TW387896B - Novel dipeptide and tripeptide mimic compounds for treating Parkinson's disease - Google Patents

Abstract

The invention relates to a protodrug made of L-dopa in coupled with D-phenylglycine or D-p-hydroxyphenylglycine and the dipeptides thereof that is capable of enhancing the oral bioavailablity of the protodrug and delaying the internal metabolic rate of decarboxylation for the L-dopa to prolong its half-life. In the experimental animal model of anti-Parkinson's disease, compound 2d can mitigate the rotation behavior of the rat with damaged gray matter of the brain that is stimulated by (+)toluene-iso-propylamine. The compound 2d has an anti-Parkinson's disease activity equivalent to L-dopa and does not cause the contraction of the pulmonary artery and vasa deferens, indicating that no dopamine-like side effect such as hypertension leading cardiovascular diseases. Such drug is useful in the treatment of patients suffered from Parkinson's disease with hypertension.

Description

Printed by the Industrial and Consumer Cooperatives of the Central Bureau of the Ministry of Economic Affairs of the People's Republic of China. A7 __B7___ V. Description of the Invention (1) Background of the Invention L-Duba [2-Amino-3- (3,4-dihydroxyphenyl) propionic acid] is Prodrugs of dopamine are also the best choice for clinical treatment of Parkinson's disease, but L-dupa in most circulations cannot penetrate blood brain disorders (AUCesF / AUCp | asma = 12/100) [Olanow, CW, Gauger LL, Cedarbaum JM Temporal Relationships between Plasma and Cerebrospinal Fluid Pharmacokinetics of L-Dopa and Clinical Effect in Parkinson Disease. Annals Neuro. 1991, 29, 556-559], so a large amount of L_ Durbar is needed but L- Dopa is easily decarboxylated in the human peripheral circulation and metabolized to form dopamine, causing side effects such as pulmonary artery contraction [83 巾 634 久 丁 ^^ 1 ^ (^ 1_-Dopa in Parkinson Disease: A 20 Year follow-up. Trends Pharmacol. Sci. 1981 297-299], and the oral bioavailability of L-Duba was only 33% at a dose of 1000 mg / day, and the bioavailability between patients and between patients was quite variable, Its amphoteric amino acid-like structure is the oral bioavailability of L-Duba The reason for the great invention Summary of the invention The present invention designs and prepares a series of L-dubar bis- and tri-peptide derivatives as a dopamine prodrug, which not only improves the oral bioavailability of L-dubar, but also can The peptide transport mechanism delivers the prodrug to menstrual blood-brain disorder (BBB) to the central nervous system (CNS), and exerts pharmacological effects of dopamine against Parkinson's disease. The present invention synthesizes a series of duba with one of the following formulas [ 2-amino-3- (3,4-dihydroxyphenyl) propionic acid] bis- or tri-peptide derivatives ... (Please read the precautions on the back before filling in this page)

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、 1T h line This paper's standard is applicable to China National Standard (CNS > A4 specification (2 丨 OX 297 mm) 83.3. 10,000 V. Description of the invention (

nh2 A7 B7 \

(I) wherein η is 0 or 1, preferably 1; R is hydrogen or hydroxyl; Ji ·! Is hydrogen and latch 2 is -hydrogen 'C1-4 alkyl, which has-selected from-(^, -81 ^ -3 (^ 3, -NH2, -NHC (= NH) NH2, -COOH, phenyl, hydroxyphenyl, indolyl, and imidazolyl substituted C «| _4 alkyl or substituted with a Ci_6 alkoxy C * | _4 alkyl group, preferably R2 is hydrogen, methyl or hydroxymethyl; or R1 and R2 are both trimethyl groups. Preferably, R1 and R2 are all trimethyl groups. The present invention The author also synthesized [2-amino-3- (3,4-dihydroxyphenyl) propionic acid] bis peptide peptides as follows:

COOK NH „

Η-C-Ν-C-C —CH | | II I Rl »R3 〇 H

(Please read the notes on the back of the page before filling in this page) Γ- -Packing • I--Booking bags of the Central Working Group of the Ministry of Economic Affairs of the Central Bureau of Work and Consumer Cooperatives, where R3 is hydrogen; R4 is phenyl or p-hydroxybenzene Group; or only 3 and R4 are combined into a trimethyl group. The invention also discloses a medicinal composition for treating Parkinson's disease, which comprises a medically effective amount of [2 · amino-3 (3,4-dihydroxyphenyl) propan-4- Quickly use Chinese National Standards (CNS), 8 specifications (2 × 0 × 297 mm) 83. 3.10,000 Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 __B7___ V. Invention Description (3) Acid] Part 2- Or a tri-peptide derivative or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier or diluent combination thereof. The invention also discloses a medicinal composition for treating Parkinson's disease, which comprises a medically effective amount of [2-amino-3- (3,4-dihydroxyphenyl) propionic acid] bis as the above formula (丨 丨). -Or a tri-peptide derivative or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier or diluent combination thereof. Brief Description of the Figures Fig. 1 (a) shows the time course of the concentration of Compound 1a in blood after arterial injection of Compound 1a. Figure 1 (b) shows the blood concentration of compound 1a over time after oral administration of compound 1a. Figure 2 shows (A) the increase in pulmonary artery contractility caused by dopamine (1 mg / ml) perfusion, but (B) compound 2d ( 1 mg / ml) does not increase the contraction of this vascular smooth muscle. Figure 3 shows that (A) dopamine (1 mg / ml) causes contraction of the vas deferens smooth muscle and (B) compound 2 d (1 mg / m I) does not. Detailed description of the invention Prodrugs refer to drugs that are structurally modified to improve the pharmacokinetics of known drugs, and are the development direction of new drugs. The concept of using a chemical delivery system in prodrug design is also particularly important. Research shows that a specific di-peptide-mediated carrier transport system in the small intestine is responsible for amino-yS-lactam (amino- / 9- (please read the note on the back before filling in this Page) Γ-Pack

