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Publication numberUSRE38460 E1
Publication typeGrant
Application numberUS 09/799,127
PCT numberPCT/CN1995/000100
Publication dateMar 9, 2004
Filing dateDec 26, 1995
Priority dateDec 28, 1994
Fee statusLapsed
Publication number09799127, 799127, PCT/1995/100, PCT/CN/1995/000100, PCT/CN/1995/00100, PCT/CN/95/000100, PCT/CN/95/00100, PCT/CN1995/000100, PCT/CN1995/00100, PCT/CN1995000100, PCT/CN199500100, PCT/CN95/000100, PCT/CN95/00100, PCT/CN95000100, PCT/CN9500100, US RE38460 E1, US RE38460E1, US-E1-RE38460, USRE38460 E1, USRE38460E1
InventorsDayuan Zhu, Xican Tang
Original AssigneeShanghai Institute Of Materia Medica Chinese Academy Of Sciences
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Huperzine A derivatives, their preparation and their use
US RE38460 E1
Abstract
The present invention relates to novel huperzine A derivatives of formula (II), wherein Y is
or R″ and Y together form ═CH; R is (C1-C5) alkyl,
wherein n is 0 or 1, X is H, (C1-C5) alkyl; (C1-C5) alkyloxy; nitro, halogen, carboxy, alkyloxycarbonyl, hydroxymethyl, hydroxy, amino substituted by bis-(C1-C5) alkyl; —(CH2)m COOZ, wherein m=0-5, Z is H or (C1-C5) alkyl; —CH═CH—G, wherein G is phenyl, furanyl, carboxy, alkyloxycarbonyl; and dihydro- or tetrahydro-pyridyl substituted by (C1-C5) alkyl at the nitrogen atom; R′ is H, (C1-C5) alkyl, pyridoyl, benzoyl substituted by (C1-C5) alkyloxy; R″ is H or (C1-C5) alkyl; processes for their use as acetylcholinesterase inhibitor.
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Claims(25)
We claim:
1. A huperzine A compound having tile following structural formula
wherein Y and —R″ together form═CH, R is
X is hydrogen, C1-C5 lower alkyloxy, nitro, halogen, hydroxymethyl, hydroxy, amino substituted by two C1-C5 lower alkyls or —CH═CH—G group, is phenyl or furanyl and R′ is hydrogen.
2. A method of treating myasthenia amyasthenia by inhibiting cholinesterase comprising administering a huperzine A compound according to claim 1 10to a patient in need of such treatment in an amount effective to inhibit cholinesterase.
3. A method of treating dysmnesia, caused by a failure in central cholinergic system by inhibiting cholinesterase comprising administering a huperzine A compound according to claim 1 10to a patient in need of such treatment in an amount effective to inhibit cholinesterase.
4. A method of inhibiting cholinesterase comprising administering a huperzine A compound according to claim 1 10in an amount effective to inhibit cholinesterase to a patient in need of such treatment.
5. A method of inhibiting cholinesterase according to claim 4, wherein said cholinesterase is an acetylcholinesterase.
6. A method of inhibiting cholinesterase according to claim 4, wherein the cholinesterase is butyrylcholinesterase.
7. A method of improving memory impairment comprising administering a huperzine A compound according to claim 1 10in an amount effective to improve mnemory imnpairmientmemory impairment to a patient in need of such treatment.
8. A compound according to claim 1 10, wherein R″ and Y are ═CH, prepared by a process of condensing huperzine A and the corresponding substituted aldehyde in an anhydrous solvent.
9. A method of inhibiting cholinesterase according to claim 4, wherein said huperzine A compound exhibits weaker inhibition effect on butyrylcholinesterase than huperzine A.
10. A huperzine A compound of the formula
wherein
Y and —R″ together form a ═CH group;
R is
wherein X is selected from the group consisting of hydrogen, C 1 -C 5 lower alkoxy, nitro, halogen, hydroxymethyl, hydroxy, amino substituted by two C 1 -C 5 lower alkyls and —CH═CH—G,
wherein G is phenyl or furanyl; and
R′ is hydrogen.
11. A huperzine A compound of the formula
wherein
Y and —R″ together form ═CH;
R is selected from the group consisting of:
and R′ is hydrogen.
12. A huperzine A compound of the formula
wherein
Y and —R″ together form ═CH; and
R is
13. A huperzine A compound of the formula
wherein
Y and —R″ together form ═CH; and
R is
wherein each X is independently selected from the group consisting of hydrogen, methoxy, nitro, halogen, hydroxymethyl, and hydroxy;
and R′ is H.
14. A method of treating amyasthenia by inhibiting cholinesterase comprising administering a huperzine A compound according to claim 11 to a patient in need of such treatment in an amount effective to inhibit cholinesterase.
15. A method of treating amyasthenia by inhibiting cholinesterase comprising administering a huperzine A compound according to claim 12 to a patient in need of such treatment in an amount effective to inhibit cholinesterase.
16. A method of treating amyasthenia by inhibiting cholinesterase comprising administering a huperzine A compound according to claim 13 to a patient in need of such treatment in an amount effective to inhibit cholinesterase.
17. A method of treating dysmnesia caused by a failure in central cholinergic system by inhibiting cholinesterase comprising administering a huperzine A compound according to claim 11 to a patient in need of such treatment in an amount effective to inhibit cholinesterase.
18. A method of treatment dysmnesia caused by a failure in central cholinergic system by inhibiting cholinesterase comprising administering a huperzine A compound according to claim 12 to a patient in need of such treatment in an amount effective to inhibit cholinesterase.
19. A method of treating dysmnesia caused by a failure in central cholinergic system by inhibiting cholinesterase comprising administering a huperzine A compound according to claim 13 to a patient in need of such treatment in an amount effective to inhibit cholinesterase.
20. A method of inhibiting cholinesterase comprising administering a huperzine A compound according to claim 11 in an amount effective to inhibit colinesterase to a patient in need of such treatment.
21. A method of inhibiting cholinesterase comprising administering a huperzine A compound according to claim 12 in an amount effective to inhibit colinesterase to a patient in need of such treatment.
22. A method of inhibiting cholinesterase comprising administering a huperzine A compound according to claim 13 in an amount effective to inhibit colinesterase to a patient in need of such treatment.
23. A method of improving memory impairment comprising administering a huperzine A compound according to claim 11 in an amount effective to improve memory impairment to a patient in need of such treatment.
24. A method of improving memory impairment comprising administering a huperzine A compound according to claim 12 in an amount effective to improve memory impairment to a patient in need of such treatment.
25. A method of improving memory impairment comprising administering a huperzine A compound according to claim 13 in an amount effective to improve memory impairment to a patient in need of such treatment.
Description

This application is the national phase of PCT/CN95/00100, filed Dec. 26, 1995, published as WO96/20176 on Jul. 4, 1996.

