f]azc~pino.~
i i ~ l ~ ~ d i lwith
~ i ~GIyoi
~i~~
Estrr Mrrhyl Aceicil ( G M H A J
Ton solution of the corresponding dibenz[h,,flazepines (30mmol, la:7.080
.
wasaddedGMHA
g, lb:7.140g. lc: 7 . 5 6 0 ~1d:7.560g)iiiCHCli(150cm3)
( l a , lc: 300 mmol. 36.00 g, lb, Id:140 mmol. 16.80 g). After 2 h reflux the
reaction mixture was cooled to rooni tcmperature, washed with water (3 x
50 cm3) and dried (Na2SO4). The crude products formed after evaporation
were purified by crystallization from EtOH (2a. 2b) or were chromatogruphed on silica gel with CHC11:acetone 3:l (2c, Rt = 0.31) or 1,2-dichloroethancacetone 2: I (2d,RF=0.42).
Yield: 7.04 g (72 V'). imp 157-158 "C (EtOH), 'H-NMR: 2.85. 3.40 (m,
4H. 10, 1 I-H). 3.80 (a, 3H, CH3). 4.65 (d. J = 6.3 Hz. IH. 0 - H ) , 5.45 (dd. J
=6.3 Hz. lH,C-H),5.82(d..l=8.4Hr. lH.N-Hj.7.3-7.5 (m.XH,aroniatic
H), after adding D2O the C-H triplet changed to a doublet with 8.4 Hz
coupling constant, SO the J C H - h H = 8.4 HL and JCH-OH= 6.3 HZ.- EI-MS f f l / Z
(%) = 326 (2) [M'I, 309 IM+-CH3, I]. 238 (30) [S-carboxainido-l0,1 l - d hydro-dibenz[h,flazepine]. 192 [ 10,Il -dihydro-dibenz[b,flazepine, 1001,
Anal. (Ci sH18N2Oqj.
10-0x0- 10,I 1 - d i h y d r o - 5 H - 5 - ~ u ~ b o . ~ a i i i i ~ l ~ ~ - N - ( ~ - lw
i ~i d~ ~ r ~ ~ x ~ - ~ i c i ~ t i c
mrtlijl e.~ter.)dihens~h,,f]a;el,i,lr
(212)
Yield: 7.14 g (70 %), mp 167-168 "C (EtOH). 'H-NMR: 3.4 (s, H, 0-H),
3.79(s,3H.CH1),3.85(d.J= 13Hz, IH).1.37(d.J=4Hr,O.SH),4.44(d,
J = 4 Hz, 0.5F1) I I-Hr. 5.44 (d, J = 6.7 H/. 0.SH ), 5.50 (d, J = 6.7 H/, 0.5H
C-H). 6.0 (t. ./= 8.4 Hz, IH. N-H), 7.3-7.7 (ni. 7H, aromatic H), 8.1 1 (d. IH,
9.0 HI. Ar-9-H). In [DhIllMSO the 1 1 -Hz appeared as two broad doublets at
3.85 ppm and at 4.34 ppm (IH. J = 13 HL).-EI-MS in/; (%) = 340 (2) [M'],
252 (30) [M+-CHOCOOCH31, 209 (100) [ 10-oxo-10.1 I-dihydrodiben~[h,flazepine],Anal. ( C I ~ H I ~ N Z O ~ ) .
10,I I - E p o q - 10,I I -dili~dro-SH-i-ccir-ho.~uiiiitlo-h'-(cc-h?.dro.n.acrric
ticid
fnrt/iy/ e,Strr)dihei7~[h,f/(~~(,~7~ti(~
(2d)
Yicld: 7.14 g (70%).mp: 173-74 "C (EtOH), 'H-NMR: 3.70 (5,3H, CHi),
4.14 (d, J = 6.3 Hr. IH, 0 - H j, 4.29 (s, 2H, 10, 1 I-H), 5.48 (dd, J = 8.5 Hz,
I H . C - H j , 5 . 6 8 ( d , J = 8 . 5 H ~ ,lH,N-H),7.3-7.5(in,8H,arornaticH).After
adding D2O the C-H triplet changed to a doublet with 8.4 Hz coupling
constant.- EI-MS in/: ( % j = 340 (2) [M+], 251 (4) [M+-CHOHCOOCH?J,
Anal. ( C I X H I ~ N Z O S ) .
