Method of obtaining piperazine-containing hydrocarbons or acid-additive salts thereof

专利摘要:
1. Bis-(piperazinyl- or homopiperazinyl) alkanes of the general formula I see diagramm : EP0122488,P21,F1 wherein R1 , R2 , R3 and R4 which may be identical to or different from each other, are each hydrogen, alkyl having 1 to 4 carbon atoms, hydroxyl, alkoxy having 1 to 4 carbon atoms, alkanoyloxy having up to 4 carbon atoms, halogen, trihalomethyl, di-C1-4 alkylamino, C1-4 alkoxycarbonyl, nitro, cyano or acyl having 1 to 3 carbon atoms ; R5 and R6 , which may be identical to or different from each other, are each hydrogen, methyl, hydroxyl, carboxyl, C1-4 alkoxycarbonyl, hydroxymethyl, phenyl or p-chlorophenyl, R7 and R8 are each hydrogen or methyl ; j and k are integers from 0 to 3, their sum being no more than 4 ; m and n are integers from 0 to 3, their sum being no more than 4 ; A is -CH2 - or -CH2 CH2 - ; or R5 and R7 together or R6 and R8 together are oxo, provided k or m is other than O ; or R5 and R7 together and R6 and R8 together are oxo, provided k or m are other than O ; R9 and R10 , which may be the same or different, represent hydrogen or from one to four methyl substituents on the carbon atoms of the piperazine ring (A = -CH2 -) ; R11 , R12 , R13 and R14 , which may be identical to or different from each other, are each hydrogen or methyl ; or R11 and R12 together and/or R13 and R14 together are oxo ; and X is alkylene of 1 to 2 carbon atoms, optionally hydroxy-substituted with the proviso that when A = -CH2 -, R1 to R14 are hydrogen and j, k, m and n are each zero, then X cannot be 1,2-ethylenediol, and physiologically acceptable acid addition salts thereof.
公开号:SU1574174A3
申请号:SU864027087
申请日:1986-03-12
公开日:1990-06-23
发明作者:Девлин Джон；Мекнейль Даниель；Кеирнс Джеймс；Барсумян Эдвард
申请人:Берингер Ингельгейм Лтд (Фирма)；
IPC主号:

专利说明:

The invention relates to a process for the preparation of new piperazine derivatives having valuable pharmacological properties and which can be used in medicine.
The purpose of the invention is a method of obtaining new piperazine derivatives with higher antiallergic and anti-inflammatory activity.
 Sh
Example 1. Tetrahydrochloride 1,3-bx-4- (4-chloro-3-trifluoromethylbenzyl) -1-piperazine propane (compound 1).
A mixture of 11.5 g of 3-chloro-4-tri-fluoromethylbenzyl chloride, 5.3 g of 1,3-bis (1-piperazinyl) propane, 50 g of ethanol and 7.0 g of triethylamine is heated under reflux for 16 h. Then the reaction mixture is evaporated in vacuo, the residue is mixed with 150 ml of water and the mixture is extracted 5 times with ether in a quantity of 100 ml. The combined ether extracts are washed 3 times with a 1M solution of sodium carbonate | in an amount of 100 ml each, dried with magnesium sulfate, filtered and evaporated to a yellow oil (6.8 g). This oil is dissolved in
100 ml of hexane and filtered. The filtrate is extracted 3 times with 2% aqueous acetic acid in an amount of 20 ml each, and the desired product is found in the second or third extract (the test is carried out by thin layer chromatography). These extracts are combined, strongly alkalinized with 2N. caustic soda and extracted with 100 ml of a mixture of simple ether and hexane (1: 1). The extract is dried with anhydrous potassium carbonate and then the solvent is evaporated. The resulting oil (2.6 g) is dissolved in 10 ml of methanol. After adding a saturated solution of hydrogen chloride in ether, a white precipitate is obtained. Then, E.E.E., 50 ml of ether is added, the precipitate is filtered off and recrystallized from methanol. Compound 1 is obtained in the form of colorless crystals, i.e. pl. 265-268 ° С (decomposition at -250 ° С). Output 28% of theory.
Example 2. 1,3-bis 4- (4- -chlorophenyl) -1 -piperazinshlpropane
(compound 2).
A mixture of 10 g of 4-chlorophenethyl chloride, 5.3 g of 1,3-bis (1-piperazinyl) pro- nan, 50 g of ethanol, and 7.0 g of triethylamine is heated under reflux for 16 h. The reaction mixture is evaporated under reduced pressure and the residue is mixed with 150 ml of water. The resulting mixture is extracted 5 times with 100 ml of ether and the extracts are washed 3 times with TOO with ml of 1N. sodium carbonate solution. The resulting broadcast. The aqueous solution is extracted 3 times with 300 m 1N. hydrochloric acid. Fit Extra