The present invention relates to semi-synthesis of natural product, and particularly to alkaloid and analogues thereof.

In the past ten years a lot of researches have been made in foreign countries about application of choline esterase inhibitor to enhance the function of the intracerebral cholinergic system for the treatment of presenile dementia. Although delightful results of research have been obtained, there still exist some defects; at the time of producing the treatment effect, there occurs a relatively serious toxic side reaction; and the duration of the effect is relatively short.

In recent years China has isolated from a Chinese herb Lycopodium serratum Thunb., a new alkaloid huperzine A (5R, 9R, 11E)-5-amino-11-ethylidene-5,6,9,10-tetrahydro-7-methyl-5,9-methylene cycloocta [b] pyridyl-2(1H)-one having the formula (I)

Upon a pharmacological study it is proved that it exhibits highly effective reversible anticholinesterase activity, and has selective inhibitory effect on intracerebral acetylcholinesterase (U.S. Pat. No. 5,177,082). In foreign countries modification of the structure of huperzine A has been carried out and analogues of huperzine A have been synthesized in hopes of discovering therefrom compounds having anticholinesterase activity [J. Org. Chem. 56, 1991(4636-4645)] and finding a method of synthesizing huperzine A [U.S. Pat. No. 4,929,731]. However, neither a good method nor an analogue having a better effect has been found so far.

The present invention has made use of the excellent resources of Chinese herbs in China to design a semi-synthesis starting from huperzine A, in the hope of finding among a great variety of huperzine A derivatives compounds having better treatment effect and lower toxicity than the existing huperzine A.

The present invention is carried out through the following steps:

1. Using alcohols such as ethanol as extraction solvent, from the plant Lycopodium serratum Thunb., the residue obtained is concentrated, and then treated with an inorganic acid (such as hydrochloric acid). The aqueous layer is neutralized with alkali (such as ammonia water, NaOH), after which an organic solvent (such as chloroform) is used to extract the total alkaloid. After the treatment, separation by layer chromatography is carried out to produce the compound of the formula (I).

2. After condensation is carried out between the compound of the formula (I), and the corresponding substituted aldehyde or the corresponding substituted acyl chloride or acid anhydride in anhydrous solvent, a compound of the formula (II) is obtained.

When Y is —C═O or —R″, Y is ═CH, R is C1-C5 lower alkyl;

n=0,1, X is hydrogen, C1-C5 lower alkyl, C1-C5 lower alkyloxy, nitro, halogen, carboxy, alkyloxycarbonyl, hydroxymethyl, hydroxy, amino substituted by bis-C1-C5 lower alkyl; —(CH2)m COOZ group, m=0-5, Z is hydrogen or C1-C5 lower alkyl; —CH═CH—G group, G is phenyl, furanyl, carboxy, alkyloxycarbonyl; dihydro or tetrahydropyridyl substituted by C1-C5 lower alkyl at the nitrogen atom;

R′ is hydrogen, C1-C5 lower alkyl, pyridoyl, benzoyl substituted by C1-C5 lower alkyloxy;

R″ is hydrogen and C1-C5 lower alkyl.

When Y is C═O, R is C1-C5 lower alkyl,

n=0,1, X is hydrogen, C1-C5 lower alkyloxy, carboxy, alkyloxycarbonyl, pyridyl, dihydro or tetrahydropyridyl substituted by C1-C5 lower alkyl at the nitrogen atom; —(CH2)m COOZ group, m=0-5, Z is hydrogen or C1-C5 lower alkyl; —CH═CH—G group, G is phenyl, furanyl, carboxy, alkyloxycarbonyl;

R′ is hydrogen, C1-C5 lower alkyl, pyridoyl, benzoyl substituted by C1-C5 lower alkyloxy;

R″ is hydrogen and C1-5 lower alkyl.

When R″, Y are ═CH, R is

n=0, X is hydrogen, C1-C5 lower alkyl, C1-C5 lower alkyloxy, nitro, halogen, hydroxy, hydroxymethyl, amino substituted by bis-C1-C5 lower alkyl; —CH═CH—G group, G is phenyl, furanyl;

R′ is hydrogen and C1-C5 lower alkyl.

Huperzine A derivatives:

No. Y R R′ R″
No. 1 C═O HOOC—CH2CH2 H H
No. 2 C═O C6H5CH2 H H
No. 3 C═O CH3 CH3
No. 4 C═O H H
No. 5 C═O H
No. 6 C═O H H
No. 7 C═O 4-CH3OC6H4 H H
No. 8 C—O 2,3,4-(CH3O)3C6H2 H H
No. 9 C═O 2,3,4-(CH3O)3C6H2 H
No. 10 C═O (CH3)2CH— H H
No. 11 C═O C6H5 H H
No. 12 C═O 2-py H H
No. 13 C═O 3-py 3-py-CO— H
No. 14 C═O 4-py H H
No. 15 C═O 2-HOOC—C6H4 H H
No. 16 C═O trans-HOOCCH2CH═CH— H H
No. 17 CH H
No. 18 CH H
No. 19 CH H
No. 20 CH H
No. 21 CH H
No. 22 CH H
No. 23 CH H
No. 24 CH H
No. 25 CH H
No. 26 CH H
No. 27 CH H
No. 28 CH H
No. 29 CH H
No. 30 CH H
No. 31 CH H
No. 32 CH H
No. 33 CH H
No. 34 CH H
No. 35 CH H
No. 36 CH H
No. 37 CH H
No. 38 CH H

Pharmacological effect of huperzine A derivatives:

