Abstract:
&#34;Derivatives of 9-aminoacridine characterized by psychothropic, antiamnestic and lipid-regulating activities&#34;. 
     New chemical compounds derived of 9-aminoacridine with a general formula are presented: ##STR1## where R=H or CH 3  R 1  =H, CH 3 , or Br 
     R 2  =H, CH 3   
     R 3  =--C 1  -C 5  alkyl phenylmethyl, substituted phenylmethyl or diethylaminoethyl 
     X=C=O, or CHOH, Y=CH 2  or 
     X+Y=CH=CH 
     and their salts with organic and inorganic acids. 
     The target compounds were obtained by a reaction of substituted nitriles of anthranilic acid with dimedone and subsequent cyclization of intermediate enaminonitriles to the corresponding 9-amino-3,4-dihydroacridine-1(2H)-ones. The reduction of the compounds or their alkylated or aralkylated at 9-aminogroupe derivatives results in corresponding alkanols, which on dehydratation give 9-amino-3,4-dihydroacridines. 
     In animal experiments the derivatives of 9-aminoacridine in question showed psychothropic, antiamnestic and lipid-regulating activities and less toxicity as compared with known reference drugs.

Description:
This application is a continuation of Ser. No. 08/211,127 filed Jan. 7, 1993 now abandoned which is a 371 of PCT/RU92/00096 filed May 6, 1992. 
    
    
     TECHNICAL FIELD 
     The development refers to new chemical compounds, particularly to the derivatives of 9-aminoacridine, which show psychotropic, antiamnestic and lipid-regulative activity and may be used in medical practice to treat psychic diseases, in particular senile dementia of Alzheimer&#39;s type, as well as diseases connected with disturbances of lipid metabolism. 
     PRIOR ART 
     The drug tactine (Summers W. K. et all.//New Engl. J. med. 1986, Vol. 315, No. 20, p. 1241) is widely used abroad in Alzheimer&#39;s disease clinics; a new original drug amiridine has been developed at National Research Center for Biologically Active Compounds (USSR Patent Application N 4076765 from 01.07.86. A61K 31/47; U.S. Pat. No. 4,735,953, cl. 514,313, 1988; BRD Patent N 3231571, A 61K 31/47,1988). ##STR2## 
     The drawbacks of the above drugs are their comparatively high toxicity, side effects of cholinergic nature (tremor, diarrhea, salivation), and toxic effect of tactine on liver. 
     Derivatives of 9-aminoacridines having a general formula ##STR3## with a structure similar to that of claimed compounds and possessing psychotropic and memory stimulative activity are known (European Patent Application N 0179383 C07D 219/10, -1985; Shutske G. M. et al.//J. Med. Chem. -1989, 32, 1805-1813; Shutske G. M. et al.//J. Med. Chem. -1988, 31, 1279-1282). 
     Shortcoming of these compounds is a comparatively high toxicity and as a consequence of this--a low therapeutic index. 
     Structure analogues of the claimed compounds having a formula are known (European Patent Application N 0371388, C07D 219/10, -1990) ##STR4## where ##STR5## which are inhibitors of acetylcholinesterase; however, there is no information on their antiamnestic and lipid-regulative activity. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Derivatives of 9-aminoacridine represented by the formula ##STR6## where R=H or CH R1=H,CH3 or Br 
     R2=H or CH3 
     R3=C 1  -C 5  alkyl, arylmethyl or, diethylaminoethyl X=C=O or CHOH 
     Y=CH 2  or 
     X+Y=CH=CH 
     and their pharmaceutically acceptable acid addition salts are disclosed. 
     The preparation of the compounds is performed following the scheme ##STR7## 
     The compounds having the formula V-VII are prepared by interaction of the corresponding substituted nitrile of aminoanthranilic acid I with dimedone II and subsequent cyclization of the hydrochloride of the substituted 2- (5,5-dimethyl-5-oxocyclohex-1-enyl) amino! benzonitrile III thus obtained into substituted 9-amino-3,3-dimethyl-3,4-dihydroacridine-1(2H)-ones IV; alkylation of compounds IV with aryl- or arylalkylhalogenides into 9-alkyl(arylakyl)-amino-3,3-dimethyl-3,4-dihydroacridine-1(2H)-ones V; reduction of the compounds IV and V into 9-alkyl(arylalkyl) amino-3,3-dimethyl-1,2,3,4-tetrahydroacridine-1-ols VI; dehydratation of the compounds VI into 9-alkyl(arylalkyl)amino-3,3-dimethyl-3,4-dihydroacridines VII. 
     The invention is illustrated with following examples. 
     EXAMPLE 1 
     2- 5,5-dimethyl-3-oxocyclohex-1-enyl)amino!benzonitrile hydrochloride (IIIa) 
     6 ml of concentrated hydrochloric acid were added to a solution of 4.72 g (0.04 mol) of anthrsnilonitrile (Ia) in 80 ml of THF with stirring, after 15 min 5.6 g (0.04 mol) of dimedone (II) were added, the mixture was heated under reflux with stirring for 12 h, the precipitate was filtered off, washed with acetone and dried. The mother liquor was concentrated to 1/3 of the initial volume, the precipitate was filtered off, washed with acetone and dried. Precipitates were combined to give 9.1 g (82%) of IIIa, m.p. 214-215 (i-PrOH). 
     EXAMPLE 2 
     2- (5,5-dimethyl-3-oxocyclohex-1-enyl)amino!-3,6-dimethyl-benzonitrile hydrochloride (IIId) 
     6 ml of concentrated hydrochloric acid were added to a solution of 5.84 g (0.04 mol) of 3,6-dimethylanthranilonitrile (Ib) in 80 ml of THF with stirring, after 15 min 5.6 g (0.04 mol) of dimedone (II) were added, the mixture was heated under reflux with stirring for 14 h, the precipitate was filtered off, washed with acetone and dried. The mother liquor was concentrated to 1/4 of the initial volume, the precipitate was filtered off, washed with acetone and dried. Precipitates were combined to give 10.5 g (87%) of IIId, m.p. 208-209 (i-PrOH). 
     Compounds IIIc-g (Table 1) were prepared in an analogous manner. 
     EXAMPLE 3 
     9-amino-3,3-dimethyl-3,4-dihydroacridine-1(2H )-one (IVa) 
     To a Suspension of 27.7 g (0.1 mol) of enamine hydrochloride IIIa in 200 ml of dry THF 27.6 g (0.2 mol) of K 2  O 3  powder and 0.5 g CuCl were added, the mixture was heated under reflux with stirring for 5 h, the hot solution was filtered, the precipitate on the filter was washed with water and dried- Organic mother liquor was evaporated to 1/5 of the original volume, the precipitate was filtered off, washed with water, dried and combined with the former precipitate. Recrystallization from aqueous EtOH gave 21.4 g (89%) of IVa, m.p. 223-224. 
     EXAMPLE 4 
     9-amino-3,3-dimethyl-3,4-dihydroacridine-1(2H)-one (IVa) 
     To a suspension of 27.7 g (0.1 mol) of enamine hydrochloride IIIa in 300 ml of dry dioxane 27.6 g (0.2 mol) of K 2  CO 3  powder and 0.5 g CuBr were added, the mixture was heated under reflux with stirring for 5 h, the precipitate was filtered off, washed with water and dried. Organic mother liquor was evaporated to 1/5 of the original volume, the precipitate was filtered off, washed with water, dried and combined with the former precipitate. Recrystallization from aqueous EtOH gave 21.8 g (91%) of IVa, m.p. 223-224. 
     Compounds IVc-1 (Table 2) were prepared in an analogous manner. 
     EXAMPLE 5 
     9-benzylamino-3,3-dimethyl-3,4-dihydroacridine-1(2H)-one (Va). 
     To a solution of 4.8 g (0.02 mol) of the amine IVa in 70 ml of dry DMSO 2.8 g (0.05 mol) of KOH powder were added, the mixture was stirred for 1 h, then 0.8-1 ml of benzyl chloride was added, the solution was allowed to stand overnight, then poured into 350 ml of water, stirred for 0.5 h, left to stand for a day, the precipitate was filtered off, washed with water, dried and recrystallized from aqueous EtOH to give 5.8 g (88%) of Va, m.p. 169-170. 
     Compounds Vb-3-(Table 2) were prepared in an analogous manner. 
     EXAMPLE 6 
     9-benzylamino-3,3-dimethyl-3,4-dihydro acridine-1(2H)-one (Va). 
     The mixture of 2.4 g (0.01 mol) of the amine IVa, 1.4 g (0.011 mol, 1.27 ml) of benzyl chloride, 0.5 g of Bu 4  NB r , 75 ml of CH2C12 and 50 ml of 50% aqueous NaOH was vigorously stirred for 20 h, then poured into 200 ml of ice water, an organic phase was separated, the aqueous phase was extracted with chloroform, (4×50 ml), combined extracts were evaporated, the residue was recrystallized from aqueous EtOH to give 5.8 g (88%) of Va, m.p. 169-170. 
     Compounds Vo (Table 2) were prepared in an analogous manner. 
     EXAMPLE 7 
     9-benzylamino-3,3-dimethyl-1,2,3,4-tetrahydroacridine-1-ol (VIe). 
     To a suspension of 3.3 g (0.01 mol) of a in 80 ml of absolute THF 0.42 g (0.011 mol) of lithium aluminium hydride was added at 0-5, the mixture was stirred for 2 h under nitrogen current at the same temperatur.e, au excess of lithium aluminium hydride was decomposed by subsequent adding of saturated solution of ammonoum chloride and 30% aqueous potassium hydroxide. An organic phase was separated, the solvent was evaporated, the residue was recrystallized from aqueous EtOH to give 3.2 g (96%) of VIe, m.p. 175-176. 
     Compounds VIa-d,f-j (Table 3) were prepared in an analogous manner. 
     EXAMPLE 8 
     9-benzylamino-3,3-dimethyl-3,4-dihydroacridine-1(2H)-one hydrochloride (VIIe). 
     The solution of 3.32 g (0.01 mol) of VIe in a mixture of 40 ml of EtOH and 5 ml of concentrated HCl was heated under reflux for 1 h. The solvent was evaporated, the residue was recrystallized from aqueous EtOH to give 3.36 g (98%) of VIIe, m.p. 236-237. 
     Compounds VIIa-d (Table 4) were prepared in an analogous manner 
     Psychoneurotropic activity of the declared compounds and their influence on learning and memory were observed using unbred male (18-20 g) mice and 180-200 g) rats, held at standard conditions (room temperature 21°-22° C., 12-hours lighting schedule, food and water ad libitum). 
     All the compounds in question underwent the following tests: 
     Acute toxicity was studied by the method of Kerber with intra peritoneal drug injection. 
     Psychotropic activity test included the influence of drugs on animal behavior, motor activity, on the effects of hexenal (30 and 60 mg/kg), arecoline 925 mg/kg, and apomorphine (2 mg/kg). The drugs were applied intraperitoneally in the dose of 1/2o of LD. 6 mice were in the each experimental group. 
     Step-down test was used to study the influence of drugs on learning and memory in mice using the model of amnesia achieved by the injection of the central ACh-receptors inhibitor scopolamine (Sc). 
     
