synthesis and anticonvulsant activity of substituted tetrahydropyran amides and amines

.

8. 9.

i0. ii. 12. 13.

N. Z. Tugusheva, L. V. Ershov, V. G. Granik, et al., Khim.-farm. Zh., No. I0, 830-835 (1986). J. Buggy and O. D. Fink, Hypertension Research, New York (1982), pp. 355-356. R. D. Bunag and J. Buttenfield, Hypertension, ~, 875-879 (1982). C. H. Cashin, W Dawgon, E. A. Kitchen, et al., Pharmacology, 29, 330-335 (1977). F. E. D'Amour and D. L. Smith, J. Pharmacol. Exp. Ther., 72, 74-80 (1941). J. Litchfield and F. Wilcoxon, J. Pharmacol. Exp. Ther., 96, 99-113 (1949). G. Woolfe and A. McDonald, J. Pharmacol. Exp. Ther., 80, 300-315 (1944).

SYNTHESIS AND ANTICONVULSANT ACTIVITY OF SUBSTITUTED TETRAHYDROPYRAN AMIDES

AND AMINES

N. S. Arutyunyan, L. A. Akopyan, R. G. Paronikyan, and N. E. Akopyan

UDC 615.213.012.1

In continuation of studies on 4-substituted tetrahydropyrans, it was of interest to ob- tain substituted amides and amines in the series and to examine their biological activity, since some aminoalcohols of this type display biological activity [2].

Reaction of 2,2-dialkyl-4-benzyl(or phenyl)-substituted tetrahydropyran-4-ylacetic acids (I-III) [i] with thionyl chloride affords the acid chlorides (IV-VI). The latter were used in subsequent reactions without further purification, since they decompose on distillation. On reaction with amines and ammonia, they gave the amides (VII-XV). Reduction of these, and of the nitriles (XXVII-XXIX) [I] with lithium aluminohydride (LAH) gave the amines (XVIII-XXIII) and (XXIV-XXVI) respectively. Hoffman decarbonylation of the amides by treatment with sodium hypobromite in alkaline solution gave the amines (XVI, XVII), containing one carbon atom less than the starting amides.

~ Rt

"-... R, IX(~ 7 o2X t•

R ~ g . ~ -~ .,z2~"-.,2cz22" ,,2~'-,12~7

R=CH3 (I, II, IV, V, VII, VIII, X--XIII, XVI--XXI, XXIV, XXV, XXVlI, XXVIII); EL (Ill, VI, IX, XlV, XV, XXlI. XXIII, XXVI, XXIX); Rh=Ph (I, Ilk IV, Vl, VII, IX--XlI, XlV--XVI, XVIII, XX--XXIV, XXVI, XXVlI, XXIX}; CH~Ph (II, V, VIII, XIII, XVlI. XIX_ XXV, XXVlII); R2=NH2 (VII--IX, XXIV-- XXVI); N-pyrrolidyl(Xll , X VIII); N-piperidyl(Xl, XIII, XlV, XIX, XX, XXII); N-morphylyl (k, XXI, XXIII).

The structures of the products were proved by their PMR, IR, and mass spectra.

EXPERIMENTAL (CHEMISTRY)

IR spectra were obtained on a UR-20 (East Germany) in Vaseline grease, and mass spectra on an MX-1320. PMR spectra were obtained on a Varian T-60 (USA) with TMS as internal standard. TLC was carried on Silufol UV-254 plates (Czech SSR), developer iodine vapor. The elemental analyses were in agreement with the calculated values.

2~2-Dialkyl-4-benzy](or phenyl)tetrahydropyran-4-ylcarbony1 Chlorides (IV-VI). To a mixture of 0.12 mole of one of the acids (I-III) [i] and 0.15 mole of formamide in i00 ml of dry benzene was added dropwise with stirring 0.15 mole of thionyl chloride. The mixture was then

A. L. Mndzhoyan Institute of Fine Organic Chemistry, Academy of Sciences of the Armenian SSR, Erevan. Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 24, No. 5, pp. 29-31, May, 1990. Original article submitted July 18, 1989.

