Electronic factors in drug-receptor interactions - Journal of Medicinal

Comparison between theoretical and experimental electric dipole moments of selectedN, N-dimethylaniline derivatives. John M. Clayton , George E. Bass ...
0 downloads 0 Views 364KB Size
.January 1970

KOTES

1,2,3,4,6,7,12,12a-0ctahydro-2-phenylpyrazino-

[2',1' :6,l]pyrido[3,4-b]indole JOHSW.SCHULI:NBI:RG A N D I)OS.U,DF. P.4~1,: Sterling-W:inthrop R r s m - c h Institute, Renssrlrrrr, .l-ew York 12144 Rrcriticd Srptenihcr 10, lYSB

We wish to report the .synthesis of the title compound (11) which ive believe represents a new ring system. The iiidole I1 of potential interest to us because of its structural relationship to the major tranquilizer oxypertine (I). The tricyclic ester I11 was prepared in two steps from tryptophane by a literature method.2 Treatment of 111 with ClCH,COCl furnished the amide I V which was heated with P h S H , in Cellosolve to afford the cyclized product T-. Reduction of JT with LBH provided the desired amine 11. I n contra5t to oxypertine, compound I1 is not a C S S depressant. It failed to potentiate hexobarbital at 100 mg kg po in mice.Ib At a dose of 1 mg/lrg PO in mice. I1 produced a 91% increase in spontaneous activity, whereas oxypertine had caused a marked decrease. l a

H I1 .4

0

COOC,H,

H

YVONKE C. ~ I A R T I S Chemical Pharmacology Department, Scienti'c Laboratories, Abbott Laboratories, .Yorth Chicago, Illinois 60064 Received J u n e 30, 1969

TABLE I P o m x c u OF NICOTINIC ACIDDERIVATIVES AS IKHIBITORS OF ACETYLCHOLINE ESTERASE^

0

111, R = H

Compound

Frontier orbital density,f

Xicotinic acid Nicotinamide 3-Acetylpyridine Ethyl nicotinate

0.262 0.616 0.667 0,699

V

Experimental Section'

-

Ethyl 2- (Chloroacety1)-1,2,3,4-tetrahydro-S"pyrido [3,4-b] indole-3-carboxylate (IV).-A solution of 11.3 g (0.10 mole) of ClCH,COCl in 15 ml of CHCla was added over 40 miri to a stirred solution of 10.0 g (0.041 mole) of ethyl 1,2,3,4-tetrahydro9H-pyrido [3,4-b]indole-3-carboxylate(111)2 in 200 ml of CHCla. The mixtiire was refluxed for 6 hr, 20 ml of MeOH was added, arid the solvent was removed in vacuo. The crystalline residue was recrystallized from CsHs-n-heptane (charcoal) to give 11.0 g ( 8 4 5 ) of tan prisms, m p 143-143". A n a l . (C16H&lN203)

c1, N.

(1) (a) 9. Archer, D .

Electronic Factors in Drug-Receptor Interactions

h'C,H-

H

IV, R = COCH,Cl

2,3,6,7,12,12a-Hexahydro-2-phenyIpyrazino [2',1' :6,l)pyrido[3,4-b]indoIe-1,4-dione (V).-A mixture of 18.0 g (0.056 mole) of IS; (above), 6.7 g (0.072 mole) of PhSH2, arid 300 ml of Cellosolve was refluxed 18 hr. The solvent was removed in vacuo, the residue was extracted with hot, EtOAc, and the extracts were washed with dilute aqueous HC1 and aqueous PiaC1. Removal of the EtOAc left a residue which could be crystallized directly. However, it was preferable to chromatograph the material on silica. Elution with EtOAc gave a solid which was washed with Et,O, then recrystallized from EtOAc to furnish 10.3 g (56%) of tat1 prisms, m p 254-257'. A n a l . (C20HliK302)C, H, S . 1,2,3,4,6,7,12,12a-Octahydr0-2-phenyIpyrazino [2',1' :6,1]pyrido[3,4-b]indoIe (II).-A mixture of 5.70 g (0.01i mole) of V, 3.3 g (0.088 mole) of LAH, and 500 ml of dry T H F was refluxed for 48 hr. After cooling, aqueous T H F was added, and the mixture was filtered. The insoluble material was washed with hot T H F and the solvent was removed from the combined filtrates t o give a dark residue which was chromatographed on silica. Elution wit8h CoHe-EtoO gave crystal* which were recrystallized from C & hept'ane to furnish 1.54 g (30%) of tan product, mp 228-232". Anal. (C20H2*X3)C, H, S .

