Ijprsonline vol2 15

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Published on February 17, 2014

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Abstract
The compounds of the invention are solid crystallines stable to the light and heat. They show an interesting activity in preventing the depression from reserpine at doses which do not cause any untoward side efiects of the parameters considered. The study of the examined products shows a slight calming action. The first symptoms of toxicity are observed at about 1000-12000 rug/kg. by oral route. At the tested doses, the compounds are without anticonvulsive and antitremorin activity. At higher doses they potentiate barbituric hypnosis. The following table illustrates the antidepressing activity of 4H-3-carboxamidomethyl-l,3-benzoxazine-2-one to reserpine in comparison with the antidepressing activity of imipramine. 1.4H-3-carboxamidomethyl-1,3-benzoxazine- 2-one 37.9 grams of ethyl glyciuate hydrochloride were dissolved in 400 cc. of ethanol and 33.5 g. of salicylic aldehyde were added. It is refluxed for half an hour and cooled. 38 cc. of triethylamine and g. of Raney nickel are then added whereafter hydrogenation is carried out at room temperature and under atmospheric pressure. After hydrogen adsorption was complete, the mixture was filtered and the alcohol evaporated 01f. The residue was taken up with acidified water, extracted with ether to eliminate part of the byproducts, consisting mainly of o.cresol, then made alkaline with ammonia and extracted with ethyl acetate. The solvent was removed in vacuo and the residue crystallized from ether/ petroleum ether. 36.7 g. of o-hydroxybenzyl-aminoacetic acid ethyl ester melting at 47 C. are obtained.

Int. J. Pharm. Res. Sci., 2014, 02(1), 89-97. www.ijprsonline.com ISSN: 2348 –0882 ============================================================================ Preparation of 2H-3(o,p-dinitrophenyl)-3,4-dihydro-Methoxy1,3-benzoxazine PC-Model Studies and Biological Activity Dilesh Indorkar*1, Aruna Parteti1,OP Chourasia1 and SN Limaye1 1 Department of Chemistry, Dr. H. S. Gour University (PG CWA& GDC Sausar) Sagar (M.P.)-470003 E-mail: dileshindorkar@yahoo.in --------------------------------------------------------------------------------------------------------------------------------------ether. 36.7 g. of o-hydroxybenzyl-aminoacetic acid Abstract The compounds of the invention are solid ethyl ester melting at 47 C. are obtained. crystallines stable to the light and heat. They show Keyword;- l,3-benzoxazine ,Reserpine, chloroan interesting activity in preventing the depression benzoxazine. from reserpine at doses which do not cause any Introduction untoward side efiects of the parameters considered. In the present work benzoxazine, methoxy The study of the examined products shows a slight benzoxazine and chloro-benzoxazine groups were calming action. The first symptoms of toxicity are selected for the study. A brief history on synthetic observed at about 1000-12000 rug/kg. by oral route. methods, physical and chemical properties of the At the tested doses, the compounds are without selected heterocycles have been dealt in this chapter anticonvulsive and antitremorin activity. At higher [1].Benzoxazine is an oxazine ring with an oxygen doses they potentiate barbituric hypnosis. The atom next to the nitrogen. These are unsaturated following table illustrates the antidepressing activity aromatic heterocyclic compounds that contain a ring of 4H-3-carboxamidomethyl-l,3-benzoxazine-2-one with four carbon atoms, one oxygen atom and one to reserpine in comparison with the antidepressing nitrogen atom [2]. Benzoxazine are found in some activity of imipramine. 1.4H-3-carboxamidomethylnatural products such as ibotenic acid. They also 1,3-benzoxazine- 2-one 37.9 grams of ethyl form the basis for a number of drugs, including the glyciuate hydrochloride were dissolved in 400 cc. of COX-2 inhibitor valdecoxib (bextra) [3]. Not only ethanol and 33.5 g. of salicylic aldehyde were among heterocyclic compounds in general but also added. It is refluxed for half an hour and cooled. 38 among related oxazine. This is because benzoxazine cc. of triethylamine and g. of Raney nickel are then product the typical properties of the aromatic system, added whereafter hydrogenation is carried out at which are in fact, more pronounced in these room temperature and under atmospheric pressure. derivatives, together with high liability of the ring After hydrogen adsorption was complete, the under certain conditions, particularly at the nitrogenmixture was filtered and the alcohol evaporated 01f. oxygen bond [4].Heterocyclic compounds are those The residue was taken up with acidified water, cyclic compounds in which one or more of the ring extracted with ether to eliminate part of the carbons are replaced by another atom [5]. The nonbyproducts, consisting mainly of o.cresol, then carbon atom in such rings are referred to as hetero made alkaline with ammonia and extracted with atom. The most common hetero atom are Nitrogen, ethyl acetate. The solvent was removed in vacuo Oxygen and Sulphur, [6] but the other atoms such and the residue crystallized from ether/ petroleum 89

