CA2102681A1 - 9-aminoacridine derivatives possessing psychotropic, antiamnestic and lipid-regulating activity - Google Patents

Abstract

ABSTRACT
The invention is concerned with novel 9-amino-acridine derivatives having the general formula:
wherein R is H or CH3; R1 is H, CH3 or Br; R3 is H, C1-C5 alkyl, arylmethyl or diethylaminoethyl; X is C = O or CHOH; and Y is CH2; or X together with Y
represent CH = CH, and their pharmaceutically acceptable acid addition salts. The 9-aminoacridine derivatives of the invention exhibit psychotropic, antiamnestic and lipid-regulating activities.

Description

.'~,' '~1' ~
~` ~102~81 9-A~iINOACRIDINE DERIVA~IVES POSS:E:SING P~YCHO~ROPIC, A~TIAllql~STIC AI~'D hIPID-R:~GU~A~IVE AC~IVI~Y

Technic al f ield ~ he invention refers to new chemical compounds, parti-culary to the derivatives of 9-aminoacridine, which show psyohotropic, antiamnestic and lipid-regulative activity and may be used in medical practice bo treat psychic diseases, in part-i-oular sensile dementia of Alzheimer's type, as well as diseases connected with disturbances of l ip id metab ol ism . ;:
Prior art ~ he drug tacrine (Summers W.~:. et all//New En~l~ J.
med. 1986, Vol. 315, I~o. 20, p. 1241) is widely used abroad in Alzj~eimer' g disease clinics: a new original drug amiridine has been developed (USSR Patenb Applica- .
tion No. 4076765 from 01.07.86. A61E 31/47; USA Pàtent No. 4735953, al. 514/313, 1988; PRG Patent No. 3231571, A61E 31/47, 1977) .

M~O ~0,~~
f ~e a~ ~;of~e - `
The drawback of the ab ove drugs is ; ~ -:
comparatively high toxiciby, side ef~ects of cnolinergic `
nature (tremor, diarrhea, salivation), and toxic effect @~'' 21~2~
C

. . , of tacrine on liver.
Derivatives of 9-aminoacridines naving the general -~
formula ~Q~

with a structure similar to that of- claimed compounds a~ld .
possessing psychotropic and memory stimulative activity -are known (~uropear~ Patent ~plication ~o. 0179383 C07D
219/10,-1985: Shutske g.m.et al.//J. Dqed. Chem.-1989, 32, 1805-1813; Shutske, g.m. et al.// J. Med. Chemn -1988, 31, 1279-1282.
~ he shortcomings of these compounds are a comparati-vely high boxioity ~d as a consequence o~ this - a low therapeutic index.
The structure analogues oî claimed compound6 ~aving the general formula are known (~3uropean Patent ~pplication No. 03713~8, C07~ 219)~10, -1990).

~A

where ~_~A ~ J~,R~ R1 ,?", 2 ~ 0 2 ~ 8 ~ ~
. ...

whicn are inhibitors of acetylcholinesterase; however, tnere is no i~formation on their antiamnestic and lipid- :
-regulative activiby.
Detailed description of the invention ~ -~
Derivatives of 9-aminoacridine~represented by the ~eneral formula R ~j R ~ ,X

where P. = H,CE3 R~l= H,CH3,3r ~2= E,CH
R3_ alkyl-C1-C5,arylmethyl, diethylaminoethyl = C=O, CHOH, Y = CH2 ~ ~ Y = CH = CH
and their salts with organio and inorganic acids possessing psyohotropic, antiamnestic and lipid-regulative aativi-ty are disclosed. ~ ;
~he preparation o~ the compounds is per~.ormed follow~
in~ the scheme 0 ,1~ J ~

+~3 ~ ~ 3 ~J~h1~ 3 -- ,R3 3 : : :

~3 ~ ; ~
\~3tl~ dz ''~ v ~0~ 3 3 ~ y/~

. 21~2~81 ~:

~ he target compounds having formulae IV - v-II are -prepared by interaction of t~e corresponding substituted r,i~rile of anthranilic acid I with dimedone II and ~ -subsequent cyclization of the hydrochloride of the substi-tuted 2- L(5,5-dimethyl-3-oxocyclohex-1-enyl)amino~benzo- -nitrile III thus obtained into substituted 9-amino-3, 3-dimebhyl-3,4-dihydroacridine-1 (2~)-ones IVs alkylation of compounds IV with alkyl- or arylalkylhalogenideq into 9-alkyl~arylalkyl)-amino-3,3-dimethyl-3,4-dihydroacridine--1(2E)-ones V: reduction of oompounds IV and V into 9-alkyl(arylalkyl)amino-3,3-dimeth~1-1,2,3,4-tetrahydroac-ridine-1-ols VI; dehydration of oompounds VI into --9-alkyl(arylalkyl)amino-3,3-dimethyl3,4-dihydroaoridines VII.
The in~ention is illustrated with follo~ ng c~amples.

ExamPle 1 2-r5,5-dimethyl-3-oxooyclohex-1-enyl)amin~ benzonit-rile hydrochloride (IIIa) ` -6 ml of oonoentrated hydroohlorio aoid were added to a solution o~ 4.72 g (0.04 mol) of anthranilonitrile 1, -(Ia) in 80 ml of ~F with stirring, after 15 min 5.6 g (0.04 mol) of dimedone (II) were added, the mixture was heated on boiling with stirring for 12 h, the preoi-pitat~ ~as filtered off, washed with acetone and dried.
~he mother liquor was oonoentrated to 1/3 of the initial ~1026~

volume, the precipitate was filtered off, washed with acetone and dried. Precipitates were combined to give 9.1 ~ (82~o) of IIIa, m.p. 214-215 isopropa~ol.

