TW393454B - Novel benzamides and pharmaceutical composition thereof for use as inhibitor of cysteine protease - Google Patents

Description

A7 B7 Patent Application No. 861 17691 Revised Chinese Manual (March 88) V. Description of Invention (4)

〇 In addition, some people have been working on the development of reversible non-phthalate calpain inhibitors. JP 8183759, JP 8183769, JP 8183771, and EP 520336 describe the addition of dipeptides derived from saturated carbocyclic rings, such as cyclohexane, or saturated heterocyclic rings, such as hexahydropyridine, to these peptide inhibitors instead. Amino acid, a novel calpain inhibitor is obtained. In addition, it has been described that it is derived from a compound of the formula ^ phenylΛΛ aryl group 020, especially a compound in which the aryl group is a phenyl group, and this phenyl group may have a simple substituent such as an alkyl group (WO 95/09838 WO 93/14082; WO / 12140; EP 363284; J 59206-344 and DT 205079). It is not known whether the substituent on the phenyl ring affects the inhibitory activity of the compound. The object of the present invention is to provide a non-peptide benzamidine with improved activity. The inventors found that this purpose can be benzamidine of formula I (please read the precautions on the back before filling this page)-Λ Order Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (R2) r η

Ν '.' CHO Η R3

And their tautomeric and isomeric forms, and, where appropriate, their physiologically acceptable salts are reached, of which: this paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) A7 A7

V. Description of the invention G The present invention relates to a novel benzyl ammonium tower and its disease control enzymes are cells of the cysteine protease group ... in a variety of cells. The high-concentration white enzyme is required. High-concentration live white enzyme, Maiprotein 1 or micro-protease, is different from the subheading 11 or milli-calpain. The former is activated by calcium ion concentration. The latter is activated at the millimolar concentration of calcium ion (ρ Dica 'Int. J. BioccW 22 (8) 199〇, 81122). There are still others and other enzymes (calenzyme) (Kee et al., B101. Chem. Hoppe_Seyler, 376 (9) (1995), 523 9). Calpain is considered to play an important role in a variety of physiological activities. Includes: regulatory 'proteins, such as protein kinase c, cytoskeletal proteins (〇 1105] ^ 1 to 31? 1 ^ 411) (such as ^ 18? 2 and spectrin (81 ^ (; 出 11)) Muscle protein, protein involved in platelet activation, protein involved in mitosis and other HJ Barrett equals Life Sci. Niu (1991), 1659-69 and KK Wang equals Trends in Pharmacol. Sci., U (1994), 412-9 Cleavage of proteins in the bloodstream; protein breakdown in rheumatoid arthritis and neuropeptide metabolism. High calpain levels have been measured in a variety of pathophysiological processes, such as cardiac ischemia (such as myocardial infarction), kidney or central nervous system ( (Such as stroke). Inflammation, muscular dystrophy, cataracts of the eye, damage to the central nervous system (such as trauma), and Alzheimer's disease (see κ. K. Wang, supra). So imagine that these diseases are related to excessive intracellular calcium levels. Highly related. For this reason, the feed-dependent process is over-activated and can no longer be physiologically adjusted. Therefore, it is necessary to _ _ 4-This paper size applies to Chinese national standards (CNS > A4 specifications (210X297 mm> Suppression -~ * (Please read the precautions on the back,-> this page)

* 1T The staff of the Central Standards Bureau of the Ministry of Economic Affairs has eliminated the cooperative seal of the cooperative. V. Description of the invention (2 Μ7) The excessive activation of the protease from the consumer cooperative of the Central Standards Bureau of the Ministry of Economic Affairs can also lead to pathophysiological processes. Inhibitors can be used to treat these diseases. This idea has been proved by multiple studies. Seung-Chyul Hong is equivalent to its in Stroke 25 (3) (1994), 663-9 and RT Bartus is equivalent to its in Neurological Res. 12 (1995 ), 249-58, published reports showing the role of calpain inhibitors in acute neurodegenerative diseases or ischemia, such as those seen after stroke. The need for calpain inhibitors improved after experimental brain trauma. Memory function and neuromuscular disorders (KE Saatman et al. Proc. Natl. Acad. Sci. USA, £ 1, (1996), 3428-3433) »CL Edelstein is equal to Proc. Natl. Acad. Sci. USA, 21 ( (1995), 7662-6, reported the observation of the need for calpain inhibitory renal effects on hypoxia-injured g. Yoshida, Ken Ischi equal to Jap. Circ. J. 59 (1) (1995), 40-8, reported that Calpain inhibitory The preparation is helpful for damage caused by ischemia or reperfusion. Because calpain inhibitor is required to inhibit the release of -AP4 protein, it can be used as a therapeutic agent for Alzheimer's disease (J. Higaki et al., Neuron, U (1995), 651-59). The release of interleukin-1 π is also inhibited by on-demand protease inhibitors (N. Watanabe et al., Cytokine 6 (Color) (1994), 597-601). Someone It is further shown that calpain inhibitors are required to have cytotoxic effects on tumor cells (E. Shiba et al. 20th Meeting Int. Ass. Breast Cancer Res., Sendai Jp, 1994, 25-28 Sept., Int. J. Oncol. 5 (Suppl ·, · (1994), 381) ° For other applications requiring calpain inhibitors, see KK Wang in Trends in Pharmacol. Sci., 15. (1994), 412-8). A description of calpain inhibitors. However, it is mainly believed to be read first-prepare-back note ~ meaning. Item Page Pack 1 Ding Line The paper size is applicable to China National Standard (CNS} A4 Specification (2 丨 0 X 297 (Mm) A7 B7 V. Description of the invention (3 Please read it first. Back: Note: Item 4 'This page is not reversed or peptide Preparations. Irreversible inhibitors are generally alkyl compounds, which have the disadvantage of non-selective reactions in the body or are unstable. Therefore, these inhibitors often have unwanted side effects such as toxicity, so their use is limited, or they are useless. Irreversible inhibitors include, for example, epoxide E 64 (EB McGowan et al., Biochem. Biophys. Res. Commun. 158 (1989), 432-5), a-paint (11 · Angliker et al. ,, J. Med. Chem. 35. (1992), 216-20) and disulfides (R. Matsueda et al., Chem. Lett. (1990), 191-194). The Ministry of Economic Affairs ’Central Standards Bureau ’s labor-consumption cooperation. Many of the known reversible inhibitors of cysteine phthalase, such as calpain, are peptide aldehydes or ketones, especially dipeptides and tripeptides, such as Z -Val-Phe-H (MDL 28170) (S. Mehdi, Trends in Biol. Sci. 1-6 (1991), 150-3) and compounds described in EP 520336. Under physiological conditions, peptide aldehydes often have disadvantages, for example, they are unstable due to their reactivity (JA Fehrentz and B. Castro, Synthesis, 1983, 676-678), can be quickly metabolized and have low water solubility. (Aqueous solution is important for intravenous application), or it is slower to pass through the cell membrane, such as blood brain disorder and neuron cell membrane (requires calpain is an intracellular enzyme, any inhibitor must enter the cell). Therefore, the most well-known skin inhibitors MDL 28170, AK 275 and AK 295 (Seimg-Chuyl Hong et al., Stroke 25Γ3) (1994), 663-669; RT Bartus et al., J. Cerebral Blood Flow and Metabolism , 14 (1994), 537-544) Animals have been used for pharmacological studies, but the effects of these substances can only be manifested in infrequent treatments, such as intraventricular or intra-arterial injection. Therefore, the use of calpain-reducing peptide aldehydes or ketones for the treatment of diseases is limited or unhelpful. 6-This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 Patent Application No. 861 17691 Amendment of Chinese Manual (March 88) V. Description of Invention (4)

〇 In addition, some people have been working on the development of reversible non-phthalate calpain inhibitors. JP 8183759, JP 8183769, JP 8183771, and EP 520336 describe the addition of dipeptides derived from saturated carbocyclic rings, such as cyclohexane, or saturated heterocyclic rings, such as hexahydropyridine, to these peptide inhibitors instead. Amino acid, a novel calpain inhibitor is obtained. In addition, it has been described that it is derived from a compound of the formula ^ phenylΛΛ aryl group 020, especially a compound in which the aryl group is a phenyl group, and this phenyl group may have a simple substituent such as an alkyl group (WO 95/09838 WO 93/14082; WO / 12140; EP 363284; J 59206-344 and DT 205079). It is not known whether the substituent on the phenyl ring affects the inhibitory activity of the compound. The object of the present invention is to provide a non-peptide benzamidine with improved activity. The inventors found that this purpose can be benzamidine of formula I (please read the precautions on the back before filling this page)-Λ Order Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (R2) r η

Ν '.' CHO Η R3

And their tautomeric and isomeric forms, and, where appropriate, their physiologically acceptable salts are reached, of which: this paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 5. Description of the invention (5 A7 B7 R1 is phenyl, hydrazone, quinoline, isoquinoline, tetrahydro4line, tetrahydroisoquinoline 'pyridine' pyrimidine, pyridine, slotted cultivation, oxazoline , Oxoline, pyrimidine, benzotephene, benzofuran, furan, or indole. Here, the aromatic ring or heteroaromatic ring can be substituted by three R4 groups, R2 is hydrogen'gas' bromine, fluorine, there is Or without Ci_C4-hydrocarbyl group, _NHC〇_ CVCV alkyl group--NHCOPh, -NHCO; group, -NHSC ^ -Cu-alkyl group-CONH2, COOH, -COO-Cu-alkyl group, -O-Cw alkyl -'- CO-NH-Cw alkyl, no 2 or NH 2 substituted phenyl, is a q-C6- hydrocarbon group, which may carry cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo A heptyl, adolyl, phenyl, pyridine or fluorenyl ring, which may be substituted with one or two R4 groups or a _SCH3 group. It is a ^ bamboo alkyl group, -O-Ci-Cc alkane Radical, OH, Cl, F, Br, I, CF3 Ν02, NH2, CN, COOH, COO-CVC4-alkyl, -NHCO-CVCV alkyl, -NHCOPh " specific bite, (R5 each is hydrogen, C-4-alkyl or a ring in common), _s. 2_Cl_c4-alkyl or -SO2Ph j is a single bond '-^! ^) ^,-^! ^) ^-. -^! ^). -, ^^ !; ^ "-(CH2) 〇- >-(CH2) m-S0- (CH2) o-»-(CH2) m-S02- (CH2) 〇- »-CH = CH-, -CsC-, -CO-CH = CH_, -CHNCH-CO-,-(CH2) m-CO- (CH2). -,-(CH2) m-NR5CO- (CH2). ·, (R5 = H, Cw group,-(CH2) m-CONR5- (CH2).-'-(CH2) m-NHS02- (CH2) .-,-(CH2) m-S02NH- (CH2) -, -NH-CO-CH = CH-, -CH = CH-CO-NH- or phenyl substituted with or without R2 group, is a number of 1 or 2,

R

R

X -8-This paper size applies Chinese National Standard (CNS) Α4 specification (210X297 mm) Please read * Read · Back · Notes-Item ί Binding Line A7 __________B7___ V. Description of Invention (6) m Yes The number of 0, 1, 2, 3 or 4 and 0 is a number of 0, 1, 2, 3 or 4 "The compound of formula I can be used as a racemate or as a pure enantiomer or as a non-mirror stereoisomer. If pure enantiomeric compounds are required, these compounds can be prepared by conventional methods for the analysis of racemic compounds of formula I, or their intermediates using suitable optical activity assays or acids. Alternatively, the enantiomeric compounds can also be used commercially Commercially available compounds such as optically active amino acids. The present invention also provides meso or tautomeric compounds of compounds of formula I, such as compounds in which the hydrazone group of formula I exists as a dilute alcohol. Some of these are novel Compound I may contain a basic or acidic group. In this case, the compound may exist in the form of a physiologically acceptable salt thereof. These salts may be prepared by reacting the compound with a suitable acid or base. A suitable acid is, for example, Hydrochloric acid, citric acid, tartaric acid, lactic acid Phosphoric acid, acetic acid, formic acid, maleic acid, fumaric acid, malic acid, succinic acid, malonic acid, methosulfuric acid, and benzoic acid. The test is suitable, in particular, sodium hydroxide Hydrogen, ammonia, and simple organic amines. The better-printed formula I benzamidoaldehyde is printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economics, where R2 is hydrogen, Ci_C4_fluorenyl, fluorine, gas or bromine. R3 is a CHr phenyl group, this group may be substituted by R4, and R1 ′ X, η ′ m and 〇 are as defined above. The benzamidine aldehyde according to the present invention can be prepared by various routes, such routes See the following synthesis scheme. 0-9- This paper size is applicable to Chinese National Standards (CNs) A4 specifications (210X297 mm). 5. Description of the invention (Synthesis scheme (R2) n, Rl —

COOH R3 A7 B7

R3 gasification

2-HN ^ C〇〇H

V 1, NH (CH3) OH 2. Remove protective group

R3 CONH ^ CON [CH ^ OH VII R3 people (Please read the precautions on the back first f this page)-equipment ·

R3 HjN ^ CONfCHJOH (R2) n

Enter Yunyuan -β

R3 Λ + HjN COY (R2) n

Rl-

VIII

R3 CONH / CO-Y line IX · Dumpling production by the Ministry of Economic Affairs of the Central Bureau of Standards and Consumption Co-operation Consumption Du Benzhi Derivatives of benzoic acid II are linked to the appropriate amino alcohol III to prepare the corresponding benzamidine hydrazone IV. To achieve this, conventional peptide coupling methods can be used, such as those described in C.R. Larock, Comprehensive Organic Transforamtion, VCH Publisher, 1989, page 972, or Houben-Weyl, Methoden der organischen Chemie, 4th edition, E5, Chapter V. 10- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 Printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (8). It is preferably activated with the formula IΓ " Acid derivatives in which the acid group COOH is converted into a COL group. L is a leaving group such as C1, imidazole, and N-hydroxybenzotriazole. This activated acid is then reacted with amine to form amidine IV. This reaction is carried out in an anhydrous inert solvent such as methane, tetrahydrofuran and dimethylformamide at -20 ° C to + 25 ° C. These pure derivatives IV can be used in various conventional oxidation reactions (see CR Larock, Comprehensive Organic Transformations, VCH Publisher, 1989, page 604 onwards) such as Swern + and Swern-like oxidation (1 '.!' · Tidewell, Synthesis 1990, 857 -70), oxidation of sodium aldehyde / TEMPO (S.L. Harbenson et al., Supra) or Dess-Martin reagent (j. Qrg Chem. Short (1983), 4155) to the aldehyde derivative of the invention. This reaction is preferably carried out in an inert aprotic solvent such as dimethylformamide, tetrahydrofuran or dichloroγ-alkane using an oxidizing agent such as DMSO / pyridine xS03 or DMSO / oxidase, depending on the method used. (See above). Alternatively, phenylarsinoic acid II may be combined with amine hydroxamic acid derivative phenylarsinoaldehyde I. To this end, the same anti & Hydroxamate derivatives VI can be prepared with protected amino acids V and light amine trans &. As described above, the aforementioned method for preparing amidine is used. The protective agent, Boc, is cleaved by conventional methods, such as trifluoroacetic acid. The resulting stupid amylase aminohydroxamic acid VII can be reduced to be converted into the aldehyde of the present invention, for example, using gasification chain as a reducing agent at -60 to 0 ° C in a inert solvent such as tetrahydropfrango test. One method can also be made into benzamidine carboxylic acid or acid derivative IX, such as vinegar or amidine, and then converted into the aldehydes of the invention by reduction method (please read the precautions on the back before A. Benwa )-Binding '11-Wood paper size applicable to China National Standard (CNS) A4 (210X297 mm) A7

