SA04250283B1 - Derivatives of amidomethy1-substituted1-(carboxyalkyl)-cyclopentylcarbonylamino-benzazepine-N-acetic acid - Google Patents

Abstract

Abstract: The invention relates to the description of a new group of compounds that inhibit the activity of neutralizing endopeptidase (NEP) and/or human soluble endopeptidase (hSEP) enzymes. These compounds have the following general formula: where R4, R3, R2, R1 are substitutes having the mentioned meanings from During the description, as well as drugs containing these compounds, and in particular those drugs suitable for the treatment or prevention of cardiovascular disease, sexual dysfunction, and/or adverse conditions associated with apoptosis.

Description

B Derivatives of Amidomethyl-substituted 1-(carboxyalkyl)-cyclopentylcarbonylamino- chenzazepine-N- acetic acid, their manufacturing process, intermediate products for their preparation, and medicines containing these compounds. FULL DESCRIPTION BACKGROUND: The present invention relates to an aminomethyl-substituted-1-(alkyl carboxyl)-pentylcarboxylamino-benzazepine-17 = amidomethyl-substituted1-(carboxyalkyl)-cyclopentylcarbonylamino-benzazepine-N acetic acid -acetic acid 0 useful for example in the prevention and/or treatment of cardiovascular diseases; specifically heart disease; specifically heart failure and high blood pressure; including secondary types of hypertension such as essential hypertension; RES from and/or treatment of infertility and/or prevention and/or treatment of various diseases associated with cell death; As well as medicines containing these compounds and more than that; The invention relates to a process for preparing aminomethyl-substituted benzazepine-N-acetic acid and intermediates through this process. Sexual dysfunction (SD) is a clear clinical problem that may affect both males and females. The causes of sexual dysfunction (SD) may be physical or psychological. No, the main cause of organic impotence is vascular diseases; such as those associated with high blood pressure or diabetes; Or prescribed medications and/or mental illnesses, ie depression. Psychological factors include fear; Anxiety and personal problems between the two parties. ED stands as an obstacle to sexual performance ¢ and reduces self-esteem and affects personal relationships and causes psychological pressure on the patient. Yes, cell death is related to the form and nature of the histological process; maintaining blood coagulation systems; vital defence; Cell death plays an important role in preserving the life of v individuals and when obstructing the death process that is genetically controlled, either in the embryo or after birth; The process of physiological death of cells increases or decreases significantly, which leads to various organic and functional diseases. Drugs that inhibit cell death can be used as agents to prevent and treat diseases that act by triggering the physiological death of cells. The benzazepine derivatives “benzoxazepine” and “neutral benzopeptases” (1850-) were denied in the application of the European patent (US 5.677.297) EP 0 733 642 Al = (In addition, the compounds described in this context have Less properties to inhibit the enzyme endothelin converting enzyme (=ECE) endothelin 0. Among other preferable pharmacological properties are compounds with the same structural domain as stated in European Patent 1 M 642 0733 EP What is denied in the following patents M 863 830 0 WO 00/48601 Al « (=US 5.783.53) EP « (820 .482 .6 105 h) and also has 01/03699 US -2003-0040512-A1). 952. 327) WO = (). Derivatives of phosphonic acid substituted for benzapineone - N = yo-acetic acid (benzothiazepine-N-acetic acid) with double permeability of the enzymes ECE, NEP have been included in European and American patents. (=US 5.952.327) EP 0916 679 Al Pharmaceutical preparations are known from the application of the international patent WO 02/094176 A2 containing compounds with compound activity Li NEP metal loprotease enzymes Lise As well as IGS5 "Yo also has active properties on the heart and blood vessels. Also suitable formulations for such combination preparations are the compounds included in the European patent applications EP 0 733 642 Al as well as EP 0 916 679 Al. The activity of enzyme 1055 through the invention; as well as its functional role related to heart disease; through the application of the global patent WO 01/36610 Al The aforementioned enzyme 1055 - (=hSEP) is known as “human soluble endopeptidase” Soluble human endopeptidase Yo

Ya

¢ It is stated in the international patent application WO 99/88726 Al “that there are certain ECE inhibitors useful for the treatment or cessation of erectile dysfunction. European Patent 1 719 097 1 EP includes the use of NEP inhibitors for the treatment of ED sal (75-). 8 The international patent application WO 02/06492 Al includes antibodies and activators of a specific polypeptide with secreted endopeptidase activity (=SEP) and describes the US patent application 20030045449 US Matrix-metalloprotease inhibitors are useful for treating neurodegenerative diseases. Among the problems associated with the invention is that al he matrix-metalloprotease includes a wide range of protease inhibitors, as well as; According to the patent application; metalloproteases must be used in a pharmaceutical composition that also contains an N-NOS inhibitor US Patent Application 2002/0013307 US states the use of Yo vasopeptidase inhibitors to treat or inhibit the progression of learning disorders; as well as the treatment and/or prevention of impotence. 260-266 (2004) As described by M.

Sumitomo et al. Clinical Cancer Research Chemotherapy chemosensitization for androgen-dependent prostate cancer by NEP 0 - General description of the invention One of the objectives of the present invention was to provide new active substances with compound activity to inhibit NEP enzymes and 11580 as well as ECE is appropriate for the prevention and/or treatment of disorders or diseases of the heart and blood vessels; in particular weakness of the heart muscle; specifically heart failure; including secondary forms of hypertension such as primary and renal (Yeo) hypertension pulmonary and/or treatment and/or prevention of impotence and/or prevention and/or treatment of many problems associated with cell death

Eh, and we have recently found that a group of derivatives of amidomethyl -substituted -1 (carboxy (US) pentylcarbonylaminocyclo-benzazepine - 16-acetic acid 1 -(carboxyalkyl)-cyclopentylcarbonylamino-benzazepine-N- acetic acid according to the present invention exhibits activity Li. for 11850 enzymes as well as HSEP 0 » to some extent ECE and therefore is suitable for the prevention and/or treatment of cardiovascular disorders or diseases, especially myocardial infarction specifically J myocardium; this includes secondary forms of hypertension such as primary, renal and pulmonary hypertension and/or treatment and/or prevention of ED and/or prevention of Jif treatment of many problems associated with the death of Lal Ya Detailed description of the invention In the detailed description of the invention, the objective of the invention is to prepare derivatives amidomethyl-substituted 1-(carboxyalkyl)-cyclopentylcarbonylamino- benzazepine-N- acetic acid with the formula ¥ ¢ 0 3 b R 1 ol ~ re” = 800 N 0 _a 9 Vo 00 e represents hydrogen or a bio-changed ester group; hydroxyalkyl ¢ and then hydroxyl group 01 of which is treated by 0 esterified with Ca.s-alkanoyl or an amino acid precipitate ¢l 1X4 amino acid ¢ Ya

. C represents Cpohydroxyalkyl “Cpa-alkoxy-C-alkyl ¢ Cpaalkyl optionally substituted by a second hydroxyl group and the hydroxyl groups optionally esterified by an esterified with an amdecylamine or an amino aid precipitate” or ( Alkyl) ¥ Amino - Joel Arala.b,© - Mnastas 111(2a-m©) » Alkyl 0 cycloalkyl-olmden-john Csz-cycloalkyl-Cy4-alkyl ; An alkyl phenyl 1 in a 0 - support whose phenyl group is optionally replaced by (Y=) once by an alkyl or “C,. 4-alkoxy-180-oxoalkyl Cyg-oxoalkyl ¢ phenylcarbonylmethyl filament whose phenyl group is optionally replaced by a mercisne or 0 by Jf Alah-,©; Cru-alkoxy and/or halogen or =Y oxoazepanyl 2-oxoazepanyl + or; 1 and le R? represent alkylenes 1′0′ and ll-sell ¢ whose methylene groups are optionally replaced one to two times by a carbonyl ; Nitrogen ; oxygen Ss sulfur optionally substituted once by a hydroxy ; Yo optionally treated by esterified Jiu with Cp.4-alkanoyl or an amino acid precipitate mad 5 ¢ Cpu-hydroxyalkyl « Cp4-alkyl » amino acid optionally hydroxyl group by esterification with C,4-alkatyl alkanoyl or amino acid precipitate ¢ or phenyl Jud or benzyl ; Also - RY stands for hydrogen or a group that forms a biologically variable ester; 0 - As well as the physiologically compatible salts of the acids of formula and/or the physiologically compatible acidic addition salts of the compounds of formula 1 . What is more, it is an objective of the present invention to provide medicines containing Formula 1 compounds. What's more; An object of the present invention is a process for preparing the formula compounds or intermediate products of this process. to and the compounds of Formula 1 or other compounds described in the present invention include substitutes or contents of Cpgealkyl; Straight or forked chain and represent alternatives

In compounds of formula 1 halogen + or fluorine 0 fluorine or chlorine or bromine. It is preferable to use chlorine as a disinfectant.” The alternatives include 2-1; linear or branched and preferably acetylated as -Caa-alkanoyl and in compounds of formula 1 ; The hydroxyl groups are processed by the ester with an amino acid precipitate; These amino acids may be amino acids from Ja 8 amino acids, natural or unnatural, and from amino acids that can be used, for example; Those selected from the group that SY mac NY ee aminohexanoic acid (norleucine ¢ "-aminopentanoic acid (norleucine) =) asparagine ) aspartic acid ¢ cysteine 7 4 ; dihydroxyphenylalanine (td. 0 3,4-dihydroxyphenylalanine (= dopa) glutamine ¢ glutamic acid parsed glutamic » glycine » histidine ; isoleucine ¢ leucine » lysine » methionine » orthenine —o oY - Yo ornithine (= 2,5-diaminovaleric acid) ¢ =o-oxo-?-pyrrolidinecarbonic acid (pyroglutamic acid) 5-0xo-2-pyrrolidinecarbonic acid pyroglutamic acid) =( ; phenylalanine ¢ proline » serine ¢ threonine « thyronine » tryptophan © tyrosine and valine SEL is the preferred amino acid residues from CNT alanine Y- + asparagine glutamine; glycine isoleucine leucine; Ornithine ¢ phenyl O— 52 ¢ phenylalanine CT proline and valine -valine The compounds of formula 1 represent derivatives of EE carboxylic acid dicarboxylic acid optionally treated by ester with a group of esters Bioflexible. Ba, vo bioelastic esters of formula 1 biostable prodrugs (Jl) from free acids; then ; Compounds of Formula 1 may appear mono- or di-esters.

A

bioelastic or esters, depending on the form of intake; It is preferable to use free acid pasters; The latter is preferred for intravenous administration. Cleavage groups are prepared under functional conditions in vivo; with The compounds that make up the esters 1 release bioavailable derivatives from the compounds of the formula, specifically Cra-alkyl, and suitable examples for this are groups. “SR! Bioplastic 65 > ¢ isopropyl and n-propyl isopropyl and p-propyl “ethyl and ethyl” methyl methoxymethyl ¢ Cr4-alkyloxy-Cis-alkyloxy-C 4-alkyl and groups specifically the hexyl 6 C37-cycloalkyl; and methoxyethoxymethyl cycloalkyl groups « Cy-cycloalkyl-C; 4-alkyl Js and 0-cyclohexyl cyclohexyl groups (J); And groups 17 and 7<- dicyclopropylmethyl, specifically cyclomethylpropyl 0

JS or phenyl Jui « N-N-di-(Cy.4-alkyl)amino-C _s-alkyl amino alkyl

Ci ya once or the phenyl ring the mal-+©1-0Ga1p optionally substituted in the phenyl or alkoxy ring with “maltarn” or by means of the © alkyl chain by means of a halogen” i.e. the two adjacent alkyls; And di-carbon atoms groups of alkylene p(21107160-+.,©) linked to two carbon atoms optionally substituted in the dioxolanylmethyl oxolanyl ring No alkanyloxyal alkyl alfaba-Zhan to the apical bridging ¢ Cpg-alkyl by the alkyl dioxolane ring Crealkyl JS by 0xy-Cr-alkyl optionally substituted at the oxy-alkyl carbonyl group [oxy]-JY]-1 double as esters or [[(ethyl) esters) carbonyl] -1- (RS) Example + 1-[[(Ci.4-alkyl)carbonyl]oxy]C; 4-alkyl ester (RS)-1-[[(ethyl)carbonyl]oxy]-2-methylpropyl oxy]-?- methylpropyl Y.

Y.Yoshimara et al, or F.W. Sum et al., ioorg. Med. Chem, Lett. G (1999) 1924-1926) The Carboyl Shp or The sournal Anibiotics 39/9 (1986) 1329-1342) for cycloxy)carbonyl[oxy]alkyl ester [1-1 as 1-carbonate esters - (RS) and better » 1-[[(C4-7-cycloalkyloxy)carbonyl]oxy] Ci.a-alkyl esters (Joa) [cycloalkyloxy] oxy] decreases vo

K. Kubo et al., J. Med. (see ¢ (RS)-1-[[(cyclohexyloxy)carbonyl]ethyl (= cilexetil)

Yo q?-dual Y= or "-oxo Chem. 36 (1993) 2343-2349, cited as "Kubo et al." Content 2-0x0-1,3-dioxolan-4-y1- C, 4-alkyl esters oxolan-;- yl-alkyl ester; preferably dioxolan ring optionally on a double bond in the dioxolan ring dioxolan-;- yl-methyl) = medoxomel = F Vm oxo Y = medoxolen-0 (kubo et al. For preparation » see S-methyl-2-0x0-1,3-dioxolen-4-yl-methyl (= medoxomil ° - Oo) - methyl (= methyl) SY Vk -" or and represents . 2-0x0-1,3-dioxolan-4-yl-methyl (= (methyl)ethylenecarbonate) carbonate) biochangeable ester-containing group optionally substituted group from phyl to 7; and the best is 1 and may contain an alkyl chain with “phenyl-Cye-alkyl alkyl chlorobenzyl” = Y to a carbon atom and denotes an optionally substituted benzyl; Specifically to 0 and represents the constituent group of the ester » 4-chlorobenzyl or ;- chlorobenzyl 2-chlorobenzyl optionally substituted; its phenyl group is replaced by a bio variable J low SRY carbon group that may contain * to 4 ; And the best is the alkylene chain of alkylene, specifically the formation of andeles; The constituent group of the bio-changed ester is represented by the group of ATOLLA-Y©-00107AH »LAH-M:© optionally substituted; The Ji group — alkanoyloxy 0 is straight or bifurcated. ethyl)carbonyl]oxy]-2-methylpropyl > methoxyethoxymethyl (iis ethoxy [[((hexiocyclo)carbonyl] -10- (RS) +» (RS)-1-[[(isopropyl)carbonyljoxy]ethyl - 7 5-methyl-2-0x0-1,3-dioxolen-4-yl-methyl « [[(cyclohexyloxy)carbonyl]oxy]ethyl Ye or 2-0x0-1,3-dioxolan-4-yl-methyl oxo-1a©#- diioxolane-;-ylmethyl-(RS)-1-[[(ethoxy)carbonyl]ethyl Ji) [[(ethoxy)carbonyl]oxy]-1-(RS ) - “Jf « methyl Jie » hydrogen and 82 preferably represent hydrogen; 3-hydroxypropyl or 7-hydroxypropyl 2-hydroxyethyl Ji optionally esterified pu is optionally treated by hydroxyl group each Hydroxyl group Yo .amino acid or cog-alkanoyl amino acid precipitate with alkanoyl

Youn

1 amino-alkyl za-+.,1671(280100-0l00.4-2)¢ and two (Js) groups and 83 representing sal can each exist separately. More specifically "(alkyl) Cou-alkyl Js] (Co)z-alkylamino-C 4-alkyl "alkyl-malb©-mansd d(alkyl-mm)" includes "alkyl ? - Alkyl “oleh-©-monas-alkyl-“(Mr00(0)) and 1” alkyl amino” lang on the amino group (Co)z-alkylamino-C, 4-alkyl 0 (Ci.4) )r-alkylamino-C 4-alkyl 5' bonded with alkyl (PN) (171)80H-0,4; the primary unsubstituted (= NH) group predominates, ©-absorbed1 (00.4(0)(0). ) on the amino group 4-alkyl "J alkyl aminto- by means of the alkyl nucleus - (0) and linked with the secondary alkyl Lala inferred by the amino group on (Cra)-alkylamino-C4-alkyl and overpowering 'alkyl' Amino-alkyl “Cy y-alkyl(en) (cr) conjugated with a third (Cra)-alkyl substituted by an alkyl amino group sid of 0-methoxy “isopropyl alkyl (en) (60) I give them © . It is preferably represented as 83 hydroxy -Y isopropyl or - 2-hydroxyethyl hydroxyyl -7 « methoxyethyl Ji and the hydroxyl group is optionally treated by 3-hydroxypropyl-acetyloxy-p-propyl-0 Aminoyl amine or amino acid precipitate » or - methoxy - « cyclopropylmethyl ; » 3-acetyloxy-n-propyl |0 methoxyphenyl-4 » 4-methoxybenzyl ;-methoxybenzyl 2-methoxybenzyl ? + 0 4-methoxyphenylethyl igyl dimethyl butyl =) sko -* » I-naphthylmethyl naphthyl-1 « phenyl-2-oxoethyl J) phenyl-7-oxo » 3-0x0-1 ,1-dimethylbuty] -7( - 0 +6 2-(4-methoxyphenyl)-2-oxoethyl oxoethyl-7-(Jd ?-methoxy (-" 7 ¢ (Co.a-alkyl)ramino -C; 4-alkyl (alkyl)amino-alkyl ¢ 3-(2-oxoazepanyl) oxoazepanyl) -amino-n-propyl or (methyl)aminoethyl « dimethylamino-n-propyl] alkylene (p-anola-.pt; Lee R3 methylene groups representing 183 and ¢ piperidine; piperidine morpholine its own morpholine da ug is optionally replaced by methylene ¢ 4-hydroxypiperidine 4-hydroxypiperidine - 4 ¢ 4 -ketopiperidine ;-ketopiperidine Yo

VY

Treated by ester optionally with alkanoyl and dimethylene at 0 amino acid residue at pyrrolidine or pyrrolidine piperazine hydroxyl group; Preferably alkyl oleal piperazine; A- 0 hydrogen, preferably representing “18 hydrogens.”

