TWI332947B - Amidomethyl-substituted 1-(carboxyalkyl)-cyclopentylcarbonylamino-benzazepine-n-acetic acid derivatives, process and intermediate products for their preparation and medicaments containing these compounds - Google Patents

Description

1332947 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to a novel iota-(carboxyalkyl)-cyclopentylcarbenylaminobenzoxanthene substituted by a guanamine methyl group. -N-acetic acid derivative, which can be effectively utilized for, for example, prevention and/or treatment of cardiovascular diseases or conditions, especially cardiac insufficiency 'especially congestive heart failure; hypertension, second type containing hypertension, potato Such as essential hypertension, renal hypertension and / or lung 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 apoptosis related to apoptosis And also related to drugs containing these compounds. Further, the present invention relates to a process for preparing the novel benzzepine-N-acetic acid derivative substituted with amidomethy 1 and an intermediate product thereof. Sexual dysfunction (S D) is a major clinical problem that affects both men and women. The cause of sexual dysfunction may be organ and psychological factors. The organicity of sexual dysfunction is typically caused by vascular diseases such as vascular diseases associated with high blood pressure or diabetes, prescription drugs and/or mental illnesses such as depression. Psychological factors include fear, performance anxiety, and interpersonal conflict. Sexual well-being is a manifestation of impaired sexual performance, suspected low self-esteem, and the breakdown of personal relationships, which involve personal suffering. Apoptosis is closely related to the development of the body during development and the development of tissues, the maintenance of the body, and the biological defense, and its cell death plays an important role in the life of the body. When the death program regulated by the gene is blocked due to congenital factors, the cell society is over-induced or inhibited, causing different disorders, thus causing the disease. It has a substance that inhibits cell growth. It can be read as a medicine having a lion and a treatment caused by a cell; a disease caused by perinatal (4) 7 1332947 [Prior Art] Benzene azatrixene-, benzoxazepine, which is active against cardiovascular And benzothiazepine-N-acetic acid derivatives, which have a significant inhibitory effect on neutral endoPePtidase 'NEP, which has been determined by EP 0 733 642 Al (= The patent of US 5,677,297) is known. Furthermore, the compounds described herein have less inhibitory properties to endothelin-converting enzyme (ECE). Other advantageous pharmacological properties of the compound falling within the structural formula of EP 0 733 642 A1 are from 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. The benzzepinone-N-acetic acid derivative substituted with phosphoric acid has a combined inhibitory effect on neutral endopeptidase and endothelin converting enzyme, and is disclosed in the patent EP 0 916 679 A1 ( =US 5,952,327). An agent obtained from the WO 02/094176 A2 patent, which contains a compound which has an advantageous combination of inhibiting metalloprotein hydrolysis from each enzyme in the neutral month of the bond, and intrinsic to each of the IGS5 functions and has a The vascular has the property of being active. Compounds which are suitable as such a combination are also compounds which fall within the scope of the patents of EP 0 733 642 A1 and EP 0 916 679 A1. The enzyme i〇S5 will be understood in the context of the present invention and its physiological role in relation to cardiovascular diseases, which is essentially known from the WO 01/36610 A1 patent. The above-mentioned enzyme jgs5 is also known as human soluble endopeptidase (hSEP). It is known from the patent WO 99/55726 A1 that certain thiol inhibitors of endothelin-converted purines are effective for treating or inhibiting, in particular, erectile dysfunction. 8 1332947 Patent EP 1 097 719 A1 discloses the use of a neutral monthly endonuclease inhibitor as a treatment for sexual dysfunction (FSD) in women. Patent WO 02/06492 A1 discloses, in particular, an antibody and inhibitor of a specific polyamino acid having a soluble secreted endo-segment (=SEP) activity. The matrix-metalloprotein hydrolysate per inhibitor is effective in treating neurodegenerative disorders as described in the patent application US Pat. No. 3,45,449. And the problems associated with the invention 'the first is that the matrix-metal proteolytic enzyme inhibitor comprises a broad group of proteolytic inhibitors, and the second is that according to the application, the metalloprotein hydrolysers must be used every time. In the composition of the agent containing the N-NOS inhibitor. U.S. Patent Application No. US 2002/0013307 teaches the use of vasopressin inhibitors to treat or slow the progression of cognitive dysfunction' and to treat and/or prevent dementia. M. Sumitomo et al. (see Clinical Cancer Research 1〇 (2004) 260-266) describe the chemical sensitization of phenotypic cancers that are unrelated to androgen (andr〇gen) by neutral endopeptidase (chemosensitizati〇n). SUMMARY OF THE INVENTION One object of the present invention is to provide a novel active substance having a combined action for inhibiting neutral temperament tangent enthalpy, human soluble glutinous ligaments, and endothelin-converting enzymes. It is especially suitable for the prevention and/or treatment of cardiovascular diseases or diseases, especially cardiac insufficiency, especially congestive heart failure; hypertension, second type including hypertension such as essential hypertension, high kidney Blood pressure and/or lung hypertension; and/or prevention and/or treatment of sexual dysfunction, and/or prevention and/or treatment of adverse events associated with apoptosis. It has now surprisingly been found that a new group of 1-(carboxyalkyl)-cyclopentylcarbenylamino-benzenecycloazene-1-in-acetic acid derivatives substituted by a guanamine methyl group according to the present invention has been discovered. It is characterized by the inhibition of the neutral endonuclease and the functional map of the human soluble endo-inhibition of each of the enzymes, and also has a certain degree of inhibition on endothelin conversion. It appears to be suitable for the prevention and/or treatment of cardiovascular diseases or disorders, especially cardiac insufficiency, especially congestive heart failure; hypertension, a second type of hypertension, such as essential hypertension, renal rain and blood pressure And/or pulmonary hypertension; and/or prevention and/or treatment of sexual dysfunction, and/or suitable and/or treatment of adverse events associated with apoptosis. The subject of the present invention is a novel 1 - (decaminated alkyl)-cyclopentylcarbamoylamino-benzenecycloazitol acetate derivative substituted by amidoxime group of the formula I.

Wherein R1 is a hydrogen atom or a functional group forming a biolabile ester, R2 is a hydrogen atom; an alkyl group having 1 to 4 carbon atoms or a hydrogenoxy group containing 1 to 4 carbon atoms, wherein The oxime moiety may be optionally esterified with an alkano group or an amino acid residue having 2 to 4 carbon atoms, and R3 is an alkyl group having 1 to 4 carbon atoms; and contains 1 to 4 carbons. Alkyl aryl group - an alkyl group having 1 to 4 carbon atoms; a hydroxyalkyl group containing from 4 to 4 argon atoms, which may be optionally substituted by a second hydroxy group, and a hydroxyl group thereof Each can be optionally esterified with a crotch group or an amino acid residue having 2 to 4 carbon atoms; (alkyl group having 0 to 4 carbon atoms) 2 amine group - 1332947 to 4 carbons In the case of an alkyl alkane group, the substituent may be a linear type or a bifurcated type. Ethyl fluorenyl is a more preferred alkyl fluorenyl group having 2 to 4 carbon atoms. The hydroxyl group in the compound of formula I is esterified with an amino acid residue which may be derived from a natural or non-natural alpha- or beta-amino acid. Suitable amino acids which can be exemplified are selected from the group 'which contains alanine, 2-aminohexanoic acid (= norleucine, norleucine), 2-aminopentanoic acid (= n-decylamine) Acid, norvaiine), arginine, asparagine, aspartic acid, cysteine, 3,4-dihydrophenylalanine (=dopa, Dopa), glutamine, glutamic acid, glycyne, histidine, isoleucine, leucine, lysine (lysine), methionine, guanamine (= 2, 5-diaminopentanoic acid), 5-oxo-2-P pyrrole (=pyramine), Pyr〇giutamic acid), phenylalanine, proline, serine, threonine, thyronine, tryptophan, road Amino acid (tyrosine) and valine. More preferred are selected from the group consisting of alanine, aspartame, glutamine, glycine, isoleucine, leucine, lysine, ornithine, phenylalanine, proline and proline. The amino acid residue of the group. The compound of the formula I represents a dicarboxylic acid derivative which is optionally esterified by a functional group forming a biolabile ester. The biostable ester of formula I generally refers to a free acid precursor ("precursor) which can be administered. Monoesters or diesters of the compounds of formula I can then be produced. Depending on the form administered, the preferred ones are bio-unstable esters or free acids, the latter being particularly suitable for intravenous (=i.v.) administration. The functional groups of the bioavailable derivatives of the compounds of the formula I can be cleaved under physiological conditions in vivo to release the functional groups R1 and Han 4 of the biolabile esters. Suitable examples for this case are alkane 12 1332947 bases having 1 to 4 carbon atoms, especially methyl, ethyl, η-propyl and isopropyl; alkoxy groups having 1 to 4 carbon atoms - containing 1 Alkoxy group to 4 carbon atoms - alkyl group having 1 to 4 carbon atoms, particularly methoxyethoxymethyl; cycloalkyl group having 3 to 7 carbon atoms, especially a ring Hexyl group; a cycloalkyl group having 3 to 7 carbon atoms - a group having 1 to 4 rear atoms, particularly a cyclopropylmethyl group; N, N-di- (containing 1 to 4 carbon atoms) Alkylamino group - an alkyl group having 1 to 4 carbon atoms; a phenyl group or a phenyl group - an alkyl group having 1 to 4 carbon atoms, which may be optionally selected from a phenyl ring, containing 1 to An alkyl group of 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms is substituted 1 to 2 times, or an alkylene group having 1 to 4 carbon atoms bonded to two adjacent carbon atoms. Substituted by a chain; dioxoylylmethyl' can be optionally substituted with an alkyl group having 1 to 4 carbon atoms on the diterpene ring; an alkoxy group having 2 to 6 carbon atoms (alkanoylox y)- an alkyl group having 1 to 4 carbon atoms which may be optionally substituted with an alkyl group having 1 to 4 carbon atoms in the oxygen-alkyl group having 1 to 4 carbon atoms; Bu [[(alkyl containing 1 to 4 carbon atoms) carbon sulfhydryl] oxy] alkyl esters having 1 to 4 carbon atoms, such as (RS)-l-[[(isopropyl)carbon 醯Oroxy]ethyl or (RS)-l-[[(ethyl)carbenyl]oxy]-2-methylpropyl (for preparation see, for example, FW Sum. et al., Bioorg. Med. Chem. Lett. 2 (1999) 1921-1926) or Y. Yoshimura et al. 'The Journal of Antibiotics 翌/9 (1986) 1329-1342); carboxylic acid esters such as 1-[[(containing 4 to 7 carbon atoms) Cycloalkoxy)carbenyl]oxy]alkyl esters having 1 to 4 carbon atoms' preferred (RS)-l-[[(cyclohexyloxy)carbenyl]oxy] Ethyl (= cilexetil; for preparation, see, for example, K. Kubo et al. 'J. Med. Chem. (1993) 2343-2349, hereinafter referred to as "Kubo et al.") or oxo-1,3- Ethoxy-4-alkenyl-alkyl esters having 1 to 4 carbon atoms which are optionally selected to contain a double bond on the dioxane ring, more preferably methyl 2-oxo- 1,3-dioxo-4' alkenylmethyl (= 13 1332947 medoxomH, for example, see Kubo et al.) or 2-oxo-1,3-dioxa-4-alkenyl-methyl (=(Methyl)ethylene carboxylic acid). If the functional group forming the bio-labile ester is a phenyl group optionally substituted with an alkyl group having 1 to 4 carbon atoms, the functional group may contain an alkylene chain having 1 to 4 It prefers 1 carbon atom, and prefers to represent a benzyl group which can be optionally substituted, especially 2-chlorobenzyl or 4-chlorobenzyl. If the functional group forming the bio-labile ester means a phenyl group which may be optionally substituted, wherein the benzene ring of the functional group is substituted by a low-carbon alkyl chain, the functional group may contain 3 to 4, preferring 3 carbon atoms and especially indanyl. Wherein, if the functional group forming the bio-labile ester means an optionally substituted alkyl group having 2 to 6 carbon atoms - an alkyl group having 1 to 4 carbon atoms, the content 2 to 6 The alkyl alkane group of one carbon atom may be a linear type or a bifurcated type. R1 is more preferred as a hydrogen atom, ethyl, methoxyethoxymethyl, (RS)-l-[[(isopropyl)carbenyl]oxy]ethyl, (RS)-l- [[(ethyl)carbenyl]oxy]-2-methylpropyl, (RS)-l-[[(cyclohexyloxy)carbenyl]oxy]ethyl, 5-methyl-2- Oxo-1,3-dioxin-4-mercapto-methyl, 2-oxo-1,3-dioxa-4-phenyl-methyl or (RS)-l-[[(ethoxy Carboxylidene]oxy]ethyl. R2 is more preferred as a hydrogen atom, a methyl group, an ethyl group, a 2-hydroxyoxyethyl group or a 3-hydrogenoxypropyl group, and each of the hydroxyl groups may be optionally selected to be an alkane having 2 to 4 carbon atoms. Mercapto or an amino acid residue is esterified. If R3 has the meaning of (alkyl group having 0 to 4 carbon atoms) 2 amine group · an alkyl group having 1 main 4 carbon atoms, then one or two alkyl groups having 〇 to 4 carbon atoms may be mutually Appear in mutual influence. More specifically, the "amino group (containing an alkyl group having 4 to carbon atoms) - an alkyl group having 1 to 4 carbon atoms" means that it contains "(carbon atom-free) 2 alkylamine" a group - an alkyl group having 1 to 4 carbon atoms", "(without carbon atoms) (containing 1 to 4 carbon atoms) alkylamino group - having 1 to 4 alkyl groups of 14 1332947 carbon atoms" and " (containing 1 to 4 carbon atoms) 2-alkylamino group - an alkyl group having 1 to 4 carbon atoms. "(without breaking the atom) 2-alkylamino group - an alkyl group having 1 to 4 carbon atoms" is intended to mean that an unsubstituted primary amine group (=NH2) is attached to one to four carbon atoms. An alkane group; "(without carbon atoms) (containing i to 4 carbon atoms) alkylamino group - an alkyl group having 1 to 4 carbon atoms" is intended to name a secondary amine group which is (containing 1 to 4 carbon atoms) - substituted by an alkyl group, and attached to an alkidine group having 1 to 4 carbon atoms; "(containing 1 to 4 carbon atoms) 2 alkylamino group-containing An alkyl group of 1 to 4 carbon atoms" is intended to name a tertiary amino group which is substituted by an alkyl group having 1 to 4 carbon atoms and which is bonded to a pyridyl group having 1 to 4 carbon atoms. . R3 is more preferred than isopropyl; methoxyethyl; 2-hydroxyoxyethyl or 3-hydroxyoxypropyl, each of which can be optionally selected to contain 2 to 4 carbon atoms. Ester alkyl or an amino acid residue esterified; 3-ethyloxy-n-propyl; cyclopropyl fluorenyl; 2-methoxybenzyl, 4-methoxyphenylhydrazino 4-methoxyphenethyl; 2,4-dimethoxybenzyl; naphthylmethyl; 3-oxo-l,l-dimethylbutyl; phenyl-2-oxo 2-(4-methoxyphenyl)-2-oxoethyl; 3-(2-cyclohexane); (alkyl containing fluorene to 4 carbon atoms) 2 amine-containing 1 An alkyl group of up to 4 carbon atoms, especially dimethylaminopropyl, (decyl)aminoethyl or amine-n-propyl. If R2 and R3 are together an alkylene group having 4 to 7 carbon atoms, the thiol moiety thereof may be optionally substituted or optionally substituted, and may be optionally selected in each case. Morpholine; piperididine; 4-ketopiperidine; 4-hydroxyoxypiperidine, optionally having an alkylene group containing 2 to 4 carbon atoms or a The amino acid residue is esterified; the preferred one is piperazine, p pyrrolidine. R4 is more preferred as a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a p-methoxybenzyl group, an N,N-di-(alkyl group having 1 to 4 carbon atoms) amine group. - 15 1332947 Alkyl group having 1 to 4 carbon atoms, (RS) small [[(isopropyl)carbenyl]oxy]ethyl, (RS)-l-[[(ethyl)carbenyl] Oxy]-2-methylpropyl, (King melon cyclohexyloxy)carbenyl]oxy]ethyl, 5-methyl-2-oxo-l,3-dioxa-4-enyl- Methyl, 2-oxo-1,3-dioxa-4-indolyl-indenyl or (rs)-1-[[(ethoxy)carbenyl]oxy]ethyl. The compound of formula I is particularly selected from the group consisting of carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1//-1-benzenecyclohexene. 4-enyl]amino}carbenyl)cyclopentyl]hydrazino 4_[isopropyl(methyl)amino]-4-oxobutanoic acid (32); 2-UHUH carboxymethyl )-2-oxo-2,3,4,5-tetrahydro-1 private 1-benzenecyclohexylenetriene_3·alkenyl]amino}carbomethyl)cyclopentyl]methylhydrazine_4_ (dimethylamino)·4 oxobutanoic acid (54); 2-{[1-({[1-(carboxyindolyl)-2-oxo-2,3,4,5-tetrahydro- 1/M-benzenecyclohexaatrien-3-yl]amino}carbenyl)cyclopentyl]methyl b 4_(diethylamino)_4oxobutyric acid (55); 2-{ [M{[H-Leptylmethyl)-2-oxo-2,3,4,5-tetrahydro-I//]·benzenecycloazin-3-enyl]amino}carbenyl Cyclopentyl]methyl b 4_[(2-hydroxyoxyethyl)amino]-4-oxobutanoic acid (43); 2_{[1·({[1-(methyl)methyl) ·2.Oxo-2,3,4,5·tetrahydro-1//small benzenecyclohexanyl-3-mercapto]amino}carbomethyl)cyclopentyl]methyl}_4-[ (3-Hydroxypropyl)(methyl)amino]-4-oxobutanoic acid (56); 2_{[丨-({[1-(carboxymethyl)-2-oxo-2,3 ,4,5-tetrahydro-1仏1_benzenecycloazadiene·_3-womenyl]amino group Stuffed base) 辕 pentyl] methyl}_4-(4-oxygen brigade bite_1_construction)-4-oxobutyric acid (57); 2·{[1-({[1-(carboxyl) ))-2-oxo-2,3,4,5-tetrahydro-1仏1_benzenecycloazapidine-3-indenyl]aminocarbocarbyl)cyclopentyl]methyl} -4-oxo_4_[4_(L_Aminooxy)>*endridin-1-yl]butyric acid (68); 1332947 2-{[1-({[1-(carboxymethyl) -2-oxo~2,3,4,5-tetrahydro-1//-1-benzene-cyclohexaazain-3-enyl]amino-carbenyl)cyclopentyl]fluorenyl} _4_morpholinyl-4-oxobutanoic acid (66); 2-{[1-({|>(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro- 1 from 1-phenylcycloazin-3-yl-3-amino]aminocarbyl)cyclopentyl]methyl}-4-oxo-4-(4-oxo-precipitate-1-phenyl) Butyric acid (45); 4-[bis(2-hydroxyoxyethyl)amino]-2-{[1-({[1-(t-methyl))-2-oxo-2,3,4 ,5-tetradec-1-y-1-1-phenylcycloazin-3-ylidene-3-amino]amino}carbenyl)cyclopentyl]methyl}-4-oxobutanoic acid (58); 2- {[卜({[1-()-[2-(2-)-)-oxo-2,3,4,5-tetrahydrobenzenecyclohexadien-3-yl]amino}carbon} Cyclopentyl]methyl}-4_{ethyl[3-(ethylamino)propyl]amino}-4-oxobutanoic acid (52), and 2~{[1_({[1_(竣Methyl)-2-oxo -2,3,4,5-tetrahydro-1-l-phenylcycloazin-3-enyl]amino}•carbonyl)cyclopentyl]methylindole_4_[[2_ (Dimethylamino)ethyl](methyl)amino]-4-oxobutanoic acid (59), 4-[(3-aminopropyl)(ethyl)amino]_2-{[ 1_(丨[〗 _(carboxymethyl)2 oxo-2'3,4,5-tetrahydro-1 private 1_benzene ring nitroxanthene _3_mercapto]amino}carbon fluorenyl) ring Pentyl]methyl}-4-oxobutyric acid (67), and —2·{[1-({[ΐ·(carboxymethyl)_2_oxo-^7^tetrahydroanthracene small benzene ring Nitrogen-hexa-3-amino]amino}-carbo-yl)cyclopentyl]methyl}_4_{methyl[2-(methylamino)ethyl]aminooxybutyric acid (68), Ϊ The physiologically compatible salts of the acids of the compounds of the formula 1 and the biologically unrefined vinegars and/or the compounds of the formula 1 are physiologically compatible acid addition salts. 4 ττ, according to the present invention, the new compound and its salts are obtained as a compound of the general formula 11, 1332947

