a review on pharmacological profile of morpholine derivatives
TRANSCRIPT
Naim MJ.; Int. J. Pharmacol. Pharm. Sci. (2015) 3:1; 40-51. 40
International Journal of Pharmacology and Pharmaceutical Sciences 2015; Vol: 3, Issue: 1, 40-51
.
Research Article ISSN: 2394-613X
A review on pharmacological profile of Morpholine derivatives Mohd Javed Naim
1, Ozair Alam
1*, Md Jahangir Alam
1, Perwaiz Alam
2 and Neelima Shrivastava
1
1Department of Pharmaceutical chemistry, Faculty of Pharmacy, Jamia Hamdard
New Delhi-110062, India 2College of Pharmacy, Shree Ganpati Institute of Technology
Ghaiabad-201302, India
*Corresponding Author
ABSTRACT
Morpholine, an aromatic organic heterocycle scaffold possesses one nitrogen & an oxygen atoms of six-membered ring. It is a
multipurpose lead compound developed by chemical designing for active molecules which are pharmacologically potent. This
review summarizes the in vitro & in vivo pharmaceutical chemistry inquiries for morpholine analogues. Morpholine nucleus
shows a broad spectrum of pharmacological profile, thus, in recent years, scientists have explored this moiety. This review shows
current tendency in the morpholine analogues and reveals their potent Pharmacophoric activities.
Key words: Morpholine; Heterocyclic compound; Pharmacological profile.
INTRODUCTION
Morpholine is an organic chemical compound (O(CH2CH2)2NH) containing nitrogen and oxygen heterocyclic six membered
ringand is considered an important building blocks in the field of medicinal chemistry field [1-3]. The parent compound
morpholine or 1-oxa-4-azacyclohexane has become commercially available in USA in 1935; since that time, it becomes one of the
most widely used heterocyclic secondary amines. Morpholine derivatives are very essential in the drug discovery process and
stimulate research in broad spectrum of biological activity study [4].This class of heterocyclic compounds; have found great
significance in modern years due to their variety of pharmacological activities including analgesic, anti-inflammatory, anticancer,
antidepressant, HIV-protease inhibitors, appetite suppressant,local anaesthetic, antiplatelet, selective inhibitor of protein kinase C,
antitumor, neuroprotective, antifungal, anti-tuberculosis, anti-parasitic, anti-malarial, hypolipidemic and hypocholesterolemic
activities [5-9].
Morpholine is a fairly strong base (pKa 8.7, lower than that of piperidine) and potent solvent and is widely used in industry and
organic synthesis [10]. It is often selected as starting material for the preparation of enantiomerically pure α-amino acids [3, 4], β-
amino alcohols [11], peptides [12], as well as building blocks for the synthesis of biologically active compounds [13]. Various
functionalized morpholine occur in nature. Some synthetic biologically active compounds containing a morpholine ring are used
in medical practice.
These classes of compounds have been utilized extensively by the pharmaceutical industry in drug design, because of the
development in pharmacokinetic properties that it can bestow. The pharmacological utility of lead molecules containing the
morpholine entity is widespread, particularly; N-substituted morpholines are drug molecules with a broad spectrum of
Naim MJ.; Int. J. Pharmacol. Pharm. Sci. (2015) 3:1; 40-51. 41
pharmacological activities. The Linezolid [14]antibiotic having a morpholine cycle is commercially available antimicrobial agent.
Aprepitantis a substance which is neurokinin 1 (NK1) receptor antagonist and it is the first drug approved by Food and Drug
Administration for the management of vomiting and chemotherapy-induced nausea. Formermoleculesdisplayed an anti-
schizophrenic activity via interaction with the N-methyl-D-aspartate receptor in the brain. A selective inhibitor of epidermal
growth factor Timolol (non-selective beta-adrenergic receptor antagonist indicated for treating glaucoma) Moclobemide [15],
Emorfazone (anti-inflammatory drug and analgesic) [16], Phenadoxone (Heptalgin, opioid analgesic), anti-depressants Reboxetine
[17] and Gefitinib [18], appetite suppressants Phenmetrazine (Preludin, 3-methyl-2-phenylmorpholine) and 2-benzylmorpholine
and Canertinib , Fenpropimorph ( R = 4-t-BuC6H4; fungicide) [19], and antibacterial drugs Finafloxacin , Levofloxacin [20].