In the present invention a calorimetric method reported by Ellman was used to determine the effect of inhibition of the pharmaceutical on enzyme activity. The total volume of the solution of the enzyme activity reaction was 4 ml, which contained 0.3 mmol/L of acetylcholin iodide (acetylcholinesterase substrate), or 0.4 mmol/L of butyrylcholin iodide (butyrylcholinesterase substrate), 1 ml of the buffer solution of 25 mmol/L of phosphate of pH 7.4, and water to make up to 4 ml (including the amount of the enzyme solution and the testing reagent added afterwards). After the solution was kept at 37 C. for 5 minutes, 0.1-0.2 ml of enzyme solution (red cell membrane or serum of rat) was added, or 0.1-0.3 ml of the testing reagent was added at the same time. The solution was kept at the same temperature for another 8 minutes. Then 1 ml of 3% of sodium lauryl sulphate was added to terminate the reaction. Finally 1 ml of 0.2% 5,5-dithio-2,2′-nitro-benzoic acid solution was added for developing. “721” spectrophotometer was used to determine the density of light at 440 nm. A solution without addition of the pharmaceutical to inhibit the enzyme activity was used as a control (100%). A diagram was plotted with the percentage of the remaining enzyme activity against gram molecule concentration of the pharmaceutical, so as to obtain the dose of the pharmaceutical at 50% of inhibition of the enzyme activity, i.e., IC50. The results of the test showed that all the derivatives exhibited inhibition effect on acetylcholinesterase; derivatives No. 1, No. 17, No. 18 and No. 19 exhibited remarkable inhibition effect on acetylcholinesterase; their effect was slightly weaker than that of huperzine A, but apparently stronger than that of physostigmine and galanthamine. They exhibited weaker inhibition effect on butyrylcholinesterase (pseudo enzyme) than huperzine A. Derivatives No. 1 and No. 17 exhibited greater selective inhibition effect on acetylcholinesterase than huperzine A (see Tables 1, 2 and 6). A study on kinetics of enzyme indicated that the combination of derivatives No. 17, No. 18 and No. 19 respectively with acetylcholinesterase was reversible.

The two memory model test, mouse passive escape operation (Platform jumping method) and 8-arm maze spatial distinction operation of rat, indicated that both derivatives No. 18 and No. 19 exhibited very strong effect, similar to that of the compound of formula (I), on improving memory (see Tables 3 and 4).

The critical toxicity test on mice indicated that LD50 of derivatives No. 18 and No. 19 were smaller than, only ⅓ of, that of the compound of formula (I) (see Table 5).

TABLE 1
In-vitro anticholinesterase effect of huperzine
A derivatives (determined by colorimetric method)
concentration for inhibition
of 50% of enzyme activity
(IC50 μM)
acetylcholin- butyrylcholin-
esterase esterase IC50 ratio
Compound No. (AChE) (BuChE) BuChE/AChE
1 0.348 380.19 1092.5
2 9.05 >346.7
3 3.63 >331.1
4 >12.88 58.9
5 >10.96 >275.4
6 >12.3 >309.1
17 0.172 199.5 1159.9
18 0.151 107.2 709.9
19 0.145 104.7 722.1
10 >15.85 109.6
11 >14.45 363
compound(I) 0.06309 63.09 1000
Physostigmine 0.251 1.259 5.02
galanthamine 1.995 12.59 6.3

AChE taken from rat's red cell membrane. BuChE taken from rat's serum.

TABLE 2
In-vitro anticholinesterase effect of huperzine
A derivatives
concentration for
inhibition of 50%
of enzyme activity
(IC50 μM)
acetyl- butyryl-
cholin- cholin-
esterase esterase IC50 ratio
Compound No. MW (AChE) (BuChE) BuChE/AChE
huperzine A 242 0.0977 100.0 1023.3
 1 342 0.3475 380.2 1094.1
12 376 0.1259 251.2 1995.2
15 390 0.6310 502.0 795.6
17 428 0.1718 199.5 1161.2
18 376 0.1514 107.2 708.2
19 406 0.1445 104.7 724.6
20 346 0.1778 125.9 708.1
21 420 0.1413 158.5 1121.3
22 406 0.1259 125.9 1000.0
23 362 0.2512 199.5 794.2
24 362 0.1000 158.5 1585.0
25 378 0.1585 251.2 1584.9
27 356 0.1259 100.0 794.3
MW: molecular weight

AChE taken from homogenate of rat's cortex. BuChE taken from rat's serum.

TABLE 3
Improvement by huperzine A derivatives on the
condition of memory impairment caused by scopolamine in
passive escape operation
No. delitescence of
dosage of get-down Δ
Group (mg/kg ip + po) mice (sec SEM)
physiological saline + −+− 20 71.9 12.9
physiological saline
scopolamine + 2+ − 20 29.5 2.7
physiological saline
scopolamine + 2 + 0.2 20 67.7 11.7**
derivative No. 18 3 + 0.3 20 64.0 9.8*
2 + 0.4 20 48.7 6.9
physiological saline + −+− 18 81.7 19.0
physiological saline
scopolamine + 2+ − 23 32.8 8.2
physiological saline
scopolamine + 2 + 0.1 11 48.9 12.6
derivative No. 19 2 + 0.2 16 71.6 14.5
2 + 0.3 21 99.8 16.4**
2 + 0.4 18 92.2 15.5*
Δ: Once trained, the mice were administered, and tested after 24 hours. comparison with the physiological saline group P < 0.01
**comparison with scopolamine group *P < 0.05, **P < 0.01

TABLE 4
Improvement by huperzine derivatives on the
condition of memory impairment caused by scopolamine in
spatial distinction operation
No. of mistakes in
operation before reaching
the standard Δ
X + SEM)
dosage No. refer-
(mg/kg of ence working
Group ip + po) rats memory memory
physiological saline + −+− 24 0.42 0.1  0.08 0.01
physiological saline
scopolamine + 0.2+ − 6 1.67 0.21 0.33 0.42
physiological saline
scopolamine + 0.2 0.1 6 1.33 0.21 1.33
derivative No. 19 0.49**
0.2 0.3 6 0.33 0.17
0.21** 0.17**
physiological saline + −+− 24 0.33 0.13 0.08 0.006
physiological saline
scopolamine + 0.125+ − 6  2.0 0.45 2.0 0.52
physiological saline
scopolamine + 0.124 + 0.2 6 0.67 0.33
derivative No. 18 0.33** 0.13**
physiological saline + −+− 14 0.21 0.11 0.07 0.07
physiological saline
scopolamine + 0.15+ − 7 2.14 0.14 2.57 0.29
physiological saline
scopolamine + 0.15 + 0.25 10 0.57 0.86
huperzine A 0.30** 0.14**
Δ: 8-arm maze test. After trained to reach the standard (no. of mistake less than one per day for three successive days), the rats were tested. The rat first entering the arm on which there is no food is taken as the reference emory mistake. The rat re-entering the arm on which there is food is taken as the working memory mistake, comparison with the physiological saline group P > 0.01
**comparison with scopolamine group P < 0.01

