TWI342311B - Novel derivatives of 2-hydroxytetrahydrofuran and their use as medicaments - Google Patents

Description

PRODUCT DESCRIPTION OF THE INVENTION The present invention relates to a novel derivative of 2-hydroxytetrahydrofuran which has an inhibitory activity against calpain and/or an activity of capturing reactive oxygen species (ROS). . The invention also relates to a process for its preparation, a pharmaceutical preparation containing the same, and its use for therapeutic purposes, in particular as a calcium activin inhibitor and for the selective or non-selective capture of reactive oxygen species. In the possible roles of calcineurin and ROS in physiology and pathology, novel derivatives according to the present invention may be advantageous or convenient for the pathological treatment of such enzymes and/or the residues of such residues. Effects, in particular: - Inflammation and immune diseases such as rheumatoid arthritis, pancreatitis, multiple sclerosis, inflammation of the stomach-intestinal system (ulcer or non-ulcerative enteritis, Crohn's disease); Cardiovascular and cerebrovascular diseases including, for example, arterial hypertension, septic shock, ischemic or hemorrhagic heart or cerebral infarction, local anemia, and disorders associated with platelet aggregation; - disorders of the central or peripheral nervous system, such as neurodegenerative diseases This particular mention is a brain or spinal cord wound disease, subarachnoid hemorrhage, epilepsy, aging, senile dementia including Alzheimer's disease, Huntington's disease, Parkinson's disease, peripheral neuropathy; - cachexia : - Hearing loss; - Osteoporosis; 1342311 - Muscular malnutrition; • Proliferative diseases such as atherosclerotic stenosis recurrence: - Cataract; - Organ transplantation; Immunity and viral diseases such as lupus erythematosus, AIDS, parasitic and viral infections, diabetes and its complications, multiple sclerosis; - cancer, - all pathological features are excessive ROS production and / or activation of calcine activin By. In all of these pathologies, experimental evidence confirms the involvement of ROS (Free Radic. Biol. Med. (1 996) 20, 6 7 5 - 7 05 ; A ntioxid . Health. Dis. ( 1 997) 4 (Handbook Of Synthetic Antioxidants), 1-52), and the involvement of 13⁄4 promoter proteinases (Trends Pharmacol. Sci. (1994) 15, 412419; Drug News Perspect (1 999) 12, 73-82). For example, antioxidants reduce brain damage associated with cerebral infarction or experimental cranial wounds (Acta. Physiol. Scand. (1 994) 1 5 2, 349-350; J, Cereb. Blood Flow Metabol. (1 9 9 5 1 5,948-952: J Pharmacol Exp Ther (1 997) 2, 895-904), and a calcium activin inhibitor (Proc Natl Acad Sci USA (1 996) 93,342 8-3 3 ; Stroke, (1 998) 29, 152-158; Stroke (1994) 25, 2265·2270). The applicant has described in the patent application PCT WO 0 1 /32654 that the heterocyclic compound has the same activity as the inhibitory activity of the calcium activin and the oxygen-reactive pattern. The heterocyclic compound of the patent application is equivalent to the formula (A1) 1342311 Α-Χ-Ν-Υ I Η

(Al) wherein R1 represents a hydrogen atom, -OR3, -SR3, a keto group, or a cyclic acetal group, wherein R3 represents a hydrogen atom, an alkyl group, an arylalkyl group, a heterocycloalkylcarbonyl group, an alkylcarbonyl group, an aryl group A carbonyl or aralkylcarbonyl group, wherein the alkyl, aryl or heterocycloalkyl group may be substituted with one or more identical or different substituents selected from the group consisting of alkyl, OH, alkoxy, nitrate a group, a cyano group, a halogen or -NR4R5, R4 and R5 independently represent a hydrogen atom or an alkyl group, or R4 and R5 together with a nitrogen atom attached thereto form an optionally substituted heterocyclic ring, and R2 represents a hydrogen atom, an alkyl group, and an aromatic group. Or an aryl group, the aryl group being optionally substituted by one or more identical or different groups selected from: -OR6, -NR7R8, halogen, cyano, nitro or alkyl, wherein R6, R7 And R8 independently represents a hydrogen atom, an alkyl group, an aryl group, an arylalkyl group, an alkylcarbonyl group, an arylcarbonyl group or an aralkylcarbonyl group; A particularly represents a substituted substituted thioglycol; X represents -(CH2)n-, -(CH2)n-CO-, -N(R45)-CO-(CH2)n-CO-, -N(R45)-CO-D-CO-, -CO-N(R45)-D-CO- , -CO-D-CO-, -CH = CH-(CH2)n-CO- '-N(R45)-(CH2)n-CO- '-N(R45 )-CO-C(R46R47)-CO- ' -0-(CH2)n-C0- ' -N(R45)-CO-NH-C(R46R47)-CO- '-CO-N(R45)-C (R46R47)-CO-, -S-(CH2)n-CO- or -Z-CO-; -9- 1342311 D represents an optionally substituted phenyl group; Z represents a heterocyclic ring, and R45 represents a hydrogen atom or an alkyl group. , R46 and R47 independently represent a hydrogen atom, an alkyl group, an aryl group or an aralkyl group, and the alkyl group and the aryl group thereof may be optionally substituted; R48 and R49 independently represent a hydrogen atom, an alkyl group or a -COR5Q group, or R48 and R49 thereof The attached nitrogen atom forms an optionally substituted heterocyclic ring, R5° has a hydrogen atom, an alkyl group, an alkoxy group or a —nr51r52 group, and R51 and R5 2 independently represent a hydrogen atom or an alkyl group, or R51 and R52 are attached thereto. The nitrogen atoms together form an optionally substituted heterocyclic ring; N is an integer from 0 to 6; Y represents -(CH2)p-, -C(R53R54)-(CH2)P-, -C(R53R54)-CO- R53 and R54 independently represent a hydrogen atom, an alkyl group, an aralkyl group, and the aryl group thereof may be optionally substituted by one or more identical or different substituents, and the substituent is selected from the group consisting of: 0H, halogen, nitro, alkyl, Alkoxy, -NR55R56, R55 and R50 independently represent a hydrogen atom 'alkyl or -COR57 group, or R55 and R56 attached thereto The subunits together form an optionally substituted heterocyclic ring, R57 represents a hydrogen atom, an alkyl group, an alkoxy group or a -NR58R59 group, R58 and R59 independently represent a hydrogen atom or an alkyl group, or r58 and r59 together with a nitrogen atom to which they are attached form Selecting a substituted heterocyclic ring; P is an integer from 0 to 6;

