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Ether Derivatives of 3-Amino-12-propanediols V. Syntheses and Pharmacological Activities of 5-Cycloalkoxymethyloxazolidines and NSubstituted Derivatives

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598
Chalina, Dantchev, Georgiev and Mitova
Arch. Pharm.
[2,3-Dichlor-4-(3-ethyl-5,7-dihydro-5-oxo-furo[3,4-b]pyridin-2-y~)-~henoxy]-e~igs~ure
(6)
Aus 4b, wie bei 5a beschrieben. Man extrahiert mit CHCI,. Der Ruckstand wird in verd. NaOH
aufgenommen. Nach Ausschutteln mit CHC13Wird die wiisrige Phase mit verd. HCI angesauert und
gekiihlt. Nach 2d wird abgesaugt. Fast farblose Kristalle, Schmp. 147’ (EtOHA-I,O). Ausb.: 41 %
d. Th. C,7H13CIzN0,~2 HzO (418.2) Ber. C 48.8 H 4.10 N 3.3 Gef. C 49.0 H 3.81 N 3.3 MoL-Masse
381 (ms).
Literatur
*** Vergleiche die Reaktion von 2-Amino-2-penten-4-onmit Keton-Mannich-Basen”.
1 Aus der geplanten Dissertation W. Diiwel, FU Berlin.
2 E. J. Cragoe Jr., Diuretic Agents, ACS Symposium Series 83, S. 56 und 19Off. et loc. cit., Am.
Chem. SOC.Washington, D. C. 1978.
3 H. J. Roth und R. Troschiitz, Arch. Pharm. (Weinheim) 310, 48 (1977).
4a V. Boekelheide und W. J. Linn, J. Am. Chem. SOC.76,1286 (1954).
4b 0.H. Bullitt jr. und J. T. Maynard, J. Am. Chem. SOC.76,1370 (1954).
4c J. A. Berson und T. Cohen, J. Am. Chem. SOC.77, 1281 (1955).
[Ph 961
Arch. Pharm. (Weinheim) 319, 598-603 (1986)
Ether Derivatives of 3-Amino-l,2-propanediols, Vlo)
Syntheses and Pharmacological Activities of 5(Cycloalkoxymethy1)oxazolidinesand N-Substituted Derivatives
Elena Chalina*,Damian Dantchev, Atanas Georgiev+ and Kamelia Mitova
Medical Academy, Faculty of Pharmacy, Dunav 2, lOOOSofia, Bulgaria
Chemical and Pharmaceutical Research Institute, Sofia, Bulgaria
Eingegangen am 7. Juni 1985
+
The 5-(cycloalkoxymethyl)oxazolidines 5a, b and their N-substituted derivatives 3s-j were
synthesized by reaction of the aminopropanols 40, b and Za-j with formaldehyde. Some of the
compounds were found to have moderate f3-blocking activity and 3b and 3h were found to have
considerable antiarrhythmic activity.
Etherderivate des 3-Amino-1,2-prop~diols,5. Mitt.: Synthese und phannakologische Aktivitat
von 5-(Cydoalkoxymethyl)-oxazolidinenund N-substituierten Derivaten
Es wurden die 5-(Cycloalkoxymethyl)-oxazolidine Sa, b und ihre N-substitutierten Derivate 3a-j
durch Umsetzung der Aminopropanole 4a, b und 2a-j mit Formaldehyd synthetisiert. Die
03654233/86/0707-0598$ M.SO/O
Q VCH Vedagsgesellschaft mbH, D-6940 Weinheim, 1986
319186
Ether Derivatives of 3-Amino-l,2-propanediols
599
pharmakologischePriifung ihrer Hydrogenmaleate ergab eine maI3ige 0-blockierende Wirkung. Bei
3b und 3h wurde eine bedeutende antiarrhythmische Aktivitat nachgewiesen.
In the search for new more effective 0-adrenoblocking agents, a considerable place is occupied by
investigations related to structural changes in the side chain of aryloxypropanolamines. The
0-blocking properties of the compounds are retained when the aminopropanediol chain is introduces
into a furan"'), dioxan') or dihydro-1,4-oxazine4)ring. The 3,4-dihydro-3-hydroxyy-l
,5-benzoxazocines') block the 0-adrenergic receptors to a significant degree. The activity of these compounds is of
interest since the N-containing function (C=N) differs from that of the other 0-blocking substances
(C-NH). Moreover, the benzoxazocine configuration conforms with difficulty to the structural
requirements of the contemporary theory concerning the mechanism of action of 0-blockers at a
molecular level. Among the 0-blocking agents with a modified side chain some aromatic oxime ethers
are enbounteredbs), showing &-selectivity.
