1-[5-arylfurfurylidene)amino]hydantoins. a new class of muscle relaxants

4
September 1967 LIUSCLE RELAXANT HYDANTOINS 807 I-[(5-Arylfurfurylidene)amino]hydantoins. A New Class of Muscle Relaxants H~KHY 13. SNPI)ER, ,JH., CHARLES 8. DAVIS, ROBERT I<. BICKERTON, AND ROBERT P. HALLIDAY Research and Daelopment Department, The AYorwich Pharmacal Company, Xorwich, .Yew York 13816 Recezved January 85, 1967 A series of l-[(.i-arylfurfurylidene)amitio] hydantoiiis was synthesized and t,he rnmpniinds were screened for These cwmpoiiud.: were prepared by rotidetisitig :-aryl- The iiitrrtnec1i;tte :~ldehytles wet'^ tnatle t)y roiiplitig The 1-aniiiio- The cwiplitig (~i' 4-Iiit lobeiizeiie- drreeiiiiig data are their efferts on the flexor reflex in the anesthetized rat. 2-fiimldehydes with I-amitrcihq-tlatrtoilr hytirorhlotide. ;~i.yltliiizoiriiim rhlot%les with 2-fiwaldehyde in aqrieoiis aretotie iisitig riipt,ic rhloridr iis a vatalyst. imidazolidiiiciiie derivative of .i-(3-1iilrophei~yl)-%-fii~~ldehytle was pt,rpared. tliitzoiiiiini rhloride wii h 2-1 hiophetiec,art)osaldehyde atid 2-:welyli'iit,aii was ~c.c.ornpli~lied. pwseiited 1 oget het, \Tit h a dinciissioii of struct8iri,e-act ivit y caorrelat ioris. During the course of another investigation of sub- stituted furans, 1-( [.?-(p-nitrophenyl)furfurylidene]- amino ]hydantoin (7) was prepared and tested for its ability to alter the flexor reflex in the hind limb of the cat. It was found that 7 produced an inhibition of the polysynaptic pathway n-hich was suggestive of centrally mediated muscle relaxant activity. Because of the nature and degree of activity of 7, the synthesis of analogs to investigate structure-activity correlation was initiated. Chemistry.-t-tilizing the method of Akashi and Oda, I the appropriate aryldiazonium chlorides (1) and 2-furaldehyde (2) were roupled in aqueous acetone with cupric. chloride as the catalyst (see Scheme I). Davis SCHEME I 1 2 HCI H K N y O A r Q C H O v+ 4 ArGH=NN-y=o w 3 7-20 and T,ougheed2 demonstrated that the coupling of an aryldiazoniuni chloride (1, Ar = CsH4Br-p) with 2 did occur at the 5 position of %furaldehyde. The in- termediate aldehydes 3 were condensed directly with 1- aminohydantoin hydrochloride (4) to give the amino- hydantoin derivatives 7-20. The unsubstituted arylhydantoin 5 was prepared from 4 and aldehyde 3 (Ar = C6&) which was synthe- sized by the formylation of 2-phenylf~ran.~ The cata- lytic reduction of the nitrohydantoin derivative 7 in absolute ethanol proceeded smoothly to give the amino- hydantoin 21 (see Scheme 11). The %substituted de- rivatives of hydantoin 7 (22, 23) were prepared by ating its sodium salt 6 with an appropriate alkyl e. It was possible to synthesize hydantoin 24 by condensing 7 with 4-vinylpyridine in pyridine solu- tion. Alkylation of 7 at position 3 of the hydantoin ring was indicated by an examination of the infrared spectra of 22-24. These spectra all contained two absorption pealis in the 1'700- and 1760-1780-~m-~ regions which are characteristic of hydantoins and 5- substituted hydantoi~is.~ The infrared spectrum of 7 also has carbonyl absorption pealis at 1710 and 1760 cm-I. Hydantoin derivatives 25-28 were made by condens- ing 5-(2-fury1)-2-f~raldehyde,~ 4-phenylbenzaldehyde,e 3-(4-nitrophenyl)-%-thiophenecarboxaldehyde, and 2- acetyl-5-(5-nitrophenyl)furan, respectively, with 4. The reaction of aldehyde 3 (A4r = C6H4X02-p) with l-aniinoiiiiidwzolidinoiie-~i yielded the imidazolidinone derivative 29. Pharmacology.--All of the compounds were screened in the anesthetized cat by the method of Berger.8 This procedure was used to detect inhibition of a polysynaptic pathway. Inhibition of this reflex has been considered by many investigators to be indicative of centrally mediated muscle relaxant activity.8-lO The extremely low water solubility of these compounds prompted the use of dimethyl sulfoxide (DJISO) as a vehicle. Unfortunately, DMSO in doses of 0.2-0.3 ml/kg produced transient inhibition of the flexor re- flex. Thus, compounds which transiently inhibit this reflex may have been masked by the vehicle. Since DRlSO was used, its toxicity imposed another limiting factor and it was not possible to administer doses of test compounds larger than 20 nig/kg; a compound which might have been active at a larger dose ap- peared inactive in this test. Thus, an active com- pound was defined as one which produced greater inhibition of the reflex than mas produced by the ve- hicle alone and which showed this activity at less than 20 nig/lig. The evaluation of mephenesin" by these rigid parameters might have resulted in classifying it as inactive. The results of the screening are shown in Table I in the form of a classification designated by + (group I), ++ (group 111, and +++ (group 111). For the purposes of this paper, the following definitions were used: group I (minimal activity) represents com- pounds which inhibited the reflex less than 30% or had an apparent duration of activity of less than 15 min ; group 11 (moderate activity) represents com- (4) L J I<ellam\, 'The Infrared Spectra of Complex Molecules," John (5) T Reichstein, \ Grussner, and H Zschokke Zfeli Chrm Acta, 16, (6) ixailable from ildrich Chemical Co (T) J G Michels and G Ge\er, J Am Chrm Sor 78, 5349 (1956) (8) r hl Rerger, .I Pharmacol Ezptl Therap 96, 213 (1919) (9) T C I<rirke, D Papandrianos, I. J 13rarinlck and C; L Hassert, Jr , (10) 4 P Rosdko\rqki, J I'har,natol k.Jptl Therap 129, 75 (1960) (11) Generic name for 3-o-to~ox~-1,2-propanedlol Ti ile) and Sons, Inc 1066 (1932) Nen York Arrh Intern I'harmacodyn 134, 116 (1961)

