Synthesis and pharmacological activities of 1,8-naphthyridine derivatives.

Article abstract of DOI:10.1248/bpb.25.798

In the present study, a series of 2-substituted-4-methyl-7-amino/4,7-dimethyl-1,8-naphthyridines were synthesized and characterized by IR, 1H-NMR and elemental analysis. The compounds were investigated for anticonvulsant (125, 250 mg/kg), cardiac and antimicrobial activities. The compounds were screened for antibacterial activity against gram (+) bacteria (Staphylococcus epidermidis, Bacillus subtilis, Enterococcusfaecalis and Micrococcus luteus) and gram (-) bacteria (Proteus vulgaris, Pseudomonas aeruginosa, Escherichia coli and Salmonella typhi). All the compounds except 2-(3'-phenylaminopropyloxy)-4-methyl-7-amino-1,8-naphthyridine exhibited significant anticonvulsant activity. The anticonvulsant activity of 2-(3-morpholino-2'-hydroxypropyloxy)-4-methyl-7-amino-1,8-naphthyridine, 2-(3'-diphenylamino-2'-hydroxypropyloxy)-4-methyl-7-amino-1,8-naphthyridine and 2-(3'-diethanolamino-propyloxy)-4,7-dimethy-1,8-naphthyridine at the dose of 250 mg/kg were found to be equivalent to diazepam (5 mg/kg). Sympathetic blocking activity was observed with 2-(3'-phenylamino-2'-hydroxypropyloxy)-4-methyl-7-amino-1,8-naphthyridine, 2-(3'-diethanolamino-2'-hydroxypropyloxy)-4-methyl-7-amino-1,8-naphthyridine and 2-(3'-diphenylamino-2'-hydroxypropyloxy)-4-methyl-7-amino-1,8-naphthyridine only. All the compounds were devoid of antibacterial activity against the tested bacteria.

Full text of DOI:10.1248/bpb.25.798

798
Notes
Biol. Pharm. Bull. 25(6) 798—802 (2002)
Vol. 25, No. 6
Synthesis and Pharmacological Activities of 1,8-Naphthyridine Derivatives
Joseph THOMAS LEONARD,* Revuluri GANGADHAR, Sundararaj KISHORE GNANASAM,
Somasundaram RAMACHANDRAN, Muniyandy SARAVANAN, and Seshaiah Krishnan SRIDHAR
Department of Pharmaceutical Chemistry and Pharmacology, Vel’s College of Pharmacy; Old Pallavaram, Chennai-600
117, India. Received January 28, 2002; accepted March 20, 2002
In the present study, a series of 2-substituted-4-methyl-7-amino/4,7-dimethyl-1,8-naphthyridines were syn-
1
thesized and characterized by IR, H-NMR and elemental analysis. The compounds were investigated for anti-
convulsant (125, 250 mg/kg), cardiac and antimicrobial activities. The compounds were screened for antibacter-
ial activity against gram (؉) bacteria (Staphylococcus epidermidis, Bacillus subtilis, Enterococcus faecalis and Mi-
crococcus luteus) and gram (؊) bacteria (Proteus vulgaris, Pseudomonas aeruginosa, Escherichia coli and Salmo-
nella typhi). All the compounds except 2-(3؅-phenylaminopropyloxy)-4-methyl-7-amino-1,8-naphthyridine exhib-
ited significant anticonvulsant activity. The anticonvulsant activity of 2-(3-morpholino-2؅-hydroxypropyloxy)-4-
methyl-7-amino-1,8-naphthyridine, 2-(3؅-diphenylamino-2؅-hydroxypropyloxy)-4-methyl-7-amino-1,8-naphthyri-
dine and 2-(3؅-diethanolamino-propyloxy)-4,7-dimethy-1,8-naphthyridine at the dose of 250 mg/kg were found to
be equivalent to diazepam (5 mg/kg). Sympathetic blocking activity was observed with 2-(3؅-phenylamino-2؅-hy-
droxypropyloxy)-4-methyl-7-amino-1,8-naphthyridine, 2-(3؅-diethanolamino-2؅-hydroxypropyloxy)-4-methyl-7-
amino-1,8-naphthyridine and 2-(3؅-diphenylamino-2؅-hydroxypropyloxy)-4-methyl-7-amino-1,8-naphthyridine only.
All the compounds were devoid of antibacterial activity against the tested bacteria.