, tT c The size of the paper is applicable to the Chinese National Standard (CNS) A4 specification (2 丨 0X297 mm) 83. 3.10,000 A7 B7 printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (4) lactam ) Absorption of antibiotics [Okano, T., Inui, K., Maegawa, H., Takano, M., Hori, R. H + coupled uphill transport of aminocephalosporins via the dipeptide transport system in rabbit intestinal brush-border membranes. J Biol. Chem. 1986, 261, 14130-14134; Dantzig, AH, Bergin, L. Carrier-mediate uptake of cephalexin in human intestinal cells. Biochim. Biophys. Res. Commun. 1988, 155, 1082-1087; Inui, K., Okano, T., Maegawa, H., Kato, M., Takano, M., Hori, R. H + coupled transport of po cephalosporins via dipeptide carriers in rabbit intestinal brush-border membranes: difference of transport characteristics between cefixime and cephradine. J. Pharmacol. Exp. Ther. 1988, 247, 235-247; Wang, HP, Bair, CH, Huang, JD Uptake of cefadroxil derivatives into rat intestinal brush-border membrane ves icles. J. Pharm. Pharmacol. 1992, 44, 1027-1029], such amine-yS-lactam antibiotics have a triple peptide structure, and most of them have D-phenylglycine or D-p- "Hydroxyphenylglycine" is a dipeptide intermediary delivery system that has few restrictions on the mass structure and is widely accepted [Bai, 丄 PF, Amidon, GL Structural specificity of mucosal-cell transport and metabolism of peptide drugs: implication for oral peptide drug delivery. Pharm. Res. 1992, 9, 969-978], so a dipeptide containing D-phenylglycine or D-p-hydroxyphenylglycine was used as a tool for delivery Low bioavailability of oral agents to increase absorption through the small intestine should be the ideal drug design approach. This study group demonstrated in vitro absorption studies of brush border membrane cysts in the small intestine of rats that this dipeptide has a high affinity for small intestine carrier mediator delivery system proteins [Wang, Η. P ·; Lu, Η · H ·; Lee, 丄 S ·,,--6 ·. *, The standard for Chinese version is CNS A4 (2 丨 0X 297mm) 83.3.10,000 (Please read the notice on the back first (Fill in this page again)-Assemble and order i-line print by the Central Standards Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, printed A7 _B7_ V. Description of the invention (5)

Cheng, CY; Mah, JR; Hsu, WL; Yen, CF; CJ; Kuo. HS. Intestinal Absorption Studies on Peptido Mimetic Prodrugs of a-Methyldopa. J. Pharm. Pharmacol. 1996, 48 (2), in press. 2. Wang, Η. P .; Huang, JD; Cheng, CY; Bair, CH; Lee, JS; Chee, PJ Studies on the Uptake of Dipeptides in Brush Border Membrane Vesicle from Rat Intestine, Chin. Pharm. J. 1995 , 47, 23-35.] Lit. It is encouraged in the present invention to use such amino acids and their dipeptide derivatives to prepare a series of L-duba prodrugs. The small intestinal absorption effect of this kind of prodrug is evaluated by jejunal perfusion test in living rats and bioavailability measurement in rabbits. The anti-Parkinson's effect of the drug of the present invention is to measure the rat substantia nigra (+)-methyl Changes in rotational behavior caused by methamphetamine stimulation * Side effects related to dopamine in the peripheral system were assessed by contraction of the pulmonary arteries and vas deferens of male guinea pigs. Chemical analogs of dipeptide prodrugs of dopamine, such as compound 1a (D-phenylglycine-L-duba) -1b (D-p-hydroxyphenylglycine-L-duba) The N-terminal protected amino acid and L-dubabenzyl ester are condensed in the presence of dicyclohexylcarbodiimide (DCC) and N-hydroxybenzotriazole (HOBt), and then deprotected (process, A dopamine-like dipeptide prodrug with the opposite amino acid sequence, such as compound 1c (L-duba-D-phenylglycine) -1d (L-duba-L-proline), is It is obtained by combining N (Boc) -L-duba with the corresponding benzyl amino acid (Scheme 2). A tri-peptide prodrug, such as 2a (D-phenylglycine-L-serine) -Duba), 2b (D-p-hydroxyphenylglycine-L-serine)--7-(Please read the precautions on the back before filling in this note), install,? R line 83. 3. 10.000 Printed by A7 __B7_ ___ only the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the Invention (6) Durban>, 2c (D-phenylglycine-L-proline-L-dubar) and 2d (D-p-hydroxyphenylglycine-L-proline-L-duba) is obtained by combining the N-terminally protected dipeptide with L-dubabenzyl ester and deprotection (Scheme 3) -Intestinal suction After the test drug and the rat small intestinal mucosa suspension were cultured at 37 ° C for 2 minutes, 81% of the natural L-glycine-L-phenylalanine dipeptide had been decomposed, however, D-phenylglycine -L-proline-L-duba (2d) was cultured for 90 minutes in the same culture medium and still remained 94 ± 0.03% (n = 2), indicating that the peptide-like prodrugs of this type have considerable stability in the intestine Intestinal absorption test can be carried out. The preliminary small intestinal absorption test is to use a single dose of the drug to perform rat jejunal perfusion test on the same rabbit to determine the blood concentration of the rat, and then a single dose of the drug is injected into the rabbit's arteries and administered orally to determine the drug. Kinetic parameters to calculate oral bioavailability. The results of the jejunal perfusion experiments of compounds 1a-1c, 2a-2d are shown in Table 1. The blood concentrations of prodrugs 1a, 1c, 2b, and 2c were 6 0 ~ 100 times. This data shows that these prodrugs are better absorbed in the small intestine than their parent drug L-Dubar. (Please read the precautions on the back before filling out this page) Home Standard (CNS) Α4 Specification (210 × 297 mm) 83. 3. 10,000 V. Description of Invention (A 7 B7 ㈣ H00C-C-CH2 Η L-Duba 0 Η

0Η ΒηΟΗ / 6Ν HCI ㈣ 0Η

0Η Η 0 Η 7a-7b 1) TFA / CH2CI22) H2 / Pd (OH) 2 (Please read the precautions on the back before filling out this page) η • Installed, 1T Consumer Affairs Cooperative, Central Bureau of Standards, Ministry of Economic Affairs Seal

Compound

R column 1a 1b

H D-H-C (Ph) Gly-L-Dopa-OHOH D-H-C (p-HOPh) Gly-L-Dopa-OH Process Private paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 83.3. 10,000 A7B7

