Abstract

A series of propanolamine and alkylamine analogues of fluoxetine (7–26, 28–31) were synthesized and assessed for their anorexigenic and antidepressant activities. Effect of various substituents at C-4 aryl position of fluoxetine has also been studied. Most of the propanolamine analogues (7–13, 16–26) displayed significant anorexigenic activity but interestingly they were devoid of antidepressant activity whereas anorexigenic as well as antidepressant activity was retained in the alkylamine series (28-31). Compounds 10 and 26 emerged as the most active compound and anorexigenic activity was better (83.67% and 82.45%) compared to fluoxetine (81.25%).

Graphical abstract

We report the synthesis and biological evaluation of a series of propanolamine and alkylamine analogues of fluoxetine (7–26, 28–31). Among them compounds 10 and 26 displayed anorexigenic activity better than the parent compound.

Keywords: Propanolamine; Appetite suppressants; Obesity; SSRIs

Article Outline

1. Introduction

2. Chemistry

3. Results and discussion

4. Conclusion

5. Experimental

5.1. Chemistry

5.1.1. N-Methyl-3-phenyl-3-(4-trifluoromethylphenoxy)propanamine (4a)

5.1.2. N-Methyl-3-phenyl-3-(4-methoxyphenoxy)propanamine (4b)

5.1.3. N-Methyl-3-phenyl-3-(4-chlorophenoxy)propanamine (4c)

5.1.4. General procedure for the preparation of oxiranylmethyl-[3-phenyl-3-(4-substituted phenoxy)propyl]-amine (5a, b, c)

5.1.4.1. Oxiranylmethyl-[3-phenyl-3-(4-trifluoromethylphenoxy)propyl]amine (5a)

5.1.4.2. [3-(4-Methoxyphenoxy)-3-phenyl-propyl]-oxiranylmethylamine (5b)

5.1.4.3. [3-(4-Chlorophenoxy)-3-phenyl-propyl]-oxiranylmethylamine (5c)

5.1.5. General procedure for the preparation of propanolamine derivatives (7–26)

5.1.5.1. 1-[N-Methyl-N-(3-phenyl-3-(4-α,α,α-trifluoromethylphenoxy)propyl)amino]-3-pyrrolidino-propan-2-ol (7)

5.1.5.2. 1-[N-Methyl-N-(3-phenyl-3-(4-α,α,α-trifluoromethylphenoxy)propyl)amino]-3-(4-phenylpiperazino)-propan-2-ol (8)

5.1.5.3. 1-[N-Methyl-N-(3-phenyl-3-(4-α,α,α-trifluoromethylphenoxy)propyl)amino]-3-(N-methyl-N-benzylamino)-propan-2-ol (9)

5.1.5.4. 1-[N-Methyl-N-(3-phenyl-3-(4-α,α,α-trifluoromethylphenoxy)propyl)amino]-3-[4-(2-pyridyl)piperazino]propan-2-ol (10)

5.1.5.5. 1-[N-Methyl-N-(3-phenyl-3-(4-α,α,α-trifluoromethylphenoxy)propyl)amino]-3-[4-(4-fluorophenyl)piperazino]propan-2-ol (11)

5.1.5.6. 1-[N-Methyl-N-(3-phenyl-3-(4-α,α,α-trifluoromethylphenoxy)propyl)amino]-3-[4-(3-chlorophenyl)piperazino]propan-2-ol (12)

5.1.5.7. 1-[N-Methyl-N-(3-phenyl-3-(4-α,α,α-trifluoromethylphenoxy)propyl)amino]-3-[4-(4-methylphenyl)piperazino]propan-2-ol (13)

5.1.5.8. 1-[N-Methyl-N-(3-phenyl-3-(4-α,α,α-trifluoromethylphenoxy)propyl)amino]-3-[4-α,α,α-trifluorotolyl-piperazino]propan-2-ol (14)

5.1.5.9. 1-[N-Methyl-N-(3-phenyl-3-(4-α,α,α-trifluoromethylphenoxy)propyl)amino]-3-[4-methylpiperazino]propan-2-ol (15)

5.1.5.10. 1-[N-Methyl-N-(3-phenyl-3-(4-α,α,α-trifluoromethylphenoxy)propyl)amino]-3-(2-phenethylamino)propan-2-ol (16)

5.1.5.11. 1-[N-Methyl-N-(3-phenyl-3-(4-α,α,α-trifluoromethylphenoxy)propyl)amino]-3-cyclohexylaminopropan-2-ol (17)

5.1.5.12. 1-[N-Methyl-N-(3-phenyl-3-(4-α,α,α-trifluoromethylphenoxy)propyl)amino]-3-morpholinopropan-2-ol (18)

5.1.5.13. 1-[N-Methyl-N-(3-phenyl-3-(4-methoxyphenoxy)propyl)amino]-3-(4-phenylpiperazino)-propan-2-ol (19)

5.1.5.14. 1-[N-Methyl-N-(3-phenyl-3-(4-methoxyphenoxy)propyl)amino]-3-[4-(2-pyridyl)piperazino-propan-2-ol (20)

5.1.5.15. 1-[N-Methyl-N-(3-phenyl-3-(4-methoxyphenoxy)propyl)amino]-3-[4-(3-chlorophenyl)piperazino]propan-2-ol (21)

5.1.5.16. 1-[N-Methyl-N-(3-phenyl-3-(4-chlorophenoxy)propyl)amino]-3-(4-phenylpiperazino)-propan-2-ol (22)

5.1.5.17. 1-[N-Methyl-N-(3-phenyl-3-(4-chlorophenoxy)propyl)amino]-3-[4-(2-pyridyl)piperazino]propan-2-ol (23)

5.1.5.18. 1-[N-Methyl-N-(3-phenyl-3-(4-chlorophenoxy)propyl)amino]-3-[4-(3-chlorophenyl)piperazino]propan-2-ol (24)

5.1.5.19. 1-[N-Methyl-N-(3-phenyl-3-(4-chlorophenoxy)propyl)amino]-3-pyrrolidino-propan-2-ol (25)

5.1.5.20. 1-[N-Methyl-N-(3-phenyl-3-(4-chlorophenoxy)propyl)amino]-3-morpholinopropan-2-ol (26)

5.1.6. General procedure for the preparation of compounds 28–31

5.1.6.1. [3-Phenyl-3-(4-α,α,α-trifluoromethylphenoxy)-propyl]-(2-pyrrolidin-1-yl-ethyl)-amine(28)

5.1.6.2. (2-Morpholin-4-yl-ethyl)-[3-phenyl-3-(4-α,α,α-trifluoromethyl phenoxy)-propyl]-amine (29)

5.1.6.3. [3-Phenyl-3-(4-α,α,α-trifluoromethylphenoxy)-propyl]-(2-piperidin-1-yl-ethyl)-amine (30)

5.1.6.4. N,N-Dimethyl-N′-[3-phenyl-3-(4-α,α,α-trifluoromethylphenoxy)-propyl]-ethane-1,2-diamine (31)

5.2. Pharmacology

Acknowledgements

References

C.D.R.I. Communication No. 6676.