~amPle 2 2- [(5,5-dimethyl-3-oxocyclohex-1-enyl) amino3 -3,6-dimebhylbenzonitri~e hydrochloride (IIId) 6 ml of` concentrated h~droohloric acid were added to a solution of 5.84 g (0.04 mol) o~ 3~6-dimethylanthra_ ~
nitrile ~IIc) in 80 ml of dioxane with stirring, after ;
15 min 5.6 g (0.04 mol) of (II) were added, the mixture was heated on boiling with stirring fPr 14 h, the preci- ~
pit~te was filtered off, washed with acetone and dried. ~ ~-~he mother liquor was concentrated to 1/4 of the initial volume, the preoipitaze was filtered off, washed with ..~ .. ~
aoetone and dried. Precipitates were combined to gi~e 10.5 g (87~) of IIId, m.p. 208-209 isopropanol. ;
, ~
Compounds IIIc-g (Table I) were prepared ~n a~ ana-logous manner.
ExamPle 3 9-amino-3~3-dimetnyl-3~4-dihydroacridi~e-1(2~)-one ¦~
(IVa) ~'- ' , 1 . : . -:. :: ~
To a suspension fo 27.7 ~ (0.1 mol~ o~ enamine hyd-rochloride IIIa in 200 ml of dry THF 27.6 g (0.2 mol) of X2C03 powder and 0.5 g (CuCl were àd~ed, the mixture was heated under reflux with stirring for ~ h. the hot ' "' 2~02~8~

solution was ~ ered, t~e precipitate on the ~ilter was washed with water and dried. Organic mother liqueu~was evaporated to 1/5 o~ t~e original ~olume, t~e precipitate was f`iltered of~, washed with water, dried and combined with trle ~ormer precipitate. Recrystallization ~rom a~ue-ous ~tOH ga~e 21.4 g ( 89~o) of IVa, m.p. 223 - 224.
Exam~le 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 hydroohloride IIIa in 300 ml of dry dioxane 27.6 g (0.2 mol) o~`~2C03 powder and 0.5 g CuBr were added, the mixbu-re was heated under reflux with stirring for 5 h, the precipitate was ~iltered o~f, washed with water a~d dried.
Organic mob~er li~ueur was evaporated to 1~5 of t~e ori~
ginal volume, t~e precipitate was filtered of~, w~shed with water, dried and combined witb the former precipita~
te. ~ecrystallization from aqueous EtOH gave 21.8 e (91%) o~ IVa, m.p. 223 - 224.
¢ompounds IV-c-I (Table 2) were prepared by an ~na-Iogous ~anner.
ExamPle 5 .
9-benzylamino-3,3-dimetbyl-3,4-dihydroacridine-1 (2H)-one (Va) o a solution of 4.8 g (0.02 mol) of t~e amine IVa in 70 ml o~ dry ~lSO 2.8 g (0.05 mol) Q~ ~OH powder were ~ ;:: ' ' :` .$;i~ "~ - :X~,.: -: ' ::: . ~ . .. . ;

2lo2~8l . . .

added, the mixture was stir~ed for 1 h, then 0.8-1 ml o~ benzyl chloride was added, the ~olution was allowed to sta~d overnig~t, the~ poured into 350 ml o~ ~ater, stir-red for 0.5 h, left to sba~d for a day, the precipitate was ~iltered o~f, was~ed wit~ water, dried and recrysballi- -zed from aqueous EtOH to give 5.8 g (88%) of Va, m.p.
169 - 170.
Compounds Yb-j (Tabie 2) were prepared by t~e analo~
gous mAnner. ~~
Example 6 9-benzylamino-3,3-dimethyl-3,4-di~ydroacridine-1 t2H)-one (Va).
T~e mixture of 2.4 g (0.01 mol) of the amine IVa.
1.4 g (0.011 mol. 1.27 ml) of benzyl ohloride, 0.5 g of ~ ;
Bu4~Br, 7$ ml of CH2C12 and 50 ml o~ 50~ aqueous ~aOH was vigorouæly stirred for 20 h, then poured into 200 ml of iae water, an organic phase was separated, t~e a~ueous phase was eXtracted with chloroform, (4 x 50 ml), combin-ed extraot~ were evaporated, t~e residue was reorystal-lized ~rom aqueous EtO~ to give 5.8 g (88%) of Va, m.p. 169 - 170.
Compou~s Vo (2able 2) were prepared by an analogous manner. -ExamPle 7 9-benzylamino-3,3-dimebnyl-1,2,3,4-tetrahydroacri-dine-~-01 (VIe) ~o a suspension of 3.3 g (0.01 mol) o~ Ya in 80 ml 210 2 6 8 ~
, . .', _ 3 OL &bsolute TL~ 0~2 g (~511 mol) OI lithium al~minium -~
hydride was ~dded at O - 5, the mirture ~7aS stirred ~or 2 h under nitrogen current at the s~me temperature, an f~.cess of lithium aluminium hy2ride ~as decomposed by sub-~equent adding of saturated solution Df ~rr~onium chloride and 3~ aqueous potassium hydro.ide. An organic phase -was separated, the solvent was evaporated, the residue , was recrystallized from aqueous EtOH to give 3.2 g (96 o~ VIe, m.p. 175 - 176.
Compounds VIa-d, f~ able 3) were prepared by an analogous manner.
Exam31e 8 ~ ;
9-benzylamino-3,3-dimethyl-3,4-dihydroacridine-1 (2H)-one hydrochloride (VIIe).
~ he solutlon of 3.32 g (0.01 mol) of VIe ln a mixture of 40 ml of EtOH and 5 ml of concentrated HCl was heated under re~lu~ ior 1 h. The solvent was evaporated~ the residue was recry~tallized from aqueous EtOH to give 3.35 g (9~ of VIIe, m.p. 236 - 237.
Compounds VIIa-d (~able 4) were prepared by an analo-gous manner.
Ps~choneurotropic activit~ of declared compounds .
~nd their influence on learning and memory in e~periment were ob~erved using unbred male 1&-20 g mice and 1~0-200 ~ rats, held at standard conditions (room temperature 21 - 22- C, 12 hours li~hting schedule, food and water ~ j"~ ;, " ~ ~ , . i;i C, i S ~ i ?, .