TABLE 5
Critical toxicity of huperzine A derivatives on
mice (Bliss method)
mg/kg p.o. (95% confidence limit)*
Compound LD50 LD50
compound (I) 3.1(3.5-3.8)  4.6(4.2-5.1) 
derivative No. 18 9.6(7.3-12.5) 14.4(12.9-16.4)
derivative No. 19 11.1(9.6-12.9)  14.1(15.5-20.5)
*10 mice per group, with equal no. of males and females.

Test of each pharmaceutical was carried out using 4-5 dosage group.

Mortality within 7 days was observed.

TABLE 6
In-vitro anticholinesterase effect of huperzine
A derivatives
inhibition activity
Compound AChE BuChE
No. 1(μM) IC50(M) 10(μM) BuChE/AChE
(18) 90.2 8.4 10−8 0 >500
(20) 83.7 9.4 10−8 0 >500
(21) 84.9 1.0 107  0 >500
(22) 68.7 0
(23) 34.4 0
(15) 60.8 0
(24) 78.3 2.8 10−7 0 >100
(25) 62.0 0
(27) 84.0 1.1 10−7 3.3 >500
(26) 79.7 1.8 10−7 1.1 >300
(16) 80.7 2.1 10−7 1.8 >200
(14) 76.4 3.6 10−7 2.5 >100
(44) 85.6 1.1 10−7 1.8 >500
(45) 87.0 1.0 10−7 1.8 >500
(46) 78.7 2.9 10−7 1.2 >100
E-2020 86.2 6.6 10−8 2.9 >500
huperzine A 88.3 1.2 10−7 0 >500

The results of the above pharmacological study show that derivatives No. 17, No. 18 and No. 19 are highly effective selective inhibitors of acetylcholinesterase and have lower critical toxicity than compound (I). Hence, it can be deduced that they have prospect of clinical application and development for use in the treatment of relieving serious amyasthenia and of dysmnesia caused by failure in central cholinergic system.

EXAMPLE 1 Preparation of Derivative No. 2

Compound (I) (0.50 mmole) into 5 ml three-neck flask was weight out. 20 ml of anhydrous pyridine was added to dissolve compound (I). While cooling in ice-bath, phenyl acetyl chloride (0.55 mmole) was added dropwise. Then the whole mixture was stirred overnight at room temperature (25 C.). When thin-layer chromatography indicated substantial disappearance of the starting materials, the reaction was stopped. Pressure was reduced by means of water pump to vaporize pyridine. Separation was carried out using silica gel layer chromatography. Elution was carried out with dichloromethane:acetone:methanol=5:45:5 to produce the crude product, which was recrystallized using a mixed solvent of acetone and petroleum ether to produce the product with 75% yield.

UV λmax=229 nm (∈=17360); λmax=316 nm(∈=9320); [α]D 25 C.=29.43; 1HNMR: [CDCl3]; 3H 6.31(1H,d,J=9.9 Hz); 4H 7.20 (1H,d,J=9.9 Hz); 10H 2.89(2H,m); 9H 3.52 (1H,m); 8H 5.38(1H,d,J=5.0 Hz); 14-H 1.62(3H,d,J=6.7 Hz); 13-H 5.08(1H,q,J=6.7 Hz); 6-H 2.15,2.45(2H,m); 12-H 1.50(3H,s); 2′,4′-H 7.36(2H,m); 3′,5′-H 7.29(2H,m); 6′-H 7.24(1H,m); 7′-H 3.59(s); MS(m/z) 360(M+) 345 269 252 227 224 210(100%) 91; mp: 171-173 C.; IR: υmax 3280, 1660(s), 1620(s), 1550, 1450, 1350, 1300, 1175, 1130, 840, 620 cm−1

The same process was used to prepare derivatives No. 3, No. 5, No. 6, No. 7, No. 8, No. 9, No. 10, No. 11, and No. 13.

EXAMPLE 2 Preparation of Derivative No. 4

Compound (I) (0.5 mmole) into 50 ml three-neck flask was weight out. 20 ml of anhydrous pyricline to dissolve compound (I) was added. While cooling in ice-bath, DBU (0.6 mmole) was first added, and then 0.55 mmole of hydrochloric acid pyridine-2-formyl chloride was added. The whole mixture was placed overnight at room temperature. When thin-layer chromatography determination indicated substantial completion of the reaction, pressure was reduced by means of water pump to vaporize pyridine. Separation was carried out using silica gel layer chromatography. Elutioni was carried out with dichloromethane:acetone:methanol=50:45:5 to produce the crude product, which was recrystallized using a mixed solvent of acetone and petroleum ether to produce the product with 74% yield.

UV λmax=226 nm (∈=1.35104); λmax=264 nm (∈=5.4103); λmax=315 nm (∈=5730); [α]D=77.85; 1HNMR: [CDCl3]; 3-H 6.36(1H,J=9.2 Hz); 4-H 7.44(1H,J=9.2 Hz); 10-H 3.05(2H,m); 9-H 3.74(1H,m); 8-H 5.42(1H,d,J=4.7 Hz); 14-H 1.65(3H,d,J=6.6 Hz); 13-H 5.35(1H,q=6.6 Hz); 6-H 2.42(2H,s); 12-H 1.55(3H,s); 2′-H 8.58(1H,m); 4′-H 7.85(1H,m); 5′-H 7.48(1H,m); 6′-H′ 8.15(1H,m); MS(m/z) 347(M+), 241(100%) 169, 149, 106, 95, 79, 71, 55; mp: 170-171 C.; IR: umax 3450, 2900, 1660(s), 1615(s), 1530(s), 1460, 1300, 1180, 1140, 1000, 830, 750 cm−1

The same process was used to prepare derivatives No. 12 and No. 14.

