Long-acting prodrugs of rasagiline, preparing methods and uses thereof

Abstract

Provided are a long-acting prodrug of Rasagiline, which has application in the treatment of Central Nervous System diseases such as Parkinson's disease, preparation method and use thereof. The long-acting prodrug of Rasagiline has a structure of formula (I), wherein T is absent, or T is selected from ##STR00001##
each of R.sub.1 and R.sub.2 is independently selected from H, D, and alkyl; W is absent, or W is selected from (CH.sub.2).sub.n, wherein n is an integer selected from 1 to 15; X is absent, or X is selected from (CH.sub.2).sub.m, wherein m is an integer selected from 1 to 10; Y is absent, or Y is selected from —C(═O)NH—, —NHC(═O)—; R.sub.3 is selected from substituted or unsubstituted C.sub.1-C.sub.30 alkyl, substituted or unsubstituted C.sub.2-C.sub.30 alkenyl, substituted or unsubstituted C.sub.2-C.sub.30 alkynyl, substituted or unsubstituted C.sub.3-C.sub.30 cycloalkyl, cholane aliphatic group, —R.sup.3a—C(═O)O—R.sup.3b, —R.sup.3a—OC(═O)—R.sup.3b, —R.sup.3a—C(═O)NH—R.sup.3b, —R.sup.3a—NHC(═O)—R.sup.3b, —R.sup.3a—S(═O).sub.1-2O—R.sup.3b and —R.sup.3a—OS(═O).sub.1-2—R.sup.3b. ##STR00002##

Claims

1. A long-acting prodrug of Rasagiline or a stereoisomer, or solvate thereof, wherein the long-acting prodrug of Rasagiline has a structure of formula I: ##STR00036## wherein, both T and W are absent; each of R.sub.1 and R.sub.2 is independently selected from H, D, or C.sub.1-4 alkyl; X is selected from (CH.sub.2).sub.m, wherein m is an integer selected from 1 to 10; Y is selected from —C(═O)NH—, or —NHC(═O)—; and R.sub.3 is selected from linear or branched, saturated or unsaturated C.sub.7-C.sub.27 alkyl.

2. The long-acting prodrug of Rasagiline or a stereoisomer, or solvate thereof according to claim 1, wherein R.sub.1 is H or D, R.sub.2 is methyl, H or D; each of R.sub.1 and R.sub.2 is independently H, D, or methyl.

3. The long-acting prodrug of Rasagiline or a stereoisomer, or solvate thereof according to claim 1, wherein R.sub.3 is —CH═CHR.sub.4, wherein R.sub.4 is selected from phenyl substituted with one or more groups selected from OH, or alkoxy.

4. The long-acting prodrug of Rasagiline or a stereoisomer, or solvate thereof according to claim 1, wherein the long-acting prodrug of Rasagiline is selected from one of the following compounds: ##STR00037## ##STR00038## ##STR00039## ##STR00040##

5. A pharmaceutical composition, comprising the prodrug of Rasagiline or a stereoisomer, or solvate thereof according to claim 1, and a pharmaceutically acceptable carrier or excipient.

6. A method of preventing and/or treating a central nervous system disease in a subject in need thereof, comprising administering the prodrug of Rasagiline or a stereoisomer, or solvate thereof according to claim 1, or the pharmaceutical composition wherein, the medicament is a long-acting drug.

7. The method according to claim 6, wherein the central nervous system disease is Parkinson's disease.

8. A long-acting prodrug of Rasagiline or a stereoisomer, or solvate thereof, wherein the prodrug of Rasagiline has a structure of formula II: ##STR00041## wherein r is an integer from 1 to 10 and R.sub.3 is linear C.sub.7-C.sub.27 alkyl; wherein r is an integer from 1 to 6 and R.sub.3 is linear C.sub.9-C.sub.25 alkyl; or wherein r is an integer from 3 to 6 and R.sub.3 is linear C.sub.11-C.sub.25 alkyl or R.sub.3 is linear C.sub.11-C.sub.21 alkyl.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) Some of the embodiments will be described in detail, with reference to the following FIGURES, wherein like designations denote like members, wherein:

(2) FIG. 1 depicts a drug-time curve of Rasagiline after it was intramuscularly injected into a beagle.

DETAILED DESCRIPTION

(3) The present disclosure will be further described by the following examples. However, the examples are not intended to limit the protection scope of the present disclosure.

Example 1 Preparation of methyl ((Rasagiline-N-formyl)oxy)-palmitate (Referring to International patent application WO2013088255)

(4) ##STR00013##

(5) 1.0 g of Rasagiline-N-chloromethyl formate and 0.3 g of TBAI were dissolved in THF/DMF (5+4 mL), and then 1.5 g of potassium palmitate was added to obtain a mixture. The mixture was heated at 57° C. overnight under the protection of argon. After the reaction was stopped, THF was removed through rotary evaporation. 30 ml of isopropyl ether was added and stirred for 10 minutes. After a filtering, a filtrate was successively washed with water (15 mL filtrate) and saturated NaHCO.sub.3. Then the washed filtrate was dried by anhydrous sodium sulfate and concentrated. The concentrate was purified through silica gel column chromatography (PE:EA=20:1 to 10:1), so as to obtain 0.76 g of a viscous product, with a yield of 41.53%.

(6) .sup.1H-NMR(CDCl.sub.3, 400 MHz) δ 7.26 (m, 2H), 7.19 (m, 2H), 5.87 (m, 2.5H), 5.78 (m, 0.5H), 4.17 (d, J=14.0 Hz, 0.5H), 4.02 (d, J=14.0 Hz, 0.5H), 3.62 (d, J=14.0 Hz, 0.5H), 3.52 (d, J=14.0 Hz, 0.5H), 3.06 (m, 1H), 2.86 (m, 1H), 2.47 (m, 1H), 2.36 (m, 2H), 2.24 (m, 1H), 2.21 (s, 0.5H), 2.15 (s, 0.5H), 1.64 (m, 2H), 1.28 (m, 24H), 0.88 (t, J=5.2 Hz, 3H).

(7) ESI-MS, C.sub.30H.sub.45NO.sub.4 (483.3), a measured value of 506.4[M+Na].sup.−.

