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Synthesis and Structure-Activity Relationship of Some New -Blocking Agents with Possible ╨Ю┬▒-Adrenoreceptor Activity.

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387
S A R of &Blocking Agents
Synthesis and Structure-ActivityRelationship of Some New P-Blocking
Agents with Possible a-Adrenoreceptor Activity
Jhos Bergmann and K6lmh Taklcs'
CHINOIN Research Centre, H-1325 Budapest, Hungary
Received May 29.1989
A series of new phenoxypropanolamiw with cyclic guanidine and isothiourea moieties has been prepared and investigated for non-specific& and
a-adrenoreceptor activity by receptor binding experimentson crude rat brain
membrane.Some of them [94 lOc] possess affinity for both& and a-adrenoreceptors.
Synthese und Zusammenhihge mischen Struktur und Aktivitiit von
einigen neuen &Blockern mit potentieller Aktivitiit gegeniiber a-Adrenorezeptoren
Einige neue Phenoxypropanolaminemit zykiischen Guanidin- und Isothiohamstoff-Seukturelementenwurden hergestellt und gegenUber unspezifischen J- und a-Adrenorezeptoren durch Rezeptorbindungsexperimente an
Rattenhim-Membm Priiparaten gepriift. Zwei Derivate [94 104 zeigten
Afthitilt gegenilberbeiden Typen von Adrenorezeptoren
In developing new 8-adrenoreceptor blocking drugs there has been a
trend to produce single chemical entities incorporating dual activity').
Combination of 8-blockers with a-adrenoreceptor antagonists in a single
molecule has been proved to be useful for antihypertensivetreatment2'.
Our approach to design of novel &blockers with possible
a-adrenoreceptor activity has focused on the combination of
cyclic guanidine and isothiourea moieties to phenoxypropanol-amines (Fig. 1) structurally related to known a-adrenoreceptor antagonists3).
In this paper we report on the synthesis and structure-activity relationship of a series of new compounds related to
Y3
.
QN
0 T A r n i n e
OH
X=
m
s
Positions of substituents in the benzene nucleus:
ortho (a), para (b)and meta (c)
Figure 1
N
1 CH3S-(
3-5 a-c
2 Ht
3 OH-
-
). HIlEtOHl
N
Ac
H
OH
OH
6-0 a-c
9-11 a-c
12 - I&
Compound
A
3, 6, 9, 12
4, 7, 10, 13
5, 8, 11, 14
-HWCH3)3
1,2,3,4-tetrahydroisoquinolino
-HNCH~CH~-C~H~(OCH~)Z
Scheme 1
Arch. f h r m . (Weinheim)323,387-391(1990)
OVCH Verlagsgesellschaft mbH. D-6940 Weinheim, 1990
0365-6233/90K)707-0387$03.50
+ .25/0
388
Bergmann and TakLs
the formula mentioned above (Fig. 1). As shown in Scheme
1, alkylation of ortho (la), para (lb) and meta (lc) nitrophenoles with epichlorohydrin afforded the glycidic ethers
2a, b, c which were condensed with the appropiate amines.
Anilines 6-8a, b, c were obtained by catalytic hydrogenation of compounds 34a, b, c. The heterocyclic moieties
were introduced by nucleophilic displacement of 2-methylmercapto-2-azolines in good yields. N-Acetyl protection as
a modification of Najer's method4' is necessary to avoid
side reactions.
Pharmacology
Experimental Part
M P Boetius microhotstage, uncorrected. - 'H-NMR-spectra: Bruker WP
80.80 MHz; TMS i n t stand. - MS: JEOL D-300. all compounds show parent peaks corresponding to the theoretical values. - Purity was checked by
TLC.
GeneralProcedurefor the Preparation of 3-(Nitrophenoxy)-l,2epoxypropanes Za-c
To a solution of 40 g (1.0 mol) NaOH in 500 ml water 126.5 g (0.91
mol) of the appropriate nitrophenol (la, b, c) was added, and the mixture
was stirred for 30 min. After the addition of 100 ml of epichlorohydrin the
mixture was stirred at ambient temp. for 8 h and extracted 3x with 100 ml
of CH&.