Wherein R101 and R4〇l are each independently of each other, each of which is an acid protecting group and reacts with a compound of formula III,

R2—NH III wherein R 2 and R 3 have the meanings indicated above, and if R 2 and/or R 3 contain a free hydroxyl group, the functional groups interact with the compound of formula IV, if necessary, Cj. 3-C(0)-X xv wherein X represents a leaving gr〇Up or interacts with an amino acid derivative protected by a suitable protecting group, right R and/or R4. Does not represent the desired formation of bio-labile esters and/or if R2 and/or R3 contain protection based on any amino acid residues present, such functions are based on the desired compound in any desired order , when the time is closed or individually, the 10,000-type cut, and if necessary, in each case, the 18 1332947 acid functional group is converted into a bio-unstable ester functional group, and if necessary' The acid formed by the formula I is converted into its physiologically compatible sleeping class, or the salt of the acid of the formula I is converted into a free acid and/or the age of the formula I is converted into its acid addition salt. The class 'or acid addition salt is converted to the free test of the general formula I. In each case, the salts of the physiologically compatible salts of the acids of the formula I are suitably 'alkaline gold metal, alkaline earth metal or ammonium salt, for example, sodium or calcium salts thereof, It is physiologically compatible with 'pharmacologically neutral organic salts with amines such as amine water, diethylamine 'tertiary butylamine' N-methylglucosamine, choline, or with amino acids Salts such as those formed by arginine. If the substituent R2 and/or R3 in the compound of the formula contains a basic functional group, especially a nitrogen atom, the compounds of the formula I may exist in the form of acid addition salts. The physiologically compatible acid addition salts of the compounds of formula I are conventionally distinguished from inorganic acids, for example with sulfuric acid, phosphoric acid or hydrogen acid, or with organic acids, for example Containing a low carbon number fatty monocarboxylic acid, a dicarboxylic acid or a tricarboxylic acid such as maleic acid, fUmaric acid, tartaric acid, citric acid Acid) 'Or a salt formed with a sulphonic acid such as a low-condensation alkanesulphonic acid such as methanesulphonic acid. Traditionally, as a protecting group for protecting a carboxylic acid functional group, an acid protecting group R1G1 and R4G1 can be selected, which can be further removed by a conventional method. "It is known as a protecting group for a carboxylic acid, such as McOmie," Protective Groups in Organic Chemistry, Plenum Press (hereafter referred to as "McOmie"), and Greene, Wuts, "Protective Groups in Organic Synthesis", Wiley Interscience Publication (hereafter referred to as "Greene"), each of which is up to date Version. The reaction of the functional group forming the biolabile ester can also be used as the acid protecting group 19 1332947 and the reaction of the carboxylic acid of the formula ιι can also be conveniently obtained from, for example, peptide chemistry and suitable for the formation of guanamine. It is carried out in the presence of coupling reagents. An example of a coupling agent that forms a reactive acid derivative by in situ reaction with a free acid to form a guanamine with a free acid. In particular: ethyl chloroformic acid, thiol carbonic acid (alkylcarbodiimide), such as cycloalkylcarbodiimide, such as dicyclohexylcarbocene, or N-(3-dimethylaminopropyl)-oxime-ethyl Indole diamine (=EDC), carbonyldiimidazole and NMolow* alkyl-2-halopyridinium salt, especially a halogen salt or toluenesulfonic acid salt. The reaction in the presence of a coupling agent can be at -30. (: to +50. (: at a temperature such as a solvent containing a commercial hydrocarbon and/or an aromatic hydrocarbon solvent, and optionally arbitrarily operated in the presence of the above-mentioned acid-bound amine. a compound of the formula II and a compound of the formula III in which r2 and/or r3 contain a free hydroxyl group, and in the compound obtained by the reaction, the compounds may, if necessary, be carried out by conventional methods and formula IV. The compound is reacted. In the compound of the formula IV, the cleavage group X represents, for example, a peptidine, which is preferred to represent a gas atom. The compound of the formula II and the compound of the formula III, wherein R2 and/or R3 contain free hydrogen and oxygen In the compounds obtained by the reaction, the compounds may, if necessary, be reacted with an amino acid derivative protected by a suitable protecting group by a conventional method. Suitable amino acid protecting groups and The method of excising or selectively excising it is technically known, for example, from McOmie or Greene. A suitably protected amino acid derivative is commercially available or can be prepared by a conventional method. Indenyl R1()1 and R, if they do not represent any of the desired functional groups and/or protecting groups that form biolabile esters, may be present in any of the existing amines of scale 2 and/or R3 The acid moiety can be removed by conventional methods, and if necessary, 22 (1) 2947 selectively reacts a compound obtained from a compound of the formula π with a compound of the formula ff1. The compound of the formula I can be obtained from the reaction mixture. Separated and, if necessary, can be purified by a conventional method such as high performance liquid chromatography (=HPLC). The starting compound of the formula II is a novel compound which is suitable as an intermediate product for the preparation of a new product. The active substance, for example, for the preparation of a compound of the formula I. The compound of the formula II can be prepared from the reaction compound of the formula V,

^, R is an acid protecting group, and Rl01 has the above meaning, and is combined with formula VI

The meaning of the acid-protected double base is reacted, and then the method of the reaction is carried out by a conventional method =, = furnace. This reaction can be conventionally carried out as an amino acid grouping W, for example, according to the above-mentioned reaction of a compound of the formula π with a compound of the formula m 23 1332947. In order to avoid secondary reduction of the face, it may be advantageous to remove the acid protecting group r5 by a method which is not operated in an assay solution, and then to select the corresponding acid protecting group R5. The amines of the general formula III are basically known or can be prepared from conventional compounds by conventional methods. The acid derivative of the formula IV having reactivity is basically known or can be prepared from a conventional compound by a conventional method. These compounds are linear or bifurcated, carboxylic acid derivatives having 1 to 4 carbon atoms. The compound of the compound of the formula V can be obtained from the acryl vinegar (aCfyUc ester) derivative of the formula YU.

Wherein R1Q1 and R5 have the above meanings and are obtained by reacting with cyclopentanecarboxylic acid. The reaction can be carried out in an organic solvent under the conditions of Michael condensation reaction by a conventional method, and the solvent exhibits an inert state under the reaction conditions, that is, a cyclopentanecarboxylic acid and a strong base capable of forming a cyclopentane carboxylic acid dianion. The reaction 'and subsequent reaction with an acrylate derivative of the formula VII. Suitable solvents are ethers, especially cyclic ethers such as THF. Suitable strong bases are non-nucleophilic organic alkali metal guanamines or alkali metal low carbon number alkane such as diisopropyl decylamine or η-butyl lithium salt. A convenient procedure is to react a cyclopentane carboxylic acid in THF with twice equivalents of η-butyllithium salt and then reacting the reaction mixture with a compound of formula VII. 24 1332947 The temperature of this reaction can range from -80 ° C to 〇 ° C. The compounds of the formula vi are known, for example, from the patent EP 〇 733 642 A and may be in the form of racemates or on the pure form of the isomer according to the method described herein or a method analogous thereto. Prepared. The compound of formula VII can be a compound of formula VIH,

Wherein R5 represents an acid protecting group which is obtained by acetylation of a desired alcohol with a desired method. The compound of the formula VIII can be, for example, from an itaconium nicate anhydride under the conditions of conventionally opening a sorghum base, and an agent capable of forming an acid protecting group R5, such as a correspondingly substituted alcohol. Class, reaction comes. In the above reaction, the asymmetric center of the starting compound of the formula V and the formula V is unchanged, so that it is determined by the type of the starting compound that the isomer-like compound of the formula I can be obtained or It is a mixture of isomers. To prepare a stereochemically homogeneous compound of formula I, it is convenient to react a stereochemically homogeneous compound of formula V with a stereochemically homogeneous compound of formula W. If a pure mirror image-isomer of the formula V is reacted with a racemic isomer of the formula VI, or a racemic isomer of the formula V is reacted with a pure mirror image-isomer of the formula VI In each case, a mixture of two diastereomers can be obtained, either at the stage of the compound of the formula π or at the stage of the compound of the formula I, if necessary, The method is divided into 25 1332947. The reaction of an isomeric compound of the formula v with a νΐϋ isomeric compound produces a corresponding mixture of four isomers which can be separated, if necessary, by known methods, for example using 分离ριχ on a possibly asymmetrical separation material. Separation method. The compound of the formula V has an asymmetric center on a carbon atom having a radical -COOR", and can be obtained by synthesizing a propionate derivative in the form of a racemic isomer of the formula νπ. Optically active compounds can in principle be used from racemic isomeric mixtures by methods which are known per se, for example chromatographic separation methods on asymmetric separation materials, and with appropriate optical readings such as alpha _methylmethamine, dnehcmidine or pseudoephedrine react with each other, and by fractional crystalhsation of the resulting salt to separate into its optically active enantiomer (as obtained). a compound of the formula and its pharmacologically distinct element, which is characterized by its advantageous pharmacological properties. The turning point is that the substance is a ruthenium-like peptide cleavage enzyme. Neutral endonuclease is an enzyme. , which cuts the endogenous diuretic (four) ^ sparse), too for example. Atrial natriuretic peptide (= ah. Because it has an inhibitory effect on the activity of neutral peptide endonuclease II, the improvement of these substances (4) will be attacked by the endo-type enzyme of the trait, (diuretic steel, especially the atrium) The biological activity of natriuretic peptide and its effective life' is therefore suitable for the treatment of the pathological problems of the positive effects of occupational hormonal effects. The most important (four) is the treatment of vascular dysfunction, especially read dysfunction, especially congestive heart failure. In the case of congestive heart failure, the increase in the vascular resistance caused by reflex will occur in the reduction of the (four) doses induced by heart disease f. This means that the myocardium does not start to rise against the rise and then collects the blood. This situation leads to a vicious circle that increases the heart's overwork and makes the situation even more awkward. The vascular resistance is increased: also: the cause of the action on the blood vessels, endothelin ET leads to the endothelium. The endogenous vasoconstrictor substance with the strongest force is known to be produced by the large endothelium Big-ET-D of 26 1332947. The enzyme is involved in the conversion of large endothelin to endothelin according to different enzymes. In many cases, in the case of congestive heart failure, because of reduced cardiac output and increased end-force, the blood canister phenomenon occurs in the pulmonary circulation and in the heart two:

in. Therefore, an increase in the wall tension of the heart muscle occurs in the auricle and ventricle I domains. In this case, the secret of the heart is now the function of the internal classification, and the secretion, especially the atrial diuretic, is too much in the bloodstream. Because of its significant vasodilation and the effect of diuretic/diuretic, the atrial diuretic system makes the reduction of the resistance of the last golden tube and the blood volume of the circulating towel decrease. This silk is the front load and the after load is significantly reduced. This constitutes a continuous protection system of endogeneity. This positive endogenous mechanism is limited' because of the very short-lived half-life of the natriuretic peptide in plasma towels. The reason for this county is that the hormone is very rapidly decomposed by the neutral peptide endonuclease. The compound according to the present invention reduces the activity of the endothelin converting enzyme by inhibiting the activity of the endothelin converting enzyme, and also reduces the production of endothelin, so that the end vascular resistance is increased, which eventually causes Myocardial overwork is soothing. These results further exemplify that the substance according to the present invention causes a higher concentration of atrial natriuretic sodium and atrial diuretic sodium as a result of inhibiting the activity of the neutral peptide endogenous strip. This condition should result in an enhancement of the endogenous mechanism of the adiponectin-dominant-to-dirty protection and confers an efficient use of the substance of formula I for enhancing the diuretic/sodium diuretic activity induced by atrial natriuretic sodium. Neutral lunar endonuclease is involved not only in the breakdown of atrial endopeptidase, but also in the breakdown of endothelin. It can be seen that the pure mid-endo-chain endonuclease inhibition, in addition to the increased concentration of atrial natriuretic sodium, also causes an unfavorable increase in the concentration of endothelin. For this reason, a mixed neutral virginase, human soluble peptide chain incision _ and a (four) case of endothelin-converting enzyme inhibition characteristics with the reduction of gallbladder benefits, because it inhibits urinary urinary atrial retinal It is decomposed by Taitai I (inhibited by neutral temporary endonuclease), and at the same time, it inhibits endothelin<production (inhibited by human soluble endopeptidase and endothelin converting enzyme). Therefore, the positive influence may be accompanied by a purely neutral rituximastat inhibitor (ie, an undesired increase in endothelin concentration). The compound of the formula I is characterized by the neutral peptide endonuclease, the inhibition of the human soluble endonuclease, and the lesser combination of the (10)-converting enzyme inhibitor, so that the compound according to the invention appears to Particularly suitable for and / or treatment of pathological problems 'such as problems or ah, such as vascular disease or disease, especially cardiac dysfunction' including acute continuation of New Zealand, and especially congestion and diarrhea; Blood pressure, including a second type of hypertension such as essential hypertension, high kidney pressure and/or lung hypertension: rhythm failure, narrowness. The disease is not i% muscle; ^ plug's myocardial stenosis caused by peripheral surgery, myocardial embolism prognosis is not ^, read society, congestive, ill, hypertrophic obstructive cardiomyopathy, hypertrophic non-occlusion, disease, primary record Disease, money inflammation, pericarditis and / or larger breastfeeding, especially human (9) membranous inflammation. The compound of the formula also has the use of hoof and/or treatment for damage to the money, especially the knowledge of the myocardium. The drug 'in particular' is a cytostatic agent, which is more difficult or uncomfortable. Toxic (4) induced resistance; abdominal analgesic cerebral ischemia, peripheral vascular disease, hypoxic hemorrhage, chronic obstructive pulmonary disease (COPD), kidney disease (renal failure), arteriosclerosis, and larger Mammals' f is a person's _ straight or painful adenocarcinoma. One shows that f is a compound of formula 1 because of its effect on regulating blood pressure, especially its effect on blood pressure, which is good for New Zealand money (10). 28 1332947 Description of Pharmacological Test Methods The sample numbers quoted are for the preparation examples described below. 1. Moon-chain endo-inhibition double inhibition effect Lie test to prove that the substance according to the invention is in neutral to the inner moon

Glu-His-Val-Val-Pro-Tyr-G^ ® t ^ ^ ^ " Hydrolysis of the activity of sputum, in the in vitro standard test, the measured value of the substance to be tested From the 'value. - and there are: 1C5. The value is the concentration at which the test substance is inhibited by 50% of the enzyme activity in the neutral chain. Test buffer solution: 100 mM TrispHXO, ΜΟιηΜίν^ Enzyme: soluble, human recombinant neutral endopeptidase Crine Professor's mother solution of the University of Montreal, Canada: in 2 mM Tris pH 7.0, ^ Operating solution: test solution for mother solution Dilution to 24§/1111 Substance: MCa*-Asp takes Qin Trp to refer to wTyr-Gly-Leu; a large endothelin (Big-ΕΤ-Ι) analogue that annihilates Laoguang, that is, a metalloprotein hydrolysate g, especially in the middle of the endo-chain endonuclease and coffee, can be obtained from the fluorescent signal detection I to obtain the fluorescence of the MCA fluorescent chromophore at the beginning due to the presence of the "quenching agent Dpa" Disappeared. *Mca = (7-methoxycoumarin _4_alkenyl) = (3-[2, U-Schottylphenyl]-heart 2, 3-diaminopropenyl) from Wolfenbiittel, Germany P〇iypeptide Lab〇rat〇ries mother liquid: ΙΟΟμΜ test substance in the test buffer: all of these substances are dissolved in the D pair (1 () should be), and diluted with the test 29 1332947 buffer solution to Concentration tested. 70μ1 test buffer solution, 1〇μ1 enzyme working solution and 1〇μ1 test substance solution mixed In an Eppendorf container ' and pre-incubated at 37 ° C for 15 minutes (= min.). Then add 1 μl of the mother substrate solution, and place the batch test group at 37. Incubate for 60 minutes. The reaction of the enzyme was stopped at 95 ° C for 5 minutes. After centrifugation (Heraeus Biofoge B, 3 minutes), the liquid supernatant fraction was studied by HPLC according to the following description. The substrate was subjected to reverse phase HPLC (CC 125/4 Nucleosil). The 300/5 C18 RP column, together with the CC 8/4 Nudeosil 100/5 C18 pre-column 'Macherey-Nagel from Dttren, Germany, was isolated from the cleavage product. Here, the 6 〇μ1 test mixture was injected into the HPLC. At the sample injection point' and the column is rushed at a flow rate of 1 ^1/min with the following slope:

Mobile phase A : 100% H20 + 0.5 M H3P〇4 pH 2.0 mobile phase B : 100% acetonitrile + 0.5 M H3P〇4 〇 to 2 minutes 20% B 8 to 1 〇 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 month too sword test is absorbed at 214 nm, and used The excitation wavelength was 328 nm and the release wavelength was 393 nm. When the enzyme cuts off the moon too, the fluorescent chromophore (=Mca) and the quencher are offset in different months of the fragment, which reduces the effect of quenching, which causes an increase in fluorescence. The fluorescence signal (corresponding to the surface 'A) of the jjpLc peak increase containing the unquenched Mca fluorescent chromophore is taken as the calculation of the step. This signal is used to compare with a sample containing (=a inhibitor) or no (=A*m) test substance of formula I. The value of "% suppression" is calculated based on the area of individual peaks by the following formula: 〇/〇 suppression = 100* (1-A suppression / A control) 30 1332947 All samples are in two repeats, The inflammation thus calculates the average value. The standard inhibitor (10 nM thiorphan) and the solvent control (0.1% DMSO) were measured as if they were quality control at each run. In this test model, the test substance of the formula I listed in the following table has the following IC5G values: 'monthly endonuclease for p-month endonuclease

Substance for humans to prove that according to the 〉 monthly 太 链 链 酉 酉 酉 酉 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. ’ ’ 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该

The hydrolysis of Thr Pr〇-Glu-His-Val-Val-Pro-Tyr-Gly-Leu-Gly-CO〇H 0 肽 peptide endonuclease activity was studied in an in vitro fresh test. In this test, the measured value of the inhibitory effect of the test substance is its Ic value. An IQ having a test substance that inhibits enzyme activity. The value is the concentration at which the test substance is inhibited by 50% inhibition of the enzyme activity per human enzyme in the soluble peptide chain. Test buffer solution: l〇0raMTrispH7〇, 25〇mM Naa enzyme: plus the soluble soluble endopeptidase of His6, the exosome from the Belgium 'Ghent lnn〇geneties mother solution: 53 mg/ml at 20 mM HEPES pH 7.2, 5% glycerol, 〇''% Tween20' 100 mM purity above 99. /. In NaCl, the operating solution: the mother solution is diluted to 1 〇mg/ml with the test buffer solution.