Het represents a heterocyclic ring, and an addition salt of the compound of the formula (A1) with a mineral and an organic acid or with a mineral and an organic base, -10- 1342311 wherein the compound of the formula (A1) has the following exceptions, wherein Het represents Tetrahydrofuran or tetrahydropyran, R3 in the OR3 group of R1 represents a hydrogen atom, an alkyl group, an arylalkyl group, a heterocycloalkylcarbonyl group (having a heterocycloalkyl group branched via a carbon atom), an alkyl group - an aryl group Carbonyl or aralkylcarbonyl, when R2 is hydrogen and γ is -(CH2)p· group of p = 0, then X does not represent -CO-N(R45)-C(R46R47)- having R45 = R46 = H CO-. Applicants have now surprisingly found that the compounds of formula (I) described below have the same inhibitory activity as calcinein and capture the activity of the counter-oxidative oxygen species, with improved properties in the cell penetration project. Thus, the subject matter of the invention is a compound of formula (I)

Where: A represents

Wherein R1, R2, R4, R5 and R6 independently represent a hydrogen atom, a halogen atom, an OH group, an alkyl group, an alkoxy group, a cyano group, a nitro group or a Nr7r8 group 'R7 and R8 independently represent a hydrogen atom, an alkyl group or - The C0R9 group 'R9 represents a hydrogen atom 'alkyl or alkoxy' 1342311 R3 represents a hydrogen atom, an alkyl group or a -cor1g- group,