Fig. 1: Pharmacological profile of morpholine and its derivatives
Several enzyme inhibitors as well as various receptor antagonists and agonists are well known along with morpholine-containing
derivatives. Selective norepinephrine inhibitors (antidepressants) [21], HER (Human Epidermal Growth Factor Receptor) kinase
inhibitors, glucosidase inhibitors [22], P38 MAP kinase inhibitors, PI3K kinase inhibitors (used in tumor chemotherapy),
phosphoinositide 3-kinase inhibitors, FLT3 (thirosine) kinase inhibitors, urease inhibitors, cysteine protease inhibitors, selective
SV2 receptor agonists, D-dopamine receptor agonists, 5-lipoxygenase inhibitors (5-LO), V3 vasopressin receptor antagonists, σ
receptor antagonists, nicotine acetylcholine receptor antagonist HL-60, A431, HS27, HEP-G2, HT29, KV, K562 human cancer
cell growth inhibitors and neuropeptide NPY-Y5 receptor antagonists, and antiviral, analgesic, antibacterial, anti-inflammatory
agents and anticonvulsants were described [23-26]. Morpholines have also found applications as catalysts and ligands in
asymmetric addition of organo-zinc compounds to aldehydes [27], amides (synthesis of γ-lactones, synthesis of δ-lactones &
lactams) and cyclization of enals with ketones [28], aldolization, indoles with unsaturated aldehydes, alkylation of Heck cross-
coupling of aryl halides with alkenes, Michael addition of α,β-unsaturated aldehydes to 1,3-diketones, Buchwald–Hartwig
amination of (hetero) aryl chlorides. Numerous morpholine derivatives are now commercially existing e.g., 4-(4, 6-dimethoxy-
1,3,5-triazin-2-yl)-methylmorpholinehydrochloride (DMTMM) has been extensively used in the current years in the synthesis
Naim MJ.; Int. J. Pharmacol. Pharm. Sci. (2015) 3:1; 40-51. 42
of carboxylic acid amides and esters, N-Methylmorpholine-N-oxide (NMO) is used as co-oxidant and highly polar solvent[29].
Fig. 2: Marketed drugs containing morpholine scaffold.
PHARMACOLOGICAL PROFILE
Anti-cancer agents
Wang,et al., has designed, synthesized and characterized a series of m-(4-morpholino-1,3,5-triazin-2-yl)benzamide and evaluated
their anti-proliferative activities against HCT-116 cell and MCF-7 cell at 10 µM by MTT assay. Compounds (1) 3-(4,6-
dimorpholino-1,3,5-triazin-2-yl)-5-(trifluoromethoxy)benzamide exhibited potent anti-proliferative activities. According to
western blot assay; this compound can block the PI3K/Akt/mTOR pathway and Hoechst staining assay indicated that this
compound can cause morphological changes and induce apoptosis of HCT-116 cells[30].
Wang,et al.,has designed, synthesized and characterized a series of m-(4-morpholinoquinazolin-2-yl)benzamide and evaluated
their anti-proliferative activities against two human cell lines (HCT-116 and MCF-7). Compounds with IC50 values below 4 mM
were further evaluated against U-87 MG and A549 cell lines. Among the evaluated compounds, compound (2) 3-(6,7-dimethoxy-
4-morpholinoquinazolin-2-yl)-5-(trifluoromethoxy) benzamide displayed a remarkable anti-proliferative effect in vitro and also
caused morphological changes on the basis of the hoechst staining assay. The Western blot assay further suggested that this
compound can block the PI3K/Akt/mTOR pathway [31].
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Senwar,et al., has synthesized a series of new spirooxindole-derived morpholine-fused-1,2,3-triazole derivatives from isatin spiro-
epoxides and evaluated them for their anti-proliferative activity against selected human tumor cell lines of lung (A549), breast
(MCF-7), cervical (HeLa), and prostate (Due-145). Compound (3) 3'-ethyl-4,7-dihydrospiro [[1,2,3] triazolo[5,1-c][1,4]oxazine-
6,1'-inden]-2'(3'H)-one showed excellent growth inhibition against A549 cell line with IC50 values ranging between 1.87-4.36
mM, as compared to reference standards 5-flourouracil and doxorubicin [32].
Ibrahim,et al., designed and synthesized four series of condensed pyrrolo[1,2-c]pyrimidines as PI3K inhibitors and evaluated
them for their inhibitory activity and selectivity toward different PI3K isoforms. Compound (4) 5-ethyl-3-(morpholin-4-ylmethyl)-
6-thioxo-5,6,8,9,10,10a-hexahydropyrimido[5,4-e]pyrrolo[1,2-c]pyrimidin-1(2H)-one and (5) 5-ethyl-3-(3-hydroxyphenyl)-1-
morpholino-6-thioxo-1,2,5,6,8,9,10,10a-octahydropyrido[3,2-e] pyrrolo[1,2-c]pyrimidine-2-carbonitrile proved to be highly
potent and selective PI3Ka inhibitors (IC50 ¼ 0.1-7.7 nM). Also, the target compounds exhibited cytotoxic activity against
cervical cancer cell line HeLa that over-expresses p110α (0.21-1.99 mM) [33].