Sense of mass. Mca-Asp-I] e-Ala-Trp-Phe-Dpa-Thr-Pro-Glu-His-Val-Val-Pro-T yr-Gly-Leu-Gly-COOH; A large endothelin (Big-ΕΤ-Ι) analogue mother; a solution of glutamic acid _ ΙΟΟμΜ in the test buffer solution from Wolfenbtittel, Germany P test substance: all of these substances are dissolved in DMSO (10 mM) And diluted to the concentration tested with the test buffer solution. The test and the operation of the HPLC method were carried out in accordance with the above-described method for determining the inhibitory effect of the test substance on the neutral peptide incision g per in vitro. 1 phosphor 之 phosphoramidon is used as a standard inhibitor in the HPLC method. In this test model, the test substance of the general formula I listed in Table 2 below has the following IC5Q values: · A test substance inhibits human pour serotonin endonuclease in vitro & 32 1332947

3. 4 μ 细 -1) , in order to prove that the substance according to (4) has an inhibitory effect on the production of endothelin from large endothelin 'transfer substance inhibits large endothelium to endothelin due to endothelin converting enzyme and related enzymes such as human soluble The hydrolysis of the activity of the endopeptidase enzyme was studied in an in vitro standard assay. Endothelin is an endogenous strong vasoconstrictor. An increase in the concentration of endothelin in the blood causes an increase in blood pressure. When the injection of large endothelin is injected, the degree of blood pressure rise is determined by the endothelin produced by large endothelin catalyzed by large endothelin catalyzed by yeast 33 1332947. The inhibitory effect of these substances on the increase in blood pressure caused by the injection of large endothelin was measured as a measure of the effect of the substance on the inhibition of the enzyme. Rats (Spmgue-Dawley, CRLD = Charles heart were anesthetized with 1 mg/kg Rompun/ Ketavet 1:1. A blood pressure transducer (Statham) was inserted into the carotid artery to detect blood pressure. Insert a jugular vein into the sleeve The tube is administered with the test substance, and the other jugular vein is used for the administration of large endothelin. After the rest time of 2 minutes, the rats are given the test substance corresponding to the formula I, and the concentration is usually 1〇^〇 1/kg, or a shaped drug. After 5 minutes, inject a large endothelin of 5 nmol/kg into the sputum minute. Contraction (sap = systolic arterial pressure) and diastolic (DAp = diastolic arterial pressure) blood pressure And heart rate, each measured before administration of the test substance or prior to administration of large endothelin, and in each test after the administration of large endothelin, the blood pressure transducer is measured every 5 minutes by a conventional method. The time is as long as 3 minutes. The maximum value of blood pressure rise and the maximum decrease in heart rate caused by large endothelin are calculated from the measured values when the effect of large endothelin is maximized ( Typically after 5 minutes) and injection The difference between the values measured before the input of large endothelin. Furthermore, the integral value of the blood pressure curve under the influence of large endothelin was determined for 30 minutes (AUC = area under the curve). The AUC value is available for large The message of the extent of action and duration of action of endothelin, or the message that the effect of large endothelin is reduced by the test substance; therefore, the AUC value, in addition to providing the maximum effect of large endothelin, can also provide The message of the action of the test substance, for example, on the matter, that is, the test substance does not, for example, affect the action of large endothelin, but greatly accelerates the action of resolving large endothelin. The maximum inhibitory effect of SAP on the amount of inhibition produced by intravenous administration of the test substance, compared with the administration of the excipient, 34 1332947 is described in Table 3 below: Table 3: In vitro test of the antihypertensive properties of the test substance The maximum effect of the sample number large endothelin on contractile arterial blood pressure was inhibited by the relevant test substance, compared to the control group 2 - 53 3 -94 4 -95 8 -113 14 -59 (3μιηο1) 16 -45 17 -46 20 -67 21 -43 23 -40 24 -54 26 -53 29 -49 32 -52 34 -78 35 -63 38 -48 (3μιηο1) 44 -75 59-98 67 -109 68 -108 35 1332947 The compound of formula i also exhibits some inhibition of the endothelin-converted purine. The inhibitory effect of the substance of formula I on endothelin conversion g can be It has been proven in in vitro standard tests. The compound of formula I is a dual acting compound which is capable of inhibiting neutral endostase and human soluble endonuclease, and is also useful for the prevention and/or treatment of sexual dysfunction. Clinically, sexual dysfunction has been distinguished into female sexual dysfunction (PSD) disorders as well as male sexual dysfunction (MSD) disorders (see) vielman, A. & Gingell, JC (1999). The epidemiology and pathophysiology of erectile Dysflmctioi LJUrology 161: 5-11, hereinafter referred to as "Melman et al. 1999"). The present invention has a dual-acting compound capable of inhibiting neutral peptide endo-cuts and human soluble I-chain in-segment g-slices, especially compounds of the general formula, particularly ii, in preventing and/or male sexual dysfunction (eg Male erectile dysfunction - MED). Another advantage of the compounds of formula I in this indication is that their action profile has a degree of inhibition of endothelin converting enzyme. Male sexual dysfunction is generally associated with erectile dysfunction, known as male erectile dysfunction (=MED) (see Benet, AE et al. (1994), Male erectile dysfunction assessment and treatment options. C07Sp. TheY· 20: 669-673) hereinafter referred to as "Benet et al. 1994". Male erectile dysfunction is defined as: "Cannot achieve and/or maintain penile erection for sexual performance (see NIH Consensus Development Panel on Impotenee (1993). NIH Consensus Conference Impotence. JA. Μ· A. 270: 83) "." The prevalence of erectile dysfunction (=ED), which has been assessed to all degrees (mild, moderate, and complete impotence), is 52% for men between the ages of 40 and 70, and for men over the age of 70. Higher ratios (Melman et al. 1999). This condition has a significant negative impact on the quality of the life of the patient and his or her partner, often causing anxiety 36 1332947 and increased tension, which leads to depression and lack of self-esteem. Twenty years ago, male erectile dysfunction was primarily thought to be a psychological condition (Benet et al. 1994), and today everyone knows that for most patients, there is a cause of organism. Therefore, there has been a lot of progress in identifying the mechanisms of normal penile erection and the pathology of male erectile dysfunction. If the dual-acting compound of the present invention is capable of inhibiting neutral in-chain cleavage and human soluble dentate g, especially compounds of formula I, and for treating female sexual dysfunction, treating females Sexual arousal disorder (= FSAD) is preferred. The best definition of female sexual dysfunction is that women have difficulty or cannot find satisfaction in sex. Female sexual dysfunction is a generic term for several different female sexual dysfunctions (Leiblum, SR (1998). Definition and classification of female sexual disorders, int. J. Impotence Res., 10, S104-S106; Berman, JR, 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 in stimulating or climactic, have painful intercourse or a combination of the above problems. There are several types of illnesses, medications, injuries, or physical problems that can cause female sexual dysfunction. The still evolving treatments are tailored to the treatment of specific female sexual dysfunction subtypes, mainly sputum and sexual sensation. The best sense of female sexual dysfunction is compared with the stage of normal female sexual reaction: sexual desire, excitement and orgasm (Leiblum, SR (1998). Definition and classification of femaie sexual disorders. Int. J. imp 〇tence Res” 10, SI04-S106). Sexual desire or desire is the driving force of sex. Its appearance often includes when and when it feels interesting <accompaniment-(four)' or when it is exposed to other sexual temperament 37 1332947 Excitability is the reaction of blood vessels to sexual stimulation β and an important factor is genital bloodless, and includes vaginal separation of synovial fluid, vaginal prolongation and increased genital sensitivity. The climax is reaching the peak during the excitement. It is tight and comfortable. Therefore, 'when women are unable to have enough or satisfying reactions at any stage of these stages', they are usually sputum, excitement or high _, that is, pure female sexual dysfunction. Female sexual dysfunction The categories include libido vitality disorders, cold sensation, orgasm disorders, and sexual behavioral pain disorders. "Although the compounds of the present invention improve genital stimulation Reaction (such as women's frigidity), when so to whom, such compounds may also be accompanied by the improvement in pain with intercourse Jie it had been tense and uncomfortable, and therefore the treatment of other types of female sexual dysfunction. Therefore, in accordance with a particular aspect of the present invention, there is provided a method of using the compound of the present invention for the preparation of a medicament for treating or preventing sexual dysfunction, cold sensation, orgasm disorder, and sexually active pain disorder, and more preferred for treatment or It is a preventive cold sensation, an orgasm disorder, and a sexual behavioral pain, preferring treatment or preventive coldness. If women have no or little desire for sex, and there is no or little sexual idea or fantasies, there is a lack of sexual activity. This type of female sexual dysfunction may be caused by a low concentration of testosterone due to menopause caused by natural menopause or surgery. Other causes include illness, drugs, burnout, depression, and anxiety. The sexual sensation of women's characteristics is that sexual organs do not respond adequately to sexual stimuli. The genital organs have not undergone hyperemia on the characteristics of normal sexual excitement. Poor lubrication of the vaginal wall', thus causing pain during sexual intercourse. The climax may be hindered. The cold may be due to decreased estrogen secretion during menopause or after childbirth and during lactation, as well as diseases due to vascular factors such as diabetes and arteriosclerosis. Other causes include diuretics, antihistamines, antidepressants, 38 1332947 such as selective serotonin reuptake inhibitors (=SSRIs) or sputum therapy. Sexually transmitted pain disorders (including painful intercourse and vaginal fistula) are characterized by pain caused by insertion, and may be due to drugs that reduce the secretion of lubricating fluid, ectopic tissue of the neurite, pelvic inflammatory disease, inflammatory bowel disease Or the urethra is caused by the problem. The prevalence of female sexual dysfunction is difficult to estimate because the term covers several (four) issues, and some of these disorders are statistically difficult, and because of the interest in treating female sexual dysfunction is very recent. ... many women's sexual problems are not directly related to the process of aging women, that is, related to diffuse diseases such as diabetes or high blood pressure. Since female sexual dysfunction contains several subtypes of f, its performance a symptom is at different stages of the sexual response cycle, so there is no single treatment. At present, the main focus of treatment of female sexual dysfunction is psychological or relationship. The problem] the treatment of female sexual dysfunction is gradually developing, because more and more clinical and basic scientific research is investigating medical problems. On the other hand, the complaints in terms of pathophysiology are not entirely psychological problems. In particular, the rhetoric may have become the vascui〇geneic dysfUnction of all female sexual aspects (such as female sensation ) the individual of the factor and 5. So far, there are no licenses available to treat women. The drug (10) contains drugs that are administered to the female (localized ^ as a hormone replacement therapy), mixed or modified (four), such as =sp_e or t_dQne. The choice of fresh treatment is often unsatisfactory due to low efficacy or side effects. Because the new search for pharmacology = law to turn women's records of Wei Shiyi students interested, (four) branch contains the following few people ~ Li,; F need a physician to get the sex spray agent, to study the drug candidate, Includes drugs that have been approved for other treatments. The drugs such as 39 1332947 include hormone preparations, testosterone, or a combination of estrogen and sputum copper, and vascular drugs that have recently been shown to be effective against male erectile dysfunction. However, none of these drugs has been shown to be effective in treating female sexual dysfunction. The Diagnostic and Statistical Manual (DSM) IV of the American Psychiatric Association defines feminine coldness as: "Persistence or relapse incompetence to achieve or maintain sufficient sexual stimulation to stimulate the swelling response until completion of sexual activity. It will definitely cause obvious pain and social difficulties." Excitatory reactions 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. The study of couples with sexual dysfunction found that 76% of women complained of sexual dysfunction, and 30 to 50% of women in the United States had experience with female sexual dysfunction ^german,j R,

Bem sister, L. Α·,·Μη, T J. et al. (1999), Femde sexual dysfunction:

Anatomy, physiology, evaluation and treatment options. Curr Opin Urology, 9, 563-568). Female sexual sensation is a prevalence of sexual dysfunction that affects premenopausal, menopausal, and postmenopausal (hormone replacement therapy (HRT)) women with associated concomitant conditions such as depression, cardiovascular Conditions, diabetes, and genitourinary conditions. The main result of female sexual coldness is the lack of congestion/expansion, lack of lubrication and lack of genital pleasure. The secondary result of female sexual coldness is the reduction of libido, the pain during sexual intercourse, and the difficulty of reaching orgasm. It has recently been hypothesized that vascular factors can be used as a basis for at least a part of patients with feminine and cold sensation symptoms (Goldstein et al. 'Int. J. Impot· Res., 10, S84-S90, 1998), and on animal experiments. The data supports this view by Jin Hongwei et al., Int. J. Impot. Res, 9, 27-37, 1997). It is known that inhibitors of soluble endopeptidase increase the vaginal and clitoral blood flow 40 1332947 which is stimulated by the pelvic nerves and caused by the intestinal tract (=VIP) acting on the blood vessels. And β also knows that the inhibitory side of the cleavage peptide cleavage enzyme will increase the yin of the yin, which is acted upon by the vascular reading peptide and by the gods. Thus, the advantages of the present invention are to provide a means to re-establish a normal sexual excitement reaction, i.e., to increase the blood flow of the bribe to promote blood in the vagina, the vaginal and labia. * This transfer will cause vaginal (4) fluid leakage outflow: Increase the secretion of lubricating fluid, increase vaginal compliance and increase the sensitivity of the vagina. Thus, the present invention provides a method for re-establishing or enhancing the response to normal sexual excitement. For the bribe of a woman in this article, it means that the reproductive organs are composed of - (four) and external groups. The internal organs are located in the pelvic cavity and are composed of the ovaries, the printing tube, the uterus and the vagina. The organ is located outside the genitourinary septum and below the pelvic arch. It contains the pubic lice, 'macular labia, labia, clitoris, vaginal vestibule, vaginal vestibular ball, XGray^s Anatomy, CD Clemente, 13th American Edition eR.J. Levin teaches that "men and female reproductive organs are embryonicly developed from common tissue primordia, and the structures of male and female reproductive organs are claimed to be mutually homologous. Therefore, The clitoris is homologous to the penis, while the labia is homologous to the scrotum (Levin, RJ (1991), Exp. Clin. Efzdocrinol., 98, 6169). Regarding male sexual dysfunction, especially male erectile dysfunction, penile erection is a hemodynamic event that depends on the balance of contraction and relaxation of the cavernosal smooth muscle and the distribution of penile blood vessels (see Lemer, SE et al. (1993) A review of erectile dysfonction: new insights and more questions. J. Urology 149: 1246-1255). The cavernosal smooth muscle is also referred to herein as a corporal smooth muscle or a plural sense corpus cavernosa. The relaxation of the smooth muscle of the cavernous body causes an increase in the blood flowing into the trabecular space of the cavernous body, causing it to expand toward the surrounding capsule, and compressing the vein of the deflation. This condition causes a significant increase in the blood pressure of the cavernous body, which leads to an erection (see Nayl〇r, A. 1332947 Μ. (1998) «> Endogenous neurotransmitters mediating penile erection. Br. X Urology 81: 424-431) ' Citation "Naylor, 1998"). The changes that occur during the erection are complex and involve a high degree of coordinated control of the surrounding and central nervous system and the endocrine system (Nayl〇r, 1998). The contraction of the body smooth muscle is regulated by the innervation of sympathetic adrenaline by the a-adrenergic receptor after the active cell junction. "Male erectile dysfunction may be related to an increase in smooth muscle tone in the cavernous body. However, the relaxation process of the body smooth muscle is partly dominated by the nerve conduction of non-adrenal, non-choline (=NANC). Many other NANC neurotransmitters other than nitrogen oxides (=Ν0) are found in the penis, such as peptides related to the calcitonin gene (=CGRP) and intestines that act on blood vessels (νιρ) . The main negative and the relaxation factor that dominates this relaxation is NO, which is synthesized from oxynitride (=NOS) 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 the body smooth muscle tension may help NO to induce relaxation of the cavernous body. When a male is in sexual excitement, NO is released from neuronal cells and endothelial cells, and is combined with and activated by soluble guanylate cyclization @〇〇(:) located in smooth muscle cells and endothelial cells. This causes an increase in the concentration of cyclic guanylate 3',5'-monophosphate (cGMP) in the cells. This increase in cGMP concentration leads to relaxation of the cavernous body, which is due to the decrease in the concentration of intracellular calcium ions ([Ca2+]i), which is believed to be related to the activation of protein kinase G (protein kinase G). Probably because the Ca2+ pump and the K+ channel activated by Ca2+ are activated). It has recently been pointed out that c-type diuretic sodium S (=CNP) also plays a role in male erectile dysfunction, which interacts with guanylate cyclization immobilized on the cell membrane from every B (=GC-B), the enzyme is It is expressed in the cavernous tissue of humans. Stimulates guanylate cyclization 42 1332947 Enzyme B causes an increase in intracellular eGMP, which results in smooth muscle relaxation. PDE-5_agents such as silkenafH' are inhibited. The tear is broken down to increase the cGMP in the cells of the seaweed body. The presence of P-inhibitors in the absence of eGMp in the presence of NO is inactive, and there is no activity. The current (unstimulated) rate of cGMP production in the glare tissue is quite low, and the PDE-5 inhibitor is hostile. Inhibition of cGMp breakdown is not sufficient as an erectile response in the absence of simultaneous stimulation of the tacrolimus cyclase. Increasing the concentration of the diuretic steel will increase the concentration of eGMp in the cells due to the formation of cGMP. Therefore, increasing the concentration of _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ However, due to its different mechanism of action, that is, increasing the production of cGMp compared to inhibiting the decomposition of eGMP, (4) Na 5 or the method of decomposing _ urinary peptide are considered to be additive, so make a reasonable It is assumed that combining the two types of sputum mines with only PDE_5 can not be effective. : Wang is now found in the vascular skin of the corpus callosum. It has been found in the reticular tissue of the corpus cavernosum, indicating the release of intestinal peptides acting on blood vessels in the role of penile erection. The action of the intestine of the blood vessels is too much, and its action is thought to be promoted by the increase of cAMP, thus complementing the effect of increasing the concentration of cGMp drugs. Intracavernous injection of gastrointestinal peptides (in combination with the use of ... adrenergic receptor antagonist phentolamine) in patients with erectile dysfunction b was found to be a safe and effective treatment with a response rate of 67% ( Enough erection of sexual intercourse). Endonuclease 'neutral endopeptidase and human soluble peptide chain incision strips, both of which will break down the c-type diuretic sodium and the intestinal tract that acts on the blood vessels too, thus limiting the diuretic c-type The effect of sodium peptide and intestinal peptide acting on blood vessels on cavernosal smooth muscle. Inhibition of c-type natriuretic peptide and its action on the intestinal tract of the blood vessels will result in an increase in the availability of vasoactive factors such as sputum, thereby increasing the blood flow into the corpus cavernosum 43 1332947, which should eventually lead to an improvement in erectile function. Experimental data from rabbits showing a significant increase in blood pressure in the sponge and blood flow to the female genitalia after administration of a neutral endopeptidase inhibitor (see patent W002/079143) 'can be found Support for this argument. Furthermore, a gene encoding the pro-inhibitor sialorphine pre-symbol (SMR1) was discovered (see User, Η. M., Zelner D. J) McKenna KE, Me Vary KT (2003) » 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) is significantly down-regulated in a rat model of neurogenesis erectile dysfunction ( More than 80 times), indicating that in this condition, it may strengthen the activity of the neutral month too-key endo-cutting quotient, and become the cause of the development of erectile dysfunction. The pharmacological test method description refers to the sample number cited below. Examples of preparations The inhibitory effect of the compound used in the present invention on c-type diuretic sodium and on the intestinal tract of the blood vessels is measured by an in vitro enzyme test according to the following method: Enzyme: a) Human soluble skin chain Endonuclease (sol hu)(his)6; or: addition of His6 human soluble endopeptidase exogenous site mother solution: 53 pg/ml at 20 mM HEPES pH 7.2, 5% glycerol, 0.005% Tw Een 20,1 mM NaQ with a purity higher than 99%, operating solution: mother solution diluted to 5 pg/ml with test buffer solution Supplier: Belgium, Ghent's Innogenetics. The preparation and purification of this protein is performed as WO02/ b) Neutral endopeptidase (prepared from the cortex of porcine kidney) 094176 Mother solution. 120 pg/ml in 20 mM bis Tris, purity greater than 95% Operating solution: Mother solution diluted with test buffer solution To 5 pg/ml 1332947 Supplier: Dr. Philippe Crine, University of Montreal, Canada Quality: a) Intestinal month acting on blood vessels too b) Type c diuretic sodium month too (32-53) Mother solution: 100 μΜ in test buffer solution Middle supplier: Bachem test buffer solution from Weil, Leipzig, Germany: 100 mM Tris pH 7.0, 250 mM NaCl All test substances were incubated in DMSO to mM and further diluted with test buffer. Activity test method 80 μΐ Test buffer solution ' 10 μΐ enzyme operating solution (neutral monthly endo-chain endonuclease or human soluble monthly oligo-chain) and 10 μΐ month mother solution (acting on vascular intestinal peptide or c-type natriuretic peptide) Mixed in an Eppendorf Vessel, and incubated at 37 ° C 120 min. Heat to 95 ° C for 5 minutes to stop the reaction of the enzyme. After centrifugation (Heraeus BiofUge B ' 3 minutes), the liquid supernatant fraction was analyzed by hplc. Inhibition test method 70 μΐ test buffer solution ' 10 μΐ enzyme solution (neutral endopeptidase or human soluble S-chain endolyzer) and 10 μΐ of the test compound mother solution mixed in an Eppendorf container 'And pre-incubated for 15 minutes at 37 °C. Then, 10 μL of the peptide mother solution (intestinal peptide acting on blood vessels or c-type natriuretic peptide) was added, and the reaction mixture was incubated at 37 ° C for 60 minutes to carry out the hydrolysis reaction of the enzyme. Heat to 95 C for 5 minutes to stop the enzyme reaction. After centrifugation (Heraeus Biofiige B, 3 minutes), the liquid supernatant fraction was analyzed by HPLC. Separation of the remaining substrate from the decomposition product, using reverse phase HPLC with a CC 125/4 Nucleosil 300/5 C1S RP column and a CC 8/4 Nucleosil 100/5 C18 pre-column (from Macherey-Nagel of Dtiren, Germany). Here, 60 μM of the reaction sample was injected into the HPLC, and then the column was eluted at a flow rate of 45 1332947 at 1 ml/min with the following gradient: Solution A: 1 〇〇%H20 + 0.5 Μ Η3Ρ04 pH 2.0 Each liquid B: 100% Acetonitrile + 0.5 Μ H3P04 0 to 2 minutes 5% Β 8 to 10 minutes 90 〇 / 〇 β 2 to 7 minutes 5 to 50% Β 10 to 12 minutes 90 to 5 〇 / 〇 β 7 to 8 minutes 50 Up to 90% Β All skins are detected by absorption at 214 nm (UV spectroscopic analysis). The percentage of hydrolysis (=%) is calculated according to the following equation, based on the fact that the peak area of the enzyme containing sample Y is not decomposed, S is too large, and the sample containing the same concentration >9 is too long without enzyme (blank group) : % Hydrolysis = 100* (blank group - Y) According to the calculation of % inhibition, an inhibitor containing sample X is not decomposed into too much (acting on the intestinal tract of blood vessels or c-type diuretic sodium I too) The area of the wave ♦ is calculated by the following equation compared with the sample containing only the moon too (blank group) or the moon too enzyme without the inhibitor (control group): % inhibition = 1 〇〇 * (χ - control Group) / (blank group - control group) All samples were repeated in two replicates and the average was used. A solvent control (0.1% DMSO) was added to each of the tests awaiting. The c-type natriuretic sodium and the intestinal tract that acts on the blood vessels are cut off in vitro by neutral temporal endo-streptase and human soluble endopeptidase. Human soluble endopeptidase cleaves both peptides faster than neutral endopeptidase, as shown in Table 4 below: Production of intestinal peptides (=νπ>) and c-type natriuretic peptides =CNp) Decomposition by neutral endopeptidase (=NEp) or human soluble endopeptidase (= hSEP) rate 46 CNP decomposition hSHP hour decomposition

Soluble I: bisexual "cutting t-like decomposition. In this test model, the intestines acting on the blood vessels have the IC50 values listed below: 5 (the test substance i_5_ · the test substance for decomposition C-shaped Lizhong melon blood Affects heart,. and the urine noodle month too (=CNP) and hSEP acting on the decomposition of the sample number CNP decoding]S^gp inhibition ----- (-M) Μ__lo.i General malady

The decomposition of VIP hSEP NEP j^5〇^(nM) IC5〇(nM) 3.1 compounds are also suitable for the prevention and/or treatment of diseases associated with apoptosis, such as: neurodegenerative disorders, such as ischemic Stroke, cerebral ischemia, traumatic brain injury, acute disseminated encephalomyelitis, amyotrophic lateral sclerosis (ALS), retinitis pigmentosa, impaired mild cognitive ability, Almheimer's disease, skin Pick's disease, Alzheimer's disease, progressive nuclear paralysis, subcortical dementia, Wilson disease, multiple infarction, arteriosclerotic dementia, AIDS-related dementia, Cerebral metamorphosis, cerebral spinal cord degeneration syndrome, Friedreichs ataxia, dysfunctional telangiectasia, brain damage associated with epilepsy, spinal cord injury, leg movement syndrome (restless legs) Syndrome), Huntington's disease and Parkinson's disease, striated substantia nigra disease, cerebral vasculitis, granulosa cerebral musculoskeletal, neurological properties 1332947 Neuronal ceroid lipofiiscinosis, spinal muscular atrophy, lysosomal storage disorders associated with the central nervous system, leukoencephalopathy, urea cycle deficiency disorders, hepatic encephalopathy, renal encephalopathy, metabolic encephalopathy, porphyria , bacterial or viral meningitis and meningoencephalitis, prion disorders, neurotoxic compound poisoning, Guillain Barre syndrome, chronic inflammatory neuropathy, polymyositis, skin Muscle inflammation, radiation-induced brain damage; gastroenterology such as irritating colorectal disease, and inflammatory bowel disease, Crohn's disease and ulcerative colitis, celiac disease, Helicobacter pylori gastritis Other infectious gastritis, necrotizing enterocolitis, pseudomembranous enterocolitis, radiation-induced enterocolitis, lymphocytic gastritis, graft versus host disease, acute and chronic pancreatitis; liver disease such as alcoholic hepatitis , viral hepatitis, metabolic hepatitis, autoimmune hepatitis, radiation-induced liver Inflammation, cirrhosis, hemolytic uremic, glomerulonephritis, lupus nephritis; viral disorders such as fulminant hepatitis; joint disorders such as trauma and osteoarthritis; suppression of immune function or immune dysfunction , especially autoimmune disorders such as primary inflammatory muscle disorders, chronic neutropenia, thrombotic thrombocytopenic purpura, rheumatoid arthritis, primary thrombocytopenic purpura, autoimmune hemolytic syndrome , anti-phospholipid antibody syndrome, myocarditis, multiple sclerosis and its subclass-related recurrence-alleviation of multiple sclerosis, second-stage progressive multiple sclerosis, primary progressive multiple sclerosis, Progressive relapsing multiple sclerosis, acute multiple sclerosis, benign relapsing multiple sclerosis or asymptomatic multiple sclerosis, optic neuromyelitis (Devic's syndrome), lymphocytic sag Body inflammation, Grave's disease, Addison's disease, parathyroidism, diabetes First type, systemic lupus erythematosus, pemphigus vulgaris, large vesicular pemphigus, psoriatic arthritis, endometrial tissue ectopic, autoimmune 48 1332947 testicular inflammation, autoimmune erectile dysfunction, Sarcoidosis, Wegener's granulomatosis, autoimmune deafness, sji5gfen, sji5gfen, s, autoimmune uveoretinitis, interstitial cystitis, Gude Goodpasture's syndrome and fibromuscular pain; vertebral dysplasia, such as dysplastic anemia; dermatological conditions, including pemphigus vulgaris, cutaneous muscle inflammation, atopic dermatitis, Hernoch -Henochschoniein, purple spot, acne, systemic sclerosis, sebaceous leakage of the stratum corneum, excessive skin obesity, chronic proliferative dermatitis, keratosis, cutaneous sclerosis, interstitial granulomatosis , psoriasis, bacterial infection of the skin, skin rickets, leprosy, leishmaniasis, leukoplakia, toxic epidermal necrolysis, Steven Johnson ( StevenJohnson) Syndrome, sebaceous adenoma, alopecia, skin light damage, hardened atrophic moss, acute skin wounds, incontinentiapigmenti, skin heat damage, rash pustulosis, mossy skin disease, skin allergies Vasculitis, cytotoxic dermatitis; conditions in the inner ear such as auditory hairy cell death and hearing loss caused by auditory trauma, auditory hairy cell death induced by aminoglycoside and hearing loss, Hearing loss induced by ototoxic drugs, periorbital fistula, cholesteatoma, cochlea or month 1J ischemic, Meniere's disease, radiation-induced hearing loss, induced by bacterial or viral infection Hearing loss and primary hearing loss; transplantation aspects such as graft-to-host disease, rejection of transplanted organs such as acute and chronic heart, lung, kidney, skin, cornea, bone marrow or liver; wound healing and tissue rejection. 1-(Alkylalkyl)-cyclopentylcarbenylamino-benzene ring SL hexamethylene τ-indole-wound acid derivative of formula I substituted by indoleamine methyl group for prevention and treatment and apoptosis The utility of the associated adverse disorder can be demonstrated in an appropriate animal model for predicting anti-apoptotic activity. 49 1332947 Description of Pharmacological Test Methods The sample numbers quoted are for the preparation examples described below. 1. Traumatic Brain Injury: Delayed Apoptosis of Neuronal Cell Death Contusion Device: The contusion device consists of a stainless steel tube with a length of 40 cm and a hole between 1 cm apart to prevent air from being compressed inside the tube. The 230- to 270-gram Wistar adult chloral hydrate is anesthetized with an intravenous injection of 400 mg/kg, and the skull on the right half of the brain is cut, and then a weight is dropped. The device resting on the bottom surface of the dura mater is placed perpendicular to the surface of the skull, and then a force of 380 g X cm generated by a 20 gram weight is selected to create a brain contusion. A wound of up to 2.5 mm on the surface of the brain prevents mechanical stab wounds in the dura mater. In terms of three-dimensional stereoscopic tropism, the center of the bottom plate is 1.5 mm behind the front bunker and 2.5 mm at the side of the front bunker. Rats were perfused with a solution containing 4% polyformic acid (paraformaldehyde) in phosphate buffer 3 days after brain injury. Intraventricular injection: 5 to 15 μΐ of the compound was administered from the intraventricular (=i.c. ν.) using a Hamicon syringe. The injection was carried out for 5 minutes and the following three-dimensional spatial stereotactic coordinates were used 15 minutes to 8 hours after trauma: the previous bregma is related, AP = -0.5 mm ' L = -2 mm, and V = - 5.5 (Swanson, LW (1992) Brain Maps: Structure of the Rat Brain, Elsevier, Amsterdam) ° Analysis of hippocampal type: hippocampus The damage of the CA3 subregion is sterologically used in trauma Three days after injury, at the level of five different rostrocudals, extending from 10.21 to 11.21 mm (Swanson, LW (1992) Brain Maps: Structure of the Rat Brain, Elsevier, Amsterdam) and the inner and outer axes were measured . To quantitatively assess the damage of nerve cells in the hippocampus, a three-dimensional spatial stereoscopic disector technique 50 1332947 (Cruz-Onve, LM & Weibel, ER (1990) Am. J. Physiol. 258, L148- L156) used it to estimate the concentration of the cone-shaped nerve cells on the number πν). An unbiased calculation frame (0.05mmx〇.〇5mm; double-sector height 001 mm and a high-caliber eyepiece (x 4〇) are used for sampling. The identification of normal nerve cells is due to the presence of typical nuclei It has a clear nucleus and a distinct nucleolus 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 that enters the CA3 subregion and is closely packed with cone-shaped cells. The detachment line connecting the two ends of the dentate granule cell layer is considered to be the junction between the c A 3 and CA4 subregions. In this experimental model, the test substance of Example 3 elicited a dose-related neuroprotective effect. When the test substance of Example 3 was administered from the ventricle for 8 hours after injury, there was still significant neuroprotective effect. The test substance of Example 3 was administered to Wis such as a mouse from the ventricle 15 minutes after the trauma. The dose response of its neuroprotective effect was measured. The determination of the concentration of nerve cells in the CA3 hippocampal subregion was as described in the method, on the left side of the rat treated with the vehicle, and on the left side of the wound, and in the age of The treated rats were on the right side of the trauma, and at the six dimensional three-dimensional stereotactic level of the three-dimensional stereotactic tendency (=SEM) of the three-dimensional spatial stereotacticity (=SEM) of the rats treated with the test substance of Example 3. The measurement 'and its results are listed in Table 6. In all of the following tables, the number ("η") indicates the number of rats that can be used in each group. : CA3 hippocampal neuron concentration, cell χ 1〇3/mm3 trending three-dimensional Space stereogenic excipient left side; (η = 10) excipient right side; (η = 10) Example 3 compound, 3 pg (n = 10) Example 3 compound, 10 pg (n = 10) Example 3 compound, 30 pg (n= 10) 51 1332947 10.21 159.00±3.62 91.20±7.60 98.40±4.39 108.60±4.30 108.40±3.15 10.41 158.20±3.03 87.20±8.17 89.00±5.05 108.60±5.34 105.20±5.76 10.61 157.20±2.88 66.80±7.68 72.80± 6.01 111.40±7.09 94.20±5.10 10.81 159.60±2.99 56.80±5.96 84.20±6.47 112.00±6.42 83.20±7.10 11.01 152.40±2.99 51.40±6.89 86.00±7.44 111.40±7.11 80.20±7.45 11.21 151.60±2.47 71.60±8.22 95.40±6.96 119.20 ±3.70 90.00±9.24 —^---- '心iiy.2u±j./u w.uu±y./4 Injection of excipients caused a decrease in the concentration of nerve cells in the hippocampus of CA3 to 35% of the control value, while injection of 3, 10 or 30 slightly The test substance partially inhibits the loss of nerve cells in the hippocampus, and the dose is 1 最为 which is most effective. The results of the analysis of variance (ANOVA) showed that the sample 3 &<〇〇〇1; each group of n=1〇) of the test substance ^ all three kinds of the amount of damage in the silk (3) hippocampus Wei _ loss has significant, righteousness Protection effect. In addition, AN〇VA also showed a significantly better neuroprotective effect than the dose of 3 or 30 pg. Example 3 The test substance was measured by the intraventricular administration of utai^ into mice after 2, 4 or 8 hours of trauma, and the time window of neuroprotection was measured (1). Ca3 The determination of the concentration of nerve cells in the jujube field is as described in the method. In the right side of the rat treated with the compound of the Formula 3 compound, the six kinds of sputum ' 隹 ster ster ster ster ster ster ster ster ster ster ster ster ster ster ster ster ster ster ster ster ster ster ster ster ster ster ster ster ster ster ster ster ster ster ster ster ster ster Book T in Table 7. -- Trends III. Dimensional space t body CA3 hippocampal neuron concentration, Γ~·--- cell xl〇3/m m3 profile agent right side; (η=8) Example 3 compound, 2 hours; (η= 8) Example 3 compound '4 hours; (n=8) Example 3 compound, 8 hours; (n=8) U〇^2l 72.30±4.80 72.20±5.70 62.00±4.90 52 1332947 10.41 50.65±7.30 68.10±6.30 65.90± 8.80 53,00^^ 44 10.61 49.35士8.76 60.80i5.60 63.00±6.30 53.00:t6 〇〇10.81 51.21±7.97 60.20 soil 9.40 60.50±10.50 52.5〇i4 48 11.01 54.80±10.30 63.00±11.7〇62.20±13.50 61.8〇 ±4 A9. 11.21 60.00±13.00 67.70±14.〇〇66.30±15.90 -----γ·ΤΟ 65.9〇i4 Q〇 The amount of nerve cells in the hippocampus of CA3 was reduced by 35% of the control value. Intraventricular injection of 10 pg of the sample 3 test substance partially arrested the loss of nerve cells in the hippocampus. The ANOVA results showed that the test substance of Example 3 had a significant therapeutic effect on the loss of nerve cells in the CA3 hippocampus at all three time points (at 2 hours and 4 hours' p<〇.〇〇i; at 8 Hours, p<〇〇u. 2, Adriamycin volume: anti-apoptotic activity of Wistar rats weighing 200 to 250 grams with chloral hydrate, 4 〇〇mg/kg, anesthesia' and will The Alzet osmotic mini pump (2ML1) is subcutaneously (=s, implanted. The pump has been filled with excipients or a solution containing the appropriate concentration of the compound of the invention, and is implanted in the 纟! Then on the first, second and third days, adriamycin was given three equal daily doses of '5 mg/kg intraperitoneal injection. The rats were euthanized 5 days after the first injection of adriamycin, and the whole body was covered with 4% polyoxymethylene. (paraformaldehyde) in phosphate buffer solution. Heart, liver and kidney are then removed and embedded in stone ants. TUNEL staining method 1 is promoted by terminal deoxyacid transferase> Notch end labeling method (TUNEL ) According to the histological analysis, the organ is fixed In the next 5 days, biliary burial of people. _L dye-series. The commercial specification on the ΙΟμτη thick stone fairy tablets using Ap〇pTag peroxidase enzyme called Germany, Heidelberg, 0眶Appligene, s 7100). A brief description such as ^ = sheet quality = 2 rational and endogenous catalase suspicion ^ blade is cultivated in fear of money, followed by tearing enzyme operation (labeled as 53 1332947 digoxigenin dUTP nucleotides added to DNA free 3, _ 〇 H end), (37 〇 c, 1 hour). Section in stop/wash buffer (37 ° C, 30 min), then use anti-digoxigenin antibody conjugate (30 min), then use DAB was stained (Deisenhofen 'Sigma, Germany) and stained slightly with methylgreen. In this test model, the test substance of Example 4 gave significant protection to the heart, liver and kidneys. It is toxic by adriamycin because it significantly reduces the density of TUNEL-positive cells among the three organs. This effect is dose-dependent at doses of 100 mg/kg and is best on a daily basis.