Rl() represents a hydrogen atom or an alkyl group or an alkoxy group, and w represents a bond or -CH2-CH2-, -CH=CH-, -0-, -S- or -NR11., wherein Ru represents a hydrogen atom or Alkyl: X represents -CO-, -Y-CO·, -0-Y-C0 - or - nr12-y-co-, γ represents an alkylene group or a haloalkyl group, and R12 represents a hydrogen atom, an alkyl group or -COR13 group, R13 represents a hydrogen atom, an alkyl group, a haloalkyl group or an alkoxy group, and AA each represents a natural amino acid, a reactive chemical functional side chain (such as a carboxylic acid, an amine, an alcohol or a hydrazine). The natural amino acid of the group is protected as an alkyl or aralkyl ester (for acid functional groups), alkyl, aralkyl carbamate, or alkyl or aralkyl carboxamide (for amines) Functional group), alkyl or aralkyl ether or alkyl or aralkyl sulfide type or alkyl or aralkyl ester type (for alcohol and mercapto functional groups) or final formula -NR14-(CH2)p -CR15R16-CO-form, wherein P represents deuterium or 1, R14 represents a hydrogen atom or an alkyl group, R15 represents a hydrogen atom or an alkyl group and R16 is a hydrogen atom, an alkyl group, a haloalkyl group, a phenyl group, a cycloalkyl group, a ring Alkylalkyl or alkenyl, or R15 and R16 and attached carbon The formation of a saturated carbocyclic ring (and preferably 3 to 6 carbon atoms) of 3 to 7 carbon atoms '-(AA) 2- group may also represent a formula -NRl7-(CH2)3-CH(R18)- a carbonyl derivative of CO-, wherein R17 represents a hydrogen atom or an alkyl group and R18 represents a hydrogen atom or an alkyl group; η represents 2 or 3; and finally R represents a hydrogen atom or an alkyl group or a -CO-R19 group, wherein R19 represents a Base (ugly, especially methyl: -12- 1342311 or a salt of such a compound. Alkyl or alkylene means a straight or branched alkyl group having from 1 to 12 carbon atoms unless otherwise specifically indicated or An alkyl group, and preferably 1 to 6 carbon atoms. Haloalkyl or haloalkyl means that at least one hydrogen atom in the alkyl or alkylene group is substituted by a halogen atom. Alkenyl group unless otherwise specified otherwise It means a straight or branched alkenyl group having 2 to 12 carbon atoms, and preferably 2 to 6 carbon atoms. A cycloalkyl group means a cycloalkyl group having 3 to 7 carbon atoms unless otherwise specified. The alkoxy group means a straight or branched alkoxy group and has 1 to 6 carbon atoms unless otherwise specified. The aryl group means a carbocyclic ring unless otherwise specified. Carbocyclic aryl means a carbocyclic aryl group having 1 to 3 fused rings. Finally, a halogen atom means an atom selected from the group consisting of fluorine, chlorine, bromine and iodine atoms. It means an aralkyl group and a cycloalkylalkyl group, and the alkyl group, the aryl group and the cycloalkyl group constituting the same have the same meanings as defined above. The natural amino acid means valeric acid (Val) and leucine (Leu) ), isoleucine (ILe), methionine (Met), phenylalanine (Phe), aspartic acid (Asn), glutamic acid (Glu), glutamic acid (Gin), Histamine (His), lysine (Lys), arginine (Arg), aspartic acid (Asp), glycine (Gly), alanine (Ala), serine (Ser), crisp Amine (Thr), tyrosine (Tyr), tryptophan (Trp), cysteine (Cys) or proline (Pro). Linear or branched alkyl groups having from 1 to 6 carbon atoms are especially methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl and tert-butyl, pentyl, neopentyl Base, isopentyl, hexyl, isohexyl. A cycloalkyl group having 3 to 7 carbon atoms particularly means a cyclohexyl group. Carbocyclic aryl particularly means phenyl, naphthyl and 1342311 phenanthryl, preferably phenyl and naphthyl, and more preferably phenyl. Haloalkyl means especially -CF3 group. Finally, a haloalkyl group means, in particular, a -CF2- group. Examples of protected functional groups carried by the natural amino acid side chain include, inter alia: - a protected acid functional group in the form of a methyl, ethyl, tert-butyl or benzyl ester; - a tert-butyl or benzylamine a benzylamine carbamate in the form of a formate or acetamide, a protected amine functional group of acetamide; a third butyl, benzyl ester or piperane or a protected alcohol function in the form of an acetamyl group And a protected oxime ester functional group or methyl thioester form in the form of a methyl thioester. Preferably, the compounds of the invention have at least one of the following characteristics: * R1, ! ^2! ^4, R5 and R6 independently represent a hydrogen atom 'halogen atom or an alkyl group, an alkoxy group or an NR7RS group; * R3 represents a hydrogen atom, a methine or a -COR9 group, wherein R9 represents a methyl group or a third butoxy group; * w represents a bond or -CH2-CH2-, -CH = CH-, -0 - or -S- group, especially a bond or -CH2-CH2-, -0- or -S- group; * X stands for - C0-, -Y-C0 - or - 0- Y-C0-; *-(AA)-containing amino acid independently selected from natural amino acids, 3-methylproline, n-proline, phenyl Glycine, vinyl glycine and 2-aminobutyric acid; * η represents 2: *R represents a hydrogen atom or a methyl group. More preferably, the compound of the present invention is a compound having at least one of the following characteristics: -14- 1342311 *1, 112, 4, 115 and r6 independently represent a hydrogen atom or an alkyl group or an alkoxy group (and, more preferably Preferably, R1 'R2, R4 'R5 and R6 are all hydrogen atoms). *R3 represents a hydrogen atom or a methyl group (and more preferably a hydrogen atom); *w represents -0 - or -S-, more preferably -S-; * X represents -Y-C0 - or -0-Y- C0-; * -(AA)n- represents (AAh'AA1)- group, these AA1 represent Leu and AA2 represents a group consisting