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September 1967 LIUSCLE RELAXANT HYDANTOINS 807

I-[(5-Arylfurfurylidene)amino]hydantoins. A New Class of Muscle Relaxants

H ~ K H Y 13. SNPI)ER, ,JH., CHARLES 8. DAVIS, ROBERT I<. BICKERTON, AND ROBERT P. HALLIDAY

Research and Daelopment Department, The AYorwich Pharmacal Company, Xorwich, .Yew York 13816

Recezved January 85, 1967

A series of l-[(.i-arylfurfurylidene)amitio] hydantoiiis was synthesized and t,he rnmpniinds were screened for These cwmpoiiud.: were prepared by rotidetisitig :-aryl- The iiitrrtnec1i;tte :~ldehytles wet'^ tnatle t)y roiiplitig

The 1-aniiiio- The cwiplitig ( ~ i ' 4-Iiit lobeiizeiie-

drreeiiiiig data are

their efferts on the flexor reflex in the anesthetized rat . 2-fiimldehydes with I-amitrcihq-tlatrtoilr hytirorhlotide. ;~i.yltliiizoiriiim rhlot%les with 2-fiwaldehyde in aqrieoiis aretotie iisitig r i i p t , i c rhloridr iis a vatalyst. imidazolidiiiciiie derivative of .i-(3-1iilrophei~yl)-%-fii~~ldehytle was pt,rpared. tliitzoiiiiini rhloride wii h 2-1 hiophetiec,art)osaldehyde atid 2-:welyli'iit,aii was ~c.c.ornpli~lied. pwseiited 1 oget het, \Tit h a dinciissioii of struct8iri,e-act ivit y caorrelat ioris.