S~f1rhe.Fi.c
of Com/'o~4nd.\3 and 4
Compound (2a) or (2b) (2.6 mmol. 0.842 g or 0.847 g respectively),
/I-TsOH (0.2 mmol, 40 mg) and the corresponding glycol ( 5 cm3)were stirred
at 70 "C fou two hours. Water was then added (20 cm" and extracted with
CHCl1. The organic phase was dried and evaporated under reduced pressure.
The resulted yellow oil was flash chromatographed on silicagel (CHCImcetone 3: 1 or CHC13:acetone 1 : I ) yielding compounds 3 and 4 as colourless or
pale yellow oils.
SH-.5-Ctirho uaniido-N-[(cc/-o.~ir-3-ol-/~roporlc.i(
I ~o\a~.?~ol-i,,oi)trrir
g l ~ r ~ , ~ ~ v l ~ ~ t ~ ) ] d i h e (3a
i ~ ~j [ l ~ , , f ~ a ~ ~ ~ ~ ~ i i i i ~
Ylcld: 0.465 g(45 C/C),0il.Kf=O.l4inCHC13:
acetone3:1, 'H-NMR: 3.1
(br. s, 2H, OH) 3.65 (ni, 6H, glycol-CH.), 4.25 (t. J = 6.0 Hz. IH, CHOC(O)),4.31 (t, J = 6 Hz. IH, CH-OC(0)j. 5.48 (d, J = 8.5 Hz, IH, C-H),
5.72 (d. J = 8.5 Hz, IH, N-H). 6.95 (s, 2H. 10. 1 1 -H) 7.3-7.5 (m. 8H, aromatic
(%) 399 ( 5 ) [M++l],337 (40) [M+-(OCHXH2)OHI, 237
HI.- TSP-MS d;
( 100) 15-NHC(Oj-dibenz[l~,~luacpinc],
Anal. (C?I HzLNzO~).
5H-5-Crirhon-ai1iido-N-[(a-l,4-dio.rcr-6-01-1i~~,tcriic)(
1.4-dio.ici-h-ol-hc~..rtrrlegl\oxy/r!lnte/ ldihm~[h,,f]-trzr~piiie
(3b)
Yield: 0.416 g (33 %), oil, K f = 0.12 in CHC1i:acetone 3: I, 'H-NMR: 3.3
(s, broad 2H. OH) 3.5-3.8 (m, 14H, glycol-CH?), 4.25 (t. J = 6 Hz. IH,
, CH-OC(O)), 5.60 (two singlets, 2H, C-H,
CH-OC(O)), 4.35 (1, J = ~ H LI H,
N-H), 6.92 (\,2H. 10. 11-Hj 7.3-7.5 (m, 8H, aromatic H).-TSP-MS i d : (%)
487 ( 5 ) [M++l], 425 (20) [M+-(OCHKH2)2OH], 237 (100) IS-NHC(OjAnal. (C?sH3nN?Oxj.
dihenzl h,,fla~epinel,
553
Potentially CNS Active Dibenz[bf azepine Derivatives
SH-5-Carboxumido-N-I(cL-1,4,7-rrioxa-9-ol-decune)(l,
4,7-trioxu-9-01
decane-glyox)ilute)Idiben7[b,,f]uzepine(3ac)
Yield: 0.521 g (35 '3%). oil, K f = 0.11 in CHC11:acetone 3:1, 'H-NMR: 2.8
(s, broad 2H, OH) 3.7 (m, 22H, glycol-CHz), 4.3 (m. 2H, CHz-OC(O), 5.55
(d, J = 8.5 H L , IH, C-H), 5.72 (d, J = 8.5 Hz, I H, N-H), 6.92 (s, 2H, 10, 1 I-H)
7.3-7.5 (m, XH, aromatic H).- TSP-MS d z ('36) 575 (1) [Mt+l], 425 (10)
[M-(OCHzCHz)30H]), 237 (100) [5-NHC(O)-dibenz[h,flazepine], 222 (35)
[5-C(O)-dibenz[b,,flazepineI, Anal. ( C Z Y H ~ ~ N ~ O I O ) .
