S-substituted-2-amino-3-mercaptopropionate derivative, preparation method and application thereof

Abstract

The present invention relates to a S-substituted-2-amino-3-mercaptopropionate derivative, a preparation method and an application thereof. The S-substituted-2-amino-3-mercaptopropionate derivative in the present invention has a structure of a formula (A). The present invention also includes an application of the S-substituted-2-amino-3-mercaptopropionate derivative serving as a medicine for treating and/or preventing neurodegenerative diseases, particularly Alzheimer's disease. ##STR00001##

Claims

1. A S-substituted-2-amino-3-mercaptopropionate derivative selected from the group of compounds consisting of: ##STR00022##

2. Any one of a medicinal acid addition salt, a solvate, a polymorphism, an enantiomer or a racemic mixture of the S-substituted-2-amino-3-mercaptopropionate derivative according to claim 1.

3. The medicinal acid addition salt of claim 2, wherein the medicinal acid addition salt is selected from salt formed by the S-substituted-2-amino-3-mercaptopropionate derivative and sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, tartaric acid, fumaric acid, maleic acid, citric acid, acetic acid, formic acid, methanesulfonic acid, p-toluenesulfonic acid, oxalic acid or succinic acid.

4. A pharmaceutical composition comprising the S-substituted-2-amino-3-mercaptopropionate derivative according to claim 1 and a pharmaceutically acceptable carrier selected from the group consisting of a diluent, a flavoring agent, a solubilizer, a lubricating agent, a suspending agent, an adhesive, and an expanding agent or a medicinal addition salt thereof.

5. A pharmaceutical composition comprising any one of the medicinal acid addition salt, the solvate, the polymorphism, the enantiomer or the racemic mixture of the S-substituted-2-amino-3-mercaptopropionate derivative according to claim 2 and a pharmaceutically acceptable carrier selected from the group consisting of a diluent, a flavoring agent, a solubilizer, a lubricating agent, a suspending agent, an adhesive, and an expanding agent.

6. A method of treating a neurodegenerative disease comprising administering the S-substituted-2-amino-3-mercaptopropionate derivative according to claim 1 to a patient in need thereof.

7. The method according to claim 6, wherein the neurodegenerative disease is senile dementia.

8. A method of treating a neurodegenerative disease comprising administering any one of the medicinal acid addition salt, the solvate, the polymorphism, the enantiomer or the racemic mixture of the S-substituted-2-amino-3-mercaptopropionate derivative according to claim 2 to a patient in need thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) Embodiments below are used for further illustrating the present invention, rather than limiting the present invention.

Embodiment 1

2-(t-butyloxycarbonylamino)-3-propinyl mercaptopropionic acid (II)

(2) ##STR00011##

(3) There are steps of: dissolving 25 g of 2-amino-3-propinyl mercaptopropionic acid I into 250 mL of tetrahydrofuran, adding 35 g of di-tert-butyl dicarbonate ester, stirring to be uniform, adding 500 mL of saturated sodium bicarbonate solution, heating to 50° C. and reacting for 12 hours, cooling, neutralizing with 1M of diluted hydrochloric acid until a pH value is equal to 7; extracting with ethyl acetate, drying an organic phase with anhydrous sodium sulfate, filtering and removing a drying agent, and evaporating to dryness, thereby obtaining 35 g of a light yellow oily matter 2-(t-butyloxycarbonylamino)-3-propinyl mercaptopropionic acid (II) having a yield of 86%.

(4) .sup.1H NMR (400 MHz, DMSO): δ 12.78 (s, 1H), 7.16 (d, 1H), 4.13-4.09 (m, 1H), 3.39-3.37 (m, 2H), 3.17-3.16 (m, 1H), 3.07-3.02 (m, 1H), 2.84-2.79 (m, 1H), 1.39 (s, 9H). MS: m/z 258 [M−1].sup.−.