Int. J. Pharm. Res. Sci., 2014, 02(1), 89-97. www.ijprsonline.com ISSN: 2348 –0882 ============================================================================ as Boron, Phosphorous, or Silicon can also be members of heterocyclic rings. Preparation of Comp.-3 Sub.-o,m,p Cl/NO2 derivatives of methoxy 1,3-benzoxazine. OMe OMe NH2 OH OH C2H5OH O + N Step-I X X Step-II OMe NaBH4 OMe O HCHO N Step-III OH NH X X X1 = 09 = o-chloro- group, 10 = m-nitro- group, 11=p-nitro-group, 12, 0-nitro-group, 13=m-nitro- group,14=P-nitrogroup, 15= 2, 4-dinitro- group, 16= 4-bromo- group. (0.05mole) in methanol and the mixture was stirred Step-I. Preparation of 2-(aryliminomethoxy)for 30 minute at room temperature. The mixture methylphenol A mixture of 2-Hydroxy 3-methoxy was then poured in to ice cold water. The compound benzaldehyde 2.44 gm (0.02mole) and appropriate separated, was filtered off and crystallized from aromatic amine (0.02mole) in ethanol (20ml) was ethanol to yield (2-arylamino)-methyl phenol. refluxed on water bath for 30 min. crystalline residue Step-III. Preparation of 2H-3-(aryl)-3, 4was obtained on cooling the reaction mixture. The dihydro-1, 3-benzoxazine product was dried and crystallized from chloroform3, 2-(aryl amino) methyl phenol (0.05mole) petroleum ether (1:4v/v] to furnish 2-(arylimino) and formalin 37% (1ml) were refluxed in ethanol methyl phenol. The amines taken for (Mbenz.09), 0(20ml) for 6 hrs. The product separated out after chloro-aniline, (Mbenz.10), m-chloro-aniline, pouring the reaction mixture in to ice cold water (Mbenz.11), p-chloro-aniline, (Mbenz.12) 0-nitroand then filtered and crystallized from ethanol to aniline, (Mbenz.13), m-nitro-aniline, (Mbenz.14) pyield methoxy 2H-3–(aryl)-3, 4 –dihydro-1, 3– nitro aniline, (Mbenz.15) o.p.-dinitro-aniline, benzoxazines (Mbenz.16), p-bromo-aniline. Step-II. Preparation of 2-(arylamino)-methylphenol Sodium borohydride (0.3gm) was added to a solution of 2-(aryl amino) methyl phenol 90