Key words 1,8-naphthyridine; aryloxyaminopropane; anticonvulsant; sympatholytic
1,8-Naphthyridines were reported to possess antibacter- heating was continued at 100 °C for 30 min. On cooling the
ial,1,2) antimycobacterial,3) antitumor,4) antiinflammatory,5) reaction mixture, the product was separated out, filtered,
antiplatele,6) gastric antisecretary,7) antiallergic,8) local anaes- dried under vacuum and recrystallized by using methanol–
thetic9) and benzodiazepine receptor activity.10) 1,8-Naph- ether (1 : 1). Yieldϭ37.1%, mp 301—302 °C. 1H-NMR
thyridines were also reported to be associated with positive (CDCl3) d: 7.22—7.56 (m, 3H, 3, 5, 6H), 5.72—6.05 (s, 2H,
ionotropic,11) b-adrenergic blocking12) and antihypertensive13) 7-NH2), 3.89—4.09 (s, 1H, 2-OH), 3.07—3.26 (s, 3H, 4-
activities. Aryloxyaminopropanes were reported to posses CH3). IR (KBr) cmϪ1: 3435 (O–H), 3154 (N–H), 1413
CNS depressant,14) neuroleptic,15) antiarrhythmic,16) hypoten- (C–H), 783, 720 (Ar-H). Anal. Calcd for C9H9N3O: C, 61.70;
sive17) and b-adrenergic activity.18,19) Therefore, it was envis- H, 5.18; N, 23.99. Found: C, 61.88; H, 5.04; N, 24.14.
)
aged that chemical entities with both 1,8-naphthyridine and
Synthesis of 2-Hydroxy-4,7-dimethyl-1,8-naphthyridine20
aryloxyaminopropane moieties would result in compounds of 2-Hydroxy-4,7-dimethyl-1,8-naphthyridine was synthesized
interesting biological activities. in a similar manner as 2-hydroxy-4-methyl-7-amino-1,8-
In the present study, a series of 1,8-naphthyridine deriva- naphthyridine, using 2,6-diamino-pyridine instead of 2-
tives were synthesized. The compounds were characterized amino-6-methyl-pyridine. Yieldϭ40.2%, mp 232—233 °C.
1
by IR, H-NMR spectral and elemental analysis. The com- 1H-NMR (CDCl3) d: 7.58 (s, 1H, 3-H), 6.31—6.84 (d,
pounds were evaluated for anticonvulsant activity at the dose Jϭ8.2 Hz, 2H, 5, 6H), 3.87—4.11 (s, 1H, 2-OH), 3.26—3.74
level of 125 and 250 mg/kg by maximal electroshock (s, 3H, 7-CH3), 2.09—2.49 (s, 3H, 4-CH3). IR (KBr) cmϪ1:
method, cardiac activity on isolated frog heart and antimicro- 3289 (O–H), 1409 (C–H), 792, 729 (Ar-H). Anal. Calcd for
bial activity against several kinds of gram (ϩ) and gram (Ϫ) C10H10N2O: C, 68.95; H, 5.79; N, 16.08. Found: C, 69.18; H,
bacteria.
6.08; N, 15.95.
Synthesis of 2-(2؅,3؅-Epoxypropyloxy)-4-methyl-7-amino-
1,8-naphthyridine 2-Hydroxy-4-methyl-7-amino-1,8-
naphthyridine (0.1 mol, 17.5 g) was added to epichlorhydrine
CHEMISTRY
Melting points were determined in open capillary tubes (0.1 mol, 9.3 g, 7.8 ml) in the presence of 15 ml of 10% alco-
and are uncorrected. IR spectra was recorded (in KBr) on holic potassium hydroxide. The reaction mixture was re-
1
Bomem FT-IR spectrophotometer M.B Serial II. H-NMR fluxed for 4 h. On cooling the product was separated, filtered,
spectra were recorded on 300 MHz Bruker DPX 200. The dried under vacuum and recrystallized using chloroform–
1H-chemical shifts are reported as parts per million down- ether (1 : 1). Yieldϭ48.4%, mp 215—216 °C. 1H-NMR
field from tetra methyl silane (Me4Si). Microanalyses for C, (CDCl3) d: 8.04 (s, 1H, 3-H), 7.54—7.83 (d, Jϭ7.9 Hz, 2H,
H, N were performed in Heraeus CHN Rapid Analyzer. 5, 6H), 6.72—6.94 (s, 2H, 7-NH2), 3.42—3.67 (d, Jϭ5.2 Hz,
Analyses indicated by the symbols of the elements are 2H, 3Ј-CH2), 3.21—3.40 (d, Jϭ6.3 Hz, 2H, 1Ј-CH2), 2.98—
withinϮ0.4% of the theoretical values. 1H-NMR and IR 3.21 (s, 3H, 4-CH3), 2.67—2.91 (m, 1H, 2Ј-CH). IR (KBr)
spectra were consistent with the assigned structures.