Embodiment 2

2-(t-butyloxycarbonylamino)-3-propinylmercaptopropionic acid-4-(3-thio-3H-1,2-dithio-5-alkenyl) phenol ester (IVa)

(5) ##STR00012##

(6) There are steps of: dissolving 3 g of 2-(t-butyloxycarbonylamino)-3-propinyl mercaptopropionic acid II, 1 g of 4-(3-thio-3H-1,2-dithio-5-alkenyl) phenol IIIa and 4 g of HBTU into 50 mL of tetrahydrofuran, slowly dripping 2 mL of triethylamine into a reaction solution, and reacting at a room temperature for 12 hours; adding 100 mL of water, extracting with ethyl acetate, washing an organic phase with 1M of diluted hydrochloric acid, a saturated sodium bicarbonate solution and a saturated sodium chloride solution in sequence, and drying the organic phase with anhydrous sodium sulfate; filtering and removing a drying agent, evaporating to dryness, and performing column chromatography (a ratio of petroleum ether to ethyl acetate is 4:1), thereby obtaining 1.1 g of 2-(t-butyloxycarbonylamino)-3-propinylmercaptopropionic acid-4-(3-thio-3H-1,2-dithio-5-alkenyl) phenol ester (IVa) having a yield of 53%.

(7) .sup.1H NMR (400 MHz, DMSO): δ 8.02 (d, 2H), 7.83 (s, 1H), 7.73 (d, 1H), 7.31-7.29 (m, 2H), 4.49-4.44 (m, 1H), 3.48 (s, 2H), 3.24 (s, 2H), 3.08-3.02 (m, 1H), 1.43 (s, 9H), MS: m/z 468 [M+H].sup.+.

Embodiment 3

2-amino-3-propinylmercaptopropionic acid-4-(3-thio-3H-1,2-dithio-5-alkenyl) phenol ester (Va)

(8) ##STR00013##

(9) There are steps of: dissolving 0.5 g of 2-(t-butyloxycarbonylamino)-3-propinylmercaptopropionic acid-4-(3-thio-3H-1,2-dithio-5-alkenyl) phenol ester (IVa) into 20 mL of dichloromethane, adding 2 mL of trifluoroacetic acid, and reacting at a room temperature for 6 hours; adding 3N of hydrochloric acid, continuously stirring for 2 hours, separating a water layer, evaporating water to dryness, and performing column chromatography (a ratio of dichloromethane to methanol is 10:1), thereby obtaining 0.23 g of 2-amino-3-propinylmercaptopropionic acid-4-(3-thio-3H-1,2-dithio-5-alkenyl) phenol ester (Va) having a yield of 60%.

(10) .sup.1H NMR (400 MHz, DMSO): δ 9.19 (s, 3H), 8.05-8.03 (m, 2H), 7.84 (s, 1H), 7.45-7.43 (m, 2H), 4.63-4.60 (m, 1H), 3.59-3.56 (m, 2H), 3.37-3.31 (m, 3H), MS: m/z 368 [M+H].sup.+.

Embodiment 4

2-(t-butyloxycarbonylamino)-3-propinylmercaptopropionic acid-4-formyl phenol ester (IVb)

(11) ##STR00014##

(12) There are steps of: dissolving 3 g of 2-(t-butyloxycarbonylamino)-3-propinyl mercaptopropionic acid II, 2 g of 4-hydroxybenzaldehyde IIIb and 5 g of HBTU into 50 mL of tetrahydrofuran, adding 2 mL of triethylamine, and reacting at a room temperature for 12 hours; adding 100 mL of water, extracting with ethyl acetate, washing an organic phase with 1M of diluted hydrochloric acid, a saturated sodium bicarbonate solution and a saturated sodium chloride solution in sequence, and drying the organic phase with anhydrous sodium sulfate; filtering and removing a drying agent, evaporating to dryness, and performing column chromatography (a ratio of petroleum ether to ethyl acetate is 3:1), thereby obtaining 3.6 g of 2-(t-butyloxycarbonylamino)-3-propinylmercaptopropionic acid-4-formyl phenol ester (IVb) having a yield of 85%.

(13) .sup.1H NMR (400 MHz, DMSO): δ 10.01 (s, 1H), 8.03 (d, 2H), 7.73 (d, 1H), 7.37 (d, 2H), 4.49-4.44 (m, 1H), 3.48-3.47 (m, 2H), 3.24-3.18 (m, 2H), 3.07-3.01 (m, 1H), 1.42 (s, 9H), MS: m/z 464 [M+H].sup.+.

