3-furyl-2-cyano-2-acrylamide derivative, preparation method therefor, pharmaceutical composition and use thereof

Abstract

Disclosed are a 3-furyl-2-cyano-2-acrylamide derivative with epidermal growth factor receptor (EGFR) inhibitory activity and pharmaceutical acceptable salt thereof, together with preparation method thereof, pharmaceutical composition comprising the compound, and application of the compound in treating senile dementia (AD). The new compound is shown as formula I, wherein R.sub.1 is selected from the group consisting of H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl and C.sub.3-C.sub.6 cycloalkyl; R.sub.2 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl and heteroaralkyl; X is selected from the group consisting of CH.sub.2, NH, O and S; m and n are all integers greater than or equal to zero. ##STR00001##

Claims

1. A compound of formula I, or a pharmaceutical acceptable salt thereof: ##STR00015## wherein R.sub.1 is H; R.sub.2 is aryl substituted by halogen; X is (CH.sub.2).sub.n or (CH.sub.2).sub.nY, wherein n is an integer greater than or equal to zero; Y is NH, O or S; and m is an integer greater than or equal to zero.

2. The compound or pharmaceutical acceptable salt thereof according to claim 1, wherein n is 0, 1, 2, 3, 4 or 5.

3. The compound or pharmaceutical acceptable salt thereof according to claim 1, wherein m is 0, 1, 2, 3, 4 or 5.

4. The compound or pharmaceutical acceptable salt thereof according to claim 1, wherein R.sub.2 is halophenyl.

5. The compound or pharmaceutical acceptable salt thereof according to claim 4, wherein R.sub.2 is selected from the group consisting of p-fluorophenyl, p-chlorophenyl, and p-bromophenyl.

6. The compound or pharmaceutical acceptable salt thereof according to claim 1, wherein the compound is selected from the group consisting of: ##STR00016##

7. A compound of formula I, or a pharmaceutical acceptable salt thereof: ##STR00017## wherein R.sub.1 is selected from the group consisting of H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl and C.sub.3-C.sub.6 cycloalkyl; R.sub.2 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, and heteroaralkyl; X is (CH.sub.2).sub.n or (CH.sub.2).sub.nY, wherein n is an integer greater than or equal to zero; Y is NH, O or S; and m is an integer greater than or equal to zero.

8. The compound or pharmaceutical acceptable salt thereof according to claim 7, wherein n is 0, 1, 2, 3, 4 or 5.

9. The compound or pharmaceutical acceptable salt thereof according to claim 7, wherein m is 0, 1, 2, 3, 4 or 5.

10. The compound or pharmaceutical acceptable salt thereof according to claim 7, wherein R.sub.1 is selected from the group consisting of methyl and ethyl.

11. The compound or pharmaceutical acceptable salt thereof according to claim 7, wherein R.sub.2 is selected from the group consisting of C.sub.6-C.sub.15 heteroaryl, and C.sub.6-C.sub.15 heteroaralkyl.

12. The compound or pharmaceutical acceptable salt thereof according to claim 11, wherein R.sub.2 is ##STR00018## wherein p is an integer of 0-5.

13. The compound or pharmaceutical acceptable salt thereof according to claim 12, wherein p is 0, 1, 2, 3.

14. The compound or pharmaceutical acceptable salt thereof according to claim 7, wherein the compound is selected from the group consisting of: ##STR00019##

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 illustrates the comparison chart for the anti-senile dementia effect of 3-furan-2-cyano-2-acrylamide derivatives.

DETAILED DESCRIPTION OF THE INVENTION

(2) 1-bromo-2-(2-methoxyethoxy)ethane is purchased from Shenyang OllyChem Technology Co., Ltd., and other reagents are purchased from Sinopharm Chemical Reagent Co., Ltd. in Beijing.