Example 2 Preparation of methyl ((Rasagiline-N-formyl)oxy)-naphthalene Acetate

(8) ##STR00014##

(9) 0.9 g of Rasagiline-N-chloromethyl formate and 0.25 g of TBAI were dissolved in 15 mL of acetonitrile, and 0.92 g of potassium naphthalene acetate was added to obtain a mixture. The mixture was heated at 60° C. for 5 hours under the protection of argon. After the reaction was stopped, the solvent was removed through rotary evaporation, and then 20 mL of ethyl acetate was added to for dissolution. Then the mixture was successively washed with saturated NaHCO.sub.3 (10 mL×3) and saturated NaCl (10 mL), dried by anhydrous Na.sub.2SO.sub.4. After a filtration and rotation to dryness, 1.38 g of a brown pulpy crude product was obtained. The crude product was recrystallized through methanol to obtain 0.65 g of a white solid powder, that is a pure methyl ((Rasagiline-N-formyl)oxy)-naphthalene acetate.

(10) .sup.1HNMR(CDCl.sub.3, 400 MHz) δ 8.01 (dd, J=14.8, 8.4 Hz, 1H), 7.84 (m, 2H), 7.5 (m, 4H), 7.22 (m, 3H), 7.09 (m, 1H), 5.90 (m, 1.5H), 5.82 (dd, J=14.8, 6.0 Hz 1H), 5.54 (t, J=8.0 Hz, 0.5H), 4.16 (s, 1.07H), 4.13 (s, 0.93H), 4.08 (d, J=18.4 Hz, 0.51H), 3.87 (d, J=18.4 Hz, 0.54H), 3.53 (d, J=18.4.6 Hz, 0.49H), 3.39 (d, J=18.4 Hz, 1H), 3.03 (m, 1H), 2.87 (m, 1H), 2.82 (m, 1H), 2.76 (m, 1H), 2.46 (m, 0.5H), 2.26 (m, 0.5H), 2.15 (m, 1.5H), 1.93 (s, 0.5H).

(11) ESI-MS, C.sub.26H.sub.23NO.sub.4 (413.1), a measured value of 436.1 [M+Na].sup.+.

Example 3 Preparation of methyl ((Rasagiline-N-formyl)oxy)-stearate (Referring to International patent application WO2013088255)

(12) ##STR00015##

(13) 2.0 g of Rasagiline-N-chloromethyl formate and 0.56 g of TBAI were dissolved in 40 mL of DMF, and 3.2 g of potassium stearate was added to obtain a mixture. The mixture was heated at 65° C. overnight under the protection of argon. After the reaction was stopped, 80 ml of water was added, and then 80 mL of isopropyl ether was added for extraction. The extract was successively washed with saturated NaHCO.sub.3 (30 mL×2) and saturated NaCl (30 mL), and dried by anhydrous sodium sulfate. After a filtration and rotation to dryness, 4.32 g of a crude product was obtained. The crude product was purified by silica gel column chromatography (PE:EA=10:1), so as to obtain 3 g of a brown pulpy product with a yield of 51.55%.

(14) .sup.1HNMR (CDCl.sub.3, 400 MHz) δ 7.25 (m, 2H), 7.19 (m, 2H), 5.87 (m, 2.5H), 5.66 (m, 0.5H), 4.12 (d, J=17.6 Hz, 0.5H), 3.98 (d, J=17.6 Hz, 0.5H), 3.57 (d, J=17.6 Hz, 0.5H), 3.47 (d, J=17.6 Hz, 0.5H), 3.06 (m, 1H), 2.85 (m, 1H), 2.46 (m, 1H), 2.37 (m, 2H), 2.24 (m, 1H), 2.16 (s, 0.5H), 2.10 (s, 0.5H), 1.64 (m, 2H), 1.26 (m, 28H), 0.88 (t, J=6.4 Hz, 3H).

(15) ESI-MS, C.sub.32H.sub.49NO.sub.4 (511.37), a measured value of 534.2 [M+Na].sup.+.

Example 4 Preparation of methyl ((Rasagiline-N-formyl)oxy)-pivalate

(16) ##STR00016##

(17) 2.0 g of Rasagiline-N-chloromethyl formate and 0.56 g of TBAI were dissolved in 30 mL of DMF, and then 1.38 g of potassium pivalate was added to obtain a mixture. The mixture was heated at 60° C. overnight under a protection of argon. After the reaction was stopped, 80 ml of water was added, and then 80 mL of isopropyl ether was added for extraction. The extract was successively washed with saturated NaHCO.sub.3 (30 mL) and saturated NaCl (30 mL), and dried by anhydrous sodium sulfate. After a filtration and rotation to dryness, a crude product was obtained. The crude product was purified through silica gel column chromatography (PE:EA=15:1) to obtain 1.89 g of a light yellow pulpy product, with a yield of 75.60%.

(18) .sup.1HNMR (CDCl.sub.3, 400 MHz) δ 7.25 (m, 2H), 7.19 (m, 1H), 7.16 (m, 1H), 5.85 (m, 2.5H), 5.84 (m, 0.5H), 4.13 (d, J=14.4 Hz, 0.5H), 3.99 (d, J=14.4 Hz, 0.5H), 3.56 (d, J=14.4 Hz, 0.5H), 3.47 (d, J=14.4 Hz, 0.5H), 3.06 (m, 1H), 2.87 (m, 1H), 2.46 (m, 1H), 2.24 (m, 1H), 2.16 (s, 0.5H), 2.11 (s, 0.5H), 1.23 (m, 9H).

(19) ESI-MS, C.sub.19H.sub.23NO.sub.4 (329.16), a measured value of 330.1[M+H].sup.+.

Example 5 Preparation of methyl ((Rasagiline-N-formyl)oxy)-icosanoate (Referring to International patent application WO2013088255)

(20) ##STR00017##

(21) 1.73 g of Rasagiline-N-chloromethyl formate and 0.50 g of TBAI were dissolved in 30 mL of DMF, and 3.0 g of potassium icosanoate was added to obtain a mixture. The mixture was heated at 60° C. overnight under the protection of argon. After the reaction was stopped, 80 ml of water was added, and then 80 mL of isopropyl ether was added for extraction. The extract was successively washed with saturated NaHCO.sub.3 (30 mL) and saturated NaCl (30 mL), and dried by anhydrous sodium sulfate. After a filtration and rotation to dryness, 1.55 g of a light yellow semisolid product was obtained through silica gel column chromatography (PE:EA=15:1), with a yield of 43.78%.