Embodiment 5

2-amino-3-propinylmercaptopropionic acid-4-formyl phenol ester (Vb)

(14) ##STR00015##

(15) There are steps of: dissolving 0.5 g of 2-(t-butyloxycarbonylamino)-3-propinylmercaptopropionic acid-4-formyl phenol ester (IVb) into 20 mL of dichloromethane, adding 2 mL of trifluoroacetic acid, and reacting at a room temperature for 6 hours; adding 3N of hydrochloric acid, continuously stirring for 2 hours, separating a water layer, evaporating water to dryness, and performing column chromatography (a ratio of dichloromethane to methanol is 10:1), thereby obtaining 0.28 g of 2-amino-3-propinylmercaptopropionic acid-4-formyl phenol ester (Vb) having a yield of 76%.

(16) .sup.1H NMR (400 MHz, DMSO): δ 10.04 (s, 1H), 9.18 (s, 3H), 8.04-8.03 (m, 2H), 7.83 (s, 1H), 7.46-7.45 (m, 2H), 4.62-4.61 (m, 1H), 3.61-3.57 (m, 2H), 3.38-3.30 (m, 3H), MS: m/z 264 [M+H].sup.+.

Embodiment 6

2-(t-butyloxycarbonylamino)-3-propinylmercaptopropionic acid-4-benzyl alcohol phenol ester (IVc)

(17) ##STR00016##

(18) There are steps of: dissolving 3 g of 2-(t-butyloxycarbonylamino)-3-propinyl mercaptopropionic acid II, 4 g of p-hydroxybenzylalcohol IIIc and 6 g of HBTU into 25 mL of tetrahydrofuran, slowly dripping 3 mL of triethylamine into a reaction solution, and reacting at a room temperature for 12 hours; adding 100 mL of water, extracting with ethyl acetate, washing an organic phase with 1M of diluted hydrochloric acid, a saturated sodium bicarbonate solution and a saturated sodium chloride solution in sequence, and drying the organic phase with anhydrous sodium sulfate; filtering and removing a drying agent, evaporating to dryness, and performing column chromatography (a ratio of petroleum ether to ethyl acetate is 5:1), thereby obtaining 3.0 g of 2-(t-butyloxycarbonylamino)-3-propinylmercaptopropionic acid-4-benzyl alcohol phenol ester (IVc) having a yield of 70%.

(19) .sup.1H NMR (400 MHz, DMSO): δ 7.65-7.63 (d, 1H), 7.38-7.36 (d, 2H), 7.07-7.05 (d, 1H), 5.26-5.24 (m, 1H), 4.51-4.50 (m, 2H), 4.45-4.36 (m, 1H), 3.47 (brs, 2H), 3.23-3.21 (m, 1H), 3.19-3.16 (m, 1H), 3.05-2.99 (m, 1H), 1.42 (s, 9H), MS: m/z 366 [M+H].sup.+.

Embodiment 7

2-amino-3-propinylmercaptopropionic acid-4-benzyl alcohol phenol ester (Vc)

(20) ##STR00017##

(21) There are steps of: dissolving 0.5 g of 2-(t-butyloxycarbonylamino)-3-propinylmercaptopropionic acid-4-benzyl alcohol phenol ester (IVc) into 20 mL of dichloromethane, adding 2 mL of trifluoroacetic acid, and reacting at a room temperature for 6 hours; adding 3N of hydrochloric acid, continuously stirring for 2 hours, separating a water layer, evaporating water to dryness, and performing column chromatography (a ratio of dichloromethane to methanol is 10:1), thereby obtaining 0.21 g of 2-amino-3-propinylmercaptopropionic acid-4-benzyl alcohol phenol ester (Vc) having a yield of 57%.

(22) .sup.1H NMR (400 MHz, CD.sub.3OD): δ 7.47-7.45 (m, 2H), 7.24-7.22 (m, 2H), 4.71-4.69 (m, 1H), 4.65 (brs, 2H), 3.59-3.52 (m, 3H), 3.43-3.37 (m, 1H), 2.83-2.82 (m, 1H), MS: m/z 266 [M+H].sup.+.