Zhu,et al.,designed and synthesized a series of 7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives and characterized by 1H
NMR, 13
C NMR, MS and HRMS spectrum. All synthesized compounds were evaluated for their inhibitory activity against mTOR
kinase at 10 µM level. The most promising compound (6) (E)-2,6-dimethoxy-4-((2-(4-morpholino-7,8-dihydro-5H-
thiopyrano[4,3-d]pyrimidin-2-yl)hydrazono)methyl)phenol showed strong antitumor activities against mTOR kinase, H460 and
PC-3 cell lines with IC50 values of 0.80 ± 0.15 lM, 7.43 ± 1.45 lM and 11.90 ± 0.94 lM, which were 1.28 to 1.71-fold more active
than BMCL-200908069-1 (1.37 ± 0.07 lM, 9.52 ± 0.29 lM, 16.27 ± 0.54 lM), respectively [34].
Rewcastle,et al.,synthesized a range of 4-substituted derivatives of the pan class I PI3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-
di-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474) in a search for more soluble analogs. Compound (7) 3-(2-
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(difluoromethyl)-1-(4,6-dimorpholino-1,3,5-triazin-2-yl)-1H-benzo[d]imidazol-4-yloxy) propan-1-amine was found to be the most
potent derivatives along with good aqueous solubility (25 mg/mL for the hydrochloride salt) [35].
Zhu,et al., synthesized a series of 2-hydrazinyl-4-morpholinothieno[3,2-d]pyrimidine derivatives and evaluated their cytotoxic
activities against five cancer cell lines. The most promising compound (8) (E)-4-(2-(2-((1-(3-fluorobenzyl)-1H-indol-3-
yl)methylene)hydrazinyl)thieno[3,2-d]pyrimidin-4-yl)morpholine showed strong cytotoxic activities against H460, HT-29 and
MDA-MB-231 cell lines, which were 1.7-to 66 .5-folds more active than 2-(1H-Indazol-4-yl)-6-((4-(methylsulfonyl)-1-
piperazinyl)methyl)-4-(4- morpholinyl)thieno [3,2-d] pyrimidine(GDC-0941) [36].
Zhu,et al., synthesized three series of 4-morpholinothieno[3,2-d]pyrimidine derivatives containing aryl methylene hydrazine
moiety and were evaluated for their cytotoxicity against three cancer cell lines (H460, HT-29, MDA-MB-231). The most
promising compound (9) (E)-4-(2-(2-(benzo[d][1,3]dioxol-5-ylmethylene)hydrazinyl)-6-((4-(methylsulfonyl)piperazin-1-
yl)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine bearing 3,4-methylenedioxy phenyl group, showed excellent cytotoxicity
against H460, HT-29 and MDA-MB-231 cell lines with IC50 values of 0.003 μM, 0.42 μM and 0.74 μM, which was 1.6- to 290-
fold more potent than GDC-0941 [37].
Zhu,et al., synthesized two novel morpholine-containing silicon (IV) phthalocyanines, of which compound (10)bis(2-(N-methyl-
morpholine)) ethoxyphthalocyaninatosilicon di-iodide exhibited high photodynamic activity towards B16 melanoma tumour cells
with an IC50 value of 0.30 µM [38].
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Anti-microbial agents
Yancheva,et al., synthesized a novel didepsipeptide(11) member of the family, 6-(propan-2- yl)-3-methyl-morpholine-2,5-dione
which was characterized by IR, 1H-NMR and
13C-NMR spectral data and the structure and relative stability of the
diastereoisomers, tautomers and anionic derivatives of 6-(propan-2-yl)-3-methyl-morpholine-2,5-dione were studied by DFT. It
showed maximum potency against Escherichia coli[39].
Panneerselvam,et al., synthesized a novel series of Schiff bases of 4-(4-aminophenyl)-morpholine which were then characterised
by IR, 1H-NMR,
13C-NMR, Mass spectral and elemental analysis and were screened for antibacterial (Staphylococcus aureus
(ATCC 9144), Staphylococcus epidermidis (ATCC 155), Bacillus cereus (ATCC 11778), Micrococcus luteus (ATCC 4678), and
Escherichia coli (ATCC 25922)) and antifungal 9Candida albicans (ATCC 2091) and Aspergillus niger (ATCC 90290) activities.
Compound (12) 4-(4-(4-Hydroxy-benzylidene-imino)phenyl)-morpholine was found to be the most potent antimicrobial agent
having MIC of 25, 19, 21, 16, 29, 20 and 40 µg/ml against S. aureus, S. epidermidis, B. cereus, M. luteus, E. coli, C. albicans and
A. niger, resp [40].
Araki,et al., prepared a series of novel 7-substituted l-cyclopropyl-6,8-difluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acids and
tested them for antibacterial and convulsive activities in combination with nonsteroidal anti-inflammatory drug. Compound (13)
(7-(2-(aminomethyl)morpholino) derivative )was found to be most potent and showed better gram-positive activity than
quinolones, such as ciprofloxacin, norfloxacin, and ofloxacin and equipotent gram-negative activity with those of norfloxacin and
ofloxacin but inferior to that of ciprofloxacin. Convulsive activities of 7-morpholino derivatives in combination with NSAID drug
fenbufen or its metabolite biphenylacetic acid markedly diminished as compared to those of 7-piperazino derivatives in the
electrophysiological, biochemical, and behavioural experiments [41].
