Quantitative structure-activity relationships for substituted aminotetralin analogues. I: Inhibition of norepinephrine uptake

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  • Quantitative Structure-Activity Relationships for Substituted Aminotetralin Analogues. I: Inhibition of Norepinephrine Uptake

    KI H. KIM', FATIMA BASHA, ARTHUR HANCOCK, AND JOHN F. DEBERNARDIS Received November 27, 1991, from the Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064. Accepted for publication September 10, 1992.

    Abstract 17 Quantitative structure-activity relationships of 57 substi- tuted aminotetralin analogues, an overview of their syntheses, and their pharmacological activity are described in this study. Lipophilic substitu- ents at R, as well as the overall lipophilicity of the molecule contribute toward increasing the inhibitory potency. An ethyl group is preferred, and a group larger than a propyl is not desirable as a nitrogen substituent. Among the ring substituents examined, an hydroxy group at the R, position and either an unsubstituted R, position or a methoxy substituent at the R, position increase the inhibitory potency, whereas a methoxy group at the R, position decreases inhibitory potency.

    Biogenic catecholamines, such as dopamine and norepi- nephrine (NE), and indolamines, like 5-hydroxytryptamine (5-HT), have been considered to play an important role in the pathogeny of depression. It is believed that the action of antidepressant agents is a result of facilitated action of neurotransmitters by inhibition of the uptake of the en- cephalic amines. Thus, effective NE uptake inhibitors without undesirable pharmacological properties would be beneficial. Because the classical antidepressant drugs, such as imipramine and amitriptyline, have side effects and deficiencies,' the search for novel agents continues. For many years much emphasis has been placed on the discov- ery of nontricyclic compounds referred to as "nonclassical" antidepressants.2-s

    In this paper, we describe the quantitative structure- activity relationship (QSAR) of 57 substituted aminotetralin analogues (I) for their inhibitory activity against NE uptake.

    Experimental Section Inhibition of NE Uptake-The testing of compounds for activity

    as inhibitors of NE uptake in vitro followed procedures described by Snyder and Coyle.9 Male Sprague-Dawley rats were decapi- tated, and regions of their brains were dissected according to the procedures of Glowinski and Iversen.10 Hypothalamic tissue was homogenized in 10 volumes of 0.32 M sucrose with a Teflon/glass Potter-Elvehjem tissue grinder. The homogenate was centrifuged a t 1000 x g for 10 min, and the supernatant containing synapto- somes was harvested and used in the assay. Aliquots of tissue (100 pL) were added to 750 pL of Kreb's solution (composition in mM; NaC1, 118; KCl, 4.0; CaCl,, 1.13; KH,PO,, 1.12; MgSO,, 1.20; NaHCO,, 2.4; D-glucose, 5.0; Na,EDTA, 1.5; ascorbic acid, 1.0; and pargyline, 12.5 pM; pH = 7.4; aerated with 95% 0,, 5% CO,), 50 pL of test compound dissolved in 0.3 mM ascorbic acid and diluted in water, and 100 pL of [,H]NE (final concentration -100 nM). Tissues were incubated for 4 min at 37 "C, rapidly vacuum filtrated over Whatman GFB filters, and washed with 0.9% NaC1. Nonspe- cific uptake was estimated in duplicate samples incubated at 0 "C. Data were analyzed as described previously to obtain IC,, values11 [IC,, values represent the concentrations (pmol) of compound that produced 50% inhibition of NE uptake]. Desipramine, imipramine, and mazindol were used as reference compounds.

    Syntheseslz.13-The compounds in Table I could be grouped into two different categories, the unsubstituted benzoisoindolines and 3-aryl-substituted benzoisoindolines, based on their synthesis. The

    Scheme I

    KCNlMeOH, AcOH wcN 1) T E N J A C h 2) MeOWHCl R 96% R R

    CN CN 111 I V II

    Scheme II

    syntheses of the unsubstituted benzoisoindolines were carried out via several different routes, two examples of which are shown in Scheme I. Scheme I1 outlines the typical procedure for method A. The unsaturated nitrile 111 was prepared14 in two steps from the corre- sponding tetralone 11. The addition of trimethyl (TM)-SCN with Lewis acid catalysis15 gave the TM-protected cyanohydrin, which was dehydrated with MeOH-HCl or POCI,-pyridine to afford the desired compound 111 in 7040% yield. The 1,4 addition of KCN to the unsaturated nitrile 111 afforded a 1 : 1 mixture of dinitrile IV in 95% yield. The hydrolysis of the dinitrile IV with HBr in CH,Cl,, followed by dimethyl formamide (DMF)-H,O treatment, gave only the cis imide V in 40-75% yield. The yield was variable depending on the substituent at the 8 position of the aromatic ring. The alkylation of the imide V, followed by reduction with diborane in THF afforded the desired isoindoline 1-39 in 50-75% yield. This synthetic sequence, although long, was functionally useful and selective for preparing most of the compounds listed in Table I.