of the following amino acids: natural amino acid, 3-methylproline, Pro-amine, phenylglycine, vinyl glycine, and 2-aminobutyric acid (and more preferably (ΑΑ^-ίΑΑ1)-yl, these AA1 represent Leu and AA2 represents an amine selected from the group consisting of Group of base acid groups: Leu, Lys, Val, 3-methylproline, n-proline, phenylglycine, ethylene glycine, and 2-aminobutyric acid; * R represents a hydrogen atom. In particular, the present invention relates to a compound selected from the group consisting of the following formula (I): -N-(10H-phutthiam-2-ylcarbonyl)-L-leucine-L-leucine-1 ^-[(35)-2-Methoxytetrahydrofuran-3-yl]-1^ leucine amide; -N-(10H-phutthiam-2-ylcarbonyl)-L-leucine- L-Acetyl-N, [(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucine amide; -N-(10H-morphin-2-ylcarbonyl)glycine Base->^-[(38)-2-methoxytetrahydrofuran-3-yl]-L-leucine decylamine: -Ν-(10Η·Pentyl-2-ylcarbonyl) leucine - _[(35)-2-methoxytetrahydrofuran-3-yl]-L-leucine guanamine; -Ν6-[(benzyloxy)carbonyl]-Ν2-(10Η-morphothelazine-2 -ylcarbonyl)-amino acid-heart-[(35)-2-methoxytetrahydrofuran-3-yl]-L-leucine decylamine; -15- 1342311 -1-U0H-morphine tillage-2 -ylcarbonyl)-L-proline-l-tOS)-2-methoxytetrahydrofuran-3-yl]-L-leucine amide; -N-(10H-morphin-2-yl) Carbonyl)glycine-yl-p-amine-[(35)-2-hydroxytetrahydrofuran-3-yl]-L-leucine; -N-(10H-phthylthiophen-2-ylcarbonyl) leucine Hydroxytetrahydrofuran-3-yl]-L-leucine decylamine: -N6 -[(benzyloxy)carbonyl]·Ν2-(10Η-morpholino-2-ylcarbonyl)-amino acid-NMoS)-2-hydroxytetrahydrofuran-3-yl]-L-leucine guanamine; -1-(10H-morpholino-2-ylcarbonyl)-L-proline group->^-[(33)-2-hydroxytetrahydrofuran-3-yl]-L-leucine guanamine; -N-(10H-Phenothione-2-ylcarbonyl) leucine-N-[(3S)-2-(ethenyloxy)-tetrahydrofuran-3-yl]-L- leucine Amine: -(1011-phthylthiam-2-ylcarbonyl)-amino acid-;^-[(35)-2-hydroxytetrahydrofuran-3-yl]-L-leucine amide; · (10Η-Phenothyridin-2-ylethyl)-L-leucine-N-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucine guanamine; -0-(Tertiary Butyl)-N-(10H-Brothidin-2-ylethylidene)-L-Lesinyl-NMOS)-2-Methoxytetrahydrofuran-3-yl b- Amine leucine; -N-(10H-cyano-4-indanyl)-L-alanine-3-cyclohexyl-1^-[(3 5)-2-methoxytetrahydrofuran -3-yl]-L-alanine decylamine; -N-(10H-morpholino-2-ylethyl)-L-leucine--^-[(35)-2-hydroxytetrahydrofuran -3-yl]-L-leucine decylamine: ·0-(Tertiary butyl)-Ν-(1〇Η-morphothelin-2-ylethyl -L-serinate-N-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L-leucine amide; -16- 1342311 -N-(10H-morphine tillage-2 -L-alanine-3-cyclohexyl•"-[(Μ)-2-hydroxytetrahydrofuran-3-yl]-L-alanine decylamine; -N-[3-(10H -morpholino-2-yl)propanyl]-L-leucine-Ni-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucine amide; [3-(1011-Phenothiont-2-yl)propanyl]-1-leucine-1--[(35)-2-hydroxytetrahydrofuran-3-yl]-L- leucine Amine; -N-[(10H-morpholino-2-yloxy)ethenyl]-L-leucine--:^-[(35)-2·methoxytetrahydrofuran-3-yl] -L - leucine decylamine: -!^-[(1011-morphothi-2-yloxy)ethinyl]-glycine group 41-[(35)-2. methoxytetrahydrol Phenyl-3-yl]-L-leucine guanamine: -N-[(10H-Phenothione-2-yloxy)ethenyl]-L-alanine-methoxytetrahydrofuran-3 -yl]-L- leucine guanamine; -N-[(10H-phthathiam-2-yloxy)ethinyl]-L-proline-l-[[33]-2 -methoxytetrahydrofuran-3-yl]-L-leucine decylamine; -N-[(10H-phutthiam-2-yloxy)ethenyl]-L-alanine----[ (35)-2 -methoxytetrahydrofuran-3-yl]-L-leucine decylamine; -N-methyl-N-[(10H-morphothen-2-yloxyethyl)glycine-based -[(35)-2-methoxytetrahydrofuran-3-yl]-L-leucine guanamine; -N-[(10H-phthathiam-2-yloxy)ethenyl]-D- Amidino-yl)-]-methoxytetrahydrofuran-3-yl]-L-leucine decylamine; -3 -methyl-N-[(10H-phthathiam-2-yloxy) Ethyl]-L-proline--amp;-[(33)-2-methoxytetrahydrofuran-3-yl]-L-leucine amide; -1^-[(35)-2 -Methoxytetrahydrofuran-3-yl]-N2-((2S)-2-{[(10H-Phenylthio-2-yloxy)-ethenyl]amino}butyl)-L-白amine Hydrazide; -17- 1342311 -N-[(10H-Phenylthiam-2-yloxy)ethinyl]-L-n-decylamino-Ni-[(3S)-2-methoxy Tetrahydrofuran 3-yl]-L· leucine amide; -N-[(10H-phthathiam-2-yloxy)ethinyl]-L-serinyl-1^-[(33) 2-methoxytetrahydrofuran-3-yl]-L· leucine amide; -N-[(10H-phthathiam-2-yloxy)ethenyl]-L-cylamine thiol- "-[(35)-2-Methoxytetrahydrofuran-3-yl]-L-leucine guanamine; -!^-[(35)-2-methoxytetrahydrofuran-3-yl]-N2-( ( 2S)-2-{[(10H-morpholino-2-yloxy)ethenyl]amino}-2-phenylethenyl)-L-leucine guanamine; -with-[(33 )-2-methoxytetrahydrofuran-3-yl]-N2-((2S)-2-{[(10H-morpholino-2-yloxy)ethenyl]amino}but-3-ene ))-L- leucine decylamine; -2-methyl-N-[(10H-phthathiam-2-yloxy)ethenyl]alanine group•>^-[(3 5) 2-methoxytetrahydrofuran-3-yl]-L-leucine guanamine; -Ν-[(1〇Η-morphindol-2-yloxy)ethinyl]-glycine thiol- 1^-[(33)-2-Methoxytetrahydrofuran-3-yl]-L-proline decylamine: -N-K10H-morphothion-2-yloxy)ethinyl]-glycine Mercapto-3-cyclohexyl-N1-[(3 S )-2-methoxytetrahydrofuran-3-yl]-L-alanine decylamine; -Ν·[(1〇Η-phthymphazin-2- Ethyloxy)ethinyl]-glycine-yl-N-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-phenylalanine decylamine; -Ν·[(1〇Η -morphothion-2-yloxy)ethinyl]glycidyl-N2-isobutyl-1^-[(35)-2-methoxytetrahydrofuran-3-yl]glycine decylamine : -Ν-[(1〇Η-Phenothiont-2-yloxy)ethinyl]-L-leucine-N-[(3S>-2-hydroxytetrahydrofuran-3-yl]-L -White Acid decylamine; -N-[(10H-phthathiam-2-yloxy)ethinyl]-glycine-yl-^4(35)-2-hydroxytetrahydrofuran-3-yl]-L-white Amidoxime: -18- 1342311 -N-[(10H-Phenothione-2-yloxy)ethenyl]-L-alanine-1^-[(35)-2-hydroxytetrahydrofuran- 3-yl]-L-leucine amide; -1^-[(丨011-morpholino-2-yloxy)ethenyl]-1^valine--41-[( 35)-2-hydroxytetrahydrofuran-3-yl]-L-leucine guanamine; -N-[(10H-phutthiam-2-yloxy)ethenyl]-propylamine-yl---[ (38)-2-hydroxytetrahydrofuran-3-yl]-L-leucine guanamine; -N-methyl-N-[(10H-cyanosin-2-yloxy)ethenyl]glycine Mercapto-1^-[(38)-2-hydroxytetrahydrofuran-3-yl]-L-leucine decylamine;