Analgesic and Anti-inflammatory activity
Smelcerovic,et al., synthesized two cyclodidepsipeptides, 3-(2-methylpropyl)-6-(propan-2-yl)-4-methyl-morpholine-2,5-dione
(14) and 3,6-di(propan-2-yl)-4-methyl-morpholine-2,5-dione (15) and evaluated them for inhibitory activity against xanthine
oxidase (XO) in vitro and XO in rat liver homogenate as well as for anti-inflammatory response on human peripheral blood
mononuclear cells (PBMCs). Both of cyclodidepsipeptides showed excellent activity [42].
Naim MJ.; Int. J. Pharmacol. Pharm. Sci. (2015) 3:1; 40-51. 46
Khanum,et al., synthesized hydroxy benzophenones and benzophenone-N-ethyl morpholine ethers and carried out the results of
anti-inflammatory activity by carrageenan-induced hind paw oedema test in rats in vivo. Compound (16) (4-methoxyphenyl)(3-
methyl-4-(2-morpholinoethoxy)phenyl)methanone was found to be most potent [43].
Takaya,et al., prepared various 2-alkyl- or 2-alkenyl-4-alkoxy-5-(substituted amino)-3(2H)-pyridazinones to examine analgesic
and anti-inflammatory activities. Compound (17) 4-ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone was found to be the most
potent compound as an analgesic-anti-inflammatory agent as compared to phenylbutazone [44].
Muscle paralyzing agents
Donahoer,et al., synthesized monoquaternaryN-(w-phthalimidoalky1)-X-alkyl piperidiniumiodides in which morpholine was
substituted for piperidine. It has been shown to possess paralyzing striated muscle activity. Compound (18)N-( 6-
phthalimidohexyl)-n'-benzylmorpholiniumiodide was found to be most active in paralyzing striated muscle in frogs (Rana
pipiens) by lymph sac injection [45].
Anti-parasitic agents
Kuettel,et al., synthesized a new series of 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine derivatives by two synthetic
routes and carried out in vitro assay against Trypanosoma strains, Leishmaniadonovani, and Plasmodium falciparum K1.
Compound (19) 4-(3-(4-phenoxyphenyl)-1H-pyrazol-5-yl)morpholine showed maximum potency with an IC50 value of 1.1 µM
[46].
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Human Neurokinin-1 receptor antagonists
Hale,et al., carried out the regioselective dibenzylphosphorylation of 3-(((2R,3S)-2-((S)-2-(3,5-
bis(trifluoromethyl)phenyl)propyl)-3-(4-fluorophenyl)morpholino)methyl)-1H-1,2,4-triazol-5(4H)-one followed by catalytic
reduction in the presence of N-methyl-D-glucamine yield the compound (20) 2-(S)-(1-(R)-(3,5-bis(trifluoromethyl) phenyl)
ethoxy)-3-(S)-(4-fluoro)phenyl-4-(5-(2-phosphoryl-3-oxo-4H,-1,2,4-triazolo)methyl morpholine, bis(N-methyl-D-glucamine) salt.
This compound has a 10-fold lower affinity for the human NK-1 receptor and was identified as a novel, water-soluble prodrug
suitable for intravenous administration [47].
Anti-hyperlipidemic & Anti-oxidant activity
Ladopoulou,et al., reported the synthesis of new morpholine derivatives which varied in aromatic substitution on the morpholine
ring. These morpholine derivatives simultaneously suppresses cholesterol biosynthesis through SQS inhibition (IC50 range for the
most active compounds; 0.7-5.5 µM) while exhibiting a significant protection of hepatic microsomal membranes against lipid
peroxidation (IC50 range for the most active compounds; 73-200 µM). Compound (21) 3-(phenanthren-2-yl)octahydropyrido[2,1-
c][1,4]oxazin-3-ol hydrobromide was found to be most potent [48].
Chrysselis,et al., carried out the synthesis and evaluation of antioxidant and hypocholesterolemic activity of 2-biphenylyl
morpholine derivatives, which were found to inhibit the ferrous/ascorbate induced lipid peroxidation of microsomal membrane
lipids. Compound (22) 2-(4-biphenyl)-4-methyl-octahydro-1,4-benzoxazin-2-ol was found to be most potent having an IC50 value
of 250 µM. This compound decreases total cholesterol, low density lipoprotein, and triglycerides in plasma of Triton WR-1339
induced hyperlipidemic rats by 54%, 51%, and 49%, respectivelyat 28 µmol/kg (ip) [49].