Int. J. Pharm. Res. Sci., 2014, 02(1), 89-97. www.ijprsonline.com ISSN: 2348 –0882 ============================================================================ Table 1: Physical data of compounds. Name 2H-3(o,p-dinitrophenyl)-3,4-dihydro-Methoxy1,3-benzoxazine Mol.Wt. 331 OMe M.P.°C 120 NO2 O Yield (%) 78 Mol.For. N C15H13N3O6 C% Found Calcu. 54.38 54.39 Elemental Analysis NO2 H% Found 3.96 N% Calcu. 3.92 Table 2: IR Characterization of compounds. Group type Vibration mode -CH (str.) in–OCH2 -CH (str.) in –NCH2 -C-N (str.) in –NCH2 Oxazine ring C-O(str.) in –OCH2 -CH (bend.) in–OCH2 -CH (bend.) in –NCH2 -CH (str.) C=C (str.) Aromatic ring -CH (bend.) C-H(str.) in-OCH3 Ar-OCH3 C-O (str.) in Ar-OCH3 Found 12.64 Frequency (cm-1) 2910.55 2845.12 1233.49 1059.79 1509.23 1356.48 3039.55,3011.15 1602.77 1018.44 2880.46 166.55 C-N(str.) in Ar-NO2 Ar-NO2 Calcu. 12.69 519.46 N-O (str.) in-NO2 1356.57 Table 3: 1HNMR Characterization compounds. Signal No. Chemical shift (in δ ppm) 1. 2. 3. 4. 7.16-7.70 4.56 3.51 3.78 Multiplicity Multiplet Singlet Singlet Singlet Relative no. of protons 6 2 2 3 Inference Ar-H -OCH2 of Benzoxazine ring -NCH2 of Benzoxazine ring -OCH3 of Ar-OCH3 91

Int. J. Pharm. Res. Sci., 2014, 02(1), 89-97. www.ijprsonline.com ISSN: 2348 –0882 ============================================================================ Table-4: PC-Model Studies of Methoxy benzoxazine derivatives. Compound Code Mebenz.9 Mebenz.10 Mebenz.11 Mebenz.12 Mebenz.13 Mebenz.14 Mebenz.15 Mebenz.16 Position 12 13 Substituent 2 – Cl 3 – Cl B.L. CN 1.460 1.463 B.A NC. 120.67 121.02 14 4 – Cl 1.463 121.02 12 2-NO2 1.462 120.13 13 3-NO2 1.463 121.05 14 4-NO2 1.463 120.85 12,14 2,4-diNO2 1.458 120.63 14 4 – Br 1.461 121.16 The overall variations in the dipole moment and maximum minimization energy values are in good agreement with the IR spectral frequencies for these compounds. This perfect co-relation between the theoretical data and the experimental characterization supports the steric justifications extended for various substituents. The validity of the PC Model simulated data has been examined separately by comparing these Dihedral Angle N-C 162.37 165.39 C- Mol. Volu. 276 276 VD Dip.Mo W m. 8.03 4.197 2.11 26.18 10.3 166.70 276 2.479 0 517. 178.47 286 2.312 4 11.3 173.00 286 1.895 6 29.9 165.95 286 1.736 6 10.5 167.10 331 1.512 1 10.7 167.76 323 1.089 4 values with the electrical polarizability values obtained from the theoretical values as described by Hansch for various substituents at various position for the present set of synthesized compounds. The following table (Table 4.12) records the electrical polarizability for the said substituents of series II along with their dipole moment values. OMe 1 7 8 O 6 12 2 13 11 9 5 10 4 R1 14 N 3 16 15 2H-3-(4’-Chlorophenyl)-3,4-dihydro-7-methoxy 1,3- Benzoxazine 92

Int. J. Pharm. Res. Sci., 2014, 02(1), 89-97. www.ijprsonline.com ISSN: 2348 –0882 ============================================================================ Table 5: Characterization and Chemical Shift of 13 Compound code Benzx.7, diNO2 –ph Inference 157.6 O 89.5 NO2 133.9 128.1 119.6 N 120.9 129.0 6 148.7 NO2 138.8 122.2 55.9 145.7 128.6 Compound code Mebenz. – Structure: OMe NO2 O N Relative no.of carbon (δppm) (O-C-N) (C-NO2) (N-C) NO2-Ar Stru. 114.1 C NMR data (C),89.5, (C), 138.2,133.2 (C), 55.9 (C), 119.6,128.1,116.4, 145.7, Benzene Ring (C), 114.1, 128.1, 120.09,129.0,122.0, ,157.6 PC Model values MMX Energy Str Bnd Str Bnd Tor VDW QQ DM HF SE 4.747 0.959 3.64 0.097 11.471 11.365 2.784 1.895 31.59 20.2 93

