close

Вход

Забыли?

вход по аккаунту

?

Synthesis and Ca-Antagonist Activity of Some Benzhydryl Derivatives.

код для вставкиСкачать
873
Ca-Antagonist Activity of Benzhydryl Derivatives
Synthesis and Ca-Antagonist Activity of Some Benzhydryl Derivatives
Stefan0 Corsano*,Giovannella Strappaghetti, and Elsa Di Domenico
Insititute of Pharmaceutical Chemistry, University of Perugia, via del Liceo, 06100 Perugia, Italy
Livio Brasili and Maria Teresa Picchio
Department of Chemical Sciences, University of Camerino, via S. Agostino 1,62032 Camerino (MC), Italy
Received December 27,1988
The preparation of a series of benzhydryl derivatives is described. Their activities as Calcium-antagonists were evaluated on the taenia coli of the guineapig. These new compunds show lower activities as Ca-antagonists than Cinnnri7inp
_-.I._.
Synthese und Ca-Antagonist-Aktivitt einiger Benzhydryl-Derivate
Calcium-antagonists are a very heterogeneous group of
agents with dissimilar structural, electrophysiologic and
pharmacological properties. In the field of the benzhydryl
derivatives, Cinnarizine (la), and Flunarizine (lb), are calcium-antagonists used on account of their antivasoconstrictor properties”, in the control of some symptoms associated
with cerebrovascular disorders”. Prenylamine (lc),is well
known as coronary dilatato9’. Recently N,N’-dimethy1-N[3,3-di-(4-fluorophenyl)propyl-N’-(3,4,5-trimethoxybenzyl)
ethylenediamine (2a), was synthesized showing a competitive Ca++-antagonistactivity, with a potency similar to Verapamil and slightly higher than that at Diltiazem4).
The purpose of the present study was the synthesis of new
benzhydryl derivatives with the general formula:
where X or Y are oxygen, sulphur atom, amino or methylamino functions and R group represents substituted aromatic or heterocyclic rings, in order to check their calciumantagonist activity. Furthermore we have synthesized compounds 7, 9, 16,and 17,in which the benzhydryl group is
linked through the 2-thioethylamino- and 2-oxyethylamino
group with one of the two moieties of W-4101(2b)(’).
Scheme 1 shows the processes employed in the preparation of some benzhydryl derivatives. Compounds 3 and 14
were alkylated with cinnamyl bromide (4), 2-(2,6-dimethoxyphenoxy)ethylbromide (6), 2-tosyloxymethyl-1,4-benzodioxane (8). l-bromo-3-phenylpropane (10)and with 2phenoxyethylbromide (12), respectively, affording compounds 5,7,9,11,13and compounds 15,16,17,18and 19.
The reaction between N-benzhydryl-N,”-dimethylethylenediamine (20) with 3-cinnamyl bromide (4)and 2phenoxyethylbromide(12),(Scheme 2) gave compounds 21
and 22, respectively, while compound 24 was prepared
form 3,3-diphenylpropylamine(23)with cinnamyl bromide
Die Dmtellung einer Sene von Benzhydryl-Derivaten wird beschrieben.
Ihre Wirksamkeiten als Ca-Antagonisten wurden ermittelt. Diese Verbindungen sind als Ca-Antagonisten weniger wirksam als Cinnarazin.
(4).
lb
R = P
lc
(”WB-4101 is an a,-antagonist with very high activity; for the connection between a-antagonists and calcium-antagonists
see Arch. Pharm. (Weinheim) 321, 171 (1988).