(22) .sup.1HNMR(CDCl.sub.3, 400 MHz) δ 7.25(m, 2H), 7.18 (m, 2H), 5.85 (m, 2.5H), 5.78 (m, 0.5H), 4.12 (d, J=17.6 Hz, 0.5H), 3.98 (d, J=17.6 Hz, 0.5H), 3.57 (d, J=17.6 Hz, 0.5H), 3.47 (d, J=17.6 Hz, 0.5H), 3.06 (m, 1H), 2.86 (m, 1H), 2.47 (m, 1H), 2.37 (m, 2H), 2.24 (m, 1H), 2.16 (s, 0.5H), 2.10 (s, 0.5H), 1.64 (m, 2H), 1.26 (m, 32H), 0.88 (t, J=6.8 Hz, 3H).

(23) ESI-MS, C.sub.34H.sub.53NO.sub.4 (539.4), a measured value of 562.3 [M+Na].sup.+.

Example 6 Preparation of methyl ((Rasagiline-N-formyl)oxy)-hyodeoxycholate

(24) ##STR00018##

(25) 1.48 g of Rasagiline-N-chloromethyl formate and 0.44 g of TBAI were dissolved in 8 mL of DMF, and 2.3 g of hyodeoxycholic acid was added to obtain a mixture The mixture was heated at 60° C. overnight under the protection of argon. After the reaction was stopped, 30 ml of saturated NaCl and 40 mL of ethyl acetate were added and stirred well. An organic phase was separated, and successively washed with saturated NaCl (30 mL), water (30 mL, stirring), saturated NaHCO.sub.3 (30 mL), and saturated NaCl (30 mL), followed by being dried by anhydrous sodium sulfate. After a filtration and rotation to dryness, 1.4 g of a white foamed product was obtained through silica gel column chromatography (PE:EA=3:1 organic phase), with a yield of 40.23%.

(26) .sup.1H-NMR(CDCl.sub.3, 400 MHz) δ 7.25 (m, 2H), 7.17 (m, 2H), 5.85 (m, 1.6H), 5.78 (s, 1H), 5.66 (m, 0.4H), 4.12 (d, J=17.6 Hz, 0.53H), 4.05 (m, 1H), 3.98 (d, J=17.6 Hz, 0.47H), 3.62 (m, 1H), 3.57 (d, J=17.6 Hz, 0.47H), 3.48 (d, J=17.6 Hz, 0.53H), 3.07 (m, 1H), 2.87 (m, 1H), 2.42 (m, 2H), 2.35 (s, 1H), 2.27 (m, 1H), 2.16 (s, 0.47H), 2.11 (s, 0.53H), 1.86 (m, 6H), 1.65 (m, 2H), 1.38 (m, 9H), 1.12 (m, 10H), 0.91 (m, 6H), 0.63 (s, 3H).

(27) ESI-MS, C.sub.38H.sub.53NO.sub.6 (619.39), a measured value of 642.2 [M+Na].sup.+.

Example 7 Preparation of methyl ((Rasagiline-N-formyl)oxy)-biotin methyl ester

(28) ##STR00019##

(29) 1.5 g of Rasagiline-N-chloromethyl formate, 2.0 g of biotin methyl potassium salt and 0.44 g of TBAI were dissolved in DMF, and they were kept reacting at 60° C. overnight under the protection of argon. After the reaction was stopped, 30 ml of saturated NaCl and 40 mL of ethyl acetate were added and stirred well. An organic phase was separated, and was successively washed with saturated NaCl (30 mL×3), water (30 mL×2), saturated NaHCO.sub.3 (30 mL) and saturated NaCl (30 mL), followed by being dried by anhydrous sodium sulfate. After a filtration and rotation to dryness, 1.9 g of a white solid powder product was obtained through silica gel column chromatography (EA-EA/MeOH=10:1), with a yield of 70.90%.

(30) .sup.1H-NMR(CDCl.sub.3, 400 MHz), δ 7.25 (m, 2H), 7.18 (m, 2H), 5.89 (s, 1H), 5.81 (m, 3H), 5.05 (s, 1H), 4.52 (m, 1H), 4.33 (m, 1H), 4.13 (d, J=18.0 Hz, 0.5H), 4.01 (d, J=18.0 Hz, 0.5H), 3.60 (d, J=18.0 Hz, 0.5H), 3.50 (d, J=18.0 Hz, 0.5H), 3.17 (m, 2H), 3.09 (m, 1H), 2.90 (m, 2H), 2.78 (s, 0.6H), 2.75 (s, 0.4H), 2.44 (m, 3H), 2.27 (m, 1H), 1.72 (m, 2H), 1.49 (m, 2H), 1.18 (m, 2H).

Example 8 Preparation of methyl ((Rasagiline-N-formyl)oxy)-ferulate

(31) ##STR00020##

(32) 3.8 g of ferulic acid protected by TBS was added to a mixed solution of 3.0 g of Rasagiline-N-chloromethyl formate, 2.0 g of DIPEA and 0.9 g of TBAI in acetonitrile, following by being stirred at 45° C. overnight. After the reaction liquid was removed through rotation to dryness, the resulting concentrate was added with PE (60 mL), EA (20 mL), and water (50 mL), and stirred to layer. An organic phase was separated, and successively washed with saturated NaHCO.sub.3 (30 mL), 0.05 mol/L diluted HCl (40 mL), water (40 mL), saturated NaCl (40 mL), and dried by anhydrous sodium sulfate. After a filtration and rotation to dryness, 15 mL of DCM was added for dissolution, and then, 1.68 g of triethylamine trihydrofluoride was added for deprotection. Then the reaction liquid was rotated to dryness, and EA (60 mL) was added for dissolution, a mixture was obtained. The mixture was successively washed with water (30 mL, in succession) and saturated NaCl (30 mL), and dried by anhydrous sodium sulfate. After a filtration and rotation to dryness, 30 mL of methyl tert-butyl ether was added to the concentrate and beat, and a white solid powder was obtained through silica gel column chromatography (DCM). Methyl tert-butyl ether was used to beat twice, and 1.16 g of a white solid powder product was obtained.