Proceeding from these data we directed our efforts towards the synthesis of compounds,
in which the hydroxyl and the amino groups of the side chain of l-cycloalkoxy3-amino-2-propanols, described in our previous communicatione") are introduced into an
oxazolidine ring.
This structural change leads to reduction of the possibilities for a free rotation round the
C-C bond and a limitation of conformations number. The distance between those
molecular sections, responsible for the P-blocking activity, is also changed.
The present communication describes the synthesis of 3-alkyl-5-(cycloalkoxymethyl)oxazolidines.
The starting cycloalkylglycide ethers l a 4 and cycloalkoxyaminopropanols2a-j and 4a,
b (Schemes 1 and 2) were prepared according to the methods described in a previous
communicationg). The synthesis of 3,5-disubstituted oxazolidines was accomplished
through the interaction between aminopropanols 2a-j with formaldehyde at a molar ratio
1 : 2 (Scheme 1). Experiments were carried out with formalin and paraformaldehyde. The
yields in the first case are 3040%. The condensation of 2a-j with paraformaldehyde runs
with greater yields: 65-72 %. Water, eliminated during the reaction was azeotropically
distilled off with benzene. The reaction time was determined by means of TLC.
The compounds 3a-j were isolated and identified as bases and hydrogen maleates (Table 1). The
structure of the compounds was confirmed by data from the IR-spectra. The bands for OH- and
NH-groups, which are present in the spectra of the starting aminoalcohols are missing in the
IR-spectra of oxazolidine bases in chloroform. They show the three bands in the 1200-1100 cm-'
range characteristicfor the oxazolidinesystem. The IR-spectra of compounds 5a, bin a capillary layer
possess besides these three bands also a band at 1680 cm-', attributed to a double bond in an
azomethine group and a weak, broad band for associated OH- and NH-groups in the range 3560-3150
cm-'. These data confirm the fact that the condensation products of 4a, b with formaldehyde are a
mixture of two tautomeric forms cyclic and open (Scheme 2), being in an equilibrium. Such a
tautomerism is described for some similar compounds").
-
The first step is the formation of an addition product A. Further on the reaction can flow
in two directions: elimination of a water molecule and formation of a heterocycle 5 or
dehydration to alkylidenaminoalcohol 6, followed by intramolecular addition and
formation of the same heterocycle.
600
Chalina, Dantchev, Georgiev and Mitova
Arch. Pharm.
The data from the spectrum of Sa in tetrachloromethane at a concentration of 3.1F3 moYl suppose
the presence of intramolecular hydrogen bonds. A broad, intense band at 3450 cm-l and weaker
bands at 3590 and 3150 cm-’ are evidence for a high degree of chelation.
Scheme 1
ROH
+
C~~-;CHCH,Cl
1. BFg ’ (C2H&O
2. NaOWH20
+ ROCH,C,H;CH,
la-d
NH2R’
ROCH,CHCH,NHR‘
RoHzCQN-R,
HCHO
___+
I
OH
2a- j
3a- j
R
2, 3
1
a
b
c
d
+
0
0
cyclopentyl
cyclohexyl
cycloheptyl
cyclooctyl
a
b
C
d
e
f
8
h
i
j
R
cyclopentyl
cyclopentyl
cyclopenty1
cyclohexyl
cyclohexyl
cyclohexyl
cycloheptyl
cycloheptyl
cyclooctyl
cyclooctyl
R’
CHMez
CMe3
CHzCHMez
CHMe2
CMe3
CH2CHMe2
CHMez
CMe3
CHMez
CMe3
The IR-spectra of hydrogen maleates of 3a-j in nujol, besides the characteristic three bands, show
also bands in 2700-2400 cm-’ range, confirming a salt structure.
Scheme 2
ROCH,C,H;CH,
0
NH3
la, b
+
[
ROCHZCHCHZNHZ
I
HCHO
__*
OH
4a, b
‘I
ROCH,CHCH,NH-CH,
ROH,C-
AH
----r
0,kH
5a. b
OH
ROCH,CH-CH,
I
AH .N
H,C”
6a, b
194,596
a
b
R
cyclopentyl
cyclohexyl
319186
601
Ether Derivatives of 3-Amho-l,2-propanediolr
~~
Tab. 1:Synthesized compounds
Cornpound
Yield
%
Bp
OC/Pa
Molecular
formula
Calcd.
