Method of producing derivatives of 2-[(aminoalkyl)amino]-1-phenylalkanole-1 or pharmaceutically acce

专利摘要:
Amino-alcohol derivatives of the formula, where R, is a straight or branched alkyl group having 3 to 8 carbon atoms, R2 and R3 are each a lower alkyl group, or R2 and R3 form a 5- to 7-membered ring together with the adjacent nitrogen atom which may have an oxygen atom attached thereto, R. is a hydrogen atom or a lower alkyl group, R5 is a hydrogen atom or a lower alkyl group, X is a hydrogen or halogen atom or a lower alkyl or lower alkoxy group, and n is an integer of 2 or 3, and acid addition salts thereof, are effectively useful as medicines and agricultural chemicals. Processes are also disclosed for preparing such compounds.
公开号:SU1433409A3
申请号:SU853957801
申请日:1985-09-27
公开日:1988-10-23
发明作者:Масаки Митсуо；Синозаки Харухико；Сатох Масару；Моритох Наоя；Хасимото Коити；Камисиро Тосиро
申请人:Ниппон Кемифар Ко.,Лтд (Фирма)；
IPC主号:

专利说明:

The invention relates to a process for the preparation of HOBttx derived 2- (aminoalkyl) amino -1-phenyl-alkanol-1 of the general formula
(I) OB.4 RS R
CH-CH-N- (CH.
I EZ. one
where R is right or branched
C — C — alkyl;
R and RJ - either a lower alkip or together with the adjacent nitrogen atom form a 5 7-membered cycle, which may include an oxygen atom; R - hydrogen or lower C.-C-alkyl
Rj is hydrogen or lower alkyl; X is hydrogen or halogen, lower
alkyl or lower alkoxy; n 2 or 3,
or their pharmacologically acceptable salts, which block the binding of glutamic acid in the neuromuscular muscles, as well as inhibit anemic cerebral stiffness.
The aim of the invention is to develop a process for the preparation of new derivatives (a ffialkoalkyl) amine -1-phenyl-alkanol-1, which exhibit higher pharmacological activity in blocking the binding of glutamic acid and suppressing anemic infant stiffness.
Example 1. Dihydrochloride (1RS, 2 SR) -5-metsh1-1-fensh1-2- (3-piperidinopropylamino) -hexanol-1 (co 21),
A mixture of (1RS, 2SR) -2-amino-5-metsI--1-phenylhexanol-1 415 mg, 2 mmol) and 1- (3-chloropropyl) -piperidine (324 mg, 2 mmol) is melted at 70 ° C in nitrogen atmosphere. The mixture was heated at 110 ° C for 3 hours. After cooling, the reaction mixture was dissolved and heated in ethanol, followed by the addition of concentrated hydrochloric acid (0.2 ml). After that, the mixture is cooled, the precipitated crystals are collected by filtration and rinsed with ethanol. The crystals are recrystallized from ethanol to

obtain 0.27 g of the title compound as white crystals (yield: 33%), T, pl. 266-267 with (decomp.), IR (KBG, "aksm: 3290, 2945, 2650, 2550,.