                                           TABLE I__________________________________________________________________________2- (5,5-Dimethyl-3oxocyclohex-1-enyl)amino!benzonitriles__________________________________________________________________________IIIW              M.p. IR spectrum                       Found, %n/n   R  R.sup.1    R.sup.2       HX °C.               ν, sm.sup.-1                       C  H  N  Cl1  2  3  4  5  6    7       8  9  10 11__________________________________________________________________________Wa H  H  H  HCl          214-215               2800-2400,2230                       65,10                          6,40                              9,68                                12,76               1680,1575,1550               1480WB H  H  H  -- 187-188               3230,3150,3090,                       74,57                          6,94                             11,70               3060,3030,2230               1590,1570,1520               1475Wc H  Br H  HCl          &gt;250 2800-2400,2230                       50,23                          4,80                              7,37                                 9,89               1600,1550,1515Wd CH.sub.3 H  CH.sub.3       HCl          208-209               3150,2800-2400                       67,36                          7,16                             9,2                                11,42               2220,1605,1570,               1530We H  CH.sub.3    CH.sub.3       HCl          239-241               2800-2400,2220                       67,42                          7,11                              8,67                                11,49               1600,1530,1515Wf H  CH.sub.3    H  HCl          209-210               2800-2400,2220                       65,77                          6,62                              9,78                                11,90               1595,1560Wg H  H  CH.sub.3       HCl          207-208               3130,2800-2400                       66,29                          6,62                              9,71                                11,72__________________________________________________________________________                           reaction              Calculated, %                           time,                               Yield,     Empirical Formula              C  H  N   Cl h   %     12       13 14 15  16 17  18__________________________________________________________________________     C.sub.15 H.sub.16 N.sub.2 O.HCl              65,10                 6.19                    10,12                        12,81                           2   93     C.sub.15 H.sub.16 N.sub.2 O              74,97                 6,71                    11,66     C.sub.15 H.sub.15 BrN.sub.2 O.HCl              50,66                 4,54                    7,88                         9,97                           5   87     C.sub.17 H.sub.20 N.sub.2 O.HCl              66,99                 6,95                    9,19                        11,63                           14  87     C.sub.17 H.sub.20 N.sub.2 O.HCl              66,99                 6,95                    9,19                        11,63                           14  89     C.sub.16 H.sub.18 N.sub.2 O.HCl              66,09                 6,59                    9,63                        12,19                           5   98     C.sub.16 H.sub.18 N.sub.2 O.HCl              66,09                 6,59                    9,63                        12,19                           21  73__________________________________________________________________________ 
    