cmϪ1: 3240 (N–H), 1406 (C–H), 1240 (epoxide C–O), 1120
Synthesis of 2-Hydroxy-4-methyl-7-amino-1,8-naph- (ether C–O) 812, 790 (Ar-H). Anal. Calcd for C12H13N3O2:
thyridine20) Ethyl acetoacetate (0.1 mol) was added to 2- C, 62.33; H, 5.63; N, 18.17. Found: C, 62.54; H, 5.85; N,
amino-6-methyl-pyridine (0.1 mol) and heated to 130 °C for 17.98.
1 h. Then, 5 ml of concentrated sulphuric acid was added and
General Method of Synthesis of 1a to 1d One hun-
To whom correspondence should be addressed. e-mail: alabarae@yahoo.com
© 2002 Pharmaceutical Society of Japan

June 2002
799
dredth moles of the corresponding 1,8-naphthyridine was 16.69. Found: C, 57.36; H, 5.36; N, 16.96.
added to 0.01 mol of the appropriate amine in the presence of
Synthesis of 2-(3؅-Chloropropyloxy)-4,7-dimethyl-1,8-
20 ml of 10% alcoholic potassium hydroxide and refluxed for naphthyridine 2-(3Ј-Chloro-propyloxy)-4,7-dimethyl-1,8-
4 h. On cooling, the products were separated, filtered, dried naphthyridine was synthesized in a similar manner as 2-(3Ј-
under vacuum and recrystallized using 1 : 1 acetone–diethyl chloro-propyloxy)-4-methyl-7-amino-1,8-naphthyridine
ether (1a, 1b, 1d) and 1 : 1 methanol–diethyl ether (1c).
using 2-hydroxy-4,7-dimethyl-1,8-naphthyridine instead of
2-(3Ј-Phenylamino-2Ј-hydroxypropyloxy)-4-methyl-7- 2-hydroxy-4-methyl-7-amino-1,8-naphthyridine. Yieldϭ54.4%,
1
amino-1,8-naphthyridine (1a): Yieldϭ40.2%, mp 248— mp 200—201 °C. H-NMR (CDCl3) d: 7.85 (s, 1H, 3-H),
1
249 °C. H-NMR (CDCl3) d: 7.98 (s, 1H, 3-H), 7.32—7.81 7.63—7.75 (d, Jϭ7.8 Hz, 2H, 5, 6H), 3.42—3.90 (m, 4H, 1Ј,
(d, Jϭ8.1 Hz, 2H, 5, 6H), 7.14—7.25 (s, 1H, NH), (m, 5H, 3Ј-CH2), 3.12—3.35 (s, 3H, 7-CH3), 2.85—3.05 (s, 3H, 4-
2Љ, 3Љ, 4Љ, 5Љ, 6ЉH), 5.78—5.94 (s, 2H, 7-NH2) 3.68—3.94 CH3), 1.15—1.23 (m, 2H, 2Ј-CH2). IR (KBr) cmϪ1: 1409
(m, 4H, 1Ј, 3Ј-CH2), 3.32—3.68 (s, 3H, 4-CH3), 3.15—3.29 (C–H), 1142 (C–O), 811, 792 (Ar-H), 742 (C–Cl). Anal.
(s, 1H, 2Ј-OH), 0.92—1.35 (m, 1H, 2Ј-CH). IR (KBr) cmϪ1: Calcd for C13H15ClN2O: C, 62.27; H, 6.05; N, 11.17. Found:
3455 (O–H), 3341 (Ar-NH2), 3125 (C–H), 1425 (C–N), 1325 C, 61.99; H, 5.76; N, 11.44.
