A Series of Coumarin Derivatives with Central Stimulating ilctivitc
h series uf S-disubstituted aniinunietiiyl tierivativcs o f iiictltusy- :tiid I i ~ ~ l r ~ ~ s ~is~tlesc~rihetl. ~ ~ ~ ~ i ~Tiicsc ~ ~ : ~ r i ~ i s (*(impoundspossess central nervous system ytimulatury ucltivity b u t of ii lotvver degree than the corresponding c~hrornoneand flavone derivatives.
Joiigcbreur's observatioii' oii the pharmacological cquivalerice between coumariti aiid cliromone derivatives as coronary dilators? prompted us to verify whether t,he centrally st,irnulat,iiigactivity of a group of S-disubstituted 7-methoxy- aiid 7-hydroxy-8-aminoaiethylchromones and flavones" was retained in coumarin isomers. For this purpose we have synthesized a number of S-disubstituted amiiioinethyl derivatives of 7-metlioxy- and 7-liydroxycoumariiis, as well as 5-, 0-, aiid 8-methoxy- aiid hydroxycoumariiis in order to ascertain suitable positions of the osygeii function (methoxyl or hydroxyl groups) aiid of the basic chain for best central act,ivity. S-Disubstituted amiiiometliyl derivatives of metlioxycouinariris were prepared by chloromethylation' of the niethoxycoumariiis specified below. Sirice thc formation of two isomers was possible, the structure of the resulting products had to be proved expeiiineiitally. Chlorornethylation of 3-i~iethoxy-~-niet'hyl:3-pheuylcouniari1i gave a chlorine-free product, which analyzed for a methylenebis derivative but was not furt'her investigated. :3,4-Dimethyl-, 3-phenyl- arid . h i et~hyl-3-phenyl-6-methoxycoumarin furnished oiily the 7-chloromethyl derivatives. ?'heir structure was proved in the case of 3,4-dimetliy1-ti-metlioxycouniari1i l)y reductioii of its chlorometliyl derivative t,o ti-metlioxy-:j,4,i-trimethylco~iniariii identical with an aut'lietitlic sample prepared by the Kostaiiecki-ltobiiiSOII acylat'ion of 2-hydroxy-+metliy1-5-inethoxyacetopheuo~ie with propionic anhydride aiid sodium pi.0pioilate. :3,4-Dirnethyl-, 3-etliyl-l-niet,hyl-, alid -1nicthyl-3-pheiiyl-i-i~ietIi~jxycouniariii yielded a rnixt'urv of 6- and 8-chloromet~hplderivatives. The structure of ( w l i isoiiwr \vas established by comparitig its reduction derivative with the coixspoiiding 8- or 8-methylcoiimarin prepared by the E(ostanecki-€iobinson acylat'ioii of the met,hyl substitut,ed 2-hydroxy-4-methosyacetopheiione. h i the case of I-etliyl-i-methoxy-8plic~iylcoumari~i,oiily the 8-chlorometliyl derivative was ohtaiiied; its st~.iictui.ewas Iwogiiized through tliv prese~ictci n the infrared spectriuii of a strong hand a t 820 cni:--I attributable to tlie out of plaiie vihratioiis of' t,wo adjacent free Iiydrogeri atoms at C5 and ('6. 'I'liih inay t)c cwiifimied i i i the position of tliis Imid at 802 820 c ~ n~. - i i' i a gixmp of :~,4.7,8-tetrasubstitutedcoli. l , i l e > n . / ' l , ~ , ~ , ~ , , ~ , o d90, ~ , ~381 ~ , , (l(45L'j. from tiiis lahoratury o n tile actil-ity oi e t h y l 7 flavonusyncetate (Reroriiils) arid of vaiioiia etliyl :I,-l-~lisul,stitritcil i r,oiiiriariniisyacrtates voiifiriiieri tlie ahox e fincling. ,5etiil;:ir. I+'. llliisnianu, a n i l h i . .l. 3
,
.S, Setliria. . I . O,,,, ( ' / # e , , , , , 2 5 , 171:1 I ! l l i O ~ i l l ( t i 1 ) . ,le-.\ciil>e thr ,,liloroinetli\lhtiiIii r,i
nrl
j r
8-Methoxy-3-phenyl-5-piperidinomethylcoumarin.--'To:t s d u tion of 2.2 g. of 5-c.hlc~roriieth~l-S-inethosy-3-phen~lc~oumariri iri 50 nil. of ethanol, 1 g. of piperidine was added and the mixturc: refluxed for 5-6 hr. After evaporation of the solvent the residue was suspended in water, filtered, washed with water, and dried in uucz(o. On crystallization from ethanol 1.2 g. of white crystalline product, m.p. l70-171", was nbtained. Anal. Calcd. for C22H2aT03: S ,4.01. Found: S , 3.96. Tht! hydrochloride salt was a white solid which melted at, 208-210". A d . Calcd. for C22H24C1S03:C1, 9.19; N, 3.63. Foi~ntl: C1,9.05; N, 3 . i 5 .
8-Dimethylaminomethyl-3-ethyl-4-methyl-7-hydroxycoumarin Hydrochloride (I).-To a solution of 4 g. of 3-ethyl-7-hydroxy-4niethylcoumnrin iri 150 nil. of absolute ethanol, 2.25 nil. OF dirnethylainine and 2 nil. uf 407' aqueous formaldehyde were
Ilarch, 1964
M.p., 0C.b
165
CENTRALLY STIMULATING COUMARINS
Hydrochloride salts ---% chlorineCalcd. Found
.
