前苏联专利SU1297727A3 Method for producing n-cycloalkylalkanoyl piperazines or their physiologically compatible salts with

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权利要求

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专利摘要:
The invention relates to a class of substituted piperazines, in particular substances of the general formula I RI-N, cis-ch2.
公开号:SU1297727A3
申请号:SU843713674
申请日:1984-03-23
公开日:1987-03-15
发明作者:Оэпен Герхард；Энгель Юрген；Яковлев Владимир；Тимер Клаус
申请人:Дегусса Аг (Фирма)；
IPC主号:

专利说明:

The invention relates to a process for the preparation of new compounds, N-cycloalkylalkanoylpiperazines of the general formula
RI-: N () N-pine2CH2-2
de
(
W
f5
20
R, pyrimidyl, chloropyrazinyl or
phenyl radical, which, if necessary, may be substituted by fluorine, bromine, alkoxy with 1-6 carbon atoms, alkenyloxy with 3-6 carbon atoms, phenylalkoxy with 1-4 carbon atoms or alkanoylamino with 2-6 carbon atoms, alkylamino with 6 carbon atoms or dialglamino with 1-6 carbon atoms;
the 3,3-dimethyl-bicyclo (2,2,1) hept-2-yl radical or the radical of a saturated cycloalkyl with 5-6 carbon atoms, 25 of their physiologically compatible soybeans with acids that have analgesic activity.
The purpose of the invention is to obtain new piperazine derivatives with zoological spectrum of biological properties, known structural analogues. Example 1. 1- (3-Methoxy-phenyl) -4- {3-cyclohexyl-propionyl) -piperazine.
I. To a mixture of 0.06 mol (11.5 g) - (3-methoxyphensh) -piperazine and 0.06 mol (6.1 g) of triztilamine in 100 ml of absolute toluene with stirring and at room temperature, drop by drop 0.06 mol (10.5 g) of 3-cyclohexyl propionic acid chloride. At the end of the addition, the mixture is additionally stirred for an additional 3 hours at room temperature. The triethylammonium hydrochloride formed is filtered off and the filtrate is concentrated in vacuo. The residue is dissolved in 60 ml of acetone and mixed with dropwise AND 6 ml of n. isopropanol solution of hydrochloric acid. The hydrochloride is precipitated and recrystallized from methyl ethyl ketone. Output 9.9 g, so pl. hydrochloride 175-176 C.
35
40
45
50
II, A mixture of 0.05 mol (7.8 g). 3- cyclohexane propionic acid, 0.05 mol (9.6 g) S - (3-methoxy phenes1-piperazine and 0.05 mol (10.3 g) N, N-dicyclohexylcarbodiimide, dissolved
five
0
five
about
five
0
five
0
55
150 ml of anhydrous methylene chloride, stirred for 7 days at room temperature. At the end of the reaction, the product is filtered off from the formed dicyclohexyl urea, the filtrate is concentrated in vacuo and the crude product, as indicated above, is taken up in hydrochloride. The output of 3.7 g, so pl. hydrochloride 175-176 C.
Iii. A mixture of 0.05 Miles (8.5 g) of 3-cyclohexylpropionic acid methyl ester, 0.06 mol (11.5 g) of N- (3-methoxyphenyl) -piperazine dissolved in 100 ml of toluene, is boiled under reflux for 8 hours and the alcohol (methyl) formed during the reaction is distilled off. At the end of the reaction, the solvent was removed in vacuo. The crude product, as described, was added by adding (6N rot, an isopropanol solution of HCl to the hydrochloride and, for further purification, the recrystallized from methyl ethyl ketone. Yield: 4.6 g, mp. 175-176 ° C.
Analogously to Example 1, the compounds listed in Table 1 are prepared.
The test results for the analgesic effect of the pain sensation due to electric current and toxicity are shown in Table 2.
The detachment of the smaller ones was placed in an arena with a bottom grid, through which the young were annoyed with a current pulse (rectangular). The strength of the current was increased until the animals started (pain threshold) to respond to this squeak (vocalization). The analgesic effect of substances was expressed in percent as an increase in the pain threshold compared with the control group treated only with an indifferent basis of the drug.
Toxicity was determined by intravenous injection. It is listed as LDyg (in mg / kg), at which 50% of the animals studied died.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining N-cycloalkylalkanoyl piperazines of the general formula
