The Chemosynthesis And Pharmacological Action Of Two New Type Alkylamine Drugs

Alkylamine drug is a kind of drug-contained alkylamine groups including chemical drugs and traditional Chinese medicine.At present,there are no reports to show that alkylamine drugs play roles simultaneously in both anti-fatigue and immune enhancement.Based on the analysis of references about pharmacological action,clinic application of alkylamine drugs and traditional Chinese medicine-contained alkylamine groups,it can be concluded that alkylamines have roles simultaneously in both anti-fatigue and immune enhancement.In order to validate the above-mentioned conclusion,two new type alkylamines including N-butyl-N-isopropylamine and benzyl amine isopropyl phosphonic acid were synthesized by chemical method.In recent years,the pharmacological action of macamides has been observed and thus,macamides,as a positive control drug,was chemically synthesized in our experiment.The mice were used as the experimental animals to confirm that two new type alkylamine drugs were low toxic and have roles simultaneously in both anti-fatigue and immune enhancement.The results were as follows:Experiment 1 Chemical synthesis of two new type alkylamine drugsTwo new type alkylamines,e.g.,N-isopropyl-N-butylamine and(2-(benzylamino)propan-2-yl)phosphonic acid,were chemically synthesized by one pot method.N-isopropyl-N-butylamine was synthesized by the reaction of bromobutane with isopropylamine in alkaline conditions,and its yield was 84.6%.(2-(benzylamino)propan-2-yl)phosphonic acid was synthesized with benzylamine,phosphorous acid and acetone by the mannes reaction principle,and its yield was 78.5%.Additionally,under the catalysis of 1-hydroxybenzotriazole and carbodiimide,macamides was synthesized with hexadecanoic acid and benzylamine,and its yield was 71.2%.Two new type alkylamine drugs were identified by mass spectrometry and IFNrared spectroscopy.Also,the conventional physical and chemical properties of two new type alkylamine drugs were determined by capillary tube method,liquid density measuring apparatus and Abbe refractometer.The results showed that N-isopropyl-N-butylamine was light yellow liquid and was insoluble in water,and its boiling point and density were 122-123 ? and 0.7409g/cm3.(2-(benzylamino)propan-2-yl)phosphonic acid was light yellow solid,and its melting point and solubility were 178 ? and 24.5g/100mL.Macamides was white or gray solid and was insoluble in water,and its melting point was 85-87 ?.Experiment 2 Toxicity of two new type alkylamine drugsLD50 of acute toxicity was measured by intragastrical administration in mice.LD50 of N-isopropyl-N-butylamine was 2661 mg/kg,LD50 of(2-(benzylamino)propan-2-yl)phosphonic acid was 3495 mg/kg,and LD50 of macamides was 2851 mg/kg.In the subacute toxicity,500mg/kg body weight intragastric administration with continuous administration of 15 days(once a day)showed no abnormal changes of the clinical and gross observation.Histologically,no abnormal changes were also found in the liver,spleen and kidney of the two new type alkylamine groups when compared to control groups.Experiment 3 Anti-fatigue test of two new type alkylamine drugs in miceThe mice were treated with N-isopropyl-N-butylamine and(2-(benzylamino)propan-2-yl)phosphonic acid with 100 mg/kg and 200 mg/kg,respectively.The positive control group was set with macamides by 50mg/kg.The normal saline group was set as the blank control group.The experiment was performed by intragastrical administration with 1 day 1 time,continuous 7d.Parameters of anti-fatigue were detected by using methods of anthrone-sulfate,ELISA,stress test,male sexual function test and weight loss test.The results showed that two new type alkylamine drugs,e.g.,N-isopropyl-N-butylamine and(2-(benzylamino)propan-2-yl)phosphonic acid made mice prolong swimming time,and improve the survival ability under extreme cold,heat stress and hypoxia stress,and improve mating ability,shorten the latent period of mating,and increase mating frequency within 1h from the beginning of mating when compared to control groups.The blood glucose and hepatic glycogen contents,and muscle ATP and hepatic ATP levels were increased,and the serum urea nitrogen contents,lactic acid contents and lactate dehydrogenase activity after exhaustive exercise were decreased in the two new type alkylamine drugs groups.The improvement ofglycogen and ATP contents was the basis of pharmacological action of the two new type alkylamine drugs in anti-fatigue.At the same time,the Lee's index was lower and serum leptin contents were higher in two new type alkylamine drugs groups than those in control groups.Experiment 4 Immune enhancement of two new type alkylamine drugsThe methods were as same as those in anti-fatigue study.The immune parameters were detected by using methods of carbon clearance test,macrophage phagocytosis test,lymphocyte E-rosettes assay,T lymphocyte transformation test,flow cytometer,ELISA and PCR.When compared to control groups,the two new type alkylamine drugs could increase the under-mentioned immune indexes,e.g.,splenic and thymic growth indexes which showed that the two new type alkylamine drugs could improve splenic and thymic development,and macrophage phagocytosis function,T lymphocyte activity,splenic lymphocyte transformation rate,spleen and serum IgA,IgG,IgM contents,and splenic and serum IL-2,IL-6,IL-10,IL-12,IFN-y and TNF-a contents.Also,the mRNA expression of cytokines in the spleen was up-regulated,which was the molecular basis of the increased cytokine contents.Conclusions and innovationsFirstly,the two new type alkylamine drugs,e.g,N-butyl-N-isopropylamine and benzyl amine isopropyl phosphonic acid,are successfully synthesized by chemical method.Secondly,the two new type alkylamine drugs are low toxic.Last,the two new type alkylamine drugs have roles simultaneously in both anti-fatigue and immune enhancement.The above-mentioned conclusions and innovations are firstly reported at home and abroad.