During the course of another investigation of sub- stituted furans, 1-( [.?-(p-nitrophenyl)furfurylidene]- amino ]hydantoin (7) was prepared and tested for its ability to alter the flexor reflex in the hind limb of the cat. It was found that 7 produced an inhibition of the polysynaptic pathway n-hich was suggestive of centrally mediated muscle relaxant activity. Because of the nature and degree of activity of 7, the synthesis of analogs to investigate structure-activity correlation was initiated.

Chemistry.-t-tilizing the method of Akashi and Oda, I the appropriate aryldiazonium chlorides (1) and 2-furaldehyde (2) were roupled in aqueous acetone with cupric. chloride as the catalyst (see Scheme I) . Davis

SCHEME I

1 2

HCI H K N y O

A r Q C H O v+ 4 A r G H = N N - y = o w 3

7-20

and T,ougheed2 demonstrated that the coupling of an aryldiazoniuni chloride (1, Ar = CsH4Br-p) with 2 did occur at the 5 position of %furaldehyde. The in- termediate aldehydes 3 were condensed directly with 1- aminohydantoin hydrochloride (4) to give the amino- hydantoin derivatives 7-20.

The unsubstituted arylhydantoin 5 was prepared from 4 and aldehyde 3 (Ar = C6&) which was synthe- sized by the formylation of 2-phenylf~ran.~ The cata- lytic reduction of the nitrohydantoin derivative 7 in absolute ethanol proceeded smoothly to give the amino- hydantoin 21 (see Scheme 11). The %substituted de- rivatives of hydantoin 7 (22, 23) were prepared by

ating its sodium salt 6 with an appropriate alkyl e. I t was possible to synthesize hydantoin 24

by condensing 7 with 4-vinylpyridine in pyridine solu- tion. Alkylation of 7 at position 3 of the hydantoin ring was indicated by an examination of the infrared spectra of 22-24. These spectra all contained two

absorption pealis in the 1'700- and 1760-1780-~m-~ regions which are characteristic of hydantoins and 5- substituted hydantoi~is .~ The infrared spectrum of 7 also has carbonyl absorption pealis at 1710 and 1760 cm-I.

Hydantoin derivatives 25-28 were made by condens- ing 5-(2-fury1)-2-f~raldehyde,~ 4-phenylbenzaldehyde,e 3-(4-nitrophenyl)-%-thiophenecarboxaldehyde, and 2- acetyl-5-(5-nitrophenyl)furan, respectively, with 4. The reaction of aldehyde 3 (A4r = C6H4X02-p) with l-aniinoiiiiidwzolidinoiie-~i yielded the imidazolidinone derivative 29.

Pharmacology.--All of the compounds were screened in the anesthetized cat by the method of Berger.8 This procedure was used to detect inhibition of a polysynaptic pathway. Inhibition of this reflex has been considered by many investigators to be indicative of centrally mediated muscle relaxant activity.8-lO The extremely low water solubility of these compounds prompted the use of dimethyl sulfoxide (DJISO) as a vehicle. Unfortunately, DMSO in doses of 0.2-0.3 ml/kg produced transient inhibition of the flexor re- flex. Thus, compounds which transiently inhibit this reflex may have been masked by the vehicle. Since DRlSO was used, its toxicity imposed another limiting factor and it was not possible to administer doses of test compounds larger than 20 nig/kg; a compound which might have been active at a larger dose ap- peared inactive in this test. Thus, an active com- pound was defined as one which produced greater inhibition of the reflex than mas produced by the ve- hicle alone and which showed this activity at less than 20 nig/lig. The evaluation of mephenesin" by these rigid parameters might have resulted in classifying it as inactive. The results of the screening are shown in Table I in the form of a classification designated by + (group I), ++ (group 111, and +++ (group 111). For the purposes of this paper, the following definitions were used: group I (minimal activity) represents com- pounds which inhibited the reflex less than 30% or had an apparent duration of activity of less than 15 min ; group 11 (moderate activity) represents com-

