Electronic Structures of Some N-Alkyl- Substituted ... - ACS Publications

:is described by Baltaly, et a?.1), 10 in1 of 1 -V XaOH, and 10 nil of chloroforni was slowly added 0.25 nil of methyl chloroformate. Stirring was con...
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WILLIAM PAULPURCELL

294

(see below) showed no melting point, depression iinp tg8-202°). The infrared spectra as Siijol mulls were also very similar to oii(: on, another crystal form of tlie picr:ttr, nil) ined by recry>talliaation from SO(.; 2-rnrihrisyet1i:iiiol. . I d . C d ~ dfor Cv,H&-801ij: ( ~ " 50.7: , H, 4 k"o1uid: c, 50.5; H, 4.85; 5, 1i3.s. Methylurethan of the Dimer Id and Reduction to 1b.-To ;in iw-cold, st>irredinixture of 300 m g of Ia dihydrochloride (prepared :is described by Baltaly, et a?.1),10 in1 of 1 -V XaOH, and 10 nil of chloroforni was slowly added 0.25 nil of methyl chloroformate. Stirring was continued for 1 fir a t rooiii temperature. The inixture was acidified with coiic'eiitrnted HC1 and stirred for 10 riiin. The layers were separated, and the aqueous layer was estracted with aiiother 10 in1 of chloroform. The chloroform ) and evaporated in i'ucuo to leave 333 mg whose infrared spectrum was i n agreement p ( C 4 of uretli:in J. The itreih;iti (320 rng) ' S R S redirc.etl with 0.60 g of IJiAlH4iri 'PIIF holiition k~:; refliixing for 16 hr. The xolveiit was evapor:itcd arid after decompo:iition of iiie hydride mixtiire with water,

Bis(2-methoxy-5-bromoacetylphenyl)methane(VIII).-To a iiiisl w e of 2.0 g (6.4 mmoles) of l)ii;(2-inethoxy-5-acetylpheiiyl)nicthaiie iii 50 1111 of THF was added 4.6 g (12.2 mmoles) of 1 ririie thylplieii~-l:trifrii(iiiiurritribroriiide. The mixture was stirred tit room teniperature for 3.5 hr :ind evnporated in z'acuo, and the ly with water. The crude yellow xilid W : L ~ w\-a,hed thoro i benzene wa31i. Rerryctalniateri:tl (2.4 g ) w i s collected af f'ortled 1.25 g (417;), i n p limtion f'rci i i i 2-met hosyethanc ,

Yol. 0

dryneh;., taken up in water, and treat,ed with sodium bisulfite. The resulting suspension was acidified to pH 2 with 6 LY H(Y, ruid the solid was collected by filtration and washed with wit cr The white crystalline material wis triturated with ab~olnto riiethanol, yielding 2.19 g (85y0), mp >300. Anal. Calcti for C17HI8O4: C, 64.5; €I, 5.10. Vourrd: C;; (i4.1 : H, 5.1 I . Bis(2-methoxy-5-dimethylcarbamoylphenyl)methane(XI).- -A niixture of 0.3 g (0.95 mmole) of bis( 2-methoxy-5-carboxyml of SOCl, was refluxed 6 hr and evapopheny1)methane and .i rated in vaci~o. The acid chloride was freed of SOCI, by t,hc addition :iiid evaporation (in vacuo) of a few iiiilliliters of mhydrous benzene. Tn 0.33 g (0.9:) nimolej of the acid chloride i n S ml uf cold CH2C1, was added, dropwise, 2 nil of nrihydroii-. tiiniethylamint~ iii 2 ml of cold methylene chloride. After araiiding :it rooin teiiiperature 15 lir. the mixture was washed x i t h water, and the CH2C1, layer was sepamted, dried (JIgSOI), and cv:aporated z'ti v m u o t o yield 0.24 g of giimrny rna1eri:il. \Z-hc.ii irwted Tvith ciher, the gum yielded 0.18 g of yello\v rr;. l k r w t allizat ioii from benzene--cyclohexarie gave 0.1:i g i iiip I 19-122'. AI] aiialytical haniple had mp 123-125'. .lr~cil. C a l i d fur ~21H&?OI: C, f18.1; H, 7 . 0 7 : S , 7.>(;. Folitid: (:>(j7.8; €1, 7.14; ?;, 7 2 J . Bis(2-methoxy-5-dimethylaminomethylphenyl)methaneUihydrochloride (XU).- -To a chilled suspension of 0.74 g ( 19.4 iiiniolesj of TdAlH, in 20 ml of anhpdrous THF its added 1.2 g (:3.2 ni111ole;i) of bi~(2-riiethox~-ci-dimethylcarbainoylphet~~~Ijmethalie. Tlie mixture was refluxed 12 hr and chilled, and the reinairiing unchanged hydride was decomposed b y the addition of :tl)solute cttlianc~lfollon-ed by a few milliliters of wat.er. 7 l 1 ~ mixture w i n cv:iporated in I ~ U C U O t o tiear dryness. Tho whit e ~siispetisioiiwas \v:tshed thornughly with ethyl ether :tiid filtered, : i i i r l the ethered estract \vas sep:irxted and dried (JIgSOr). I~;vaporatioiiin rocico yielded a clear gum, which, wheii taken 1111