(33) 1H-NMR (CDCl3, 400 MHz), δ 7.74 (m, 1H), 7.25 (m, 2H), 7.19 (m, 2H), 7.12 (dd, J=8.0, 2.0 Hz, 1H), 7.07 (m, 1H), 6.96 (s, 0.52H) 6.95 (s, 0.48H), 6.34 (dd, J=16.0, 11.2 Hz, 1H), 6.00 (m, 3H), 5.88 (t, J=8.0 Hz, 0.52H), 5.72 (t, J=8.0 Hz, 0.48H), 4.15 (dd, J=18.0, 2.8 Hz, 0.48H), 4.03 (dd, J=18.0, 2.8 Hz, 0.52H), 3.96 (s, 3H), 3.60 (dd, J=18.0, 2.8 Hz, 0.48H), 3.51 (dd, J=18.0, 2.8 Hz, 0.52H), 3.09 (m, 1H), 2.88 (m, 1H), 2.49 (m, 1H), 2.27 (m, 1H), 2.19 (s, 0.48H), 2.12 (s, 0.52H).

(34) ESI-MS, C.sub.24H.sub.23NO.sub.6 (421.15), a measured value of 422.1 [M+H].sup.+.

Example 9 Preparation of methyl ((Rasagiline-N-formyl)oxy)-chenodeoxycholate

(35) ##STR00021##

(36) 1.14 g of DIPEA was added to a mixed solution of 1.7 g of Rasagiline-N-chloromethyl formate, 2.7 g of chenodeoxycholic acid and 0.5 g of TBAI in acetonitrile and DMF (20+5 ml), followed by being stirred at 45° C. overnight. After the reaction liquid was rotated to dryness and added with EA for dissolution, a mixture was obtained. The mixture was successively washed with saturated NaCl (30 mL×2), 0.05 mol/L diluted HCl (30 mL×2), water (30 mL), saturated NaHCO.sub.3 (30 mL) and saturated NaCl (30 mL), and dried by anhydrous sodium sulfate. After a filtration and rotation to dryness, 1.21 g of a white solid product was obtained through silica gel column chromatography (PE/EA=3:1), with a yield of 30.25%.

(37) .sup.1H-NMR(CDCl.sub.3, 400 MHz) δ 7.25 (m, 2H), 7.17 (m, 2H), 5.85 (m, 2.24H), 5.78 (s, 0.76H), 4.12 (d, J=17.6 Hz, 0.5H), 3.98 (d, J=17.6 Hz, 0.5H), 3.85 (m, 1H), 3.57 (d, J=17.6 Hz, 0.5H), 3.47 (m, 1.5H), 3.06 (m, 1H), 2.86 (m, 1H), 2.43 (m, 2H), 2.35 (s, 1H), 2.28 (m, 2H), 2.18 (s, 0.5H), 2.11 (s, 0.5H), 1.98 (m, 2H), 1.82 (m, 4H), 1.70 (m, 2H), 1.40 (m, 12H), 1.15 (m, 6H), 0.99 (m, 2H), 0.92 (m, 6H), 0.66 (m, 3H).

(38) ESI-MS, C.sub.38H.sub.53NO.sub.6 (619.39), a measured value of 642.2 [M+Na].sup.+.

Example 10 Preparation of methyl ((Rasagiline-N-formyl)oxy)-ursodesoxycholate

(39) ##STR00022##

(40) 1.5 g of Rasagiline-N-chloromethyl formate was added to a mixed solution of 1.0 g of DIPEA, 2.8 g of ursodesoxycholic acid and 0.44 g of TBAI in acetonitrile and DMF (20/5 ml), followed by being stirred at 45° C. overnight. After the reaction liquid was rotated to dryness and added with EA for dissolution, a mixture was obtained. The mixture was successively washed with saturated NaCl (30 mL×2), 0.05 mol/L diluted HCl (30 mL×2), water (30 mL), saturated NaHCO.sub.3 (30 mL) and saturated NaCl (30 mL), and dried by anhydrous sodium sulfate. After a filtration and rotation to dryness, 1.51 g of a white solid product was obtained through silica gel column chromatography (PE/EA=3:1 to 1:1), with a yield of 42.78%.

(41) .sup.1H-NMR(CDCl.sub.3, 400 MHz), δ 7.25 (m, 2H), 7.17 (m, 2H), 5.84 (m, 2H), 5.77 (s, 1H), 4.12 (d, J=18.0 Hz, 0.55H), 4.05 (m, 1H), 3.98 (d, J=18.0 Hz, 0.45H), 3.62 (m, 1H), 3.57 (d, J=18.0 Hz, 0.55H), 3.48 (d, J=18.0 Hz, 0.55H), 3.07 (m, 1H), 2.86 (m, 1H), 2.42 (m, 2H), 2.35 (s, 1H), 2.26 (m, 2H), 2.16 (s, 0.45H), 2.10 (s, 0.55H), 1.87 (m, 6H), 1.67 (m, 3H), 1.37 (m, 10H), 1.13 (m, 8H), 0.91 (m, 6H), 0.63 (m, 3H).

(42) ESI-MS, C.sub.38H.sub.53NO.sub.6 (619.39), a measured value of 642.2 [M+Na].sup.+.

Example 11 Preparation of methyl ((Rasagiline-N-formyl)oxy)-deoxycholate

(43) ##STR00023##

(44) 1.5 g of Rasagiline-N-chloromethyl formate was added to a mixed solution of DIPEA, deoxycholic acid and TBAI in acetonitrile and DMF (20+5), followed by being stirred at 45° C. overnight. After the reaction liquid was rotated to dryness and added with EA for dissolution, a mixture was obtained. The mixture was successively washed with saturated NaCl (30 mL×2), 0.05 mol/L diluted HCl (30 mL×2), water (30 mL), saturated NaHCO.sub.3 (30 mL) and saturated NaCl (30 mL), and dried by anhydrous sodium sulfate. After a filtration and rotation to dryness, 2.1 g of a white solid product was obtained through silica gel column chromatography (PE/EA=3:1 to 1:1), with a yield of 59.50%.