     
                                           TABLE 2__________________________________________________________________________9-Amino-3,3-dimethyldihydroacridine-1(2H)-ones V__________________________________________________________________________                        M.p., IR spectrumn/n   R  R.sup.1    R.sup.2       R.sup.3              HX        °C.                              sm.sup.-11  2  3  4  5      6         7     8__________________________________________________________________________1ya   H  H  H  H      --        223-224                              3285, 3110, 3060,                              1630, 1615, 1605,                              1560, 15401yb   H  H  H  H      HCl       &gt;300  3320, 3230, 3060,                              2670, 2710, 1630,                              1570, 15301yc   H  B  H  H      --        247-248                              3330, 3180, 1640,                              1610, 1595, 1555,                              15301yd   H  B  H  H      HCl       &gt;280  3200, 3070, 2700,                              1650, 1620, 1570,                              15301ye   CH.sub.3 H  CH.sub.3       H      --        142-143                              3450, 3180, 1630,                              1600, 1570, 15401yf   CH.sub.3 H  CH.sub.3       H      HCl       208-209                              3250, 3130, 1630,                              1580, 1560, 15401yg   H  CH.sub.3    CH.sub.3       H      --        168-170                              3350, 3260, 3240,                              3200, 3070, 1630,                              1615, 1570, 15401yh   H  CH.sub.3    CH.sub.3       H      HCl       &gt;270  3270, 3075, 2720,                              1630, 1570, 15301yi   H  CH.sub.3    H  H      --        244-245                              3330, 3270, 3180,                              1640, 1610, 1570,                              15301yj   H  CH.sub.3    H  H      HCl       &gt;280  3350, 3250, 3110,                              2720, 1630, 1570,                              15401yk   H  H  CH.sub.3       H      --        174-175                              3400, 3270, 3210,                              1610, 1605, 1570,                              15501yl   H  H  CH.sub.3       H      HCl       &gt;280  3350, 3230, 1640,                              1570, 1530ya H  H  H  C.sub.6 H.sub.5 CH.sub.2              --        169-170                              3030, 1605, 1580,                              1570, 1560, 1520yb H  H  H  C.sub.6 H.sub.5 CH.sub.2              HCl       231-233                              3350, 2730, 2600,                              2360, 1850, 1820,                              1640, 1625, 1605,                              1530yc H  H  H  2,4-(CH.sub.3).sub.2              --        130-132                              3500-3100, 1620,       C.sub.6 H.sub.3 CH.sub.2                              1580, 1560, 1520__________________________________________________________________________Found       Empirical    Calculated, %                                Yield,C   H   N   Formula      C   H   N   %9   10  11  12           13  14  15  16__________________________________________________________________________75,35    7,02   11,66       C.sub.15 H.sub.16 N.sub.2 O                    74,97                        6,71                            11,66                                9664,96    6,59    9,71       C.sub.15 H.sub.16 N.sub.2 O.HCl                    65,10                        6,19                            10,12                                9056,38    4,30    8,47       C.sub.15 H.sub.15 BrN.sub.2 O                    56,44                        4,74                             8,78                                2350,17    4,64    7,99       C.sub.15 H.sub.15 BrN.sub.2 O.HCl                    50,66                        4,54                             7,88                                9676,11    7,42   10,35       C.sub.17 H.sub.20 N.sub.2 O                    76,09                        7,51                            10,44                                8567,43    7,16    8,70       C.sub.17 H.sub.20 N.sub.2 O.HCl                    66,99                        6,95                            11,63                                9775,71    7,30   10,21       C.sub.17 H.sub.20 N.sub.2 O                    76,09                        7,51                            10,44                                9966,61    6,60    8,70       C.sub.17 H.sub.20 N.sub.2 O.HCl                    66,99                        6,95                             9,19                                9475,09    6,95   10,84       C.sub.16 H.sub.18 N.sub.2 O                    75,56                        7,13                            11,02                                9865,88    6,58    9,61       C.sub.16 H.sub.18 N.sub.2 O.HCl                    66,09                        6,59                             9,63                                9275,67    7,24   11,06       C.sub.16 H.sub.18 N.sub.2 O                    75,56                        7,13                            11,02                                9765,77    6,33    9,30       C.sub.16 H.sub.18 N.sub.2 O.HCl                    66,09                        6,59                             9,63                                9480,21    6,80    8,23       C.sub.22 H.sub.22 N.sub.2 O                    79,95                        6,71                             8,48                                88                                3671,62    6,52   10,08       C.sub.22 H.sub.22 N.sub.2 O.HCl                    72,02                        6,32                             7,64                                9480,73    7,56    7,50       C.sub.24 H.sub.26 N.sub.2 O                    80,41                        7,31                             7,81                                75__________________________________________________________________________1  2  3  4  5      6         7     8__________________________________________________________________________yd H  H  H  2,4-(CH.sub.3).sub.2              (Z)-(CHCOOH).sub.2                        163-165                              3400, 3200, 2660,       C.sub.6 H.sub.3 CH.sub.2                              1900, 1700, 1640,                              1620, 1595, 1530ye H  H  H  4-ClC.sub.6 H.sub.4 CH.sub.2              --        144-145                              3400, 3200, 1615,                              1585, 1560, 1525yf H  H  H  4-ClC.sub.6 H.sub.4 CH.sub.2              HCl       247   3360, 2600, 2450,                              2350, 1850, 1650,                              1630, 1610, 1590,                              1580, 1530yg H  H  H  CH.sub.3              --        119-120                              3200, 3120, 1615,                              1580, 1570, 1530yh H  H  H  CH.sub.3              HCl.0,5H.sub.2 O                        261-262                              3480, 3430, 3250,                              3150, 2600, 1800,                              1630, 1615, 1600,                              1550yi H  H  H  C.sub.2 H.sub.5              --        145-146                              3350, 3190, 3060,                              1605, 1585, 1570,                              1525yj H  H  H  C.sub.2 H.sub.5              HCl.H.sub.2 O                        236-237                              3500, 3430, 2600,                              1630, 1620, 1600,                              1580, 1530yk H  H  H  C.sub.3 H.sub.7              --         87-88                              1615, 1595, 1570,                              1530yl H  H  H  C.sub.3 H.sub.7              HCl.0,5H.sub.2 O                        205-206                              3500, 3430, 3260,                              3150, 2730, 2540,                              1830, 1630, 1615,                              1600, 1530ym H  H  H  30-C.sub.3 H.sub.7              --         84-85                              3350, 1615, 1600,                              1570, 1530yn H  H  H  30-C.sub.3 H.sub.7              HCl.0,5H.sub.2 O                        240-241                              3500, 3430, 3370,                              3270, 3200, 2660,                              1700, 1630, 1605,                              1530yo H  H  H  C.sub.4 H.sub.9              --         87-88                              1625, 1610, 1600                              1570, 1530yp H  H  H  C.sub.4 H.sub.9              HCl.H.sub.2 O                        220-221                              3520, 3450, 2370,                              3270, 3200, 2660,                              1700, 1630, 1605,                              1530yq H  H  H  30-C.sub.4 H.sub.9              HCl.0,5H.sub.2 O                        240-241                              3500, 3430, 3370,                              3270, 3200, 2660,                              1700, 1630, 1605,                              1530yr H  H  H  (C.sub.2 H.sub.5).sub.2 N              2HCl      264-265                              3250, 3150, 2600,       CH.sub.2 CH.sub.2      2430, 1830, 1690,                              1640, 1620, 1590,                              1540__________________________________________________________________________9   10  11  12           13  14  15  16__________________________________________________________________________70,71    6,50    C.sub.24 H.sub.26 N.sub.2 O.C.sub.4 H.sub.4 O.sub.4                    70,87                        6,37    7872,48    5,97    7,99       C.sub.22 H.sub.21 ClN.sub.2 O                    72,42                        5,80                             7,68                                9666,32    5,96    6,98       C.sub.22 H.sub.21 ClN.sub.2 O.HCl                    65,84                        5,53                             6,9875,68    7,47   10,66       C.sub.16 H.sub.18 N.sub.2 O                    75,56                        7,13                            11,01                                7664,20    6,81    9,20       C.sub.16 H.sub.18 N.sub.2 O.HCl.                    64,10                        6,72                             9,34                                88       .0,5H.sub.2 O75,82    7,38   10,79       C.sub.17 H.sub.20 N.sub.2 O                    76,09                        7,51                            10,44                                9163,56    7,26    8,43       C.sub.17 H.sub.20 N.sub.2 O.HCl.H.sub.2 O                    63,25                        7,18                             8,68                                9076,12    8,25    9,69       C.sub.18 H.sub.22 N.sub.2 O                    76,56                        7,85                             9,92                                4566,27    7,60    8,61       C.sub.18 H.sub.22 N.sub.2 O.HCl.                    65,94                        7,38                             8,54                                92       .0,5H.sub.2 O76,75    7,67    9,59       C.sub.18 H.sub.22 N.sub.2 O                    76,56                        7,85                             9,92                                6266,29    7,64    8,25       C.sub.18 H.sub.22 N.sub.2 O.HCl.                    65,94                        7,38                             8,54                                89       .0,5H.sub.2 O77,45    8,37    9,79       C.sub.19 H.sub.24 N.sub.2 O                    76,99                        8,16                             9,45                                74                                3565,37    8,15    8,15       C.sub.19 H.sub.24 N.sub.2 O.HCl.H.sub.2 O                    65,04                        7,36                             7,98                                8366,29    7,64    8,25       C.sub.19 H.sub.24 N.sub.2 O.HCl.                    65,94                        7,38                             8,54                                88       .0,5H.sub.2 O61,49    7,80    9,71       C.sub.21 H.sub.29 N.sub.3 O.2HCl                    61,16                        7,58                            10,19                                28__________________________________________________________________________1  2  3  4  5      6         7     8__________________________________________________________________________ys H  H  H  C.sub.4 H.sub.9              (Z)-CHCOOH).sub.2                        156-157                              3400, 2650, 1850,                              1640, 1620, 1600,                              1540yt H  H  H  C.sub.4 H.sub.9              HOOCCH.sub.2 CH.sub.2 COOH                        111-113                              2700-2400, 1920,                              1700, 1650, 1620,                              1600, 1540yu H  H  H  C.sub.4 H.sub.9              2-HOC.sub.6 H.sub.4 COOH                        129-130                              2550, 1930, 1660,                              1640, 1620, 1600,                              1570, 1540yv H  H  H  C.sub.4 H.sub.9               ##STR8## 224-225                              3170, 3040, 2650, 1930, 1720, 1670,                              1610, 1530yw H  H  H  C.sub.4 H.sub.9               ##STR9## 151(pa3π)                              3470, 2600, 1960, 1720, 1650, 1620,                              1600, 1570, 1540yx H  H  H  C.sub.4 H.sub.9              HOOCCOOH  149-151                              2650, 1900, 1720,                              1640, 1620, 1600,                              1540yy H  H  H  C.sub.4 H.sub.9              H.sub.3 PO.sub.4.3H.sub.2 O                        225-226                              2650, 2400, 1930,                              1640, 1620, 1605,                              1535yz H  H  H  C.sub.4 H.sub.9              H.sub.2 SO.sub.4.H.sub.2 O                        178-179                              3370, 3070, 1640,                              1620, 1605, 1540yaa   H  H  H  C.sub.4 H.sub.9              5-NO.sub.2 -2-Cl                        146-147                              2350, 1950, 1660,              C.sub.6 H.sub.3 COOH                              1630, 1610, 1540,                              1520ybb   H  H  H  C.sub.5 H.sub.11              --         72-73                              1620, 1590, 1570,                              1520ycc   H  H  H  C.sub.5 H.sub.11              HCl       206-208                              2520, 1870, 1630,                              1615, 1520__________________________________________________________________________9   10  11  12           13  14  15  16__________________________________________________________________________66,57    6,84    C.sub.19 H.sub.24 N.sub.2 O.C.sub.4 H.sub.4 O.sub.4                    66,97                        6,84    8966,28    7,04    C.sub.19 H.sub.24 N.sub.2 O.C.sub.4 H.sub.6 O.sub.4                    66,65                        7,30    9271,39    6,87    C.sub.19 H.sub.24 N.sub.2 O.C.sub.7 H.sub.6 O.sub.3                    71,87                        6,96    8563,60    6,44    C.sub.19 H.sub.24 N.sub.2 O.C.sub.5 H.sub.4 N.sub.2 O.sub.4                    63,70                        6,24    8861,89    6,90    C.sub.19 H.sub.24 N.sub.2 O.C.sub.6 H.sub.8 O.sub.7                    61,46                        6,60    9365,75    6,93    C.sub.19 H.sub.24 N.sub.2 O.C.sub.2 H.sub.2 O.sub.4                    65,27                        6,78    9150,52    7,13    C.sub.19 H.sub.24 N.sub.2 O.H.sub.3 PO.sub.4.3H.sub.2                    50,88                        7,42    7654,93    6,90    C.sub.19 H.sub.24 N.sub.2 O.H.sub.2 SO.sub.4.H.sub.2 O                    55,32                        6,84    9562,65    5,87    C.sub.19 H.sub.24 N.sub.2 O.C.sub.7 H.sub.4 ClNO.sub.4                    62,71                        5,67    8777,79    8,70    8,76       C.sub.20 H.sub.26 N.sub.2 O                    77,38                        8,44                             9,02                                4269,62    7,70    7,60       C.sub.20 H.sub.26 N.sub.2 O.HCl                    69,25                        7,85                             8,08                                91__________________________________________________________________________ 
    
