TWI364279B - - Google Patents

Description

1364279 IX. Description of the invention: [Technical field to which the invention pertains] - 1,1,2,3,4·tetrahydroisolation of 1quinoline (l,2^4-tetrahydrois〇quinoline)^^^ Feeding materials, their financial methods and pharmaceutical compositions containing them. </ STRONG> [Prior Art] Alzheimer's disease (A1zhdmer, s disease, ad) is a type of persistent neurological loss that is caused by non-hydrolyzable toxic proteins in the brain. In the year of brewing, Germany-based neuropathology pen ois intestine imer) when a brain tissue was dissected from a demented woman with severe dementia, she found her brain _ New-some abnormal series (4) (4) and throwing fiber tangles (10) (4). The study found that these plaques are composed of non-hydrolyzable proteins and cause inflammation and death of brain nerve cells. "Haymer disease is named after the name of this chain scholar. Alzheimer's disease patients are mainly caused by damage to the brain cortex and the nerve cells that shoot the hippocampus, which leads to the patient's disappearance. The + phase is recorded as forgetfulness, and the daily performance is __, _hGrt her_ _ loss, _ employment relative to shirt, symptoms are serious cognitive impairment, difficult to social life, leading to inability to understand the content of the conversation, unable to solve the problems of life functions such as food intake, drinking water, and finally succumb to the bed and sea Newfoundland lost the accident in Chile, or died of long-term bed rest, reduced immunity, and caused other infectious diseases (such as sepsis, pneumonia, etc.). The disease period of A4 is about 125 years. The average patient has a life of 1364279 from the time of the death to the death. Statistically, women are more likely than men to have, 11% of the population over 65 years of age have an opportunity to suffer, and about 5% of those over 80 years of age have the opportunity to suffer from this condition, so it is also known as Alzheimer's disease. One of the pathological features of A Hyunmei disease is the deposition of amyl〇id plaque in the brain, which is composed mainly of pamyl〇id_peptides (Ap). The β-type starch-like peptide (Αβ) is not a direct product of the gene, but is a product obtained by first-produced a starch-like precursor egg ★-white matter which is cleaved by a different enzyme. The starch-like precursor protein (amyloid precursor • ^ you111, ^1*) is a single transmembrane protein with two pathways of decomposition: one is via alpha-type • a-secretase and gamma-secretase (γ) -secretase), after sequential cleavage, produces soluble starch-like precursor protein a (soluble amyi〇id precurs〇r pr〇tein a, sApp〇t); the other pathway is cleavage via beta-secretase (P_secretase) , and then cleavage by γ-type secretase, can produce insoluble β-type amyloid peptide (Αβ) ^ in the brain cells of patients with Alzheimer's disease, may be the proteolysis of starch-like precursor protein (ΑΡΡ) The process is mostly through the decomposition of ρ-type secretase and 丫-type cleavage, and the production of more ρ-type visceral peptides (Qi Bu due to the secretion of sputum-type secretase on the starch-like precursor protein (Αρρ) Different points will produce different sizes of non-soluble β-type sin-peptide _ 'the Αβ42 is more toxic, and easy to fibrillate to form a poly-complex' and accumulate as the core of the plaque, which in turn makes other species #β Type of starch wins (Αβ) Β40) More glutinously accumulates on these plaques. It is found that the proportion of Αβ42 in all brains of Alzheimer's disease is higher than that of normal people. The γ-type secretion is found by cell layer and pharmacological studies. The enzyme is an aspartic acid protease (aSp_l_ease)' and is regulated by γ-type secretase, which is considered to be an important direction in the treatment of Alzheimer's disease. However, another therapeutic direction is related to the regulation of α-type. The proteolytic enzyme 6 1364279 protein cleavage process (proteolyticproce ♦ this process is through the α-type secretase gamma). __ powder precursor protein (app), produces a soluble class of powder precursor protein α (s〇lubIe qing loid ΡΓ颜—Na α'mine), which hinders the production of insoluble β-type starch peptide (Αβ). It has been found that the proteolytic pathway of α-type secretase can be promoted by mitogens. (mitogen-activated protein ki_, ΜΑΡΚ) pathway regulation. ΜΑρΚ , _ pathway is a series of mitogen-activated protein kinases (mit〇gen_activated protdn ^ &amp; coffee, ^ Κ) and extracellular signal-regulated proteins The activation of the enzyme (extmcelkHar Signal-rcgulated #Pn&gt; tein), which is also important for the treatment The direction of Zheimer's disease. The development of drugs for patients with early Alzheimer's disease mainly uses drugs to relieve the symptoms of patients with early Alzheimer's disease. The US Food and Drug Administration (FDA) has approved four drugs to improve memory and slow the progression of Alzheimer's disease. The first drug is approved Taknin (he is e, the trade name is Cognex). The drug has many side effects, including too much hepatotoxicity, and it is not good for improving the memory effect. 4 The two new drugs are De Neng Pei (~Which (five), the trade name is AiYi Xin' (AneePt)) 'Rifus Dijmo's vastigmine 'brand name is Resin (Exelcm)) and galantamine (galantamine 'brand name is profit Remy (Remi_, these drugs have been shown to improve memory and less effect on the field. Tak Ning and De Neng Pei (〇如印_ two drugs by blocking the activity of the lining lining enzyme (linesterase) Inhibition of the decomposition of acetoxygenin (acet^ch〇line). Both drugs can increase the content of yoghurt to alleviate the loss of memory, and help patients to focus on the daily living (4) action. Can not cure Ami Mo, can only alleviate the symptoms of Azerbaijan 1364279 and these drugs are not effective for everyone, the effect is limited to early and mid-term Alzheimer's disease. Therefore, prevention and early diagnosis of Az Haimoia is still the current bottleneck in medical care. There are still many missing items in the habits, which is not a good designer, and 亟•· to be improved. V It is known that soluble starch precursor protein a (sAPPa) is neurotropic and neuroprotective (neuroprotective). Activity, against oxidative φ and excitotoxic damage. Recently, a type of monoamine oxidase B (MAO-B) inhibitor, rasagmne, and lei were found. Sajilan contains a carbamyl-containing derivative TV-3326 in a neuroblastoma (neur〇blast〇ma) SH-SY5Y and PC12 cell line via mitogen-activated protein kinase (MEK) Regulates the proteolytic process of the starch-like precursor protein (APP), which in turn stimulates the neuroprotective soluble starch-like precursor protein a (sAPPc〇), and another well-known B-type monoamine oxidase inhibitor, selegiline, Studies in a variety of preclinical model organisms have been shown to increase left levodopa (levodoPa) to cause neuroprotective effects by treating ParkinSOn (S-dise). The results showed that selegiline hydrochloride and rasagiline can increase the release of soluble starch-like precursor protein α (sAPpa) by MEK-dependent pathways. In summary, secretase (secretase) The regulated starch precursor protein (APP) can have two protein cleavage pathways, which influence the intracellular pathway and extracellular signal-regulated protein kinase (ERK) activation to affect the pro-powder precursor protein (APP) protein cleavage pathway, inducement The starch precursor protein (^p) protein cleavage pathway is oriented toward the non-dural powder-producing pathway regulated by α-type secretase 1364279 〇KmamylQ1dQgenie pathway) 'and thus hinders the insoluble (4) class powder _ _ 产生 ' Inhibition of γ-type secretase activity 'to reduce the production of insoluble β-type starch succulent (Qiu) ' @ 可 可 starchy secret egg from f (APP) egg self-mixing process toward (4) '^^±^c , 5|.^t(non-amyloidogenic pathway) JX J. The soluble starch-like precursor protein a (sAppa). Therefore, by directly or indirectly controlling the activity of γ-type secretase to affect the starch-like precursor protein (App) protein cleavage pathway can be used as a new direction for the treatment of Alzheimer's disease. In the case of the inventor of the present invention, in view of the shortcomings derived from the above-mentioned Azheimer's disease drugs, although the heart has been given a good gift, and after many years of painstaking research, the research has finally succeeded in the development of this article 1,2 '3,4-tetrahydroisoindole derivative, a process for its preparation and a composition containing the same. [Summary of the Invention]