Wistar rats were given intravenously acjriamycin at the highest dose of 15 mg/kg. The test article of Example 4 was administered at a daily dose of 2 〇, 50 or 1 〇〇 mg/kg and administered subcutaneously for a total of 5 days by means of an Alzet osmotic mini pump. Animals were euthanized 5 days after the first injection of adriamycin and were instilled into the heart, and the heart, liver and kidneys were then treated for TUNEL staining. It is in the name of TUNEL % cells, and its measurement is as described in the method. The results of each organ (heart, liver, kidney) were the average density of the TXJNEL positive cells ± standard deviation of the control group and the different test groups (example 4 test substance 2, 5 or 100 mg / kg daily) It was measured and is listed in Table 8 below. Table 8: TUNEL positive cells/π^3 X 1〇2 Heart liver kidney Adriamycinb (η = 24) 5.417 ± 0·14ό 10.420±0.275 9.43 8±0.198 + Example 4 compound 20 mg/kg (η = 10) 4.350 ±0.248*** 8.750±0.301** 7.900±0.306*** +example 4 compound 50 mg/kg (n= 10) 3.700±0.260*** 8.250±0.271*** 7.850±0.587** 54 1332947 +example 4 Compound 3.550 soil 0.157 *** 7.450 ± 0.329 *** 6.300 ± 0.260 *** 100 mg / kg (n = 10) Example 4 The test substance reduced the cytotoxicity of adriamycin in a dose-dependent manner in all three organs. The comparison between the experimental groups was performed by the indent's test method ("Ρ<0·01;***P<〇〇〇1 compared to the vehicle treated with the vehicle). The invention also provides a method of treating or preventing a vascular disorder in a mammalian or human heart and/or a disorder associated with apoptosis comprising administering an effective amount of a compound of formula I to the subject in need thereof. The present invention further provides a method for treating or preventing sexual dysfunction in a mammal and a human having an effective amount capable of inhibiting an intermediate limb endonuclease or a human soluble endopeptidase A double acting compound, especially a compound of the formula I according to the invention. The compounds of formula I can be administered in conventional pharmaceutical compositions. The dosage used can vary depending on the individual' and will naturally vary depending on the condition being treated and the type of medication used. In general, however, a pharmaceutical form containing a main component of 0.2 to 500 mg', especially 10 to 200 mg, of each of the other ingredients 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 be in the range of 0.001 to 1 mg/kg/hr. The above dosage is explained by taking the general case as an example. Such compounds may be included with conventional pharmaceutical adjuvants and/or excipients, in solid or liquid pharmaceutical compositions in accordance with the present invention. Examples of solid pharmaceutical compositions are compositions which can be administered orally, such as tablets, coated tablets, capsules, powders or granules, or suppositories. These pharmaceutical compositions may contain, in addition to conventional pharmaceutical adjuvants, such as lubricants or tablet breakers, inorganic and/or organic excipients such as talc, lactose or conventional pharmaceuticals. starch. A liquid pharmaceutical composition, such as a suspension or emulsion of a main ingredient, may contain a conventional diluent, such as water, oil, and/or a suspending agent, such as polyethylene glycol, etc., which may also be added as an auxiliary agent. Such as preservatives, flavoring agents, etc. The main component can be mixed with pharmaceutical adjuvants and/or excipients in a conventional manner to prepare a prescription. In the case of preparing a solid dosage form, the main component can be mixed, for example, with a co-agent and/or an excipient in a conventional manner, and can be granulated by a wet or dry granulation method. The granules or powder can be directly poured into a capsule or compressed into a tablet core by a conventional method. If necessary, the tablets may be coated with a conventional method. [Embodiment] The following examples are intended to further illustrate the invention without limiting its scope. The mass spectrum was measured using the following method: HPLC-MS: API100 Quadrupol mass spectrometer (pE Applied Bi〇systems) was connected to an LC200 (PE). Electronic jet ionization iectr〇Spray j〇nis_ ation) ' Forward mode of operation. Scan range m/z ι〇〇 to 1〇〇〇. Software MassChrom 1.2. Xterra® column (4.6 mm X 50 mm, 2.5 μΐΏ) Solvent system: water (10 mM ammonium acetate 'pH 5) and acetonitrile, linear gradient from 5% acetonitrile to 95% in 10 min. Example 1: Ethyl-2-{[(3S)-l-({[l-(2-tert-butoxy-2-oxoethyl)-2-oxo-2, 3,4,5 · Tetrahydrobenzenecyclohexylene-3-enyl]amino}carbonyl)cyclopentyl]methyl}-4-(isopropylamino)-4-oxobutanoate

56 1332947 A) 91.9 ml of benzyl alcohol was added to 99.07 g of itaconic acid anhydride, and the mixture was stirred at 65 ° Cir for 8 hours (= h). The crystals produced upon cooling were slurried with 35 ml of n-hexane/diethyl ether in a mixture of 2:1 (v/v), and the solvent was removed by filtration. The obtained crude product was dissolved in 150 ml of diethyl ether in a warm state, and then recrystallized by adding 8 ml of hexane to hexane. The combined mother liquor is reduced and recrystallized according to the above procedure, and the crystals obtained are finally added to the main yield. 12 gram of 2_[(2-benzyloxy)-2-oxoethyl]acrylic acid was obtained, which was used in the next step without further purification, 1H-NMR (CDC13): 7.35, m, [5]; 6.47, s, [1]; 5.83, s, [1]; 5.15, s, [2]; 3.40, s, [2] ppm. B) (10) g of 2-[(2-benzyloxy)_2_oxoethyl]acrylic acid obtained above is suspended in 100 ml of methyl-tertiary butyl ether (=MTBE), and 〇. Add 5 ml of pyridine to it. Then, 47 ml of thionyl chloride was added dropwise thereto, and the resulting mixture was heated under reflux for 1 to 5 hours to boiling. After cooling to room temperature, it was evaporated to about dryness under reduced pressure. The residue obtained was dissolved in 50 ml of methane and added to a solution in a trickle at 5 ° C. It consisted of 16 ml of ethanol and 36.5 ml of triethylamine in 150 ml. Composition in dichloromethane. After the addition was completed, stirring was continued for about 1 hour at about 〇 °C. Then, it was washed twice with 250 ml of water each time. One time, it was washed with 1 ml of a dilute aqueous solution of sodium hydrogencarbonate, and the last time 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 15 (TC) yielded 56.3 g of 2-mercaptosuccinic acid 4-benzyl ester-1-ethyl ester which was directly subjected to no further purification or identification. For the next reaction C) 118 ml of diisopropylamine was dissolved in 3 liters of dry tetrahydrofuran (=THF) under nitrogen pressure 57 1332947, and the solution was cooled to ΟC. 340 ml of 2.5 Μ n-butyllithium was added to the η-hexane solution in the argon-containing solution, and after the completion of the addition, the hydrazine was continued. Underarm, mix with sandalwood for 45 minutes. Then, a solution of 45 g of cyclopentanecarboxylic acid dissolved in 100 ml of dry tetrahydrofuran was dropped into the resulting mixture by trickle to 5 ° C, and the mixture was then Stir at 0 ° C for 2 hours. The mixture was cooled to -8 (TC, a solution of 72.6 g of the above-mentioned 2 methylene succinate _4-benzyl ester-1-ethyl ester (from several batches / person of total Cao) dissolved in 100 A solution of THF in tetrahydrofuran was added dropwise thereto. The mixture was then stirred at _75 ° C for 2 hours, then 1.5 liters of 2N aqueous hydrochloric acid was added. After thawing and phase separation, the aqueous phase was used. Ethyl acetate (=EA) was extracted twice. The organic phase was combined and dried over sodium sulfate. The solvent was evaporated under reduced pressure, while the volatiles were distilled at 2 mbar and 140 °. Separation and removal under C. The residue remaining after distillation was chromatographed on silica gel (mobile phase: ethyl acetate / n-hexane 1:6 to 1:7 v/v), and the result was 22 8 g ( 1-[4-(Benzyloxy)_2_(ethoxycarbino)_4_oxobutyl]cyclopentanecarboxy^ ; !H-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 丨[[4_(benzyloxy)_2_(ethoxycarboyl)H-oxygen obtained as above Butyl]cyclopentyl acid (from a total of several batches) is dissolved in 435 ml of one methyl chloride. 39.5 grams of tertiary butyl seven 3S) _3_amino-2 oxo_2 , 3,4,5-tetrahydro]-1//- phenyl hexanyl sulphate (for preparation, see Ep 7 3 642A1) 18·3 a gram of oxybenzotriene (hydr) 〇Xybenz〇triazole) and 60 liters of 林 林 林 added to the solution, then 52 grams of EDCxHCl added to form a mixture, then stirred at room temperature for 58 1332947 overnight. The solvent was then evaporated under reduced pressure. The remaining residue was dissolved in 750 ml of ethyl acetate. The organic phase was washed twice with 1 ml of 2N aqueous hydrochloric acid solution twice, and washed twice with 100 ml of water each time. 100 ml of saturated common brine solution was washed once and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the remaining residue was dried under an oil vacuum (5 x 1 〇 2 mbar). Produced 87.9 g of 2-{[(3S)-l-({[(l-(2-tert-butoxy-2-oxoethyl)-2-oxo-2, 3, 4, 5- Tetra-argon-1 ugly small benzene ring nitrogen hexamethylene-3-hydrazinyl)amino]carbenyl] Cyclopentyl)methyl <RTI ID=0.0>>&&&&&&&&&&&&&&&& E) 87.9 g of the above obtained 2-{[(3S)-l-({[l-(2-tris-butoxy-2-oxoethyl)-2-oxo-2, 3, 4,5-tetrahydro-Utl-benzenecyclohexatrien-3-enyl]amino}carbomethoxy)cyclopentyl]methyl}succinic acid 4-benzylidene-1-ethyl ester In 600 ml of ethyl acetate (=EA), 20 g of palladium on activated carbon (Pd/C) was added thereto. The mixture was then hydrogenated under a hydrogen pressure of 1 bar for 2 hours, then the reaction mixture was filtered over Cdlite. The filtered cake was then washed with 1.5 liters of ethyl acetate. The combined organic phases were evaporated in a very large amount 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. The aqueous phase was acidified with concentrated potassium hydrogen sulfate solution and extracted three times with 200 mL of ethyl acetate each time. After drying on sodium sulfate, it was evaporated under reduced pressure. The remaining residue was dried under oil vacuum to give 71 g of 3-{[l-({[(3S)-l-(2-tri-butoxy-2-oxoethyl))- 2-oxo-2,3,4,5-tetrahydro-l/fi-benzenecyclohexatriene_3-alkenyl]amino}carbonyl)cyclopentyl]methyl}-4- Oxy- 4-oxobutanoic acid, as a white foam, 'H-NMR (CDC13): 7.31-7.17, m, [3]; 7.11,d,[0.5]; 7.08, d, 59 1332947 [0.5]; 6.81, d, [0.5]; 6.73, d, [0.5] ° The intermediate product obtained in this case can be separated into its cis-transformation by the high-performance liquid chromatograph. The intermediate product utilizes the following 2 = stationary phase: 740 grams of alcohol (85: 15); UV detector column · LC80-1, 23.4 X 8 cm; ChiralpakAD, 20 μ, · mobile phase: heptane/isopropylation Cycle time: 45 minutes;, analysis: fixed wide Chiralpak AD ' 2〇μ; mobile phase: neon / isopropanol 9 1 (ν / ν), flow rate · 2 ml / min; cycle time · 15 minutes. When the retention time (retention (4) is u.6 minutes, take the first isomer of 30 grams, which is given the name of "reU", and carries the _c〇〇r] official base. Related to, the isomer is (3"rdl")-3-{[l-({[(3S)-l-(2-tertiary butoxyoxyethyl)) 2 oxo _ 2,3 ,4,5-tetrahydrobenzenecyclohexanyltrienyl-3-ylindolyl]amino}carbonyl)cyclopentyl]methyl}-4-ethoxy-4-oxobutanoic acid; 1H-NMR (CDa; 〇: 7.3im 7.09, 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]. When the retention time is 6.5 minutes, obtain a second stereoisomer of 33 grams, giving it the name "rel2", related to the asymmetric center "*CaJ carrying the -COOR1 functional group. 'The isomer is (3"rel2',)-3-{[l-({[(3S)-l-(2-tert-butoxy-2-oxoethyl)-2-oxo) -2,3,4,5-tetrahydro-1//-1-phenylcyclohexatrien-3-yl]amino}carbenyl)cyclopentyl]ethyl b 4_ethoxy 4_oxobutyric acid; 1H-NMR (CDCl3): 7.31-7.17, m,[3]; 7.11, d,[2]; 6.81,d,[1]; 4.60, 4.56, 4.35, 4.31, AB- Q., [2]; 4.4 8, m, [1] ; 4.10, m, [1]; [a]D = -136° (1% dissolved in sterol). 丄 947 Therefore F) 4 gram from the above 3-{ [l-({[(3S)-l-(2-tertiary butoxy-2-oxoethyl)_2_oxo-2,3,4,5_tetrahydroxin small benzenecycloazide _3_Amino]amino}, aryl)cyclopentyl]methyl b 4_ethoxy-4-yl oxane was dissolved in 15 ml of dichloromethane, and the solution was cooled to 〇 After 〇c, 112 ml of triethylamine oxime and 0.7, 7 I of ethyl ethacetic acid vinegar (ethyi chi〇r〇f〇rmate) were slowly added dropwise thereto, and then the mixture was stirred underneath. After 3 minutes, 0.94 ml of isopropylamine was added thereto, and the sanding was continued for 3 hours. The solvent was evaporated in a large amount under reduced pressure, and the remaining residue was subjected to 100 ml of acetic acid. In the vinegar, the organic phase is saturated with 5 〇 ml of saturated sulphuric acid solution H _ times with saturated common saline solution, and dried on sodium sulphate, and added in a large amount under reduced pressure. The remaining residue is The oil was pulverized, resulting in 429 grams of the title compound, which was light yellow oil 'MS: [M + H] +: 586; m / z: 53G; 484; 425. Example 2: a 2-{[(3S)-l-({[l-(carboxyindenyl))_2-oxo-doping tetrachloro(6)-p-benzoxazenium·3·glycosyl]amine-based carbon Stuffed base) cyclopentyl]methyl}ice (isopropylamine)_4·oxobutyric acid

OH 9.97 g of the bed of ethyl 2 {[(10) bi-butoxy-2-oxoethyl)-2-oxo-2,3,4,5·tetrazole] obtained from the above 1E) Benzene = _ ^ 胺 基 碳 碳 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Solid sodium hydroxide was added thereto in a stirred manner. Stirring was continued overnight, and the solvent was evaporated in a very large amount under reduced pressure, and the residue was dissolved in ethyl acetate (100 ml). The 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 saturated aqueous brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was dried <RTI ID=0.0> Example 3: (2"reir')-2-{[(3S)_l-({[l-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1/M- Phenylcyclohexatrien-3-enyl]amino}-carbenyl)cyclopentyl]fluorenyl}-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, 25 X 8 cm; stationary phase: Chiralpak AD, 2 μμ; Phase: heptane/isopropanol 85 : 15 (ν/ν) + 〇.1% ν/ν trifluoroacetic acid (=TFA); UV detection; flow rate: 1 ml/min; cycle time: 15 minutes; analysis : Column: DAICEL Chiralpak AD; Length: 25 mm; diameter: 4.6 mm; mobile phase: n-New_ml, 2 propanol·ml, 2 ml of trifluoroacetic acid; flow rate: 0.8 ml/min; : 3 minutes. 62 1332947 When the retention time is 13.5 minutes, 130 mg of the stereoisomer (==title compound) of the next younger brother is obtained, and the "codon 1" is called, and the COOR1 is carried. The asymmetric center of the functional group "*Ca" relates to the 'anonymous solid, which precipitates from EE; iH_NMR (methanol): 7 37_7 2, claw, 4.71, 4.43, 4.38, AB_q.; 4.4, m, (1) ;3.9〇, m,(1);3' shoulder, claw (1)6' 2.22-2.60, m,[2] ; 2.48_2 〇, m,[12]; 11〇, d,[6, soluble in methanol); melting point :145. 〇 (when the retention time is 16.2 minutes, the second stereoisomer is obtained under these conditions, giving it the name "如" and the asymmetric center carrying the _C〇〇Ri functional group" *Ca"Related" Example 4: {(3S)-3_[( {1 _[(2"rel 1 ")-2-(ethoxycarbomethoxy)_4_(isopropylamino)_4_oxobutyl Cyclopentyl}-carbenyl)amino]oxo-^,^-nitrogen-benzene-cyclohexadien-1-conazole}acetic acid

Will (29 grams of ethyl (2"!^11,}2_{[purchasing small ((1)_(2 tertiary butoxy-2-oxoethyl)-2-oxo-2,3,4,5 -tetrahydrobenzenecyclohexylsynenyl]amino}carbenyl)cyclopentyl]methyl}_4-(isopropylamino)_4_oxobutyrate (prepared as in Example 1 but with HPLC) Separation of the obtained 1-(2-secondary butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1//-1-benzene ring nitrogen 63 Jene·3-mercapto]amino}carbenyl)cyclopentyl]methyl}_4•ethoxy-4-4 oxobutyric acid as an intermediate product of step 1E), dissolved in 30 ml of two Methyl chloride, and 7 ml of two-fold trifluoroacetic acid. The mixture was allowed to stand overnight, then dissolved in peracetic acid under reduced pressure. The residue was transferred to ethyl acetate (8 ml). Then it is washed with water until it becomes pH neutral. The organic phase is dried on sulfuric acid #3, and then read and evaporated in a very large amount under reduced pressure. 3 〇 millimeters per person per person added to the residue and mixture again Steaming under reduced pressure. The residue was dried under EtOAc (EtOAc) EtOAc. h nmr (CDCD: 7 33, claw, [4]; 6·82, d, [1]; 5.86, d, [1]; 4.64, m, [1]; 4.54, 4.50, 4.46, 4.42, AB- Q.; 3.20'm, [1]; 1.23, [3];]〇9, [6] ; [a]D: _155. (1% dissolved in methanol) Example 纟: B_base (2" Rell'&gt;2-(1)_«[(Talk 1-(2-Tris-butoxy 1-oxoethyl)-2-,-2,3,4,5-tetrahydro-1Η small benzene ring nitrogen Triene _3 · methoxy] amine} carbon aryl) cyclofilament] fluorenyl} 4_[(3_hydroxypropyl) amide oxime oxobutyrate.

