TW200524874A - Amidomethyl-substituted 1-(carboxyalkyl)-cycolpentylcarbonylamino-benzazepine-n-acetic acid derivatives, process and intermediate products for their preparation and medicaments containing these compounds - Google Patents

Abstract

Described are novel compounds with neutral endopeptidase (NEP) and/or human soluble endopeptidase (hSEP ) inhibitory activity of the general formula I, wherein the substituents R1, R2, R3 and R4 have the meanings given in the description and also medicaments containing these compounds, in particular medicaments suitable for treating or preventing cardiovascular diseases, sexual dysfunction and/or adverse conditions associated with apoptosis.

Description

200524874 IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to a new type of 1- (carboxyalkyl) -cyclopentylcarbamido-phenylcycloazepinetriene substituted by amidinomethyl. -N · acetic acid derivatives, which can be effectively used, for example, in the prevention and / or treatment of cardiovascular diseases or conditions, especially cardiac insufficiency, especially congestive heart failure; hypertension, including type 2 hypertension such as hypertension Essential hypertension, renal hypertension, and / or pulmonary hypertension, and / or effective use in the prevention and / or treatment of sexual dysfunction and / or effective use in the prevention and / or treatment of apoptotic-related disorders, And also related to medicines containing these compounds. Furthermore, the present invention relates to a method for preparing the novel benzazepine-N-acetic acid derivative substituted with amidomethyl and an intermediate product of the method. Sexual dysfunction (SD) is a major clinical problem affecting men and women. Sexual dysfunction may be caused by organ sexual and psychological factors. The sexual aspect of sexual dysfunction organs is typically caused by vascular diseases such as those associated with high blood pressure or diabetes, by prescription drugs and / or mental illnesses such as anxiety disorders. Psychological factors include fear, performance anxiety, and interpersonal conflict. Sexual dysfunction detracts from sexual performance, degrades self-esteem, and disrupts personal relationships, which include personal suffering. Cell death is closely related to the physical and tissue development during the development process, the maintenance of constant internal environment, and biological defense, and its cell death plays an important role in maintaining the life of an individual. When the death process regulated by genes is blocked by innate or acquired factors, apoptosis is over-induced or inhibited, which causes dysfunction of different organs, resulting in illness. Drugs with an inhibitory effect on apoptosis can be used as drugs with the ability to prevent and treat diseases caused by apoptotic driving 200524874 [Prior art] Benzcycloazepine- and benzocycloazepine that are active on cardiovascular Benzene (benzoxazepine) and benzoxazepine derivatives, which have a significant inhibitory effect on neutral endopeptidase (NEP), have been regulated by EP 0 733 642 A1 (= US 5,677,297). In addition, the compounds described in this article have less inhibitory properties on endothelin-converting enzyme (ECE). Other advantageous pharmacological properties of compounds falling within the structural range of ep 0 733 642 A1 are given by EP 0 830 863 Al (= US 5,783,53) > WO 00/48601 A1 (= US 6,482,820) and WO 01/03699 A1 (= US-2003_0040512-A1) and other patent cases. Benzozepinone-N-acetic acid derivative substituted by phosphoric acid, which has a combined inhibitory effect on neutral peptide endonuclease and endothelin converting enzyme, disclosed in patent case EP 0 916 679 A1 (= US 5,952,327). The medicament obtained from the WO 02/094176 A2 patent contains a compound which has a beneficial combination of inhibiting the hydrolysis of metal proteolysis, per enzyme, neutral moon chain incision, and IGS5, and has a particular effect on the heart. Blood vessels are active in nature. Compounds suitable as the combination preparation are also compounds falling within the scope of EP 0 733 642 A1 and EP 0 916 679 A1. The enzyme igs5 will be understood in the context of the present invention and its physiological role in relation to cardiovascular disorders, which is essentially known from the patent WO 01/36610 A1. The aforementioned enzyme igS5 is also known as "human soluble endopeptidase" (hSEP). It is learned from patent case WO 99/55726 A1 that certain thiol inhibitors that convert endothelin to G-strip are effective in treating or inhibiting erectile dysfunction in particular. 200524874 Patent case EP 1 097 719 A1 discloses utilization Endoenzyme inhibitors are used to treat female sexual dysfunction (FSD). Patent case WO 02/06492 A1 discloses a specific polyamino acid antibody and inhibitor, which has a soluble secreted endogenous chain-cutting g (= SEP) activity. It is described in patent application US 20030045449 that matrix-metal proteolysis @per inhibitor is effective in treating neurodegenerative disorders. The problems related to the invention are the first is matrix-metal proteolysis, each inhibitor contains a broad proteolysis 脒 inhibitor family, and the second is that according to the application, these metal proteolytic enzymes must be used In a pharmaceutical composition containing an N-NOS inhibitor. The published patent application US 2 002/0013307 teaches the use of vasostatin S inhibitors to treat or soothe the progress of cognitive dysfunction, and to treat and / or prevent dementia. M. Sumitomo et al. (See Clinical Cancer Research 1Q (2004) 260-266) describe the use of a neutral peptide endonuclease to cause chemosensitization of androgen-independent, such as line cancer, chemosensitization . [Summary of the Invention] An object of the present invention is to provide a novel active substance having a combined effect of inhibiting enzymes such as neutral moon-chain endonuclease, human soluble moon-chain endonuclease, and endothelin converting enzyme. Particularly suitable for the prevention and / or treatment of cardiovascular diseases or disorders, especially cardiac insufficiency, especially congestive heart failure; hypertension, including the second type of hypertension such as essential hypertension, renal hypertension and / Or pulmonary hypertension; and / or prevention and / or treatment of sexual dysfunction, and / or prevention and / or treatment of apoptosis-related adverse symptoms. Surprisingly, a new group of 1- (carboxyalkyl) -cyclopentylcarbamidoamino_benzenecycloazepinetriene_N-acetic acid derivatives substituted with amidomethyl according to the present invention has been surprisingly found. It is characterized by its inhibitory effect on neutral moon-chain incision noodles and human soluble endokines. 200524874 Moon-chain incision on each type of enzyme, and it also has a certain degree of inhibition on endothelin conversion. , So it seems suitable for the prevention and / or treatment of cardiovascular diseases or conditions, especially cardiac insufficiency, especially congestive heart failure; hypertension, including the second type of hypertension such as essential hypertension, kidney Hypertension and / or pulmonary hypertension; and / or prevention and / or treatment of sexual dysfunction, and / or suitability and / or treatment of apoptotic-related disorders. The subject of the present invention is a brand new μ (carboxyalkyl) -cyclopentylcarbamido-phenylcycloazepine-triacetic acid derivative substituted by amidinomethyl, of general formula I,

Wherein R1 is a hydrogen atom or a functional group that forms a biostable ester, R2 is a hydrogen atom; an alkyl group containing 1 to 4 carbon atoms or a oxyalkyl group containing 1 to 4 carbon atoms, of which hydrogen The oxo moiety can be optionally esterified with an alkyl or monoamino acid residue containing 2 to 4 carbon atoms, and R3 is an alkyl group containing 1 to 4 carbon atoms; containing 1 to 4 carbon atoms Alkoxy group-an alkyl group containing 1 to 4 carbon atoms; a hydroxyalkyl group containing 1 to 4 carbon atoms, which may be optionally substituted by a second hydroxyl group, and the hydroxyl portion of each Each can be optionally esterified by an alkyl or amine residue containing 2 to 4 carbon atoms; (alkyl group containing 0 to 4 carbon atoms) 2 amino group-200524874 containing 1 to 4 Carbon alkyl groups; Cyclofluorenyl groups containing 3 to 7 carbon atoms; Cycloalkyl groups containing 3 to 7 carbon atoms-alkyl groups containing 1 to 4 carbon atoms; Phenyl-containing 1 to 4 Carbon atom alkyl group, the phenyl portion of which can be optionally substituted by alkyl groups containing 1 to 4 carbon atoms, alkoxy groups containing 1 to 4 carbon atoms, and / or i elements 1 to 2 times ; Naphthyl-containing fluorene 1 to 4 Carbon alkyl groups; oxoalkyl groups containing 3 to 6 carbon atoms; phenylcarbonylmethyl groups, of which the phenylene moiety can be freely chosen to be alkyl groups containing 1 to 4 carbon atoms Group, alkoxy groups containing 1 to 4 4 carbon atoms, and / or oxoazepine, or 2-cycloazahexane oxoazepanyl) are substituted 1 or 2 times, or R2 and R3 together contain 4 to 7 carbons Atomic alkylene group, the methylenyl group is optionally substituted by carbofluorenyl, nitrogen, oxygen, and / or sulfur atoms 1 to 2 times, and it can be optionally selected to be 1 time by hydroxyl groups It can be optionally substituted by alkanoyl or monoamino acid residues containing 2 to 4 carbon atoms; alkyl groups containing 1 to 4 carbon atoms; containing 1 to 4 Hydroxyalkyl group of 2 carbon atoms, the hydroxy group can be optionally esterified with alkyl or monoamino acid residues containing 2 to 4 carbon atoms; phenyl or benzyl, and φ R4 is a hydrogen atom or a functional group forming a biostable ester, and the physiologically compatible salts of the acid of the general formula I, and / or the physiologically acceptable compounds of the general formula I Salts are added with mutual compatible acids. Furthermore, one subject of the present invention is a pharmaceutical product containing a compound of general formula I. Furthermore, one object of the present invention is a method for preparing a compound of the general formula I and an intermediate product of the method. The substituents in the compound of the general formula I or other compounds described in the summary of the present invention are alkyl groups containing 1 to 4 carbon atoms, and each of the substituents may be linear or branched. The substituents in the compounds of the general formula I represent functional elements, so the suitable ones are fluorine, chlorine or bromine. Chlorine is preferred. Where a substituent contains 2 11 200524874 to 4 atomic interfering radicals, the substituent may be a straight bond type or a branched type. Acetate is the preferred group of burned donkeys with 2 to 4 carbon atoms. In the compound of the general formula I, the hydroxyl group is esterified with amino acid residues, and these amino acid residues may be derived from natural or unnatural α- or β-amino acids. A suitable amino acid that can be used as an example ^ is selected from the group 'which contains alanine, 2-aminohexanoic acid (== n-leucine' norleucine), 2-aminovaleric acid (= n Norine (norvaline), arginine, asparagine, aspartic acid, cysteine, 3,4-dihydrophenylalanine (= Dopa, dopa), glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, Lysine, methionine, ornithine (= 2, 5-diaminovaleric acid), 5-oxo-2-chrysene carbonate (= pyroglycine) Acid, pyrogiutamic acid), phenylalanine, proline, serine, threonine, thyronine, tryptophan , Tyrosine, and valine. Preferred are selected from alanine, asparagine, glutamine, glycine, isoleucine, leucine, lysine, guanine, phenylalanine, proline, and valine And other amino acid residues. The compound of the general formula I represents a dicarboxylic acid derivative, which can optionally be esterified with a functional group forming a bio-labile ester. Biologically labile esters of the general formula I generally refer to free acid precursors (= "prodrugs") to which they can be administered. Monoesters or diesters of the compounds of formula I can then be produced. Depending on the form of administration, the more preferred ones are biostable esters or free acids, the latter being particularly suitable for intravenous (= i.v.) Administration. The functional group of the bioavailable derivative which can be cut off under physiological conditions in vivo and releases the compound of the general formula, and the functional groups Ri and R4 which form bio-labile esters are suitable. A suitable example in this case is an alkane 12 200524874 group containing 1 to 4 carbon atoms, especially methyl, ethyl, η-propyl and isopropyl; an alkoxy group containing 1 to 4 carbon atoms-containing 1 Alkoxy to 4 carbon atoms-an alkyl group containing 1 to 4 carbon atoms, especially methoxyethoxymethyl (〇 ^ 11 (^) ^ 11〇 \) ^^ 1 ^ 1); Cycloalkyl containing 3 to 7 carbon atoms, especially cyclohexane; cycloalkyl containing 3 to 7 carbon atoms-alkyl containing 1 to 4 carbon atoms, especially cyclopropylmethyl; N, N-di- (alkyl group containing 1 to 4 carbon atoms) amine group-alkyl group containing 1 to 4 carbon atoms; phenyl or phenyl-alkyl group containing 1 to 4 carbon atoms, It can optionally be substituted on the benzene ring by a prime, an alkyl group containing 1 to 4 carbon atoms or an alkoxy group containing 1 to 4 carbon atoms, or substituted by one or two Adjacent carbon atoms containing 1 to 4 carbon atoms replaced by alkylene chain; dioxolanylmethyl (dioxolanylmethyl), which can optionally be selected on the asthma ring by alkyl groups containing 1 to 4 carbon atoms Substituted; alkoxyl groups containing 2 to 6 carbon atoms (alk anoyloxy)-an alkyl group containing 1 to 4 carbon atoms, which can optionally be substituted on the oxygen-alkyl group containing 1 to 4 carbon atoms by an alkyl group containing 1 to 4 carbon atoms; diesters such as 1-[[(alkyl groups containing 1 to 4 carbon atoms) carbofluorenyl] oxy] alkyl alcohols containing 1 to 4 carbon atoms, such as (RS) -1-[[(isopropyl) carbons Si group] oxy] ethyl or (RS) -l-[[(ethyl) carbamyl] oxy] -2-methylpropyl (for preparation, please refer to, for example, F · W · Sum · et al., Bioorg · Med · Chem · Lett · 2 (1999) 1921-1926) or Υ · Yoshimura et al., The Journal of Antibiotics 翌 / 9 (1986) 1329-1342); carboxylic acid esters such as l-[[(containing 4 to Cycloalkoxy with 7 carbon atoms) Carbofluorenyl] oxy] Alkyl esters containing 1 to 4 carbon atoms, which is smaller than (RS) [[(Cyclohexaneoxy) Carbofluorenyl] Oxy] ethyl (= cilexetil; for preparation, see, for example, K. Kubo et al., J. Med. Chem. M (1993) 2343-2349, hereinafter referred to as "Kubo et al.") Or 2_oxo-1 , 3-Dioxadienyl-alkyl esters containing 1 to 4 carbon atoms, which can optionally contain a double bond on the dioxane ring, the preferred one is 5- 2-oxo-1,3-dioxalenyl-methyl (== 13 200524874 medoxomil 'for preparation see Kubo et al.) Or 2-oxo ^ 3 1-pin-4-enyl -Methyl (= (methyl) ethylene carboxylic acid). If the formation of biological instability; ^ group means a phenyl group that can be optionally substituted-containing 1 to 4 carbon atoms, this functional group may contain an alkylene chain, which contains 1 to 4, prefers one carbon atom, and prefers to represent benzyl which can be substituted at will, especially 2-chlorobenzyl or 4-chlorobenzyl. If a biostable group is formed, a functional group means a phenyl group that can be optionally substituted, wherein the benzene ring of the functional group is replaced by an alkylene chain with a low carbon number. This functional group may contain 3 Up to 4,

Preference is given to 3 carbon atoms and especially in indanyl. And if the functional group that forms a biostable ester means a sulfonyl group containing 2 to 6 carbon atoms-a fluorenyl group containing 1 to 4 carbon atoms can be optionally substituted, it should contain 2 to 6 Alkyl groups of one carbon atom can be linear or branched. The preferred meanings of R1 are hydrogen atom, ethyl group, methoxyethoxymethyl group, (RS) -1-[[(isopropyl) carbamyl] oxy] ethyl group, (RS) _H [( (Ethyl) carbofluorenyl] oxy] -2_methylpropyl, (RS) -l-[[(cyclohexaneoxy) carbofluorenyl] oxy] ethyl, 5 · methyl orthooxo-1,3 _Diox-4-enyl-methyl, 2-oxo-1,3-diox-4-enylmethyl, or

(RS) -1-[[(ethoxy) carbofluorenyl] oxy] ethyl. R2 is more preferably meaning hydrogen atom, methyl group, ethyl group, 2-hydroxyethyl group or 3-hydroxypropyl group. Each hydroxyl group can be freely chosen to be an alkane containing 2 to 4 carbon atoms. Amido or monoamino acid residues. If the meaning of R3 is (alkyl group containing 0 to 4 carbon atoms) 2 amine group-alkyl group containing 1 to 4 carbon atoms, one or two alkyl groups containing 0 to 4 carbon atoms may be mutually Appear without affecting each other. To make it clearer, the "(Aromatic group containing G to 4 carbon atoms) 2 amine group_probable group containing 1 to 4 carbon atoms" table " ^ contains the meaning "(excluding carbon atoms) 2 "Alkylamino_Alkyl containing 1 to 4 carbon atoms", "(without carbon atoms) (1 to 4 minus atomic bolylamino · alkyl containing 1 to 4 14 200524874 carbon atoms", and " (Contains 1 to 4 carbon atoms) 2-alkylamino group-alkyl group containing 1 to 4 carbon atoms "." (Without carbon atoms) 2-alkylamino group-group containing 丨 to 4 carbon atoms "Alkyl" is intended to name an unsubstituted primary amine group (= NH2) attached to an alkane (s) group containing 1 to 4 carbon atoms; "(without carbon atoms) (containing 1 to 4 carbon atoms) "Alkylamino group-alkyl group containing 1 to 4 carbon atoms" is intended to name a secondary amine group which is replaced by a (containing 1 to 4 carbon atoms)-alkyl group and is attached to a group containing 1 to 4 Alkane group of 1 carbon atom; "(containing 1 to 4 carbon atoms) 2-alkylamino group-alkyl group containing 1 to 4 carbon atoms" is intended to name a tertiary amine group, which is contained 1 to 4 carbon atoms, and substituted For alk (phenyl) groups containing 1 to 4 carbon atoms. R3 is more preferably meaning isopropyl; methoxyethyl; 2-hydroxyethyl or 3-hydroxypropyl, each hydrogen The oxy group can be optionally esterified by a sulfanyl group or a monoamino acid residue containing 2 to 4 carbon atoms; 3-ethoxyloxypropyl; cyclopropylmethyl; 2 · methoxy Phenylfluorenyl, 4-Methoxyphenylfluorenyl; 4-Methoxyphenethyl; 2,4-Dimethoxybenzyl; 丨 naphthylfluorenyl; 3-oxo-1,1- Dimethylbutyl; phenyl-2-oxoethyl; 2- (4-methoxyphenyl) -2-oxoethyl; 3- (2-cycloazahexane); (containing 0 to Alkyl group of 4 carbon atoms) 2 amine group-alkyl group containing 1 to 4 carbon atoms, especially difluorenylamino group-η-propyl, (meth) aminoethyl or amine group-η -Propyl. When the right R and R3 are a sintered group containing 4 to 7 carbon atoms, the methylenyl group can be substituted or substituted at will. In each case, Are you free to choose 4 (morph〇line); piperidine (piperidine); 4-ketopiperidine; 4-hydroxypiperidine, on this hydroxyl group can be freely selected to contain 2 It is esterified with alkanoyl or monoamino acid residues up to 4 carbon atoms; the preferred ones are piperazine and prololidine. The preferred meaning of R4 is hydrogen atom, Alkyl groups containing 1 to 4 carbon atoms, p-methoxyphenylphenyl, N, N-di- (alkyl groups containing 1 to 4 carbon atoms) amino groups-15 200524874 containing 1 to 4 carbon atoms Alkyl group, (RS) small [[(isopropyl) carbofluorenyl] oxy] ethyl, (RS) -H [(ethyl) hydrocarbyl] oxy]> 2-methylpropyl, (rs) -1 _ [[(cyclohexaneoxy) carbofluorenyl] oxy] ethyl, 5-methyldifluoren-4-yl-fluorenyl, 2-oxo-1,3-difluoren-4-fluorene -Amidino or (RS) _1-[[(ethoxy) carbon || yl] oxy] ethyl. # Compounds of general formula 1 are particularly favored by those selected from this group, whose composition consists of 2-{[1-({[1- (retylmethyl) -2 • oxo-2,3,4,5- Tetrahydro-1 //-1_benzenecycloazepinetrisamidine-3-fluorenyl] amino} carbonate) cyclopentyl] methylbull 4- [isopropyl (methyl) amino] -4- Oxobutanoic acid (32); 2 _ {[1-({[1- (carboxymethyl) -2-oxo-2,3,4,5 · tetrahydrobenzenecycloazahexatriene-3_yl ] Amine} Carbofluorenyl) cyclopentyl] methyl 4- (dimethylamino) -4-oxobutanoic acid (54); 2-{[1-({[1- ( ) -2-oxo-2,3,4,5-tetrahydro-1 where 1_benzenecycloazahexatriene_3_mianyl} amino} carbofluorenyl) cyclopentyl] methylb ' (Diethylamino) _4-oxobutanoic acid (55); 2 _ {[1-({[1- (carboxyfluorenyl) -2-oxo_2,3,4,5-tetrahydro_1払 1_benzenecycloazepinetriene_3_fluorenyl] amino} carbofluorenyl) cyclopentyl] methyl 4-[(2-Hydroxyethyl) (methyl) amino> 4- Oxobutanoic acid (43); ^ {[^ ({0 (carboxymethyl) _2_oxo-2,3,4,5-tetrahydro-1 // _ 1_benzenecycloazahexatriene-3_ Fluorenyl] amino} carbofluorenyl) cyclopentyl] methyl} _4 _ [(3-hydrooxypropyl) (methyl) amino] '' oxobutanoic acid (56); 2 _ {[1- ( {[1- (carboxymethyl) -2-oxo-2,3,4,5-tetrahydro-1 // _ 1_benzenecycloazepine -3-fluorenyl] aminocarbonylcarbamyl) cyclopentyl] methyl-4- (4-hydroxide-imidin-; 1-alkenyl) 4-oxobutanoic acid (57); 2_ {| > ((| > (Carboxyfluorenyl) -2-oxo-2,3,4,5-tetrahydro_1 // _ 1_benzenecycloazepinetriene_3_fluorenyl) amino ) Cyclopentyl] fluorenyl 4-oxo_4_ [4_ (l_valaminefluorenyloxy) hexidine-1-enyl] butanoic acid (68); 16 200524874 2-{[丨-({ [1- (Chlorylmethyl) _2_oxo_2,3,4,5-tetrahydro_1private-1_benzenecycloazatriene_3_alkenyl] aminopentacarbyl) cyclopentyl [Methyl] methyl} _4_morpholine_4_alkenyloxyoxobutanoic acid (66); 2 _ {[1 _ ({[1_ (carboxymethyl) _2 · oxo-2,3,4,5-tetra Hydrogen_1fan 1_benzenecyclonitrodifluorenyl] aminocarbanyl) cyclopentyl] methyl} -4_oxo_4_ (4_oxopyridine-1 · alkenyl) butane Acid (45); 4- [mono (2-hydrogenethyl) amino] -2-{[1-({[1- (carboxymethyl) _2_oxo-2,3,4,5-tetra Hydrogen-1 // small benzenecycloazahexatriene_3-fluorenyl] amino} carbofluorenyl) cyclopentyl] methyl 4-oxobutanoic acid (58); 2 _ {[1 _ ({[1 -(Carboxymethyl) -2-oxo-2,3,4,5 · tetrahydro-1 / M_benzenecycloazepine hexamethylene group] amino group} carbofluorenyl group) cyclopentyl] methyl group } -4_ {ethyl (ethylamino) propyl] amino group 4-oxobutanoic acid (52), And 2-{[1-({[1- (carboxymethyl) -2-oxo-2,3,4,5-tetrahydro-1 // _ 1_benzenecycloazepine trisene alkenyl] amine Carbocarbyl) cyclopentyl] methyl} _4 _ [[2- (dimethylamino) ethyl] (methyl) amino] _4 · Arobutyric acid (59), 4 _ [(3_ Aminopropyl) (ethyl) amino] _2 _ {[1 _ ({[1- (carboxymethyl) 1oxo-2'3,4'5-tetrahydrobenzenecycloazahexatriene_3_ene Group] amino} carbofluorenyl) cyclopentyl] methyl} -4-oxobutanoic acid (67), and carboxymethyl) _2_oxo-2,3,4,5-tetrahydro_1fan 1-benzenecycloazepinediene alkenyl] amino} _carbofluorenyl) cyclopentyl] methylbu 4_ {methyl [2_ (methylamino) ethyl] amino} _4_oxobutane Acid (68), together with the physiologically compatible acids of the compounds of the general formula I and their bio-labile esters, and / or the physiologically compatible acid addition salts of the compounds of the general formula Ϊ . According to the invention, the general formula! The acquisition of a brand new compound and its salts is a compound of formula II, 17 200524874