Ls - Bi )=( Amy f - 8 + + p-methoxybenzyl methoxybenzyl [[(isopropyl)carbonyl] oxy] -1- RS) + N.N-di(Co.s-alkyl)amino- C, 4-alkyl m (RS)-1-[[(ethyl)carbonyl]oxy]-2- (RS) « (RS)-1-{[(isopropyl)carbonyl Joxylethyl ethyl oxo “Y= methyl -© + (RS)-1-[[(cyclohexyloxy)carbonylJoxylethyl « methylpropyl ' 5-methyl-2-0xo-1,3-dioxolen-4-yl-methyl oculin -¢~ yl — Methyl (SDT 1-2-0x0-1,3-dioxolan-4-yl-methyl dioxolan ~~ yl-methyl -v )-oxo-"oxy[ethyl Rat] Imductivity(6077) ]]-1-(165). {[1-({[1 ~(carboxymethyl)-2-0x0-2,3,4,5-tetrahydro- 1H-1-benzazepin-3-yl]amino }- carbonyl)cyclopentyl methyl } -4-[isopropyl] (methyl)amino] -4-oxobutanoic acid (32); 2-({[1-({[1 -(carboxymethyl)-2-0x0-2,3 4,5-tetrahydro-1H-1 -benzazepin-3) -yljJamino}- yo carbonyl)cyclopentyl] methyl } -4-(dimethylamino)-4-oxobutanoic acid (54); 2-{[1-({[1 -(carboxymethyl)-2-0x0-2,3,4) ,5-tetrahydro-1H-1 -benzazepin-3-yl]amino }- carbonyl)cyclopentyl] methyl }-4- [diethylamino)-4-oxobutanoic acid (55); 2-{[1-({[1 -(carboxymethyl)-2-0x0-2,3 ,4,5-tetrahydro-1H-1 -benzazepin-3-yljamino }- carbonyl)cyclopentyl] methyl }-4- [ (2-hydroxyethyl)(methyl)amino] -4-oxobutanoic acid 7 (43); 2-{[1-({[1 -(carboxymethyl)-2-0x0-2,3 4,5-tetrahydro-1H-1 -benzazepin-3-ylJamino }- carbonyl)cyclopentyl] methyl }-4- [( hydroxypropyl)(methyl)amino] -4-oxobutanoic acid (56); 2-{[1-({[1 -(carboxymethyl)-2-0x0-2,3 4,5-tetrahydro-1H-1 -benzazepin-3-yljamino }- Yo carbonyl)cyclopentylJmethyl }-4-(4- hydroxypiperidin-1 -yD-4-oxobutanoic acid (57); 2-{[1-({[1 -(carboxymethyl)-2-0x0-2,3 ,4,5-tetrahydro-1H-1 -benzazepin-3) -yl]amino }- carbonyl)cyclopentylJmethyl }-4-0x0-4- [4-(L-valyloxy)piperidin- I-yllbutanoic acid (68); 2-{[1-({[1 -(carboxymethyl))- 2-0x0-2 ,3,4,5-tetrahydro-1H-1 -benzazepin-3 -ylJamino}- v, carbonyl)cyclopentyl methyl } -4-morpholin-4-yl-4-oxobutanoic acid (66);

VY

2-{[1-({[1-(carboxymethyl)-2-0x0-2,3 ,4,5-tetrahydro-1H-1 -benzazepin-3-ylJamino}- carbonyl)cyclopentylJmethyl }-4-0x0-4 -(4-0x0 piperidin-1-yl)butanoic acid (45); 4-[bis(2-hydroxyethyl)-2-{[1-({[1 -(carboxymethyl)-2-0x0-2,3 ,4,5-tetrahydro-1H-1-benzazepin-3-yl]lamino} carbonyl )cyclopentyl methyl }-4-oxobutanoic acid (58); 2-{[1-({[1-(carboxymethyl)-2-0%0-2.3 -4,5-tetrahydro-1H-1-benzazepin-3-ylJamino} - ° carbonyl)cyclopentyl]methyl }-4- [[2- (dimethylamino)ethyl] (methyl)amino]-4- oxobutanoic acid (59); 4-[(3-aminopropyl)(ethyl)amino]-2-{[1-({[1 -(carboxymethyl)-2-0x0-2,3,4,5- tetrahydro-1H-1-benzazepin-3) -yl)amino} -carbonyl)cyclopentyl methyl }-4- oxobutanoic acid (67) and Ye 2-{[1-({[1-(carboxymethyl)-2-0x0-2,3 4,5-tetrahydro-1H) -1-benzazepin-3-yl amino} - carbonyl)cyclopentylmethyl }-4-{ methyl[2- (methylamino)ethyljamino }-4- oxobutanoic acid (68); physiologically derived bioelastic and physiologically compatible salts esters with esters from the acids of the compounds of formula and/or salts of pharmacologically compatible acid addition 90.1 from the compounds of the physiologically compatible formula and their salts of 1 and according to the invention; We get the new compounds from the formula

G.

HO

N

Maud | TI 0 N 0 A 001;+M with a compound of acid each representing an acid-protective group ¢ R40! aR fol Cus Yo. The general form. 3c RZ—NH III where 182 and 83 represent the following;

ARERR

VY

They contain free hydroxyl groups; And if desired, they can be reactants RY and/or 5 with a compound of the general formula ;:

C1 5-C(0)-X Iv where * is a leaving set; or with a derivative of an amino acid by a suitable © protecting group. RI! and/or 890 do not represent the required bio-altered ester constituent groups + SSR?pie JS G55 ¢ aad fn id nen cd fds le sane pf RO in compounds produced simultaneously or separately in any order required ; The acid functions can be released at will in each case and converted to flexible ester groups

Lyn 0 to physiologically compatible salts or 1 and if desired + the acids resulting from formula 1 and/or bases of formula a are converted to acids 1 salts of the acids of formula are converted to their acidic addition salts Or acidic addition salts that convert 1. to free bases of formula 15. Among the salts that are pharmaceutically compatible with formula 1 are alkali metal salts or alkaline-earth metal ammonium. » such as sodium, potassium, or calcium derived salts; and compatible neutral organic salts derived with amines, i.e. amines, for example ammonia and diethylamine; and triple tert | butylamine ¢ 0 and —N methyl glucamine 0 N-methylglucamine or chlorine “choline” or amino acids such as arginine “and in Formula 1 compounds” contains substitutes R* and/or RY base groups; specifically nitrogen; Formula 1 compounds may appear as acidic addition salts. Physiologically compatible acidic addition salts are the usual salts with inorganic acids such as yo-sulfuric acid, phosphoric acid, or hydrohalic acids, and the best is hydrochloric acid + or with acids ‎Yo

0 aliphatic monocarboxylic; such as monocarboxylic acids, low organic acids such as tricarboxylic acids, or aliphatic di- or tricarboxylic acids, or tartaric acid; or fumaric acid or fumaric acid » maleic acid, such as 0 sulphonic acids, citric acid, low-methanesulphonic acid, such as alkanesulphonic acids | © The usual protection groups can be chosen to protect the functions of the carboxylic acid; Which can be derived again, RY, as protection groups for acid!0!8 and carboxylic acid, using the known methods. The protective groups are suitable for carboxylic acids ;

McOmie, "Protective Groups in Organic for example such as those at IK Chemistry", Plenum Press (cited as "McOmie' hereinafter), Ve in Greene, Wuts, Protective Groups in Organic Synthesis", Wiley Interscience Publication Bio-variable such as ester modern versions; ester constituent groups can also be used acid protection groups The compounds obtained at its reactor according to 1 represent the compounds of formula ?with the compounds of formula © in these cases the esters of the formula 1 Those groups which RH 8 and are suitable acid protecting groups can be optionally cleaved or inserted optionally and independently and examples of acid protection groups that can be cleaved under different conditions, which may also represent bioelastic esters; The low unbranched “ethyl JAY” Jie alkyl groups, the low dS alkyl groups can cleavage relatively easily under alkaline conditions; such as tertiary butyl lower alkyl and phylylmethyl groups + trifluoroacetic acid optionally substituted trifluoroacetic acids in the phenyl ring such as benzyl which can be easily cleaved phenylmethyl by hydrogenolysis or under basic conditions; and the phenyl group is methylated by the alkoxy phenyl ring inferred once or more to the phenylmethyl Yo ring; which is cleaved p-methoxybenzyl; like ; a-methoxybenzyl lower alkoxy low Voy yo mT om chloro ESF » 7; readily sa-active under benzoquinone conditions - +) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (=DDQ) 10-cyano; Or protection groups, ceric ammonium nitrate or citric ammonium nitrate (DDQ=), which can be easily cleaved by silicon-containing fluoride ions, and the expert in the field is familiar with the appropriate protection groups to obtain . fluoride inos M in the form of the required substitution. “chiral carbon atoms contain two chiral carbon atoms 1 and the compounds of the formula contain, specifically; A carbon atom carries the amide side chain in the * position of the benzazepine skeleton, as can (Ca*=) "008" and a carbon atom bearing (=Cb*) benzazepine skeleton and includes . stereoisomeric compounds exist in four stereoisomer forms - 0 and stereoisomeric enantiomers of the present invention are mixtures of stereoisomers; It is preferable to use 1 pure isomeric compounds of formula Lad; Enantiomers and preferred compounds are . 1 isomerically lateral isomeric compounds in an amide where the carbon atom is the carrier of the amide chain 1 formula compounds in the "5" position. And according to the atom, benzazepine skeleton, the position? For the benzazepine Vo carbon deficient 0+ “0008 moiety bearing” structure; Preferably in the form of compounds (see experiments). It can be derived from “REL according to the invention by design 1 the formula at the center “RELL” by means of analogous observations of suitable compounds of the preferred form ”. ,

2 Can acids of formula ¥ be reacted with amines of formula? According to the appropriate methods for the formation of amide groups by aminoacylation, carboxylic acids with the formula SY and their reactant derivatives can be used as agents to remove field formations. And renewing; Anhydrous acid compounds and mixed acid halides represent reactive derivatives. Therefore, chlorides can be used

acid chlorides Yo or acid bromides of the formula ? Or mixed esters of formula acids? With low substituted sulphonic acids

a

optionally by halogen; Jie methanesulphonic acid or trifluoromethanesulphonic acid; Or aromatic sulphonic acids such as benzenesulphonic acids or with benzenesulphonic acids substituted by alkyl or halogens such as toluenesulphonic acids or bromobenzenesulphonic acids The treatment can be carried out by acylation of an organic solvent, solvent Jala, at: e, under jelly conditions, at temperatures between -10 °C and the boiling temperature; Suitable solvents include aromatic hydrocarbons such as dichloromethane or Yo, aromatic hydrocarbons such as benzene or toluene, or cyclic ethers such as tetrahydrofuran. THF) or dioxane or mixtures of these solvents can be treated by acylation, specifically if a mixture of anhydrous acids is used from the formula? with sulphonic acid as a curing agent; In the presence of an acid-binding reagent. Examples of suitable acid-binding agents are; Soluble organic bases in the reaction mixture such as tertiary nitrogen ¢ bases such as tert.-lower alkylamines and pyridines such as triethylamine + and tripropylamine « and N - N-methylmorpholine and pyridine ¢ and - dimethylaminopyridine 4-dimethylaminopyridine + and - diethylaminopyridine 4-diethylmainopyridine or - pyrrolidine and pyridine 4-pyrrolidinopyridine. Additional organic bases can act as solvents at the same time. And if acids of formula ¥ themselves are used as acyl-treatment agents; Amino compounds of formula ¥ can be reacted with carboxylic acids Yo of formula ? In the presence of a known inclusion reagent such as the appropriate peptide chemistry for amide formation. It is AL A the coupling reagents that Yor

VY

It helps to form amide 1n: with free acids by reacting to form a reactive acidic derivative: ethyl chloroformate “the topical acid with the acid”

Js as 0 » alkylcarbodiimides Alkyl carbodiimides 0 ethyl chloroformate

Ft as dicycloalkylearbodiimides carbodiimides = N-(dimethylaminopropyl)-©) = Nf dicyclohexylcarbodiimide cycloimide 0 ¢« (-EDC) N-(3-dimethylaminopropyl)-N “-ethylcarbodiimide” Y= and 7-low alkyl carbonyldiimidazole salts or halides, specifically halides ¢ N-lower alkyl-2-halopyridinium salts halopyridinium The reaction can be carried out in In the presence of a coupling reagent, toluenesulphonates toluene sulphonates to +32700) solvents such as SY-halogenated hydrocarbons at a temperature of 0 and/or aromatic solvents and optionally in the presence of an amine-binding aromatic hydrocarbons: as previously described. With 1 and in the compounds that we obtain by reacting the compounds of the formula Boa can the compounds of the formula “; where 82 and/or 13 comprise the hydroxyl groups cf reacted when necessary in a known way with the compound of the formula; . and in the compounds of the formula 0 represents the leaving group 72 halogens; the best is chlorine. Reacting them in a known way with a derivative of an amino acid that is protected by suitable and preparing the appropriate protection groups for amino acids along with the les © group

Greene, R. McOmic Methods for inserting or optionally deriving them are known in the art; For example, suitable protected amino acid derivatives are commercially available or can be prepared in a known way. Unless you're RY GR! Protection groups can splinter; and/or represent bss include any desired groups constituting the ester :88:6 Yo variant in 82 and/or 83 ; Likewise, amino acid groups can protect any part of an amino acid A

Ya

Optionally split it from the compounds that we obtain by reacting the compounds of the formula? Liquid Z (HPLC=)© New compounds suitable as intermediates for the preparation of 1 The starting compounds of formula * can be prepared as compounds of formula . 1 New active substances such as the preparation of formula compounds by reacting compounds of the general formula ©; 0

A

»

R10100C | or v 0 is an acid protecting group and !8 within the aforementioned sense; with BERS compounds where 0 : general formula 6; “”- b “N 9” _a 0084 previously mentioned; The acid protecting groups are cleaved by the RY method, as they represent such as “known aminocrylations, and the reaction can be carried out in a known way for the amino rings.” The method similar to what was previously mentioned about reacting compounds of formula A with compounds of formula 1? To avoid unwanted secondary reactions; It is preferable to cleavage protecting groups of Jal groups by a method that does not work in an alkaline medium and thus acid RS RY suitable acid protection

Yor

Amines are the formula amines? known alone or can be prepared in a known manner. Derivatives of the active acid or Formula 4 are known by themselves or can be prepared in a known way as these compounds and these are linear or 0-branched carboxylic acid derivatives. Compounds of formula © can be prepared by reacting ester derivatives of formula Vil VII R*100C where RS and GR represent what has been mentioned; With cyclopentanecarboxylic acid ba. The reaction can be carried out by the well-known method, Michael condensation conditions in an inert organic solvent Jeli conditions are induced by reacting cyclopentanecarboxylic acid with a strong base capable of forming anion SD 0 of cyclopentanecarboxylic acid cyclopentanecarboxylic acid; The resulting reaction with a derivative of (Se) ve acrylic acrylic ester of formula 7 . A suitable solvent is ethers. specifically the cyclic ethers (THE). Suitable strong bases include non-nucleophilic organic alkali metal amides or alkali metal lower alkyls such as lithium ditsopropylamide or p. -Butyllithium n-butyllithium » Also, cyclopentanecarboxylic acid is reacted in THF with equals of p-butyllithium n-butyllithium, then the reaction mixture is reacted with a compound

Formula 7. The reaction temperature can be between -0 and -0 degrees Fahrenheit. The compounds of formula + are known; for example daw; By European patent EP 0 733 642 Al; They may be prepared in racemate 05 or in isomerically pure 0 form according to the methods described herein or similar methods. Formula 1 compounds can be prepared by treating compounds of general formula A with an ester. where RY stands for acid protecting group; In a known way with alcohol required. VIII HOGC Ve For example, compounds of formula A can be obtained by reacting itaconic acid anhydride under known conditions, opening the anhydrous group with a reagent capable of forming a protective group for acid 87, such as alcohol replaced by compatibility. and in the interactions described above; The hyposymmetric centers in Yo starter compounds of formula 0 are not altered and the compounds of formula 6 are not altered; So that pure formula 1 compounds or isomerically mixed mixtures can be identified depending on the type of starting compounds. For the preparation of stereochemical compounds of formula 1 ; Stereochemically reacted Aap all © stereochemically compounds of formula 3 and if a pure compound is enantiomerically reacted | 00 of 1 dal ¢ Js nal) is made on a mixture of the stereoisomers in each case; It can be separated when needed at the stage of compounds of formula “or the stage of compounds of formula 1 in a known way and its reactor produces racemic compounds of formula © with racemic compounds of formula + compatible mixtures of 4 isomers

isomers + can be separated when needed by a known method » such as HPLC separation on suitable asymmetric separation services. Compounds of the formula © have a hyposymmetric center at the carbon atom that carries the “COOR’™”™ moiety and are obtained at gma dl from acrylic ester derivatives of the formula GV in the form of racemates. Obtaining mainly optically active compounds from racemic mixtures in a known manner, such as chromatographic separation on deficient separators or reactants with photoactive bases such as Cal-methylbenzylamine, a-methylbenzylamine or cinchonidine pseudoephedrine Then separation into optical antimorphoses by fractional crystallization of the resulting salts. Formula 1 compounds and their pharmacologically compatible Ly salts have many beneficial pharmaceutical properties. Specifically, these substances inhibit the enzyme NEP. NEP is an enzyme to break down internal sodium peptides (ANP) Jie and because of the inhibitory activity on NEP - these substances are able to improve the biological activity and useful life of the sodium repelling peptides that attack them NEP, and the determination of ANP, and thus is suitable for the treatment of diseases affected by such hormones, the most important of which are cardiovascular diseases, specifically weak heart muscle. Specifically Ja congestive heart muscle. In the case of Js, the heart muscle; The peripheral vascular resistance increases due to the decrease in the YS of the heart's pumping rate due to patients, which means that the heart muscle has to be exposed to peripheral resistance. This leads to a vicious cycle of stress on the heart, which worsens the situation; The increase in peripheral resistance is controlled by the vasoactive Lal peptide endothelin 1 (=ET-). Endothelin is the strongest vasoconstrictor in the body; it is produced from the precursor H? | (=Big-ET-1) As currently known, Yan

YY hSEP and ECE enzymes including “ET1” to (=Big-ET-1) convert many enzymes (07/0 441776). As a result of the decrease in the blood leaving the heart and the increase in peripheral resistance, the theory of back pressure of blood appears on the pulmonary circulation and the heart itself. As a result, the tension on the cardiac muscle increases in the region of the atria © in the blood. Because of the activity of ANP and the chambers and in In this case, the heart acts as a gland that secretes natriuretic / water, 180 leads to a decrease in peripheral resistance de SU dilated and a decrease in blood volume in the circulatory system. This leads to a decrease in the load before and after the heart. This represents an internal system To protect the heart, but this positive internal system is the reason for plasma ANP is characterized by its short half-life in plasma, as it is 0

NEP is rapidly broken down by the hormone so that the hormone releases endothelin and the compounds of the current invention reduce the production of endothelin and thus reflect the increase in peripheral resistance hSEP as well as the activity of ECE by inhibiting activity, which reduces the effort on the heart . The following results suggest that the materials according to the invention inhibit and increase the duration of its activity, and this leads to ANP, which leads to an increase in the level of NEP activity 1 1 to protect the heart and gives the compounds of the internal ANP formula that depends on LL ad a strengthening Diuretic / sodium ANP is very effective in terms of potentiating activities not only but also in the breakdown of endothelin and means ANP in the breakdown of NEP and does not interfere completely leads to an unwanted increase in the levels of endothelin in addition to NEP so that The inhibition of ECE and a percentage of the inhibitors of SEP and NEP and for this reason ¢ we see that a mixture of . ANP-; At the same time, inhibition of NEP formation (by blocking NEP) is beneficial as it prevents degradation. As a result, the effect of ECE and hSEP can be improved by endothelin (by inhibiting myelin (specifically its undesirable increase). The NEP side effects of ¢ hSEP and NEP inhibitors such as 1 inhibitors and the combined activity of the formula compounds of the present invention make them suitable for the prevention and/or treatment of ECE “to a higher extent” of diseases Such as disorders or diseases of the heart and blood vessels, especially muscle weakness

79r heart + as acute and chronic J tal of myocardium, specifically congestive heart failure; As well as high blood pressure (Ly) in that secondary types such as primary high blood pressure; renal and/or pulmonary; heart failure; angina; a heart rhythm disorder; myocardial infarction; myocardial infarction; © and late myocardial infarction; myocardial hypertrophy; non-obstructive hypertrophic cardiomyopathy; cardiomyopathy without an apparent cause; heart muscle infections; And inflammation of the membranes surrounding the heart and / or inflammation of the internal heart in mammals, especially humans. Formula 1 compounds may also be used to prevent, treat, or damage the heart; specifically the muscular part of it; caused by toxic doses of drugs; 0, especially cytostatic agents; Specifically, the antibiotics or chemicals that cause this, as well as angina; brain anemia; peripheral vascular disease; spider web hemorrhages; chronic obstructive pulmonary disease (COPD); crisis ¢ and kidney disease (renal failure; atherosclerosis; and pain pain in cases of colon, rectal, or prostate cancer in upper bracts Jie ¢ larger mammals Ye humans) and surprising is the effectiveness of these Formula 1 After parenteral administration Relative to blood pressure regulating activity Specifically blood pressure lowering Description of pharmacological test methods Example numbers relate to the described preparation Lad the following: -1 - In vitro test for inhibitory activity on HEP of compounds In order to elucidate the inhibitory activity of the compounds according to the invention on NEP; Blas the inhibition of the compounds was tested on the methyl degradation of the -polypeptide Mca-Asp-lle-Ala-Trp-Phe-Dpa-Thr-Pro -Glu-His-Val-Val-Pro-Tyr-Gly-Leu-Gly-COOH produced by the enzymatic activity of NEP by a standard in vitro test.In this test Yo the ICsp values were the special By measuring the inhibitory activity of the selected compounds

