Method for synthesis of trisubstituted amines or theirs pharmacologically acceptable salts in the fo

专利摘要:
Compounds of the formula I …<IMAGE>… in which… R1 denotes hydrogen, an alkyl or alkenyl radical, a cycloalkyl or cycloalkenyl radical or an optionally substituted monocyclic aromatic or heteroaromatic radical,… R2 and R3 denote an alkyl radical or together denote a ring,… R4 denotes an optionally substituted monocyclic aromatic or heteroaromatic radical,… R5 denotes hydrogen, nitrile, carboxylic acid ester or an optionally substituted monocyclic aromatic or heteroaromatic radical,… R6 denotes hydrogen, nitrile, carboxylic acid, carboxylic acid ester, carboxylic acid amide or hydroxymethyl,… X denotes a valence line or the methylene group,… Y denotes a valence line or an optionally substituted alkyl or alkenyl radical, and… Z denotes a valence line, an oxygen atom or the carbonyl group,… and their pharmacologically tolerable salts and optical isomers, process for their preparation and pharmaceutical preparations containing these compounds for the treatment of cardiac and circulatory disorders.
公开号:SU1731044A3
申请号:SU894613618
申请日:1989-02-24
公开日:1992-04-30
发明作者:Тсаклакидис Кристос；Ляйнерт Херберт；Фройд Петер
申请人:Берингер Маннхайм Гмбх (Фирма)；
IPC主号:

专利说明:

The invention concerns a process for the preparation of new trisubstituted amines of the general formula
"
K2 R3
,
N
% -Z-Y-0-CH, -CH-CH2-C-R,
  | s
R0
in which R ,,
isobutyl, metal, isopentyl, phenyl which can be substituted by halogen, methoxy or methyl, furyl, thienyl or pyridyl;
S
-317
Cg and 1C — each ethyl or together with the nitrogen atom to which they are bound form a pyrrolidine ring;
R is phenyl, which may be substituted by halogen or methoxy, thienyl or pyridyl; R-- hydrogen, carbethoxy, nitrile, phenyl, which may be substituted by halogen, xyl or methylene dioxyl, thienyl, pyridyl;
R is hydrogen, nitrile, carbmethoxyl, carbethoxyl carboxyl, hydroxymethyl;
X is a valence bond or a methylene group; Y is a valence bond of or or (CH2) 2 groups;
Z is oxygen or valence bond0
The invention also encompasses pharmacologically acceptable salts of these compounds, racemates, or optical isomerism.
Compounds of general formula I have a vascular-relaxing effect and can be used for the treatment of cardiovascular diseases,
The purpose of the invention is to develop a process for the preparation of new substituted amines with a higher relaxing effect on vessels.
Example 1 2,2-bis- (4-methoxyphenyl) -4- (1-pyrrolidino) -5-isobutoxy-valeric acid ethyl ester
To an ice-cooled suspension of 5.9 g (0.15 mol) of lithium aluminum hydride in 250 ml of absolute tetrahydrofuran is added dropwise, with stirring, 27.1 g (0.1 mol) of isobutyl ether 2 (1-pyrrolidine). ) 3-iso-butoxy-propionic acid in 100 ml of absolute tetrahydrofuran so that the reaction temperature does not exceed 10 ° C. After the addition is complete, the reaction mixture is stirred for another 30 minutes at room temperature, immediately after that it is mixed with 40 ml of water, sucked off, the precipitate is washed three times with 50 ml portions of tetrahydrofuran and from the combined filter
0444
tetrahydrode is distilled off under vacuum in a vacuum. furan. The remaining yellow oil is then distilled under vacuum.
17.5 g (87%) of 1-isobutoxy-2 (1-pyr rolidino) -3-hydroxypropane „are obtained as the main fraction (b.pip. at 0.05 mmHg 90 ° C).
To cooled to 0 ° C solution
16.1 g- (0.09 mol) 1 isobutoxy-2- (1-pyrrolidino) -3-hydroxypropane in 100 ml of 1.2 dichloroethane is added dropwise 7.6 ml (12.4-g 0.1 mol) of thionyl- chloride in 50 ml of 1,2-dichloroethane "By
At the end of the 5th addition, the reaction mixture is stirred for another 3 hours at room temperature, then an excess of thionyl chloride and the solvent is evaporated on a rotary evaporator.
0 and the residue is taken up in 100 ml of methylene chloride. The solution of methylene chloride is immediately washed twice afterwards with a saturated solution of sodium bicarbonate in 50 ml portions and
5 once with water, dried over sodium sulfate and evaporated in vacuo. Vacuum distillation of the crude product at Tekshi (0.06 mm., 78 ° C) yields 12.5 g (71.2% of 1-isobutoxy-20 (1-pyrrolidino) -3-chloropropane.
To a suspension of 0.27 g (0.011 mol) of sodium hydride in 50 ml of dry toluene and 5 ml of dry dimethylformamide is added dropwise with stirring a solution of 3.3 g (0.011 mol of ethyl 4,4-dimethoxy-diphenylacetic acid ester in 10 ml dry toluene and then stirred for another 30 minutes at room temperature
0 Immediately after this, a solution of 2 g (0.009 M) of 1-isobutoxy-2- (1-pyrrolidino) 3 chloropropane in 10 ml of dry toluene is added and the reaction mixture is heated for 2 hours at 100 ° C. After cooling toluene under vacuum, the residue is mixed with 10 ml of a saturated solution of ammonium chloride and the aqueous mixture is shaken three times with methyl enchloride, taken in portions
0 20 ml After drying the combined. the organic phases over sodium sulfate; methylene chloride is evaporated onto a po; a yellow evaporator and a yellow oily residue were chromatographically purified. The yield was 2.3 g (53%, colorless oil) of 2,2-bis- (4-methoxy phenyl) -4- (1-pyrrolidine 6) butoxy-valeric acid ethyl ester.