(N–H), 1109 (C–O), 850, 790 (Ar-H). Anal. Calcd for
C18H20N4>O2: C, 66.65; H, 6.28; N, 17.27. Found: C, 66.80; dredth moles of the corresponding 1,8-naphthyridine was
H, 6.41; N, 16.91. added to 0.01 mol of the appropriate amine in the presence of
General Method of Synthesis of 2a to 2j One hun-
2-(3-Morpholino-2Ј-hydroxypropyloxy)-4-methyl-7- 20 ml of 10% alcoholic potassium hydroxide and refluxed for
amino-1,8-naphthyridine (1b): Yieldϭ36.2%, mp 261— 5 h. On cooling, the products were separated, filtered, dried
1
262 °C. H-NMR (CDCl3) d: 7.85 (s, 1H, 3-H), 7.11—7.62 under vacuum and recrystalized using 1 : 1 acetone–diethyl
(d, Jϭ7.7 Hz, 2H, 5, 6H), 6.84—7.05 (s, 2H, 7-NH2), 3.71— ether (2a, 2b, 2c, 2f) and 1 : 1 methanol–diethyl ether (2d, 2e,
4.11 (m, 4H, 1Ј,3Ј-CH2), 3.34—3.61 (s, 3H, 4-CH3), 3.12— 2g, 2i, 2j) and diethyl ether (2h).
3.33 (s, 1H, 2Ј-OH), 2.82—3.01 (m, 8H, 2Љ, 3Љ, 5Љ, 6Љ-CH2–),
2-(3Ј-Phenylaminopropyloxy)-4-methyl-7-amino-1,8-
0.94–1.34 (m, 1H, 2Ј-CH). IR (KBr) cmϪ1: 3405 (O–H), naphthyridine (2a): Yieldϭ15.6%, mp 284—285 °C. 1H-
3105 (Ar-NH2), 1421 (C–H), 1384 (C–N), 1124, 1046 NMR (CDCl3) d: 7.87 (s, 1H, 3-H), 7.31—7.74 (d, Jϭ8.0
(C–O), 810, 762 (Ar-H). Anal. Calcd for C16H22N4O3: C, Hz, 2H, 5, 6H), 7.14—7.31 (s, 1H, NH), 6.41—6.68 (m, 5H,
60.36; H, 6.96; N, 17.60. Found: C, 60.29; H, 6.82; N, 17.82. 2Љ, 3Љ, 4Љ, 5Љ, 6ЉH), 5.76—5.93 (s, 2H, 7-NH2), 3.84—4.06
2-(3Ј-Diethanolamino-2Ј-hydroxypropyloxy)-4-methyl-7- (m, 4H, 1Ј, 3Ј-CH2), 3.60—3.76 (s, 3H, 4-CH3), 0.65—1.30
amino-1,8-naphthyridine (1c): Yieldϭ42.8%, mp 254— (m, 2H, 2Ј-CH2). IR (KBr) cmϪ1: 3241 (Ar N–H), 1391
1
255 °C. H-NMR (CDCl3) d: 7.49 (s, 1H, 3-H), 6.71—7.25 (C–H), 1370 (C–N), 1322 (N–H), 1145 (C–O), 822,804 (Ar-
(d, Jϭ8.0 Hz, 2H, 5, 6H), 6.14—6.35 (s, 2H, 7-NH2), 3.47— H). Anal. Calcd for C18H20N4O: C, 70.11; H, 6.54; N, 18.17.
3.78 (m, 4H, 1Ј, 3Ј-CH2), 3.05—3.34 (s, 2H, 2Љ-(OH)2), Found: C, 70.35; H, 6.71; N, 18.42.
2.88—2.99 (m, 8H, 1Љ, 2Љ-(CH2)2), 2.62—2.71 (s, 3H, 4-
2-[3Ј-(4Љ-Nitrophenylamino)-propyloxy]-4-methyl-7-
CH3), 2.23—2.62 (s, 1H, 2Ј-OH), 0.94—1.32 (m, H, 2Ј-CH). amino-1,8-naphthyridine (2b): Yieldϭ40%, mp 180—181 °C.
IR (KBr) cmϪ1: 3410 (O–H), 3142 (Ar-NH2), 1421 (C–H), 1H-NMR (CDCl3) d: 7.87 (s, 1H, 3-H), 7.31—7.66 (d,
1350 (C–N), 1132 (C–O), 806,791 (Ar-H). Anal. Calcd for Jϭ7.9 Hz, 2H, 5, 6H), 7.09—7.31 (s, 1H, NH), 6.46—6.67
C16H24N4O4: C, 57.13; H, 7.19; N, 16.66. Found: C, 56.91; (m, 4H, 2Љ, 3Љ, 5Љ, 6ЉH), 5.74—5.99 (s, 2H, 7-NH2), 3.88—
H, 7.44; N, 17.01.