Structure-Activity Relationship
Removal of the solvent gave oils which were clystallized:
The compounds synthesized were assayed for& and a- 3-(2-Nitrophenoxy)-l2-epoxypropan(h)
Yield 92 %, m.p. 62-63'C (isopropanol). - 'H-NMR (CDCI3): 6 (ppm) =
adrenoreceptor affinity by receptor binding test using a
crude rat brain membrane preparation. The affinity of test 2.4-3.0 (m, 2H. CH2Oepoxide), 3.2-3.5 (m, 1H. CH2-CH-), 3.7-4.5 (m.
derivatives to the J-and a-adrenoreceptors was estimated 2H, O-CH2-h 6.8-7.9 (m, 4H-aromat.). - GH9N04 (195.2) Calc. C 55.4 H
by measuring their ability to inhibit 3H-dihydroalprenolol 4.65 N 7.2 Found C 55.5 H 4.60 N 1.2.
(3H-DHA)5)or 3H-dihydroergocryptin(3H-DHE)6)accord3-(4-Nitrophenoxy)-l,2-epoxypropan(Zb)
ing to the methods described. The compounds were tested in
Yield 93 %, m.p. 68-7o'C (isopropanol). - 'H-NMR (CDC13): 6 (ppm) =
lo3 nM concentration, propranolol was used as reference
and the affinity was quantified as inhibitory constant value 2.4-3.0 (m,2H, CH2Oepoxide). 3.2-3.6 (m, IH, CH2-C&). 3.7-4.4 (m,
(Ki, nmol/L)'). The values of J-adrenoreceptor affinity are 2H, 0-CHz-), 7.7 (m, 4H-aromat.). - C9HgN04 (195.2) Calc. C 55.4 H 4.65
N 7.2 Found C 55.4 H 4.50 N 7.2.
reported in Table 1:
3-(3-Nitrophenoxy)-I2-epoxypropan(2c)
Tab. 1
Compound
9a
9b
9c
10a
10b
1OC
lla
llb
llc
12
13
14
FJropranolol
A
ten-butylamino
ten-butylamino
ten-butylamino
1,2,3,4-tetrahydroisoquinolino
I ,2,3,4-tetrahydroisoquinolino
1,2,3.4-tetrahydroisoquinolino
3.4-dimethoxy-phenethylamino
3.4-dimethoxy-phenethy lamino
3.4-dimethoxy-phenethylamino
tert-butylamino
1,2,3,4-tetrahydroisoquinolino
3,4-dimethoxy-phenethylamino
3H-DHA Binding
Ki,nM (m S.E.)
*
100f 6
2610 f 32
4200 f 350
1240 f 78
10520 f 560
1 1 9 0 f 85
330 f 23
1830 f 93
280 f 14
780 f 55
4150 f 249
1 5 0 f 11
6.0
The results show that higher J-adrenoreceptor affinities
were obtained when the benzene nucleus bears the substituents in ortho position (9-lla, 12-14). The 3,4-dimethoxyphenethylamine (11, 14) and isothiourea (12-14) moieties
conferred also higher potency than the others. Two compounds exhibited a-adrenoreceptor affinity, as shown in
Table 2:
Tab. 2
Compound
A
3H-DHE Binding
& S.E.)
Yield 89 %, m.p. 64-WC (benzene). - 'H-NMR (CDC13): 6 (ppm) = 2.32.8 (m, 2H, CHzO-epoxide), 3.0-3.4 (m, lH, CH2-CfI-), 3.5-4.4 (m, 2H, 0CH2-). 6.9-7.9 (m,4H-aromat.). - CgHgO, (195.2) Calc. C 55.4 H 4.65 N
7.2 Found C 55.5 H 4.52 N 7.2.
GeneralProcedurefor the Preparation of I -Nitrophenoxy-3-substituted
amino-2-propanols 3-5 a-c
A mixture of the appropriate glycidic ether Za, b, c (19.5 g, 0.1 mol) and
60 ml of tert-butylamine or 100 ml of ethanol containing 16.0 g (0.12 mol)
of 1,2,3.4-tetrahydroisoquinolineor 21.7 g (0.12 mol) of 2-(3,4-dimethoxypheny1)ethylamine was refluxed for 4 h. Evaporation in vacuo gave the
base, which was treated with ethanolic HCI. After evaporation the residue
was triturated with ether, filtered off and recrystallized from isopropanol:
1-(2-Nitrophenoxy)-3-(tert-butylamino)-propan-2-ol
HCI (3a)
Yield 90 %, m.p. 113-1 14'C - 'H-NMR (DMSO-d6): 6 (ppm) = 1.50 (s.
9H, 3 CH3). 3.00-3.65 (m, 2H, CH2-N), 4.05-4.45 (m, 2H, O-CH2-), 4.504.95 (m, lH, CH-CH2-). 6.05 (br, IH, OH), 6.85-8.00 (m, 4H-aromat.).
