Anticonvulsants. 4. Metharbital and phenobarbital ... - ACS Publications

Jul 9, 1973 - Julius A. Vida,* Mary L. Hooker, Carlos M. Samour. Kendall ... 0. 3, R = CH3. 4, R = C4H9. The synthesis of the 1,3-dialkyl derivatives ...
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1378 Journal ofMedicinal Chemistr?. 1973, Vol. 16, N o . 12

bromide was obtained in 85% yield from hexyl bromide and :l.HCI (1.5 hr. 80"). m p 179-181". A n a ( . (C20H32BrNO2) C. H. N. Br. I-Heptyl-4-m-hydroxyphenyl-4-propionylpiperidine( I O ) Hydrobromide. This was obtained in 78% yield as described for 9 using heptyl bromide: plates, m p 147--149". from Me2CO. .4nci/. (CZ1H34BrN02) C. H , N. Br. 1 -Allyl-~-rn-hydroxyphenyl-4-propionylpiperidine( 1 1) Hydrobromide. T h e yield of 11.HBr (allyl bromide, 7 h r ) was 74%: plate$. m p 192-1933" (from EtOHI. .4nui. (CliHZ4BrS021 C. H Hr. N. I -Cyclopropylmethyl-4-m-hydroxyphenyl-4-( 1 -hydroxypropy1)piperidine (12). A mixture of 2.4 g of 1, :3.8g of cyclopropylcarbonyl chloride, 12 ml of Et3N. and 70 ml ot CH2C12 wab refluxed for .3 hr and evaporated to dryness. The residue was dissolved in c s & and H 2 0 . The c& layer was washed with 10% HCI. saturated SaHCO3. and H 2 0 , successively. dried,i and evaporated to give 4.2 g of the 3' 0-dicarbonyl compound: I' 1750. 1703.1640 cm This was reduced with 3.6 g of LiAlH4 in 100 ml of refluxing T H F (24 h r ) giving, after t h e usual work-up. 2.7 g ( 8 7 % ) of 12: m p 180-182" (from EtOHJ: ,I1' 289. A n n / ((118H27N02) C, H. S. I -Cyclopropylmethyl-l-n-hydro~~phenyl-4-propionylpiperid i n e (13) Hydrobromide. AczO (7.c5m l ) . 1.5 g of 12, and 22.5 ml of DMSO were stirred a t room temperature for 65 hr. treated with and extracted with icc-HzO. made alkaline with 12 .M ",OH. (~"('13. T h e C:H(:13 w a s washed with H20 and evaporated to give an oil h-hich vas dissolved in 10% S a O H - E t O H . This solution was refluxed for 3 hr. t h e E t O H was distilled. H 2 0 was added to the residue, and the resultant solution was washed with CHC13 and then made alkaline with 12 .VI NH4OH. The liberated base was dissolved in CHC13 and dried.: Evaporation left 1.0 p of oil which contained some 12. Column chromatography on '30 g ofsilica gel ( 9 : l AcOEt-EtOH as eluent) gave 0.93 g i52'7~1of 13 whose ..Inn; hvdrobromide 1 from E t O H ) melted at 254-?55'. I(:lkH26BrN02) C,H. Br. N. Oxidation of 12 by the Oppenauer method icyclohexanone. alu-

I'icia. Hooker. .'amour. Keinhard

minum isopropoxide) pave YO% of 13.

Acknowledgments. LVe are grateful t o Louise Atwell and Bonnie McSeal for analgesic data. to Bettie Leis anti Arthur E . .lacobson lor probit analysis of these data. and to Paula F'arisius. .4lice Wong. and Byron Baer for elemental analyses. All are from this laboratory. \Ye gratetully acknowledge. toci. a generoub hupply ot I-cyano-J-rn methoxyphenj-1- I -methylpiperidinP from Ciha-[;eigy. Basel. A(; References