Yi of the test material, the activity of the combing enzymes is the concentration of the test material, where the ICs, dad

NEP from the enzymatic activity of the enzyme Jo Stop You “Vv pH pH ad mM Tris 0: buffer 01106l sodium g sodium chloride soa mM University of Montreal; Canada Prof Crine Recombinant Human NEP « Enzyme: soluble triglycerides; 01 μg/mL in 001: stock solution pH A

PH Working solution: Stock solution with buffer solution diluted to pH Bottom layer: iea™Asp-lle-Ala-Trp-Phe-Dpa**-Thr-Pro- Glu His-Val-Val-Pro-Tyr -Gly Lew. Gly. COOH Yo any substrate fluorescence-treated metalloprotease Big-ET-1 and italics ECE-1 and NEP are determined by a scintillation signal ¢, specifically metalloproteases coumarin iscothym-17/( = *Mca "inert" Dpa by the presence of MCA and an aminopropionyl flash) SEY OY - 1. ; - Dinitrophil [-CY] =F) = -;-yl) + and **

Polypeptide Laboratories, has (3-[2,4-dinitrophenyl]-L-2,3-diaminopropionyl) Vo

Wolfenbuttel, Germany. μmol test material buffer: 0: stock solution mM) was done and diluted to a test concentration with 0 DMSO. Dissolve all subjects in buffer. 1 μl of working enzyme solution and 01 L of 70 microliters of buffer solution »and sr and Eppendorf microliter sample of the test material solution was incubated in vessel #0 and the enzymatic reaction was done by heating for 01 min at 01 VY for the test period minutes) done » Heraeus Biofuge B, 3 min) and after centrifugation. LI minutes for the following determinations. Bk HPLC supernatant test by

Yo reversed-phase HPLC, and the bottom layer was separated from the cleavage products by (CC 125/4 Nucleosil 300/5) and from RP column with CC 8/4 Nucleosil 100/5 C18 01. For this purpose, precolumn was injected. from Macherey-Nagel, Duren, Germany). The column was rinsed at an HPLC rate of µl of reaction mixture at the injection point of the sample ml/min with the following range: 1 Gino

Mobile phase A: 1.5 + 11:0 7000 mol, 11:70 pH Yor Mobile phase B: 70001 acetonitrile + 0.5 mol, 11:50

zero-? Minute 01-8 YAR Minute .Razb

1-7 minutes 11-00 Lord 1-0 minutes 6 b

B 7.0 min 1-19 YAN min h 1 0 nm YY E By absorption at peptides All peptides have been determined by blinking with an excitation wavelength of 78 nm and a release wavelength

TAY nm. And upon enzymatic cleavage of the peptide ¢ the fluorophore (=Mea) and also 0 Hamid terminate in the form of different peptides; reduce the suppression efficiency. This leads to an increase in blinking. An increment of the blinking signal (corresponding to surface A) of the HPLC peak of a peptide with an inactivated Mea fluorophore is used for the following calculations and this signal of samples was compared with (=A inhib) and without (=A inhib) test subjects. control) of formula 1 ; The value of "inhibition" was calculated on the basis of the corresponding apex areas according to the following formula: (for a set of lot -100*) 1 = inhibition %. All samples were measured in pairs, and their average values were calculated, and the standard inhibitor was measured. 01 nM theophran (thiorphan) and solvent control (DMSO 14.1) as a quality control measure each time. In this optional model, the value of 0.10 for compounds of Formula 1 in Table 1 was as follows : Yor

Table 1: NEP inhibitory activity of test subjects in vitro. a AB 17/4 —v test tube of the hSEE-inhibiting activity of the compounds in order to demonstrate the inhibitory activity of the compounds according to the invention on NEP; The activity of huis compounds on hydrocracking of a polypeptide -Mca-Asp-I le-Ala-Trp-Phe-Dpa-Thr-Pro-Glu-His-Val-Val-Pro-Tyr-Gly- was tested. Leu-Gly-COOH© produced by hSEP enzymatic activity by a standard in vitro test. In this test, the values of 90 and 10 were for measuring the inhibitory activity of the specific compounds. And count

The value of the ICs for the test substance with enzyme-inhibiting activity is the test substance concentration Coa 0 75 enzymatic activity is inactivated [1585. Test separator: 001 mM triple pH You ) 7.0 pH mM NaCl.

° enzyme: His6-tagged hSEP ectodomain from Innogenetics, Ghent, Belgium Stock solution: © mg/mL in 01 mmol HEPES; pH V,Y pH ¢ 70 Glycerol Vee Tween20 70.006 « glycerol mMol

grams of sodium chloride, NaCl; purity > 8%

Working solution: Stock solution with buffer solution diluted to 100 mg/mL. Ye substrate: Mca-Asp-lle-Ala-Trp-Phe-Dpa-Thr-Pro-Glu-His-Val-Val-Pro-Tyr- Gly-Leu-Gly-COOH and similar Big-ET-1 is flashing.

Stock solution: 100 micromoles in a buffer of:

Polypeptide Laboratories, Wolfenbuttel, Germany.

Test Substances: All subjects were dissolved in DMSO (01 milligrams) and diluted to 10 concentration to be tested by the test separator.

The testing and the HPLC process were performed in the same way in a predetermined manner to determine

The in vitro inhibitory activity of test subjects on NEP is presented as 01 nM

Phosphoramidone as a standard inhibitor in the HPLC process

And in this test model; What were the ICs of the test compounds of formula 1 7 described in Table ? as follows:

schedule? : hSEP am iY inhibitory activity of test subjects in vitro

Ya

,0 | 43 7 R “- test tube of the inhibitory activity of substances on the ET-1 composition of Big-ET-1 in in order to demonstrate the inhibitory activity of the compounds according to the present invention on the ET-1 composition of Big-ET-1 ; The inhibitory activity of the test compounds on the hydrocrack © 818-27-1 to 87-1 was tested as a result of the enzymatic activity of BCE and related enzymes such as hSEP in a live bd test. 21-1 is a potent vasoconstrictor endogenous substance. 0 and an increase of 1-27 leads to an increase in blood pressure. When injecting BigET-1; blood pressure increases to the extent that ET-1 is produced by cleavage of 318-21-1 prepared by the enzyme and as a measure of the enzyme-inhibiting activity of the compounds; Inhibitory activity was determined

Big-ET-1 increased blood pressure induced by injection of 1 0 by (Sprague-Dawley, CRLD= Charles Rive) ovens were anesthetized in (statham) and a pressure vector 1 : 1 Rompan was introduced The carotid artery was inserted into the cervical jugular vein / ketavel / kg / liter to measure blood pressure, and a bronchiole was inserted into the cervical jugular vein to take a minute ¢ Furan 01 was given and another to take 318-21-1. After a period of complete rest

Yan

Test Substance of Formula 1 at a Concentration of 01 μmol/kg ; or vector and after © minutes; #9 nano-mol/kg 318-81-1 was injected over a period of one minute. Systolic blood pressure (SAP), diastolic blood pressure (DAP), and heart rate were measured before taking the substance or before administering 318-51-1. In each case, the measurement was done every five minutes for 1 minute after Take 318-27-1 using the transfer-l pressure in a known way. The maximum blood pressure increase lll of BigET-1 and the maximum decrease in heart rate were calculated from the measured values as the difference between the value measured at the moment of maximal activity of 318-27-1 (specifically after © minutes) and the value measured before Big ET-1 injection and more; Blood pressure curve 0 was determined under the influence of 3:8287-1 1 sad min Auc (=area under the curve) and the AUC value provides information on total extension and the time of activity of 318-07-1 or its decrease by these substances ; Thus the AUC value - in addition to the larger 38:851-1 activity can provide additional information on the effect of substances; For JA's sake not to affect ; or weak effect on maximal 318-27-1 activity; And the decline of this activity accelerated. 0 The sill ratio of 318-21-1 was determined to be greater on systolic pall pressure (SAP) after parenteral administration of test subjects compared to ingestion of the carrier in the table? Lad follows. Table *“: Live Tests of Anti-hypertensive Properties of Test Substances Example #7 Substance-Related Inhibition of Big-ET-1 J Max on SAP in Front of Control v. : to a certain extent. ECE Enzyme 1 Inhibiting Properties Formula materials appear in a standard test in 1 of ECE Formula materials can demonstrate the inhibitory properties of enzyme tube. Formula 50. is useful in the prevention and/or treatment of hSEP and NEP© sexual dysfunction to SD dysfunction and in the clinic; Male sexual dysfunction (MSD) and female sexual dysfunction (FSD) were subdivided (see Melman, A. & Gingell, J. C. (1999). The epidemiology and pathophysiology of erectile dysfunction. J Urology 161 : 5 - 11, hereinafter cited as “Melman.ADC specifically; hSEP and NEP, dual action compounds of the invention capable of inhibiting 0 (eg; MSD) are particularly useful for the prevention and/or treatment of 1 formula compounds

Ya

In this 1 and other advantages of the formula compounds (MSD) functional erectile dysfunction

Domain ECE is domain activation and usually accompanies orthostatic sexual dysfunction; erectile dysfunction; It is called: (see Benet,, A. E. et al (1994), Male erectile dysfunction assessment and treatment ° options. CO7Sp. TheY. 20: 669-673) hereinafter cited as “Benet et al. 1994"). Dysfunctional erectile dysfunction is defined as “the inability to reach and/or Ls SU and maintain an erection of the penis for satisfactory sexual performance.” See, for example, what was stated in (see NIH Consensus Development Panel on Impotence). (1993).NIH Consensus Yo

Conference Impotence. JA. M. A. 270: 83) ¢ of all grades (minor (=ED)) We estimated the prevalence of functional erectile dysfunction (ED) years with increased Ve, moderate and complete infertility up to 757 men from 560 to 560 and the condition had a negative impact Great on the efficiency of (Melman et al. 1999) years V + ratio when exceeding the life of the patient and his companion, which leads to increased anxiety and stress, which leads to frustration 0 primarily mental illness MEP and poor self-esteem. While since Two years was considered, but it is now known that for most patients there is (Benet et al. 1994) an organic cause as well.As a result, there has been progress in determining the method of erection.

MED of normal and pathological anthers in hSEP and NEP and when using dual agent compounds capable of inhibiting Yo; and treatment of FSD in treatment 1 of the invention; Specifically, female sexual formula (FSAD) compounds with difficulty or inability of women to FSD (Gl) sal, and sexual dysfunction is known as obtaining sufficient satisfaction during sexual expression. The term dysfunction includes several female sexual diseases: FSD, female sexuality, Yo

P (Leiblum, 5. R. (1998). Definition and classification of female sexual disorders. Int.

J. Impotence Res., 10, 5104-5106: Berman, J.R., Berman, L. & Goldstein, 1. (1999).

Female sexual dysfunction: incidence, pathophysiology, evaluations, and treatment options. Urology, 54,385-391.). 0 and AN may have a weakness in desire; or difficulty counseling or reaching an orgasm; Or pain with sexual intercourse or a group of these problems. Different types of illnesses, medications, injuries or psychological problems may lead to female sexual dysfunction 750 . Therapeutic approaches aim to treat specific subtypes of FSD; Specifically, problems of desire ¢ FSD and counseling. The best division for female sexual dysfunction patients is 0, based on the phases of the normal female sexual reaction; the desire ; Counseling and orgasm (Leiblum. 5. R. (1998). Definition and classification of female sexual disorders. Int. J.

Impotence Res., 10, S104-5106). 0 Desire is the primary motive for sexual expression. Its symptoms include sexual thoughts when accompanying the desired person or when exposed to sexually exciting situations. Counseling is the dad's vascular response to sexual urges; Among its parts, Adel is the fullness of the sexual organs and includes wetting the vagina; And elongation and increase the sensation / sensitivity of the organ. An orgasm is the release of the sexual tension that was born during counseling, and therefore; Jue disease appears in female sexual function (FSD) when a woman shows an inadequate or unsatisfactory reaction in any of these phases, namely desire and counseling; and orgasm. Female sexual dysfunction (FSD) categories include pathologies of the Yo-stage of desire; Or the counseling phase or orgasm as well as sexual pain. Although the compounds of the invention improve the reaction to sexual excitement, sexual pain disorders. LS) is the case in female sexual arousal disorder, but it may also improve the s (as in female sexual arousal disorder) restlessness associated with intercourse and the treatment of other sexual diseases. Thus, according to Wajh Special for the invention; the compound of the invention is used in the preparation of a medicine for the treatment or prevention of diseases of low sexual desire; or sexual consultation and orgasm and sexual pain; and the best for the treatment or prevention of sexual consultation diseases; orgasm and sexual pain diseases And the best in the treatment or prevention of agitation diseases

AL sexuality and the disease of weak sexual desire appears if the woman has no or no desire for sex and has few sexual thoughts. The reason for this may be low levels due to either natural or surgical interruption of the menstrual cycle. Other causes include pathological testosterone ¢; Medicines, fatigue, depression and anxiety. 0 drill Poor response FSD It is characterized by female sexual dysfunction

BOLI of sexual organs for sexual arousal. The sexual organs are not filled. The sexual organs are not filled as they would during normal sexual arousal. the vagina decreases; Intercourse will be painful. This may hinder orgasm. And Jaa can get wet when the cycle is interrupted or oestrogen The reason for the diseases of the consultation is the decrease in estrogen 5 after childbirth and during lactation; besides the sick; With vascular components such as diabetes and atherosclerosis. Among other reasons; treatment with diuretics; and serotonin antidepressants, such as serotonin reuptake inhibitors, allergic antidepressants, or antihypertensive agents (= SSRIs) and dyspareunia (including sexual pain disorders Cua Thy Ye with pain). Resulting from penetration and may be caused by some drugs that reduce wetness (vaginismuc and pelvic inflammation; inflammatory bowel disease or system problems “endometriosis” as well as because the term includes urinary FSD and it is difficult to measure sexual dysfunction in many females Of the problems, it is difficult to measure some of them, and because the interest in treating dysfunction is relatively recent. FSD Female sexuality Yo A

Ye Many female sexual problems coincide either directly with the process of growing up sugar and blood pressure and because of Bie sexual dysfunction age or chronic diseases contain many types that show symptoms in separate phases FSD female for the sexual reaction cycle; There is no single treatment.

° The current treatment of female sexual dysfunction (FSD) jue focuses on psychological or relationship issues. The treatment of female sexual dysfunction (FSD) is gradually developing as a basic and clinical science. These studies are concerned with analyzing the medical problem. The sexual complaint of females is not psychological in all pathological conditions; Especially for individuals who suffer from vascular dysfunction

(FSAD J) 0 contributes to the general female sexual complaint. There are currently no licensed medications for the treatment of female sexual dysfunction (FSD). Pharmacological treatment includes taking estrogen (Ll) topically or as a replacement therapy for hormones) ¢ and androgens and drugs that change the psychological state such as buspirone or trazodone. These treatment options are not considered satisfactory due to low efficiency and side effects. Since the interest in dyslexia

ve female sexual function FSD recent; Treatment consists of the following: functional counseling; sexual emollients in pharmacies; test volunteers; As well as medicines that are used in other cases. These drugs consist of hormonal agents; Ld testosterone or combinations of oestrogen and testosterone and more recently useful vasodilator drugs in MED. It is not yet clear that these drugs are effective in treating

FSD GY) Sexual Dysfunction - 0 : includes reference

The Diagnostic and Statistical Manual (DSM) IV of the American Psychiatric Association defines FSAD patients as “recurrent or persistent inability to access or maintain sexual arousal until completion of sexual activity and Flay may maintain The wetness

Yo The reason is frustration or personal difficulties. Counseling consists of decongestion

pelvis wet the vagina; the extension and utilization of the external sexual organs; Yo

Yo turmoil, frustration and/or personal difficulties. Studies of Vo-vo sexual dysfunction in couples show that up to 777 women have sexual dysfunction and that 0% of women in the United States of America display sexual dysfunction in females FSD (Berman, J. R., Berman, 1 Butt Werbin, T. J. et al. (1999). Female sexual dysfunction: Anatomy, physiology, evaluation and treatment options. Curr Opin

Urology, 9.563-568) This sexual disease is widespread and affects females before, around and after menopause (treatment and accompanying frustration; heart disease, diabetes and HRT diseases. Hormonal replacement is weakness of fullness / bloating; and wetness. FSAD. Urinary system The primary effects for 0 patients are a decrease in desire FSAD and the pleasurable sensation of the sexual organs Secondary effects for patients with sexual intercourse include pain during sexual intercourse and difficulty in reaching orgasm One of the recent theories is that there is a vascular base for one part At least of the FSAD patients (Goldstein et al., Int. J. Impot. Res., 10. 584-590. 1998) had symptoms (Park et al., Int. J. Impot. Res. , 9.27-37,1997) with animal data supporting this view. 05 Promote an increase in blood flow in the vagina and clitoris. SEP is known to be an inhibitor of pelvic nerve signaling as well as vasoactive intestinal peptide (-710) and of The vagina a Sa and VIP neurorelaxin enhance SEP which are also known to be inhibitors and therefore; the present invention is useful and provides a means to restore normal sexual intercourse; specifically increasing blood flow leading to fullness of the vagina, clitoris and labia Y ; And increase the response of Lea BU and this leads to increased wetness in the vagina through the transmission of Jaga vaginal and increase sexual sensitivity. And therefore ; The present invention provides a means to restore or enhance the natural sexual response. The term external female sexual organs means “the genitals consist of an internal group and an external group. The internal group is located inside the pelvis and consists of the ovaries, uterine tubes, uterus and vagina YO and the external organs are located above the urogenital diaphragm and under the pelvic arch. It consists of From the knees, the labia majora and minora, the clitoris, the vestibules of the vulva, the bulb of the vestibule, and the glands

Yoni

Greater vestibule: ‎(Gray's Anatomy, C.D.

Clemente, 13th American Edition) Levin denies. 87 that because "the male and female genital organs emerge from a common tissue in the fetus; there is a great similarity in the composition of the male and female genital organs; therefore the clitoris is similar to the penis and the lips are similar to the sac: Levin,

R.

J. (1991), Exp.

Clean.

Efzdocrinol., 98,6169). ° Regarding male sexual dysfunction (MSD); specifically MED; Penile erection is a blood-moving process that depends on the balance of muscle contraction and relaxation

The soft tissues of the corpus cavernosum and the blood vessels of the penis see:

(see Lerner, 5. E. et al (1993). A review of erectile dysfunction: new insights and more question.

J.

Urology 149: 1246-1255). Yo The muscles of the corpus cavernosum are known as the soft muscles of the corpus cavernosum or the corpus cavernosum dal st in general. The relaxation of the corpora cavernosa leads to an increase in blood flow in the spaces between the corpora cavernosa, which leads to its extension in front of the surrounding membranes and pressure on the veins.

leaked. This raises the pressure of the cavernous blood, which leads to an erection (see: Naylor, A.

M. (1998). Endogenous neurotransmitters mediating penile erection.

Vo Br.

J.

Urology 81: 424-431), hereinafter cited as "Naylor, 1998"). The changes that occur during erection are complex and require a high degree of systemic control of the peripheral and central nervous systems; and the hormonal system (Naylor, 1998). Contraction of the corpora cavernosa is controlled by sympathetic nerves that secrete noradrenaline 0 by activating a-adrenoceptors in the cavernous post nerve connections. MED may be accompanied by an increase in internal muscle contraction In any case, the relaxation of the corpora cavernosa partly depends on non-adrenergic (= NANC) non-cholinergic neurotransmitter, and there are many other NANC neurotransmitters in the penis; (=NO) such as the peptide related to the Yo-calcitonin gene (GRP) as well as VIP.The main relaxant responsible for the relaxation is NO manufactured from Aland ss Loorginire nitric oxide manufacturer (=NOS) ‏

Yo

for (see e.g.