V V. Description of the invention () H0

Sfz = \ ιΗζ

HO λ-CH2-C— COOH

L-t ± E (Boc) 2〇 / Ns ^ C〇3 50% THF (aq) / N2

HO

HCIHN or \ NHBoc COOBn Γ ^ \ II HO-»/ \ —CH '一 C—C—N—C——H COOBn 9d (Please read the precautions on the back before filling out this page) -Installation-Η O R3 R4 10c-10d 1) TFA / CH2Cl2 2> H2 / Pd (OH) 2 f Λ HO V- v NH2 COOH \ 1 1 HO— (, CH f / 2 | Μ | 1 'Η O R3 r4 VJ R3 r4

, 1T Γ Printed by the quasi-station Zhengong Consumer Cooperative in the Ministry of Economic Affairs 2 columns 1c 1d

H Ph LH-Dopa-DC (Ph) Gly-OH -CH? -CH? -CH?-LH-Dopa-L-Pro-OH Process 2 10-This paper size applies Chinese National Standard (CNS) A4 specification (210X297 83. 3. 10,000 V. Description of the invention (___ NBo, _Oi ~ NBoc COOH Η5a-5b

R = H, OH A7B7

Rj R2 I 8 HN—C—COOBn K H H, CHpH or CH2-CH2-CH2 DCC / HOBT / Na 2C〇3 CH2C12 or t NBoc Ri R2 I = C-—C ——N C — OOOSn II 5H ° H 11a-11d

H2 / Pd (OH) 2MeOH

. NBoc R | Bz R— ^ C -C—N

Η O DCC / HOBT 012 <: 12 or two Df ^ NHBoc R1 R2

C-COOH sH 12a-12d OH COOBn —V

H2N—C H 6 (Please read the notes on the back before filling this page) f • Binding

H OH COOBn, / C-C-N —C —C — N—C— CHjg- II Η O13a-13d 4 1) TFA / CH2CI2 2) H2 / Pd (OH) 2 Γ line, __. NH2 Central N- <

OH COOH, _ / 1 Όήζ-U \ _OH

\ fur Η O Ri R2 I = -N—C—ΟΙ II Η O compound R Ri r2 tri 2a Η H ch2oh DHC (Ph) Gly-L-Ser-L. Dopa-OH 2b OH H ch2oh □ -Η-Οίρ -ΗΟΡ ^ Οχ-Ι-βθΓ-Ι-Οορβ-ΟΗ 2c Η -CH2 ~ CH 2 ^^ 2 ~ 0-Η-Ο (Ρ ^ Θ1γ-1-ΡΓ〇-1-0ορΒ-ΟΗ 2d OH -CH2- CH2-CH2- DHC (p-HOPh) Glv-L-Pr0-LD〇Da-OH Scheme 3 83. 3. 10,000 A7 B7 V. Description of the invention (1 ()) Table 1 Rat jejunal perfusion experiment with a single dose of drug Results Compound a sequence experiment times Blood concentration mg / mL (average sem) 1a DHC (Ph) Gly-L-Dopa-OH 4 64.65 ± 5.45 1b DHC (p-HOPh) Gly-L Dopa-OH 4 0.60 ± 0.01 1c LH-Dopa-DC (Ph) Gly-OH 4 104.00 ± 12.98 2a DHC (Ph) Gly-L-Ser-L- Dopa-OH 6 8.49 ± 1.36 2b DHC (p-HOPh) Gly ^ L-Ser- L- Dopa-OH 4 62.11 ± 3.53 2c DHC (Ph) Gly-L-Pro-L- Dopa-OH 4 84.66 ± 6.00 2d DHC (p-HOPh) Gly-L-Pro- L-Dopa-OH 6 4.37 ± 0.45 L -Duba • 3 1.24b (Please read Note 1P on the back before filling this page)

C. Installation. Ordering and printing

a_ The perfusion concentration of each compound was 0.1 mM b. The blood concentration was measured by one mouse, and the other two were unable to detect duba. The oral bioavailability of prodrugs was measured in New Zealand white rabbits. Six fasting New Zealand white rabbits were injected with prodrug 1a (10 mg / kg, equivalent to 5.97 mg / kg L-Duba) through the ear artery, and their blood concentration curves over time were shown in Figure 1 (a) . After a two-week extermination period (wash-, 12- Tai Mi "&?; Hu Hu Zhong Tuan Pu Ding; ayjt f CNS} A4 size (2 丨 0X297) 嫠 83. 3. 10,000 Central Ministry of Economic Affairs Industrial and consumer cooperatives printed A7 B7 _15. Description of the invention (11) out period), the same white rabbit was orally administered with prodrug 1a and its blood concentration curve over time was shown in Figure 1 (b). The kinetic parameters of the two grant methods are listed in Table 2. Figure 1 (b) shows that compound 1 a is rapidly absorbed after oral administration, with a bioavailability of 76 (± 24)%. It shows that D-phenylglycine is an effective delivery tool for the parent drug through the small intestine. Table 2 Compound 1a Pharmacokinetic parameters after oral and arterial injection

Cmax tmax AUC M / 2 Absorption of some compounds (ufl / mL) (min > (ug.min / mL) (min) 1%) 1a Oral 8.29 ± 3.39 13 ± 5 484.24 ± 91.14 61 ± 23 76 ± 24 13 Artery Injection of 43.22 ± 8.41_563.05 ± 107.06 51 ± 26__ Pharmacological effects The animal test of anti-Parkinson's disease is a model of male Wistar rats with unilateral substantia nigra injured by 6-hydroxydopamine. [Hudson 丄 L .; Levin. DR; Hoffer, BJ A Sixteen-Channel Automated Rotometer System For Reliable Measurement of Turning Behavior in 6-Hydroxydopamine Lesioned and Transplanted Rats. Cell Transplantation 1993, 2, 507-514; Hudson 丄 L, Van Horne C. G ·; Stromberg I ·; Brock. S ·; Clayton, 丄; Masserano, 丄; Hoffer, Gerhardt, GA Correlation of Apomorphine and Amphetamine Induced Turning With Nigrostriatal Dopamine Content in Unilateral 6-Hydroxydopamine Lesioned Rats. Brain Res. 1993, 626, 167-174], our previous research also showed that 6-hydroxy-1 3-(please read the note on the back before writing this page) Γ. 1 * 1? ft ^ ηκίς, technical preparation, 83. 3. 10.000 A7 B7 V. Description of the invention (12) Rats with unilateral substantia nigra damage caused by gidubamide (+ buprofen (0.05 mg / kg subcutaneous injection) rotation motion under stimulation * and confirmed that more than 90% of the animals that rotate more than 300 rpm have exhausted more than 90% of the dopamine in their brain "shows that this model can be used as brain There is no animal experimental model of dopamine in the experiment. Therefore, in the experiment of the present invention, 6-hydroxydupamine was used to induce univentricular substantia nigra damage. These animals were tested with methamphetamine-induced rotation of more than 300 rpm Model of drug anti-Parkinson's disease. In the study of the present invention, the test drug L-duba was injected intraperitoneally 1 to 2 hours before subcutaneous injection of (+)-methamphetamine (0.4 0 mg / kg). Or compound 2d, and then measure the number of mouse rotations. As shown in Table 1, compound 2d significantly inhibited the rotation of mice induced by (+)-methamphetamine. Compound 2d has a slightly higher activity than L-duba. Table 3 L-Duba and compound 2d p ((+)-methamphetamine initiated The influence of the rotation moves the mouse striatal damage change (please read the notes on the back of its Complete this page)

