Journal of Medicinal Chcmislry, 2.9'70,Vol. 12, S o . 6 colorless crystals, mp 215-216". Anal. (C111112ClNe)C, 11, N. .4 mixt,ure of the 2-amino-4-phenethylaminu-6-chlorrrs-triaaine (3.7 g, 0.015 mole) and 2-piperazinone17 (3.0 g, 0.03 mole) in HYO (160 ml) was stirred under reflux for 2 hr. After cooling, the precipitat,e was collected by filtration, washed with H a , and recrystd from I>RIF-H?O to give 83 as white crystals: nmr (in CFsCOOH) 7 1.39 (b s, 2 H, HNCO), 2.66 (b s, 7 H, C&, KH,), 5.25 (a, 2 H, CHzCO), 5.81-6.72 (m, 6 H), and 6.98 (t, 2 H, CsHsCHz ). 2-Amino-4-phenethylamino-6-pyrrolidino-s-triazine Maleate (81).-To a suspension of 2-amino-4-phenethylamino-6-chloros-triazine (6.2 g, 0.025 mole) in H2O (120 ml) was added dropwise pyrrolidirie (3.6 g, 0.05 mole) with stirring below 5'. The mixture was refluxed for 2 hr, cooled to room temperature, and extracted wit.h CHC1,. The extract was concent,rated in vacuo leaving a syrup. The maleate was prepared by adding maleic acid (2.0 g, 0.017 mole) in MeOH (10 ml) to the syrup (7.0 g). A solid was obtained, which was recrystd from AIeCN to give 81 as colorless needles. Method B. 2-n-Butyl-4,6-bis(cyclohexylamino)-s-triazine (16).-Cyclohexylamine (8.0 g, 0.08 mole) was added to a soln of 2-n-but.yl-4,6-dichloro-s-triazirie (4.2 g, 0.02 mole) in H?O (100 ml) under cooling with ice-water. The mixture was refluxed for 2 hr and t,hen cooled to room temperature. The precipitate was collected and recrystd from hexane to give 16 as white crystals. 2-Methyl-4,6-bis( phenethy1amino)-s-triazine (60).-A soln of phenethylamirie (4.8 g, 0.04 mole) in CHC13 (20 ml) was added to a soln of 2-methyl-4,6-dichloro-s-triazine (3.2 g, 0.02 mole) in CHCl, (80 ml) and then a s o h of K2C03 (8.2 g, 0.06 mole) in HZO (10 ml) was added. The soln was stirred at room temp for 2 hr. The reaction mixture was washed (HzO), dried (Xa2SOa), and concentrated in vacuo to give an oily residue which was recrystd from EtOH to give 60 as white crystals. Method C. 2-Chloro-4,6-bis(3-oxopiperazin-l-yl)-s-triazine (93).--A s o h of 2-piperaainoiie (4.0 g, 0.04 mole) in HzO (40 ml) was added to a suspension of 2,4,6-trichloro-s-triazine(I, 3.7 g, 0.02 mole) and Na2C03(4.2 g, 0.04 mole) in CHC1, (50 ml) with
1089
stirring a t 50" for 1 hr. After cooliug, the precipitates were collected, washed with hot Me2C0, and then recrystd from DblF with activated charcoal to give 93 as white granules. 2-Piperidino-4,6-bis( ethoxycarbonylmethylamino)-s-triazine (156).-To a soln of NaHC03 (8.4 g, 0.1 mole) in H20 (240 ml) was added a s o h of 2,4,6-trichlorus-triazine (I, 18.4 g, 0.1 mole) in Me&O (160 ml) at. 0" and then a s o h of ethyl glycinate.HC1 (13.9 g, 0.1 mole) and NaHC03 (8.4 g, 0.1 mole) in HZO (100 ml). The mixture was stirred a t 45' for 2 hr. The precipitate was collected and recrystd from EtOH to give 90. To a s o h of 90 (12.6 g, 0.04 mole) in CHCl3 (3.50 ml) was added a soln of piperidine ( 3 4 g, 0.04 mole) in CHCl, (40 ml) and a soln of K2CO3 (5.6 g, 0.04 mole) in H2O (40 ml). The mixture was stirred at room temp for 2 hr. The CHC1, layer was sepd, dried (Sa?SOa),and coned in vacuo. The residue was recrystd from i-PrOH to give 156. Method D. 2-Amino-4-phenethylamino-6-n-butyl-s-triazine (67).-Phenethylbiguanide.HCl (24.2 g, 0.1 mole) was added to a NaOJle sohi prepared from Ka (2.3 g) and AIeOH (80 ml) and the ppt,d NaCl was filtered off. Ethyl valerate (17.0 g, 0.1 mole) was added to the filtrate at -40". The reaction mixture was diluted with HzO (800 ml) and kept in an ice box overnight. The ppt was collected by filtration and recrystd from i-PrOH to give 67 as colorless crystals. Other Method. 2-Methyl-4-pyrrolidino-6-n-butylamino-striazine (%).-A mixture of 94 (6.4 g, 0.036 mole) wit8h n-BuBr (4.9 g, 0.036 mole) was heated in a sealed tube at 190-200' for 2 hr. After cooling, the reaction mixture was dissolved in H 2 0 (50 ml) and then filtered. The filtrat'e was treated wit,h satd XaHC08 solti to yield a ppt. This was recrystd from i-PrOH€I20to give 98 as white needles.