Arch. Pharm. (Weinheim)322.873-878 (1989)
OVCH VerlagsgesellschaftmbH, D-6940 Weinheim, 1989
0365-6233/89/1212-0873 $02.50/0
Corsano and coworlrers
874
-
1 5 x = o
1 9 X = O
12
1 4 X = O
I
11
18
7 x=s
16 X=O
x=s
x=o
8
Scheme 1
1 7 X=O
Scheme 2
Arch. Pharnr. (Weinheim) 322,573-878 (1989)
875
Ca-Antagonist Activity of Benzhydryl Derivatives
Scheme 3
Finally the synthesis of compounds 27 and 30 was accomplished by standard procedures (Scheme 3): Alkylation of 2(3-phenyl-2-propeny1thio)ethylamine (25) with diphenylchloromethane (26) and alkylation of 2-(3-phenyl-2propeny1)-I-bromoethyl ether (28) with benzhydrylamine
(29), respectively, gave compounds 27 and 30.
Financial support from Ministry of Public Education is gratefully
acknowledged.
Experimental Part
MPs: Reichert microhotstage device, uncorr. - IR-spectra: Beckman Acculab 5 (CC14).- 'H-NMR-spectra: Varian EM 390.90 MHz, CDC13, TMS
int. stand. MS: Varian Mat 31 1, all compounds show parent peaks corresponding to theoretical values. - Purity was checked by TLC.
-
2-(Diphenylmethylihio)eihylamine (3)
0.9 g 2-thioethylamine hydrochloride (1.1 . 10' mole) was added to a
solution of 0.38 g of sodium in 15 ml of anhydrous EtOH. An EtOH solution (5 ml) of 1.5 g (7
mole) of diphenylchloromethane was added
and the mixture was refluxed for 3 h. The mixture was concentrated in
vacuo. Sodium carbonate solution was added to the residue; extraction with
Et20 and removal of the solvent after drying gave an oil that was purified
by CC on alumina Brockmonn 11, using EtZO/CHC13 I:]; yield 40%. - 'HNMR (CDCl3): 6 (pprn) = 1.35 (s, 2H; NHz), 2.3-2.9 (m, 4 H 2 CH'), 5.1
(s, 1H; CH-C~HS),6.9-7.4 (m, 10H aromat).
2-(Diphenylme~hylthio)N-(3-phenyl-2-propenyl)e~hylamine
(5)
A mixture of 0.730 g (3 . l W 3 mole) of 3,O.N g (2 .
mole) of 4 and
2 g of anhydrous Nap203 in 30 ml of abs. EtOH was stirred under reflux
for 24 h. It was cooled and filtered. The filtrate was evaporated under reduced pressure: the residue was diluted with N NaOH and extracted with
CHzC12, removal of solvent after drying gave an oil which was purified by
CC on alumina Brockmann 11, using Et20/CH2Cl2 1:l; yield.50%. - 'HNMR (CDC13): 6 (ppm) = 1.6 (s, 1 H NH), 2.4-2.7 (m, 4 H S-CHz-CHz-N),
3.2 (d, 2H. J = 7 Hz, C&-CH=CH), 5.1 (s, 1H; CI3(C&5)3, 5.9-6.5 (m,
2 H C&=CH-CH2), 6.9-7.4 (m, 15H aromat.). The corresponding hydrochloride shows m.p. 131-133'C. - C24HzaS . Cl(395) Calc. C 72.9 H 6.5
N 3.5 Found C 73.4 H 6.6 N 3.7.
1.5 g of anhydrous Na2C03 was stirred under reflux for 27 h. It was cooled
and filtered. The filtrate was evaporated under reduced pressm. The
residue was treated with N NaOH. extracted with CHCI3; removal of solvent after drying gave an oil which was chromatographed on alumina
Bruckmann 11, using ether/CH2Clz 1:l yield 40%. 'H-NMR (CDC13): 6
(ppm) = 1.3 (s, lH, NH), 2.6 (t, 2H. J = 6 Hz, CH2-S). 2.8 (t,4 H J = 6 Hz,
CHz-N-CHd, 3.7 (s, 6 H 2 OCH3). 4.1 (t, 2 H J = 6 Hz, CH2-0). 5.1 (s,
1 H Cg(c&&), 6.4 (d, 2 H J = 9 Hz, H-~rtho10 OCH3). 6.9 (t, 1H; J = 9
Hz, H-metha to OCH3). 7.0-7.4 (m, 10H aromat.). The corresponding hydrochloride shows m.p. 108-11o'C. - C25H3$'ISO3 . Cl(459) Calc. C 65.3
H 6.5 N 3.0 Found C 65.8 H 6.9 N 3.4.