0091-159X/90/2405-0349512.50 �9 1991 Plenum Publishing Corporation 349

TABLE i. 2,2-Dialkyl-4-benzyl(or phenyl)tetrahydropyran-4-ylacetamides (VII-XV) and 4-Aminomethyl(or 4-8-aminoethyl)-2,2-dialkyl-4-benzyl(or phenyl)tetrahydropyrans (XVI, XXVI)

Compound drochloride) ~ .., (hydrochlorJde) I ride (oxalate),~

VII 54 0,61 (45) CIsH2~NO2 -- VII I 64,5 0,64 200/3 CI6H2aNO2 -- IX 83 0,51 (I 15) C,6H2aNO~ -- X 84 0,59 (79) C,gH27NOa --

XI 74 0,57 (148) C2oH29NO2 -- XII 75 0,62 198/3 C,gH~TNO2 --

X111 55 0,75 205--207/2 C21Hal NO~ XIV 74 0,60 198--200/2 C2,HalNO2 -- XV 63 0,64 206/2 C~oH~NOa --

XVI 82 (0,68) 117/2 C,4H2,NO 247 XVII 64 (0,62) 195 (CIsH24NOCI) 195

XVIll 70 (0.66) 157--160/2 ClgH29NO 192 XIX 53 (0,70) 187-- 189/3 C2I HasNO 182 XX 60 (0.50) 165-- 167/2 C2oH3~ NO 171

XXI 62 (0,68) 171/2 C ~gH29NO2 223 XXII 67 (0,60J 169/2 C~IHaaNO 180

XX1 I1 65 (0,72) 159/2 C2oHal NOt 203 XX1V 83 0,58 136/1 C~sH~aNO 215 XXV 74 0.63 151/2 Ct6H~sNO (163)

XXVI 81 0,67 143/1 Cj6H2sNO (168)

*Eluents: (VII), (VIII) hexane-acetone (i:i); (IX), (Xll), (XIII), (XV) hexane-acetone (1:2); (X), (XI), (XIV) acetone-hexane-ethanol (4:6:1); (XVI-XIX), (XXII-XVI) ethanol-DMF-acetone (1:2:2); (XX) acetone-hexane-ethanol (1:1:2); (XXI) acetone- DMF-ethanol (2:2:1); nD 2~ - XVI: 1.5410; XXIV; 1.5400; XXV: 1.5370; XXVI:I.5350.

heated for one hour at 60~ cooled, the solution decanted from the solid, and the viscous mass remaining after removal of the benzene and excess formamide (yield of crude product 80- 90%) used without prior purification in the following reactions.

2~2-Diglkyl-4-benzyl(or phenyl)tetrahydropyan-4-ylacetamides (VII-IX). A. In a flask were placed 0.i mole of one of the acid chlorides (IV-VI) and 150-200 ml of 25% aqueous ammonia, the flask stoppered securely, and kept for two days at room temperature. Following removal of excess ammonia and water, the residual viscous mass was distilled in vacuo, or dis- solved in alcohol and crystallized from water, the crystals filtered off, washed with water, and dried in a vacuum desiccator over phosphorus pentoxide. The constants are given in Ta- ble i.

B. Amides (X-X-V). To 200 ml of an ether solution of the secondary amine was added slowly an ether solution of 0.i mole of the acid chloride (IV-VI). On the following day, the precip- itated secondary amine hydrochloride was filtered off, washed wih ether, and the ether removed to give a viscous mass which was distilled in vacuo. The constants are given in Table I.