(4) L J I<ellam\, 'The Infrared Spectra of Complex Molecules," J o h n

( 5 ) T Reichstein, \ Grussner, and H Zschokke Zfeli Chrm Acta, 16,

(6) ixailable from ildrich Chemical Co (T) J G Michels and G Ge\er , J A m Chrm Sor 78, 5349 (1956) (8) r h l Rerger, .I Pharmacol Ezptl T h e r a p 96, 213 (1919) (9) T C I<rirke, D Papandrianos, I. J 13rarinlck and C; L Hassert, Jr ,

(10) 4 P Rosdko\rqki, J I'har,natol k.Jpt l Therap 129, 75 (1960) (11) Generic name for 3-o-to~ox~-1,2-propanedlol

T i ile) and Sons, Inc

1066 (1932)

Nen York

A r r h Intern I'harmacodyn 134, 116 (1961)

21 7

t 24

6

22.23

pounds which inhibited the flexor reflex 3OYc, or greater, with durations greater than 15 mi11 but less than GO min; and group I11 (greatest activity) represents compounds n hich inhibited the flexor reflex 30yc, or greater, with durations in excess of GO niiri. The doses in Table I refer to the lowest level which pro- duced the greatest inhibition uqing this rating system. All of the compounds in group 111 produced signs of muscle re1:ixation when administered ixitraperitorieally to mice.

Although these conipounds appear to be centrally acting muscle relaxants, borne degree of inhibition ( i f

the respoiise to motor nerve stimulation was also ob- served. This inhibition of the responw to motor ittwc stimulatioii wa5 d ~ v a y 5 less than thc inhibitiori observed following sensory nerve itimulatiori. Fur- ther work is necessary t o clarify the contribution of t h k peripheral effect.

Structure-Activity Relationships. - -L\ny niodificntion of the basic structure of 7 resulted iii u clecreuse 111

muscle relaxant activity (flexor reflex inhibitiori) . difficult to quaiitit:ite this activity. tlrc

A. Position Isomers.-The position of the nitro group on the herizerie ring greatly influeiiced activity. The para isomer (7) was the most active arid the metu (8) and ortho (9) successively less active. Introduction of a second group into the p-nitrobenzeiie ring resulted i i i decreased activity (10, 11).

B. Replacement of the p-Nitro Group.-Substitu- tiom of this type redwed activity to a varying degree. The more active compounds contained the following

wns a fairly activ ourid, replacement n i th Rr (15) a n t i 17 (16) tlecre, tivity markedly.

C. Modification of the Hydantoin Ring. Subi t i t II-

tioiis on the hydairtoiir rritrogeir in g c ~ ( ~ : t l signifir:trit Iy

eralizations were made.

gruu1)s: SH2 (21), C S (18), sild C1 (12). Slthough 12

reduced activity (22 -24). Replacement of the I - c*:trbonyl grriul) of the hydantoin ring ni th met hyl(1iic. reduced activity only to :I small degree (29).

D. Miscellaneous Structural Modifications. -When the p-riitropheiiyl riiig replaced by a 2-fury1 ring. there n cis consitlerciblc of wtivity (25). Substitti- ion of the fury1 ring 111 7 for ti thieiiyl ring rcsultcd I I I

:L marked decrea5e i i i :tcti\ ity (27). .I similar decw iri itctivity oceurrcd whcn t tic :tldehydic hydrogen ut 7 is rcylaced by :i iiiethyl group (28). Finally, tlic uw of :L 4-~,heiiyl(ljheiivl) groul) I I L t h c p1:tre of S-(p-nitrci- 1)heiiyl)-2-fiiryl group climiriishctl :ivt ivity ~ ~ o r i s d ~ r ~ ~ h l y (26).