~ .
- 21 026~81 g :

ad libitum).
All the co-lpounds in question under~7ent the i`ollowing tests~
Acite to~icity was studied by the method OL ~I;erber ~ith the ~ntra peritoneal drug injection, Psychothropic activity test included the influence ~-- o~ dru~s on animal beh~vior, motor activity, on-the effects of he~enal (30 and 60 mg/kg), arecoline 925 mg/kg, apomor-phine (2 mg/kg), The drugs were ap~lied intraperitoneally ~ ~
in the dose of 1/20 of ~D. 6 mice were in the each e~pe- ~ -rimental group. -~
Step-do~ntest Wa8 used to study the influence of-drugs on learning and memory in mice on the model of amne-sia achieved by the in;ection of the central ~Ch-recep-tors inhibitor æcopolamine.
i , The in~luence of drug3 on the refle~ conditioning in rats was studied by the P~SSivY avoidance test in condi-tions of 50~o ac~uiæition. ~he e~fect of substa~ce was ... . . . . . . .. ~
estimated by the increase o~ the relati~e number of learn-, ed animals with respect to that of control group. The test substances were applied intraperitoneally 20 min be ore training in the doæe of 0.1 mg/~g, at which the reference drug amiridine was effective in the p~ssi~e avoidance test. ~he other re~erence drug - noothropic agent piracetam - was applied in the dose 250 mg/kg 60 min before trainin~. Amnestic syndrome wa~ simulated -~
.
.

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~ilB H ~1 3001650 ~ ),t 1560,~5~0 Yilc C4~b HCl 1630 ~6~ i6I0, - 1560, i~0 Y~ C6~4C~ ~{C~ 3i630 ;~0 ~603 ~5'~
Yj~e. C6H~C~ llC~ ~''37 31903~~~

Y~ 6~5C~ iiOOCC,l~,~CH,~COOH 17~0 1'~
i6~, I67lJ, l;j60, ,,~ C~O~
Yilg C6~C~ ~OJ ~ 8 ~

Y~lft C6i~;t~ 5~ i6~0'~ 0 lo70 Y;~l, C6I~CH~ ~C6H4cOoH ~3~ 50 i6~g i60 . 1~0, ~0 Yllj C6~15C~ H ~~~ Ig~
1650,~ 0, 16I~, O ~/ 1570,1~() . :;
Yl~J~ C6H5C~ ~COO~I 104-105 30 0 3~97~ ~.'66~g ~{ ~6~,I6;~0,~ 0, ~)A a ~ =H ' ~;

2102681 7~ee ~
-2I - ( - C0/2f~ h ~
_ I BTU~D~ I e ~ d. ~ ~ y~e~

. . t 1 i : ~
1 7 ~ 9 ' I I0 ! I I I 12 1 13 ~;J,l;~ 7,0;~3I C15~16N~ 80,3~ 7,19 I2,49 9B
Gd, ,'l ~,~3iO,5i C~ iiCl 69,;)~ 6,~7 I0,74 g6 6 7,9~ Ci9~ HCI 7~.0~ 7,~5 8,84 95 ~)~ 7~ 5,~7,45 C,~l~lCIN~ CI 6a,57 5,76 7,27 96 7~,06 6,647,t~ C,~ii,;~ ' HC~ 7~,~I 6,61 7,~8 96 'J~,03 ~,~3 C~H~I~ C4~1604 7~,~0 6,5~ 9g ','G, ~r,7 6, I0 C~ C6H~ 76,~36 6,~ 00 ~ ,~ 6,6~ C,~2H~-C6~JO~ 76,86 6,~ 8~

76,5d 6,~ C2,~ c7}~ 76,~7 6,~4 ~3 6;~,0~ 5,~I C221i~N,~ C5H4/~,~04 68,g~ 5,57 98 65,~ 6,3~ C~ 2-C643~)7 66,39 5,97 9~

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1530 , Y~h~C6H5CH~ C6H5CH~C()OH I03-I04 3~350''~i 1'~O

Y~C6HSCH.~ oc6H4c~,cf~ ~ L6iO,~5~0.~5~0 Y~aC6H5CH,~ COO~I: O,SH,;,~O 191-19~ 19~0 17~0,169~
I630, I6~0, I590, Yllp C6H5CH~ HOOCCH~ tpasn.) 3I~800 ~
Yn& ~C6fi~C~ H~P04 3H,;~0 Z34~ 400 I6;~30,16~0 I600,15~0, 15~5 Yll*-C6H CH. H~S`O 1,~ .H O i6I-lG~ 80-300û,5 ~ 4 ~ ~700-~400jI~, .. 16~00~I600~1570, Y~S C6H~C~ 11O -~-ClC~I COOH ~00-~1 3~SO,Z~00-~400, 2 ~ 3 I9~,1660,16~0, 1610,~ 0,~
Ynt ~6H~C~ ~3C(O) 1~1 HcH;~COOI~ 137~ 7~400,19~3(), Y&~l C6H5CH ~ OOCC~ iCOOH ~I4~ ~70,~iO,l~
I6i3l) I640,1610, ~70 1~0 ~.