    For method B (Scheme III), an intramolecular Diels-Alder reaction was used as the key step for the construction of the B and C rings of the isoindoline nucleus. The Diels-Alder precursor VIII was synthe- sized starting with the known benzocyclobutane acid chloride VII.16 Thermolysis of the allyl-amide VIII in o-dichlorobenzene afforded the desired tricyclic amides IX as a 1 : 1 cis :trans mixture that could be easily separated by flash column chromatography. Alkylation of the amide (Scheme III), followed by reduction of the N-alkylated amide with diborane, afforded the desired benzoisoindoline, 1-39.

    The main synthetic approach used to obtain all of the 3-aryl- substituted benzoisoindolines 40-46 is outlined in Scheme N. The 1,4 addition of dithiane anion to unsaturated nitriles 111 gave the l,4-Michael addition products as a mixture of cis and trans isomers X. The mercuric chloride-catalyzed dithianeketal exchange in eth- ylene glycol-tetrahydrofuran (THF) at reflux yielded the correspond- ing k&& XI.

    The reduction of the nitriles XI to the aminomethyl compounds XI1

    0022-3549/93/0400-0355$02.50/0 Q 1993, American Pharmaceutical Association

    Journal of Pharmaceutical Sciences 1 355 Vol. 82, No. 4, April 1993

  • Table I-Physicochemical and Structural Variables Used in Equations 1 and 2 and the Observed and Calculated Log l/IC= Values of Amlnotetralln Analogues with Equation 1

    1 2 3 4 5 6 7 8 9

    10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57

    DesiDramine lmipiamine M az i n d o I

    Me Et Me Me Me C,H4-2-furanyl C,H4Ph(3,4-(OMe),) H C,H40H Et Me H Me Me Me

    Mi? Et Et Pr Et

    Me C,H4Ph(3-F)

    Me Me H Me C3H,Ph(3-OMe) Et

    Pr C,H4Ph(3-OMe) Et Me C,H4-2-furanyl C,H4-Pthiophenyl C,H4Ph Et H C,H,Ph C,H,Ph H Me H CH,Ph(3-OMe) H Me Me Me Me Me Me

    C,H,Ph(3-F)

    Et Et

    d -

    H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H CH,Ph H H CH,Ph CH,Ph(3-OMe) CH,Ph CH2Ph(3-OMe) CH,Ph(3-F) CHgPhQ-F)

    CHiPh CH,Ph CH,Ph CH-Ph CHiPh CH,Ph(3-F)

    H H H H H H H H H H H H H Ph(3,4-OMe2) H H H H H Me H H H H H H H H H Ph H H H H H H H H H H H H H H H H H H H H H H H H H H H -

    -

    OCOtBu OMe OH CI H H H OMe OH H H OMe OMe OMe OMe OMe OMe H H OMe OMe OMe SMe OMe H CI OH OH CI OMe OMe OMe OMe Br OMe OMe CI OMe OMe OH Br OMe OMe OMe H OMe H H H H H H OMe H H OMe OMe - - -

    OCOtBu H OH H OMe OMe OMe H OH H H H H OMe H OMe H OMe OMe H H H H H OMe

    K? OH

    K k e H H H H H H H H H OH H H H H OMe OMe OMe OMe OMe H OMe OMe H OMe H H H - - -

    H H H H H H OMe H H H H H H H H H H H H H H H H H H CI H H CI H H H H H H H H H H H H H H H H H H H H H H H H H H H H - - -

    Me OH Me OCH,C=CMe, OCzH4Ph H H CSHePh H

    OC3H,Ph(4-F) C,H,Ph H Bu H H H H OMe C,H,Ph C,H,Ph OMe OC,H,Ph H H C4H,Ph H H H H OC4H,Ph H OMe H OC,H4Ph H H H H OMe H H H H H H H H H H H H H H H H

    - -

    a Concentration in pM/kg of compound required for 50% inhibition of NE uptake. Calculated using CLOGP program.14 Concentration in nM/kg; the following values were reported by Javitch and co-workers (Javitch, J. A.; Blaustein, R. 0,; Snyder, S. H., Mol. Pharmacol. 1984, 25, 35): desipramine (7 nM), imipramine (58 nM), and mazindol (2 nM). -, Not applicable.