     
                                           TABLE 3__________________________________________________________________________9-Amino-3,3-dimethyl-1,2,3,4-tetrahydroacridine-1ols YI*.sup.)__________________________________________________________________________YI                      M.p.,                        IR spectrumn/n   R.sup.3  HX          °C.                        ν, sm.sup.-11  2        3           4    5__________________________________________________________________________YIa   H        --          200-202                        3370,3195,3040,                        1645,1585,1575YIB   H        (Z)-HOOCCH═CHCOOH                   150-152                        3480,3320,3100,                        1615,1560,1495YIc   C.sub.4 H.sub.9       --          142-143                        3300,3200-2500                        1610,1570,1555YId   C.sub.4 H.sub.9       (Z)-HOOCCH═CHCOOH                   133-134                        3240,3150,3100,                        3050,2740,2640,                        1640,1585,1525YIe   C.sub.6 H.sub.5 CH.sub.2       --          175-176                        3380,3220,3060,                        3040,1610,1580,                        1550,1520YIf   C.sub.6 H.sub.5 CH.sub.2       (Z)-HOOCCH═CHCOOH                   170-171                        3310,2700,1640,                        1610,1590,1560,                        1530YIg   4-ClC.sub.6 H.sub.4 CH.sub.2       --          179-180                        3380,3160,1615,                        1580,1560YIh   4-ClC.sub.6 H.sub.4 CH.sub.2       (Z)-HOOCCH═CHCOOH                   171-172                        3260,3090,3040,                        2700,1640,1610,                        1570,1520YIi   2,4-(CH.sub.3).sub.2 C.sub.6 H.sub.4 CH.sub.2       --          89-90                        3300,3230,3060,                        1620,1580,1560,                        1510,1495YIj   2,4-(CH.sub.3).sub.2 C.sub.6 H.sub.4 CH.sub.2       (Z)-HOOCCH═CHCOOH                   155  3260,3230,3150,                   (pasπ.)                        3090,3040,1680                        1630,1610,1580,                        1530__________________________________________________________________________Found, %            Calculated, %                            Yield,C  H  N   Empirical Formula               C   H   N    %6  7  8   9         10  11  12   13__________________________________________________________________________74.37   7,89 11,45     C.sub.15 H.sub.18 N.sub.2 O               74,35                   7,49                       11,56                            8764.15   6,63 7,78     C.sub.15 H.sub.18 N.sub.2 O.C.sub.4 H.sub.4 O.sub.4               63,67                   6,19                       7,82 9376.57   9,08 9,40     C.sub.19 H.sub.26 N.sub.2 O               76,47                   8,78                       9,39 9666.65   7,65 6,53     C.sub.19 H.sub.26 N.sub.2 O.C.sub.4 H.sub.4 O.sub.4               66,65                   7,30                       6,76 8979.54   7,41 8,02     C.sub.22 H.sub.24 N.sub.2 O               79,48                   7,28                       8,43 9669,54   6,48 6,34     C.sub.22 H.sub.24 N.sub.2 O.C.sub.4 H.sub.4 O.sub.4               69,63                   6,29                       6,25 8271,78   6,48 7,69     C.sub.22 H.sub.23 ClN.sub.2 O               72,02                   6,32                       7,64 9564,88   5,80 5,71     C.sub.22 H.sub.23 ClN.sub.2 O.C.sub.4 H.sub.4 O.sub.4               64,66                   5,64                       5,80 8779,61   8,28 7,30     C.sub.24 H.sub.28 N.sub.2 O               79,96                   7,83                       7,77 9370,66   7,12 5,64     C.sub.24 H.sub.28 N.sub.2 O.C.sub.4 H.sub.4 O.sub.4               70,57                   6,77                       5,88 86__________________________________________________________________________ *.sup.) R═R.sup.1 ═R.sup.2 ═H 
    
