CN1923813A - Aporphine and use of oxidized aporphine alkaloid - Google Patents

Abstract

The present invention discloses the use of aporphyrins and oxidized aporphines alkaloids. Aporphyrins and oxidized aporphines alkaloids are very effective immunosuppressants, which can be used to treat autoimmune diseases, inflammatory reactions, or autoimmune diseases and related diseases by inhibiting the proliferation of T and B lymphocytes. Disease resulting in dysfunction with tissue damage or infection, rejection of a transplant, graft-versus-host disease or allergic disease resulting from bone marrow (hematopoietic stem cell) transplantation.

Description

Uses of Aporphi and Oxidized Aporphil Alkaloids

technical field

The present invention relates to the use of the total alkaloids and alkali salts of the traditional Chinese medicine Zanshanfeng, and more specifically refers to the anti-inflammatory and immunosuppressive uses of aporphyllin and oxidized aporphyllin alkaloids obtained from them.

technical background

Zanshanfeng Fissistigma oldhamii (Hemsl.) Merr. Also known as melon wood, patchouli vine, is the root or cane of the Annonaceae (Annonaceae) plant Hemsl. Distributed in Zhejiang, Jiangxi, Fujian, Taiwan, Hunan, Guangdong, Hainan, Guangxi, Yunnan and other places. It has the effects of expelling wind and dampness, promoting blood circulation and relieving pain. It is mainly used to treat rheumatic arthralgia, low back pain, stomach pain, and bruises [edited by the editorial board of "Chinese Materia Medica". Zhonghua Materia Medica [M]. The second volume, Shanghai: Shanghai Science and Technology Press, 1997, 3.1594-1595]. Zanshanfeng is a folk herbal medicine for treating arthritis. It has been reported in the literature that its _acidic part has anti-arthritic effects; ₃₇ , S ₁₈₀ and other tumor strains all have inhibitory effect [Xu Changrui et al. Chinese Herbal Medicine, 1983, 14: 4-6].

Scholars at home and abroad have conducted many studies on the chemical components of Zanshanfeng, and have isolated 14 alkaloids, 1 furanone, 2 cyclopentenones and 2 organic acids. Zanshanfeng Syrup is a compound preparation of Zanshanfeng Syrup, which has been included in the 10th volume of the Ministry of Health's drug standard "Prescriptions of Traditional Chinese Medicine". Domestic Mao Youchang improved the formulation of the compound Zanshanfeng Syrup , has carried out patent protection for new dosage forms such as pills, granules, and mixtures. The preparation has been protected by patent application [application number: 03118278.X]. The protected total alkaloid extraction process is only a general extraction method for alkaloids, and no in-depth research has been carried out on the monomer components and content of total alkaloids. At the same time, no relevant biological tests have been carried out on total alkaloids to verify the new The extraction part of the single herbal medicine has similar biological effects to the original single herbal medicine or compound recipe.

Contents of the invention

The object of the present invention is to provide the medical application of aporphylloids, oxidized aporphylloid alkaloids, Zanshanfeng total alkaloid salts and Zanshanfeng total alkaloids.

The present inventor screens the proliferative response of model T/B lymphocytes ( Immunomodulation), platelet aggregation test (cardiovascular system, thrombosis), screening of human cyclooxygenase-2 (hCox-2) inhibitors (anti-inflammatory, analgesic) and other biological activity evaluations, the results show that: compound Zanshanfeng Syrup and Zanshanfeng total alkaloids have strong inhibitory effects on T/B lymphocytes, and their activities are equivalent. None of them have antagonism on platelet aggregation (cardiovascular system, thrombosis), and no inhibition of human cyclooxygenase-2 (hCox-2) activity; Systematic separation and purification of total alkaloids, biological activity evaluation, found that aporfi and oxidized alkaloids Pufei alkaloids have strong inhibitory activity, indicating that the anti-inflammatory activity of Zanshanfeng syrup and Zanshanfeng works through immunosuppression, and the material basis of the action is alkaloid components, thereby completing the present invention.

The present invention is implemented through the following steps:

The aporfilinoids and oxidized aporphilline alkaloids provided by the present invention are compounds represented by general formula (1) and (2) or their pharmaceutically acceptable salts or their optical isomers.

Among them, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ are selected from H, OH, O-acyl, OMe, OEt, On Pr ( ⁿ represents positive), O ⁱ Pr (i represents iso), F, Cl, Br, NH ₂ , NO ₂ or CN; R ₈ is selected from H, C ₁ -C ₁₀ alkyl, acyl. For the oxidized aporphylloid alkaloids represented by the general formula (2), when R ₂ , R ₃ , R ₅ , and R ₆ are all OMe, the compound oxoglaucine is excluded.

Compounds represented by general formula (3), (4) or their pharmaceutically acceptable salts or their optical isomers can also be used as active ingredients:

Among them, R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are selected from H, OH, O-acyl, OMe, OEt, ^On Pr (n represents positive), O'Pr (i represents iso), F, Cl, Br, NH ₂ , NO ₂ or CN; R ₆ is selected from H, C ₁ -C ₁₀ alkyl, acyl.

Study on the chemical constituents of total alkaloids from Zhanshanfeng

Zanshanfeng 4 kg, extracted 3 times with 95% ethanol, combined the ethanol extracts, recovered the solvent under reduced pressure to obtain 86g of dry extract, first dissolved and distributed with an appropriate amount of 200mL 2% hydrochloric acid and 100mL chloroform, and then used 100mL chloroform for the acidic aqueous phase Extract again 2 times, then adjust the pH of the aqueous phase to 9-10 with ammonia water, extract 3 times with 100 mL of chloroform, combine the chloroform phases, concentrate under reduced pressure to obtain 32 g of total alkaloid samples. After silica gel (200-300 mesh) column chromatography, CHCl ₃ -CH ₃ OH gradient elution, and MCI column chromatography (CH ₃ OH-H ₂ O gradient elution), Sephadex LH-20 (CH ₃ OH elution De) and ODS column chromatography, obtain compound cinnamon (calycinine), 275mg), cinnamon (N-methyl-2,3,6-trimethoxymorphinandien-7-one, 28mg), calycinine Xylopine, 220mg, crebanine, 12mg, isolaureline, 5mg, asimilobine, 15mg, 3-methoxycitrulline A (3-methoxycalycinine , 13mg), corytuberine (corytuberine, 12mg), 4,5-dioxodehydroxapine (4,5-dioxodehydroxyasimilobine, 33mg), isoboldine (isoboldine, 25mg), oxidized citrulline Oxocalycinine (10mg), sea papaverine (glaucine, 7mg), norcepharadione B (norcepharadione B, 6mg), oxylopine (6mg), 1,2,3 Methoxylated aporphine (1,2,3-trimethoxyoxoaporphine, 25 mg).

