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Synthesis and Action on the Central Nervous System of 3-Substituted 2-Phenyl-23-dihydro-4H-132-benzoxazaphosphorin-4-one 2-Oxide and 2-Sulfide Derivatives.

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Synthesis and Action on the Central Nervous System of 3-Substituted
2-Phenyl-2,3-dihydro-4H-l,3,2-benzoxazaphosphorin-4-one
2-Oxide
and 2-Sulfide Derivatives
Krzysztof Kostka a)*, Marek Porada '), Elzbieta Zyner a) ,Wanda Pakulska '), and Anna Szadowskab)
"Institute of Chemistry, Faculty of Pharmacy, Medical University, I Muszynskiego Str., 90-151 Lo&, Poland
b'
Chair of Pharmacology, Medical University, 90-15 1 Lodz, Poland
Key Words: 2-Phenyl-2,3-dihydro-4H-l,3,2-benzoxazaphosphorin-4-one
2-oxide and 2-suFdederivatives;
.
.
central nervous system activity
aoH
Summary
+
C-NHR
Ph P(0)CIz
or
Ph P(S)Cb
N-R
The synthesis of 3-substituted 2-phenyl-2,3-dihydro-4H-1,3,2II
U
benzoxazaphosphorin-4-one 2-sulfide derivatives is described.
0
The action of a series 2-oxide (14) and 2-sulfide (7-12) derivatives on the central nervous system has been evaluated. ComTable 1. 3-Substituted 2-phenyl-2,3-dihydro-4H-1,3,2-benzoxazaphospounds 1-4,6,7-10 exhibit neuroleptic activity. Derivatives of
phorin-4-one 2-oxide and 2-sulfide derivatives.
sulfide series act as antiserotoninergic drugs.
A
Introduction
2-Oxide
1
R
-H
2-Sulfide 7
There is a little information in the literature concerning
2,3-dihydro-4H-1,3,2-benzoxazaphosphorin-4-onederivatives. The large interest in the heterocyclic compounds with
phosphorus atom prompted us to work out the synthesis and
to study their chemical and biological features.
In earlier work we published the synthesis of 2-phenyl-2,3dihydro4H- 1,3,2-benzoxazaphosphorin-4-one2-oxide derivatives [ 1-31. Some of these compounds as well as 2-[bis(2-chloroethyl)amino]-2,3-dihydro-4H1,3,2-benzoxazaphosphorin-4-one 2-oxide derivatives exhibit cytostatic activity [2,3].
Behavioural changes observed in animals prompted us to
undertake full screening investigation concerning the influence of the above compounds on central nervous system.
Moreover we also synthesized a series of other derivatives
with a sulfur instead of an oxygen atom at position 2 of the
heterocyclic system. We expected that these compounds to
be less toxic and to exhibit a long-term activity because of the
possibility to link proteins [4-61.
2
3
4
5
6
-CH3
-C2H5
-Ph
-CH2Ph
-NHCH3
8
9
10
11
12
The structure of the compounds as well as their homogeneity was established by data from spectral analyses (IR, 'H
NMR, 31PNMR), and elemental analyses.
Pharmacology
The action of compounds 1-12 on the central nervous
system was evaluated in mice and rats using nine behavioural
tests. The approximate LD50 (ALD~o)of the compounds and
their effect in six testes are given in Tables 2 and 3.
The tested compounds (except for 5 and 11) significantly
reduced the spontaneous locomotor activity in mice, thus they
exhibit sedative action. Compounds 1, 2, 3, 5, and 7-12 (7
not significantly) diminished the amphetamine-induced hypermotility in mice, but only compound 10 attenuated the
apomorphine-induced stereotypy in rats.
Compound 10 also produced hypothermia in rats. Thus the
results obtained suggest that compound 10 may act as a
classic neuroleptic drug. None of the tested compounds exerted anxiolytic activity in four plates test. Compounds 2,4,
and 5 exhibited weak anticonvulsive activity as they preChemistry
vented the tonic seizures and mortality of mice in pentetrazole
shock test. Compounds 2,3, and 7-12 prevented the m-chloThe compounds of 2-phenyl-2,3-dihydro-4H-1,3,2-benz-rophenylpiperazine (m-CPP)-hyperthermia in rats. This oboxazaphosphorin-4-one 2-oxide and 2-sulfide derivatives servation suggests antiserotoninergic activity only for
were synthesized in the reaction of the corresponding sali- compounds 7,8,9,11, and 12 because compounds 2,3, and
cylic amide with dichlorophenylphosphine oxide and its thio 10 by themselves induced hypothermia in rats. None of the
compounds shortens the immobility time of mice in the
analogue.