n q
five
0
alkalinized 2 n. sodium hydroxide solution and the product is extracted 3 times with 200 ml of ether each time. The ether extract is dried with magnesium sulfate, filtered, evaporated and the residue is recrystallized from heptane. Compound 2 is obtained as a crystalline product, mp. 87-88 ° C. Yield 42% of theory.
I
Analogously to Examples 1 and 2, the following compounds were obtained:
tetrahydrochloride 1, 3-bis 4- (4-chlorobenzyl) -1 piperazinyl propene (compound 3), so pl. 261-274 ° C (decomposition, ethanol / water). The output of 31% of theorium, 1, 3-bis (4- (4-chlorobenzyl) -1-piperiraine -2-oxypropane (compound 4), so pl. 85-86,5 ° C (heptane) . Output 26% of theory,
1,4-bis 4- (4-chlorobenzyl) -1 piperazinsL butane hemihydrate (compound 5), mp. 101-105 ° C. Yield 30% of theory;
1,3-bis (4-benzyl--1-piperazinyl) propane tetrahydrochloride, (compound 6), mp. 250-265 ° C. Yield 20% of theory;
1,3-bis-4- (4- -fluorobenzyl) -1-piperazinyl propane tetrahydrochloride (compound 7), m.p. 228-237 sS (decomposition, ethanol / water). Yield 22% of the theory of nitrihydrochloride 1, 3-bis 4- (4-chlorobenzyl) -1-piperazinyl-β-oxopropane (compound 8), mp 222-250 ° C (decomposition; ethanol / water). Yield 27% of theory1;
1,3-β-bis L4- (4-chlorobenzyl) -1-piperazinyl -1 -1-methylpropane tetrahydrochloride hemihydrate (compound 9), mp. 228-232 ° C. Output 30% of theory.
1,3-bis Ј4- (4-chlorobenzhydryl) -1-piperazinyl. propane dihydrochloride dihydrate (compound 10), mp. 163-169 ° C (decomposition). Output 23% of theory
1,3-β-bis tetrahydrochloride monohydrate (4-phenacyl-1-piperazinyl (propane (compound I), m.p., D 94-204 ° C. Yield 24% of theory,
1,3-bis 4- (2-phenyl-2-hydroxyethyl) -1-piperazinyl propane tetrahydrochloride (compound 12), mp 233-240 ° C. Exit 36% of theory.
1,3-bis (4-phenethyl-1-piperazinyl) propane dihydrochloride dihydrate (co51
unity 13), tp.2Yu-225 ° C. Yield 41% of theory;
1,3-bis G4- (4-chlorobenzyl) -1-piperazinyl -1, 3g-dioxopropane dihydrochloride monohydrate (compound J4), mp. 199-206 ° C (ethanol). Output 40% of theory,
tetrahydrochloride 1, 3-big-i-phenyleth-O-piperazinyl propane (compound 15), so pl. 236-246 ° C (decomposition, ethanol / water), Yield 37% of theory j
tetrahydrochloride dihydrate 1,3, - -bis bis 4- (4-chlorobenzyl) -2,5-dimethyl-1-piperazinyl} propane, (compound 16), mp 204-214 ° C. Output 36% of theory}
1,3-bis 4- (4-methoxybenzyl) -piper zinyl propane (compound 17), so pl. 86-87 ° C (heptane). Output 35% of theory;
1,3-bis | 4- (3,4-dichlorobenzyl) -1-pshterasinyl propane tetrahydrochloride (compound 18), mp. 245-2518С. Yield 41% of theory
1,3-bis 4- (2-chloro-benzyl) -1-piperazinyl propane tetrahydrochloride (compound 19) mp. 251-255 ° C (ethanol / water). Output 33% of theory},
1,3-bis 4- (4-methylbenzyl) -1-piperazinylZpropane tetrahydrochloride (compound 20), m.p. 245-252 С (decomposition). Output 42% of theory}
1,3- | H- (3-chlorobenzyl) -1-piperazinyl propane dihydrochloride monohydrate (compound 21), mp. 248-257 ° С (decomposition, water). Yield 43% of theory:
1,3-β-bis tetrahydrochloride monohydrate (4-chlorophenyl propyl -1-piperazinyl 5 propane (compound 22)) mp: 245-246 ° C. Yield 45% of theory;
1,3-bis 4- (4-hydroxybenzyl -1-piperazinyl propane (compound 23), mp. 1 97–201 ° C. Yield 39% of theory,
1,3-bis L- (4-β-bromobenzyl) -1-piperazinyl propane tetrahydrochloride (compound 24), mp 237-243 ° C. Output 28% of theory;
746
1,3-bisЈ4- (4-chloro-benzyl) -1-homopiperazinyl propane tetrahydrochloride (compound 25), mp. 218-224 ° C (decomposition, aqueous ethanol). Output 22% of theory,
1,3-bis (4-chlorophenyl) butyl -1-piperazinyl propane tetrahydrochloride (compound 26), mp, 213-217 ° С (decomposition, ethanol). Yield 25% of theory Ј
1,3-bisЈ4- (4-acetoxybenzyl) -1- piperazinyl propane (compound 27) mp 102-105 ° С (heptane). Output 38% of theory
tetrahydrochloride 1, 3-bis 4- (4-butoxybenzyl) -1-piperazinyl propane (compound 28), mp 207-218 ° C (ethanol / water). Exit 44% of theory
, 1,3-bis 4- (4-. chlorobenzyl-2,3,5,6-tetramethyl-1-piperazinyl propane tetrahydrochloride (compound 29). Yield 26% of theory.
1,3-bis (4-chlorophenyl) propyl-β-homopiperazinyl propane tetrahydrochloride (compound 30). Yield 34% of theory /
1,3-bis 4- (4-chlorobenzyl) -1 -homopiperazinyl -1, 3-dioxopropane dihydrochloride (compound 31). Yield 39% of theory.
The better activity of the proposed piperazine-containing compounds in comparison with the known compound is confirmed by the results of the test in the concentration test, which provides 50% inhibition (KT5o) of histamine release from human leukocytes, shown in the table.
The proposed compounds have the same toxicity as the known compound, i.e. 1000 mg / kg (oral, mouse).