(304.8) Calc. C 51.2 H 6.94 N 9.2
10.85 (br, 2H. NH2*). - C13H21C1N~04
C1 11.6 Found C 51.0 H 6.86 N 10.0 CI 11.5.
I -(4-Nitrophenoxy)-3-(tert-butylamino)-propan-2-ol
HCI (3b)
Yield 92 %. m.p. 186-188'C. - 'H-NMR (DMSO-dd: 6 (ppm) = 1.15 (s.
9H, 3 CH3). 2.50-3.05 (m, 2H, CHz-N). 3.88-4.18 (m, 3H, 0-CH2-CH).
5.95 (br, lH, OH), 7.05 (m,2H-aromat.), 8.22 (m. 2H-aromat.), 10.85 (br,
2H. NH;). - C I ~ H ~ ~ C I(304.8)
N ~ O Calc.
~
C 51.2 H 6.94 N 9.2 Cl 11.6
FoundC51.1 H6.92N9.1CI 11.7.
Ki,nM (M
9a
1OC
ten-butylamino
1,2,3,4-tetrahydroisoquinolino
360 f 18
1610 f 97
I -(3-Nitropheno~)-3-(tert-burylamino)-propan-2-01
HCI (3c)
. .
Yield 89 %, m.p. 129-131'C. - 'H-NMR (DMSO-4): 6 (ppm) = 1.34 (s,
9H. 3 CH3). 2.72-3.28 (m, 2H, CH2-N), 3.78-4.21 (m,2H. O-CH2-), 4.25-
Arch. Pharm. (Weinheim)323,387-391(1990)
389
S A R of 8-Blocking Agents
4.62 (m. lH, CH-CHz-), 6.12 (br, lH, OH), 7.08-8.00 (m, 4H-aromat.),
11.20 (br, 2H, NH2>. - C13H21ClN204(304.8) Calc. C 51.2 H 6.94 N 9.2
C1 11.6FoundC51.1 H6.85N9.1 CI 11.7.
and washed with MeOH. The filtrate was evaporated to give a yellow oil.
which was crystallized from isopropanol:
1-(2-Aminophenoxy)-3-(tert-bwylomino)-propan-2-01HCl (6a)
1-(2-Nitrophenoxy)-3
-(I 2 3,4-tetrahydroisoquinoolino)-propan-2
-01 HCl
(4a)
Yield 87 %, m.p. 99-1Ol'C. - 'H-NMR (DMSO-Q: 6 (pprn) = 1.12 (s,
9H, 3 CH3). 2.20-2.83 (m. 2H, CH2-N), 3.62-4.10 (m, 3H, 0-CH2-CH),
5.96 (br, lH, OH), 6.70-7.25 (m, 4H-aromat.), 10.15 (br, 2H, NH2').
C13H23ClN202 (274.8) Calc. C 56.8 H 8.43 N 10.2 C1 12.9 Found C 56.7 H
8.49 N 10.0 C1 12.8.
Yield 83 8,
m.p. 172-173'C. - 'H-NMR (DMSO-4): 6 (ppm) = 2.90 (m,
4H, N-CHz-CHz-), 2.68-3.05 (m, 2H, CH-C&-N). 3.82 (s, 2H, N-CHZ-isw
quinoline), 3.94-4.33 (m, 3H, 0-CH2-CH). 5.37 (br, lH, OH), 7.08 (m,
4H-aromat. isquinoline), 6.95-7.98 (m, 4H-aromat.). - C18H21CIN~04
1-(4-Aminophenoxy)-3-(tert-butylomino)-propan-2-01HCl (6b)
(364.8) Calc. C 59.3 H 5.86 N 7.7 CI 9.7 Found C 59.0 H 5.64 N 7.6 (39.8.
1-(4-Nitrophenoxy)-3-(1,2,3,4-tetrahydroisoquinolino)-propan-2-ol
HCl
(4b)
-
Yield 87 %, m.p. 175-176'C. 'H-NMR (DMSO-4): 6 (pprn) = 2.75 (m,
4H, N-CHz-CHz-), 2.31-3.00 (m, 2H, CH-W-N), 3.67 (s, 2H, N-CHz-ise
quinoline), 3.72-4.13 (m, 3H, 0-CH2-CH), 5.30 (br, lH, OH), 7.04 (m, 4Haromat. isoquinoline), 6.90-7.97 (m, 4H-aromat.). - C18H21ClN204 (364.8)
Calc.C59.3H5.86N7.7C19.7FoundC59.1 H5.72N7.7C19.7.