IR spectrum: Vmax, cm-1: VII-IX, 1590, 1610 (Ph), 1650 (CO), 3200, 3300 (NH2); X-XW, 1590, 1610 (Ph), 1640 (CO). PMR spectra, 6, ppm: (VIII) (CDCI3), 0.6 s and 1.2 s (3H each, 2-(CH3)2) , 1.5-2.7 m (6H, 3.5-CH2, CH2CO), 3.6-3.9 m (2H, 6-CH2), 4.6 and 5.45 hr. s (2H, NH2), 7.4 s (5H, Ph); (VIII) (CC14) , 1.20 s [6H, 2-(CH~)=], 1.33-2.5 m (4H, 3.5-CH2), 2.5-3.0 m (2H, CH=CO), 3.43-3.83 br.s (2H, CH2Ph), 3.93-4.3 m (2H, 6-CH2), 4.70 s and 4.9 br. s (2H, NH2), 7.17 s (5H, Ph); (IX) (CDCI3): 0.6 t [3H, CH3(Et)] , 1.15 s (3H, 2-CH~), 0.8-2.8 m [8H, 3.5-CH 2, CH 2 (Et), CH2CO], 3.6-3.9 m (2H, 6-CH=), 4.5 s and 5.8 s (2H, NH=), 7.4 s (5H, Ph); (X) (CCI~): 0.6 s and i.i s [3H each, 2-(CH~)2] , 1.6-2.25 m (4H, 3.5-CH2), 2.27-2.6 m (CH=NCH=), 2.6-3.0 m (2H, Ch2CO), 3.1-3.33 m (4H, CH2OCH2), 3.5-3.77 m (2H, 6-CH2), 7.23 s (5H, Ph); (XI) (CDCI3): 0.57 s and 1.07 s [3H each, 2-(CH3)2], 1.2-2.6 m [14H, C-(CH=)v-C], 2.6-3.17 m (2H, CH=CO), 3.4-3.73 m (2H, 6-CH2), 6.87-7.33 m (5H, Ph). Mass spectrum of (VII), m/z (rel. int., %): M + (247(48), 233 (49), 191 (48), 190 (16), 189 (144), 180 (41), 174 (45), 173 (i00), 171 (17), 170 (15), 146 (16), 145 (48), 131 (I00), 130 (48), 117 (24), 115 (34), 103 (48), 98 (84), 91 (72)" Ell: M + 301 (63), 245 (ii), 216 (15), 175 (21), 173 (47), 152 (14), 131 (45), 129 (12), 115 (13), 114 (36), 113 ( i 0 0 ) , 103 (15), 97 (19) , 91 (19), 85 (13), 70 (13), 55.

2~2-Dimethyl-4-benzyl(or phenyl)-4-aminomethyltetrahydropyran (XVI, X-VII). To a solution of 12 g (0.3 mole) of sodium hydroxide in 120 ml of water was added dropwise with stirring at -5~ 4.3 g (0.027 mole) of bromine, and the mixture kept for 30 min at this temperature. To the resulting solution was added rapidly with stirring at -3 to -5~ 0.033 mole of the amide (VII) or (VIII). Cooling was withdrawn, the mixture kept for one hour, and the temperature

350

TABLE 2.

Com- pound

Comparative Anticonvulsant Activity of Tetrahydropyrans

IAntagonism to max- [Prevention ~ Prevention of nicotine T ~ imum electric shock, ~arecoline !convulsions, ED 5 o, Acute daily or ED50 , mg/kg [mg/kg|nrem~ ~.u50,[m~/k ~I b ~ toxicity, LD50 l~ineMES ~alco- lacreco-

XVII 56 (40,6--77,9) Inactive Inactive 240 (205--280) 4,28 -- -- XIX 50 (41,3--60.5) Inactive Inactive 140 (129,6--151,2) 2,8 -- -- XX 79 (75,2--82,95) 62 {40--96) 62 (56,3--68,2) 250 (188--332.5) 3,17 4,03 4,03

XXI 110 (93--128,7) I n a c t i v e 35 (15.2--80.5) 340 (313,4--368,9) 3,09 9,71 -- XXII 62 (50,9--75,6) Inactive 53 (43,4--64,66) 210 (I80--245,7) 3,39 3,96 --

XXII1 I n a c t i v e ~ I n a c t i v e 48 (35,8--64.3) 190 (172,8--209) - - 3,96 - - Pufemid 77 (52,7--I12,3) I n a c t i v e 190 (146--251) 2150 (1930--2390) 27,9 II,3 2

N o t e : R a n g e o f v a r i a t i o n g i v e n i n b r a c k e t s a t P 0 . 0 5 . TI = L D s 0 / E D 5 0 .

then raised to 80~ and maintained at this value for 45 min. After cooling, the mixture was extracted with chloroform, dried over potassium carbonate, and the solvent removed. The residual amine (XVI) or (X-VII) was distilled in vacuo. Their constants are given in Table I.