EXAMPLE 2 phenyl 2- (2-pyridyl) (1 pyrrolidino) 5-isobutoxy valeronitrile
1.1 g (mmol) of 2-pyridyl-phenyl are added to a suspension of 0.15 g (6.2 mmol) of 100% sodium hydride in 20 ml of dry toluene.
-acetonitrile in 5 ml of dry toluene and the mixture is heated for 10 minutes to 100 ° C. Immediately after this, a solution of 1.1 g (5 mmol) of 1-iso-butoxy 2- (1-pyrrolidino) -3-chloropropane in 5 ml is added dropwise. dry toluene and heat the reaction mixture for 2 hours at the boiling point of the frigma. After cooling, toluene is evaporated on a rotary evaporator, the residue is mixed with 10 ml of saturated ammonium chloride solution, the aqueous mixture is shaken three times with methylene chloride, taken in 20 ml portions, and the combined organic phases are dried over sodium sulfate. After removing the solvent and chromium - tographic purification of the crude product is obtained 1.2 g (64%) of a colorless oil - 2 phenyl-i2- (2-pyridyl) -c4- (t-pyrrolidino) -5-e-butoxy-valeronitrile „
Example 3. 2,2-Diphenyl-4 (and, M-diethyl) -amino-5-isobutoxy-valeric acid ethyl ester
To a mixture of 64 ml of isobutanol, 155 ml of concentrated caustic soda and 2 g of tetrabutylammonium bromide are added dropwise with vigorous stirring 217 ml of eiochlorohydrin so that the reaction temperature does not exceed 40 ° C. After the completion of the dropping, the reaction mixture is stirred for another 2 hours, then mixed with 500 ml of ice-water, the organic phase is separated, the aqueous phase is shaken 2 more times with methylene chloride, taken in 50 ml portions, and the combined organic phases are dried over sodium sulfate. After evaporation of methylene chloride on a rotary evaporator, the residue is distilled into a vacuum cleaner. At 40 mmHg and 66 - 70 ° C, 72% of isobutylglycidyl ether is obtained,
A solution of 5.2 (0.04 mol) isobutyl glycidate ether and 5.2 ml (0.05 mol of diethylamine in 60 ml of absolute ethanol is boiled for 20 hours at reflux temperature. Immediately thereafter, ethanol and excess diethylamine are evaporated on rotary evaporator and residue is chromatographed
-
t
ten
15
20
25
thirty
35
40
45
50
55
for purification, 6.9 g (85%) of 1-isobutoxy-2 hydroxy-3- (H, M-diethenp) - aminopropane are obtained in the form of a colorless oil. To a solution of 3 g (14.6 mmol) of 1-isobutoxy- 2 tidroxy-3 (K, M-diethyl) amino-propane in 20 ml of 1,2-dichloroethane 1.2 ml (16.4 mmol) of thionyl chloride in 10 ml of 1,2-dichloroethane Directly ™ are added dropwise at room temperature but immediately after that The reaction mixture is heated to reflux for 2 hours, cooled, shaken twice in 50 ml portions of saturated sodium bicarbonate solution and the organic phase is dried over sodium sulfate. After it has been removed solvent, the residue is chromatographed over silica gel to give 2 g (62.5%) 1 January isobutoxy-2-hlbr-3- (N-diethyl) - aminopropane as a colorless oil
To a stirred suspension of 200 mg (8.3 mmol) of sodium hydride in 30 ml of dry toluene and 1 ml of dimethylformamide was added 2 g (8.3 mmol) of diphenylacetic acid ethyl ester in 10 ml of dry toluene at room temperature and immediately thereafter. heat the mixture for 20 minutes to 80 ° C. After this, a solution of 1.6 g (7.2 mmol) of 1-isobutoxy 2-chloro-3-№, M-diethyl-aminopropane in 5 ml of dry is added dropwise at 80 ° C. toluene and heated to reflux for an additional hour. After cooling, the reaction mixture is mixed with 20 ml of a saturated solution of ammonium chloride, organic The separate phase is separated and dried over sodium sulfate. After removing the solvent, the crude product is purified by chromatography. 1.4 g (46%) of 2,2-diphenyl-4- (N, N-diethyl) -amino-5-isobutoxy-valeric ethyl ester are obtained. acid as colorless oil
Example 4, 2,2-Diphenyl 4 (1-pyrrolidino) -5 butoxy valeric acid ethyl ester,