V. Description of the invention (9 For the printing method of the Central Standards Bureau of the Ministry of Economic Affairs and the Industrial Cooperative Cooperative, see RC Larock, Comprehensive Organic Transforamtions, VCH Publisher, 1989, pages 619-26. This phenylamidoaldehyde I is a cysteine protease (If calpain I and 11 and cathepsin B and L are required) inhibitors, so it can be used to control diseases related to the need to split protease and / or cathepsin activity. Therefore, the benzamidine aldehyde I of the present invention can treat nerves Degenerative diseases, such as seen after ischemia, trauma, subarachnoid hemorrhage, and / or stroke, and / or for neurodegenerative diseases such as multiple infarct dementia, Alzheimer's disease, and / or Huntington's disease and / or for the treatment of myocardial injury caused by myocardial ischemia, renal injury after renal ischemia, skeletal muscle injury, muscular dystrophy, injury caused by smooth muscle cell proliferation, coronary arteries Spasm, cerebral vasospasm, ocular cataract and / or angioplasty after stenosis. In addition, the benzamidine group · I can also be used for chemotherapy of tumors and their metastases, and / or for Treatment of diseases with increased interleukins such as inflammation and / or rheumatism. The inhibitory activity of this benzamidine group I was determined using an enzyme test, which is a practice commonly used in the literature, that is, the inhibitory enzyme activity is determined5 〇% The concentration of inhibitor used (= IC50). In this way, the inhibitory activity of benzamidine group on calpain I, calpain 11, and cathepsin B is required. 0 cathepsin B-test The inhibition of cathepsin b was determined by a method similar to that published by S. Hasnain et al. In J. Biol. Chem. 268 (1993), 235-40. Two microliters of inhibitor solution (final concentration) prepared with the inhibitor and DMSO : I〇〇Juin to 〇〇〇1 # m) plus 88 microliters of cathepsin B (Cathepsin-12 obtained from human liver-this paper size applies Chinese National Standard (CNS) A4 specifications (2 丨 0 X 297 mm) Please read · Read the following: Item Λ Binding V. Invention Description (10) A7 B7 Member of the Central Standards Bureau of the Ministry of Economic Affairs (Consumer Cooperation) Printing B) (Calbiochem), at 500; uM buffer Diluted to 5 units). In this experiment, incubate at room temperature (25 ° C) for 60 minutes, and add 10 μl of 10 mM Z-Arg-Arg-pNA (in a buffer containing 10% DMSO) to start the reaction. The reaction was monitored at 405 nm with a microtiter plate reader for 30 minutes. IC50 値 was then determined from the maximum slope. Requires calpain I and II tests in a buffer containing 50 mM Tris-HCl, pH 7.5; 0.1 M NaCl; 1 mM dithiothreitol; 0.11 mM CaCl2. Fluorescent calpain-based matrix Suc-Leu-Tyr- AMC (25 mM, dissolved in DMSO, Bachem / Switzerland) (Sasaki et al. J. Biol. Chem. 1984, Vol. 259, 12489-12494) was used to study the inhibitory properties of calpain inhibitors. Separation of human-required calcium from red blood cells by methods similar to Croall and DeMartino (BBA 1984, Vol. 788, 348-355) and Graybill et al. (Bioorg. &Amp; Med. Lett. 1995, Vol. 5, 387-392) Protease "After several color analysis steps (DEAE-Agarose Gel, Phenyl Agarose Gel, Superdex 200 and Blue Agarose Gel), the purity of the enzyme obtained is> 95%, according to SDS -PAGE, Western blot analysis and N-terminal sequencing. The decyl light of the cleavage product 7-amino-4-fluorenylcoumarin (AMC) was measured by Spex-Fluorolog; lex = 380 nm and λβχ = 460 nm. After 60 minutes of measurement, it was found that when the experiment was performed at 12 ° C, the cleavage of the matrix was linear and the autocatalytic activity of calpain was low (see Chatterjee et al. 1995, Bioorg. &Amp; Med. Chem. Lett., Vol. 6, 6, 1619-1622). Experiments with inhibitors and DMSO solutions that require calpain substrates should have a final DMSO concentration of no more than 2%. -13- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297mm) Please read first. Read this and note the item printed on the page by the Central Standards Bureau of the Ministry of Economic Affairs and printed by the Cooper ’s Consumer Cooperative. V. Description of the invention (11) In a typical experiment, 10 microliters of matrix (final concentration of 250 / ί1η) and then 10 microliters of #_ calpain (final concentration of 2 micrograms / ml, that is 18 ηM) are added to 1 ml of containing Inside a small pool of buffer. The cleavage of the matrix by calpain was measured for 15 to 20 minutes. Then 10 microliters of inhibitor (50 or 100 " M DMSO solution) was added, and the inhibition of lysis was measured for 40 minutes. Calculate Ki 値 according to the conventional reversible inhibition equation, ie Ki =, where 1 = inhibitor concentration, vc = start speed before adding inhibitor, and v reaction speed at equilibrium. Ki < 0.5 #M measured with 2-phenyl · N- (3-phenylpropane_ι_aldehyde_2_yl) benzamide (Example 30). Therefore, this derivative is very similar to N- (1-3- allyl-propan-l-yue · _2_yl) benzamide (mR · Angelastro et al., J. Med_ Chem. 1990, 33, 11-13) is more effective. Decomposition of tyrosine kinase pp60src in platelets caused by calpain. After activation of platelets, tyrosine kinase pp60src is cleaved by calpain. Oda et al. Reported this in detail in J. Biol. Chem., 1993, Vol. 268, 12603-12608. It was shown that cleavage of pp60src was inhibited by calpeptin, a calpain inhibitor. This novel substance was also tested for its cellular effect according to this document. Human blood treated with citric acid was centrifuged at 200 gravity for 15 minutes. Collect platelet-rich plasma using platelet buffer (platelet buffer: 68 mM NaCn, 2.7 mM KC1, 0.5 mM MgCl2 x 6 H20, 0.24 mM NaH2P04 x H20, 12 mM NaHC03, 5.6 mM glucose, 1 mM EDTA, pH 7.4) Make a 1: 1 dilution. After centrifugation and washing with platelet buffer once, the platelets were adjusted to 107 cells / ml. Isolate human platelets at room temperature 0-14-This paper size is in accordance with Chinese National Standard (CNS) Λ4 specification (210X297 mm) Printed by A7 B7, Shellfish Consumer Cooperative, Central Standards Bureau, Ministry of Economic Affairs 5. Description of the invention (12) In this experiment At 37 ° C, the isolated platelets (2x106) were cultured at 37 ° C for 5 minutes at different inhibitor concentrations (dissolved in DMSO). Platelets were activated with l " m Ionophor A23187 and 5 mM CaCl2. After 5 minutes of incubation, the platelets were centrifuged briefly at 13,000 rpm, and the platelets were suspended in SDS sample buffer (SDS sample buffer: 2011 ^ 1 ^ -HC1, 5 mM EDTA, 5 mM EGTA, 1 mM DTT, 0.5 mM PMSF, 5 μg / ml leupeptin, 10 pepsin inhibitor, 10% glycerol and 1% SDS). Proteins were separated in a 12% gel, and pp60src and its 52 kilodalton and 47 kilodalton cleavage products were identified by Western blotting. The polyclonal rabbit antibody anti-Cys-src (pp6 (Tsie)) was purchased from Biomol Feinchemi-kalien (Hamburg, FRG). The primary HRP-conjugated secondary antibody (Boehringer Mannheim, FRG ·) was used to determine the primary anti-ceremony Western blotting was performed in a known manner. Quantitatively, pp60src was quantitatively determined by optical density using non-activated (control 1: no lysis) and ionophor and trans-treated platelets (control 2: equivalent to 100% lysis) as controls. Lysis. ED505 is equivalent to the inhibitor concentration, and the color response intensity of the 60 kDa beam is equivalent to the intensity of control 1 plus control 2 divided by 2. Glutamic acid-induced neuronal cell death in the skin layer DW Choi, MA Maulucci-Gedde and AR Kriegstein in " Glutamate neurotoxicity in cortical cell culture ", J. Neurosci. Z (1987), 357-368. Cortical hemispheres were isolated from 15-day-old mouse embryos Individual cells were obtained by enzymatic (trypsin) decomposition method. These cells (glial cells and cortical nerves-15-this paper size applies to Chinese National Standard (CNS) A4 specifications (210X 297) (Li) --------- Installation--.-(Please read the notes on the back ^ _ write this page) Order the A7 __B7_ of the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs Explanation (13) Protocells) were planted in 24 concave dishes. Three days later (laminin-coated dishes) or seven days later (ornithine-coated dishes). FDU (5-fluoro-2- Deoxyuracil nucleoside) was treated as mitosis. 15 days after cell preparation, glutamate was added to cause cell death (15 minutes). After glutamate was removed, calpain was required. 24 hours later, the cells were measured Lactate dehydrogenase (LDH) in the culture supernatant was used to assess the damage to the cells. The cells of NT2 cells caused by the drug died in the human cell line NT2 (precursor cells, Stratagene GmbH), and the cell death was caused by calcium in ionophor Caused by the presence of Α231δ7. 105 cells / cavity were placed in a microtiter dish 20 hours before the experiment. Thereafter, the inhibitors were cultured in various concentrations in the presence of 2.5 micromolar ionophor and 5 micromolar. Cells. After 5 hours, 0.5 mL of XTT (Cell Proliferation Kit II 'Boehringer Ma nnheim). After about 17 days, use Easy

Reader EAR 400 (SLT) measures optical density according to the manufacturer's instructions. The optical density of half the cell death was calculated from control experiments with cells but without inhibitors and cultured in the presence or absence of inophor. In many neurological and psychiatric diseases, glutamate activity is increased, leading to excessive excitement or poisoning of the central nervous system. So a substance that inhibits the effects caused by our amino acid salts can be used to treat these diseases. Glutamine antagonists, including in particular NMDA antagonists or modulators thereof, and AMPA antagonists are suitable as drugs for the treatment of neurodegenerative diseases (Huntington's disease and Parkinson's disease), hypoxia, hypoxia , And diseases caused by ischemia after stroke, can also be used as antiepileptics, antidepressants and

Anxiolytics (refer to Arzneim, Forschung 1990, 40, 511-514 · TIPS -16- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) ---- --------- Equipment-• *-. First (please read the notes on the back A ·? Δ page first) Order A7 B7 V. Invention Description (14 1990, 11, 334-338 and Drugs of the Future 1989, 14 (11 ), 1059-1071)-Excited amino acid (= eaa) in the brain leads to extreme excitement and the animal dies after short-term spasms. Β These symptoms can be given systematically (eg intraperitoneally) to the central nervous system. EAA antagonists inhibited. Because the excessive activation of EAA receptors in the middle frame nervous system plays an important role in the development of various neurological diseases, EAA antagonists that have been identified in vivo tests can be considered as suitable treatments for such central nervous system diseases These diseases include local and global cerebral ischemia, trauma, epilepsy, and various neurodegenerative diseases such as Huntington's disease and Parkinson's disease. It has been found that calpain inhibitors are also required in cell culture Guaranteed for cell death caused by ΕΑα Activity (Η · Cauer et al., Brain Research 1993, 607, 354-356; Yu Cheg and AY Sun, Neurochem. Res. 1994, 19, 1557-1564). Surprisingly, the present invention requires calpain inhibition The agent is active even against EAA-induced spasms (such as NMDA or AMpA), so it has been shown to have therapeutic use in the above-mentioned central nervous system diseases. The pharmaceutical preparation according to the present invention includes a therapeutically effective amount of Compound I and a conventional pharmaceutical adjuvant Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs ---------- ^ — I. '-* &Quot; Jingxian read the notes on the back page} When ordering for local external use, such as loose, For creams or sprays, the active compound may be a conventional concentration. The amount of the active compound is generally from 0.001 to 1% by weight, preferably from 0.01 to 0.1% by weight. For internal use, a single dose given to the formulation contains 01 to 100 mg / kg body weight. This preparation can be given one or several doses per day, depending on the type and severity of the disease. 17- A7 A7 Printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs B7 V. Description of the invention (15) Varies depending on required method used ' The medicinal preparation of the present invention contains conventional carriers and diluents in addition to the active compound. A pharmaceutical adjuvant suitable for topical application 疋 ethanol isopropanol 'ethoxylated sesame oil, ethoxylated digital sesame oil, polyacrylic acid, polyethylene glycol Glycol, paraffin oil, paraffin gum and wool oil. Suitable pharmaceutical auxiliaries for internal administration are, for example, lactose, propylene glycol, ethanol, starch, talc and polyvinylpyrrolidone. These preparations may also contain antioxidants such as tocopherol and butylated hydroxyanisole and butylated hydroxytoluene, taste improving additives, stabilizers, emulsifiers and lubricants. Compounds other than the active compound in the formulation and compounds used in the manufacture of pharmaceutical preparations are non-toxic and compatible with the active compound. These pharmaceutical preparations are produced in a conventional manner, for example, by mixing conventional carriers and diluents with an active compound. These pharmaceutical preparations can be administered by various methods, for example, oral administration, parenteral administration such as intravenous infusion, subcutaneous administration, intraperitoneal administration, and local administration. Formulations can be, for example, lozenges, emulsions, solutions for infusion or injection, pastes, creams' gels, creams, lotions, powders, and sprays. Examples Example 1 N- (But-1-yl-2-yl) -2-((E-2-phenylethylene · butyl) amido) benzamide

NH 〇 人 〇 • 18- This paper size is applicable to Chinese National Standard (CNS) A4 (· 21〇χ297 公 楚) --------- Batch water---. * (Please read the back first (Notes on this page)

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (16) a) 2-Amino-N- (but-1 · ol_2 · yl) benzamidine 10.0 g (61 mmol) isatinic anhydride and 11 g (123 6 mmol) of 2-amino-1-butanol were heated in 200 ml of tetrahydrofuran under reflux for 8 hours. Tetrahydrofuran was then removed under reduced pressure, and the resulting residue was distributed between a 2M aqueous sodium hydroxide solution and ethyl acetate. The ethyl acetate phase was dried and concentrated under reduced pressure to give 10.5 g (82%) of the product. b) N- (but-1-ol-2-yl) -2-((E-2_phenylethen-1-yl) amido) benzidine is 1 g (5 mmol) The prepared intermediate 1 & and 0.06 g (6 mmol) of triethylamine were dissolved in 50 ml of tetrahydrofuran. At 0. (: Add 0-95 g (5.7 millimoles) of cinnamidine chloride dissolved in a little tetrahydrofuran dropwise at a rate such that the temperature is lower than 5 ° C. This mixture is stirred for 1 hour. The reaction is then decompressed After concentration, the resulting residue was distributed between a 2M aqueous solution of sodium hydroxide and ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The obtained crude product was boiled in ether and then filtered with suction to obtain 1; 1 g (56%) ) Product. C) N- (but-1-aldehyde-2-yl) -2 _ ((E-2-phenylvinyl-1-yl) fluorenyl) benzidine will be dissolved in 5 ml of digas methane 1.1 grams (14 millimoles) of dipyridyl hydrazone inside was slowly added dropwise to 0.9 grams (7 millimoles) of grasshopper gas in 35 ml of anhydrous digas methane at -60 to -50 ° C. This mixture was stirred for 15 minutes. Then, 2 g (6 mmol) of intermediate 1 b dissolved in 10 ml of digas methane was added dropwise, and the temperature was maintained below -50 ° C during the dropwise addition. This mixture was then stirred for another 30 minutes. Add 1.5 grams (15 millimoles) of triethylamine, -19- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) --------- packing--: (Please read the notes on the back of Alit first page). Ordering economy · Deng Central Standards Bureau Shellfish Consumer Cooperatives Co., Ltd. Yinli A7 B7 V.-Explanation (17) The mixture is heated to room temperature. The reaction mixture was washed with water, and the organic phase was dried and concentrated under reduced pressure. The residue was treated with ether and filtered off with suction. 0.4 g (20%) of the product was obtained. MS: m / e = 336 (M +). Example 2 N- (butyl-1-carbox-2-yl) -2-((2-fluorenyl) amido) benzamide

a) N- (but-1-ol-2-yl) -2-((2-fluorenyl) amido) benzamide is used in step lb method with 1 g (4.8 millimoles) of intermediate la and 0.95 g (5 mmol) of 2-naphthalenemethane gas was reacted to obtain 1.05 g (62%) of the product. b) N- (but-1-aldehyde) -2- (〇naphthyl) amido) benzamide. 0-9 g (2.5 millimoles) of intermediate 2a was used in step lc with diamido After purification of oxidized β from Yaki / grass gas by chromatography (eluent: toluene / acetone = 17/3), 78 mg of product was obtained. 'H-NMR (d6-DMS0): ^ = 1.0 (3H); 1.6-2.0 (2H); 4.3 (1H); 7.2-8.8 (11H); 9.0 (1H); 9.7 (1H) and 12.1 (IH) ppm. Example 3 N- (butyl-1-fluoren-2-yl) -3-((2-fluorenyl) fluorenyl) benzamide-20- This paper is in accordance with China National Standard (CNS) 2IOX297 mm) I!, Γ— II n II Order I n ^ (Please read the note on the back Λ '?? this page) · "V. Invention Description (18) A7 B7

A) N- (3-Ethoxycarbonylphenyl) -2-Pyrolyl-based Fermented Amine Dissolve 6.6 ml of triethylamine in 0-5 * C 9 ml (47.5 mmol) of 2-methylformamidine in 50 ml of tetrahydrofuran was added to 7-5 g (45.5 mmol) of ethyl 3-aminobenzoate dissolved in 150 ml of tetrahydrofuran. The mixture was stirred for about 1 hour. The mixture was then triturated and the residue was concentrated under reduced pressure. The resulting solid was treated with acid and suction filtered again. 9.3 g (64%) of the product were obtained. b) 3- (2-fluorenylamido) benzoic acid. 9.0 g (28 mmol) of the 3a product was dissolved in 100 ml of tetrahydrofuran, and 2.7 g (113 mmol) of 50 ml of water was used. ) Lithium hydroxide treatment. The mixture was stirred at room temperature until the reaction was completed (about 6 hours). Tetrahydrofuran was removed under reduced pressure, and the resulting aqueous phase was acidified with 2M hydrochloric acid. The precipitate was filtered off with suction to obtain 7.8 g (95%) of the product. c) 0.8 g (7.7 mmol) of N- (but-1-olyl) -3 · ((2 · fluorenyl) fluorenyl) benzamide at 0 ° C will be dissolved in a little tetrahydrofuran Ethyl formate was added dropwise to 2 g (69 mmol) of intermediate 3b and 0.8 g (7.9 mmol) of triethylamine dissolved in 50 ml of anhydrous tetrahydrofuran. An additional 0.6 g (6.7 mmol) of 2-aminobutanol was added dropwise at -20 to -10 ° C. This mixture was stirred at room temperature for 16 hours. Dehydrotetrahydrofuran is removed under reduced pressure, residue -21-This paper size applies Chinese National Standard (CNS) A4 specification f 210X297 mm) ---------- & — (Read the precautions on the back before reading A: Horse page) Order

•--I-I 1 · A7 B7 V. Description of the invention (19) The residue is distributed between water and ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The product was boiled with ether and filtered off with suction. 5 g (58%) of the product were obtained. d) N- (but-1-acid-2-yl) -3-((2-phenyl) amido) benzamide is used in step lc to remove i 3 with dimethyl sulfoxide / oxalor chloride. Grams (35 millimoles) of intermediate body 3 c oxidation. After chromatography and purification (eluent: toluene / acetone = 1/1), 0.24 g (18%) of the product was obtained. ^ -NMR (d6-DMSO): d = 1.0 (3H); 1.6-2.0 (2H); 4.2 (1H); 7.3-8 · 8 (10Η); 8.9 (1H); 9.4 (1H) and l 0.5 (lH) ppm. Example 4. (S) -N- (3-Phenylpropan-1-acid-2-yl) -2- (3-elideyl) aminobenzylamine ¾ .. *-. (Please first (Read the notes on the back of this page.)