IR spectrum, ~max, cm-l: XVI, XVII, 1580, 1590 (Ph), 3300, 3380 (NHa). PMR spectrum, 5, ppm: (XVI) (hydrochloride, CC14): 0.63 s and 1.2 s [3H each, 2-(CH3)2] , 1.33-2.86 m (6H, 3.5-CH2, CHgN) , 3.66-3.9 m (2H, 6-CH2) , 7.33 s (5H, Ph), 7.6-8.0 br. s (2H, NH2); (XVII) (hydrochloride, CC14): 1.3 s [6H, 2-(CH3)2], 1.46-1.8 m (4H, 3.5-CH2), 2.9-3.2 m (4H, CHgPh , CHaN), 3.6-3.9 m (2H, 6-CH2), 7.3 s (5H, Ph), 8.8 br. s (2H, NH2). Mass spectrum, m/z (rel. int., %): XVI: M + 219 (26), 188 (68), 175 (20), 173 (25), 157 (22), 145 (98), 131 (i00), 103 (61), 91 (57), 77 (19)

2~2-Dialkyl-4-benzyl(or phenyl)-4-~-heterylethyltetrahydropyran (XVIII-XXIII). To a solution of 4 g (0.i mole) of LAH in i00 ml of dry ether was added dropwise with stirring 0.058 mole of one of the amides (X-XV) in i00 ml of THF, the rate of addition being such that the mixture boiled. It was then boiled for 20 h, cooled to -10~ in an ice-salt bath, and treated successively with 4 ml of water, 4 ml of 15% sodium hydroxide solution, and 12 ml of water. The solution was decanted from the solid, the solvent removed, and the residue distilled in vacuo. The constants are given in Table i.

!R spectrum, Vmax, cm-l: XVIII-XXIII: 1590, 1610 (Ph). PMR spectrum, 6, ppm: (XVIII) (CDCI3): 0.6 s and 1.15 s [3H each, 2-(CH3)n] , 1.5-2.9 m [16H, (C-CH:-C)8], 3.6-3.9 m (2H, 6-CH2), 7.35 s (5H, Ph); (XXI) (CCI,): 0.56 s and I.i s [3H each, 2-(CH2)2], 1.33-1.86 m (6H, tetrahydropyranyl-4-CH2, 3.5-CHa), 1.86-2.5 m (6H, CH2NCH2) 2, 3.3-3.83 m (6H, 6-CH 2, CH2OCHa), 7.26 s (5H, Ph); (XXII) (CC14): 0.47-0.8 t [3H, J = 7 Hz, CH3(Et)], 1.0 s (3H, 2-CH3), i.i- 1.83 m [14H, 3.5 CH2, CH2(Et), tetrahydropyranyl-4-CH2, piperidyl N-($,~,7-CH2)], 1.83-2.33 m (6H, CH2NCH2)2, 3.33-3.8 m (2H, 6-CH2), 7.26 s (SH, Ph); (XXIII) (CCI~): 0.6 t [3H, CH3(Et)] 1.18 s (3H, 2-CH3), 0.65-2.40 m [14H, 3.5-CH2, CH2CH2NCH2)2, CH2(Et)],3.4-3.87 m (6H, 6-CH 2, CH2OCH2), 7.33 s (SH, Ph). Mass spectrum, m/z (rel. int., %): XXII: M + 315 (28), 286 (20), 246 (15), 245 (81), 217 (16), 216 (29), 131 (27), 112 (21), 103 (13), 98 (i00), 91 (21), 87 (63), 55 (30), 38 (45).

2,2-Dialkyl-4-benzyl(or phenyl)-4-~-aminoethyltetrahydropyran (XXIV-XXVI). A. To a solution of 4 g (0.i mole) of LAH in i00 ml of dry ether cooled in an ice-salt bath was added dropwise a solution of 0.05 mole of the appropriate nitrile (XXVII-XXIX) [i] in i00 ml of dry ether, the temperature of the mixture being kept at 0 i 2~ Stirring was continued for one hour, and the mixture worked up as in the preceding preparation.

B. As in the preparation of amines (XVIII-XXIII), from 4 g (0.i mole) of LAH in I00 ml of dry ether and 0.04 mole of the appropriate amide (XV-IX) in 50-60 ml of THF and boiling for 20 h there were obtained 50-60% of the amines (XXIV-XXVI). The amines obtained by the two methods were identical by GLC and IR, PMR, and mass spectroscopy. Their constants are given in Table 1.