The object of the present invention is to provide a novel 1,2,3,4-tetrahydroisoindolyl derivative, which is chemically modified by 1'2,3,4-tetrahydroisoquinoline, through a chemical synthesis step. Finally, a novel 1'2,3,4-tetrahydroisoquinoline derivative having the structure of the formula (I) is obtained, wherein the ruler and the town are as defined herein. A second object of the present invention is to provide a process for the preparation of a novel 1,2,3,4-tetrahydroisoquinoline derivative having the structure of the formula (1), wherein R1 and the illusion are as defined herein. A purpose is to provide a pharmaceutical composition comprising a novel tetrahydroisoquinoline derivative having a novel i 234 tetrahydroisoquinoline derivative having the structure of formula (1), To treat Alzheimer's disease, wherein R1 and R2 are as defined herein. Some of the B-type early oxidase B'MAO-B inhibitors include: 9 (S) 1364279 Resagmne, Rezagill contains a derivative of aminomethyl (carbamyi read _ derivative) TV-3326 * selegiline (four) egmne), which related path (ERK• ed _ fresh) _ flour precursor protein (APP) protein cleavage The process, in turn, reduces the production of the insoluble beta brain powder peptide (Αβ), and the extracellular signal regulates the egg kinase (which) • activation can indirectly regulate the release of the soluble powder precursor protein a (sAppa). Therefore, these indole-type monoamine oxidases inhibit the diagnosis of visceral _Hypermia. It is known that these β-type monoamine oxidases have a partial chemical structure of Propa^gylamine, and it is found that the structure is important for the activation of the ERK signal, but it is not related to the inhibition of the B-type monoamine oxidase activity. In addition, a conventional acetylcho-esterase inhibitor can be used to treat Alzheimer's disease. Such acetylcholinesterase inhibitors often have carbam〇yi. In order to achieve the above object, the inventors of the present invention used commercially available u, 3,4 tetrahydroisophthalein (1'2'3'4-tetmhydroisoquino Hne) as a reaction starting material (3), and carried out by chemical synthesis reaction. The cultivation of different functional groups to produce a new "hydrogen isoindene derivative. Through chemical steps (4) to (f), Uad, a new derivative of U, 3,4-tetrahydroisoindole, and 12, that is, # has the formula of Figure 1 (the derivative of the structure η, the towel ri and K2 are as defined herein. - The purpose of the present invention is the chemical synthesis method of the first embodiment, 1, 2, 3,4-tetrahydroisoporphyrin is modified to form a chemical structure with a quinoid monoamine oxidase inhibitor, and a chemical structure similar to that of an aconitin (aCetylCh〇linesterase) inhibitor. ), and further explore the role of these derivatives in the activation of ERK and the release of soluble powdered precursor protein a (sAppa). It is known that the reduction of ERK pathway will inhibit the activity of sputum secretase. 'Further in the second example to explore whether these derivatives are active for the 丫10 1^64279 secretase实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施a compound, wherein the towel Ri has a structure of the formula (Π), m is a b, 2, 3 or 4. In a preferred embodiment, the claw is i, and the phantom is pr〇pargyl, or R1 has the structure of the formula (ΙΠ), and η is Bu 2, 3 or 4. In the preferred embodiment, 'η is 卜, then R1 is cyprofen methyl (IV). R2 has the structure of the formula (IV), and the lanthanide is selected from methyl (-qing, ethyl or propyl^(-(CH2)2CH3); R4^^f^(-CH3) &gt; 6^( CH2CH3)^^^(-(CH2)2CH3)* In a preferred embodiment, R3 is an f group (even) and R4 is a fluorenyl group (even), and the phantom is Ν·ethyl Nf ^^(N- Ethyl-N-methylamino); R2 ^ , ^ wherein x is selected from -ch2-, oxygen or sulfur, and in a preferred embodiment, x is _cH2_, then the illusion is 吼 吼 py py py py; A structure of the formula (5), wherein the γ is selected from the group consisting of argon, or R 2 has the structure of the formula (5), wherein the γ is selected from the group consisting of sulphur, oxygen or sulfur, in a preferred embodiment. Where Y is oxygen, then R2 is 1-ophelyl (10) 〇rph〇linyl) (structure of Figure 1), or a pharmaceutically acceptable surface form, and a suitable pharmaceutically acceptable excipient or carrier The pharmaceutical composition is used for treating diseases in which nerve cells are necrotic due to an increase in insoluble protein powder map, resulting in memory and learning loss, dementia, and diseases in which cognitive processes are impaired. Diseases in which the cognitive process is impaired include, but are not limited to, Alzheimer's disease or other dementia 1364279, or Parkinson's Disease.

Such excipients include, but are not limited to, diluents, fillers, binders, disintegrants, lubricants, and the like. Wherein the excipient includes, but is not limited to, microcrystalline cellulose, polyvinylpyrrolidone (PVP), corn granules, modified starches, sodium starch glycolate , resin, gelatinized starch: powder, gelatin, polyethylene glycol (PEG), polyvinyl alcohol, hydroxypropyl cellulose, methyl cellulose , hydroxymethyl cellulose, hydroxypropyl methylcellulose, and the like. The present invention is exemplified by the following examples, but the present invention is not limited by the following examples. EXAMPLE I Chemical Synthesis of 1,2,3,4-Tetrahydroisoquineline Derivatives As shown in Figure 1, the present invention is 1,2,3,4-tetrahydroisoquinoline (1, 2, 3, 4-tetrahydroisoquinoline) as a reaction starting material (3) (purchased from Sigma-Aldrich Co., USA) 'Modification of different functional groups by chemical synthesis reaction to produce a novel derivative having the structure of formula (I). R2a0IXIr1 (|&gt; The chemical synthesis steps of the novel 1,2,3,4·tetrahydroisoquinoline derivatives of the present invention are as follows: 12 1364279 Step (8): N-trifluoro 6-yl-l, 2, 3 , 4-tetrahydroisoquinoline (4) Preparation 丨, 2'3'4·® Hydroisoquine (3) (8 ml, 60 mmol) was dissolved in di-methane (CH2a2) solution and then dripped A solution of ice-cold dichloromethane (32.4 ml) containing trifluoroacetic anhydride (CF3CO 2 〇) (9 ml), followed by an ice-cold environment for 3.5 • · hours. A solution of potassium oxide (KOH) (4.74 g, 85 mmol) dissolved in water (72 ml) was added as described above. After stirring at room temperature for two hours in the solution, the mixture was extracted with dichloromethane and then magnesium sulfate ( The organic layer was dried. The residue was applied to a silica gel c〇lumn (n-hexane / ethyl acetate (EtOAc) = 3:1 as eluent) Purified to obtain 9.92 g of N-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline (4) (Yield 72%). Thin layer chromatography (TLC) /?f = 0.58 (n-hexane / B) Ethyl ester = 1: Measured by 1H NMR (d-solvent: CDC13 (nuclear magnetic resonance apparatus, Varian Gemini, 300 MHz), δ 7.29 - 7.19 (m, 4H, Aryl /is); 4.80 (s, 2H, Ph - CH2 - N); 3.91 - 3.86 (m, 2H, Ph - CH2 - CH2 - N); 3.00 (br s, 2H, Ph - CH2 - C//2 - N), then by fast atom bombardment mass spectrometry ( Fast Atom Bombardment Mass Spectrometry, FABMS) is known to be CiiHi〇NOF3 ' m/z: . 230 (M+l). Step (b): 7-Chloroacetyl-N-trifluoroethylidene-1,2 Preparation of 3,4-tetrahydroisoquinoline (5) A chloroacetyl chloride (15 ml) was dropped into a suspension of dioxo (162 ml) in which a vaporized aluminum was dissolved. (A1C13) (24.16 g) 'The temperature was 0 to 5 ° C' and after 20 minutes of action in an argon atmosphere, the suspension was allowed to stand at room temperature. The intermediate N-trifluoroethylidene•1,2,3,4-tetrahydroisoindole (4) (9.29 g, 40 mmol) was added to the mixture at room temperature for 13 1364279 over 30 Minutes After the mixture was stirred for an additional 3 hours, it was added to ice water (4 〇 7 ml). After the mixture was stirred for another 5 hours, the layer to be separated was separated. The aqueous layer was extracted using di-methane (2 χ 200 ml). The organic layer was washed with water (2×240 ml) and 5% aqueous sodium hydrogen carbonate (NaHC.sub.3) (3×240 ml). After drying the organic layer, the solvent is evaporated to dryness to obtain 7 氯47 g * white solid 7-chloroacetamidine-N-trifluoroethane-yl-i,2,3,4-tetrahydroisoquinoline. - (7-Chloroacetyl-N-trifluoroacetyl-l, 2,3,4-tetrahydroisoquinoline) (5) (yield 88%). Thin layer chromatography (TLC) = 0.4 (Zhenghexin/ethyl acetate = 3:1). Mp: 120-122 0C. The alignment 'δ 7·78 (q, /= 4 Hz, 1H, Aryl Η), 7.34 - 7.26 (m, 2H, Aryl), 4.87 (s, 2H,

Ph-Ci/2 - N), 4.67 (s, 2H, - CH2 - C = 0), 3.95 - 3.87 (m, 2H, - CH2 - N), 3.06 _ 3.01 (m, 2H, Ph-C// 2_), by the fast atom bombardment mass spectrometry (FABMS), the molecular formula is C13HnN02ClF3, m/z: 306 (M+ 1). Step (c): Preparation of 7-chloroethyloxy-N-trifluoroethylhydrazine-1,2,3,4-tetrahydroisoquinolinium 7-glycol-N-di-I Base-1,2,3,4-tetrahydroisoindole (5) (8.4 LV, 27111111 〇 1) dissolved in anhydrous dichloromethane (58 ml) solution, then 3-chloroperoxybenzene 3-chloroperoxybenzoic acid (mCPBA) (12.3 g) was added to the solution. The suspension was ice-cooled to 〇 ° C, and trifluoroacetic acid (2.0 ml) was added dropwise to the ice-cold suspension for more than 5 to 10 minutes. The reaction flask was shielded from light and allowed to stand at room temperature for 3 to 5 days, poured into water (100 ml), and neutralized using an ammonium hydroxide solution. The layers were separated and the aqueous layer was extracted using a gas-purifying mixture (60 ml). Finally, it is purified on a silica gel chromatography column (with hexane/ethyl acetate = 2:1 as eluent) to obtain 4.24g.

14 1364279 7-Chloroacetoxy-N-triflu9roacetyl-l, 2,3, 7-Chloroacetoxy-N-triflu9roacetyl-l, 2,3, 4-tetrahydroisoquinoline) (6) (yield 48 ° / 〇). Thin layer chromatography (TLC) private = = 0.5 (positive hexane / ethyl acetate = 3:1) » Alignment, δ by 1H NMR (d-solvent: CDC13) (nuclear magnetic resonance apparatus 'Varian Gemini, 300 MHz) 7.20 .· (t, J = 7 Hz, 1H, Aryl H), 7.01 - 6.93 (m, 2H, 2H, Aryl Hs), 4.75 (s, 2H, • - Ph-CH2 - N), 4.33 (s, 2H, CO - CH2 - ), 3.90 - 3.82 ( m, 2H, N - CH2 -), 2.97 - 2.92 (m, 2H, Ph · C / /2 -) 'by the fast atom bombardment mass spectrometry (FABMS) The molecular formula is CbHuNC^CIFs, 322 (M+ 1). Step (d): 7-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (7) is prepared by containing 7-glycoloxy-N-trifluoroethenyl-1, 2,3,4-tetrahydroisoquinoline (6) (3.6 g, 11 mmol) in methanol (MeOH) (100 ml), 15% aqueous sodium thiomethoxide (NaSCH) at 20 ° C 〗) (10 ml, 107 mmol). After reacting for 2 hours, the mixture was acidified to pH 1 with 3N hydrochloric acid (HC1). 7-Hydroxy-l,2,3,4-tetrahydroisoquinoline hydrochloride salt (7) φ ( The yield was 54 ° / 〇) » / ? f = 〇. 2 (digestive gas / sterol = 5: 1). Alignment was determined by 1H NMR (d-solvent: heavy water. (D2〇)) (nuclear magnetic resonance apparatus, Varian Gemini, 300 MHz), δ 7.15 - 7.00 (m, 3H, 2H, Aryl Hs), 4·22 (d, · / = 6 Hz, 2H, Ph-CT/2 - N), 3.80 - 3·58 (m, 2H, Ph-C//2 - CH2 - N), 2.65 (t, 5.4 Hz, 2H, Ph- C/f2 - CH2 - N), and the molecular formula is C9HuNOHC, w/z: 186 (M+ 1) by fast atom bombardment mass spectrometry (FABMS). 7-Hydroxy-i,2,3,4-tetrahydroisoquinoline hydrochloride (7) using propargyl bromide, respectively, having a partial (π) partial structure or a cyclic propyl group Base (S) 15 1364279 (cyclopropylmethyl bromides), having a partial structure of the formula (dish), performing an N-alkylation reaction in an alkaline environment, and performing step (e), respectively 7-HydiOxy-N-piOpargyl-l,2,3,4-tetrahydiOisoquinoline (8) or 7-基-N-cyclopropanol "methyl-1,2,3,4-tetrahydroisoquinoline