To a mixture of 7.6 g (70.4 mmol) of benzyl alcohol and 0.2 g of tetrabutylammonium in 16 ml of concentrated caustic soda are added dropwise with vigorous stirring at 15–20 ° С for 20 min. 21.7 ml (277 ml). mmol) of ethylhydrogen “Immediately after this, the reaction mixture is stirred for another 3 hours at 40 ° C. After cooling, the reaction mixture is mixed with 50 ml of ice water, the organic phase is separated and the iodine
The phase is shaken twice with methylene chloride, taken in portions of 20 ml each. After drying the combined organic phases over sodium sulfate and evaporation of the solvent on a rotary evaporator, 11.5 g of crude benzylglycidyl ether 11.5 g of crude benzylglycidyl are obtained. the ester is dissolved in 30 ml of absolute ethanol and mixed with 2.5 ml of nirrolidine. Immediately after this, the reaction solution is allowed to reflux for 3 hours until the reflux temperature is then evaporated.
ammonium, the organic phase is separated and dried over sodium sulfate. After removal of the solvent, the crude product is purified by column chromatography. 1.7 g (47%) of 2,2-diphenyl-4 (1 pyrrolidino) zyloxy-valeric acid ethyl ester are obtained in the form of a colorless oil.
Example 5. 2,2-Dipheyl-4- (1-pyrrolidino) -5- (2 picolyl) -oxivaleric acid ethyl ester
To a mixture of 50 ml (0.52 mol) pyridine-2-carbinol and 8 g (0.025 mol) of tet-
pyrrolidine on a rotary evaporator, 5 rabutilammonium bromide in 200 ml of the residue was mixed with 100 ml of water, the aqueous solution was shaken three times with methylene chloride, taken in 50 ml portions, and the combined organic phases were dried over sodium sulfate. After evaporation the solvent (methylene chloride) on a rotary evaporator the residue is distilled in vacuum, Obtained at 0.05 mm Hg and 114 - 118 ° C, 15.2 g (92%) 1 benzyloxy 2-hydroxy 3- (1-pyrrolidino) propane in a colorless liquid
To a solution of 3.4 (14.5 mmol) of 1-benzyloxy 2-hydroxy-3- (1-pyrrolidino) - propane in 30 ml of 1,2-dichloroethane, 1.2 ml (16.4 mmol a) thionyl chloride in 10 ml of 1,2-dichloroethane. Immediately after this, the reaction solution is heated for 2 hours to reflux, then cooled, shaken twice in portions with 50 ml of saturated sodium bicarbonate solution and the organic phase is dried over sulfated sodium hydroxide with vigorous stirring. 190 ml are added dropwise at 15-20 ° C. , 4 mol) epichlorohydrin. Immediately after this, the reaction mixture is stirred overnight at room temperature, then it is mixed with 500 ml of ice-water, the organic phase is separated, the aqueous phase is extracted three times
 ether and dry the combined organic phases over sodium sulfate. After evaporation of the solvent and an excess of epichlorohydrin on a rotary evaporator, 57.8 g of crude picolyl 30 of glycidyl ether are obtained. 57.8 g of crude 2-glycolglycidyl ether are dissolved in 100 ml of ethanol and combined with 58 ml of pyrrolidine. Immediately after this, the reaction mixture is heated for 1 hour at 50 ° C, then the solvent and the excess of pyrrolidine are evaporated and the residue is distilled in vacuo. Get 57 g (69%) of 1- (2-picolyl) -oxy-2-hydroxy-3- (1-pyrrolidino) -propane.
35
sodium fatoma o After evaporation of the solution; to T.kip / 0.01 133 C.
the residue is chromatographed over silica gel. 2.5 g (68%) of 1 - benzyloxy-2 chloro-3- (1-pyrrolidino) - propane are obtained,
To a stirred suspension of 200 mg (8.3 mmol) of sodium hydride in 20 ml of dry toluene and 1 ml of dimethylformamide were added 2 g (8.3 mmol) of diphenylacetic acid ethyl ester in 10 ml of dry toluene at room temperature and immediately thereafter. heat the mixture for 20 minutes to 80 ° C,
To a solution of 48 g (0.2 mol) of 1- (2-pyolyl) -oxy-2-hydroxy-3- (1-pyrrolidino) propane in 600 ml of 1,2-dichloroethane is added dropwise at room temperature 45 ml of thionyl chloride in 100 ml
1,2-dichloroethane. Immediately after this, the reaction mixture is heated to reflux for 4 hours, then it is cooled and poured into 500 ml.
5Q ice water. Thereafter, the organic phase is separated and extracted