Among them, r1g1 and r4G1 are independent of each other, each of which is an acid protecting group, and reacts with the compound of the general formula III,

III

Where R2 and R3 have the meanings mentioned above, if R2 and / or r3 contain a free hydroxyl group, these functional groups will react with the compound of general formula IV if necessary,

0 ^ 3-0 (0) ^ iv where X represents a leaving group or reacts with an amino acid derivative protected by a suitable protecting group, if R101 and / or R4G1 does not represent The required formation of biolabile esters and / or if R2 and / or R3 contain protection based on any amino acid residues present, these functions are performed simultaneously in any required order in the resulting compound Or it can be continuously excised separately, and if necessary, the acid functional group shown in 18 200524874 is converted into a bio-labile ester functional group in each case, and if necessary, the general formula I Acids are converted to physiologically compatible salts, or salts of acids of general formula I are converted to free acids and / or bases of general formula are converted to acid addition salts, or acid additions Salts are converted into free formulas of general formula. In each case, suitable salts of the physiologically compatible acids of the acids of the general formula I are alkali metal, alkaline earth metal or ammonium salts, for example, the sodium, sodium or calcium salts thereof, It is physiologically compatible, pharmacologically neutral organic salts and amines such as amine water, diethylamine, tertiary butylamine, methylgranine, choline, or with amino acids such as sperm Salts formed by amino acids. If the substituents R2 and / or R3 in the compound of the general formula J contain a basic functional group, especially a nitrogen atom, the compounds of the general formula I may exist in the form of acid addition salts. Physiologically compatible acid addition salts of compounds of general formula j are traditionally associated with inorganic acids, such as with sulfuric acid, phosphoric acid, or hydrogen acid, prefer hydrochloric acid, or with organic acids, such as Contains low-carbon fatty mono-, di- or tri-carboxylic acids such as maleic acid, fumaric acid, tartaric acid, citric acid ), Or with acid swollen, remember acid), such as low carbon number of alkanesulphonic acid (alkanesulphonic acid) 'such as methanesulphonic acid salts. Traditionally, as the protecting group for protecting the carboxylic acid functional group, the acid protecting groups R1G1 and R4G1 can be selected, which can then be removed by conventional methods. Those who are suitable as protecting groups for carboxylic acids are known from 'e.g. McOmie, "Protective Groups in Organic Chemistry", Plenum Press (hereinafter referred to as "McOmie"), and Greene, Wuts, "Protective Groups in Organic Synthesis", Wiley Interscience Publication (hereafter referred to as "Greene"), each of which is the latest version. Functional groups that form bio-labile vinegars can also be used as acid protecting groups. 19 200524874 In these cases, the compounds obtained after the reaction of the compounds of formula II and formula III represent compounds according to the general formula of the invention. Suitable acid-protecting groups are especially such functional groups, which can be selectively removed or selectively implanted, and are independent of each other. It can be used in different conditions, and it can also be used as a biological instability _ functional acid protecting group. Examples include: non-branching low-carbon number filaments, such as ethyl, which can be tested in I * It can be easily cut off under the conditions of low carbon number, such as tertiary butyl, which can be easily cut off with an acid such as difluoroacetic acid; the phenyl group can be optionally substituted in the benzene ring f as desired. Group, which can be decomposed (hyd zero noiysis) or = choose to be cut off under secret conditions; benzyl substituted on the benzene ring with a low-carbon alkoxy group more than once, such as Phenylmethyl (= ethOXy ^ nzyl), which can be oxidized, for example, at 2, dichloro5, cyano 1,4-benzone (-DDQ) or ammonium nitrate (from coffee ammomium) It can be easily removed under the action of nitrate), or the well-known silicon-containing protective group can be easily removed with gas ions. Those skilled in the art are familiar with selecting the appropriate protecting group to obtain a desired substitution form. The compound of the general formula I contains two asymmetric carbon atoms, that is, a carbon atom having an amidine branch at the third position of the backbone of benzenecycloazepine ditriene (*) and a "-COOR1" Carbon atom of a radical (= Ca *). These compounds can therefore exist as a total of four isomers. The invention includes two mixtures of stereoisomers and mirror isomers, and also includes compounds of the general formula I which are pure on the isomers. More preferred are the compounds of the general formula that are pure on isomers. The special double preference is a compound of the general formula I, in which the carbon atom having the amidine branch at the third position of the backbone of the benzazepine has a rs "configuration. As for the asymmetric carbon atom "* Ca" having the atom chart of "_c〇〇〇1", the configuration of the compound of the general formula I preferred in the context of the present invention is temporarily given the configuration rreU "(see 200524874 experimental part). The preferred "rell" configuration on the asymmetric carbon atom "* Ca" is likely to be the same as the "S" configuration, which can be traced to similar observations made on compounds of appropriate and known configuration. The reaction of the acids of the general formula II with the amines of the general formula III can be carried out according to a method conventionally used to generate an amido group by aminoacylation. Carboxylic acids of the general formula η or their reactive derivatives can be used as amidines. Especially mixed acids and acid compounds are suitable reactive derivatives. Therefore, acid gaseous compounds or acid bromides such as acids of the general formula II, or acids and organic sulfonic acids of the general formula II, for example, with acids having a low carbon number and can be optionally substituted by dentin, such as formic acid The acid is either trifluoromethane, or with an aromatic hydrocarbon sulfonic acid, such as benzenesulfonic acid, or with a stupid sulfonic acid substituted by a low-carbon alkyl or sulfone, such as toluenesulphonic acid) or bromobenzenesulphonic acid, the esters produced by mixing can be used. The tritiation reaction can be carried out in an organic solvent, which exhibits an inert phenomenon under the temperature reaction conditions between -20 ° C and room temperature (= rt). Suitable solvents are pixel-containing hydrocarbons such as methylene chloride or aromatic hydrocarbons such as benzene or toluene, or cyclic ethers such as tetrahydrofuran or THF) or dioxane or the like A mixture of solvents. The fermentation reaction can be operated conveniently in the presence of an acid binder, especially if an anhydride formed by mixing a general formula II acid and a sulfonic acid is used as an acidifying agent. Examples of suitable acid binding agents are organic bases, which are soluble in tertiary nitrogen tests, such as tertiary low-carbon alkylamines and pyridines, such as diethylamine, tripropylamine, N_methyl Morine, pyridine, 4-dimethylaminopyridine, 4-monoethylamino p-bite or 4-pn-p-pyridine (4-pynOiidinopyridine) in a reaction mixture. Organic bases used in excess can also be used as solvents at the same time. If the acids of the general formula II are used as hydrating agents, the reaction between the amine compounds of the general formula m 21 200524874 and the carboxylic acids of the general formula π can also be easily learned from, for example, peptide chemistry and applicable to It is carried out in the presence of CO Upling reagents. Examples of coupling agents that promote the formation of amidoamines with free acids by reacting with free acids in situ to form a reactive acid derivative. In particular: ethyl chloroformate, carbon-based diamine Amines (also; ^ 1130 仙 111 丨 (16), such as cycloalkylcarbodiimide, such as dicyclohexylcarbamidine diamidine i or 疋 N- (3-monomethylamine Propyl) -N'-ethyl carbodiimide (= EDC) 'carbonidiimidazole and N-lower alkyl_2- halopyridinium salt), especially a halide or toluene xanthate. The reaction in the presence of a coupling agent can be at _30. (: to +50.) (: hydrocarbons such as halogen containing halogen In the solvent of the compound and / or the aromatic hydrocarbon solvent, and optionally can be conveniently operated in the presence of the above-mentioned acid-binding amines. The compound of the general formula II and the compound of the general formula III, wherein R2 and / or R3 contains Free hydroxyl group, among the compounds obtained by the reaction, these compounds can be, if necessary, conventionally converted to the general formula IV Compounds of the general formula IV. For example, the leaving group X represents an autogen, and more preferably represents a chlorine atom. The compound of the general formula Π and the compound of the general formula III, wherein r2 and / or r3 contains free oxygen Among the compounds obtained by the reaction, these compounds can, if necessary, be reacted in a conventional manner with an amino acid derivative protected by an appropriate protecting group. Suitable amino acid protecting groups and their Methods for the removal or selective removal of these are technically known from, for example, McOmie or Greene. Appropriately protected amino acid derivatives are commercially available or can be prepared by conventional methods. Protection R and R, provided that they do not represent any of the required functional groups for the formation of biostable esters, and / or protecting groups, which may be present in any of the amino acid moieties present in R2 and / or R3, may Excision with conventional methods and, if necessary, 22 200524874 selectively from compounds of general formula r and compounds of general formula II. ~ Compounds of general formula I can be obtained at appropriate ages, and when Available The method is, for example, purification with high-performance liquid chromatography (= HPLC). * The starting compound of state 11 is a completely new compound, which is suitable as an intermediate product for the preparation of a completely new active substance, such as the preparation of the general formula τ Compounds: Compounds of general formula II can be prepared from reaction compounds of general formula V,

Wherein R is an acid protecting group, and R1G1 has the above meaning, and is combined with the general formula VI

It has the above-mentioned meaning, and is prepared by reacting it, and then cutting the acid saccharyl R5 by a conventional method. This reaction can be carried out in a conventional manner as an aminoamidine, for example, as the method for reacting a compound of the general formula η with a compound of the general formula in 23 200524874 according to the above. To avoid undesired secondary reactions, it may be advantageous to remove the acid-protecting group R5 by a method that does not require operation in an alkaline solution, and then select the appropriate acid-protecting group R5. ~ The amines of the general formula III are basically known or can be prepared from conventional compounds by conventional methods. Reactive acid derivatives of the general formula IV are basically known or can be prepared from conventional compounds by conventional methods. These compounds are linear or branched and contain several carboxylic acid derivatives of 1 to 4 carbon atoms. Compounds of general formula V can be prepared from acrylic esters of general formula VII,

VII wherein R1G1 and R5 have the above meanings and are obtained by reacting with cydopentanecarboxylic acid. The reaction can be carried out in a conventional method under Michael condensation reaction conditions in an organic solvent. The solvent is inert under the reaction conditions, that is, cyclopentanecarboxylic acid and a strong base capable of forming a cyclopentanecarboxylic acid dianion Reaction and subsequent reaction with a propionate derivative of general formula VII. Suitable solvents are ethers, especially cyclic ethers such as THF. Suitable strong bases are non-nucleophilic organic alkali metal amines or low-carbon-alkanes such as lithium diisopropylamide or η-butyl lithium salts. A convenient procedure is to react cyclopentanecarboxylic acid in THF with twice the equivalent of the butyl lithium salt, and then further react the reaction mixture with a compound of formula VII. 24 200524874 The temperature of the reaction can be between -80 ° C and 0 ° C. Compounds of general formula VI are known from, for example, patent EP 0733 642 A1, and can be based on their racemates or on pure forms of the selected isomers. The method described in this article is similar to this Prepared by the method. • Compounds of general formula VII can be composed of compounds of general formula VIII,

HOOC〆 ^

VIII wherein R5 represents an acid protecting group, and is prepared by esterifying a desired alcohol with a conventional method. Compounds of general formula VIII can be reacted, for example, from itaeonic aeid anhydride under conditions known to open acid anhydride groups, with a reagent capable of forming an acid protecting group R5, such as a correspondingly substituted alcohol, To get. In the above reactions, the asymmetric centers of the starting compounds of the general formula V and VI have not changed. Therefore, the type of the starting compound should be used to determine whether the compound of the general formula I can be obtained in the form of pure isomeric compounds. A mixture of isomers. To prepare a stereochemically homogeneous compound of general formula I, a convenient method is to react a stereochemically homogeneous compound of general formula V with a stereochemically homogeneous compound of general formula VI. If a pure mirror image isomer compound of the general formula V is reacted with a racemic isomer compound of the formula VI, or a racemic isomer compound of the general formula V is reacted with a pure mirror image isomer of the general formula VI In each case, a mixture of two cis-trans isomers (diastereomers) will be obtained in the stage of the compound of the general formula II or the stage of the compound of the general formula I, if necessary, it can be known The method is divided into 25 200524874 ^ racemic isomers of formula v and VI cycloisomers yield a corresponding mixture of four isomers, which can be separated, if necessary, using known methods' for example, may be asymmetric The separation method of the muscle c on the separation material. "Has an asymmetric center on the atom A" and "carbon atom", and can be obtained by the synthesis of the racemic isomer compound form _ derivative of the general formula VII. In principle, optically active compounds can be obtained from racemic isomeric mixtures in a way that is already known, such as the use of chromatographic separations that are misaligned or qualitative, or money that is optically active. For example, α-methylsmethylamine, dnehGnidine or pseudoephedrine react with each other, and the obtained salts are separately crystallized (fractionai crystallisation) to separate into its optical enantiomers ( antipode). Compounds of general formula I and their pharmacologically compatible salts are characterized by advantageous pharmacological properties. What is special is that these substances inhibit the enzyme neutral moon chain endonuclease. Each of the neutral skin chain incisions is an enzyme that cuts off endogenous natriuretic peptides, such as atrial natriuretic peptide (= ANP). Due to their inhibitory effects on the activity of neutral endonucleases, these substances can improve the biological activity of natriuretic peptides, especially atrial natriuretic peptides, which are attacked by neutral moon chain endonucleases. Effective lifespan 'is therefore suitable for treating pathological problems that are positively affected by this type of hormones'. The most important thing is to treat cardiac vascular problems, especially cardiac insufficiency, especially congestive heart failure. In the case of congestive heart failure, the increased vascular resistance due to reflexes can occur due to a decrease in the excretion portion induced by a cardiac disorder. This means that the heart muscle has to start pumping blood against the load after the rise. This situation leads to a vicious cycle that increases heart strain and makes the situation worse. The increase in the terminal vascular resistance is also due to the effect of Yueta, an endothelin (= ET-1) on the blood vessels. Endothelin is currently the most potent endogenous vasoconstrictor substance, and is produced by 26 200524874 pro-progressive substance endothelin (= Big-ET-l). According to the prior art, there are many different enzymes involved in the step I polymerization of large endothelin into endothelin, especially the enzyme endothelin converting enzyme and human soluble endonuclease, etc. (see, for example, WO 02/094176) . In the case of congestive heart failure, as the cardiac output decreases and the terminal vascular resistance increases, the back pressure of the blood can occur in the pulmonary circulation and in the heart itself. Therefore, an increase in the wall tension of the heart muscle can occur in the area of the auricles and ventricles. In this case, the heart exhibits its function as an endocrine organ, and the secretion of sodium, especially atrial diuretic, is too high in the bloodstream. Due to its significant vasodilatation and diuretic / diuretic effects, atrial diuretic natriurea causes a decrease in terminal vascular resistance and a decrease in blood volume in circulation. The result is a significant reduction in preload and postload. This constitutes an endogenous cardioprotective mechanism. This positive endogenous mechanism is limited because atrial natriuretic peptide has only a very short half-life in plasma. The reason for this phenomenon is that the hormone is very quickly broken down by the neutral moon-chain endonuclease. The compounds according to the present invention reduce the production of endothelin by inhibiting the activity of endothelin converting g, and also inhibiting the activity of human soluble peptide endonucleases. Myocardial overwork relieves. These results further stated that the substance according to the present invention caused a higher concentration of atrial natriuretic sodium hexamidine due to the inhibition of the activity of the neutral menstrual chain incision S, and the prolonged action time of atrial sodium diuretic sodium. This condition should cause the endogenous mechanism of the cardioprotective effect dominated by atrial natriuretic natrium and strengthen the diuretic / diuretic activity of substances of general atrial diuretic steel II. . Neutral endonucleases are involved not only in the degradation of atrial endonucleases, but also in the degradation of endothelin. It can be seen that each inhibitory effect of pure neutral menstrual chain incisions will not only increase the concentration of atrial natriuretic natriuretic levels, but also cause an unfavorable increase in endothelin concentration. For this reason, a characteristic map of the inhibitory effect of a mixed neutral moon chain endonuclease, human soluble endonuclease, and a certain proportion of endothelin-converting enzyme should be considered particularly beneficial because it inhibits sodium diuretic / diuretic atrial • Digestion of urinary sodium and sodium too (because it is inhibited due to the neutral moon-chain incision), and at the same time inhibit the production of endothelium and hormones (inhibited by the human soluble peptide endonuclease® and endothelin converting enzyme). Therefore, the positive influence may occur with the concomitant effect of a purely neutral moon-chain incision inhibitor (ie, an undesired increase in endothelin concentration). Characteristic map of the combined action of compounds of general formula I as neutral moon-chain endonucleases, human soluble peptide endonucleases, and a smaller part as endothelin-converting g inhibitors, so that according to the present invention The compounds appear to be particularly suitable for the prevention and / or treatment of pathological problems, such as problems or conditions, such as cardiovascular diseases or conditions, especially cardiac insufficiency, including acute and chronic heart failure, and especially congestive heart failure ; And high blood pressure, including the second type of hypertension such as essential hypertension, renal hypertension and / or pulmonary hypertension; heart failure, stenosis, arrhythmia, myocardial embolism, myocardium caused by peripheral surgery Embolism, poor prognosis of myocardial embolism, cardiac hypertrophy, congestive cardiomyopathy, hypertrophic obstructive cardiomyopathy, hypertrophic non-obstructive cardiomyopathy, primary cardiomyopathy, myocarditis, pericarditis, and / or larger mammals, especially humans Endocarditis. Compounds of general formula Z can also be beneficially used for the prevention and / or treatment of heart damage, especially myocardial damage, and their traditional medicines, especially cytostatics, prefer cytostatic antibiotics or tritium chemicals to the heart. Caused by toxic doses; abdominal colic, cerebral ischemia, terminal vascular disease, hypoarachnoid hemorrhage, chronic obstructive pulmonary disease (= COPD), asthma, kidney disease (renal failure), arteriosclerosis, and Large mammals, especially humans, have pain due to colorectal or prostate cancer. What is remarkable is that the compounds of the general formula I produce surprisingly good effects after intravenous administration due to their effect on regulating blood pressure, especially their effect on regulating hypertension. 28 200524874 Pharmacological test method description The example number cited refers to the effect of 5 minus the radiant trait of the present invention _ Dicer inhibits the peptide Mea_Asp_iieAia_Trp_phe_DpaT__ ^^ al_Val_PrO_Tyf_Gly_Leu_Gly_co-H ^ 4 The effect of 'transformation' was studied in in vitro standard tests. In this test, the measured value of the inhibitory effect of the test substance is its%. Value. —The IQo value of the test substance with inhibitory activity is the concentration at which the test substance is inhibited by 50% of the neutral peptide enzyme activity. Test buffer solution: 100 mM Tris pH 7 (), 25 () mM Naa Enzyme: Soluble, human recombinant neutral peptide endonuclease Professor Crine, University of Montreal Canada Mother solution: 100 pg / ml in 20 mM Tris pH 7.0 Operating solution: The mother solution is diluted to 2gg / ml with test buffer solution. Mca * -Asp-Ile-Ala-Trp-Phe-Dpa **-Thr-Pro-Glu-His-Val-Val-P roTyr- Gly-Leu-Gly-COOH; a large endothelin (Big-ET-1) analogue that quenches fluorescence, that is, a metal proteolytic enzyme, especially the neutral endoprotease and ECE- The mass of 1 can be detected by the fluorescent signal. The fluorescence of the MCA fluorescent chromophore disappears in the early stage due to the presence of the "quenching agent" Dpa. * Mca = (7-methoxycoumarin-4-enyl) ** Dpa = (3- [2, 4-dinitrophenyl] -L-2, 3-diaminopropanyl) Polypeptide Laboratories mother solution from Wolfenbtittel, Germany: 100 μM in test buffer solution Chinese test substance: All these substances are dissolved in DMSO (10 mM) and diluted with test 29 200524874 test buffer solution to the concentration tested. 70 μ1 of test buffer solution, 10 μl of enzyme operation solution and 10 μl of test substance solution were mixed in an Eppendorf container, and were preliminarily at 37 ° C. (: Incubate for 15 minutes (= min ·). Then add 10 μ1 of the substrate solution and incubate the test group at 37 ° C for 60 minutes. Heat to 95 C for 5 minutes to terminate the enzyme Reaction. After centrifugation (Heraeus BiofugeB, 3 minutes), the liquid supernatant was studied by HPLC according to the following instructions. The mass was obtained using reverse-phase HPLC (CC 125/4 Nucleosil 300/5 C18 RP column 'with CC 8/4 Nucleosil 100/5 Cm pre-column, Macherey-Nagel from Dtiren, Germany) was separated from the lysate. Here, 60 μ1 of the test mixture was injected into the sample injection site of the HPLC, and the column was injected with 1 ml The flow rate per minute is charged at the following slope:

Mobile phase A: 100% Η20 + 0.5 M H3P04 pH 2.0 Mobile phase B 100% acetonitrile + 0.5 M H3P04 0 to 2 minutes 20% B 8 to 10 minutes 60 to 90% B

2 to 6 minutes 20 to 60% B 10 to 13 minutes 90% B 6 to 8 minutes 60% B 13 to 15 minutes 90 to 20% B All monthly tests are based on absorption at 214 nm and excitation Measured at 328 nm and 393 nm. When the enzyme is cut off, the fluorescent chromophore (= Mca) and the quencher are offset in different lunar rupture slices, which reduce the quenching effect, which results in an increase in fluorescence. In the case of unquenched Mca fluorescent chromophores, the fluorescence signal (corresponding to the surface, A) in the peak increase is used as a further calculation. This signal is used for comparison with samples containing the test substance of Formula I or containing (= A_) the test substance of formula I. The value of "% suppression" is calculated by the following formula based on the area of individual waveguides:% suppression = 100 * (1-A suppression / A control) 200524874 All (samples are based on two repeated stiffnesses, and from this The average value was calculated. The standard inhibitor (10 nM thiorphan) and the solvent control (〇1% DMS〇) were measured as well as the quality control on each run. The IC5G values described below: Example number $ 5〇 (neutral moon-chain endonuclease) 3 17.9 10 37 16 20.0 17 < 1 19, 18.2 20 12.9 21 ------------ 16.9 23 10.6 24 11.1 25 15.5 27 7.8 31 4.0 32 13.8 43 3.2 59 12 63 9 Human soluble | In vitro testing for the production of in-chain t is to prove that the substance according to the present invention has 31 2. 200524874 inhibitory effect on human soluble endoglucanase. And other substances inhibit the polymorphic Mca_Asp_Ile_Ala_Trp_phe_Dpa_

The conversion of Thr-Pro_Glu-His_Val-Val-Pro_Tyr-Gly_Leu-Gly-COOH due to the activity of human soluble endopeptidase enzymes has been studied in in vitro freshness tests. In this test, the measured value of the inhibitory effect of the test substance is its IC% value. -The value of 1 (: 5 () of the test substance with inhibitory enzyme activity is the concentration of the test substance when the human soluble peptide endonuclease enzyme activity is inhibited by 50%. Test buffer solution: 100mM TrispH7.0, 250mM Naei enzyme : The outer part of human soluble peptide endonuclease with His6 is from Belgium, Gnoent's Innogenetics mother solution: 53 mg / ml in 20 mM HEPES pH 7.2, 5% glycerol, 0.005% Tween20, 100mM purity is higher than 99% In NaCl, the operating solution ·· master solution is diluted to 10 mg / ml with the test buffer solution

Substance: Mca-Asp-Ile-Ala-Trp-Phe_Dpa-Thr-Pro_Glu_His_Val-Val_Pr (> T yr-Gly_Leu-Gly-COOH;-a large endothelin that quenches fluorescence (Big-ΕΤ-1) Analogue mother solution: 100 μM Polypeptide Laboratories from Wolfenbtittel, Germany in test buffer solution Test substance: All these substances are dissolved in DMSO (10 mM) and diluted with the test buffer solution to the concentration tested. Test The operation of the HPLC method was performed according to the method for measuring the inhibitory effect of the test substance on the neutral peptide endonuclease in vitro. 10 nM phosphoramidon was used as the standard inhibitor in the HPLC method. In this test model, The test substances of the general formula I listed in Table 2 below have the following IC50 values:: i Test substance inscribed in the body chain 32 200524874 Example number IC50 (human soluble moon-chain incision g per) 2 21.4 3 7.8 10 25.3 16 15.0 17 24.0 19, 9.5 20 36.3 23 17.3 24 27.0 25 3.4 27 26.8 28 11.9 31 12.3 43 2.9 56 2.5 59 4.0

3. · Inhibition of endothelin (ET_η) in vitro by endotoxin (Big_ET-l) in mice in vitro. In order to prove that the substance according to the present invention has an inhibitory effect on endothelin produced by large endothelin, these substances Inhibition of the conversion of large endothelin into endothelin due to endothelin converting enzyme and related enzymes such as human soluble peptide endonuclease enzyme activity hydrolysis studies in standard experiments in vitro. Endothelin is an endogenous strong vasoconstriction substance. Increased blood endothelin concentration will increase blood pressure. The degree of increase in blood pressure when large endothelin is injected is determined by the endothelin produced by large endothelin due to enzyme 33 200524874. The inhibitory effect of other substances on the increase in blood pressure induced by injection of large endothelin was used as a measure of the inhibitory effect of these substances on rats. (Sprague-Dawley, CRLD = Charles River) at j mg / kg

Rompun / Ketavet was anesthetized 1: 1. A blood pressure transmitter (Statham) # was inserted into the cervical artery to detect blood pressure. One jugular vein was inserted into a tube to administer the test substance, and the other jugular vein was used to administer macroendothelin. After a 20-minute rest period, the rats are given the corresponding test substance of general formula I, usually at a concentration of 10 pmol / kg, or an excipient. After 5 minutes, Q5 nmol / kg of large endothelin was injected by 丨 minutes. The systolic (SAP = systolic arterial pressure) and diastolic (DAp = diastolic arterial pressure) blood pressure and heart rate are each measured before the test substance is administered or before the endothelin is administered, and each test is administered before Endothelin was then measured every 5 minutes using a blood pressure transmitter using conventional methods. The maximum value of the increase in blood pressure induced by large endothelin decreases at a rate of 0 < taking a large value is calculated from the measured value when the effect of large endothelin is exerted to the maximum (typically after 5 minutes) And the difference between the measured parameters before the injection of human endothelin. Riding, the integral value of the blood pressure curve under the influence of large endothelin was established for 30 minutes (just = the area under the forest). The AUC value provides information on the extent and duration of the action of macroendothelin, or provides information on the decrease of the role of macroendothelin as a test substance; therefore, the value of p, provides the maximum value of In addition, it can also provide information about the effects of substances, such as on this matter, that is, the test substance such as: or 疋 only slightly affects the effect of large endothelin, but it greatly accelerates the effect of withdrawing endothelin. . a ^ The greatest effect of endothelin on systolic arterial blood pressure (SAP) is the percentage of 生 生 born after intravenous administration of f, compared with the administration, 34 200524874 is described in Table 3 below: Table 3: Tests Example of in vitro test of antihypertensive properties of substances: The greatest effect of large endothelin on systolic arterial blood pressure is inhibited by the relevant test substance%, compared with the control group 2 -53 3 _94 4 -95 8 -113 14 _59 ( 3μηιο1) 16 -45 17 -46 20 -67 21 -43 23 -40 24 -54 26 -53 29-49 32 -52 34 -78 35 -63 38 _48 (3μηιο1) 44 -75 59 -98 67 -109 68 -108 35 200524874, the compound of general formula i also shows a certain degree of "inhibitory effect on endothelin converting enzyme." The inhibitory effect of substances of general formula I on endothelin converting enzyme can be demonstrated in standard tests in vitro. The compound of the general formula I is a dual-acting compound capable of inhibiting neutral skin endonuclease and human falling peptide endonuclease, and is also suitable for preventing and / or treating sexual dysfunction. Clinically, sexual dysfunction has been divided into female sexual dysfunction (FSD) disorders and male sexual dysfunction (MSD) disorders (see Mdman, A. & Gingell, JC (1999). The epidemiology and pathophysiology of erectile dysflmction Jurology 101: 5-11, cited below by rMelman et al. 1999 "). The compound of the present invention has dual effects, which can inhibit neutral endoprotease and human soluble tauronic acid endocutase g, especially the compound of the general formula, which is particularly beneficial for prevention and / or male sexual dysfunction (such as male Erectile Dysfunction-MED). Another advantage of the compound of general formula I in this indication is that it has a certain degree of inhibitory effect on endothelin-converting g-strips on the action profile. Male sexual dysfunction is generally related to erectile dysfunction, which is known as erectile dysfunction (= MED) (see Benet, A. E. et al. (1994), Male erectile dysfunction assessment and treatment options. C07Sp TheY.20: 669-673) (hereinafter cited by "Benet et al. 1994"). Male erectile dysfunction is defined as: "Inability to achieve and / or maintain penile erections to meet sexual performance (see NIH Consensus Development Panel on Impotence (1993). NIH Consensus Conference Impotence · JA. MA 270: 83)" has been The prevalence of erectile dysfunction (= ED) with all degrees assessed (mild, moderate, and complete impotence) was 52% among men aged 40 to 70, compared to men aged over 70 Higher (Melman et al. 1999). This condition has a significant negative impact on the quality of life of the patient and his partner, and often causes anxiety 36 200524874 and increased stress, which leads to depression and lack of self-esteem. Twenty years ago, male erectile dysfunction was mainly considered a psychological disorder (Benet et al. 1994), and today it is known that for most patients, there are fundamental organic causes. Therefore, many advances have been made in identifying the mechanisms of normal penile erections and the pathology of male erectile dysfunction. If the dual-acting compound of the present invention can inhibit neutral peptide endonuclease and human soluble I-chain endonuclease, especially the compound of general formula I, and it is used to treat female sexual dysfunction, then treat women Sexual arousal disorder (= FSAD) is preferred. The best definition of female sexual dysfunction is when a woman has difficulty or cannot find satisfaction in sex. Female sexual dysfunction is a collective term for several different types of female sexual dysfunction. Leiblum, S.R. (1998). Definition and classification of female sexual disorders. Int. J. Impotence Res., 10, S104 -S106; Berman, J.R. Berman, L. & Goldstein, I. (1999). Female sexual dysfunction: Incidence, pathophysiology, evaluations and treatment options. Urology, 54, 385-391). Women may lack sexual desire, Have difficulty with excitement or orgasm, pain during intercourse, or a combination of the above problems. There are several types of illnesses, drugs, injuries, or physical problems that can cause female sexual dysfunction. Therapeutic methods that are still under development are focused on treatment The special subtypes of female sexual dysfunction are mainly sexual desire and sexual coldness. The category of female sexual dysfunction is best defined by comparing the stages of sexual response with normal women: sexual desire, excitement and orgasm (Leiblum, S.R. (1998). Definition and classification of female sexual disorders. Int. J. Impotence Res ”10, SI04-S106) o Sexual desire or desire is the source of sex Force. The appearance often includes sexual thoughts when you are with a partner you find interesting, or when exposed to other sexual stimuli. 37 200524874 Excitation is the response of blood vessels to sexual stimulation. One important factor is genital congestion, which includes vaginal secretion of lubricating fluid, vaginal extension, and increased genital sensitivity. ~ Orgasm is the relief of sexual tension that reaches its peak during excitement. Therefore, female sexual dysfunction occurs when a woman's inadequate or satisfying response at any of these stages is usually sexual desire, excitement, or orgasm. The categories of female sexual dysfunction include insufficiency of sexual desire, sexual coldness, orgasm, and pain in sexual behavior. Although the compounds of the present invention improve the genital response to sexual stimuli (such as sexual cold in women) 'When so, these compounds can also improve the accompanying pain, the tension and discomfort associated with sexual intercourse, and therefore treat Other types of female sexual dysfunction. Therefore, according to a special point of view of the present invention, there is provided the use of the compound of the present invention in the preparation-Crane for treatment or lion sexual insufficiency disorder, sexual cold feeling, orgasm disorder, and sexual behavior pain disorder, more preferably for treatment Or prevent cold chills, orgasm disorders, and pain during sexual behavior, prefer treatment or prevent cold chills. If women have no or little desire for sex, and no or little sexual thoughts or fantasies, there is an impediment to sexual desire. This type of female sexual dysfunction may be caused by too low testosterone levels due to natural menopause or menopause caused by surgery. Other causes include illness, drugs, burnout, depression, and anxiety. Sexual coldness in women is characterized by the sexual organs not responding sufficiently to sexual stimulation. The genitals do not undergo congestion with normal sexual arousal characteristics. Poor lubrication of the vaginal wall can cause pain during intercourse. Orgasm may be hindered. Cold sensation may be due to decreased estrogen secretion during menopause or after childbirth and during lactation, and due to vascular diseases such as diabetes and arteriosclerosis. Other reasons include receiving diuretics, antihistamines, and antidepressants. 38 200524874 For example, selective inhibitors of serotonin resorption (= M along S). Treatment of blood pressure agents. Pain in sexual behavior (including pain during intercourse and vaginal spasms) is characterized by pain caused by insertion and may be due to drugs that reduce the secretion of lubricating fluid, ectopic endometrial tissue, inflammatory conditions of the pelvic cavity, and inflammatory large bowel conditions Or caused by problems with the urethra. The prevalence of female sexual dysfunction is difficult to estimate because the term covers several types of problems, some of which are statistically = difficult, and because interest in treating female sexual dysfunction is very recent. Many women's sexual problems are not directly related to the aging process of women, but also to diffuse diseases such as diabetes or hypertension. Because there are several subtypes of female sexual dysfunction, they show symptoms at different stages of the sexual response cycle, so a single treatment. At present, the main focus of treating female sexual dysfunction is psychological or relationship problems. The treatment of female sexual dysfunction is gradually being developed, as more and more clinical and basic scientific research has been devoted to the discussion of this medical problem. Women's complaints about sex are not entirely psychological problems in pathophysiology, especially for those vasculogeneic dysfunctión (such as women) Sexual cold)). So far, no drug has been licensed for the treatment of female sexual dysfunction. Estrogen (locally or as a hormone replacement therapy), androgens or mood-changing drugs, such as buspi_e or trazodone. The choice of these treatments is often unsatisfactory due to the inefficiency of the accepted system. Because of his interest in using drugs to treat dysfunction such as Chen, the treatment core includes the following points: ~ counseling, sexual lubricants obtained without a doctor's prescription, and drug candidates in the study 'include Has been approved as a medicine for other problems. The 39 200524874 and other drugs include hormonal preparations, testosterone or a combination of estrogen and testosterone, and vascular drugs that have recently been proven effective for male erectile dysfunction. However, none of these drugs has been shown to be effective in treating female sexual dysfunction. The American Psychiatric Association's Diagnostic and Statistical Manual (DSM) IV defines female coldness as ... "Sustained or recurrent inability to reach or maintain sufficient sexual excitement to lubricate the expansion response until completion of sexual activity. This disorder It will definitely cause obvious pain and social difficulties. " Excitatory responses include pelvic vascular congestion, vaginal secretion of lubricating fluid, and swelling of the external reproductive organs. This disorder causes significant pain and / or social difficulties. Studies examining couple sexual dysfunction Studies have shown that 76% of women complain of sexual dysfunction, and 30 to 50% of women in the United States have experience with female sexual dysfunction (Berman, j. R.,

Berman, L.A. "Werbin, T.J. et al. (1999), Female sexual dysfunction:

Anatomy, physiology, evaluation and treatment options. Curr Opin Urology, 9, 563-568). Sexual coldness in women is a highly prevalent sexual dysfunction that affects women before, during and after menopause (hormonal replacement therapy (HRT)). Related concomitant conditions such as depression, cardiovascular disease, diabetes, and genitourinary conditions. The main results of female sexual coldness are lack of congestion / swelling, lack of lubrication, and lack of genital pleasure. The secondary consequences of female sexual coldness are decreased sexual desire, pain during intercourse, and difficulty reaching orgasm. Recently, it has been hypothesized that vascular factors can be used as a basis for at least some patients with female cold symptoms (Goldstein et al., Int. J. Impot. Res., 10, S84_S90, 1998), and data from animal experiments Support this view (Park et al. 'Int · J · Imot · Res' 9, 27-37, 1997). It is known that inhibitors of soluble endopeptidases increase the stimulation by the pelvic nerve and by the action on blood vessels. Vaginal and clitoral blood flow induced by intestinal moon too (V VIP) 200524874, JL also knows that soluble inhibitors of tsuki enzymes in the moon chain will increase the isolation of the intestinal moon that acts on blood vessels and that it is caused by nerves. The relaxation of the vaginal wall. Therefore, the advantage of the present invention is that it helps to provide a method as a response to re-establish a normal sexual excitement, that is, to increase blood flow of the genitals to promote vaginal, clitoral and labial congestion. Phenomenon will cause the vagina to increase the secretion of lubricating fluid, increase vaginal compliance and increase vaginal sensitivity through the leakage of serous fluid. Therefore, the present invention provides a method for re-establishing or Strong normal sexual excitement. For the female genitals in this article, it means "the reproductive organs are composed of an internal and external group. The internal organs are located in the pelvic cavity and are composed of the ovaries, fallopian tubes, uterus and vagina The external organs are located on the outer surface of the genitourinary diaphragm and below the pelvic arch. It contains the clitoris, labia majora and labia minora, clitoris, vaginal vestibule, vaginal vestibule, and larger other vestibular glands. "(Gray's Anatomy, C. D. Clemente, 13th American

Editi〇n "RJLeVin teaches that, because" male and female reproductive organs are embryologically developed from a common tissue primordium, and the structures of male and female reproductive organs are claimed to be homologous to each other. Therefore, The clitoris is homologous to the penis, while the labia is homologous to the scrotum "(Levin, R.J. (1991), Exp. Clin. Efzdocrinol., 98, 6169). Regarding male sexual dysfunction, especially male erectile dysfunction, penile erection is a hemodynamic event, which depends on the balance between the contraction and relaxation of the cavernous smooth muscle and the distribution of penile blood vessels (see Lerner, SE ·, etc. (1993). A review of erectile dysfunction: new insights and more questions. J. Urology 149 ·· 1246-1255). Cavernous smooth muscle is also referred to herein as corporate smooth muscle or multiple sense corpus cavernosa. The relaxation of the corpus cavernosum smooth muscle causes an increase in the blood flowing into the trabecular space of the corpora cavernosa, which causes it to expand toward the surrounding capsule and compress the bleeding veins. This condition results in a significant increase in cavernosal blood pressure, which results in an erection (see Naylor, A. 41 200524874 M. (1998) 〇 Endogenous neurotransmitters mediating penile erection. Br. J. Urology 81: 424-431), hereinafter referred to as " (Naylor, 1998). The changes that occur during the erection are complex and need to involve a highly coordinated control of the surrounding and central nervous system and endocrine system with each other (aylor, 1998). The contraction of body smooth muscle is regulated by the neuron innervation of sympathetic epinephrine through α-% adrenaline burned after activation of activated cell A. Erectile dysfunction in men may be related to increased smooth muscle tension in the cavernous body. However, the relaxation process of body smooth muscle is partly dominated by non-adrenaline and non-choline (= NANC) nerve conduction. Many other NANC neurotransmitting substances other than nitrogen oxides (= N〇) were found in the penis, such as peptides (= CGRP) related to the caictotonin gene and intestinal function of blood vessels (VIP). The relaxation factor that mainly dominates this relaxation is NO, which is synthesized from nitrogen oxide synthesis g per (=; ^ 〇8) from L-arginine (see, for example, Taub, H.C. et al. (1993 ), Relationship between contraction and relaxation in human and rabbit corpus cavemosum. Urology 42: 698_704). Some people think that reducing body smooth muscle tension may help NO to induce relaxation of the cavernous body. When men are sexually excited, NO is released from neuronal cells and endothelial cells, and binds to and binds to soluble guanylate cyclization @ 条 (8〇 (:) located in smooth muscle cells and endothelial cells. Activation, resulting in an increase in the concentration of cyclic guanylate 3,5, -monophosphate (cGMP) in the cell. This increase in cGMP concentration leads to relaxation of the cavernous body, which is due to the concentration of intracellular ions ([Ca2 +] i) Reduction, through an unexplained mechanism, which is thought to be related to the activation of protein kinase G (probably due to activation of Ca2 + pumps and activation of κ + channels activated by Ca2 +). It is pointed out that c-type diuretic sodium Yuetai (= CNP) also plays a role in male erectile dysfunction, and it interacts with guanylate cyclization g bar B (= GC-B) fixed on the cell membrane. This enzyme is expressed in In human cavernous tissue. Stimulation of guanylate cyclization 42 200524874 Enzyme B will increase cGMP in cells and result in relaxation of smooth muscle. Brain inhibitors, such as sildenafll, will inhibit cGMp decomposition and cause intracellular cavernous tissue CGMP increase The P inhibitor is inactive in the absence of a c (} Mp-producing stimulant, for example, in the absence of NO, and is not active.) This finding indicates that the basic (unsuccessful) composition of eGMP production in cavernous tissue is comparable. Low, so cGMP degradation inhibited by PDE-5 inhibitors is not without stimulating ornithine cyclase at the same time; 1 as an erectile response. Increasing the concentration of risperidin will be caused by the increase in cGMP production The concentration of qi in cells is increased. Therefore, increasing the concentration of cavernosal group _ riliside will have a similar effect to ㈣ pDE_5. However, due to their different mechanism of action, that is, increasing cGMp production compared to The methods of inhibiting the decomposition of cGMP, inhibiting PDE_5, or degrading naldiuretic peptides are considered additive, respectively. Therefore, a reasonable assumption is made, that is, the combination of the two materials is only acid_5 and the peach reaction is suppressed. Patients will be particularly effective. The nerve fibers that currently act on the intestines of the blood vessels have been found in the reticular tissue of the cavernous body, indicating that the release of intestinal peptides on the blood vessels affects penile erections. Role, acting on the vascular intestine Yuetai, its effect is believed to be promoted by the increase in cAMp < increase the cGMP concentration of drugs. Injection in the cavernous body of patients with erectile dysfunction to enter the blood vessel intestine Yuetai (combined use of adrenaline receptor Antagonist (phentdamine) was found to be a safe and effective treatment, with a response rate of 67% (sufficient for sexual intercourse erections). Moon-chain endogenous purlins, neutral moon-chain endonucleases, and human soluble moons Both of the tai-chain incision noodles break down c-type diuretic natriuretic peptides and ileal natriuretic peptides that act on blood vessels. Therefore, c-type natriuretic peptides and intestinal peptides that act on blood vessels have limited effects on corpus cavernosum smooth muscle. Inhibition of c-type diuretic sodium moonlight and its degrading effect on vascular intestinal moonlight will increase the availability of these vascular relaxation factors, thus increasing blood flow into the cavernous body 43 200524874, which should eventually lead to erectile function improve. Based on experimental data on rabbits, it is shown that blood pressure in the cavernous body and blood flow in the female genital organs have significantly increased after administration of a neutral endoprotease inhibitor (see patent case W002 / 079143). Find support for this argument. Furthermore, a gene encoding the endogenous inhibitor sialorphine (SMR1) was discovered