(7-Hydroxy-N-cyclopropylmethyl-1,2,3,4-tetrahydroisoquinoline) (9) ° Step (e-l> : 7-hydroxy-N-propynyl-1,2,3,4-tetrahydrogen Preparation of isoquinoline (8) first 7-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (7) (1.7 g, 11 mmol) and potassium carbonate (KAO3) (3 g, After stirring in a solution of methyl cyanide (CH3CN) (phantom ml), a solution of 80% propynyl bromide (1.3 ml, 11 mmol) was added to the above solution. The reaction mixture was continuously stirred under a nitrogen atmosphere. After </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Purification in a silica gel chromatography column (with dichloromethane/methanol = 9:1 as eluent) to obtain a 7-hydroxy-N-propynyl-1,2,3 of 110 mg of a brown solid. , 7-Hydroxy-N-propargyl-l, 2,3,4-tetrahydroisoquinoline (8) (yield 50%). 沢f = 0.4 (dioxane/sterol) =9:1).mp: 82 - 83 0C. Alignment was determined by A NMR (d-solvent: CDC13) (nuclear magnetic resonance apparatus, Varian Gemini, 300 MHz), δ 6.91 (d, 8.1 Hz, 1H, Aryl H), 6.60 (d, J = 8.1 Hz, 1H, Aryl H), 6.38 (s, 1H, Aryl H), 3.69 (d, J= 23 Hz, 2H, Ph- CH2 - N), 3.51 (d, J = 1.8 Hz, 2H, N - CH2 - C^C - )5 2.84 (t, J=4 Hz, 4H, Ph-CH2-CH2-N), 2.31 α·/ =2Ηζ, 1H, C3 CH), and the molecular formula is C12H13NO, m/z: 188 (M+ 1) by fast atom bombardment mass spectrometry (FABMS). Step (e-2): Preparation of 7-hydroxy-N-cyclopropanemethyl-1,2,3,4-tetrahydroisoquinoline (9) 16 1364279 First 7-hydroxy-1,2,3, 4-tetrahydroisoquinoline hydrochloride (7) (0.9 g, 6 mmol) and potassium carbonate (2.0 g, I2 mmol) were dissolved in methyl cyanide (18 ml), then 96 A solution of % (bromomethyl) cyclopropane (0.6 ml, 6.3 mmol) was added to the above solution. The reaction mixture was stirred overnight under a nitrogen atmosphere for 25 hours. * The mash was washed with water and the water-layer was extracted with ethyl acetate (20 ml X 2 ). The organic layer was dried using an anhydrous sulfuric acid lock (MgS04). The residue was purified in a Shixia gel chromatography column (digestion/methanol = 9:1 as eluent) to obtain 0.37 g of a yellow solid 7-hydroxy•-N-cyclopropene. Base-1,2,3,4-tetrahydroisoquineline (7-Ι1γώΌχγ-Ν-ο>^1ορΐΌργ1ηΐ6ϋ^1-1,2,3,4-ί6ΐΓα1ιγ(1ϊ·ί^&lt;^ιήηο1ίη6) (9 (yield 57%). Thin layer chromatography (TLC) outside = 0.3 (two gas methane / methanol = 9:1). mp: 118-1190 C. by iHNMRW-solvent: CDC13) (nuclear magnetic resonance apparatus, Varian Gemini, 300 MHz) Alignment ' δ 6.87 (d, */= 8.1 Hz, !H, Aryl H), 6.58 (dd, 8.1 Hz, 2.1 Hz, 1H, Aryl H); 6.24 (d, /= 2.1 Hz) , 1H, Aryl H), 3.58 (s, 2H, Yh-CH2 - N), 2.87 (dd, J= 5 Hz, 4H, Ph-C//2 - CH2 - N), 2.48 (d, / = 7 Hz, 2H, N - CH2); 1.13 - 1.10 (m, φ 1H); 0 61 - 〇.57 (m, 2H), 0.21 (q, */=4.8 Hz, 2H) ' Again by fast atom bombardment mass spectrometry Technique-study (FABMS) knows that the formula is Ci3H17NO, w/2: 204 (Μ + 1)» Finally, 7-carbyl-N-propynyl-1,2,3,4-tetrahydroisoquinoline ( 8) and 7-hydroxy_:^-cyclopropanemethyl-1,2,3,4-tetrahydroisoquinoline (9)' respectively added n, n_ A similar compound of the N'N-dialkylcarbamyl chloride (R2_c〇-Cl) (10a-d) in a methyl cyanide solution, wherein the R2 knife is N-ethyl _]^__ Amino 〇sj_Ethyl-N-methylamino), I-0 Pyr 咬 ( (1 Pyrrolidyl) 1_石比派基 (i_piperidinyi) or 丨_弗弗琳基 (i_M〇rph〇linyl); 1364279 A structure having the formula (IV), (V), (VI) or (W) as shown in Fig. 1; therefore, the similar compound (R2-CO~Cl) (10a-d) is N-ethyl-N-曱, respectively. N-ethyl-N-methyl-carbamoyl chloride (10a), pyrrolidine carbonyl chloride (10b), piperidinel carbonyl chloride. (10c) And Muffin carbonyl

(morpholine carbonyl chloride) (lOd), after the step (f), the derivatives la-d and 12a-d of i,2,3,4-tetrahydroisoquinoline are respectively obtained. The above-mentioned N-ethyl-N-methyl-carbamoyl chloride (10a), pyrrolidine carbonyl chloride (10b), chlorhexidine chloride (piperidine carbonyl chloride) (10c) and morpholine carbonyl chloride (lOd) are not available on the market. Therefore, the literature (1) can be used by using a phosgene (ph). 〇Sgene)'s solution of t笨iuene is synthesized 10a-d 〇step (f-Ι): a common step for preparing the derivative ua-d of 1,2,3,4-tetrahydroisoquineline First, 7-hydroxy-N-propynyl-1,2,3,4-tetrahydroisoquineline (8) (1 equivalent) is mixed and dissolved in methyl cyanide solution, and uniformly mixed into an ice-cold mixed solution. The similar compound (M-C0^1) (10a~d) of N,N-dialkylamine formazan chloride was added to each of the above-mentioned ice-cold mixed solutions (four groups in total), and the mixture was uniformly mixed. Then, 60% sodium hydride (60% NaH dissolved in mineral oil, 1.3 equivalent) was added to the four groups of the mixture in the form of a drop, and the four reaction mixtures were stirred at room temperature under an argon atmosphere for 2 hours. After the solvent was evaporated in vacuo, water was added and extracted three times with ethyl acetate. The organic layer was further mixed with sulfuric acid (MgS04), and evaporated to a vacuum in a vacuum towel. The residue was purified by column chromatography to obtain four, 2, 3, 4-tetrahydroisophthalocyanine. The final product of the derivative (1) a_d). Step (f-2): Preparation of 1,2,3,4-tetrahydroisoquinoline derivative 12a _ d common step 18 1364279 first 7 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Hydrogen Ionon $ (Im equivalent) solution is dispensed in a solution of methyl ether, mixed evenly into an ice-cold mixed solution, and then Ν, Ν-dialkylamine methyl hydrazine, her compound? ^0-01) Participants in each of the above -_ cold mixed solution (four groups) 'mixing _, then 60% sodium hydride (60% of the surface dissolved in mineral oil, i 3 equivalents) • Add four groups of mixtures in drops In the four groups of reaction mixtures, respectively, at room temperature and chlorine atmosphere for 2 hours. After the solvent was volatilized in a vacuum, water was added and extracted three times with acetic acid. The organic layer was dried again with a sulfuric acid lock (N. 4) and then evaporated to dryness in vacuo. The residue was purified by a # _ chromatography column to obtain the final product of four derivatives of 1,2,3,4·tetrahydroisoindole (12a-d). Step number (f_l-l): 7-(Nf-N-ethylamine alkoxy)-N-propynyl-i, 2,3,4_tetra-argon isoquinoline (lla) Preparation 7 -N-ethyl-N-methyl-carbamoyl Chloride) (10a), mix and carry out the step (f^), and purify it with a silica gel chromatography column (with ethyl acetate/positive home = 2:1 as eluent) to obtain propynyl group and N_B. 7-(N-methyl-N-ethylaminemethomethoxy)-N-propynyl+2,3+tetrahydroisoindolyl (β-(N-Methyl-) N-ethylcarbamoyloxy)-N-propargyl-l, 2,3,4-tetrahydroisoquinolin e) (lla) (yield 50%). By 1H NMR (d-solvent: CDC13) (nuclear magnetic resonance instrument, Varian