Taub, H.

C. et al (1993). Relationship between contraction and relaxation in human and rabbit corpus cavernosum.

Urology 42: 698-704). It is approved that the decrease in the muscle tone of the corpus cavernosum may help NO to cause relaxation in the corpus cavernosum. and during male sexual counseling; NO is released from nerves and inner cells and binds to and activates soluble glucocorticoid cyclase (600) present in muscle and inner cells; which leads to an increase in the levels of field guanosine “© monophosphate” (cGMP) inside the cell. It leads to an increase in eGMP This leads to relaxation of the corpus cavernosum due to lowering intracellular calcium concentration ([687]) in ways that are believed to be unknown, including activation of G protein kinase (due to activation of 0 pumps and activated Ca'0 and 1 channels). Recently, it was shown that a natriuretic peptide of type (=CNP)2 may also play a role in MED; it acts as a membrane-bound guanylyl cyclase B (=GC-B). It appears in the corpus cavernosum tissue. GC-B signaling leads to an increase in cGMP inside the cell, and thus muscle relaxation. The cPDES inhibitors Ye, such as sildenianyl, increase cGMP within the corpus cavernosum tissue by inhibiting its breakdown. PDES inhibitors are inactive in the absence of an activator of cGMP formation, ie the absence of 110. This information suggests that the basal (unactivated) rate of cGMP formation in the corpus cavernosum is low, so that inhibition of cGMP breakdown by PDES would be insufficient. Sufficient to induce an erection without consequent activation of guaylyl cyclase. Increasing the ONP concentration raises the cellular concentration of CGMP; by increasing the formation. Thus, “increasing the concentration of CNP in the corpus cavernosum has similar effects as inhibiting PDES.” Because of the different nature of their respective activities; Any increase in cGMP inhibits its breakdown; It is possible to combine the inhibition of 0885R with ONP degradation and lead to greater efficacy in patients unresponsive to PAES inhibitors alone. Yo found nerve GL that secretes VIP in the Jal network dorpus cavernosum; It may play a role in releasing VIP during erection. We think that the effects of a

YA: VIP led was controlled by increasing cAMP and thus supplemented with Jal gall which raises 75 and in ED patients ¢ we found that injection of VIP into the corpus cavernosum (with anti COLE a For adrenaline, phentolamine (a-adrenoceptor antagonist phentolamine) is a safe and effective treatment; with a response rate of 737 (erections sufficient for sexual intercourse °). NEP endopeptidases and hSEP break down both CNP And VIP, thus limiting the effect of CNP and VIP on the corpus cavernosum, and inhibiting CNP and cracking VIP will increase the availability of these vasodilating factors, which lead to increased blood flow to the corpus cavernosum, which improves blood flow. In support of this, we found experimental Ye data in rabbits, which show a clear increase in blood pressure in the corpus cavernosum and genital blood flow to females by not generalizing NEP Laie (see patent application (WO 02/079143 dalla) Moreover, we found that the (SMR) gene representing the first peptide of sialorphine inhibiting endogenous NEP (see User HM., Zelner D.J., Mcckenna K.E., McVary K.T. (2003). Microarray analysis and description of SMR1 gene in rat penis in a post-radical prostatectomy Yo model of erectile dysfunction.

J Urol; 170(1):298-301) is decreased >80-fold in the mouse model of neurogenic ED suggesting that this disease+ has NEP activity that may increase and contribute to ED. Description of the pharmacy test method. a Example numbers relate to Bly the preparation described Lad follows: Inhibition of the enzymatic concentration of ONP and VIP compounds by the compounds used according to the invention was measured in an in-tube enzymatic assay according to the following method: Enzymes: hSEP (sol hu) His6 -tagged hSEP ectodomain (i stock solution: oY µg/mL in Yo mM HEPES; pH 1,7 10 YO glycerol; ...7/6) Ale 001 Tween20 rm Coase anys IS purity > Jae Working solution: Stock solution diluted with buffer solution to © µg/mL.

Ye Available from © innogenetics, Ghent, Belgium. Protein preparation and purification is carried out as stated in WO 094176/02 b) NEP prepared from porcine cortex. Stock solution: 171 µg/mL in Te m-3 ; oe culture > Jao Working solution: Stock solution diluted with buffer solution to © µg/mL 0.

Dr. Philippe Crine, Univ. of Montreal, Canada : Available in lower classes a) VIP b) (oY = YY) CNP 0 Stock solution: 100 μg in buffer.

Bachem, Weil am Rhein, Germany : sa Available buffer: 001 mmol trinitrate pH You 7.0 pH mmol sodium chloride. All these compounds were dissolved in DMSO at 100 mol and diluted with No by buffer solution. Activity assay process 80 μl of test separator + and 01 μl of working solution NEP and hSEP as well as 01 μl of buffer solution VIP and CNP were mixed in a tube Eppendorf for 171 minutes at 7127°C and the enzymatic reaction was terminated by heating to 40°C for ¥ minutes. Inhibition test process Ve μl of buffer solution was mixed; and 01 μL of the enzyme working solution (NEP) and ©052) and 01 μL of the test compound solution into an Eppendorf Yo container and initially incubated at V0 for 0 min. then ; 01 µL of Yo

Peptide buffer solution (VIP) and CNP and the reaction mixture was incubated at 77 °C for Te min to allow enzymatic hydrolysis. The enzymatic reaction was terminated by heating to 51 °C for t min. and after centrifugation (Heraeus Bioluge B) » ? minutes) the filtrate was subjected to HPLC ° and in order to separate the EU substrate from the cleavage products; The HPLC method was used with a RP 300/5 CC 125/4 Nucleosil column and a CC 8/4 Nucleosil 100/5 C18 precolumn (Macherey-Nagel, Duren, Germany). 01 µl of reaction samples were in HPLC and a Janay column was rinsed at a flow of 1 mL/min with the following domain: 0 7000 solution: A 11:0 + 0, + 11:50 mol. pH Yee Solution 8 : 7001 acetonitrile + ©,+ mol H3PO4 zero - ? 705 min 8 01-8 min BZ V-Y 171-01 min B Joo min 0 - M 8375 A-Y Yo min 0—+4/3. All peptides are determined by absorption at ¥VE nanometers (UV Spectrophotometer). And the percentage (7) of hydrolysis was calculated based on the maximum surface area of the unhydrolyzed peptide of an enzyme containing sample Y in relation to a receptacle containing the same concentration of peptide without an enzyme (empty) by the following reaction 0: Hydrolysis = 001* (empty - (Y) and the calculation of 7 inhibition is based on the maximum area of the non-degraded peptide VIP) and (CNP of an inhibitor containing X Aad compared to samples containing only a free peptide) or a peptide and enzyme without Inhibitor (control) according to the following equation: (X) *001 = Ldn) / vo - control) / (null - control). Yon

All samples were passed in pairs and the average values were calculated. A solvent control (75.1 01456) was added to each test run. CNP and VIP were cleaved by NEP and hSEP in vitro. Their cracking was faster with hSEP than with NEP; As shown in the table; ight © table; The cracking rates of VIP and CNP by NEP or hSEP showed that the solutions carried the decomposition at a time of 7 711 1 1 a and the test compounds layers of the invention were able to give decomposition of CNP and VIP by NEP and SEP and in this test model the values and 1065 for formula 1 compounds were as in Table 0 Led the following: (J gaa) © : Cracking grants of CNP and VIP by compounds TEST: Inhibition of cracking NEP cracking VIP cracking with Example No. L Cs (nM) ICso (nM) ICs, (nM) ICso (nM) and Y1 01 Formula 1 compounds are for the prevention of and/ Or treat different cases associated with the death of khadia cells. Among the examples mentioned are: nerve eroding diseases such as stroke due to anemia 0 cerebral anemia; head injuries; acute disseminated encephalomyelitis and meningitis; lateral sclerosis with atrophy (ALS), retinitis pigmentosa 05 ¢ and mild intellectual impairment; Alzheimer's disease; CD disease and dementia with old age; advanced supranuclear paralysis; subcortical dementia and Wilson disease; Multiple infarcts ¢ Dementia due to atherosclerosis ¢ Associated dementia

£y

for AIDS; Cerebellar erosion and myelodysplastic syndromes ¢ and Friedreich's ataxia; ataxia, vasodilation; epilepsy related to cerebral atrophy; spinal injuries; instability leg syndrome  Huntington's disease and Parkinson's disease; and eat the black layer; and vasculitis

© cerebrovascular disease and encephalopathy; neuropathic steatopathy; spinal muscular atrophy; lysosome storage diseases with central nervous system dysfunction » mononucleosis; urea cycle defects; cer Sl encephalopathy and renal encephalopathy; metabolite; porphyria; And bacterial or viral meningitis and inflammation of the brain and meninges. viral diseases; and poisoning by vehicles

0 nerve poisoning; and Guyane-Barre syndrome; neuropathy due to chronic infections; flaccid paralysis; dermatomyositis; brain atrophy = due to radiation; and digestive diseases such as irritable bowel syndrome and intestinal infections; such as Crohn's disease and ulcerative enteritis; underground disease; gastritis due to Helicobacter pylori and other stomach infections due to infection; or

ve semi-membranous endocolitis. enteritis due to play); and lymphatic intestinal infections; patch disease in front of the host; acute and chronic pancreatitis; and liver diseases such as; hepatitis caused by alcohol; or viruses; or metabolic, immunological, or radiation-induced; or to cirrhosis of the liver; erythropoietic syndrome and elevated uric acid; inflammation of the kidneys; and inflammation of the kidneys due to lupus

red YL; Viral diseases such as acute hepatitis: joint diseases; specifically the immunological Jie inflammatory myopathy; a low white blood cell count; a low blood platelet count; rheumatoid joints; Reasonable low blood platelet count

the unknown; autoimmune erythropoietic syndromes; antiphospholipid antibody syndromes; and inflammation of the heart muscle. multiple sclerosis; and its types such as multiple sclerosis

repeated yo; secondary-advanced multiple sclerosis; advanced recurrent multiple sclerosis; severe multiple sclerosis; And benign recurrent multiple sclerosis non-existent multiple sclerosis

for symptoms; neuritis and optic neuritis (Devic's disease); lymphocytic hypophysitis and Grave's disease; and Merv Addison; decreased secretions of the parathyroid glands (Aa) and sugar; red lupus; gypsy pemphigus; pemphigus globulus; psoriatic arthritis; endometriosis and orchitis eld; and immune 0 erectile dysfunction; lymphoma and Wagner's disease; immunological deafness; Gujran's disease; autoimmune + retinitis, interstitial cystitis, Jude-Pasteur syndrome, muscle aches and fibres; and poor myeloid growth such as anemia as a result of not manufacturing its components; and skin diseases such as gypsy pemphigus; dermatomyositis; immune dermatitis; Henoch-Schnöllen disease; acne; systemic sclerosis; sebaceous skin cell proliferation ¢0 and somatic skin cell proliferation; chronic proliferative dermatitis; hardness of keratin formation; scleroderma and stratified dermatitis; psoriasis; bacterial skin infection; leprosy and leishmaniasis; vitiligo and toxic skin death; and Steven Johnson syndrome » and sebaceous adenomas; baldness and photodamage to the skin; lichen; rash; autoimmune cutaneous vasculitis; cytotoxic dermatitis; and diseases of the inner ear such as hearing loss causing LA death; hair loss and hearing loss; hearing loss, death of hearing hair cells due to aminoglycosides, hearing loss due to detrimental drugs, perilymphatic fistula, cholesteatoma, poor blood flow to the vestibule; Meniere's disease; hearing loss as a result of radiation, bacterial, or viral fibrosis, or without a known cause; organ transfer; Jee; patch in front of Yo; the host; acute and chronic rejection of heart failure; or to the lung or kidney; or skin; or to the cornea, marrow, or liver; wound healing; tissue rejection. 54 30 methyl amido acid derivatives can be clarified; The amidomethyl-substituted 1-(carboxyalkyl)-cyclopentylcarbonylamino-benzazepine-N- acetic acid Yo of Formula 1 is intended for the prevention and treatment of various conditions associated with apoptosis in animal models with potential for anti-apoptotic activity.

t¢ PHARMACY LAY) DESCRIPTION OF METHODS Example numbers relate to the preparation of prescribed examples including:

Al Brain injuries: cellular nerve death 1- The bruising device. The bruising device shall be made of stainless steel tube

OB cm to prevent air from being compressed in the tube. 1 56 cm long was anesthetized; perforated every 0 grams ; by Chloral Hydrate YY - 171 Wistar juvenile type mg / kg; A cerebral opening was made over the right hemisphere of the brain, 5560 » chloral hydrate; The device and weight were placed on a foot plate on the surface of the dura mater in the form of a centimeter issued by the weight of X grams of TAL perpendicular to the surface of the skull, and a force of milligrams VY was chosen (causing a contusion in the brain; a decrease was allowed to occur Ye exceeds 0 in the dry layer A chamical was done on the surface of the brain to prevent mechanical perforation 1 mm next to the fontanelle and Yoo was installed 1.8 mm behind and centered the foot plate The flow of mice for a period of “days after brain injury by a solution containing; 7 paraformaldehyde in Vasyl Phosphate.

ICV) Intraventricular injection: The compounds were ingested into the cerebral ventricles yo

A= min 105 µl injected over © 11 min —o — syringe size Hamilton mm da mm Y= L = mm 1# = AP: hours after infection using the following coordinates (Swanson, L. W. (1992) Brain Maps: Structure of 0.0 = 7 m in relation to the Rat Brain, Elsevier, Amsterdam). Stereotactic CA3 morphometric analysis in the hippocampus Atrophy was determined in the field of the hippocampus. 0 m Ae 11.01 to 0.71 at caudal convergent planes extending from © (Swanson, L. W. (1992) Brain Maps: Structure of the Rat Brain, Elsevier,

Amsterdam). Loss of a sa ily and during the medial-lateral axis three days after injury (Cruz-Orive, L. M. & : neuron in the hippocampus; a Yo (NV) stereoscopy system was used for digital densitometry Weibel, E. R. (1990) (Am. J. Physiol. 258, L 148-1156)

m of pyramidal nerves, undisturbed counting frames of 106 mm (106 mm) were used, with a dissected height of (ie lle 1.01) and a high-aperture system (x) £0) for sampling, and normal neurons were identified by By the presence of nuclei corresponding to clear nuclear material and definite nuclear surrounded by cytoplasm containing Nissl material The © boundary between subdomains CA2 and CAB was a point where the dilated arrangement of major pyramidal cells transforms into condensed pyramidal cells in the subdomain CAS dendrocyte Jal ball between the lateral ends of the dentate granule cell layers was a link between the 5 subdomain .CA4 .In this model, + the example test substance ¥ produced a dose-dependent neuroprotective effect of 0. We observed Neuroprotective effect when the test substance was taken from example A until hours after injury. The dose response of the neuroprotective effect of the test substance was measured when administered 1.67 after adult Wistar vertebrae injury. Neuronal densities were determined in the field of the hippocampus CA3 + standard error of measurement (SEM) in + stereotactic striatal levels in the uninjured left side of the rats do treated with the carrier and the injured right side of the rats treated with the carrier and the rats treated with the test subject from example ¥ and the results are illustrated In Table Led 1 and in all of the following tables: The number (0") indicates the number of phasors for each group. 0 | Table + : CAS horn neuronal densities gd] 01 x 1" cells/mL Je level 1 (left transporter n) | right transporter n) example compound © | example compound Ve oF | Compound Example Linear F 01 (01 <- ©” μg | μg *1 on) μg (V+=n) 0 (V+=n)

Aha thief ‎¥,494+Y049,7 | Yoo, A | LEVEAL TRIGGER BA LEVEAL INJECTION OF THE VECTOR INJECTION OF THE VECTOR RESERVED TO REDUCE NEURAL DENSITY IN THE CA3 CA3 CAMERA TO 775 OF THE CONTROL VALUES WITH INJECTION OF “+10”; or Yoo µg of Jia test material To partial prevention of neuronal loss in the goal oven, the dose of 01 micrograms was the most effective. Analysis of Variation (FANOVA™) showed that there was a clear protective effect of treatment on neuronal loss in 683 of all three doses tested sald test example? P) > m .,. 01 = n c for each group); An ANOVA showed that a dose of 10 μg induced more bacillus protection than Vole all μg or Yo μg. The time window for the neuroprotective effect of the example test subjects* was measured at 0 - ingestion of Chey? or; Or A hours after the adult Gl Sala. Neuronal densities were determined in 683 subfields as described in the Methods. Densities of CA3 neurons (SFA) were measured at +stereotactic levels in the injured right side of rats treated with either a vector or test compound in the example ? The results were presented in the table feb lad V Vo table: nerve densities in CA3 cells “01 x / mm”. Right Carrier Level | Compounds of example 1 YF Compounds of example fr | compounds eg; Stereotactic (A= nm) clock (A= n) clock (A=n) delw A | (A=n).

1 0 l pa CH l 6 tgm Injection of the vector decreased the density of CA3 neurons by 7705 from ad control and injection of 01 μg of test substance from example 7 into the ventricles of the brain prevented neuronal loss in Amon century. ANOVA showed that there was a significant effect of the treatment with the test substance in the example ¥ on the loss of neurons in 3e at the three points (9 > vee) at ,7; hour ; f © < 01 for (lela A "-adriamycin toxicity; determination of anti-apoptotic activity) Wistar rats weighing YOO = 060 g were anesthetized with chloral hydrate 5060 mg/kg 6 and were Alzet 0 micro-osmotic subcutaneous (S.C.) and Sb pumps were implanted with either a carrier or a solution containing the compounds of the invention at an appropriate concentration and primed prior to implantation; the animals were given adriamycin in three equal daily doses. © mg / kg on days 1, Y and ?. The herthranes were treated with euthanized for © days after the first injection of adriamycin and were fed with a solution containing It Ve paraformaldehyde In a phosphate separator, the heart, liver and kidneys were removed and cultured in paraffin with TUNEL stain for TUNEL-based histological analysis. The organs were subsequently fixed for 06 days in paraffin and then TUNEL staining on paraffin sections 01 micrometer thick using (Apoptag peroxidase (Oncon Appligene, Heidelberg, Germany) ve 57100) according to the manufacturer's instructions. In short; ARERR!

And after the first treatment by proteinase k and suppression of peroxidase

internal; The sections were incubated in a neutralization separator and then with TAT working force enzyme (includes

dUTP nucleotides tagged by digoxygenin to the tip of a button

free from 1 (DNA hr; 71”m) . The sections were incubated in a removal/washing interval (71° min; L; then with a peroxidase-linker anti-digoxigenin).

Adds Yi) then DAB prelayer (Sigma, Deisen hofeu, Germany) 5 Dyeing is done

Reverse by methylene green

And in this test model; The test substance showed adriamycin in the heart

Cua reduced the density of TUNEL-positive cells in the three organs 0; adel, this effect on dose with a dose of 100 mg/kg per day

are the most effective.

Adriamycin Wistar rats were administered with a cumulative dose of Yo mg

/ kg non-orally and the test compound in the example was ingested; Under the skin

In doses of YL, © or 100 mg / kg per day by Alzet Vo osmotic micro-pumps for © days. And the animals were treated by Greece

They were fed by heart 0 days after the first injection of adriamycin and the heart was treated

The kidneys and liver were stained with TUNEL, and the density of TUNEL positive cells was determined as is

described in the methods. The results of each organ were measured (heart aS “heart ¢ kidney” (kidney).

as mean densities of TUNEL-positive cells (SEM) for the control groups and the different x. test groups (Ye); or +9 a; Or 100 mg/kg per day of compound

Example test ;) and are explained in Table A below.