H.H. Onp. l'.Oh-ishi. and E. 1,. 5lay. ./, .Llr>ci ( ' / 7 ( , r ~ suhmitted for publication: i h ) E;. LV. Bentley and A . \ V . ('o\van. A n n u R P L ,I'harrnnc.oi . , 1 I . 2x1 (1971I . ( 2 ) A . \V. I). Avison and A . I.. Morrison. .I ( ' h ~ r n 119501. 131 11. 51. Ahdel-\Ionem and I-'. S. Portoghese. ./ . l l ~ d / i f n? 13, 208 i1972I. ( 4 ) .I. D.Albright and L. Goldman. A r n ~ r .('h!,rn. S o < , x!), 2416 119671:\V. \V, Epstein and F. \V. Sweat. ( ' h c m K c , ! , fii. 247 i 1967I . ( 5 ) T'. L). Perrine. 1,. Atwell, I. 13. 'l'ice. A . E,.lacohson. and E. I,. S1ay.J i'h(irr71. .Sei, 61,86(1972). (61 .J. E. \'illarreal. "Advances in Slental Science." \'(>I. 11. 13. '1~. Harris. \V. 5lcIsaac. and C . K. Schuster. Ed.. I'niversity oi Texas Press. Houston. Texas:. 1970.p p 8:3~-116. (7)H . \I-. Koaterli1z. .J. A . H . Lord. and A . J . \Vatt in "Agoniht and Antagonist Actions of Sarcotic Analgesic Dru Kosterlitz. H . 0..I. ('ollyer. and .J. E . \.illarreal, illan. London-Sen. York. 1972,pp 45-62. Xrcher. N . F. Albertson, I,. S.Harris. A . K.Piewon, anti . I . Bird..] .W(Jri. ( ' h i , r n . . i, 123i19641, 191 H. lloriyarno. H . Yamamoto. H. Nagata. and 'I. Tomaki. .lapanehe Paten; 7U.:31.664 (1970): ('hem .-I hcir . i 4 . 9987fir ( 1 ) (ai

11971 1

Anticonvulsants. 4. Metharbital and Phenobarbital Derivatives1 ,Julius A Vida.* Mary L. Hooker, Carlos M Samour. K t n d a l l ( ')mpnni Lerington Wa\\athusett\ 021 71

and .John F. Reinhard Department of Pharmacoiog?, G'raduare School of Pharmac?. and Allied Health i'rofe,srivr~. .Vortheastern iziwrsit:, Boston. Massachusetts 021 15. Received Jul? 9, 197.3 Several metharhital and phenobarbital derivatives were tound to p o s s e a potent anticonvulsant activity and >et were either devoid of the marked hypnotic effects of the parent compounds or displayed very weak hypnotic activit y . Particularly active compounds were the monomethoxymethyl derivative ot phenobarbital 131. the l-methyl-:Ibutoxymethyl deri\-ative of phenobarbital i 12).and the X-methoxymeth>-lderivatiw of'metharhital ( 101.

\Ve reported previously* that 1.3-bis(alkoxyrnethyl) derivatives of phenobarbital possess marked anticonvulsant activity against both maximal electroshock and pentylenetetrazole induced seizures and yet are devoid of the hypnotic effects associated with the parent compound. It was rep0rted3.~that the prototype of the 1,3-bis(alkoxymethy1)phenobarbital series: 1,3-bis(methoxymethyl)phenobarbital (DMMP, 16) is converted to three major metabolites in the rat. which in order of decreasing quantities are: 1methoxymethylphenobarbital (3), phenobarbital ( l ) , and 1-methylphenobarbital (15). It was also reported5 that in man, the major metabolites that accumulate in plasma as a result of DMMP administration in order of decreasing quantities are: phenobarbital, 1-methylphenobarbital, and 1-methoxymethylphenobarbital. In addition. smaller amounts of 1,3-dimethylphenobarbital( 7 ) and l-methyl3-methoxymethylphenobarbital (14) have been identified in human plasma.

As a result of these discoveries we became interested in finding out whether the 1-alkyl. 1-alkoxymethyl, 1.3-dialkyl, and 1-alkyl-3-alkoxymethyl derivatives cif 5.3-diethylbarbituric acid and 5-ethyl-5-phenylbarbituric acid would display anticonvulsant properties. Chemistry. The synthesis of l-benzgl-5-ethyl-S-phen~lbarbituric acid (2) was accomplished from 5-ethyl-5phenylbarbituric acid (1) with benzyl chloride in the presence of sodium hydroxide by a reported procedure.6 As expected, this procedure yielded a mixture of unsubstituted. monosubstituted, and disubstituted benzyl derivatives ot' 5-ethyl-5-phenylbarbituric acid, as observed by tlc. Separation of the predominant product. l-benzyl-5-ethyl-5phenylbarbituric acid, from the mixture was achieved b y column chromatography and crystallization. The synthesis of 1-alkoxymethgl derivatives of' 5-ethyl5-phenylbarbituric acid. 3 and 1, was accomplished by an unequivocal method.; The dilithium salt of thiophenohr-

Journal of Medicinal Chemistry, 1973, Vol. 16, No. 12 1379

Metharbital and Phenobarbital Derivatives

bital was converted into N,S-bis(alkoxymethy1)thiophenobarbital ( 5 or 6) by in situ treatment of the dilithium salt with 2' mol of chloromethyl alkyl ether. The N,Sbis(alkoxymethy1)thiophenobarbitals were converted to N-alkoxymethylphenobarbital derivatives by oxidation with peroxytrifluoroacetic acid (Scheme I). Scheme I