(A) (S) -2-Amino-N- (3-phenylprop-1-ol-2-yl) benzamide. This product is produced by step la 5 g of (S)-(-)-2-amino-3-phenyl-1 · propanol and isatoic anhydride were prepared. 3.6 g of product were obtained. b) (S) -N- (3-Phenylpropan-1-ol-2-yl) -2- (3-«» Bidyl) Benzylamine is 1.0 g (3.7 mmol) ) Intermediate 4a was dissolved in 25 ml of pyridine and mixed with 0.7 g (3.9 mmol) of soot gas hydrochloride each time at 0 ° C, mixing a little at a time. The reaction mixture was stirred for several hours (DC control). The mixture was then concentrated under reduced pressure. The obtained crude product (about 2 g) was used as it is for the next reaction. -22- This paper size applies to Chinese National Standards (CNS) A4 specifications (2 丨 0X297). A7 B7 V. Description of the invention (2) C) (S) -N- (3_phenylpropan-1-aldehyde _2.yl) _2_ (3-pyridyl) amidobenzylamine. 2 g of intermediate were oxidized with dimethylsulfenic acid / oxalochlorine in step lc. After chromatographic analysis and purification (eluent: toluene / propane = ιη), 0.17 g of product was obtained. MS: m / e = 373 (M +). Example 5 (S) -N- (3-Phenylpropanyl 1_aldehyde_2_yl) _2_ (2_fluorenyl) fluorenylbenzidine.

_ CONH ^^ CHO

CC --------- Private Clothing II (Please read the precautions on the back of AV ·; page of this page) Printed Button (S): N- (3-phenyl Propyl-i_ol_2_yl) _2_ (2_stubyl) Benzaminobenzylamine 1.5 g (5.6 mmol) intermediate 4a and 1.2 g (6.3 mmol) The gas was reacted in step 4b, yielding 4 g (58%) of the product. b) (S) -N_ (3-Phenylpropan-1-aldehyde-2-yl) -2- (2-fluorenyl) amidobenzylamine using grass gas / dimethyl in step lc Iridium oxidized 12 g (47 mmol) of intermediate 5a. 0.5 g (42%) of the product were obtained. MS: m / e 422 (M +). Example 6 (S) -N- (3 · Phenylpropanyl 1_aldehyde_2_yl) -3 · (2 · fluorenyl) amidobenzylamine a) -5 Line-23- This paper Standards apply to Chinese National Standards (CNS) A4 specifications (210 × 297 mm) A7 _______B7 V. Description of invention (21)

a) (S) -N- (3-Phenylpropan-1-ol_2-yl) -3- (2-amidinofluorenyl) benzylamine 2 g (6.8 mmol) intermediate 3b is reacted with (S) -2-amino-3-phenyl-1-propanol in the method of step 3c. The product was obtained (34%). b) (S) -N- (3-Phenylpropan-1-yl · _2 · yl) · 3 · (2 · fluorenyl) aminobenzidine Grasshopper gas oxidized 0.9 g (2 [mmol) of intermediate 6a. After chromatographic analysis and purification (eluent: toluene / acetone = 3/1), 0.2 g (22%) of the product was obtained. MS: m / e = 422 (M +). Example 7 (S) -2 < 2-Phenyl-1-ethyl) fluorenylamino-N- (3-phenylpropionaldehyde_2_yl) benzamide ---,-* * (Please First read the notes on the back Λ.¾ this f) printed by the Central Consumers Bureau of the Ministry of Economy

a) (S) -2- (2-Phenyl-1-ethyl) fluorenylamino-N- (3-phenylpropan-2-yl) benzidine-24 (CNS) A4 specification (210X297 mm) ~~-A7 B7 V. Description of the invention (22) _3 g (2.2 mmol) of N-hydroxybenzotriazole (HOBT) and 1.3 g (6.6 mmol) Ear) n '-(3-dimethylaminopropyl) -N-ethylcarbodiimide (EDC) (batch) was added successively to 1.5 g (6.6 mmol) of 50 ml of digas methane. 2- (2-phenyl-1-ethyl) benzoic acid, ΐ · 0 (6.6 mmol) (S): 2-amino-3-phenylpropan-1-ol and 1.4 ml '(9.9 Millimoles) within triethylamine. This mixture was stirred at room temperature for 16 hours. The reaction mixture was then diluted with a large amount of ethyl acetate, washed twice with 2M hydrochloric acid successively ', twice with a 2M sodium hydroxide aqueous solution, and three times with water. The organic phase was dried and concentrated under reduced pressure. The residue was precipitated with methane / petroleum ether. This gave 1.85 g (79%) of the product. b) (S) -2- (2-Phenyl-1-ethyl) amino-N- (3-phenylpropan-1-yl-2-yl) benzidine is used in step lc method. Methyl sulfoxide / grass gas oxidized 16 g (4.5 mmol) of intermediate 7a. 0.7 g (46%) of the product was obtained. ^ -NMR (CDC13): ί = 2.8-3.4 (6H); 4.9 (1H); 6.1 (1H); 7.0-7 · 6 (14Η) and 9.8 (lH) ppm 0 Example 8 (S) -3-benzene Methylmethyl-N- (3-phenylpropan-1-yl-2-yl) benzylamine 5 \:-(Please read the precautions on the back + .¾ page),-° Central Standard of the Ministry of Economic Affairs Printed by Bureau Consumers Cooperative

-25- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 V. Description of the invention (23) a) Phenylbenzyl-N- (3-phenylpropylbenzidine) In step 3c, 2 g (8.8 mmol) of 3-benzylidenebenzoic acid was reacted with (S) -2-amino-3-phenyl_1 · propanol. 25 g (79%) ) Product. B) (S) _3 · benzyl-N- (3_phenylpropanyl_1_ road_2_yl) benzylamine. 2 g (5.6 mmol) of step 1c method Intermediate 8a is oxidized. Purification by chromatographic analysis (eluent: digas methane / methanol == 〇: 1) 1.2 g (61%) of the product was obtained. MS: m / e = 357 (M +). Example 9 (S) -2-Benzylmethyl-N- (3-epiylpropan-1-ethan-2-yl) benzylamine

--------- t .------ IT ------. ^ (Please read the precautions on the back before fringing this page). Γ Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Preparation of a) (S) -2-benzylidene-N- (3-phenylprop-1-ol-2-yl) benzylidene In the method of step 3c, 2-benzylidenebenzoic acid and ( s) -2-amino-3-phenyl-1 -propanol reaction. 2.6 g (86%) of the product were obtained. b) (S) -2-Benzamyl-N- (3-phenylpropan-1-aldehyde-2-yl) benzylamine. 2.4 g (6.7 mmol) of the intermediate in step 1 c. 9a was oxidized with dimethylarsine / grassland gas. Purification by chromatography (eluent: toluene / ethyl acetate = 20/1) yielded 0.5 g (21%) of the product. MS: m / e = 357 (M +). -26- This paper size applies Chinese National Standard (CNS) A4 specification (2 丨 〇χ297mm) Printed by the Consumers 'Cooperative of the Central Government Bureau of the Ministry of Economic Affairs A7 Β7-Five' Description of Invention (24) Example 1 0 (S) -3- (l-Fanyl) amido-N- (3-phenylpropan-1-ene · j-yl) benzamide

a) 3- (1-Aminomethylamino) benzoic acid at 0 ° C, 73 grams (38 millimoles) of 1-Teamate gas dissolved in 25 ml of tetrahydrofuran was added dropwise to 100%. 5 grams (36.5¾ moles) of 3-aminobenzyl alcohol in 10 ml of anhydrous tetrahydrofuran and 10 ml (73 mmol) of triethylamine. This mixture was stirred at 0 ° C for 1 hour. The mixture was then concentrated under reduced pressure 'and the residue was distributed between ethyl acetate and 2M hydrochloric acid to crystallize the product. 7.8 g (74%) of the product were obtained. b) (S) -3- (Broxy) amido-N- (3-phenylprop-1-ol_2.yl) benzimidamine according to step 7a with 1 g (3.4 mmol) The reaction of ioa with (s) -2-amino-3-phenyl-1-propanol gave 1.1 g (76%) of the product. c) (S) -3- (l-. ^. yl) aminoamine-N-+ (3-phenylpropan-1-yl · _2-yl) phenylaminoamine. 1_0 g ( 2.3 millimoles) Intermediate iOb was oxidized with dimethylsulfine / grass gas. 0.35 g (35%) of the product was obtained. iH-NMR (CDC13) K1 (2H); 4.6 (1Η); 7.0 · -8 · 4 (18Η) and 9,6 (lH) ppm 0 Example 1 1 (S) -4- (2 · Phyl) Styrylamine-N- (3-phenylpropan-1 · da-2-yl) benzylamine -27- This paper size applies to Chinese national standards (CNS > Α4 size (21 ο X 297 mm). _ I-: (Please read the notes on the back and fill in the Η · copy to buy) Thread 5. Description of the invention (25) A7 B7

a) 4- (2-Sulfuryl) phosphonium aminobenzoic acid • 5 g (36.5 mmol) of 4-aminobenzoic acid was reacted with 2-methylformamidine chloride in step 10a to obtain 6.6 g (62%) Product> (S) _4_ (2.Tea) aminopropyl-1-ethan'-2-yl) benzamide. 1.0 g (3.4 mmol) of intermediate was used in step 7a. 11a was reacted with (S) -2-amino-3-phenyl-1-propanol to obtain 0.9 g (62%) of the product. (S) -4- (2-trifluoro) amino-N- (3-phenylpropan-1-e · _2-yl) benzylamine 0.8 g (1.9 mmol) ) Intermediate lib is oxidized with dimethylarsine / grassroot gas. After chromatographic analysis and purification (eluent: digas methane / methanol = 15/1), 0.4 g (53 0/0) of the product was obtained. ^ -NMR (d6-DMSO): ί = 2.9 (1Η); 3.3 (1H); 4.5 (1H); 7.0-8.3 (14H); 8.6 (1H); 8.8 (1H); 9.6 (1H) and 10.6 ( lH) ppm. Example 1 2 (S) -2-〇Stubyl) sulfenamido-N- (3-phenylpropan-1-aldehyde-2-yl) benzamide b) c) ------ --- 1-- \ · (Please read the precautions on the back ^ 舄 this page) Printed by the Central Consumers Bureau of the Ministry of Economy

a) (S) -2- (2-fluorenyl) sulfenamidino-N- (3-phenylprop-1-olyl) benzidine amine-28- This paper is in accordance with the Chinese National Standard (CMS) ) A4 size (210X 297 mm) A7 B7 b) V. Description of the invention (26) 1.5 g (5.6 millimoles) of amidino · N ♦ phenylpropanyl alcohol_2 benzylamine in step 4b method Reacts with M-based tritium. 0.67 g of product was obtained. (s) -2- (2-Methenyl) sulfenamido_N_ (3-phenylpropionaldehyde-methaneformamide 'was used to process 0.6 g (1.3 mmol) of intermediate 12 & It was oxidized with dimethyl sulfene / grass chloride. After chromatographic purification (eluent: toluene / acetone = 1/2), 0.4 g of product was obtained. MS: m / e = 458 (M +) Example 1 3. (S) -2-fluorenyl-N- (3-phenylpropan-1-aldehyde_2 · yl) benzidine amine --------- batch coating 丨-'' . Please read the notes on the back > \ '

1T a) Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Consumer Cooperatives b) (S) -2-Amino-N- (3-phenylprop-1-ol_2-yl) benzylamine at 0eC Dissolve 2 ^ g in a little digas. 』Mmole) 2_ Benzyl benzamidine 1.3 g (86 mmol) (s) _2_amino_3 was added dropwise to 35 ml of digas methane and 20 ml of sodium hydroxide aqueous solution. Phenylpropan-1-ol. This mixture was stirred for about 30 minutes. The organic phase was separated, dried and concentrated under reduced pressure. 2.7 g (91%) of the product were obtained. (S) -2-Methenyl-N- (3-phenylpropan-1-yl-2-yl) benzamide. 2 g (5.8 mmol) of intermediate 13a with dimethylformamide in step 1 c. Oxidation of kiwi / grass gas produced 1.5 g (75%) of the product. -29- M Zhang scale is applicable to Chinese National Standard (cNS) ^ 4 specifications (210X297 mm printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7-V. Description of the invention (27)! H-NMR (d6-DMSO ): = 2.8 (1H); 3.3 (1H); 4.0 (2H); 4.5 (1H); 7.0-7 · 5 (1Η); 8.8 (1H) and 9.5 (lH) ppm. Example 1 4 (S)- 6-Methyl-2- (2-naphthyl) aminoamine-N- (3-phenylpropan-1-yl_2-yl) phenylamine

a) (S) -2-Aminofluorenyl-N- (3-phenylpropan-1-yl-2-yl) benzamide will be 5 g (28.2 mmol) in 150 ml of tetrahydrofuran. (Ear) 5-methyl competing red anhydride and 4.3 g (28.5 mmol) (S) -2-amino · 3-phenyl-1-propanol were heated at reflux for about 8 hours. The mixture was then concentrated under reduced pressure, and the residue was distributed between ethyl acetate and 2M aqueous sodium hydroxide solution. The organic phase was dried and concentrated once under reduced pressure. The residue was treated with ether to give 3.2 g (39%) of the product. b) (S) -6-methyl-2- (2-fluorenyl) amido-N- (3-phenylpropionin-alcohol ^ -yl) benzamidine using step 10a method 2 g (7¾ Mol) Intermediate Wa reacts with 2-zylamine gas. 2.7 g (77%) of the product were obtained. c) (S) -6-methyl-2- (2-fluorenyl) amido-N- (3-phenylpropanyl-aldehyde-2-yl) benzamidine in step 1 c method will be 2 G (4.6 mmol) of intermediate 14b was oxidized with dimethylsulfinium / trifluoroacetic anhydride. Purified by chromatographic analysis (eluent: 4-30) This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) II Pack--.-* (Please read the note on the back to write A (This page) -5 A7 ______B7___ 5. Description of the invention (28) Hydrofuran / toluene / ethyl acetate = 5/10/5), 1 g (50%) of the product is obtained. MS: m / e = 436 (M +). Example 1 5 (S) -2-phenyloxymethyl-N- (3-phenylpropyl-i_aldehyde-2-yl) benzamide

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs a). (S) -2-Phenyloxymethyl-N- (3-phenylpropan-1-ol-2 · yl) benzamide in step 7a Methods Two grams (8.8 millimoles) of 2-phenyloxymethylphenylarsinic acid were reacted with (S) -2-amino-3-phenyl-1-propanol. 2.7 g (84%) of the product were obtained. b) (S) -2-Phenyloxymethyl-N- (3-phenylprop-1-yl-2-yl) benzamide. 2g (5.5 millimoles) of Body 15a is oxidized with difluorenyl sulfoxide / trifluoroacetic anhydride. After chromatographic analysis and purification (eluent: benzene / ethyl acetate = 10/1), 1.6 g (79%) of the product was obtained. MS: m / e = 3 59 (M +) 0 Example 1 6 (S) -4-Benzamyl-N- (3-phenylpropan-1-ethan-2-yl) benzylamine

This paper size applies the Chinese National Standard (CMS). A4 scale (210X297 mm) A7 B7 V. Description of the invention (29) a) (sl · 4-benzylidene-N- (3-phenylpropyl_1_ Alcohol_2 · yl) benzylamine using step 3c with 3 g (13 mmol) of diphenylketone-4 carboxylic acid and (S) -2-amino-3-phenyl-1-propanol Reaction. 32 g (67%) of the product 0 b) (S) _4-benzyl-N- (3-phenylpropan-1-yl-2-yl) benzylamine were prepared. The method of step 3c 2.4 g (6.7 mmol) of intermediate 16a were oxidized with dimethylsulfinium / trifluoroacetic anhydride. After chromatographic analysis and purification (eluent: toluene / ethyl acetate = 10/1), 0.3 g (13.0 / 0) of the product was obtained. MS: m / e = 357 (M +) 0 Example 1 7 (S) -2- (E-: 2-phenyl-1-ethylfluorenylphenylpropan-1-yl-2-benzyl) benzamine $--.--(Please read the notes on the back \ 先 this page)