Int. J. Pharm. Res. Sci., 2014, 02(1), 89-97. www.ijprsonline.com ISSN: 2348 –0882 ============================================================================ Table 7 : Z-Matrix Parameters for Compounds of as obtained from PC Model Precise gnorm=0.01 Mebenz.14 1 C 0.000000 0 0.000000 0 0.000000 0 000 2 C 1.400825 1 0.000000 0 0.000000 0 100 3 C 1.399224 1 120.008621 1 0.000000 0 210 4 C 1.400653 1 119.988075 1 0.000000 1 321 5 C 1.399192 1 120.020966 1 0.000000 1 432 6 C 1.400848 1 119.984863 1 0.000000 1 543 7 C 1.103118 1 120.012062 1 -180.000000 1 543 8 O 1.103109 1 119.992279 1 180.000000 1 654 9 N 1.256616 1 117.430649 1 -180.000000 1 754 10 C 1.315407 1 123.193153 1 0.000000 1 865 11 C 2.958652 1 178.238083 1 -180.000000 1 975 12 C 1.400824 1 179.198380 1 0.000000 1 11 9 7 13 C 1.399223 1 59.189919 1 0.000000 1 11 9 7 14 C 1.400648 1 119.988480 1 180.000000 1 13 11 9 15 C 1.399192 1 120.020782 1 0.000000 1 14 13 11 16 C 1.400847 1 119.984947 1 0.000000 1 15 14 13 17 N 1.100001 1 119.948837 1 180.000000 1 15 14 13 18 O 1.103110 1 119.999214 1 -180.000000 1 123 19 C 1.154034 1 174.933609 1 -180.000000 1 18 1 2 20 H 1.100002 1 119.938850 1 -180.000000 1 231 21 H 1.099999 1 119.955444 1 180.000000 1 321 22 H 1.099998 1 120.041443 1 -180.000000 1 432 23 H 1.110107 1 105.007965 1 55.221603 1 754 24 H 1.110109 1 105.007980 1 -55.221447 1 754 25 H 1.110108 1 111.363655 1 -121.582985 1 10 8 6 26 H 1.110109 1 111.363625 1 121.583176 1 10 8 6 27 H 1.109933 1 109.999001 1 -180.000000 1 19 18 1 28 H 1.109878 1 110.000053 1 59.998360 1 19 18 1 29 H 1.109879 1 110.000046 1 -59.998112 1 19 18 1 30 H 1.100001 1 120.059509 1 180.000000 1 12 11 9 31 H 1.100001 1 119.955246 1 0.000000 1 13 11 9 32 H 1.100000 1 120.041367 1 -180.000000 1 14 13 11 33 H 2.918083 1 126.647446 1 -85.301239 1 16 15 14 34 O 4.072706 1 88.442802 1 104.511551 1 17 15 14 35 O 1.514127 1 128.087860 1 26.447401 1 17 15 14 94

Int. J. Pharm. Res. Sci., 2014, 02(1), 89-97. www.ijprsonline.com ISSN: 2348 –0882 ============================================================================ Table: 8 Antibacterial activityof Methoxy Benzoxazine-derivatives antibacterial activity zones of inhibition (mm) E. coli Compound code 2% 10 8 9 12 12 10 11 12 15 Mebenz.9 Mebenz.10 Mebenz.11 Mebenz.12 Mebenz.13 Mebenz.14 Mebenz.15 Mebenz.16 Standard drug 4% 11 10 12 12 13 12 12 16 18 Bacillus subtalis 2% 11 12 8 15 10 13 13 16 16 4% 14 15 10 18 11 12 14 19 19 Pseudomonas alcaligens 2% 4% 8 10 10 13 11 12 12 15 13 15 11 14 13 14 10 13 14 16 Salmonella sp. 2% 12 9 10 14 12 8 9 13 14 4% 13 11 12 16 14 10 10 11 13 eb en .1 0 M eb en .1 1 M eb en .1 2 M eb en .1 3 M eb en .1 4 M eb en .1 5 M eb en .1 6 M eb en .9 M n. dr ug 20 18 16 14 12 10 8 6 4 2 0 st a Concentration % Fig.3.2b. Antibacterial activity of methoxy benzoxazine derivatives. (Bacillus subtalis ) Compound Code 2% 4% 95