Example 1: Preparation of 2-cyano-N-(4-fluorophenyl)-3-(5-hydroxymethyl-2-furyl)-2-acrylamide (JK-01A)

(3) ##STR00010##

Step 1: Preparation of 2-cyano-N-(4-fluorophenyl) acetamide

(4) 4-fluoroaniline (11.1 g, 0.1 mol), 2-cyanoacetate acid (8.5 g, 0.1 mol), EDCI (19.2 g, 0.1 mol), HOBt (13.5 g, 0.1 mol) and Et.sub.3N (20.2 g, 0.2 mol) were dissolved in CH.sub.2Cl.sub.2 (200 mL), and stirred at room temperature overnight. Distilled water (100 mL) was added, the liquid layers obtained was separated, the aqueous layer was extracted with CH.sub.2Cl.sub.2 (50 mL×2), the mixed organic layer was successively washed with distilled water (50 mL×2) and saturated brine (50 mL×1), dried with Na.sub.2SO.sub.4, concentrated. The residue was separated by a silica gel column (PE/EA=3:1) to give 15.0 g of a white solid with a yield of 84.0%.

(5) NMR Detection:

(6) .sup.1H NMR (400 MHz, DMSO-d.sub.6): 3.89 (s, 2H), 7.18 (m, 2H), 7.56 (m, 2H), 10.39 (s, 1H).

Step 2: Preparation of 2-cyano-N-(4-fluorophenyl)-3-(5-hydroxymethyl-2-furyl)-2-acrylamide

(7) 2-cyano-N-(4-fluorophenyl) acetamide (2.0 g, 11.2 mmol), 5-(hydroxymethyl) furan-2-carbaldehyde (2.1 g, 16.8 mmol) and 1-methylpiperazine (1.1 g, 11.2 mmol) were dissolved in CH.sub.3OH (50 mL), and stirred at room temperature overnight. The solid was collected by filtration, washed with CH.sub.3OH (50 mL) to give 1.1 g of a yellow solid with a yield of 36.0%.

(8) NMR Detection:

(9) .sup.1H NMR (400 MHz, DMSO-d.sub.6): 4.54 (d, 2H), 5.56 (m, 1H), 6.68 (d, 1H), 7.20 (m, 2H), 7.41 (d, 1H), 7.68 (m, 2H), 8.07 (s, 1H), 10.26 (s, 1H).

Example 2: Preparation of 2-cyano-N-[2-(1H-indol-3-yl) ethyl]-3-(5-hydroxymethyl-2-furyl)-2-acrylamide (JK-03A)

(10) ##STR00011##

Step 1: Preparation of N-[2-(1H-indol-3-yl) ethyl]-2-cyano acetamide

(11) 2-(1H-indol-3-yl) ethylamine (16.0 g, 0.1 mol), 2-cyanoacetate acid (8.5 g, 0.1 mol), EDCI (19.2 g, 0.1 mol), HOBt (13.5 g, 0.1 mol) and Et.sub.3N (20.2 g, 0.2 mol) were dissolved in CH.sub.2Cl.sub.2 (200 mL), and stirred at room temperature overnight. Distilled water (100 mL) was added, the liquid layers obtained was separated, the aqueous layer was extracted with CH.sub.2Cl.sub.2 (80 mL×2), the mixed organic layer was successively washed with distilled water (80 mL×2) and saturated brine (80 mL×1), dried with Na.sub.2SO.sub.4, concentrated. The residue was separated by a silica gel column (PE/EA=1:1) to give 18.0 g of a white solid with a yield of 79.0%.

(12) MS Detection:

(13) MASS(ESI+) m/z=228 (M+H).sup.+.

Step 2: Preparation of 2-cyano-N-[2-(1H-indol-3-yl) ethyl]-3-(5-hydroxymethyl-2-furyl)-2-acrylamide

(14) N-[2-(1H-indol-3-yl) ethyl]-2-cyanoacetamide (3.0 g, 13.2 mmol), 5-(hydroxymethyl) furan-2-carbaldehyde (1.1 g, 8.8 mmol) and 1-methylpiperazine (1.3 g, 13.2 mmol) were dissolved in CH.sub.3OH (50 mL), and stirred at room temperature overnight. The solid was collected by filtration, washed with CH.sub.3OH (50 mL) to give 1.7 g of a yellow solid with a yield of 58.0%.