2102~81 Ta~e4 -23- ( c~ n~l eo~

7 ! 8 1_ ~ _ t 10 t I I t IX 1 '~i3,~3~ 6,4;~ C~H~,~- C~60~ 7j,7g 6,46 9 .,; ~
7~ C~ C~B0.~ 79.g7 6,71 8 '~.,76 .7,II- ~o~ I003 74,67 6,~

6i,G3 6,2I C~ 4-. . 69,7~ 6,0~ 81 i~
0,5 7~,0~3 6,60 C~~ C3H404 71,75 6,26 6~
;j6,~ 6,~ CC~il,2;21l~-H~4-~1,,0 56,55 6,70 95 `::

6~,07 6,36 C,~ 04 - 60, 11 6,19 ` 8~
1,5H,j~0 ` ~ ~ -67,~ ~,iY ` C,j~ i4CI~I/04 67,50 5,08 9~

6,43 C,~ CgY71l~O;~ 7~,37 6,77 96 ~;

72,I5 6,~ C~H~J~-C4il 0 7~,54 6,0~ 98 by 20 days applicati~n Ol Sc at the dæil~ dose oi 1 mg/k~
intraperitoneally. ~3 assess the anti ~lnestic e-~fectQ oi declared substances and reierence drugs they were aplied in the course of 1C days immediately alter cancellatiDn o~
~copolamine in3ection. Pas~ive avoidance test was perfo~m~
ed in 24 hours aiter the last aoplicati~n of test prepara- ~-tions.
~ Contractile acti~ity of isolated smooth muscle organs , , , ~guinea_pig ilium, rat testicles) under the action of test qubstances was studied by the methDd oi ~lattner with the use of ACh and adrenallne.
hcetylchDlinesterase inhibition under the action of preparati~ns ~Jas assesQed by the spectrophotometric techni- ;
que oi Ellman on the enzyme from hum~n erythrocytes.
Ionic permeabilities of e~.citable membranes under the action of drugs were studied by the ~olta~e clamp techni-que in the Ranvier node of the i'rog; - `~
~ ticroviscosity oi membranes oi brain synaptosomes was studied with the use of molecular probe pirren. 3r~in tis- ~-sue homogeniz~tion and preparation oi synaptosomes were per- ~---formed by the method of De Robertis.
Since the substances in question are the derivati~es o~ ~minoacridine tacrin has been also used as a reference drug along with amiridine and piracetam.
The results oi the study of ph~rmacolD~,ical activity Cl substances in question are summarized in Table 5.
~ -"'".
. , ....

~:

2102~81 : ~:
~" . .
. ,., .

All the substances can be attributed to the clas~ of mo ~
derately and low t3xic ones since L~ varied in ~he limits 3~ 4~ - 1C00 m~/kg bei~g ~reater than 1~0 m~/k~ in the main group o~ substances vrhich is a substantial advantage ~ith respect to reference drugs amiridine ~nd tacrine hav- -~--ing ~D 35 and 52 mg/kg, respectively ~
. .~ ,~
The main ~roup of substances increased motor activity by 40 - 90~0; ~est substances magnified the elfect of areco-line by 30 - 66~J ~ndicating to the involvement o~ ohDli-nergic mechanisms in their pharmacolo~ical activ~ty, t~lrough tl1eir ability to inhibit acetylchDlinesterase was less Dronounced than that of relerence drv~s. They did not e-lDect the contractile activity of smooth musclues in con-trast to amiridine. ~here$ore their side effects o~ choli-ner~c origin (tremor, salivation, diarrea) are less .. . .. . . .. . . . .. . .
eY.pres~ed in comparison with re~erence drug and vrere ob- ~
. . .. . . .. . . .. . .
served only at toxic doses. ~here was no substantial in~
, . . . . .. .. . .. .. . . . ... . ~ . . . .
~luence of test ~reparations on the effectæ of he~enal ~ ~ ~
.
and apomorphine. ~ ~
hs revealed by passive avoidance test most D~ the sub- -stances (IVlD, va, Vu, VIk, VIIb, YIId, VIIe, VIIi, ~
VIIo, VIIp, VIIq, VIIr) 9tatisticalIy æi~ni~icant imp-roved per~orm~noe of norrial rats, the substances Vd, VIId, VIIe being as eD~ective in improving learning and memory as amiridine and piracet~m. Ho~eYer they h~ve an advanta~e over amiridine being 1~VJ toxic;

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:~ntialllnestic activitv and some Dhvsiological effect of new aminc)acridine derivati ve5 511b5- r~ntiamnestic ~loc~ of r~ChE inhi- The-shift of acti-tar,ce activity in k -channels bition vation region of ~:
SteD-down test IC (M) IC ~M) ~ charlrlels ` ::
!% of mice Substance lowest ith latenc~ ~ concentrations CCIt off) in ~. Producing measurable . shift of 1-2 mV
'JIIe ~5 1 10 1.~ 10 ; 10 ','Ib 0 1 10 1.2 10 :: 10 '~f 0 5 10 8.0 10 no r-~f-fect ~D .~5 1 10 ~.5 10 : 10 IVb 0 no effect ~.5 10 no effect IId ~0 1 10 6.0 10 ~ 10 ~.'d ?0 1 10 1 . 0 10 '; 10 - .
'~IIb ~5 no effect 7.5 10 ~; 10 '.'Ij 0 . 1 10 .~.0-10- ~ no effect VIi 0 1 10 1.0 10 no effect -~
Vb 0 1 10 no effect no effect '~IIi ~5 ~ 10 1.0 10 C 10 Vaa ~5 5 10 0.0 10 ~: 10 : :~
Tacrine ~3 5 10 3.5 10 C 10 :
Arniricline ~3 ~ 5 10 1.5 10 C 10 :~

. .
,;, .

