CS270599B2 - Method of alkylendiamine derivative preparation - Google Patents

Abstract

Process for the preparation of the general compound of Formula I, wherein A is a group of Formula II, where R 1 is straight or branched O 2 alkyl the group or phenyl group, R 2 is straight or a branched alkyl group C 3-8 phenoxy or phenyl and m and n are the number 0 and i 2, with the condition, ie ■ + n is not more than 3, and B is hydrogen, or A is a group of Formula III wherein R 1 is a straight or branched-chain 3-8 alkyl group or phenyl and k is 0 to 3, and B is straight or branched alkyl the group, p is the number 2 to 6 and q is face 4 to 7, consisting of an amine reaction compounds of formula IV are halogenated a compound of the formula V. Al- - the kylendlamine derivative is preferably used as a glutamate blocker.

Description

The present invention relates to a process for the preparation of an alkylenediamine derivative. Alkylsndiamine derivatives are preferably used as glutamate blockers.

It is generally known that glutamate serves as an excitatory transporter in corals. Furthermore, glutamate is also believed to be an effective example of exoipitic transmission in the mammalian central nervous system. Glutamic acid methyl ester is a known glutamate blocker which is effective in inhibiting the above glutamate function. However, the γ-methyl ether function of glutamate blocking glutamate is observed only when ee is used at a high concentration such as 10 ^-2 to 10 ^-3 M. Thus, the methyl ester is not satisfactory for practical use as a glutamate blocker.

It is further reported * that Diltiazem and Caroberin also show inhibition of glutamate function, see Chemietry of living Body, Japan, 30/2 /: 82-91, 1979. systems, such as anticholinergics to aeotylcoline and antihietamines to hietamine. For example, Diltiazem and Caroberin at a dose of 2x 10 “ ⁴ M are effective only at such low levels that it inhibits approximately 30% of dopolarisaco induced in the use of glutamic acid (1 χ ΙΟ ⁴ M) not open muscle of the first pair of legs of cancer · No further effect manifested by these known compounds selective.

The present invention relates to a process for the preparation of an alkylenediamine derivative of formula I

- W _p

(I), where

A is a group of formula II

R 1 is CH 2 -CH ² R 2) - (II), wherein R ¹ is a straight or branched alkyl group having 3 to 8 carbon atoms or a phenyl group, R ² is a straight or branched alkyl group having 3 to 11 carbon atoms , the alkoxy group containing 3 to 8 carbon atoms, the phenoxy group or the phenyl amane is headed 0 to 2, provided that m + n is not more than 3, and B is hydrogen or

A is a group of formula III

R ³ - (CH ₂ ) _k - (III), wherein R ³ is a straight or branched alkyl group having 3 to 8 carbon atoms or a phenyl group and the number 0 to 3, and B is a straight or branched alkyl group containing 3 up to 11 carbon atoms, p is a number from 2 to 6 and q is a number from 4 to 7, which is characterized in that ee does not react the amine compound of general formula IV

A - NH

B (IV) wherein A and B have the abovementioned meaning, and the halogenated compound of formula V j 1 ^C1 - ^H ^ ^2} q ^(V) 'where p and q are as defined above.

The reaction of the compound of formula IV and the compound of formula V is preferably carried out in the presence of thionyl chloride and in chloroform and at a temperature between room temperature and 16 ° C.

The alkylenedlamine derivative of the invention is particularly useful as a glutamate biocator. The glutamate blocking effect of the alkylenedlamine derivative according to the invention is up to 100-fold or better than the effects of known glutamate blockers such as N-methylsulfuric acid, Diltiazem and Carobell.

It is known that convulsions occur when a glutamic acid injection is injected into the brain. Thus, the alkylenediam derivative of the present invention exhibiting an excellent glutamate blocking effect is a valuable pharmaceutical preparation for neuriatry caused by an unbalanced nervous system or abnormal irritation of the muscle contraction.