    356 I Journal of Pharmaceutical Sciences Vol. 82, No. 4, April 7993

  • Table 1-Continued

    obs calcd dev

    4.588 4.698 4.958 5.008 5.031 5.180 5.187 5.221 5.244 5.267 5.289 5.292 5.349 5.359 5.408 5.408 5.420 5.431 5.494 5.500 5.500 5.508 5.522 5.555 5.568 5.568 5.602 5.698 5.759 5.769 5.795 5.795 5.844 5.920 5.920 5.920 5.958 6.003 6.028 6.051 6.119 6.120 6.130 6.139 6.153 6.271 6.284 6.436 6.500 6.681 7.161 7.173 7.221 7.236 7.31 8 7.552 7.568 7.934 6.978 9.222

    4.847 4.641 4.832 5.198 4.966 5.339 5.262 5.087 5.251 5.462 5.474 5.034 5.371 5.603 5.182 5.663 5.733 5.487 5.605 5.419 5.781 5.677 5.775 5.708 5.653 5.670 5.568 5.752 5.386 5.789 5.972 5.756 5.869 5.906 5.794 5.592 5.690 5.555 5.703 6.149 5.961 6.712 5.822 5.999 6.496 6.943 6.496 6.421 6.589 6.900 6.873 6.780 6.996 6.780 6.807 7.406 7.499 - - -

    -0.259 0.057 0.126

    0.065 -0.189

    -0.159 -0.075

    -0.007 -0.195 -0.184 0.257

    -0.021 -0.244 0.226

    -0.255 -0.312 -0.055 -0.1 1 1 0.080

    -0.281 -0.169 -0.252 -0.152 -0.085 -0.101 0.033

    -0.053 0.372

    -0.019 -0.176 0.039

    -0.025 0.01 3 0.126 0.328 0.267 0.447 0.325

    -0.098 0.157

    -0.591 0.308 0.139

    0.134

    -0.343 -0.672 -0.212 0.014

    -0.088 -0.218 0.288 0.393 0.225 0.456 0.51 1 0.146 0.069 - - -

    25.800 20.000 11.000 9.800 9.300 6.600 6.500 6.000 5.700 5.400 5.130 5.100 4.470 4.370 3.900 3.900 3.800 3.700 3.200 3.160 3.160 3.100 3.000 2.780 2.700 2.700 2.500 2.000 1.740 1.700 1.600 1.600 1.430 1.200 1.200 1.200 1.100 0.992 0.936 0.889 0.760 0.757 0.740 0.726 0.703 0.535 0.520 0.366 0.316 0.208 0.069 0.067 0.060 0.058 0.048 0.028 0.027

    1 1.63=

    0.60' 105.2'

    4.525 4.982 2.249 5.148 5.039 4.156 3.927 5.282 1.021 6.008 3.647 4.865 6.128 3.388 5.089 4.479 4.685 4.596 4.950 3.461 6.657 6.128 4.521 6.097 5.093 3.587 5.404 1.600 2.741 3.940 6.626 5.398 5.093 4.914 5.568 4.869 3.647 4.156 4.596 3.697 4.385 4.094 4.950 5.479 4.094 4.859 4.094 4.859 4.237 5.164 5.083 4.940 4.940 4.940 5.021 5.469 5.612 - - -

    0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 2.791 0.000 0.000 2.791 2.71 0 2.791 2.710 2.934 2.934 2.934 2.791 2.791 2.791 2.791 2.791 2.934 - - -

    0.649

    0.649 1.361 2.016 0.000 0.000 3.025 0.000 2.545 0.000 2.688 3.025 0.000 2.236 0.000 0.000 0.000 0.000

    -0.081 3.025 2.746

    -0.081 2.545 0.000 0.000 3.804 0.000 0.000 0.000 3.074 0.000 0.000

    -0.081 2.016 0.000 0.000 0.000 0.000 0.000

    -0.081 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000

    -0.667

    - - -

    0 0 0 0 0 1 1 0 1 0 1 0 0 1 0 1 1 1 1 0 0 0 0 0 1 1 0 1 1 1 0 1 1 0 0 1 1 1 1 1 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 - - -