Embodiment 8

Bis(2-(t-butyloxycarbonylamino)-3-propinylmercaptopropionic acid)-4-benzyl alcohol-1-phenol diester (IVd)

(23) ##STR00018##

(24) There are steps of: dissolving 6 g of 2-(t-butyloxycarbonylamino)-3-propinyl mercaptopropionic acid II, 4 g of p-hydroxybenzylalcohol IIIc and 12 g of HBTU into 100 mL of tetrahydrofuran, slowly dripping 10 mL of triethylamine into a reaction solution, and reacting at a room temperature for 12 hours; adding 100 mL of water, extracting with ethyl acetate, washing an organic phase with 1M of diluted hydrochloric acid, a saturated sodium bicarbonate solution and a saturated sodium chloride solution in sequence, and drying the organic phase with anhydrous sodium sulfate; filtering and removing a drying agent, evaporating to dryness, and performing column chromatography (a ratio of petroleum ether to ethyl acetate is 6:1), thereby obtaining 4.6 g of bis(2-(t-butyloxycarbonylamino)-3-propinylmercaptopropionic acid)-4-benzyl alcohol-1-phenol diester (IVd) having a yield of 65%.

(25) .sup.1H NMR (400 MHz, DMSO): δ 7.67-7.65 (m, 1H), 7.45-7.43 (m, 3H), 7.12-7.10 (m, 2H), 5.16 (s, 2H), 4.44-4.41 (m, 1H), 4.27-4.24 (m, 1H), 3.46 (brs, 2H), 3.40-3.39 (m, 2H), 3.23-3.16 (m, 3H), 3.09-3.05 (m, 2H), 2.90-2.85 (m, 1H), 1.42 (s, 9H), 1.38 (s, 9H), MS: m/z 607 [M+H].sup.+.

Embodiment 9

bis(2-amino-3-propinylmercaptopropionic acid)-4-benzyl alcohol-1-phenol diester (Vd)

(26) ##STR00019##

(27) There are steps of: dissolving 0.5 g of bis(2-(t-butyloxycarbonylamino)-3-propinylmercaptopropionic acid)-4-benzyl alcohol-1-phenol diester (IVd) into 20 mL of dichloromethane, adding 2 mL of trifluoroacetic acid, and reacting at a room temperature for 6 hours; adding 3N of hydrochloric acid, continuously stirring for 2 hours, separating a water layer, evaporating water to dryness, and performing column chromatography (a ratio of dichloromethane to methanol is 10:1), thereby obtaining 0.26 g of bis(2-amino-3-propinylmercaptopropionic acid)-4-benzyl alcohol-1-phenol diester (Vd) having a yield of 78%.

(28) .sup.1H NMR (400 MHz, DMSO): δ 9.17 (brs, 3H), 8.19 (brs, 3H), 7.58-7.55 (m, 2H), 7.29-7.26 (m, 2H), 5.28 (d, 1H), 4.59 (t, 1H), 4.40 (t, 1H), 4.18 (t, 1H), 3.58-3.44 (m, 5H), 3.35-3.32 (m, 2H), 3.22-3.18 (m, 2H), 3.14-3.09 (m, 1H), MS: m/z 407 [M+H].sup.+.

Embodiment 10

2-(t-butyloxycarbonylamino)-3-propinylmercaptopropionic acid-4-nitro-1-butanol ester (IVf)

(29) ##STR00020##

(30) There are steps of: dissolving 3 g of 2-(t-butyloxycarbonylamino)-3-propinyl mercaptopropionic acid II, 1 g of 4-nitro-1-butanol IIIf and 4 g of HBTU into 50 mL of tetrahydrofuran, slowly dripping 2 mL of triethylamine into a reaction solution, and reacting at a room temperature for 12 hours; adding 100 mL of water, extracting with ethyl acetate, washing an organic phase with 1M of diluted hydrochloric acid, a saturated sodium bicarbonate solution and a saturated sodium chloride solution in sequence, and drying the organic phase with anhydrous sodium sulfate; filtering and removing a drying agent, evaporating to dryness, and performing column chromatography (a ratio of petroleum ether to ethyl acetate is 5:1), thereby obtaining 2.0 g of 2-(t-butyloxycarbonylamino)-3-propinylmercaptopropionic acid-4-nitro-1-butanol ester (IVf) having a yield of 48%.

(31) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 5.41-5.39 (m, 1H), 4.48 (brs, 1H), 4.15-4.12 (brs, 2H), 3.39-3.36 (m, 2H), 3.29-2.99 (m, 4H), 2.27-2.26 (m, 1H), 1.91-1.88 (m, 2H), 1.79-1.76 (m, 2H), 1.38 (s, 9H), MS: m/z 361 [M+H].sup.+.