144- 147". .I , c d

(:alCd for Ci&B 1-1: 3.S:); Ur, ; X 1 . C, 48.2: H, 3.W; Br, Bis( 2-methoxy-5-carboxyp e ( S ) . --To GO nil of \v:irin (60" j "Sanichlor" blea 2.54 g (S.l mrnolesj of Iiis( 2-niethosy-.j-acetyli)}ietiyl jniethaiie in 200 ml of methanol. 'The mixture w:w stirred at 60' for 2 hr, then 10-nil portioiis ol bkadl w f x e added until :t per>i.-teiit atnrcli-iodide te$t was obt:iiiied. 'rhc niistrirc was t l i e i i iiv:ipor:ttcd in rucuo t o i i w r Fil~ind:

.1nnl. Voiiii(1:

C ' ; ~ l i d for C23H3612N202: C', 14.1: H! 5 . 7 5 ; 1, C', 44.4; I € . > . G :T, -tO..i.

.40.(;.

Electronic Structures of Some N-Alkyl- Substituted Amides of In teres t as Cholinesterase Inhibitors'

f~ep(ct.liitr~til oJ' f ' / i ( i i , i i i u ( , ~ , ! i luiid ~ ~ ~ f.I~cdicitinl l

C ' I ~ w i i d r g ,C7niuei.sil!/os T e n

Iteceiuecl A u g u s t 12, 1 ! 6 5 Electroiiic striictitres were calciilated for 18 N-alkyl-subjtititted amides which are of interest as choliiiesterasc iiihibitors. The electron densities were calculated from molecular orbital approximations. Y o simple relationship was ohserved hetneen t,he net charge a t the carbonyl carbon or uarhonyl oxygen and the corresponding c-holinesternse inhibitory property; however, the activity iiicreaaes rather smoothly as the amide nitrogen liecomes more positive.

inhibitors. Although the calculations are inherently \Ye 1 ~ e been 1 interested in (norrelating physicochemicxl 1)ar:mietcrs with the cholinesterase inhibitory prol)approximate, it is not the absolute magnitudes of thc crties of 1-dccyl-3- [(IY-alkyl)- arid 1-decyl-3- [(S,S- reqults which we emphasize. Instead, we wish to tlialliy1)-substituted carbariioyl]piperidines2 and, more classify or rank certain homologs which vary systeniatircwntly, have initiated niolerular orbital calculations cally arid gradually by one structural alteration at :L t o give clcctron densities a t the atomic sites of these time, and coinpare relative electron densities with biochemical response.3 Also, we wish to evaluate yuantitatively the view4 that inhibition is related to the electrc( 1 , This research is briiir silplwrte

4 l

C', met 11) 1

I

I:,

Ha, meth>l C, inethgleiie HP, methylene C, ethyl, terminal Ha, ethyl C, methyl H,, methyl C, Iriethyletie H1, methyleiie C, ethyl, trrrnuinl Hj, ethyl

j(S,S-&alkyl)-substituted carbamoyl ]piperidines7 arc giveri in Table T'. E'roni (*omparisonof Tables 11-IV with Table V, orie (sari see that there is no simple relationship or trend bet\vccii the elertrori density at the cwbonyl rarbori or (wboiiyl oxygen arid thc rorrehpondiiig activity : lio\vcvcr, ihe eltv~trorideiiqity at the aniclc Iijtrogeii iiicreaws rather 5moothly with increasing values of 1," or, cxlressecl uiother i v q , Ihc :ivt ivity increases :I\

thc Iiitrogeri ; i t ~ ~ becomes i i more p o i t i v ~ . P'igui,c 1 is a plot of artivity (Ijo, Table V) against t h e net charge on the amide iiitrogeri (Table 11) and the line is thcl least-square5 line of these points. An interpretation of these arid other rciulti is rv1)orted ~ I the I following I)aper.9

PARTITIOX COEFFICIENTS A N D CHOLINESTERASE IKHIBITIOK

N a y 1966

297

TABLEV CHOLINESTERASE IKHIBITORY PROPERTIES O F 1-DECYL-3-[ (N-ALKYL)- AKD 1-DECYL-3-[( N,N-DIBLKYL)SUBSTITUTED CARBAMOYL]PIPERIDINES

: 0.26

0.25 0.24

g 0.21

NRiRz

0

.$ 0.20

z

0.19

0.18

c

0.14

0.13

1

Iso, Af

x

1065

6 . 23b NHCH3 3.4gb NHCzHj 1.37b N(CH3)z 2.17b N( C2&)2 0.53" N(CJ%)z 0. 105d a Molarity of inhibitor effecting 507, inhibition. See ref 7b. See ref 7a. J. G. Beasley, unpublished data. 2"

2

3 41

4

x

6

5

105.