4.17 (m, 4H, 1Ј, 3Ј-CH2), 3.65—3.88 (s, 3H, 4-CH3), 0.86—
2-(3Ј-Diphenylamino-2Ј-hydroxypropyloxy)-4-methyl-7- 1.28 (m, 2H, 2Ј-CH2). IR (KBr) cmϪ1: 3367 (Ar N–H), 1524
amino-1,8-naphthyridine (Id): Yieldϭ33.4%, mp 270— (N–O), 1426 (C–H), 1370 (C–N), 1303 (N–H), 1112 (C–O),
1
271 °C. H-NMR (CDCl3) d: 7.14—7.66 (m, 3H, 3, 5, 6H), 841, 783 (Ar-H). Anal. Calcd for C18H19N5O3: C, 61.18; H,
6.22—7.14 (m, 10H, N(C6H5)2), 5.85—6.16 (s, 2H, 7-NH2), 5.42; N, 19.82. Found: C, 60.94; H, 5.66; N, 20.06.
3.66—4.00 (m, 4H, 1Ј, 3Ј-CH2), 3.24—3.66 (s, 3H, 4-CH3),
2-[3Ј-(4Љ-Hydroxyphenylamino)-propyloxy]-4-methyl-
2.95—3.24 (s, 1H, 2Ј-OH), 1.35—1.56 (m, 1H, 2Ј-CH). IR 7-amino-1,8-naphthyridine (2c): Yieldϭ40.1%, mp 170—
1
(KBr) cmϪ1: 3450 (O–H), 3291 (Ar-NH2), 1435 (C–H), 1361 171 °C. H-NMR (CDCl3) d: 7.81 (s, 1H, 3-H), 7.30—7.67
(C–N), 1118 (C–O), 812, 790 (Ar-H). Anal. Calcd for (d, Jϭ7.8 Hz, 2H, 5, 6H), 7.15—7.29 (s, 1H, NH), 6.47—
C24H24N4O2: C, 71.98; H, 6.04; N, 13.99. Found: C, 72.29; 6.71 (m, 4H, 2Љ, 3Љ, 5Љ, 6ЉH), 5.74—6.00 (s, 2H, 7-NH2),
H, 5.72; N, 14.31.
4.31—4.77 (s, 1H, 4Ј-OH), 3.86—4.16 (m, 4H, 1Ј, 3Ј-CH2),
Synthesis of 2-(3؅-Chloropropyloxy)-4-methyl-7-amino- 3.63—3.84 (s, 3H, 4-CH3), 0.92—1.28 (m, 2H, 2Ј-CH2). IR
1,8-naphthyridine One tenth moles of 2-hydroxy-4-methyl- (KBr) cmϪ1: 3425 (O–H), 3340 (Ar N–H), 1414 (C–H), 1394
7-amino-1,8-naphthyridine was added to 0.1 mol (15.7 g, (C–N), 1320 (N–H), 1110 (C–O), 830, 792 (Ar-H). Anal.
10.5 ml) of 1-bromo-3-chloropropane in the presence of Calcd for C18H20N4O2: C, 66.65; H, 6.21; N, 17.27. Found:
15 ml of 10% potassium hydroxide and refluxed for 10 h. On C, 66.35; H, 5.94; N, 17.14.
cooling, the product was separated, filtered, dried under vac-
2-(3Ј-Diethanolaminopropyloxy)-4-methyl-7-amino-1,8-
uum and recrystallized using chloroform–ether (1 : 1). naphthyridine (2d): Yieldϭ15.7%, mp 291—292 °C. 1H-
1
Yieldϭ31%, mp 210—211 °C. H-NMR (CDCl3) d: 8.26 (s, NMR (CDCl3) d: 7.42 (s, 1H, 3-H), 6.31—6.81 (d, Jϭ8.1
1H, 3-H), 7.99—8.10 (d, Jϭ8.1 Hz, 2H, 5, 6H), 6.37—6.62 Hz, 2H, 5, 6H), 6.06—6.24 (s, 2H, 7-NH2), 3.41—3.89 (m,
(s, 2H, 7-NH2), 2.46—2.81 (m, 4H, 1Ј, 3Ј-CH2), 2.38—2.44 4H, 1Ј, 3Ј-CH2), 3.06—3.41 (s, 2H, 2Љ-(OH)2), 2.34—2.97
(s, 3H, 4-CH3), 1.12—1.31 (m, 2H, 2Ј-CH2). IR (KBr) cmϪ1: (m, 8H, 1Љ, 2Љ-(CH2)2), 2.07—2.35 (s, 3H, 4-CH3), 1.16—
3242 (N–H), 1396 (C–H), 1124 (C–O), 811, 797 (Ar-H), 754 1.64 (m, 2H, 2Ј-CH2). IR (KBr) cmϪ1: 3427 (O–H), 3196 (Ar
(C–Cl). Anal. Calcd for C12H14ClN3O: C, 57.26; H, 5.61; N, N–H), 1385 (C–H), 1360 (C–N), 1096 (C–O), 834, 824 (Ar-

800