5H-5-Curboxumido-N-[(a-1,4,7,
I0-tetraoxu-12-ol-dodecun~~(1,4,7,10-tetruoxu-l2-ol-dodecune-glyoxylute)]di~en~[b,f]uzepine
(3d)
Yield: 0.895 g (52 %),oil, Rr= 0.21 in CHCl3:acetone 1:1, 'H-NMR: 3.0
(s, 2H, OH) 3.6 (m. 30H, glycol-CH2), 4.25 (m, 2H, CH-OCHz), 5.50 (d, J
=8.5Hz, IH,C-H),5.65(d,J=8.5Hz, lH,N-H),6,92(s,2H, 10, 11-H),
7.3-7.5 (m, XH, aromatic H).- TSP-MS m/z (lo) 663 (2) [M+l+], 469 (40)
[M-(OCH2CH2)40HJ, 237 (100) 15-NHC(0)-dibenz[bfazepine]. 222 (70)
[5-C(O)-dibenz[h,flazepine], Anal. (C33H46N2012).
Pharmacological Methods
Ten (for MES test) or six (for protection of the reserpine induced decrease
of spontaneous motility test) CFLP male and female mice per group were
used. The solid drugs were suspended in 1% carboxymethyl cellulose (CMC)
while the oils were dissolved in 1 % DMSOIwater.
All compounds were injected intraperitoneally in a volume of 10 ml/kg.
Efect on Muximul Electroshock Seizures[6J
Test drugs and vehicles were administrated intraperitoneally 30 min before
subjecting the animals to maximal electroshock through corneal electrodes.
Protection against seizures was defined as abolition of the hind limb tonic
extensor component of seizures.
Protection uf the Reserpine Induced Decreusing of Spontaneous Motility on
Mice
The test was performed by the method of Hacksell[" in photoelectric
activity cages. The animals were injected subcutaneously with 3 mgkg
10,l I-Dihydro-5H-5-curbomido-N-[(~-l
-oxa-3-ol-propane)(l-oxu-3-o1-reserpine. The drugs to be screened were administrated three hours later. The
animals were placed in the test cages and put into the motility meters 30 min
propane-glyoxylatej]-dibenz[b,.f]uzepine
(4a)
later. Motor activity was then measured after 5 min acclimatisation time for
Yield: 0.697 g (67 %),oil, Rf= 0.17 in CHCI3:acetone 3: 1,'H-NMR: 2.85,
20 min. The motility measured on drug-treated mice gave the test value (T).
3.40 (m, 4H, 10, 11-Hz), 3.75 (m. 6H, glycol-CHz), 4.20 (t. IH, CH-OC(O),
Reserpinized mice, injected vehicle only, gave the minimum values (M). The
J=4Hz),4,25(t, lH,CH-OC(O),J=4Hz),5.55(d, l H , C - H , J = X S H z ) ,
control group injected vehicle only gave the control value (0.
The AD %
5.90(d, IH,N-H,J=8.5Hz),7.3-7.5(m,8H,aromaticH),3.0(broads,2H,
protection was calculated by the following rule:
OH).- TSP-MS m/z (5%) 401(5) [M+l+], 339 (100) [M-(OCHzCHz)OH)],
Anal. ( C ~ I H Z ~ N C,
~ OH,~N.
),
AD % = 1 0 0 (~( T - M ) I ( C - M ) )
10,I I -Dihydro-SH-5-carboxamido-N-[(a-1,4-rlii)xu-6-ol-hexune)(1,4-dioxu-6-ol-hexane-glyox~lute)]dibenz[b,,f]uzepine
(4b)
Yield: 0.469g(37%),oil,Rf=0.19inCHC13:acetone 1:1, 'H-NMR: 2.80,
3.40 (m, 4H, 10, 1I-CHz), 3.75 (m, 14H, glycol-CHz), 4.25 (t, J = 4 Hz, IH,
CH-OC(O)), 4.35 (t, J = 4 Hz, IH, CH-OC(O)), 5.68 (d, J = 8.5 Ha, IH,
C-H), 5.85 ( d , J = 8.5 Hz, IH, N-H), 7.1-7.4 (m, XH, aromatic H), 2.85 (br.
s. 2H, OH).- TSP-MS m / z ('3%) 489 ( 5 ) [M++l], 383 (100) [Mt(OCHzCHz)20H], Anal. (C25H3zNzOx).