Embodiment 11

2-amino-3-propinylmercaptopropionic acid-4-nitro-1-butanol ester (Vf)

(32) ##STR00021##

(33) There are steps of: dissolving 0.5 g of 2-(t-butyloxycarbonylamino)-3-propinylmercaptopropionic acid-4-nitro-1-butanol ester (IVf) into 20 mL of dichloromethane, adding 2 mL of trifluoroacetic acid, and reacting at a room temperature for 6 hours; adding 3N of hydrochloric acid, continuously stirring for 2 hours, separating a water layer, evaporating water to dryness, and performing column chromatography (a ratio of dichloromethane to methanol is 10:1), thereby obtaining 0.26 g of 2-amino-3-propinylmercaptopropionic acid-4-nitro-1-butanol ester (Vf) having a yield of 72%.

(34) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 5.52-5.43 (m, 1H), 4.52-4.48 (m, 1H), 4.25-4.22 (m, 2H), 3.42-3.39 (m, 2H), 3.34-2.31 (m, 4H), 2.29-2.25 (m, 1H), 1.92-1.90 (m, 2H), 1.82-1.79 (m, 2H), MS: m/z 261 [M+H].sup.+.

Embodiment 12 Drug Efficacy Study on Compounds in the Present Invention

(35) Memory functions of mice are injured by scopolamine, and effects of improvement of tested materials on the memory functions of the mice are observed.

(36) Experimental Materials:

(37) Animals: ICR mice, male, 20-22 g, purchased from Institute for Experimental Animals in Chinese Academy of Medical Sciences, certification number: SCXK (JING) 2014-0004.

(38) Agent: scopolamine (J&K Company), donepezil reagent (TCI Company).

(39) Tested materials: 4 tested materials and a positive-drug donepezil are provided by Tasly Group. Dosage of administration: administered by tested materials according to 80 mg/kg weight, administered by donepezil according to 5 mg/kg weight, an administration volume of 2 ml.

(40) Experimental Steps of:

(41) purchasing 60 mice, and enabling the mice to adapt to an environment for three days; dividing the mice into 6 groups randomly, wherein a blank control group includes 10 mice, the rest mice are contained in administration groups, and each administration group includes 10 mice; respectively administering the tested materials and positive drug, performing intragastric administration for 7 days, putting the mice into a darkroom to adapt to the environment on the fifth day during administration, electrifying the darkroom on the sixth day during administration, training the mice to elude the darkroom, and training each mouse once; testing on the seventh day, administering with scopolamine by 3 mg/kg within 20 minutes before testing, and recording time of the mice entering the darkroom for the first time and a number of times of the mice entering the darkroom within 3 minutes during testing.

(42) Experimental Results:

(43) TABLE-US-00001 TABLE 1 Influences of tested materials on latency and error times of mice with memory disorders caused by scopolamine entering the darkroom (x ± s, n = 10) Group Latency (s) Error times Model group 47.0 ± 55.6 4.6 ± 4.2 Donepezil 49.5 ± 71.6 6.8 ± 5.4 SPRC 50.5 ± 69.7 3.8 ± 4.0 Va 55.8 ± 61.3 4.7 ± 4.6 Vb 53.2 ± 59.4 4.1 ± 3.7 Vc 66.8 ± 57.1 2.4 ± 1.3 Vd 63.6 ± 69.5 2.6 ± 3.3 Vf 60.2 ± 61.3 2.4 ± 2.3

CONCLUSION

(44) Passive avoidance response is a common method used commonly to detect learning and memory functions of small animals. With respect to a passive avoidance test, by means of a feature that rodents like darkness and keep in a dark place, the rodents are stimulated in the dark to escape to a bright place to acquire memory, and the passive avoidance test is a type of passive avoidance response experiments. The passive avoidance test has a short experimental period and is applicable to rapid drug screening. The scopolamine may inhibit release of acetyl choline, so as to form learning and memory disorders. The passive avoidance test is a stable learning and memory disorder modeling method and has excellent model reproducibility. The compounds Vc, Vd and Vf have a trend of decreasing the error times of the mice with memory impairment entering the darkroom and a trend of increasing the latency of the mice with memory impairment entering the darkroom, and activities of the compounds are all obviously better than the activity of the SPRC.