Vol. 25, No. 6
H). Anal. Calcd for C16H24N4O3: C, 59.98; H, 7.55; N, 17.49. vulsant activity at the dose of 125 and 250 mg/kg. The anti-
Found: C, 60.21; H, 7.69; N, 17.66. convulsant dose was selected between the minimal effective
2-(3Ј-Diphenylaminopropyloxy)-4-methyl-7-amino-1,8- dose and maximal non-lethal dose. All the compounds were
naphthyridine (2e): Yieldϭ35.9%, mp 298—299 °C. 1H- soluble in water and administered to the animals as a solution
NMR (CDCl3) d: 7.06—7.82 (m, 3H, 3, 5, 6H), 6.14—7.06 in triple glass distilled water. The compounds were also
(m, 10H, N(C6H5)2), 5.74—6.04 (s, 2H, 7-NH2), 3.65—3.92 screened for cardiac activity on isolated frog heart. Wistar al-
(m, 4H, 1Ј, 3Ј-CH2), 3.04—3.48 (s, 3H, 4-CH3), 1.02—1.26 bino rats (150—200 g) of either sex were procured from
(m, 2H, 2Ј-CH2). IR (KBr) cmϪ1: 3370 (Ar N–H), 1425 King Institute, Guindy, Chennai. They were kept in colony
(C–H), 1370 (C–N), 1120 (C–O), 841, 783 (Ar-H). Anal. cages at 25Ϯ2 °C, relative humidity 45—55%. under 12 h
Calcd for C24H24N4O: C, 74.97; H, 6.29; N, 14.57. Found: C, light and dark cycle. All the animals were acclimatized for a
75.11; H, 6.04; N, 14.49.
week before use. Small frogs (Rana tigrina, 60—120 g) were
2-(3Ј-Piperidinopropyloxy)-4-methyl-7-amino-1,8-naph- procured locally and used on the same day. Unpaired Stu-
thyridine (2f): Yieldϭ25%, mp 304—305 °C. 1H-NMR dent-t-test21) was performed to ascertain the significance of
(CDCl3) d: 7.15—7.40 (m, 3H, 3, 5, 6H), 5.81—6.15 (s, 2H, the exhibited anticonvulsant activity of the compounds.
7-NH2), 3.80—3.92 (m, 4H, 1Ј, 3Ј-CH2), 2.81—3.35 (m,
Anticonvulsant Activity22) The anticonvulsant activity
10H, 2Љ, 3Љ, 4Љ, 5Љ, 6Љ-CH2–), 1.34—2.21 (s, 3H, 4-CH3), of the synthesized compounds were tested against maximal
1.30—1.42 (m, 2H, 2Ј-CH2). IR (KBr) cmϪ1: 3292 (Ar electroshock induced convulsions in rats. Wistar albino rats
N–H), 1434 (C–H), 1396 (C–N), 1135 (C–O), 781, 725 (Ar- (nϭ6) of either sex were selected by random sampling tech-
H). Anal. Calcd for C17H24N4O: C, 67.97; H, 8.05; N, 18.65. nique. The compounds were administered at the dose level of
Found: C, 68.27; H, 7.88; N, 18.94.
125 and 250 mg/kg orally by intragastric tube 30 min prior to
2-(3Ј-Morpholinopropyloxy)-4-methyl-7-amino-1,8-naph- an electric shock of 150 mA current for 0.2 s. Diazepam
thyridine (2g): Yieldϭ30%, mp 131—132 °C. 1H-NMR (5 mg/kg, oral) was used as the standard drug. The percent-
(CDCl3) d: 7.14—7.38 (m, 3H, 3, 5, 6H), 5.73—6.09 (s, 2H, age protection of the compounds is presented in Table 1.