Arch. Pharm. Pharm.Med. Chem.
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1997
0365-6233/97/0707-0203 $17.50 +SO10
204
Kostka. Porada, Zyner, Pakulska, and Szadowska
Table 2. The pharmacological results of 2-phenyl-2.3-dihydro-4HI .3,2-benzoxazaphosphorin-4-one-2-oxide
derivatives.
ALDso
(g/k@
Compd i.p
p.o
Dose i.p.
mEk
(Ratio of
ALDso)
Control group
1
2.0
>2.0
200 (1/10)
loo (1/20)
( 1/40)
25 ( 1/80)
50
2
1.5
>2.0
150(1/10)
75 (1120)
37.5(I /40)
I8.8( 1/80)
3
0.5
1.2
4
1.25
>2.0
5
1.25
>2.0
6
1.25
>2.0
50 (1110)
25 ( 1/20)
1 2 . 31/40)
6.3(1/80)
3.2(11160)
125 (1/10)
6 2 31/20)
3 l.3( 1/40)
125(1/10)
62.5(I /20)
3 1.3
1/40)
I5.7(1/80)
125 (1/10)
62.31/20)
Spontaneous
locomotor
activity (% of
control values)
30minn = 10
Amphetamine
hypermotility
(% of
control values)
3 0 m i n n = 10
Apomorphine
stereotypy,
mean scores
n= 6
l O O f 12.5
100.0 f 5.3
8.0 f 0.59
10
4
4
Pentetrazole shock
n = 10
Number of mice
with
MortalClonic Tonic ity
seizures seizures
A/ ("C)
maximum
effect in
3h n = 5
m-CPP
hyperthermia
At ("C)
Effect in 2 h
n=6
+1.1
42.5f 7.I b)
34.4f 4.8c)
56.2f 6.7b)
75.I f 6.9
20.5f 3.5c )
69.1f13.4
6.8f 0.36
10
4
3
+0.5
+3.1
58.0 f 10.7 b)
60.9f 9.7b)
39.8f 13.7b)
71.4f 8.9
17.5f 3.3c)
53.4f 13.0
7.8f 0.7
8
1
0
-0.7
+0.4
43.I f 7.7c)
59.9f 10.9a)
32.3k 6.9c)
31.3 f 10.7c)
46.9f 7.9c)
30. I f 5.3 c)
53.0k 7.2b)
62.7k 4.4a)
69.2k 9.6
20.3f 4.3c) 8.I f 0.4
49.8f 13.3a)
9
5
5
-0.9
+0.2
7
1
1
-1
.o
+0.2
3 1 . 5 f 3 . 7 ~ ) 7.1f0.6
50.5f 12.4b)
62.9f 6.9c)
71.3f 19.9
6
1
1
+0.5
+2.0
79.8f 9.4
5
4
3
-0. I
+2.2
62.5f 7.5c)
80.2f 9.I
111.8f 11.6
7.2f0.51
9.0 f 0.79
Mean values and SEM are given: statistically significant differences at a) p< 0.05;
b) p< 0.01: c) p< 0.001.
behavioural despair test, which is regarded as the most universa1 model of evaluation of the antidepressant action. None
of the compounds exhibited analgesic activity in the writhing
test in mice.
The
Obtained
us to
Some structureactivity relationships of the investigated compounds:
Experimental
Chemistry
Melting point (uncorrected): Mikro-Heiztisch Boetius.- Elemental analyses: Perkin-Elmer 2400 (C,H,N,P).- IR spectra: Specord M-80 spectraphotometer.- 'H NMR and 3'P NMR spectra: Tesla BS 567A and Bruker
AC 200F (100 and 80 MHz).
sedative actions of the 2-sulfide derivatives are similar to
that of the corresponding 2-oxide derivatives;
General Method for the
of 2 ~ p ~ e n ~ 1 ~ 3 c R ~ ~ 2 , 3 . ~ i h y d r o .
4H-1.3,2-benzo.razaphosphorin-4-one
2-sulfide derivatives
2-sulfide derivatives possess, in general, antiserotoninergic activity;
To a solution of corresponding salicylic amide (30 mmol) in anhydrous
toluene (40ml) was added at boiling temp. phenylphosphonothioic dichloride (40mmol).