Table A: TUNEL-positive cells/mm'.01

[ow This is Yo

£9 compound example 4 4 70 ms 64,3600 h 4) be *#* | VEAVOL A Bach FEEL | (g/kg = m) 1) + compound example; CL g/kg (n = 01) The test compounds in the example have reduced; The toxic effect of adriamycin in the three organs depends on the dose. Comparisons between groups were made using the 00 < ef .,.1 < 0** test (Student _ compared to vector-treated mice). 0 The present invention also provides a method for the treatment or prevention of cardiovascular diseases and/or the treatment of many cases of dalad of cell death in mammals and humans involving ingestion of an effective amount of a compound of formula 1. The present invention also provides for the treatment or prevention of dysthymia Sexual function in mammals and humans involves ingesting an effective amount of a dual functioning compound 0 capable of inhibiting NEP and ©1582; specifically the compound of formula 1; according to the invention. All 1 dn compounds can be taken in regular pharmaceutical formulations. The doses used vary independently and will naturally vary according to the type of disease being treated and the substance used. And in general; and on each; Pharmaceutical forms with a Vo of the active substance ranged from 1.7 to 8060 mg; specifically 0 to Yeo milligrams; of the active substance for each dose suitable for administration in humans and large mammals. The agents of the present invention may also be administered by intravenous injection; At a dose ranging from 10-50 mg / kg / hour. These doses are representative of the average case. The compounds may be contained according to the present invention; With the additions of Yor

other pharmacy and/or excipients. in solid or liquid formulations. Examples of solid pharmaceutical compounds are oral formulations + tablets; Coated tablets, capsules, powders, granules or suppositories. These pharmaceutical compositions may contain organic and/or inorganic excipients such as talcum; or

oo lactose or starch; In addition to drugstore additives; Such as lubricants or brittle agents 0 And liquid pharmaceutical formulations (Jie) Fifth suspensions with active compounds may contain usual diluents (Jia) Water; oils; and/or suspending agents such as polyethylene glycols and the like, and other additives may be added; such as preservatives, flavor enhancers, and the like.

01 The active substances may be mixed and formulated with pharmaceutical additives and/or excipients in a known manner. and in order to prepare solid pharmaceutical JS; The active substances can be mixed with additives and/or excipients in a convenient way and wet or dry granulation can be done. Granules or powder can be poured directly into capsules or pressed into tablets in a convenient way. It can be packaged in a known way when

ve need. The following examples are illustrative of the invention; without limiting the field.

The mass spectra were measured using the following method: HPLC-MS; API100 Quadrupol mass spectrometer (PE Applied Boisystems) with LC200 pump (PE). Electrospray ionization; Positive state scan field

50 X jis a £1) Software MassChrom 1.2.Xterra® column 0001 to 001 mz 0 µm. V0 mm ; 01( Dissolution system: acetonitrile water Jo linear field of ¢ acetonitrile nitrile sid )* pH min. 01 to 956/7 in acetonitrile

: 1 Example Yo

Ethyl 2-{{(3S)-1- ({[1-(2-tert.

Butoxy-2-oxoethyl)-2-0x0-2,3,4,5-tetrahydro-1H4-1-benzazepin-3-ylJamino} carbonyl)cyclopentylmethyl}-4-(isopropylamino)-4-

oxobutyrate

PY 0 m has a “0 lsh” JN of z

(i) 9.9 mL benzyl alcohol was added to 9.59 ethaconic acid anhydride and the mixture was stirred for A hours at

‎mS ~ g boys a 53 Je To ga tl ld) pe alt Jee iy. 51

n-hexane/diethyl ether? 10: (volume / volume) and the solvent was filtered out. The resulting ore was dissolved in Yoo milliliter of diethyl ether in a state

n-hexane mL p-hexane Ar was heated and crystallized again by adding 0 and the combined aqueous alkali solution was reduced; And recrystallization according to method 0 above, and the resulting crystals were added to the basic amount. And it was obtained

0 g of 2-[(2-benzyloxy)-2-oxoethyljacrylic acid was used directly in reaction A without further purification » , 6.47 , 5 ;[5] 1H-NMR (CDCI3): 7.35, m,

s, [2]; 3.40, s, [2] ppm. ,5.15 :[1] ,8 ,5.83 :[1]. ppm.

b A suspension was made from 100 grams of 2-[(2-benzyloxy)-2-oxoethyllacrylic ass

0 in 0 mL methyl-tertiary butyl ether (=MTBE) methyl-tert. butylether

And 0.9 milliliter of pyridine was added to it. 7 was added; ml of thionyl chloride by dripping and the resulting mixture was heated for 1 ½ h under reflux cooling to boiling and after cooling to CRE it was evaporated to dryness at reduced bua . The resulting _ precipitate was dissolved in On mL dichloromethane and added by drop in zero = © 5 to oy 3.7 mL ethanol 11 mL receptor solution containing chloromethane Ss i ms Yo. triethylamine triethylamine 1 hour at the end of the addition; The flip has been completed for . dichloromethane is about zero. Then it was washed in suspension with 790 ml water each time; Once with dilute and in Jl sodium bicarbonate milliliter sodium bicarbonate solution 0 ° moderator. The organic phase was dried at the end once with a salt solution and evaporated under reduced pressure. Sodium sulphate 2-g of oY acid was distilled and that gave Ven mbar and 1015 the resulting precipitate at or directly Aan and it was used without methylenesuccinic acid-4-benzylester-1 -ethylester, for the following reaction. 0 in L diisopropylamine isopropylamine SE 118 mM (z) was dried and nitrogen was dried under nitrogen (=THF) tetrahydrofuran (J 5 5 ua quaternary mole YO mL of Vow solution up to 0 um Jp la) was added drying to n-hexane in p-hexane n-butyllithium gram of p-butyllithium solution Another minute at zero at fo the receiving solution and the stirring was completed for a period of 0 The end of the addition Then a solution of 0 pounds cyclopentane carboxylic acid was distilled into the resulting mixture at Gla 7117 ml 001 in cyclopentanecarboxylic acid - an hour at zero, and the cooling was until 1, and the mixture was stirred for a period of a0= 4 ua 2-methylenesuccinic acid gram YY, and a solution of M0 was added as before (total quantity of patches Polymers) in acid-4-benzylester-1-ethylester, Ye by distillation, and after the phases were separated + THE 0 milliliters were extracted and the organic phases were synthesized + (JA) (BA) the aqueous phase twice with acetate and the solvent was evaporated. sodium sulphate and dried on sodium sulfate organic phases at low pressure and volatile substances were separated by distillation at 07 ml of the precipitate after distillation on chromatography and produced by chromatography. PVE bar and ve 7 : 1 to 1 : 1 p-hexane acid | EA (mobile phase silica gel).

Yon oy 1-[4-(benzyloxy)-2-(ethoxycarbonyl)-4- 1 g YV,A vol) aaa 1H-NMR (CDCI3): 7.33, m, [5]; 5.10, s, [2]; ¢ oxobutyl]cyclopentanecarboxylic acid 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]. 1-[4-(benzyloxy)-2-(ethoxycarbonyl)-4- b +( 9.59 g of cyclocarboxylic acid gL ty oxobutyl]cyclopentanecarboxylic acid was previously dissolved in total on multiple patches ) in Lad as cyclopentanecarboxylic acid is chloromethane and 4,5 was added? 1 gram tributyl SE milliliter £70 tert. Butyl-[(3S)-3-amino-2-0x0-2,3,4,5-tetrahydro)- 1H-benzazepin-1-yl]acetate gram hydroxy YAY; and EP0733 642 AL acetate (production see European patent ys) to a solution of morpholine mL morpholine T+ and hydroxybenzotriazole benzotriazole to the resulting mixture in one part and then EDCxHCI g oF receiving Stirring at room temperature was then added, the solvent was evaporated at reduced pressure, 001 was withdrawn, and the organic phase was washed twice with EA 1 mL of Vou precipitating in 001 mL aqueous hydrochloric acid each Once; and twice by NC ml vo liter saturated usual aqueous salt solution and dried on 001 Me water each time and once by that the solvent was evaporated under reduced pressure and drying continued (Cie. sodium sulfate bar) Thus, it was possible to obtain lle "01 x 5 (residual residue in a vacuum oil pump 2-{[(3S)-1-(2-tert. Butoxy-2-oxoethyl)-2-0x0-2,3,4, 5-tetrahydro- contains 47.5 grams of 1H-1-benzazepin-3-yl]amino }carbonyl)cyclopentyl methyl } succinic acid-4- Ye in the form of yellow oil + and is used without a benzylester-1 Next -ethylester. 2-{[(3S)-1-(2-tert.Butoxy-2-e) A mixture was made consisting of 7.9 grams of oxoethyl)-2-0xo0-2,3 ,4,5-tetrahydro-1H-1 -benzazepin-3- with yl]amino }carbonyl)cyclopentylJmethyl } succinic acid-4-benzylester-1-ethylester Yo palladium grams on activated carbon 10 and (BA =) milliliters of ethyl acetate 0

You of Bar 1 After that, the mixture was hydrogenated for two hours under a hydrogen pressure of (PAC 2), after which the Cellite filter cake was washed, and then the mixture was filtered on a filter. liters of lyte, then the combined organic phases were evaporated under reduced pressure 0.9 by cyclohexane (1:1; volume / volume) [EA] 000 milliliters of EA and the precipitate was placed in sodium carbonate Js Jas milliliters of You were extracted twice using 0 semi-saturated each time. Then the aqueous phase was acidified with sodium sulphate concentrated potassium hydrosulfate solution and then extracted *” 18 milliliters each time. After drying over sodium sulfate, 0010 was evaporated using under reduced pressure. Then Dry the remainder of the precipitate using an oil pump under 3-{[1-({[(3S)-1-(2-tert. Butoxy-2-0xoethyl)}-2- vacuum to obtain 1g of 0 0x0 -2,3,4,5-tetrahydro-1H-1-benzazepin-3-ylJamino [Al-Jada'a] [Al-Ja'ad] is a cursed (1-Ligno taste) - 1H-NMR (CDCI3): 7.31-7.17, « in the form of white foamy The intermediate compound can be separated. The product in this case, when needed, is converted into pure binary stereoisomerization (HPLC) components using high-performance liquid chromatography Vo grams of intermediate product by separation using Ve, thus the following method can be obtained:

Column: 1080-1, 23.48 cm; stationary phase: 740 p ChiralpakAD, 20 pu; mobile phase: heptane/isopropanol (85:15); UV detection; cycle time: 45 minutes;

Analysis: stationary phase: Chiralpak AD, 20 u; mobile phase: heptane/isopropanol Ye 9:1 (v/v), flow rate 2ml/min; cycle time: 15 minutes. A gram of isomer 71 minutes to 11.6 can be obtained after a waiting time of ("rel1")-3-{[1-({[(38)-1-(2-tert. Butoxy-2) - The first interstitial; the designator urges the name of oxoethyl)-2-0x0-2,3,4,5-tetrahydro- 1-benzazepin-3- yllamino}carbonyl)cyclopentylmethyl}-4- ethoxy-4-oxobutyric acid, 1H- NMR Yo (CDCI3): 7.31–7.18, m, [3]; 7.09, d, [1]; 6.74, d, [1]; 4.53, 4.48, 4.37, 4.32, AB-Q., - 00011, as [2]; 4.48, m, [1]; 4.11, m, [1].

You oo g of the YY isomer on Js asl) with a waiting time of 1.0 min; Tm that has a relation with a deficient center ("rel2") the second interstitial marked (3"rel2")-3-{[1- with the set "00021" = ¢ under the name "Ca" JL) (({(3S)-1-(2-tert.butoxy-2-oxoethyl)-2-0x0-2,3 ,4,5-tetrahydro- 1H-1-benzazepin-3-yl]Jamino} carbonyl)cyclopentyl]ethyl}-4- ethoxy-4-oxobutyric acid, 1H-NMR° (CDCI3): 7.31-7.17, m, [3]; 7.11, d, [2}; 6.81, d, [1]; 4.60, 4.56, 4.35, 4.31, AB-Q, in methanol).7[2]; 4.48, m, [1]; 4.10, m, [1]; and 1l] (1 3-{[1-({[(3S)-1-(2-tert.butoxy-2-oxoethyl)-2-) a mixture was made consisting of £g (5 0x0-2, 3,4,5-tetrahydro-1H-1-benzazepin-3-ylJamino }carbonyl)cyclopentyl methyl } - chloromethane ALT milliliters of V0 previously produced with ¢ 4- ethoxy-4-oxobutyric acid, Ve Milliliters of triethylamine 00, and after cooling this solution to zero, dichloromethane, which is ethyl chloroformate Ji, milliliters of chloroformate “VY triethylamine Ji, 0.14 minutes at zero, then Pr sad is added slowly in stages and stirred The mixture was at ale uv and the stirring was continued for isopropylamine, milliliters of isopropylamine 001, the solvent was evaporated at low pressure and the remaining precipitate was drawn out in Jia VO several times through the organic phase, after which the organic phase was washed. EA in milliliters of a saturated aqueous solution of potassium hydrosulfate (04 mL) and then with a salt solution and an aqueous sodium sulphate was evaporated; It was dried on sodium sulfate pada solvent under low pressure. Then the remaining precipitate was dried in an oil vacuum pump to obtain 4,795 grams of the title compound in the form of amber oil 0.

MS: [M+H]": 586; m/z: 530; 484; 5 2-{[1-({{(3S)-1-({[1-(carboxymethyl)tert.butoxy-2-oxoethyl) )-2-0x0-2,3,4,5- tetrahydro-1H-1-benzazepin-3-ylJamino }carbonyl)cyclopentyl]methyl}-4- (isopropylamino)-4-oxobutyric acid. Yo

Yon

05 A 1 N H N 8 OH 0 8 “ 0 o OH was grown and then a mixture consisting of 9.997 grams of ethyl 2-{[1-({[ 3S)-1-({[1-(2-tert.butoxy-2-oxoethyl)-2-0x0-2,3,4,5-tetrahydro-1H-1 -benzazepin-3- .ylJamino }carbonyl)cyclopentylJmethyl } -4-(isopropylamino)-4-oxobutyrate acid ° obtained from step (1) by dissolving it in 0 milliliters of a 0:1 water/ethanol mixture; volume/vol) and 1.14 grams of solid NaOH sodium hydroxide added with stirring. Stirring continued overnight; after that the solvent was evaporated under low pressure and then the remaining precipitate was withdrawn in 0 milliliters of EA. Then Then neutralization 0 was then extracted three times by BA The combined organic phases were then washed with 00 milliliters of saturated normal salt solution and dried over sulfate using an oil vacuum pump to yield 0.08 grams of the title compound. Example?: (2"rell")-2-({[(3S)-1-({[1-(carboxymethyl)-2-0x0-2,3 ,4,5-tetrahydro-1H-1- Vo benzazepin-3-yl]Jamino }carbonyl)cyclopentylJmethyl} -4-(isopropylamino)-4- oxobutyric acid, PR I N H No Ox rel A OH 0 pe o “A OH Youd

£00 mg of a stereoisomer mixture was obtained from the example ? Previous according to the following steps: HPLC separation was done using

Column: 1080-1, 25 x 8 cm; stationary phase: ChiralpakAD, 20 sans mobile phase: heptane/isopropanol (85:15) (v/v) + 0.17 v/v trifluoroacetic acid (= TFA); UV detection; flow rate: 1 ml/min.; cycle time: 15 minutes; °

Analysis: column: DAICEL -Chiralpak AD, length: 250 mm; diameter: 6 mm; mobile phase: n-heptane 800 ml, 2-propanol 200 ml, TFA 2 ml; flow rate: 0.8 ml/min; analysis time: 30 minutes. 7 under these conditions and then obtaining ual ¢ after a waiting time of 0 minutes milligram of the first stereoisomer (= title compound); denoted by 0 minus the symmetry “and 0©**” holding the set Sell that has a relationship with “7

EE; 1H-NMR (methanol): 7.37- as a white solid ¢ precipitated with “-COOR1” 7.2 Bl [4]: 4.76, 4.71, 4.43, 4.38, AB-Q., 4.4, m, [1] ; 3.90, m, [1]; 3.40. m, [1]: 2.22 - in methanol); Mp.: 72.60, m, [2]; 2.48-2.0, m, [12}; 1.10, 4d, [6]; [a]p=-90° (0.5 145°C. Yo) and after a waiting time of 7 minutes; under these conditions an isomer that has a relationship with the symophrenic center "rel2" was obtained with the sign 0 interstitial Second.’-.000©1” “and the 0*“ carrier of the group Example: {(3S)-3-[({1-[(2”rell”)-2-ethoxycarbonyl)-4- (isopropylamino)-4- A oxobutyl]cyclopentyl } carbonyl)amino]-2-0x0-2,3 ,4,5-tetrahydro- 1H-1-benzazepin-1- yl}amino }acetic acid,

PA I

N

H = rel 0 oO 0 0 /

OH ethyl (2"rel1")-2-{[(3S)-1-({[1-(2-tert.butoxy-2-oxoethyl)-2-ox0- al a 4,749 dissolved 2,3 ,4,5-tetrahydro-1H-1-benzazepin-3-ylJamino} carbonyl)cyclopentyl]methyl }-4- Yo

Youd oA

Alles (isopropylamino)-4-oxobutyrate (prepared analogously (3"1ell")-3-{[(3S)-1-(2-tert.butoxy-2- 5 ) sa ll); but 1 of what is mentioned in the example (oxoethyl)-2-0x0-2,3,4,5 -tetrahydro-1H-1 -benzazepin-3- resulting from ylJamino} carbonyl)cyclopentyl methyl }-4-ethoxy- 4-oxobutyric acid from all Ye. To be dissolved in al ‘ (— 1) and used as an intermediate product from the stage HPLC °, after which the mixture was left overnight. TFA in milliliters of VY dichloromethane and the organic phase was washed with water until it was at a TEA number of 1001 milliliters in neutral pH. The organic phase was dried on sodium sulphate, then milliliters of toluene were evaporated twice in each 0 ©0, the solvent was evaporated at low pressure, then 0 cases were added to the precipitate, then the mixture was evaporated again under low pressure. Then drying the remaining 1 gram of YA compound from the precipitate in an oil pump under vacuum to obtain 1H-NMR (CDCI3): 7.33 m, [4]; 6.82, d, [1]; 5.86, ¢ Heading as white foamy d, [1]; 4.64, m, [1]; 4.54, 4.50, 4.46, 4.42, AB-Q., 3.20, m, [1]; 3.90, m, [1]; 1.23, [3]; in methanol). Z1.09, [6]; [a}p:- 155° (1 Yo eg Ethyl (2"rel1")-2-{[1-({[(3S)-1-(2-tert.butoxy-2-oxoethyl)- 2-0x0-2,3 ,4,5-tetrahydro- 1H-1-benzazepin-3-ylJamino }carb onyl)cyclopentylJmethyl }-4- [(3- hydroxypropyl)amino-4-oxobutyrate acid 1

HO” "py 10 0 f r ~_-C 0 / 0

J od

Y.

Ethyl (3"rel1")-3-{[1-({[(3S)-1-(2-tert. butoxy-2-oxoethyl)-2-oxo- then dissolve £7g 2,3, 4,5-tetrahydro-1H-1 -benzazepin-3-yl]amino} carbonyl)cyclopentyl] methyl } -4-

eq (Preparation of a binary stereoisomer mixture according to ethoxy-4-oxobutyric acid and HPLC was done e) Then the stereoisomers were subsequently separated using (1)

VAY was then added. dichloromethane 01 milliliter dichloromethane dissolving in 778 milligrams of tetramethylaminopyridine 3-amino-1-propanol per milliliter of ; to this receiving solution with EDC of 1.11 grams of dimethylaminopyridine © then the mixture was evaporated under low pressure ¢ and the precipitate was withdrawn ¢ aclu and after 0 milligrams of Ya was stirred and then The organic phase was shaken twice with the remaining EA mL Yue in and after 1 dilute aqueous solution of potassium hydrogen sulfate pH 161150, each time (mL each Yo) that the organic phase was washed twice with saline aqueous saturated once; After that, it was dried on sodium sulfate, then the solvent was evaporated under low pressure Ye, and then dried using an oil pump under vacuum to obtain; grams of

MS: [11+11]: 602; m/z: 546, « white foamy resin gil) the title compound in Fig. 500, 425: 111-3111 (CDCI3): 7.32-7.18, m, [3]; 7.12, d, [2]; 6.63, with [1]; 6.49, tr, [1]; . 4.57, 4.63, 4.34, 4.30, AB-Q., [2]; 4.51, m, [1]; 4.11, m, [2]; 3.57, tr, [2].