Ri-T O o H CH2-H2
where R, is pyrimidyl, chloropyrazinyl or phenyl radical, which, if necessary, may be replaced by fluorine.
312
bromine, alkoxy with 1-6 carbon atoms, alkenyloxy with 3-6 carbon atoms, phenylalkoxy with 1-4 carbon atoms or alkanoylamino with 2-6 carbon atoms, alkylamino with 1-6 miocarbon or dialkylamino with I-6 carbon atoms ;
Rj is a 3,3-dimethyl-bicyclo (2,2,1) hept-2-yl radical or a saturated cycloalkyl radical with 5-6 carbon atoms,
or their physiologically compatible salts with acids, characterized in that the compound of the general formula
Z7
Rr-nr
where R, has the indicated meanings, is reacted with a compound of the general formula
z; X,
I
where Z is a group of the formula -CO (CE) R, where R has the indicated meanings; X - chlorine, bromine, iodine or group
Formulas - OR, where R is hydrogen or lower alkyl, followed by isolation of the desired product in the free state or as an acid addition salt.
T a b l and c a
DOS
As in 5.3 measure 3
Och-,
OS2N
Cyclo-12.6 hexyl
3
,9
2.6
, 2
3-cyclohexylpyropionic acid acid chloride
198-199 11.5 g (2-methoxyphenylZ- (HC1-salt) piperazine and 12.9 g of chlorohydride, 3-dimethylbicyclo (2.2.1) hept-2-yl) -propionic acid
175 12.4 g N- (2-ethoxyphene- (HC1-salt) nyl) piperazine and 12.9 g of acid chloride, 3-dimethylbicyclo (2.2.1) - hept-2-yl-propionic acid
155-; 56 9.6 g N- (2-methoxy-phenyl (HC1-salt) nyl) -piperazine and 7.1 g
Z-cyclopentylpropionic acid
147-148 12.4 K- (2-ethoxyphenyl) - (HGl-salt) piperazine and 10.5 g
3-cyclohexylpropionic acid chloride
146. 13.2 g of K- (2-n-propyl- (HC1-salt) hydroxyphenyl) -piperazine and 10.5 g of 3-cyclohec: n:
mr
Continued-tab.
SNS (SNS) 7.
.ОСН2-СН СН2
. . OCH2SbN5
10 Cyclo-11.5 86-87
hexyl
eleven
12
13
, Bnns,
14
15
// (C2H5) g
// Cyclohexyl
- NHCOCHc
sixteen
NFTCOG H
, 2 59-63
(Basis)
3 36-39
(Basis)
1.5 86-87
5.0
N, 9
, 0
,five
,five
, 2
173-175 (HC1-salt)
134-136 NS 1-salt
52.54 (Foundation)
89-91 (Foundation)
77
(Basis)
107-108 (Basis)
, 0 93-94
(Basically bath)
silpropionic acid
acid chloride
13.2 g of K- (2-isopropyloxyphenyl) -piperazine
and 10.5 g of 3-cyclohexyl propionic acid
acid chloride
13 g of L- (2-allyloxyphenyl) -piperazine and 10.5 g of 3-cyclohexylpropionic acid chlorohydride
16.8 g of K- (2-benzyloxy-phenyl) -piperazine and 10.5 g of 3-cyclohexylshropionic acid chloride
7.8 g of 3-cyclohexyl pro-pionic acid and 9.6 g
N- (4-methoxyphenyl) -piperazine
10.8 g of N- (2-fluorophenyl) piperazine and 10.5 g of 3-cyclohexyl-propionic acid chlorohydride
14.5 g of H- (2-bromofensh1) piperazine and 10.5 g of 3-cyclohexylpropionic acid chloride
11.5 g of N- (2-methylaminophenyl) piperazine and 10.5 g of 3-cyclohexylpropionic acid chloride
13.9g of H- (2-diethylaminophenyl-piperazine and 10.5 g of 3-cyclohexylpropionic acid chloride;
13.1 g of N- (2-acetaminophenyl) piperazine and 10.5 g of 3-cyclohexylpropionic acid chloride
13.9 g of N- (2-propionyl-aminophenyl) -piperazine and 10.5 g of acid chloride
18
nineteen
N
X)
N
TS
C1
X)
TSf
Cyclohex
21
, 5 175-177
(NS I-salt)
, 1104-105
(Base)
0.7 95-96
(Basis)
, 3 butter
Rf 0.72
, 8 134-136
(NA 1-salt)
V-cyclopropic acid
9.7g of phenylpiperazine and 10.5 g of 3-cyclohexylpropionic acid chloride
9.8g of K-pyrimidyl- (2) -piperazine and 10.5 g of 3-cyclohexylpropionic acid chloride
19.8 g N-2-chloro-pyrazinyl (6) -piperazine and 10.5 g 3-cyclohexyl propionic acid chloride
12.2 g of N- (2-dimetypamienophensht) piperazine and 10.5 g of 3-cyclohexylpropionic acid chloride
10.3 g of H- (2-ethoxyphenyl-piperazine and 7.1 g of 3-cyclopropyl cropic acid.
The Rf value was determined on silica gel plate for thin layer chromatography (Si60 F254 Merck, Darmstadt). Solvent: chloroform - methanol - NH 95: 4: 1
Table 2
2 3 4 5
50 43 50 50 50
4000 1500
4000 2000
Note:
1 compound A
SSCHSO-T 4-SbN5
compound j
СНзСНгСО-1 (-СбК5
compound C
(
SNSO,
SHCHOCh-jO
VNIIPI Order 800/64
-CH2CH SOTirage 372
Random polygons pr-tie, Uzhgorod,
-CH2CH SOTirage 372
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法律状态:

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