(15) NMR Detection:

(16) .sup.1H NMR (400 MHz, DMSO-d.sub.6): 2.91 (m, 2H), 3.47 (m, 2H), 4.51 (d, 2H), 5.53 (m, 1H), 6.64 (d, 1H), 6.98 (m, 1H), 7.07 (m, 1H), 7.17 (d, 1H), 7.33 (m, 2H), 7.59 (m, 1H), 7.93 (s, 1H), 8.42 (s, 1H), 10.83 (s, 1H).

Example 3: Preparation of 2-cyano-N-[2-(1H-3-indolyl) ethyl]-3-{5-[2-(2-hydroxyethoxy) ethylamino]-2-furyl}-2-acrylamide (JK-05A)

(17) ##STR00012##

Step 1: Preparation of 2-cyano-N-[2-(1H-3-indolyl) ethyl]-3-(5-bromo-2-furyl)-2-acrylamide

(18) N-[2-(1H-indol-3-yl) ethyl]-2-cyanoacetamide (5.0 g, 22.0 mmol), 5-bromo-furan-2-carbaldehyde (2.5 g, 14.6 mmol) and 1-methylpiperazine (2.2 g, 22.0 mmol) were dissolved in CH.sub.3OH (100 mL), and stirred at room temperature overnight. The solid was collected by filtration, washed with CH.sub.3OH (50 mL) to give 4.5 g of a yellow solid with a yield of 81.0%.

(19) MS Detection:

(20) MASS(ESI.sup.+) m/z=385 (M+H).sup.+.

Step 2: Preparation of 2-cyano-N-[2-(1H-3-indolyl) ethyl]-3-{5-[2-(2-hydroxyethoxy) ethylamino]-2-furyl}-2-acrylamide

(21) 2-cyano-N-[2-(1H-3-indolypethyl]-3-(5-bromo-2-furyl)-2-acrylamide (4.5 g, 11.7 mmol) and 2-(aminoethoxy) ethanol (2.54 g, 17.6 mmol) were dissolved in pyridine (30 mL), stirred at 40° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by preparative liquid chromatography to give 1.2 g of a brown solid with a yield of 25.0%.

(22) MS Detection:

(23) MASS(ESI.sup.+) m/z=409 (M+H).sup.+.

Example 4: Preparation of 2-cyano-N-(4-fluorophenyl)-3-[5-(2,5,8-trioxa-nonyl-1-yl)furan-2-yl]-2-acrylamide (JK-06A)

(24) ##STR00013##

Step 1: Preparation of 2-(2,5,8-trioxa-nonyl-1-yl) furan

(25) To a solution formed by furfuralcohol (2.0 g, 20.4 mmol) dissolved in tetrahydrofuran (100 mL) NaH (1.5 g, 61.3 mmol) was added, followed by the addition of 1-bromo-2-(2-methoxyethoxy)ethane (7.5 g, 40.8 mmol), and the reaction liquid was stirred overnight. The reaction mixture was extracted with ethyl acetate, and the extract was washed with distilled water, dried with anhydrous sodium sulfate, concentrated to dryness under reduced pressure, the residue was purified by a silica gel column to give 3.5 g of a pale yellow oil with a yield of 85.7%.

(26) MS Detection:

(27) MASS(ESI.sup.+) m/z=223.1 (M+Na).sup.+.