Gemini '300 MHz) alignment, δ 7.08 (d, /= 8 Hz, 1H, Aryl H); 6.88 (d, 7 Hz, 1H, Aryl H), 6.80 (s, 1H, Aryl H), 3.76 ( s, 2H, Ph-CH2 - N), 3.50 (ds 7 = 2 Hz, 2H, N - CH2 - CCH), 3.42 (q, /=7 Hz, 2H, N - CH2 - C//3), 3.04 - 2.81 (m, 7H, N - CH3, ?h-CH2 - CH2 - N), 2.28 - 2.26 (m, 1H, C = CH), 1.25 - 1.15 (m, 3H, N - CH2 _ CH3); IR (KBr): v cm·1 = 3300, 2923, 1715. The molecular formula is Cl6H2〇N2〇2,w/2: 273 (M + υ. Step (f-1-2): 7-(1-砒砒啶录) Preparation of -Ν_propynyl-cut-phase nitrogen isoindole (1) 7-trans-base-Ν'propynyl-1,2,3,4·tetrahydroisoindole (8) with squama bite (pyrrolidine) Carbonyl chloride) (lOb)^^, , .·正正(10)=2:1 #进行洗液)Purification 'available with propynyl and p-tree base 7_(1_秘•-咬氧氧)- N-propynyl], 2,3,4·tetrahydroisocarboline (7K1-Pyrrolidinecarbamoyloxy)-N^ropargyl-1, 23^ (lib) (yield 53%). Alignment was determined by 1H NMR (d-solvent: CDC13) (nuclear magnetic resonance apparatus, Varian • Gemini, 300 MHz), δ7.08 (d, 8 Hz, 1H, ArylH), δ 6·91 (dd,·/= 8

Hz, 2 Hz, 1H, Aryl H), 6.83 (d, / = 2 Hz, 1H, Aryl H), 3.81 (s, 2H, Ph-C//2), 3.55 - 3.44 (m, 6H, 2 N - CH2 - CCH), 2.94 - 2.90 (m, 4H, N - CH2 - CH2), 2.30 (t, J - 3 Hz, 1H, C = CH), 1.98 - 1.89 (m, 4H); IR (KBr) : v cm'1 = 3375, 2951, 1715. The molecular formula was found to be C17H20N2O2, w/z: 285 (M + 1) by fast atom bombardment mass spectrometry (FABMS). Step (f-1-3): Preparation of 7-(1-ethylidene carbonyloxy)-N-propynyl-1,2,3,4-tetrahydroisoquineline (11«1)

Mixing 7-trans-N-propynyl-1,2,3,4-tetrahydroisoquineline (8) with piperididine carbonyl chloride (10c) to carry out step (f-1), After purification by a silica gel chromatography column (ethyl acetate / n-hexane = 2:1 as eluent), 7-(1_砒派pyridineoxycarbonyl) having propynyl group and μ砒pyridinyl group can be obtained. -N-propynyl-1,2,3,4-tetrahydroisoquinoline (7-(Piperidinecarbamoyloxy-N-propargyl-1,2,3,4-tetrahydroisoquinoline) (llc) 50%). Mp: 72-73 0C. Alignment was determined by HNMR (d-solvent: CDC13) (nuclear magnetic resonance apparatus, Varian Gemini, 300 MHz), δ 7.08 (d, J = 8 Ηζ, 'Η, Aryl H), 6.87 (dd, J = 8 Hz) , 2 Hz, 1H, Aryl H), 6.80 (d, J = 2 Hz, 1H, Aryl H), 3.77 (s, 2H, 20 1364279

Ph-CH2 - N), 3.52 (t, 7- 15 Hz, 4H, N - CH2 - ), 2.94 - 2.85 (m, 4H, Ph-C//2 -CH2 - N); 2.28 (t, J- 2 Hz, 1H, C = CH), 1.63 (s, 6H,); IR (KBr): v cm'1 = 3255, 2926, 1717. The molecular formula was found to be C18H22N202, w/z: 299 (M + 1) by fast atom bombardment mass spectrometry (FABMS). * Step (f_1_4): Preparation of 7·(1_?Fronincarbonyloxy)·Ν_propynyl-1,2,3,4-tetrahydroisoquinoline (lld) •- 7_经基- N-propynyl-1,2,3,4·tetrahydroisoindole (8) and morpholine carb〇nylchloride (10d) are mixed and subjected to the step (f-丨), using a gelatin chromatography tube Purification by column (ethyl acetate·/hexane = 2:1 as eluent), 7_(丨·························· Alkyl, 2,3,4-tetrahydroisoquinoline (7-(l-Morpholinecarbamoyloxy. N-propargyl-l, 2,3,4-tetrahydroisoquinoline) (lid) (yield 82%). By 1H NMR (d-solvent: CDC13) (nuclear magnetic resonance instrument, Varian

Gemini '300 MHz) alignment, δ 7.10 (d, ·/= 8.4 Hz, 1H, Aryl Η), 6.90 (dd, 8.4 Hz, 2.4 Hz, 1H, Aryl H), 6.81 (d, J= 2.4 Hz, 1H, Aryl H), 3.83 - 3.56 (m,

12H, 2 - OCH2CH2N - , Ph-CH2 - N, N - CH2 - C = CH), 2.96 - 2.92 (m, 4H, Ph-Ci/2 - CH2 - N), 2.32 (t, J = 2.4 Hz, 1H, - C^CH); IR (KBr): v cm-1 = 3232, 2951, 1706. Further, by fast atom bombardment mass spectrometry (FABMS), the molecular formula is Ci7H20N2〇3, w/z: 301 (M + 1) 〇 step (f-2-1): 7-(N-methyl-N-ethyl Preparation of N-cyclopropanemethyl-1,2,3,4-tetrahydroisoquinoline (Ua) 7-Hydroxy-N-cyclopropanedecyl-1,2,3,4 - Tetrahydroisoquinoline (9) is uniformly mixed with N-ethyl-N-methyl-carbamoyl chloride (10a), and then step (f-2) is carried out. 'Using a silica gel chromatography column (using dichloromethane y sterol = ι〇: ι as an eluent) to obtain 21 1364279 with cyclopropanemethyl and N-ethyl-fluorenylmethylamine 7-(N-Methyl-N-ethylaminemethyl oxime)·Ν-cyclopropanone-U,3,4-tetrahydroisoquinoline (7-(N-Methyl-N-ethylcarbamoyloxy) -N-cyclopropylmethyl-l,2,3,4-tetrahydrois oquinoline) (12a) (yield 50%). Alignment was determined by 1H NMR (d-solvent: CDC13) (nuclear magnetic resonance apparatus 'Varian Gemini, 300 MHz), δ 7.06 (d, J = 8 Hz, 1H, Aryl H); 6.84

(s, 1H, Aryl H); 6.81 (s, 1H, Aryl H); 3.71 (s, 2H, Ph-C/f2 - N); δ 3.44, 3.39 (dd, J = 7 Hz, 2H, CH3 - N - CH2CH3); 3.03 - 2.75 (m, 7H, CH3 - N - CH2CH3, Ph-CH2 - CH2 - N); 2.42 (d, 7 = 6 Hz, 2H, N - CH2); 1.24 - 1.17 (m, 3H, -CH3); 1.14-0.94 (q, J = 7 Hz, 1H); 0.58-0.52 (m, 2H); 0.19-0.14 (m, 2H); IR (KBr): v cm·1 = 2924, 1715. The molecular formula was found to be C17H24N2O2, w/z: 289 (M + 1) by fast atom bombardment mass spectrometry (FABMS). Step (f-2-2): Preparation of 7-(1-pyrrolidinyloxy)-N-cyclopropanemethyl-1,2,3,4-tetrahydroisoquinoline (12b) -N-cyclopropanone methyl-1,2,3,4-tetrahydroisophthalocyanine (9) is uniformly mixed with pyrrolidine carbonyl chloride (10b) and then subjected to the above step (f_2), After purification by using a Shixi gum chromatography column (using a second rate of methylaxyl/methanol=20:1 as an eluent), 7-(1) having a propyl propyl group and a 1-pyrrolidyl group can be obtained. - 砒pyridinylcarbonyloxy)-N-cyclopropanylmethyl-1,2,3,4-tetrahydroisophthalocyanine (7-(1 -Pyrrolidinecarbamoyloxy)-N-cyclopropylmethyl-1,2,3,4-tetra -hydroisoquinoline) (12b) (yield 50%). Alignment was determined by 1H NMR (d-solvent: CDC13) (nuclear magnetic resonance apparatus, Varian Gemini '300 MHz), δ 7.08 (d, "/= 8.1 Hz, 1H, Aryl H), 6.90 (d, J = 8.1 Hz) , 1H, Aryl H); δ 6.84 (s, 1H, Aryl H), 3.80 (s, 2H, Ph-C//2 -N), 3.54 (t, J = 5.1 Hz, 2H, N - CH2 - ) , 3.46 (t, J = 5.1 Hz, 2H, N - CH2 -), 22 1364279 2.92 (br s, 4H, Ph-CH2 - CH2 - N); δ 2.51 (d, J = 4.8 Hz, 2H, N - CH2 - C - ); 1.92 (br s,4H, - (3⁄4 - C//2 - ); δ 1.03 (br s,1H); 〇·58 (dd,6.3 Hz, 1'5 Hz, 2H); 0'20 (d, "/= 1.5 Hz, 2H); IR (KBr): v coffee-1 = 2876, 1715. The molecular formula is c18H24N2〇2, w/z by fast atom bombardment mass spectrometry (FABMS). : 301 (M+ 1). Step (f-2-3) : 7-(1-祉派咬氧氧)-N-Cyclopropanylmethyl-1,2,3,4_tetrahydroisophthalide (12&lt;:) Manufactured • Prepare 7-hydroxy-N-cyclopropanemethyl-1,2,3,4-tetrahydroisoquinoline (9) with hydrazine carbonyl chloride (? Carbonyl chloride) (10c) Mixing and carrying out step (f-2) 'purification with a phthalocyanine chromatography column (digestive methane/methanol = 12:1 as eluent), which can be obtained with a cyclic propyl group and a Foundation 7-(ι_ί比派点氧氧)-Ν-环丙院methyl-1,2,3,4-tetrahydroisophthalocyanine (7-(l-Piperidinecarbamoyloxy)-N-cyclopropylmethyl-l,2 , 3,4-tetrahydroisoquin oline) (12c) (yield 50%) by NMR (d-solvent: CDC13) (nuclear magnetic resonance apparatus, Varian