A) Ethyl 2- (E-2-phenyl-1-vinyl) benzoate. 8.9 g (38.9 mmol) of 2-bromobenzoate, 5.1 g (49 4 mmol) of styrene. 0.18 g (0.8 mmol) of diacetate, 0.48 g (1.6 mmol) of tri-o-tolylphosphine and 5 g (49.1 mmol) of triethylamine in 90 ml of acetonitrile at 100 ° C The reaction was performed for 3 hours, and then the mixture was filtered, and the filtrate was diluted with ethyl acetate, washed with water, dried, and concentrated under reduced pressure. 10.2 g (100%) of the product were obtained. b) 2- (E · 2-phenyl-1-vinyl) benzoic acid-32- __________------ ^ __ This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) Employees 'Cooperatives of the Central Standards Bureau of the Ministry of Online Economics Printed A7 B7 by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. Ear) Sodium hydroxide was heated under reflux in 100 ml of water for 10 hours. The mixture was then diluted with water and washed with ether. The aqueous phase was acidified with 1M hydrochloric acid and the product was deposited. 6.2 g (70/0) of the product were obtained. c) (S) -2- (E'_2-phenyl-1-ethylfluorenyl) _N- (3-phenylprop-1-olyl) benzidine is 1.0 g in step 7a (4.5 mmoles) Intermediate 17b was reacted with 0.67 g (4.5 moles) of (s) -2-amino-3 -benzyl-1-propanol. 1.5 g (94%) of the product were obtained. d). (S) -2- (E-2-Methenyl-1 -ethenyl) -N- (3-phenylpropan-1-yl-2-benzyl) benzidine 1.5 g (4.2 mmol) of intermediate 17c was oxidized with dimethylsulfinium / trifluoroacetic anhydride. After chromatographic analysis and purification (eluent: two gases. Methane / methanol = 20/1), 0.85 g (58%) of the product was obtained. MS: m / e = 355 (M +) »Example 1 8 (S) -2- ·% -Ethyl-Ethyl-N "-( 3-phenylpropane-1 -pyridin-2-yl) benzamide

a) Ethyl 2-phenylethynyl benzoate is 11.5 g (50.2 mmol) of 3-bromobenzoate, 6_15 g (60,2 -33-). This paper is applicable to China National Standards (CNS) A4. Specifications. (21〇X297mm) --------- install!-. ·--(Please read the note on the back 4 I page j Γ-丁 _ 、-= s Central Department of Economic Affairs Printed by Standard Bureau Shellfish Consumer Cooperative A7 B7 V. Description of the invention (31) Millimolar) phenylacetylene, 0.16 g of bis (triphenylphosphino) palladium (Π) digas and 0.08 g of broken sea bream (I ) Heated under reflux in 10 ml of anhydrous triethylamine for 6 hours. This mixture was diluted with rhenium, washed with water, dried, and concentrated under reduced pressure. The residue was purified by chromatography (eluent: n-heptane / ethyl acetate After the ester = 10/1), 11.3 g (91%) of the product was obtained. B) 2-Phenylpropynylbenzoic acid, 100 g of tetrakispermine, 11 g (44 mmol) of intermediate iga and 4.9 g (8.8 mmol) of hydroxide dissolved in 200 ml of water were mixed and the mixture was heated at reflux for 8 hours. Tetrahydrofuran was then evaporated under reduced pressure, and the remaining aqueous phase was washed with ether. The aqueous phase was acidified with dilute hydrochloric acid and extracted with ethyl acetate. After drying and concentration, 9.5 g (98%) of the surface was prepared. c) (S) -2-Phenylethenyl-N- (3-phenylprop-1-ol-2-yl) benzylamine using step 7a with 2 g (9 mmol) of intermediate 18b was reacted with (S) -2-amino-3-phenyl-1-propanol 'and purified by chromatographic analysis (eluent: toluene / acetone = 10/1) to obtain 1.2 g (38%) of the product. . d) (S) -2-Phenylethyl-N- (3-phenylpropan-1-yl-2-benzyl) benzamide. 1.0 g (2.8 mmol) of intermediate by step lc method 18c was oxidized with dimethyl fluorene / trifluoroacetic anhydride. After chromatographic analysis and purification (eluent: methane / ethyl acetate = 10/1), 0.14 g (14%) of the product was obtained. MS: m / e = 353 (M +). Example 1 9 (S) -2- (2-Tetramethylfluorenyloxy) -N- (3-phenylpropane-1-acid · 2-yl) benzylamine-34- This paper is applicable to China Standard (CNS) Α4 is now available (210X297 mm) '' ---------- #--.-F Read the Precautions on the back page first) Order-Line V. Description of Invention (32

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs a) Ethyl 2- (2-trisyloxy) phenylbenzoate was added in batches of 3.9 g (35 mmol) of tertiary-butoxide. 5 milliliters (33 millimoles) of salicylic acid in 5 ml of dimethylformamide. After about 15 minutes, 7.3 g (33 mmol) of 2- (bromomethyl) fluorene was added, and the reaction mixture was heated at 1 P (TC for about 3 hours. The reaction mixture was then poured into ice water and extracted with ethyl acetate The product. The organic phase was dried and concentrated under reduced pressure. 9.15 g (95%) of the product was obtained. B) 2- (2-fluorenylmethyloxy) benzoic acid was hydrolyzed by 8 g (3.4 mmol) in step 3.b. Ear) Intermediate i9a. 7 g (64%) of the product were obtained. c) (s) -2- (2-Aminomethyloxy) _N- (3-phenylpropan-1-ol-2-yl) benzamide in the method of step 7a with 2.45 g (8.8 mmol) Ear) Intermediate 19b was reacted with 0-fluorenyl-amino-3-phenyl-1-propanol and purified by chromatography (eluent: toluene / tetrahydrofuran / triethylamine = 20 ^ 0/0, L1 g (28%) of the product was obtained. D) (s) -2- (2-Aminomethyloxy) -N- (3-phenylpropan-1-aldehyde-2-yl) benzylamine 1-5 g (3.6 mmol) of intermediate 19c was oxidized with dimethyl sulfoxide / trifluoroacetic anhydride in step 1c. 1.3 g (87%) of the product were obtained. ^ -NMR (d6-DMS0): δ = 2.9 (1H); 3.2 (1H); 4.6 (1H); 5 3 -35- This paper size applies to Chinese national standards (CNS > A4 size (2 丨 OX297 mm) ) ~ ---- --------- Refer to--. *.-C Please read the notes on the back ".. copybook 艽) Thread A7 B7 V. Description of the invention (33) (2H) 6.9-8.1 (16Η); 8.6 (1Η) and 9.6 (lH) ppm. Example 2 0 (S) -4- (2-theylmethyloxy) -N- (3-phenylpropanyl-i_while_2-yl) benzamide

Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs a) The 4- (2-fluorenylmethyloxy) benzoic acid ethyl ester was added in batches of 3.9 g (35 mmol) of tertiary-butoxide. 5 g (33 mmol) of methyl benzoate in 0 ml of dimethylformamide. After about 15 minutes, 7.3 g (33 mmol) of 2 · (bromomethyl) benzene was added, and the reaction mixture was heated at 100 ° C for about 3 hours. The reaction mixture was then poured into ice water and the product was extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. 8.4 g (88%) of the product were obtained. b) 4- (2-fluorenylmethyloxy) benzoic acid. Hydrolysis of 8 g (3.4 mmol) of intermediate 20a according to step 3b. 2.3 g (30%) of the product were obtained. c) (S) -4- (2-fluorenylmethyloxy) -N- (3-phenylpropanyl-i-alcohol-2-yl) benzamide in the method of step 7a using 2.3 g (8.3 Millimolar) intermediate 20b was reacted with (s) -2-amino-3-phenylpropanol to give 2 95 g (87%) of the product. d) (S) -4- (2-fluorenylmethyloxy) -N- (3-phenylpropan-i-aldehyde · 2-yl) benzidine. -5 g (3.6 mmol) of intermediate 20c was oxidized with dimethyl fluorene / trifluoroacetic anhydride. 096 g (64%) of the product was obtained. -36- Miscellaneous ruler and common side standard (CNS) M specifications (with 297 cm) ---------- install!--'-(Please read the precautions on the back first. Two (This page)-6 lines · «ml

A7 ______ B7 V. Description of the invention (34) 'H-NMR (d6-DMSO): ^ = 2.9 (1H); 3.2 (1H); 4.3 (1H); 5.3 (2H); 7.0-8 · 0 (16Η) 8.6 (1Η) and 9.5 (lH) ppm. Example 2 1 (S) -4- (2-trimethylamino) fluorenyl-N- (3-phenylpropan-1-acid_2-yl) benzylamine

a) 4- (2-Methylmethylamino) methylbenzoic acid is prepared by reacting 2.5 g (15.5 mmol) of 4-aminomethylbenzoic acid with 2-methylformamidine gas in step 4b to obtain 2.1 g (42%) of the product. b) (S) -4- (2 · Threonylamino) methyl_N- (3-phenylpropanol-2-yl) benzamide. In step 3c, 1.4 g (4.6 milligrams) Mol) Intermediate 21a is reacted with (S) -2-amino-3-phenyl-1-propanol to obtain 1 g (55.0%) of the product. c) (S) -4- (2-Fanylamido) fluorenyl_N- (3-phenylpropan-1-az-2-yl) benzylamine will be 0.8 g (1.8 mmol) Intermediate 21b was dissolved in 10 ml of anhydrous dimethyl sulfene and treated with 116 g (73 mmol) of sulfur trioxide-pyridine complex in 10 ml of dimethyl fluorene. The mixture was stirred at room temperature for 16 hours. The mixture was then poured into water and the precipitate was filtered off with suction. 0.65 g (82%) of the product was obtained. * H-NMR (d6-DMSO): ό = 2.9 (1H); 3.3 (1H); 4.5 (1H); 4.6 -37- This paper size applies Chinese National Standard (CNS) A4 specification (21 OX297 public epidemic) '' '---------- Installation-,---(Please read the precautions iC on the back first .. write this page) Threading A7 B7 of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Description of the invention (35) (2H); 7.1-8 · 1 (15Η); 8.5 (1Η); 8.8 (1Η); 9.2 (1Η) and 9.6 (1Η) ppm 0 Example 2 2 (S ) -3- (2-Lycyl) sulfenamidinyl-N- (3-phenylpropan-1-aldehyde · 2-yl) benzidine

A)-3 · (2 · Acetobacco Amino) Benzoic Acid in Step 4 of the Ministry of Economic Affairs uses 5 grams (35.5 mmol) of 3_aminobenzoic acid and 8 3 g (36.5 millimoles) of 2-fluorenylfluorene was reacted to obtain 105 g (89%) of the product. B) (s) -3- (2-trifluoro) sulfenamido_ Ν · (3_phenylpropyl_ 丨 _ol · 2_yl) benzidine-using step 7a with 1 gram (3 "millimolar) intermediate 223 and (phen_2_amino-3- Phenyl-1-propanol was reacted to give 2 g (86%) of the product. C) (S) _3- (2-fluorenyl) sulfenamido-N- (3-phenylpropan-l-aldehyde _2_yl) benzamidine * In step 1c, 1.0 g (2.2 mmol) of intermediate 22b was oxidized with dimethylphosgene / grass gas. MS: m / e = 458 (M +). Example 2 3 (S) -2- (2-Phenyl) amino-4-nitro-N- (3-phenylpropylxiaoyue__2 · yl) benzidine-38 This paper is applicable to China National Standard (CNS) A4 specification (2 丨 〇 X 297 mm) J ---- installation-(Please read the precautions on the back ^ \ "page), 11. Line V. Description of the invention ( 36) A7 B7

a) 2- (2-Amidinoamido) -4-nitro-benzoic acid, using step 4-7 method with 20 g (0.11 mmol) 2-amino-4-nitrobenzoic acid and 2- Naphthyl benzamidine gas reaction to obtain 22.3 g (61%) of the product 0 b) _ '(S) -2- (2-naphthyl) amido-4-acyl-N- (3-phenyl Propan-1-ol_2-yl) methamphetamine, 2 g (59.5 mmol) of intermediate 23a is reacted with (s) _2-amino-3-phenyl-1-propanol in step 3c , 2.5 g (90%) of the product were obtained. c) (S) -2- (2-Cyclosyl) amido-4-nitro-N- (3-phenylpropanyl), and benzamidine is prepared by step 21c. 1.1 grams (2.3 millimoles) of intermediate 23b were oxidized to give 1-10 grams (92%) of the product. MS: m / e = 467 (M +). Example 2 4 (S) _4- (8-Quinolinylsulfenamido) -N- (3-phenylpropanyl-2-yl) benzidine printed by Shellfish Consumer Cooperative of Central Standard Bureau of Ministry of Economic Affairs amine

This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) A7 Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs __ B7 V. Description of the invention (37) a) 4- (8_ + Leji sleep base Ethyl amine) ethyl benzoate was reacted with 2 g (12 mmol) of 4-amino benzoic acid ethyl ester with 8-phosphonosulfonyl chloride in step 10a to obtain 3.5 g (82%) of the product. " b) 4- (8_quinolinesulfonamidoamido) benzoic acid. 3.3 g (9.3 mmol) of 24a and 1.6 g (27.8 mmol) of potassium hydroxide in 100 ml of water were added at 95 °. C was heated for 45 minutes. This mixture was then neutralized with acetic acid, and the formed precipitate was sucked. 17 g (57%) of the product were obtained. c) · (S) -4- (8-4Polinolinylsulfenamido) -N- (3-phenylprop-1-ol-2-yl) benzidine 'method in step 7a (S) -2-amino-3-phenyl-1-propanol was reacted with 1.5 g (4-6 mmol) of intermediate 24b to obtain 1.2 g (58%) of the product. d) (S) -4_ (8-Pyridinylsulfenamidino) -N- (3-phenylpropan-1-aldehyde-2-yl) benzene. Formamidine. In step 21c, 1 g (2.2 mmol) of the intermediate was oxidized to yield 0.8 g (58%) of the product. lH-NMR (d6-DMSO): tf = 2.8 (lH); 3.2 (lH); 4.3 (lH); 7.0-7.3 (7H); 7.5 (2H); 7.7 (3H); 8.2 (1H); 8.4 ( 2H); 8.7 (1H); 9.1 (1H); 9.5 (1H) and 10.6 (lH) ppm. Example 2 5 ----- L ------ install-(Please read the precautions on the back i. ¾ this page), tT line (S) -4- (2. -N- (3-phenylpropan-1_aldehyde-2-yl) benzamide

-40- This paper size applies to Chinese National Standard (CNS) A4 specification (21 ×: 297 mm) A7 _______B7_ ___ V. Description of the invention (38) a) 4- (2-fluorenylthiomethyl) benzoic acid Ping ester dissolves 16.8 grams (0_1 mole) of sulfanyl 2-phenol and 21.3 grams (0.21 mole) of ethyl amine in 300 ml of tetrahydrofuran. At 0. 〇 24 g (0.1 mol) of methyl 4- (bromomethyl) benzoate was added dropwise! 00 ml of a solution in tetrahydrofuran. The mixture was stirred for 2 hours, then filtered, and the filtrate was concentrated under bismuth. The residue was recrystallized from n-heptane to obtain 27.2 g (84%) of the product. b) 4- (2-fluorenylthiomethyl) benzoic acid-hydrolyze 25.9 g (42 mmol) of intermediate 25a with 2M sodium hydroxide ethanol solution in step 31b to obtain 11.9 g (96%) of the product . c) ⑻-4 · (2 · theyl) thiomethyl-N- (3-phenylpropan-1-yl-2-benzyl) benzamide using the method of step 7a with 5.7 g (37 mmol) ) (S) -2-Amino-3-phenyl-1-propanol was reacted with 11 g (37 mmol) of intermediate 25b to give 95 g (60%) of the product. d) ⑻-4- (2- # based) thio-fluorenyl-N- (3_phenylpropyl · ι_ap_2_yl) benzamidine printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs-II -n Γ— I—--I ----- n I ^ '-CPlease read the notes on the back first> N · .Written book * 1T · Wire 5 grams (2.3 millimoles) in step 2lc method ) Intermediate 25c was oxidized to give 0.9 g (18%) of the product. lH-NMR (d6-DMSO): δ = 2.9 (1H); 3.3 (1H); 4.4 (2H); 4.5 (1H); 7.0-7.9 (16H); 9.8 (1H) and 10.5 (lH) PPm. Example 26 (S) -2_phenoxy-N- (3-phenylprop-1-yl-2-yl) benzamide-41-This paper is in accordance with Chinese National Standard (CNS) 210X297 male Chu) A7

a) (s) -2-Benzyl-N- (3-phenylpropanyl alcohol-2-yl) benzylamine in step 3c using 7.3 g (48 mmol) ) _2_Amino_3_phenyl · 1-propanol was reacted with 10.7 g (50 mmol) of 2-phenoxybenzoic acid. 17.3 g (100%) of the product were obtained. b) (S) -2-Phenyllactyl-N- (3-phenylpropan-1-ethan-2-yl) benzamide. According to the method of step 21c, 16.1 g (46 mmol) of intermediate 26a was oxidized. 10.3 g (64%) of the product was obtained "'H-NMR (d6-DMSO): d = 2.9 (1H); 3.2 (1H); 4.5 (1H); 6.7-7.7 (14H); 8.4 (1H); and 9,4 (lH) Ppm. Example 2 7 (S) -4- (2-Amidinofluorenyl) fluorenylamino_N- (3-phenylpropionaldehyde_2-yl) benzamide — _ (Please read the notes on the back first, write this page * 1Τ ·