1590, 1445, 1285, 1130, 1090, 950, 735, 700.
PRI mme R 2. Dihydrochloride (1RS, 2RS) -5-methyl-1-phenyl-2- (3-piperidino-propshmino) -hexanol-1 (comp. 22).
A mixture of (1RS, 2RS) -2-amino-5-methyl-. -1-phenylhexanol-1 (1.04 g, 5 mmol) and 1- (3-chloropropsh1) -piperidine (0.81 g, 5 mmol a) melted at 70 ° C in a nitrogen atmosphere, the mixture is then heated at 110 ° C to 120 ° C for 3 hours. After cooling, the reaction mixture is dissolved with heating in ethanol, and then concentrated hydrochloric acid (0.5 mp) is added. The mixture is concentrated and the residue is crystallized by treatment with ethanol and hexane. The crystals are collected by filtration, washed with a mixture of ethanol and hexane, and then recrystallized from a mixture of ethdnol and hexane, to obtain 1.24 g of the title compound as white crystals (yield 61%). Mp. 250-251 ° C (decomp.). IR (KVG, 1m.s.s): 3310, 2950, 2640, 1590, 1450, 1050, 760, 700,
PRI me R 3, (1RS, 2RS) -1-phenyl-2- (3-piperidino-propylamino) octanol-1 Dihydrochloride (Compound 28),
A mixture of (1RS, 2RS) -2-amino-17Phenylocanol-1 (1.77 g, 8 mmol) and 1- (3-chloropropyl) -piperidine (1.29 g, 8 mmol) is melted at 70 ° C in nitrogen atmosphere. The mixture is then heated at 110-120 ° C for 3 hours. The reaction mixture is dissolved with heating in ethanol, and then concentrated hydrochloric acid (0.67 ml) is added. Ethyl acetate is added and the mixture is allowed to stand. The precipitated crystals were collected by filtration and washed with ethyl acetate and then with hexane to obtain 1.96 g of the title compound as white crystals (yield 59%). M.p. 231-234 C (decomp.). IR (KBG,): 3310, 2925, 2700, 1585, 1450, 1055, 760, 700.
PRI me R 4. Dihydrochloride (IRS, 2SR) -5 - MeTmT-1-phenyl-2- (2-piperidinoethyl) -hexanol-1 (comp. 41).
A mixture of (1RS ,, 2SR) -5-methyl-phenyl-2-aminohexanol-1 (1.04 g, 5 mol) and 1- (2-chloroethyl) -piperidine (0.74 g, 5 mmol) is melted at 70 ° C in a nitrogen atmosphere. Then the mixture is heated at 110-120 ° C for 3 hours. “After
cooling the reaction mixture is dissolved in water. The solution is alkalinized 2 n. NaOH solution and then extracted with ether. The ether extract is washed twice with water and once with brine, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was dissolved in acetone (20 ml), then concentrated hydrochloric acid (0.74 mp) was added. The precipitated crystals are collected by filtration and washed with acetone. The crystals were recrystallized from ethanol (10 mp) - ether (2 ml) to obtain 0.34 g of the title compound as white crystals (17% yield). M.p. 223-22A C (times). IR (KBg, j ,,, cm M: 3260, 2950, .2700, 2470, 1600, 1450, 1200, 1050, 740, 700.
PRI me R 5. Dihydrochloride (1К5,25К) -5-methyl-1-fennp-2- (3-piperidinopropylamino) -hexanol-1 (com. Unit 9).
A mixture of (1K8, 25K) -2-amino-5-metsh1 -1 -1 phenylhexanol-1 (1.04 g, 5 mmol) and 1- (3-chloropropyl) -piperidins (0.81 g 5 mmol) in benzene ( 10 ml) are boiled under reflux for 40 hours. After cooling, the reaction mixture is concentrated under reduced pressure. The residue was dissolved in ethanol (10 ml), and then 6N was added. HC1 in ethanol (2 MP). The precipitated crystals are collected by filtration and then recrystallized from ethanol to obtain 1.15 g of the title compound as white crystals (yield 57%). M.p. 266-267 s.
Example 6. Dihydrochloride (1K8,25K) -5-metip-1-fensh1-2- (3-psh1ervdinopropylamino) -hexanol-1 (co-unit 9).
A mixture of (1K5, 288K) -2-amino-5-methyl--1-phenylhexanol-1 (1.04 g; 5 mmol), 3-piperndinopropyl tosylate hydrochloride (2.00 g, 6 mmol) and sodium bicarbonate (1 , 05 g; 12.5 mmol) in ethanol (10 mp) are boiled under reflux for 1 hour. After cooling, ether (100 ml), water (50 ml) and 2N were added to the reaction mixture. NaOH solution (5 ml) and the resulting mixture is shaken thoroughly. The ether layer is separated and washed thrice with water, once with brine, and then, after drying, concentrated under reduced pressure. The residue is dissolved
from 0
five
Q
d -
0
in ethanol and 6N is added to the solution. HC1 in ethanol (1.5 MP). The precipitated crystals are collected by filters