The recent report by Cammarata' presented electronic mechanisms by which a drug and its receptor may interact. Pertinent equations for testing these mechanisms were also included. However, not all of the examples were tested statistically, and in one case a more rigorous analysis of the data was possible, yielding evidence in support of the mechanism. The following calculatioris have been performed on data in the above paper. The relationship between frontier orbital charge density at the carbonyl carbon (f)and the potency of some nicotinic acid derivatives as inhibitors of acetylcholine esteraqe was noted2 (Table I ) . The following equation

I

I

145

----Obsd

PIS----7 Calcd, Calcd, eq 1 eq 2

0.3 1.2 2.3 3.1

0.146 2.03 2.23 2.47

1.23 2.18 3.15

was derived by us from the data by a least-squares technique. The correlation coefficient is not signifipIj0 = -1.247

+ 5 322f (t

=

i^

=

0 868

F1,2

=

6 16

2.48) (1)

IV. Wylie. L. S. Harris, T. R. Lewis, J . W.Schuien-

berg, BI. R. Bell, R. K. Kullnig, and A . Arnold, J . Amer. Chem. Soc., 84, 1306 ( 1 9 6 2 ) ; (b) D . W.Kylie and S. Archer. J . M e d . Pharm. Chem., I , 932 (1962). (2) J . LehIen and C. Fan, Bull. Soc. Chim. Fr., 1866 (1959). (3) D a t a supplied by the Department of Pharmacology. (4) Melting points were taken in capillaries and are uncorrected. Analytical results were determined by BIr. Ii. D. Fleischerand staff. Where analyses are indicated O d y by symbols of the elements, the analytical results obtained for those elements were within f0.470 of the theoretical values. Ir spectra of all compounds are compatible with t h e assigned structures.

cantly different from 281-0.~ If the nicotinic acid is omitted from the series (it is the only compound which would be in an ionic form a t the p H of the studies) the (1) A . Cammarata, J . M e d . Chem.. 11, 1111 (1968). (2) .4 Inouye, Y. Shinagawa, and Y. Takaishi, Arch. Intern. Pharmacodun. 144, 319 (1963). (3) N. Draper and H. Smith. "Applied Regression Analysis," John !Vile) &: Sons, Inc., Ne\\ Tork, S . Y.,1966.

folio\\ irig equation may be calculated. This equ:Ltiori pI50 =

it

2 3 . lj - 13 0 10 18)

=

i'

0 995 P'lJ

=

104

(2)

=

is 31.0 iiot stiiti-tically significant. Thus there is 1 1 0 atatistical evidence that there is ii rel:ition.hip bet\\-eeii erie,.;. It would be iriteresting to havc a more exteiihive .et of cotnpouridi to te.t in thi, respect. A .ccoiid example of clectroiiic f:ictur. in drug interwctiorii is the npp:treiit relatioiiyhip hetweeri the theoretically based valucc for the total electronic chnrgc 011 the amide riitrogeti ( q h ) mid e potency of carbamoylpiperidirie. :I+ choliiie.tcr inhibitor.' ( T ~ h l r11)

I'urcell, et al.,> reported that "at IC> served cholinesterase inhibit ion ca from a linear relationship bet\veen log Ij0and log (partit8ioticoefficient) ," a n empirical or experimental value. Electronic factors were ~ l s thought, o to be important but no regressioii equations were giveii. In our calculatiotih t>hefollowing relationship \rere found. Thus, the em-

pIs0 = 3 , 0 4

+ 8. 1l 6 q ~ (t

pIj0 = 4 . 1 7

=

).