Compound citrusine A:

White needle crystal (CHCl ₃ -CH ₃ OH), mp 156°C, orange (+) in the reaction of potassium bismuth iodide reagent; molecular formula: C ₁₈ H ₁₇ NO ₄ ; EI-MS m/z: 311[M] ⁺ , 310[M-1] ⁺ , 294[M-17] ⁺ , 282[M-29] ⁺ , 267, 252, 238, 224, 209, 181, 152, 126, 119, 90; ¹ H NMR (CDCl ₃ )δ: 6.60 (1H, s, H-3), 6.50 (1H, s, H-8), 6.46 (1H, s, H-10), 6.09, 5.95 (2H, d, J=1.2Hz, O -CH ₂ O), 3.81 (3H, s, OCH ₃ -9); ¹³ C NMR (CDCl ₃ ) δ: 160.7 (C-9), 155.1 (C-11), 145.8 (C-2), 138.9 ( C-1), 139.2(C-7a), 129.7(C-1b), 128.3(C-3a), 114.6(C-1a), 111.3(C-11a), 107.8(C-8), 107.6(C -3), 102.5(C-10), 100.1(O-CH ₂ -O), 55.4(OCH ₃ -9), 53.7(C-6a), 43.1(C-5), 39.0(C-7), 29.7 (C-4). The above MS, ¹ H NMR and ¹³ C NMR data and the reported citrusine A [Xu Changrui (Xu CR), Xie Ping (Xie P), Zhu Ying (Zhu Y) et al. Studies on the chemical constituents of citrus wood (1 )[J]. The compound is citrusine A.

Compound guaforenin:

White needle crystal (CHCl ₃ -CH ₃ OH), mp 112-113°C, orange (+) in the reaction of potassium bismuth iodide reagent; molecular formula: C ₂₀ H ₂₃ NO ₄ ; EI-MS m/z: 341[M] ⁺ , 326[M-CH ₃ ] ⁺ , 313[M-CO] ⁺ , 298[M-CH ₃ -CO] ⁺ , 282, 270, 256, 139; ¹ H NMR (CDCl ₃ ) δ: 6.80 (1H , s, H-8), 6.63 (1H, s, H-5), 6.36 (1H, s, H-4), 6.33 (1H, s, H-1), 3.88 (3H, s, OCH ₃ - 2), 3.85 (3H, s, OCH ₃ -3), 3.80 (3H, s, OCH ₃ -6), 3.72 (1H, d, J=6.0Hz, H _β -9), 3.35 (1H, d, J=18.0Hz, H _α -10), 3.06 (1H, dd, J=6.0, 18.0Hz, H _β -10), 2.60 (2H, m, H-16), 2.46 (3H, s, N-CH ₃ ), 1.92 (2H, m, H-15); ¹³ C NMR (CDCl ₃ ) δ: 181.1 (C=O), 161.6 (C-14), 151.6 (C-6), 148.5 (C-3) , 148.2(C-2), 130.0(C-12), 128.7(C-11), 122.6(C-8), 119.0(C-5), 110.5(C-1), 108.7(C-4), 60.9(C-9), 56.4( _OCH3-3 ), 56.1( _OCH3-2 ), 55.3(C-6), 45.7(C-16), 42.4(C-13), 41.7(N- _CH3 ), 41.0 (C-15), 32.8 (C-10). The above MS, ¹ H NMR and ¹³ C NMR data are consistent with the data of citrusin [Wu JB, Cheng YD, Chiu NY, et al.Planta Med, 1993, 59(1): 179-180.] reported in the literature , and identified the compound as citrusin.

The compound kanoline:

White needle crystal (CHCl ₃ ), orange (+) in reaction with bismuth potassium iodide reagent; molecular formula: C ₁₈ H ₁₇ NO ₃ ; EI-MS m/z: 295[M] ⁺ , 294[M-1] ⁺ , 280[M-17] ⁺ , 282[M-29] ⁺ , 265, 251, 236, 221, 208; ¹ H NMR (CDCl ₃ ) δ: 8.02 (1H, d, J=8.7Hz, H-11) , 6.87 (1H, dd, J=2.4, 8.7Hz, H-10), 6.79 (1H, d, J=2.4Hz, H-8), 6.53 (1H, s, H-3), 6.06, 5.93 ( 2H, d, J=1.2Hz, O-CH ₂ -O), 3.84 (3H, s, OCH ₃ -9); ¹³ C NMR (CDCl ₃ ) δ: 159.0 (C-9), 146.8 (C-2 ), 137.3(C-1), 139.2(C-7a), 129.7(C-1b), 128.3(C-3a), 114.6(C-1a), 111.3(C-11a), 107.8(C-8) , 107.6(C-3), 102.5(C-10), 100.7(O-CH ₂ -O), 55.5(OCH ₃ -9), 53.7(C-6a), 43.7(C-5), 37.8(C -7), 29.7 (C-4). The above MS, ¹ H NMR and ¹³ C NMR data are consistent with the biscuitine reported in the literature [Xu Changrui (Xu CR), Xie Ping (Xie P), Zhu Ying (Zhu Y), etc. Chinese herbal medicine (Chin Tradit HerbDrugs), 1983, 14(4): 4-6; Roblot F, Hocquemiller R and Cave AJ Nat Prod, 1983, 46(6): 862-873.] The data were consistent, and the compound was identified as linanthine.

Compound Colibanine:

The reaction of potassium bismuth iodide reagent is orange (+); mp 115-117℃, molecular formula: C ₂₀ H ₂₁ NO ₄ ; ESI-MS m/z: 340[M+H] ⁺ ; ¹ H NMR(CDCl ₃ )δ : 8.02(1H, d, J=8.7Hz, H-11), 6.88(1H, d, J=8.7Hz, H-10), 6.53(1H, s, H-3), 6.06, 5.92(2H, d, J=1.2Hz, O-CH ₂ -O), 3.91 (3H, s, OCH ₃ -9), 3.82 (3H, s, OCH ₃ -8), 2.59 (3H, s, N-CH ₃ ) . The above ¹ H NMR data are consistent with the colibanine data reported in the literature [Guinaudeau H, Leboeuf M and Cave AJ Nat Prod, 1983, 46(6):761-835.], and the compound was identified as colibanine.