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、 1T Male laborer's consumption cooperation with the Central Naked Associate Bureau of the Ministry of Economic Affairs of China. The amount of time to rotate the compound (mg / kg) (hours) a. The number of tests (revolutions / hour) Control saline--19 552 ± 47 L-Duba 4.2 1 2 2 87 ± 86 2d 9.6 1 6 223 ± 95 2d 9.6 2 6 247 ± 67 3 Interval time line of (+) _ methylphenylisopropylhydrazine after 1 · -duba or compound 2d treatment before injection 2,000 Taiji Paper Size Uses China National Standards (CNS) A4 Specification (2 丨 0X 297mm) Printed on A7 B7 by Zhengong Consumer Cooperative of Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of Invention (13) L-DU Bar is rapidly metabolized to dopamine in the peripheral circulation, causing pulmonary artery constriction and causing cardiovascular side effects. This study examined the effects of compound 2d and dopamine on the resting-state contractile force of male guinea pigs (250-350g) pulmonary artery and vas deferens smooth muscle. Each experiment was repeated at least 3 times, and the average response before and after administration was compared by Student's test, with p < 0.0 5 as the significant difference. Pulmonary arterial contractility increased significantly after continuous perfusion of dopamine (Figure 2A) 'but continuous perfusion of compound 2d (1mg / ml > 1 minute did not contract significantly, (Figure 2B). Vas deferens during continuous perfusion of dopamine (1mg / ml) caused contraction after 1 minute (Figure 3A), but continuous perfusion of compound 2d (1 mg / ml) did not cause contraction (Figure 3B), showing that compound 2d does not have the dopamine-like side effect on smooth muscle contraction. In the present invention Design and synthesize a series of pseudo- and tri-peptide dopamine prodrugs, in which the non-essential amino acid D-phenylglycine or D-p-hydroxyphenylglycine is directly or via an essential amino acid L-dubar is used as an oral delivery tool. These mimic di- or tri-peptide dopamine prodrugs have higher blood concentrations in the rat small intestine perfusion test than clinically used L-duba. Compound 2d in The rabbit study also showed that it has an oral bioavailability of more than 76%, showing good oral absorption. The present invention also shows that injection of methamphetamine into substantia nigra damaged rats can cause large Mouse's self-rotating 8 L-Duba and synthetic L-Duba The peptide derivative can reduce this rotation. However, the effect of the synthetic peptide derivative is higher than that of L-Duba, which shows the possibility of treating Parkinson's disease, and the peptide compound is not similar to dopamine Pulmonary Artery Caused by -15-(. Please read the precautions on the back before filling in this page) f-Assembling and ordering the Taipan board ruler (CNS) A4 size (210X297 mm) 83 3.10,000 Printed by A7 _B7_, Shellfish Consumer Cooperative, Central and Quasi-Ministry Bureau of the Ministry of Economic Affairs 5. Description of the invention (14) and the effect of vas deferens smooth muscle contraction, without increasing blood pressure and causing side effects in the cardiovascular system. Novel invention useful for patients with Parkinson's disease. Experimental materials KCI, NaCI, NaOH, ascorbic acid, sodium taurocholate, carbamate, mannitol, trifluoroacetic acid (TFA), sodium 1-pentanesulfonate and Sodium dodecyl sulfate was purchased from Sigma, Immerk, Aldrich and Wako, all of analytical grade. HP LC grade acetonitrile, tetrahydrofuran (THF) and methanol were purchased from Alpus Chemical Company. Melting point (Buchi 510 capillary melting point Device> Unknown Positive. Infrared spectroscopy was measured with Perkin-Flmer 1760, and nuclear magnetic resonance spectroscopy was recorded with Bruker 80 or 300 MHz NMR> Mass spectrometry and high-resolution mass spectrometry (HRMS) with Finnigan MAT 4510 and JEOL JNS-D300 mass spectrometer, respectively. Performed by Perkin-FImer 140C. Intestinal mucosal suspensions were prepared from male Wistar mice (200-350g) for perfusion investigation. The same mice (150-17 59) were used for rotation and smooth muscle contraction experiments. ^ |-(: (?-HO-Ph) GlyOH = D-p-hydroxyphenylglycine, L-Pro = L-proline, L-Dopa = L-duba; DCC = bicyclohexyl carbonization Diimine, HO Bt = 1-Hydroxybenzotriazole. General Synthesis Method A. Boc protecting group substitution reaction -16 *-. ; A4 size f 210X297 mm) 83 · 3. J0,000 Γ Γ ----------, ¢ ------ IT ------ ^ (Please read the note on the back first Please fill in this page again.) Printed by A7 __B7_ of the Central Standards Bureau of the Ministry of Common Carriage. __B7_ V. Description of the invention (^) 15 Dissolve (Boc) 20, sodium carbonate and amine compounds in the ratio of 1: 2: 1 Molar ratio. Tetrahydrofuran / water solvent system (彳: 1 v / v). After stirring at room temperature for 24 hours, the tetrahydrofuran was distilled off, adjusted to pH 1-2 with potassium hydrogen sulfate, and extracted with ethyl acetate three times. After drying over magnesium sulfate and filtering, the concentrated solid was emptied and recrystallized to obtain the target substance. B. The peptide coupling reaction dissolves the N-terminal protected acid component and the C-terminal protected amine component with HOBt and DCC in dioxane at a molar ratio of 1: 1: 1: 1.1, and stirs at room temperature until After the reaction was completed, the precipitate was first decanted, and the filtrate was concentrated in vacuo and partitioned with ethyl acetate and potassium hydrogen sulfate aqueous solution (5%). The ethyl acetate solution was combined, dried over magnesium sulfate, and filtered. After the filtrate was concentrated in the air, it was chromatographed as necessary to obtain the coupling peptide. C. Boc deprotection Dissolve the Boc-protected amine compound in trifluoroacetic acid and dichloromethane solution (1: 1 v / v), stir at room temperature and evaporate the volatile components, then add n-hexane to make Precipitation yielded the de-Boc product. D. Hydrolysis of Benzyl Ester Dissolve benzyl peptide or N-Cbz protected amine compound in methanol, and hydrolyze with 14.7 psi hydrogen under the catalysis of 20% Pd (OH) 2 / C. After confirming the completion of the reaction, the catalyst was filtered off, and the solvent was distilled off to obtain a benzyl-free product. A. -17- (Please read the note on the back and fill in this page) h • Pack.