EXAMPLE 3 Preparation of Derivative No. 19

Compound (I) (0.5 mmole) was weight out into 50 ml three-neck flask. Anhydrous ethanol and 4,6-dimethoxy-2-hydroxy benzaldehyde (0.51 mmole) were added. The mixture was heated slightly under reflux. Through a water segregator part of the ethanol was vaporized continuously. The solvent in the reaction was constantly replenished. The reaction was carried out for several hours and the reaction state was constantly determined by means of thin-layer chromatography. When the reaction was completed, the pressure was reduced to remove the ethanol to produce a solid crude product, which was recrystallized using a mixed solvent of acetone and petroleum ether to produce the product with 92% yield.

The same process was used to prepare derivatives No. 17, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, and 43.

Derivative No. 19

m.p. 207-210 C.; MS: m/z 406(M+); 391(M+-CH3), 351(M+-C4H7); 1H NMR (CDCl3); 1-H 13.12(1H,br,s); 3-H 6.41(1H,d,J=9.1 Hz); 4-H 7.25(1H,d,J=9.1 Hz); 6-H 2.85 (2H,s); 8-H 3.45(1H,d,J=4.7 Hz); 9-H 3.61(1H,m); 10-H 2.85(2H,m); 12-H3 1.60(3H,s); 13-H 5.22(1H,q,J=7.7 Hz); 14-H3 1.25(3H,d,J=7.7 Hz); 2′-OH 14.58(1H,br,s); 3′-H 5.57 (1H,s); 4′-OCH3 3.79(3H,s); 5′-H 5.85(1H,s); 6′-OCH3 3.70 (3H,s); 7′-H 8.15(1H,s); IR: υmax 3480(m), 2960(s), 2930(s), 2870(s), 1670(s), 1620(s), 1540(s), 1450(s), 1330 (s), 1300 (s), 1218(sh), 1186(m), 1155(s), 1110(s), 1080(m), 1050(m), 1000(m), 930(m), 840(s), 730(m), 670(m), 610(m), 520(s) cm−1.

Derivative No. 20

1H NMR (CDCl3): 1-H 12.72(1H,br,s); 3-H 6.34(1H,d, J=9.4 Hz); 4-H 7.11(1H,d,J=9.4 Hz); 6a-H 2.79(1H,d,J=16.0 Hz); 6b-H 2.75(1H,d,J=16.0 Hz); 8-H 5.41(1H,d,J=5.0 Hz); 9-H 3.63(1H,m); 10a-H 2.95(1H,dd,J=16.6, 4.9 Hz); 10b-H 2.27(1H,d,J=16.6 Hz); 12-H 1.57(3H,s); 13-H 5.07(1H,q,J=6.8 Hz); 14-H 1.55(3H,d,J=6.8 Hz); 2′-OH 13.77(1H,br,s); 3′-H 6.94(1H,d,J=8.4 Hz); 4′-H 7.30(1H,t with small splitts, J=8.4 Hz); 5′-H 6.85(1H,t with small splitts, J=7.4 Hz); 6′-H 7.22(1H,dd,J=7.4, 1.6 Hz); 7′-H 8.31(1H,s); MS: 346(M+), 331, 317, 303, 291, 253, 239, 226, 210, 197, 184, 167, 128, 121, 97. IR: υmax 3420, 2900, 1660, 1620, 1580, 1560, 1500, 1460, 1420, 1380, 1350, 1280, 1205, 1150, 1120, 1080, 1010, 970, 910, 840, 790, 755(s), 650, 630, 610, 520 cm−1

Derivative No. 21;

1H NMR (CDCl3); 1-H 12.87(1H,br,s); 3-H 6.32(1H,d, J=9.4 Hz); 4-H 7.07(1H,d,J=9.4 Hz); 6a-H 2.79(1H,d,J=16.0 Hz); 6b-H 2.75(1H,d,J=16.0 Hz); 8-H 5.43(1H,d,J=5.0 Hz); 9-H 3.63(1H,m); 10a-H 2.97(1H,dd,J=16.0, 4.0 Hz); 10b-H 2.18(1H,d,J=16.0 Hz); 12-H 1.58(3H,s); 13-H 5.14(1H,q,J=6.8 Hz); 14-H 1.57(3H,d,J=6.8 Hz); 2′,6′-2H 7.04(2H,s); 7′-H 8.25(1H,s); 3′,5′-2(OCH3) 3.87(6H,s); 4′-OCH3 3.84 (3H,s); MS: 420(M+), 405(M+-CH3), 391, 365, 351, 313, 284, 239, 226, 210, 196, 181, 140, 124. IR: υmax 2940, 1660(s), 1590, 1560, 1500, 1565, 1420, 1370, 1330, 1300, 1230, 1190, 1130(s), 1005, 960, 930, 840, 770, 735, 725, 660, 605, 540, 530 cm−1.

Derivative No. 22

1H NMR(CDCl3): 1-H 13.03(1H,br,s); 3-H 6.34(1H,d,J=9.4 Hz); 4-H 7.14(1H,d,J=9.4 Hz); 6-H2 2.73(2H,s); 8-H 5.39(1H,d,J=4.7 Hz); 9-H 3.61(1H,m); 10a-H 2.94(1H,dd, J=16.8, 4.9 Hz); 10b-H 2.27(1H,d,J=16.8 Hz); 12-H 1.55 (3H,s); 13-H 5.09(1H,q,J=6.8 Hz); 14-H 1.54(3H,d,J=6.8 Hz); 2′-OH 14.39(1H,br.s); 3′-OCH3 3.87(3H,s); 4′-OCH3 3.85(3H,s); 5′-H 6.43(1H,d,J=8.7 Hz); 6′-H 6.91(1H,d,J=8.7 Hz); 7′-H 8.14(1H,s); MS: 406(M+), 391(M+-CH3), 373, 351, 239, 226, 197, 182, 167, 139, 101; IR: υmax 3450-3350 (br), 2940(m), 1660(s), 1620(s), 1555, 1510, 1455, 1415, 1290, 1270(s), 1210, 1110(s), 1060, 970, 930, 835, 785, 695, 675, 640, 625 cm−1.