Step 2: Preparation of 5-(2,5,8-trioxa-nonyl-1-yl) furan-2-carbaldehyde

(28) A mixed solution of DMF (1.7 g, 22.5 mmol) and 1,2-dichloroethane (45 mL) was stirred and cooled to 0° C., and POCl.sub.3 (3.0 g, 20.1 mmol) was slowly added dropwise with a controlled dropping rate to make the temperature of the reaction solution lower than 25° C. To the reaction mixture, a solution formed by 2-(2,5,8-trioxa-nonyl-1-yl) furan (3.0 g, 15.0 mmol) dissolved in 1,2-dichloroethane (45 mL) was slowly added dropwise with a controlled dropping rate to make the temperature of the reaction solution lower than 25° C. The mixture obtained was stirred at room temperature overnight after completion of addition dropwise. To the reaction mixture, a saturated solution of sodium bicarbonate (200 mL) was slowly added dropwise, then extracted with diethyl ether (3×200 mL), the mixed extract was washed successively with distilled water and saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated to dryness under reduced pressure, the residue was purified by a silica gel column to give 3.1 g of a pale yellow oil with a yield of 91.3%.

(29) MS Detection:

(30) MASS(ESI.sup.+) m/z=251.2 (M+Na).sup.+.

Step 3: Preparation of 2-cyano-N-(4-fluorophenyl)-3-[5-(2,5,8-trioxa-nonyl-1-yl)furan-2-yl]-2-acrylamide (JK-06A)

(31) 2-cyano-N-(4-fluorophenyl)acetamide (4.0 g, 22.4 mmol), 5-(2,5,8-trioxa-nonyl-1-yl)furan-2-carbaldehyde (3.4 g, 14.9 mmol) and 1-methylpiperazine (2.2 g, 22.4 mmol) were dissolved in CH.sub.3OH (50 mL), stirred at room temperature overnight. The solid was collected by filtration, washed with CH.sub.3OH (50 mL) to give 1.6 g of a yellow solid with a yield of 27.6%.

(32) MS Detection:

(33) MASS(ESI.sup.+) m/z=411.3 (M+Na).sup.+.

Example 5: Preparation of 2-cyano-N-[2-(1H-3-indolyl) ethyl]-3-[5-(1, 4,7,10-tetraoxa-undecane-11-yl)furan-2-yl]-2-acrylamide (JK-07A)

(34) ##STR00014##

Step 1: Preparation of 2-[2-(2-bromoethoxy) ethoxy] ethanol

(35) Triglycol (12.2 g, 81.3 mmol) was dissolved in dichloromethane (150 mL), stirred and cooled to 0° C., and then carbon tetrabromide (12.0 g, 27.1 mmol) and triphenylphosphine (7.8 g, 29.8 mmol) were added. The reaction mixture was stirred at room temperature for 2 h, the solvent was distilled off under reduced pressure, the residue was purified by a silica gel column to give 4.8 g of a pale yellow oil with a yield of 27.7%.

(36) NMR Detection:

(37) .sup.1H NMR (400 MHz, CDCl.sub.3): 3.35 (t, 2H), 3.44 (t, 2H), 3.53 (m, 4H), 3.58 (t, 2H), 3.68 (t, 2H).

Step 2: Preparation of 2-(8-bromo-3,6-dioxa-octane-1-yl)tetrahydropyran

(38) 2-[2-(2-bromoethoxy) ethoxy]ethanol (4.2 g, 19.8 mmol) was dissolved in diethyl ether (150 mL), slowly added dropwise by 3,4-dihydro-2H-pyran (2.5 g, 29.7 mmol) under stirring, the reaction mixture was stirred at room temperature for 1 h. To the reaction liquid, NaHCO.sub.3 was added for neutralization, then the reaction mixture was filtered, evaporated under reduced pressure to remove the solvent and excess 3,4-dihydro-2H-pyran, the residue was purified by a silica gel column to give 4.1 g of a pale yellow oil with a yield of 69.7%. NMR detection:

(39) .sup.1H NMR (400 MHz, CDCl.sub.3): 1.40-1.85 (m, 6H), 3.35-3.85 (m, 14H), 4.55-4.62 (m, 1H).