-
2-(Diphenylmethylihio)N-(2-methylbenzodio~ne)ethylamine
(9)
1.2 g (3.9 .
of 2-(diphenylmethylthio)ethylamine (3) and 0.780 g
(2.5 .
mole) of 2-tosyloxymethyl-1,4-benzcdioxane
(8f' in 50 ml of 2methoxyethanol were stirred for 14 h at llo'C. After cooling, the solvent
was evaporated in vacuo and the crude residue was chromatographed on
alumina Brockmann I1 using EtzO-Ethylacetate 1:l; yield 50%. - 'H-NMR
(CDC13): 6 (pprn) = 1.8 (s, 1 H NH), 2.5-2.8 (m, 6 H S-CH2-CHz-N-CH2),
3.8-4.2 (m, 3H; 0-CH2-CH-0). 5.1 (s, 1H; C€I(GH5)2), 6.7 (s, 4H aromat.,
H-benzodioxane ring), 7.0-7.4 (m, 1OH aromat.). The corresponding oxalate Shows m.p. 188-19o'C. - C~&Y,NO$
(481) C ~ CC. 64.8 H 5.6 N 2.9
Found C 64.5 H 5.5 N 2.8.
2-(Diphenylmeihylthio)N-(3-phenylpropyl)e~hylamine
(11)
mole) of 2-(dipheUsing the procedure used to prepare 5 0 . 7 g (2 .
nylmethy1thio)ethylamine (3) was added to 0.380 g (1.9 . 1W3 mole) of 1bromo-3-phenylpropane(lo) in 30 ml of abs. EtOH and 2 g of anhydrous
NazC03; 11 was obtained and chromatographed on aluminaBrockmaitn 11.
using Et20-Ethylacetate 1:l; yield 45%. - 'H-NMR (CDC13): 6 (pprn) = 2.1
(s, 1H; NH), 2.4-2.8 (m, 10H; 5CH3, 5.2 (s, 1H Cjj(Cd-I5)3,7.O-7.5 (m,
15H aromat.). - The corresponding oxalate shows m.p. 179-181'C.
CZ~H~~N
(451)
O ~Calc.
S C 69.1 H 6.4 N 3.1 Found C 69.3 H 6.5 N 3.4.
-
2-(Diphenylmethyl1hio)N-(2-phenoxyethyl)e1hylamine
(13)
Using the same procedure to prepare 5.0.720 g (2.9.
mole) of 3 was
mole) of 2-phenoxyethylbromide (12), 13 was
added to 0.4 g (2 .
chromathographed on alumina Brockmann I1 using Et20/CH&lz 1:1,
CH2C12; yield 50%. - 'H-NMR (CDCl3): 6 (ppm) = 2.1 (s, 1H NH),2.63.0 (m, 6 H 3CHz), 4.0 (t, 2 H J = 6 Hz, CH2-O), 5.2 (s, 1 H CB(C&)z).
2-(Diphenylmethylthio~~-[2-(2,6-dime1ho~pheno~)ethyl]ethylamine
(7)
6.8-7.6 (m, 15H aromat.). - The Correspondinghydrochloride shows m.p.
A mixture of 0.730 g (3 .
mole) 3 and 0.520 g (1.9 .
mole)
1 10-112'C. - C&6NOS.CI (399) Calc. C 69.1 H 6.51 N 3.5 Found C 69.5
2-(2,6-dimethoxyphenoxy)ethyl bromide (6)5' in 30 ml of abs. EtOH and
H 6.9 N 3.4.