Furthermore, the alkylenedlamine derivative is a valuable agrochemical, especially an insecticide, because it is effective in blocking transmission at the neuromuscular junctions of insects, in which glutamic acid serves as an excitatory transporter at neuromuscular junctions, thereby reducing insect activity. ·

It was further confirmed that the alkylenedlamine derivative of the invention has low both acute and subacute toxicity. In the alkylenedlamine derivative of the present invention, the above substituent R 1 is preferably a straight or branched alkyl group having 3 to 8 carbon atoms such as propyl, isopropyl, butyl, isobutyl, pentyl, Isopentyl, hexyl, heptyl, octyl or 2-ethylhexyl or phenyl.

The above-mentioned substituent R is preferably a straight-chain or branched alkyl group having 4 to 8 carbon atoms such as butyl, isobutyl, pentyl, leopentyl, hexyl, heptyl, octyl or 2-ethylhexyl. Alternatively, the substituent R is preferably a straight or branched alkoxy group having 4 to 8 carbon atoms such as butoxy, isobutoxy, pentyloxy, Isopentyloxy, hexyloxy, heptyloxy, octyloxy or 2-ethylhexyloxy.

In the alkylenedlamine derivative according to the invention, m, * n and k are preferably 0 or 1, p is preferably 2 or 3 and q is preferably 5, 6 or 7.

An alkylenedlamine derivative of the invention is a compound wherein a heteroaryl group such as piperidinyl, pyrrolidinyl or perhydroazepinyl is attached to the carbon atom of the alkylamine via the nitrogen of the heterocycle. Therefore, alkylenedlamine can form a salt with a non-binding organic or inorganic acid. Examples of organic acids are oxalic, fumaric, maleic, citric, tartaric, p-toluenesulfonic and methanesulfonic acids. Examples of inorganic acids are hydrochloric, sulfuric, nitric, hydrobromic and phosphoric acids,

The alkylenediemin derivative of the invention ee may be used in the form of a salt with any acid for use as an ineectyl, but should be in the form of a salt with a pharmaceutically acceptable acid. Examples of this acid are hydrochloric, fumaric, maleic and methanesulfonic acid.

Typical examples of alkylenediamine derivatives of the invention are given below.

1-] 3-] 4-methyl-1- (3-methylbutyl) pentylamino] propyl] piperidine: 1-3-] 4-methyl-1- (3-methylbutyl) pentylamino] propyl] pyrrolidine: .-] 3 -] 4-methyl-1- (3-methylbutyl) pentylamino] propyl] perhydroazepine: 1-] 3-] 4-methyl-1- (3-methylbutyl) pentylamino] propyl] perhydroazoline;

- 2 2-] 4-methyl-1- (3-methylbutyl) pentylamino} ethyl] piperidine:

1-] 4-] 4-methyl-1- (3-methylbutyl) pantylamino] butyl] piperidine:

1-] 5- [4-methyl-1- (3-methylbutyl) pentylamino] pentyl] piperidine:

1-] 3- (1-pentylhexylamino) propyl] piperidine:

1- [3-] 4,4-dimethyl-1- (3,3-dimethylbutyl) pentylamino] propyl] piperidine;

1-] 3-] 2,3-dimethyl-1- (3-methylbutyl) pentylamino] propyl] piperidine:

1-] 3-] 1- (1-ethylpropyl) -4-methylpentylamino] propyl] piperidine-1-] 3-] 4-methyl-1- (2-phenylethyl) pentylamino] propyl] piperidine:

1-] 3-] 4-methyl-1- (3-phenylpropyl) pentylamino] propyl] piperidine:

1- Γ 3- [5-methyl-2- (2-phenylethyl) hexylamino] propyl] piperidine:

1-] 3- (benzyl-5-methylhexylamino) propyl] piperidine:

1-] 3- (3-benzyl-6-methylheptylamino) propyl] piperidine:

1-] 3- (6-methyl-3-phenylheptylamino) propyl] piperidine:

1-] 3-] 1- (3-methylbutyl) hexylamino propyl] piperidine:

1-] 3-] 4,4-dimethyl-1- (3-methylbutyl) pentylamino] propyl] piperidine:

1-] 3- (1-benzyl-4-methylpentylamino) propyl] piperidine

1- [3- (4-methyl-1-phenylpentylamino) propyl] piperidine:

1-] 3- (5-methyl-1-phenylhexylamino propyl] piperidine:

1-] 3- (3-laopropoxy-1-phenylpropylamino) propyl] piperidine:

1-] 3-] 2- (3-dimethylbutyloxy) -2-phenylethylamino] propyl] piperidine:

1-] 3-] 2-Phenoxy-2-phenylethylamino] piperidine:

5-phenyl-2- (3-piperidinopropylamino) propyl -3-methylbutanoate:

1- Γ 3- (1-benzyl-4-methylpentylamino) propyl] pyrrolidine:

1- Γ 3- (5-methyl-2-phenylhexylamino) propyl] pyrrolidine:

1- [3- (1-benzyl-4-methylpentylamino) propyl] perhydroazepine:

1- Γ 2- (1-benzyl-4-methylpentylamino) ethyl] pyrrolidine:

1- Γ 2- (1-benzyl-4-ynylpentylamino) ethyl] piperidine;

1-] 2-] 4-methyl-1- (3-methylbutyl) pentylamino] ethyl] piperidine:

1-] 3-] bis (3-methylbutyl) amino] propyl] piperidine:

1-] 3- [N- (3-methylbutyl) -N- (4-methylpontyl) amino] propyl] piperidine:

-] 3-] N- (3-methylbutyl) -N- (5-methylhexyl) amino] propyl] piperidine:

1-] 3-] N-hexyl-N- (3-methylbutyl) amino] propyl] piperidine:

1- Γ 3-] β-heptyl-N- (3-methylbutyl) amino] propyl] plperidine:

1-] 3-] N- (3-methylbutyl) -N-octylamino] propyl] piperidine:

1-] 3-] N- (3-methylbutyl) -N-nonylamino] propyl] piperidine:

1- [3- [N- (3,3-dimethylbutyl) -N- (3-methylbutyl) amino] propyl] piperidine;

1- [4- [H- (3-ethylbutyl) -N- (5-methylhexyl) amino] butyl] piperidine: 1- [2- [N- (3-methylbutyl) -N- (5- methylhexyl) amino] ethyl] piperidine; 1- [3-CN- (3-methylbutyl) -N- (5-methylhexyl) amino] propyl] pyrrolidine; 1- [3- [N- (3-methylbutyl) -N- (5-methylhexyl) amino] propyl] perhydroazine;

1- [3- [N, N-bie (3,3-dimethylbutyl) amino] propyl] piperidine;

1- [3- [N - (- benzyl-4-methylpentyl) -1- (3-methylbutyl) amino] propyl] piperidine.

The alkylenediamine derivative of the present invention can be used as an excipient in various forms of conventional pharmaceutical preparations, such as powders, granules, tablets, injections and darts.

The alkylenediamine derivative of the present invention can be used as a medicine for neuriatry at a dose of 0.1 to 50 mg / day in the injection mixture and 1 to 500 mg / day in the composition for oral administration. However, the dose of ee may vary depending on the age, conditions and condition of the patient.

The invention will be further described in the following examples.

Synthesis Example 1 1- [3- (1-Pentylhexylamino) propyl] piperidine

1 / To a solution of 5.11 g of 6-undecanone in 20 ml of ethanol is added successively a solution of 3.47 g of hydroxylamine hydrochloride in 6 ml of water and a solution of 4.77 g of potassium hydroxide in 6 ml of water. The resulting mixture was heated at reflux for 3 hours. The reaction mixture was then poured into 150 ml of ice-containing water. The resulting aqueous mixture was acidified by the addition of 2N hydrochloric acid and extracted with benzene. The organic layer was washed with saturated aqueous sodium chloride solution and evaporated under reduced pressure to remove the solvent. 5.57 g (corresponding to the theoretical amount) of 6-undecanone oxime are obtained as a pale yellow substance.