Derivative No. 23

1H NMR(d6-DMSO): 1-H 11.48(1H,br,s); 3-H 6.13(1H, d,J=9.4 Hz); 4-H 7.07(1H,d,J=9.4 Hz); 6a-H 2.68(1H,d,J=16.7 Hz); 6b-H 2.59(1H,d,J=16.7 Hz); 8-H 5.48(1H,d,J=4.7 Hz); 9-H 3.65(1H,m); 10a-H 2.77(1H,dd,J=16.3, 4.0 Hz); 10b-H 2.28(1H,d,J=16.3 Hz); 12-H 1.59(3H,s); 13-H 5.05 (1H,q,J=6.8 Hz); 14-H 1.60(3H,d,J=6.8 Hz); 2′-OH 14.40 (1H,br,s); 3′-H 6.18(1H,s); 4′-OH 10.09(1H,br,s); 5′-H 6.30 (1H,d, with small splitts, J=8.4 Hz); 6′-H 7.31(1H,d,J=8.4 Hz); 7′-H 8.47(1H,s); MS: 362(M+), 347, 319, 307, 242, 226, 210, 197, 167, 137. IR: υmax 3500-2800(br), 1665(s), 1625(s), 1605(s), 1550, 1540, 1450, 1345, 1300, 1230, 1180, 1120, 1080, 975 cm−1.

Derivative No. 24

1H-NMR(CDCl3): 1-H 13.09(1H,br,s); 3-H 6.37(1H,d,J=9.4 Hz); 4-H 7.15(1H,d,J=9.4 Hz); 6-H2 2.76(2H,s); 8-H 5.42(1H,d,J=5.0 Hz); 9-H 3.60(1H,m); 10a-H 2.96(1H,dd, J=16.5, 4.9 Hz); 10b-H 2.32(1H,d,J=16.5 Hz); 12-H 1.56 (3H,s); 13-H 5.11(1H,q,J=6.8 Hz); 14-H 1.58(3H,d,J=6.8 Hz); 2′-OH 13.09(1H,br,s); 3′-OH 9.83(1H,br,s); 4′-H 6.68 (1H,dd,J=8.1, 1.5 Hz); 5′-H 6.57(1H,t,J=7.8 Hz); 6′-H 6.91 (1H,dd,J=7.6, 1.5 Hz); 7′-H 8.08(1H,s); MS: 362(M+), 347 (M+-CH3), 307, 253, 239, 226 197, 167, 149, 138, 137, 109, 92, 81. IR: υmax 3500-2800(br), 1660(s), 1625(s), 1545, 1460, 1370, 1275, 1240, 1120, 1080, 1060, 1020, 835, 775, 740(s), 640, 630, 525 cm−1.

Derivative No. 26

1HNMR(CDCl3): 1-H 13.10(1H,br,s); 3-H 6.33(1H,d J=9.4 Hz); 4-H 7.12(1H,d,J=9.4 Hz); 6-H2 2.75(2H,s); 8-H 5.41(1H,d,J=4.8 Hz); 9-H 3.62(1H,m); 10a-H 2.95(1H,dd, J=16.5, 4.9 Hz); 10b-H 2.27(1H,d,J=16.5 Hz); 12-H3 1.57 (3H,s); 13-H 5.08(1H,q,J=6.8 Hz); 14-H 1.54(3H,d,J=6.8 Hz); 2′-OH 14.36(1H,br,s); 3′-OCH3 3.86(3H,s); 4′-H 6.83 (1H,dd,J=7.9, 1.5 Hz); 5′-H 6.76 (1H,t,J=7.9 Hz); 6′-H 6.89(1H,dd,J=7.9, 1.5 Hz); 7′-H 8.27(1H,s); MS: 376(M+), 361, 346, 331, 306, 270, 253, 239, 226, 210, 197, 167, 152, 109, 106, 82. IR: υmax 3450-3360, 2940-2980, 1660(s), 1620(s), 1555, 1465(s), 1255(s), 1190, 1170, 1115, 1085, 970, 930, 840, 780, 740, 680, 640, 630, 520 cm−1.

Derivative No. 27

1HNMR(CDCl3): 1-H 12.80(1H,br,s); 3-H 6.34(1H,d,J=9.4 Hz); 4-H 7.07(1H,d,J=9.4 Hz); 6-H2 2.72(2H,s); 8-H 5.40(1H,d,J=5.0 Hz); 9-H 3.61(1H,m); 10a-H 2.94(1H,dd, J=16.2, 3.6 Hz); 10b-H 2.17(1H,d,J=16.2 Hz); 12-H 1.56 (3H,s); 13-H 5.08(1H,q,J=6.8 Hz); 14-H 1.57(3H,d,J=6.8 Hz); 2′,6′-2H 7.45(2H,dd,J=6.8, 1.4 Hz); 3′,5′,8′-3H 7.30 (3H,m); 4′-H 7.06(1H,m); 7′-H 6.99 (1H,d,J=15.9 Hz); 9′-H 8.06(1H,d,J=8.1 Hz); MS: 356(M+), 341(M+-CH3), 327, 301, 265, 237, 226, 210, 197, 167, 131, 115, 91, 77. IR: υmax 3600-3400(br), 2950-2850(br), 1660(s), 1632, 1620, 1550, 1465, 1445, 1300(m), 1175, 1115, 975, 825, 750(s), 690(s), 630, 620, 520 cm−1.

Derivative No. 28

1HNMR(CDCl3): 1-H 12.76(1H,br,s); 3-H 6.38(1H,d,J=9.3 Hz); 4-H 7.12(1H,d,J=9.3 Hz); 6a-H 2.81(1H,d,J=16.0 Hz); 6b-H 2.78(1H,d,J=16.0 Hz); 8-H 5.46(1H,br,s); 9-H 3.67(1H,m); 10a-H 3.00(1H,dd,J=16.4, 4.5 Hz); 10b-H 2.31 (1H,d,J=16.4 Hz); 12-H 1.62(3H,s); 13-H 5.07(1H,q,J=6.6 Hz); 14-H 1.60(3H,d,J=6.6 Hz); 2′-OH 13.76(1H,br,s); 3′-H 6.94(1H,d,J=8.7 Hz); 4′-H 7.29(1H,dd,J=8.7, 2.3 Hz); 5′,6′,7′,8′-4H 7.25(4H,m); 11′-H 8.30(1H,s); MS(m/z): 396(M+, 3%), 381(M+-CH3,1), 226(2), 172(4), 144(2), 127(1), 115 (5), 85(13), 71(22), 57(100). IR(KBr): 3408, 1660, 1626, 1479, 1280 cm−1.