1-(3-Ni~rophenoxy)-3-(123,4-tetrahydroisoquinolino)-propan-2-ol
HCl
(44
Yield 89 %. m.p. 128-129'C. - 'H-NMR (DMSO-G): 6 (ppm) = 2.96 (m,
4H, N-CHz-CHz-), 2.75-3.10 (m, 2H, HC-C&-N), 3.93 (s, 2H, N-CHz-ise
quinoline), 4.02-4.40 (m, 3H, 0-CH2-CH). 5.80 (br, lH, OH), 7.10 (m, 4Haromat. isoquinoline), 7.05-8.02 (m, 4H-aromat.). - ClsH~1CIN204(364.8)
Calc.C59.3H5.86N7.7CI9.7FoundC59.1H5.91 N7.5CI9.6.
-
Yield 91 %. m.p. 187'C. - 'H-NMR (DMSO-Q: 6 (ppm) = 1.13 (s, 9H,
3 CH3). 2.65-3.13 (m, 2H, CH2-N), 3.77 (d, J = 6 Hz,2H, O-CH2-), 4.25
(m, lH, CHz-CII), 5.84 (br, lH, OH), 6.50 (m, 2H-aromat.), 6.71 (m,2Haromat.), 8.70 (br, 2H, NH2+).- CI3Hz3C1N2O2(274.8) Calc. C 56.8 H 8.43
N 10.2C1 12.9FoundC56.6H8.50N 10.1 C1 12.8.
I -(3-Aminophenoxy)-3-(~ert-butylamino)-propan-2-01
HCl (6c)
Yield 88 %, m.p. 85-87'C. - 'H-NMR (DMSO-d6): 6 (ppm) = 1.16 (s,
9H, 3 CHd, 2.78-3.20 (m, 2H, CH2-N), 3.70 (d, J = 6 Hz, 2H, 0-CH2-),
4.10 (m. lH, CHz-CK). 5.88 (br, lH, OH), 5.90-7.00 (m, 4H-aromat.), 8.92
(br, 2H, NH2'). - C13H23ClN202 (274.8) Calc. C 56.8 H 8.43 N 10.2 CI
12.9 Found C 56.7 H 8.48 N 10.1 CI 12.8.
1-(2-Aminopheno~)-3-(123,4-tetrahydroisoquinolino)-propan-2-01
HCl
(7a)
Yield 80 %, m.p. 85-86'C. - 'H-NMR (DMSO-&): 6 (ppm) = 2.70 m,
4H. N-CHZ-CH~-).
2.52-2.85 (m.2H, CH-C&-N). 3.60 (s, 2H. N-CH2-isw
1-(2-Nitrophenoxy)-3-[2-(3,4-dimethoxyphenyl)-ethylamino]-propan-2-01 quinoline). 3.76-4.1 1 (m, 3H, 0-CH2-CH), 5.60 (br, lH, OH), 6.85 (m, 4HHCl (5a)
aromat. isoquinoline). 6.80-7.32 (m, 4H-aromat.). - ClsH23CIN202 (334.8)
Yield 85 %, m.p. 193-194'C. - 'H-NMR (DMSO-a: 6 (ppm) = 2.75Calc. C 64.6 H 6.92 N 8.4 C1 10.6 Found C 64.4 H 6.95 N 8.2 C1 10.6.
3.40 (m, 6H, CH-C&-N-C&-C&-), 3.95 (s, 6H, (OCH3)2), 4.10-4.32 (m,
3H, 0-CH2CH). 5.80 (br, 1H. OH), 6.80-6.97 (m, 3H-aromat. phenethyl1-(4-Aminophenoxy)-3-(123.4-tetrahydroisoquinolino)-propan-2-ol
HCl
amine) 7.05-7.72 (m, 4H-aromat.). 10.10 (br, 2H, NH2'). - C19H&INz06
(7b)
(411.8) Calc. C 55.4 H 6.12 N 6.80 CI 8.6 Found C 55.2 H 6.31 N 6.7 C1
Yield 79 %, m.p. 154-156'C. - 'H-NMR (DMSO-&): 6 (pprn) = 2.86 (m,
8.7.