It is recrystallized from ethanol to give 0.73 g of the title compound as white crystals (yield 36%). M.p. 266-267 ° C (decomp.).
EXAMPLE 7 Methyl Ester (1RS, 2SR) -5-MeTHn-1 -1 -1-phenyl-2- (3-piperidinopropylamino) -hexanol-1 Methyl Diphloromethane (Compound 59).
To a solution of (1K5,28K) -5-methyl-1-phenyl-2- (3-piperidino-propylamino) -hexanol a-1 (1.66 g, 5 mmol) in toluene (25 ml) added sodium hydride (0.14 g, 6 mmol) and the mixture is refluxed for 1 hour. Methyl tosylate (1.12 g, 6 mmol) is added to the reaction mixture and the resulting mixture is boiled under reflux. after cooling, after cooling, the mixture is washed twice with water and once with brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on neutral alumina (alumina 40 g, eluent: chloroform) to obtain 1.1 g of an oily substance. To a solution of the substance in acetone (20 mp) was added concentrated hydrochloric acid (0.1 mp) and the mixture was concentrated under reduced pressure. The residue was recrystallized from acetone (10 mp) - ethanol (0.2mp) to obtain 0.45 g of the title compound as white crystals (yield 21%). M.p. IBS-UI C.I.I. (KBG, „ax cm-): 3360, 2940, 2640, 1570, 1450, 1120, 1095, 1060, 1010, 740, 695.
Examples 8-48. Under the conditions of Example 1, starting from the corresponding 2-amino-1-fensch-1-alkanols-1 and tertiary, the desired products are obtained, indicated in Table. one.
The study of the biological effect of the compounds is carried out as follows.
The following 2- (aminoalkyl) amyl -1 -1-phenylalkanol-1 derivatives are used as known structural analogues.
Comparative Compound 1: Digidrochloride (1RS, 2SR) -1-phenyl-2- (2-piperidinethylethylamino) propanol-1.
Comparative compound 3: dihydrochloride (1KZ, 28K) -2 - (2-morpholino ethylamino) -1-phenylpropanol-1.
Comparative compound. 2; cyppe-chloride (1E5., 23K) -1-phenyl-2 (2-pyrrolidinoethylamino) -propanol- 1, Comparative compound 4: dihyd ™ cooled (1K5,25K) -2- (2-dimethylami-Yoethylgano) - 1-phenylpropanol-1. ; Comparative compound 5i toluperonson hydro | sluoride.
I Example 49: A study on the blocking of glutamic acid in the neuromuscular junction of cancer of the feet.
I The study of this effect was carried out by the known methods of Ishida and ShinozakId. The dissection of the anterior muscle ™ of their legs of the cancer is used as experimental materials. A neuromuscular sample is kept in a bath in a physiological solution, mmol; NaCl 195; CaCl | 18; KC1 5.4; tris-maleate buffer (pH 7.5, 10), glucose 11, at room temperature and at a constant flow rate. A glass microscope filled with a 3 molar solution of KC1 was introduced into the central part of the muscle fiber in order to trace the intracellular changes in the potential of the muscular cell membrane.
The blocking effect of each studied compound on the binding of glutamic acid is estimated as the percentage of depolarization inhibition, which is induced by L-glutamic acid (10 mol) used in Lane with a 5-minute pretreatment with a solution of the compound under study (2 x Ymole ), The results are presented in Table. 2
Rum 50 Study of the inhibition of rat anemic cerebral stiffness.
The study of this effect of the compounds is carried out in a manner known as Fukuda et al. Vistar male rats (body weight 270-350 g) are kept on their backs and incised under anesthesia. After that, the trachea and the common carotid arteries are exposed, a cannula is inserted into the trachea, and the bilateral common carotid arteries and the esophagus are then tied up twice and cut off.
After that, the occipital bone is exposed, which is drilled through
0
five
0
five
0
five
0
five
0
five
a circular opening to double-tie the central artery through the center. When each rat is subjected to anesthesia, its forelimbs become stiff. The measurement is carried out using the recorded electromyographic (EMG) muscle response of the forelimb (triceps brachii) of the rat in a stationary state. EMG pulses are converted to accumulated values every 10 s and recorded as a histogram on the recorder.