Figure 1.-Net charge at the amide nitrogen atom of l-decyl3-[(alkyl)- and 1-decyl-3-[( N,N-dialky1)-substituted carbamoyl]piperidines us. the coiresponding cholinesterase inhibition.

Acknowledgment.-The author wishes to thank Dr. Charles W. Sheppard for his kind assistance in computer programming and Miss Joan S. Hendrix for her help in operating the IBM 1620 computer. ,41so, we are grateful to the Xational Science Foundation and the Walter Reed Army Institute of Research for their support of this research. This paper is contribution Xo. 42 from the Army Research Program on Malaria.

Application of Partition Coefficients, Electric Moments, Electronic Structures, and Free-Energy Relationships to the Interpretation of Cholinesterase Inhibition1 WILLIAMP. PURCELL, JAMES G. BEASLEY, RONALD P. QUINTANA,

bND

JUDITH A. SINGER

Department of Pharmaceutical and ,Vedicinal Chemistry, University of Tennessee College of Pharmacy, Memphis, Tennessee 58103 Received December 14, 1966 Cholinesterase inhibition of some N-alkyl-substituted amides is interpreted in the light of their partition coefficients, electric dipole moments, electronic structures calculated from the Huckel molecular orbital method, and free-energy relationships. At least 7-57, of the observed cholinesterase inhibition can be accounted for from a linear relationship between log 160 and log (partition coefficient). The activities of seven mono(carbamoy1piperidino)decanes are explained in terms of electronic, stereochemical, and hydrogen-bonding factors. The inhibitory properties of several mono- and bis[3-(N,N-diethylcarbamoyl)piperidino]alkanea are discussed from considerations of the smooth curves obtained from plotting l/ZjO against n, the number of carbon atoms in the alkyl chain. I t is believed that the mono derivatives have competing electronic and hydrophobic factors which contribute to the activity, while the inhibition of the bis compounds can be approximated nicely from the Bn C. Linear free-energy relationships indicate that the inhibitors under parabolic equation, l/Z, = An2 study have similar binding modes. A model for the inhibitor-enzyme complex is proposed which has points of attachment (1) a t the anionic site between the carboxyl group of the enzyme and the positively charged quaternary ring nitrogen of the inhibitor, and (2) a t the esteratic site in the form of a quasi-ring formed from association of (a) the serine hydroxyl oxygen of the enzyme with the amide nitrogen of the inhibitor, and ( b ) the serine hydroxyl hydrogen of the enzyme with the amide oxygen.

+

+

The inhibitory effect upon isolated human plasma pseudocholinesterase (acylcholine acylhydrolase, EC 3.1.1.8) systems produced by series of substituted arylalkylaminopropionamidesz~3and of piperidinecarboxamide derivatives4s5 has been studied extensively.

I n continuing investigations designed to elucidate structureactivity relat,ionships in these series, we have (1) measured dielectric properties,6--s (2) calculated electronic struct'ures,g (3) applied regression analyses1O to the structure-activity data, (4) evaluated surface-

(1) This research is being supported b y the National Science Foundation (GB-2381/B-15989). Computer facilities were provided through U. S. Public Health Service Grant HE-09495. (2) A. Lasslo, P. D. Waller, A. L. hleyer, and B. V. R a m a Sastry, J . M e d . PhaTm. Chem., 2, 617 (1960). (3) -1.Lasslo, P. D. Waller. a n d G. J. Epperson, ibid., 6, 26 (1963). (4) A. Lasslo, J. G. Beasley. G. G . Nelms, and G. J . Epperson, ibid., 6, 811 (1963).

(5) J. G. Beasley, R. P. Quintana, and G. G. Nelms, ibid., 7 , 698 (1964). (6) W.P. Purcell, J . P h y s . Chem., 68, 2666 (1964). (7) W.P. Purcell and J. A. Singer, ibid., 69, 691 (1965). (8) W. P. Puroell, J. G. Beasley, and R . P. Quintana, B i o c h i m . B i o p h y s . Acta, 88, 233 (1964). (9) W.P. Purcell, J . Med. Chem., 9, 294 (1966). (10) W.P. Purcell, B i o c h i m . B i o p h y s . Acta. 1011, 201 (1965).