11 / To a solution of 1.85 g of the product obtained above in 140 ml of ethanol was added 140 ml of 2N aqueous sodium hydroxide solution, followed by the addition of 1.7 g of Baney nickel in one portion. The resulting mixture was stirred for 1 hour, filtered, and washed successively with water and ethanol. The filtrate and washings were combined, diluted with water and then extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride solution and evaporated under reduced pressure to remove the solvent. A light yellow oil is obtained. This oil was subjected to silica gel column chromatography (eluent: chloroform-methanol) to obtain 1.0 g of 6-undecanamine as a colorless oil, yield: 58.5%.

111 / A mixture of 0.85 g of the product obtained above and 0.88 g of 1- (3-chloropropyl) piperidine was heated under a nitrogen atmosphere at 110 DEG-120 DEG C. for 3 hours. The reaction mixture was cooled and dissolved in ethanol. To the resulting solution was added 0.41 mL of concentrated hydrochloric acid. The mixture was stirred and then allowed to stand with the addition of ethyl acetate. The precipitated crystals were filtered off, washed with ethyl acetate and dried to obtain 64 mg of crude crystalline product. The product was recrystallized from ethanol-ethyl acetate to give 54 mg of the dihydrochloride of the title compound as a white crystalline product, yield 29.5%. M.p .: 233-235 ° C.

Synthesis Example 2 1- [3- (4-Methyl-1- (3-methylbutyl) pentylamino] propyl] piperidine

1 / To a solution of 5.11 g of 2,8-dimethylnonan-5-one (m.p .: Io3-103 ° C) 2 533.12 Pa, prepared by oxidation of 2,8-dimethylnonan-5-ol with chlorine lime; 2'-Dimethylnonan-5-ol is prepared by reacting ethyl formate and isoamylmagnesium bromide in 20 ml of ethanol. An aqueous solution of 3.47 g of hydroxylamine hydrochloride in 6 ml of water and a solution of 4.77 g of potassium hydroxide in 6 ml of water are added stepwise. The mixture is heated to reflux. The reaction mixture was poured into 150 ml of ice-containing water. The aqueous mixture was acidified by the addition of 2N hydrochloric acid and extracted with benzene. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent. 5.21 g of 2,8-diaethylnonan-5-one oxime are obtained as a light brown oil, yield: 93.7%. . ('

11 / To a solution of 2.78 g of the product obtained above in 60 ml of ethanol ee was added 60 ml of 2N aqueous sodium hydroxide, followed by 4.32 g of Raney alloy in one portion. The resulting mixture was stirred for 3 hours, filtered and washed successively with ethanol and water. The filtrate and washings were combined, diluted with water and then extracted with chloroform. The extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure to remove the solvent. The crude product containing 2,8-dimethylnonen-5-amine is obtained. This is isolated in the form of oxalate, the oxalate is reacted with aqueous sodium hydroxide solution to give the free base.

111. A mixture of 1.55 g of the above product and 1- (3-chloropropyl) piperidine is heated at 120 DEG C. for 3.5 hours under a nitrogen atmosphere. The reaction mixture was cooled and dissolved in 10 ml of ethanol. To this solution was added 0.75 ml of concentrated hydrochloric acid and ethyl acetate to a total volume of 10 ml. The precipitated crystals are filtered off. The crystals were treated with aqueous sodium hydroxide solution and extracted with chloroform to give an oil. The oil was triturated by silica gel column chromatography (eluent: chloroform-methanol) to give the title compound as an oil.

A slightly excess of 6N hydrochloric acid-ethanol is added to the ethanol solution containing the above free base. The mixture is concentrated to dryness. The residue was recrystallized from ethanol-ethyl acetate to give the dihydrochloride of the title compound as a white crystalline product * mp: 249-25 ° C (dec.).

Synthesis Example 3-21

According to Examples 1 and 2, the following compounds were prepared.

Syn.př.č.