Will be 4.2 grams (3"1^11")-3-{[1-({[foot_1_(2_tris-butoxy-2-oxoethyl)-2-oxo-2,3, 4,5-tetrahydro-1//small cyclohexane tris-___associated]amino} carbaryl) pentyl] fluorenyl-ethoxy oxobutyric acid (according to Example 1) The preparation of the cis-trans isomer mixture) followed by separation of the cis-trans isomer by the muscle C method was dissolved in 64 1332947 in 30 ml of di-methane. U7 ml of 3-amino-1-propanol, 235 mg of dimethylamine was added to the lake and 1.61 g of EDC was added to the solution under stirring. After 1 hour, the mixture was evaporated to dryness under reduced pressure, and the residue was dissolved in ethyl acetate (1 ml), and the organic phase was extracted twice with 30 ml of aq. The organic phase was washed twice with 30 ml of a saturated aqueous solution of the common salt and dried over sodium sulfate, and then the solvent was evaporated in a very large portion under reduced pressure. The remaining residue was dried under vacuum in vacuo to give 4 g of the title compound as a white foamy resin, MS: [M+H]+: 602; m/z: 546; 500; 425; -NMR (CDC13): 7.32-7.18, m,[3]; 7.12, d,[2]; 6.63, d, [1]; 6.49, tr,[1]; 4.57, 4.63, 4.34, 4.3〇, AB -Q. [2]; 4.51, m, [1] ; 4.11, m, [2] ; 3.57, tr, [2]. Example 6: Ethyl (2"rell")-4-{[3-(ethyloxy)propyl]amino}-2-{[l-({[(3S)-L· (2-3) Grade butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzene ring nitrogen trisphate·_3_alkenyl]amino}carbonium Base) cyclopentyl]methyloxobutyrate.

1 gram of ethyl group obtained in the above Example 5 (2"rell,,)-2-{[l-(丨[(;3S&gt;*1 -(2·2?-butoxy-2-oxoethyl) _2_oxo-2,3,4,5 tetrahydro·1H small benzene ring aziridine-3-enyl]amino]}carbon fluorenyl) cyclopentyl] decyl hydroxypropyl The indole-4-oxobutanoate was dissolved in 2 ml of dichloromethane, and 34 〇μ^ 65 1332947 of chlorinated chloride was added thereto. After 90 minutes, the solvent was evaporated in a large amount under reduced pressure. The remaining residue was dissolved in 20 ml of dichloromethane, and washed with 1 mL of aq. dil. sodium bicarbonate, then dried over magnesium sulfate and solvent evaporated. The remaining residue was chromatographed on silica gel (mobile phase: ethyl acetate / η-hexane 7:3 v/v). Part of the product was under vacuum (5 x 10-2 m) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; ”3-[({l-[(2S)-4-{[3-(Ethyloxy)propyl]amino}}}}-(ethoxycarbomethoxybutoxy) ring Pentyl}carbonyl)amino]-2-oxo-2,3,4,5-tetrahydro-exo small benzenecycloazin-3-yl}acetic acid

929 grams of ethyl (2''rell,,)_4_{[3_(ethyloxy)propyl]aminotridecyloxy-2-oxoethyl)_2_ obtained in the above Example 6 Dairy-2,3'4,5-tetrahydro-111-1-benzenecycloazenetriene_3_alkenyl]amino}carbonyl)-cyclof-yl]methyl^-4-oxo Butyrate was dissolved in 1 mL of dichloromethane, and 2 2 liters of &lt;difluoroacetic acid was added thereto. The mixture was allowed to stand overnight, and then the solvent was evaporated in a large amount under reduced pressure. The residue was transferred to 3 g of ethyl acetate in ethyl acetate. The organic phase was washed with water until it became pH neutral and again under reduced pressure. A large amount of bursts were made, and the remaining residue was fumigated twice with 10 ml of toluene each time. </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; 4]; 6.67, 4 [1]; 6.59, tr, [1]; 4.69, 4.64, 4.35, 4.30, AB-Q., PI; 4.63, m, [1]; 4.17, m,[1] ; 4.09 , q, [2]; 3.33, m, [1]; 3.15, m, [2]. Example 8: ((3S)-3-{[(l-(2"rell")-2-ethoxycarbyl)-4-[(3-decyloxypropyl)amino M-oxo Butyl]cyclopentyl}-carbenyl)amine; j_2-oxo-2,3,4,5-tetrahydro-1H-1-benzenecycloazinium small)acetic acid.

580 mg of ethyl small (2-3-tert-butoxy•2_oxoethyloxo-2,3,4,5-tetrahydro-1仏1-benzenecycloazide-3- Alkyl}amino}}carbomethyl)cyclopentyl]methyl]_4-[(3-hydroxypropyl)amino-4-yl-oxobutanoate (for preparation, see Example 5) Trifluoroacetic acid was reacted with each other according to the method described above in Example 4. After purifying the resulting crude product by column chromatography (stationary phase: EtOAc: mobile phase: ethyl acetate/methanol 9:1 (v/v)), the title compound Resin, 1h nmr 7.34-7.15, m, [4], 6.76, tr, [1]; 6.61, d, [1]; 4.75, 4.71, 4.20, 4.16, AB-Q., [2]; 4.57, m [1] ; 4.09, q, [2] ; MS: [M+H]+: 546; [a]D = -112.5' (1% in methanol). Example 9: 67 1332947 2-{[H{[(3S)_l-(monomethyl)-2-oxo-2,34,5.tetrahydrobenzenecyclohexanetrien-3-enyl]amine Benzylcarbenyl)cyclopentyl]methyl b 4_[(3-hydroamino)-4-oxobutanoic acid

Will 6.43 grams of ethyl Qing 2-{[1_({[(3)(3_3)-butoxy 2oxy-ethyl)-2-oxo-2,3,4,5-tetrahydrogen 1-phenylcyclohexamethylenetrimium each]amino},carbomethyl)cyclopentyl]methyl-4-[(3-methoxypropyl)amino]-4-oxobutanoate (Prepare for preparation, see Example 5) Dissolve in a mixture of 140 ml of water and ethanol 1:1 (v/v), and add 4.28 g of solid sodium hydroxide to it with stirring. After 15 hours, solvent Evaporation under reduced pressure. The residue was dissolved in 1 mL of ethyl acetate ethyl acetate and washed twice with aqueous sodium hydrogen sulfate. The aqueous phase was extracted twice with 30 ml of ethyl acetate. The combined organic phases were washed twice with 3 mL of a common brine solution each time and then dried over sodium sulfate. Evaporation of the solvent yielded 5.41 g of the title compound. Example 10 (2 "rell") -2-{[l-({[(3S)-H-carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1/M-benzenecycloazinotriene-3-ene Amino]amino}carbenyl)cyclopentyl]methyl}·4-[(3·windlacylpropyl)amino]-4·oxobutyric acid 68 1332947

800 mg of the mixture of the isomers obtained in the above Example 9 were separated by HpLC according to the method described below: 吁 足 足 . Nucleosl 1 100-10 ; Column: 250 mm in length, 20 mm in diameter; flow rate: 8 ml /min; mobile phase: n•g-burn (8 ml), 2 propanol (200 ml) 'trifluoroacetic acid (1 ml). , Analysis: Stationary phase: EC 250/4 Nucleosil 100-10; Column: length 25 〇. mm 'diameter 4 mm; flow rate: 1.5 ml / min; mobile phase: 0_ g ^ (8 〇〇 ml, 2 C Alcohol (200 ml), trifluoroacetic acid (1 mL).

When the retention time is 7.89 minutes, the first stereoisomer (=title compound) under these conditions is obtained in 2 mg, giving the name rrU", φ and carrying the "-C00Rl" functional group. The asymmetry center "*Ca" is related; b-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,[1]; 2.65, m, [1]. When the retention time is 4.47 minutes, the second stereoisomer under these conditions is obtained, given the name "re12" and the asymmetric center carrying the "_c〇〇Ri" functional group "*Ca "related. Example 11: 2-{[l-({[(3S)-l-(2-ethoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-l /fl-Phenylcyclohexanyltrienyl-3-phenyl-amino]carbenyl)cyclopentyl]methyl b 4_[(3_69 1332947 argonoxypropyl)amino]-4-oxobutyl acid

800 mg of 2-{[i-({[(3S)-l·(数基φ)methyl)_2_oxo-2,3,4,5**tetrahydro-1 obtained according to the above Example 9 _1_1-Benzocycline-3-phenyl]amino}carbonyl)cyclopentyl]methyl}-4-[(3-hydroxypropyl)amino]_4-oxo Butyric acid (a mixture of isomers) was dissolved in 15 ml of dimethylformamide (=DMF). 302.5 mmol of cesium carbonate (CsAO3) and 169 g of ethyl bromide were added to the solution at room temperature with stirring. After stirring overnight, it was diluted with 42 ml of water and 21 ml of methylene chloride, and then the aqueous phase was extracted with a gas. The solvent was evaporated in large amount under reduced pressure, and the residue was separated by column chromatography (stationary phase: broken gum; mobile phase: ethyl acetate (100%) vs. EE/methanol 7:3 (v/v)) . The portion of the product of φ was dried under an oil-bath vacuum (5×1 〇·2 mbar) to give 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- {[ 1 -({[(3 S)-1 -(2-tert-butoxy-2-oxoethyl)-2-oxo-2) ,3,4,5-tetrahydro-1H-1-cyclohexazol-3-enyl]aminocarbenyl)cyclopentyl]methyl}-4-(isopropylamino)-4_ Oxygenation, 1332947

2.6 g of ethyl 2_{[(3S)_H{[1_(2_tris-butoxyoxyethyl)-2-oxo-2,3,4,5-tetrahydro_1//_1 _Benzenecyclohexylenetriene_3_fluorenyl]amino}carbomethoxy)cyclopentyl]methyl}-4-(isopropylamino)_4_oxobutanoic acid (for preparation, see Example _D; The solution was dissolved in 52 ml of ethanol, and a solution of 710 mg-g of solid sodium hydroxide dissolved in 52 ml of water was added to the solution. After 3 minutes, the solution was acidified with a dilute potassium hydrogen sulfate aqueous solution. Up to about pH 2, then the aqueous phase was extracted three times with 50 liters of ethyl acetate each time. The combined organic phases were dried on sulfur-acid money and the solvent evaporated very much under reduced pressure. The remaining residue was chromatographed on a dream gel (mobile phase: ethyl acetate/cyclohexane 2:1 v/v). The product portion was dried under an oil vacuum (5χ1〇-2 mbar). The result was 2 2 g (title compound 'which was a white foamy resin, MS: [M+H]+: 558; m/z: • 502, 425, 397, 323. Example 13 # ... 4-muroleylmethyl _2, {[ 1 -( {[(3 SM ♦ ternary butoxy-2-oxoethyl)·2_ oxo-2,3,4,5-tetrahydro-1 private 1. Cyclohexyl ring nitrogen three women -3_ associative yl] amine Jibu carbonate yl) cyclopentyl] methyl mu-(isopropylamino oxobutanoate

71 1332947 300 mg of 2-{[l-({[(3S)-l-(2-tert-butoxy-2-oxoethyl)-2-oxo-2,3) ,4,5-tetradec-1/M-benzenecyclohexatrien-3-enyl]amino}carbomethoxy)cyclopentyl]methyl}-4-(isopropylamino)-4-oxo The butyric acid was dissolved in 5 liters of dichloromethane. 33 mg of 4-dimethylaminopyridinidine (=DMAP), 85 mg of 4-chlorobenzyl alcohol and 124 mg of EDC X HC1 were added to the solution, followed by stirring overnight. The mixture was diluted with 5 ml of dichloromethane, and the organic phase was washed successively with 2 ml of a dilute aqueous potassium hydrogen sulfate solution and with a saturated aqueous salt solution. The organic phase was dried over magnesium sulfate, and the solvent was evaporated to dryness in a very large amount under reduced pressure. The residue was chromatographed on silica gel (mobile phase: ethyl acetate / cyclohexane 3: 2 v/v). Drying of the product in vacuo (5×2·2 mbar) afforded 320 g of the title compound as white as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as ass as : 626/628; 576, 484, . 425. Example 14: {(38)-3-[({1-[2-{[(4-Chlorobenzyl)oxy)carbenyl]_4-(isopropylamino)-4-oxobutyl Alkyl]cyclopentyl}carbenyl)amino]-2-oxo-2,3,4,5-tetrahydro-1//-1-φ phenylcyclohexanyl-1-phenyl}acetic acid

318 g of the 4 benzyl group obtained from above: small (2_tertiary butoxy oxyethyl)-2-oxo-2,3,4,5-tetrahydrobenzene hexamethene _3-alkenyl]amino-carbocarbyl)cyclopentyl]methyl}·4-(isopropylamino) glacial 1332947 isotethane hydride dissolved in 11 ml of methylene chloride, and To the solution was added 1 08 m of trifluoroacetic acid, and the mixture was stirred overnight. The solvent was then evaporated in large portions under reduced pressure. 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 again evaporated in large portions under reduced pressure, and the remaining residue was then evaporated with 5 ml of toluene. The title compound was obtained as a white foamy resin, MS: [M+H]+: 626/628; m/z: 657, 484, 425. Example 15: (2-methoxyethoxy)methyl_2- {[ 1 -({[(3S)_丨·(2_tris-butoxy-2-oxo-ethyl)-2 -oxo-2,3,4,5-tetrahydro-1 ugly-1_benzenecycloazidetriazol-3_indolyl]amino}carbyl)monopentyl]methyl]·_4-( Isopropylamino)_4-oxobutyric acid

Oxo 2,3,4,5-tetrahydro-1//_1-benzenecycloazindol-3-yl-amino]carboyl)cyclopentyl]methyl(isopropylamino) Isobutyric acid (see Example 12 for preparation) was dissolved in 5 ml of sulphur. To the solution, 33 mg of DMAP '74 μl of methoxyethoxymethyl carbonitrile and 90 μM of triethylamine were added. The reaction mixture was then stirred overnight, then diluted with 5 ml of dimethyl sulphide, and the organic phase was washed successively with 3 ml of dilute aqueous potassium hydrogen sulphate and with saturated aqueous saturated brine. The magnesium is dried, while the solvent is heated to dryness in a very large animal atmosphere, and the remaining residue is chromatographed on the crushed rubber (mobile phase · Ethyl acetate 2:1 ν / ν). The oil was dried under vacuum 73. The result was 191 g of the title compound, ms: [M+H]+: 646; m/z: 590, 540, 484, 425 » Example 44: Ethyl (2''relmi[ 1-({[(10)-1-(2-ethoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1 ugly-1_stupylcyclohexane Alkenyl-3-enyl]amino}carbenyl)cyclopentyl]methyl}-4-[(3-hydroxypropyl)amino]- 4_oxobutanoate

^ 140 mg of {(3s)_H({1_[(2''reI1,,)_2·(ethoxycarbo-.ylisopropylaminooxybutyl]cyclopentyl}-carbon Amino]-2-oxo-2'3'4'5-tetrahydrol-l-l-benzene-nitroxanthene-1_arylene}acetic acid (for preparation, see Example 4) dissolved in 3 In liters of ethanol, add ~ drops of concentrated sulfuric acid to the solution, and then the mixture is stirred at room temperature for 2 days. The paste is then evaporated in large amount under reduced pressure, and the remaining residue is dissolved in 5 liters of acetic acid. The organic phase is washed twice with 2 ml of aqueous solution of sodium hydrogensulfate each time. After drying on sodium sulfate, the solvent is evaporated to dryness under reduced pressure. The residue is chromatographed on the gelatin. Phase: Ethyl acetate/cyclohexane 8:2 (v/v)). Obtained 46 mg of the title compound as a white foam, Ms: [M+H]+: 574; m/z: 528, ;丨(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 Sit compounds listed in Table 9 below can also be prepared according to the method described in the above examples or according to a method similar thereto. : 74 1332947 Table i: Other compounds of formula i Example number R1 R2 R3 R4 Ca* Fabrication cb* Fabrication [M+H]+ 16 Η 甲methoxyethyl Η Racemic S 518 17 Η Η 3- (2-oxoazepanyl) 消 racemic S 571 18 ethyl-(CH2)2-0-(CH2)2- 消 racemic S 558 19 Η -(C: i2)2_〇-(CH2)2_ Η Rell S 20 Η Η 4-methoxyphenyl _ 2-oxoethyl hydrazine Racemic S 608 21 Η Η 3-oxo-1,1-dimethylbutyl hydrazine Racemic S 558 22 Η 苯基 phenyl- 2-miloethyl hydrazine racemic S 578 23 Η 环 cyclopropane methyl hydrazine racemic S 514 24 Η Η 4-methoxybenzyl hydrazine racemic S 580 25 Η Η 4-methoxyphenethyl消 racemic S 594 26 Η Η 2-methoxybenzyl hydrazine racemic S 580 27 Η 曱 phenylhydrazine 消 racemic S 550 28 Η 曱 曱 Η S S S 474 29 Η Η 2-(4 -decyloxyphenyl)_2-lactylethylhydrazine racemic S 636 30 ethyl hydrazine methoxyethyl hydrazine rell S 546 31 Η Η 2-methoxybenzyl hydrazine racemic S 580 32 Η Isopropyl hydrazine racemic S 516 33 ethyl hydrazine 3,4-dimethoxybenzyl oxime racemic S 638