Al

Ethyl (2"rell")-4-{[3-(acetyloxy)propyl]Jamino}-2-{{1-({[(3S)-1-(2-tert.butoxy-2-oxoethyl)-2 -0x0-2,3,4,5-tetrahydro-1H-1-benzazepin-3- ylJamino }carbonyl)cyclopentylJmethyl }-4- oxobutyrate 0 0 Alopecia N H 0 : No [rel Qa 0 N Q o “HA ot

Ethyl (2"rel1")-2-{[1-({[(3S)-1-(2-tert.butoxy-2-oxoethyl)-2-g of 1 0.0x0-dissolved 2,3,4,5-tetrahydro-1H-1-benzazepin-3-ylJamino [ carbonyl)cyclopentylJmethyl } - milliliters per 10 seconds in o from example 4-[(3-hydroxypropyl)-amino -4-oxobutyrate

(b) chloromethane and V+ μl of acetyl chloride. After 0.6 minutes had passed, the solvent was evaporated under reduced pressure, then the remainder of the precipitate dain gg in Yo milliliters EA was withdrawn Then, washing with Yo al milliliter of sodium bicarbonate dilute aqueous solution, then drying on magnesium sulphate 5, then evaporation under low pressure, and then treatment of the remaining on silica gel by chromatography (phase The mobile hexane_gh / 1 EA: ¥ volume / volume) then the resulting fractions were dried in an oil pump with vacuum (H x 10 mbar) thus producing 4 grams of the compound in the form of colorless oil ¢ MS: [M+H]: 644, m/z: 588, 542, 482, 425 1 Example 7: (3"rel1")-3-[({ 1-[(3S)-4-{[ 3-(acetyloxy)propyl]amino} -2-(ethoxycarbonyl)-4- ‎oxobutyl]cyclopentylJcarbonyl)amino]-2-ox0-2,3,4,5-tetrahydro-1H-1 -benzazepin-1- yl}acetic acid 0 N 0 Me 1 NO 0 0 ~~ yama o OH 59 574 milligrams of (2"rel1")-4-{[3-] are dissolved (acetyloxy)propyl]lamino}-2-{[1- Jf ‎({[(3S)-1-(2-tert.

Butoxy-2-oxoethyl)-2-0x0-2,3,4,5-tetrahydro-1H-1-benzazepin-3- ‎ylJamino}carbonyl)-cyclopentyllmethyl}-4-oxobutyrate from Example 1 in 01 milliliters of AD dichloromethane with YoY milliliters of TFA . Then the mixture was left all night; Then the solvent was evaporated under reduced pressure and the residue 0 in SULT was withdrawn from BA . After that, the organic layer was washed with water until the pH became neutral, then it was evaporated under low pressure, and the remaining residue Ci ye was smoked using 0 milliliters of toluene each time. Then then

0 saad foamy resin (milligrams) of the title compound; In the form of resin, Vou add. Color MS: [11+11]: 588; m/z: 542, 482, 425; 17-111 (CDCI3): 7.33-7.14, m, [4]; 6.67, d,

[1]; 6.59, tr, [1]; 4.57, 4.69, 4.64, 4.35, 4.30, AB-Q, [2]; 4.63, m, [1]; 4.17, m, [1]; . 4.09, q, [2]; 3.33, m, [1]; 3.15, m, [2]. °

A Example ((3S)-3-{[(1-{(2"rel1")-2-ethoxycarbonyl)-4-[(3-hydroxypropyl)amino]-4- oxobutyl]cyclopentyl]carbonyl) amino]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1- yl}acetic acid

HO” “oN 1

Qu reli a Oo 0 0

Oh

Ye

Ethyl (2"rel1")-2-{[1-({[(3S)-1-(2-tert.butoxy-2-mg yl-OA oxoethyl)-2-ox0-2, 3,4,5-tetrahydro- 1 H-1-benzazepin-3- yl]amino] }carbonyl)cyclopentyl}methyl }-4-[(3-hydroxypropyl)-amino-4-oxobutyrat according to the method mentioned from TFA (prepared in example 0) where the compound reacted with ape on a crude product using Js mall, except for the example. After purification, the silica gel phase (stationary phase: silica gel) can be chromatography. Thus, it is possible to obtain (aan / volume 1: 9 ethanol ethanol / BA: milligram constant) in the form of colorless resin Yeo) addressing compound 1H-NMR (CDCI3): -7.34 7.15, m, [4]; 6.76, tr, [1]; 6.61, d, [1]; 4.75, 4.71, 4.20, 4.16, in 7AB-Q., [2]; 4.57, m, [1]; 4.09, f [2]; MS: [M+H]+: 546; [a]p = -112.5° (1 Ye .methanol) 14 Example 2-{[1-({[(3S) )-1-(carboxymethyl)-2-0x0-2,3,4,5-tetrahydro- 1 H-1-benzazepin-3- ylJamino }-carbonyl)cyclopentyllmethyl }-4-[(3-hydroxypropyl)-amino- 4-oxobutyric acid Yo

> H : O : 1 OH 0 N© Jd Ng OH Then dissolve 7 g ethyl ethyl (2S)-2-{[1-({[(3S)-1) -(2-tert.butoxy-2-oxoethyl)-2- 0x0-2,3,4,5-tetrahydro-1H-1-benzazepin-3-ylJamino} carbonyl)cyclopentylimethyl}- 4-[( 3-hydroxypropyl)-amino-4-oxobutyrate a See method of preparation in example M (in 5 106 milliliters of (1:1 axa / vol) of water and 3 ethanol and then add 6 grams of sodium hydroxide (NaOH) annealing with stirring and after Vo hour; Then the solvent was evaporated under low pressure ¢ and then the r was withdrawn and put into Yeo milliliters of EA and then washed again with ov dda milliliters of KHSO4 solution. Then, the extraction of the aqueous phase, two milliliters of EA each time, then drying on sodium sulphate | 0 . After that, the solvent was evaporated to obtain (0.8 grams) of the title compound. Example: 01 (2"rel1™)-2-{[1-({[(3S)-1 -(carboxymethyl)-2-0x0-2,3,4,5-tetrahydro- 'H-1 - ‎benzazepin-3-yl]amino }carbonyl)cyclopentyl]methyl }-4-[(3 -hydroxypropyl)-amino- 4-oxobutyric acid Vo 1 licens Mi N 0 OH rel 0 0 O OH Ave milligrams were separated from the resulting isomer mixture in the residual 4 using HPLC technology according to the following steps: Stationary phase: 10-100 Nucleosil «

B column: Yo.

J shall millimeters ¢ diameter Ye millimeters; Convergence rate Ae mm/min ¢ Mobile phase: n-heptane n-heptane (mL) (+ 7-propanol Y + +) 2-propanol mL) 1 (TFA mL). Assay: 10-10 EC 250/4 Nucleosil ¢ Column: YOu mm long; Qatar ; milliliters ¢© flow rate: 1.5 milliliters/min; Mobile phase: n-heptane (850 mL); 7-propanol (Yo +) 2-propanol milliliters) « 1 ( TFA milliliters). Retention time of Y, AQ min ¢ and this induces ag yb then yields 1 mg of the first stereoisomer (= title compound); with the sign “rell” and related to the center minus the alphanumeric “*Ca” with the set 00041 “ m, [4]; 4.78, 4.73, 4.43, 4.38, AB-Q., [2]; 4.41, m, [1]; 3.93, Ve 7.38 :(00,0) H-NMR .m, [1]; 3.56, tr [2]; 3.40, m, [1]; 3.31, m, [1]; 3.22, m, [1]; 2.78, m, [1]; 2.65, m, [1] retention time ty , ¢ min and under these conditions then obtain the second stereoisomer; The one with the tag “rel2” and associated with the center minus “0*” and the one with the combination ,00017.”. \o Example: 11 2-{{1-({[(3S)-1(2-ethoxy-2-oxoethyl)-2-0x0-2,3,4,5-tetrahydro- 'H -1 -benzazepin-3- yl}amino }carbonyl)cyclopentylimethyl }-4-[(3-hydroxypropyl)amino]-4-oxobutyric acid HO” “TN H 0 OH 0 N © pm 0 7 0 Ys then Ave dy mg of 2-{[1-({[(3S)-1-(carboxymethyl)-2-0x0-2,3,4,5-tetrahydro - 1H-1-benzazepin-3-ylJamino }carbonyl)cyclopentylJmethyl }-4-[(3- hydroxypropyl)amino]-4-oxobutyric acid (isomer mixture obtained according to Yond

For example 4 in veo milliliters of dimethylformamide (DMF =) dimethylformamide then 017.5 mg of cesium carbonate and 08:00 and 115 mg of ethyl bromide were added at room temperature room with a flip. After stirring overnight ¢ the mixture was diluted with 7 lb Alle of water and 71 mL of dichloromethane the all phase was extracted using SD chloromegan then the solvent was removed by evaporation under reduced pressure and the residue treated Chromatography (stationary phase: silica gel; mobile phase (7000 EA: to Y: VY MeOH/EE EEN / volume) after that and then drying the product using Can ing 4A na vacuum) Ye XO = mbar) to obtain 01 g of aqua in the form of foam resin Ye

MS: [M+H]": 546; m/z: 453, 425, 379; 'H-.NMR (CDCls): 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].

NY Example 2-{[1-({[(3S)-1-(2-tert.butoxy-2-oxoethyl)-2-0x0-2,3,4,5-tetrahydro-lH-1- benzazepin-3-ylJamino }-carbonyl)cyclopentyl methyl } -4-(isopropylamino)-4- Vo oxobutyric acid AL 1 N H N 0 OH 0 0 0 07 then dissolve 7,6 g-L ethyl 2-{[(3S)-1-({[1-(2-tert. butoxy-2-oxoethyl)-2-oxo- 2,3,4,5-tetrahydro- 'H- 1-benzazepin-3-yl]amino }carbonyl)cyclopentylJmethyl }-4- (isopropylamino)-4-oxobutyrate Ye (see method of preparation for Example 1) in oy milliliters of ethanol. Then 0 mg of solid sodium hydroxide in 0 milliliters of water was added to the receiver solution after 0? min.

Acidify the mixture with potassium hydrogen sulfate solution until the pH reaches 011 to ? Then phase A was extracted three times by ov mL EA. The combined organic phases were dried over magnesium sulfate; Then the solvent was evaporated under reduced pressure, then the residue was chromatographically treated on Ni-silica gel (mobile phase: EA / cyclohexane 107 v / v) 0. After that, the product was dried using an oil pump under vacuum (0 7). # “01 mbar) and thus it was possible to obtain YY grams of the title compound in the form of foamed pal resin; MS: [M+H]”: 558; m/z: 502, 425, 397, 323. Example NY 4-chlorobenzyl-2-{[1-({[(3S)-1-({[1-(2-tert.butoxy-2-oxoethyl)-2-0x0-2,3,4) ,5- 0 tetrahydro- ' H-1-benzazepin-3-yl]amino } carbonyl)cyclopentyl methyl } -4- (isopropylamino)-4-oxobutyrate PN N H Cl 0 N Td 6 N 0 grew J + 0 and then dissolved 100 mg of 2-{[1-({[(3S)-1-(2-tert.butoxy-2-oxoethyl)-2 -0x0- 2,3,4,5-tetrahydro-' H-1-benzazepin-3-ylJamino} carbonyl)cyclopentyl methyl }-4- Yo (isopropylamino)-4-oxobutyric acid ex in *mlqr of AB dichloromethane Then YY mg of =f dimethyl sud pyridine (DMAP =) 4-dimethylaminopyridine « 5 mg of alcohol ;- 4-chlorobenzyl alcohol was added and 174 mg of EDCXHCI, and after the addition, the mixture was stirred all night, then the mixture was diluted with 0 slike of dichloromethane, and the organic phase [AY] was washed several times each time with a milliliter of a diluted Mathieu solution

Potassium hydrogen sulfate and then with a saturated aqueous normal salt solution. Then the organic phase was dried on magnesium sulfate »then the solvent was reduced to dryness under low pressure and the residue was treated chromatographed on silica gel (mobile phase: EA / hexane aaa Y : Y cyclohexane ils © volume). After that, the product was dried using an oil pump with a vacuum (H 1 Je bar), thus producing TY gram of the title compound in the form of a white foam; MS: [M+H]": 682/684; m/z: 626/628, 576, 484, 425 .00 Example: {(3S)-3-[({1-[) 2-{[(4-chlorobenzyl)oxy]carbonyl } -4-(isopropylamino)-4-oxobutyl] cyclopentyl] carbonyl)amino]]-2-oxo0-2,3,4,5-tetrahydro- 'H -1-benzazepin-1-yl }acetic acid PA I N H Cl 0 J 4 OH \o FAA dissolved from 4-chlorobenzyl- 2-{[(3S)-1-(2-tert.butoxy-2-oxoethyl)-2-0x0-2,3,4,5- tetrahydro- !H-1-benzazepin-3-yl]amino }-carbonyl)cyclopentyl jmethyl } -4- (isopropylamino)-4-oxobutyrate in 11 milliliters of dichloromethane, then 0.1 milliliter of TFA was added and the mixture was stirred overnight. The solvent was then evaporated under reduced pressure, then the Cad residue was withdrawn under reduced pressure, and the residue Ye. After that, the solvent was evaporated under low pressure, and then the residue was smoked using 0 milliliters of toluene, and thus it was possible to obtain

Ben Ali Y.0 milligram m of the title compound in the form of a white foamy resin ' MS: [M+H]': 626/628; m/z: 657, 484, 425 Example yo (2-methoxyethoxy)methyl-2-{[1-({[(3S)-1 -(2-tert.butoxy-2-oxoethyl)-2-0x0-2,3,4,5- tetrahydro- ' H-1-benzazepin-3-yljamino} carbonyl)cyclopentyljmethyl}-4- ° (isopropylamino)-4-oxobutyric acid AL N H N 0 N PR 0 0._0 grew 4 Reply how o—¢ 010 milligrams of 2-{[1-({[(3S)-1-(2-tert. butoxy-2-oxoethyl)-2-0x0-2, 3,4,5- tetrahydro- !{-1-benzazepin-3-ylJamino }carbonyl)cyclopentyljmethyl ( -4- (isopropylamino)-4-oxobutyric acid 00 (method of preparation for example (VY) In © milliliters of ALD dichloromethane, then YY mL of Sa VE 1 DMAP > of methoxyethoxymethyl chloride and 50 μL of triethylamine were added Then the mixture was stirred overnight, then diluted by >05 0 milliliters of Al dichloromethane and the organic phase was washed several times each time with dda lp 7 milliliters of an aqueous dilute solution of potassium hydrogen sulfate pH 101150 and a solution of Aqueous saturation of ordinary salt. The organic phase was dried on magnesium sulphate; Then the solvent was evaporated under reduced pressure and the residue was treated chromatography on silica pa (mobile phase Yo: EA / cyclohexane l vol / vol) and then the resulting LAL 1 was dried using an oil pump under vacuum to obtain 1511 JRM of the title complex » 425, 484, 540, 590 MS: [M+H]*: 646; m/z:

M Ethyl (2"rel1")-2-{[1-({[(3S)-1-(2-ethoxy-2-oxoethyl)-2-0x0-2,3 4,5-tetrahydro-'H -1- benzazepin-3-yllamino] }carbonyl)cyclopentyl methyl }-4-[(3 -hydroxypropyl)-amino- 4-oxobutyrat A 1 N it 0 N 0 : 8 61 u /_ 3 0 dissolved 100 mg {(3S)-3-[({1-[(2"rel1")-2-ethoxycarbonyl)-4- (isopropylamino)-4- oxobutylJcyclopentyl }-carbonyl)amino] -2-0x0-2,3,4,5- tetrahydro-1H-1-benzazepin-3-yljacetic acid (for preparation, see example 4) and is dissolved in ? milliliter of ethanol and add 0 drops of 0 acid | Concentrated sulfuric acid, after which the stirring continued for two days at room temperature 0. After that, the solvent Caan was applied at low pressure, then the oud was withdrawn and placed in © milliliters of EA. The organic phase was washed twice with an aqueous solution of sodium hydrogen sulfate (sodium bisulfate) each time. After drying over sodium sulfate, the solvent was separated by distillation under reduced pressure, then the remaining Vo was treated by chromatography on silica gel (mobile phase: EA / cyclohexane + : axa) ¥ / volume) (Sl) to obtain a compound Title as foamy white ¢ MS: [M+H]: 574;m/z: 428, 323, '"H-NMR (CDCl3): 7.33-7.11, m, [4]; 6.69, m, [1]; m, [1]; 4.79, 4.75, 4.34, 4.30, AB-Q., [2]; 4.48, m, [1] , 6.44 . It is also possible to prepare the compounds of formula (1) mentioned in the following table 4 according to the preparation process mentioned in the previous examples, or by following similar methods: Table 4: Other compounds of pigment (1)

Jefe aa EEE rr a oxoethyl dimethylbutyl methoxyphenylethyl 636 5 rac H 2-(4- H ethyl va methoxyphenyl)-2- oxoethyl dimethoxybenzyl

nor methoxyphenylethyl l "saba a rac ceme me | w| 5 | » a S rac | Methoxy isopropyl H H 23 590 ethoxy methyl re (CHa),- TEE OH)-CH,- CH,0H

except a ew | ow | ow NAL (CHy)o- “7 a ee) valine)-(CH,),- ow |v | | sa |u| touches | sa cmon |e | wv | Ha sa ha no f| conomen[wn| Te ha eg 14 Tert.

Butyl 2-{[1-{(35)-1-(2-tert.

Butoxy-2-oxoethyl)-2-0x0-2,3,4,5-tetrahydro- H- 1- ‎benzazepin-3-yl]amino } carbonyl)cyclopentyljmethyl}-4- (4-hydroxypiperidin-1-yl )-4- oxobutanoate

L HO OD Lav N 0 0 0 bhl ¢ ro 0 {Reaction of 00 grams of 2-[(2-benzyloxy)-2-oxoethyl]acrylic acid Preparation method is given in Example 1a) with £Y milliliters of thionyl chloride » 47 milliliters of tert-th-butanol. butanol and 011 milliliters of pyridine: according to the steps mentioned before through the parasol (1b) to obtain 4 grams of ?- methylenesuccinic acid -1- - butyl ester 2-methylenesuccinic acid -4-benzylester-1-tert. butylester « 277:7 [1+11]. b Reaction of 1 gram of 2-methylenesuccinic acid-4-benzylester-1-tert.butylester as previously obtained by reacting with 1.8 lbs of (AL yo) diisopropylamine; 001 milliliters of a 1 molar solution of n-butyllithium lithium in hexane — 11 n-hexane milliliters of cyclopentanecarboxylic acid according to the steps given by 1( Jad c) for sol 4.9" grams of 1-[4-(benzyloxy)-2-(tert. .Butoxycarbonyl)-4-oxobutyl]cyclopentanecarboxylic acid Vo C reacted 0.8 grams of compound 1 -[4-(benzyloxy)-2-(tert.

Butoxycarbonyl)-4- oxobutyl]eyclopentanecarboxylic acid obtained previously with Y,V0 pl pa from tert.

Butyl-[(3S)-3-amino-2-0x0-2,3,4,5-tetrahydro)- 1H-benzazepin-1-yl]acetate (see preparation method mentioned in EP 0733 642 Al according to the process given by Example 1d) to obtain “1 pg of the compound 2-{[(3S)-1-({[1-(2-tert.