Compound isomeric laurine:

The reaction of potassium bismuth iodide reagent is orange (+); mp 108-110℃, molecular formula: C ₁₉ H ₁₉ NO ₃ ; ESI-MS m/z: 310[M+H] ⁺ ; ¹ H NMR(CDCl ₃ )δ : 8.01 (1H, d, J=8.7Hz, H-11), 6.87 (1H, dd, J=1.8, 8.7Hz, H-10), 6.83 (1H, d, J=1.8Hz, H-8) , 6.52 (1H, s, H-3), 6.07, 5.94 (2H, d, J=1.5Hz, O-CH ₂ -O), 3.85 (3H.s, OCH ₃ -9), 2.57 (3H, s , N—CH ₃ ). The above ¹ H NMR data are consistent with the isomeric laurine [Guinaudeau H, Leboeuf M and Cave AJ Nat Prod, 1983, 46(6): 761-835.] data reported in the literature, and the compound is identified as isomeric lauryl.

Compound papoline:

The reaction of potassium bismuth iodide reagent is orange (+); mp 177-179℃, molecular formula: C ₁₇ H ₁₇ NO ₂ ; EI-MS m/z: 267[M] ⁺ , 266[MH] ⁺ , 252[M- 15] ⁺ , 236[M-31] ⁺ , 224[M-43] ⁺ , 206; ¹ H NMR (CDCl ₃ ) δ: 8.28 (1H, d, J=7.5Hz, H-11), 7.24～7.30 (3H, m, H-10, 9, 8), 6.69 (1H, s, H-3), 3.59 (3H, s, _OCH3-1 ), 2.57 (3H, s, N- _CH3 ). The above ¹ H NMR data are consistent with the data reported in the literature for papoline [Guinaudeau H, Leboeuf M and Cave AJ NatProd, 1983, 46(6): 761-835.], and the compound was identified as papapoline.

Compound 3-methoxycitrulline A:

White needle crystal (CHCl ₃ -CH ₃ OH), mp 165°C, orange (+) in reaction with potassium bismuth iodide reagent; molecular formula: C ₁₉ H ₁₉ NO ₅ ; EI-MS m/z: 341[M] ⁺ , 310[M-1] ⁺ , 326[M-15] ⁺ , 310[M-31] ⁺ , 296, 282, 267; ¹ H NMR (CDCl ₃ ) δ: 6.49 (1H, d, J=2.4Hz, H-10), 6.44 (1H, d, J=2.4Hz, H-8), 6.07, 5.93 (2H, d, J=1.5Hz, O-CH ₂ -O), 4.03 (3H, s, OCH ₃ -3), 3.80 (3H, s, OCH ₃ -9); ¹³ C NMR (CDCl ₃ ) δ: 160.3 (C-9), 154.5 (C-11), 140.5 (C-3), 140.2 (C- 1), 138.8(C-7a), 134.1(C-2), 130.8(C-1b), 120.8(C-3a), 111.4(C-11a), 108.7(C-1a), 107.8(C-8 ), 103.5 (C-10), 100.1 (O-CH ₂ -O), 59.7 (OCH ₃ -3), 55.5 (OCH ₃ -9), 53.9 (C-6a), 42.9 (C-5), 39.0 (C-7), 24.4 (C-4). The above MS, ¹ H NMR and ¹³ C NMR data are consistent with the 3-methoxycitrulline A reported in the literature [Guinaudeau H, Leboeuf M and Cave AJ Nat Prod, 1983, 46 (6): 761-835; Roblot F , Hocquemiller R and Cave AJ Nat Prod, 1983, 46 (6): 862-873.] The data are consistent, and the compound is identified as 3-methoxycitrulline A.

Compound Corydalis tuberine:

White needle crystal (CH ₃ OH), mp 240°C, orange (+) in the reaction of potassium bismuth iodide reagent; molecular formula: C ₁₈ H ₂₁ NO ₄ ; EI-MSm/z: 327[M] ⁺ , 326[M- 1] ⁺ , 312[M-15] ⁺ , 310[M-31] ⁺ , 284[M-43] ⁺ , 266; ¹ H NMR (DMSO-d ₆ ) δ: 6.78 (1H, d, J=8.1 Hz, H-9), 6.62 (1H, d, J=8.1Hz, H-8), 6.13 (1H, s, H-3), 3.72 (6H, s, OCH _{3 -2,} 10), 2.63 ( 3H, s, N-CH ₃ ); ¹³ C NMR (DMSO-d ₆ ) δ: 149.1 (C-2, 10), 146.3 (C-1), 144.6 (C-11), 128.2 (C-1b) , 125.2(C-3a), 122.0(C-7a), 121.1(C-11a), 119.9(C-1a), 116.6(C-8), 110.3(C-9), 110.0(C-3), 62.5 (C-6a), 55.8 (OCH ₃ -10), 55.5 (OCH ₃ -2), 42.0 (N-CH ₃ ), 34.0 (C-7), 26.9 (C-4). The above MS and ¹ H NMR data are consistent with the data of Corydalis tuber alkaloid [Guinaudeau H, Leboeuf M and CaveA.J Nat Prod, 1975, 38(4): 275-338.] reported in the literature, and the compound is identified as Corydalis tuber alkali.

Compound 4,5-dioxodehydrobaporine:

Red powder, mp 278-280°C, red (+) in the reaction of potassium bismuth iodide reagent; insoluble in methanol, chloroform, water and other solvents; yellow-green fluorescence in acetone and ethanol. UV(CH ₃ OH)λ _max (logε)243(4.03), 287(4.62), 302(4.58), 315(4.56), 383(4.77), 444(4.63)nm; IRυ _max (KBr)cm ^-1 : 3540, 3476, 3183, 1671, 1615, 1398, 1297; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ4.05 (3H, s, OCH ₃ -1), 7.48 (1H, s, H-7) , 7.64, 7.65 (2H, m, H-9, 10), 7.91 (1H, m, H-8), 8.09 (1H, s, H-3), 9.44 (1H, m, H-11), 10.72 (1H, s, OH-2), 12.01 (1H, s, NH); ¹³ C NMR (DMSO-d ₆ , 100MHz) δ59.6 (CH ₃ , CH ₃ O-1), 111.9 (CH, C- 7), 117.0 (CH, C-1), 117.2 (C, C-1b), 124.0 (C, C-1a), 124.7 (C, C-3a), 126.0 (C, C-11a), 126.6 ( CH, C-10), 127.1 (CH, C-11), 127.8 (CH, C-9), 128.3 (CH, C-8), 130.3 (C, C-6a), 132.4 (C, C-8a ), 151.0 (C, C-2), 152.8 (C, C-1), 155.6 (C, C-5), 177.0 (C, CO); ESI-MS m/z 294[M+H] ⁺ , 292 [MH] ⁺ ; HRESI-MS m/z 294.0761 (calc for C ₁₈ H ₁₁ NO ₅ 294.0766). The above data are consistent with the data of 4,5-dioxodehydrobaporine [Hans A, Dieter F, Reiner WJ Nat Prod, 1991, 54 (5): 1331-1336.] reported in the literature, and the compound is identified as 4 , 5-dioxodehydrobaporine.