4H, N-CHz-CHz-), 2.48-3.10 (m, 2H, CH-C&-N), 3.68 (s, 2H, N-CH2-ise
quinoline), 3.83-4.40 (m. 3H, 0-CH2-CH), 5.70 (br, lH, OH), 6.58 (m, 2Haromat.), 6.82 (m, 2H-aromat.), 7.13 (m. 4H-aromat.isoquinoline). C18H23ClNz02 (334.8) Calc. C 64.6 H 6.92 N 8.4 C1 10.6 Found C 64.3 H
6.80 N 8.4 Ci 10.4.
1-(4-Nitrophenoxy)-3-[2-(3,4-dimethoxyphenyl)-ethylamino]-propan-2-01
HCl (5b)
-
Yield 81 %, m.p. 147-149'C. 'H-NMR (DMSO-a: 6 (pprn) = 2.523.15 (m, 6H. CHZ-N-CH~-CH~-),
3.88 (s, 6H, (OCH3)3, 3.90-4.25 (m, 3H,
0-CH2-CH), 5.75 (br, lH, OH), 6.67-6.83 (m, 3H-aromat. phenethylamine), 6.95 (m, 2H-aromat.), 8.18 (m, 2H-aromat.), 9.88 (br. 2H, NH2+).C19H&IN206 (41 1.8) Calc. C 55.4 H 6.12 N 6.8 C1 8.6 Found C 55.3 H
6.05 N 6.7 C18.9.
1- ( 3 - N i t r o p h e n o x y ) - 3 - [ 2 - ( 3 . 4 - d i m e f h o x y p h e a n - 2 - o 1
HCl (5c)
-
Yield 80 %, m.p. 128-13o'C. 'H-NMR (DMSO-Q: 6 (ppm) = 2.853.58 m, 6H, CH~-N-CHZ-CH~-),
4.05 (s, 6H, (OCH3)3, 4.13-4.47 (m, 3H,
O-CH2-CH). 5.70 (br, lH, OH), 6.90-7.02 (m, 3H-aromat. phenethylamine), 7.10-7.85 (m, 4H-aromat.), 10.15 (br, 2H, NH29, - C19H@N206
(411.8) Calc. C 55.4 H 6.12 N 6.8 C1 8.6 Found C 55.3 H 6.19 N 6.6
CI 8.8.
GeneralProcedurefor the Preparation of 1-Aminophenoxy=3-~ubstituted
amino-2-propanols 6-8 a-c
A solution of the appropriate compound 3-5 a,b,c (0.06 mol) in 100 ml
of MeOH was added to a sluny of 5 % Pd/C (4.0 g) in 250 ml of MeOH
and hydrogenated at 5 am. for 4 h. The catalyst was removed by filtration
Arch. Pharm. (Weinheim)323,387-391(1990)
1 -(3-Aminophenoxy)-3-(l23,4-te~rahydroisoquinolino)-propan-2-ol
HCl
(7c)
Yield 80%. m.p. 128-13o'C. - 'H-NMR (DMSO-Q: 6 (pprn) = 2.402.77 (m. 2H. CH2-N). 2.80 (m,4H. N-CH2-CH2-), 3.60 (s, 2H. N-CH2-isoquinoline), 3.864.28 (m, 3H, 0-CH2-CH), 5.75 (br. lH, OH), 7.00(m, 4Haromat. isoquinoline), 6.55-7.30 (m, 4H-aromat.). - Cl8H23CINz02 (334.8)
Calc.C64.6H6.92N8.4C110.6FoundC64.4H6.81 N8.2C1 10.5.
1-(2-Aminophenoxy)-3-[2-(3.4-dimethoxyphenyl)ethylamino]-propan-2-01
HCl (8a)
Yield 77 %, m.p. 184-185'C. - 'H-NMR (DMSO-Q: 6 (pprn) = 2.473.15 (m, 6H, CH2-N-CH2CH2-), 3.57 (s, 6H. (OCH3)3, 3.52-4.13 (m, 3H,
0-CHz-CH), 5.53 (br, lH, OH), 6.62-6.75 (m, 3H-aroma~phenethylamine).
6.90-7.40 (m. 4H-aromat.). 10.00 (br. 2H, NH2+). - C19H27CIN204
(382.9)
Calc. C 59.6H 7.14 N 7.3 CI 9.3 FoundC 59.5 H7.15 N 7.2 C19.3.
1-(4-Aminophenoxy)-3-[2-(3,4-dimethoxyphenyl)ethylamino]-propan-2-01
HCl (8b)
Yield 74 %, m.p. 158-159'C. - 'H-NMR (DMSO+ 6 (ppm) = 2.603.22 (m, 6H, CH2-N-CH2-CH2-),3.68 ( 8 , 6H, (OCH3)z),3.60-4.23 (m, 3H
390
0-CH2-CH), 5.84 (br, IH, OH), 6.70-6.88 (m, 3H-aromat.phenethyIamine),
7.05 (m, 4H-aromat.). 8.87 (br, 2H, NH?). - CI9H2,CIN2O4 (382.9) Calc.