Butoxy-2-oxoethyl)-2-0x0-2,3,4,5- vy tetrahydro-1H-1-benzazepin-3-ylJamino } carbonyl)cyclopentylJmethyl } succinic . acid-4-benzylester-1-tert. butylester 2-{[(3S)-1-(2-tert.Butoxy-2-oxoethyl)-2-0x0- grams of 171 Alee tam(2 2,3,4,5-tetrahydro- 1H - 1-benzazepin-3-yl]Jamino } carbonyl)succinic acid-4- Previously prepared and treated with 7 grams of benzylester-1-tert. butylester ° on activated carbon, after which water was added (palladium hydrate of 1.5 bar hydrogen per hour under pressure of hydrogen 11) for 1 gram of 10 e) to obtain 1( According to the steps mentioned by step 4-tert.Butoxy-3-{[1-({{(3S)-1-(2-tert.Butoxy-2-oxoethyl)-2-0x0-2, 3,4,5- tetrahydro-1H-1-benzazepin-3-ylJamino} carbonyl)cyclopentylJmethyl ( -4- Vo oxobutanoic acid; MS: [M+H]+: 573; m/z: 517, 461; 1H- NMR (CDCI3): 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] 4-tert.Butoxy-3-{[1-({[(3S)-1-(2-tert.Butoxy-2-e) dissolved }1.1 grams of oxoethyl)-2-0x0-2,3,4,5-tetrahydro-1H-1-benzazepin-3- 1 ¢ preformed yllamino}carbonyl)cyclopentyllmethyl }-4-oxobutanoic acid; ¥.+ add dichloromethane chloromethane ALS milliliters of VA and dissolve in and after cooling at Safram in an ice bath; Ethyl chloroformate is added drop by drop to the receiving solution. After that, the mixture was stirred in milligrams of ;-hydroxypiperiden TIT min. Then Ve was added for Lal, then the mixture was stirred all night. Then 4-hydroxypiperidine was diluted and washed with an aqueous solution of potassium bisulfate and then with EA using saline solution. Then the organic layer was dried on magnesium sulfate and hexane was treated [EA: chromatography on a silica gel column (Sal) Yo

Vit Mechanol [EA then by BEA (volume / volume) done by 1 : 1 annular

(no) axa/vol) thus yielding 098 of the title compound as a white foamy compound 425, 397, 323 MS: [M+H]+: 656; m/z: Example: 01 2-{[1-({[1-(carboxymethyl)-2-0x0-2,3 ,4,5-tetrahydro- !H-1-benzazepin-3- ‎ylJamino }carbonyl)cyclopentyl] methyl } -4-ox0-4-[4-(L-valyloxy)piperidin-1- ° yl]butanoic acid; 1 L NH H bonded to OH 0 NO grown o OH ]| 548 milligrams of tert dissolved. butyl-2-{[1-({[(3S)-1-(2-tert.

Butoxy-2-oxoethyl)-2-0x0-2,3,4,5-tetrahydro- H-1-benzazepin-3-yl]amino} carbonyl)cyclopentyl]methyl }-4-(4- Ye ! hydroxypiperiodin-1-yl)-4-oxobutanoate is dichloromethane. Then )© milligrams of YAY DMAP , milligrams of BOC-L-valine and 176 milligrams of EDC . And then flipping for a while? 01 hours using EA, then washing with an aqueous solution of potassium sulfate 15150 and salt solution 0. After that, the organic layer was dried on magnesium sulfate 10480610170, then the residue was treated on a chromatography column using a gel. silica gel (EA : liquid phase / cyclohexane (aaa) 10 : 1 / vol) other than to pure EA) thus Zi XY. (00 mg of -1 (-4) tert.butoxy-3-{[1-({[(3S)-1-(2-tert.

Butoxy-2- (oxoethyl)-2-0x0-2,3 ,4,5-tetrahydro- 'H-1 -benzazepin-3- yl]amino }carbonyl)cyclopentyl methyl} -4-oxobutanoyl)piperidin- 4-yl-N-(tert. Yon

(Butoxycarbonyl)-L-valinate, MS: [M+H]+: 855; m/z: 699, 643, 625, 425, 397, 235, 323. b) 00 mg of 1-(tert.butoxy-3-{[1-({[(3S)-1-(2-tert.butoxy-2-oxoethyl)-2-0x0-2, 3,4,5-tetrahydro- 7-1 -benzazepin-3- yl]amino }carbonyl)cyclopentyljmethyl } -4-oxobutanoyl)piperidin-4-yl-N-(tert.o Butoxycarbonyl)-L- valinate according to the record before; It is dissolved in 14 milliliters of dichloromethane and 0.44 milliliters of trifluoroacetic acid, which is added to the receiving solution. And then stir all night while getting rid of the solvent and excess acid by evaporation under low pressure. Then M was added to the remaining Ve precipitate and the organic layer was washed with a saturated solution of sodium bicarbonate until the pH reached ; . Then, the aqueous layer was extracted twice by EA, then the combined organic layers were dried on magnesium sulfate, after that the solvent was evaporated under reduced pressure, and the remaining after evaporation was diluted using an oil pump with vacuum to obtain 70 mg of (Cf) gall in the form of foamy white yo « 425, 397,323 MS: [M+H]: 643; m/z: Example of VY Tert.

Butyl 2-{[1-({[(3S)-1-(2-ethoxy-2-oxoethyl)-2-0x0-2,3,4,5-tetrahydro- 'H-1-benzazepin-3 -yl]amino }carbonyl)cyclopentyljmethyl }-4- [isopropyl(methyl)amino]-4-oxobutanoate AL N H cm 0 0 0 0 i 0 R_+- 76 XY. { reaction pl joa 01 aged 1-[4-(benzyloxy)-2-(tert.

Butoxycarbonyl)-4- oxobutyljcyclopentanecarboxylic acid (for preparation see article 14b and you provided a ethyl-[(3S)-3-amino-2-0x0-2,3,4,5-tetrahydro-1H-1-) reaction with per gram of (then prepared by methods similar to what was mentioned through the patent benzazepin-1-yl]acetate 1) according to the method mentioned through the example (EP 0 733 642 Al European No. D) in order to obtain YAN grams of 4-benzyl-1-tert.Butyl-2-{[1-({[(3S)-1- (2-ethoxy-2-oxoethyl)-2-0x0-2,3,4 ,5-tetrahydro- !H-1-benzazepin-3-© .yl]Jamino }carbonyl)cyclopentylJmethyl } succinate b) 1 YA, gram of 4-benzyl-1-tert.Butyl-2-{ was treated [1-({[(3S)-1-(2-ethoxy-2-oxoethyl)-2-0x0-2,3,4,5-tetrahydro-1H-1-benzazepin-3- ylJamino }carbonyl) cyclopentyljmethyl} succinate .as previously obtained from oe by ¢ alg treated with 5 grams of activated charcoal and then hydrated the mixture for 0.01 hour under hydrogen pressure of 0.7 bar according to For the aforementioned through example (1 e) to obtain 17 grams of 4-tert. butoxy-3- {[1-({[(3S)-1-(2-ethoxy-2-0xoethyl)-2-0x0-2,3,4,5-tetrahydro- 1H-1-benzazepin- 3-yl]amino }carbonyl)cyclopentyljmethyl }-4-oxobutanoic acid, [M+H]+: 545; m/z: 489 Vo 4-tert. butoxy-3-{[1-({[(3S)-1-(2-ethoxy-2-0xoethyl)-2- grams of ¥ Jelid ( 0x0-2,3,4,5-tetrahydro-1H) -1-benzazepin-3- 888 was reacted with ¢ yl]carbonyl)cyclopentylimethyl }-4-oxobutanoic acid with 1 microliter of methylisopropylamine according to the steps of the method mentioned before in Example 1) and ) to obtain 1.1 g of the title compound as the MS compound: [M+H]*: 600:: m/z: 544 « foamy sand

VY Example 2-{[1-({[(3S)-1-(2-ethoxy-2-oxoethyl)-2-0x0-2,3,4,5-tetrahydro- 1 H-1-benzazepin -3- yl]amino }carbonyl)cyclopentyllmethyl}-4-{isopropyl(methyl)amino]-4-oxobutanoic acid Yo vy

PY1

N

cm H

O N

OH 0 NO ° rice 0 tert. butyl 2-{[1-({[(3S)-1-(2-ethoxy-2-oxoethyl)-2-) 559 mg of 0x0-2,3,4,5-tetrahydro-1H-1 was dissolved -benzazepin-3- yl]amino } carbonyl)cyclopentylJmethyl ( -4- [isopropyl(methyl)amino]-4- mL YA as obtained by Example 14; dissolved in 8 mL trifluoro-oxobutanoate Acetic acid 0.95 of dichloromethane was added to the mixture, and after that, the mixture was stirred overnight, then 0% of the solution received, trifluoroacetic acid, the solvent was evaporated and the acid increased under low pressure, then Ht was added to Sodium bicarbonate pH was dried until pH 01. The organic layer was dried on magnesium sulfate, then the organic layer was dried on magnesium sulfate, and the remainder was treated on column chromatography using a gel (volume) and then changed to / axa ) 101 cyclohexane / EA: silica (pure liquid phase) and thus it was possible to obtain 0?; milligrams of the title compound on the / EA

MS: [M+H]: 544 Foam White Figure; yo

VY Example 1-[(Ethoxycarbonyl)oxy] 2-{[1-({[(3S)-1-(2-ethoxy-2-oxoethyl)-2-0x0-2,3,4,5- tetrahydro-1H-1-benzazepin-3-ylJamino } carbonyl)cyclopentyl methyl } -4-[isopropyl(methyl)amino]-4-oxobutanoate

Ya

A, yb 0 N ~_0- 0.0 0 N 0

TT os 0 0 2-{[1-({[(BS)-1-(2-ethoxy-2-oxoethyl)-2-0%0-2,3,4,5- milligrams from 011 done dissolve tetrahydro- 1H-1-benzazepin-3-ylJamino }carbonyl)cyclopentylJmethyl } -4- ; VY (for preparation see example [isopropyl(methyl)amino]-4-oxobutanoic acid) μl of triethylenediamine AY was then added to DMF μl of 1 μg dissolved in oo Ao milligrams of solid potassium carbonate and Yes triethylamine

Lb dal) after that it was stirred. chloroethylethylcarbonate from chloroethyl ethyl carbonate and washed several times with potassium bisulfate BA overnight, then diluted with a salt solution. Then, the organic layer was dried on magnesium sulfate and the residue was treated with hexane / EA: Jil silica (the Sa phase on a chromatographic column using Ye volume)) and thus 1 mg of the title compound (aaa) 10 could be obtained: Toroidal MS: [M+H]: 660; m/z: 526, 449, 310, 253 « white foam

Ve example 1-{(Ethoxycarbonyl)oxy]ethyl 2-{[1-({[(3S)-1-(2-{1- [(ethoxycarbonyl)oxy]ethoxy}-2-oxoethyl)-2 -0x0-2,3,4,5-tetrahydro-1H-1- \o benzazepin-3-yl]amino }carbonyl)cyclopentyljmethyl}-4- [isopropyl(methyl)amino]-4-oxobutanoate 0 N 0 M > 000 0 0 a a 0 ethyl 2-{[1-({[(3S)-1-(2-tert-butoxy-2-oxoethyl)-2- Ji) mg of ove and then dissolve ‎ 0x0-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino } carbonyl)cyclopentyl Jmethyl } - Ye.

4-[isopropyl(methyl)amino]-4-oxobutanoate (see example YY; Blas synthesis of valence (Y);) was dissolved in 10 milliliters of DMF. Then, YAY was added. A microliter of chloroethylethylcarbonate, then added VOA mg of cesium carbonate CsCO3 and Av mg of potassium iodide 0 solid, after which it was stirred for 0 hours at a temperature of a Ve temperature and the mixture was diluted by 1 M then washed twice with water After that the organic layer was dried on magnesium sulphate and the remaining was treated by chromatography on silica gel (liquid phase: cyclic; then changed to [EA] hexane Cyclic 1:1 (volume/volume)) to obtain ?10 mg of the title compound in foamy form 0 white 614, 480 MS: [11+11] : 748; m/z: example 1 capsule: {[(3S)-3-[({1-[2"rel1")-2-ethoxycarbonyl)-4- lc (isopropylamino)-4-oxobutyl]cyclopentyl ( -carbonyl )amino]-2-0x0-2,3,4,5- tetrahydro-1H-1-benzazepin-1-yl]acetic acid: 0 Capsules are produced with the composition WA for each capsule: capsule {[(3S)-3-[({1-[2"rel1")-2-ethoxycarbonyl)-4-(isopropyl-amino)-4- oxobutyl]cyclopentyl }-carbonyl)amino]-2 -0x0-2,3,4,5-tetrahydro- 1H-1-benzazepin-1- yl]-acetic acid: acetic acid 0 milligrams Ya corn starch 0 milligrams lactose 0 Lactose mg EA- Enough Active Ingredients Mixed; Corn starch and lactose in a blender to form a homogeneous mixture using EA. The paste was pulverized and the resulting granules were placed in a suitable YO container and dried at 0 mm to remove the solvent. The dry granules were passed through a crusher and mixed in a mixer with the following auxiliaries:

As Milligram © © Talcum Magnesium stearate, milligrams, 4 corn starch, each with a capacity of 4060 milligrams (= capsule size zero). capsules, then poured into capsules

Claims (1)