~ -~o- 2102681 ~able 7 ~ntiamnestic acti~.~ity oF substance VD in rats on the model of amrle-3tic sYndrome . .. ~
~ru~. Dose Fassive avoidance Microviscosit~
~:luration of(mg/k:s) latency ~sec) changes in % to ar~L~lication control 'in da~s) _ ____ _ _ Control - 160.0 + 12.4 100 ScoL~olamine (Sc) 1 70.4 + 10.5 131.2 20+i.0 (saline) SC ~ VD 1 + 1 170 . :~5 + 14 . 9 93 . 8 ~ 0 + 1 0 Sc+amiridine 1+1 149.0 + 11.7 105.0 20+10 ~ -. .~. :: '.
Sc+tacrine 1+1 169.0 + 14.a 97.2 . ~ ~
.~0+ 1 0 '. . :, '-' ' 8C ~Di racetam 1+250 162. ~ + 1~. 3 102.6 '~0~
* - D'~ 0. 05 with resDect to control ~rouu - D 0.05 with resDect to scoDolamine ~roUD~
`~

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~ -~I- 2102681 ~
~ .able 8 ~ritiamr)estic acti~it~ Or vp s.lb5tance in Dld r~ts DrLIg Dose Passive avoidance Microvisco- Cholesterol cll.lration oF (mg/kg) latency in 7 5ity chan~es content in ~Pulicationdays after ~% to ront- synaptosomes ~in days) training ~5ec) rol) ~% From t.otal lipid . .
-' content) '~
Control I - 109.6 + 24.7 100 28.2 + 2.
~3 month) Control II ~- 47.5 + 13.3 132 39.6 ~ 0.7 (18 month) VD 1 169. 4 + 10.5 97.9 30.1 + ~.4 .
(20) ~miridine 1116.1 + 16.9 101.7 ~3.2 + 0.8 `~
(20) T~crine 1163.4 + 16.5 101.4 39.7 + 1.4 ~ h (20) Pir~cetam250120.0 + 24.3 101.8 35.1 + 1.0 (20) ::
* - p~.Ø0S with resPect to control I
- pC0.05 with respect to control II ~:
+ _ pr,0,05 with respect to Vp gro~P

' I
. ' ' ':

.
. ' .
, s - -`" 2102681 - 32 - , The ~esults o~ the Step-d3~m test V;it.1 scDpDl~r.ine induced a~nesia in mice are p~esented in Ta~le 5. ~he .
substances VIIe,VP, VIIb, VIIi, Vaa sho~jed pronDunced ,~
~ntiamnestic activity, c~mparable ~ith tnat of a,~iridine ,,~'~
and tacrine. , The therapeutic e'fects o~ a~niridine and tacrine are ;~
oo~m'only attrlbuted to their ability to block -ootass1um ",,~',,", pe~.neability and to inhibit acetylcholinesterase. However ,' ths data of Table 6 suggest that drugs ~ntiæmnestic acti~
vity is most closely relatea to their ability to induce ,-, the shif't of potassi1l~ pe~meability activation re~ion to "''', '', the hyperpolarization values of rnembrane potential. In ~ ~, vivo conditions this effect may be tant~nount to the in- - ~"'~ '~"`, crease of restin~, ~embrane potentiel of nerve cells th,us ~roviding rnore safe ~eneration of action potential espesi- ''; ','' ally in nerve cells with decreased e~.citability. The ef~
fect may provide a new approach in the search for drugs with antiamnestic act~vity. ' ' '~
Por more detailed study the substance Vp was chosen '~
be~use of its most pronounced capzbility to induce the ~--sA1ift of ~otassium peri,~eability voltage dependency ~nd sub- '~ -stantial ~ntia~nestic activit~ ~ith lower toxicity ~D = ~-= 200 - 22 m~kg) than that of amiridine and tacrine. On the model o~ amnestic syndrDme induced by multiple scopo-lamine injection substance Vp i~proved performance in passive avoiaance test in the 10 days ap~lication course .

` 2102681 - 33 - ' to the level achieved under the treat ent witn re-erence dru~s (~able 7). The i~provement of refle~ c~nditioning was a,ccompanied by the nor.~alizing ol microt~iscosit~r 3~
brain s~naptosomes increased i-n the an~mals ~7ith ~mnestic syndrome.
~able 8 illustrated tne data o,btained ~ith the use ' o~ old,(18~month) rats, ~? days~course of treatment with substance V~ improved ~erfor~ance of old rats in passive '-~
avoidance test more-si~,ni~~ican'tly than in 6 month adult rats, YJhile re~erence drugs improved learning and memory only to the level achievea in 6 month rats. Improvement o~
anima--l performance w~s accompanied by the normalizing o brain synaptosomes microviscosity under the action of all . .,, , the substances tested. In addition to that amiridine &nd ~, substance ~p normalized the cholesterol content of brain . . .. . ~ . .
synaptosomes. ~he latter observation indicate to the .. . ... . ... . . . . . .
possible inter~erence of amiridine and sub~tance TFp into the processe o~ atherogenesis ~n old animals.
~ ipid-re~ulative activit~r of the deolared compounds - derivatives of 9-aminoacridine - ~JQs ev~luated in vitro using rat adipocytes. ~dipocytes ~7ere separated ~rom adipose tissue of testis appendages of aged male rats. ' ~, a compositicn analysis u~as per:~ormed by the metllod of thin-layer chromatograp~y.
~ uantitative analysis of phospholipids t,~, mono -and diac~lglj;cerides (liIDG), triacyl~lycerides (~G~, free ~S~