Int. J. Pharm. Res. Sci., 2014, 02(1), 89-97. www.ijprsonline.com ISSN: 2348 –0882 ============================================================================ Table 9: Antifungal activity of Methoxy Benzoxazine derivatives Antifungal activity zones of inhibition (mm) Penicillium Rhizoctonia Aspergillus flavus citrinum bataticola Compound code 2% 4% 2% 4% 2% 4% Mebenz.9 11 13 13 15 9 11 Mebenz.10 09 11 10 15 12 16 Mebenz.11 17 20 15 18 17 20 Mebenz.12 10 12 9 13 12 15 Mebenz.13 9 10 14 10 11 12 Mebenz.14 10 11 12 14 10 13 Mebenz.15 9 14 10 10 13 17 Mebenz.16 10 12 10 15 13 14 Standard drug 15 20 16 19 17 22 Aspergillus niger 2% 12 10 14 12 8 12 10 12 18 4% 15 13 17 14 12 15 14 13 21 Fig.3.2a. Antifungal activity of methoxy benzoxazine derivatives ( Penicillium citrinum ) 18 16 14 12 10 8 6 Compound code eb en .1 6 M eb en .1 5 M eb en .1 4 M eb en .1 3 M eb en .1 2 M eb en .1 1 M eb en .1 0 M eb en .9 M n. dr ug 4 2 0 st a Concentration % 20 2% 4% 96

Int. J. Pharm. Res. Sci., 2014, 02(1), 89-97. www.ijprsonline.com ISSN: 2348 –0882 ============================================================================ References G.N. Mukhopadhya, “History of Indian Medicines”. Calcutta University, 324, 11,1992 . C.H. Collens, “Microbiological Method”, Butterworth Co., London, 297, 43, 1994. Freeman, “Text Book of Microbiology”, Boba, W.B. Saunders Co., Toronto, 21st Edn, 1979. T. Rosebury and R.J. Dubos “Bacterial and Mycotic Infection of Man”, J.B. Lippincott company, Philadelphiya, 3rd ed. 1958. R.K. Bansal, V.K. Jain, N. Gupta and P.G. Jones “Heterocyclic Chemistry Tetrahedron.”, 157, 58, 2002. E.S. Goll, P.C. Jurs. “Prediction of the normal boiling points of organic Compounds from molecular Strutures with a computational neural net work model, J Chem. Inf. Comput. Sci.”, 974, 39, 1999. S.N. Limaye, D.Sc. thesis, Dr. H.S. Gour University, Sagar (M.P). India, 1994. N.T. Carnall P.R. Fields and K.Rajnak. “J. Chem. Phys.,” 4472, 14, 1968. S. Harikrishna, S.P. Shrivastava, S.N.Limaye and J.T.Rao “E.J. Chem.”, 182, 2, 2005. C.Hansch, “J. med. Chem.,” 11,2, 1967. D.K.Indorkar, S.N.Limaye and O.P.chourasia “Asian.J. Chem.”, 1095, 09, 2012. S. Bhosale, S. Kurhade, V. P. Uppuleti, P. Palle and D. Bhuniya, Tetrahedron Letters, 50, Issue 27, 3948-3951, 08 July 2009. Jose Leeis Gancia Ruano, Cristina Fajardo and M. Rossrio Maitim, Tetrahedron Letter, 61, 4363-4371, 2005. R. Iglesias, J.L. Serrano and T. Sierra, Liquid Crystals, 22, 37, 1997. 97

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