The mixture was refluxed for 2040 h (pipe filled with CaC12). The
solution was evaporated to half its volume and left overnight. The precipitate
was filtered off, dried, and crystallized.
introduction of a phenyl group into position 3 of the
2-phenyl-2,3-dihydro-4H- 1,3,2-benzoxazaphosphorin-4one 2-sulfide system led to the neuroleptic activity ofthe
compound. Replacement of the sulfur atom by the oxygen
atom in position 2 attenuated this action.
2-Phenvl-2,3-dihydro-4H1,3,2-benzoxazaphosphorin-4-one
2-sulfide (7)
Yield 6.2g (75%). mp 143-144"C (benzene).- Anal. CltHloN02PS.- 1R
(KBr): v = 3060 cm-' (NH), 1710(GO).- 'H NMR (CDCI~):6 = 6.34(s,
IH, NH), 7.02-7.65(m,9H, aromatic H).- "P NMR (CDCI): 6 = 131.1.
Arch. P h a m P h a m Med. Chem. 330,203-206 (1997)
205
2.3-Dihydro-4H- I ,3,2-benzoxazaphosphorin-4-ones
Table 3. The pharmacological results of 2-phenyl-2,3-dihydro-4H1,3,2-benzoxazaphosphorin-4-one
2-sulfide derivatives.
ALDw
( dkg )
Compd i.p
p.0
Dose i.p.
mgk
(Ratio of
ALDso)
Control group
7
8
9
0.35
0.75
0.35
1.5
1.2
>2.0
10
0.75
1.5
11
>2.0
>2.0
Spontaneous
locomotor
activity (% of
control values)
30minn = 10
Amphetamine
hypermotility
(% of
control values)
3 0 m i n n = 10
Apomorphine
stereotypy,
mean scores
n= 6
lOOf 12.5
100.0f 22.8
7.6 f 0.22
10
4
3
62.0 f 10.3
7.5 f 0. I7
9
3
3
+0.2
+0.3
>2.0
maximum
effect in
3 h II = 5
m-CPP
hyperthermia
Ar ( " C )
Effect in 2 h
II
=6
+1.2
53.2 k 9.4 b)
17.5 (l/20)
8.8 (1/40)
4.4 (1/80)
46.7 f 3.8 c)
51.2f3.9b)
63.4 f 7.6 a)
75 (1/10)
2 1 . 6 f 5 . 6 ~ ) 47.2f7.2a)
52.2 f 1 1.8 a)
84.0f 10.7
7.9f0.20
9
3
2
+o. I
-0.3
37.5 (l/20)
18.8 (1/40)
35 (1110)
20.1*2.4c)
6.8k1.7~)
7.5f0.43
9
4
4
+o. I
-1.3
17.5 (l/20)
77.3 f 9.4
80.2 k 21.3
75 (1/10)
37.5 (1/20)
18.8 (1/40)
48.7f7.4b)
66.4 f 14.5
34.4f6.1a)
44.8 k8.0 a)
70.0 f 9.2
6.6k0.31a)
8
2
2
-1.8
4.7
29.2 f 8.8 a)
7.5 k 0.22
10
3
3
4.4
-I .3
7.6f0.45
8
3
3
4.I
+0.3
200(1/10)
67.4 f 11.8
42.5 rt 8.1 a)
74.5 f 9.8
50 ( 1/40)
0.75
Af ("C)
35 (1110)
loo (l/20)
12
Pentetrazole shock
n = 10
Number of mice
with
MortalClonic Tonic ity
seizures seizures
75 (1110)
46.8 f 6.0 b)
37.5 f 9 . 0 a)
37.5 (1/20)
18.8 (l/40)
5 1.7 f 12.4 a)
34.5 k 16.6
90.8 f 18. I
Mean values and SEM are given; statistically significant differences at a) p < 0.05; b) p < 0.01; c) p < 0.001
2-Phenyl-3-methyl-2,3-dihydro-4H-l,3,2-benzoxazaphosphorin-4-one 2-Phenyl-2-benzyl-2,3-dihydro-4H1.3,2-hen~ox~r~~i~~ho
~pIiorir1-4-~111~
2-sulfide(8)
2-suljide (11)
Yield3.9g (45%),mp 161-163 "C (cyclohexane).-Anal.C~4H1~NO~PS.-Yield4.9g(45%), mp 163-164"C(cyclohexane).-Anal. C2oHIhNOzPS.IR (KBr): v = 1742 cm-' (GO).- 'H NMR ([D6] acetone): 6 = 3.21-3.19
IR (KBr): v = 1732 cm-' (C=O).- ' H NMR (CDCI?):6 = 3.51-3.44 (d. JHH
= 7 Hz, JHP= 2 Hz, 3H, CH3), 6.95-7.75 (m, 9H, aromatic H).- "P
(dd, JHH
= 8 Hz, 2H. CH?), 7.06-8.67 (m, 14H, aromatic H).- ? ' P NMR (CDCII): 6 =
132.3.