Tang Jin, a paper ruler on the 1T line, uses China National Standards (CNS) A4 specifications (210X297 gong) 83.1 10,000 Printed Poly A7, Shellfish Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs _ ^ _ B7__ V. Description of the Invention (^) 1 〇 DN (Boc) -C (Ph) Gly-L-Dopa-OBn This product is obtained from DN (Boc) _C (Ph) Gly-OH and L-dopa-OBn through process B (88% yield): mp 7 1-72 ° C. DH.C (Ph) Gly-bDopa-OH (1a) This product is obtained from DN (Boc) -C (Ph) Gly-L-Dopa-OBn through processes C and D (yield 88 %): mp 76-78 ° C; HRMS (FAB ·) C17H17N2O5 m / z: calculated 値 329.1137 (MH)-; determined 値 329.1 1 34. LN (Boc) -Dopa-DC (Ph) Giy-OBn This product Synthesized from N (Boc) -Dopa and D-phenylglycinyl benzyl ester by process B (65% yield): mp 69-70 ° C. LH-Dopa »DC (Ph) Gly-OH (1c) This compound was synthesized from L -N (Boc) -Dopa-DC (Ph) Gly-OBn through processes C and D (yield 59%). · Mp 216 ° C decomposition; HRMS (FAB ·) C17Hi7N2 0 5 m / z: Calculate 値 32 9.1 1 37 (MH) '; determine 値 329.1 1 34. LN (Boc) -Dopa-L-Pro-OBn This compound was prepared from L-N (Boc) -Dopa and L-flat ester through process B. Synthesis (46% yield): mp91-93 ° C. LH-Dop3-L ~ Pro-0H (1d) -18- { Please read the note on the back of the page before filling in this page} -le Paper Speed Standard China National Standard (CNSi) A4 Specification (2 丨 0X297 mm) 83. 3.10,000 A7 B7 Printed by Consumer Cooperatives 5. Description of the invention (17) This compound was synthesized from L-N (Boc) -Dopa-L-Pro-OBn via processes C and D (yield 31%): mp 63-64 ° C; HRMS ( FAB_) Cl4H17N205 m / z: Calculate 値 2 9 3 · 1 1 3 7 (M-H); determine 値 293.1 1 29. DN (Boc) -C (p-HOPh) Gly-L-Pro-OBn this The compound was synthesized from DN (Boc) -p-hydroxyphenylglycine and benzyl L-proline through process B. It was a white powder (yield 77%); mp 2 04. C; IR (KBr) cm · 1: 3327 (width), 2928, 2851, 1742 (υ C = 〇), 1719 (υ C = 0), 1645 (υ C = Ο), 1627, 1574, 1537, 1518 , 1244, 1224, 1185, 1173; 1Η NMR (80 MHz, DMSO-d6), 51.33 (s, 9Η, t-butyl), 1.50-2.00 (m -Cj) [2-Cy2-CH2-N proline Acid), 5.10 (s, 2H, Ph-Cjy2-), 5.25 (dd, J = 7.27 Hz, 1 Η, α-H proline), 5.55 (d, J = 8 Hz, 1H. Α -H pairs Hydroxyphenylglycine), 6.69 & 7.13 (ABq, J = 8.38 Hz, 4H, HO-C6H4-), 7.33 (s, 5H, Ph-H) ppm.DN (Boc) -C (p-HO -Ph) Gly-L-Pro-OH This compound is prepared from DN (Boc) -C (/ > -HOPh) Gly-L-Pro-OBn through process D, and is a white powder (yield 96.0%). After purification, it was used for the next reaction. DN (Boc) -C (p-HO-Fh) Gly-L-Pro-L-Dopa-OBn This compound ranges from DN (Boc) -C (p-HO-Ph) Gly-L-Pro-OH and L- Prepared by dubapene ester (yield 72%), white powder; mp 110-112 ° C; 1H-NMR (400 MHz, CDCI3}: 5 1.28 (s, 9H, t-butylHs), 1.35- 1.70 (mjH.-Chb- .-IS- (Please read the precautions on the back before filling in this page) Γ. Binding line This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 83. 3.10,000 A7 B7 Printed by the Central Ministry of Economy and the Zhuhai Baygong Consumer Cooperatives 5. Description of the invention (18) CM2-CH2-N proline acid), 2.60-2.66 (m, 1H, catechol-Cy2- ), 2.87-2.89 (m, 1H, -CH2-CH2-CH2-N >, 3.03-3.05 (m, 1 Η, catechol-〇ϋ2-), 3.36 (m, 1H, -CH2-CH2-CH2 -N), 4.41 (d, J = 6.0 Hz, 1H, Pro-aH), 4.69-4.73 (m, 1H, catechol-CH2-CM), 5.03 & 5.09 (ABq, J = 12.2 Hz, 2H , Ph-CH2-). 5.25 (d, J = 7.6 Hz, 1H, HO-Ph-CH), 5.85 (d, J = 7.6 Hz, 1H, N ^ Boc), 6.38 (d, J = 8.0 Hz, 1H, catechol H>, 6.45 (s, 1H, catechol H), 6.61 (d, J = 8.0 Hz, 1H, catechol H), 6_66 (d, J = 8.0 Hz, 2H, HO-Ph) , 7.04 (d, J = 8.0 Hz, 2H, HO-Ph), 7.40 (d, J = 8.3 Hz, Pro-CONH) ppm. DHC (p-HO-Ph) Gly-L-Pro-L-Dopa-OH (2d). This compound is obtained from DN ( Boc) -C〇o-HO-Ph) Gly-L-Pro-L-Dopa-OBn prepared by processes C and D (yield 89%), white powder; mp 62 eC; 1H NMR (400 MHz , D2〇): 5 1.53-1.58 (m, 4H, -Ctj2-Ctl2-CH2-N proline), 2.79-2.85 (m, 2H, catechol-CM2-), 2.99 (dd, J = 5.9 , 14.1 Hz, 1H, catechol-CH2-), 3.38-3.48 (m, 2H, -CH2-CH2-Ctl2-N), 4.29 (dd, J = 3.2, 9.5 Hz, 1H, Pro-aH ), 4.53 (dd, J = 5.9, 8.7 Hz, 1H, catechol-CH2-CH), 5.16 (s, 1H, HO-Ph-Cy), 6.59 (d, J = 8_0 Hz, 1H, catechin Phenol H), 6.67 (s, 1H, catechol H), 6.78 (d, J = 8.0 Hz, 1H, catechol H), 6.83 (d, J = 8.6 Hz, 2H, HO-Ph), 7.20 (d, J = 8.6 Hz, 2H, HO-Ph) ppm ·, HRMS (FAB +) for C22H25N3O7 / 77 / z: Calculation 値 444.1771 [M + H] +, determination 値 444.1775. Drug stability test Small intestinal mucosal suspension The degradation of the compounds in the liquid is according to the method of Hu et al. [P harm. Res. 1 989,6,66-70]., -20- (Please read the precautions on the back before filling in this page) s Standards apply to Chinese national standards CNS) A4 grid (210X297 mm) 83. 3.10,000 EC Industrial and Consumer Cooperation Du Printed A7 _____B7 V. Description of the invention (19) Remove the bowel from the beginning of the jejunum to the end of the ileum from male Wistar rats Segment, flip to reveal the inside "After washing the mucosal layer with normal physiological saline, collect it with a microscope slide, and then dilute it with an ice-cold isotonic sucrose solution. 彳 · 9 (v / v) -suspension is ultrasonically shaken for 200 seconds Centrifuge at 2500 rpm for 5 minutes. The mucosal suspension is ready for stability studies immediately after preparation. A methanol solution 100 # of a test compound (1 m horse / ml) was diluted with 2.4 ml of isotonic mannitol buffer (ρΗ = 6.5) as a stock solution. Mix the 100% # stock solution with an equal volume mucosal suspension, and incubate in a 37 ° C water bath, then take samples at intervals of 0 to 60 minutes. 200 μ | Each sample solution was denatured with methanol (0.8 ml), centrifuged at 14000 rpm for 5 minutes, and each of the supernatants was taken for 20-10 0 ^ 1 for HPLC analysis. Gly-Phe and the compound 2d were chromatographed on a Lichrospher 100 RP-18 column (Merck, 5 / mx3.9mm). The mobile phase of Gly-Phe is 30% acetonitrile and 70% containing 0.05%. Sodium lauryl sulfate 0.1 ^ Λcitrate buffer solution (pH = 3.0) »flow rate 0.8-1.0 ml / min. The mobile phase of compound 2d is a solvent system containing acetonitrile: methanol: ammonium phosphate buffer (0.1M, pH2.0) = 2: 2: 6 containing sodium dodecyl sulfate (0.05% w / v), and the flow rate is 1.0 ml. /Minute. Preparation of perfusion solution for small intestine perfusion test According to the method of Lu et al. (J. Pharm. Sci 1992, 81, 21-25), a perfusion solution was prepared, containing 5mM KCI, 100 mM common salt, 10 yang 1 \ / 11 \ ^ 3, 6! 111 \ / 10-glucose, test compound and 0.02% ascorbic acid were used as antioxidants, and adjusted to pH 6 with NaOH. Use -21-This paper is suitable for the size of the Chinese National Standard (CNS) A4 (210X297 mm) 81 3.10,000 ---------- Γ—Packing ------ · Order- ----- £ line (please read the note on the back before filling this page) A7 B7 Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (20) W escor 5 5 0 0 Osmotic pressure The osmotic pressure was measured by a meter (Wescor, L og η, UT. USA), and the osmotic pressure was adjusted to 300 soil 10 mOsm / kg with table salt. The concentration of L-dubar and the prodrug used in the perfusion solution was 0.1 mM. Each perfusion solution was vented with nitrogen for 10 minutes before the experiment to prevent oxidation of the test compound. Mouse perfusion The mice were dissected according to the method of Lu et al. (J. Pharm Sci 1 992, 8 1, 21-25). Wistar male rats were fasted overnight (16-20 hours), anesthetized by intramuscular injection of urethane (1.5 g / kg body weight), and placed on a heat pad to maintain body temperature. Laparotomy was performed longitudinally from the central line, and the perfusion fluid was collected by inserting a catheter at the distal end of the jejunum 5-1 10 cm. The operating area is covered with paraffin membrane to reduce the body temperature caused by evaporation. Catheters and syringes are covered with aluminum foil to prevent oxidation of the test compound. A syringe pump (Stoelting, KD Scientic, USA) was used to drive the perfusion solution at the beginning of the jejunum at a flow rate of 0.2 ml / min. The jejunum segment was prewashed with drug-free buffer for 10 minutes before perfusion of the test solution. After the perfusion, the pipe samples were collected every 0 minutes to confirm that the water and solute were transported to a stable state. After 90 minutes of perfusion, 2 ml of blood was drawn from the heart vessels and centrifuged at 3000 rpm for 10 minutes. The plasma was collected and stored immediately at -20 ° C. Plasma was filtered directly through a 0.2 # m filter membrane for HPLC analysis. Bioavailable single-dose arterial injection. A single dose of prodrug 13 or 1 ^ _DUBA was passed through the ear artery at 6-22. (Please read the notes on the back before filling out this page)