Compound isopoldine base:

White needle crystal (CHCl ₃ ), mp 178-180°C, orange (+) in the reaction of potassium bismuth iodide reagent; molecular formula: C ₁₉ H ₂₁ NO ₄ ; EI-MS m/z: 327[M] ⁺ , 326[ M-1] ⁺ , 312[M-15] ⁺ , 295, 284[M-43] ⁺ , 269, 253; ¹ H NMR (CDCl ₃ ) δ: 8.02 (1H, s, H-11), 6.78 ( 1H, s, H-8), 6.53 (1H, s, H-3), 3.91, 3.90 (6H, s, OCH _{3 -2} , 10), 2.54 (3H, s, N-CH ₃ ); above MS , ¹ H NMR data are consistent with the data of isopoldine [Anis E, Ais I, Ahmed S, et al.Chem Pharm Bull, 2002, 50 (1): 112-114.] reported in the literature, and the compound is identified as Isoboldine.

Compound oxidized citrusine A:

Red powder, mp 276-278℃, orange (+) in the reaction of potassium bismuth iodide reagent; combined with ¹ H NMR, ¹³ C NMR and HREI-MS (m/z 321.0623[M] ⁺ ), its molecular formula is deduced as C ₁₈ H ₁₁ NO ₅ ; its ¹ H NMR δ _H 8.73 (1H, d, J=5.1Hz, H-5), δ _H 7.95 (1H, d, J=5.1Hz, H-4), δ _H 7.41 (1H, s, H-3), δ _H 7.34 (1H, d, J=2.7Hz, H-8), δ _H 6.85 (1H, d, J=2.7Hz, H-10), δ _H 6.34 (2H, s , O-CH ₂ -O-1, 2), δ _H 4.02 (3H, s, OCH ₃ ) and oxoisocalycinine [Hocquemiller R, Debitus C, Roblot F, et al.J Nat Prod, 1984, 47 (1): 353-362.] are similar; its ¹ H- ¹ H COZY shows that the proton of δ _H 8.73 is remotely correlated with the proton of δ _H 7.95, and the proton of δ _H 7.34 is long-range correlated with the proton of δ _H 6.85; its NOESY spectrum shows that the proton of δ _H 8.73 The proton of δ _H 7.95 has NOE effect with aromatic proton, δ _H 7.95 proton has NOE effect with δ _H 7.41 proton, OCH ₃ of δ _H 4.02 has NOE effect with δ _H 7.34 and δ _H 6.85 aromatic proton, so as to determine the OCH ₃ substitution The position should be at 9 digits. According to the above data, compound G-15 was identified as oxocalycinine. The compound is a new compound named oxocalycinine through literature search.

Physicochemical and spectral data of oxidized citrusine A: red powder, mp 276-278℃, orange (+) in the reaction of potassium bismuth iodide reagent; UVλ(nm): 384.0, 277.2, 245.0, 208.8, 357.8; ¹ H NMR (300MHz, DMSO-d ₆ ) δ: 4.02 (3H, s, OCH ₃ ), 6.34 (2H, s, O-CH ₂ -O-1, 2), 6.85 (1H, d, J=2.7Hz, H-10), 7.34 (1H, d, J=2.7Hz, H-8), 7.41 (1H, s, H-3), 7.95 (1H, d, J=5.1Hz, H-4), 8.73 ( 1H, d, J=5.1 Hz, H-5); ¹³ C NMR (75.0 MHz, DMSO-d ₆ ) δ: 55.5 (CH ₃ , CH ₃ O-9), 101.5 (CH, C-10), 102.1 (CH ₂ , O-CH ₂ -O), 102.7 (CH, C-8), 107.9 (CH, C-3), 113.6 (C, C-8a), 122.4 (C, C-1a), 124.0 ( CH, C-4, 1b), 134.2 (C, C-11a), 135.4 (C, C-3a), 144.0 (C, C-1), 144.1 (CH, C-5), 146.5 (C, C -2), 152.2 (C, C-11), 156.8 (C, C-6a), 160.3 (C, C-9), 181.3 (C, CO); EI-MS m/z: 321[M] ⁺ (100), 320(55), 295(38), 292(20), 293(13), 277(11), 266(10), 265(51), 252(10), 250(42), 234 (13), 222(23), 166(15), 164(27), 139(10), 84(52), 66(56); HREI-MS m/z: 321.0623 (calc for C ₁₈ H ₁₁ NO ₅ 321.0637).

Compound sea papaverine:

The reaction of potassium bismuth iodide reagent is orange (+); mp 226-227℃, molecular formula: C ₂₁ H ₂₅ NO ₄ ; EI-MS m/z: 355[M] ⁺ , 354[M-1] ⁺ , 340[ M-15] ⁺ , 324[M-31] ⁺ , 308, 297, 281, 265, 250, 162, 140; ¹ H NMR (CDCl ₃ ) δ: 8.10 (1H, s, H-11), 6.79 ( 1H, s, H-8), 6.59 (1H, s, H-3), 3.93 (3H, s, OCH ₃ -9), 3.91 (3H, s, OCH ₃ -10), 3.89 (3H, s, OCH ₃ -2), 3.66 (3H, s, OCH ₃ -1), 2.56 (3H, s, N-CH ₃ ); above MS, ¹ H NMR data and the sea papaverine reported in literature [Guinaudeau H, Leboeuf M and Cave AJ Nat Prod, 1975, 38 (4): 275-338.] The data are consistent, and the compound is identified as sea papaverine.