Step 3: Preparation of 2-[10-(furan-2-yl)-3,6,9-trioxa-decane-1-yl]tetrahydropyran

(40) To a solution formed by furfuralcohol (2.0 g, 20.4 mmol) dissolved in tetrahydrofuran (100 mL) NaH (1.5 g, 61.3 mmol) was added, followed by addition of 2-(8-bromo-3,6-dioxa-octane-1-yl)tetrahydropyran (12.1 g, 40.8 mmol), and the reaction liquid was stirred overnight. The reaction mixture was extracted with ethyl acetate, and the extract was washed with distilled water, dried with anhydrous sodium sulfate, concentrated to dryness under reduced pressure, the residue was purified by a silica gel column to give 5.1 g of a pale yellow oil with a yield of 79.5%.

(41) MS Detection:

(42) MASS(ESI.sup.+) m/z=337 (M+Na).sup.+.

Step 4: Preparation of 2-(10-hydroxy-2,5,8-trioxa-decane-1-yl)furan

(43) Pyridine p-toluenesulfonate (3.1 g, 14.0 mmol) was dissolved in absolute ethanol (150 mL), 2-[10-(furan-2-yl)-3,6,9-trioxa-decane-1-yl]tetrahydropyran (4.0 g, 12.7 mmol) was then added. The reaction mixture was warmed to 55° C., stirred for 12 h with heat preservation, concentrated to dryness under reduced pressure, the residue was purified by a silica gel column to give 2.4 g of a pale yellow oil with a yield of 82.1%.

(44) MS Detection:

(45) MASS(ESI.sup.+) m/z=253 (M+Na).sup.+.

Step 5: Preparation of 5-(10-hydroxy-2,5,8-trioxa-decane-1-yl)furan-2-carbaldehyde

(46) A mixed solution of DMF (1.7 g, 22.5 mmol) and 1,2-dichloroethane (45 mL) was stirred and cooled to 0° C., then POCl.sub.3 (3.0 g, 20.1 mmol) was slowly added dropwise with a controlled dropping rate to make the temperature of the reaction solution lower than 25° C. To the reaction mixture, a solution formed by 2-(10-hydroxy-2,5,8-trioxa-decane-1-yl)furan (3.5 g, 15.0 mmol) dissolved in 1,2-dichloroethane (45 mL) was slowly added dropwise with a controlled dropping rate to make the temperature of the reaction solution lower than 25° C. The mixture obtained was stirred at room temperature overnight after completion of addition dropwise. To the reaction mixture, a saturated solution of sodium bicarbonate (200 mL) was slowly added dropwise, then extracted with diethyl ether (3×200 mL), the mixed extract was washed successively with distilled water and saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated to dryness under reduced pressure, the residue was purified by a silica gel column to give 3.4 g of a pale yellow oil with a yield of 87.8%.

(47) MS Detection:

(48) MASS(ESI.sup.+) m/z=281 (M+Na).sup.+.

Step 6: Preparation of 2-cyano-N-[2-(1H-3-indolyl)ethyl]-3-[5-(10-hydroxy-2,5,8-trioxa-decane-1-yl)-2-furanyl]-2-acrylamide

(49) N-[2-(1H-indol-3-yl) ethyl]-2-cyanoacetamide (5.0 g, 22.0 mmol), 5-(10-hydroxy-2,5,8-trioxa decane-1-yl)furan-2-carbaldehyde (3.8 g, 14.6 mmol) and 1-methylpiperazine (2.2 g, 22.0 mmol) were dissolved in CH.sub.3OH (100 mL), stirred at room temperature overnight. The solid was collected by filtration, washed with CH.sub.3OH (50 mL) to give 5.3 g of a yellow solid with a yield of 77.6%.

(50) MS Detection:

(51) MASS(ESI.sup.+) m/z=490 (M+Na).sup.+.