Naim MJ.; Int. J. Pharmacol. Pharm. Sci. (2015) 3:1; 40-51. 48
Selective and potent gastric prokinetic agents.
Kato,et al., synthesized a new series of N-[( 2-morpholinyl)alkyl]benzamides and evaluated them for their gastric prokinetic
activity by determining effects on the gastric emptying of phenol red semisolid meal and of resin pellets solid meal in rats and
mice. Compound (23) 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chloro-2-methoxy benzamide showed potent and selective
gastric prokinetic activity along with a weak dopamine D2 receptor antagonistic activity [50].
Tyrosinase inhibitors
Hamidian,et al., synthesized six new compounds containing morpholine and 5(4H)-oxazolone rings and were characterized by IR,
1H-NMR, mass spectroscopy and elemental analysis. Compound (24) (Z)-4-benzylidene-2-(4-((E)-(4-
morpholinophenyl)diazenyl)phenyl) oxazol-5(4H)-one was found to be most potent as compared with Kojic acid as standard [51].
CONCLUSION
The article is focused on different targets of morpholine derivatives which can be explored with different inhibitors/activators for
better treatment of lifestyle diseases.
CONFLICT OF INTEREST
The authors confirm that this article content has no conflicts of interest.
ACKNOWLEDGEMENT
The authors gratefully acknowledge the Dr. Ozair Alam, Assistant Professor Dept. of Pharmaceutical chemistry, F/o Pharmacy,
Jamia Hamdard; New Delhi, for its esteemed guidance.
REFERENCES
1. Review of morpholine and its derivatives, Merck Index, 12th ed. published by Merck & co, Whitehouse Station, NJ,
1996; 1074-5.
2. Pushpak, M.; Bekington, M. Synthesis of substituted 4-(3-alkyl-1,2,4-oxadiazol-5ylmethyl)-3,4-dihydro-2H-1,4-
benzoxazinesand 4-(1H-benzimidazol-2-ylmethyl)-3,4-dihydro-2H-1,4benzoxazines. Tetrahedron Lett. 2006;
47(44):7823-7826.
3. Zhou, G.; Zorn, N.; Ting, P.; Aslanian, R.; Lin M.; Cook John. Development of Novel benzomorpholine class of
diacylglycerol acyltransferase I inhibitors. Med. Chem. Lett. 2014; 5(5): 544-549.
4. Achari, B.; Sukhendu, B.M.; Dutta, P.; Chowdhury, C.; Perspectives on 1, 4-benzodioxions,1, 4-benzoxazines and their
2, 3- dihydro derivatives. Synlett. 2004; 14:2449-2467.
5. Panneerselvam, P.; Pradeepchandran, R.V.; Sreedhar,S.K. Synthesis, characterization and biological activities of novel 2-
methyl-quinazolin-4(3H)-ones. Indian J. pharm. Sci. 2003; 65(3): 268-273.
Naim MJ.; Int. J. Pharmacol. Pharm. Sci. (2015) 3:1; 40-51. 49
6. Brown, G.R.; Foubister, A.J &Stribling D. Synthesis and resolution of 3-substituted morpholine appetite suppressants
and chiral synthesis via o-arylhomoserines. J. Chem. Soc. Perkin Trans. 1987; 1: 547.
7. El-masry, A.H.; Fahmy, H.H.;Abdelwahed, A. S..H.Synthesis and Antimicrobial Activity of Some New Benzimidazole
Derivatives. Molecules.2000; 12:1429.
8. Duhalde, V.; Lahillie, B.; Camou, F.; Pedeboscq, S.; Pometan, J.P; Proper use of antibiotics: Aprospective study on the
use of linezolid in a French university hospital. Pathologie. Biologie. 2007; 55(10): 478-481.
9. Marireau, C.; Guilloton, M.; kartst, F. In vivo effects of fenpropimorph on the yeast Saccharomyces cerevisiae and
determination of the molecular basis of the antifungal property. Antimicrob Agents Chemother.1990; 34(6): 989-993.
10. Sawargave, S.P.; Kudale, A.S.; Deore, J.V.; Bhosale, D.S, Divse, J.M; Chavan, S.P; & Borate, H.B. One-step synthesis
of 4-alkyl-3-aryl-2,6-dicyanoanilines and their use in the synthesis of highly functionalized 2,3,5,6,7- and 2,3,4,5,7-
substituted indoles. Tetrahedron Lett 2011; 52: 5491.
11. Segat-Dioury, F.; Lingibé, O.; Graffe, B.; Sacquet M-C.; Lhommet G. A General Synthesis of enantiopure 1,2-
aminoalcohols via chiral morpholinones. Tetrahedron 2000; 56: 233-248.