X-binding-booking Γ The size of the paper wave is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 83. 3.10,000 Printed A7 _ B7 by the Consumers ’Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Fasting New Zealand white rabbits weighing 2.5-3.0 kg were injected. Blood samples were taken from the other ear artery at a heparin-containing syringe interval within 1 minute to 3.5 hours, and then treated with extraction buffer (containing 1 mole of Tris per liter and 20 grams of EDTA, pH 8.6), and then treated with alumina. 100 grams absorption. This alumina was extracted with an acidic buffer and analyzed by HPLC. Single-dose alpha administration The white rabbits used above were given a single-dose prodrug 1a in a feeding tube after a two-week wash-out period. Blood samples were taken from the ear artery in a heparin-containing syringe at a certain interval within 3 minutes to 3.5 hours. Immediately after the treatment, 0.05M table salt and 0.001M Na2EDTA / 0.1M phosphate buffer were used as the mobile phase for ion exchange. Column for H PLC analysis "with electrochemical detector at 0.7 50V oxidation voltage. In this experiment, dihydroxybenzylamine was used as the internal standard. The maximum blood concentration (Cmax) of prodrug 1a, the time to reach the maximum blood concentration (Omax), the area under blood concentration-time (AUC), and the terminal half-life (t1 / 2) were measured. Pharmacokinetic parameters (tmax, Cppax, AUC, ti / 2) fi * measured from oral and arterial administration tests. Calculated as oral absorption percentage. HPLC conditions were used to analyze l-duba and compounds in plasma samples from perfusion experiments. HPLC included an automatic sampler (Model 717, Waters. Millipore, Miford, MA, USA), solvent delivery pump (Model 600E, Waters), Variable Wavelength Detector (Type 484 or 486, -23- (Please read the note ^^ on the back before filling this page)

