Berillo D.A., Turmukhanova M.Zh., Ahmedova Sh. S.

Al-Faraby Kazakh National University, Almaty, Kazakhstan

Synthesis and biological activity of iminoethers of 2-methyl-2-aminoderivatives of propane acid

α-aminonitriles are suitable syntones for introduction of various functional groups which allow enlarging the range of potentially biologically active nitrogen containing organic compounds.

In this work the result on synthesis and biological activity of iminoethers of 2-methyl-2-aminoderivatives of propane acid are reported. We have synthesized α-aminonitriles of heterocyclic, aromatic and aliphatic amines and their derivatives (codes 1a-d) and screening for some kinds of biological activity has been carried out.

The results of primary biological screening of N-isobutyronitrilpiperidine and its derivatives I (a-c) are presented in tables 1-4.

Table 1 – acute toxicity of compounds I (a-d) when being introduced intraperitoneously to white mice.

The name of compounds	LD50 when being introduced intraperitoneously to white mice, mg\кg
amidoxime 2-methyl-2-N-piperidylpropane acid (I а)	300
amid succinate of 2-methyl-2-N-piperidylpropane acid (I b)	519,4+21,48
2-methyl-2-N-piperidylpropane acid (I c)	100
Nitrile hydrochloride 2-methyl-2-N-piperidylpropane acid (1 d)	100
streptomycin	213,8 +22,61
Klemastine	154,0+12,1
Lidocaine	95,0+13,1

It follows from the data in Table 1 that amidoxime (Ia) and amid succinate of 2-methyl-2-N-piperidylpropane acid (Ib) have low toxicity, while 2-methyl-2-N-piperidylpropane acid (Ic) and nitrile hydrochloride of 2-methyl-2-N-piperidylpro-pane acid (Id) have the same toxicity comparable to preparation Lidocaine which is widely used in medical practice.

Table 2 – Spasmolitic activity of nitrile derivatives of 2-methyl-2-N-piperidyl-propane acid I (a-d) of all tested compounds, nitrile hydrochloride of 2-methyl-2-N-piperidylpropane acid (Id) revealed activity.

Index of compounds	Change of length of intestines after compound administration	Activity by acetylcholine a spasm (1 mg acetylcholine / 1 mL of medium)	Activity by histamine a spasm (1 mL histamine /1 mL medium)
I а	Increase 1mm	Decrease. 3mm	Increase 1mm
I b	Increase 2mm	Decrease. 2mm	Decrease. 4mm
I с	Increase 4mm	Increase. 2mm	Decrease. 4mm
I d	Сокр. 1mm	0	0
“No-shpa”	0	0	0
Klemastine	+1	+1	+1
Acetylcholine	-	4,0	-
Histamine	-	-	4,0

Table 3 Antibacterial activity of nitrile 2-methyl-2-N-piperidylpropane acid (Id) and streptomycine after 24 hours of incubation in Beal-peptone broth (the growth of bacteria when diluted 1/100)

The name of compounds	Escherichia coli	Sal.chol.suis	Salmonella typhymurium	Staphylococcus aureus
I d	2	2	2	2
streptomycin	0	0	0	0
MPB (Control crops without introduction antibacterial compounds)	4	4	4	4

Nitrile hydrochloride 2-methyl-2-N-piperidylpropane acid (Id) reveals antibacterial activity, however, by the expressiveness of the effect, the activity of compound (Id) is not comparable to the preparation of comparison streptomycin [1].

Table 4 Analgesic activity of nitrile hydrochloride of 2-methyl-2-N-piperidylpropane acid (Id) on the model “Tail-flick”.

Index of compounds	Speed of approach of effect	Duration of analgesia	Duration of full analgesia
I d	5 minutes	165,0+11,2	45,3+7,1
Tramal	5 minutes	75,0+9,1	-

Compound (Id) possesses a spasmolytic and moderate antibacterial activity as well as a marked analgesic activity and authentically surpasses Tramal having shown a higher analgetic activity than Tramal. It causes a complete analgesia and, hence, has a greater range of pharmacological action [1].

Thus, it is stated that nitrile hydrochloride of 2-methyl-2-N-piperidylpropane acid (Id) (Scheme 1) has shown a high analgesic activity, moderate spasmolitic and antimicrobial activity, however, this compound is highly toxic, this being an unfavorable factor for practical use, while 2-methyl-2-N-piperidylpropane acid (Id) its amidoxime and amide possess all the above mentioned properties of N-isobutyronitrilepiperidine, except high toxicity. The investigation on the biological activity of nitrile derivatives of 2-methyl-2-N-piperidylpropane acid have shown that in going from nitrile to its derivatives. Toxicity of substances decreases in the series acid > amidoxime > amide.

In this connection, with the aim of searching for new potentially biologically active compounds we have synthesized a number of iminoethers of 2-methyl-2-N-aminoderivatives of propane acid (6-10) from the corresponding aminonitriles according to the scheme given below.

The structure of the obtained compounds (1-10) is verified by the data of physico-chemical methods of analysis.

Reference

[1] №22043 The innovative patent R.K. D.A. Berillo, Sh.S. Ahmedova, S.N. Shin, O.A. Berillo Nitrile 2-methyl-2-N-piperidylpropane acid possessing a spasmolitic, analgetic and antimicrobial activity. (15.12.2009), bulletin №12.