The Consumer Cooperative of the Central Bureau of Standards of the Ministry of Online Economics, Consumer Cooperatives, a) 4_ (2-Tetramethyl) Ethyl Aminobenzoic Acid Ethyl Acetate, 10 grams (53 millimoles) of acetic acid and 9 in 150 ml of anhydrous tetrahydrofuran G (56 millimoles) of carbonyldiimidazole were mixed, and the mixture was heated at reflux for 1 hour. Then 8.9 g (3 mmol) of ethyl 4-aminophenylarsonate was added, and the mixture was heated at reflux for another 3 hours. Then the mixture -42- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 gong) The Central Consumers Bureau of the Ministry of Economy Staff Consumer Cooperatives A7 B7___ 5. Description of the invention (40) Decompression and concentration. The residue was treated with 600 ml of water and the product precipitated. 16.6 g (92%) of the product were obtained. b) 4- (2-Stilbylfluorenyl) phosphonium aminobenzoic acid 15.2 g (46 millimoles) of intermediate 27a were hydrolyzed with lithium hydroxide according to step 3b. 13.7 g (98%) of the product were obtained. c) (S) -4- (2-Dimethylmethyl) fluorenylamino-N- (3-phenylprop-1-ol-2-yl) benzidine. Using step 27a, 10.3 g (34 Millimolar) intermediate 27b was reacted with (S)-. 2-amino-3-phenyl-1-propanol to obtain 7-9 g (53%) of the product. d) (S) -4_ (2_: fluorenylmethyl) fluorenylamino-N- (3-phenylpropan-1-aldehyde-2-yl) benzene. fluorinated amine (7.4 g) in step 21c 7 mmol) of intermediate 27c was oxidized to give 2.1 g (28%) of the product. W-NMR (d6-DMSO): "= MS (ESI): m / e = 436 (M +). Example 2 8 4- (fluoren-2-ylthiooxymethyl) -N-((S) -3-phenylpropan-1-an-2-yl) benzamide

a) 2- (4--2-ylthiooxymethyl) benzoic acid vinegar at 0 ° C 25.8 g (42 mmol) potassium persulfate dissolved in 300 ml of water was added dropwise to 850 ml of methanol Within the intermediate 25 & within. Apply this 43- & wave scale to China National Building Standard (CNS) A4 specification (21 × 297 mm) ------------ install--* {Please read the back (Notes on this page), 1TB, Central Standards Bureau, Ministry of Economic Affairs, Consumer Goods Cooperatives, Printing A7 ___ B7 ___ 5. Description of Invention (41) Stir for 1 hour. Then about 1 liter of water was added and the precipitated product was filtered off with suction. 13.2 g (92%) of the product were obtained. b) 4- (fluoren-2-ylethoxymethyl) benzoic acid Hydrolyze 12.7 g (39 mmol; ΐ) of intermediate 28a with sodium hydroxide ethanol / water solution in step 3 lb. 11.5 g (94%) of the product were obtained. c) 4- (fluoren-2-ylthiooxyfluorenyl) -N-((S) -3-phenylprop-1-ol-2-yl) benzamidine using 10.2 g of step 7a ( 3 1 millimolar) Intermediate 28b is reacted with (S) -2-amino-3-phenyl-1-.propanol > to obtain 8.7 g (61%) of the product. d) 4- (fluoren-2-ylthiooxymethyl) -N-((S) _3-phenylpropan-1-aldehyde-2-yl) benzamidine was oxidized by 7.46 g in step 21c (17 mmol) Intermediate 27c, yielding 4.2 g (55%) of the product. 'H-NMR (d6-DMSO): ά = 2.9 (1H); 3.2 (1H); 4.2 (1H); 4.5 (2H); 7.0-8.1 (16H); 8.8 (1H) and 9.5 (lH) ppm » Example 2 9 (S) -4- (naphthalen-2-yl) continylfluorenyl_N-((S) -3-propanylpropan-1-yl-2-phenyl) benzidine

a) 4- (naphthalene-2-ylthiooxymethyl) -N-((S) -3 -benzylpropan-1-ol-2-yl) benzamide 4 -44-paper size Applicable to China National Standard (CNS) A4 specification (2 丨 0 × 297). ^ Ί-^ --- install-- (please read the precautions on the back first! C write this page to order A7 B7 V. Description of the invention ( 42) Under cooling, add 5.1 g of 55% strength (16.1 mol) 3_gas perbenzoic acid in batches to 3.45 g (8.1 mmol) of 500 ml of digas methane (S) -4 -Phenyl-2-thiomethyl-N- (3-theylpropan-1-yl-2-yl) benzamide (intermediate 25c). This mixture was stirred at room temperature for 16 hours. Reaction The solution was washed three times with a 20% strength sodium sulfite aqueous solution. The organic phase was dried and concentrated under reduced pressure. 0.5 g (I 4%) of the product was obtained. B) (S) -4- (naphthyl) sulfonamilide-N- ((S) -3 · Phenylpropion d-aldehyde · 2-yl) Phenylamine was oxidized with 0.4 g (0.9 mmol) of intermediate 29a by the method of step 21c to obtain 0.36 free (88%) of the product. 'H-NMR (d6-DMSO): ^ = 2.9 (1H); 3.3 (1H); 4.5 (1H); 4.9 (2H); 7.0-7.3 (6H); 7.5 ^ 7.9 (5H); 8.0-8.3 ( 4H); 8.4 (1H); 8.8 (1H) and .9.5 (.lH) ppm. Example 3 0 (S) -2-phenyl-N-((S) · 3-phenylprop-1-aldehyde) benzamidine: —IM .---- 装 —. *. {Please first Read the notes on the back 1C Write this page

, 1T

Department of Economics, Consumer Standards Cooperation, Central Standards Bureau of the Ministry of Industry and Commerce of the People's Republic of China, Duaqi Packing a) (S) -2-Phenyl-N-((S) -3-phenylpropan-1-ol-2-yl) benzidine In the method 3a, 2 g (10 mmol) of 2-phenylbenzoic acid was reacted with (S) -2-amino-3-phenyl-1-propanol to obtain 2.1 g (64%) of the product. b) (S) -2-Phenyl-N-((S) -3-phenylpropan-aldehyde-2-yl) benzidine is oxidized by step 21c to 1.0 g (3 mmol) of intermediate 30a, produced -45- This paper size applies to Chinese National Standards (CNS) A4 specifications (210 × 297 public envy) A7 ______B7_________ V. Description of the invention (43) 0.4 g (40%) product. ^ -NMR (d6-CDCl3): d = 2.9 (1H); 3.0 (1H); 4.7 (1H); 5.9 (1H); 6.9-7.7 (14H) and 9.4 (1H) ppm. Example 3 1 (S) -2- (E-2- (King-2 -yl) -ethenyl-1 -yl) -N- (3-phenylpropan-1-yl-2-yl) benzamidine Amine ^

---- ^ --.— --- Installation-•-,. · (Please read the notes on the back to write this page) Line a) 2- (E-2- (荇 -2- 基)- Vinyl) ethyl benzoate: 29.7 grams (0.13 moles) of 2-vinylnaphthalene in 200 ml of acetonitrile, 25 grams (0.16 moles) of ethyl 2-bromobenzoate, 22.5 ml (0.16 moles) Triethylamine, 0.54 g of palladium diacetate and 1.44 g of triphenylphosphine were heated to 100 C for 20 hours. The reaction mixture was then poured into water, and the mixture was repeatedly extracted with ethyl acetate. The organic mandarin was concentrated under reduced pressure, and the residue was purified by chromatography on silica. Produced 34 grams (71%) of the Ministry of Industry and Economics Central Standards Bureau staff consumption cooperation. b) 2- (E-2- (Tea_2_yl) -Ethylene_Buyl) benzoic acid Dissolve 34 g (112.5 mmol) of middle Zhao 3la in 2000 ml of tetrahydrofuran. Treat with 9-5 g (168 7 mmol) of 80% strength potassium hydroxide dissolved in 150 ml of water. The reaction mixture was heated at reflux for 10 hours. The reaction mixture was then acidified with concentrated hydrochloric acid and extracted with ethyl acetate (CNS) (21 (3 ^ 297 mm) 'A7 B7

V. Description of the invention (44) The β organic phase is washed with water, dried and concentrated under reduced pressure. The β residue is treated with a little ethyl acetate, and filtered with suction. 23.8 g (78%) of the product were obtained. c) (S) -2- (E-2 · (trial-; 2-yl) -acetamidin-1-yl) -N- (3-phenylpropylq-alcohol_2yl) benzamidine Step 3c: 1 g (3.6 mmol) of intermediate 311? Is reacted with 0.055 g of _ (3-6 moles: pe) (s) -2-amino-3-phenyl-1-propanol. 11 g (75%) of the product were obtained. d) (S) _2_ (E-2- (naphthalene_2_yl) -vinyl-1-yl) -N- (3 · phenylpropionate-2-yl) benzamidine in step 21c Oxidation of 0.9 g (2.2 mmol) of intermediate 3U yielded 0.57 g (66%) of the product. MS (ESI): m / e = 405 (M +). Example 3 2 (S) -2, (E-2- (3,4-dimethoxyphenyl) _ethylene q • yl) _n_ (3phenylpropionaldehyde-2-yl) benzidine M , CO --II --------- I--,--(Please read the note on the back first C. Write this page) * ^ τ Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standardization of the Ministry of Economic Affairs ^

a) 2_ (E-2_ (3,4-monomethoxyphenyl) -ethenyl_1-yl) benzoic acid ethyl acetate using step 31a with 5 g (30.5 mmol) 3 4_ di Methoxystyrene and ethyl 2-bromophenylarsinate are within 120% in dimethylformamide. 〇 Response. 1.2 g (4%) of the product were obtained. -47- This paper size applies to Chinese national standards ((: called 8 4 test (21 {^ 297 mm) line A7 B7 V. Description of the invention (46) b) 2- (Ε-2 · (3,4_ 二Hydroxylphenyl) ethene + yl) benzoic acid was hydrolyzed with 22M mole of intermediate 22a in 4M sodium hydroxide solution according to step 3.b, to obtain 6.2 g (98%) of the product. 0⑻ · 2 · (3,4 · dimethoxyphenyl) · ㈣ + yl) yang-phenylpropan-1-ol · 2 · yl) benzylamine in step 7a using U (3.5 mmol Ear) Intermediate milk is reacted with ammonium-2-amino-3-phenylpropanol to obtain 3 g (90%) of the product. d) ⑻-2- (E · 2- (3,4-dimethoxyphenyl) _acetamidine_u) _N_ (3phenylpropan-1-aldehyde-2-yl) benzamide is another step 2. The lc method oxidizes 1 g (2'4 mmol) of intermediate 32c to obtain 1 g (100%) of the product. H-NMR (d6-DMSO); d = 2.9 (1H); 3.2 (1H); 3.8 (6H); 4.5 (1H); 6.9-7.6 (12Η); 7.8 (2H); 8.8 (1Η) )) And 9.7 (lH) ppm »Example 33 (s) -6-methyl · 3_ (2 · fluorenyl) amido-N_ (3-phenylpropionaldehyde) benzamide: .-. (Please read the notes on the back ^ '"

'1T Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs a)

(S) -2-Methyl-N- (3-phenylpropanyl alcohol-2_yl) -5-nitrobenzamide in step 3c with 5 g (27.6 mmol) 2 -Methyl-5-nitrobenzene? Acid with 4.2 g (27.6 mmol) (S) _2-amino_3 • phenyl_;! _Propanol should be used. 7.5 g (87%) of the product were obtained. Line-48- This paper size applies to Chinese National Standard (CNS) A4 specification (2I0X297 mm) A7 B7 V. Description of the invention (46) b) (S) _5-Amino-2-methyl-N- (3- Phenylpropan-1-ol-2-yl) benzamide. 6.3 g (20 mmol) of intermediate 33a was dissolved in 150 ml of ethanol, and 0.5 g of palladium / carbon (10%) was added and hydrogenated. The mixture was then filtered, and the filtrate was reduced and concentrated. 4.9 g of product were obtained. c) (S) -6-methyl_3- (2: fluorenyl) amido _] ^-(3-phenylprop-1-ol-2-yl) benzamidine is used in step 3a One gram (3.5 millimoles) of intermediate 33b was reacted with toluidine. 1.2 g (78%) of the product were obtained. d) (S) -6-methyl-3- (2-stubyl) amido-N- (3-phenylpropan-1-acid-2-yl) benzamidine 1 g (2.3 mmol) Ear) Intermediate 33c was oxidized by the method of step 21c to obtain 1.0 g (100%) of the product. ^ -NMR (d6-DMSO): ά = 2.2 (3H); 2.8 (1H); 3.3 (1H); 4.5 (1H); 7.0-8.2 (13H); 8.6 (2H); 8.8 (1H); 7.7 ( 1H) and 10.5 (1H) ppm. Example 3 4 (S) -3-methyl-4- (2-fluorenyl) amino-N- (3-phenylpropan-1-yl-acid_2_yl) benzidine _ ^- -^ 1.-. (Please read the note on the back first f .. write this page to order the shellfish consumer cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ¥ system

a) (S) -3 -Methenyl-N- (3-phenylprop-1-ol-2-yl) -4-chlorobenzylamine in step 3c with 5 g (27-6 mmol) ) 3-methyl · 4-nitrobenzyl-49- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) A7 B7 V. Description of the invention (47> Acid and 4.2 g (27.6 mmol) (A) (s) _2-amino · 3-phenyl q-propanol reaction. 7.1 g (82%) of the product was obtained. B) (S) -4-amino-3-methyl-N · (3_ Phenylpropyl] -alcohol-2-yl) benzamidine Hydrogenated 7 g (22 3 mmol) of intermediate 3 fluorene in step 33b. 5.6 g (8.8%) of product was obtained. C) (s) _3_methyl-4- (2-fluorenyl) amido-N- (3-phenylpropanol_2_yl) benzyl Amidine is reacted with naphthalene methyl chloride with 1 g (35 mmol) of intermediate 3 in the method of step 3a. 1.3 g (83%) of the product were obtained. d) (S) · 3 · formamidine-4_ (2-fluorenyl) amidoamine_N_ (3_phenylpropanyl q —aldehyde_2_yl) benzamidine 1 g (2.3¾ mole) The body 34c was oxidized by the method of step 21c to obtain 0.95 g (96%) of the product. MS (ES, I): m / E = 43 6 (M +). Example 3 5 --I ---------. (Please read the note on the back first 'CV write this page order the Central Standard Vehicle Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, India Fan (S) -4-phenyl Sulfenamidino-N- (3-phenylpropanyl-1-acid_2_yl) benzidine

a) 4-Phenylaminophenethylacetate Dissolve 5 g (30.3 mmol) of 4-aminobenzoic acid ethyl ester in 100 ml of pyridone at 0 ° (: with 4.1 Milliliter (31.8 millimoles) of benzylsulfonium is mixed drop by drop. This mixture is stirred for 3 hours "and then the mixture is concentrated under reduced pressure -50-This paper size is in accordance with China National Standard (CNS) A4 specifications (210X297 mm) Line A7 B7 V. Description of the invention (48) The condensed residue is recrystallized from ethanol. 7.3 g (85/0) of the product is obtained. B) 4-phenylsulfenamidophenylbenzoic acid is converted by step 31b. 7 g (22.9 mmol) of intermediate 35a was hydrolyzed with a 4 M aqueous sodium hydroxide solution under reflux. 59 grams (94%) of the product were obtained. c) (S) -4-Phenylamino-N- (3-phenylpropan-1-ol-2-yl) benzamide. According to step 7a, 2 g (7.2 mmol) ) Intermediate 351) is reacted with (8) -2-amino-3-phenyl-1-propanol. 19 g (65%) of the product were obtained. d) (S) -4-phenyliminofluorenylamino-N- (3-phenylpropan-1-azol-2-yl) benzidine is prepared by the method of step 21 and 1 g (2.4 mmol) ) Intermediate 35 (1 oxidation, 0.9 g (94%) product was obtained. 'H-NMR (d6-DMSO): i = 2.8 (3H); 3.2 (1H); 4.3 (1H); 7.0-7.9 (14H) ); 8.7 (1H); 9.5 (1H) and 10.6 (lH) ppm. Example 3 6 (S) -2-Methyl-5_ (2-fluorenyl) imino-amino-N- (3-phenyl Propyl-i-tap-2-yl) benzamidine-^ ------- packing-.--(Please read the precautions on the back of this page first) Staff of Central Bureau of Standards, Ministry of Economic Affairs Printed by a cooperative