7-NH2), 3.66—4.03 (m, 4H, 1Ј, 3Ј-CH2), 3.04—3.45 (s, 3H,
Cardiac Activity23) Isolated frog heart was mounted
4-CH3), 2.71—3.00 (m, 8H, 2Љ, 3Љ, 5Љ, 6Љ-CH2–), 0.79—1.24 using normal amphibian ringer solution. The effect of the
(m, 2H, 2Ј-CH2). IR (KBr) cmϪ1: 3292 (Ar N–H), 1436 compounds on the rate and force of contraction was observed
(C–H), 1324 (C–N), 1135 (C–O), 827, 781 (Ar-H). Anal. from 1 to 80 mg. The effect of the compounds at 40 mg con-
Calcd for C16H22N4O2: C, 63.55; H, 7.33; N, 18.53. Found: centration with simultaneous administration of adrenaline
C, 63.71; H, 7.04; N, 18.23.
2-(3Ј-Diethanolaminopropyloxy)-4,7-dimethy-1,8-naph-
(10, 20, 30 mg) was also studied (Table 2).
Antibacterial Activity (Paper Disc Diffusion Method)24)
thyridine (2h): Yieldϭ40.2%, mp 274—275 °C. 1H-NMR The antibacterial activity of the synthesized compounds was
(CDCl3) d: 7.43 (s, 1H, 3-H), 6.31—6.80 (d, 2H, 5, 6H), performed by paper disc diffusion method against gram (ϩ)
3.44—3.88 (m, 4H, 1Ј, 3Ј-CH2), 3.12—3.44 (s, 3H, 7-CH3), bacteria (Staphylococcus aureus, Bacillus subtilis, Entero-
2.53—2.97 (s, 2H, 2Љ-(OH)2), 2.30—2.53 (m, 8H, 1Љ, 2Љ-
Table 1. Anticonvulsant Activity of the Compounds
(CH2)2), 2.17—2.30 (s, 3H, 4-CH3), 0.94—1.28 (m, 2H, 2Ј-
CH2). IR (KBr) cmϪ1: 3366 (O–H), 1405 (C–H), 1390
Compound
Dose (mg/kg)
% Protection
(C–N), 1122 (C–O), 819, 784 (Ar-H). Anal. Calcd for
C17H25N3O3: C, 64.12; H, 7.89; N, 13.16. Found: C, 63.94;
H, 8.12; N, 12.88.
1a
1b
1c
1d
2b
2c
2d
2e
2f
125
250
125
250
125
250
125
250
125
250
125
250
125
250
125
250
125
250
125
250
125
250
125
250
125
250
5
10.21*
29.64***
41.20***
98.51***
24.09***
40.11***
48.17***
98.5***
17.7**
37.72***
22.42**
55.21***
9.82*
2-(3Ј-Piperidinopropyloxy)-4,7-dimethyl-1,8-naphthyri-
dine (2i): Yieldϭ25.6%, mp 286—287 °C. 1H-NMR (CDCl3)
d: 8.40 (s, 1H, 3-H), 7.24—7.54 (d, 2H, 5, 6H), 3.89—4.16
(m, 4H, 1Ј, 3Ј-CH2), 3.15—3.75 (s, 3H, 7-CH3), (m, 10H, 2Љ,
3Љ, 4Љ, 5Љ, 6Љ-CH2–), 1.67—1.92 (s, 3H, 4-CH3), 0.54–1.67
(m, 2H, 2Ј-CH2). IR (KBr) cmϪ1: 1382 (C–H), 1324 (C–N),
1118 (C–O), 882, 705, (Ar-H). Anal. Calcd for C18H25N3O:
C, 72.20; H, 8.41; N, 14.03. Found: C, 71.98; H, 8.69; N,
13.76.
2-(3Ј-Morpholinopropyloxy)-4,7-dimethyl-1,8-naphthyri-
dine (2j): Yieldϭ25.4%, mp 120—121 °C. 1H-NMR (CDCl3)
d: 8.35 (s, 1H, 3-H), 7.26—7.65 (d, 2H, 5, 6H), 3.19—3.90
(m, 4H, 1Ј, 3Ј-CH2), 2.77—3.03 (s, 3H, 7-CH3), 2.13—2.67
(m, 8H, 2Љ, 3Љ, 5Љ, 6Љ-CH2–), 1.66—1.89 (s, 3H, 4-CH3),
0.53—1.55 (m, 2H, 2Ј-CH2). IR (KBr) cmϪ1: 1381 (C–H),
1335 (C–N), 1119 (C–O), 886, 705 (Ar-H). Anal. Calcd for
C17H23N3O2: C, 67.95; H, 7.69; N, 13.94. Found: C, 68.24;
H, 7.91; N, 14.21.
25.91***
19.3**
36.3***
5.41
11.12*
2g
2h
2i
20.84**
41.18***
44.6***
98.5***
18.44**
39.26***
29.46**
48.15***
98.5***
2j
PHARMACOLOGY
Diazepam
pϽ0.05, pϽ0.01,
pϽ0.001 compared to control.