Gemini, 300 MHz) Determination of the alignment ' δ 7·06 (d, "/= 8.4 Hz, 1H, Aiyl H); 6.86 (dd, /= 8.4 Hz, 2.4 Hz, 1H, Aryl H), 6.80 (d, J = 2.4 Hz, 1H, Aryl H), 3.71 (s, 2H, Ph-C/^ - N), 3.57 (br s, 2H, N - CH2 - ), 3.50 (br s, 2H, N - CH2 - ), 2.92 - 2.81 (m,4H, Ph-C% _ C/^2 _ N), 2.44 (d, «7= 6_9 Hz, 2H, N - C//2), 1.62 (br s, • 6H 1.00 - 0.95 (m, 1H); 0.59 - 0.53 (m, 2H); 0.20 - 0.15 (m, 2H); IR (KBr): v cm'1 = 2924,1717. Further, by fast atom bombardment mass spectrometry (FABMS), the molecular formula is C19H26N2O2, w/z: 315 (M+ 1) 〇 step (f-2_4): 7_(1_fphelinooxy)-N-cyclopropane Preparation of methyl-I,2,3,4-tetraindole 啥## 7-hydroxy-N-cyclopropanone methyl-1,2,3,4-tetrahydroisoquineline (9) After mixing the iFrine carbonyl (丨〇d) iS) 23 1364279, after performing the above step (f-2), use a silica gel chromatography column (with dichlorocarbyl/methanol = 1 〇: 1 for elution) After purification, liquid can be obtained with cyclopropanemethyl and 丨 _ whiffinyl 7-(1-whufolin carbonyl)-N-cyclopropanemethyl- oxime; ^· tetrahydroisophthalocyanine (7 -(l-Morpholinecarbamoy]〇xy)-N-cyclopropylmethyl-l,2,3,4-tetrahydroisoqui noline) (Ud) (yield 51%). By Η NMR (d-solvem : CDC13) (nuclear magnetic resonance instrument,

Varian Gemini, 300 MHz) Alignment, δ 7.08 (d, 8.2 Hz, 1H, Aryl H), 6.86 (d, J = 8.2 Hz, 1H, Aiyl H), 6.81 (s, 1H, Aryl H), 3.75 - 3.57 (m, 10H, O - (CH2 -CH2)2 - N - , Ph-Ci/2 - N), 2.90 (t, J= 5.7 Hz, 4H, - C//2 - N ), 2.80 ( t, J = 5.7 Hz, 4H, Ph-CH2 - ), 2.42 (d, J = 6.6 Hz, N - CH2 - ), 0.98 - 0.92 (m, 1H), 0.59 - 0.53 (m, 2H), 0.19 - 0.15 (m, 2H); IR (KBr): v cm1 = 2924, 1717. The molecular formula was c18H24N203, w/z: 317 (Μ + 1) by fast atom bombardment mass spectrometry (FABMS). Finally, via steps (8) to (f), the derivatives ua_d and I2a of 1,2,3,4-tetrahydroisosine having the structure of formula (1) (wherein R1 and the meaning of the text) are respectively obtained. -d.

Example 1 Analysis of the &lt;y_secretase Inhibitory Ability of 1,2,3,4-Tetrahydroisoindolin Derivatives Since these derivatives are similar in chemical structure to selegiline and rasagiline' Therefore, in the present example, it was tested whether the derivatives have the activity of inhibiting the activity of γ-secretase and thereby regulating the proteolytic process of the amyloid precursor protein (amyi〇id precurs〇r pr〇tdn, APP). In the present example, the type-secretase activity was measured in a τ·2〇 cell line using the qUantitative cell-based assay method disclosed in the literature (7) and the literature (7). &lt;5) 24 1364279 In order to measure the activity of γ-type secretase, it is first necessary to produce a stable transfected cell T-20. In the present embodiment, the following steps are described as follows: 1. The construction of the C99-Gal4-VP16/TO (C99-GV/TO) plastid is disclosed in the literature (2). The construction method has been briefly described as follows. Precursor protein (app) • Can be cleaved by alpha-secretase or beta-secretase to form C83 (starch-like precursor protein)

a fragment of .-C end containing 83 amino acids) or C99 (c-terminal of the starch-like precursor protein containing 99 amino acids), which is cleaved by γ-type secretase to produce an intracellular region of the starch-like precursor protein (APP φ intracellulardomain, A fragment of AICD). Using Gene Recombination Technology to App^^GaW-VPM (APP-GV) as a DNA Template 'This template is a plastid obtained from Dj·. Mark Bothwell &lt;Univerisity of Washington, Seattle, WA) where ApP695 DNA fragment is compiled ( Enc〇de) A full-length starch precursor protein (App) protein fragment of 695 amino acids, GaW is the transcription factor of yeast, and VPi6 is a viral transcription activator, (2) The specific primer is subjected to a polymerase chain reaction (PCR) to obtain a DNA sequence fragment of C99-Gal4-VP 16 (C99-GV) Φ. This DNA fragment (C99-GV) was then cloned into the PcDNA5/T0 vector (purchased from Invitrogen) to generate a plastid C99-Gal4-VP16/TO (C99-GV) which was induced by tetracyciine. /TO). 2. Construction of Gal4-Luc plastids The construction method has been disclosed in the literature (2). Briefly, in order to construct a vector having luciferase suitable for stable transfected cells, the pFR_Luc vector is Gene recombination technology, the genomic reporter luciferase complete open reading frame (〇pen reading — e) (S &gt; 25 1364279 DNA sequence and its upstream Gal4 promoter sequence (Gal4 binding sequence) It was cloned into the pBudCE4.1 vector (purchased from invitr〇gen). Finally, the plastid was cleaved with a restriction enzyme to cleave the DNA of the Cyt〇megai〇virus (CMV) driver on the pBudCE4.1 plastid. Sequence removal 'self-ligati〇n', Gal4 promoter-driven lucifemse reporter construct Gal4-Luc, which contains Gilson's resistance, can be used to drive Gal4 promoter-driven lucifemse reporter construct Gal4-Luc Screening marker for ze〇cin_resistant 3. Cell culture T-REx293 cell line can be purchased from invitrogen using 1% fetal fevine serum (FBS) and 5 pg/ml Blasticidin DMEM culture (Dulbecco's modified Eagle's medium) cultured cells were cultured in a humidified cell culture chamber at ambient temperature of 37 ° C and 5% carbon dioxide (C〇 2 ). The T-REx293 cell line was human embryonic kidney cells (Human embryonic cells). Kidney cells, HEK293) Improved cell line 4. Stable transfercted cell line producing T-20

The method for producing stably transfected cells has been disclosed in the literature (2). Briefly, the cells are cultured in the above-mentioned medium in a culture dish of 1 cm, and after the cell density exceeds 5%, the original medium is replaced. Equal amounts of C99-GV/TO (5 pg) and Gal4-Luc (5 pg) plastids with FuGENE 6 transfection agent (purchased from Roche Applied Science) in 8 ml of DMEM medium containing 10% fetal bovine serum ) - added to the medium for transfection. Transfected T-REx293 cells were cultured in 10% fetal bovine serum, 200 pg/ml hygromycin, 250 pg/ml zeocin, and 5 pg/ml betomycin ( In the DMEM medium of blasticidin, 26 1364279 The above mixed medium is abbreviated as DMEM-HZB. Individual cells derived from a single cell can then be isolated from a population of antibiotic resistant cells and cultured into individual cell lines. The individual independent cell lines described above were cultured in a 96-well culture dish containing 5 pg/ml tetracycline (tetraCyCiine) and 1 〇μΜ of compound E (compound E) in DMEM-HZB medium (obtained from. Dr. Michael Wolfe, Harvard Medical School's Brigham and Women's Hospital, Compound E is a gamma-type secretase. The cells were then lysed and added to a steady-Glo luciferase assay reagent (purchased from Promega). The luciferase signal was read by a VictorLight® microPlate luminometer (purchased from PerkinElmer). The best criteria for the stable transfected cell line, which is the cell line that inhibits the luciferase signal induced by tetracycline, so τ_2〇 is selected from the above cell lines. The cell line 'cell-based γ-secretase assay uses a cell-based γ-secretase assay in the literature (2). Cell-based gamma-type secretase assay with T-20 cell line has been revealed