(See User, Η · M ·, Zelner D · J ·, McKenna κ ··, Me Vary κ · T (2003) 〇 Microarray analysis and description of SMR1 gene in rat penis in a post-radical prostatectomy model of erectile dysfunction. J Urol. · 170 (1): 298-301) was significantly down-regulated (more than 80 times) in the atmospheric model of erectile dysfunction of neurogenesis, indicating that in this disease, the neutral moon-chain may be strengthened The activity of endogenous quotients is also the cause of developing erectile dysfunction. Description of Pharmacological Test Methods The example numbers cited refer to the preparation examples described below. The inhibitory effect of the compounds used in accordance with the present invention on the degradation of c-type diuretic sodium moonlight and intestinal moonlight acting on blood vessels is measured in an in vitro enzyme test according to the following methods: Enzymes · a) Human soluble endo-endonuclease ( sol hu) (his) 6; or: Human soluble masterbatch endothelial endonuclease outside solution with His6: 53 pg / ml at 20 mM HEPES pH 7.2, 5% glycerol, 0.005% Tween 20, 10. MM NaQ with a purity of more than 99%. Operating solution: the mother solution was diluted to 5 pg / ml with test buffer solution. Supplier: Innogenetics, Ghent, Belgium. The preparation and purification of this protein are as described in WO 02/094176 b) Neutral peptide endonuclease (prepared from the cortex of pig kidney) Mother solution · 120 pg / mi at 20 mM bis Tris, purity higher than 95% operating solution: The mother solution was diluted to 5 pg / ml with the test buffer solution. 44 200524874 Supplier · Dr. Philippe Crine, University of Montreal, Canada · a) Intestinal peptide acting on blood vessels b) Type c natriuretic peptide ( 32-53) Ma Luo solution · Supplier of 100 jiM in test buffer solution · Germany, Bachem test buffer solution at Weil riverside, Germany: 100 mM Tris pH 7.0, 250 mM NaCl All test substances are dissolved in DMSO to imM And further diluted with test buffer solution. Activity test method 80 μΐ test buffer solution, 10 μ1 enzyme operation solution (neutral peptide endonuclease or human soluble moon chain endonuclease) and Ιο μΐ peptide mother solution (acting on the blood vessel intestinal month or type c) Diuretic steel) was mixed in an Eppen (jorf container and incubated at yc for 120 minutes. Heated to 95 ° C for 5 minutes to stop the enzyme reaction. After centrifugation (Heraeus BiofogeB '3 minutes), the liquid supernatant portion was jjplc analysis. Inhibition test method 70 μΐ test buffer solution, 10 μΐ enzyme operation solution (neutral peptide endonuclease or human soluble moon chain endonuclease) and 10 μ1 of a test compound mother solution mixed in one Eppendorf container and pre-incubate for 15 minutes at 37 ° C. Then add 10 μΐ peptide mother solution (intestinal peptide acting on blood vessels or c-type natriuretic peptide), and place the reaction mixture at 37 ° C Incubate for 60 minutes to allow the enzyme hydrolysis reaction to proceed. Heat to 95 ° C for 5 minutes to stop the enzyme reaction. After centrifugation (Heraeus BiofbgeB, 3 minutes), the liquid supernatant portion is analyzed by HPLC. The residue is separated from the decomposition products In terms of quality, reverse-phase HPLC technology is used, which has CC 125/4 Nucleosil 300/5 C! 8 RP columns and CC 8/4 Nucleosil 100/5 C18 pre-columns (from Germany) 3iiren's Macherey -Nagel). Here, 60 μ60 of the reaction sample was injected into the HPLC, and then the column was stripped at a flow rate of 45 200524874 at 1 ml / min with the following gradient: Solution A: 100% Η20 + 0.5 μM H3P04 pH 2.0 Solution B : 100% acetonitrile 10.5 Μ H3P04 0 to 2 minutes 5% B 8 to 10 minutes 90% Β 2 to 7 minutes 5 to 50% B 10 to 12 minutes 90 to 5% B 7 to 8 minutes 50 to 90% Β All diethyl ether is detected by absorption at 214 nm (ultraviolet spectral analysis). The percentage of hydrolysis (=%) is based on the peak area of the diethyl ether that has not been decomposed by diethyl ether. In a sample containing the same concentration of S but no enzyme (blank group), it is calculated by the following equation: ° / 〇Hydrolysis = 100 ** (blank group-γ) Based on the calculation of% inhibition, a sample containing The inhibitor of X has not been decomposed to produce too much (intestinal tract that acts on blood vessels or c-type diuretic natriuretic peptide). Samples from the (blank group) or peptides and enzymes (control group) without inhibitors are calculated from the following equation:% inhibition = 100 * (χ_control group) / (blank group_control group) All All samples are duplicated and the average is used. A solvent control (0.1 ° / dDMSO) was added to each pending test. The c-type diuretic naloxone and the intestinal moonlight acting on blood vessels are cut off in vitro by a neutral moonchain endonuclease and a human soluble peptide endonuclease. Human soluble peptide endonuclease cuts two peptides faster than neutral peptide endonuclease, as shown in Table 4 below: 'Production d: intestinal skin (= VIP) acting on blood vessels and type C diuretic Skin (; = CNp) Degradation rate by neutral peptide endonuclease (= NEP) or human soluble peptide endonuclease (== hSEP) 200524874

The decomposition of VIP hSEP__Νβρ According to the current situation,-/ w 4 I jt. I wr / 4 ihj ^ l yi jr Soluble peptide endonuclease decomposes c-type natriuretic peptide and peptides acting on blood vessels . In this test model, the subjects listed in the general formula in Table 5 below have the ic5G values listed below: The test substances produced are useful for the decomposition of C-type diuretic sodium month (= CNP) and the intestinal skin that acts on blood vessels ( = vip), decomposition by sample number inhibition of CNP decomposition hSEP NEP IC5〇 (nM) IC.n (nlU) VIP decomposition of hSEP NEP IC5〇 (nM) IC50 (nM) 4 1.0 10.1 3.1 3.1 General formula The compounds of I are also suitable for the prevention and / or treatment of apoptotic-related diseases. The diseases mentioned are, for example, neurodegenerative disorders such as ischemic stroke, cerebral ischemia, traumatic brain injury, acute disseminated encephalomyelitis, amyotrophic lateral sclerosis (ALS), pigmented retinitis, Mild impaired cognitive ability, Alzheimer's disease, Pick's disease, Alzheimer's disease, progressive supranuclear palsy, subcortical dementia, Wilson disease, multiple Infarct, arteriosclerotic dementia, AIDS-related dementia, brain degeneration, cerebral spinal cord deterioration syndrome, Friedrdchs ataxia, maladjusted telangiectasia, and epilepsy Brain damage, spinal cord damage, restless legs syndrome, Huntington's disease and Parkinson's disease, striatum nigra degeneration, cerebral vasculitis, Glandular cerebral myopathy, neurotic ant 200524874 neurocemic lipofoscinosis, spinal muscular atrophy, and involvement of the central nervous system Ferrite storage disorders, white matter disorders, urea cycle defect disorders, hepatic encephalopathy, kidney encephalopathy, metabolic encephalopathy, porphyria, bacterial or viral meningitis and Piece Goods meningoencephalitis, protein infection ⑦ ^. … Illnesses, intoxication with divine compounds, Guillain Barre syndrome, chronic inflammatory neurological disorders, polymyositis, dermatomyositis, brain damage due to radiation; gastrointestinal diseases such as irritant Colon disease, as well as inflammatory colitis, Crohn's disease and ulcerative colitis, celiac disease, Helicobacter pylori gastritis and other infectious gastritis, necrotizing enterocolitis, pseudomembrane enterocolitis, causes Enterocolitis, lymphocytic gastritis, graft-versus-host disease, acute and chronic pancreatitis, radiation sickness, liver diseases such as alcoholic hepatitis, viral hepatitis, metabolic hepatitis, autoimmune hepatitis, radiation sickness Hepatitis, cirrhosis, hemolytic uremia, glomerulonephritis, lupus nephritis; viral disorders, such as explosive hepatitis; joint disorders, such as trauma and osteoarthritis; suppressed immune function or immune function Incomplete disorders, especially autoimmune disorders, such as primary inflammatory muscle disorders, chronic neutropenia, blood Thrombocytopenic purpura, rheumatoid arthritis, primary thrombocytopenic purpura, autoimmune hemolytic syndrome, antiphospholipid antibody syndrome, myocarditis, multiple sclerosis and its recurrence in the sub-categories of diagnosis-remission of multiple Multiple sclerosis, second grade multiple multiple sclerosis, primary progressive multiple sclerosis, progressive relapsing multiple sclerosis, acute multiple sclerosis, benign relapsing multiple sclerosis, or asymptomatic multiple Sclerosis, Optic Neuromedulitis (Devic's Syndrome), Lymphocytic Pituitary Inflammation, Grave's Disease, Addison's Disease, Parathyroid Insufficiency Disease, type 1 diabetes, systemic lupus erythematosus, pemphigus vulgaris, bullous pemphigoid, psoriasis arthritis, endometrial tissue ectopic, autoimmune 48 200524874 testicular inflammation, autoimmune erectile function Disorders, sarcoidosis, Wegener's granulomatosis, autoimmune deafness, Sjohori (willow, autologous Epidemic uve retinitis, interstitial cystitis, Goodpasture's syndrome, and fibromyalgia; spinal hypoplasia, such as hypoplastic anemia; dermatological conditions, including vulgaris Sores, dermatomyositis, atopic dermatitis, Henoch_Schonlein purpura, acne, systemic sclerosis, sebum leakage, stratum corneum disorder, skin obesity cell hyperplasia, chronic proliferative dermatitis, Keratosis, Dermatosclerosis, Sarcoidosis, Psoriasis, Bacterial infections of the skin, Dermatosis, Leprosy, Leishmaniasis of the skin, White spot disease, Toxic epidermal necrosis Lytic disease, Steven Johnson syndrome, sebaceous adenoma, baldness, light damage to the skin, sclerosing atrophic lichen, acute skin wounds, incontinentia Pigmenti, heat damage to the skin, eruptive impetigo, Lichen-like skin disease, skin allergic vasculitis, cytotoxic dermatitis; diseases in the inner ear 'as heard by hearing trauma Perceived hair cell death and hearing loss, auditory hair cell death and hearing loss induced by amine glycosides, hearing loss induced by ototoxic drugs, perilymphatic fistula, cholesteatoma, cochlea or Ischemia, Meniere's, hearing loss due to radiation, hearing loss due to bacterial or viral infections, and primary hearing loss; transplantation, such as the pathology of the graft to the host, Rejection of transplanted organs such as acute and chronic heart, lung, kidney, skin, cornea, bone marrow or liver; wound healing and tissue rejection. The effect of 1- (carboxyalkyl) -cyclopentylcarbamido-phenylcycloazatriene acetate derivative substituted by amidomethyl in general formula I in the prevention and treatment of apoptotic-related ailments can be Proven in appropriate animal models for predicting anti-apoptotic activity. 49 200524874 Description of pharmacological test methods The referenced example numbers refer to the preparation examples described below. 1 · Extra-traumatic brain_injury, dysmenorrhea cell death Contusion device: The contusion device consists of a stainless steel tube with a length of 40 cm, and a hole is drilled at a distance of 1 cm to prevent air from being compressed in the tube. Wistar adult rats from 23 to 270 grams of ehlolai hydrate were injected intravenously at 400 mg / kg, anesthetized, and the skull on the right half of the brain was incised, followed by a weight guide The device dropped on the bottom plate resting on the surface of the dura is placed perpendicular to the surface of the skull ', and then the force of 380 grams X cm generated by a 20-gram knot code was selected to create a brain contusion. Injuries up to 2.5 mm on the surface of the brain can prevent mechanical puncture of the dura mater. In terms of three-dimensional spatial stereotacticity, the center of the bottom plate is 1.5 mm in front 1¾ and 2.5 mm in the side of the front chimney. Large breasts were perfused and fixed with a solution containing 4% paraformaldehyde dissolved in phosphate buffer solution 3 days after the fine beta was received. Intraventricular injection: 5 to 15 μΐ of the compound is administered from the intraventricular (= i · c · V ·) using a Hamilton syringe. The injection was performed for 5 minutes, and the following three-dimensional spatial stereotactic coordinates were used from 15 minutes to 8 hours after trauma: the former was related, AP = _0.5 mm, L = -2 mm, and V = -5.5 (Swanson, LW (1992) Brain Maps: Structure of the Rat Brain, Elsevier, Amsterdam) ° Hippocampal type determination analysis: Hippocampus CA3 subregional damage is stereologically applied to Three days after trauma injury, it was extended from 10.21 to 11.21 millimeters on five different levels of rostrocaudal (Swanson, LW (1992) Brain Maps: Structure of the Rat Brain, Elsevier, Amsterdam) and applied across its medial and lateral axes Determination. In order to quantitatively evaluate the damage of neurons in the hippocampus, the three-dimensional spatial stereology of the dual sector technology 50 200524874 (Cruz-Orive, L.M. & Weibel, E.R. (1990) Am. J. Physiol. 258, L148-L156) used it to estimate the numerical concentration of cone neurons (Nv). An unbiased calculation frame (0.05 mm X 0.05 mm, the south of the shoulders is 0.00 mm and a high-aperture eyepiece (X 40) is used for sampling. Normal nerve cells are identified by it There is a typical nucleus with a clear nucleus and a distinct nucleoli surrounded by a cytoplasm containing Nissl *. The boundary between the CA2 and CA3 subregions is considered to be a loosely arranged large cone-shaped cell entering the CA3 subregion. Where tightly arranged cone-shaped cells. The solitary line connecting the two ends of the dentate granular cell layer is considered to be the junction between the CA3 and CA4 subregions. In this experimental model, the dose-correlation of the test substance of Example 3 elicited Neuroprotective effect. When the test substance of Example 3 was administered from the ventricle up to 8 hours after trauma, the neuroprotective effect was still significant. When the test substance of Example 3 was administered from the ventricle to adult rats 15 minutes after trauma, The dose-response of its neuroprotective effect was measured. The nerve cell concentration in the CA3 hippocampal sub-region was determined as described in the method. On the left side of the rats treated with excipients, the left side was not perceived, and CA3 nerve cell concentration ± standard deviation (= SEM) on the right side of the traumatized rats on the right side of the trauma and on the six three-dimensional stereotactic 2 levels of rats treated with the test substance of Example 3 ) Were measured, and the results are listed in Table 6 below. In all cases, the number ("η") indicates the number of heterozygous rats. 4 ^: CA3 hippocampal nerve cell concentration, cell x 103 / mm3 tends to the left of the three-dimensional dimensional hierarchy excipient; (n = 10) the right of the excipient; (n = 10) Example 3 compound, 3 (η = 10) Example 3 compound, 10 pg (n = 10) Example 3 Compound, 30 pg (n = 10) 51 200524874 10.21 159.00i3.62 9L20 soil 7.60 98.40rb4.39 108.60 soil 4.30 108 40 soil 3 15 10.41 158.20 ± 3.03 87.20 ± 8.17 89.00 ± 5.05 108.60 ± 5.34 105 20 ± 5.76 10.61 157.20dz2.88 66.80 soil 7.68 72.80i6.01 111.40 soil 7.09 94 20 ± 5 10 10.81 159.60 soil 2.99 56.80 ± 5.96 84.20 soil 6.47 112 · 00 ± 6 · 42 ί 20 soil 7 10 11.01 152.40 ± 2.99 51.40 ± 6.89 86.00 ± 7.44 111.40 ± 7.11 δ〇90 + 7 4S 11.21 151.60 ± 2.47 71.60 soil 8.22 95.40 ± 6.9 6 119.20 ± 3.70 otuu Gong / · 90.00 soil 9.24 Injection of excipients reduced the concentration of nerve cells in CA3 hippocampus by 35% of the control value, and injection of 3, 10 or 30 pg of the test substance of Example 3 partially inhibited the hippocampus The loss of mesangial cells is most effective at a dose of 10 tons. Analysis of the variance ("ANOVA") results show that all three marriages of the test substance of Example 3 (ρ <0.001; η = 10) have significant significance in the treatment of neuronal loss in the hippocampus of CA3. Protection effect. In addition, AN0VA also showed significantly better neuroprotective effect than the dose of 10 or 30 pg. • Example 3 When the test substance was administered to Wistar adult rats from the ventricle at 2, 4, or 8 hours after trauma, the time window for measuring its neuroprotective effect was increased.神经 The nerve cell concentration in the hippocampal subregion was determined as described in the method. For rats treated with excipients or 3 compounds, they were shot right after trauma. Six tendencies in the f-dimensional space were measured (standardized deviations of the concentration of phrenic nerve cells on the level of stupidity, and the results are listed in In Table 7 below: M: CA3 hippocampal nerve cell concentration, cell x 10Vmm3 to the right of the excipient; (n = 8) Example 3 compound, 2 hours; (n = 8) Example 3 compound, 4 hours; (η = 8) Compound of Example 3, 8 hours; (n = 8) 72 · 30 ± 4 · 80 ------— J22〇 ± 5.70 62.00 ± 4.90 Trend ^ i-dimensional spatial stereo level 10.21 5 ^ 21 ± 5.81 52 200524874 10.41 50.65 soil 7.30 68.10 soil 6.30 65.90 ± 8.80 53.00 soil 6.44 10.61 49.35 soil 8.76 60.80 ± 5.60 63.00 soil 6.30 53 · 00 ± 6 • 10.81 51.2U7.97 60.20 ± 9.40 60 · 50 ± 10.50 52 · 50 ± 4.48 11.01 54.80 ± 10.30 63.00 ± 11.70 62.20 ± 13.50 61.80 ± 4.48 11.21 60.00 ± 13.00 67.70 ± 14.00 6630 ± 15.90 65.90 ± 4.90 The injection of excipients resulted in a decrease in the concentration of nerve cells in the hippocampus of CA3 by 35%. Intraventricular injection of 10 pg of Example 3 test substance partially inhibited the hippocampus Cell loss. ANOVA results show that the use of the test substance of Example 3 at all three time points has a significant therapeutic effect on the loss of nerve cells in the hippocampus of CA3 (at 2 and 4 hours, ρ < 0.001 At 8 hours, ρ < 0.01). 2. Basicity of Adriamycin: determination of anti-apoptotic activity. Wistar rats weighing 200 to 250 grams were anesthetized with chlorohydrazine hydrate, 400 mg / kg, And the Alzet permeable minipump (2ML1) was implanted subcutaneously (== s · e ·). The pump has been filled with excipients or a solution containing an appropriate concentration of the compound of the present invention, and it is ready to be installed Animals then received & (1 also 11 ^ 丨 11 three equal daily doses, 5 11 ^ / 1 ^ intraperitoneal injection on the first, second and third days. Rats received the first injection of adriamycin He was euthanized for 5 days, and the whole body was decorated with a solution containing 4/0 paraformaldehyde in phosphate buffer solution. The heart, liver, and kidneys were then removed and buried in paraffin. TUNEL staining method: As for the histological analysis based on the dUTp Notch End Labeling Method (TUNEL) promoted by terminal deoxynucleotide transfer, the organs were fixed at 40 ° C for 5 days' and buried in the stone ballast. TUNEL staining was performed on 10 μm thick paraffin sections using ApopTag hydrogen peroxide (Germany, Heidelberg, Oncor Appligene, S 7100) according to the manufacturer's instructions. A brief description is as follows. After pretreatment with proteolytic enzymes and peroxidase and elimination of endogenous hydrogen peroxide, the sections are incubated in a balanced buffer, followed by manipulation with TdT enzyme (labeled 53 200524874 digoxigenin dUTP core). Add the nucleotide to the free 3, -OH end of the DNA), (37 ° C, 1 hour). Sections were stopped / washed in buffer (37 ° C, 30 minutes), then conjugated with anti-digoxigenin (30 minutes), and then DAB substrate (Germany, Deisenhofen, Sigma) was developed and methylated The green (methylgreen) is slightly reversed. In this test model, the test substance of Example 4 gave significant protection to the heart, liver, and kidneys from the toxicity of adriamycin, as it significantly reduced the density of TUNEL-positive cells in the three organs. This effect was dose-dependent at a dose of 100 mg / kg, with daily best results.