SLi

SCH20R 5,

R

6,R

= CH, = C,H,

0 3. R = CH, 4 , R = C,H,

The synthesis of the 1,3-dialkyl derivatives of 5-ethyl5-phenylbarbituric acid (7-9) was achieved by alkylation8 with chloroformic esters (Scheme 11). Scheme I1

O@ I

I

OLi

0 7 , R = CH, 8,R = C2Hj 9,R = C,H,CH,

Mixed alkylalkoxymethyl derivatives were prepared by alkylation of the 1-alkyl derivatives of barbituric acids with chloromethyl alkyl ethers in the presence of base. The respective derivatives of metharbital, 10 and 11, and phenobarbital, 12-14, were synthesized by this method (Scheme 111). Scheme I11 CICH,OR, I

8

R1"Y"H 0

base

2, R, = C,H,CH,; R, = C,H, 15, R, = CH,; Rs = C,H, 17, R , = C H , ; R, = C , H j

0

10, R , = C H , ; R, = CH,; R , = C,H, 11, R, = CH,; R, = C,H,; R, = C,H, 12, R, = CH,; R, = C,H,; R, = C,H, 13, R, = C,H,CH,; R, = CH,; R, = C,H, 14, R, = C H , ; R, = CH,; R, = C,H,

Pharmacology. Various 1-alkyl and 1,3-dialkyl derivatives of barbiturates have been reported in the l i t e r a t ~ r e . ~ With the exception of mephobarbital and metharbital, both currently available anticonvulsant drugs, and 1,3dimethylphenobarbital, which in animals is metabolically converted to mephobarbital, no other alkyl derivatives of barbiturates are reported to possess considerable anticonvulsant properties. On the contrary, many alkyl derivatives of barbiturates are claimed to have convulsive properties. 9 We found that 1,3-dimethylphenobarbital( 7 ) displayed as potent anticonvulsant activities against maximal electroshock- and pentylenetetrazole-induced seizures as did mephobarbital (15). At the same time, the hypnotic activity and acute toxicity of 7 were also approximately the same as those of mephobarbital. On the other hand, 1,3diethylphenobarbital (8) was devoid of anticonvulsant activity, while 1,3-dibenzylphenobarbital (9) and l-benzylphenobarbital (2) displayed very weak anticonvulsant activity. Compounds 2, 8, and 9 had no hypnotic activity except a t lethal dosage. 1-Methoxymethylphenobarbital (3), one of the metabolic products of 1,3-bis(methoxymethyl)phenobarbital (DMMP, 16), possessed anticonvulsant activity against maximal electroshock seizures in the potency range of DMMP (16). Compound 3 had outstanding potency against pentylenetetrazole-induced seizures suggesting potential therapeutic usefulness in petit mal epilepsy. Compound 3 possessed definite, although weak hypnotic activity compared to that of phenobarbital ( 1 ) . It is of interest that DMMP (16) is completely devoid of hypnotic activity. Compound 3 was less toxic than phenobarbital (1) with death resulting from respiratory paralysis following progressive CNS depression, 3-n-Butoxymethylphenobarbital (4) displayed moderate anticonvulsant activity against pentylenetetrazole and weak activity against maximal electroshock-induced seizures (Table I). We reported previously1 that 1-methyl-3-methoxymethylphenobarbital (14) was more effective against pentylenetetrazole than either mephobarbital or DMMP (16), suggesting potential therapeutic usefulness in petit mal epilepsy. Conversely, compound 14 was less active against maximal electroshock seizures than either mephobarbital or DMMP. 1-Methyl-3-butoxymethylphenobarbital ( 12) was as effective against maximal electroshock seizures as, and more effective against pentylenetetrazole-induced seizures than, compound 4. Compound 13, l-benzyl-3methoxymethylphenobarbital was more effective against maximal electroshock than compound 2 but much less effective than compound 3. The activity of compound 13 against pentylenetetrazole was about the same as that of compound 2. Compounds 4, 12, and 13 displayed no hypnotic activity except at lethal dosage. l-Methyl-3-methoxymethyl-5,5-diethylbarbituric acid ( 10) displayed good anticonvulsant activity against both maximal electroshock- and pentylenetetrazole-induced seizures. 1-Methyl-3-butoxymethyl-5,5-diethylbarbituric acid (11) was much less effective against both maximal electroshock and pentylenetetrazole than compound 10. Compounds 10 and 11 were devoid of hypnotic activity. The parent compound, metharbital (17), also displayed potent anticonvulsant activity against both maximal electroshock- and pentylenetetrazole-induced seizures; however, it was also hypnotic.