L1l
--%
nitrogenCalcd. Found
RLp., 0C.b
"yylu
--'% nitrogeoCalcd. Found
129-131 138-140 78-80 108-110 94-96 162-164 153-155 127-129 104-106 173-175
4.64 4.62 4.85 4.43 4.41 4.43 4.41 5.36 4.85 4.63
4.72 4.50 4.97 4.52 4.15 4.37 4.41 5.15 4.98 4.50
3.53 3.30 3.41 3.84 3.53 3.39 3.75 3.48 3.68 3.50 4.97 4.18
86-88 103-105 160-161 171-172 141-142 218-220 211-212 131-133 158-160 129-132 181-183 170-171 121-1 22 144-146 138-140 118-119 159-161
5.07 3.99 3.99 3.83 4.15 3.71 3.68 3.83 4.53 4.15 3.99 4.01 3.99 3.83 3.85 5.67 4.84
5.15 3.85 4.06 3.89 4.14 3.72 3.72 3.61 4.30 3.99 3.82 3.96 3.84 3.94 4.04 5.61 4.82
4.32 4.49 3.61 3.63 3.74 4.05 4.12
4.32 4.55 3.42 3.68 3.58 4.17 3.94
134-136 105-106 185-187 153-155 115-117 164-166 171-1 73
4.88 5.09 3.99 4.01 4.15 4.53 4.62
4.68 4.01 4.13 3.97 4.61 4.56
10.97
4.30
4.24
105-107
4.85
5.08
10.29 9.78 11.74
4.14 3.89 4.70
3.95 3.84 4.63
131-1 35 142-144 124-125
4 64 4.33 5.36
4.12 4.27 5.46
245 (dec.) 260 idec.) 215-218 228-230 230-232 236-238 163-165 230-232 206-209 222-224 204-206 330-332 140-142 194-196
10.49 10.43 10.88 10.08 10.02 10.08 10.02 11.91 10.88 10.49 10.43 11.37 9.14 9.14
10.72 10.46 10.65 10.09 9.84 10.33 9.81 11.91 10.77 10.71 10.64 11.43 8.85 9.10
4.14 4.12 4.30 3.98 3.96 3.98 3.96 4.70 4.30 4.14 4.14 4.49 3.61 3.61
4.30 4.24 4.43 3.80 3.71 3.93 3.94 4.72 4.32 4.35 4.15 4.44 3.48 3.77
215-216 228-230 205-207 257-258 215-216 257-258 208-210 244-245 238-239 275-276 247-248 255-259
8.56 8.53 8.82 10.25 9.48 9.14 9.19 9.14 8.82 8.86 12.50 10.88
8.63 8.42 8.79 9.99 9.50 9.41 9.05 8.96 8.67 8.82 12.46 10.77
3.38 3.37 3.49 4.05 3.74 3.61 3.63 3.61 3.48 3.50 4.94 4.30
10.95 11.37 9.14 9.19 9.48 10.25 10.43
10.93 11.27 9.07 8.89 9.49 10.00 10.23
10.88 10.49 9.85 11.91
dec.
259-260 258-260 228-231 243-246 195-198 248-250 245-238
5.08
dec.
222-227 dec.
240-241 250-253 244-245 for the free bases.
added. The mixture was heated under reflux for 8 hr. and then evaporated. The residue was taken up in alcoholic hydrochloric acid and the resulting solution was evaporated to dryness. On crystallization of the crude product from ethanol-ether 2.8g. of white solid, m.p. 196-198', was obtained. Anal. Calcd. for ClEH2oClNO3: C1, 11.91;N, 4.70. Found: C1, 11.83;K,4.58. 3-Ethyl-8-formyl-7-hydroxy-4-methyIcoumarin(III).-To a solution of 3.1g. of 3-ethyl-7-hydroxy-4-methylcoumarin in 30 ml. of acetic acid 6.2g. of hexamine was added and the mixture stirred at 100"for 6hr. The solution was treated with 40 ml. of hot lOy0 zqueous hydrochloric acid, stirred for 15 min., and allowed to stand overnight. The separated solid was collected and washed with water. After drying in vucuo 0.5 g. of white crystalline product, m.p. 150-152', was obtained.
Anal. Calcd. for C13H1z04: C, 67.23; H, 5.21. Found: C, 67.10;H, 5.30. 7,8-Dihydroxy-3-ethyI-4-methyleoumarin (IV).-A solution of 1.1 g. of 3-ethyl-8-formy1-7-hydroxy-4-methylcoumarin (111) in 40 ml. of 10% sodium hydroxide waa added dropwise t o 10 ml. of 5% hydrogen peroxide. The mixture, after stirring for 1 hr., became dark and a solid separated. Acidification with dilute hydrochloride acid completed the precipitation of the product which was filtered, washed with water, and dried. On crystallization from ethanol a white crystalline solid, m.p. 222-224", was obtained. Anal. Calcd. for ClZH1204:C, 65.45;H, 5.50. Found: C, 65.41;H, 5.58. -4mixture melting point of this product with an authentic sample of 7,8-dihydroxy-3-ethyl-4-methylcoumarin prepared according to Chakravarti' wm not depressed.