twice in portions of 50 ml of hydrochloric acid. Then, at 80 ° C, sediments of 1N are added dropwise. The combined aqueous phase of a thief is 2 g (7.9 mmol) of 1-benzyloxy-2-weakly acidified (pH 8-9) 1 and caustic chloro-3- (1 pyrrolidino) propane in 5 ml of 55 ml of sodium. After that, the alkaline solution of dry toluene is heated for 2 hours and shaken in portions of the reflux temperature. After cooling, 100 ml of methylene chloride, the compounds are dried, the reaction mixture is mixed with the organic phases above sul-20 ml of a saturated sodium chloride solution with sodium fate and the solvent is evaporated.
5 rabutilammonium bromide in a 200 ml container
when centered caustic soda with vigorous stirring, 190 ml (2.4 mol) of epichlorohydrin are added dropwise at 15–20 ° С. Immediately after this, the reaction mixture is stirred overnight at room temperature, then it is mixed with 500 ml of ice-water, the organic phase is separated, the aqueous phase is extracted three times
ether and dry the combined organic phases over sodium sulfate. After evaporation of the solvent and an excess of epichlorohydrin on a rotary evaporator, 57.8 g of crude picolyl glycidyl ether are obtained. 57.8 g of crude 2-glycolglycidyl ether are dissolved in 100 ml of ethanol and combined with 58 ml of pyrrolidine. Immediately after this, the reaction mixture is heated for 1 hour at 50 ° C, then the solvent and the excess of pyrrolidine are evaporated and the residue is distilled in vacuo. Get 57 g (69%) of 1- (2-picolyl) -oxy-2-hydroxy-3- (1-pyrrolidino) -propane.
five
To a solution of 48 g (0.2 mol) of 1- (2-pyolyl) -oxy-2-hydroxy-3- (1-pyrrolidino) propane in 600 ml of 1,2-dichloroethane is added dropwise at room temperature, 18 ml thionyl chloride in 100 ml
1,2-dichloroethane. Immediately after this, the reaction mixture is heated to reflux for 4 hours, then it is cooled and poured into 500 ml.
water with ice. Thereafter, the organic phase is separated and extracted
on a rotary evaporator,
Get 50 g
(96.6%) crude 1 (2-picolyl) (1-lirrolidino) -propane. 10 g (0.04 mol) of 1 (2-picolyl) hydroxy-2-chloro-3- (1-pyrrolidino) propane and 12 g (0.05 mol) of diphenylacetic acid ethyl ester in 100 ml of dry dimethylformamide, mix the solution with 1.2 g (0.05 mol) of hydride hydride and heat immediately after this the reaction mixture for 1 h at 80 ° C. After that, the cooled reaction mixture is mixed with 200 ml of a saturated ammonium chloride solution and shaken three times with 50 ml portions ml of methylene chloride. After drying the combined organic phases over sodium sulfate and evaporation of the solvent, the residue is chromatographed over silica gel. 9.2 g (50.3%) of the expected compound are obtained in the form of a light yellow oil, which crystallizes as
rubbing, m.p. .
The table shows a number of compounds obtained similarly about
PRI me R 6 "the Separation of the racemates of the compounds of General formula 1, shown in the compound of example 5,
4.6 g of racemic 2,2-diphenyl-4- (1-pyrrolidino) -5 (pyridyl-2-methyloxy) -valeric acid ethyl ester are dissolved in 50 ml of ethanol. 3.8 g of (-) - dibenzoic acid are added, heated for 30 minutes to 60 - 70 ° C and left overnight at room temperature. Then the precipitated precipitate is sucked off and recrystallized 3 more times from ethanol. The crystallized crystal purified in this way is suspended in methylene chloride and the suspension is mixed with dilute ammonia. The organic phase is separated and dried over sodium sulfate. After the solvent is distilled off, the residue is recrystallized from isohexane / ethyl acetate. 1.2 g of () -2,2-diphenyl-4- (1-pyrrolidino) -4- (1-pyrrolidino) -5- (pyridyl-2-methyloxy) -valerianic acid ethyl ester are obtained with m.p. . 89 - 90 ° С and oOj: -43.9 ° С (с: 1, ethanol) о
Separating racemates of racemic 2,2-diphenyl-4- (1-pyrrolidino) -5- (2-methyl-hydroxy) -valerianic acid ethyl ester with (+) - diphenoyl tartaric acid gives (+) - 2 2-diphenyl-4- (1-