All the synthesized compounds were screened for anticon-

June 2002
801
Table 2. Cardiac Activity of the Compounds
Compound
Concentration
1 mg to 80 mg of 1a
40 mg of 1aϩ10 mg of adrenaline
40 mg of 1aϩ20 mg of adrenaline
40 mg of 1aϩ30 mg of adrenaline
1 mg to 80 mg of 1c
40 mg of 1cϩ10 mg of adrenaline
40 mg of 1cϩ20 mg of adrenaline
40 mg of 1cϩ30 mg of adrenaline
1 mg to 80 mg of 1d
40 mg of 1dϩ10 mg of adrenaline
40 mg of 1dϩ20 mg of adrenaline
40 mg of 1dϩ30 mg of adrenaline
10 mg
Effect on systole
1a
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
1c
1d
Normal
Normal
Normal
Adrenaline
Positive ionotropic
and chronotropic
Fig. 2. Depiction of Presence of Pharmacophore in 1c Similar to Sympa-
tholytic Drugs
the microorganism (matched to McFarland barium sulphate
standard) and poured into the petri dish to give a depth of
3—4 mm. The paper discs impregnated with the test com-
pounds (1 g/ml in water) were placed on the solidified
medium. The plates were refrigerated for two hours at 4 °C
and then incubated at 37 °C for 24 h at the end of which the
zone of inhibition was observed.
RESULTS AND DISCUSSION
The protection of the animals against maximal elec-
troshock induced convulsions of the synthesized compounds
were screened at the dose levels of 125 and 250 mg/kg. The
compounds were screened for cardiac activity using isolated
frog heart. The antibacterial activity of the synthesized com-
pounds was tested against gram (ϩ) bacteria (Staphylococcus
epidermidis, Bacillus subtilis, Enterococcus faecalis and Mi-
crococcus luteus) and gram (Ϫ) bacteria (Proteus vulgaris,
Pseudomonas aeruginosa, Escherichia coli and Salmonella
typhi) by paper disc diffusion method.
All the synthesized compounds exhibited significant anti-
convulsant activity except 2a. The active compounds exhib-
ited dose dependant anticonvulsant activity. The anticonvul-
sant activity of 1b, 1d and 2h at the dose of 250 mg/kg were
found to be equivalent to Diazepam (5 mg/kg). The anticon-
vulsant activity of the compounds with respect to 2Ј-hy-
droxy-7-amino-1,8-naphthridine series (1a—d) was found
to be in the order of diphenylaminoϭmorpholinoϾdi-
ethanolamino. The anticonvulsant activity of the compounds
with respect to 7-amino-1,8-naphthridine series (2a—g) was
found to be in the order of p-hydroxyanilinoϾmorpholinoϾ
diphenylaminoϾdiethanolamino. The anticonvulsant activity
Fig. 1. Synthetic Scheme
coccus faecalis and Micrococcus luteus) and gram (Ϫ) bacte-
ria (Proteus vulgaris, Pseudomonas aeruginosa, Escherichia
coli and Salmonella typhi). The sterilized (autoclaved at
120 °C for 30 min), liquefied nutrient agar (40—50 °C) was
inoculated (1 ml/100 ml of medium) with the suspension of

802
Vol. 25, No. 6
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C., Saccomanni G., Farmaco., 56, 311—318 (2001).
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of the compounds with respect to 7-methyl-1,8-naphthridine se-
ries (2h—j) was found to be in the order of diethanolaminoϾ
morpholino. It was also observed that 7-substitution in the
1,8-naphthyridine plays a significant role in the anticonvul-
sant activity (except 1b) since methyl substituted compounds
2i, 2j and 2h exhibited significantly higher protection than
the corresponding amino substituted compounds 2f, 2g and
2d, respectively.
Compounds 1a, 1c and 1d exhibited potential cardiac ac-
tivity. The cardiac activity exhibited by these compounds
may be correlated to the presence of the pharmacophore sim-
ilar to the chemical functionality present in b-adrenergic
blocking agents (Fig. 2). Compounds 1a, 1c and 1d did not
exhibit chronotropic or ionotropic activity when administered
alone but when concurrently administered with adrenaline,
the compounds exhibited significant sympatholytic action.
The compounds were completely able to block the effects of
adrenaline (10, 20, 30 mg). All the synthesized compounds
were devoid of antibacterial activity against the tested bacte-
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