Example 6: Test for Anti-Senile Dementia Effect of Compounds JK-01A, JK-03A, JK-05A, JK-06A and JK-07A

(52) Feeding of Fruit Flies with Senile Dementia:

(53) In all tests, w.sup.1118 (isoCJ1) was used as a control gene system, referred to as the “2U”. Progeny fruit flies with disease carrying P35 and H29.3 were obtained by integration of fruit flies carrying elav-GAL4.sup.c155 (referred to as P35) and fruit flies carrying Aβ42 (UAS-Aβ42; referred to as H29.3). The first generation of fruit flies obtained by hybridization was used for behavioral testing. Details as follows:

(54) Control Fruit Flies:

(55) TABLE-US-00001 F0 2U ♀ × H29.3 ♂ (w/w; +/+) (w/Y; UAS-Aβ42/cyo) or (+/Y; UAS-Aβ42/cyo) ↓ F1 2U*H29.3 ♂ (+/Y; UAS-Aβ42/+)

(56) AD Fruit Flies:

(57) TABLE-US-00002 F0 P35 ♀ × H29.3 ♂ (elav/elav; (w/Y; UAS-Aβ42/cyo) +/+) ↓ F1 AD ♂ (elav/Y; UAS-Aβ42/+; +/+)
Feeding of AD Fruit Flies:

(58) All the fruit flies were reared in an environment with a temperature of 24° C., relative humidity of 40% RH. On the first day, newborn male 2U*H29.3 fruit flies and male AD fruit flies were picked out and put into glass bottles (there were about 120 fruit flies in each bottle). During administration period, these fruit flies were placed in an environment with a temperature of 28° C., relative humidity of 42% RH. From the second day to the eighth day, the fruit flies were transferred into new glass bottles 4 hours later after administration. All the fruit flies were placed in an environment with a temperature of 28° C., relative humidity of 42% RH until 1 hour before Pavlovian olfactory learning test.

(59) Administration for AD Fruit Flies

(60) On the first day of eclosion dispensation of drugs was conducted, the second day administration was carried out. The respective initial amount of compounds JK-01A, JK-03A, JK-05A, JK-06A and JK-07A was 10 mg, and the final concentration was 100 μM. Each group had two glass bottles of flies which were administered 50 μl within seven days (from the second day to the eighth day). During administration period, since some fruit flies died naturally or for other causes, about 100 flies were remained in each bottle when Pavlovian olfactory test was conducted on the ninth day.

(61) Pavlovian Olfactory Learning Test:

(62) The fruit flies were placed on the automatic training device for training. In training, a group of about 100 flies first contacted with one kind of odor (octanol or methyl cyclohexanol) accompanied by electric shocks (an electric shock of 60 V for 3.5 s at 1.5-s intervals) for 60 s, rested at 45-s intervals, and then contacted with another kind of odor (methyl cyclohexanol or octanol) without electric shocks for 60 s. To test the “immediate memory” (also called “learning”), flies after the training were immediately sent to the T-maze choice point, and allowed to choose between two kinds of odor, the learning and memory index PI (Performance index) in every test was calculated according to the number of flies choosing each kind of odor. PI=0 represented 50:50, meaning that fruit flies could not remember the odor accompanied by electric shocks, PI=100 represented that 100% of the flies remembered the odor accompanied by electric shocks. Learning test was carried out in a darkroom with a temperature of 25° C., relative humidity of 70% RH. The fruit flies entered the darkroom to be familiar with the environment 1 hour before test.

(63) Statistical Analysis:

(64) The test data was analyzed and plotted by employing GraphPad Prism.

(65) Test Results:

(66) In the activity test, the olfactory short-term memory impairment tests of healthy flies with the same genetic background and without administration, AD flies without administration, AD flies administrated positive or negative control drugs and AD flies administrated test drugs were carried out at the same time, their learning and memory indexes were calculated, and the learning and memory index of AD flies administrated test drugs was compared with those of healthy flies with the same genetic background, AD flies, AD flies administrated positive or negative control drugs to evaluate the anti-senile dementia effect of test compounds. A relatively higher learning and memory index of AD flies administrated test drugs represented a stronger anti-senile dementia effect of test compounds.