The compound norcetidone B:

Yellow powder, mp 274-276°C, red (+) in the reaction of potassium bismuth iodide reagent; insoluble in methanol, chloroform, water and other solvents; yellow-green fluorescence in methanol. UV(CH ₃ OH)λ _max (logε): 213(4.35), 235(4.32), 240(4.32), 301(4.23), 313(4.69), 441(4.75)nm; IR υ _max (KBr)cm ^-1 : 3475, 3458, 2947, 1711, 1584, 1391, 1291, 1128, 738; ¹ H NMR (DMSO-d ₆ , 400MHz) δ4.03 (3H, s, OCH ₃ -2), 4.07 (3H, s, OCH ₃ -1), 7.46 (1H, s, H-7), 7.64, 7.65 (2H, m, H-9, 10), 7.89 (1H, m, H-8), 8.09 (1H, s , H-3), 9.37 (1H, m, H-11), 12.02 (1H, s, OH-5); ¹³ C NMR (DMSO-d ₆ , 100MHz) δ: 56.5 (CH ₃ , CH ₃ O- 2), 60.1 (CH ₃ , CH ₃ O-1), 112.6 (CH, C-3), 112.7 (CH, C-7), 118.2 (C, C-1b), 123.6 (C, C-1a) , 124.6 (C, C-3a), 125.9 (C, C-11a), 126.9 (CH, C-10), 127.2 (CH, C-11), 128.0 (CH, C-9), 128.4 (CH, C-8), 130.1 (C, C-6a), 132.4 (C, C-8a), 152.7 (C, C-2), 153.9 (C, C-1), 155.5 (C, C-5), 176.8(C, CO); EI-MSm/z[M] ⁺ 307(100), 279(71), 264(34), 263(24), 236(50), 221(41), 209(41) , 193(56), 181(48), 164(66), 150(33), 125(21), 111(19), 97(29), 83(54), 69(29), 43(21) _; HREI-MS m/z 307.0848 (calc. for _{C18H11NO5 307.0845} ). The above data are consistent with the data reported in the literature of the genus genus vinedione B [Hans A, Dieter F, Reiner WJ Nat Prod, 1991, 54(5): 1331-1336.], and the compound is identified as the genus Stephanedione B.

Compound oxidized cinnamonine:

Red powder, mp 319-321℃, the reaction of potassium bismuth iodide reagent is red (+); molecular formula: C ₁₈ H ₁₁ NO ₄ ; EI-MS m/z: 305[M] ⁺ , 290[M-15] ⁺ , 275, 247, 234, 217, 204, 176, 149, 117; ¹ HNMR (CDCl ₃ ) δ: 8.87 (1H, d, J=5.1Hz, H-5), 8.48 (1H, d, J=9.0 Hz, H-11), 7.99 (1H, d, J=2.7Hz, H-8), 7.73 (1H, d, J=5.1Hz, H-4), 7.26 (1H, dd, J=9.0, 2.7 Hz, H-10), 7.09 (1H, s, H-3), 6.33 (2H, s, O-CH ₂ -O), 3.99 (3H, s, OCH ₃ -9); above MS, ¹ H NMR The data are consistent with the data reported in the literature for oxidized cinnamon [Roblot F, HocquemillerR and Cave AJ Nat Prod, 1983, 46(6): 862-873.], and the compound was identified as oxidized cinnamon.

Compound 1,2,3-methoxy-oxidized aporfi:

Orange powder, mp 188℃, the reaction of bismuth potassium iodide reagent is red (+); molecular formula: C ₁₉ H ₁₅ NO ₄ ; EI-MS m/z: 321[M] ⁺ , 306[M-15] ⁺ , 291 , 278, 263, 248, 235, 220, 192, 164; ¹ H NMR (CDCl ₃ ) δ: 9.04 (1H, d, J=8.4Hz, H-11), 8.90 (1H, d, J=5.7Hz , H-5), 8.15 (1H, d, J=5.7Hz, H-4), 8.50 (1H, dd, J=8.1, 1.5Hz, H-8), 7.68 (1H, m, H-10) , 7.47 (1H, m, H-9), 4.17 (3H, s, OCH ₃ ), 4.09 (3H, s, OCH ₃ ), 4.05 (3H, s, OCH ₃ ); the above ¹ H NMR data and literature reports The data of 1,2,3-methoxy-oxidized aporfi[Bohlmann F, Zdero C, Ziesche J.Phytochemistry, 1979,18(8):1375.] are consistent, and the compound is identified as 1,2,3-methoxy Oxygen oxidation of aporfi.

Biological Activity Test:

1. Study on the mechanism of action of Zanshanfeng Syrup and Zanshanfeng in treating rheumatoid arthritis

Zanshanfeng syrup screening sample preparation: commercially available Zanshanfeng syrup is passed through macroporous adsorption resin (D101 type), washed with distilled water, discarded, then washed with 95% ethanol, concentrated under reduced pressure to send to in vitro organisms. Scientific evaluation sample 1.

Zanshanfeng 95% ethanol extraction sample preparation: Zanshanfeng medicinal materials were heated and boiled with 95% ethanol for 3 times, each time for 3 hours, the extracts were combined, concentrated under reduced pressure to obtain sample 2 for in vitro biological evaluation.

Zanshanfeng total alkaloid sample preparation: Zanshanfeng 95% ethanol extraction sample was first dissolved and distributed with an appropriate amount of 2% hydrochloric acid and chloroform, and the acidic aqueous phase was extracted twice with chloroform, and then the pH of the aqueous phase was adjusted to 9- 10. Extract three times with chloroform, combine the chloroform phases, concentrate under reduced pressure to obtain Sample 3 for in vitro biological evaluation.

Preparation of Zanshanfeng total alkali salt: Zanshanfeng medicinal material is heated and boiled with 2% sulfuric acid to extract 3 times, each time for 3 hours, combined extracts, applied to macroporous resin, washed with water, discarded, and then 95% ethanol After washing and concentrating under reduced pressure, sample 4 was sent for in vitro biological evaluation.

We chose in vitro biological evaluation models related to rheumatoid arthritis --- T/B lymphocyte proliferation response (immune regulation), platelet aggregation test (cardiovascular system, thrombosis), human cyclooxygenase-2 (hCox-2) inhibitor screening (anti-inflammatory, analgesic) Systematic evaluation of the above samples, found that the above four have strong inhibitory effect on T/B lymphocytes, and platelet aggregation test (cardiovascular system, Thrombosis), human cyclooxygenase-2 (hCox-2) inhibition (anti-inflammatory, analgesic), etc. did not show activity.