Wistar rats were administered intravenous adriamycin at the highest dose of 15 mg / kg. The test substance of Example 4 was administered subcutaneously for a total of 5 days at a daily dose of 20, 50, or 100 mg / kg via Alzet osmotic minipumps. Animals were euthanized 5 days after the first injection of adriamycin, and were perfused into the heart, and the heart, liver, and kidneys were then processed for TUNEL staining. The mobility of TUNEL ㈣ cells was determined as described in the method. The results of each organ (heart, liver, kidney) were measured in the control group and different test groups (Example 4 Test substance 20, 50, or 100 mg / kg daily) Mean density ± standard deviation of TUNEL positive cells And are listed in Table 8 below. Yield: TUNEL-positive cells / mm3 χ 1〇2 Adriamycinb (η = 24) 5.417 ± 0 · 146 10.420 ± 0.275 9.438 ± 0 · 198 + Example 4 compound 4.350 ± 0.248 *** 8.750 ± 0.301 ** 7.900 ± 0.306 *** 20 mg / kg (n = 10) + Example 4 compound 3.700 soil 0.260 *** 8.250 ± 0.271 *** 7.850 soil 0.587 ** 50 mg / kg (η = 10) 54 200524874 + Example 4 Compound 3.550 ± 0.157 *** 7.450 ± 0.329 *** 6.300 ± 0.260 *** 100 mg / kg Γη = 10) Example 4 The test substance reduced adriamycin cells in a dose-dependent manner in all three organs toxicity. The comparison between the experimental groups was performed by the student's test method (** P <0.01; *** P < 0.001 compared to rats treated with excipients). The invention also provides a method for treating or preventing cardiac and vascular disorders and / or apoptosis-related ills in mammals and humans, which comprises administering to a subject in need thereof an effective amount of a compound of formula I. The present invention further provides a method for treating or preventing sexual dysfunction in mammals and humans, which comprises administering to a subject in need thereof an effective amount capable of inhibiting a neutral moon-chain endonuclease or a human soluble moon-chain chain. Di-acting double-acting compounds, especially a compound of formula I according to the invention. Compounds of general formula I may be administered using conventional pharmaceutical compositions. The dosage used may vary according to individual circumstances, and will naturally vary according to the condition to be treated and the type of drug used. In general, however, the main ingredient contains a pharmaceutical form of 0.2 to 500 mg ', especially 10 to 200 mg. Each dose of the main ingredient is suitable for administration to humans and larger mammals. The medicament of the present invention can also be administered by intravenous injection, and the dose may range from 0.1 to 1 mg / kg / hr. The above doses are taken as examples to illustrate the general situation. These compounds may be included with traditional pharmaceutical adjuvants and / or excipients, according to the present invention, in solid or liquid pharmaceutical compositions. Examples of solid pharmaceutical compositions are compositions which can be taken orally, such as tablets, coated tablets, capsules, powder or tincture granules, or tincture suppositories. These pharmaceutical compositions may contain, in addition to traditional pharmaceutical adjuvants, such as lubricants or tablet breakers, inorganic and / or organic excipients such as talc, lactose or Temple powder. Liquid pharmaceutical compositions, such as suspensions or emulsions of the main ingredients, may contain common thinners 55 200524874, oil's and / or suspending agents such as polyethylene glycol and the like. Others can also be added (adjuvants, such as preservatives, flavoring agents, etc.) can be mixed with the auxiliary and / or agents used in conventional methods. For the preparation of solid dosage forms, the main ingredients can be combined with auxiliary _Mixed by traditional methods, and can be pulverized or dry granulated & granulated. And the particles or powder can be directly poured into capsules or pressed into cores by traditional methods. If necessary, The tablets may be coated.

[Embodiment] The purpose of the following examples is to further illustrate the present invention without limiting its scope. The mass spectrum is measured using the following methods:

HPLC_MS: API100 Quadrupol mass spectrometer (PE Applied Biosystems) connected to an LC200 pump (PE). Electron spray ionization (Electrospray ionis-ation), forward operation mode. The scanning range is from m / z to 1000. Software MassChrom 1.2. Xterra® column (4 · 6 mm X 50 mm, 2.5 m) Solvent system: water (10 mM ammonium acetate, pH 5) and cyanocyanine, linear slope from 5% cyanohydrin to 95% in 10 minutes

SiLLL ethyl-2-{[(3S) -l-({[l- (2-tertiary butoxy-2-oxoethyl) -2-oxo-2, 3,4,5-tetra Hydrogen_ι // _ ι_benzenecycloazepinetris_3 • fluorenyl] amino} carbofluorenyl) cyclopentyl] methyl 4- (isopropylamino) oxobutyrate

200524874 A) 9 L of 9 ml of benzalcohol was added to 99 07 g of itacic acid anhydride, and the mixture was subjected to 65 t at h). The crystals generated during cooling were made into mud with 35 ml of a mixture of n_hexane and 2 ^^ y, and the county was removed. The obtained was dissolved in 150 liters of diacetic acid in the warm state, and ribs were added to recrystallize. The combined mother test solution is in accordance with the above method: 70% of the obtained crystals are finally added to the main yield. Get 120 grams. : Methyl and 2-oxoethyl] propanoic acid, which is used directly in the next reaction without further purification, 1H-NMR (CDC13): 7.35, m, [5]; 6.47, s, [1] 5.83, s [n • chuan [2]; 3.40, s, [2] ppm. 'L' '·', B) 100 g of the benzyloxyoxoethyl] propionic acid obtained in the above was suspended in 100 ml of methyl tertiary butyl ether (= MTBE), and 05 ml of pyridine was added thereto. Then 47 ml of thiony chloride was added dropwise thereto, and the resulting mixture was heated under reflux for 1.5 hours to boil. After cooling to room temperature, it was evaporated to dryness under reduced pressure. The obtained residue was dissolved in 50 ml of dichloromethane and added dropwise to a receiver solution at 0 to 5 ° C. It consisted of 16 ml of ethanol and 36.5 ml of triethylamine in 150 ml. Composition in ml of dichlorofane. When the addition was completed, stirring was continued at about 0 ° C for 1 hour. Then, it was washed twice with 250 ml of water each time, once with 100 ml of a dilute sodium bicarbonate aqueous solution, and finally with a saturated common saline solution. The organic phase was dried over sodium sulfate and evaporated as much as possible under reduced pressure. The residue obtained by distillation at 0.015 mbar and 150 t: yielded 56.3 g of 2-methylenesuccinic acid 4-benzyl ester-1-ethyl ester, which was used directly without further purification or identification. Response in the next step. C) Dissolve 118 ml of diisopropylamine under nitrogen pressure 57 200524874 in 3 liters of dry tetrahydrofuran (= THF), and cool the solution to 0 ° C. 340 ml of 2.5 M n-butyllithium in n-hexane solution was added to the nanoreceptor solution, and after the addition was completed, stirring was continued at 0 ° C for 45 minutes. Then, a solution of 45 g of cyclopentanecarboxylic acid dissolved in 100 ml of dry tetrahydrocran was dripped into the resulting mixture at 0 to 5 ° C, and The mixture was then stirred at 0 ° C for 2 hours. Cool the mixture to -8 ° C, dissolve a 72.6 g 2-benzylidene succinate-4-benzyl ester-1-ethyl ester (from a total of several batches) as obtained above in 100 ml The solution formed by tetrahydrofuran was added dropwise. The mixture was then stirred at -75 ° C for 2 hours, and then 1.5 liters of 2N aqueous hydrochloric acid solution was added. After debinding and phase separation, the aqueous phase was treated with acetic acid. The extract was extracted twice with ethyl acetate (== ΕΑ), and the organic phases were combined and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the volatile substances were distilled by distillation at 0.02 mbar and 140 ° C. It was separated and removed. The residue after distillation was analyzed on silica gel (mobile phase: ethyl acetate / η-hexane: 1: 6 to 1: 7 v / v), and the result was 22.8 g of 1- [ 4- (Benzyloxy) -2- (ethoxycarbonyl) · 4-oxobutyl] cyclopentanecarboxylic acid; ^-NMR (CDC13): 7.33, m, [5]; 5.10, s , [2]; 4.04, m, [2]; 2.88, m, [1]; 2.80-2.48, AB-Q ·, [2]; 2 · 2-2 · 1, m, [2]; 1 · 7-1 · 4, m, [6]; 1.20, tr, [3]. D) 49.5 g of l- [4 · (benzyloxy) -2- (ethoxy) obtained as above base Carbofluorenyl) -4-oxobutyl] cyclopentanecarboxylic acid (from a total of several batches) was dissolved in 435 ml of dichloromethane. 39.5 grams of tertiary butyl _ [(38) _3_amino group_2_oxo-2, 3,4,5-tetrahydro] -1 //-benzenecycloazahexatriene-1_fluorenyl ] Acetate (refer to EP 0 733 642 A1 for preparation), 18.3 g of hydroxybenzotriazole and 60 ml of morphine were added to the receiving solution. 52 grams of EDCxHCl was then added to the resulting mixture in one portion, followed by stirring at room temperature 58 200524874 overnight. The solvent was then evaporated under reduced pressure, and the remaining residue was dissolved in 750 ml of ethyl acetate. The organic phase was washed twice with 100 ml of a 2N aqueous hydrochloric acid solution each time, twice with 100 ml of water each time, and once with 100 ml of a saturated common saline solution, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the remaining residue was dried under an oil pump vacuum (5 x 10 mbar) ', resulting in 87.9 g of 2 _ {[(38) -1 _ ({[((1- (2 -Tertiary butoxy-2-oxoethyl) -2_oxo-2,3,4,5-tetrahydrobenzenecycloazepine triamidine | alkenyl) amino] carbofluorenyl} cyclopentyl ) Methyl) succinic acid_4_benzyl @@-1-ethyl ester, which is a pale yellow oil, which is used directly in the next reaction without further purification or identification. Ε) 87.9 g of 2-{[(3S) -l-({[l- (2-tertiary butoxy-2-oxoethyl) -2-oxo-2, 3, 4, 5-tetrahydro-1 dissolves from 1-benzenecycloazepinetrien-3-enyl] amino} carbofluorenyl) cyclopentyl] methyl} succinic 4-phenylphenyl ester In 600 ml of ethyl acetate (= EA), and 20 grams of activated carbon palladium (Pd / C) was added thereto. The mixture was then hydrogenated under a hydrogen pressure of 1 bar for 2 hours, and then the reaction mixture was filtered on Cellite. The filtered cake was then washed with 1.5 liters of ethyl acetate, and the combined organic phases were evaporated in large amounts under reduced pressure. The residue was dissolved in 500 ml of ethyl acetate / cyclohexane (1: 1, v / v) and extracted twice with 200 ml of a half-saturated sodium carbonate solution each time. The aqueous phase was acidified with a concentrated potassium hydrogen sulfate solution and extracted three times with 200 ml of ethyl acetate. After drying on sodium sulfate, it was evaporated under reduced pressure. The remaining residue was dried under an oil pump vacuum, resulting in 71 g of 3-{[l-({[((3S) -1- (2-tertiary butoxy-2-oxoethyl) _2 _Oxo-2, 3, 4, 5-tetrahydrobenzylazepinetrien-3-enyl] amino} carbofluorenyl) cyclopentyl] methyl} -4-methoxy-4-oxy Butanoic acid, white foam; 1H-NMR (CDC13): 7.31-7.17, m5 [3]; 7.11, d, [0.5]; 7.08, d, 59 200524874 [〇 · 5]; 6.81, d [0.5]; 6.73, d, [0.5]. The intermediate product obtained in this case can be separated into the pure components of the cis-trans isomers by preparative high performance liquid chromatography (HPLC) if necessary. The 70 g of intermediate product obtained above was isolated using the following = separation. Column: LC80-1, 23.4 X 8 cm; Stationary phase: 74.0 g ChiralpakAD, 20 μ; Mobile phase: Heptane / isopropanol (μ: Er; UV detection analysis: Stationary phase: Chiralpak AD, 20 μ; Mobile phase · Heptane / isopropanol 9 · 1 (ν / ν); flow rate: 2 ml / min; cycle time · 15 minutes. When the retention time is 11.6 minutes, the first type is obtained 30 grams of stereoisomers, which is given the "reU" name, and is related to the _c00Rl = asymmetric center "* ca", which is a tertiary butoxy_2_ (Oxoethyl) _2_oxo_ 2,3,4,5-tetrahydro-1 // small benzene ring nitrogen trimethyl_3_fluorenyl] amino} carbofluorenyl) cyclopentyl] methyl } _4_ethoxy_4 · oxobutanoic acid; iH-NMR ^ CDClJ: 7.31_mm PI. 7.0 · 9, d, [1]; 6.74, d, [1]; 4.53, 4.48, 4.37, 4.32 , AB-Q ·, [2]; 4.48, m, [1]; 4.11, m, [1]. 5 When the retention time was 6.5 minutes, 33 grams of the second stereoisomer was obtained, given the "re12" name, and the asymmetric center "* Ca" carrying the _c〇〇〇i functional group "Related, the isomer is (3" rel2 ")-3-{[l-({[((3S) -l_ (2-secondary butoxy-2-oxoethyl) -2-oxo _2,3,4,5-tetrahydro-1 // small benzenecycloazetadiene-3-fluorenyl] amino} carbofluorenyl) cyclopentyl] ethylbuthyl 4-ethoxyloxy Butyric acid; 1H-NMR (CDC13) · 7.31-7.17, m, [3]; 7.11, d, [2]; 6.81, d, [1];

4.6054.56, 4.35, 4.31, AB-Q., [2]; 4.48, mJl]; 4.10, m Γ11 · "α1 I _136 ° (1% dissolved in methanol). ', 〇200524874 F) will 4 g of 3-{[1-({[(3S) -1- (2-tertiary butoxy_2_oxoethyl) -2-oxo-2,3,4,5- Tetrahydro-1 where 1-benzenecycloazepinetriene_3_fluorenyl] amino} carbofluorenyl) cyclopentyl] methyl} _4_ethoxy_4_oxobutanoic acid is dissolved in 15 ml of Dichloromethane. After the receiver solution is cooled to 0 ° C, 1.12 ml of triethylamine and 0.77 ml of ethyl chloroformate are slowly continued in a trickle manner. It was added thereto, and the mixture was stirred at 307 for 30 minutes. Then 0.94 ml of isopropylamine was added thereto, and stirring was continued at OOc for 3 hours. The solvent was largely evaporated under reduced pressure, and the remaining The residue was dissolved in 100 ml of ethyl acetate. The organic phase was washed once with 50 ml of a saturated aqueous solution of potassium hydrogen sulfate, once with a saturated common salt solution, and dried over sodium sulfate, and the solvent was Evaporated very much under reduced pressure. The retentate was threaded under a vacuum of oil f, which resulted in 4.29 g of the title compound as a pale yellow oil, MS: [M + H 广 586; m / z: 530; 484; 425. Example 2 · A 2-{[(3S) small ({[1- (carboxymethyl peak oxo_2,3,4,5_tetrachlorobenzenecycloazepine hexamethylene_3_diluted] amine group) _carbon Donkey) cyclopentyl] methyl M_ (isopropylaminobutyric acid

Add 9.97 g of ethyl 2 · ([⑽ small secondary butyl butyl-2-oxoethyl) _2 · oxo_2,3,4,5_tetrahydroxan benzene obtained from the above 1E) Cyclohexanehexamidine_3 · fluorenyl] amino} -carbofluorenyl) cyclopentyl] methyl} ice (isopropylamino) ice oxobutano salt dissolves in 20G ml of water / ethanol mixed solution ( 1: 1, v / v), and add 6 ingredients 61 200524874 grams of solid sodium hydroxide to it with stirring. Stirring was continued overnight, and the solvent was evaporated in large amounts under reduced pressure, and the remaining residue was dissolved in 100 ml of ethyl acetate. This aqueous phase was neutralized with a saturated aqueous solution of potassium hydrogen sulfate and extracted three times with ethyl acetate. The combined organic phases were washed with 100 ml of a saturated common saline solution and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the remaining residue was dried under oil pump vacuum, resulting in 5.59 g of the title compound. Example 3: (2 "rell")-2 _ {[(3S) -l-({[K carboxymethyl) -2_ oxo-2,3,4,5-tetrahydro-1 / M · benzene ring nitrogen Hexamidine_3_alkenyl] aminocarbanyl) cyclopentyl] methyl} _4- (isopropylamino) -4-oxobutanoic acid

400 mg of the cis-trans isomer mixture obtained in the above Example 2 was separated by HPLC according to the method described below: column: LC80-1, 25x8 cm; stationary phase: ChiralpakAD, 20 μ; mobile phase: heptane / Isopropanol 85: 15 (ν / ν) + 0.1% ν / ν trifluoroacetic acid (= TFA); UV detection, flow rate · 1 ml / min; cycle time · 15 minutes; analysis · · column · · DAICEL Chiralpak AD; Length: 250 mm; Diameter: 4.6 mm; Mobile phase: 800 ml of n-heptane, 200 ml of propanol, 2 ml of trifluoroacetic acid; Flow rate: 0.8 ml / min; Analysis time: 3 minute. 62 200524874 When the retention time was 13.5 minutes, 130 mg of the first stereoisomer (= title compound) was obtained under these conditions, given its "reli" name, and carrying -C00R1 The asymmetric center "* Ca" of the functional group is related to a white solid, which is precipitated from EE; W-NMR (methanol): 7.37-7e2, m, [4]; 4/76, 4 · 71, 4.43, 4 · 38, AB-Q ·; 4.4, m, [1]; 3.90, m, [1]; 3.40, m, [1]; 2.22-2 · 60, m, [2]; 2.48- 2.0, m, [12]; U〇, d, [6]; [α] B = -90 ° (0.5% in methanol); melting point: 145 ° C. When the retention time was 16.2 minutes, the second stereoisomer was obtained under these conditions, given the "re12" name, and the asymmetric center "* Ca" carrying the _c〇〇〇i functional group "related. Example 4: {(38) -3-[({1-[(2 "Generation 11")-2- (ethoxycarbamido) -4- (isopropylamino) _4-oxobutyl]% Pentylbucarboxenyl) amino group] _2 · oxo_2,3,4,5 · tetrahydro] private-1_benzenecycloazepinetrien-1-diyl} acetic acid

4.29 g of ethyl tertiary butoxy-2-oxoethyl) -2 • oxo-2,3,4,5-tetrahydro-1 //-1-phenylcycloazepinetriene-3 _Fluorenyl] amine} amyl)% pentyl] methyl 4- (isopropylamino) -4-oxobutanoate (prepared following Example 1 but separated from that obtained by HPLC (3 " rell ,,)-3-{[lW [(3S) _ l- (2-secondary butoxy-2-oxoethyl) -2-oxo-2,3,4,5-tetrahydro- 1 / 7-1-benzene ring nitrogen 63 200524874 Hexatriene-3-enyl] amino} Carbofluorenyl) cyclopentyl] methyl} _4_ethoxy_4_oxobutanoic acid as a step 1E intermediate product), dissolved in 30 ml of digas methane, and ^ ml of trifluoroacetic acid was added. The mixture was left overnight, and then the solvent and excess trifluoroacetic acid were evaporated under reduced pressure. The remaining residue was dissolved In 100 mM ethyl acetate, while the organic phase looks at the silk until it becomes pH-stable. The organic phase is placed in sulfuric acid ^, bright, and the reducing agent evaporates in a very large amount under reduced pressure. 30mmol ^^ each Added to the residue and the mixture was evaporated again under reduced pressure, and the remaining residue was exposed to oil and vacuum under vacuum, resulting in 2 · 8 males, which were white foam; 1h_nmr 7 6.825d? [1]; 5.86 η m,? LJ? 3.20, m, [1]; U3 ^ 1]; 4 · 4 ^ 4 * 42 > AB'Q ^ product, Pj, 1.09, [6]; [a] D: · 155 (1/10/0 dissolved in methanol). ^ ^ T ^ ^ Miqi, photo field, wind, cyclazine, and hydrazine] amine group} carbon soil soil group P4 _ [(3. Hydroxypropyl) amino] -4-oxobutanoate.