12. Trabocchi, A.; Krachmalnicoff, A.; Menchi, G.; Guarna, A.;Synthesis and conformational studies of a hybrid β-alanine-
morpholine tetramer, Tetrahedron, 2012; 68: 9701.
13. Walker DP, Eklov BM., Bedore, M.W.,Practical Synthesis of 3-Oxa-6-azabicyclo[3.1.1]heptane hydrotosylate; A novel
morpholine-based building block, synthesis, 2012; 44: 2859.
14. Tosi, G.; Zironi, F.; Caselli, E.; Forni, A.; and Prati, F.; Biocatalytic asymmetric synthesis of (S)- and timolol, Synthesis,
2004; 1625.
15. Shvaika, OL.;Osnovisintezulіkars ’kikhrechovin (Principles of Synthesis of Medicines), Donets’k: SkhіdniiVidavn.
Dіm, 2002.
16. Assaf, G.; Cansell, G.; Critcher, D.; Field, S.; Hayes, S.; Mathew, S.; and Pettman, A. application of a process friendly
morpholine synthesis to ( S, S)-Reboxetine, Tetrahedron Lett., 2010; 51: 5048.
17. Hanlon, S.P.; Camattari, A.; Abad, S.; Glieder, A.; Kittelmann, M., Lütz, S.; Wirz, B.; and Winkler, M.; Human FMO2-
based microbial whole-cell catalysts for drug metabolite synthesis, Chem. Commun., 2012; 48: 6001.
18. Tatsumi, Y.; Yokoo, M.; Senda, H.; and Kakehi, K. Therapeutic efficacy of topically applied KP-103 against
experimental tinea unguium in guinea pigs in comparison with amorolfine and terbinafine.Antimicrob. Agents
Chemother.,2002; 46: 3797.
19. D.S. and Li, J.J.; Eds.; Hoboken, N.J. The Art of Drug Synthesis, Johnson,: Wiley, Canada, 2007, 71-81.
20. Yang, Q.; Ulysse, L.G.; McLaws, M.D.; Keefe, D.K.; Haney, B.P.; Zha, C.; Guzzo, P.R.; and Liu, S. Palladium-
catalyzed α-arylation reactions in total synthesis., Org. Process Res. Dev., 2012; 16: 499.
21. Burland, P.A.; Osborn, HMI.;Turkson, A. Synthesis and glycosidase inhibitory profiles of functionalised morpholines
and oxazepanes, Bioorg. Med. Chem., 2011; 19: 5679.
22. Keldenich, J.; Michon, C.; Nowicki, A.; and AgbossouNiedercorn, F. Synthesis of a chiral key intermediate of
neurokinin antagonist SSR 240600 by asymmetric allylic alkylation. Synlett, 2011; 2939.
23. Meìtro, T.-X.; Cochi, A.; Pardo, DG.; and Cossy, J. Asymmetric synthesis of an antagonist of neurokinin receptors: SSR
241586. J. Org. Chem., 2011; 76: 2594.
24. Lukas, R.J.; Muresan, A.Z.; Damaj, M.I.; Blough, B.E.; Huang, X.; Navarro, H.A.; Mascarella, SW.; Eaton, JB.;
Marxer-Miller, SK.; Carroll, FI. Synthesis and characterization of in vitro and in vivo profiles of hydroxybupropion
analogues: aids to smoking cessation. J. Med. Chem., 2010; 53: 4731.
25. Sun, X.; Niu, L.; Li, X.; Lu, X.; Li, F. Characterization of metabolic profile of mosapride citrate in rat and identification
of two new metabolites: Mosapride N-oxide and morpholine ring-opened mosapride by UPLC-ESI-MS/MS. J. Pharm.
Biomed. Anal., 2009; 50: 27.
Naim MJ.; Int. J. Pharmacol. Pharm. Sci. (2015) 3:1; 40-51. 50
26. Dave, R. and Sasaki, N.A. β-Amino alcohols derived from (1R,2S)-norephedrine and (1S,2S)-pseudonorephedrine as
catalysts in the asymmetric addition of diethylzinc to aldehydes, Tetrahedron: Asymmetry, 2006; 17: 388.
27. Raup, D.E.A.; Cardinal-David, B.; Holte, D.; Scheidt, KA. Cooperative catalysis by carbenes and Lewis acids in a highly
stereoselective route to gamma-lactams. Nat. Chem., 2010; 2: 766.
28. R.M, An introduction to the chemistry of heterocyclic compound 2nd
edn. John wiley& sons, Inc compounds. 1976, 348.
29. Schmidt, A.K.C.; Stark, CBW.Tetrapropylammoniumperruthenatecatalyzed glycol cleavage to carboxylic (di)acids, Org.
Lett., 2011; 13: 5788.