Found
C
H
3a
60,s
125- 127/533,2
C12H23N02
(213,311
6 7,6
67,s
10,9
10,8
3b
68.0
128- 130/533,2
C13H25N02
68,7
68,6
11,l
11,2
(227,341
68,7
68,6
11,l
11,2
(227,34)
3c
64,O
126-1 28/53 3,2
13H25 No2
3d
5 9,s
130-134/933,1
C13H2SN02
(227,341
68,7
68,8
11,l
11,l
3e
57,s
157 -16O/ 1066,4
C14H27N02
(24 1,36)
69,7
69,8
11,3
11,3
3f
54,s
154- 156/1066,4
C14H27N02
(24 1,36)
69,7
69,6
ii,3
11,2
3g
62,O
156-159/933,l
C14H27N02
(241,361
69,7
69,9
11,3
11,2
3h
51,s
158-160/933,1
C15H29N02
(255,391
70,s
70,3
11,s
11,6
3i
52,O
151-153/933,1
C15H29N02
(255,39)
70,s
70,s
11,s
11,3
3j
53,s
161-163/933,1
C16H31N02
( 26 9,4 21
71,3
71,s
11,9
11,8
5a
65,4
121-126/799,8
C9H17N02
(171,23)
63,l
63,l
10,o
10,l
5b
67,7
124-1 29/799,8
C10H19N02
(185,261
64,8
64,s
10,3
10,2
N
The compounds are pharmacologically investigated for a hypotensive, antiarrhythmic
and f3-blocking a~tivity'~).
The most pronounced hypotensive activity is found for
compounds3h and 3g, whose applicationin a dose of 5 mg/kg reduces the arterial pressure
with 43 and 40 % respectively.
All compounds influence the hypotensive and positive chronotropic effect of
isoprenaline, which indicates the presence of p-blocking activity. This activity is more
602
Chalina, Dantchev, Georgiev and Mitova
Arch. Pharm.
weakly pronounced in comparison with the P-blocking activity of compounds with an open
aminopropanediol chain. Compounds 3h and 3b show an antiarrhythmic effect with the
same duration as that of propranolol.
Experimental Part
MP: Boetius microscope (uncorr.). ZR: UR-20 Spectrophotometer Carl Zeiss, Jena. TLC: Silufol
UV-254 (Kavalier, Czechoslovakia),n-hexane chloroform/acetone/ethanol4: 4 : 1 : 1v/v, Detect.:
12.
Preparation of compounds 3a-j and Ja, b, General method
20 mmol paraformaldehyde were added to 10 mmol aminoalcohol, dissolved in 20 ml benzene. The
mixture was stirred at 80-90°C for 7-12 h (TLC). Water, eliminated during the condensation was
azeotropically distilled. The excess of paraformaldehyde was filtered. The product was fractionated i.
vac. and transformed into a salt by means of a saturated ether solution of maleic acid.
3-Zsopropyl-5-(cyclopentyloxymethyl)-oxazolidine
(34
IR(Capil1ary layer): 1180, 1165, 1105 cm-'. 3a-Hydrogen maleate: m.p. 89-92' (ethyl acetate).
C16H27NO6 (329,38) Calcd.: C 58,3 H 8,2 N 4,2 Found: C 58,4 H 8,3 N 4,2.
3-Tert.-butyl-5-(cyclopentyloxymethyl)-oxazotid~ne
3b) IR(Capil1ary layer): 1180, 1160, 1105 cm-'.
3b-Hydrogen maleate: m.p. 119-122" (ethyl acetate/ethanol 1,2 : 1). C1#,9NO6
59,4 H 8,s N 4,l Found: C 5 9 3 H 8,s N 4,2.
(343,41) Calcd.: C
3-Zsobutyl-5-(cyclopentyloxymethy1)-oxazolidine
(3c): IR(Capillary layer): 1185, 1160, 1100 cm-'.
3c-Hydrogen maleate: m.p. 73-75' (ethyl acetate). c17H29No6 (343,41) Calcd.: C 59,4 H 8,5 N 4,l
Found: C 59,s H 8,3 N 4,l.
3-Zsopropyl-5-(cyclohexyloxyrnethyl)-oxazolidine(M):
IR(Capillary layer): 1185, 1160, 1105 cm-'.
3d-Hydrogen maleate: m.p. 94-96' (ethyl acetate/ethanol 1,5 : 1). Cl,H29N06 (343,41) Calcd.: C
59,5 H 8,5 N 4,l Found: C 59,6 H 8,s N 3,9.
3-Tert.-butyl-5-(cyclohexyloxyrnethyl)-oxazolidine
(3e): IR(Capil1ary layer): 1190, 1160, 1100 cm-'.
3e-Hydrogenmaleate: m.p. 134-136" (ethyl acetate). C@31NO6 (357,44) Calcd.: C 60,s H 8,5 N 3,9
Found: C 603 H 8,s N 3,9.
3-ZsobutyW-(cyclohexyloxymethyl)-oxazolidine (30: IR(Capil1ary layer): 1190, 1165, 1105 cm-l.