1- [3- (1-Benzyl-4-methylpentylamino) propyl] piperidine, m.p. 228-231 ° C (dec.: as dihydrochloride) 1- [3- (4-Methyl-1-phenylpentylamino) propyl] piperidine, mp 211-215 ° C (dec., as dihydrochloride) 1- [3- (3-Isopropoxy-1-phenylpropylamino) propyl] piperidine, m.p. 199-2 ° C (dec., as dihydrochloride) 1- [3- [2- (3-Methylbutyloxy) -2-phenylethylamino] propyl] piperidine, m.p. 193-199 ° C (as dihydrochloride.)

3-phenyl-2- (3-piperidinopropylamino) propyl 3-methylbutanoate, mp 189-19 ° C (dec., As dihydrochloride) 1- {3- (4-Methyl-1- (2-phenylethyl) pentylamino] propyl) piperidine, mp 22-223 ° C (dec., as dihydrochloride) 1- [3- (3-Benzyl-6-methylheptylamino) propyl] piperidine, m.p. 229-233 ° C (dec., as dihydrochloride) 1-Q3 - [4-Methyl-1- (3-phenylpropyl) pentylamino] propyl] piperidine, mp 181-181.5 ° C (dec. As dihydrochloride)

CS 270599 32 1- [3- [2,3-Dimethyl-1- (3-methylbutyl) pentylamino] propyl] piperidine, m.p.

181 ° C (dec., As difumarate) 1- [3- [1- (1-Ethylpropyl) -4-methylpentylamino] propyl] piperidine, mp 21-212 ° C (dec., As dihydrochloride) - [3- [4,4-Dimethyl-1- (3,3-dimethylbutyl) pentylamino] propyl] piperidine, mp 282-284 ° C (dec., As dihydrochloride) 1- [3- [1- (3- Methylbutyl) hexylamino} propyl-piperidine, mp 233-236 ° C (dec., As dihydrochloride) 1- [3- [4,4-Dimethyl-1- (3-methylbutyl) pentylamino] propyl] piperidine, m.p.

263 ° C (dec., As dihydrochloride) 1- [3- [4-methyl-1- (3-methylbutyl) pentylamino] propyl] pyrrolidine, mp 248-25 ° C (dec., As dihydrochloride) 1- [3-Q4 ~ Methyl-1- (3-methylbutyl) pentylamino] propyl] perhydroazepine, m.p.

226 DEG C. (dec., As dihydrochloride) 1- [3- (4-Methyl-1- (3-methylbutyl) pentylamino] propyl] perhydroazocine 1- [3- [4-Methyl-1- (3-methylbutyl) pentylamino] ethyl] ethyl] ] plperidine, mp 261-263 ° C (dec., as dihydrochloride)

2o 1- [4- [4-Methyl-2- (3-methylbutyl) pentylamino] butyl] piperidine, mp 263-266 ° C (dec., As dihydrochloride) 1- [5- [4-Methyl-1- ( 3-methylbutyl) pentylamino] pentyl] piperidine, mp 225-227 ° C (dec., As dihydrochloride)

Comparative example

Effect of glutamate blockade on cancer neuromuacular joints

Evaluation of the glutamate blocking effect is performed according to the method of Ishida et al. (J. Physiolo., 298-319 (198)), and Shinozaki et al. (Comp. Bioohem. Physlal, 7oc, 49-58 (1981)).

The open muscle of the first pair of cancer legs is used in more detail for the experiment described below.

The neuromuscular sample is fixed in a vessel and physiological saline solution (composition: NaCl / 195 mM), CaCl ₂ (18 mM), KCl (5.4 mM), Trls-maleic acid buffer) is circulated in the vessel at a constant rate. pH 7.5, 10 mM (and glucose (11 mM)).

An glass microelectrode filled with 3M KCl solution is inserted into the middle part of the muscle fibers and the change in electrical voltage in the sarcolemma is measured intracellularly.