a) 2-fluorenyl-N- (3-phenylprop-1-ol-2-yl) -5-nitrobenzidine amine according to step 3c with 5 g (27.6 mmol) 2-methyl, 5-nitrobenzoic acid is reacted with (S) -2-amino-3.phenyl-1-propanol. 7.5 g (87%) of the product were obtained. -51-This paper size applies to Chinese National Standard (CNS) A4 specification (2 丨 〇 < 297 mm) A7 B7 V. Description of the invention (49) b) 5-amino-2-methyl-N -(3-Phenylpropan-1-ol-2-yl) benzidine. Hydrogenation of 6.3 g (20.4 mmol) of intermediate 36a in step 33b. 4.9 g (86%) of the product were obtained. c) (S) -2-Methyl-5- (2-naphthyl) sulfenamidinyl_N_ (3-phenylpropanol-2-yl) benzidine. In step 4b, use 1 Grams (3.5 mmol) of intermediate 3 讣 and 2_trimethylammonium chloride. 1.2 g (73%) of the product were obtained. d) (S) -3-fluorenyl-5- (2-phenyl) sulfenamidino · N_ (3 · phenylpropanyl- 丨 -aldehyde-2_yl) benzidine. One gram (2.1 millimoles) of intermediate 36c was oxidized to obtain 0-65 grams (66%) of the product. ! H-NMR (d6-DMSO): d = 2.0 (3H); 2.8 (1H); 3.2 (1H); 4.5 (1H); 6.9-7.5 (8H); 7.6-7.9 (3H); 7.9-8.2 ( 3H); 8.3 (1H); 8.5 (1H); .9_5 (1H) and 10.3 l (lH) ppm. Example 3 7 (S) -4-methyl-3- (2-stubyl) sulfenamido_N- (3-phenylpropan_1_aldehyde_2-yl) benzamidine (please first Read the notes on the back 1C Write this page-3 Staff Consumer Cooperatives, Central Standards Bureau, Ministry of Economic Affairs

a) Methyl-N- (3-phenylpropan-butanol · 2-yl) -4-nitrobenzylamine, 5 g (27.6 mmol) 3 · methyl_4 by step 3 c method _Nitrobenzoic acid is reacted with (S) -2-amino-3-phenyl-1-propanol. 71 grams (82%) were obtained -52- The paper size is in accordance with the Chinese National Standard (CNS) A4 specification (2 丨 0 乂 297 mm) kl _____ B7 V. Description of the invention (so) Product ab) 4-Amine- 3-methyl-N- (3-phenylpropan-1-ol_2-yl) benzylamine was hydrogenated in a method of step 33b to 7 g (22.3 mmol) of intermediate 37a. 5.6 g (89%) of the product were obtained. c) (S) _4_Methyl_3- (2-: fluorenyl) iminofluorenylamino-N- (3-phenylpropanyl_alcohol_2_yl) benzidine is used in step 35a 1.5 g (5.3 mmol) of intermediate 3 7b was reacted with 2-methylformamidine gas. 1.4 g (56%) of the product were obtained. d) (S) -4-Methyl-3- (2-fluorenyl) iminoamine_N- (3-phenylpropyl_i-pyridin_2_yl) benzoylamine Oxidation of 1.1 g (2.3 mmol) of intermediate 37c yielded 1.0 g (92%) of the product. ^ -NMR (d6-DMSO): ά = 2.1 (3H); 2.9 (1H); 3.2 (1H); 4.3 (1H); 7.0-8.2 (13H); 8.2 (2H); 8.7 (1H); 9.5 ( 1H) and 9.8 (1H) ppm 0 Example 3 8 '(S) -6-methyl-3-phenyliminoamino-N- (3-phenylpropan-1-yl-2-yl) benzene Formamidine ^ Pack--* '1 (Please read the note on the back K' write this page) -s Printed by the Shellfish Consumer Cooperative, Central Bureau of Standards, Ministry of Economy

a) (S) -6-Methyl-3-phenylideneamine-N- (3-phenylpropan-1-ol-2-yl) benzamidine-53- This paper is for China National Standards (CNS) A4 specifications (2 丨 OX'297 mm) A7 B7 V. Description of the invention (51) In the method of step 35a, 1 g (3.5 mmol) of intermediate 36b is reacted with benzene and krypton gas. 1.2 g (83%) of the product were obtained. b) (s) · 6-methylphenylsulfenamido-N- (3-phenylpropi-i-aldehyde-2-yl) benzamidine 1g (2 · 4 Millimolar) intermediate 38a was oxidized to obtain 0.8 g of product. ^ -NMR (de-DMSO): i = 2.0 (3H); 2.8 (1H); 3.2 (1H); 4.4 (1H); 6.9-7.8 (13H); 8.6 (1H); 9.5 (1H) and 10.2 (1H) ppm. Example 3 9 (S) -3-phenyliminoamino-N- (3-phenylpropan-1-e · _2-yl) benzylamine

Packing-• One (Please read the precautions on the back ^ \ '., Write this page) Printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs a) (S) -N- (3_ 木 基 丙 -1- Alcohol 2_yl) -4_nitrobenzylamine 5 g (33 mmol) (S) _2_amino_3_phenyl · propanol with 6.1 g (33 Millimolar) 3_nitrobenzene tritium gas reaction. 9.2 g (93%) of the product were obtained. b) (S) · 4 · amino-N- (3 · phenylprop-1-ol) benzamide. According to the method of step 33b, 9.1 g (30.3 mmol) of intermediate 39a was hydrogenated. 8.4 g (100%) of the product were obtained. c) (S) -3-phenyliminoamino-N- (3-phenylprop-1-ol · 2 · yl) benzamide using step 3 5a method with 1 g (3.7 mmol) ) Intermediate 39b reacts with benzene to make chlorine. 0.72 g (48%) of the product was obtained. -54- This paper size applies to Chinese National Standard (CNS) A4 specification '(210X297 mm) A7 B7 V. Description of the invention (52 d) (S) -3-phenyliminofluorenylamino-N- (3- Phenylpropan-1-yl-2-phenyl) benzamide was oxidized in an amount of 0.6 g (1.5 mmol) of intermediate 39c by step 21c to obtain 0.55 g (93%) of the product. MS: m / e = 408 (M +). Example 4 0

(S) -4- (E-2- 4-year-old * -2-yl-1-ethenyl) -N- (3-phenylpropanyl-pyridin-2-yl) benzidine

---.. '(Please read the precautions on the back of the first page ^ Write this page) Printed by the Consumer Cooperatives of the Central Standard Vehicle Bureau of the Ministry of Economic Affairs a) 4- (E · 2-naphthol-1-ethene Methyl) benzoic acid Dissolve 4.5 g (26.4 millimoles) of 2-Ethyl ethyl hydrazone and 4.3 g (26.4 millimoles) of 4-methyl ethyl benzoic acid methyl vinegar in 100 ml of methanol, then use 16 Treated with 4 mL of a 4 M aqueous sodium hydroxide solution. This mixture was stirred for about 1 hour. A large amount of water was added, and the mixture was stirred for 72 hours. The mixture was then acidified with concentrated hydrochloric acid to form a precipitate, which was filtered off with suction and recrystallized from ethanol. 7.2 g (90%) of the product were obtained. b) (S) -4- (E-2-fluorenol-2-yl-1-vinyl) -N- (3-phenylprop-1-ol · 2-yl) benzamidine in step 7a Methods 1.2 g (7.6 mmol) of (S) -2-amino-3-phenyl-1-propanol was reacted with 2.3 g (7.6 mmol) of intermediate 40a to obtain 2.1 g (64%). product. c) (S) -4_ (E-2 · Wan · 2_yl-1-Ethyl) _N- (3-phenylpropan-1-acid-2-yl) 55- This paper is applicable to China Standard (CNS) A4 specification (2Ι0χ297 cm) Thread A7 _____B7__ V. Description of the invention (53) Benzoxamine oxidizes 0.7 g (1.65 mmol) of intermediate 40b by step 21c to obtain 0.66 g (92 %)product. MS: m / e = 433 (M +). Example 4 1 (S) -3- (E-2 -Teijin -2 -yl-1_ethynyl) -N- (3-privylpropion-1 -z -2 -yl) methanamine

a) 4- (E_2-fluorenol · 2-yl-1-vinyl) benzoic acid: 4.5 g (26.4 mmol) of 2-ethenylfluorene and 4 g (26.4 mmol) of 3-fluorenyl Benzoic acid is reacted in step 40a. 7.4 g (93%) of the product were obtained. b) (S) -3- (E · 2-fluorenol-2-yl-1-vinyl) -N- (3-phenylprop-1-ol-2-yl) benzamidine with step 7a Methods 0.6 g (4 mmol) of (S) -2-amino-3-phenyl-1-propanol was reacted with 1.2 g (4 mmol) of intermediate 41a. 1.5 g. (87%) of product were obtained. c) (S) -3_ (E-2-Amphenol-2_yl-1-vinyl) -N- (3-phenylpropan-1-aldehyde_2_yl) benzamidine ... 'To step Method 21c oxidizes 1 g (2.3 mmol) of intermediate 41b to obtain 0.91 g of product. Printed by the Consumers 'Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs-56- This paper size applies to the Chinese National Standard (CNS) A4 specification (2 丨 0X297 mm)' 'Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 54) MS: m / e = 433 (M +). Example 4 2 (S) -N- (4-methylthio-1-butan-2-yl) -3- (2-fluorenylsulfenamido) benzidine

a) (S) -N- (4-methylthio-l-butanol_2-yl) -3- (2-fluorenylsulfenamido) benzamide is used in step 7a with 2 g (3 Millimolar) 3_ (2_fluorenylsulfenamido) phenylarsinic acid (intermediate 22a) is reacted with (S) -2-amino-4-methylthio-1-butanol to obtain 1.6 G (59%) of product. b) (S) -N- (4-fluorenylthio-1-butyraldehyde-2-yl) -3- (2-fluorenylsulfinamido) benzidine is 1.0 g (in step 21c) 2,5 mmol) of intermediate 42a was oxidized to obtain 0.74 g (75%) of the product. MS: m / e = 442 (M +) ° Example 4 3 (S) -4- (2-fluorenyl) amido-2- (E-2-phenylethylene-: ^ yl) _n_ (3_benzene Dipropanal-2-yl) benzamidine (Please read the note on the back first C1V. Write this page • Binding

A7 ___B7 of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the Invention (55) a) 2-Bromo-4-nitro-benzoic acid will be 75 grams (0_35 mole) of 2-bromo- 4-nitrotoluene, 12 ml whole 336 and 39 g (0_47 mole) sodium bisulfate are heated to 80 ° C. The mixture was stirred thoroughly, and then 183 g (1.16 mol) of potassium peroxysalt was added in portions. This mixture was then heated at reflux for 4 5 minutes. The mixture was mashed with dream soil, and the mash was concentrated under reduced pressure to about 700 ml. This aqueous solution was acidified with concentrated hydrochloric acid and the product was precipitated. 45 grams (53%) of the product were obtained. b) 2-Bromo-4-nitro-benzoic acid ethyl ester 44.5 g (0.18 mol) of intermediate 43a was added to 450 ml of ethanol and carefully treated with 45 ml of concentrated sulfuric acid. This mixture was then heated at reflux for 4 hours. The mixture was poured into ice water, and the product was extracted with ethyl acetate. The organic phase was washed with an aqueous sodium hydrogen sulfate solution and water, dried, and concentrated under reduced pressure. 50.4 g (100%) of the product were obtained. c) Ethyl 4-nitro-2- (E-2-phenylethen-1-yl) benzoate was used in step 31a with 50 g (0.18 mole) of intermediate 43b and styrene in dimethylfluorene. The amine reacts at reflux temperature. 35 g (65%) of the product were obtained. d) 4-nitro-2- (E · 2-phenylethen-1-yl) benzoic acid. Hydrolysis of 35 g (0.12 mol) of intermediate 43c with aqueous sodium hydroxide according to step 31b. 29 g (92%) of the product were obtained. e) (S) -4-nitro-2- (E-2-phenylethylene_-fluoren-yl) -N- (3-phenylprop-1-ol-2-yl) benzamide Step 7a method uses 5.6 grams (37.1 millimoles) (S) -2-amino-3-phenyl-58- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) Please read the back Note tii, write this page.

* 1T 1-line A7 B7 Printed by the Bayong Consumer Cooperative of the Central Standard Vehicle Bureau of the Ministry of Economic Affairs Ⅴ. Description of the invention (56) -1-propanol reacts with 10 g (37.1 mmol) of intermediate 43d. 11.3 g (76%) of the product were obtained. f) Fluoro-4-amino-2- (E-2-phenylethylfluorenyl) -N_ (3-phenylpropanol_2_'yl) benzidine. 10 g (24.9 mmol) Moore) Middle Li 43 e was hydrogenated in 200 ml of tetrahydrocran in the presence of 3 grams of Raney nickel. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. Recrystallization from ethanol yielded 62 g (69/0) of the 'product. g) (S) -4_ (2 · # group) amido-2 · (Ε-2 · phenylethenyl group) _N- (3-phenylprop-1-ol-2-yl) Benzophenamine was reacted in step 10a 'with 1 g (2.7 mmol) of middle Zhao 43 f in 2-trifluoromethane. 1.2 g (86%) of the product were obtained. f) (S) -4- (2_Teayl) amino group-2_ (E-2-phenylethylfluorenyl-i_yl) _n_ (3-phenylpropyl-1 -pyridyl-2 -yl) table Methamidine oxidized 43 g of 1.0 g (1.9 mmol) of intermediate in the method of step 21c. 0.75 g (76%) of the product was obtained. MS: m / e = 524 (M +) 0 Example 4 4 (S) -3- (2-Fanyl) iminoamido-N- (3-pent-1-hept-2-yl) benzyl amine

a) (S) -3- (2-triphenyl) sub-continuous amine-N- (3-phenylpropan-1_ol_2_yl) benzene-59- This paper is in accordance with China National Standard (CNS) ) A4 specification (210X297mm) 03-.. Please read the notes on the back h \ write this page A7 B7, description of the invention (S7) 2 g (6.1 mmol) of formamide in step 7a 3- (2-Amidinosulfenamido) benzoic acid (Intermediate 22a) was reacted with D, L-2 · amino-i-pentanol to obtain 1.9 g (76%) of the product. b) (S) -3- (2-triyl) sub-continued. Amino-N- (3-phenylpropylpyridin-2-yl) benzamide was prepared by step 21c with 1.3 g (3.2 mmol). Mol) intermediate 44a is oxidized. 1.3 g (100%) of the product were obtained. ^ -NMR (de-DMSO): δ = 0.9 (3H); 1.1-1.9 (4H); 4.1 (1H); 7.1-8.1 (10H); 8.3 (1H); 8.6 (1H); 9.4 (1H) and 10.5 (lH) ppm. Example 4 5 Alcohol) N- (Amino-2-N- (butyl-1-azol-2-yl) benzylamine Please read the precautions on the back first to write this page. Pack-

* 1T

Printed by the Consumer Cooperatives of the Central Bureau of Quasi-Staff of the Ministry of Economic Affairs a) 3- (2-fluorenyl) sulfenamido-N- (but-1-ol-2-yl) benzamide is used in step 7a method 2 G (6.1 mmol) of 3- (2-sulphenylsulfenamido) benzoic acid (Intermediate 22a) and D, L-2-amino-1-butanol, 1.3 g (54%) )product. b) 3- (2-stubyl) sulfenamidinyl-N- (but-1-aldehyde-2-yl) benzylamine is used to oxidize 1 g (2.5 mmol) of intermediate 45a by step 21c. . 0.55 g of product were obtained. ^ -NMR (d6-DMSO): (J = 1.0 (3H); 1.7 (1H); 1.9 (1H); 4.1 (1H); 7.1-8.1 (9H); 8.3 (2H); 8.6 (1H); 9.5 (1H) and 10.6 (1H) -60- This paper size applies to Chinese national standards (CNS > A4 ^ format (2 丨 0X297) 芨 5. Description of the invention (

Ppm Example 4 6-way-2-yl) benzylamine 3- (2_fluorenyl) sulfenamido_N · (3 · indole_3_ylpropyl

, CH〇 Prop-1-ol-2-yl) benzene Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

a) 3- (2-¾: yl) sulfenamidino · N_ (3_indole_3_ylformamidine = method used in step 7a! gram millimolar) Amino) benzoic acid (intermediate 22a) was reacted with d, L_3_indole_3_propylpropanol to obtain 0.9 g (60%) of the product. b) 3- (2-naphthyl) sulfenamidinyl_N_ (3indole_3_ylpropanyl- 丨 _aldehyde 丨 -yl) benzylamine is used to process 8-8 g (1 · 6 millimolar) intermediate 46a is oxidized. 0.71 g (90%) of the product was obtained. MS: m / e = 497 (M +). Example 4 7 (S) -N- (3-cyclohexylprop-1-aldehyde-2-yl) -3- (2-fluorenyl) sulfenamidobenzylamine