=

0 . (XI6

F1,q =

3 . 77 (3)

1.94)

+ 0.3Ulrr

=

I.

0.992

F1,4 =

279

(4)

2%

(2)

( t = 16.71) $60

=

3,47

+ I . U q x + 0 . G237r (t

=

2.06) ( f

= 1'

Iti.16)

=

0. 997

F2.3 =

pirically derived Haiisch TT coiist:iiit6 for the octaiiol H?O system is the only statistically sigriificant predictor of iuhibitor potency. However. there is a significant cori*el:ttioii between the empirical TT value arid the theoreticdly based y s ( r = 0.761, t = 3.10- p < 0.05). This relntioiisliip illustr:tte> t I)(> frtquently observed iiitcrtlependeiice of tlir vuious physical chemical parameters ivithiii :I s;ci*icsof drug molecules. (For example, Iiogai's aiid (':inimaixta' have recciitly reported on the corwhtioii of superde1oc:~liz:ibilit~~ mid total absolute ch:trgc density with octariol- bufffer partition coefficients for :i relie. of :ironiatic molecules.) Because of such itit.crdepciideiicc I-)et\xen what oiie would label electroiiic factors :itid \\.hat is thought of as hydrophobic and lipophilic parameters one must he cautious iii postulating the mechanism of drug nctioii on the ba t,urc --activitystudies :~loiie. 4 ) \ \ , 1'. l ' \ i r c c ~ l l . . I . .l/erl. Chrrn.. 9 , 294 i l Y i i t i ) . (.-,I \\'. 1'. l'iircrll .J. (;. Ilraslry. El. P. Quintana. and J. .ISinrer. . ihiri.. 9, Z4i \ l < l U f i ) . ( t i ) . I . I n a s a . T. l:iijita, and ('. lianwli. iI,ifi., 8 , 150 I.lY65I. s i r 1;. d . Royt'rS an11 . \ . ( ' a m m a r a t a . iln,/.,12, 692 (1969).

January 1970

KOTES

able3 which was given the value of 1.0 for the phenyl derivatives and zero for the bensamides. This variable would incorporate factors which differ from one series as a whole to the other series, such as the different geometry of the two sets.) Equation 7 is much more appropriate to test the hypothesis because the values for the variables have a larger variation and there are more observations which thus increases the degrees of freedom. I n eq 7 all three electronic parameters contribute significantly to the prediction of antibacterial activity. Thus Cammarata's suggestion that these drugs interact with the receptor in a frontier-controlled reaction is supported by this equation. The above examples point out the necessity of testing apparent structure-activity relationships with statistical methodq. Thus two examples of apparent correlation between electronic factors and inhibitor potency were shown to be not statistically significant. The amount of variation in a factor used in a regression equation must be large enough that experimental error or round off in the computer does not influence the results. Because of the correlation between the various theoretical and empirical parameters one must be cautiou.; in interpreting the meaning of such studies.

nicotinamide-adenine dinucleotide (SA4D)dependent systems by these agents. Such observations led us to prepare a series of P-amino ketones derived from 4piperidinoacetophenone ; such a series would permit us to examine the possible effects on such inhibition as they relate to the specific structure of the p-amino ketones in question. Thus, all amino ketones studied (Table I) had cyclic amine components with one exception (6) and all possessed a large cyclic component at the para position in the original ketone.

147

T ~ I I LIL B-Aw~soK L T O K 5 ~ lield,

hip

NRiRz

NO

- nW o

I

R

Oca

183-188

49 ClsH&l?N?O?

20i-211

37 C?OH31C12N202

CH

I1

-hAO Y C H

111

--.3 190-192

38

CIoH,?Cl?S20

11.