Test to measure γ-type secretase activity. In the present example, the test and its cell strain were used to measure 1,2,3,4-tetrahydroisoindoline (1,2,3,4 also let Liu (!1*〇18(^11111〇11116)) Derivatives for the analysis of sputum-type secretase activity. Τ-20 cell line containing 10% fetal bovine serum (FBS), 2〇〇μβ/ιηι effect hygromycin (hygromycin), 5 pg/ml betomycin (blasticidin) and 250 pg/ml zeocin DMEM medium (DMEM-HZB) were cultured. T-20 cells stably transfected with C99-GV and Gal4-Luc plastids were trypsinization. The strain was isolated from the culture dish and washed with Phosphate Buffered Saline (PBS), and the cells were resuspended using 27 1364279 DMEM-ΗΖΒ medium, and then the suspension cells were 2 χ 〇 4 cells / 5 〇 μΐ The density of the holes was plated in a 96-well culture dish and cultured in an incubator at 37 ° C for 24 hours. The respective derivatives of the invention (lla-d and 12a-d) were 1% diterpene. After dissolving Dimethyi sulfoxide (DMSO), it was diluted with DMEM-HZB medium containing 1 pg/mi tetracycline (tetracycUne) to a final concentration of 1 μμ. Inhibition of γ-type secretase: For the activity test, each of the above 10 μΜ of each derivative (lla-d and 12a-d) was added to each of the above-mentioned cultured D-cells at 37° C. (: Environment culture) After 24 hours, the same volume of Steady-Glo luciferase assay reagent (purchased from promega) was added directly to each well to stop the reaction using a VictorLight Microplate luminometer (purchased from PerkinElmer). To read the luciferase signal value of each hole. The activity of each group of derivatives inhibiting γ-type secretase activity is a three-repeat independent test. If the stable transfected cell line τ_2〇 does not contain a tetracyclic ring 1% of tetracycline, after DMS0 was reacted, the fluorescence signal value read was 'this activity was doubled. In the same parallel test, the luciferase reporter gene was used. For example, the luciferase reporter gene under the control of CMV driver is used as a control group in φ. In this example, the T-20 cell strain contains 1% DMSO and 1 , Pg/ml tetracycline. (tetracycline) medium As a positive control group; the τ_2〇 cell line was treated with a medium containing 1% DMS0 as a negative control group; the other groups contained different compounds (10 μΜ), 1% DMS0 and 1 pg/mi tetracycline The medium was treated with Τ_2〇 cell strain as a test group of different compounds. Briefly, the Τ-20 cell line was induced by tetracycline to express the C99-GV protein fragment on the cell membrane, and the C99-GV fragment was cleaved by the γ-type secretase, and the ACID-GV fragment was obtained from the cell 28 1364279 membrane. The upper release binds to the Gal4 driver binding region to drive the luciferase expression, whereas the secretase activity is inhibited by the inhibitor, and the luciferase expression is decreased or not expressed. 6. Statistical Analysis « The experimental data were presented as mean soil standard deviation (SD), and each derivative in each experiment was followed by three fine-field tests. A single analysis of the galactic compilation. · Perform statistics to analyze the results of various different derivatives in biological experiments. IWtS, stest is used to compare results between individual compounds. In all of the examples, p &lt; 〇〇 5 is shown to be significant. 7. Results The three groups of group 12a, e, and d (d) at the concentration of 10 μΜ in Figure 2 were in the positive control group, and the three groups of 12 μ, 12, c, and d were able to inhibit the γ-type secretase activity of about 35 72. %, while the test group of mSagiline and other i, 2, 3, and ternary tetrahydroisoindole derivatives reduced the activity of γ-type secretase by about 6_15% relative to the positive control group. Therefore, it was confirmed that the 1,2,3,4-tetrahydroisoquinoline derivative having the structure of the formula (wherein R1 and R2 are as defined) can inhibit the activity of the sputum-type secretase.

Example 3 1,2,3,4-tetrahydroisoquineline derivative cytotoxicity test In the present invention, animal cells are tested for 1,2,3,4-tetrahydroisoindolin derivatives for cytotoxicity to cells. , including but not limited to, Human embryonic kidney eells (HEK293), and other animal cells suitable for testing cytotoxicity. In a preferred embodiment, the animal cell is Human embryonic kidney cells (HEK293)&apos; to test whether the 1,2,3,4-tetrahydroisoquinoline derivative is cytotoxic to cells.

(S 29 1364279 1. Cell culture culture Human embryonic kidney cells (HEK293) (purchased from Invitrogen) using a 10% fetal bovine serum (FBS) and oi mg/ml green Human embryonic kidney cells were cultured in penicillin and streptomycin DMEM medium (Dulbecco's modified Eagle's medium), T-20 as its progeny--the reproductive cell line and γ-30 are in the literature (3) ) Revealed in a humidified cell culture chamber at ambient temperature 37 (... and 5% carbon dioxide (C02) concentration. φ 2. Cytotoxicity test T-20 cell line at a density of 5 x 104 cells / 100 μΐ / hole Tiled in each well of a 96-well culture plate, 'different derivatives containing 10 μM (lla-d, 12a-d) were added to the culture medium of each well for 24 hours at 37 °C. CellTiter 96® Aqueous Non-Radioactive Cell Proliferation (CellTiter 96® Aqueous Non-Radioactive Cell Proliferation)

Assay) (from Promega) measures the number of viable cells by colorimetric method. This system consists of a novel tetra-tetrazolium compound 3-(4,5-dimethylindole-2- yl)-5-(3-carboxymethyl)-2-(4-sulfobenzene) -2H-tetrathiazol-2-yl-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2 H-tetrazolium, inner salt, MTS And an electron coupling reagent (phenazine methosulfate (PMS)). MTS is reduced by cell biology into a formazan compound that is soluble in tissue culture medium. The absorbance of the formazan compound at 490 nm can be directly measured on a 96-well plate using a Synergy HT ELISA plate reader (purchased from BioTek) without additional treatment. The dehydrogenase in the metabolically active cells converts the MTS into a liquid soluble formamidine 30 1364279. The amount of formazan product represented by the absorbance measured at 490 nm is directly proportional to the number of active cells in the culture. In the present example, the number of viable cells was measured by the above measurement method. The method is to add 2 μM of the MTS/PMS combined solution to each well of the 96-well culture dish after 24 hours of culture, at a temperature of 37. (: Culture for 3 hours, then use the Synergy HT ELIS A plate reader to measure the absorbance of the survival-cell iMTS converted to formazan at a wavelength of 490 nm. The number of viable cells is at a wavelength of 490 nm. The ratio of absorbance is calculated. The survival rate of viable cells in 1% DMS medium is defined as the survival rate of ι〇0%. The background absorbance is defined as the number of cells in each well. Absorbance value. In this example, the T-20 cell strain was treated as a positive control group with a medium containing 1% DMS〇 and 1 μ§/ιη1 tetracycline; the T-2〇 cell line was used. The medium was treated as a negative control group containing 1% DMS, and the other groups were treated with a medium containing different compounds (1 μμΜ), 1% DMS0 and 1 pg/ml tetracycline, respectively. As a test group of different compounds. 3. Statistical analysis

4. The results are shown in Figure 3, the human embryonic kidney cell (HEK293) progeny cell line T-20, in each group of derivatives test group, cell viability and positive control group, negative control group Compared with the rasagiline test group, there was no significant difference, confirming the 1,2,3,4-tetrahydroisoquinoline derivative having the structure of formula (I) wherein R1 and R2 are as defined herein. There was no significant cytotoxicity against the human embryonic kidney cell line (HEK293). 31 (s &gt; 1364279 Example 4 Analysis of inhibition of type B monoamine oxidase by 1,2,3,4-tetrahydroisoquineline derivatives Some of the type B monoamine oxidase B inhibitors were identified in the literature (4). These include: rasagiline, rasamyl-containing derivative TV-3326 and selegiline hydrochloride (10) , in), via ERK-related pathways (ERK- Related pathways regulate the release of amyloid precursor protein (App) protein. The process of indirect regulation of the release of soluble starch-like precursor protein a (sAPPa), which indirectly reduces the insoluble beta-type starch peptide (Αβ) Therefore, these type B monoamine oxidase inhibitors may be used to treat Alzheimer's disease. These type B monoamine oxidase inhibitors have a partial structure of pr〇pargylamine' and are found in the literature (5). It is important for the activation of the signal, but it is not related to the inhibition of the activity of the type B monoamine oxidase. Therefore, the present invention uses the chemical synthesis step described in the first embodiment to repair the u,3,4-tetrahydroisoquinoline aU^tetmhydrOisoquinoline) It is decorated with a chemical structure similar to that of selegiline or rasagiline hydrochloride, and modified to have a chemical structure similar to that of an acetylch〇Unesterase inhibitor. To explore the possible roles of the derivatives with similar structure to the B-type monoamine oxidase inhibitor (Ua_d and for the proteolytic protein proteolysis process). Firstly, purify the type B monoamine oxidase (MA〇_B) from the mouse cerebral cortex. Then, the derivatives were tested for the inhibition of the activity of the type B monoamine oxidase. 1. The fluorescence test measures the monoamine oxidase protein content in the brain of the mouse. The F344/N.°〇's male mouse is broken (decaP secret zed) and the brain is taken out. Brain cortex 'to obtain type B monoamine oxidase (Ma〇b). The extracted cerebral cortex was immersed in phosphoric acid 32 1364279 _ buffer (potassium phosphate buffer (PBS) solution', frozen in liquid nitrogen, then -80 Store at °C for three days. Then immerse the frontai cortex homogenate in 〇·ι μ of 4. (: Potassium acetate buffer (PBS) (ρΗ7.4) Centrifuge at 14,000 rpm for 10 minutes. The supernatant can be obtained as a source of B-type monoamine oxidase (MA0-B). The standard solution contains • Ο·1 M potassium silicate buffer (PBS) and albumin (albumin). Formulated into different concentrations of ladders. degrees. 10 μΐ of each of the standard solutions of different concentration gradients was added, and 2 μ μ of the BCA reagent was added to mix. In the same way, dilute the supernatant from the cerebral cortex and use it as a storage solution # (St〇cksolution), take 10 μΐ from the storage solution, and add 200 μL of BCA reagent to mix into a sample solution. The standard solution and the sample solution were then incubated together at a temperature of 37 〇c for 3 minutes. 200 μΐ was taken from each of the above solutions, and added to a 96-well culture dish, and the protein content was measured at a fluorescence of 595 nm using a fluorescence microplate reader. 2. B-type monoamine oxidase (MA〇_B) activity inhibition test will be 11; / 1111 horseradish peroxidase (11 槪 1 ^ 111 ^ 〇 咖 coffee, 1 ^)), 1 should be benzylamine (benzylarmne) and 50 μΜ Amplex red is dissolved in 〇·ι M PBS and added to the % hole culture tray. • The above supernatant containing B-type monoamine oxidase (ΜΑ〇·Β) (protein content, 8 μμ (4), and then the preparation Each group of the contacts was converted into (10) 丨 with DMSO, and the bridging solution was added to each hole. These mixtures were allowed to act at room temperature for 6 minutes, and the absorbance value was measured with a camping light analyzer and the IQ was calculated by the following formula. %: The half-degree of inhibition is defined as the concentration required for the inhibitor to inhibit the activity of the enzyme by 5% in the present embodiment. Inhibition rate (%) = 1 - [(Experimental group OD595 / protein - experiment) Group OD595)/blank group 〇d595]x 1〇〇% 33 1364279 OD595: Absorbance value at a wavelength of 595 nm Protein: refers to the protein content of the control group 3. Statistical analysis is as described in Example 2. Table 1 Inhibition B Type monoamine oxidase (MAO-B) activity and logP value of 1,2,3,4-tetrahydroisoindole derivatives lla-d, 12a-d" Compound R2 IC5〇(μ Μ) log production _ Rezaglan 2.1 soil 0.6 2.295 11a N-ethyl-N-methylamino 21.5 soil 1.0 2.252 lib 1-pyridyl b pyridine group 13.9 ±0.5 2.235 11c 1- stone than base 115.7 soil 2.2 2.632 lid 1-Ferlingen 18.7 士1.6 1.567 12a N-ethyl-N-methylamino 12_8 士2.0 2.688 12b I-0 ratio 17 each bite base 14.9 士 1.1 2.671 ψ 12c 1-stone ratio bite base 11.6 士0.7 3.088 , 12d 1-?Ferlingen 18.5 soil 0.8 2.033 Calculate lipophilicity by CAChev. 6.1 software 4. The results are shown in Table 1, although 1,2,3,4-tetrahydroisoquino The morphological derivative (113-(1) has a lower inhibitory ability than rasagiline, but these derivatives (lla-d) can inhibit the indole monoamine oxidase when the IC5 is 10-20 μΜ (ΜΑ0- Β) 50% activity. However, if the 1,2,3,4-tetrahydroisoquinoline (S) 34 1364279 derivative (lla-d) propargyl is composed of cyclopropane fluorenyl (cycl Substituting 〇pr〇pyhnethyi) to obtain an anthracene, 2,3,4-tetrahydroisoquinoline derivative (^^^. ^Yi^tetrahydroisoquinoline derivative "仏·# The B-type monoamine oxidase (MAO-B) activity inhibition test showed that the ability of each derivative of 12a_d to inhibit the activity of type B monoamine oxidase (MAO-B) was similar to that of lla-d. At the same time, the fat-soluble WPoP^icity was calculated by CAChe v 6丄' software. 'The derivatives 12a-d and 11a-d were found to have similar size--and lipophilicity (increased logP value about 〇·45), which is convenient. For the preparation of a drug (the fat-soluble log /> value of a general drug is about 2-5). Therefore, it is confirmed that it has a structure of the formula (j) (wherein R1 • and the illusion are defined) 1, 2, The 3,4-tetrahydroisoquineline derivative can be used to inhibit the activity of type B monoamine oxidase (MAO-B). Example 5 Analysis of ERK activation ability of 1,2,3,4-tetrahydroisoquineline derivatives Msagiline or selegiline can be used to regulate ERK-related pathways