C 59.6 H 7.14N 7.3 CI 9.3 Found C 59.5 H 7.18 N 7.2 CI 9.2.
Bergmann and Takks
(CHz)z-imidazolidine), 3.75 (s, 2H, N-CH2-isoquinoline). 3.82-4.40 (m,
3H. 0-CHz-CH), 6.90 (m, 4H-aromat.), 7.15 (m, 4H-aromat. isoquinoline),
8.15 (s. 2H, (NH)24midazolidine). - Cz1H26N402 (366.5) Calc. C 68.8 H
7.15 N 15.3 Found C 68.8 H 7.06 N 15.1.
I -(3-Aminophenoxy)-3-[2-(3.4-dimethoxyphenyl)ethyl~ino]-propan-2-ol
HCl (8c)
243-[3-(I,23,4-Tetrahydroisoquinolino)-2-hydroxypropoxy]phenyl]imino-imidazolidine (1Oc)
Yield 79 %, m.p. 132-133'C. - 'H-NMR (DMSO-Q: 6 (ppm) = 2.493.30 (m. 6H, CH~-N-CHZ-CH~-),
3.64 (s, 6H, (OCH3)z). 3.60-4.25 (m, 3H,
0-CHz-CH), 5.82 (br. 1H. OH), 6.00-6.28 (m, 3H-aromat.phenethylamine).
6.48-7.10 (m. 4H-aromat.), 8.90 (br, 2H. NHz+). - Cl9H2,C1N2O4 (382.9)
Calc. C 59.6 H 7.14 N 7.3 CI 9.3 Found C 59.5 H 7.1 1 N 7.2 CI 9.4.
General Procedurefor the Preparation of 2-(3-Substituted
amino-2-hydroxypropoxy)phenylimino-imidazolidines9-11 a-c
A solution of the appropriate 6-8 a,b,c (0.03 mol) and N-acetyl-2methylmercapto-2-imidazolin(9.4 g. 0.033 mol) in EtOH (150 ml) was refluxed for 8 h. The mixture was evaporated and the residue was dissolved
in ethanolic HCI (150 ml) and refluxed for 2 h. Removal of the solvent
gave oils which were converted to the free bases by aqueous NaOH and
extraction with CHzC12. Evaporation of the org. extracts gave oils, which
were crystallized from proper solvents:
Yield 91 %, m.p. 123-124'C (isopropanol). - 'H-NMR (CDCI3): 6 (ppm)
= 2.52-3.38 (m, 6H, CH-C&-N-C&-C&-),
3.65 (s, 4H, (CH&-imidazolidine), 3.72 (s, 2H. N-CHz-isoquinofine), 3.78.4.15 (m, 3H, 0-CHz-CH),
6.50-6.85 (m, 3H-aromat.), 7.11 (m, 4H-aromat. isoquinoline), 7.19 (m.
1H-aromat). 8.20 (s, 2H, (NH)2-imidazolidine). CzlH2$4402 (366.5)
Calc. C 68.8 H 7.15 N 15.3 Found C 68.7 H 7.10 N 15.1.
-
2-[2-[3-[[2-(3.4-Di~thoxyphenyl)ethyl]amino]-2-~droxypropoxy]phenyllimino-imidazolidine (Ila)
Yield 87 %, m.p. 149'C (isopropanol). - 'H-NMR (CDCI3): 6 (ppm) =
2.58-3.25 (m, 6H, Cft-N-CftCft-), 3.60 (s, 4H, (CH&-imidazolidine),
3.70 (s, 6H, (OCH3)z). 3.58-4.17 (m, 3H, 0-CH2-CH), 6.70-6.85 (m, 3Haromat.phenethylamine), 6.95-7.38 (m, 4H-aromat.). - C u H g 4 0 4 (414.5)
Calc. C 63.7 H 7.29 N 13.5 Found C 63.6 H 7.15 N 13.6.
2-[2-[3-(Tert.bu~lamino)-2-hydroxypropoxy]phenyl]imino-imidazolidine 2-[4-[3-[[2-(3,4-Dimethoxyphenyl)ethyl]amino]-2-hydroxypropoxy](9a)
phenyllimino-imidazolidine(11b)
Yield 88 %, m.p. 56-58'C (benzene). - 'H-NMR (CDCI3): 6 (ppm) =
Yield 92 %, m.p. 136-138'C (benzene). 'H-NMR (CDC13): 6 (ppm) =
1.35 (s. 9H, 3 CH3). 2.55-2.78 (m, 2H, CHI-N). 3.53 (s. 4H. (CH&-imida2.7 1-3.44 (m, 6H. CH-C&-N-C&-C&-).