Table 1. The compound preparation and the activity of different extraction parts of Zanshanfeng to inhibit the proliferation of T and B cells sample IC ₅₀ (ug/mL) inhibits T cell proliferation IC ₅₀ (ug/mL) inhibits B cell proliferation 1 7.26±0.28 6.03±0.23 2 15.42±0.33 15.48±0.29 3 3.24±0.18 3.24±0.16 4 1.42±0.12 1.10±0.08 Cyclosporine A 1.34±0.3nM 184±29nM

From the data in Table 1, it can be shown that the total alkaloids of Zanshanfeng can represent the active ingredient of Zanshanfeng syrup that inhibits the proliferation of T and B cells. Through several in vitro biological evaluation models related to rheumatoid arthritis, the clinical treatment of rheumatoid arthritis with Zanshanfeng Syrup works through the mechanism of immunosuppression.

3. Zanshanfeng immune biological activity screening experiment

Model name: Proliferative response and cytotoxicity experiments of T and B lymphocytes

Screening method: BALB/C mouse spleen lymphocytes can undergo a series of changes in morphology and metabolism under the stimulation of mitogen ConA and LPS, transform into mother cells, and differentiate and proliferate. In this experiment, ConA (ConA) 5ug/ml was added to induce the proliferation of T lymphocytes. Add LPS (lipopolysaccharide) 10ug/ml to induce B lymphocyte proliferation. Cell proliferation was quantified by 3H-TdR incorporation method. Mitochondrial dehydrogenase in living cells can reduce the yellow color of MTT to blue formazan, and the production of formazan is directly proportional to living cells. After dissolving in an organic solvent, the OD value can be detected with a microplate reader.

Test system: in vitro

Table 2. The activity of inhibiting T and B cell proliferation of monomers isolated from Zhanshanfeng 95% ethanol extract sample IC ₅₀ (uM) inhibits T cell proliferation IC ₅₀ (uM) inhibits B cell proliferation calycinine 4.86±0.03 2.93±0.02 N-methyl-2,3,6-trimethoxy-Morphinandien-7-one >30 >30 xylopine 5.69±0.04 8.10±0.05 crebanine >30 >30 isolaureline >30 >30 asimilobine >30 >30 3-methoxycalycinine 6.86±0.27 5.54±0.31 corytuberine >30 >30 4,5-dioxodehydroxyasimilobine >30 >30 isoboldine 24.00±2.37 29.67±3.15 oxocalycinine 0.81±0.06 0.56±0.04 glaucine >30 >30 norcepharadione B >30 >30 oxylopine 4.33±0.43 7.54±0.61 1,2,3-trimethoxyoxoaporphine >30 >30 CsA 1.34±0.3nM 184±29nM

From Table 2, the active ingredients that inhibit the proliferation of T and B cells are mainly aporphi and oxidized aporphi alkaloids. It is reported that certain aporphi and oxidized aporphi alkaloids are used as dopamine agonists for the treatment of Parkinson's syndrome, migraine, sexual dysfunction, etc. (US2005143408); Alkaloids can prevent and treat local ischemic diseases by preserving or increasing endothelial nitric oxide synthase (CN1566100); ), duodenal ulcer (GB2105323) and so on. Bulgarian scientist Stefan Philipov et al. have reported that oxidized aporfi oxoglaucine has immune regulation function (Pharmacological Research, 1997, 35(4): 267-272; 2000, 41(1): 101-107; Diagnostic Microbiology and Infection Disease, 2000, 38 :17-20). With the exception of oxoglaucine, aporphi and oxidized aporphi alkaloids have not been reported to have immunosuppressive activity. Oxocalycinine is a novel compound discovered by the present inventors to have strong immunosuppressive activity.

Aporphi and oxidized aporphi alkaloids of the general formula (1), (2), (3) and (4) as active ingredients of the present invention are derived from plants, for example, Fissistigma oldhamii (Hemsl.) Merr. It is the root or cane of the plant Annonaceae (Annonaceae) Annonaceae. It has the effects of expelling wind and dampness, promoting blood circulation and relieving pain. It is mainly used to treat rheumatic arthralgia, lumbago, stomach pain, and bruises [edited by the editorial board of "Chinese Materia Medica". Zhonghua Materia Medica [M].

The immunosuppressant of the present invention is not limited to agents containing aporphil in purified form and oxidized aporphil alkaloids as active ingredients. It may be a medicament containing total alkaloids, total alkaloid salt extracts of plants such as Zanshanfeng as active ingredients including aporphim and oxidized aporphyl alkaloids. The root or cane extract can be in lyophilized powder form or liquid form.

Description of drawings

Fig. 1 is the proton nuclear magnetic resonance spectrum of compound Oxocalycinine.

Fig. 2 is the carbon nuclear magnetic resonance spectrum of the compound Oxocalycinine.

Detailed ways

Example 1:

1000 grams of Zhanshanfeng cane or root (collected from Jiangxi), heat extraction 3 times with 2% sulfuric acid aqueous solution (3800 milliliters for the first time, 3000 milliliters for the second time, 3000 milliliters for the third time), 3 hours each time, filter Then apply D101 macroporous resin, wash with water first, then wash with 20%, discard, elute with 50% ethanol aqueous solution, and concentrate under reduced pressure to obtain 6.4 grams of total alkali sulfate sample. The content of total alkaloid sulfate (calycinine sulfate as reference substance, weight ratio) measured by ultraviolet spectrophotometry is 53.4%. The contents of calycinine sulfate and xylopine sulfate measured by HPLC were 6.4% and 4.8%, respectively.

Example 2:

1000 grams of Zhanshanfeng cane or root (collected from Jiangxi), heat extraction 3 times with 2% sulfuric acid aqueous solution (3800 milliliters for the first time, 3000 milliliters for the second time, 3000 milliliters for the third time), 3 hours each time, filter Finally, adjust the pH to 8-9 with ammonia water, then adjust to 30% ethanol solution with ethanol, apply D101 macroporous resin, elute with 30% and 90% ethanol aqueous solution, and concentrate 90% of the eluted fraction under reduced pressure to obtain Total alkali sample 4.9 grams. The total alkaloid content (with calycinine as reference substance, weight ratio) measured by ultraviolet spectrophotometry is 59.8%. The contents of calycinine and xylopine measured by HPLC were 5.7% and 5.3%, respectively.