The striking .i(*tivlty ot 7 : t ~ i d it. S O ~ ~ ~ U I I I SLtlt 6 t>:1\

l)roml'ted : ~ i i irrtmisive iiivc*tigatioii i i i t c i the iiioclc' 01 :ictioii of t h ( w u)iiipouiid\. Th th of tliex? rompoui i t l~ : ~ r c riiitlwy,oing ev:ilu:it i i r i i : t i 1)oi~i l ) lc i ~ i i * ( , k rc1:rx:trii

TABLE I 1- [ (*?-ARYLFVRFL-RYLIDENE) \MINO] HYD \STOISS

T O . A r R 5 CaHsb H 6 CsH4X02-p NZl

8 9

10 1 1 12 13 14 15 16 17 18 19 20 21 22 2 3 24 25

H €1 €I H H H H H H H H H H H H C H I C H ~ O H (CH4sCHs CH?C'H4-CsH4X H

27

Yield, N P , OC %

258-260 94 229-231 dec 61

2i9-280 16 246-24T 33 224-226 :32 256-250 45 267-269 44 275-277 44 274-276 62 244-246 97 284-285 42 264-265 14 205-207 40 281-285 dec 65 264-270 57 320 dec 31 269-270 52 245.5-24T 92 201.5-202 92 227-230 98 241-24:: 83

24T-302 02

29,5-208 13

28i-288 dec 38

283-284 45

Re- crystn

sol- venta Formula

D . .

B D D A G D D F A C R G 13 A I3 A E C C

13

C

c

A

----Calcd. %- -Found, %- C H K C H P i

62.45 4 . 1 5 15.21 62.52 4.33 15 T8 41.18 4.20 1 3 . i 2 4 1 . 5 2 4.39 13.40

53.50 53.50 53.50 54.88 48 22 55.37 49.72 48.47 48.30 5 8 . 5 4 53.42 61.22 61,;s 5i.51 59.15 53 63 58. Bi 60.14 55. GO

3.21 li.83 53.28 3.16 3.21 17.83 53.62 3.32 3.21 1T .83 53.33 3 . O i 3.69 li.07 54.92 3.44 2.60 16.Oi 48.42 2.61 3.32 13.84 55.34 3.20 2 . 6 8 2O0.9i 49.93 2.68 2.44 11.30 48.56 2.72 2.90 12.Oi 48.28 2.85 3.51 14.63 58 54 3.63 2.99 12.46 53.40 3.85 3.42 19.04 61.15 3.68 4.21 13.50 61.58 4.47 3.54 13.41 57.il 3 . i 5 4.25 19.71 59.24 4 33 3.94 15.64 53.58 3.98 4.90 15.13 5 8 . 4 1 4.82 4.09 16.70 59.iO 4 01 :$.SO 16.21 55 59 3.58

1 i . Y i 18.10 l i 69 16 68 15,86 13.i8 21.03 11.18 12.15 14 74 12.43 18 66 13.36 13.25 19 Y8 15.61 15.19 16.5i 16. 1 5

68.81 4.69 1 5 . 1 2 68.Y1 4.62 1:3.00

54 88 3 69 17 01 54 81 3 82 16 80

56.00 4.03 18.66 55.78 4.23 18.39

Flexor reflex act .