AN Claims: 1) Compounds having the general formula 1-1 0 : UN N R1OOC 0 N > A 00 where v ¢ is a bio-change ester or a hydrogen ester group Jie 3; Cra-hydroxyalkyl hydrochloride or “hydrogen” Jia R? 8 is treated Cp.4-alkanoyl with esterified thereof by the ester hydroxyl group 1 ¢ and also ¢ amino acid or 7 amino acid precipitate optionally inferred Cy 4-hydroxyalkyl « Cy4-alkyl; Cpu-alkoxy- Cj4-alkyl Th represents A again and the hydroxyl group is treated by hydroxyl group 4 or Cy4-alkanoyl with alkatoyl optionally esterified by hydroxyl groups Ye C;.7-cycloalkyl-¢ (Cp.4-alkyl)2amino-C,.4-alkyl; ; or its amino acid precipitate 11 amino acid phenyl group The phenyl group » phenyl-Cj4-alkyl ¢ Ci4-alkyl VY ™ halogen is replaced once by a “damaged and/or halogen (Y=) optionally from VY « phenylcarbonylmethyl ¢ C36-0xoalkyl » naphthyl its Ve optionally once or twice by phenyl group replacing the phenyl group or 2-oxoazepanyl or ¢ halogen + LR “Off” and/or Halogen 4 counted as B; and their methylene groups (Shia or 8 together R? VY ¢ carbonyl) are optionally replaced one to two times by carbonyls methylene groups YA optionally replaced by sulfur and/or sulfur with oxygen «nitrogen 3 AY 7 by hydroxy-7 + optionally treated by esterification a— esterified Cys-alkanoyl 71 or cul Cpe-hydroxyalkyl « Cpa-alkyl « amino acid « "| and optionally hydroxyl treated by esterification esterified with Cps-alkanoyl or an amino acid precipitate “or phenyl or benzyl” and also; ester fim] or a hydrogen-forming group representing hydrogen 87 ve Yo and acidic variable as well as physiologically compatible 5 salts of va acids of formula 1 and/or physiologically compatible yy compounds of the present invention providing medicines containing compounds of formula 1.1 ?- Compounds of formula 1 pursuant to claim 1 where 'biovariable ester or hydrogen ester group representing hydrogen R!Y R?v representing Cyu-alkyl ¢ hydrogen or Cpg-hydroxyalkyl, so that it is; - its hydroxyl group optionally substituted by the canoyl; Cy4-alkanoyl ° « and + of the Cpalkoxy-Cra-alkyl » Crgalkyl ¢ optionally substituted with a group vy has a second hydroxyl group and its m-hydroxyl groups are optionally substituted by Cy 4-alkylamino-Ci s-alkyl « Cpe-alkanoyl . Cs.7-cycloatkyl q ¢ Alkylation 0 - 0,0-7-010 encapsulation “phenyl-C4-alkyl” phenyl group 00 optionally substituted by one or two of the Cra-alkyl groups ¢ C.s-alkoxy 1 and/or halogen; naphthl-Ci4-alkyl ; Cag-oxoalkyl; phenyl carbonyl methyl 7 ; Its phenyl group is optionally substituted VY by one or (dd) of a Cys-alkyl “doal and/or halogen; or 2-oxo0azepanyl Vt¢ or R*yo or rR? together they form Caq-alkylene ¢ with the methylene group yy optionally substituted by one to two of the carbonyl groups « 1 nitrogen » oxygen and/ or sulfur and is optionally substituted AY substituted hydroxyl group “Cig-hydroxyalkyl ¢ Cis-alkyl” with either VA or phenyl benzyl; vinyl oxygen; Cyg-alkanoyl oxygenation optionally by any of 4 ; and benzyl Y. are biochangeable; ester or a hydrogen ester group representing hydrogen * 71 and/or formula 1 acids of physiologically approved acids and physiologically compatible salts yy of physiologically approved Physiologically, the salts resulting from the addition of 1.yy acid to compounds of the formula Hydrogen JAGR! ; where 1 according to claim 1 are compounds of the formula *-1 fue oa SA) or methoxy “ethyl or ethyl ¢ hydrogen Y (RS)-1-[[(isopropyl)carbonyl]ethyl, ( RS)-1- «methoxyethoxymethyl v [[(ethyl)carbonyl]-oxy]-2-methylpropyl, (RS)-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl, ¢ 5-methyl-2-o0x0-1 ,3-dioxolan-4-yl-methyl or (RS)-1-[[(ethoxy)carbonylJoxy] -ethyl. °H AGRE; where 1 according to claim 1 are compounds having the formula mt or ?*- 2-hydroxyethyl hydroxyethyl-7 ¢ ethyl “methyl methyl” hydrogen Y hydroxyl hydroxyl group JS The ¢ 3-hydroxypropyl aminoacid is an optionally substituted esterified by or a 4-amino acid residue representing the isopropyl RY; where 0 according to claim 1 are compounds of the formula #0 -or 2-hydroxyethyl -Y ; Each 3-hydroxypropyl hydroxyl group is hydroxypropyl -* 1 or the Cy4-alkanoyl acid residue is optionally esterified and substituted by the hydroxyl group ¢ « 2-methoxybenzyl + cyclopropylmethyl » 3-acetyloxy-n-propyl ¢ amino acid Amino Ht ¢ 2,4-dimethoxybenzyl ¢ 4-methoxyphenylethyl + 4-methoxybenzyl 1 ¢ phenyl-2-oxoethyl ¢ 3-0x0-1,1-dimethylbutyl ¢ 1-naphthylmethyl L At « dimethylamino-n-propyl ¢« 3-(2-oxoazepanyl) ¢ 2-(4-methoxyphenyl)-2-oxo-ethyl A .amino-n-propyl or (methyl)aminoethyl q) together represent 83 JR? protection ) where 5 acid is according to 1 compounds of the formula + 0 1 - 4 ; 4-ketopiperidine; 4 - piperidine ketopyridine; piperidine morpholine 7 Cog optionally esterified by esterified ¢ 4-hydroxypiperidine v hydroxyl ester on the 1t-amino acid hydroxyl group or a 1-amino acid residue pyrrolidine or piperazine; piperazine group o hydrogen ASR; where 0 according to claim 1 are compounds of formula 1-7 ¢ p-methoxybenzyl J—— 3a- mefoxybenz ¢ Cr4-alkyl « hydrogen Y (RS)-1-[[(isoproyl)carbonyl ]oxy]-ethyl ¢ N,N-di-(C;4-alkyl)amino-C;.4-alkyl v (RS)-1- ¢«(RS)-4-[[(ethyl)carbonyl}oxy ]-2-methylpropyl « ¢ 5-methyl-2-0x0-1,3-dioxolen-4-yl-methyl « [[(cyclohexyloxy)carbonyl]oxy]-ethyl eh .(RS)-1-[[(ethoxy)carbonylJoxy]ethyl or 2-0x0-1,3-dioxolan-4-yl-methyl 1; They are selected from a group consisting of 1 according to claim 1 compounds having the formula mA of: Y 2-{[1-({[1-(carboxymethyl)-2-0x02,3 4,5-tetrahydro- 1H-1-benzazepin-3-ylJamino }- ¥ carbonyl)cyclopentyl methyl }-4-[isopropyl(methyl)amino]-4-oxobutanoic acid; ¢ 2-{[1-({[1-(carboxymethyl)-2-0x02,3,4,5-tetrahydro-1H-1-benzazepin-3 -yl]Jamino}-©carbonyl)cyclopentylJmethyl }-4-( dimethylamino)-4-oxobutanoic acid; 1 2-{[1-({[1-(carboxymethyl)-2-0x02,3,4,5-tetrahydro-1H-1-benzazepin-3-ylJamino}- L carbonyl)cyclopentyl]methyl }- 4-diethylamino]-4-oxobutanoic acid; A Ao 2-{[1-({[1-(carboxymethyl)-2-0x02,3,4,5-tetrahydro-1H-1 -benzazepin-3-yljamino}- q carbonyl)cyclopentylJmethyl}-4-[(2) -hydroxyethyl)(methyl)amino]-4-oxobutanoic acid; 11 2-{[1-({[1-(carboxymethyl)-2-0x02,3,4,5-tetrahydro-1H-1-benzazepin-3-ylJamino [- VY carbonyl)cyclopentyl]methyl}-4-[ (3-hydroxypropyl)(methyl)amino]-4-oxobutanoic \y acid; \§ 2-{[1-({[1-(carboxymethyl)-2-0x02,3,4,5-tetrahydro-1H-1-benzazepin-3-ylJamino }- Vo carbonyl)cyclopentyl]methyl }-4- [(4-hydroxypiperidin-1-yl)-4-oxobutanoic acid; \ 2-{[1-({[1-(carboxymethyl)-2-0x02,3,4,5-tetrahydro- 1H-1-benzazepin-3-ylJamino}- XY, carbonyl)cyclopentylJmethyl }-4-ox0- 4-[4-(L-valyloxy)piperidin-1-yl]butanoic acid; VA 2-{[1-({[1-(carboxymethyl)-2-0x02,3,4,5-tetrahydro-1H-1-benzazepin-3-ylJamino }- 19 carbonyl)cyclopentyl]methyl }-4-morpholin -4-yl-4-oxobutanoic acid; Y. 2-{[1-({[1-(carboxymethyl)-2-0x02,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]Jamino }- Y carbonyl)cyclopentylJmethyl}-4- oxo-4-(oxopiperidin-1-yl)butanoic acid; YY 4-[bis(2-hydroxyethyl)amino]-2-{[1-({[1-(carboxymethyl)-2-0x02,3,4,5-tetrahydro-) 1H-1-benzazepin- 3-yl]amino }-carbonyl)cyclopentyl}methyl ( -4-oxobutanoic acid; Yi 2-{[1-({[1-(carboxymethyl)-2-0x02,3,4,5-tetrahydro- 1 H- 1-benzazepin-3-yl Jamino }- Yo carbonyl)cyclopentyl]lmethyl }-4-{ ethyl[3-(ethylamino)propyl]amino }-4-oxcbutanoic Yu acid; Xv 2-{[1-({[1] -(carboxymethyl)-2-0x02,3,4,5-tetrahydro- 1 H-1-benzazepin-3-ylJamino }- YA carbonyl)cyclopentyl]methyl}-4-[[2-dimethylamino)ethyl](methyl) amino]-4- Yq oxobutanoic acid; 2 4-[(3-aminopropyl)(ethyl)amino]-2-{[1-({[1-(carboxymethyl)-2-0x02,3,4,5-vy tetrahydro-1H-1-benzazepin-3) -yl]amino } -carbonyl)cyclopentylJmethyl }-4- wy oxobutanoic acid; vy D 2-{[1-({[1-(carboxymethyl)-2-0x02,3,4,5-tetrahydro-1H- 1-benzazepin-3-ylJamino}- ve carbonyl)cyclopentyl]methyl}- 4-{ methyl[2-(methylamino)ethyl] amino }-4- vo oxobutanoic acid; 71 vy with the hygroscopically elastic esters derived and compatible salts Lin gd pe aud physiologically YA from the acids of 45 compounds and/or acid addition salts pharmacologically compatible physiologically va from the formula compounds .1 \ 4 - Compounds of Formula 1 according to any of the foregoing claims; Where is the Y carbon atom deficient in symmetry carrying an amide side chain in the v position? From the benzazepine skeleton it has the stereostructural form "5". -0-1 a pharmaceutical composition containing a pharmacologically significant amount Y of a compound of formula 1 of claim 1; together with appropriate pharmaceutical adjuvants and/or excipients. -11 1 Use ol compounds having the formula Ga, 1 for protective element p in the preparation of 4 sl x used in the prevention and/or treatment of cardiovascular disorders or diseases. 1-1 Use pursuant to Clause 11; Where 0 cardiovascular disorders or diseases are selected from a group consisting of congestive heart failure; v hypertension including secondary types jie primary hypertension ; and renal and/or systolic blood pressure. SV Y 1 Use for compounds of formula 1 under claim 0 ; Where it is used in the preparation of drugs for the prevention and / or treatment of adverse conditions associated with physiological death .adverse conditions associated with apoptosis Lal y AY -0 1 use in accordance with claim 17; where it represents the associated adverse cases Y for physiological death Adverse conditions associated with apoptosis Wall Any of: v Nerve erosion diseases such as stroke due to anemia Ischemic stroke ¢ anemia ¢ cerebral ischemia ¢ head injuries Traumatic brain ° acute diffuse meningeal injury; lateral sclerosis with muscular dystrophy (ALS); 1 and retinitis sD; mild cognitive impairment and Alzheimer's disease; Pick's disease; dementia with old age A senile dementia; advanced supranuclear paralysis; subcortical dementia and q Wilson's disease; multiple infarcts; dementia due to atherosclerosis; Aly, who is associated with AIDS; JSG Cerebellar and Spinal Degeneration Syndromes; Friedreich's ataxia 1; ataxia, vasodilation; deaths related to fall ¢ atrophy and spinal injuries; dea Yl instability syndrome; Huntington's disease VY and Parkinson's disease; And eat the black layer ¢: ¥ and cerebral vasculitis; encephalopathy and muscular dystrophy; wallVo neuropathy and spinal muscular atrophy; lysosomal storage diseases with CNS1¢ impairment and mononucleopathy; urea cycle defect disorders VY ¢, hepatic encephalopathies, Fall YA renal encephalopathies, metabolic encephalopathies (4), porphyria, bacterial or viral meningitis, and encephalitis 7 and meningeal membranes. viral diseases; poisoning by neurotoxin 9 compounds; Jubien-Barre syndrome; neuropathy due to chronic infections; YY and flaccid paralysis; dermatomyositis; and brain atrophy - due to radiation, diation-induced brain damage YY ¢ and digestive diseases such as IBS, Y ¢ and intestinal infections, 0 such as Crohn's disease and ulcerative enteritis; underground disease; Yo and gastritis due to Helicobacter pylori gastritis and infections other infectious AA due to infection; or semi-membranous endocolitis. and inflammation 71 and disease of the patch in front of the host; 0 intestine due to radiation; Lymphatic intestinal infections, acute and chronic pancreatitis; and liver diseases such as; hepatitis caused by alcohol or viruses; metabolic, immune, or radiation-induced; or liver function v4; erythropoietic syndrome and hyperuricemia; and inflammation of the kidneys; kidney infection due to lupus erythematosus; And viral diseases such as acute hepatitis 2: and joint diseases; specifically immunological such as inflammatory myopathy; vy white blood; a low blood platelet count; rheumatoid LOA b and reduced number of joints; a low platelet count of unknown cause; and syndromes 2, the breakdown of immune blood cells; Syndromes of anti-phospholipid Yo ¢ and myocarditis. and multiple sclerosis ¢ antiphospholipid antibody syndromes v1 b and its types such as recurrent multiple sclerosis; secondary-advanced multiple sclerosis; Saal cilia Wy and severe multiple sclerosis 0 Advanced recurrent multiple YA Benign asymptomatic multiple sclerosis; and inflammation of the nerves and nerve membrane vq; Devic's syndrome ocular (Devic's disease 2; Addison's disease, Grave's disease ¢ lymphocytic hypophsitis 51 hypoparathyroidism; diabetes; lupus ¢ 20018008 disease 3 erythematosus; pemphigus gypsy; pemphigus balls; psoriatic arthritis + endometrial proliferation; autoimmune orchitis; autoimmune erectile dysfunction; leiomyomas; Wagner's disease; autoimmune deafness; Sjögren's disease; autoimmune retinitis; endocystitis; Judd's syndrome Pasteur and muscular and fibrous pains; poor myeloid development such as anemia due to a failure to synthesize its components; skin diseases such as 1 gypsy pemphigus; dermatomyositis; autoimmune dermatitis; ga's disease; systemic ossosis purpura; and acne Henoch-Schonlein Henoch-Schonlein £9 Physical dermatitis WA inflammation and proliferation of sebaceous skin cells ¢ systemic sclerosis ou ¢ ADSL ; chronic dyskeratosis dermatosis ; keratin dysgenesis 0) Yad father-in-law « bacterial infections and stratified dermatitis; psoriasis; bacterial skin infection oY; vitiligo, toxic epidermal necrolysis, Stevens' syndrome, leishmaniasis, and leprosy; and leishmaniasis “sebaceous adenoma and tumors of the sebaceous glands” ¢ Steven Johnson of lichen; rash «photodamage of the skin and photodamage to the skin alopecia oo cutaneous; autoimmune cutaneous vasculitis; and cytotoxic dermatitis; Hearing loss and death of hearing hair cells due to amino oA and hearing loss due to drugs harmful to hearing aminoglycoside oq all glycosides, anemia cholesteatoma, perilymphatic fistula and cholesteatoma 1.; hearing loss due to Meniere's disease and Meniere's disease 1¢ vestibular to vestibular +1 or without a known cause; organ transmission viral or bacterial viruses or lung bacteria such as host frontal patch disease; acute and chronic heart transplant rejection; or lung + bone marrow or liver corneal or cornea skin or skin ¢ kidney or kidney +: tissue rejection and wound healing; and healing liver transplants 10; where VY represents adverse conditions associated with physiological apoptosis of gamma Y v nerve eroding diseases such as stroke due to anemia; cerebral anemia; head injuries; acute disseminated encephalomyelitis and meningitis; lateral sclerosis with . muscular dystrophy (ALS); chromatography retinitis; simple thought impairment; 1, Alzheimer's disease; Beck's disease; his dementia with old age; advanced paralysis above 7 core; Subcortical dementia, Wilson disease, and multiple infarcts A, multiple infarcts, due to atherosclerosis; agnosia] associated with ADS; cerebellar erosion and cerebellar and spinal cord erosion syndromes1; Frederick's ataxia; ataxia, vasodilation; epilepsy related to cerebral atrophy; 11 and spinal injuries; instability leg syndrome; and Huntington's disease Yon Huntington's disease 7 and Parkinson's disease; JS black striatonigral degeneration yy; cerebral vasculitis   mitochondrial encephalo-myopathies  neuronal ceroid lipofuscinosis  spinal muscular atrophies  3 and particle storage diseases a “ALJ lysosomal storage disorders lead yy central nervous system; mononucleosis; urea cycle defect disorders "7" hepatic encephalopathies "11" renal encephalopathies "and metabolic encephalopathies" 7 "prophyria" and bacterial meningitis or viral meningitis 711, meningoencephalitis, meningoencephalitis, viral YY diseases, poisoning by neurotoxins, Guillain-Barre syndrome YY¢ and chronic inflammatory neuropathy, flaccid shawl Y¢, inflammation of skin polymyositis and muscles dermatomyositis « and brain atrophy - Yo due to radiation .radiation-induced brain damage 1 - Use pursuant to claim 17; Where the adverse reactions associated with 0 of the physiological death of cells represent adverse conditions associated with apoptosis, any of the diseases of the digestive system such as irritable bowel syndrome and intestinal infections; such as Crohn's disease $010:5 and ulcerative colitis; Celiac disease ° ¢ and gastritis due to Helicobacter pylori gastritis + and other gastric infections due to infection » or semi-membranous internal colitis. y and radiation-induced enteritis; lymphocytic gastritis “A” and the patch disease in front of the host; and chronic acute Gall's inflammation. -11-1 use lig for protection element “1; Where, Jay is the adverse conditions associated with 0 of the physiological death of the cells, adverse conditions associated with apoptosis, any of the diseases Ya v liver quot; autoimmune hepatitis caused by alcohol; or viruses; or metabolic, immune, or irradiation-induced; or to cirrhosis of the liver; and syndrome. erythrocyte breakdown and elevation of uric acid; inflammation of the kidneys; and 1 kidney infection due to lupus erythematosus. YA 1 — use according to claim VY where Y represents adverse conditions associated with apoptosis, i.e., viral diseases such as acute fullminant hepatitis. 1 14 Use in accordance with claim 07; Where Y represents adverse conditions associated with apoptosis, any of the diseases. joints such as trauma and osteoarthritis. -01-1 Use in accordance with claim 07; where y represents adverse conditions associated with physiological cell death | adverse conditions associated with apoptosis ual . immunodeficiency or immunodeficiency; especially autoimmune diseases such as inflammatory myopathy (De) ¢; low white blood LOLS count 0, low platelet count ¢°, rheumatoid arthritis, low platelet count of unknown cause 0; And the syndromes of breaking immune blood cells ¢ and antiphospholipid antibody syndromes 7 antiphospholipid antibody syndromes «myocarditis A. multiple sclerosis; And its types such as recurrent multiple sclerosis and secondary advanced multiple sclerosis; advanced recurrent multiple sclerosis ¢ and severe/severe multiple sclerosis; benign recurrent multiple sclerosis; asymptomatic multiple sclerosis; And inflammation of the nerves 11 and the optic nerve membrane (Devic's syndrome <li disease; lymphocytic hypophysitis VY, Grave's disease 0 yy, Addison's disease) and decreased secretion of the gland Jared Eldergisa You nl Diabetes Sw Vs « hypoparathyroidism ) ¢ 1 p0; and systemic lupus erythematodes yo; pemphigus pemphigus vulgaris, bullous pemphigoid 7, psoriatic arhtritis, VY endometriosis, autoimmune orchitis, and autoimmune erectile dysfunction. erectile dysfunction, sarcoidosis, Wegener's granulomatosis, and autoimmune deafness. Y. and Sjogren's disease » and autoimmune uveoretinitis 711; Internal cystitis, Pasteur's body syndrome, YY muscle and fiber pain. -"1 \ use according to protection element VY, where it represents adverse conditions associated with 7 physiological death. Use according to Claim 17, where Y represents adverse conditions associated with physiological cell death (Y) adverse conditions associated with apoptosis, i.e. pemphigous vulgaris, dermatomyositis ¢ and infections atopic dermatitis; Henoch-Schonlein purpura; acne, systemic sclerosis 1 and seborrheic keratosis; somatoform (da) cells; inflammation chronic proliferative skin; keratin dysgenesis; scleroderma A; stratified dermatitis; psoriasis and bacterial skin infection; leprosy; leishmaniasis 9 » and vitiligo Al—adl & 5a 5 vitiligo toxic epidermal necrolysis « 01 Steven Johnson syndrome and sebaceous adenoma 11; baldness and photodamage to the skin; lichen; rash; autoimmune cutaneous vasculitis; and cytotoxic dermatitis. iy use pursuant to claim 17; Where YY 1 represents any of the adverse conditions associated with apoptosis, physiological Wal & gall Y, an auditory injury causing hair cell death and hearing loss; Jie inner ear, hearing loss, and hearing hair cell death. due to aminoglycosides ¢, hearing loss due to hearing-damaging drugs, aminoglycoside fistula °, anemia of blood flow to the vestibule ¢, chloesteatoma, cholestatic lipoma 1 L Ménière; Hearing loss due to radiation, bacteria, viruses, or without a known cause.; Where VF represents adverse conditions associated with Y-cell apoptosis, cases caused by organ transplantation; such as the disease of the patch in front of the host; refusal v or “skin”; acute and chronic heart transplantation ¢ bone marrow-or liver-transplants or corneal marrow °; Where 07 represents the adverse conditions associated with the physiological death of Y cells according to the protection element Yo \ any of the adverse conditions associated with apoptosis, cases related to recovery from injuries and rejection of transplanted tissues. v 2) day al A method for preparing compounds her -Y1 3 R® > N R? Ho Y R'COC 0 N 0 A COOR* where v BRD is a hydrogen or biochangeable ester group; 5 1 represents Cpr4-alkyl “hydrogen” or mole 9 4-700; And it is processed 1 hydroxyl group of which by esterified with C,.4-alkanoyl 7 or an amino acid precipitate ¢ as well as ¢ Cpa-alkoxy-Cra-alkyl 1 Cia-alkyl Jia R' A « MILLAH 007: RT Optionally quenched 4 by a second hydroxyl group and the hydroxyl groups \ optionally treated by an ester with Cy4-alkanoyl OR precipitate Csiy-cycloalkyl-Cj.4- ¢ Cag-cycloalkyl ¢ (Co4-alkyl),amino-C4-alkyl ¢ amino acid 1 phenyl-Ci4-alkyl ¢ alkyl VY¢ filament assembly is replaced The fifth phenyl group has yy optionally aged 1-?once by C4-alkoxy ¢ Cig-alkyl and/or halogen ¢ 2-oxoazepanyl \¢ " or methylene and methene groups are replaced by ¢ Cyp-alkylene together representing 3 JR? their yo ¢ carbonyl nitrogen optionally one to two times by carbonyl yg optionally substituted once by sulfur and/or oxygen sulfur ¢ nitrogen VY or + Cy4-alkanoyl esterified; optionally treated by a hydroxy ester VA and the “Ci.4-hydroxyalkyl group” of the hydrolysed acid is treated as an amino acid precipitate 4 Cpa-alkanoyl with optionally esterified by the hydroxyl ester of the hydroxyl group v . as well as “benzyl J—or phenyl or phenyl amino acid or a biologically variable 7' esterified amino acid precipitate or a hydrogen ester-forming group representing the hydrogen of R*YY and/or the salts acids from physiologically compatible acids Ay yp from compounds having physiologically compatible acid resulting from the addition of acid Ys dA 11 ; It is characterized by a complex reaction having the general formula 1 of formula yg HO N 1 11 1000m N 0 0 : 00084 _a for no where RY SRO ; They are independent of the other and each of them represents a YA protecting group of an acid ¢ and reacts with a compound of the general formula ?: R3 II; | S R2—NH 1 Yq 2 where “8 or R® have the same definition as above; 1 and where 8 and/or 83 contain free hydroxyl groups ; If desired, vy can be reacted with a compound of the general formula; : Ci3-C(O)-X IV YY X Cua is a leaving group; Or with Fide an amino acid protected by an appropriate protective group vo. vi where RIO or YR represent the required groups constituting the esterified vv bio-varying ester and/or 182 and/R® include protecting groups in any amino acid A precipitate present ¢ These are successively cleaved into the resulting compounds in the form of = or in the form of singly transforming into ester salt groups .ester 0; > and JS of them sequentially cleaved into the resulting compounds at the same time or each separately in any 1 order required and the acid functions can be fired die acid at will in each case 1 and converted to the resulting 5 acid groups of formula 1 into salts of an converted to 1 free and/or race bases of formula acids converted into Acids 1 of formula 'v 1' convert to their acidic formula β or acidic addition salts 0 3 R~y Re 7 0 fo R1COC 0 N 0 a 0600 (11): Compounds with the general formula ?-71-1 HO N RW¥QOC 11. 0 N 0 wmya where 1 01c represents a protective group For acid 880 and: acid represents a protective group for acid R01.ARAN