Acknowledgments.-The authors \\ish to thank Dr. S. Ogihara, President of Kyorin Pharmaceutical Co., Ltd., for his deep interest and continuous encouragement. We are grateful to Rlr. A. Saito, A h . S . Watanab?, and Mr. T. Umezawa for their expert technical assistance.
( l i ) S.R. Aspinall, J . B m e r . Chem. Soo., 62, 1202 (1940).
Synthesis and Pharmacological Evaluation of a,a-Disubstituted Naphthylacetaldehydes GIANFRANCO PALA, * ARTURODONETTI, -ANTONIO A I A N T E G A N I , ELDAC R E S C E N Z I , BRUNO L U J I A C H I , AND GERJIANO COPPI Research Laboratories of Istituto De Anguli, 20139 Xilan, Italy Received J u n e 1 , 1970 Thirty-eight a,a-disubstituted naphthylacetaldehydes were prepared for extensive pharmacological screenitig. Some of the compounds displayed marked antipyretic, analgetic, and antiinflammatory activity. None of the other actions investigated revealed anything of particular interest.
As part of our program in the field of naphthalene compounds, we have prepared for pharmacological screening 38 naphthylacetaldehydes of the general structures I and 11, in which R was an alkyl or aminoalkyl group and S A A was a tertiary amino group. CHO
able amounts of the related naphthylalkylamines,' which were removed from the reaction mixture by fract,ional precipit'ation before dist'illing. Reducing agent and reaction coridit'ions were dependent on tmhesteric hindrance of t'he nitriles. When the amines were not separated, subsequent distillation gave low yields of the aldehydes, due t'o formation of hhe related Schiff bases. I n one case (24), the Schiff base (111)was isolated arid CWCHJz
I
I: substituted a t position 1 11: substituted a t position 2
Reduction of the appropriate nitriles with LAH or lithium mono- and diethoxyaluminohydrides afforded the desired naphthylacetaldehydes together with vari* To whom correspondence should be addressed.
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(1) G . Pala, A . Donetti, C. Turba, and S.Casadio. J . .]fed. Chem.. 13. 668 (1970).
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Diuretic act (rat) test void control vol
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a The results are expressed in arbitrary uiiit,s (higher the value, higher the effect,). * Carrageeiiin-iiiduced edema. c The compounds were tested orally a t 100 mg/kg, t'he standard phenylbutazone at 50 mg/kg. d The compounds were tested orally at 100 mg/kg, the standard dihydrochlorothiazide a t 10 mgikg. e The compounds were tested orally at 100 Ing/kg, the st,andard chlorpropamide a t 50 mg/kg.
basified with 10()6 NaOH. The product which separated at, pH S-8.5 was extracted (Et,zO)and worked up as described in met,hod A t o give 30.7 g of 5 as a colorless oil, bp 150-152' (0.15 mm). 1-Dimethylamino-3-aminomethyl-3- (a-naphthyl)-4-methylhexane1 (7.1 g) precipitated at pH 11. Method C. 2-(a-Naphthyl)-2-(2-morpholinoethyl)pentanal (29).-Et'OH (15.4 g, 0.334 mole) was dropped a t 5' for 20 min into a stirred suspension of LAH (6.36 g, 0.167 mole) in EtpO (500 ml). Bfter an additional 30-min stirring, a solution of apropyl-a-( 2-morpholinoethyl)-l-naphthylacet~onitrile (45 g, 0.139 mole) in Et20 (200 ml) was added to t,he mixture during 1 hr. The mixture was then refluxed fur 3 hr with stirring, cooled, aiid caut,ioudy decomposed wit,li 5 ,V €IC1 (270 nil). After 15 hr
stirring at room temperature, the aq layer wab heparatNedaiid basified with 10% NaOH. The product which separated at pH 3.1-6.5 was extracted (Et20) and worked up as described in method A to give 25.9 g of 29 as a colorless oil, bp 179-180" (0.1 mm). N - [3-Aminomethyl-3-( a-naphthyl)hexyl] morpholinel (2.4 g ) precipitated at p H 11.
Results and Discussion Thc most interesting results of the pharmacological screening are giveii in Table 11. Test procedures and