(45) .sup.1H-NMR(CDCl.sub.3, 400 MHz) δ 7.25 (m, 2H), 7.18 (m, 2H), 5.85 (m, 2.55H), 5.65 (m, 0.45H), 4.12 (d, J=17.6 Hz, 0.45H), 3.98 (m, 1.55H), 3.60 (m, 1H), 3.57 (d, J=17.6 Hz, 0.45H), 3.48 (d, J=17.6 Hz, 0.55H), 3.06 (m, 1H), 2.87 (m, 1H), 2.45 (m, 2H), 2.35 (s, 1H), 2.27 (m, 2H), 2.17 (s, 0.45H), 2.11 (s, 0.55H), 1.82 (m, 5H), 1.61 (m, 10H), 1.40 (m, 7H), 1.26 (m, 2H), 1.11 (m, 3H), 0.98 (d, J=4.8 Hz, 3H), 0.91 (s, 3H), 0.67 (d, J=2.4 Hz, 3H).

(46) ESI-MS, C.sub.38H.sub.53NO.sub.6 (619.39), a measured value of 642.2 [M+Na].sup.+.

Example 12 Preparation of methyl ((Rasagiline-N-formyl)oxy)-icosanamidohexanoate

(47) ##STR00024##

(48) 0.5 g of Rasagiline-N-chloromethyl formate was added to a mixed solution of 0.46 g of DIPEA, 0.5 g of icosanamidohexanoic acid and 100 mg of TBAI in THF/DMF (40+10 mL), followed by being stirred at 60° C. overnight. After the reaction liquid was rotated to dryness and added with isopropyl ether for dissolution, a mixture was obtained. The mixture was successively washed with 0.05 mol/L diluted HCl (30 mL×2), water (30 mL), saturated NaHCO.sub.3 (30 mL) and saturated NaCl (30 mL), and dried by anhydrous sodium sulfate. After a filtration and rotation to dryness, 0.22 g of a white solid powder product was obtained through TLC (PE/EA=2:1), with a yield of 17.74%.

(49) .sup.1H-NMR(CDCl.sub.3, 400 MHz) δ 7.25 (m, 2H), 7.18 (m, 2H), 5.85 (m, 2.5H), 5.66 (m, 0.5H), 5.54 (brs, 1H), 4.12 (d, J=23.6 Hz, 0.46H), 3.98 (d, J=23.6 Hz, 0.55H), 3.57 (d, J=23.6 Hz, 0.46H), 3.48 (d, J=23.6 Hz, 0.54H), 3.24 (m, 2H), 3.07 (m, 1H), 2.86 (m, 1H), 2.42 (m, 3H), 2.26 (m, 1H), 2.15 (t, J=10.4 Hz, 2H), 1.63 (m, 4H), 1.50 (m, 2H), 1.28 (m, 32H), 0.88 (t, J=8.8 Hz, 3H).

(50) ESI-MS, C40H64N2O5 (652.48), a measured value of 653.5 [M+H]+.

Example 13 Preparation of methyl ((Rasagiline-N-formyl)oxy)-icosanamidobutanoate

(51) ##STR00025##

(52) 0.4 g of Rasagiline-N-chloromethyl formate was added to a mixed solution of 0.2 g of DIPEA, 0.2 g of 4-icosanamidobutanoic acid and 50 mg of TBAI in THF/DMF (40+10 mL), followed by being stirred at 60° C. overnight. After the reaction liquid was rotated to dryness and added with isopropyl ether for dissolution, a mixture was obtained. The mixture was successively washed with 0.05 mol/L diluted HCl (30 mL×2), water (30 mL), saturated NaHCO.sub.3 (30 mL) and saturated NaCl (30 mL), and dried by anhydrous sodium sulfate. After a filtration and rotation to dryness, 0.15 g of a white solid powder product was obtained through TLC (PE/EA=2:1), with a yield of 15.95%.

(53) .sup.1H-NMR(CDCl.sub.3, 400 MHz) δ 7.25 (m, 2H), 7.19 (m, 2H), 5.87 (m, 2H), 5.67 (m, 1H), 4.33 (brs, 1H), 4.11 (d, J=18.0 Hz, 0.44H), 3.98 (d, J=18.0 Hz, 0.56H), 3.58 (d, J=18.0 Hz, 0.44H), 3.48 (d, J=18.0 Hz, 0.56H), 3.29 (m, 2H), 3.07 (m, 1H), 2.86 (m, 1H), 2.44 (m, 3H), 2.24 (m, 1H), 2.15 (m, 3H), 1.86 (m, 2H), 1.57 (m, 2H), 1.25 (m, 32H), 0.88 (t, J=6.8 Hz, H).

(54) ESI-MS, C.sub.38H.sub.60N.sub.2O.sub.5 (624.45), a measured value of 647.4 [M+Na].sup.+.

Example 14 Preparation of methyl ((Rasagiline-N-formyl)oxy)-stearamidobutanoate

(55) ##STR00026##

(56) The methyl ((Rasagiline-N-formyl)oxy)-stearamidobutanoate was prepared according to the method of Example 13, the product was obtained as a white solid powder with a yield of 22.6%.

(57) .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 7.25 (m, 2H), 7.19 (m, 2H), 5.92-5.60 (m, 4H), 4.11 (d, J=18.0 Hz, 0.44H), 3.98 (d, J=18.0 Hz, 0.56H), 3.58 (d, J=18.0 Hz, 0.44H), 3.48 (d, J=18.0 Hz, 0.56H), 3.31 (m, 2H), 3.07 (m, 1H), 2.87 (m, 1H), 2.43 (m, 3H), 2.25 (m, 1H), 2.15 m, 3H), 1.87 (m, 2H), 1.60 (s, 2H), 1.25 (m, 28H), 0.88 (t, J=6.7 Hz, 3H).

(58) ESI-MS, C.sub.36H.sub.56N.sub.2O.sub.5 (596.42), a measured value of 619.7 [M+Na].sup.+.

Example 15 Preparation of methyl ((Rasagiline-N-formyl)oxy)-palmitamidobutanoate

(59) ##STR00027##

(60) The methyl ((Rasagiline-N-formyl)oxy)-palmitamidobutanoate was prepared according to the method of Example 13, and the product was obtained as a white solid powder with a yield of 30.9%.