I

Activation of the ERK-related pathway, and activation of this pathway can directly or indirectly regulate alpha-secretase&apos; to regulate the amyloid precursor protein (App) protein cleavage process. Therefore, in this example, a derivative of a derivative chemical structure consisting of 1,2,3,4-tetrahydroisoquineline and having a cyclopropylmethyl composition and an amine formazan group was tested. Whether the substance can significantly regulate the ERK-related pathway. 1. Cell culture as described in Example 2. 2.1,2,3,4-Tetrahydroisoquinoline Derivatives for the activation of £1^ using anti-phospho- extracellular signal-regulated kinase 1 /2 antibody (anti-phospho-ERK 1 (purchased from Cell Signaling Technology) 'and anti-extracellular signal-regulated kinase 1/2 antibody 35 1364279 (anti- ERKl/2) (purchased from Cell Signaling Technology) to measure the activated state (disc acidification) of ERK»T-20 cell line to 5xl05 The density of cells/well was cultured in DMEM medium containing 10% fetal bovine serum and cultured for 18 hours at 37 ° C. These cells were then cultured in DMEM containing 1 pg/ml tetracycline. The medium was cultured at 37 ° C for 18 hours. Before the activated ERK test, the above DMEM medium containing 1 pg/ml of tetracycline was replaced with DMEM medium containing 0.5% fetal bovine serum, and then added.测试μΜ test the derivative to carry out the reaction. After the reaction, the cells are placed on ice to stop the reaction, and

The medium was drained. After removing the cells, 50 mM Tris-HCl (pH 8.0), 150 mM sodium hydride (NaCl), 5 mM ethylenediaminetetraacetic acid (EDTA), 1 mM original was used. Sodium orthovanadate, 1% Triton X-100, and protease- and phosphatase-inhibitor cocktails are used to lyse cells. BCA reagent (purchased from Pierce) was used to measure protein concentration. Each group of cell lysates was prepared to contain 50 pg of protein, and electrophoresis was carried out by using 12% SDS-polyacrylamide electrophoresis gel to separate proteins of different molecular weights, and then electrophoresed and then immunized. Immunoblot, an antibody against anti-phospho- extracellular signal-regulated kinase 1/2 (anti-phospho-ERKl/2) to discriminate between phosphorylated (activated) ERK and anti-extracellular signal-regulated kinase 1/2 The antibody (anti-ERKl/2) was used to discriminate the ERK of the non-squamized (non-activated state). In the present example, the T-20 cell line was treated with a medium containing 1% DMSO and 1 pg/ml tetracycline as a positive control group; the other groups contained different compounds (10 μM), The τ·20 cell strain was treated with 1% DMS0 and 1 pg/ml tetracycline medium as a test group of different compounds.

&lt;S 36 ^364279 3. Statistical analysis The same as described in the second embodiment. Table 2. Relative activation of ERK by 1,2,3,4-tetrahydroisoquine derivatives (treated with derivatives)

Cell group vs. untreated cell group) Compound activated extracellular signal-regulated kinase l/2 (p-ERK/ERK, 0/〇) Positive control group 100 Rezaglan 131 ± 14 12a 131 ± 10 12c 155 ± 28*12d 138 ±39 5 Master: p-ERK/ERK indicates squaricized extracellular signal-regulated kinase 1/2 relative to non-squaricized extracellular signal-regulated kinase 1/2. Each value is presented as a mean soil standard deviation (SD). * represents PC0.05, which is significantly different from the control group. As shown in Table 2, 7-(1-indolylcarbonyloxy)-N-cyclopropanemethyl-1,2 obtained by substituting R1 for cyclopropanemethyl and R2 for 1-indopyridyl group, 3,4-tetrahydroisoquinoline (7-(l-Piperidinecarbamoyl〇xy)-N-cycl〇pr〇pyimethyl-l,2,3,4-tetrahydroisoquin 〇line)(12c) ' 10 μΜ 12c test group Compared with the 1 〇μΜ rasagiiine test group, the ability to activate ERK was 1.2 times better than that of the Rezagillin test group, and PC0.05 was significantly different in statistical analysis. The l2a and 12d test groups and the Rezagillin test group have similar abilities to activate ERK, confirming the l, 2, 3, 4-4 with the structure (where R1 and R2 are as defined)

&lt;S 37 1364279 Hydrogen isoquinoline derivatives have the ability to activate ERK. Example 6 1,2,3,4-Tetrahydroisoindolin Derivatives 8 from 1&gt;〇[Analysis of the degree of release. Conventional B-type monoamine oxidase inhibitor (IV) can directly or indirectly activate the ERK-related pathway (ERK_re- Kiss's regulation of the starch-like precursor protein (App) protein cleavage process leads to the indirect regulation of the release of the soluble progesterone protein αφΑΡΡα), which indirectly inhibits the insoluble-type P-type starch peptide. It was confirmed in Example 5 that 4_tetrahydroisoindole derived #, , C and d have the ability to activate. Therefore, in the present example, the γ-3 〇 cell line was subjected to a test for the degree of release of 1,2,3,4-tetrahydroisoindole derivatives (12a, . and phantom # sAppa. 1. γ-30 cell strain And its culture is shown in the literature (3) and (6), which is briefly described as follows. The literature is transfected with pS7 Chister ovary cen (CH0 cell) to obtain γ 3 . 〇 stably transfected cell lines. γ-30 stably transfected cell lines exhibit full-length amyloid precursor protein (Αρρ) and human PS1, Aph-la2, and Pen-2 proteins (Human PS, ΑρΜα2, and pen_2), • As a _ a type of decomposed amyloid precursor egg from the (App) of the New Zealand cells. 2. 1,2,3,4-tetrahydroisoquinoline derivatives affect the release of sAPPa analysis will be The corresponding cell lysates of the corresponding groups in Example 5 were formulated into the same protein content, and electrophoresis was performed by SDS-PAGE to separate proteins of different molecular weights, and an anti-study soap antibody (6Ε10) was used (purchased from the United States). ChemicomCo·) performs the Western blotting method (WestemB丨〇t). In this example, the γ·30 cell strain is used as a medium containing 1% DMSO. As a negative control group; the other groups were treated with a medium containing different compounds (1〇μΜ), 1% 〇Μ80, and 1 μ§/ιηΙtetracycline, respectively, as a test group of different compounds. 38 364279 3 · Statistical analysis. Same as described in Example 2. 4. Results γ-30 stable (4) Cell line expression of full-length ship powder egg (four) protein (Liao) and human PS Aph-1 α2, and Pen-2 protein. When α-type secretase decomposes the amyloid precursor protein, it produces a soluble starch-like precursor protein a (sApPa), so it can be used to detect whether the compound trans-soluble starch-like precursor protein a (sAPPa) Released. The system uses the single anti-body (6E1G) of ΑβΜ7 for Western blotting, _ soluble starch-like precursor protein (sAppa), and the result is as shown in Figure 4A. The three groups of experimental groups (10), e and d) had more soluble protein precursor protein a (sAppa) protein than the negative control group, and the 12c test group was compared with the Rezagillan test group. Soluble class powder precursor protein a (SAP) measured by the test group P is good. Then the results of the western point ink method are quantitatively analyzed. 'The result is shown in Figure 4B TF ' 1,2,3,4·tetrahydroisodamine derivative (12a, e and d test group) It can promote the release of soluble fine powder precursor protein α. The 12c test group has better promotion effect than the Rezagillan test group. Therefore, it has been confirmed to have the structure of (j) (its &quot;i and illusion Definitions > 4 - Tetrahydroisophthalate can be used to promote the release of soluble starch precursor protein a (sAPPa). The present invention provides a novel U3,4_tetrahydroisoindole derivative, in particular to a 1,2,3,4_tetrahydroisoindole derivative which can be used for chemotherapy Alzheimer's disease. In order to inhibit the production of sAPPa by inhibiting the activity of sputum-type secretase, thereby reducing the production of β-type sclerotin. It therefore reflects potential neuroprotective activity and can be used to treat the pathological mechanisms of Alzheimer's disease. 39 &lt; S ') 1364279 The present invention provides the following advantages: 1, 2, 3, 4 · money dissimilar material, due to the structure of formula (1) 'where R1 and R2 as defined in the text 'tested to inhibit the secretion of sputum secretase activity, thereby inhibiting the production of Αβ' can be used for treatment Alzheimer's disease. The present invention provides a (3) (10) hydrogen heterogeneous contact with a structure such as formula (1) 'wherein R1 and as defined herein' have been experimentally confirmed to have a relative antibacterial type of sulphate inhibitor, which is better. ERK activation ability and better ability to promote sAppa release can be used to treat Alzheimer's disease. The invention provides the species (1)' wherein R1 and R2 are as defined herein, and it is confirmed by experiments that the γ-type secretase activity can be inhibited simultaneously, thereby inhibiting the production of Αβ, and activating the erk pathway to promote the release of sAppa, which can be used for treatment. Alzheimer's disease. The detailed description above is a detailed description of a possible embodiment of the present invention, and the embodiment of the present invention is intended to be limited to the embodiments of the present invention. In the scope of the patent in this case. To sum up, this case is not only innovative in terms of method, but also able to enhance the above-mentioned multiple force effects compared with the use of customary articles. It has fully complied with the statutory invention patent requirements of novelty and progressiveness, and applied for it according to law. You are requested to approve the invention patent. Apply for the case, in order to invent the invention, to the sense of virtue. BRIEF DESCRIPTION OF THE DRAWINGS Fig. - is a flow chart for preparing a W'4·tetrahydroisodimide derivative in the embodiment - a diagram showing 1,2,3,4-tetrahydroisoindole in the examples. Lin derivative inhibits the activity of sputum-type secretase; . 胄三为实三中, i, 2, 3, 4· tons of biological cytotoxicity test; Figure 4 Α is the real four towels to (2) heart hydrogen The heterodyne derivative affects the miscellaneous starch--precursor protein a (SAPPa) release of the Western blotting method results; - ^ four 8 is the real _ four towels with l2,3,4, hydrogen different 011# derived Na Analysis of the relative release degree of the miscible starch-like precursor protein a (SAPPa). Φ [Explanation of main component symbols] None [References] 1. Prozorovski, YB; Pavlova, LV; Suslova, IM; Belozerova, LV; Kokushkina, AV; Sazonova, AV Russ. J. Appl. Chem. 1995, 68, 589 -593. 2. Liao, YF; Wang, BJ; Cheng, Η. T.; Kuo, LH; Wolfe, MSJ Biol. Chem. 2004, 279,49523 - 49532.