     
                                           TABLE 4__________________________________________________________________________9-Amino-3,3-dimethyl-3,4-dihydroacridines.sup.y11*)__________________________________________________________________________                  M.p. IR spectrumn/n   R.sup.3     HX           °C.                       v, sm.sup.-11  2      3            4    5__________________________________________________________________________y11a   H      --           154-155                       3320, 3140, 1645,                       1570y11b   H      HCl          300  3330, 3170, 2760,                       1650, 1630, 1590,                       1560, 1540y11c   C.sub.4 H.sub.9     HCl          192-193                       3240, 2710, 2650,                       1630, 1620, 1610,                       1560, 1530y11d   4-ClC.sub.6 H.sub.4 CH.sub.2     HCl          222-223                       3230, 3100, 2730,                       1630, 1620, 1600,                       1545, 1525y11e   C.sub.6 H.sub.5 CH.sub.2     HCl          236-237                       3190, 3100, 3060,                       3030, 2720, 1625,                       1600, 1550y11f   C.sub.6 H.sub.5 CH.sub.2     HOOCCH.sub.2 CH.sub.2 COOH                   93-94                       3340, 2600, 1920,                       1720, 1710, 1650,                       1620, 1570, 1660,                       1540y11g   C.sub.6 H.sub.5 CH.sub.2      ##STR10##   137-138                       3250, 2550y11h   C.sub.6 H.sub.5 CH.sub.2      ##STR11##   151-152                       3220, 2550, 1940, 1650, 1620, 1570, 1550,                       1530y11i   C.sub.6 H.sub.5 CH.sub.2     2-HOC.sub.6 H.sub.4 COOH                  134-135                       3250, 3060, 2650,                       1940, 1620, 1605,                       1580, 1550y11j   C.sub.6 H.sub.5 CH.sub.2      ##STR12##   220-221                       3280, 3130, 2600, 1940, 1705, 1670, 1650,                       1630, 1610, 1570, 1530y11k   C.sub.6 H.sub.5 CH.sub.2      ##STR13##   104-105                       3430, 3375, 2620, 2040, 1950, 1670, 1650,                       1630, 1570, 1560, 1525__________________________________________________________________________Found, %  Empirical   Calculated, %                           Yield,C  H   N  Formula     C  H   N  %6  7   8  9           10 11  12 13__________________________________________________________________________80,15   7,05  12,31     C.sub.15 H.sub.16 N.sub.2                 80,32                    7,19                        12,49                           9868,71   6,58  10,51     C.sub.15 H.sub.16 N.sub.2.HCl                 69,09                    6,57                        10,74                           9671,96   7,95   8,53     C.sub.19 H.sub.24 N.sub.2.HCl                 72,02                    7,95                         8,84                           9568,74   5,44   7,45     C.sub.22 H.sub.21 ClN.sub.2.HCl                 68,57                    5,76                         7,27                           9675,06   6,64   7,62     C.sub.22 H.sub.22 N.sub.2.HCl                 75,31                    6,61                         7,98                           9672,03   6,88   C.sub.22 H.sub.22 N.sub.2.C.sub.4 H.sub.6 O.sub.4                 72,20                    6,52   9976,87   6,10   C.sub.22 H.sub.22 N.sub.2.C.sub.6 H.sub.5 NO.sub.2                 76,86                    6,22   9076,42   6,60   C.sub.22 H.sub.22 N.sub.2.C.sub.6 H.sub.5 NO.sub.2                 76,86                    6,22   8276,58   6,12   C.sub.22 H.sub.22 N.sub.2.C.sub.7 H.sub.6 O.sub.3                 76,97                    6,24   8369,02   5,91   C.sub.22 H.sub.22 N.sub.2.C.sub.5 H.sub.4 N.sub.2 O.sub.4                 68,92                    5,57   9865,98   6,32   C.sub.22 H.sub.22 N.sub.2.C.sub.6 H.sub.8 O.sub.7                 66,39                    5,97   99__________________________________________________________________________1  2      3            4    5__________________________________________________________________________y11l   C.sub.6 H.sub.5 CH.sub.2     C.sub.6 H.sub.5 COOH                  128-129                       3220, 2400, 1950,                       1650, 1620, 1570,                       1530y11m   C.sub.6 H.sub.5 CH.sub.2     C.sub.6 H.sub.5 CH.sub.2 COOH                  103-104                       3230, 2500, 1920,                       1650, 1620, 1570,                       1550, 1525y11n   C.sub.6 H.sub.5 CH.sub.2     4-HOC.sub.6 H.sub.4 CH.sub.2 CH.sub.2 COOH.                  122-123                       3550, 3230, 2660,     .H.sub.2 O        2600, 1940, 1650,                       1610, 1570, 1540y11o   C.sub.6 H.sub.5 CH.sub.2     HOOCCOOH: 0,5H.sub.2 O                  191-192                       3320, 3100-2500,                       1920, 1720, 1690,                       1630, 1620, 1590,                       1580, 1550, 1520y11p   C.sub.6 H.sub.5 CH.sub.2     HOOCCH.sub.2 COOH                  130-131                       3280, 2600, 1950,                  (pa3π.)                       1620, 1560, 1530y11q   C.sub.6 H.sub.5 CH.sub.2     H.sub.3 PO.sub.4.3H.sub.2 O                  234-235                       3280, 3100-2600,                       2400, 1630, 1620,                       1600, 1570, 1525y11r   C.sub.6 H.sub.5 CH.sub.2     H.sub.2 SO.sub.4.1,5H.sub.2 O                  161-162                       3280-3000,                       2700-2400, 1630,                       1620, 1600, 1570,                       1530y11s   C.sub.6 H.sub.5 CH.sub.2     5-NO.sub.2 -2-ClC.sub.6 H.sub.3 COOH                  200-21                       3250, 2700-2400,                       1950, 1660, 1620,                       1610, 1570, 1515y11t   C.sub.6 H.sub.5 CH.sub.2     CH.sub.3 C(O)NHCH.sub.2 COOH                  137-138                       3340, 3260,                       2700-2400; 1980,                       1660, 1630, 1590,                       1560y11u   C.sub.6 H.sub.5 CH.sub.2     (Z)-HOOCCHCHCOOH                  146-147                       3270, 2650, 1900,                       1680, 1640, 1610,                       1570, 1530__________________________________________________________________________6  7   8  9           10 11  12 13__________________________________________________________________________79,80    6,43  C.sub.22 H.sub.22 N.sub.2.C.sub.7 H.sub.6 O.sub.2                 79,79                    6,46   9279,52    6,78  C.sub.22 H.sub.22 N.sub.2 C.sub.8 H.sub.8 O.sub.2                 79,97                    6,71   8574,76    7,11  C.sub.22 H.sub.22 N.sub.2.C.sub.9 H.sub.10 O.sub.3.                 74,67                    6,87   86     .H.sub.2 O69,60    6,21  C.sub.22 H.sub.22 N.sub.2.C.sub.2 H.sub.2 O.sub.4.                 69,72                    6,09   81     .0,5H.sub.2 O72,08    6,60  C.sub.22 H.sub.22 N.sub.2.C.sub.3 H.sub.4 O.sub.4                 71,75                    6,26   6856,48    6,45  C.sub.22 H.sub.22 N.sub.2.H.sub.3 PO.sub.4.3H.sub.2 O                 56,55                    6,70   9560,07    6,36  C.sub.22 H.sub.22 N.sub.2.H.sub.2 SO.sub.4.                 60,11                    6,19   86     .1,5H.sub.2 O67,25    5,19  C.sub.22 H.sub.22 N.sub.2.C.sub.7 H.sub.4 ClNO.sub.4                 67,50                    5,08   9272,04    6,48  C.sub.22 H.sub.22 N.sub.2.C.sub.4 H.sub.7 NO.sub.3                 72,37                    6,77   9672,15    6,22  C.sub.22 H.sub.22 N.sub.2.C.sub.4 H.sub.4 O.sub.4                 72,54                    6,09   98__________________________________________________________________________ .sup.*) R = R.sup.1 = R.sup.2 = H 
    