Arch. Pharm. (Weinheim) 3-32.87.7-878(1989)
876
Corsano and coworkers
2-Benzhydryl-1
-aminoethylether (14)
2-BenzhydrylN-(2-phenoxyeihyl)aminoethylether(19)
16 g (5.4 .
mole) of 2-benzhydryl-1-bromoethyl
ether7)in 30 ml abs.
EtOH with liquid NH3 were heated at 1 W C in an autoclave for 16 h. After
cooling the mixture was evaporated under reduced pressure. The residue
was treated with N NaOH and extracted with CH2C12. Removal of solvents
after drying gave an oil which was purified by CC on alumina Brockmann
I1 eluting with Et20/CH2C12; yield 40%. - 'H-NMR (CDCI3): 6 (ppm) =
1.6 (s, 2 H NHz), 2.8 (t, 2 H J = 6 Hz, CH2-N), 3.4 (t. 2H; J = 6 Hz, CH2O), 5.3 (s, IH cg-c&,), 7.3 (s, 10H aromat.).
Using the procedure to prepare 5, 0.660 g (2.9 .
mole) 14 were
added to 0.45 g (1.9 . 10" mole) of 2-phenoxyethylbromide (12); compound 19 was obtained and chromatographed on alumina Brockmann I1
using CH2CI,; yield 40%. - 'H-NMR (CDC13): 6 (ppm) = 2.1 (s. 1H; NH),
2.7-3.0 (m, 4H; CHz-N-CHz), 3.5 (t, 2H; J = 6 Hz, CH2-O), 4.0 (t, 2 H J =
6 Hz, CH2-O), 5.3 (s, 1H; CH-C&), 6.7-6.9 (m,5H aromat), 7.0-7.3 (m,
1OH aromat.). - The corresponding hydrochloride shows m.p. 159-162'C. C23H26N02 . Cl(383) Calc. C 72.0 H 6.7 N 3.6 Found C 72.4 H 6.8 N 3.5
2-BenzhydrylN-(3-phen~l-2-propenyl)aminoethylether(15)
N-Benrhydryl-N'-(3-phenyl-2-propenyl)-NN
-dimethyl-ethylenediamine
A mixture of 0.340 g (1.5 .
mole) of 14 and 0.2 g (1 .
mole) of
cinnamyl bromide (4) in 30 ml of abs. EtOH and 2 g of anhydrous Na2C03
was stirred under reflux for 24 h. It was cooled and filtered, the filtrate was
evaporated in vacuo. The residue was treated with N NaOH and extracted
with CH2C12. Removal of the solvent after drying gave an oil which was
purified by CC on alumina Brockmann I1 eluting with etherethylacetate
1:l yield 40%. - 'H-NMR (CDCI3):6 (ppm) = 2.5 (s, 1 H NH), 2.8 (t. 2H; J
= 6 Hz, CH2-N) 3.4 (d, 2H; J = 7 Hz, C b - C H K H ) , 3.6 (t, 2H; I = 6 Hz,
CHz-0). 5.3 (s, 1H; q - C & ) , 6.1-6.5 (m, 2 H CH_=CH,CH2),7.2 (m, 15H
aromat.). - The correspondingoxalate shows m.p. 110-112'c.- C26H27NO5
(433) Calc. C 72.0 H 6.2 N 3.2 Found C 71.9 H 6.1 N 3.4.
(21)
A mixture of 0.3 g (1.2 .
mole) of N-benzhydryl-N,N'-dimethylethylenediamine') (20). 0.2 g (1 .