3. Bakshi, P.; Liao, YF; Gao, J.; Ni, J.; Stein, R.; Yeh, LN; Wolfe, MSJ Biomol. Screening 2005, 10, 1 - 12. 4. Yogev-Falach, M.; Amit, X; Bar-Am, 0.; Youdim, Μ. BH FASEB J. 2003, 17,2325 - 2327. 5. Bar-Am, 0.; Yogev-Falach, M.; Amit, T. Sagi, Y.; Youdim, Μ. BHJ Neurochem. 2004, 89, 1119 - 1125. 6. Kimberly, WT; LaVoie, MJ; Ostaszewski, BL; Ye, W.; Wolfe, MS; Selkoe, DJ Proc. Natl Acad. Sci. USA 2003,100, 6382 - 6387.

Claims (1)

Correction replacement page for September 22, 100. 1. A 1,2,3,4-four different 啥 ( (1,2,3,4 七加1^(11&quot;〇丨5{^11丨11〇丨a derivative selected from the group consisting of the following compounds: 7_(]^_methyl_^_ethylaminemethoxine)_N_cyclopropanemethyl-1,2,3, 4-(N-Methyl-Ne^iylcarbamoyloxy)-N-cyc]opropylmethyl- l,2,3,4-tetrahydroisoquinoline), 7-(1-stone it) N-cyclopropene methyl-i, 2,3,4_tetrahydroisoquinoline (7--N-cyclopropylmethyl- l,2,3,4-tetra-hydroisoquinoline), 7-(1-stone ratio bite Oxygen)-N-cyclopropanemethyl-1,2,3,4-tetrahydroisoquinoline (7-(! -Piperidinecarbam〇yi〇xy)_ N-cyclopropylmethyl- 1,2,3,4-tetrahydroisoquinoline) 7-(1-Mflindine oxy)-N-cyclopropanemethyl-1,2,3,4-tetrahydroisoquineline (7-(1-]^〇17)11〇111^3 〇 1 (^1 kidney)-N-cyclopropylmethyl-l, 2,3,4-tetrahydroisoquinoline). 2. The derivative according to claim 1, wherein the derivative is 7-(N-methyl-Nethyl -N-Methyl-N-ethylcarbamoyloxy-N-cyclopropylmethyl-1,2,3, 4-tetrahydroisoquinoline) ° 3. Derivative as described in claim 1 of the patent application, which is 7-(1-5 bis octyloxy)~N-cyclopropanemethyl-1,2 ,3,4-tetrahydroisocarboyloxy-N-cyclopropylmethyl-l,2,3,4-tetra-hydroisoquinoline ° 4. Derivatives as described in claim 1 The derivative is 7-(1-indolylcarbonyloxy)-N-cyclopropanyl-1,2,3,4-tetrahydroisoquinoline (7-(1 -Piperidinecarbamoyloxy)-N-cyclopropylmethyl -1,2,3,4-tetrahydroisoq 42 1364279 September 22, 100 revised replacement page uinoline). For example, if you apply for a full-time 丨 丨 丨 , , , , 贿 贿 贿 贿 贿 贿 四 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 环 环 环 环 环 环The method of the derivative comprises the following steps: Step (4): reacting 1,2,3'4-tetrahydroisoindole with a trifluoroacetic acid needle and a hydroxide to obtain a &gt; 1-triethanyl group -1,2,3,4-tetrahydroisophthalocyanine; Step (b-wide N-three chaotic ethyl-hydrogen-like hydrogen-isoindole and chloroacetic acid chloride and gasification reaction to obtain 7- Ethylene-N-trifluoroethylidene-tetrahydroisoquinoline; Step (c): 7-epi-N-trifluoroethyl--, 2,3,4-tetrahydroisoquine The porphyrin is reacted with hongqi peroxybenzoic acid to obtain 7-gas ethoxycarbonyl_N-trifluoroethenyl-1,2,3,4-tetrahydroisoquinoline; Step (d): reacting 7-gas ethoxycarbonyl-N-trifluoroethyl fluorenyl-1,2,3,4-tetrahydroisoindolin with hydrazine thiolate to obtain 7-carbyl group- 1,2,3,4·tetrahydroisoindole hydrochloride; step (e): 7-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride and cyclopropanemethyl bromide, And reacting with potassium bromate to obtain 7-hydroxy-N-cyclopropanyl-i,2,3,4-tetrahydroisoindole; and step (f): 7-trans-N-cyclopropane Hyun•Mercapto-1,2,3,4·tetrahydroisoindole, with N-ethyl-N-methylaminomethylguanidinium chloride, 1-pyrrolidinylmethylhydrazine, hydrazine-hydrazide The reaction of hydrazinyl chloride or buffaloyl thiol-based gas and sodium hydride to obtain hydrazine, 2,3,4·tetrahydroisoquinoline derivative as described in claim 1 Things. 43 13.64279 t, September 22, pp. 22 Amendment Replacement page Pharmaceutical composition 'includes 4 as described in the scope of the patent scope, qi derivative or pharmaceutically acceptable salt type, and appropriate medicine An acceptable excipient or a pharmaceutical composition according to item 7 of the patent application is for inhibiting sputum-type secretase activity. 9. The pharmaceutical composition of claim 7 is prepared by the activation of extracellular signal-regulated protein kinase (ERK)^^#, the release of the sexual starch-like precursor protein α. 10_ The pharmaceutical composition of claim 7 of the scope of the patent application is for simultaneously inhibiting the activity of the sputum-type secretase and the pathway of activating the extracellular lysing kinase (4) llular clerk ERK), thereby promoting the soluble starch-like precursor The release of protein ^. 11. The pharmaceutical composition according to claim 7 for treating a disease caused by an increase in insoluble amyloid beta, resulting in necrosis of nerve cells, loss of memory and learning function, dementia and impaired cognitive processes thereof . 12. The pharmaceutical composition according to claim 11, wherein the disease in which the cognitive process is impaired is Alzheimer's disease or other dementia, or Parkinson (sDisease). 13. The pharmaceutical composition of claim 7, wherein the excipient can be a diluent, a filler, a binder, a disintegrant, a lubricant. 14. The pharmaceutical composition of claim 7, wherein the excipient can be microcrystalline cellulose or polyethylene. Polyviny丨pyrrolidone (PVP), corn starch, modification; modified starches, socjium starch glycolate, resin, gelatinized starches, sugars, polyethylene glycol 1364279 September 22, 100 correction (polyethylene glycol, PEG), polyethylene (poly^nyl alc〇h〇l), hydroxypropyl cellulose, methyl cellulose, methylol Hydroxymethyl cellulose, hydr〇xypr〇pyl methylcellulose 〇 ε: to· 45 1364279 A i'r. sAPP (雷一吉,3⁄4 ri 7;r'i test group 12a test group 12c test 乜12d child test 15/3⁄4 :ΞΗ!:ί'--Ξνζ θ Control: Ιί!β;':1 〉::'"H:L'f1 ' ... Ray: Eguilan vs. 12a test group 12c test group 12d<->:: Figure 4B