NMR (CDCI3): 6 = 143.2.
2-Phenyl-3-erhyl-2,3-dihydro-4HI,3,2-benzoxazaphosphorin-4-one
2-sulfide(9)
2-Phe1~yl-3-nmi1iom~fhyl-2.J-c/i/~~dr~1-4H/,3.
~ - ~ ~ I I ~
4-one 2-suljid~(12)
Yield 6.1 g (67%). mp 159-161 "C (CC14).- Anal. C15H14N02PS.- IR
(KBr): v = 1718 cm-' (C=O).- 'H NMR ([&I acetone): 6 = 1.03-1.16 (t,
JHH = 4 Hz, 3H. C h ) , 3.01-3.12 (quint, JHH=4Hz, 2H, CH2). 7.04-7.58
(m.9H.aromaticH).-"PNMR([Dt,] acetone): 6 = 121.1.
Yield 6.1 g (67%). mp 90-92 "C (ethyl ethdethyl acetate).- Anal.
C I ~ H I ~ N ~ O ~IRP S(KBr):
. - v = 3045 cm-' (NH), 1724 (C=O).- 'H NMR
(CDC13):6= 1 . 1 3 - 1 . 2 5 ( t . J ~ ~ = 4 H Z . 3 H . C H ~ ) , 5 . 9 7lH,NH).7.15-8.12
(s.
(rn,9H. aromatic H).-3'P NMR (CDC13): 6 = 121.4.
2,3-Diphenyl-2,3-dihydro-4H1,3,2-benzoxazaphosphorin-4-one
2-suljide
Pharmacology
~ I . ~ ~ I ~ ~ I ~ ~ / I ~ ~
(10)
Yield 7.4 g (70%). mP 179-181 "c(n-ProPanol).- Anal. ClYH14N02PS.IR(KBr): V = 1776cm-l (c=o).- IHNMR (CDCh): 6=7.01-7.99 (m. 14H,
aromatic H).-31P NMR (CDCI3): 6 = 119.3.
Arch. Pham. Pharm.Med. Chem. 330,203-206 (1997)
Swisswhitemice(18-25g)ofeithersexandmale Wihtarrats (150-200g).
fed on a standard diet, were used. The investigated compounds were administered i.p. or (in the writhing test) p.0. as suspension in an aqueous I %
solution of methylcellulose.
206
Drugs: D-amphetamine sulfate (Sigma), apomorphine hydrochloride (Sandoz), pentetrazole (Cardiazolum, Polon), m-chlorophenylpiperazine (mCPP, Institute of Pharmacology, Polish Academy of Sciences).
The approximate LDso (ALD5o) values were determined according to the
Deichmann and Le Blanck method [7]. The pharmacological screening
incluced the following tests: spontaneous and amphetamine-induced locomotor activity (in photoresistant cages) in mice, apomorphine-induced
stereotypy in rats [8], pentetrazole shock in mice, four plates test in mice [9],
rectal body temperature in rats, m-CPP-induced hyperthennia in rats [lo],
behavioural despair test in mice [ I I], writhing test in mice [12]. The tested
compounds were administered 60 min before examination except for the
behavioural despair test in which compounds were injected once daily for
14 days. Amphetamine (5 mg/kg s.c.), apomorphine (2.5 mgkg s.c.), pentetrazole (85 m a g s.~.),m-CPP (10 mgkg i.p.), and 3% acetic acid solution
(0.1ml i.p. in the writhing test) were given 60 min after the tested compound.
The effect of the compounds was examinedduring 30 min in the spontaneous
and amphetamine-induced locomotor activity tests, in the pentetrazole test
and in the writhing test, during 60 s after the 15 s exploration period in the
four plates test, during 6 min in the behavioural despair test (60 min after the
last dose of tested compounds), during 1 hat 15 min intervals in the apomorphine-stereotype test, and during 3 h at 30 min intervals in the rectal body
temperature test and in the m-CPP-induced hyperthermia test.
Kostka, Porada, Zyner. Pakulska, and Szadowska
References
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Received March 19, 1997 [FP199]
Arch. Pharm.Phurm. Med. Chem. 330,203-206 (1997)
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dihydro, phenyl, system, derivatives, central, benzoxazaphosphorin, oxide, synthesis, sulfide, nervous, one, 132, action, substituted
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