mole) of 3-phenyl-2-propenylbromide (4) and 1.5 g of anhydrous K2CO3 in 20 ml of 2-butanone was stirred
under reflux for 24 h. It was cooled and filtered. The filtrate was evaporated in vacuo; the residue was alkalinized with N NaOH and extracted
several times with CHzC12, dried on Na2S04 and evaporated in vacuo. The
resulting oil was chromatographed on alumina Brockmann 11, using Et20;
yield 40%. - 'H-NMR (CDC13): 6 (ppm) = 2.1 (s, 3 H N-CH3), 2.2 (s, 3H;
N-CH3), 2.5-2.6 (m, 4H; N-CH2-CH2-N), 3.1 (d, 2 H J = 7 Hz, C&CH=CH), 4.3 (s, 1H CE-C~HS),6.0-6.5 (m,2 H CHa--CH2), 7.0-7.4
(m, 15H aromat.). The corresponding hydrochloride shows m.p. 90-93'C. C2d31N2. Cl(406) Calc. C 76.8 H 7.6 N 6.8 Found C 76.4 H 7.2 N 6.4.
2-BenzhydrylN-[2-(2,6-dimethoxyphenony)ethyl]aminoethylether(16)
A mixture of 0.340 g (1.5 . lo" mole) 14 and 0.260 g (1
mole) 2(2,6-dimethoxyphenoxy)ethyl bromide (6) in 60 ml of abs. EtOH and 4 g
anhydrous Na2C03was stirred under reflux for 26 h. It was cooled and filtered. The filtrate was evaporated in vacuo, the residue was treated with N
NaOH and extracted with CHC13 Removal of the solvent after drying gave
an oil which was purified by CC on alumina Brockmann I1 eluting with
Et20-CH2Cl, 1:1, yield 40%. - 'H-NMR (CDCI3): 6 (ppm) = 2.5 (s, 1 H
NH), 2.8 (m, 4 H CH,-N-CHz), 3.5 (t, 2H; J = 6 Hz, CH2-0), 3.6 (s, 6 H 2
OCH3), 4.1 (1, 2 H J = 6 Hz, CH2-0). 5.3 (s, 1H Cg-csH~),6.4 (d, 2H; J =
9 Hz, H-ortho to OCH3). 6.9 ("t", lH, J = 9 Hz, H-metha to OCH3), 7.1-7.3
(m,1OH aromat.). - The corresponding oxalate shows m.p. 119-121'C. C27H31NOg (497) Calc. C 65.2 H 6.2 N 2.8 Found C 65.5 H 6.4 N 3.2.
N-Benzhydryl-N'-(2-phenoxyethyl)-NJV'-dimethyl-ethylenediamine
(22)
Using the procedure used to prepare 21, 0.4 g (1.6 . l o 3 mole) of Nbenzhydryl-N,N'-dimethylethylenediamine
(20) was added to 0.2 g (1 .
l o 3 mole) 12. Compound 22 was obtained and chromatographedon alumina Brockmann 11, using Et2O/CH2C12 1:l; yield 40%. - 'H-NMR (CDCI3):
6 (ppm) = 2.1 (s, 3H; N-CH3). 2.2 (s, 3H; N-CH-j), 2.4-2.6 (m, 4H; 2CH2),
3.6 (t, 2H; J = 6 Hz, CH2-N), 3.9 (t. 2H; J = 6 Hz, CHz-O), 5.0 (s, lH,
C€&Hs),
6.7-6.9 (m, 5H aromat.), 7.0-7.4 (rn, 10H aromat.). The comesponding oxalate shows m.p. 129-131'C. - C2,H32N205 (464)Calc. C 69.8
H 6.8 N 6.0 Found C 69.4 H 7.0 N 5.9.
N-(3-Diphenylpropyl)-N-(3-phenyl-2-propenyl)amine
(24)
A mixture of 1 g (4 .
mole) 8 in 50 ml
mole) 14 and 0.93 g (3 .
of 2-methoxyethanol was stirred under reflux for 14 h. After cooling the
solvent was evaporated in vacuo and the crude residue was chromatographed on alumina Brockmann I1 using Et20 yield 40%. - 'H-NMR
(CDC13): 6 (ppm) = 1.8 (s, 1H; NH), 2.7-2.9 (m,4H; CHz-N-CHd),3.5 (t.