权利要求:
Claims (1)
[1]
Invention Formula
50
The method of obtaining piperazine-containing hydrocarbons of General Formula
R
R,
& AT
RC
(CH {ln-C- (CH,) m-KQN-C-X-C-QN4CH) m-C4CH n
Я3Rs R7 Ke Rsiz
where R and R4 are the same or different - hydrogen, methyl, i
& AT
RC
C-X-C-QN4CH) m-C4
C, - СФ-alkoxy group - chlorine, bromine fluorine, trifluoromethyl, acetoxy group
RI is hydrogen or hydroxyl,
R4 is hydrogen or together with BV oxo-group, if m 1 and n O,
m and p 0,1,2, and their sum does not mean 3;
A is methylene or ethylene,
Rt is hydrogen or 2-4 methyl groups on the carbon atoms of the piperazine ring
K is the same or different - Eodoride or methyl, or F6 and R7 and / or Re and R ") together is an oxo group ...
X - C. alkylene, unsubstituted
or substituted with hydroxyl, or their acid addition salts, characterized in that the compound of the general form
R6
Re
HN () N-C-X-C-N PL
Hell
R5 R7 R9 R5
where Rj-R, X and A have the indicated meanings, they are reacted with a compound of the general Formula
five
fyA
RS
values are Y is halogen,
in the ratio of 1: (2-3), followed by isolation of the target product in free form or in the form of acid addition salts.
 where r4 m and n

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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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US47700883A| true| 1983-03-21|1983-03-21|

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