     The influence of drugs on reflex conditioning in rats was studied by the passive avoidance test in conditions of 50% acquisition. The effect of the compound was estimated by the increase of the relative number of learned animals with respect to that of control group. The test substances were injected intraperitoneally 20 min before training in the dose of 0.1 mg/kg, at dose the reference drug amiridine was effective in the passive avoidance test. The other reference drug--noothropic agent piracetam--was given in the dose 250 mg/kg 60 min before training. Amnestic syndrome was stimulated by 20 days application of Sc at the daily dose of 1 mg/kg intraperitoneally. To assess the autiamnestic effects of the claimed compounds, the compounds and the reference drugs they were applied in the course of 10 days immediately following cancellation of scopolamine injection. The passive avoidance test was performed within 24 hours after the last application of test preparations. 
     Contractile activity of isolated smooth muscle organs (guinea-pig ilium, rat testicles) under the action of test substances was studied by the method of Blattner with the use of ACh and adrenaline. 
     Acetylcholinesterase inhibition under the action of preparations was assessed by the spectrophotometric technique of Ellman on the enzyme from human erythrocytes. 
     Ionic permeabilities of excitable membranes under the action of drugs were studied by the voltage clamp technique in the Ranvier node of the frog. 
     Microviscosity of membranes of brain synaptosomes was studied with the use of molecular probe pirren. Brain tissue homogenization and preparation of synaptosomes were performed by the method of De Robertis. 
     Since the substances in question are the derivatives of aminoacridine, tacrine has been also used as a reference drug along with amiridine and piracetam. 
     The results of the study of pharmacological activity of substances in question are summarized in Table 5. All the substances can be attributed to the class of moderately and low toxic ones since LD varied in the limits of 40-1000 mg/kg being greater than 100 mg/kg in the main group of substances which is a substantial advantage with respect to reference drugs amiridine and tactine having LD 35 and 52 mg/kg, respectively. 
     The main group of substances increased moter activity by 40-90. Test substances magnified the effect of arecoline by 30-66% indicating to the involvement of cholinergic mechanisms in their pharmacological activity, through their ability to inhibit acetylcholinesterase was less pronounced than that of the reference drugs. They did not effect the contractile activity of smooth muscles in contrast to amiridine. Therefore their side effects of cholinergic origin (tremor, salivation, diarrea) are less expressed in comparison with reference drug and were observed only at toxic doses. There was no substautial influence of test preparations on the effects of hexenal and apomorphine. 
     As revealed by passive avoidance test most of the substances (IVf, Vd, Vu, VIk, VIIb, VIId, VIIe, VIIi, VIII, VIIo, VIIp, VIIq, and VIIr) statistically significantly improved performance of normal rats, the substances Vd, VIId, VIIe being as effective in improving learning and memory as amiridine and piracetam. However they have an advantage over amiridine as being of low toxicity. 
     The results of the Step-down test with scopolamine induced amnesia in mice are presented in Table 6. The substances VIIe, Vp, VIIb, VIIi, and Vaa showed pronounced antiatonestic activity, comparable with that of amiridine and tacrine. 
     The therapeutic effects of amiridine and tactine are commonly attributed to their ability to block potassium permeability and to inhibit acetylcholinesterase. However the data of Table 6 suggest that the drugs antiamnestic activity is most closely related to their ability to induce the shift of potassium permeability activation region to the hyperpolarizing values of membrane potential. In vivo conditions this effect may be tantamount to the increase of resting membrane potential of nerve cells thus providing more safe generation of action potential especially in nerve cells with decreased excitability. The effect may provide a new approach in the search for drugs with antiamnestic activity. 
     
                                           TABLE 5__________________________________________________________________________Pharmacological effects of aminoacridine derivatives                     Increase of dura-         Acetylcho-               Motor acti-                     tion of arecoline                             Increase of the number   Substance   LD.sub.50         linesterase               vity incre-                     induced hyper-                             of correct trails (% to   designa-   (mg/kg)         inhibition               ment (% to                     kynesis (% to                             control). PassiveNo.   tion by Kerber         IC.sub.50 (M)               control)                     control)                             avoidance test (rats)1  2    3     4     5     6       7__________________________________________________________________________1. IVb  70.0 ± 4.3         3.5 · 10.sup.-6                0     33*    302. IVd  &gt;500  5.0 · 10.sup.-5               15    20       03. IVf  40.0 ± 1.2         1.3 · 10.sup.-5                0     0       04. IVh   &gt;500 3.0 · 10.sup.-5                0    20       05. IVl  616.7 ± 23.7         6.3 · 10.sup.-7                57*   0       06. IVj  63.6 ± 8.7         3.0 · 10.sup.-5                0     30*     07. Vb   735.0 ± 21.8         no effect                80*  15      258. Vd   &gt;1000 1.0 · 10.sup.-5                90*   0       50*9. Vf   &gt;1000 8.0 · 10.sup.-5               13     0       010.   Vh   65.8 ± 4.8         4.0 · 10.sup.-7                40*  20       0   Vj   73.3 ± 8.6         1.7 · 10.sup.-6                59*  20       0   Vl   283.3 ± 35.7         3.0 · 10.sup.-6                74*   30*     0   Vn   70.2 ± 7.3         6.0 · 10.sup.-6                76*   0       0   Vp   200.0 ± 21.9         2.5 · 10.sup.-5                69*   0      25   Vq   158.3 ± 21.9         2.0 · 10.sup.-6                75*   0       0   Vr   135.0 ± 8.2         5.0 · 10.sup.-5                0    26       0   Vs   165.8 ± 14.8         7.0 · 10.sup.-6                0     0      15   Vt   210.0 ± 9.8         7.0 · 10.sup.-6                0     0       0   Vu   210.0 ± 5.8         6.0 · 10.sup.-6               20     0       30*20.   Vv   433.3 ± 7.8         7.0 · 10.sup.-6               26    15      25   Vw   125.0 ± 11.8         7.0 · 10.sup.-6               10    10      10   Vx   121.7 ± 15.5         1.0 · 10.sup.-5                0     0      25   Vy   210.0 ± 14.8         7.0 · 10.sup.-6                0     0       0   Vz   200.0 ± 21.9         7.0 · 10.sup.-6                0     0      20   Vaa  650.0 ± 11.3         7.0 · 10.sup.-6               26    25      15   VIb  63.3 ± 8.8         1.2 · 10.sup.-6                40*   66*    20   VIg  80.0 ± 2.7         0.3 · 10.sup.-5                40*   36*     0   VIi  75.0 ± 1.2         1.0 · 10.sup.-6               13     46*    15   VIj  33.4 ± 3.2         2.5 · 10.sup.-6                55*  13       40*30.   VIe  50.0 ± 8.6         1.3 · 10.sup.-6                64*  15       0   VIIb 37.5 ± 0.9         7.5 · 10.sup.-8                41*  25       40*   VIIc 33.3 ± 4.4         0.6 · 10.sup.-6               20    15      25   VIId 125.8 ± 8.9         0.6 · 10.sup.-8               28    15       60*   VIIe 158.3 ± 21.9         1.2 · 10.sup.-6               32    12       50*   VIIu 83.8 ± 5.6         2.3 · 10.sup.-6               15    12       0   VIIf 125.0 ± 15.5         6.1 · 10.sup.-6                0     0       0   VIIg 200.0 ± 21.9         5.0 · 10.sup.-7               23     0       0   VIIh 116.7 ± 10.9         5.0 · 10.sup.-7               13    28      20   VIIi   500 1.0 · 10.sup.-6               20    15       35*40.   VIIk 90.5 ± 8.         2.0 · 10.sup.-6               20    20      25   VIIl 116.7 ± 10.9         8.0 · 10.sup.-7               10    15       40*   VIIm 112.5 ± 10.9         2.7 · 10.sup.-6               15    15      25   VIIn 125.0 ± 10.9         6.3 · 10.sup.-7               11     46*    40   VIIo 62.5 ± 7.7         2.5 · 10.sup.-6               16     0       40*   VIIp 75.0 ± 3.8         8.5 · 10.sup.-7               33    21       45*   VIIq 73.3 ± 4.4         6.3 · 10.sup.-7               20     30*     45*   VIIr 69.5 ± 5.6         8.5 · 10.sup.-7                0     0       45*   Amiridine   52.0 ± 3.4         1.5 · 10.sup.-7                45*  100*     70*   Tacrine   35.5 ± 1.8         3.8 · 10.sup.-7                0     88*    2550.   Piracetam    1000 no effect                0     0       63*__________________________________________________________________________ *  statistically significant, p &lt; 0.05 
    