Dose.C mg'lip

10.0 1.0

1.0 5.0 5.0 5.0 2.5 2.5 5.0 5.0 2.5 5.0 5 0 2 . 5 2.5 10.0 5.0 2.5 5 .0 5 .0 5.0

5 . 0

2.5

2 . 5

5.0

30.0

RatingC

++ +++ +++ +++ ++ +++ ++ +++ +++ ++ ++ + ++ +++ ++ ++ +++ ++ ++ ++ ++

++

+

+

+++ ++

li A = DAIF, B = DlIF-HzO, C = DMF-95% ethanol, D = material was washed with acetone, E = 95rc ethanol (SDA-30), F = acetonitrile, and G = DMF-607c aqueous ethanol. See ref 2. c See text. d For comparison, administered in water.

In a similar manner 8-20 n-ere prepared using the appropriate aniline. Compound 27 was synthesized by the above procedure starting with p-nitroaniline and substituting 2-thiophenecarbox- aldehyde for aldehyde 2. The use of 2-acetylfuran in place of 2 gave the hydantoin derivative 28.

1-( [5-( p-Nitrophenyl)furfurylidene]amino ] hydantoin (7).-To a solution of 5-(p-nitropheny1)-2-furaldehydel (40.0 g, 0.2 mole) in 1IMF was added an aqueous solution of 4 (30.0 g, 0.2 mole). The solution was chilled and diluted with water; the crude ma- terial was collected. The infrared absorption curve of a mineral oil mull displayed peaks a t 1710 (C=O) and 1760 (C=O) cm-1.

In a similar manner, 25 and 26 were prepared by using 5-(2- furyl)-2-furaldehyde~ and 4-phenylbenzaldehyde.6 The reaction of 5-(p-nitrophenyl)-2-furaldehyde and l-aminoimidazolidi- none-27 was carried out as above to yield 29.

1-( [5-( p-Nitrophenyl)furfurylidene]amino) hydantoin Sodium Salt Tetrahydrate (6).-A slurry of 7 (20.0 g, 0.064 mole) in anhydrous methanol (200 ml) was treated with a solution of ;\'aOCH3 (3.7 g, 0.069 mole) in anhydrous methanol (200 ml). The resulting solution was stirred for 6 hr (precipitate was formed after 0.5 hr) before filtering. The orange product was air-dried for 18 hr. The infrared spectrum indicated the presence of water (band a t 3460 cm-1).

3 4 2-Hydroxyethyl)-l-( [5-(p-nitrophenyl)furfurylidene] ami- no]hydantoin (22).-To a solution of 7 (62.8 g, 0.2 mole) in I).\IF (1000 ml) was added in small portions NaH (9.6 g, 0.2

mole, of a 50% mineral oil dispersion). After the sodium salt had precipitated, 2-bromethanol (50 g, 0.4 mole) was introduced. The temperature rose to 60" and was held there for 18 hr. The dark solution was then poured into ice water (4000 ml). The solid was filtered and air-dried overnight and then at 60" for 4 hr. The infrared absorption data of a mineral oil mull indicated peaks at 1710 (C=O) and 1760 (C=O) cm-l.

In a similar manner, the K-butyl derivative 23 was prepared from 7 using n-butyl bromide as the alkylating agent. The infrared spectrum of 23 in a mineral oil mull had abiorption peaks at 1700 (C=O) and 1780 (C=O) em-'.

1 - { [5-( p-Nitropheny1)furfurylidenel amino ] -3-1244. pyridy1)- ethyllhydantoin (24).-A suspension of 7 (31.4 g, 0.1 mole), pyridine (170 ml), and 4-vinylpyridine (10.5 g, 0.1 mole) was refluxed for 27 hr. A clear solution resulted after 3-4 hr of re- fluxing. The solution was cooled and then poured into water and filtered. The filter cake was thoroughly nashed with water and dried. The infrared absorption spectrum of a mineral oil mull showed peaks a t 1730 (C-0) and 1780 ( C 4 ) cm-l.