Derivative No. 30

1HNMR(CDCl3): 1-H 10.92(1H,br,s); 3-H 6.42(1H,d,J=9.3 Hz); 4-H 7.15(1H,d,J=9.3 Hz); 6a-H 2.82(1H,d,J=17.2 Hz); 6b-H 2.76(1H,d,J=17.2 Hz); 8-H 5.47(1H,br,s); 9-H 3.69(1H,m); 10a-H 2.99(1H,dd,J=16.0, 3.7 Hz); 10b-H 2.30 (1H,d,J=16.0 Hz); 12-H 1.63(3H,s); 13-H 5.07(1H,q,J=6.8 Hz); 14-H 1.61(3H,d,J=6.8 Hz); 3′-H 6.89(1H,d,J=6.8 Hz); 4′,6′-2H 7.42(2H,m); 7′-H 8.30(1H,s); MS(m/z): 426(M++2,43%), 424(M+, 43), 411[(M++2)-CH3,42], 409(M+-CH3, 45), 369(11), 289(5), 253(18), 239(33), 226(100), 210(54), 197(47), 167(31), 128(31), 115(46), 91(32), 77(59), 57(81). IR(KBr): 3400, 1660, 1630, 1475, 1280, 823 cm−1.

Derivative No. 32

1HNMR(CDCl3): 1-H 12.70(1H,br,s); 3-H 6.39(1H,d,J=9.4 Hz); 4-H 7.11(1H,d,J=9.4 Hz); 6a-H 2.81(1H,d,J=16.2 Hz); 6b-H 2.77(1H,d,J=16.2 Hz); 8-H 5.45(1H,br,s); 9-H 3.67(1H,m); 10a-H 2.99(1H,dd,J=16.7, 4.9 Hz); 10b-H 2.31 (1H,d,J=16.7 Hz); 12-H 1.62(3H,s); 13-H 5.06(1H,q,J=6.8 Hz); 14-H 1.60(3H,d,J=6.8 Hz); 2′-OH 13.80(1H,br,s); 3′-H 6.89(1H,d,J=8.7 Hz); 4′-H 7.42(1H,dd,J=8.7, 2.4 Hz); 6′-H 7.39(1H,d,J=2.4 Hz); 7′-H 8.29(1H,s); MS(m/z): 392(M++1,11%), 391(M+,45), 376(M+-CH3,60), 242(18), 226(53), 101(28), 83(53), 59(100). IR(KBr): 3419, 1660, 1616, 1549, 1336, 833 cm−1.

Derivative No. 33

1HNMR(CDCl3): 1-H 12.40(1H,br,s); 3-H 6.42(1H,d,J=9.5 Hz); 4-H 7.15(1H,d,J=9.5 Hz); 6a-H 2.84(1H,d,J=16.3 Hz); 6b-H 2.77(1H,d,J=16.3 Hz); 8-H 5.47(1H,br,s); 9-H 3.70(1H,m); 10a-H 3.00(1H,dd,J=16.0, 4.9 Hz); 10b-H 2.39 (1H,d,J=16.0 Hz); 12-H 1.58(3H,s); 13-H 5.12(1H,q,J=6.8 Hz); 14-H 1.63(3H,d,J=6.8 Hz); 2′-OH 15.59(1H,br,s); 4′-H 8.16(1H,d,J=7.8 Hz); 5′-H 6.77(1H,t,J=7.8 Hz); 6′-H 7.46 (1H,d,J=7.8 Hz); 7′-H 8.24(1H,s); MS(m/z): 391(M+,66%), 376(M+-CH3,41), 356(45), 328(18), 288(14), 239(15), 226 (100), 210(25), 197(22), 83(61). IR(KBr): 3431, 1662, 1633, 1529, 1352, 1242, 754 cm−1.

Derivative No. 34

1HNMR(CDCl3): 1-H 12.87(1H,br,s); 3-H 6.38(1H,d,J=9.6 Hz); 4-H 7.13(1H,d,J=9.6 Hz); 6-H2 2.78(2H,s); 8-H 5.46(1H,br,s); 9-H 3.67(1H,m); 10a-H 3.00(1H,dd,J=16.5, 4.9 Hz); 10b-H 2.32(1H,d,J=16.5 Hz); 12-H 1.62(3H,s); 13-H 5.09(1H,q,J=6.7 Hz); 14-H 1.59(3H,d,J=6.7 Hz); 2′-OH 14.42(1H,br,s); 3′-OCH3 3.90(3H,s); 4′,6′-2H 6.86 (2H,m); 7′-H 8.22(1H,s); MS(m/z): 412(M++2,0.3%), 410 (M+,1.2), 395(M+-CH3,0.5), 239(1.4), 216(2), 83(100). IR(KBr): 3421, 2933, 1660, 1618, 1471, 1253, 839 cm−1.

Derivative No. 35

1HNMR(CDCl3): 1-H 12.80(1H,br,s); 3-H 6.38(1H,d,J=9.3 Hz); 4-H 7.13(1H,d,J=9.3 Hz); 6-H2 2.78(2H,s); 8-H 5.46(1H,br,s); 9-H 3.67(1H,m); 10a-H 3.00(1H,dd,J=16.7, 5.1 Hz); 10b-H 2.32(1H,d,J=16.7 Hz); 12-H 1.62(3H,s); 13-H 5.08(1H,q,J=6.8 Hz); 14-H 1.59(3H,d,J=6.8 Hz); 2′-OH 14.45(1H,br,s); 3′-OCH3 3.89(3H,s); 4′,6′-2H 7.00 (2H,m); 7′-H 8.21(1H,s); MS(m/z): 456(M+2,79), 454(M+, 7a), 441[(M++2)-CH3, 40], 439(M+-CH3,42), 401(7), 399 (8), 285(14), 239(24), 226(100), 210(33), 197(37), 83(84). IR(KBr): 3431, 1660, 1624, 1471, 1252 cm−1.