     
                       TABLE 6______________________________________Antiamnestic activity and some physiological effectof new aminoacridine derivatives                              The shift of acti-                              vation region of  Antiamnestic                K channels  activity in                 Substance lowest  Step-down test       AChE   concentrations  (% of mice Block of  inhi-  in M. producingSub-   with latency &gt;             K -channels                       bition measureablestance cut off)   IC (M)    IC (M) shift of 1-2 mV______________________________________VIIe   25         1 10      1.2 10 &lt;10VIb    0          1 10      1.2 10 &lt;10Vf     0          5 10      8.0 10 no effectVp     25         1 10      2.5 10 &lt;10IVb    0          no effect 3.5 10 no effectVIId   20         1 10      6.0 10 &lt;10Vd     20         1 10      1.0 10 &lt;10VIIb   25         no effect 7.5 10 &lt;10VIj    0          1 10      3.0 10 no effectVIi    0          1 10      1.0 10 no effectVb     0          1 10      no effect                              no effectVIIi   25         3 10      1.0 10 &lt;10Vaa    25         5 10      7.0 10 &lt;10Tacrine  33         5 10      3.5 10 &lt;10Amiridine  33         5 10      1.5 10 &lt;10______________________________________ 
    
     
                       TABLE 7______________________________________Antiamnestic activity of substance Vp inrats on the model of amnestic syndromeDrug,duration of                     Microviscosityapplication     Dose      Passive avoidance                           changes in % to(in days) (mg/kg)   latency (sec)                           control______________________________________Control   --        160.0 + 12.4                           100Scopolamine (Sc)     1          70.4 + 10.5*                           131.2*20 + 10 (saline)Sc + Vp   1 + 1     170.3 + 14.9.sup.x                           93.820 + 10Sc + amiridine     1 + 1     149.0 + 11.7.sup.x                           105.0.sup.x20 + 10Sc + tacrine     1 + 1     169.0 + 14.8                           97.2.sup.x20 + 10Sc + piracetam      1 + 250  162.3 + 13.3.sup.x                           102.6.sup.x20 + 10______________________________________ *p &lt; 0.05 with respect to control group .sup.x p &lt; 0.05 with respect to scopolamine group 
    
     
                       TABLE 8______________________________________Antiamnestic activity of Vp substancein old rats                               Cholesterol                       Micro-  content inDrug,           Passive avoidance                       viscosity                               synaptosomesduration of     latency in 7                       changes (% fromapplication   Dose    days after  (% to con-                               total lipid(in days)   (mg/kg) training (sec)                       trol)   content)______________________________________Control I   --      109.6 + 24.7                       100     28.2 + 2.2(3 month)Control II   --       47.5 + 13.3*                       132*    39.6 + 0.7*(18 month)Vp      1       169.4 + 10.5.sup.x                        97.9.sup.x                               30.1 + 2.4.sup.x(20)Amiridine   1       116.1 + 16.9.sup.x+                       101.7.sup.x                               33.2 + 0.8.sup.x(20)Tacrine 1       163.4 + 16.5.sup.x                       101.4.sup.x                               39.7 + 1.4*(20)Piracetam   250     120.0 + 24.3*.sup.+                       101.8.sup.x                               35.1 + 1.0*(20)______________________________________ *  p &lt; 0.05 with respect to control I .sup.x - p &lt; 0.05 with respect to control II .sup.+  - p &lt; 0.05 with respect to Vp group 
    
     For more detailed study the substance Vp was chosen because of its most pronounced capability to induce the shift of potassium permeability voltage dependency and substautial amnestic activity with lower toxicity (LD=200-22 mg/kg) thau that of amiridine and tactine. On the model of atonestic syndrome induced by multiple scopolamine injection substance Vo improved performance in passive avoidance test in the 10 days application course to the level achieved under the treatment with reference drugs (Table 7). The improvement of reflex conditioning was accompanied by the normalizing of microviscosity of brain synaptosomes increased in the animals with amnestic syndrome. 
     Table 8 illustrates the data obtained with the use of old rats. 20 days course of treatment with substance Vp improved performance of old rats (age 18 months) in passive avoidance test more significantly than in 6 month old adult rats, while the reference drugs improved the learning and memory only to the level achieved in 6 month old rats. Improvement of animal performance was accompanied by the normalizing of brain synaptosomes microviscosity under the action of all the substances tested. In addition to that amiridine and substance Vp normalized the cholesterol content of brain synaptosomes. The latter observation indicates to the possible interference of amiridine and substance Vo into the processes of atherogenesis in old animals. 
     Lipid regulative activity of the declared compounds--derivatives of 9-amino acridine--were evaluated in vitro--were evaluated in vitro using rat adipocytes. Adipocytes were separated from adipose tissue of testis appendages of adult male rats. Lipid composition analysis was performed by the method of thin-layer chromatography. 
     Quantitative analysis of phospholipids (PL), mono- and diacylglycerides (MDG), triacylglycerides (TG), free fatty acids (FFA), free cholesterol (FCL), and methyl esters of fatty acids (MEFA) was performed by the method of spectrophotometry. 
     The results Of studies of lipid-regulative activity of the declared compounds and probucol--the drug widely used to treat atherosclerosis (Duckley M. M. - T., Goa K. L., Price A. H., Bfogden R. N. Drugs, 1989, 37, 761-800) are presented in Tables 9-13. 
     Compounds VIIe, Vo and VIId possess the most potent effect on lipid composition of adipocytes (in absolute parameters and in relations of separate fractions). 
     Compound VIIe. Under the effect of this compound in adipocytes phospholipids content increase and simultaneous decrease of triglycerides content takes place (Table 9). The content of methyl esters of fatty acids is decreased. Increase of PL/TG ratio (Table 11) probably takes place not only at the expense of lipid synthesis in cells (Tables 10, 12) but also due to ejection of triacylglycerides into the external medium with simultaneous retention of phospholipids in a cell (Tables 10, 12, 13). A tendency towards increase of relative cholesterol ejection from a cell is observed (Table 10, 12). 
     