3.64 (s, 4H. (CHz)z-imidazczolidine), 3.77-4.20 (m, 3H, 0-CHz-CH), 5.90 (br, IH, OH), 6.80-7.60 (m,
lidine), 3.74 (s, 6H, (OCH3)3, 3.70-4.45 (m, 3H, O-CH2-CH), 6.72-7.02
4H-aromat). - C16HZ6N4o2(306.4) Calc. C 62.7 H 8.55 N 18.3 Found C
(m, 3H-aromat.phenethylamine), 7.20 (m, 4H-aromat.), 8.24 (s, ZH, (NH)z-
-
62.9 H 8.43 N 18.1.
2-[4-[3-(Tert.-burylamino)-2-hydroxypropoxy]phenyl]imino-imi&zolidine
(9b)
Yield 93 %, m.p. 126'C (benzene). - 'H-NMR (CDC13): 6 (ppm) = 1.32
(s, 9H, 3 CH3), 2.90-3.22 (m, 2H, CH2-N), 3.64 (s. 4H, (CHz)2-imidazolidine), 3.85-4.30 (m, 3H, 0-CHz-CH), 5.80 (br, IH, OH), 7.02 (m, 2H-aromat), 7.23 (m, 2H-aromat). 8.18 (s, 2H, (NH)24midazolidine). C16H2dV402 (306.4) Calc. C 62.7 H 8.55 N 18.3 Found C 63.0 H 8.42 N
18.1.
imidazolidine). - C22H&404 (414.5) Calc. C 63.7 H 7.29 N 13.5 Found C
63.5 H 7.26 N 13.4.
2-[3-[3-[[2-(3,4-Dimet~xyphenyl)ethyl]~ino]-2-hydroxypropoxyphenyllimino-imidazolidine (llc)
Yield 90 %, m.p. 146-148'C (isopropanol). - 'H-NhfR (CDCI3): 6 (pprn)
= 2.53-3.10 (m. 6H, CH-C&-N-CH2C&-), 3.68 (s, 4H, (CH2)2-imidazo-
lidine), 3.76 (s, 6H, (OCH3)d. 3.60-4.16 (m, 3H, 0-CHz-CH), 6.32-6.70
(m, 3H-aromat.), 6.74-6.96 (m, 3H-aromat.phenethylamine), 7.17 (m. 1Haromat.), 8.20 (s, 2H, (NH)z-imidazolidine). c&&o4 (414.5) Calc. C
63.7 H 7.29 N 13.5 Found C 63.8 H 7.32 N 13.4.
2-[3-[3-(Ter~.-burylamino)-2-hydroxypropoxy]phenyl]imino-imidazolidine
(9c)
General Procedure for the Preparation of 2-(3-Substituted
amino-2-hydroxypropoxy)phenylimino-thiazolidines
(12,13,14)
Yield 91 %, m.p. 115-116'C (isopropanol). - 'H-NMR (CDCI3): 6 (ppm)
= 1.15 (s, 9H, 3 CH3). 2.80 (m, 2H, CHz-N), 3.51 (s. 4H, (CHz)z-imidazolidine), 3.70-4.12 (m, 3H, 0-CHz-CH). 5.80 (br, IH, OH), 6.68-6.92 (m,
3H-aromat.), 7.22 (m, 1H-aromat.), 8.22 (s, 2H, (NH)2-imidazolidine).
- C&2dV4O2 (306.4) Calc. C 62.72 H 8.55 N 18.28 Found C 62.76 H 8.38
N 18.10
A solution of the appropriate 6-8 a (0.03 mol) and 2-methyl-mercapto-2thiazoline-HI (9.1 g, 0.033 mol) in EtOH (150 ml) was refluxed for 8 h.
Removal of the solvent gave oils which were converted to the free bases by
aqueous NaOH and extraction with CH2CI2.Evaporation of the org. extract
gave oils, which were crystallized from isopropanol:
2-[2-[3-(123.4-Tetrahydroisoquinolino)-2-hydroxypropoxy]phenyl]imino-imidazolidine (1Oa)
2-[2-[3-Tert-bu~lamino)-2-hydroxypropoxy]phenyl]imino-~hiazolidine
(12)
Yield 87 %, m.p. 116-117'C (ethanol). - 'H-NMR (CDC13): 6 (pprn) =
2.55-2.76 (m. 2H. CH-Cft-N), 2.84 (m, 4H, N-CH~-CHZ-),3.60 (s, 4H,
(CH2)2imidazolidine), 3.68 (s. 2H, N-CHz-isoquinoline), 3.80-4.20 (m, 3H,
0-Hz-CHI, 7.20 (m, 4H-aromat.isoquinoline),6.85-7.32 (m, 4H-aromat.). C21Hzfl402 (366.5) Calc. C 68.8 H 7.15 N 15.3 Found C 68.6 H 7.02 N
15.0.