30. Xiao-Meng, W.; Jing, Xu.; Min-Hang, Xin.; She-Min, Lu.; San-Qi Zhan. Design, synthesis and anti-proliferative activity
evaluation of m-(4-morpholinyl-1,3,5-triazin-2-yl)benzamides in vitro. Bioorg. Med. Chem. Letts.; 2015; 25; 1730–
1735.
31. Xiao-Meng, Wang.; Min-Hang, Xin.; Jing, Xu.; Bo-Rui, Kang.; Yan Li, She-Min Lu.; San-Qi Zhang. Synthesis and
antitumor activities evaluation of m-(4- morpholinoquinazolin-2-yl)benzamides in vitro and in vivo. Eur. J. Med. Chem.;
2015; 96; 382-395.
32. Kishna Ram, Senwar.; Pankaj Sharma.; T. Srinivasa Reddy.; Manish Kumar Jeengar.; V. LakshmaNayak.; V.G.M.
Naidu.; Ahmed Kamal.; NagulaShankaraiah. Spirooxindole-derived morpholine-fused-1,2,3-triazoles: Design, synthesis,
cytotoxicity and apoptosis inducing studies. Eur. J. Med. Chem. 2015; 102; 413-424.
33. Marwa, A. I.; Sahar, M. Abou-Seri.; Mona, M. Hanna.; Mohamed M, Abdalla,.; Nehad A. El, Sayed. Design, synthesis
and biological evaluation of novel condensed pyrrolo[1,2-c]pyrimidines featuring morpholine moiety as PI3Ka
Inhibitors. Eur. J. Med. Chem.; 2015; 99; 1-13.
34. Wufu, Zhu.; Chengyu, Sun.; Shan, Xu.; Chunjiang, Wua.; Jielian, Wua.; Mengze, Xu.; He, Zhao.; Le, Chen.; Weipeng,
Zeng.; Pengwu, Zheng. Design, synthesis, anticancer activity and docking studies of novel 4-morpholino-7,8-dihydro-
5H-thiopyrano[4,3-d] pyrimidine derivatives as mTOR inhibitors. Bioorg. Med. Chem.; 2014; 22; 6746–6754.
35. Gordon, W. Rewcastle.; Swarna, A. Gamage.; Jack, U. Flanagan.; Jackie, D. Kendall.; William, A. Denny.; Bruce, C.
Baguley.; Christina, M. Buchanan.; Mindy Chao, Philip Kestell.; SharadaKolekar.; Woo-Jeong, Lee.; Claire L, Lill.;
Alisha, Malik.; Ripudaman, Singh.; Stephen, M.F.; Jamieson, Peter R, Shepherd. Synthesis and biological evaluation of
novel phosphatidylinositol 3-kinase inhibitors: Solubilized 4-substituted benzimidazole analogs of 2-(difluoromethyl)-1-
[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474). Eur. J. Med. Chem.; 2013; 64; 137-147.
36. Wufu, Zhu.; Yajing, Liu.; Xin, Zhai.; Xiao, Wang.; Yan, Zhu.; Di, Wua.; Hongyu, Zhou,; Ping, Gong.; Yanfang, Zhao.
Design, synthesis and 3D-QSAR analysis of novel 2-hydrazinyl-4-morpholinothieno[3,2-d]pyrimidine derivatives as
potential antitumor agents. Eur. J. Med. Chem.; 2012; 57; 162-175.
37. Wufu, Zhu.; Xin, Zhai.; Qiangqiang Fu, FeiGuo.; Mei Bai, Jianqiang Wang.; Haiyan Wang, and Ping Gong. Design,
Synthesis and Anticancer activity of 4-Morpholinothieno[3,2-d]-pyrimidine derivatives bearing arylmethylene hydrazine
moiety. Chem. Pharm. Bull. 2012; 60; 1037–1045.
38. Yu-Jiao, Zhu.; Jian-Dong, Huang.; Xiong-Jie, Jiang.; Jian-Cheng, Sun. Novel silicon phthalocyanines axially modified
by morpholine: Synthesis, complexation with serum protein and in vitro photodynamic activity. Inorg. Chem. Comm.;
2006; 9; 473–477.
39. Denitsa,Yancheva.; Lalka, Daskalova.; Emiliya, Cherneva.; Bozhanka, Mikhova.; Aleksandra, Djordjevic.; Zaklina,
Smelcerovic.; Andrija, Smelcerovic. Synthesis, structure and antimicrobial activity of 6-(propan-2-yl)-3-methyl-
morpholine-2,5-dione. J. Mol. Str.; 2012; 1016; 147–154.
40. PerumalPanneerselvam.; Rajasree R., Nair.;GudaparthiVijayalakshmi.; EkambaramHarihara, Subramanian.; Seshaiah
Krishnan Sridhar. Synthesis of Schiff bases of 4-(4-aminophenyl)-morpholine as potential antimicrobial agents. Eur. J.
Med. Chem.; 2005; 40; 225–229.