: - 34 . . .......... .. .. , . .. , . . ,, , , ~ ~ .
~atty acid3 (~A), free cholesterQil (I~'CL), meth~l eshers : . .
of fatty acids (~IE~A) was.performea by the methoa of ~pec~
trophotometry. .' .
~he results of studies o~ l1pid-regul~ltive activit~ ,.'.;;,';:, o~ the declared.compound~ ~nd probucol - the dru~ ~idely used tD treat athero~clerosis (Duckley ~3.M.-~., Goa l~
Price ~.II., Brogden R.~T.,Drug3, 19t39, 37, 761-aOD) - are -i~
pre3ented in Tablé~'.9 - 13. 1 ~ .~.. ;.. '-Compound~ VIIe,l Vp and VIId p~sse~ o~ most po~ent e~fect on llpid composition o~ adipocyte3 ~tn absolute parameter~ and ln relation~ of separat~ ~ractions?. ' ''.~,,'`', Compound VIIe,'Under the ef'fect o~ thi~ compounds in .'-',~
adipocytes the increa3e of pho~pholipids content~nd si- '';.;;
multaneou~ decrea~e,lo~ tr1~1ycer~d s content take place " ~-(Table 9~ he oon;tent, Or methyl esher~ ,.of ~atty~'aold3 ' ';~
i~ deoreased. Increase of PL/~G rllation'~Table 11) pro-b~bl~ take3 place::~not only at the cxpense'of lipid synthe~
~is,.but Qlso~due.,t~o e~ection of triac~lglyceridesiinto e~ternal medium ~th,s~multaDeous retention o~ ph,o~pholi-plds in a cell ~Iable~ 10, 1,2, 13). A tendenoy towards lncre~e of relative chole~terol eject10n ~rom a cell l3 "~
ob3erved ~able 10,,12). , Compound Vp. :~,Ihis compound is analogous to ~IIe :' aocording to the e~fect on lipid, cocnpo3ition o~ adipoc~tes. -~:
~coumulabion of ;~phospholipia3 ln a cell t~able~ 9,'11, 13 enhanced e~ection o~ triacylglyceride~;into e~ternal me-dium ~Tables 10, i2) and 3harp decrea~e'in the content of . . .

~ ? _~5- 210268~ Table 9 LiDid comDosition of adiDosytes ~%) after inc~lbation in the Dresence o~ the comPo~lnds of the amino~ridine series.
F:~L - ~ho!~)holioid~. CL - cholesterol. FFA - free fattY acids, TG - triglycerides. ~EFA - methyl esher o~ fatty acids.
Compo~nds PL CL FF~ TG ~EFA
~ontrol 15,5-0,5 21,~-0,6 22,2-0.3 2~,5-0,4 18,9-076 ethanol 14,8~0,6 21,0-0,5 ~ 0.5 24,1-0.5 18,7-0,7 VIIe 21,5-2,3 22,6-1,7 20,3-0,6 20,~-1,9 15,3-1,6 VIj 18,1-1,7 22,5-1,0 2~,0-0,8 21,2-1,~ 15,2-0,6 ~p 19,1-1,0 22,9-1,9 22,1-0.9 21,5-1,9 14,2-0.~
~IId 15,5-2,6 22,4-1,0 24,5-0.7 21,2-1,~ 15,7-0,8 '~aa 14,1-0,5 22,~ 22,8-0.6 24,2-0,7 16.6-0,8 VII1 18,5-1,2 22,2-0,4 21,4-0.5 21,4-0,2 16,4-0,7 ,9-1,7 2~',8-0,9 22,4-2,4 24,1-0,6 16,8-0,6 ~IIk 17,0-1,8 ; 22,8-2,2 21,8-1,8 21,8-1,4 16,7-2.8 ~trobucol i5.5-0,6 18,~ 24.~-0.6 22,6-1,1 19,1-1,3 ,~
n=19 for control and ethanol. In all the rest cases n=~.
~ - statistically reliable differences (in comparison ~Jith ethanol), pC0,05.

2 1 0 2 6 8 1 :~
., . ~., able '0 ~iuid contellt !,') in inc~lbation medium after incobation of adiDosvtes in the Dresen~e of the comDo~lnds of aminoacridine uel-ies.
PL - DhosuholiDids. MDG - mono- and dislvcerides. CL -cholesterol. FF~ - free f~tty acids. TG - triglvcerides.
0OmDo~lnds PL ~DG CL FF~ TG
rontrol 15.3-0.5 18.5-0.5 19.~-0.3 23.1-0.S 23.9-0i5 ethanol 15.9-0.5 17.8-0.6 19.7-0.5 23,0-0.7 23.2-0.5 VIIe 14.9-1.5 15.3-2.3 20.3-1.5 24.1-1.5 25.3-1.1 'JIj - 14.6-2.1 15.3-0.9 22.3-1.1 24.2 1.4 23.4-1.4 VD 13.5-0.9 16.0-0.7 20.9-1.2 23.7-1,1 25.8-1.5 VIId 16.0~0.6 16.1-0.7 21.2-0.7 22.8-0.8 23.~-0,3 Vaa 13.5-0.4 20.4-2.8 18.8-0,6 ~2.6-1.5 24.6-1.4 VIIi 17.2-1.~ 19,2-2.8 19,4-0.8 23,1-2,8 21,1-1.6 VII~ 17.9-0.3 18,6-1.4 18.7-0.3 23.5-2,1 21.3-0.5 ~IIk 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 comDarison w~th ~ ;
ethanol). pC0.05.