- 1 3

201-205

40

Cl~H80Cl?ru'~0.0.75H20

44

C?oH3?Cl?N20

-qH

203-206

&Amino Ketones as Inhibitors of Pyruvic Acid Oxidation

IVI

YCH 1 194 Melts with decompoaition

R.IJESDH.I S. V . \ R X I , ~ ~BASHEER A L I , ' ~SURESDRA S . PARMAR, for C, H, S . Department of Pharmacology and Therapeutics, K . G's Medical College, Luckaw, I n d i a AND

W. LEWISNOBLES'^

Department of Pharmaceutical Chemistry, I'nI'rersitU of .If ississippi, University, M i s s i s s i p p i 38671 Receined J u n e .?. 1969

Substituted &-imino ketones (Table I) have elicited a variety of physiological responses; various workers

trated that compounds of this type possess analgeti~,~local anesthetmic,5-8 and ant'ibacterialg,'" activity. Luts and Nobles" observed ant'iconvulsant, analgetic, and antiinflammatory activity in a series of cyclic &amino ketones. Quastel and Wheatley have reported t,he in vitro inhibition of respiration by various anesthetics and CNS depressants; this was related to the select8iveinhibition of (1) (a) Pool Officer, Council of Scientific and Industrial Research, New

Delhi. (h) Junior Research Fellow, Council of Scientific and Industrial Research, S e w Dellii. (c) T o whom inquiries should be addressed: Office of the President, Mississippi College, Clinton, Miss. 39056. (2) ,J. J . Denton. R . J. Turner, W. B. Xeier, V. A. Lamson, and H. P. Schedl. J . A m . Chem. Soc., 71, 2048 (1949). (3) RI. Bockmulie and G . E h r a r t , German Patent 865,314 (Feh 2, 1953); Chem. I b s t r . . 63, 295 (1959). (4) P. R.J. Jaussen, U. S. Patent 3,030,372 (April 17, 1962); Chem. Abstr., 69, 2 i 8 0 (1963). ( 5 ) C. Mannich and D. Lammering, Ber.. 65, 3510 (1922). (6) F. F. Blicke and E. S. Blake, J . A m . Chem. Soc., 62, 235 (1930). ( 7 ) \V. TVilson and Z. P.Kgi, J . Chem. Soc., 1321 (1952). (8) T. Teshigahara, N i p p o n Yakurigaku Zasshi, 68, 67 (1962); Chem. Abstr., 59, 3239 (1963). (9) H. J. Florestano, hl. E. Bahler, and A . D. Chandler, J . A m . Pharm. Assoc., 46, 539 (1957). (10) R. S. Varma and W.L. Nobles, J . Pharm. Sei., 57, 1801 (1968). (11) H. A. Luts a n d W. L. Nobles, abid., 64, 67 (1965). (12) J. H. Quastel and A . H. M. Wheatley, Proc. Roy. Soe. (London), B l l 2 . 60 (1932).

Formula'

72 C16H26C12N20 .0.5HZO compounds were analyzed

* All

Biochemical Studies.-Male albino rats weighing 100-150 g kept on an ad libitum diet were sacrificed by decapitation. Rat brains were immediately homogenized in a Potter-Elvehjem homogenizer. Brain homogenates (1070, w/v) mere prepared in 0.25 ,If cold sucrose. O2uptake was measured at 37" by the conventional Warburg manometric technique with air as the gas phase.I2 The central well contained 0.2 ml of 20% KOH solution. The reaction mixture in a total volume of 3 ml contained 6.7 mJ1 AIgSO4, 20 mJf S a 2 H P 0 4in a buffer solution of p H 7.4, 1 m M adenylic acid (Na salt), 33 mJf KCl, 500 pg of cytochrome c, and 10 mM sodium pyruvate. The compounds, dissolved in double distilled water, were used at a final concentration of 0.5 mM. Results and Discussion The data in Table I1 indicate that all the @-amino ketones were found to inhibit the oxidation of pyruvic acid. Such in vitro inhibition of respiration has been shown, as noted earlier, to be exhibited by various anesthetics and CNS depressants.l 2 These results have seemingly indicated the significance of the cyclic amine moiety in the inhibitory effects thus produced by certain @-aminoketones on pyruvic acid oxidation. Concurrently, it should be noted that P-dimethylamino-Ppiperidinopropiophenone (VI), possessing dimethyl substituents in the amine moiety, was found to produce only slight inhibition under similar conditions. On the basis of this observation, it would appear that the cyclic amine group possibly plays an important role in the inhibition of pyruvic acid oxidation. I n the com-