    0 0 0 0 1 1 1 0 0 1 1 0 0 0 0 0 0 1 1 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 1 1 1 1 1 1 0 1 1 0 0 - - -

    0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 1 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 - - -

    0 0 1 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 - - -

    0 0 0 0 0 1 1 0 1 0 0 0 0 0 0 1 1 1 1 0 0 0 0 0 1 0 0 0 0 0 0 1 1 0 0 1 0 1 1 1 0 0 1 1 0 0 0 1 0 0 0 0 0 0 0 0 0 - - -

    0 1 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 1 1 0 1 0 0 0 0 0 0 1 0 0 0 1 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 - - -

    Journal of Pharmaceutical Sciences I 357 Vol. 82, No. 4, April 1993

  • 2) BH3.THF 1-39

    Scheme I l l

    CN k, I I CN R,

    111 X I

    Scheme IV

    was accomplished by catalytic hydrogenation with Raney nickel in methanol. The desired benzoisoindolines XI11 were obtained in a one-pot reaction from the hydrolysis of aminomethyl ketals XI1 with hydrochloric acid, in THF, to the keto amine. The keto amine, in equilibrium with the corresponding iminium compound, was readily reduced by sodium cyanoborohydride. The compounds XI11 were converted to the N-alkylated compounds 40-46 by alkylation under standard conditions and hydrogenation in the presence of palladium on carbon and formaldehyde.

    QSAR-The NE uptake inhibitory potencies of the substituted aminotetralin analogues are listed in Table I. The negative logarithm of IC,, values was used in the correlation analyses. Thus, a higher log 1/IC50 value represents a more potent compound.

    Physicochemical parameters investigated include the hydrophobic parameter T, log P (where P is the octanol-water partition coeffi- cient), molar refractivity (MR) for the size and/or dispersion interac- tion due to the substituents, and indicator variables for different structural variations Iy=OCH1, &+OH, IRZ=pr, IR =H, IQ=Et, and ). All parameter va ues were taken from the fiterature17 or calculated with CLOGP program.18

    For the QSAR study, the multiple regression analysis technique was employed. The regression analyses were performed using the SAS program19 on aVAX computer. The best equation was selected based on the results of all possible equations.

    Results Equation 1 shows the multiple regression equation ob-

    tained with the 57 substituted aminotetralin analogues listed in Table I.

    + 1.38(+_0.20)1%=~ - 0.22(+0.09)1&,~

    + 0.34(-cO.O8)10g P

    + 0.23(+0.12)1~~=~t + 3.09(+0.37)

    (n = 57, s = 0.274, r = 0.935, F = 32.01,

    (1) p c 0.0001, press s = 0.294)

    In eq 1, n is the number of compounds used in the analysis, s is the residual standard deviation, r is the multiple correla- tion coefficient, and press s is the average residual standard deviation of the predicted potency from the leave-one-out jackknife cross-validation analyses calculated from the cor- responding PRESS (sum of the predicted squared residuals) value. The standard error of estimation of each coefficient is given in parentheses. The variables rR3 and 7% are lipophilic constants for R3 and R, substituents, respectively. The vari- ables zR2=Et, IR2>Pr7 ZR,=H, Z%=OH, Z+H, and Z%=OCH, are indicator variables: ZRz=Et takes the value of 1 for R, = Et; ZRz,Pr takes the value of 1 for an R, substituent that is larger than a propyl group; ZhZH and ZR -OH take the value of 1 for R, = H and R, = OH, respective&; take the value of 1 for R, = H and R, = O%H,, respectively. Log P is the calculated octanol-water partition coefficient value.

    Table I lists the observed and calculated log l/IC50 values using eq 1 and the variables used in eq 1. Figure 1 is the plot of the observed and calculated (with eq 1) log l/IC50 values. The Pearson correlation coefficients between the variables used in eq 1 are listed in Table 11.

    There are five racemic compounds (45-47,50, and 51) due to the stereochemistry at R, position included in eq 1. Although the calculated activity values of these compounds do not deviate from the observed values by a larger amount, an improved equation (eq 2) was obtained when these com- pounds were excluded. Equation 2, however, provides essen- tially the same information a...

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