I0,l I -Dihydro-5H-S-carhoxamid~~-N-[(a-1,4,7-trioxu-9-ol-decane~(1,4,7-trioxa-9-ol-decane-glyo~ylute)]dihenz/b,f]u~epine
(4c)
Yield: 0.327g(22 %),oil, Rf=0.10inCHC13:a~etone3:I,~H-NMR:
2.80,
3.40 (m, 4H, 10, 11-CHz), 3.5-3.8 (m, 22H, glycol-CHz), 4.3 (m, 2H,
CHz-OC(O)), 5.68 (d, J = 8.5 HZ lH, C-H), 5.85 (d, J = 8.5 HZ lH, N-H):
7.1-7.4 (m, XH, aromatic H), 2.85 (br. s, 2H, OH).- TSP-MS m/z (%) 577
( I ) [Mt+l], 427 (10) [Mt-(OCHzCHz)30H], 222 (100) [5-C(0)-10, I l-dihydro-dibenz[b,Jazepine], Anal. (C2yH4oNzO10).
10,I I -Dihydro-SH-5-curboumido-N-[(a-1,4,7,1O-tetraoxu- 12-01-dodecm e ) ( 1,4,7,lO-retru0xu-12-ol-~10~ecane-glyoxylute)]dibenz[b,
flazepine (4d)
Yield: 0.621 g (36 %),oil,Rf=0.22 inCHC13:acetone 1:1, 'H-NMR: 2.80,
3.40 (m, 4H, 10, 11-Hz), 3.75 (m, 30H, glycol-CHz), 4.25 (m, 2H, CH2OC(O)), 5.65 ( d , J = 8.5 Hz, IH, C-H ), 5.90 (d, J = 8.5 Hz, lH, N-H), 7.1-7.4
(m, 8H, aromatic H), 3.1 (br. s, 2H, OH).- TSP-MS d z ('36) 665 (1) [Mt+l],
469 ( 1 8) [M-(OCHzCHz)40H], 222 (100) [5-C(O)-lO,I l-dihydrodibenz[b,fiazepine], Anal. (C33H48NzOiz).
Arch. Phurm. Phurm. Med. Chem. 329,551-553 (1996)
References
Part 6. I. Kohegyi, V. Galamb, J. Chem. Res.(S) 1995,216-217.
L. J. Kricka, A. Ledwith, Chem. Rev. 1974, 74, 101-123.
M. Schmutz in Handbook ofExperimental Pharmacology (ed.: H. H.
Frei and D. Janz), Springer Verlag 1985, Vol. 74, chapter 16., pp.79506.
P. Bulan, W. Froscher, Drugs of Today 1991,27,51-54.
A. Schouteeten, Y. Christidis, G. Mattioda, Bull. Soc. Chim. France
1978,11-248-254.
E. A. Swinyard, W. C. Brown, L. S. Goodman, J. Pharmacol. Exp.
Ther. 1952,106,319-330.
U. Hacksell, U. Svensson, S. Hjorth, A. Carlsson, H. Wikstrom, P.
Lindberg, D. Sanches, J. Med. Chem. 1979,27, 1469-1475.
MES-ED5ovalues (mmolkg) fromref'": (la): 0.078, (lb): 0.127, (Id):
0.059.
A. R. Gagneux In Epileptic Seizures-Behaviour-Pain (Ed.: W. Birkmayer), Huber, Bern, 1976, chapter 2., pp. 20-126.
F. Ilakz, V. Galamb, Synth. Commun. 1994, 24, 683-687.
W. Schindler (J. R. Geigy, A. G.) DE 2.01 1.087. 1970 [Chem. Abstr.
1970. 73. P109711r1.
Received: June 11, 1996 [FP130]
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