61-This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) A7 B7 V. Description of the invention (59) a) (S) -N- (3 · cyclohexylpropanol-2 · yl) _3_ (2-Methenyl) sulfenamidinyl benzamidine in step 7a with 1.5 g (4.6 mmol) of 3- (2-fluorenylsulfenamido) benzoic acid (Intermediate 223) It was reacted with (3) _2 · amino_3-cyclohexylpropanol to obtain 1.8 g (77%) of the product. b) (S) -N- (3-cyclohexylpropyl_i-aldehyde-2-yl) _3. (2-fluorenyl) sulfenamidinobenzidine. According to the method of step 21c, 1.4 g (3 mmol) Mol) intermediate 47a is oxidized. This gave 1.35 g (100%) of the product. ! H-NMR (d6-DMSO): ό = 0.8-1.9 (13H); 4.2 (1H); 7.0-8.1 (10H); 8.2 (1H); 8.6 (1H); 9.3 (1H) and 10.5 (lH) PPm. Example 4 8 (S) -4-Askyl-2- (E_2-phenyl-1-ethylenyl) -n_ (3-phenylpropanyl-i-pyridin-2-yl) benzamidine (please read first Note on the back h '• Write this page) -Pack-°

Yin Fan, an employee consumer cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, took step 21c to 0.4 g (1 mmol) (S) _4_nitro_2 · (Ε_2phenylethyl-1--1-yl) -N- (3_ Propyl-1-ol-2-yl) benzylam (intermediate 43e) is oxidized. 0.35 g (88%) of the product was obtained. MS: m / e = 400 (M +). 62- This paper size applies to Chinese national standards (CNS > A4 pits (210X297 mm) A7 V. Description of the invention (Example 4 9 (S) -4- (2-fluorenylsulfenamido) methyl) _ Ν- (3-phenylpropanal—formyl) benzylamine q >

a)

Central Ministry of Economic Affairs #Associate Bureau Consumer Cooperatives Co., Ltd. Printing V 4- (2-Based Substituted Amino) Methyl Benzoic Acid Using Step 4b, 3.8 g (25 mmol) of 4- (aminomethyl) benzoic acid Reacted with 2-sulfonium sulfonium gas to give 6.1 g (72%) of the product. (S) -4_ (2-fluorenylaminoamino) methyl_n_ (3-phenylpropan_1_ol_2_yl) benzamidine using step 7a with 3.1 g (9 mmol) Ear) Intermediate 49a was reacted with (S) -2-amino-3-cyclohexylpropyl, 1-ol to obtain 2.4 g (62%) of the product. (S) -4- (2.fluorenylidenesulfinoamino) methyl-N- (3-phenylpropan-1-eco-_2-yl) benzidine. According to step 21c, 1.6 g (3.6 The mol) intermediate 49b was oxidized to give 1.0 g (64%) of the product. ^ -NMR (d6-DMSO): S = 2.9 (1H); 3.3 (1H); 4.0 (2H); 4.5 (1H); 7.0-8.5 (17H); 8.8 (1H) and 9.5 (1H) ppm. Example 5 0 (S) -6-bromo-3- (2-fluorenylsulfenamidino) rN- (3-phenylpropan-1-yl-2 · yl) benzidine amine b) c)- 63- Wood paper scale is applicable to Chinese National Standard (CNS) A4 specification (210 × 297 mm) YI --- · * (Please read the precautions on the back of this page first) -3 line-A7 s, _B7 V. Description of the invention (61)

Printed by the Shell Standard Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs a) Ethyl 2-bromo-5-nitrobenzoate was carefully introduced into 5 5 ml of sulfuric acid, 22.9 g (0.1 mol) of ethyl 2-bromobenzoate . 16.5 ml of nitric acid (prepared at 0 ° C with 5.5 ml of 98% strength nitric acid and 11 ml of 97% strength sulfuric acid) was added dropwise at 0 ° C, and the mixture was stirred for about 1 hour. Then carefully pour the mixture into ice water. The precipitate was recrystallized from ethanol to obtain 17.7 g (64%) of the product. b) Ethyl 5-amino-2-bromophenylacetate Dissolve 10 g (.36 mmol) of intermediate 50a in 200 ml of glacial acetic acid and heat to 80 ° C. Then add 12 g (21.5 mmol) of iron powder carefully (reacted in batches). The formed precipitate was filtered off with suction, and the filtrate was concentrated under reduced pressure. The residue was acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. 6 g (68%) of the product were obtained. e) 6-Bromo-3- (2-fluorenyl) sulfenamidobenzoic acid ethyl ester In step 4b, 5.5 g (22.5 mmol) of intermediate 50b were reacted with 2-fluorenylsulfonium chloride. After purification by chromatography (eluent: toluene / ethanol = 17/3), 7 g (72%) of the product was obtained. d) 6-bromo-3- (2-fluorenyl) sulfenamidobenzoic acid was hydrolyzed by 3g (6.9-millimol) of intermediate 50c by step 3b to obtain 2.5g (89%) of the product. ) (S) -6-bromo-3- (2-fluorenylsulfenamido) -N- (3-phenylpropan-1-ol-2-yl) This paper size is applicable to China National Standard (CNS) ) A4 size (210X297mm) Please read the notes on the back to write this page. Packing. Order A7 Β7 V. Description of the invention (62) 1 g (2.5 mmol) of benzamidine in step 7 a method The body 50d was reacted with (s) -2-amino-3-phenylpropan-1-ol and purified by chromatography (eluent: ethyl acetate / n-heptane = 2/1) to obtain 0.87. G (87%) of product. (s) · 6 · Br_3- (2_fluorenylsulfenamido) _N_ (3 · phenylpropane, aldehyde_2_yl) Benzene's boat was oxidized by step 21c 0.72 g (1.3 mmol) Mol) Intermediate 50e. 0.6 g (86%) of the product was obtained. 'H-NMR (d6-DMSO): d = 2.8 (lH); 3.2 (1H); 4.5 (1H); 7.0-8.1 (12H); 8.4 (1H); 8..9 (1H); 9.6 (1H ) And 10.8 (lH) ppm. Example 5 1 (S) -4- (2-phenyl) sulfenamidinyl_n- (3-phenylpropyl-i_aldehyde_2_yl) benzidine

----------*. (Please read the notes on the back first \ {Write this page, 11 Printed by the Pai Consumer Consumer Cooperative, Central Building Standard Bureau, Ministry of Economic Affairs) 4- (2-naphthylsulfinyl) Ethylamino) benzoate was reacted in step 4b with 10 g (60 · 5 mmol) of 4-aminophenylarsonate and 13.7 g (60.5 mmol) of 2 · sulfonylsulfonium 13.6 g (64%) of the product was obtained. b) 4- (2-fluorenylideneamino) benzoic acid 13.2 g (37.1 mmol) of intermediate 51a were hydrolyzed by step 3b to obtain 11_1 g (95%) of the product. c) (S) -4- (2-: g: yl) iminofluorenylamino_n- (3-phenylpropanyl alcohol · 2-yl) benzene-65- thread The paper size is applicable to Chinese national standards ( CNS) A4 specification (210X297 mm) A7 B7 V. Description of the invention (63) Formamidine was prepared in step 7a using 1.5 g (4.6 mmol) of intermediate 51b and (S) -2-amino-3-benzene Propyl-i-ol was reacted to obtain 1.7 g (81%) of the product. -d) (S) -4- (2-fluorenyl) sulfenamido-N- (3-phenylpropan-1-aldehyde-2-yl) benzidine. 1.4 g (3 mmol) of fluorene / trifluoroacetic anhydride was used to oxidize intermediate 22b »After chromatographic analysis (eluent: toluene / propanol = 1/1), 0.12 g of product was obtained. 'H-NMR (d6-DMSO): = 2.9 (1H); 3.2 (1H); 4.3 (1H); 7.0-8 · 1 (14Η); 8.4 (2H); 8.6 (1H); 9.5 (1H) and 11.7 (lH) ppm. Example 5 2 (S) -2- (2-fluorenyl.methyl) -n_ (3-phenylpropan-1-aldehyde-2-yl) benzamide

---- 装 —,--(Please read the precautions on the back ^.

'1T Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs a) 4,4_Difluorenyl · 2 · (2- (荇 · 2_yl-Ethylmethyl) phenyl) _2 · indazole showered at -781 A 104-milliliter 1.6 M butyl solution was slowly added dropwise to 400 g of 25 g (0.14 mol) of 4,4-dimethyl · 2-phenyl-2-oxazoline and 0.1 g of tribenzene in 400 ml of anhydrous tetrahydrofuran. Inside methane. This mixture was stirred for 1 hour. The mixture was then allowed to cool to -30 ° C, and a solution of 20.3 g (0.13 mol) of 2-hydrazone in 200 ml of anhydrous i-hydrogen was added dropwise. Stir off at -20 ° C to -30T for about 1 hour. The reaction solution was then allowed to warm to room temperature and the solvent was removed under reduced pressure. Lead the residue into ice water and use ether-66-line. The paper size applies Chinese National Standard (CNS) Ad specifications (21 OX297 mm) Λ7 Β7 V. Description of the invention (64) Take the organic phase and dry it. Pressure concentrated. The residue was purified by chromatographic analysis (eluent: n-heptane / acetone = 40/3) to obtain 25.3 g (54%) of the product. B) 3- (Hydroxy-2-yl) benzopyranone. 22 g (66 mmol) of intermediate 52a were heated in a mixture of 250 ml of ethanol and 100 ml of 1 M hydrochloric acid under reflux for 2 hours. Β was removed under reduced pressure. Ethanol, the resulting precipitate was filtered off with suction. 164 g (95%) of the product were obtained. c) 3-Tetra-2-ylbenzoic acid Dissolve 16 g (61.5 mmol) of intermediate 52b in a mixture of 100 ml of tetramethylfuran and 250 liters of ethanol, and add 5 g of free / sulfate lock to hydrogenation. The mixture was then filtered and the filtrate was concentrated under reduced pressure. The residue was recrystallized from toluene to obtain 13.6 g (85%) of the product. d) (S) _2_ (2_fluorenylmethyl) -N- (3-phenylpropan-1-ol-2-yl) benzamide in the method of step 7a with 1 g (3.8 mmol) The body 52c was reacted with (S) -2-amino-3-phenyl-1-propanol to obtain 1.2 g (80%) of the product. e) (S) -2_ (2-Tetramethyl) -N- (3-phenylpropan-1-yl)>-2-yl) benzamide is oxidized by the method of step 21c to 1 g (2.5 mmol) Ear) Intermediate 52d. 1.0 g (89%) of the product was obtained. ^ -NMR (d6-DMSO): (ί = 2.8 (1Η); 3.2 (1H); 4.1 (12H); 4.4 (1H); 7.0-8.0 (16H); 8.8 (1H) and 9.4 (lH) ppm. Example 5 3 (S) -4-Ethylamino-2- (E-2-Chloyl-1-ethenyl) -N- (3-phenylpropan-1-yl · _2-yl) benzyl Phenylamine-67- This paper size is applicable to Chinese National Standard (CNS) Α4 size (210X 297 Gong) (Please read the precautions on the back before filling out this page) — installed ·, printed by 1Τ Central Consumers Bureau of the Ministry of Economic Affairs Switch A7 -------- -B7 V. Description of Invention (65)

(Please read the precautions on the back before filling out this page) a) (S) _4_ethylamido_2- (E-2-phenyl-fluorene · vinyl) _N_ (3_phenylpropyl-1_ alcohol -2 · yl) benzamidine will be 1 g (2.7 mmol) (S) _4_amino_2_ (£ _2_phenylvinyl) -N- (3-phenylpropan-1- Alcohol-2-yl) benzamide (intermediate 43f) was suspended in 50 ml of tetrahydrofuran and mixed with 0 25 ml (27 mmol) of acetic anhydride at 100 ° C. This mixture was stirred for 16 hours. The reaction was then concentrated under reduced pressure and the residue was recrystallized from ethanol. 78 g (71%) of the product were obtained. b) (S) -4-Ethylamino-2- (E-2-phenyl-1-vinyl) _n- (3-phenylpropan-1 · aldehyde-2-yl) benzidine The method of step 21c uses [blank] to oxidize 0.65 g (1.6 mmol) of intermediate 53a. 0.5 g (77%) of the product was obtained. TH-NMR (d6-DMSO) of Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs: < ^ = 2.9 (1H); 3.2 (1H); 4.6 (1H); 7-7.7 (14H); 8.0 (1H); 8.8 (1H); 9.7 (1H) and 10.1 (lH) ppm. Example 5 4 (S) -3- (8-4Polinylsulfenamidinyl) -N- (3-phenylpropan-1-aldehyde-2-yl) benzidine

This paper size applies Chinese National Standards (CNS) specifications (2 丨 () 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 ______B7 V. Description of the invention (66) a) (S) -3- (8 _Quinolinylsulfenamidinyl) -N- (3.phenylpropan-1-ol-2-yl) benzidine, using step 10a with 1.2 g (4.6 mmol) -Amino-N- (3-phenylprop-1-ol-2-yl) benzylamine (Intermediate 39b) reacts with 8-Junlinji gas. 1 g of product was obtained. b) (S) -3_ (8-Bendinylideneamine) -N- (3-phenylpropan-1-acid-2-yl) benzidine is oxidized by 0.9g (1.95 Mol) Intermediate 54a. 0.69 g (77%) of the product was obtained. ^ -NMR (d6-DMSO): S = 2.9 (1H); 3.2 (1H); 4.3 (1H); 7.0-7.9 (11H); 8.2 (1H); 8.3 (1H); 8.5 (1H); 8.7 ( 1H); 9.1 (1H); 9.5 (1H) and 10_2 (lH) ppm. Similar to the above examples, other compounds of the present invention were prepared. Example 5 5 (8) -4- (2-Fluoro-4-pyridylphenyl) amino-N- (3-phenylprop-1-aldehyde-2-yl) benzidine Matters needing attention iv

, 1T Γ line

lH-NMR (CF3COOD): ά = 3.2 (2H); 4.8 (1H); 6.7 (1H); 7.2-8.4 (14H); 9 · 0 (2Η) and 11.8 (1H) ppm. -69- This paper size is in accordance with Chinese National Standard (CNS) A4 specifications' (210X297 mm) _ A7 B7 V. Description of the invention (67) Example 5 6 (S) -2-fluoro-N- (3-phenylpropane -1-aldehyde-2-yl) -4- (4-pyridyl) benzidine

1H-NMR (CDC13): d = 3.3 (2H); 4.95 (1H); 7.2-7.6 (10H); 8.2 (1H); 8.7 (1H) and 9.7 (1Η) ppm. Example 57 N- (but-1-aldehyde-2-yl) -3- (8-quinolinyl) sulfenamidinyl benzamidine (please read the precautions on the back first ^ write this page) -pack -

Ordered by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs: m / e = 441 (M +) ° Example 5 8 N- (but-1-aldehyde-2-yl) -4- (8-quinolinyl) sulfinate Amidobenzidine

MS: m / e = 397 (M +) ° Example 5 9 3- (8-quinolinyl) sulfenamido-N- (pentan-1-aldehyde-2-yl) benzamide-70-benzyl Paper size applies to Chinese National Standard (CNS) A4 specifications · (210X 297 mm) A7 B7 V. Description of invention (68)

1H-NMR (CDC13): < y = 1.3 (3H); 1.75 (2H); 2.0 (2H); 4.7 (1H); 6.55 (1H); 7.2-7.7 (6H); 8.0 (1H); 8.3 ( 2H); 8.7 (wide); 9.1 (1Η) and 9.7 (1H) ppm. Example 6 Ο 3- (8-quinolinyl) sulfenamidino · N- (pentan · 1-aldehyde-2-yl) benzidine (Please read the precautions on the back before filling this page). .