                       TABLE 9______________________________________Lipid composition of adiposytes (%) after incubation in thepresence of the compounds of the aminoacridine series.PL - phospholipids, CL - cholesterol, FFA - free fatty acids,TG - triglycerides, MEFA - methyl esher of fatty acids.Compounds   PL       CL       FFA    TG     MEFA______________________________________control 15,5-0,5 21,3-0,6 22,2-0,3                            23,5-0,4                                   18,9-0,6ethanol 14,8-0,6 21,0-0,5 21,1-0,5                            24,1-0,5                                   18,7-0,7VIIe    21,5-2,3 22,6-1,7 20,3-0,6                            20,3-1,9                                   15,3-1,6VIj     18,1-1,7 22,5-1,0 23,0-0,8                            21,2-1,3                                   15,2-0,6Vp      19,1-1,0 22,9-1,9 22,1-0,9                            21,5-1,9                                   14,2-0,9VIId    15,5-2,6 22,4-1,0 24,5-0,7                            21,2-1,3                                   15,7-0,8Vaa     14,1-0,5 22,3-1,3 22,8-0,6                            24,2-0,7                                   16,6-0,8VIIi    18,5-1,2 22,2-0,4 21,4-0,5                            21,4-0,2                                   16,4-0,7VIIj    13,9-1,7 22,8-0,9 22,4-2,4                            24,1-0,6                                   16,8-0,6VIIk    17,0-1,8 22,8-2,2 21,8-1,8                            21,8-1,4                                   16,7-2,8probucol   15,5-0,6 18,3-1,3 24,3-0,6                            22,6-1,1                                   19,1-1,3______________________________________ n = 19 for control and ethanol. In all the rest cases n = 3. *statistically reliable differences (in comparison with ethanol), p &lt; 0,05. 
    
     
                       TABLE 10______________________________________Lipid content (%) in incubation medium after incubation ofadipocytes in the presence of the compounds of aminoacridine series.PL - phospholipids, MDG - mono- and diglycerides, CL -cholesterol, FFA - free fatty acids, TG - triglycerides.Compounds   PL       MDG        CL   FFA    TG______________________________________control 15,3-0,5 18,5-0,5 19,0-0,3                            23,1-0,5                                   23,9-0,5ethanol 15,9-0,5 17,8-0,6 19,7-0,5                            23,0-0,7                                   23,2-0,5VIIe    14,9-1,5 15,3-2,3 20,3-1,5                            24,1-1,5                                   25,3-1,1VIj     14,6-2,1 15,3-0,9 22,3-1,1*                            24,2-1,4                                   23,4-1,4Vp      13,5-0,9 16,0-0,7 20,9-1,2                            23,7-1,1                                   25,8-1,5VIId    16,0-0,6 16,1-0,7 21,2-0,7                            22,8-0,8                                   23,7-0,3Vaa     13,5-0,4 20,4-2,8 18,8-0,6                            22,6-1,5                                   24,6-1,4VIIi    17,2-1,3 19,2-2,8 19,4-0,8                            23,1-2,8                                   21,1-1,6VIIj    17,9-0,3 18,6-1,4 18,7-0,3                            23,5-2,1                                   21,3-0,5VIIk    17,5-1,6 17,9-1,8 19,2-1,0                            22,6-1,0                                   22,7-0,8______________________________________ n = 19 for control, n = 18 for ethanol. In all the rest cases n = 3. *statistically reliable differences (in comparison with ethanol), p &lt; 0,05. 
    
     
                       TABLE 11______________________________________Relation of various functions of lipids in adipocytes afterincubation of cells in the presence of compounds ofaminoacridine series.Symbols - see Table 9.Compound   FFA/TG       PL/TG   PL/CL______________________________________control    0.94         0.67    0.73ethanol    0.88.sup.+   0.61    0.70VIIe       1.00         1.06    0.95*VIj        1.08         0.85    0.80Vp         1.03         0.89    0.83*VIId       1.16*        0.73    0.69Vaa        0.94         0.58    0.63VIIj       1.00         0.86    0.83VIIk       0.93         0.58    0.61VIIl       1.00         0.78    0.75probucol   1.10*        0.69    0.84*______________________________________ n = 19 for control and ethanol. In all the rest cases n = 3. *  p &lt; 0.05 in comparison with &#34;ethanol&#34; group. .sup.+ - p &lt; 0.05 in comparison with control. 
    
     
                       TABLE 12______________________________________Relations of separate functions of lipids in incubationmedium after incubation of adipocytes in the presence ofaminoacridine derivatives.Symbols - see Table 9.Compound   FFA/TG       PL/TG   PL/CL______________________________________control    0.97         0.64    0.80ethanol    0.99         0.68    0.81VIIe       0.95         0.59    0.73VIj        1.03         0.62    0.65Vp         0.92         0.52    0.65VIId       0.96         0.67    0.75Vaa        0.92         0.55    0.71VIIj       1.07         0.81    0.89VIIk       1.10         0.84    0.96VIIl       1.00         0.77    0.91______________________________________ 
    
     
                       TABLE 13______________________________________Distribution of separate lipids between cells and incubationmedium after incubation of adipocytes in the presence ofcompounds of aminoacridine series.cells. index &#34;m&#34; le 9. Index &#34;c&#34;incubation medium.Compound       PLc/PLm  FFAc/FFAm______________________________________control        1.01     0.96ethanol        0.93     0.92VIIe           1.44*    0.84VIj            1.24*    0.95Vp             1.41*    0.93VIId           0.97     1.07*Vaa            1.04     1.01VIIj           1.08     0.93VIIk           0.78     0.95VIIl           0.97     0.96______________________________________ n = 19 for control and ethanol. In all the rest cases n = 3. *  p &lt; 0.05. 
    
     Compound Vo. This compound is aualogous to VIIe according to the effect on lipid composition of adipocytes. Accumulation of phospholipids in a cell (Tables 9, 11, 13), enhanced ejection of triacylglycerides into external medium (Tables 10, 12) and sharp decreases in the content of methyl ester of fatty acids (Table 9) are observed. 
     Compound VIId. This compound has a significaut lipolytic effect, which is proved by an increase of content of fatty acids in a cell (Table 9) and a sharp increase of FFA/TG relation in favor of fatty acids (Table 11). 
     The performed studies prove the fact, that the declared compounds have an effect on lipid cell composition. Compounds VIIe, Vo and VIId show the most potent effect. The other studied compounds also influence the lipid content. A combin&amp;tion of the described properties of the three mentioned compounds permits consideration of them as the most promising from the point of view of the development of new drugs to treat diseases connected with lipid metabolism disorders. The compounds VIIe and Vo which increase PL/TG relations and decrease cell cholesterol level, may be recommended for the study as potential anti-atherosclerotic drugs and compounds to prevent adipose degeneration of organs. Compound VIId due to its significant lipolytic effect may be considered as a drug to treat diseases accompanied by obesity. Compounds Vp and VIId are not inferior of the most effective drug in world-wide clinical practice--probucol, and compound VIIe supresses it. 
     In summary, the proposed derivatives of 9-aminoacridine have a lower toxicity thau known drugs (tacrine, amiridine) have antiamnestic activity, they are effective in comparative or lower doses ensuring a wider therapeutic range of activity of the given compounds. An additional valuable property of these compounds is lipid-regulative activity, which proves perspectiveness of mentioned compounds as anti-atherosclerotic drugs and drugs to treat diseases accompanied by lipid metabolism disorders, and in particular phospholipids (obesity, diabetes mellitus, and membronopathy of various genesis).