(61) .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 7.25 (m, 2H), 7.23-7.13 (m, 2H), 5.91-5.59 (m, 4H), 4.11 (d, J=18.0 Hz, 0.44H), 3.98 (d, J=18.0 Hz, 0.56H), 3.58 (d, J=18.0 Hz, 0.44H), 3.48 (d, J=18.0 Hz, 0.56H), 3.30 (m, 2H), 3.07 (m, 1H), 2.87 (m, 1H), 2.44 (m, 3H), 2.32-2.20 (m, 1H), 2.15 (m, 3H), 1.87 (m, 2H), 1.62 (m, 2H), 1.25 (s, 24H), 0.88 (t, J=6.7 Hz, 3H).

(62) ESI-MS, C.sub.34H.sub.52N.sub.2O.sub.5 (568.39), a measured value of 591.4 [M+Na].sup.+.

Example 16 Preparation of methyl ((Rasagiline-N-formyl)oxy)4-dodecanamidobutanoate

(63) ##STR00028##

(64) The methyl ((Rasagiline-N-formyl)oxy)4-dodecanamidobutanoate was prepared according to the method of Example 13, and the product was obtained as a white solid powder with a yield of 16.25%.

(65) .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 7.26-7.15 (m, 4H), 5.88-5.65 (m, 4H), 4.13 (d, J=18.0 Hz, 0.44H), 3.96 (d, J=18.0 Hz, 0.56H), 3.60 (d, J=18.0 Hz, 0.44H), 3.47 (d, J=18.0 Hz, 0.56H), 3.30 (t, 2H), 3.09 (m, 1H), 2.87 (m, 1H), 2.49-2.40 (m, 3H), 2.26-2.20 (m, 1H), 2.15 (t, 3H), 1.87 (m, 2H), 1.62-1.58 (m, 2H), 1.25 (s, 16H), 0.88 (t, J=6.7 Hz, 3H).

Example 17 Preparation of methyl ((Rasagiline-N-formyl)oxy)4-tetradecanamidobutanorate

(66) ##STR00029##

(67) The methyl ((Rasagiline-N-formyl)oxy)4-tetradecanamidobutanoate was prepared according to the method of Example 13, and the product was obtained as a white solid powder with a yield of 23.80%.

(68) 1H NMR (CDCl3, 400 MHz) δ 7.26-7.15 (m, 4H), 5.87-5.65 (m, 4H), 4.13 (d, J=18.0 Hz, 0.44H), 3.96 (d, J=18.0 Hz, 0.56H), 3.60 (d, J=18.0 Hz, 0.44H), 3.47 (d, J=18.0 Hz, 0.56H), 3.30 (t, 2H), 3.07 (m, 1H), 2.87 (m, 1H), 2.44 (m, 3H), 2.26-2.22 (m, 1H), 2.15 (t, 3H), 1.87 (t, 2H), 1.60 (t, 2H), 1.25 (s, 20H), 0.88 (t, J=6.7 Hz, 3H).

Example 18 Preparation of methyl ((Rasagiline-N-formyl)oxy)4-stearamidohexanoate

(69) ##STR00030##

(70) The methyl ((Rasagiline-N-formyl)oxy)4-stearamidohexanoate was prepared according to the method of Example 13, and the product was obtained ast a white solid powder with a yield of 15.90%.

(71) 1H NMR (CDCl3, 400 MHz) δ 7.26-7.17 (m, 4H), 5.87-5.48 (m, 4H), 4.14 (d, J=18.0 Hz, 0.44H), 3.96 (d, J=18.0 Hz, 0.56H), 3.60 (d, J=18.0 Hz, 0.44H), 3.46 (d, J=18.0 Hz, 0.56H), 3.20 (t, 2H), 3.06 (m, 1H), 2.86 (m, 1H), 2.46-2.35 (m, 3H), 2.29-2.20 (m, 1H), 2.16-2.12 (m, 3H), 1.68-1.52 (m, 4H), 1.38 (m, 2H), 1.26 (s, 30H), 0.88 (t, J=6.7 Hz, 3H).

Example 19 Preparation of methyl ((Rasagiline-N-formyl)oxy)4-stearoylglycinate

(72) ##STR00031##

(73) The methyl ((Rasagiline-N-formyl)oxy)4-stearoylglycinate was prepared according to the method of Example 13, and the product was obtained as a white solid powder with a yield of 51.38%.

(74) 1H NMR (CDCl3, 400 MHz) δ 7.26-7.16 (m, 4H), 5.94-5.80 (m, 4H), 4.14 (d, J=18.0 Hz, 0.44H), 3.93 (d, J=18.0 Hz, 0.56H), 3.62 (d, J=18.0 Hz, 0.44H), 3.46 (d, J=18.0 Hz, 0.56H), 3.30 (q, 2H), 3.07 (m, 1H), 2.87 (m, 1H), 2.53-2.41 (m, 1H), 2.26-2.21 (m, 3H), 2.17 (s, 1H), 1.65 (m, 2H), 1.25 (s, 24H), 0.88 (t, J=6.7 Hz, 3H).

Example 20 Preparation of methyl ((Rasagiline-N-formyl)oxy)4-docosanamidobutanoate

(75) ##STR00032##

(76) The methyl ((Rasagiline-N-formyl)oxy)4-docosanamidobutanoate was prepared according to the method of Example 13, and the product was obtained as a white solid powder with a yield of 31%.

(77) 1H NMR (CDCl3, 400 MHz) δ 7.21-7.26 (m, 2H), 7.17-7.20 (m, 2H), 5.81-5.88 (m, 2.56H), 5.65 (br, 1.44H), 4.11 (d, J=17.6 Hz, 0.44H), 3.98 (d, J=17.2 Hz, 0.56H), 3.58 (d, J=17.6 Hz, 0.44H), 3.49 (d, J=18.8 Hz, 0.56H), 3.30-3.31 (m, 2H), 3.03-3.11 (m, 1H), 2.83-2.89 (m, 1H), 2.43-2.49 (m, 3H), 2.22-2.27 (m, 1H), 2.13-2.17 (m, 3H), 1.84-1.89 (m, 2H), 1.57-1.63 (m, 2H), 1.25 (m, 36H), 0.88 (t, J=6.8 Hz, 3H).