2H. J = 6 Hz, CHzO), 4.0-4.3 (m,3H; CH2-CH-0). 5.3 (s, 1H; C€J-C&),
6.7 (s, 4H aromat., H-benzodioxane ring), 7.1-7.3 (m, 10H aromat.). The
corresponding oxalate shows m.p. 191-193'C. C2.5H27NO7 (465)Calc. C
67.0H 5.8 N3.0FoundC67.3 H5.7 N 3.2.
A mixture of 0.310 g (1.5 .
mole) 3.3-diphenylpropylamine (23),
0.150 g (1 . lo3mole) of 4 in 30 ml of abs. EtOH and 1 g of anhydrous
Na2CO3 was stirred under reflux for 21 h. It was cooled under reduced
pressure; the residue was alkalinized with N NaOH and exhacted with
CHZCl2;removal of solvent after dqnng gave an oil which was c h m a t o graphed on alumina Brockmann I1 using Et20/CH2C12 1:l; yield 40%. 'H-NMR (CDCI3): 6 (ppm) = 1.7 (s, 1H; NH), 2.2 (t. 2H; J = 6 Hz, CHz),
2.5 (t, 2H; J = 6 Hz, CHz), 3.2 (d, 2H; J = 7 Hz, QIL-CH-CH), 3.9 (t, 1H J
= 6 Hz, ClJ-CH2), 6.0-6.7 (m,2 H ClJ=CH-CH2), 6.8-7.3 (m. 15H aromat.). - The Corresponding hydrochloride shows m.p. 167-17O'C. CDH26N . CI (363) Calc. C 79.3 H 7.1 N 3.8 Found C 79.8 H 7.3 N 3.5.
2-BenzhydrylN-(3-phenylpropyl)arninoethylether (18)
2-(3-Phenyl-2-propenylthio)ethylarnine(25)
mole) 14, were
Using the procedure to prepare 15, 0.340 g (1.5
added to 0.2 g (1 . 10-3mole)of 1-bromo-3-phenylpropane (10) in 30 ml of
abs. EtOH and 2 g of anhydrous Na2C03; compound 18 was obtained and
purified by flash-cromatography on silica gel eluting with Et20/CHzC12
1:l; yield 50%. - 'H-NMR (CDC13):6 (ppm) = 1.7 (s, 1H: NH), 1.8 (t, 2H;
J = 6 Hz. CH*-N),2.4-2.8 (m, 6H; 3CHz), 3.5 k 2 H J = 6 Hz, CH2-0), 5.3
(s, 1H; CH-c&). 7.0-7.3 (m,15H aromat.). - The corresponding oxalate
shows m.p. 158-16o'C. - C26H29N05 (435) Calc. C 71.7 H 6.6 N 3.2 Found
C 72.2 H 7.0 N 3.6.
2-Thioethylamine(9.3 g, 0.12 mole) was added to a solution of 3.8 g of
sodium in 150 ml of EtOH. An EtOH solution (50 ml) of 10.6 g (6.9 . lo-'
mole) of 3-phenyl-2-propenylchloride was added to the above solution and
the mixture was refluxed for 2.5 h. The mixture was concentrated in vacuo.
Na2C03-solution was added to the residue, which was exlracted with benzene. The benzene layer was washed, dried, concentrated in vacuo, the
residue was chromatographed by flash chromatography using CH2C12;
yield 45%. - 'H-NMR (CDC13): 6 (ppm) = 1.4 (s, 2 H NH2). 2.5-3.0 (m,
4H; 2CH2),3.25 (d. 2 H J = 7 Hz. C&-CH=CH). 6.0-6.5 (m,2H; CH=ClJCH2),'7.1-7.5(m, 5H aromat.).