Amidyl) cyclopentyl] methyl'tetratyl nitrogen nitrogen CL allyl] amine} inverse isomers are mixed, for example, "" Amidino substituted for acid (preparation of cis according to Example 1E), then HPLC was used. The method was used to isolate the cis-trans isomer.) 64 200524874 was dissolved in 30 ml of dichloromethane. U7 ml of 3-amino-propanol, 235 mg of dimethylaminopyridine and 1.61 g of EDC were dissolved. The stirred solution was added to the receiving solution. After 1 hour, the mixture was largely evaporated under reduced pressure, and the remaining residue was dissolved in 100 ml of ethyl acetate, and the organic phase was diluted with 30 ml each time. Extracted twice with a hydrogen sulfate aqueous solution. The organic phase was washed twice with 30 ml of a saturated common saline solution again, and dried over sodium sulfate, and then the solvent was evaporated in a very large amount under reduced pressure. The remaining residue was evaporated. Drying under Yuzenpo's vacuum resulted in 4 g of the title compound as a white foam resin, MS: [M + H] +: 602; m / z: 546; 500; 425; ^ -NMR (CDC13): 7.32-7.18, m, p]; 7.12, d, [2]; 6.63, d, [1]; 6.49, tr, [1]; 4.57, 4.63, 4.34, 4.30, AB -Q · [2]; 4.51, m , [1]; 4 · 11, m, [2]; 3.57, tr, [2]. Example 6 · Ethyl (2 "rdl ',)-4-{[3_ (ethoxy) propyl" ] Amine group 2 _ {[1 _ ({[(38) -1_ (2-tertiary butoxy-2-oxoethyl) -2_oxo-2,3,4,5-tetrahydro-111_1 -Benzenecycloazetadiene · 3-alkenyl] amino} carbofluorenyl) cyclopentyl] methyl} 4-oxobutyrate.

1 gram of ethyl (2 "reii ,,) _ 2-{[i-({[(3S) _1- (2-tertiary butoxy-2-oxoethyl) obtained from Example 5 above was removed from oxo _2,3,4,5_tetraammonium guabbenzenecycloazahexadien-3-enyl] amino]} carbofluorenyl) cyclopentyl] methyl] _4 # 3_hydroxypropane The aminoaminoglacial oxobutyrate was decomposed in 20 ml of dichloromethane, and the acetic acid was added to it. After 90 minutes, a large amount of the solvent was evaporated under reduced pressure, and the remaining The residual material was dissolved in 20 ml of dichloromethane and washed with 10 ml of a dilute aqueous solution of sodium bicarbonate. It was then dried over magnesium sulfate, and the solvent was evaporated in a very large amount under reduced pressure, and the remaining residue The material was subjected to chromatographic analysis on silica gel (mobile phase: ethyl acetate / η-hexane 7: 3 v / v). A portion of the product was dried under oil pump vacuum (5 X 1 (Γ2 mbar), The result was 920 g of the title compound as a colorless oil, MS: [M + H]: 644; m / z: 588; 542; 482; 425. Example 7: {(3 "rell ,,)-3 -[({H (2SH _ {[3- (Ethyloxy) propyl] aminophenyl 2- (ethoxycarbamido) -4-oxobutyl] cyclopentyl} Acyl) amino] -2-oxo-2,3,4,5-tetrahydro -1H-1- phenyl ring nitrogen hexatrienyl -1- associative yl} acetate

929 mg of ethyl (2 "substituted 11 ,,)-4-{[3- (ethoxy) propyl] amino} -2 _ {[l-({[(3S ) Small (2-tertiary butoxy_2_oxoethyl) -2-oxo-2,3,4,5-tetrahydro_111_1_benzenecycloazettriene_3_alkenyl] amine Group} Carbofluorenyl) -cyclopentyl] fluorenyl} -4-oxobutanoate was dissolved in 10 ml of dichloromethane, and 2.2 ml of trifluoroacetic acid was added thereto. The mixture was added Allow to stand overnight, then the solvent is evaporated under reduced pressure, and the remaining residue is dissolved in 30 ml of ethyl acetate. The organic phase is washed with water until it becomes pH neutral, and evaporated again under reduced pressure. The remaining residue was fumigated twice with 10 ml of toluene each time. 66 200524874 Result: 750 mg of the title compound was obtained as a white foam resin. MS: [M + H] ·· 588; m / z: 542, 482, 425; b-NMR (CDC13): 7.33-7 · 14, m, [4]; 6.67, d, [1]; 6.59, ti *, [1]; 4.69, 4 · 64, 4.35, 4.30, AB-Q ”[2]; 4.63, m, [1]; 4.17, m, [1]; 4.09, q, [2]; 3.33, m, ⑴; 3. · 15, m, [2]. Example 8: ((3S) _3] [(H2 "relΓ ')-2-ethoxycarbamyl) -4-[(3_hydrooxypropyl) amino] _4 · oxobutyl] ring Amyl} _carbofluorenyl) amino] oxo_2,3,4 > tetrahydrobenzenecycloazepine hexamethylene_ 丨 _fluorenyl 丨 acetic acid.

580 mg of ethyl (2 ,, rdl ,, bu Xiao (2-tertiary butoxyoxoethyl > 2-oxo_2,3,4,5-tetrahydro_111-1-benzene Cyclohexanehexamidine_3-fluorenyl] Wenyl 丨) Carbonyl) Cyclopentyl] methyl] -4-[(3-Hydroxypropyl) amino-4-oxobutanoic acid Please refer to Example 5) to interact with trifluoroacetic acid as described in Example 4 above. After purification of the resulting crude product by column chromatography (stationary phase: silicone; mobile phase: ethyl acetate / methanol 9: 1 (v / v)), the title compound was obtained as a colorless resin. , 1H-NMR (CDC13): 7.34_7 · 15, m, [4]; 6.76, tr, [1]; 6.61, d, [1]; 4.75, 4.71, 4.20, 4.16, 々 ·, [2]; 4.57, called [1]; 4.09, q, [2]; MS: [M + H] +: 546; [a] D = soluble in methanol). Example 9: 67 200524874 Amino] -4-oxobutanoic acid 2-{[l-({[((3S) -1- (carboxymethyl) _2 • oxo_2,3,4,5_tetraammonium Cargo small benzene ring nitrogen trimethyl amidinyl] amine [carbofluorenyl] cyclopentyl] methyl} ice [(3-hydroxyoxypropyl)

6.43 grams of ethyl (gang-⑴Kunfu tertiary-butoxy-Chloroethyl) -2-lacto-2,3,4,5-tetrahydrobenzene Alkyl] Amine} Cycyl) Cyclopentyl] Methylbrphine · Hydroxypropionyl M · Oxobutyrate (v / v), and 4.28 g of solid sodium hydroxide was added thereto with stirring. After 15 hours, the solvent was evaporated under reduced pressure, and the residue was dissolved in 10 ml of ethyl acetate and washed with 50 ml of an aqueous sodium hydrogen sulfate solution. The aqueous phase was extracted twice with 30 ml of ethyl acetate each time. The combined organic phases were washed twice with 30 ml of common saline solution each time and then dried over sodium sulfate. Evaporation of the solvent gave 5.41 g of the title compound. Example U: carboxymethyl) -2 • oxo-2,3,4,5-tetrahydrobenzenecycloazepinetrien-3-enyl] amino} carbofluorenyl) cyclopentyl] methyl}- Zμ [(3-Hydroxypropyl) amino] -4-oxobutanoic acid 68 200524874

800 mg of the isomer mixture obtained in Example 9 above was separated by HPLC according to the method described below: Stationary phase: Nucleosil 100-10; column · 250 mm in length, 20 mm in diameter, flow rate: 8 ml / Minute; mobile phase: n-heptane (800 ml), 2-propanol (200 ml), trifluoroacetic acid (1 ml). Analysis: stationary phase: EC 250/4 Nucleosil 100-10; column: 250 mm in length, 4 mm in direct control; flow rate: ι · 5 ml / min; mobile phase: Bu Gengxi (800 ml, 2 propanol (200 ml), trifluoroacetic acid (; [ml).

When the retention time was 7.89 minutes, 200 mg of the first stereoisomer (= title compound) under these conditions was obtained, given the "rreu" name, and the one carrying the "-COOR1" functional group Asymmetry center "* ca" is related; ^ NMR (CD3OD): 7.38, m, [4]; 4.78, 4.73, 4.43, 4.38, AB-Q "[2]; 4.41, m, [1] 3.93, m, [1]; 3.56, tr, [2]; 3.40, m, [1]; 3.31, m, [1]; 3.22, m, [2]; 2.78, m , [L]; 2.65, m, [1]. 'When the retention time is 4.47 minutes, the second stereoisomer under these conditions was obtained, given the name "re12", and carrying " -C〇〇Rl ^ Asymmetric center of the functional group "* Ca" is related. Example 11: 2-{[l-({[((3S) _l- (2-ethoxy_2_oxoethyl) -2 • oxo-2,3,4,5_ tetragas-1 //- 1-Cyclopentylhexamidine-3-fluorenyl] amino} carbonate) cyclopentyl] methyl 69 200524874 Hydroxypropyl) amino] -4-oxobutanoic acid

800 grams of (carboxymethyl) oxo-2,3,4,5_tetrahydro-1 // heptaphenazine trimethyl_3_fluorenyl] amino group obtained according to Example 9 above} Carbofluorenyl) pentyl] fyl} -4-[(3-hydrooxypropyl) amino] -4-oxobutanoic acid (isomer mixture) dissolved in 15 ml of dimethylformamide (= DMF). 300.5 mg of cesium succinate (CszCO3) and 169 mg of ethyl bromide were added to the receiving solution at room temperature with stirring. After stirring overnight, it was diluted with 42 ml of water and 21 ml of dichloromethane, and the aqueous phase was extracted with dichloromethane. The solvent was largely evaporated under reduced pressure, and the residue was separated by column chromatography (stationary phase: silica gel; mobile phase ·· ethyl acetate (100%) vs. EE / methanol 7.3080). A portion of the product was dried under oil pump vacuum (5 X 10 * " 2 mbar), which resulted in 241 g of the title compound as a foamy resin 'MS: [M + H] +: 546; m / z: 453, 425, 379; 1H-NMR (CDC13): 7.34-7.1, m, [4]; 4.82, 4.77, 4.34, 4.29, AB-Q- · [2]; 3.62, m, [2]; 3.37, m, [3]. Example 12: 2-{[l-({[(3S) -l- (2-tertiary butoxyoxoethyl) -2-oxo_2,3,4,5-tetrahydro-1H small Benzazepine, hexamethylenetrien-3-enyl] aminocarbinyl) cyclopentyl] methyl} -4- (isopropylamino) -4-oxobutanoic acid 200524874

2.6 grams of ethyl 2-{[(3S) -l-({[l- (2-tertiary butoxy-2-oxoethyl) -2-oxo-2,3,4,5 -Tetrahydro-1 //-1-benzene edge azadiphenyl-3-enyl] amino group} carbon group) cyclopentyl] methyl (isopropylamino) glacial oxobutanoic acid Example 1) Dissolved in 52 ml of ethanol. A solution consisting of 710 mg of solid sodium hydroxide in 52 ml of water was added to the receiving solution. After 30 minutes, the solution was acidified with a dilute aqueous potassium hydrogen sulfate solution to a pH of about 2, and the aqueous phase was extracted three times with 50 ml of ethyl acetate each time. The combined organic phases were dried over magnesium sulfate, the solvent was evaporated in large amounts under reduced pressure, and the remaining residue was subjected to chromatography on a silica gel (mobile phase: ethyl acetate / cyclohexane 2: 1 v / v). The product portion was dried under oil pump vacuum (5 X 10-2 mbar), which resulted in 2.2 g of the title compound as a white foam resin, MS: [M + H] +: 558; m / z: 502, 425, 397, 323 〇 Example 13: 4-chlorobenzyl-2-{[1- ({[(3 S) _ 1 _ (2-tertiary butoxy_2-oxo (Ethyl) -2-oxo-2,3,4,5-tetrahydro-1 1-benzenecycloazahexatriene-3-fluorenyl] amino} _carbofluorenyl) cyclopentyl] methyl } -4- (isopropylamino) -4-oxobutyrate

71 200524874 300 mg of 2-{[i-({((3S) small (2-tertiary butoxy-2-oxoethyl) -2-oxo_2,3,4 , 5-tetrahydro-1 / 7-1-benzenecycloazepinetris_3_alkenyl] amino} carbofluorenyl) cyclopentyl] methyl} -4- (isopropylamino) · 4-oxo Butanoic acid was dissolved in 5 ml of dichloromethane. 33 mg of 4-dimethylaminopyridine (= DMAP), 85 mg of 4-chlorobenzyl alcohol, and 124 mg of EDC X HC1 were added to the solution 'and then stirred overnight. The mixture was diluted with 5 ml of dichloromethane, and the organic phase was washed once with 2 ml of a dilute aqueous potassium hydrogen sulfate solution and with a saturated common salt solution. The organic phase was dried over magnesium sulfate, and the solvent was evaporated to dryness under reduced pressure. The remaining residue was subjected to chromatography on a silica gel (mobile phase: ethyl acetate / cyclohexane 3: 2). v / v). The product portion was dried under a vacuum from Youbaopu (5 X 1 (T2 mbar)). As a result, 32 g of the title compound was produced. / z: 626/628; 576, 484, 425. Example 14: {(3S) -3-[({l- | > {[('chlorobenzyl) oxy] carbohydrazine 4- ( Isopropylamino) -4-oxobutyl] cyclopentyl} carbofluorenyl) amino] _2_oxo_2,3,4,5_tetrachlorobenzenecycloazahexatriene-1-ene Acetyl

318 g of 4-chlorobenzyl_2 _ {[le ({[((3S) -1- (2-tertiary butoxy-2-oxoethyl) -2-oxo- 2,3,4,5-tetrahydro-1′1-phenylcycloazahexatrien-3-enyl] amino group hinderyl) cyclopentyl] methyl group 4- (isopropylamino) Ice oxygen 72 200524874 The butyrate was dissolved in 11 ml of dichloromethane, and 108 ml of trifluoroacetylphthalein was added to the solution, and the mixture was subjected to overnight drop. The solvent was then evaporated under reduced pressure, and the remaining residue was dissolved in 10 ml of ethyl acetate. The organic phase is washed with water until it becomes pH neutral. The solvent was then evaporated again under reduced pressure, and the remaining residue was fumigated i times with 5 ml of toluene. As a result, 305 mg of the title compound was obtained as a white foam resin. MS: [M + H] '· 626/628; m / z: 657, 484, 425 〇 Example 15: 〇methoxyethoxy) methyl Tertiary butoxy_ ^ oxoethyl) -2-oxo_2,3,4,5-tetrafluorenylbenzeneazepine triammon-3-enyl] amino} carbofluorenyl) cyclopentyl ] Fluorenyl} -4- (isopropylamino) oxobutanoic acid

300 ¾: grams of 2-{[l-({[(3S)]-(2-tertiary butoxyoxoethyloxo-2,3,4,5_tetrahydrotal 1-benzene ring nitrogen Hexatriol_3_woyl] amino} _carbofluorenyl) cyclopentyl] fluorenyl} ice (isopropylamino) glacial oxobutanoic acid (for example, please refer to example ⑵ for hydrolysis for 5 liters < Dichloromethane. 33 mg of DMAP '74 μΐ <methoxyethoxychloromethane and 90% triethylamine were added to the receiver solution. The reaction was mixed and stirred overnight, then Released with 5 ml of dichloroform, and the organic phase was successively washed with 3 ml of a dilute aqueous solution of sulfuric acid and a saturated common saline solution = 1. The organic phase was placed on _magnesium, and the amount was very large under reduced pressure. The ground was dried to dryness, and the residue of tritium was subjected to chromatographic analysis on tritium (mobile phase: ethyl acetate / cyclohexylhydrazone 2: 1 ,. The product was partially vacuumed in oil pump 73 200524874

After drying, the result is 191% of toast. ^ A Brother ’s private title compound, MS: [M + H] +: 646; m / z: 590, 540, 484, 425 〇 Example 44 ethyl (2 rell) _2 _ {[ι Said that 3S is called 2_ethoxy oxoethylated oxygen ^^, tetrahydro-cabenzylcyclohexane, hydrazine, each fluorene, carbocyclopentyl] methyl} dong [(3-hydrogen Oxypropyl) amino] glacial oxobutyrate

140 mg of {(3s) _3 _ [({1 _ [(2 "reii ,,) _ 2_ (ethoxycarbamoyl) 4 (isopropyl &gt; ylamino &gt; 4-oxobutyl] cyclopentyl (Carbocarbyl) amine oxo-2'3'4,5_tetrahydro_1 // _ 1_benzidine nitrogen trimethyl_1_fluorenyl} acetic acid (see Example 4 for preparation) bath Dissolve in 3 ml of ethanol towel, add 5 drops of concentrated sulfuric acid to the solution towel, and cook the mixture at room temperature for 2 days._ Then evaporate a large amount under reduced pressure, the remaining residue will dissolve In 5 ml of ethyl acetate. The organic phase was shredded 2 times with 2 ml of bisulfate solution. After the thiosulfate was added, the solvent was dried under reduced pressure, and the residue was colored on the gum. Layer analysis (mobile phase · ethyl acetate / cyclohexane 8: 2 (v / v). As a result, 46 mg of the title compound was obtained as a white foam, Ms: [M + H] +: 574; m / z : 528, 323; 1h_Nmr (CDC13): 7 · 33-7 · 11, m, [4]; 6.69, m, [1]; 6.44, m, [1]; 4.79, 4 · 75 4.34, 4.30, AB -Q '[2]; 4.48, m, [1]. The compounds of the general formula listed in Table 9 below can also be based on the methods described in the above examples or similar to them. Process Preparation: 200524874 Disk 2: Other compounds of general formula i Example number R1 R2 R3 R4 c * Structure cb * Structure [M + H] + 16 Η Η Methoxyethyl Η Racemic S 518 17 Η Η 3 -(2-oxoazepanyl) Η racemic S 571 18 ethyl- (ch2) 2-ckch2) 2- Η racemic S 558 19 Η-(C h2) 2-o- (ch2) 2 · · Rell S 20 Η Η 4-methoxyphenyl-2-oxoethyl Η racemic S 608 21 Η Η 3-oxo, 1,1-dimethylbutyl Η ΗS 558 22 Η 苯基 phenyl-2- OxoethylΗ Η S 578 23 Η Η Cyclopropanemethyl Η Η S 514 24 Η Η 4-methoxyphenyl 曱 曱 Η 旋 S 580 25 Η Η 4-methoxyphenethylΗ Η Η S 594 26 Η Η 2-methoxybenzyl Η racemic S 580 27 Η Η benzyl Η racemic S 550 28 Η Η methyl Η racemic S 474 29 ethyl Η 2- (4-methyl (Oxyphenyl) -2-oxoethyl Η racemic S 636 30 ethyl Η methoxyethyl Η rell S 546 31 Η Η 2-methoxybenzyl Η racemic S 580 32 Η methyl Isopropyl hydrazone S 516 33 ethyl hydrazone 3,4-dimethoxybenzyl hydrazone S 638 200524874 34 ethyl hydrazone cyclopropyl hydrazone S 528 35 Et Η 2-HydroxyethylΗ Η S 532 36 Et Η 4-methoxybenzylΗ Η S 608 37 Et Η 1-naphthylmethylΗ Η S 628 38 Et Η 4 -Methoxyphenethyl hydrazone S 622 39 isopropyl hydrazone isopropyl hydrazone S 544 radical 40 n_ butyl isopropyl hydrazone S 558 radical 41 Η isopropyl methoxy racemic S 590 Ethylethoxymethyl 42 2-chlorofluorene isopropyl hydrazone S 627 benzyl 43 fluorenyl 2-nitrooxyethyl hydrazone S 518 44 see above 45 45-(ch2) 2_co_ (ch2 ) 2- ΗS S 542 46 Et-(CH2) 2-CO- (CH2) 2- ΗS S 570 47 Et-(CH2) 2-N (Bn)-(CH2) 2- ΗS 647 48 Et-(ch2) 2-s- (ch2) 2- Η Racemic S 574 49 Η-(ch2) 4- Η Racemic S 514 50 Η-(CH2) 3-CH (CH2-OH)-Η Racem S 558 ch2- 200524874

51 Η Methyl-CH2- (CHOH)-ch2oh Η Racemic S 548 52 乙基 Ethyl- (ch2) 3-nh -c2H5 Η Racemic S 573 53 Et 2-Azoethyl-2-chlorooxyethylΗ Racemic S 576 54 Η Methyl methyl Η Racemic S 488 55 Η Ethyl ethyl Η Racemic S 516 56 Η Methyl 3-chlorooxypropyl Η 旋 S 532 57 Η-(CH2) 2-CH (OH)-(CH2) 2- Η Racemic S 544 58 Η 2-Hydroxyethyl 2-hydrooxyethyl Η Racemic S 548 59 Η Methyl- (ch2) 2_n (ch3) 2 Η rell S 545 60 Η methyl- (CH2) 3-N (CH3) 2 Η racemic S 559 61 Et-(CH2) 2-CH (-0-valine)-(CH2) 2- Η racemic S 671 62 Et methyl -(CH2) 3-0-valine Η Racemic S 659 63 Η Methyl isopropyl Η rell S 516 64 甲基 Methyl- (CH2) rN (CH3) 2 Η rell S 559 65 Η Methyl- (CH2) rNH2 Η Racemic S 531 66 Η-(CH2) -0- (CH2) 2 Η Racemic S 530 67 Η Ethyl_ (CH2) 3 Ma Η Racemic S 68 Η Methyl- (ch2) 2_nh (ch3) Η Racemic S Table 9 continued: rac = racemic; Bn = benzyl 200524874 Example 69: tertiary butyl 2-{[l-({[(3S) small (2-tertiary butoxy 1 oxo (Ethyl) -2-oxo-2,3,4,5-tetrahydro-1 // small benzenecycloazetadienetrifluorenyl] amino} carbofluorenyl) ring Yl] methyl Ji Bu 4- (4 • piperidin hydroxide small enyl) oxobutanoate