-N-[(10H-morphothion-2-yloxy)ethyl)-D-proline----((33)-2-hydroxytetrahydrofuran-3-yl]-L-impamine Acid decylamine; -3-methyl-N-[(10H-morphothyridin-2-yloxy)ethenyl]-L-prolinyl-1^-[(35)-2-hydroxytetrahydrofuran -3-yl]-L-leucine amide; -heart-[(35)-2-hydroxytetrahydrofuran-3-yl]-N2-((2S)-2-{[(10H-morphine tillage- 2-yloxy)ethinyl]amino}butanyl)-L-leucine guanamine;

-N-[(10H-morpholino-2-yloxy)ethenyl]-L-n-decylamine-1^-[(35)-2-hydroxytetrahydrofuran-3-yl]-L - Indoleamine leucine; -N-[(10H-phutthiam-2-yloxy)ethenyl]-L-serinyl->^-[(35)-2-hydroxytetrahydrofuran-3 -yl]-L-leucine guanamine; -N-[(10H-cyanosin-2-yloxy)ethinyl]-L-succinylamine-1^-[(33)-2 · Hydroxytetrahydrofuran-3-yl]-L-leucine guanamine; --[(33)-2-hydroxytetrahydrofuran-3-yl]-N2-((2S)-2-{[(10H-morphine) Thio-2-yloxy)ethinyl]amino}-2-phenylethylhydrazinyl)-L-leucine guanamine; -N-[(3S)-2-hydroxytetrahydrofuran-3-yl ]-N2-((2S)-2-{[(10H-Brothidene-2-yloxy)-ethenyl]amino}but-3-enyl)-L-leucine decylamine ; -19- 1342311 -2-methyl-N-[(l OH-morpholino-2-yloxy)ethenyl]alanine-Ni-tpS)-]-hydroxytetrahydrofuran-3-yl] -L- leucine amide; -N-U10H-morpholino-2-yloxy)ethinyl]glycidyl hydroxytetrahydrofuran-3-yl]-L-proline amide; -[(1〇Η-morphothion-2-yloxy)ethinyl]glycidyl-3-cyclohexyl•>}|-[(35)-2-hydroxytetrahydrofuran-3- -1^-Alanine amide; -Ν-[(1〇Η-Phenothione-2-yloxy)ethinyl]glycidyl-N-[(3S)-2-hydroxytetrahydrofuran- 3-yl]-L-phenylalanine decylamine:

-N-U10H-morphin-2-yloxy)ethinyl]glycidyl-NM(3S)-2-hydroxytetrahydrofuran-3-yl]-N2-isobutylglycine decylamine; -Ν-[2·Methyl-2-(10H-Pentylthio-2-yloxy)propanyl]glycidyl-heart-[(35)-2-methoxytetrahydrofuran-3-yl -1^- leucine amide; -Ν·[2-methyl- 2·(10Η-morphothen-2-yloxy)propanyl]glycine-NMoS)-2-hydroxyl Tetrahydrofuran-3-yl]-L-leucine guanamine: -Heart (10,11-dihydro-51 dibenzo[1), 11 az exo-3-ylcarbonyl)-1^ leucine- Taking -[(35)-2-methoxytetrahydrofuran-3-yl]-L-leucine guanamine;

-N-(10,l 1-dihydro-5H.dibenzo[b,f]azhen-3-ylcarbonyl)-L-leucine-Ni-[(3S)-2-hydroxytetrahydrofuran- 3-yl]-L-leucine guanamine; -1^-[(5-ethenyl-10,11-dihydro-5^1-dibenzo[1), £]azet-3- Carbonyl]-L-leucine-based-[(38)-2-methoxytetrahydrofuran-3-yl]-L-leucine decylamine: -2-methyl-N-[(10H -Phenothione-2-yloxy)ethinyl]alanine-!^-[(3 5)-2-hydroxytetrahydrofuran-3-yl]-L-leucine decylamine; -20- 1342311 -N-[(3S)-2-methoxytetrahydrofuran-3-yl]-4-methyl- 2-(3-{[(10H-phutazom-2-yloxy)ethenyl]amine })propylamylamine; -N-[(3S)-2-hydroxytetrahydrofuran-3-yl]-4-methyl- 2-(3-{[(10H-morphothelin 2-yloxy) Ethyl hydrazide]amino}propyl)pentanylamine: -N-(10H-bromoquintain-2-ylcarbonyl)-L-leucine--^-[(35)-2-methoxy 4-tetrahydrofuran-3-yl]-L-leucine decylamine; -N-(10H-peptone-2-ylcarbonyl)-L-leucine-NMOS--hydroxy-tetra

Hydrofuran-3-yl]-L-leucine guanamine; or a salt thereof. The object of the invention is also a pharmaceutical, such as a compound of the formula (I) as defined above and a pharmaceutically acceptable salt of such a compound.

Pharmaceutically acceptable salts are particularly meant to mean inorganic acid addition salts such as hydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates, diphosphates and nitrates, or organic acid salts, Such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, palmitate and hard Fatty acid salt. Also included within the scope of the invention are salts which are formed from a base, such as sodium hydroxide or potassium hydroxide, when they are used. Other examples of pharmaceutically acceptable salts can be found in "Salt selection for basic drugs", Int. J. P harm. (1986), 33, 2 0 1 - 2 1 7 . The present invention also relates to a pharmaceutical composition comprising, as an active ingredient, a compound of the formula (I) as defined above or a pharmaceutically acceptable salt of the compound, and at least one pharmaceutically acceptable excipient. -21- 1342311 The pharmaceutical composition containing the compound of the present invention may be in a solid form such as a powder, granule, lozenge, gelatin capsule, liposome, suppository or ointment. Suitable solid supports can be, for example, calcium phosphate, stearic acid, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, methylcellulose 'carboxymethylcellulose sodium, polyvinylpyrrolidone and waxes. . Pharmaceutical compositions containing a compound of the invention may also be presented in liquid form, such as a solution, emulsion, suspension or syrup. Suitable liquid supports may, for example, be water, organic solvents such as glycerol or glycols, and mixtures thereof, in various proportions in water. Further, the invention relates to the use of a compound of the formula (I) as defined previously, or to a compound thereof A pharmaceutically acceptable salt for the preparation of a medicament for the treatment of all pathological features of excess ROS production and/or activation of calcinein, in particular, a group consisting of the following diseases and disorders, including inflammation and immune diseases, cardiovascular And cerebrovascular diseases, central and peripheral nervous system, osteoporosis, muscular dystrophy, proliferative diseases, cataracts, rejection after organ transplantation, and autoimmune and viral diseases. The administration of the medicament of the present invention can be carried out by a local route, an oral route, a parenteral route, an intramuscular injection, a subcutaneous injection, an intravenous injection or the like. The dosage of the product of the present invention, provided to treat the aforementioned disease or disorder, will vary depending on the method of administration, the age and weight of the subject to be treated, and the state of the latter, and will ultimately be determined by the clinician or veterinarian. These amounts, as determined by the clinician or veterinarian, are referred to herein as "therapeutically effective amounts." By way of illustration, the dosage administered according to the invention is from O.lmg to 10g, depending on the form of active ingredient employed. -22- 1342311 According to the present invention, the compound of the formula (I) can be produced by the method described below. Preparation of the compound of the formula (1) The compound of the formula (I) according to the invention can be prepared according to the synthetic route of the following Scheme 1 (in the rest of the specification, the compound of the formula (I) wherein R represents a hospital Aik is called The compound of the formula (I), the compound of the formula (I) wherein R represents a hydrogen atom is referred to as a compound of the formula (1) 2, and those of the formula (I) wherein R represents _C〇R19 are referred to as a formula ( I h compound): AX-OH + Η-(ΑΑ)-γ 11 Η