(67) Comparison between learning and memory indexes of AD flies administrated test drugs and AD flies without administration (only administrated drug sample-free solvent) was conducted by employing T test, a P value less than 0.05 represented a difference, a P value less than 0.01 represented a significant difference, a P value less than 0.001 represented a very significant difference.

(68) The test results are shown in Table 1, the data in Table 1 is plotted as shown in FIG. 1:

(69) TABLE-US-00003 TABLE 1 Comparison ofanti-senile dementia effect of drugs PI Genotype/drug (mean value) S.E.M T test 2U 90 1.22 2U*H29.3 61 4.15 P35*H29.3 26 3.82 PC 62 1.65 0.0001 JK-01A 65 0.28 0.0025 JKF-006 37 2.68 0.1531 JK-03A 56 3.02 0.0077 JKF-027 54 6.08 0.0144 JK-05A 40 0.85 0.0794 JKF-011 50 1.11 0.0139 JK-06A 67 0.34 0.0024 JK-07A 58 2.98 0.0082 Crocetin 40 4.81 0.0935 Dasatinib 56 4.62 0.0095 Erlotinib 48 1.37 0.0192

(70) The test data in Table 1 showed that, compared with drugs crocetin, erlotinib, dasatinib, JKF-006, JKF-027 and JKF-011 (disclosed in WO2012/103282A2) reported to had an anti-senile dementia effect, compounds JKF-006, JK-05A and crocetin (P>0.05) had equivalent anti-senile dementia effects, compounds JKF-027, JKF-011 and erlotinib (P<0.05) had anti-senile dementia effects, compounds JK-01A, JK-03A, JK-06A, JK-07A and dasatinib (P<0.01) had significant anti-senile dementia effects.

(71) Test data also showed that the compounds of the present invention JK-01A, JK-03A, JK-06A and JK-07A had more significant anti-senile dementia effects compared with compound JKF-006, JKF-027 and JKF-011.

(72) Thus, the compounds of the present invention JK-01A, JK-03A, JK-05A, JK-06A and JK-07A may be used for treatment or prophylaxis of Alzheimer's disease, senile dementia, neurodegenerative disease, vascular dementia, vascular cognitive impairment, cholinergic neuron degenerative lesions, and helpful for the improvement of cognitive dysfunction or learning and memory impairment.

Example 7: Preliminary Acute Toxicity Test for Compounds JK-01A, JK-03A, JK-05A, JK-06A and JK-07A

(73) Method: in the acute toxicity test, ICR mice were used and divided into six groups for administration, with 10 mice in each group and half male and half female. Due to limitations of administration concentration and dosing volume, each test drug had the maximum dosage of 6 g/kg/day, and administered orally twice with an interval of 3 hours. The control group was administrated the same volume of vehicle. Observation was conducted for 14 consecutive days after administration.

(74) Results: during the observation period, in test drug groups, no animal died; no significant difference between indexes such as action, mental state, haircolor and the like of animals in each test drug group and vehicle group was obtained by clinical observation. Additionally, the gross anatomy results showed no visible lesions in organs of animals in each test drug group. Therefore, these compounds were considered to be with a very low toxicity, and did not cause any death of the animal with a dosage of 4-6 g/kg/day, while no abnormal clinical manifestations were observed, the acute toxicity test results for each compound are shown in Table 2.

(75) TABLE-US-00004 TABLE 2 Acute toxicity results of compounds Test Number of Dosage Route of No. drug animals (mg/kg/d) administration Test result 1 Vehicle 10 6000 p.o. No death, no abnormal reaction 2 Jk-01A 10 4000 p.o. No death, no abnormal reaction 3 JK-03A 10 6000 p.o. No death, no abnormal reaction 4 JK-05A 10 5000 p.o. No death, no abnormal reaction 5 JK-06A 10 6000 p.o. No death, no abnormal reaction 6 JK-07A 10 4000 p.o. No death, no abnormal reaction