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' ~ '.::. '~ , ~ . ,. :
,: - : .:~:~
' ' '- .",', ~~7~ 2102681 ~ ~
Table 11 ~ela$ion of vari OU5 functions of liDids in adiDosYtes after incubation of cells in the Dresence oF comDounds of aminoacridine series.
Svmbols - see Table 9.
Compound FF~/T~ PL~TG PL~CL
control 0.94 0.67 0,73 ethanol 0.88 0.61 0,70 VIIe 1.00 1.06 0.95 VIj 1.08 0.85 0.80 VD 1.03 0.89 0.8~
VIId 1.16 0.73 0.69 Vaa 0.94 0.58 0.63 VII~ 1.00 0.86 0.83 VIIk 0.9~ 0.58 0.61 VIIe 1.00 0.78 0.75 Drob-lcol 1.10 0.~9 0.84 _ _ . . _ n=19 for control and ethanol. In all the rest cases n=%.
' * - DC0,05 in com~ar-ison with "ethanol" qro~lD.
+ - D~;0.05 in comDarison with,control.

, _30 2iO26~1 -.~ble 12 F.elations of sen~rate f~.lnctions of ].ioids in incubation medium after incubation of adiDosvtes in the nresenre of ~mino~cridine derivatives~

8~mbols - see Table 9.
Comoound FF~TG PL/T5 PL~CL
control ~1 0,97 0,64 0.80 eth~nol 0,~9 0.6a 0.81 : -.
VIIe 0,95 0.59 0.7~ -VIj 1Ø~ 0.62 0.65 Vo 0.~ 0.52 0.65 VIId 0.96 0.67 0.75 ::
Va~ 0.92 0.55 0.71 - :
VII~ 1.07 0.81 0.89 ~ :
VII~ 1.10 0.84 0.96 VIIC 1.00 0.77 0.91 ~'~~~ ' ' ~; ~

:. ~.
.~

: ':

. .. ~
,~
"
, ," ~',.',~

:-~ 2 1 Q 2 6 8 1 ~able 13~istribution of ser~arate liDids between cells and incubatior medium after inc~lbation of adic)osytes in the oresence of comDounds of aminoacridine series.
Svmbols - see Table 9. Inde:: c - cells. inde~: m inc~lbation medi~m.
Comc~ound PLc~PLm FFAc/FFAm ,...___ control 1 01 0 96 ethanol 0 q~ 0 92 VIIe 1 44 0 R4 VIj 1 ~4 0.95 ~P 1 41 0.9~
VIId - 0 97 1 07 Vaa 1 04 1;01 VII~ 1 08 0.9~
VIIh 0 78 0.95 VIJe 0 97 0 96 n=19 for control and ethanol.
In all the rest cases n~
;:

~ ~;
- . ~
.
,',.''~'', ~ 2 1 0 2 6 8 1 `;`................................. . ... .
!': ' - ~

met.l-,l ester o ~atty aclds ('rlable '3) are observed.
.. - . .
Compound VIId. '~his compound has a si~ni~icant lipol~tic e`fect, which is proved by increase of content of fatty acic.5 in & ceil ('~able 9) and a sha~p increase -of ~ G relation in ~avour of ~atty acids (~able 11)~ ;
r '~he performed studies prove the ~act, that the decla- ~-red compounds have an effect on lipid cell compositiDn.
'~; Compounds VIIe, Vp and VIId show the most potent e~fect. ;~-s, ~
'~he other studied compounds also in~luence on the lipid content. A co.~binat~on of de~ribed properties o~ the ! .
; three mentioned compounds allows to consider them ~he most perspective from the poi~t of view o~ the development of new drugs to treat diseases connected with lipid metabo~
~ lism disorders. '~he compounds VIIe and Vp, increasing -l PL/'~G relation and decreasing cell cholesterol level, may --i~ be recommended ~or the study as potential anti-~theroscle~
rotic dru~s and compounds to prevent adipose de~eneration o~ or~a~s. Compound VIId due to its signi~icant lipoly-tic e~lect may be considered as a perspective drug to treat diseases accompanied by Dbesit~. Com~ounds Vp and -~;
VIId are not in~erior of the most e~ective drug in ~orld-~ide clinical practice - pro~ucol, and c~mpound VIIe supresses it.
In su~mary, the ~roposed derivatives o~ 9-~1inoacri-dine have a lower toxicity than ~no~m aru~s (tacrin, ~ .

- ,'~.': ! . .
;i~! 2 1 0 2 6 8 1 _ 41 ar.Airidine~ having rmtiamnestic activity, they are e~fec-tive in comparative or lo~er doses ensurin~ a ~.~ider therapeutic range o~ activity of the given com30unds, ~ :
~ddition&l valuable property o~ these com~ounds is lipid-re~ulative activity, vJhich ~roves perspective- :~
ness o~ mentioned compounds as anti-atherosclerotic dru~s and dru~s to treat diseases acco.r,panied by lipid met&bolism disorders, and in particular phospholipids (obesity, diabets mellitus, membronopathy of various genesis).