IH-NMR (d6-DMSO) printed by the Consumer Cooperative of the Central Approval Bureau of the Ministry of Economic Affairs: i = 1.2 (3H); 1.4 (2H); 1.75 (2H); 4.1 (1H); 7.15 (2H); 7.5-7.8 (4H); 8.3 (1H); 8.4-8.7 (3H); 9.1 (1H); 9.3 (1H) and 10.5 (1H) ppm. Example 6 1 N- (pentan-1-yl-2-yl-pyridine-2-ylethen-1-yl) benzamide hydrochloride

-71-This paper size applies Chinese National Standard (CNS) A4 specification (2 丨 0X297 mm) A7 B7 _V. Description of the invention (69> lH-NMR (d6-DMSO): = 0.9 (3H); 1.4 (2H ); 1.6 (1H); 1.8 (1H); 4.4 (1H); 7_3-8.5 (9H); 8_7 (1H); 8.9 (1Η) and 9.6 (1Η) ppm. Example 6 2 (S) -N- (4-methylpentan-1-aldehyde-2-yl) -2- (E-2-pyridin_2_ylethen-1-yl) benzidine hydrochloride

HO lH-NMR (d6-DMSO): 0.9 (3H); 1.5-1.9 (3H); 4.4 (1H); 7.4- 8.2 (9H); 8.4 (1H); 8.8 (1H); 9.0 (1H) and 9.7 (1H) ppm e Example 6 3 (S) -N- (4-methylthiobutan-1-aldehyde-2-yl) -2- (E-2-pyridin-2-ylethylene-1-yl) Benzoamine Hydrochloride Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

HCT lH-NMR (d6-DMSO): ^ = 2.0 (1H); 2.3 (1H); 2.55 (3H); 2.7-3.0 (2H); 4.4 (1H); 7.5-8.5 (10Η); 8 · 8 ( 1Η); 9.2 (1H) and 9.7 (1H) ppm ° 72- (Please read the precautions on the back before filling this page)

This paper size applies to China National Standards (CNS) A4 specifications (21 297 mm) A7 B7 V. Description of the invention (70) Example 6 4 N- (butyl-1-road-2-yl) -2- (E -2-t * 比 症 -2-ylethen-1-yl) benzamide hydrochloride

MS: m / e 294 (M +)-Example 6 5 (S) · N- (3-benzylpropane-1-yl-2-ylpyridine-4-ylethylidene_1-yl) benzamide

(Please read the notes on the back before filling in this I), τ Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economy 1H-NMR (CDC13): δ = 3.3 (2H); 5.05 (1H); 6.55 (1H); 6.9 -7.8 (13H); 8.5 (2Η) and 9.8 (1Η) ppm. Example 6 6 (S) _N- (3-Phenylpropanyl-1 · z- 2-yl) -4- (2-11pyridyl) benzamide

This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) JJ. A7 _B7_ _ V. Description of the invention (71) lH-NMR (d6-DMSO): = 3.0 (1H); 3.3 (1H); 4.5 (1H); 7.1 (1H); 7.25 (3H); 7.35 (1H); 7.9-8.2 (6H); 8.7 (1H); 9.0 (1H) and 9.7 (1H) ppm. Example 67 (S) _N · (3 phenylpropan-1 -yue · -2-yl) -2 (E · 2 -Edian-2-ylethenyl 1 -yl) benzamide (please read first Note on the back of this page, please fill in this page again) Equipment-1H-NMR (CF3C00D): Xi = 3.25 (1H); 3.4 (1Η); 4 · 9 (1Η) and 7.2.8 (8Η) ppm. Example 8 (S) -N- (3-Phenylpropan-1-aldehyde-2-yl) -3- (3-pyridylsulfinamido) benzidine

T Printed by shellfish consumer co-operation, Central Bureau of Standards, Ministry of Economy

lH-NMR (d6-DMSO): d = 2.9 (1H); 3.05 (1H); 4.6 (1H); 7.0-7.7 (13H); 8.8 (1H) and 10.0 (1Η) ppm. Example 6 9 -74-

This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm). 5. Description of the invention (72 A7 B7 (S) -2 · methylN · (3-phenylpropan-1-aldehyde-2-yl) -5- (3-pyridinylsulfenamido) benzamidine-〇

lH-NMR (d6-DMSO): d = 2.0 (3H); 2.8 (1H); 3.25 (1H); 4.5 (1H); 6.9-7.4 (7H); 7.6 (1H); 8.1 (1H); 8 · 6-8 · 9 (3Η); 9.6 (1H) and 10.5 (1H) ppm 0 Example 7 0 N- (but-1-aldehyde-2-yl) > -2- (E-2-pyridin-2-yl Ethylene-1-yl) benzamidine hydrochloride

HC1 (Please read the precautions on the back before filling this page).

、 1T ▲ ▲ Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs ^ 1H-NMR (CDC13): < y = 1.0 (3H); 1.8 (1H); 2.1 (1H); 4.8 (1H); 6.5 (1H) ; 6.9-7.9 (6H); 8.5 (2H) and 9.7 (1H) ppm. Example 7 1 (S) -4-methanesulfenamido-2- (E-2-phenylethylene · 1-yl) -N- (3-phenylpropane · 1-aldehyde-2-yl) benzene Formamidine-75 This paper size is applicable to Chinese National Standard (CNS) A4 specification (210 × 297 mm) V. Description of invention (73) A7 B7

MS: m / e 448 (M +) 〇 Example 7 2 6-methyl-N- (pentan-1-aldehyde-2-yl) -3- (3-pyridylsulfinamido) benzamide

SOjNH

'CHO CH, MS: m.e = 375 (M +). Example 7 3 (S) -N- (3-benzylpropan-1 -acid · 2-yl) -4- (4-p bipyridyl) benzamide (Please read the precautions on the back before filling in this Page) Printed by the Consumer Standards Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs ^

1H-NMR (CDC13): ^ = 3.35 (2H); 5.0 (1H); 6.8 (1H); 7.2-7.9 (11H); 8.7 (2Η) and 9.75 (1Η) ppm. Example 7 4 N- (pentan-1-aldehyde-2-yl) -2- (2-pyridylmethoxy) benzamidine pinane sulfonate-76- This paper size applies to Chinese National Standard (CNS ) A4 specification (210X297 mm) 5. Invention description (74

" CHO A7 B7

CH 3SOjH 1H-NMR (CDC13): (^ = 0.9 (3H); 1.3 (2H); 1.7 (1H); 1.9 (1H); 4.7 (1H); 5.3 (2H); 7.0-7.9 (6H); 8.2 (1H); 8.6 (1H); 8.9 (1H); and 9.6 (1H) ppm o Example 7 5 N- (pentan-1-aldehyde-2-yl) -2- (3-pyridylmethoxy) benzene Formamidine Methane Sulfonate

'CHO

CH, SO, H MS: m / e = 312 (M +). Example 7 6 N- (pentyl-1 -pyridin-2-yl) -2- (E-2 -11 Biyodo-4 -ylethyn-1 -yl) benzamide (Please read the precautions on the back first (Fill in this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs

lH-NMR (d6-DMSO): ό = 1.0 (3H); 1.4 (2H); 1.7 (1H); 2.1 (1H); 77 This paper size applies to China National Standard (CNS) A4 specifications (210X297 mm) A7 _ B7______ V. Description of the invention (75) 4.5 (1Η); 6.5 (1Η); 6.9-7 · 8 (6Η); 8.5 (2Η) and 9.7 (1H) ppm Example 7 7 Ν · (丁- 1-aldehyde-2-yl) -2- (4-pyridylmethoxy) benzamide

1H-NMR (CDC13): δ = 0.8 (3H); 1.7 (1H); 2.0 (1H); 4.7 (1H); 5.25 (2H); 7.0-7.6 (5H); 8.2 (1H); 8.3 (1H) ; 8.6 (1H) and 9.6 (1H) ppm ° Example 78 N- (Hex-1 · aldehyde-2-yl) -2- (E-2-pyridin-2-ylethylene-1-yl) benzamide Hydrochloride

(Please read the notes on the back before filling out this page)% • 'Package. Order Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs MS: m / e-322 (M +). Example 7 9 (S) -4- (Quinolin-2-yl) thiomethyl-N- (3-phenylpropan-1-aldehyde-2-yl) benzamide X fumaric acid 78-benzyl Paper size applies to China National Standard (CNS) A4 specification (210X: 297 cm) 5. Description of invention (76 A7 B7

lH-NMR (d6-DMSO): ά = 2.8-3.0 (lH); 3.2-3.4 (lH); 4.5 (1H); 4.6 (2H); 6.6 (2H); 7.0-8.2 (13H); 8.8 (1H ) And 9.5 (1Η) ppm. Example 8 4- (Quinolin-2-yl) thiomethyl-N- (3-pent-1-aldehyde-2-yl) benzamide

• CHO

Yinben lH-NMR (d6-DMSO): Zhengong Consumer Cooperative, Central Standards Bureau, Ministry of Economic Affairs: ά = 0.9 (3H); 1.2-1.9 (4H); 4.2 (1H); 4.7 (2H); 7 · 3-8 · 2 (10Η); 8.8 (1Η) and 9.5 (1H) ppm. Example 8 1 2- (2-Quinolinylmethoxy) _N- (3-pent-1-aldehyde-2-yl) benzamide

CHO (诮 Please read the notes on the back before filling this page)

The size of this paper is applicable to Chinese National Standard (CNS) A4 (210X297 mm) A7 B7 V. Description of the invention (77) lH-NMR (d6-DMSO): ό = 0.7 (3H); 1.2 (2H); 1.3 -1.8 (4H); 4.3 (1H); 5.5 (2H); 7.0-8.0 (lH); 8.4 (1H); 8.8 (1H) and 9.5 (1Η) ppm. Example 8 2 N- (3-Pentan-1-aldehyde-2-yl) -4_ (7-trifluoromethylquinolin-4_yl) thiofluorenylbenzylamine

lH-NMR (d6-DMSO): ^ = 0.9 (3H); 1.2-1.9 (4H); 4.2 (1H); 4.6 (2H); 7.6 (3H); 7.9 (3H); 8.3 (2H); 8.8 (2Η) and 9.5 (1H) ppm. Example 8 3 (_S) _4- (E-2 -Different to ethyl-1-ethenyl) -N- (3-phenylpropan-1-z '· 2-yl) benzamide X Fumar acid

(Please read the notes on the back before filling this page) r --5

T ί. '· *-Printed by the Central Standards Bureau of the Ministry of Economic Affairs and Consumer Cooperatives lH-NMR (d6-DMSO): ί = 2.7-3.0 (2H); 4.2 (1H); 6.7 (2H); 7.25 (5H) 7 · 75-8 · 1 (8Η); 8.3 (2H); 8.4 (1H); 8.8 (2H) and 9.5 (1Η) ppm. Example 8 4 (S) -4_methoxy-3- (E-2-phenyl-1-vinyl) amido-N- (3-phenylprop-1--1-80- Chinese National Standard (CNS) A4 specification (210X297 male light) 3.454 A7 B7 V. Description of the invention (78) aldehyde-2-yl benzamidine

lH-NMR (d6-DMSO): = 2.9-3.1 (1H); 3.25 (1H); 4.0 (3H); 4.5 (1H); 7.1-7.7 (14H); 8.6 (1H); 8.8 (1H); 9.5 (1H) and 9.6 (1H) ppm 0 Example 8 5 4- (E-2-Isonicotino-1-ethylethyl) -N- (pentan-1 · aldehyde-2-yl) benzidine

0 (Please read the notes on the back before filling this page) lH-NMR (d6-DMSO) printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs: = l.〇 (3H); 1.25-2.0 (4H); 4.3 ( 1H); 7.9- 8.2 (8H); 8.9 (2H); 9.0 (1H) and 9.6 (1H) ppm. Example 8 6 (S) -4_methoxy-3- (E-2-phenyl-1-vinyl) fluorenylamino-N- (pent-1-aldehyde-2-yl) benzidine

-81-This paper size applies to China 1: ¾ (CNS 丨 A4 size · (210 X 297 Gongchu) 393454 a? B7 V. Description of the invention (79) lH-NMR (d6-DMSO): δ = 1.0 (3H ); 1.25-2.0 (4H); 4.0 (3H); 4.25 (1H); 7.1-7.75 (10H); 8.6 (1H); 8.75 (1Η) and 9.5 (1H) ppm. (Please read the back Please fill in this page for further information) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs / -82- This paper size applies to China National Standard (CNS) A4 (210X297 mm)

Claims (1)

Original application (October 88) ASB8C8D8 VI. Application scope of patent 393454 1. A benzamidine aldehyde (R2) n of formula I R3 CHO Printed by the Shell Standard Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs or its enantiomeric or isomeric form or its physiologically acceptable salt, where: Rl is phenyl, tea., Quinine, tetrahydro 4 ° Lin, tetrahydro Isoamidine, called dipyridine 'or benzopyrene. Here, the aromatic ring or heteroaromatic ring can be substituted with three R4 groups, and R2 is hydrogen, (VC4-alkyl, gas, bromine, fluorine,- NHCO-CVCV environment group, -NHCOPh, -NHCO-fluorenyl group, -NHSOrCn environment group, -O-Cw alkyl group, N02 or NH2, R3 is qC: 6-alkyl group, may carry cyclopropyl, cyclohexyl group, An indolyl or phenyl ring, which may be substituted by one or two R4 groups, or a _SCH3 group, which is a C1-C4-hoofyl group. -O_Ci-C4_alkyl, OH ' Cl, F, CF3 or No2, is a bond,-^! ^) ^ ·, · ^^; ^-. -^^). ·,-^ !! ^-(CH2) 0- *-(CH2) m-SO- (CH2) 0- *-(CH2) m-S02- (CH2) 0-, -CH = CH_, "_, -CO-CH = Ctt-,-(CH2) m-CO_ (CH2) 0-,-(CH2) m-CONR5- (CH2) 〇- »-(CH2) m-S02NH- (CH2) 0- > -CH = CH-CO-NH- or phenyl with or without R2 group substitution, R4 X This paper size is in accordance with China National Standards (CNS) Μ Outer Space (210X297 mm) -------- --Γ, clothing ------ order ------ ^ (Please read the precautions on the back before filling in this page) Original application (October 88) ASB8C8D8 VI. Application scope of patent 393454 1. A benzamidine aldehyde (R2) n of formula I R3 CHO Printed by the Shell Standard Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs or its enantiomeric or isomeric form or its physiologically acceptable salt, where: Rl is phenyl, tea., Quinine, tetrahydro 4 ° Lin, tetrahydro Isoamidine, called dipyridine 'or benzopyrene. Here, the aromatic ring or heteroaromatic ring can be substituted with three R4 groups, and R2 is hydrogen, (VC4-alkyl, gas, bromine, fluorine,- NHCO-CVCV environment group, -NHCOPh, -NHCO-fluorenyl group, -NHSOrCn environment group, -O-Cw alkyl group, N02 or NH2, R3 is qC: 6-alkyl group, may carry cyclopropyl, cyclohexyl group, An indolyl or phenyl ring, which may be substituted by one or two R4 groups, or a _SCH3 group, which is a C1-C4-hoofyl group. -O_Ci-C4_alkyl, OH ' Cl, F, CF3 or No2, is a bond,-^! ^) ^ ·, · ^^; ^-. -^^). ·,-^ !! ^-(CH2) 0- *-(CH2) m-SO- (CH2) 0- *-(CH2) m-S02- (CH2) 0-, -CH = CH_, "_, -CO-CH = Ctt-,-(CH2) m-CO_ (CH2) 0-,-(CH2) m-CONR5- (CH2) 〇- »-(CH2) m-S02NH- (CH2) 0- > -CH = CH-CO-NH- or phenyl with or without R2 group substitution, R4 X This paper size is in accordance with China National Standards (CNS) Μ Outer Space (210X297 mm) -------- --Γ, clothing ------ order ------ ^ (Please read the precautions on the back before filling in this page) 395454 ------ Application for patent scope A8, B8) C8 D8 is 1 The number of or 2 is a number of 0, 1, 2, 3, or 4, and the number of 0, 1, 2, 3, or 4. 2. According to the formula 1 of the scope of the patent application, benzamidine aldehyde, wherein R2 is hydrogen, Ci-CV alkyl, methoxy, fluorine, gas or bromine, and r3 is -CH2-phenyl, -CH2 -Cyclohexyl or -ch2- "? Indolyl, this group may be substituted by R4, and the definition of η m ο R1, X η, m and 0 is as described in the central claim of the Ministry of Economic Affairs Sample printed by Shelley Consumer Cooperative 3_ According to the scope of the patent application, the benzamidine aldehyde of formula I is used as an inhibitor of cysteine protease. 4. According to the scope of the patent application, the benzamidine aldehydes of formula I are used as inhibitors of glutamic acid proteases such as calpain and cathepsin B and L. 5. According to the scope of the patent application, the benzamidine aldehyde of formula I is used as a medicine for treating diseases caused by increased cysteine protease activity. 6. According to claim 1, the benzamidine aldehyde of formula I is used as a medicine for treating neurodegenerative diseases and / or neurogenic injury diseases. 7. According to the scope of the patent application, the benzamidine aldehyde of formula I is used as a medicine for neurodegenerative diseases and / or neuron damage caused by ischemia, trauma or major bleeding. 8. According to claim 1, the benzamidine aldehyde of formula I is used as a medicine for treating cerebrovascular accidents and / or skull brain injuries. 9. According to claim 1, the benzamidine aldehyde of formula I is used as a medicine for treating Alzheimer's disease and / or Huntington's disease. 1〇 According to the scope of the patent application, the benzamidine aldehyde of formula I is used for treatment 2- (Please read the precautions on the back before filling this page) 393454 ——— Scope of patent application Medicine for treating epilepsy. 1 h According to the scope of the patent application, the stupid methylamido aldehyde is used for the treatment of heart injury after myocardial ischemia, kidney injury after renal ischemia, skeletal muscle < injury 'muscular dystrophy' smooth muscle Damage caused by cell proliferation 'Coronary arterial spasm, or cerebral vasospasm, ocular cataract and / or restenosis after angioplasty drugs. 12. The benzamidine aldehyde according to formula 1 of the scope of the patent application is used as a medicine for treating tumors and their metastases. 13. According to claim 1, the benzamidine aldehyde of formula I is used as a medicine for treating diseases in which interleukin-1 is increased. W. According to the scope of the first patent application, formula I is stupid methylamidoaldehyde, which is used as a medicine for treating immune diseases, such as inflammation and rheumatic diseases. 15. A pharmaceutical composition for use as a cysteine protease inhibitor, which contains at least one benzamidine aldehyde according to formula I of claim 1. (Please read the precautions on the back before filling out this page} ¾.-Ordered by the Central Labor Bureau of the Ministry of Economic Affairs, printed by a consumer cooperative -3-