+

Experimental Section Pharmacology. All compounds were administered orally in 10% aqueous acacia suspension. Adult male albino mice (18-30 g, t M. T. Bush, personal communication.

Clda, Hooker, Samour. Kcinhard

Journal ofMedicinai Chernistr?. 2973, Vol. 26, No. 12

IJXO

Table I. P h a r m a c o l o g i c a l A c t i v i t y of M e t h a r b i t a l a n d P h e n o b a r b i t a l D e r i v a t i v e s

3

20,O (13.8-29 . O ) -340 22.5

-

4 7

-125 -21

-62 -15

8 9

> 100

1(phenobarbital)

2

None

9 8 16 7-14 2) 120 3 9 (2 7-5 61 5

100 172.5-138 0 ) >800 > 100 800 ; , 250

(500 ,750 i250

-500

None >SO0

.= 500 > 1000 > 500

,500

> 500

None

50

-25

11

100

12

-125

13

-100

14

-50

15 ( m e p h o b a r b i t a l ) 16 (DMMP) 17 (metharbitall

16 111 4-22 4) 13 5 (8-22 7) 30 (18 8-48 0 )

>;

1000

> 1000

> 1000

>500

> ;

>500 200 500 .c1000 -300 470 (376-5881 -820

l-Methoxymethyl-5-ethyl-5-phenylbarbituricAcid ( 3 ) . '1'0 '3 cooled solution of 5 (3.36 g. 0.01 moll in trifluoroacetic acid i5U m i ) was added 37% aqueous H 2 0 2 (15 ml) dropwise with caution. The solution was kept at 46-50" for 20 hr and then pciured into ice-HzO i200 g ) . The product was extracted into EtOAc and t h e solvent evaporated to provide crude 3 (2.68 g, 97%). Chromatog raphy over silica gel was used for purification. First, elution ivi1Ii CsHs-EtOAc (999:l)yielded 1 . 3 - b i s ( m e t h o x ~ m e t h ? . 1 I - 5 - e t h ~ l - ~ phenylbarbituric acid (16, 0.14 g. 1.37~). Elution with C6He EtOAc (9:lI gave pure 3 (2.5 g. 90%1.d n n i i C l q H l a S z 0 4 ) ( ' . H.

N. &V,S-Bis(nbutoxymethyl)-5-ethyl-5-phenyl-2thiobarbituric Acid ( 6 ) . Compound 6 was prepared from 5 - e t h y l - ~ , - l ) h e n ~ l - 2 thiobarbituric acid (24.8g. 0.1 moli and C1CH2C)C4Hg 1 3 2 g. 0 . 2 6 mol) in the same way as described i'or the preparwticin ( i t c ~ m pound 5 . Obtained was compound 6 (40.3 g. 96'7 I . an ( 1 1 1 . . I ~ ( J / ( C ~ Z H ~ Z S ZC. O ~H.SN. ) S. l-n-Butoxymethyl-5-ethyl-5-phenylbarbituricAcid (1). ( ~ i i i r l pound 4 was prepared from 6 (4.2 g. 0.01 mol) in the same as described for the preparation of compound :I. Ohtained \ \ a h (!)inpound 1 (2.86 g; 9 0 7 ~ )A. n d ( C ~ ~ H ~ Z NC.Z HO. ~S ). 1,3-Dimethyl-5-ethy1-5-phenylbarbituricAcid ( 7 ) . '1'0 ii aolution of j-ethyl-j-phenylbarbituric acid (23.2 g, 0.1 moll in D51F (100 m l ) was added LiH (1.75 g. 0 . 2 2 moll. The mixture was htmated to 65' and C1COOCH3 (20 g, 0.21 mol) was added over a period of 30 min. Vigorous C 0 2 evolution was ohherved. A f t e r c3() min the mixture \vas poured into ice-HZO: the product \va> tillcretl and crystallized from aqueous EtOH (100ml. ciii7~)t o :ivc> i ( 2 2 g. 8 5 7 ~ ) m . p 88-89", A n a / . ( C 1 4 H 1 6 X 2 0C~,~H. S lJ-Diethy1-5-ethy1-5-phenylbarbituric Acid ( h ) . C ' i ~ m p ~ i u n S( l was prepared from 5-ethyl-5-phenyll1arl1ituric acid 122.2 x . i). ! mol) and C1COOCzH5 ( 2 2 g. 0.2 mol) in t h e aame IS