Yield 82 %, m.p. 75-76'C. - 'H-NMR (CDC13): 6 (ppm) = 1.24 (s, 9H, 3
CH3). 2.60-2.82 (m, 2H, CH2-N). 3.21 (1. J = 6.5 Hz, 2H, CH2-S), 3.88 (t, J
= 6 Hz, 2H, CH2-N-thiazolidine), 3.80-4.16 (m, 3H, 0-CH2-CH), 5.90 (br,
lH, OH). 6.97-7.50 (m. 4H-aromat.). - C16H~N302S(323.5) Calc. C 59.4
H 7.79 N 13.0 S 9.9 Found C 59.3 H 7.71 N 12.9 S 9.8.
2-[2-[3-[123,4-Tetrahydroisoquinolino)-2-hydroxypropoxy]phenyl]-
2-[4-[3-(123.4-Tetrahydroisoquinolino)-2-hydroxypropoxy]phenyllimino-imidazolidine (lob)
Yield 93 %. m.p. 143-1WC (benzene). - 'H-NMR (CDC13): 6 (ppm) =
2.90 (m, 4H, N-CHz-CH2-), 2.63-3.05 (m. 2H,CH-CH2-N). 3.53 (s, 4H,
imino-thiazolidine (13)
Yield 81 %, m.p. 93-94'C. - 'H-NMR (CDC13): 6 (ppm) = 2.52-2.66 (m,
2H- CH-Ck-N), 2.76 (m, 4H, N-CH2-CH2-), 3.28 (I, J = 6.5 Hz, 2H,
CHz-S), 3.70 (s, 2H, N-CHZ-isoquinoline), 3.92 (t, J = 6 Hz, 2H, CH2-N-
Arch. Pharm. (Weinheim)323,387-391(1990)
SAR of p-Blocking Agents
39 1
thiazolidine), 3.75-4.13 (m, 3H, O-CH,-CH), 5.86 (br, IH, OH), 7.13 (m,
References
4H-aromat. isoquinoline), 6.90-7.28 (m, 4H-aromat.). - CZ1Hz5N3O2S
(383.5) Calc. C 65.8 H 6.57 N 11.0 S 8.4 Found C 65.5 H 6.46 N 10.9 S
1 C.T. Dollery, J. Cardiovasc. Pharm. 11 (Suppl. 2), p. 1 (1988): C.A.
109, 14187Oq(1988).
8.2.
2 D.K. Phillips, Handbook of Experimental Pharmacology, Berlin 1980.
3 A.P. de Jong and W. Sondiju, Eur.J. Pharm. 69, 175 (1981).
2-[2-[3-[[2-(3,4-Dimeihoxyphenyl)eihyl]amino]-2-hydroxypropoxy]4 H, Najer, R.Giudicelli, and J. Sette, Bull. Soc. Chim. France 1961,
phenyllimino-thiazolidine (14)
2114.
Yield 78 45, m.p. 113-114'C. - 'H-NMR (CDC13): S (ppm) = 2.50-3.12
5 R.W.Alexander, L.T. Williams, and R.J. Lefkowitz, Proc. Natl. Acad.
(m, 6H, CH-Cft-N-CftC&),
3.33 (t. J = 6.5 HI 2H, CHz-S). 3.65 (s,
Sci. 72,1564(1975).
6 D.A.Greenberg and S.H. Snyder, Life Sci. 20,927 (1977): C.A. 86,
6H, (OCH&). 3.89 (t. J = 6 Hz, 2H, CHZ-N-thiazolidine),3.60-4.18 (m,
1 8 3 5 4 2 (1977).
~
3H, 0-CH2-CH), 5.80 (br, 1H. OH), 6.65-6.88 (m, 3H-aromat. phenethyl7 J. Batky and J. G d , J. Biochem. Biophys. 12,203 (1986).
amine), 7.00-7.38 (m. 4H-aromat.). - CZ2Hz9N3O4S(431.6) Calc. C 61.1 H
6.77 N 9.7 S 7.4FoundC61.3 H6.71 N 9.6 S 7.4.
[Ph696]
Arch. Pharm.(Weinheim)323.387-391 (1990)
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