(

A) 100 grams of 2-[(2-benzyloxy) -2-oxoethyl] propionic acid (see Example 1A for preparation) and 47 ml of thionyl chloride, 43 ml of three Butanol and 110 ml of pyridine were reacted with each other according to the method described in Example 1B), which resulted in 69.8 g of 2-methylenesulfinyl-4-benzyl-1-tert-butyl ester, [ M + H] +: 277. B) 29.6 g of 2-methylene succinic acid-4-benzylhydrazone-1-tertiary-butyl ester and 41.4 ml of diisopropylamine, 200 ml of 1.6 M n- A solution of butyl li (n-butyllithium) in η-hexane and 12 milliliters of cyclopentanosinic acid react with each other according to the method described in Example 1C), resulting in 24.5 grams of 1_ [4- (benzene (Methyloxy) _2_ (tertiary butoxy carbofluorenyl) oxobutyl] cyclopentanecarboxylic acid. c) g of benzyloxy) _2- (tertiary butoxy carbon) obtained from the above-mentioned 4-oxobutyl] cyclopentanecarboxylic acid and 1175 g of tertiary butyl _ [( 3S) -3_ (Amine_2_oxo ^, diazepam, benzocycloazepine, tris- small alkenyl) acetate (for preparation see EP 0 733 642 A1) according to 78 in Example 1D) 200524874 The methods described react with each other, resulting in 21 g of tertiary butoxy_2_oxoethyl) -2-oxoj, 3,4,5-tetraargine-1 //-benzenecycloazepine Ene-3-fluorenyl] amino} carbofluorenyl) cyclopentyl] methyl} benzyl succinate + tert-butyl ester. D) 21 grams of 2 _ {[(3S) -1-({[1_ (2-tertiary butoxy-2-oxoethyl) -2-oxo_2,3,4 , 5-tetrahydro-1 //-benzenecycloazepinetrisamidine-3-fluorenyl] amino} carbofluorenyl) cyclopentyl] methyl} 4-benzyl succinate ο-tertiary butyl The ester was treated with 6 grams of activated carbon (paiia (jium on activated carbon) according to the method described in Example 1E), and hydrated for 12 hours under a hydrogen pressure of ι · 3 bar, resulting in 10 grams of 4- Tertiary butoxy_3 _ {[l-({[(3S) -l- (2-tertiary butoxy-2-oxoethyl) _2_oxo_2,3,4,5-tetra Hydrogen_1 // small benzenecycloazepinetriene_3-fluorenyl] amino} carbofluorenyl) cyclopentyl] methyl} _4_oxobutanoic acid; MS: [M + H] +: 573; m / z: 517, 461; b-NMR (CDC13): 7.31-7 · 17, m, [3]; 7.10, m, [1]; 6.80, d, [0 · 5]; 6 · 72, d, [0 · 5]; 4.60-4.30, m, [3]; 3 · 30, m, [0 · 5]; 3.17, m, [0 · 5]. Ε) will be 1 · 11 grams of 4-tertiary butoxy obtained from the above 3-3-[[1 _ ({[((3S) _1_ (2-tertiary butoxy-2-oxoethyl> &gt; 2-oxo-2 , 3,4,5_tetrahydro small benzenecycloazepinetris_3_alkenyl] amino} carbofluorenyl) cyclopentyl] fluorenyl} glacial oxobutanoic acid dissolved in 7.8 mmol 2,000 μΐ of triethylamine was added to the dichloromethane. When cooled to 0.0 in an ice bath, 222 μΐ of ethyl chloroformate was added dropwise to the receiving solution. The mixture was stirred for 30 minutes, and then 216 mg of 4-hydropiperidine was added to the solution, followed by stirring the mixture overnight. The mixture was diluted with ethyl acetate, and washed with an aqueous potassium hydrogen sulfate solution and brine. The organic The layer was dried over magnesium sulfate, and column chromatography was performed on silica gel (liquid phase: ethyl acetate / cyclohexane 1: 1 (ν / ν), changed to pure ethyl acetate, and changed to acetic acid. Ethyl ester / methanol 4: 1 (v / v)), which resulted in 550 mg of the title compound as a white 79 200524874 colored foam. MS: [M + H] +: 656; m / z: 425, 397, 323. Example 70-A 2-{[1-({[1- (Suptilylmethyl) -2_oxo-2,3,4,5-tetrazol-1 //-1_benzenecyclohexane Triamidine-3-fluorenyl] amino} carbofluorenyl) cyclopentyl] methyl} _4_oxo-4_ [4_ (L_valaminefluorenyloxy) -Hydroxy-I-Foyl] butanoic acid

A) 548 mg of tertiary butyl 2 _ {[[(((38) -1- (2-tertiary butoxy_2_oxoethyl) _2_2oxoethyl_2) , 3,4,5-tetrahydro • 1 / M-benzenecycloazepinetrienyl] amino group} carbofluorenyl) cyclopentyl] methylbudong (dongguanoxypiperidine_1_fluorenyl) 4-oxobutanoate was dissolved in 3 ml of dichloromethane. To this solution were then added 51 mg of DAMP, 182 mg of BOC-L-valine acid, and 176 mg of EDC. After stirring for 3 hours, the mixture was diluted with ethyl acetate, followed by washing with an aqueous potassium hydrogen sulfate solution and brine. The organic layer was dried over magnesium sulfate, and column chromatography was performed on Shixi gum (liquid phase: ethyl acetate / cyclohexane 1: 1 (v / v), changed to pure ethyl acetate) The result was 551 mg of 1- (4-tertiary butoxy) -3-{[l-({[((3S) -1- (2-tertiary butoxy-2-oxoethyl)- 2-oxo_2,3,4,5-tetrahydro_1H small phenylcycloazahexatrienyl (Wife)] amino} carbofluorenyl) cyclopentyl] methyl} -4-oxobutanyl) piperyl Pyridin_4-alkenyl_N- (tertiary butoxy carbofluorenyl) &gt; L_valinate, MS: [M + H] '· 855; m / z: 699, 6425, 425, 397, 323, 235. B) 551 mg of the above-obtained 1- (4-tertiary butoxy 200524874 group H-{[l-({[(3S) -l- (2_ tertiary butoxy-2 -Oxoethyl &gt; 2-oxo_2,3,4,5-tetraki_1 Η-1-benzenephosphine nitrogen hexadiene-3 · enyl] amino} carbo) cyclopentyl ] Methylbu 4-oxobutyryl) Lvdo-4-enyl (tertiary butoxy carbon cracking group) -L-methanine was dissolved in 14 ml of dichloromethane and the solution was received Add 1.49 ml of trifluoroacetic acid. After stirring overnight, the solvent and excess acid are evaporated under reduced pressure. To the remaining residue is added ethyl acetate. Ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate until the pH reached 4. The aqueous layer was then extracted 3 times with ethyl acetate, and the combined organic layers were dried over magnesium sulfate. Evaporated under reduced pressure This solvent was then dried under oil pump vacuum to obtain 310 mg of the title compound as a white foam. MS: [M + H]: 643; m / z: 425, 397, 323 Example 71: Tertiary butyl 2-{[l _ ({[((3S) _l- (2_ethoxy_2_oxoethyl) -2-oxo_2,3,4,5-tetra Hydrobenzyl hexazinetris (3_alkenyl) amino group} carbofluorenyl group) cyclopentyl group] methyl} _4_ [Xingpropyl (methyl) amino group] «4-oxobutyrate

A has mixed 20 grams of diphenylbenzyloxy ... king butoxy carbodonyl) + lactobutyl] cyclopentanosuccinic acid (for preparation see Example 69B)) and 13.4 a gram of ethyl [[Battle 3_amino group 2_oxo_2,3, pyrazine tetrahydro] from benzazine, trimethyl and 1-methyl] acyl salt (prepared according to the method described in Ep 〇733⑷M) according to 200524874 Example ID) Interacted with each other, resulting in 28 · 6 g of winter benzyl · 1-tert-butyl_2 _ {[1 _ ({[((3S) 小 (2_ethoxy- 2_oxoethyl) winter oxo 2,3,4,5-tetrahydro-lΗ-l-benzenecycloazahexatriene-3 · alkenyl] amino} carbofluorenyl) cyclopentyl] A Succinate. B) 2 &amp; 6 grams of the 'phenylfluorenyl small tertiary butyl-2-{[l-({[(3S) _; U (2-ethoxy_2_oxoethyl) &gt; 2 Oxo-2,3,4,5_ tetrahydro • 1H small benzenecycloazetadiene_3_fluorenyl] amino} carbofluorenyl) cyclopentyl] methyl} succinate according to Example 1E) The method described in the above was treated with 5 grams of activated palladium (palladium on activated carbon) and hydrogenated to hydration under a hydrogen pressure of 23 bar for 4.5 hours, resulting in 16 grams of 4_tertiary butoxy_3- {[H {[(3S) Small (2-ethoxy_2_oxoethyl) _2_oxo_2,3,4,5tetrahydro-1 //-1-benzenecycloazepinetriene Alkenyl] amino group carbofluorenyl) cyclopentyl] fluorenyl 4 • oxobutanoic acid, [M + H] +: 545; m / z: 489. C) 3 grams of 4-tertiary butoxyethoxy-2-oxoethyl) _2-oxo_2,3,4,5-tetrahydro_1good_1_benzene ring nitrogen Hexatriene-3-fluorenyl] amino} carbofluorenyl) cyclopentyl] methyloxobutanoic acid was reacted with 859 μΐ of methyl isopropylamine according to the method described in Example 1F), As a result, 1.6 g of the title compound was obtained as a white foam. MS: [m + h] +: 6〇〇; m / z: 544 〇 Example 72 2 _ {[H {[(3S) _1_ (2-ethoxy Group j · oxoethyl) _2_oxo-2,3,4,5_tetrahydro-1 //-1-benzenecycloazepine di-3-fluorenyl] amino} carbofluorenyl) ring Amyl] methyl 4- [isopropyl (methyl) amino] -4-oxobutanoic acid

200524874 507 g of tertiary butyl 2-{[1-({[((38) _1 | ethoxy_2 · oxoethyl)) ethoxy-2,3,4 obtained in Example 69 , 5-tetrahydrobenzenecycloazepine tris (fluorenyl) amino} carbofluorenyl) cyclopentyl] methyl} ice [isopropyl (methyl) amino] -4-oxobutanoate dissolved In 18 ml of dichloromethane, and 1.95 ml of trifluoroacetic acid was added to the receiving solution. After stirring overnight, the agent and the acid over 1 were evaporated under reduced pressure. Ethyl acetate was added to the remaining residue, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution until the pH of the aqueous layer (??) reached 5. The organic layer was then dried over magnesium acid. The organic layer was dried over magnesium sulfate, and column chromatography was separated on silica gel (liquid phase · ethyl acetate / cyclohexane 1: 1 (v / v) 'change to pure ethyl acetate). This gave 430 mg of the title compound as a white foam, ms: [m + H] +: 544. Example 73 1-[(ethoxycarbamoyl) oxy] ethyl 2 _ {[1 _ ({(((3S) small (2-ethoxyoxoethyl) -2-lacto-2,3 , 4,5_tetrahydrobenzenecycloazepine triammonyl] amino} acyl) cyclopentyl] methyl} -4- [isopropyl (methyl) amino] oxobutyrate

107 mg of 2- {〇 ({[(3SM_ (2-ethoxy_2_oxoethyl) _2-oxo-2,3,4 &gt; tetrahydro-If 丨 _benzenecycloazepine ; Alkenyl] amino} carbofluorenyl) cyclopentyl] methyl} -4- [isodiyl (methyl) amino] -aspartic acid (see Example 72 for preparation) dissolved in 1 mmol Add dimethylformamide. Then add 83 μΐ of 83 200524874 triethylamine, 20 mg of solid potassium carbonate, and 85 μΐ of chloroethylethylcarbonate to the solution. Stir overnight After mashing, the mixture was diluted with ethyl acetate, and then washed with an aqueous potassium hydrogen sulfate solution and brine. The organic layer was dried over magnesium sulfate, and column chromatography was performed on silica gel (liquid phase: ethyl acetate / ring Hexane 1: 1 (V / V)) yielded 41 mg of the title compound as a white foam, MS: [M + H] +: 600; m / z: 526, 449, 310, 253. Example 74 Η (ethoxycarbamyl) oxy] ethyl 2 _ {[1-({[((3S) small (2_ {1 _ [(ethoxycarbamyl) oxy) ethoxy) ethoxy-2-oxo Ethoxy) -2-oxo-2,3,4 &gt; tetrahydro-li / small benzenecycloazepinetrien-3-enyl] amino} carbofluorenyl) cyclopentyl] methyl} _4_ [ Isopropyl (methyl) amino] -4-oxobutyrate

500 mg of ethyl 2-{[l _ ({[(3S) -l- (2-tertiary butoxy-2-oxoethyloxo_2,3,4,5_tetraphosphonium ring nitrogen Hexatrienyl] amino} carbyl) cyclopentyl] methyl} [isopropyl (methyl) amino] oxobutyrate (see Example 32, the synthesis follows the example 2 ) Dissolved in 10 ml of dimethylformamide. Then 312 μΐ of diethyl chlorocarbonate, 758 mg of solid cesium carbonate (Cs2C03), and 80 mg of solid potassium iodide were added to the solution. (: After stirring for 5 hours, the mixture was diluted with ethyl acetate, and then washed twice with water. The organic layer was dried over magnesium sulfate, and column chromatography was separated on the gel (liquid phase ·· ring Hexane 84 200524874 alkane, changed to ethyl acetate / cyclohexane 1: 1 (v / v)), resulting in 360 mg of the title compound as a white oil, MS: [M + H] +: 748; m / z: 614, 480. Example I: Contains {(3S) -3 _ [({l-[(2 "rell")-2_ (ethoxycarbamido) ice (isopropylamino) -4- Oxobutyl] cyclopentyl} -carbofluorenyl) amino] -2-oxo_2,3,4,5-tetrahydro-1 / M-phenylcycloazahexatrien-1-enyl} Capsules of Acetic Acid: Each capsule Preparation of capsules containing the following composition: {(3S) -3 _ [({H (2 "rell ,,)-2- (ethoxycarbamido) _4_ (isopropyl-amino) -4-oxo Butyl] cyclopentyl} -carbofluorenyl) amino] _2_oxo_2,3,4,5-tetrahydro-177_1-phenylcycloazepine-triene-1_enyl} 20 mg Corn starch 60 mg lactose

300 mg acetoacetate

King ingredient, corn flour, and lactose are made into ethyl acetate homogeneous mixture briquettes. Grind the pieces and place the resulting mash on a suitable plate and at 45. (: Dry and read off the solvent. After the conversion, pass through a crusher and mix with the following supplements in a mixer. Talc powder 5 mg magnesium stearate 5 mg corn starch 9 mg and then filled Fill in 400 mg capsules (= capsule size 0). 85

Claims (1)