The effect of the finished glutamate blocking compound ee is evaluated by determining the inhibition of L-glutamate-induced depolarization induced by pretreatment with test fluid (2 x 10 ^{w w} 5 m) at 5 minute intervals, which is measured using L-glutamate (10 ⁴ M) for circulation.

The results are shown in Table 1.

Table 1

Test compound

Effect of glutamate blocking

Synthesis Example 1

Synthesis Example 2

Synthesis example 3%

%%

Table 1 - continued

Test compound Effect of glutamate blocking Synthesis Example 4 94% Synthesis Example 5 94% Synthesis Example 6 '^; 96% Synthesis Example 7 9o% Synthesis Example 14 97% Synthesis Example 15 ΘΘ% Synthesis Example 16 96% Synthesis Example 17 loo% Synthesis Example 18 loo% Synthesis Example 2o loo% Synthesis Example 21 loo%

P. R E D M S T OF THE INVENTION

Claims (7)

P. R E D M S T OF THE INVENTION 1. Process for the preparation of an alkylenediamine derivative of general formula I I - (CH ₂ ) _p B (I), where A is a group of formula II R 1 is CH ² -CH (R 2) - (CH 2) d (d) (II) wherein R 1 is a straight or branched alkyl group having 3 to 8 carbon atoms or a phenyl group, R ² is a straight or branched alkyl group having 3 to 8 carbon atoms; to 11 carbon atoms, an alkoxy group having 3 to 8 carbon atoms, a phenoxy group or a phenyl amane is a number from 0 to 2, provided that m + n is not greater than 3, and B is hydrogen or A is a group of formula III R ³ - (CH ₂ ) _k - (III), wherein R ³ is a straight or branched alkyl group containing 3 to 8 carbon atoms or a phenyl group and k is a number from 0 to 3, and B is a straight or branched alkyl group containing 3 to 270 carbon atoms. 32 '' having 3 to 11 carbon atoms, p is 2 to 6 and q is 4 to 7, characterized in that the amine compound of formula IV is reacted A - I (IV), B ‘. wherein Λ and B are as defined above, with a halogenated compound of formula V 01 - (ΟΉΡρ - 1Λ (CH ₂ ) _q '”(V), where paq is as defined above, 2. Process according to claim 1, characterized in that the reaction of the compound of formula IV and the compound of formula V is carried out in the presence of thionyl chloride, 3. Process according to claim 1, characterized in that the reaction of the compound of formula IV and the compound of formula V is carried out in chloroform. . 4.. Process according to claim 1, characterized in that the reaction of the compound of formula IV and the compound of formula V is carried out at a temperature between room temperature and 16 ° ° C. 5. The process according to item 1 for the preparation of an alkylenediamine derivative of general formula I (I), where A is a group of formula II 1 9 R - (CH ₂ ) _and -CH (RO- (CH ₂ ) _n - (II), wherein R ¹ is a straight or branched alkyl group having 3 to 8 carbon atoms or a phynyl group, o R is a straight or branched alkyl group having 3 to 11 carbon atoms, an alkoxy group having 3 to Θ carbon atoms, a phenoxy group or phenyl and m and n is a number from 0 to 2, provided that m + n is not more than 3, and B is hydrogen or A is a group of formula III R ³ - (CR ₂ ) _k - (III), 3 wherein R is a straight or branched alkyl group having 3 to 8 carbon atoms or a phenyl group when the number is 0 to 3, and B is a straight or branched alkyl group having 3 to 11 carbon atoms, p is the number 2 to 6, and q is a number from 4 to 6, characterized in that ae is reacted with an amine compound of general formula IV A - NH (IV), B wherein A and B are as defined above, and a halogenated compound of formula V Cl - (CH ₂ ) _p - N 2 - (CH ₂ ) _q (V), wherein paq is as defined above. 6., Process according to item 5, characterized in that the reaction of the compound of formula IV and the compound of formula V is carried out in the presence of thionyl chloride. 7.. Process according to claim 5, characterized in that the reaction of the compound of formula IV and the compound of formula V is carried out in chloroform. ¹