1-( [5-(p-Aminophenyl)furfurylidene] amino] hydantoin (21).- Compound 7 (15.7 g, 0.05 mole) was suspended in absolute etha- nol (SDA-32) (250 ml). To this suspension was added 57, Pd-C as a 50y0 mixture with water ( 3 g). The container waq placed in a Parr hydrogenator and shaken under 2.8 kg/cm? hydrogen for about 1 hr (hydrogen absorption had ceased). The temperatine roqe to 34". The reaction mixture was filtered and the filtrate was ev:tporated to yield the crnde prodllct.

The Metabolic Fate of Some Silicon-Containing Carbamates'

:\fter iicyestioii, I ) i h ( l i j ~ ( l n i x ~ t ~ ~ ~ ~ ~ l i y l ~ ~ l i i i i c ~ l ~ ~ l s i l : ~ t c t ~ d i v x r h i i i a t t b (111 j , [ t ~ y i l t ~ i ~ x y i i i t ~ ~ h ~ L ~ t l i i i i e ~ l ~ y l - ~ ~ - p l o ~ ~ y I - aibiie cahamate ( I \'), a i d l ~ i ~ ( l i ~ t i i ~ o ~ ~ r ~ ~ e ~ l i ~ l ) i ~ i e t l i ~ l - n - p r o p ) - l s i l a l l e clicd):i.riia(e (si1:~riieprol):iniate) ( \ ~ ) :iw absorbed and eliniiiiated iii the iiririe of ra 111 is eliminated lulchaiiyed. I is metabolized; bis(hydroxy- methy1)tetramethyldisiloxaiie dicarbamate \. is also met>abolized; two prod- i i c t s isolated from the iirine were a disiloxaiie \.I1 as the mitior compoiietit a t i d bis(hydroxymethyl)(2-hydrox?-- propy1)methylsilane dicarbamate (TIII) as t,he major compoiieiit. The data iiiditxtlr that dealkylation is oite of the metabolic paths for elimiiiatioii of orgaiioeilic>oii compolliids.

-1) WLS isolated from the iirine.

Although organosilicon coiiipouiids are u d both i i i

rommerce aiid in medicine, little is Bnown about their metabolic fate. Pan1 and Povcr' have provicled cvideiice that methyl w-(trimethj 1silyl)dodecoiiate and t riiiiethylsilylhexaclecane are absorbed from the gastiu- iiitcstiiial tract of rats. Dow Coriiing4 has reported that [14C']niethylpolysiloxarie is iiot excreted ns 14C02.

Our o\ui interest in the niet:tbolisni of orgaiiosilic*oii c~mipouiids was stimulated by the 1:wll of oral :wtivity of silanieprobamate (V), although it sho~ved the bailie EDjo (rotating rod) as nicprobaniatc (I) whcn it ~\-;i<

tlosed iritr:~peritoiieally.i I t \\ :ih felt t1i:rt this diflcrei1c.c in activity could be clue either to ;i l:w1\ of nbsorptioii of the silicon coinpound wheu dosed orallj or t o :I different detoxificatioii path11 a\ .

The metabolisni of I itself hns been btudied by :L number of investigators.'j Oxidation of the propyl group provides the major puthrvay of detoxification. Cnrboxymeprobainate, l;etcimeprobainate, and hj.- tlloxymeprobamate (11) have beeii identified as metabo- lites (see Scheme I). Thc relative amouiits of these riictabolites vary with t he spc&s; lion ever, thti al- cohol I1 is the major detoxification prod\ic.t.