3f-Hydrogenmaleate: m.p. 108-110" (ethyl acetate). Cl8H3,NO6(357,44) Calcd.: C 60,s H 8,s N 3,9
Found: C 60,3 H 8,6 N 4,O.
3-Zsopropyl-5-(cycloheptyloxymethy1)-oxazolidine(3g): IR(Capil1ary Layer): 1185,1165,1105 cm-'.
3g-Hydrogen maleate: m.p. 83-85" (ethyl acetate/ethanol 1,5 : 0,s). C18H31N06 (357,44) Calcd.: c
60,s H 8,s N 3,9 Found: C 60,4 H 8,$ N 4,l.
3-Tert.-butyl-5-(cycloheptyloxymethyl)-oxazolidine
(3h): IR(Capil1ary layer): 1185, 1160,1100 cm-'.
3h-Hydrogen maleate: m.p. 126129' (ethyl acetate). c19H33N06(371,46) Calcd.: C 61,4 H 8,9 N 3,7
Found C 61,4 H 9,O N 3,7.
3-lsopropyl-5-(cyclooctyloxyrnethyf)-oxazolidine
(3i): IR(Capil1ary layer): 1180, 1160, 1105. 3iHydrogen maleate: m.p. 97-99" (ethyl acetate) C19H33N06 (371,46) Calcd.: C 61,4 H 8,9 N 3,7
Found C 61,5 H 9,O N 3,9.
319186
Antiaggregatorische und Anticoagulante Oligoamine
603
3-Tert.-butyl-5-(cyclooctyloxymethyl)-oxazolidine
(3j): IR(Capil1ary layer): 1185, 1160, 1105. 3jHydrogen maleate: m.p. 132-135' (ethyl acetate). qOH35NO6 (385,49) Calcd.: C 62,3 H 9,l N 3,6
Found: C 62,4 H 9,2 N 3,6.
References
G. Fothergill and J. Osbond, Arzneim. Forsch. 27, 978 (1977).
P. Kilborn and P. Turner, Br. J. Clin. Pharmacol. 1974, 143.
R. Howe, B. Rao and M. Chodnekar, J. Med. Chem. 13, 169 (1970).
M. Chodnekar and A. Crowter, J. Med. Chem. 15, 49 (1972).
B.Basil, C. Coffe, D. Gell, D. Maxwell, D. Sheffield and K. Wooldridge, J. Med. Chem. 13,403
(1970).
6 A. Martani, M. Magli, G. Orzabsi and R. Selleri, Farmaco Ed. Sci. 30, 370 (1975).
7 J. Imbs, F. Miesch, J. Velli, G. Leclerc, A. Mann and C. Wermuth, Br. J. Pharmacol. 60,357
(1977).
8 N. Bieth and J. Schwartz, J. Med. Chem. 20, 1657 (1977).
9 D. Dantchev, A. Georgiev, E. Chalina, D. Dobreva and D. Staneva, Arch. Pharm. (Weinheim)
312, 857 (1979).
10 Part IV: E. Chalina, D. Dantchev, A. Georgiev and D. Staneva, Arch. Pharm. (Weinheim) 317,
63 (1984).
11 A. Georgiev, E. Chalina, W. Petkov and P. Manolov, Arch. Pharm. (Weinheim) 312, 881
(1979).
12 E. Bergmann, E. Gill and S . Pinchas, J. Am. Chem. SOC.75, 358 (1953).
13 D. Staneva, L. Chakarova and A. Pulev, Eksp. Med. Morfol. 21, 148 (1982); C. A. 98, 1007684.
(1983).
[Ph 1001
1
2
3
4
5
Arch. Pharm. (Weinheim) 319,603-607 (1986)
Antiaggregatorische und Anticoagulante Eigenschaften von Oligoaminen, 2.
Mitt.')
p-Phenylenbisaminoalkane
Klaus Rehse* und Ute Liikens
Institut fur Pharmazie der Freien Universitiit Berlin, Konigin-Luise-Str.2+4, loo0 Berlin 33
Eingegangen am 11. Juni 1985
Die Titelverbindungen hemmen in vitro die durch Collagen induzierte Thrombocytenaggregation in
Konzentrationen um 10 pmol/l. Bei 4 . 104m01/l wird auch die durch Thromboplastin ausgeloste
Fibrinbildung auf weniger als 25 % der Norm herabgesetzt (Quick). Substanz 6 verlangert in dieser
Konzentration die €"IT-Zeit um 12sec.
0365-6233/86/~M-0603$ M.50/0
0 VCH Verlagsgesellschaft mbH, D-6940 Weinheim, 1986
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ethers, synthese, cycloalkoxymethyloxazolidines, nsubstituted, amin, activities, pharmacological, derivatives, propanediol
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