C-loaded ·

The paper scale of the tT line is applicable to the Chinese national standard (CNS > A4 specification (2〗 0X297 mm) 83. 3. 10,000 Printed by the Shellfish Consumer Cooperative of the Bureau of Standards and Decision of the Ministry of Economic Affairs A7 _______B7____ V. Description of the invention (22) Waters), and PC 486 computer with chromatography management software (Millennium 2010, Millipore}. The analysis conditions of the L-Dubar sample of the perfusate were Spheri 5RP-18 column (ABI, 5; wm, 25 0x4.6mm), The mobile phase is methanol: 0.05M dihydrogen phosphate buffer (pH 4.6, containing 0.02M sodium 1-pentanesulfonate) = 10:90 (v / v) 'flow rate 1/0 towels / min. Drug analysis: ^ 6〇31 丨 100-5C18, column for analysis, flow rate 1.0 ml / min, methanol was used: 0.05M ammonium dihydrogen phosphate buffer solution (containing 0.1% TFA and 0.025% hydrogen Ammonium oxide) = 15: 85 (\ // 乂). Experimental data is calculated by Statworks, η tests are expressed as mean soil standard deviation (sem). Differences are tested by t-test. The effects of pharmacology on the rotation of male rats are all The rats were unilaterally injured by the same investigator by the following methods. 20 male Wistar rats weighing 1 50-1 75 g were used. Rats were injected intraperitoneally. After gibbarbital (30 mg / kg) anesthesia, place it on a stereotactic device, cut the skin on the opening cap and open it. After positioning the origin of the coordinates with Brema, a small hole is drilled with an electric drill, puncture the dura into the brain After substantia nigra, use a micro-syringe and a 26-gauge round needle (AP-4.4mm, ML 1.3mm, DV-7.8mm) to inject 6-hydroxydubamin HC 丨 solution (9 mgMml / 4. Remove the syringe, suture the incision, and wait one month to sacrifice the rat's compound prescription for experiment. During the experiment, the rat moves freely in the original cage and normally feeds water and food. When testing the rotation of the rat, place the rat in the rotation-24 -(Please read the precautions on the reverse side before filling out this page)-Binding- · The size of the paper is applicable to the Chinese national standard (CNS> A4 specification (210X297mm> 83.3.10,000 Λ Λ) Printed by a consumer cooperative A7 ____ Β7 ___ V. Description of the invention (23) In the counter, a subcutaneous injection of methamphetamine (4 # g / g, subcutaneous injection) was used to initiate rotation, and the number of rotations of the rat was measured in one hour. Rats with more than three hundred rotations in an hour were selected as the test • Test When the pharmacologically active drug, and the L- du bus to be tested by subcutaneous injection of a drug - or two hours after subcutaneous administration of methamphetamine, the number of rotations of the rats were observed _ hours, and recorded. Effects on smooth muscles After stunning male guinea pigs (250-350g), quickly remove the pulmonary artery and vas deferens smooth muscles, place them in a thermostat bath (35 ° C) containing physiological solutions, and perfuse them with physiological solutions. The flow rate of the physiological solution perfusion is 2 yang 1 / (11111. And 100% oxygen is passed. The composition of the physiological solution is as follows: (mM) NaCI 117, KCI 5.9, CaCl2 2.4, MgCl2 1.2, d-glucose 11.8, Tris 20 (pH 7.4 at 35 ° C). The contractile force of smooth muscle is converted by a GRASS FT 03 transducer and recorded by a recorder (GRASS Model 7 E poly graph). The smooth muscle is placed in a thermostat bath containing physiological solutions (3 5 ° C), equilibrate at least one hour to start the test. The perfusion time of the drug is 1 minute. The test experiment of each drug is repeated at least 3 times. The Student's test is used to compare the average response before and after drug treatment. Significant differences. The present invention has been described in conjunction with the above specific embodiments, and those skilled in the art will be able to make a variety of changes based on the above description. * The scope of the present invention includes such changes that are defined within the scope of the following patent applications and their spirit "-25 -(Please read the precautions on the reverse side before filling out this page) h-Binding ·-Dimensions The paper size applies to China National Standard (CNS) A4 (210X297 mm) 83. 3.10,000