Example 21 Preparation of methyl ((Rasagiline-N-formyl)oxy)5-palmitamidopentanoate

(78) ##STR00033##

(79) The methyl ((Rasagiline-N-formyl)oxy)5-palmitamidopentanoate was prepared according to the method of Example 13, and the product was obtained as a white solid powder with a yield of 17.6%.

(80) 1H NMR (CDCl3, 400 MHz) δ 7.21-7.26 (m, 2H), 7.15-7.19 (m, 2H), 5.81-5.87 (m, 2.55H), 5.65 (t, J=4.0 Hz, 0.45H), 5.54 (br, 1H), 4.11 (d, J=18.0 Hz, 0.45H), 3.98 (d, J=18.4 Hz, 0.55H), 3.57 (d, J=17.6 Hz, 0.45H), 3.48 (d, J=18.4 Hz, 0.55H), 3.25-3.27 (m, 2H), 3.03-3.10 (m, 1H), 2.81-2.91 (m, 1H), 2.38-2.45 (m, 3H), 2.21-2.29 (m, 1H), 2.13-2.17 (m, 3H), 1.65-1.71 (m, 2H), 1.56-1.62 (m, 4H), 1.25 (m, 26H), 0.89 (t, J=6.8 Hz, 3H).

Example 22 Preparation of methyl ((Rasagiline-N-formyl)oxy)5-stearamidopentanoate

(81) ##STR00034##

(82) The methyl ((Rasagiline-N-formyl)oxy)5-stearamidopentanoate was prepared according to the method of Example 13, and the product was obtained as a white solid powder with a yield of 14.6%.

(83) 1H NMR (CDCl3, 400 MHz) δ 7.23-7.26 (m, 2H), 7.17-7.21 (m, 2H), 5.78-5.88 (m, 2.50H), 5.65 (t, J=4.0 Hz, 0.50H), 5.51 (br, 1H), 4.12 (d, J=18.4 Hz, 0.50H), 3.98 (d, J=18.4 Hz, 0.50H), 3.58 (d, J=17.2 Hz, 0.50H), 3.48 (d, J=15.6 Hz, 0.50H), 3.25-3.28 (m, 2H), 3.03-3.11 (m, 1H), 2.84-2.90 (m, 1H), 2.40-2.48 (m, 3H), 2.22-2.29 (m, 1H), 2.13-2.17 (m, 3H), 1.66-1.69 (m, 2H), 1.59-1.63 (m, 4H), 1.25 (m, 30H), 0.88 (t, J=6.8 Hz, 3H).

Example 23 Preparation of methyl ((Rasagiline-N-formyl)oxy)4-octadecylamidosuccinate

(84) ##STR00035##

(85) Octadecylamine (3.0 g, 11.13 mmol, 1.0 equivalent) and tetrahydrofuran (60 mL) were added to 250 mL of a single-neck flask, and then 4-dimethylaminopyridine (DMAP, 408 mg, 3.34 mmol, 0.3 equivalent), diisopropylethylamine (DIPEA, 2.87 g, 22.26 mmol, 2.0 equivalent) and succinic anhydride (1.36 g, 13.36 mmol, 1.2 equivalent) were further added to obtain a mixture. The mixture was kept stirring accompanied with heating reflux for 3 days. If it was detected by TLC that octadecylamine still exist and remain unchanged, the reaction was stopped and cooled to room temperature. A concentrated HCl was added for adjusting pH to 2-3, followed by suction filtration, a filtrate was collected. The filtrate was washed once by saturated salt solution. An organic phase was obtained, and it was dried by anhydrous sodium sulfate. After a filtration, rotation to dryness, drying through an oil pump, 2.7 g of a white solid crude product, that is 4-(octadecylamido) succinic acid, was obtained to be directly used in a next step.

(86) 4-(octadecylamido) succinic acid (2.7 g, 7.3 mmol, 1.0 equivalent) and 100 mL of tetrahydrofuran were added to 100 mL single-neck flask, and then diisopropylethylamine (DIPEA, 1.88 g, 14.6 mmol, 2.0 equivalent), Rasagiline-N-chloromethyl formate (2.31 g, 8.76 mmol, 1.2 equivalent) and tetrabutylammonium iodide (TBAI, 539 mg, 1.46 mmol, 0.2 equivalent) were added to obtain a mixture. The mixture was placed at 80° C. and kept stirring for 3.5 days. If it is detected by the TLC that there some raw materials still exist and remain unchanged, the reaction was stopped and cooled to room temperature. After a filtration, washing with ethyl acetate, and rotation to dryness, dichloromethane was used for dissolution, 1 M HCl aqueous solution was used to wash once, and anhydrous sodium sulfate was used for drying. After a filtration and rotation to dryness and separation through silica gel column chromatography (PE/EA=5:1 to PE/EA=1:1), fractions were combined and rotated to dryness, and then methanol was added for dissolution. Stirring was performed at −10° C. for crystallization until solids appear, followed by rapid suction filtration. An oil pump was used to dry the filter cake, and 200 mg of a while solid, that is methyl ((Rasagiline-N-formyl)oxy)4-octadecylamidosuccinate, was obtained with a yield of 4.6%.

(87) .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 7.23-7.26 (m, 2H), 7.18-7.22 (m, 2H), 5.79-5.89 (m, 2.56H), 5.59-5.67 (m, 1.44H), 4.11 (d, J=18.0 Hz, 0.44H), 3.97 (d, J=16.8 Hz, 0.56H), 3.58 (d, J=18.8 Hz, 0.44H), 3.47 (d, J=17.2 Hz, 0.56H), 3.20-3.25 (m, 2H), 3.03-3.10 (m, 1H), 2.83-2.91 (m, 1H), 2.72-2.78 (m, 2H), 2.45-2.48 (m, 3H), 2.24-2.26 (m, 1H), 2.16 (t, J=6.0 Hz, 1H), 1.48 (m, 2H), 1.25 (m, 28H), 0.88 (t, J=6.8 Hz, 3H).

Example 24 Detection of Physicochemical Properties of the Prodrug of Rasagiline

(88) A melting point and solubility (phosphate buffer with pH of 7.4) of synthesized prodrug compounds of Rasagiline were detected, and the results are shown in table 1:

(89) It can be noted based on data from the below table that the compound of the present disclosure has a higher melting point with respect to the control group, in particular to Examples 8, 12, 13, 14, 15, 17, 20 and 23.