The effect of each compound on rigidity is evaluated as a percentage of inhibition. This percentage was first calculated by determining the area of the reduced part of the EMG pulses on the histogram 10 minutes after the physiological saline solution of each compound (3 mg / kg) was administered through the femoral vein and then according to the following equation:
d
The percentage of suppression - x 100,
where a is the area of the EMG pulse, which
decreases as a result of entering the compound under study; And the area of the EMG pulse, when it was not entered the studied compound (control).
 The results are presented in table. 3. Example51. Experience 3. Determination of acute toxicity.
Using a male, the acute toxicity level of each studied compound was determined according to the direct method. The test compound is dissolved in physiological saline and injected through the caudal (facing tail) vein. The results are presented in table. four.
Thus, as outlined in Tables 2–4, the compounds obtained by the described method, in their pharmacological activity, are associated with the blocking of glutamic acid binding (Table 2) and the suppression of anemic cerebral stiffness (Table 3) (indicators - the percentage of blocking and suppression, respectively, is significantly greater than the known structural analogs that have the same effect.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining 2- - (amine alkyl) a NOZ-1-phenylalkano-1-1 derivatives of the general formula
OR.
RS
R
Ri
CH-CH-H- (SNg) p-
1 (i)
R - right or branched
C-C-alkyl;
K-each lower alkyl or together with the adjacent nitrogen atom form a 5-7-membered cycle, which may include an oxygen atom;
hydrogen or C, -C, -papyl} hydrogen or lower alknl; hydrogen or halogen, lower alkyl or lower alkoxy} 2 or 3,
Their pharmacologically acceptable y, characterized in that 2-amino-1-phenipalkanol-1 total ula
he,
CH-CH-NH
4 RS - X n
(Xi)
Xri
R ,, Rj and X have the indicated value.
enter into interaction with a tertiary amine of the general formula
Y (CHzb-N
/ "
"(III) lz
i
ten
15
20
2 where Y is a halogen or a tnloxy group,
RI, Kz and n have the indicated value,
at a temperature of 70-130 s, if necessary, in the presence of an inert solvent such as benzene or toluene, and in the presence of a base such as sodium bicarbonate, and if necessary, a compound of the general formula (I), where R is hydrogen and R, R , R. Rj, X, n have the indicated meanings, are reacted with a base such as sodium hydride, and then are treated with an alkyl tosylate of the general formula
25
(Iv)
where R is C, -C, -apkil,
in an organic solvent such
like benzene, toluene or xylene, with
temperature from room to
with a follow-up target
product in free or as
salt.
X
OR4 RS
sn-sn-m -. (cis) pk
(a1
29IRS. 2SR
X -ZN
-CHjcaiC
SNS CHZ r-v
 Pn spz
1433A09
ten
Continued table. one
N2234-5 (nz eganol-hegsan)
4738
IRS. 2SR -SNGSN uG}
SKZ
49 39
- SMZ 1RS, 2SR - SNGOTs 11 at
5040IRS
- Otz,, 2SR - CHjCBC V
CH
514t
 -CH,
iRs, 2SR -sngsn; f-
SNS
SNC
5242. 1RS, 2RS
ЬМ1 «il-j-CHjCH-: N H H 4-CH 3243-6 (from ethanol)
CH, - /
SMZ
snoz
53431RS. 2SR -CHjCHC 3if y B H 4-OCH, 3
SNS
250-1 C "s ethanol -
5544
Cys / -V 1RS, 2SR -CHjCH. KN H 4-F3
SNS
Continued table.
H N 2-CH, .. 3
236-8 (uh voprissavala - ode)
H N 3-CH, 3
255-6 (from 901 ethanol)
in 3-CH. 3240-3 (from etmopa)
257-9 (ne ethanol - water)
250-1 C "s ethanol - water)
275-6 (ethanol - woam)
13
1433409
58
47188, 2R8 -OTSOT:
Sn, SNZ g-
jf) H H 4-C1
From “h.
SI}
2S2-3 (H1 x anol)
CHj r-v
It4S "S, 28k -CHjCHCTNu NIN3256-7 (from this" o ")
SNE
Continued tabl, 1
2S2-3 (H1 x anol)
table 2
15
23 25
97 90
27 29 31
95 93 91
Compound
3
5 21 22 35 41 43
45
Comparative Dynamics 2
3 4 5
Compound
5 15
sixteen
143340916
Continuation of table 2
99 59
30 0-50
Table3
Suppression%
17.5 18.5 65.9 42.3 21.6 23.5 16.1 90.5 ..
2.2
1.0
1.1 4.8 Table 4
LD 50, mg / kg, intra19,2
22.1 23.6
28,8
17
1A33409J8
Continuation of table 4
17 19 21 22 35 41 43 45
15.4 28.4 13.6 19.0 26.7 29.5 31.9 12.8

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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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JP59203623A|JPH0517900B2|1984-09-28|1984-09-28|

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