Ο O'

Aik (Π) (ΠΙ)

A-X-(AA)-lji η Η

0〇2

.19 Scheme 1 Preparation of the compounds of formula (I), and (1) 2 wherein hydrazine, X, hydrazine, η and R are as previously described, via an acid of the formula (Π) and an amine of the formula (ΙΠ) Condensation, standard conditions for the synthesis of peptides (M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis, 1 4 5 (S pringer - V er 1 ag, 1984)), in THF, dichloromethane or DMF' coupling agent In the presence of, for example, dicyclohexylcarbodiimide (DCC), 1,1,-carbonyldiimidazole (CDI) (J Med. Chem. (1992), 35 (23), 4644-4472) or 1-(3) -Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC or WSCI) (John Jones, The chemical synthesis of peptides, 54 (Clarendon Press, -23- 1342311)

Oxford, 1991)) and a base such as triethylamine or n,N-diisopropylethylamine 'in order to give a compound of the formula (I)! Then the formula (I), the hemiacetal functional group of the compound can be deprotected using an aqueous solution of about 2N mineral acid, for example, HC1 or HBr, using propionium as a cosolvent, thereby obtaining a half-shrinkage of the formula (1) Aldehyde derivative 'When appropriate deuteration is used, in particular, an acid anhydride (R19CO) 20 (for example, acetic anhydride) in the presence of a deuterating agent such as N,N-dimethyl-4-pyridinamine to obtain a formula ( 1) 3 compounds. Preparation of the intermediate of the formula (II): Among the non-commercial carboxylic acids of the formula (A), A, W, X, Y, R1, R2, R3, R4, R5 and R6 are as defined above, depending on the details described in detail below. Synthesis can be achieved. When X = -0-Y-C0-: In this case, the synthesis path shown in Figure 2 below can be used.

A-OH + Br-Y-COAlk -- A-〇-Y_COAlk -- A-〇-Y_C〇2H (Π.1) (Π.2) (Π.3) (Π) Figure 2 Based on this synthetic path, In the acid of the formula (II), X represents -0-Y-C0- in Scheme 2, and may, for example, be a hydroxymorphothane trap of the formula (II.1) (IMed·Chem· (1 992), 35 (4) , 7 16-24) or hydroxycarbazole (J. Chem. Soc (1 95 5), 3475-3477; J. Med. Chem. (1 964), 7, 1 5 8 -1 6 1 ). Condensation with a commercially available haloester of the formula (II.2) in the presence of a base, such as K2C03 or Cs2C03, via a hot melt in a polar solvent, such as THF or DMF, for at least 5 hours. And then to protect the intermediate to obtain the ester of the formula (II. 3) (in the case of an acid vehicle, in the case of saponification of a third butyl ester or methyl / ethyl ester), in order to lead to the formula (Π) X in the acid stands for - XO-Y-CO - base. -24- 1342311 When X = -CO-: In this case, the synthetic path shown in Figure 3 or 4 below can be used. i) X represents -CO - and w has a table _S-, _0_ or a bond: when X represents a graph of -CO- and ... represents -S-'-Ο- or a bond when the formula (Π) A thia trap, a porphyrin trap or a oxazole acid derivative may be a 2-acetylmorphotheline trap of the formula (11.4) (for example, 卩1^1'1113216 (1984), 39(1), 22-3; 81111.5 〇., (:111111· (1 968), (7), 2832-42, Pharmazie (1 966), 21(11), 645-9), 2-Ethyl phenyl morphine trap (J. Org. Chem (1 960), 25, 747-53) or 2-Ethyl group (see, for example, Heterocycles (1994), 39(2), 833-45; J Indian Chem. S o c. (1985), 62 (7), 5 3 4-6 ; J. Chem. Soc. Chem. Comm. (1985), (2), 86-7), which is acetylated with ethyl ethoxide, by toluene Heating to reflux to obtain an intermediate (II. 5 ) (J. Med. Chem. (1998), 41(2), 148-156). The intermediate (II.5) thus obtained is continuously iodine and hydrazine. A mixture of hydrazine (J. Amer. Chem. Soc. (1944), 66, 894-895) and aqueous soda treatment at 10 (rc) to obtain a carboxylic acid of the formula (π).

Illustration 3 -25- Ϊ342311

(Π)

Scheme 4 When X represents -CO- of Figure 4 and W represents -CH2-CH2- or -CH=CH-, the acid of formula (11)^ or (II) can be obtained by the formula (π.6) bis-B Preparation of thiolated derivatives (for example, J. Chem. Soc. (1973), 859-863). In the case of the morphine trap (Fig. 3), oxime-based oxidation is carried out using iodine and pyridine followed by hydrolysis in aqueous soda under heat. The compound of the formula (II) Ae thus obtained, which is a compound of the formula (Π), wherein R3 represents an ethyl hydrazide group, may optionally be subjected to additional treatment, preferably in the presence of aqueous potassium base, preferably at 15 to The carboxylic acid of the formula (II) is obtained in a period of 3 hours. When X = -Y-CO-: in X =-Y-CO-, the two synthetic routes in Scheme 5 below may reach the carboxylic acid of formula (II), depending on the starting reagent available. -26- 1342311