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.~

Claims (24)

1. 9-Aminoacridine derivatives having the general formula:
wherein:
R is H or CH3;
R1 is H, CH3 or Br;
R3 is H, C1-C5 alkyl, arylmethyl or diethyl-aminoethyl;
X is C = O or CHOH; and Y is CH2; or X together with Y represent CH = CH;
and their pharmaceutically acceptable acid addition salts.

2. 9-Amino-3,3-dimethyl-3,4-dihydroacridine-1(2H)-one and pharmaceutically acceptable acid addition salts thereof.

3. 9-Benzylamino-3,3-dimethyl-3,4-dihydro-acridine-1(2H)-one and pharmaceutically acceptable acid addition salts thereof.

4. 9-Butylamino-3,3-dimethyl-3,4-dihydroacridine-1(2H)-one and pharmaceutically acceptable acid addition salts thereof.

5. 9-Benzylamino-3,3-dimethyl-1,2,3,4-tetrahydro-acridine-1-ol and pharmaceutically acceptable acid addi-tion salts thereof.

6. 9-Amino-3,3-dimethyl-3,4-dihydroacridine-1 and pharmaceutically acceptable acid addition salts thereof.

7. 9-Benzylamino-3,3-dimethyl-3,4-dihydro-acridine-1 and pharmaceutically acceptable acid addition salts thereof.

8. 9-(p-Chlorobenzylamino)-3,3-dimethyl-3,4-di-hydroacridine-1 and pharmaceutically acceptable acid addition salts thereof.

9. A pharmaceutical composition for treating psychic diseases and diseases caused by a disturbance of lipid metabolism, which comprises a non-toxic, psy-chotropic, antiamnestic or lipid-regulating effective amount of a 9-aminoacridine derivative having the general formula:
wherein:
R is H or CH3;
R1 is H, CH3 or Br;
R3 is H, C1-C5 alkyl, arylmethyl or diethyl-aminoethyl;
X is C = O or CHOH; and Y is CH2; or X together with Y represent CH = CH;
or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier therefor.

10. A composition according to claim 9, comprising as active ingredient 9-amino-3,3-dimethyl-3,4-dihydroacridine-1(2H)-one or a pharmaceutically accept-able acid addition salt thereof.

11. A composition according to claim 9, comprising as active ingredient 9-benzylamino-3,3-dimethyl-3,4-dihydroacridine-1(2H)-one or a pharmaceutically accept-able acid addition salt thereof.

12. A composition according to claim 9, comprising as active ingredient 9-butylamino-3,3-dimethyl-3,4-di-hydroacridine-1(2H)-one or a pharmaceutically acceptable acid addition salt thereof.

13. A composition according to claim 9, comprising as active ingredient 9-benzylamino-3,3-dimethyl-1,2,3,4-tetrahydroacridine-1-ol or a pharmaceutically acceptable acid addition salt thereof.

14. A composition according to claim 9, comprising as active ingredient 9-amino-3,3-dimethyl-3,4-dihydro-acridine-1 or a pharmaceutically acceptable acid addi-tion salt thereof.

15. A composition according to claim 9, comprising as active ingredient 9-benzylamino-3,3-dimethyl-3,4-di-hydroacridine-1 or a pharmaceutically acceptable acid addition salt thereof.

16. A composition according to claim 9, comprising as active ingredient 9-(p-chlorobenzylamino)-3,3-di-methyl-3,4-dihydroacridine-1 or a pharmaceutically acceptable acid addition salt thereof.

17. Use of a 9-aminoacridine derivative having the general formula:
wherein:
R is H or CH3;
R1 is H, CH3 or Br;
R3 is H, C1-C5 alkyl, arylmethyl or diethyl-aminoethyl;
X is C = O or CHOH; and Y is CH2; or X together with Y represent CH = CH;
or a pharmaceutically acceptable acid addition salt thereof, for treating psychic diseases and diseases caused by a disturbance of lipid metabolism.

18. Use according to claim 17, wherein the 9-aminoacridine derivative used in 9-amino-3,3-dimethyl-3,4-dihydroacridine-1(2H)-one or a pharmaceutically acceptable acid addition salt thereof.

19. Use according to claim 17, wherein the 9-aminoacridine derivative used in 9-benzylamino-3,3-dimethyl-3,4-dihydroacridine-1(2H)-one or a pharmaceuti-cally acceptable acid addition salt thereof.

20. Use according to claim 17, wherein the 9-aminoacridine derivative used in 9-butylamino-3,3-dimethyl-3,4-dihydroacridine-1(2H)-one or a pharmaceuti-cally acceptable acid addition salt thereof.

21. Use according to claim 17, wherein the 9-aminoacridine derivative used in 9-benzylamino-3,3-dimethyl-1,2,3,4-tetrahydroacridine-1-ol or a pharma-ceutically acceptable acid addition salt thereof.

22. Use according to claim 17, wherein the 9-aminoacridine derivative used in 9-amino-3,3-dimethyl-3,4-dihydroacridine-1 or a pharmaceutically acceptable acid addition salt thereof.

23. Use according to claim 17, wherein the 9-aminoacridine derivative used in 9-benzylamino-3,3-dimethyl-3,4-dihydroacridine-1 or a pharmaceutically acceptable acid addition salt thereof.

24. Use according to clalm 17, wherein the 9-aminoacridine derivative used in 9-(p-chloro-benzylaminoj-3,3-dimethyl-3,4-dihydroacridine-1 or a pharmaceutically acceptable acid addition salt thereof.