Claims (1)

m ry Bulletin 丨! :) 8 (Amended in Dec. 87) 6. Scope of Patent Application 1. One of the following formula 2-amino-3- (3,4-dihydroxyphenyl) propionic acid bis- or tris -Peptide derivatives: NH, Η R, C——NCC I. 丨 丨 I 〇Η Η COOH '— η where η is 0 or 1; R is hydrogen or hydroxyl; Ri and r2 make l-C-CI 丨 丨 I 0 H -OH Please read the above note and print it printed by the Shell Standard Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Are the following amino acids: Glycine (Glycine), Alanine (Ala), Valine (Valine, Val), Leucine (. Leu), Isoleucine ( Isoleucine, lie), Serine (Ser), Threonine (Thr), Tyrosine (Tyr), Cysteine (Cysteine, Cys), Methionine (Met ), Asparticacid (Asp), Asparagine (As n), Glutamic acid (Glu), Glutamine (Gin), Aminoguanvaleric acid (Arginine, Arg), Ion Amino acids (Lysine, Lys), Histidine, His, Phenylalaline (-28-) This paper is applicable to China National Standards (CNS) A4 (210X 297 mm) m ry Bulletin丨! :) 8 (Amended in Dec. 87) 6. Scope of patent application 1. A 2-amino-3- (3,4-dihydroxyphenyl) propionic acid of the following formula- Three - peptide derivatives:. NH, Η R, C - N-C-C I I Shushu 〇Η Η COOH '- η where η is 0 or 1; R is hydrogen or hydroxyl; Ri and r2 make l-C-CI 丨 丨 I 0 H -OH Please read the above note and print it printed by the Shell Standard Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Are the following amino acids: Glycine (Glycine), Alanine (Ala), Valine (Valine, Val), Leucine (. Leu), Isoleucine ( Isoleucine, lie), Serine (Ser), Threonine (Thr), Tyrosine (Tyr), Cysteine (Cysteine, Cys), Methionine (Met ), Asparticacid (Asp), Asparagine (As n), Glutamic acid (Glu), Glutamine (Gin), Aminoguanvaleric acid (Arginine, Arg), Ion Amino acids (Lysine, Lys), Histidine, His, Phenylalaline (-28-) This paper is applicable to China National Standard (CNS) A4 (210X 297 mm) Α8 Β8 C8 D8 (revised in December 87) Printed by Phoebe Consumer Cooperative, Central Standards Bureau, Ministry of Economy, Tryptophane , Trp) 'Proline Pro. 2. For example, 2-amino 3- (3,4-dihydroxyphenyl) propionic acid bis or tri-peptide derivative in the first scope of the patent application, where 0 is 1. 3. For example, 2-amino 3- (3,4-dihydroxyphenyl) propionic acid bis or tri-peptide derivative in the scope of the patent application, wherein R1 is hydrogen and R2 is hydroxymethyl (S er ). 4. For example, 2-amino 3- (3,4-dihydroxyphenyl) propionic acid bis or tri-peptide derivatives in the scope of the patent application, wherein R1 and R2 are both trimethyl (P r 〇). 5. For example, the second or third peptide derivative of 2-amino 3- (3,4-dihydroxyphenyl) propionic acid in the scope of patent application, wherein R is a hydroxyl group. 6- As described in item 4 of the patent application, 2-amino3- (3,4-dihydroxyphenyl) propionic acid bis or tri-peptide derivatives, wherein R is a hydroxyl group. 7. The 2-amino 3- (3,4-dihydroxyphenyl) propionic acid bis or tri-peptide derivative according to item 1 of the scope of the patent application, where n is 〇 ^ 29. This paper is applicable to China National Standards (CNS > Α4 ^ Grid (210 × 297 mm) (Please read the note on the back before filling in this page)-Install., | Type 387894 80088 ABCD Patent Application Scope (Amended December 1987) 8. — A medicinal composition for treating Parkinson's disease, comprising a therapeutically effective amount of 2-amino-3- (3,4-dihydroxyphenyl) propionic acid of the following formula as an active ingredient Derivatives or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers or diluents: ^ COOHI IN— C—CH, VIII, OH n OH (please read the note on the back and fill in this page first) Packing —— Printing by the Central Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, where n is 0 or 1; R is hydrogen or hydroxyl; Ri and R2 make OH the following amino acids: Glycine, Gly, Alanine, Ala, Val, Val, Leucine , Leu), Isoleucine (lie), Serine (Ser), Threonine (Threonine, Thr), Tyrosine (Tyr), Cysteine (Cysteine, Cys), Methionine, Met, Asparticacid, Asp, Asparagine, Asn, Glutamic acid, Glu, .Glutamine, Gin, Amine-30- This paper uses Chinese National Standards (CNS) M specifications (2H) X 297 mm. Printed by the Consumers' Cooperative of the Central Bureau of the Ministry of Economic Affairs A8 387896 g8g 6. Scope of Patent Application (Amended in 1987) ) Arginine (Arg), Lysine (Lysine), Histidine (His), Phenylalanine (Ph enylalaline, Phe), tryptophane (Trp), proline (Proline, Pro). 9. The pharmaceutical composition according to item 8 of the patent application, wherein n is 10. The pharmaceutical composition according to item 9 of the patent application, wherein Ri is hydrogen and R2 is methylol (Ser). 11. For example, the pharmaceutical composition under the scope of patent application No. 9 in which Ri and R2 are both trimethyl (Pro). 12. The pharmaceutical composition according to item 8 of the application, wherein R is a hydroxyl group. 13. For example, the pharmaceutical composition under the scope of application for patent No. 11 wherein R is a radical I. 14. If you apply for a pharmaceutical composition under item 8 of the patent, where η is 0 〇_-31-This paper size applies to Chinese National Standards (CNS > 8 4 specifications (210 × 297 mm)) (Please read the note on the back first Please fill in this page again)-Packing · I. Order 387896 A8 B8 C8 D8 VI. Patent Application Park (Amended in December 1987) 15. —A kind of formula 2 -amino- 3- (3,4 -dihydroxy Phenyl) propionic acid two-peptide derivatives: COOH NH, II. Η-C-N ~ C-C —CH2 Price I | ι ·! R4 R3 0 η where R3 is hydrogen and R 4 is phenyl or P-hydroxyphenyl; or R3 and R4 are trimethyl. 16. A pharmaceutical composition for treating Parkinson's disease, comprising a therapeutically effective amount of 2-amino-3- (3,4-dihydroxyphenyl) propionic acid of the following formula as an active ingredient Peptide derivatives or their pharmaceutically acceptable salts, and their pharmaceutically acceptable carriers or diluents: H c—— cno Q .. NR CH 0H (Please read the notes on the back before filling this page) 'Order Printed by the Central Labor Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, where R3 is hydrogen and R4 is phenyl or p-hydroxyphenyl; or 83 and 84 are trimethyl. -1 «. -32- This paper is suitable for China National Standard (CNS) A4 (2! 0X 297mm)