75 1332947 34 ethyl hydrazine cyclopropyl hydrazine racemic S 528 35 Et Η 2-hydroxyethyl hydrazine racemic S 532 36 Et Η 4-decyloxybenzyl hydrazine racemic S 608 37 Et Η 1- Naphthylmethyl hydrazine racemic S 628 38 Et Η 4-methoxyphenethyl hydrazine racemic S 622 39 isopropyl hydrazine isopropyl hydrazine racemic S 544 base 40 n-butyl hydrazine isopropyl hydrazine racemic S 558 Base 41 Η Η Isopropyl methoxy racemic S 590 ethoxymethyl methyl 42 2-chloroindole isopropyl hydrazine racemic S 627 benzyl 11 Η methyl 2- methoxyethyl hydrazine racemic S 518 44 See above 45 Η -(CH2)2 -CO-(CH2)2- 消 Racemic S 542 46 Et -(CH2)2-CO-(CH2)2- 消 Racemic S 570 47 Et -(CH2) 2-N(Bn)-(CH2)2- 消 racemic S 647 48 Et -(CH2)2-S-(CH2)2- 消 racemic S 574 49 Η -(CH2)4- 消 racemic S 514 50 Η -(ch2)3-ch(ch2-〇h)- 消 racemic S 558 ch2- 1332947 51 甲基 methyl-CH2-(CHOH)- ch2oh Η racemic S 548 52 Η ethyl-(CH2)3 -NH- c2h5 消 racemic S 573 53 Et 2-hydroxyoxyethyl 2-hydroxyethyl hydrazine Racemic S 576 54 Η methylmethyl Η racemic S 488 55 Η Ethylethyl hydrazine Racemic S 516 56 Η Methyl 3- propyl propyl oxime Racemic S 532 57 Η -(CH2)2-CH(OH)-(CH2)2- 消 Racemic S 544 58 Η 2-Hydroxy-oxyethyl 2-nitrolactide ethyl Η racemic S 548 59 Η methyl-(CH2)2-N(CH3)2 Η rell S 545 60 Η methyl-(CH2)3-N(CH3) 2 消 racemic S 559 61 Et -(CH2)2-CH(-0-valine)- (CH2)2- 消 racemic S 671 62 Et thiol-(CH2)3-〇-valine Η racemic S 659 63 Η Methyl isopropyl hydrazine rell S 516 64 Η Methyl (ch2) 3-n(ch3)2 Η rell S 559 65 Η Methyl-(CH2)3-NH2 Η Racemic S 531 66 Η -(CH2 )-0-(CH2)2 消 racemic S 530 67 Η ethyl-(CH2)3-NH2 Η racemic S 68 Η methyl-(CH2)2-NH(CH3) Η racemic S Table 9 continued: Rac = racemization; Bn = benzyl

77 1332947 Example 69: secondary butyl 2-{[l-({[(3S)-l-(2-tert-butoxy-2-oxoethyl)_2_oxo-2,3,4 ,5-tetrahydro-1 good-1-benzenecyclohexylenetriene_3, alkenyl]amino}carbomethyl)cyclopentyl]methyl}-4-(4-hydrogen oxy-bite-1-归基)]_4_oxobutyrate

A) 10 gram of 2-[(2-benzyloxy)_2_oxoethyl]acrylic acid v (see Example 1A for preparation) and 47 ml of sulfoxide, 43 ml of the third grade Butanol and 110 ml of pyridine were reacted according to the method described in Example 1B) to give 69.8. g of 2-methylene succinate _4-benzyl ester tert-butyl ester [M+H ]+ : 277. #B) 29. 6 g of 2-methylene succinate 4-phenyldecyl ester-1-tributyl acrylate obtained from above and 41.4 ml of diisopropylamine, 2 〇〇 ml 1.6 M η-butyllithium (n-butyllithiiim) dissolved in n-hexane solution and 12 ml of cyclopentanecarboxylic acid were reacted according to the method described in Example 1C), resulting in 24 5 g of benzoyl Alkoxy)_2_(tertiary butoxycarbenyloxybutyl)cyclopentanyl acid. C) 15.8 g of ι·[4·(benzyloxy)·2_ obtained from above (tertiary butoxycarbenyl)-4-oxobutyl]cyclopentanecarboxylic acid with η 75 g of tertiary butyl-[(10)-3-(amino-oxo-oxo-imprint hydrogen-hydrogen b (6) Phenylcyclohexanyltriamine J acetate (for preparation, see Ep 〇 733 642 A1) is mutually reacted according to the method described in Example 1〇), 78 1332947, resulting in a 21 gram tertiary butoxy group. -2-oxoethyl)_2_oxo-2,3,4,5-tetrahydro-1//-benzenecycloazolene-3-indolyl]amino}carbenyl)cyclopentyl ]Methyl} succinic acid benzylidene ester small tertiary butyl oxime. D) 21 g of 2_{[(3S) small ({[i-(2-tris-butoxy-2-oxoethyl))-2-oxo-2,3,4, obtained from the above, 5-tetrahydro-1 tablet-benzenecycloazidetriazol-3-yl]amino}carbenyl)cyclopentyl]methyl}serperic acid _4-phenylene ester triterpene butyl ester Treated with 6 g of activated carbon face (palladium on • activated carb〇n) according to the method described in Example 1E), and hydrated for 12 hours under a hydrogen pressure of 1.3 bar, resulting in 10 g of 4-three. Butoxy-3-{[l-({[(3S)-l-(2-tert-butoxy-2-oxoethyl)-2-oxo-2,3,4,5- Tetrahydro-1/M-phenylcyclohexanyl-3-phenyl-yl]amino}carbenyl)cyclopentyl]methyl}-4_oxobutanoic acid; MS: [M+H]+ : 573; .m/z: 517, 461 ; 'H-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]. E) 1.11 g of 4-tris-butoxy-3-φ {[1-({[(38)-1_(2-tri-butoxy-2-oxoethyl))) 2-oxo-2,3,4,5-tetrahydro-1//-1-benzenecyclohexanetriazin_3·fluorenyl]amino}carbonyl)cyclopentyl]methylphenoxy Butyric acid was dissolved in 7.8 ml of dichloromethane and 3 mM of triethylamine was added. When cooled to 0 ° C in an ice bath, 222 μM of ethyl chloroformate was added dropwise to the solution. The mixture was stirred for 30 minutes, then 216 mg of 4-hydrogen oxygen bromide was added to the solution, and the mixture was stirred overnight. The mixture was diluted with ethyl acetate and washed with aqueous potassium hydrogen sulfate and brine. Drying the organic layer on magnesium sulfate' and performing column chromatography on the silicone (liquid phase: ethyl acetate / cyclohexane 1:1 (ν / ν) ' changed to pure acetic acid, into Ethyl acetate/methanol 4:1 (v/v), yielded 550 mg of the title compound as white as s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s , 323. Sharp Example 70: 2-{[1-({[1-(carboxyindenyl))-2-oxo-2,3,4,5-tetrahydro-1/M-benzenecycloazetidine-3- Amino}amino}carbenyl)cyclopentyl]methyl}-4-oxo-4-[4-(L-nonylaminooxy)piperidine-1-indenyl]butyric acid

-. A) 548 mg of the tertiary butyl 2-Ul-({[(3S)-l-(2-tert-butoxy-2-oxoethyl)-2-oxyl) obtained in Example 67 -2,3,4,5-tetrahydrobenzenecyclohexanetriene-3-indolyl]amino}carbenyl)cyclopentyl]methyl}_4_(4_hydrooxetidine-1- Alkenyl)-4-oxobutyrate was dissolved in 3 ml of di-methane. Then, 51 mg of DAMP, 182 mg of BOC-L-proline and 176 mg of EDC were added to the solution. After stirring for 3 hours, the mixture was diluted with ethyl acetate. Then the strip was washed with aqueous potassium hydrogen sulfate and brine. The organic layer was dried over magnesium sulfate and subjected to column chromatography on a mixture of silica gel (liquid phase: ethyl acetate/cyclohexane 1:1 (v/v)' changed to pure ethyl acetate) The result is 551 mg of 1-(4-tertiary butoxy)-3-{[l-({[(3S)-l-(2-tri-butoxy-2-oxoethyl)-)- 2-oxo-2,3,4,5-tetrahydro-1H-1-benzenecycloazolene-3-mercapto]amino}carbenyl)cyclopentyl]nonyl}-4-oxo代丁醯基)piperidine·4-alkenyl-N-(tertiary butoxycarbenyl)-L-proline, MS·· [M+H]+: 855; m/z: 699, 643 , 625, 425, 397, 323, 235. B) 551 mg of the above obtained 丨_(4_ tertiary butoxy 80)^M[H{[(3S)-l-(2-tris-butoxy-2-oxoethyl)_2 oxygen代·2,3,4,5_ :hydrogen-1Η-1-phenylcyclohexadiazin-3-3-amino]amino)carbyl)cyclopentyl]methyl}-4_ «_4___Ν_ (three-stage Oxycarbonate base) test acid salt solution = Η 疋 疋 疋 疋 疋 疋 疋 , , , , , , 疋 疋 疋 疋 疋 疋 , i i i i i i i i i i i i i i i i i i i i i i i Under the remaining residue, citric acid (IV) is added, and there is a mechanism to wash the strip with saturated α-hydrogen steel/gued until the pH value reaches 4. The aqueous layer was then dried over magnesium sulfate with a combined organic layer of EtOAc. Steaming under reduced pressure, the agent, and then the residual surface of the book (4), the result is gram (the title compound, which is white foamed 'MS: [Μ+Η]: 643; m/z: 425, 397, 323. Example 71: 2 3 4 - 5 1 base 2_{[H[(3S)?(2·ethoxy-2-oxoethyl)-2_oxo

VsV 虱 虱 洚 洚 氮 氮 氮 3 3 3 3 ] ] ] ] ] ] ] ] 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基

%克克I 1_[4'(stupyloxy)_2·(tertiary butoxycarbenyl)-polybutyl]cyclopentyl-based acid _Please refer to the example - male j ethyl group I Amino-based hydroxy-%, tetrahydro-H-cyclohexadiene-1-hoofyl]acetate (preparation is carried out in accordance with the method described in EP 〇 733 (4) A1) according to the method described in 1332947 Example ID), resulting in 28.6 g of 4-phenylmercapto-1-trit-butyl-2-{[l-({[(3S)-M2-ethoxy-2-oxoethyl)-2-oxo-2, 3,4,5-Tetrahydro-1H-1-benzenecycloazolene_3_indenyl]aminopurinecarbenyl)cyclopentyl]nonyl} succinate. B) 28.6 g of the above-obtained 4-benzyl-1-tertiarybutyl-2-{[H{[(3S)-l-(2-ethoxyoxyethyloxy-2,3) , 4,5·tetrahydro 1H-1-phenylcyclohexatriene-3- mentyl]amino}indenyl)cyclopentyl]methyl sulfonate as described in Example 1E) The method was carried out by using 5 g of activated carbon palladium (Poly [adium on activated carbon] and hydrogenation hydration reaction under hydrogen pressure of 2 to 3 bar for 4.5 hours] to give 16 g of 4 - tris-butoxy-3-{ [l-({[(3S)) small (2-ethoxy-2-oxoethyl)_2_oxo-2,3,4,5-tetrahydro**-1/Μ-benzene ring nitrogen Hexatrien-3-enyl]amino}carbenyl)cyclopentyl;]methyl}oxo-butyric acid '[M+H]+: 545; m/z: 489. Q 3 g of 4-tert-butoxy 3-[{-({[(3S)-l-(2-ethoxy-2-oxoethyl)_2_oxo-^) ^Tetrahydro- 丨 ^ ^ Benzene hexacyclohexaene ^- mentyl]amino}carbonate)cyclopentyl]methyl b 4 oxobutanoic acid according to the method described in Example 1 Reaction with 859 μM of methyl isopropylamine gave 1.6 g of the title compound as a white foam, MS: [Μ+Η]+: m/z: 544. Example 72 2-{[l-({[(3S)-l_(2_ethoxy-2-oxoethyl)_2_oxo-2,3,4,5_tetrahydro-ΙίΜ-benzene ring nitrogen己三埽_3_晞基]amino}carbomethyl)cyclopentyl]methyl b 4 [isopropyl(methyl)amino]-4-oxobutanoic acid

82 1332947 5〇7 mg of the third-order butyl group obtained in Example 69, thiol, 2-deuteroethyl)-2-oxo-2,3,4,5-tetrahydro-l/ M-Benzene per hexamethylene hydrazide _3 fluorenyl] amino} carbon aryl pentyl] methyl} winter [isopropyl (methyl) amine; 1 ice oxybutyrate dissolved in 18 ml In the methylene chloride, 1.95 ml of trifluoroacetic acid was added to the solution, and after stirring overnight, the solvent and excess acid were evaporated under reduced pressure. The ester was washed with a saturated aqueous solution of sodium bicarbonate until the pH of the aqueous layer reached 5. The organic layer was then dried over magnesium sulfate. The organic layer was dried over magnesium sulfate. Column chromatography (liquid phase: acetonitrile/cyclohexane 1:1 (v/v), mp mp EtOAc) ,ms: [M+H]+: 544. Example 73.1-[(ethoxycarbinyl)oxy]ethyl 2-{[l-({[(3S)-l-(2-B) Oxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1 private 1-phenylcyclohexyl-3-enyl] alkyl } Carboalkyl)cyclopentyl]methyl[isopropyl(methyl)amino]-4-oxobutyrate

107 mg of 2-{[l-({[(3S)-l-(2-ethoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydrobenzene) Cyclohexatrien-3-enyl]amino}carbenyl)cyclopentyl]methyl M-[isopropyl(methyl)amino]-4-oxobutanoic acid (for preparation, see examples) .72) Dissolved in 1 ml of dimethyl decylamine. Then, 83 μL of 83 1332947 triethylamine, 20 mg of solid potassium carbonate, and 85 μl of chloroethylethyl carbonate were added to the solution. After stirring overnight, the mixture was diluted with ethyl acetate and then washed with aqueous hydrogen sulfate solution and brine. The organic layer was dried over <RTI ID=0.0></RTI> <RTI ID=0.0> White foam, MS: [M+H]+: 600; m/z: 526, 449, 310, 253. Example 74 1-[(Ethoxycarbenyl)oxy]ethyl 2-{[l-({[(3S)-l-(2-{l-[(ethoxy ruthenyl))oxy) Ethyl]ethoxy}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1//-1-benzenecyclohexanetriene_3-alkenyl]amine Carboxymethyl)cyclopentyl]methyl}-4-[isopropyl(methyl)amino]-4-oxobutyrate

500 mg of ethyl 2-{[l-({[(3S)-l-(2-tert-butoxy-2-oxoethyl)-2-oxo-2,3,4,5) -tetrahydro-1//-1-benzene-cyclohexanetrien-3-enyl]amino}carbenyl)cyclopentyl]methyl}ice [isopropyl(methyl)amine H-oxygen Butyrate (see Example 32, Synthesis Example 2) was dissolved in 10 mL of dimethyl decylamine. Then, 312 μ of diethyl chlorocarbonate, 758 mg of solid cesium carbonate (CsAO3) and 80 mg of solid potassium iodide were added to the solution. After stirring at 60 ° C 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 subjected to column chromatography on a silica gel (liquid phase: cyclohexane 84 1332947 burned to ethyl acetate / cyclohexane 1:1 (v/v)), resulting in The title compound was obtained as a white oil. MS: [M+H]+: 748; m/z: 614, 480. Example I: Contains {(3S)-3-[(n_[(2''rell,,)_2_(ethoxycarbomethoxy)_4_(isopropylamino)·4·oxobutyl]cyclopentyl Capsules of:}}}}}}}}}}}}}}}}}}}}} Preparation of capsules containing the following composition: {(3 S)-3 - [({l-[(2''rei i,,)_2_(ethoxycarbomethoxy)_4 (isopropyl)-amino) -4_oxobutyl]cyclopentyl}-carbenyl)amino]oxo-2,3,4,5-tetrahydro-1 private 1-benzenecyclohexylene-1-enyl 2 mg of acetic acid 60 mg of corn starch 300 mg

Lactose Ethyl acetate The main component, the mixture is agglomerated. I and dry the φ crusher at 45 ° C and mix it with other adjuvants in the following: talc powder 5 mg magnesium stearate 5 mg corn starch 9 mg and then filled into 400 mg capsules (= Capsule size 〇). 85

Claims (1)