２００524874 10. Scope of patent application · L A compound of general formula I Wherein R1 is a hydrogen atom or a functional group forming a biostable ester, R2 is a hydrogen atom; an alkyl group containing 1 to 4 hindering atoms or a alkoxyalkyl group containing i to 4 carbon atoms, and its hydrogen The oxo moiety can be optionally selected by alkyl groups containing 2 to 4 carbon atoms or monoamino acid residues, and R3 is an alkyl group containing 1 to 4 carbon atoms; containing 1 to 4 Alkoxy group of 1 carbon atom-alkyl group containing 1 to 4 carbon atoms; oxyalkyl group containing 1 to 4 carbon atoms, which can optionally be replaced by a second hydroxyl group, and its hydrogen Each of the oxy moieties can be freely chosen to be vinegarized by a burned S &amp; group containing 2 to 4 carbon atoms or a monoamino acid residue; (alkyl group containing 0 to 4 carbon atoms) 2 amine group -Alkyl groups containing 1 to 4 carbon atoms; cycloalkyl groups containing 3 to 7 carbon atoms; cycloalkyl groups containing 3 to 7 carbon atoms-alkyl groups containing 1 to 4 carbon atoms; 86 200524874 benzene -An alkyl group containing 1 to 4 carbon atoms, the phenyl portion of which can be optionally selected by an alkyl group containing 1 to 4 carbon atoms, an alkoxy group containing 1 to 4 carbon atoms, and / or a prime 1 to 2 times Substitution; naphthyl_alkyl containing 1 to 4 carbon atoms; oxoalkyi containing 3 to 6 carbon atoms; phenylcarbonyl-methyl Optionally choose to be substituted with 1 to 4 carbon atoms alkenyl groups, alkoxy groups and / or ganglins containing 1 to 4 carbon atoms, or 2-cycloazahexane, or R2 And R3 is an alkylene group containing 4 to 7 carbon atoms in common, and the methylenyl group can be optionally substituted by carbofluorenyl, nitrogen, oxygen, and / or sulfur atoms 1 to 2 times, and It is free to choose to be replaced by a hydroxyl group, and it can be substituted once. It can be optionally esterified by an alkanoyl or monoamino acid residue containing 2 to 4 carbon atoms; it contains! An alkyl group having 4 to 4 carbon atoms; a hydroxyl alkyl group having 1 to 4 carbon atoms, the hydroxyl portion of which can be optionally selected by an alkyl group or an amino acid residue containing 2 to 4 carbon atoms Phenyl group or benzyl group, and R4 is a hydrogen atom or a functional group forming a biostable ester, and a physiologically compatible salt of an acid of the general formula I, and / Or physiologically compatible acid addition salts of compounds of formula I. 2. The compound of the general formula I according to item 1 of the scope of the patent application, wherein R1 is a hydrogen atom or a functional group forming a biostable ester, R2 is a hydrogen atom, and an alkyl group containing 1 to 4 carbon atoms Or a hydroxyalkyl group containing 1 to 4 carbon atoms, the hydroxyl group of which can be optionally replaced by an alkyl group containing 2 to 4 carbon atoms, and R3 is a group containing 1 to 4 carbon atoms. Alkyl groups; alkoxy groups containing 1 to 4 carbon atoms 87 200524874-alkyl groups containing 1 to 4 carbon atoms; oxyalkyl groups containing 1 to 4 carbon atoms, which can optionally be replaced by a second hydrogen The oxy group is substituted, and its hydroxyl group can be optionally selected by a fluorenyl group containing 2 to 4 carbon atoms; an alkylamino group containing 1 to 4 carbon atoms-a thiol containing 1 to 4 carbon atoms A cycloalkyl group containing 3 to 7 carbon atoms, a cycloalkyl group containing 3 to 7 carbon atoms-an acryl group containing 1 to 4 carbon atoms; a phenyl group-containing 1 to 4 carbon atoms The "phenyl group" of the phenyl moiety can be optionally substituted with an alkyl group containing 1 to 4 carbon atoms, an oxy group containing 1 to 4 carbon atoms, and / or a prime to be substituted 1 to 2 times; naphthyl -An alkyl group containing 1 to 4 carbon atoms; an oxoalkyl group containing 3 to 6 carbon atoms; a phenylcarbonylmethyl group, the phenyl portion of which can be optionally contained An alkyl group of 1 to 4 carbon atoms, an alkoxy group containing 1 to 4 carbon atoms, and / or a 1⁄2 element, or 2-cycloazahexane substituted 1 or 2 times, or R2 and R3 together are Alkylene groups containing 4 to 7 carbon atoms, the fluorenyl group portion can be optionally substituted by carbofluorenyl, nitrogen, oxygen, and / or sulfur atoms 1 to 2 times, and it can be optionally selected by The alkyl group containing 1 to 4 carbon atoms is substituted once; the hydroxyl group of the hydroxyl alkyl group containing 1 to 4 carbon atoms can be optionally selected by the alkyl group containing 2 to 4 carbon atoms Substitution; oxygen; phenyl or benzyl, and R4 is a hydrogen atom or a functional group forming a biostable ester, and a physiologically compatible salt of an acid of general formula I, and / or The compounds of general formula I are physiologically compatible acid addition salts. 3. The compound of general formula I according to item 1 of the scope of the patent application, wherein R1 is a hydrogen atom, an ethyl group, a methoxyethoxymethoxyalkyl group, (RS) -l-[[(iso88 200524874 propyl (Yl) carbofluorenyl] oxy] ethyl, (rs) -i _ [[(ethyl) amyl] oxy] methylpropyl, (RS &gt; l-[((cyclohexaneoxy) carbon Fluorenyl] oxy] ethyl, 5-methyl_2 · oxo-1,3-difluorene-4 · alkenyl · methyl, 2-oxo-1,3-dimer 4-fluorenyl- Methyl or (RSH _ [[(ethoxy) carbofluorenyl] oxyethyl. 4) Compounds according to the general formula described in item 1 of the scope of the patent application, wherein R2 is a hydrogen atom, methyl, Ethyl, 2-Hydroxyethyl, or 3-Hydroxy groups, each of which can be optionally esterified with an alkylamino or monoamino acid residue containing 2 to 4 carbon atoms 5. The compound of the general formula I according to item 1 of the scope of the patent application, in which R is isopropyl, methoxyethyl; 2-hydrooxyethyl or 3-oxopropyl, Each of the hydroxyl groups can be optionally esterified with a cyclamyl group or an amino acid residue containing 2 to 4 carbon atoms; ethoxypropyl group; cyclopropylmethyl group, 2-methyllactyl benzyl; 4-methoxybenzyl; 4-methoxyphenethyl; 2,4-dimethoxybenzyl; 丨 -naphthylmethyl; &gt; oxo ", Dimethyl butyl; phenyl-2-oxoethyl; 2- (4-methoxyphenyl) -2-oxo_ethyl; 3- (2-cycloazahexane); two Methylamino_n_propyl; (meth) aminoethyl or amine-η-propyl. 6. The compound of general formula I as described in item 1 of the scope of Shenqing patent, wherein R2 And R together are morphine; slightly lake; 4-keto trip lake; 4-hydroxyl lake, on this hydroxyl group can be optionally selected from the group containing 2 to 4 carbon atoms of the brewing group or amido group Therefore, the residues are acetic acid; slightly Qin or ρ Bi slightly, jt finished. 7. According to the compound of the general formula I described in item 1 of the scope of the patent application, wherein R4 is a hydrogen atom, containing 1 to 4 carbon atoms. Alkyl, p-methoxybenzyl, N, N-mono- (alkyl containing 1 to 4 carbon atoms) amino group · alkyl containing i to 4 carbon atoms, (RS)- l-[[(isopropyl) carbamyl] oxy] ethyl, (RS) -H [(ethyl) carbamyl] oxy] _2_methylpropyl, (RS)] _ [[( Ring 89 200524874 hexaneoxy) carbofluorenyl] Group] -ethyl, 5-methyl_2 • oxo-1,3-diox-4-enyl-methyl, 2-oxo-1,3-difluoren-4-enyl-methyl Or (RS) small [[(ethoxy) carbamyl] oxy] ethyl. 8. According to the compound of general formula I described in item 1 of the scope of patent application, it is selected from this group and its composition consists of 2-{[1-({[1- (Methoxymethyl &gt; 2-oxo-2,3,4,5-tetrahydrobenzenecycloazahexatriene each fluorenyl] amino} -carbofluorenyl ) Cyclopentyl] fluorenyl 4- [isopropyl (methyl) amino] -4-oxobutanoic acid; 2-{[1 _ ({[{carboxycarboxyfluorenyl) -2_oxo-2, 3,4,5_tetrahydro_1good small benzenecycloazatrien-3-enyl] amino} carbofluorenyl) cyclopentyl] methyl 4- (dimethylamino) -4- Oxobutanoic acid; 2-{[1-({[1- (carboxymethyl &gt; 2-oxo-2,3,4,5-tetrahydrazenecycloazatrien-3-enyl] amine Group} Carbofluorenyl) cyclopentyl] methyl} winter (diethylamino) -4-oxobutanoic acid; 2-{[1-({[卜 (carboxymethyl) -2-oxo_ 2,3,4,5_tetrahydrobenzenecycloazahexatrien-3-fluorenyl] aminocarbazone) cyclopentyl] methyl} -4 _ [(2-hydrooxyethyl) (methyl ) Amino] -4-oxobutanoic acid; 2-{[1-({[1- (carboxymethyl) -2-oxo-2,3,4,5-tetrahydro-1 / M-benzene Cycloazahexatrien-3-enyl] amino}- Carbofluorenyl) cyclopentyl] methyl 4-[(3-hydrooxypropyl) (fluorenyl) amino] -4-oxobutanoic acid; 2-{[1 _ ({[1- (carboxymethyl Yl) -2-oxo-2,3,4,5-tetrahydro-1 phenyl 1-benzenecycloazepine trisene alkenyl) amino} -carbofluorenyl) cyclopentyl) methyl 4- ( 4-Hydroxy piperidine-1-branyl) -4-oxobutanil, 2-{[1-({[1- (carboxymethyl) -2-oxo_2,3,4,5- Tetrahydro-1 // small benzenecycloazepinetrienyl alkenyl] amino} -carbofluorenyl) cyclopentyl] methyloxo 4-oxo-4- [4- (L.valamine ) Piperidine-1-enyl] butanoic acid; 200524874 2-{[1-({[1- (Erylmethyl) -2-oxo-2,3,4,5-tetrahydro-1 _Benzylazepine hexamethylenyl] amino} -carbofluorenyl) cyclopentyl] methyl} · 4_morin_4cooke-4-oxobutanoic acid; 2-{[1-({ (1- (Chlorylmethyl) _2_oxo-2,3,4,5_tetrahydro_1xun 1_benzenecycloazepine di-3-rhenyl] amino} -carbofluorenyl) Cyclopentyl] methyl} -4-oxo 4- (4-oxopropidin-1-amidino) butanoic acid; 4- [bis (2-hydrooxyethyl) amino] carboxymethyl) _2 _Oxoscale 2,3,4,5-tetrahydro-1 //-1-phenylcycloazetadiene_3synthetyl] amino} contyl) cyclopentyl] methyl} -4- Oxobutanoic acid; 2- {〇 ({[1- (carboxymethyl) -2 • oxo-2,3,4,5-tetrahydro-1private 1_ Cycloazepine _-3-fluorenyl] amino group carbamyl) cyclopentyl] methyl 丨 ice 丨 ethyl [3_ (ethylamino) propyl] amino} _4_oxobutanoic acid, 2-{[1 _ ({[1_ (Chlorylmethyl) · 2_Oxo_2,3,4,5_tetrahydrobenzenecycloazepine tris each fluorenyl] amino group carbofluorenyl) cyclopentyl [Methyl] 4-methyl [4-dimethylamino] ethyl] (methyl) amino] glacial oxobutanoic acid, 4-[(3-aminopropyl) (ethyl) amino] _2- {[1 _ ({[1_ (Carboxymethyl) _2_oxo_2,3,4,5-tetrahydro-1le-1_benzenecycloazepinetripinenyl] amino} carbofluorenyl) cyclopentyl Phenyl] methyl} -4-oxobutanoic acid, and 2 _ {[1 _ ({[1_ (a few methylmethyl) _2_oxo_2,3,4,5-tetrahydro-17 / -1-benzene Cycloazine_3_alkenyl] aminophenylcarbamyl) cyclopentyl] methylphenyl 4_ {methyl [2- (methylamino) ethyl] amino group __4_oxobutane Acid, plus the biological instability of the acid of the compound I such as 1¾ and physiologically compatible salts, and / or physiologically compatible acid addition salts of these compounds . 9. According to the above-mentioned patent, the compound of the general formula described in the item "wherein" has an asymmetry of 91 200524874 with acid-amine branched chain at the third position of the backbone of the benzene soil nitrogen hexatriene triad. The carbon atoms are in the "S" configuration. 10. A pharmaceutical composition comprising a pharmacologically effective amount of a compound of the general formula I according to item 1 of the scope of patent application, as well as traditional pharmaceutical adjuvants and / or excipients. 11. The use of a compound of the general formula I according to item 1 of the scope of the patent application as a pharmaceutical preparation for the prevention and / or treatment of diseases or diseases of the cardiovascular system. 12. The application according to item 11 of the scope of the patent application, wherein the cardiovascular disease or disease is selected from the group consisting of congestive heart failure; hypertension, including the second type of hypertension such as primary Hypertension, renal hypertension, and / or pulmonary hypertension. 13. The use of a dual-acting compound capable of inhibiting the neutral moon chain endogenous enzymes and the human soluble skin chain endogenous enzymes for the preparation of a drug for the prevention or treatment of sexual dysfunction. 14. Utilization according to item π of the scope of patent application. Compound of general formula I according to item 1 of the scope of patent application. 15. The application according to item 13 of the scope of patent application, wherein the sexual dysfunction is selected from the group consisting of female sexual dysfunction and male sexual dysfunction. 16. The application according to item 13 of the scope of patent application, wherein the sexual dysfunction is male sexual dysfunction. 17. The application according to item 13 of the scope of the patent application, wherein the sexual dysfunction is selected from the group consisting of erectile dysfunction, ejaculation dysfunction, and sexual desire disorder. 18. The application according to item 17 of the scope of patent application, wherein the sexual dysfunction is erectile dysfunction. 92 200524874 19. Applying the compound of general formula j according to item 1 of the scope of the patent application as a pharmaceutical preparation for the prevention and / or treatment of diseases related to apoptosis. Good 20. The application according to item 19 in the scope of the patent application, wherein the adverse disease related to apoptosis is a neurodegenerative disorder, such as ischemic stroke, cerebral ischemia, traumatic brain injury, acute dissemination Encephalomyelitis, atrophic lateral sclerosis, pigmented retinitis, mild cognitive impairment2: Alzheimer's disease, Pick's disease, Alzheimer's disease, progressive supranuclear palsy, cortex Lower dementia, Wilson's disease, multiple infarct disease, arteriosclerotic dementia, dementia associated with A] [DS, major degenerative disorders, cerebral spinal cord metamorphosis syndrome, Frederick's exercise ^: Peripheral disease, dystrophic capillaries, brain damage related to epilepsy, spinal cord damage, urgent leg movement syndrome, Huntington's disease and Parkinson's disease, striated substantia nigra, cerebral vasculitis, Glandular cerebral musculosis, neurogenic waxy lipofuscin, spinal muscular atrophy, lysosomal storage disorders related to the central nervous system, white matter disorders, urea cycle deficiency disorders, hepatic encephalopathy, renal encephalopathy, new Metabolic encephalitis, Porphyria, bacterial or viral meningitis and meningoencephalitis, protein protein infections, neurotoxic compound poisoning, Kiranbarr syndrome, chronic inflammatory neurological disorders, polymyositis, skin Muscle disasters are caused by lightly-fired brain damage; gastrointestinal diseases such as irritating colitis, and inflammatory colitis, Crohn's disease, and ulcerative colitis, celiac disease, Helicobacter pylori gastritis, and other infectious diseases Gastritis, bad enterocolitis, pseudomembranous enterocolitis, enterocolitis caused by radiation, lymphocytic gastritis, graft-versus-host disease, acute and chronic pancreatitis; liver diseases such as alcoholic hepatitis, Viral hepatitis, Xinchen dynasty 93 200524874 Xie hepatitis, autoimmune hepatitis, hepatitis caused by light shooting, cirrhosis, hemolytic uremia, glomerulonephritis, lupus nephritis; viral diseases such as Explosive hepatitis; joint disorders such as trauma and osteoarthritis; suppressed immune function or immune dysfunction, especially autoimmune disorders, Primary inflammatory muscle disorders, chronic neutropenia, thrombocytopenic purpura, rheumatoid arthritis, primary thrombocytopenia purpura, autoimmune hemolytic syndrome, antiphospholipid antibody syndrome, myocarditis, Multiple sclerosis and its recurrence in the diagnostic sub-category-remission of multiple sclerosis, secondary progressive multiple sclerosis, primary progressive multiple sclerosis, progressive relapsing multiple sclerosis, acute Multiple Sclerosis, Benign Relapse Multiple Sclerosis, or Symptomatic Multiple Sclerosis, Optic Neuromyelitis (David's Disease), Lymphocytic Pituitary, Grave's Disease, Edison Illnesses, Parathyroid Insufficiency, Type 1 Diabetes, Systemic Lupus Erythematosus, Pemphigus Vulgaris, Bullous Pemphigus, Psoriasis Guanlangitis, Child 4 Endometrial Tissue Ectopic, Autoimmune Gumpitis, Autoimmune erectile dysfunction, sarcomatoid disease, Wegener's granulomatosis, autoimmune deafness, Sjoy's disease, autoimmune grapes Retinitis, interstitial cystitis, Gooder Pasteur's syndrome, and fibromyalgia; spinal dysplasia, such as hypoplastic anemia; dermatological conditions, including pemphigus vulgaris, dermatomyositis, ectopic Dermatitis, Heinrich-Hunner's purpura, acne, systemic sclerosis, seborrhea, cuticles of the skin, hypertrophy of skin obesity, chronic proliferative dermatitis, keratosis, skin sclerosis, interstitial granulation Swollen skin disease, psoriasis, bacterial infections of the skin, dermatosis, leprosy, cutaneous leishmaniasis, white spot disease, toxic epidermal necrolytic disease, Stephen Strong 94 200524874 syndrome, sebaceous glands, baldness, skin Light injury, sclerosing atrophic tinea, acute skin wounds, pigmented disorders, thermal injury to the skin, eruptive impetigo, mossy skin disease, skin allergic vasculitis, cytotoxic dermatitis; disorders of the inner ear, For example, auditory hair cell death and hearing loss caused by auditory trauma, auditory hair cells And hearing loss, hearing loss stigmatized by ototoxic drugs, peri-lymphatic fistula 'cholesteatoma, scorpion or vestibular ischemia, Meniere's disease, radiation-induced hearing loss, bacterial or viral infections Stigmatized hearing loss and primary hearing loss; transplantation, such as the rejection of transplanted organs by the host's disease, acute and chronic heart, lungs, kidneys, skin, cornea, bone marrow or liver; wound healing; and Organizational exclusion. 21 · The application according to item 19 of the scope of the application for patent, wherein the adverse disease related to apoptosis is a neurodegenerative disorder, such as ischemic stroke, cerebral ischemia, traumatic brain injury, acute dissemination Encephalomyelitis, amyotrophic lateral sclerosis, pigmented retinitis, mild cognitive pumping, Alzheimer's disease, Pick's disease, Alzheimer's disease, progressive supranuclear palsy, subcortical dementia Disease, Wilson's disease, multiple infarct disease, arteriosclerotic dementia, AIDS-related dementia, cerebral degenerative disorders, cerebral spinal cord metamorphosis syndrome, Frederick's dyskinesia, dysfunctional capillary dilatation , Brain damage related to epilepsy, spinal cord damage, urgent leg movement syndrome, Huntington's disease and Parkinson's disease, striatum nigra degeneration, cerebral vasculitis, myelo-glandular cerebral muscle disease, nerves Cytochrome pigment lipofuscin, spinal muscular atrophy, 'lysosomal storage disorders related to the central nervous system', white matter disorders, urea cycle deficiency disorders, hepatic encephalopathy, Encephalopathy, Xinchen 95 200524874 Metabolic encephalopathy, Porphyria, bacterial or viral meningitis and meningoencephalitis, proteomic infections, neurotoxic compound poisoning, Kiranbarr syndrome, chronic inflammatory neurological disorders, multiple Myositis, dermatomyositis, and brain damage caused by light shooting. 22. The application according to item 19 of the scope of the patent application, wherein the adverse disease related to cell apoptosis is irritative colitis, and inflammatory colitis, Crohn's disease and ulcerative colitis, celiac disease, Helicobacter pylori gastritis and other infectious gastritis, necrotizing enterocolitis, pseudomembrane enterocolitis, enterocolitis caused by radiation, lymphococcal gastritis, graft-versus-host disease, acute and chronic pancreatitis . 23. The application according to item 19 of the scope of the patent application, wherein the adverse disease related to cell> week death is liver disease, such as alcoholic hepatitis, viral hepatitis, metabolic hepatitis, autoimmune hepatitis, cause Hepatitis, liver cirrhosis, hemolytic uremia, glomerulonephritis, and lupus nephritis. 24. The application according to item 19 of the scope of the patent application, wherein the adverse disease related to cell death is a viral disease, such as explosive hepatitis. 25. The application according to item 19 of the scope of the patent application, wherein the ill effects related to apoptosis are joint disorders such as trauma and osteoarthritis. 26. The application according to item 19 of the scope of the patent application, wherein the adverse disease related to apoptosis is a suppressed immune function or an immune dysfunction, especially an autoimmune disorder, such as primary inflammation Muscle disorders, chronic neutropenia, thrombocytopenic purpura, rheumatoid arthritis, primary thrombocytopenia purpura, autoimmune hemolytic syndrome, antiphospholipid antibody syndrome, myocarditis, multiple 96 96 24 874 Sclerosis and its recurrence in the sub-categories of diagnosis-remission of multiple sclerosis, first grade multiple sclerosis, primary progressive multiple sclerosis' progressive relapsing multiple sclerosis, acute multiple Sclerosis, benign relapsing multiple sclerosis or asymptomatic multiple sclerosis, optic neuromedulitis (David's disease), lymphocytic pituitary inflammation, Gregford's disease, Edison's disease, Parathyroid insufficiency, diabetic type 1, systemic lupus erythematosus, genus vulgaris, bullous pemphigoid, psoriasis Inflammation, endometrial tissue ectopic, autoimmune bolitis, autoimmune erectile dysfunction, sarcomatoid disease, Wegener's granulomatosis, autoimmune deafness, sjoherr's disease, autologous Immune uve retinitis, interstitial cystitis, Good Pasteur's syndrome, and fibromyalgia. 27. The application according to item 19 of the scope of the patent application, wherein the dysfunction related to apoptosis is spinal dysplasia, such as hypoplastic anemia. 28. The application according to item 19 of the scope of the patent application, wherein the ills related to cell withering are dermatological conditions, including pemphigus vulgaris, dermatomyositis, atopic dermatitis, black Nuoch_Hunner's purpura, acne, systemic sclerosis, sebum leakage, stratum corneum, skin obesity, chronic proliferative dermatitis, keratosis, skin sclerosis, interstitial bloated skin disease, psoriasis , Bacterial infections of the skin, dermatosis, leprosy, cutaneous leishmaniasis, leukoplakia, toxic epidermal necrolytic disease, Stephen Johnson syndrome, sebaceous adenoma, baldness, skin light injury, sclerosing atrophic lichen planus , Acute skin wounds, pigmentation disorders, thermal injury to the skin, rash pustulosis, thin moss skin disease, skin allergic vasculitis, cytotoxic dermatitis. 97 200524874 29. The application according to item 19 of the scope of the patent application, wherein the apoptotic-related illness is a condition of the inner ear, such as the death of hearing hair cells and hearing loss as a result of hearing trauma, Hearing hair cell death and hearing loss stigmatized by aminoglycosides, hearing loss stigmatized by ototoxic drugs, perilymphatic fistula, cholesteatoma, cochlea or vestibular ischemia, Meniere's disease , Hearing loss due to radiation defamation, hearing loss caused by bacterial or viral infections, and primary hearing loss. 30. The application according to item 19 of the scope of the patent application, wherein the apoptotic-related ailment is caused by transplantation. The graft-to-host condition, acute and chronic heart, lung, kidney, skin, Rejection of transplanted organs such as the cornea, bone marrow, or liver. 31. The application according to item 19 of the scope of the patent application, wherein the ill effects related to cell withering are wound healing and tissue rejection. 32. A method for treating a vascular disease or disease in mammals and humans, including administering a compound of the general formula described in item 1 of the scope of the patent application to a subject in need thereof— Effective amount. 33.-A method for treating sexual dysfunction of lion's milk animals and human beings', which comprises an effective amount of one of the compounds of the general formula I as described in item 1 of the subject of the application "Patent Application". 34. A method for treating or preventing dysregulation in mammals and humans related to apoptosis, comprising administering to a subject in need thereof a compound of the general formula I as described in claim 1 Effective amount. 35. A method for preparing compounds of the general formula ϊ, 98 200524874 0 c〇〇R4 r1 is a hydrogen atom il is-to form a bio-unsettled Hansersen group, R2 is a hydrogen atom; an alkyl group containing 1 to 4 carbon atoms or a hydroalkyl group containing 1 to 4 carbon atoms , Its hydroxyl group can be optionally esterified with an alkyl or amine residue having 2 to 4 carbon atoms, and R3 is an alkyl group containing 1 to 4 carbon atoms; containing Carbooxy group of 1 to 4 carbon atoms-a radical containing 1 to 4 carbon atoms; a oxyalkyl group containing 1 to 4 carbon atoms, which can be optionally substituted by a second hydroxyl group, and Each of its hydroxyl groups can be optionally esterified with an alkyl group containing 2 to 4 carbon atoms or an amino acid residue; (alkyl group containing 0 to 4 carbon atoms) 2 amine Radicals-alkyl radicals containing 1 to 4 carbon atoms; cycloalkyl radicals containing 3 to 7 carbon atoms; cycloalkyl radicals containing 3 to 7 carbon atoms-alkyl radicals containing 1 to 4 carbon atoms; -An alkyl group containing 1 to 4 carbon atoms, the phenyl portion of which can be optionally selected to be 1 by an alkyl group containing 1 to 4 carbon atoms, an alkoxy group containing 1 to 4 carbon atoms, and / or a halogen To 2 substitutions; naphthyl_ contains ^ Alkyl groups of 4 to 4 carbon atoms; oxoalkyl groups of 3 to 6 carbon atoms; phenylcarbonylmethyl, the phenyl group of which is optionally selected to contain 1 to 4 carbon atoms An alkyl group, an alkoxy group containing 1 to 4 carbon atoms, and / or a halogen, or 99 200524874 2-cyclic nitrogen hexane is substituted once or twice, or R2 and R3 together contain 4 to 7 carbons Atomic alkylene groups, in which the fluorenyl group can be optionally substituted 1 to 2 times by carbofluorenyl, nitrogen, oxygen, and / or sulfur atoms, and it can be optionally selected to be 1 by hydroxyl groups Subsequent substitution, it can optionally be esterified with an alkanoyl or monoamino acid residue containing 2 to 4 carbon atoms; an alkyl group containing 1 to 4 carbon atoms; containing 1 to Hydroxyl groups of 4 carbon atoms, the hydroxyl group of which can be optionally esterified with alkyl or amine residues containing 2 to 4 carbon atoms; phenyl or benzyl And R4 is a hydrogen atom or a functional group that forms a biostable ester, and a physiologically compatible salt of an acid of general formula I, and / or a chemical formula of general formula I It was in a physiologically interoperable content of the acid addition salts thereof, wherein the compound of formula II, II its r1g1 and R4G1 are independent of each other, each of which is an acid-protecting group, and reacts with a compound of the general formula hi III R2-NH 100 200524874 R2 and R3 have the meanings mentioned above, if R2 and / Or when R3 contains a free hydroxyl group, these functional groups react with a compound of the general formula IV when necessary, Ci_3-C (0) -X xv, where X represents a leaving group 'or 疋 and' An amino acid derivative protected by a suitable protecting group reacts with each other if R1G1 and / or R4G1 does not represent the required formation of biosectable esters and / or if R2 and / or R3 contains protection based on any amine present When these residues are on the basis of acid residues, the functionalities are based on the consecutive removal of the resulting compounds in any required order, either simultaneously or individually, and, if necessary, the acid shown in each case The functional group is converted to a biostable ester functional group, and if necessary, the acid generated by the general formula I is converted to a physiologically compatible salt thereof, or the acid salt of the general formula I is converted to a free acid And / or bases of general formula I Acid addition salts, or converted to acid addition salts of formula I free inspection. 36 · —a compound of the general formula II, 101 200524874 where r1G1 is an acid protecting group, and R4Q1 is an acid-protecting group. 102 200524874 VII. Designated Representative Map: (1) The designated representative map in this case is: (). (2) Brief description of the component symbols in this representative picture: 8. If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: 〇 COOR4