EXAMPLE 4 Preparation of Derivative No. 15

Compound (I) (0.5 mmole) was weight out into 50 μl three-neck flask. 20 ml of anhydrous pyridine was added to dissolve compound (I). While cooling in ice-bath, o-phthalic acid anhydride was added. The mixture was stirred overnight at room temperature. When thin-layer chromatography determination indicated substantial completion of the reaction, the pressure was reduced by means of water pump to vaporize pyridine. Separation was carried out using silica gel layer chromatography. The development agent dichloromethane:methanol=3:1 was used to produce the crude product, which was recrystallized using propanol to produce white powders of derivative No. 15 with 78% yield.

The same process was used to prepare derivatives No. 1 to No. 16.

1H NMR(d6-DMSO): 3-H 6.09(1H,d,J=9.4 Hz); 6-H2 2.51(2H,s); 8-H 5.44(1H,d,J=4.8 Hz); 9-H 3.56(1H,m); 10a-H 2.66(1H,dd,J=16.8, 4.6 Hz); 10b-H 2.09(1H,d,J=16.8 Hz); 12-H3 1.51(3H,s); 13-H 5.60(1H,q,J=6.8 Hz); 14-H3 1.62(3H,d,J=6.8 Hz); 3′,4′,5′ and 4-H 7.51(4H,m); 6′-H 7.73(1H,d,J=7.5 Hz); N-H(amide) 7.90(1H,br,s); COO-H 8.46(1H,br,s); IR: υmax 3650-2400, 1710, 1655, 1605, 1546, 1450, 1300 cm−1 MS m/z: 372(M+), 357, 343, 329, 242, 227, 187, 147, 104(100).

EXAMPLE 5 Preparation of Derivative No. 44

Under argon gas stream 150 mg (0.620 mmole) of huperzine A and 200 mg of 4A molecular sieve were suspended in 4 ml of benzene. 76 μl (0.86 mmol) of pyridine-3-acetaldehyde and 20 mg of p-toluene sulphonic acid monohydrate were added. After reflux for three hours, the mixture was allowed to cool, and then neutralized with triethyl amine. The reaction solution was filtered with celite. After concentration, the residue was refined through silica gel column chromatography (methanol:dichloromethane=1:20) to produce derivative No. 44, a colorless solid (183 mg, 89% yield).

The same process was used to prepare derivatives No. 45 and No. 46, with 84% and 82% yield respectively.

Derivative No. 44

NMR(CDCL3) 1.64(3H,d,J=7.0 Hz), 1.65(3H,s); 2.25 (1H,d,J=16.0 Hz), 2.82(1H,d,J=17.0 Hz); 2.86(1H,d,J=16.0 Hz), 3.07(1H,dd,J=5.0,17.0 Hz) 8.65-3.75(1H,m); 5.14(1H, q,J=7.0 Hz), 5.50(1H,d,J=5.0 Hz); 6.34(1H,d,J=8.5 Hz), 7.09(1H,d,J=9.5 Hz); 7.40(1H,dd,J=5.0,8.0 Hz), 8.28(1H,dt, J=2.0,8.0 Hz), 8.47(1H,s); 8.70-8.72(1H,m), 8.94-8.96(1H, m), MS: 331(M+), 316(base), 226; HRMS calculated value: molecular formula C22H21N2O(M+): 331.16846; experimental value: 331.16888

Derivative No. 45

NMR(CDCL3) 1.64(3H,d,J=7.0 Hz), 1.65(3H,s); 2.25 (1H,d,J=16.0 Hz), 2.82(1H,d,J=16.5 Hz); 2.86(1H,d,J=16.0 Hz), 3.07(1H,dd,J=5.0,16.5 Hz),3.61-3.70(1H,m); 5.10(1H, q,J=7.0 Hz), 5.50(1H,d,J=4.0 Hz); 6.39(1H,d,J=9.5 Hz), 7.05(1H,d,J=9.5 Hz); 7.11-7.73(2H,m), 8.41(1H,s), 8.73-8.79(2H,m), MS: 331(M+), 316(base), 226; HRMS calculated value: molecular formula C22H21N3O(M+): 331.16846; experimental value: 331.18836

Derivative No. 46

NMR(CDCL3) 1.64(3H,d,J=6.5 Hz), 1.65(3H,s); 2.24 (1H,d,J=16.0 Hz), 2.82(1H,d,J=16.5 Hz); 2.85(1H,d,J=16.0 Hz), 3.07(1H,dd,J=5.0,16.5 Hz),3.67-3.70(1H,m); 3.96(6H, s), 5.22(1H,q,J=6.5 Hz), 5.30(1H,s); 5.47-5.49(1H,m), 6.39 (1H,d,J=9.5 Hz), 7.12(1H,s), 7.15(1H,d,J=9.5 Hz), 8.29(1H, s); MS: 406(M,base), 391, 228, 167 HRMS calculated value: molecular formula C24H26N2O4(M+): 406.18926; experimental value: 406.18949

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US4929731Feb 21, 1989May 29, 1990University Of PittsburghMethod for the synthesis of huperzine A and analogs thereof and compounds useful therein
US4968672Jan 2, 1987Nov 6, 1990The United States Of America As Represented By The Department Of Health And Human ServicesAdenosine receptor prodrugs
US5104880May 1, 1991Apr 14, 1992Mayo Foundation For Medical Education And ResearchHuperzine a analogs as acetylcholinesterase inhibitors
US5177082Oct 18, 1990Jan 5, 1993Yu Chao MeiHuperzines and analogs
US5684018Dec 13, 1994Nov 4, 1997Merck & Co., Inc.Acyloxyisopropyl carbamates as prodrugs for amine drugs
Non-Patent Citations
Reference
1Kozikowski et al., "Synthesis of Huperzine A and its Analogues and their Anticholinesterase Activity", J. Org. Chem., 56:4636-4645 (1991).
2Liu et al., Can. J. Chem, 64(4):837-839 (1986).
3Qian et al., Tetrahedron Lett., 30(16):2089-90 (1989).
4Tang et al., Acta Pharmacologica Sinica, 15(2):107-110 (1994) (Abstract Only).
5Xiong et al., Acta Pharmacologica Sinica, 16(1):21-25 (1995).
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Classifications
U.S. Classification514/295, 546/97, 546/93
International ClassificationC07D401/06, C07D401/14, A61P25/28, C07D401/12, C07D221/22, C07D405/12
Cooperative ClassificationC07D401/14, C07D401/06, C07D405/12, C07D401/12, C07D221/22
European ClassificationC07D221/22, C07D401/14, C07D401/12, C07D405/12, C07D401/06
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