Naim MJ.; Int. J. Pharmacol. Pharm. Sci. (2015) 3:1; 40-51. 51
41. Kazuhiko, Araki., Tsuyoshi, Kuroda.; Satoru, Uemori.; Akihiko, Moriguchi.; Yoshifumi, Ikeda.; Fumihiro, Hirayama.;
Yoshito, Yokoyama.; EijiIwao, and Takashi kushiji. Quinolone antimicrobial agents substituted with morpholines at the
7-Position. synthesis and structure-activity relationships. J. Med. Chem.;1993, 36, 1356-1363.
42. Andrija, Smelcerovic., Miroslav, Rangelov.;Zaklina, Smelcerovic.; Andrej, Veljkovic.; Emiliya ,Cherneva.; Denitsa,
Yancheva.; Goran M, Nikolic.; ZivomirPetronijevic.; GordanaKocic. Two 6-(propan-2-yl)-4-methyl-morpholine-2,5-
diones as new non-purine xanthine oxidase inhibitors and anti-inflammatory agents. Food Chem. Toxicol.; 2013; 55;
493–497.
43. Shaukath, A. Khanum.; Bushra, A. Begum.; V. Giris.; Noor Fatima, K. Synthesis and evaluation of benzophenone-N-
ethylMorpholine ethers as anti-inflammatory agents. Int. J. Biomed. Sci.; 2010; 6(1); 60-65.
44. M. Takaya.; M. Sato.; K. Terashima.; H. Tanizawa. A new Nonsteroidal analgesic-anti-inflammatory Agent. Synthesis
and activity of4- Ethoxy-2-methyl-5-morpholino-3(2 H)-pyridazinone and related compounds. J. Med. Chem.; 1979;
22(1); 53-58.
45. Hugh B. Donahoer.; Robert J. Seiwald.; Sister Mary Marguerite Christine Neumann, B.V.M. and Kazwok Kimura.
Monoquaternary muscle paralyzing agents-II. Synthesis of N-(W-Phthalimidoalky1)-N-Alkylmorpholinium iodides. J.
Med. Pharm. Chem.; 1961; 3; 3.
46. Sabine, Kuettel.; Alfonso, Zambon.; Marcel, Kaiser.; RetoBrun.; Leonardo Scapozza, and Remo Perozzo. Synthesis and
evaluation of antiparasitic activities of new 4-[5-(4-Phenoxyphenyl)-2H-pyrazol-3-yl]morpholine derivatives. J. Med.
Chem.; 2007; 50;5833-5839.
47. Jeffrey, J. Hale.; Sander, G. Mills.; Malcolm, MacCoss.; Conrad, P. Dorn.; Paul, E. Finke.; Richard, J. Budhu.; Robert,
A. Reamer.; Su-Er W. Huskey.; Debra Luffer-Atlas.; Brian, J. Dean.; Erin M. McGowan.; William P. Feeney.; Shuet-
Hing Lee Chiu.; Margaret, A. Cascieri.; Gary, G. Chicchi.; Marc, M. Kurtz.; Sharon, Sadowski.; ElzbietaBer.; F. David,
Tattersall.; Nadia, M. J. Rupniak.; Angela, R. Williams.; Wayne, Rycroft.; Richard, Hargreaves.; Joseph M. Metzger and
D. Euan, MacIntyre. Phosphorylated morpholine acetal human neurokinin-1 receptor antagonists as water-soluble
prodrugs. J. Med. Chem. 2000; 43; 1234-1241.
48. Eleni, M. Ladopoulou.; Alexios, N. Matralis.; AnastasiosNikitakis.; Angeliki, P. Kourounakis. Antihyperlipidemic
morpholine derivatives with antioxidant activity: An investigation of the aromatic substitution. Bioorg. Med. Chem.;
2015; 23; 7015–7023.
49. Michael, C. Chrysselis.; Eleni, A. Rekka.; and Panos, N. Kourounakis. Hypocholesterolemic and hypolipidemic activity
of some novel morpholine derivatives with antioxidant Activity. J. Med. Chem.;2000; 43; 609-612.
50. Shiro, Kato.; Toshiya, Morie.; Katsuhiko, Hino.; Tatsuya, Kon.; Shunsuke, Naruto.; Naoyuki, Yoshida.; T adahiko,
Karasawa.; and Jun-ichi, Matsumoto. Novel benzamides as selective and potent gastric prokinetic agents I. Synthesis and
structure-activity relationships of N-[(2-Morpholinyl)alkyl]benzamides. J. Med. Chem.; 1990; 33;1406-1413.
51. Hooshang, Hamidian and SimaAzizi. Synthesis of novel compounds containing morpholine and 5(4H)-oxazolone rings
as potent tyrosinase inhibitors. Bio. org. Med. Chem.; 2015; 23; 7089–7094.