Example 3:

1000 grams of Zhanshanfeng cane or root (collected from Jiangxi), heat extraction 3 times with 80% ethanol aqueous solution (3800 milliliters for the first time, 3000 milliliters for the second time, 3000 milliliters for the third time), 3 hours each time, filter After concentrating to the extractum, the extractum was kneaded and dissolved with 200 ml of 2% sulfuric acid, filtered and cleared onto D101 macroporous resin, washed with water first, then eluted with 20%, 50% ethanol aqueous solution, and washed with 50% ethanol aqueous solution. The dedistillation fraction was concentrated under reduced pressure to obtain 6.0 g of total alkali salt sample. The content of total alkaloid sulfate (calycinine sulfate as reference substance, weight ratio) measured by ultraviolet spectrophotometry is 51.8%. The contents of calycinine sulfate and xylopine sulfate measured by HPLC were 6.0% and 5.1%, respectively.

Example 4:

1000 grams of Zhanshanfeng cane or root (collected from Jiangxi), heat extraction 3 times with 80% ethanol aqueous solution (3800 milliliters for the first time, 3000 milliliters for the second time, 3000 milliliters for the third time), 3 hours each time, filter After concentrating to the extractum, the extractum was kneaded with 200 ml of 2% sulfuric acid to dissolve, and after filtering, the clear liquid was adjusted to pH 8-9 with ammonia water, and then adjusted to 30% ethanol solution with ethanol, and then applied with D101 macroporous resin, Elute with 30% and 90% ethanol aqueous solution, and concentrate the fraction eluted with 90% ethanol under reduced pressure to obtain 4.7 g of total alkali salt samples. The content of total alkaloid sulfate (calycinine sulfate as reference substance, weight ratio) measured by ultraviolet spectrophotometry is 59.9%. The contents of calycinine and xylopine measured by HPLC were 5.7% and 5.2%, respectively.

Example 5:

1000 grams of Zhanshanfeng cane or root (collected from Jiangxi), heat-extracted 3 times with 2% phosphoric acid aqueous solution (3800 milliliters for the first time, 3000 milliliters for the second time, 3000 milliliters for the third time), filtered and adjusted the filtrate with ammonia water After pH to 8-9, then adjusted to 30% ethanol solution with ethanol, applied to D101 macroporous resin, eluted with 30% and 90% ethanol aqueous solution, and the eluted fraction of 90% ethanol aqueous solution was concentrated under reduced pressure to obtain the total 4.5 grams of alkali sample. The total alkaloid content (with calycinine as reference substance, weight ratio) measured by ultraviolet spectrophotometry is 58.6%. The contents of calycinine and xylopine measured by HPLC were 5.7% and 5.4%, respectively.

Embodiment 6:

1000 grams of Zhanshanfeng cane or root (collected from Jiangxi), percolated and extracted 3 times with 2% hydrochloric acid aqueous solution, each time for 3 days, the 3 times of leachate were combined, after filtration, the filtrate was adjusted to pH 8-9 with ammonia water, Then adjust to 30% ethanol solution with ethanol, apply D101 macroporous resin, elute with 30% and 90% ethanol aqueous solution, and concentrate under reduced pressure to obtain 4.8 grams of total alkali samples. The total alkaloid content (weight ratio) measured by ultraviolet method is 53.6%. The contents of calycinine and xylopine measured by HPLC were 5.9% and 4.7%, respectively.

Embodiment 7:

Preparation method of calycinine and xylopine: 20 grams of Zanshanfeng total alkali (prepared by the method in Example 2) extracted with 2% sulfuric acid aqueous solution, through silica gel (200-300 mesh) column chromatography, CHCl ₃ -CH ₃ OH gradient elution , collect CHCl ₃ -CH ₃ OH (15:1 ~ 10:1) fraction, and then MCI column chromatography, CH ₃ OH-H ₂ O gradient elution, CH ₃ OH-H ₂ O (60:40) wash The part was removed, then subjected to Sephadex LH-20 column chromatography, eluted with CH ₃ OH, combined, placed in CHCl ₃ -CH ₃ OH, placed, white needle crystals were precipitated, filtered, washed with CH ₃ OH, placed in a desiccator, 852mg of calycinine was obtained; MCI column CH ₃ OH-H ₂ O (65:35) eluted part, then Sephadex LH-20 column chromatography, CH ₃ OH eluted, combined, placed in CHCl ₃ -CH ₃ OH , placed, white needle crystals were precipitated, filtered, washed with CH ₃ OH, and placed in a desiccator to obtain 767mg xylopine.

The preparation method of calycinine sulfate: dissolve calycinine with methanol, add sulfuric acid dropwise to make the pH value reach 2, let it stand for 30 minutes, TLC detects a point, concentrate to a small volume, and go through Sephadex LH-20 column chromatography, CH ₃ OH- H ₂ O was eluted, and fractions with dark spots under ultraviolet light (254 nm) were collected, combined, and the solvent was recovered to obtain the obtained product.

The preparation method of xylopine sulfate: dissolve xylopine with methanol, add sulfuric acid dropwise to make the pH value reach 2, let it stand for 30min, TLC detects a point, concentrate to a small volume, go through Sephadex LH-20 column chromatography, CH ₃ OH- H ₂ O was eluted, and fractions with dark spots under ultraviolet light (254 nm) were collected, combined, and the solvent was recovered to obtain the obtained product.

Embodiment 8 The method for preparing oxocalycinine

i) Calycinine (G-1, 100 mg, 0.32 mmole), absolute alcohol (30 mL) and anhydrous potassium hydroxide (0.8 g) were sequentially added into a 150 mL round bottom bottle, and stirred in an oil bath at 70°C. Add (3.4g, 20mmole) benzyl bromide 10mL anhydrous DMF solution dropwise within 1 hour, react for 8 hours, cool to room temperature, filter off the inorganic precipitate, wash the precipitate with alcohol, concentrate the filtrate and washing liquid under reduced pressure The final residue was dissolved in 100mL chloroform, and impurities were continuously extracted with 10% aqueous sodium hydroxide solution (50mL) and water (50mL×3). LH-20 column chromatography, eluting with CH ₃ OH, gave N-benzyl-11-benzyloxy-xylopine (144 mg, yield 92%).

ii) Lead tetraacetate (95%, 240 mg, 0.5 mmole) was added to compound N-benzyl-11-benzyloxy-xylopine (123 mg, 0.25 mmole) in acetic acid solution (5 mL), and reacted at room temperature for 12 hours. Add water (100mL) to the reaction solution, and extract continuously with chloroform (50mL×4). The chloroform layer is then washed with saturated aqueous sodium bicarbonate (50mL), 10% aqueous sodium thiosulfate (50mL) and water (50mL×2) Continuous washing, dehydration with anhydrous sodium sulfate, concentration under reduced pressure, the resulting residue was subjected to silica gel column chromatography, and eluted with chloroform-methanol (80:1) to obtain 11-benzyloxy-oxylopine (53mg, yield 52%) .

iii) Dissolve 11-benzyloxy-oxylopine (50 mg, 0.12 mmole) in ethyl acetate (25 mL), add Pd-C (10 mg), add a hydrogen balloon, and stir overnight at room temperature. After filtering with celite, the filtrate was concentrated under reduced pressure to obtain brown oxocalycinine (38 mg, yield 98%).