IR spectrum, Vmax, cm-i: XXIV, XXV, 1590, 1610 (Ph), 3300, 3380 (NH2). PMR spectrum, 6, ppm; (XXIV) (CCI~): 0.7 s and 1.2 s [3H each, 2-(CH3)2] , 0.93 s (2H, NH2), 1.4-2.65 m (8H, 3.5-CH 2, CH2CH~N), 3.65-3.85 m (2H, 6-CH2), 7.3 s (5H, Ph); (XXV) (CC14): 0.7 s [6H, 2-(CH3)2], 1.3-2.0 m (8H, 3.5-CH 2, 4-CH 2, NH2), 2.47-2.83 m (4H, CH2Ph, CHIN), 3.47-3.73 m (2H, 6-CH~), 7.13 s (5H, Ph). Mass spectrum, m/z (rel. int., %): XXVI: M + 247 (39), 235 (15.6), 220 (14), 205 (45) 204 (36), 190 (15), 178 (28), 163 (61), 149 (23), 122 (45), 107 (I00), 82 (12), 43 (2i) .

351

EXPERIMENTAL (PHARMACOLOGY)

Thirteen compounds (VII, IX, X, XI, XIV, and XVI-XXIII) were tested in white mice weigh- ing 18-25 g for anticonvulsant activity. The compounds were administered intraperitoneally 30 min before administration of the convulsants or the application of electrical stimuli. The reference drug was the antiepileptic pufemid (para-isopropoxyphenylsuccinimide) [4].

Anticonvulsant activity was assessed in model convulsant states induced by administration of corazole, arecoline, nicotine, strychnine, or an electric current. Acute toxicities were determined in mice. The methods of study of the anticonvulsant and toxic effects, and the statistical treatment of the results and determination of the 50% effective and 50% toxic doses have been described previously [3].

Most of the test compounds were 20-40% effective at a dose of 100-200 mg/kg in preventing corazole clonic convulsions. The most interesting compound in this test was (XIII), which protected 50% of the animals from convulsions in a dose of 90 (37.5-216) mg/kg, the 50% toxic dose being 420 (350-504) mg/kg.

Table 2 shows results for the anticonvulsant activity of the compounds with respect to electrical convulsions, nicotine convulsions, and arecoline tremor. The compound most active against electric shock was (XIX) [EDs0 50 (1.3-60.5) mg/kg], and against nicotine clonic convulsions (XXI) [EDs0 35 (15.2-80.5) mg/kg], this compound also having a high therapeutic index (TI 9.71) as compared with the other test compounds.

As will be seen from Table 2, the most interesting compound in respect to its anticonvulsant spectrum was (XX), which prevented the tonic phase of maximum electric shock and had cen- tral m- and n-cholinolytic effects, i.e., it prevents nicotine tonic-clonic convulsions and arecoline tremor.

Examination of these 2,2,4-substituted 4-tetrahydropyranylacetamides and amines has shown that the most active compounds (irrespective of the alkyl substituents, dimethyl or methylethyl in the 2-position of the tetrahydropyran ring) are those in which the 4-position of the tetrahydropyran ring is occupied by the N-8-piperidylethyl- and N-B-morpholinoethyl groups (XIX-XXIII).

However, the N-piperidyl- and N-morpholylacetyl compounds (X, XI, XIV) and the acetamides (VII-IX) show very weak anticonvulsant activity, or are totally inactive.

In the maximum electric shock test, none of the compounds were superior to pufemid, but they were several times as active in preventing nicotine convulsions. All the test compounds, were, however, many times more toxic than pufemid.

The compounds were inactive against strychnine convulsions.

These 4-benzyl(and phenyl)-substituted tetrahydropyrans thus show anticonvulsant and cen- tral cholinolytic activity, the levels of which are dependent on the type of substituent pres- ent in the 4-position.

i.

2.

3.

LITERATURE CITED

N. S. Arutyunyan, K. M. Garibyan, L. A. Akopyan, et al., Arm. Khim. Zh., 29, No. 7, 438- 444 (1986). N. S. Arutyunyan, L. A. Akopyan, N. A. Apoyan, et al., Arm. Khim. Zh., 23, No. 2, 182-184 (1989). K. A. Gevorkyan, G. L. Papayan, S. G. Chshmarityan, R. G. Paronikyan, et al., Khim-Farm. Zh., 22, No. 2, 167-170 (1987).

352

synthesis and anticonvulsant activity of substituted tetrahydropyran amides and amines

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