Wherein ^ is a hydrogen atom or a sulfhydryl group which forms a biolabile ester, y is a hydrogen atom; an alkyl group having 1 to 4 carbon atoms or a oxyalkylene group having 1 to 4 carbon atoms The hydroxyl group may be optionally selected to be esterified with an alkanoyl group having 2 to 4 carbon atoms or an amino acid residue, and R3 is an alkyl group having 1 to 4 carbon atoms; Alkoxy group of 4 carbon atoms - an alkyl group having 1 to 4 carbon atoms; a phosphonium alkyl group having 1 to 4 carbon atoms, which may be optionally substituted by a second hydroxyl group, and Each of the hydroxyl groups may be optionally selected to be esterified with an alkanoyl group having 2 to 4 carbon atoms or an amino acid residue; (an alkyl group having 0 to 4 carbon atoms) 2 amine group An alkyl group having 1 to 4 carbon atoms; a cycloalkyl group having 3 to 7 carbon atoms; a cycloalkyl group having 3 to 7 carbon atoms - an alkyl group having 1 to 4 86 1332947 carbon atoms; benzene Base - an alkane group having 1 to 4 carbon atoms, the phenyl moiety of which may optionally be selected from an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, and/or a halogen 1 to 2 times Substituted; naphthyl-alkyl group having 1 to 4 carbon atoms; oxoalkyl containing 3 to 6 carbon atoms; phenylcarbonyl-methyl, phenyl moiety optionally selected An alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms and/or dentate, or 2-cyclohexyl hexane substituted 1 to 2 times, or φ R2 and R3 is alkoxy group having 4 to 7 carbon atoms in common, and the methylene group of the alkylene group having 4 to 7 carbon atoms may be optionally selected to be a carbon group, a nitrogen atom, an oxygen atom and/or sulfur. The atom is substituted 1 to 2 times, and it may be optionally substituted by one of the following groups, and the group may be a hydroxyl group which may be optionally selected to be an alkyl group having 2 to 4 carbon atoms ( Alkanoyl) is esterified with an amino acid residue; an alkyl group having 1 to 4 carbon atoms; a hydrogen oxyalkyl group having 1 to 4 carbon atoms, the hydroxyl group of which is optionally selected to contain 2 Esterified with an alkanoyl group of 4 carbon atoms or an amino acid residue; a phenyl group or a benzyl group, and R4 is a hydrogen atom or a functional group forming a biolabile ester; Wherein the functional groups forming the bio-labile esters in the substituents R1 and/or R4 are each independently selected from an alkyl group having 1 to 4 carbon atoms; an alkoxy group having 1 to 4 carbon atoms An alkoxy group having 1 to 4 broken atoms - an alkyl group having 1 to 4 carbon atoms; a cycloalkyl group having 3 to 7 carbon atoms; a cycloalkyl group having 3 to 7 carbon atoms - containing 1 To a base of 4 carbon atoms; N,N-di (alkyl group containing 1 to 4 broken atoms) amine group - alkyl group having 1 to 4 carbon atoms; phenyl or 87 1332947 is a stupid base An alkyl group having 1 to 4 carbon atoms which can be optionally selected from the group consisting of dentate, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms on the benzene ring. Substitution of 2 times, or by a burnt chain linked to two adjacent carbon atoms containing 1 to 4 broken atoms; dioxomethyl group optionally substituted on the dioxane ring Substituted with an alkyl group of 1 to 4 carbon atoms; an alkyloacidoxy group having 2 to 6 carbon atoms - an alkyl group having 1 to 4 carbon atoms, optionally selected from oxygen to 1 to 4 carbon atoms Burnt on Substituted with a calcining group of 1 to 4 carbon atoms; 1-[[(alkyl containing 1 to 4 carbon atoms) carboalkyl]oxy]alkyl ester having 1 to 4 carbon atoms; [(cycloalkoxy group having 4 to 7 carbon atoms) carbon fluorenyl] oxy]alkyl ester having 1 to 4 carbon atoms; 2-oxo-1,3-dioxa-4-enyl An alkyl ester having 1 to 4 carbon atoms which optionally has a double bond on the dioxane ring; and wherein the amino acid residues in the substituents R2 and/or R3 are independently of each other Selected from alanine, 2-aminohexanoic acid, 2-aminovaleric acid, arginine, aspartame, aspartic acid, cysteine, 3,4-dihydrophenylalanine, bran Amine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, auramine, 5-oxo-2-pyrrole, phenylalanine, guanidine Amino acid, serine, threonine, thyroxine, tryptophan, tyrosine, and valine; and physiologically compatible salts of the acid of formula I, and/or formula I a compound which is physiologically compatible with an acid addition salt β. 2. According to the scope of the patent application The compound of the formula I, wherein R1 is a hydrogen atom or a functional group forming a biolabile ester, R2 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or containing 1 88 J332947 to 4 a hydroxyalkyl group of a carbon atom, the hydroxyl group of which is optionally acetylated by an entertainment base having 2 to 4 carbon atoms, and 3 is a burnt group having 1 to 4 carbon atoms; An alkoxy group of 1 to 4 carbon atoms - an alkyl group having 1 to 4 carbon atoms; a oxyhydro group having 1 to 4 carbon atoms, which may be optionally substituted by a second hydroxyl group; And the oxime moiety thereof is optionally acetylated by a calcining base having 2 to 4 carbon atoms; an alkylamino group having 1 to 4 carbon atoms - a mercapto group having 1 to 4 carbon atoms; a cycloalkyl group having 3 to 7 carbon atoms; a cycloalkyl group having 3 to 7 carbon atoms - an alkyl group having 1 to 4 carbon atoms; a phenyl group having an alkyl group having 1 to 4 carbon atoms; The phenyl moiety may be optionally substituted one to two times with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, and/or a functional group; the fluorenyl group contains 1 to 4 Carbon source An oxoalkyl group containing 3 to 6 carbon atoms; a phenylcarbonylmethyl group having a phenyl moiety optionally selected from an alkyl group having 1 to 4 carbon atoms An alkoxy group having 1 to 4 carbon atoms and/or an anion, or a 2-cyclohexane to be substituted 1 to 2 times, or a combination of R3 and 4 to 7 carbon atoms a methylene group containing an alkylene group of 4 to 7 carbon atoms which may be optionally substituted by a perlite, a nitrogen atom, an oxygen atom and/or a sulfur atom, and which is substituted one to two times, and Optionally, it may be substituted once by a group having an alkyl group having 1 to 4 carbon atoms; a hydrogen oxyalkyl group having 1 to 4 carbon atoms, wherein the hydroxyl group portion is optionally Esterified by alkanoyl group containing 2 to 4 carbon atoms; phenyl or benzyl, and 89 R4 being a hydrogen atom or a functional group forming a biolabile ester, and Formula I The physiologically accommodating salts of the acid, and/or the compounds of the formula I are physiologically compatible acid addition salts. A compound of the formula I according to the invention of claim 1, wherein R1 is a hydrogen atom, an ethyl group, a methoxyethoxymethylalkyl group, or a (RS)-H[(isopropyl)carbenyl group. ]oxy]ethyl, (RS)-1_[[(ethyl) decyl]oxy]-2-methylpropyl, (RS)-l-[[(cyclohexyloxy)carbenyl) ]oxy]ethyl, 5-methyl-2-oxo-1,3-dioxa-4-alkenyl-methyl, 2-oxo-1,3-diox-4-enyl-methyl The group is either (RS)-l-[[(ethoxy)carbenyl]oxy]-ethyl. A compound of the formula I according to claim 1, wherein R2 is a hydrogen atom, a methyl group, an ethyl group, a 2-hydroxyoxyethyl group or a 3-hydrogenoxypropyl group, each of which is a hydroxyl group. It is optionally selected to be esterified with an alkane group having 2 to 4 carbon atoms or an amino acid residue. A compound of formula I according to claim 1 wherein R3 is isopropyl, methoxyethyl; 2-nitroethyl or 3-nitroxypropyl, each hydroxyl Either optionally esterified with an alkanoyl group having 2 to 4 carbon atoms or an amino acid residue; 3-ethyloxy-n-propyl; cyclopropylmethyl; 2-methoxy Benzomethyl; 4-methoxybenzyl; 4-methoxyphenethyl; 2,4-dimethoxybenzyl; 1-naphthylmethyl; 3-oxo-I,1 Dimethyl butyl; phenyl-2-oxoethyl; 2-(4-methoxyphenyl)-2-oxo-ethyl; 3-(2-cyclohexane); dimethyl Amino-η-propyl; (meth)aminoethyl or amino-η-propyl. A compound of the formula I according to the scope of claim 1, wherein r2 and R3 together are ρ ρ; ρ 瓜; 4- _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ The base may optionally be esterified with an alkane group having 2 to 4 carbon atoms or an amino acid residue; piperazine or pyrrole. A compound of the formula I according to the invention of claim 1, wherein R4 is a halogen atom, a alkyl group having 1 to 4 carbon atoms, p-methoxybenzyl, N,N-di- (Alkyl group having 1 to 4 carbon atoms) Amino group - an alkyl group having 1 to 4 carbon atoms, (RS)-l-[[(isopropyl)carbenyl]oxy]ethyl, RS)-l-[[(ethyl)carbenyl]oxy]methylpropyl, (RS)-l-[[(cyclohexyloxy)carbenyl]oxy]-ethyl, 5_ Methyl-2_oxo-1,3•di-H-phenyl-methyl, 2-oxo-alkenyl-methyl or (RS)-l-[[(ethoxy)-deutero)oxy ] ethyl. A compound of formula I according to claim 1 of the patent application, which is selected from the group consisting of 2-{[1-({[1-(carboxymethyl))-2-oxo-2,3 ,4,5-tetrahydro-1 ugly-1-phenylcyclohexatriene·3_indolyl]aminopyridinyl)cyclopentyl]methyl}-4_[isopropyl(methyl)amine 4-oxobutyric acid; 2_{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1 dan -3--3-稀基基]amino}carbomethoxy)cyclopentyl]methyl}-4-(dimethylamino)-4-oxobutanoic acid; 2_{[H{[H carboxymethyl )-2-oxo-2,3,4,5-tetrahydro-1 ugly-1-phenylcyclohexylenetriene_3·alkenyl]amino}carbomethyl)cyclopentyl]fluorenyl}- 4-(diethylamino)_4_oxobutyric acid; 2_{[1-({[1((carboxymethyl))-2-oxo-2,3,4,5-tetrahydro-1// M-phenylcyclohexylenetriene-3-indolyl]amino}-carbenyl)cyclopentyl]methylhydroxyoxyethyl)(methyl)amino]-4-oxobutanoic acid; ))-2-oxo-2,3,4,5-tetrahydro-UT-1-phenylcycloazindolyl]amino}deactinyl)cyclopentyl]methyl b 4_[(3 _Hydroxypropyl)(methyl)amino]-4-oxobutanoic acid; 2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5 ·Tetrahydrobenzenecyclohexylenetriene_3_alkenyl Amino}-carbomethyl)cyclopentyl]methyl b 4_(4-nitroxyl-l-enyl)-4-oxobutanoic acid; 2-{[1-({[1-( Retinomethyl)-2-oxo-2,3,4,5-tetrahydro-1 ugly-1_benzenecycloazenetriene_3·alkenyl]amino}-carbonyl)cyclopentyl Methyl b. 4-oxo-4-[4-(L-nonylamino oxy) ruthenium-1-alkenyl]butyric acid; 2-{[1-({[1-(carboxymethyl) )-2-oxo-2,3,4,5-tetrahydro-1, 1 -benzenecyclohexatrienyl-3-enyl]amino}-carbenyl)cyclopentyl]methyl} 4_Merlin-4-alkenyl-4-oxobutanoic acid; 2-{[1-({[1-(t-methyl))-2-oxo-2,3,4,5-tetrahydro) -1/Μ_benzenecycloazenetriene_3·fluorenyl]amino}-carbomethoxy)cyclopentyl]methyl b 4_oxo-4-(4-milk Butyl acid; 4-[bis(2-hydroxyoxyethyl)amino]-2_{[1-({[1-(carboxymethyl)_2-oxo-2,3,4,5-tetra Hydrogen benzene cyclohexatriazole _3_ fluorenyl] amine 棊} carbon aryl) cyclopentyl] fluorenyl}-4-oxobutyric acid; 2-{[1-({[1-(carboxymethyl) -2 - oxo-2,3,4,5-tetrahydro-1 ugly-1-phenylcyclohexatriene _3-alkenyl]amino}-carbomethoxy)cyclopentyl]methyl} _4_{ethyl[Hethylamino)propyl]amino}-4-oxobutyric acid, 2-{[1-({[1-(carboxymethyl)-2-oxo-2,3) , 4,5· Hydrogen-1 open-1-benzenecyclohexatrien-3-phenyl]aminocarbacarbyl)cyclopentyl]methyl}-4-[[2-(didecylamino)ethyl] (indenyl)amino]-4.oxobutyric acid, 4-[(3-aminopropyl)(ethyl)amino]-2-{[1-({[1-(carboxymethyl)) -2-oxo-2,3,4,5-tetrahydro-ml-benzenecycloazol-3-enyl]amino}carbenyl)cyclopentyl]methyl}-4-oxo Butyric acid, and 2-{[Η{[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1 ugly-1-phenyl ring 92 1332947 hexacene triene·3 Alkenyl]amino-carbocarbyl)cyclopentyl]methyl}·4_{methylhydrazine-(methylamino)ethyl]amino}-4-oxobutanoic acid' plus these The biologically labile esters of the acids of the compounds of formula I and - the physiologically compatible salts, and/or the compounds of formula I in physiologically compatible acid addition salts. 9. The compound of formula I according to any one of the preceding claims, wherein the asymmetric carbon atom having a guanamine branch at the third position of the backbone of the benzenecyclohexatriene is "S" structure. 10. A pharmaceutical composition comprising a pharmacologically effective amount of a compound of formula I according to claim 1 of the patent application, and a conventional ® pharmaceutical adjuvant and/or excipient. 11. Use of a compound of formula I according to claim 1 of the scope of the patent application as a medicament for the prevention and/or treatment of cardiovascular diseases or diseases. 12. The use according to claim 11, wherein the cardiovascular disease or disease is selected from the group consisting of congestive heart failure; hypertension comprises a second type of hypertension such as primary High blood pressure, kidney hypertension, and/or lung hypertension. Spring 13. An application of a compound of formula I according to claim 1 of the scope of the patent application for the preparation of a medicament for the prevention or treatment of sexual dysfunction. 14. The use according to claim 13, wherein the sexual dysfunction is selected from the group consisting of female sexual dysfunction and male sexual dysfunction. 15. The use of claim 13 wherein the sexual dysfunction is male sexual dysfunction. 16. The use according to claim 13 wherein the sexual function 93 1332947 disorder is selected from the group consisting of erectile dysfunction, ejaculation dysfunction, and libido disorders. 17. The use of claim 16 wherein the sexual dysfunction is erectile dysfunction. 18. The use of a compound of the formula I according to the scope of claim 1 for the preparation of a medicament for the prevention and/or treatment of amelioration associated with apoptosis, which is selected from the group consisting of ischemic stroke Neurodegenerative disorders such as cerebral ischemia and traumatic brain injury. 19. A process for the preparation of a compound of formula I, Wherein R1 is a hydrogen atom or a functional group forming a biolabile ester, R2 is a hydrogen atom; an alkyl group having 1 to 4 carbon atoms or a oxyalkyl group containing from 1 to 4 broken atoms, The hydroxyl moiety may optionally be esterified with an alkanoyl group having 2 to 4 carbon atoms or an amino acid residue, and R3 is an alkyl group having 1 to 4 carbon atoms; containing 1 to 4 Alkoxy group of one carbon atom - an alkyl group having 1 to 4 carbon atoms; an oxyalkyl group having 1 to 4 carbon atoms which may be optionally substituted by a second hydroxyl group' and its hydrogen oxy group The base portion can be optionally selected as 94 1332947 by an alkanopurine group having 2 to 4 carbon atoms or an amino acid residue; (anthracene group having 〇 to 4 carbon atoms) 2 amine An alkyl group having 1 to 4 carbon atoms; a cycloalkyl group having 3 to 7 carbon atoms; a cycloalkyl group having 3 to 7 carbon atoms - an alkyl group having 1 to 4 carbon atoms; benzene The base - an alkyl group having 1 to 4 carbon atoms, the phenyl moiety thereof may be optionally selected from the group consisting of a pyridyloxy group having 1 to 4 carbon atoms and/or a halogen having 1 to 4 carbon atoms. 1 to 2 Substituted; naphthyl-alkyl group having 1 to 4 carbon atoms; oxoalkyl containing 3 to 6 broken atoms; phenylcarbonylmethyl, phenyl moiety optionally Select one or two substitutions of an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms and/or dentate or 2-cyclohexane, or R2 and R3 Commonly, it is an alkylene group having 4 to 7 carbon atoms, wherein the methylidene moiety is optionally substituted one or two times by a carbon sulfonium group, a nitrogen atom, an oxygen atom and/or a sulfur atom, and Optionally, it is substituted by the following group, which may be a hydroxyl group, which may optionally be esterified with an alkanoyl or an amino acid residue having 2 to 4 carbon atoms. An alkyl group having 1 to 4 carbon atoms; a oxyalkyl group having 1 to 4 carbon atoms' having a hydroxyl group optionally selected from an alkyl group having 2 to 4 carbon atoms or a Amino acid residues are esterified; phenyl or benzyl ' and R 4 are hydrogen atoms or a functional group forming a biolabile ester, 95 1332947 wherein substituent R1 And/or the R4 + forming biolabile brewing &amp; energy bases are selected independently of each other; ^ from a burnt group containing 1 to 4 broken atoms; an alkoxy group having 1 to 4 carbon atoms Alkoxy group having 1 to 4 broken atoms - an alkyl group having 1 to 4 carbon atoms; a hetero group having 3 to 7 carbon atoms; a group having 3 to 7 carbon atoms - containing 1 to 4 Carbon atom, alkyl group; N, N-di (alkyl group having 1 to 4 carbon atoms) amine group - alkyl group having 1 to 4 carbon atoms 'phenyl group or phenyl group - containing 1 to 4 An alkyl group of a carbon atom which may be optionally substituted one to two times on the benzene ring by an anthracene, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, or It is substituted by an alkylene chain bonded to two adjacent carbon atoms having 1 to 4 carbon atoms; a dioxoalkyl group which is optionally selected to have 1 to 4 carbon atoms in the ring Substituted by an alkyl group; an alkoxy group having 2 to 6 carbon atoms - an alkyl group having 1 to 4 carbon atoms - optionally optionally contained in an oxygen group having 1 to 4 carbon atoms Substituted by an alkyl group of 1 to 4 carbon atoms i-UX alkyl group having 1 to 4 carbon atoms) carbaryl] oxo] ketone acetonide having 1 to 4 carbon atoms; H[(cycloalkoxy group having 4 to 7 carbon atoms) carbon An alkyl group having 1 to 4 carbon atoms; a 2-oxo-1,3-diox-4-enyl group-alkyl ester having 1 to 4 carbon atoms, which may be Optionally, a double bond is contained on the dioxane ring; and 96 wherein the amino acid residues in the substituents R2 and/or R3 are independently selected from alanine, 2-aminohexanoic acid, 2- Amino valeric acid, arginine, aspartame, aspartic acid, cysteine, 3,4-dihydrophenylalanine, acetoamine, face acid, glycine, histidine, Aleucine, leucine, lysine, methionine, alanine, 5-oxo-2-pyrrole, albino, valine, serine, threonine, thyroxine , tryptophan, tyrosine, and valine; also physiologically compatible salts of the acid of formula I, and/or compounds of formula I in physiologically compatible acid addition salts , characterized by a compound of formula II, R1Q1 and R4Q1, which are independent of each other, each of which is an acid protecting group, reacts with a compound of formula III, R3 R2 - NH in wherein R2 and R3 have the meanings indicated above, if R2 and/or When R3 contains a free hydroxyl group, such a group reacts with a compound of formula IV, if necessary, 97 1332947 Ci-3-C(0)-X IV wherein X represents a cleavage group' or Is an interaction with an amino acid derivative protected by a suitable protecting group, if R1G1 and/or R4Q1 does not represent the desired formation of a biolabile ester and/or if R2 and/or R3 contain protection based on any presence When on an amino acid residue, the functions are continuously removed in a desired or individual manner based on the desired compound, and, if necessary, in each case The acid functional group is converted to a biolabile ester functional group, and if necessary, the acid formed by the formula I is converted into a physiologically compatible salt thereof, or the acid salt of the formula I is converted into The free acid and / or the test of the general formula I is converted into The acid addition salt or the acid addition salt is converted into a free test of the formula I. 20. a compound of formula II, Wherein R1G1 is an acid protecting group and R401 is an acid-protecting group. 98