2-BenzhydrylN-(2-methylbenzodiomne)aminoethylether (17)
Arch.Pharm. (Weinheim)322.873-878(1989)
877
Ca-Antagonist Activity of Benzhydryl Derivatives
2-(3-Phenyl-2-propenylthio)N-benzhydrylethylamine(27)
mole) of diA mixture of 0.8 g ( 4 . lW3 mole) of 25 and 0.4 g (2 .
phenylchloromethane (26) in 20 ml of isoamyl alcohol was stirred for 12 h
at 110°C. It was cooled and evaporated in vacuo, the residue was alkalinized with N NaOH and extracted with CH2C12. removal of solvent after
drying gave an oil which was purified by flash chromatography,using hexaneether 1:l; yield 40%. - 'H-NMR (CDC13): 6 (ppm) 1.65 (s, 1H; NH),
2.6-2.8 (m, 4H; 2CH2), 3.25 (d, 2 H J = 7 Hz, C&CH=CH), 4.7 (s, IH,
CH-C~HS).6.0-6.3 (m, 2 H CH=CH-CH2), 7.0-7.3 (m, 15H aromat.). The
correspondinghydrochloride shows m.p. 193-195°C. - CsH26NS. Cl(39.5)
Calc. C 72.9 H6.5N 3.5 Found C72.7 H 6.8 N3.7.
dose - response curve was identical with the second because
the change in dose - ratio is less than two, which usually
represents a minimal correction.
The antagonist potency of the compounds was expressed
in terms of their pA values, according to J.M. Van Rossumg).These values were calculated from the ratio of the
doses (DR) of the agonist causing 50% of the maximal response in the presence and in the absence of the test compound. The log (DR-1) was calculated at two antagonist
concentrations and each concentration was tested at least
four times.
2-(3-Phenyl-2-propenyl)-I-bromoethylether
(28)
A mixture of 10 ml of benzene, 5.0 g (4 . lo'* mole) of 2-bromoethanol
and 0.250 g of conc. H2S04 was heated to 70°C and treated under stirring
with a warm solution of 4.02 g (3 .
mole) of cinnamyl alcohol in 6.5
ml of benzene. It was refluxed for 5 h, cooled, diluted with 30 ml of benzene, washed with water, dried on Na2S04 and evaporated in vacuo. The
residue was chromatographed on silica gel using hexane, hexane/Et20 1:1
as eluent; yield 60%. - 'H-NMR (CDC13): 6 (ppm) = 3.3-3.7 (m, 4H; 0CH2-CH2-Br), 4.0 (d, 2H; J = 7 Hz, C&CH=CH), 5.9-6.4 (m, 2H;
CH=C€J-CH2), 6.9-7.4 (m, 5H aromat.).
Table pA2 values of Cinnarizine (la) and related compounds as
antagonist of Ca++ induced contraction of taenia from guinea-pig
caecum.
compound
Cinnarizine (la)
5
7
9
11
13
15
16
17
18
19
21
22
24
21
30
2-(3-Phenyl-2-propenyl)
N-benzhydrylaminoethylether (30)
A mixture of 0.48 g (2 .
mole) 28,0.530 g (2.9 .
mole) of diphenylmethylamine (29) in 20 ml of abs. EtOH and 1 g anhydrous Na2C03
was stirred under reflux for 30 h. It was cooled and filtered. The filtrate
was evaporated under reduced pressure, the residue was treated with 2 N
NaOH and extracted with CHCI3; removal of solvent after drying gave an
oil which was chromatographed on alumina Brockmann 11, using hexaneEt2O 1:l; yield 40%. - 'H-NMR (CDCI3): 6 (ppm) = 2.0 (s, 1 H NH). 2.7
(t, 2H; J = 6 Hz, CH2-N), 3.5 (t, 2H; J = 6 Hz, CH2-0), 4.0 (d, 2H; J = 7
Hz, C&-CH=CH), 4.7 (s, 1 H C&C&), 6.0-6.5 (m, 2H; CFJ=CB-CH2),
7.0-7.3 (m,15H aromat.). - The corresponding hydrochloride shows m.p.
173-175'C. - C24H26NO . Cl(379) Calc. C 75.9 H 6.8 N 3.7 Found C 76.2
H 7.2 N 4.0.