Illustrative 5 is the case of the 2-acetylmorphinethiophene (W = -S-) or 2-ethylmercaptocarbazole (W represents a bond) of the formula (II.4), which is converted into a pass as previously described. The carboxylic acid of formula (II) is carried out in a Willgerodt-Kindler-type homologue physicochemical reaction (Synthesis (1 975), 35 8-375) (left part of Scheme 5). The heating of the intermediate of the formula (II.4) in the presence of sulphur and morpholine results in the formation of thiocarboxamide of the formula (II.7) (German Patent Application DE 27〇2714 and DE 1910291) via hydrolysis It is converted into a carboxylic acid of the formula (II). -27- 1342311 or (right part of diagram 5) 'When w represents -S- or bond and m is an integer greater than 1, or when w represents -CH2-CH2_ or _CH = CH1 m is greater than or equal to 1 In the case of integers, the synthesis of the carboxylic acid of the formula (Π) begins with the deuteration of the aromatic ring of the intermediate of the formula (II. 8) of the alkane chloroform of CS2, according to the Friedel-Crafts reaction conditions (J. Amer. Chem. Soc. (1946), 68, 2673-7 8 ; J. Chem. Soc. Perkin Trans. 1 (1 973), 85 9-86 1 ). The deuterated intermediate of the formula (Π.9) is then converted to the thiocarboxyguanamine derivative of the general formula (II.10), via the Willgerodt-Kindler reaction, and finally to the formula according to the chemical sequence previously described (Π ) Carboxylic acids. A morphine-form analog can also be obtained according to the Willgerodt-Kindle method, as described by J. Org. Chem. (1960), 25, 747-5. Preparation of the intermediate of formula (III): The amine-internal hemiacetal derivative of formula (m) wherein AA, R and η are as described above using the preparative route shown in Scheme 6 below. This method can produce η = 2 (the compound of the following formula (111) 2) and η = 3 (the compound of the following formula (ΙΙΙ) 3) in the compound of the formula (III). 1342311 H2N' +

Ο Gp"AA! -〇H σιι·ι)

Gp-AAUN H (ΠΙ.2)

0 0

H

Gp—AA1

OH (ΙΠ.3)

Gp—AA1 H (ΠΙ.4)

Gp-AA3-〇H Η-ΑΑ!-ψ H (IIL5)

O

Gp

Oh,

Aik H-AA^AA1-^ H (ni)2

H-AA^AA^AA1-!^ H (ΙΠ)3

Scheme 6 The amine-butyrolactone derivative of the formula (ΙΠ.2) is obtained by condensation of a protected amino acid of the formula (III.1) wherein AA1 is AA previously defined by the formula (1) An amino acid residue, and Gp is a protecting group, such as benzyl or a tert-butylamine formate, and (S)-cL aminobutyrolactone under standard conditions of the peptide, in order to Carboxylamidine intermediate of (III.2). The lactone is then reduced to the internal hemiacetal (lactol) using a reducing agent such as diisobutylaluminum hydride (DIBAL) in an inert solvent such as THF or CH2C12, preferably at a temperature below -50 °C, for example , at about -7 8 °C. The hemiacetal function of the hemiacetal derivative of the formula (ΠΙ.3) is then protected based on an alcohol vehicle, such as methanol, using a strong acid such as trifluoroacetic acid, in order to give the formula (III.4) Acetal. The amine function of the amine-acetal derivative of formula (III.4) is then deprotected according to the method described in the literature (1'.'\¥·

Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, Second edition (Wiley-Jnterscience, 1991)). Then the intermediate of the general formula (III.5) is subjected to one or two consecutive elongations of the peptide chain - to protect the -29-1342311 retaining ring' as previously described, in order to obtain individual formulas (m) 2 and (III) 3 bis-(n = 2) or tri-peptidic (n = 3) derivatives. In a particular case, the (AA2-AA1) group or the (AA3-AA2) group is substituted with a carbonyl peptide of the formula -NRl7-(CH2)3-CH(Rl8)-CO-, as shown in Figure 7 below. The previously described peptide synthesis strategy yields derivatives of the general formula (111) 2 and (ΠΙ) 3, and Scheme 7 represents only the (AA2-AAl) group via the carbonyl peptide-substituted case's (AA3-AA2) group. A similar preparation method can be used in the case of carbonyl peptide substitution.