ten
15
20
1044 1 °
pyrrolidino) -5-pyridyl-2-methyloxy) - valeric acid with so pl. 88 - 90 С iМсг + 43,9 ° С (с: 1, ethanol).
Biological testing of the synthesized compounds for pharmacological activity
Aortic segments were suspended in a 10 ml bath and connected to a dynamometer so that the stretch was 15 nN0. Then the 45-minute equilibration phase followed. The nutrient solution used in the bath (Krebs-Henseleit - solution) had the following composition: 118 mmol NaCl; KC1 4.7 mmol; MgSO 1.2 mmol; CaCl2 2.5 mmol; KH2PO 1.2 mmol; NaHCOa 25 mmol; glucose 11 mol)
Following the equilibration phase, by adding an appropriate amount from the KC1 stock solution, the KC1 concentration of the nutrient solution in the solution was increased to 4 mmol, as a result of which the segments were adjusted to a contraction. After an 80-minute contraction, test substances were added to the bath solution at a constant concentration of 10 mol / l. Test substances, depending on their effectiveness, cause relaxation, which is given in percent of preliminary contraction and is read after 25 minutes exposure. Relaxation is a measure for Ca antagonistic action of the test substances.
Below are the results of tests of a number of compounds for a relaxing effect (the higher the values indicated in the relaxation column, the more active the substances, and the comparison was made with Bepridil having a similar structure) „
Test conditions: relaxing effect on the vessels in rat aortic segments; relaxation (%) after prior reduction from 40 mmol K; the duration of the incubation period is 25 minutes; compound concentration
25
thirty
35
40
45
50
55
qi test 10 mol o
Connection (example)
Bepridil
5/17
5/14
5/14
70
71
72
five
Relaxation,%
51
74
80
80
76
93
82
98
eleven
74 76 83
Bepridyl - CЈ- (2-methylproproxy) methyl -N. Phenyl-H (phenylmethyl-1-pyrrolidineethanamine) „
As can be seen from the above data, the compounds of the invention are superior in activity to the known compound.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining tizamidine amines of the general formula
X
I
Rl-Z-Y-0-CHrCH-CHrd-K
L
ъ
h
hK3
thirty
de R | isobutyl, metal, isopente
nyl, phenyl, which may be substituted with halogen, methoxyl or methyl, furyl, thienyl or pyridyl; each ethyl, or together with the nitrogen atom to which they are bound, forms a pyrrolidine ring;
phenyl which may be substituted with halogen or methoxyl, thienyl or pyridyl; hydrogen, carbethoxy, nitrile, phenyl, which may be substituted with halogen, methoxy or methylenedioxy, thienyl,
pyridyl;
0
R4 R535
-
ten
i
R- - hydrordrd, nitrile, carbmethoxyl, carbethoxy, carboxyl, hydroxymethyl; X is a valence bond or is a CH group; Y is a valence bond or - (CHg) 2 -group; Z is oxygen or a valence bond, or their pharmacologically acceptable salts, in the form of a racemate or optically active isomers, characterized in that the Compound of the general formula
 ,
51
20
RT and Kg are different and mean
RT
chlorine or-Nf0
to
group,
are reacted with a compound of the general formula
R,
X
H.-c-R5 Re
where X, have the above meaning,
followed by isolation of the desired product as a base, pharmacologically acceptable salt, racemate or optically active isomer
1 L
hi Yeon gee,
P
VWlCZf
Cl
Example
one
2 R3
(CK3) 2-SNCH2P
ten
() 2-0 32с2Нзill
(CK3) 2- CLEAR2O
12
(СЯ3) 2-СЯСЯЯ2О
13
(CK3) 2 ESA2s2% 14
() 2-0: 0 2O
15
(CH3) 2-2iCH2ft
(CK3) 2-СЧСЯ2 (СН3) 2-СКЯ2О O.
18
(CH3) 2-c-iai2О
-Table continuation
R4
RS
%
-n
 NH2
NH2
//
NH2
with
-n
-n
6c 3
-n
17
17310А
18 Continuation of the table
nineteen
1731044
20
Table continuation
21
1731044
22 Continuation of the table
Table continuation
%
R2%
59
60
- from 261
-Sh-,
62
-CHN3
3)
-sn, OCH3
64
KK2S1
/.)
65
a) 1- o
 PI
bb
- H2Fi)
67,
-CH268
-CH2R4
five
%
X
about
-WITH
NH
-with
7
SNH2
ABOUT
ABOUT
°
-with
OS2N5
about
cg
CHOS2N5
about
-with
v ° c2H5
-hG
/
CHSS2N5
-with
OCH3
and -c
6 (СН2) 2СЙ3
ABOUT
I'm Yaz-s-o-sh
Csh3
27
1731044
28
Table continuation
29
1731044
thirty
Continuation of taolitsy
3f
%
R2, R3
KG
ЈЈЈ%
89
CH2
90
-CH0 /
C1
91
-CH.
 ABOUT
92
CH293
CU m
-SN
 Oil, 27 Oil,
3) Oil, Ј)) Oil, $ Oil, Oil, y) Oil,% J Oil,) Oil,
m / e 467. ta / e 453.
m / e 406-m / e 471. m / e 385. m / e 410c m / e 47f. t / e 487. t / e 491
Ъ Oil, 471 „
o) Oil, m / e 443.
U) Oil, m / e 471.
li) Oil, m / e 471.
NOxalate, Т0гт „125 С, acetic ester
/ S) Oil, t / e 487
It) Oil, t / e 447o
I} Oil, t / e 449 „
}}} Oil, t / e 386 „
tj) Oil, m / e 420.
i.0Oil, m / e 492 „
t / j Oil, m / e 445.
Editor L. Veselovska
Tehred M.Morgental Proofreader T.Malets
Order 1519 Circulation: Subscription
VNIIPI State Committee for Inventions and Discoveries at the State Committee on Science and Technology of the USSR 113035, Moscow, Zh-35, Raushsk nab. 4/5
1731044
- 32 Continuation of the table
four
%
6
ABOUT
-with
Bc2n5
ABOUT
- /
xy
W ° C2H5
Bc2n5
ABOUT
ABOUT

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CS274445B2|1991-04-11|

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AU3010589A|1989-08-31|

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DK90189A|1989-08-28|

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NO890803D0|1989-02-24|

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FI890903A|1989-08-28|

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HUT50800A|1990-03-28|

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KR890012990A|1989-09-19|

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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DE3806321A|DE3806321A1|1988-02-27|1988-02-27|NEW TRISUBSTITUTED AMINES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|

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