Pharmacology
Materials and Methods
Male guinea-pig (200-300 g) were killed by cervical dislocation and strips of taenia were quickly removed from the
caecum and mounted in a 10 ml organ bath containing K+depolarizing solution of the following composition (mM):
NaCl 97.53, KC1 40.24, NaH2P04 0.40, NaHC03 11.9, glucose 5.55, aerated with 5% 0 2 - 95% C02 and kept at 37°C.
The loading tension was 1 g and the contractions were recorded isometrically my means of a force transducer connected to a two channel Gemini polygraph.
The tissues were allowed to equilibrate for about 1 h before treatment with any drug. CaC12 dose-response curves
were constructed in a cumulative concentration schedule,
the first one being discarded and the second one taken as a
control. After 30 min incubation with the antagonist a third
dose - response curve was obtained. Responses were expressed as % of the maximal response obtained in the control curve. Parallel experiments, in which tissues did not receive any antagonist, were run in order to check any vanation in sensitivity. It was generally verified that the third
Arch. Pharm. (Weinheim) 322,873-878 (1989)
pA
s.e.m.
*
*
7.50 0.09
5.53 0.08
6.90 5 0.10
inact. lo-' M
6.55 0.05
6.47 f 0.04
6.25 f 0.08
6.32 i 0.01
5.71 i 0.07
6.62 f 0.12
6.09 f 0.08
6.06 f 0.03
6.15 f 0.09
6.36 f 0.09
5.36 f 0.06
5.23 rt 0.10
*
The calcium-antagonistic activity of the whole series of
benzhydryl compounds synthesized are reported in the
Table. The results indicate that all of the compounds are
weaker antagonist than Cinnarizine. Among the series of
compounds 5, 7, 9, 11, and 13, in which the benzhydryl
group is linked to a 2-thioethylamino- group and the series
of compounds 15,16,17,18, and 19, where the benzhydryl
group is linked to a 2-oxyethylamino group, compound 7 is
the most active. The couples 11-18, 13-19, show a similar
activity, while compound 9 does not show any activity.
Compounds 21 and 22, in which the benzhydryl group is
linked through the N,N'-dimethylethylenediamine group
with cinnamyl and the 2-phenoxyethyl- group are equally
active as compounds 15 and 19, while there is a drop in activity of about two orders of magnitude for compounds 27
and 3 0 finally, compound 24 shows the activity of compound 15.
References
1
2
T. Godfraind, A. Kaba, and P. Polster, Arch. Int. Phannacodyn. Ther.
172,235(1968); C.A.68, 112721w (1968).
T. Godfraind, G. Towse, and J.M. van Nueten, Drugs of Today 18.27
(1982).
878
3
4
5
6
E.Lindner. Arznein. Forsch. 10,569 (1960).
C. Casagrande, F. Santangelo,M.L. Calabi, C. Saini. R. Femni, G. Miragoli, L. Mcrlo, N. Giglioli, and C. Semeraro, Actual. Chim. n e r . 15,
119(1988).
A.P. Swain andS.K. Neagele, J. Med. Chem. 76.5091 (1954).
W.L. Nelson, J.E. Wennrestrom, D.C. Dyer, and M. Engel, J. Med.
Chem.20.880 (1977).
Corsano and coworkers
7
8
9
Z. Vejdglek, J. MetyS, J. Holubek. E. Svhtek, and M. Protiva. Collec.
Czech. Chem. Commun. 49,2649 (1984).
S. Corsano, G. Strappaghetti, and L. Brasili. Arch. Pharm. 321. 171
(1988).
J.M.Van Rossum, Arch. Int. Pharmacodyn. 143,299 (1963).
[Ph632]
Arch. Pharm. (Weinhim) 322,873-878 (1989)
Документ
Категория
Без категории
Просмотров
2
Размер файла
445 Кб
Теги
synthesis, benzhydrol, activity, antagonisms, derivatives
1/--страниц
Пожаловаться на содержимое документа