3 c H L \ I L I

( - 1 I { ( ' I I ? ( ' 1 12c((7r 4 )(C€I,OCONl I. J +

1 ( 1 1 r,c I Iofjcirc(ciiJ i ( ( ' I )CC)SI -

11 ( i rd( v ~7 fTAc i (w3 I ( ('1 i2( )CY IN i I? ): +

tI02('('I€2('11LC~CH~)~CI-I,oC'O?;I

This study is coricerried with the ideritificatioii ~ i ' the metabolites appearing in the uriiie arising from the oral dosing of some silacarbamates, bis(hydroxy- methyl) dimet h ylsilane dicarbamat e (111) , (hydrox j -

(1) Tllis revearcli mas supported 11) l'iiblic IIealtli Research Grant

(2) Alfred P. Sloan Fellon-, 1963-198i. ( 8 ) J. Paul and IT. E'. R. Pover, d r c l i . Btochenz. B i o p h y s . , 87, 312 (19601. (4) A s reported in "The Bulletin," Vol. 11, No. 4, Don. Corning Cenzer for

( 5 ) R. J. Fessenden and Marvin D . Coon, J . M e d . Chem., 8 , 604 (1963). ( 6 ) (a) 13. J. Ludwig, J. F. Douglas, L. R. Powell. AI. Meyer, and E'. A I .

ed . Pharm. Chem., 3, .53 (1461); (b) F. A I . Berper. .I. P / iarnwr .n / . E r p t l . Thrrup. , 112, 413 (1954); ( v ) 13. \ \ . :Agranoff, H . \ I . 13r:liIlev, a1111

.I. A x e l r d , P ~ o c . S O C . 12rptL H t o l . Md., 9 6 , L'ri I

C:AI13914 from the Kational Institiire of Genmal Medical Sciences.

Aid to Medical Research, Midland, Mich., April 1960, p 1.5.

1CLp>7).

methl 1)dinwthj l-~i-~~ro~)ylsilniie rnrbamate (II?), : [ l id

5 il a me p ro b arriat t 1 ( T T ) . ( ll,>t((ql I , ) l ( ' f I ~ O ( Y ) X I I. ). / ~ - ~ ~ , l l ~ ~ t ( ~ l ~ ~ ) ~ ~ ~ l I-( )('( ,s I 1 I

I l l I \ )I-( ' I I T ~ I f ( ' 1 I j )i( ' I I A )('( ) N I I - ) I

\

111 our prcvious ~ ) r l < , ~ we were :tble to slion that 111 showed iio I,harIiiucological activity (rotating rod test) at iiitraperitonezd close levels up to 300 nig, kg. 111 the present Y t u c l ) , .v\-I-ieri I11 orally dosed in rats,

material \vas isolated from the line unaltered conipou~id. So

acrvecl for this particu1:ir coiii-

pouud.

nig/ kg ip.; -\ftc>r oral dosing ~ i ' IV in rats, :hoiit 90", of the ingested SiliCOli could be detected iri the uriiit' mithiii I dais. 111 the ethyl ether extract of the ririiie, iio uric~harigeti I\ ' could be detecwd. l:rum :in ethyl acetate extraction, there I\ a s obtained a silicwii- cvntaiiiirig oi l , whieh wab >uhjected to chroni~~to- graphic. srparatioii. YOo, !\as isolatetl. The iimr spectrum of this materid showed t w sharp siiiglets aiid a broad band, which, from the cheniicd shifts arid areas under these bands, suggested that the solid ir the disiloxarie 1'1. ?'hc infrared spectrum and the elemental analysis of this iiiuterial are in agreement with this structure assign- nieiit. This metabolite aC~OLl I i t5 for 29% of the silicoii of the ingested rilacarbamatca IV. KO other silicoli nietabolites u-cr(2 det

Compountl I\' \iloTred 111 I!mj" of 15s (14s-169)

white crystalline solid, nip 66

H C CH, I I I I

IV - NH-COOCH2SiOSiCH20CONH-

HjC CHj

V I

&After oral dosing of silameprobamate, 80-90cz ot the ingested silicon was found in the urine withiii :i days. Extractiori aiid chromatographic separation afforded a solid material (mp 34-58') and :I viscous oil. T*nfortunately, iirither of these substaiiccs roulti be ubtairirtl in :LLI a i i a l y t i c a l l y pure forrii.