Example 9: Inhibition of DNFB-induced mouse delayed hypersensitivity (DTH)

Animal experiment samples:

Zhanshanfeng total alkali sulfate is prepared by the method of Example 1, and the total alkaloid sulfate content (weight ratio) measured by ultraviolet spectrophotometry is 52.8%. The contents of calycinine sulfate and xylopine sulfate measured by HPLC were 6.2% and 4.9%, respectively. The Zanshanfeng total alkaloids are prepared by the method of Example 2, and the total alkaloid sulfate content (weight ratio) measured by ultraviolet spectrophotometry is 59.8%. The contents of calycinine sulfate and xylopine sulfate measured by HPLC were 5.8% and 5.2%, respectively.

Test animals:

Balb/c pure line mice, 6-8 weeks old, were purchased from the Shanghai Experimental Animal Center of the Chinese Academy of Sciences. Animals were kept in a clean animal room at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, with a 12-hour light/dark cycle, room temperature of 24°C, and humidity of 50-60%.

Reagent:

Shandiming (cyclosporine injection, 50mg/mL) is produced by Swiss Novartis Pharmaceutical Company, batch number 143MFD0600.

experimental method:

i. Balb/c mice (female, 6-8 weeks old), each foot was sensitized with 20uL 0.5% DNFB, boosted the next day (DNFB

Soluble in [acetone: olive oil = 4:1] oil;

ii. On the 7th-9th day, the mice were challenged with 10uL 0.4% DNFB on both sides of the left ear;

iii. Orally administered once 1 hour before the challenge, and administered again 12 hours later;

iv. 24-48 hours after the attack, check each indicator.

Experimental results:

On the classic DNFB-induced delayed-type hypersensitivity (DTH) model in mice, it was tested whether Zanshanfeng total alkaloids and total alkaloids have immunosuppressive activity on cell-mediated immune responses. Oral gavage administration, once a day, 2 times in total, the results show that Zanshanfeng total alkaloid sulfate and Zanshanfeng total alkaloids can significantly inhibit the cell-mediated immune response of DTH (see Table 3).

Table 3 Inhibitory effects of Zanshanfeng total alkaloid sulfate and Zanshanfeng total alkaloids on DNFB-induced delayed hypersensitivity in mice test group Dose (mg/kg) left ear heavy right ear weight Ear weight difference mean±SD(mg) P value Control group Cyclosporine A total alkali sulfate Calycinine sulfate Calycinine sulfate Calycinine sulfate 101007550100755010050 49.333.440.241.242.142.241.840.941.541.1 25.925.727.524.524.428.524.022.428.123.8 22.4±2.17.7±0.612.7±1.316.7±1.518.7±1.813.7±1.417.8±1.918.5±1.613.4±1.517.6±1.6 <0.05<0.05<0.05<0.05<0.05<0.05<0.05<0.05<0.05

*Balb/c mice, n=10.

Claims (5)

1. A class of Zanshanfeng alkali and Zanshanfeng saline alkali include aporphim, oxidized aporphim alkaloids and their pharmaceutically acceptable salts or their optical isomers with the following structural formulas

Among them, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ are selected from H, OH, O-acyl, OMe, OEt, On Pr ( ⁿ represents positive), O ⁱ Pr (i Represents iso), F, Cl, Br, NH ₂ , NO ₂ or CN; R ₈ is selected from H, C ₁ -C ₁₀ alkyl, acyl; the oxidized aporphylloid alkaloid shown in general formula (2), When R ₂ , R ₃ , R ₅ , and R ₆ are all OMe, the compound oxoglaucine is excluded; Compounds represented by general formula (3), (4) or their pharmaceutically acceptable salts or their optical isomers are used as active ingredients: Among them, R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are selected from H, OH, O-acyl, OMe, OEt, On Pr (n represents positive), ^{O i Pr} (i represents iso), F, Cl, Br, NH ₂ , NO ₂ or CN; R ₆ is selected from H, C ₁ -C ₁₀ alkyl, acyl; It is used as an immunosuppressant in the preparation of drugs for the treatment of diseases caused by immune hyperactivity, immune disorders, and autoimmunity. 2. The medical application of Aporphim, oxidized Aporphim alkaloids and pharmaceutically acceptable salts thereof or their optical isomers according to claim 1, characterized in that they include the following compounds

calycinine N-methyl-2,3,6-trimethoxy- xylopine morphinandien-7-one crebanine isolaureline asimilobine 3-methoxycalycinine corytuberine 4,5-dioxodehydroxyasimilobine

isoboldine oxocalycinine glaucine

norcepharadioneB oxylopine 1,2,3-trimethoxyoxoaporphine 3. according to claim 1, the medical use of Aporphi, oxidized Aporphi alkaloids and their pharmaceutically acceptable salts or their optical isomers, is characterized in that it is prepared by immune hyperactivity, immune disorders Diseases caused include rheumatoid arthritis, autoimmune hepatitis, insulin-dependent diabetes, ulcerative colitis, multiple sclerosis, scleroderma, myasthenia gravis, polymyositis, autoimmune cytopenias, vascular inflammatory syndrome or systemic lupus erythematosus, allergic disease, transplant rejection. 4. according to claim 3, the medical use of Aporphi, oxidized Aporphi alkaloids and their pharmaceutically acceptable salts or their optical isomers, is characterized in that it is used in the preparation of treatment of allergic diseases including bronchial Used in the medicine of asthma, allergic rhinitis, atopic dermatitis or hay fever. 5. according to claim 3, the medical application of Aporphi, oxidized Aporfi alkaloids and their pharmaceutically acceptable salts or their optical isomers, is characterized in that it is prepared for the treatment of bone marrow hematopoietic stem cell transplantation drug application in graft-versus-host disease.

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