(90) TABLE-US-00001 TABLE 1 DATA OF MELTING POINT AND SOLUBILITY OF A PRODRUG COMPOUND OF RASAGILINE MELTING SOLUBILITY NUMBER EXMAPLE POINT(° C.) (μg/ml) 1        1 (CONTROL) <25 <5 2  2 66-70 <5 3        3 (CONTROL) <25 <5 4  4 <25 <5 5        5 (CONTROL) <25 <5 6  6 <50 <5 7  7 / 31.7 8  8 130.4-133.8 <5 9  9 <50 <5 10 10 <50 <5 11 11 <50 <5 12 12 77.2-80.8 <5 13 13 80-82 <5 14 14 76-78 <5 15 15 73-75 <5 16 16 56.1-59.4 <5 17 17 66.3-71.8 <5 18 18 58.9-64.2 <5 19 20 87.4-87.8 <5 20 21 55.4-56.2 <5 21 22 58.3-58.9 <5 22 23 75.3-77.1 <5

Example 25 Pharmacokinetics Experiment of Prodrug of Rasagiline in the Body

(91) One common male beagle was used for each group, and they were forbidden to eat for 12 hours before administering drugs, and drank water freely meanwhile. Injectable suspensions of Example 13, Example 15, Example 14, Example 20, Example 8 were intramuscularly injected in a dosage of 0.47 mg/kg Rasagiline (1.72 mg/kg, 1.56 mg/kg, 1.64 mg/kg, 1.80 mg/kg, 1.16 mg/kg of prodrug respectively after conversion). Before administering drugs and 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 18 hours, 24 hours, 48 hours, 96 hours, 144 hours, 192 hours, 240 hours, 288 hours, and 360 hours after drug administration, 1.0 mL whole blood of the beagle was collected from venous vein in front legs each time and centrifuged in an heparinized centrifuge tube at 6000 rpm for 10 minutes at 4° C., to separate blood plasma, and the blood plasma was stored to be measured at −80° C.

(92) Treatment of blood plasma sample: The blood plasma sample was placed in an ice bath; 30 μL of methanol and 20 μL of interior label (2 μg/mL apigenin dissolved in 50% methanol) were added into 200 μL of the blood plasma sample and mixed through vortex, and then 4 mL of ethyl acetate was added and mixed through vortex. After being centrifuged at 9000 g for 2 minutes, an organic phase was separated and dried in vacuum, and then 150 μL of methanol was added for re-dissolution. 30 μL of a prepared sample was taken for analyzing.

(93) Data analysis: The sample was detected by LC-MS/MS, and analyzed by a DAS 2.0 software to calculate pharmacokinetic parameters according to blood drug concentration, providing parameters such as AUC (0-t), AUC(0-∞), MRT(0-t), MRT(0-∞), C.sub.max, T.sub.max, and t.sub.1/2, etc.

(94) Experimental results: after the beagles was respectively administered the above described prodrugs of Rasagiline, the blood drug concentration of the Rasagiline is shown in Table 2. FIG. 1 is made according to data from the Table 2. It can be noted from the table 2 and table 3 that the compound of the present disclosure may be slowly, sustainably and steady released and converted into Rasagiline, achieving an effect of long-acting treatment. In particular, the releases of the prodrugs of Example 13 and Example 20 are steadier, which can well meet the requirement of the long-acting injectable suspensions. Although the prodrugs of Example 14 and Example 15 are released rapidly within 2 days after the prodrugs were administered, they are released steady after that, thus both of these two examples achieve a long-acting effect.

(95) TABLE-US-00002 TABLE 2 BLOOD DRUG CONCENTRATIONS OF RASAGILINE AFTER PRODRUGS OF RASAGILINE ARE INTRAMUSCULARLY INJECTED INTO BEAGLE DOGS Blood drug concentration of Rasagiline (ng/mL) EXAM- EXAM- EXAM- EXAM- EXAM- t(h) PLE 15 PLE 14 PLE 8 PLE 13 PLE 20 0.5 1.03 0.937 2.11 0.037 0.032 1 1.17 3.79 6.62 0.057 0.036 2 1.12 2.4 8.82 0.061 0.037 4 0.928 2.11 9.39 0.081 0.025 8 2.39 3.33 4.19 0.128 0.066 12 1.16 0.463 2.21 0.195 0.101 18 2.23 1.58 3.05 0.192 0.101 24 2.32 3.02 3.23 0.21 0.148 48 0.892 0.739 2.43 0.425 0.198 96 0.852 0.476 0.532 0.44 0.333 144 0.616 0.0803 0.385 0.224 0.325 192 0.199 0 0.238 0.172 0.214 240 0 0 0.167 0.138 0.23 288 0.0277 0 0.149 0.145 0.165 360 0 0 0 0.095 0.126

(96) After beagles were intramuscularly injected with the above described prodrugs of Rasagiline, pharmacokinetic parameters of the Rasagiline are shown in TABLE 3.

(97) TABLE-US-00003 TABLE 3 PHARMACOKINETIC PARAMETERS OF THE RASAGILINE AFTER THE PRODRUGS OF RASAGILINE ARE INTRAMUSCULARLY INJECTED INTO BEAGLES PARAM- EXAM- EXAM- EXAM- EXAM- EXAM- ETERS UNITS PLE 15 PLE 14 PLE 8 PLE 13 PLE 20 AUC.sub.(0-t) μg/L*h 187.6 135 296.5 87.7 92.8 AUC.sub.(0-∞) μg/L*h 188.9 138.4 319 94.5 124.3 MRT.sub.(0-t) h 75.1 38.3 55.2 162.5 208.4 MRT.sub.(0-∞) h 76.9 41.9 82.2 204.4 364 t.sub.1/2z h 32.4 29.5 104.8 122.3 237.2 T.sub.max h 8 1 4 64 96 C.sub.max μg/L 2.39 3.79 9.39 0.497 0.333

(98) Although the present invention has been disclosed in the form of preferred embodiments and variations thereon, it will be understood that numerous additional modifications and variations could be made thereto without departing from the scope of the invention.