H-AA3-N

I

R Schematic 7 The carbonyl peptide of the formula (III.6) can be easily carried out by the method described in the literature (for example, Int. J. Peptide Protein Res. (1 992), 39, 273-277) ° unless otherwise specified, All technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the invention pertains. Similarly, all publications, patent applications, all patents, and all references cited herein are incorporated by reference. -30- 1342311 [Embodiment] The following examples are presented to illustrate the above procedures and should not be construed as limiting the scope of the invention. EXAMPLES Example 1 : N-(10H-Brothidin-2-ylcarbonyl)-L-leucine-L-leucine-based-[(38)-2-methoxytetrahydrofuran-3 -yl]-L- leucine decylamine: 1.1) N2-[(benzyloxy)carbonyl]->^-[(33)-2-onetetrahydrofuran-3-yl]-L- leucine bismuth Amine: 3.51 g (13.25 mmol) of Cbz-L-leucine, 2_41 g (leq.) of (S)-2-amino-4-butyrolactone hydrobromide, 1.97 g of HOBT (l. Leq.) and 5.59 g (2.2 eq.) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) were dissolved in 60 ml of anhydrous DMF and then added Concentrated diisopropylethylamine of 7.64!111 (3.369.). The reaction mixture was stirred at 20 ° C for 15 hours before being poured into a mixture of ethyl acetate/water 1/1 of 20 1111. After stirring and pouring, it was continuously saturated with 1 mL of NaHC03, 50 ml of water, 100 ml. The organic solution was washed with 1 M citric acid solution and a final 100 ml of brine, dried over sodium sulfate, filtered and concentrated in vacuo to dryness. The pentane mixture was crystallized to give a white solid, mp.: 303. 1.2) N2-[(Benzyloxy)carbonyl]---[(35)-2-hydroxytetrahydrofuran-3-yl]-L-leucine decylamine: 60 ml of anhydrous dichloromethane under argon 1.24 g (3.56 mmol) of intermediate 1.1 was dissolved in a 3-neck flask. Add l〇.7ml (3eq.) of -31- 1342311 DIBAL to a solution of 1M in dichloromethane, then cool the mixture to -6 (rC, at the end of the addition, remove the ice bath and maintain stirring 1 5 Minutes, then carefully inject the reaction medium into 100 ml of 20% Rochelle salt solution, vigorously stir for 2 hours, add 1 〇〇m 1 of dichloromethane, and inject the mixture into the separation funnel. The organic phase was washed with 50 ml of water and 50 ml of brine. After drying over sodium sulfate and filtered, the organic solution was concentrated to dryness in vacuo and the residue was purified on a silica gel column. Alkane, in a ratio of from 1/1 to 8/2. White solid obtained in 72% yield, m.p.: 48-49 〇 C. 1.3) N2-[(benzyloxy)carbonyl]-Ni-[(3S 2-methoxytetrahydrofuran-3-yl]-L-leucine decylamine is added dropwise at a temperature of 20 ° C to an excess of trifluoroacetic acid (5 ml) to 0.82 g (2.34 mni 〇l) of intermediate 1.2 in 50 ml of methanol The solution was stirred at 20 ° C for 15 hours, then the reaction mixture was partially concentrated in vacuo and taken in 50 mL dichloromethane. The organic solution was washed successively with 50 ml of a saturated NaHC03 solution, 50 ml of water and 50 ml of brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was evaporated on a silica gel column (washing solution: Ethyl acetate / heptane, in a ratio of from 1/1 to 7/3) was obtained as a white solid in 80% yield. Melting point: 1 1 2 -11 3 °C. 1.4) 1^-[(33)-2-Methoxytetrahydrofuran-3-yl]-L-leucine decylamine: 2 g (5.5 mmol) of intermediate 1.3 and 600 mg of 10% Pd/C are introduced into 6 In a 0 ml methanol stainless steel reactor, the mixture was stirred under a hydrogen atmosphere of 2 atm for 1 hour. After filtering the catalyst, the methanol was evaporated in vacuo to remove the oily residue (1. 2 g; 94%). -32- 1342311 1.5) N-[(benzyloxy)indolyl]-L-leucine-Nl-[(3S)-2-methoxytetrahydrofuran-3-yl]-L- leucine Amine: The same experimental procedure was used for the synthesis of the intermediate except that the (S)-2-amino-4-butyrolactone hydrobromide was replaced with the intermediate 1.4. The product was purified on a hydrazine column (eluent: ethyl acetate / heptane 7/3) to afford a white solid yield of <RTI ID=0.0>> 1.6) L-Acetyl-based-[(35)-2-methoxytetrahydrofuran-3-yl]-L- leucine decylamine: The same experimental procedure was carried out using the intermediate 丨.4 synthesis, except Intermediate 1 · 5 Substituted intermediate 1. 3, using this reaction product, without additional purification, 0.74 g of a colorless foam was obtained in a yield of 96%. 1.7) N-[(Benzyloxy)carbonyl]-L-leucine-L-leucine-Ni-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leamine Acid amide: The same experimental procedure was carried out using the intermediate 1 · 1 synthesis except that the (S)-2-amino-4-butyrolactone hydrobromide was replaced with the intermediate 1.6. The reaction product was recrystallized from a mixture of ethyl acetate/isopentane to afford 0.96 g of a white solid in a yield of 77%. 1.8) L-Acetyl-L-leucine-N匕[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucine amide: Synthesis using intermediate 1.4 The same experimental procedure, except that the intermediate 1.3 was replaced with the intermediate 1.7, a white solid of 74.74 g, m.p.: 187. . . 1.9) 1-(10-Ethyl-10H-cyano-4-yl)ethanone 1342311 30 g (0.118 mol) of 2-ethenylthiophene and 9.28 g of (eq.) Chlorine was introduced into a 500 m crucible flask containing 150 ml of toluene, and the reaction mixture was heated to reflux for 45 minutes before introducing a new portion of 4.6 g (0-5 eq.) of ethylhydrazine chloride. Then, the reaction medium was poured onto about 200 g of ice, and after stirring, the organic phase was poured out and washed successively with 100 ml of water and 100 ml of brine, and the organic solution was dried over sodium sulfate, filtered, and concentrated to dryness using a rotary evaporator. A yellow solid (3 3 g; 100%) was obtained which was used in the next step without additional purification. 1.10) 10H-Brothine Trap-2-carboxylic acid: 24 g (0-084 mol) of intermediate 1.9 was dissolved in 55 ml of pyridine, 2 0.3 2 g (leq.) of iodine was added, and the reaction mixture was heated at 1 ° C. Minutes, then concentrated to a dry temperature at 20 ° C for an additional 20 hours before using a rotary evaporator to concentrate to dryness. '100 ml of water was added to the evaporation residue thus obtained, followed by 15 g (4.46 eq.) of small agglomerate NaOH. The mixture was then heated at 1 ° C for 1 hour, cooled with an ice bath, and the reaction mixture was washed with 100 mL of ethyl acetate and then acidified using a 50 1 1 1 N aqueous solution of HC 1 to give a rich precipitate. The latter was filtered through a Biichner funnel, washed with ethanol and dried under vacuum at 75 °C. An additional portion of the expected product can be recovered from the acidic filtrate, the latter is extracted twice with 100 ml of ethyl acetate, then the organic phase is washed with 50 ml of water and then 50 ml of brine. After drying over sodium sulfate, the organic solution is concentrated in vacuo to dryness. The total amount was 16.8 g, in a yellow solid form with a total yield of 82%, melting point: > 23 5 °C. 1342311 1 .1 1) N-(10H-Brothidene-2-ylcarbonyl)-L-leucine-L-lysine methoxytetrahydrofuran-3-yl]-L- leucine The experimental procedure for the amine peptide concentrate is the same as that for the synthesis of intermediate 1.1'. This time using 10H-phenothiazole-2-carboxylic acid (intermediate 1.10) and L-leucine-L-leucine Base-1^-[(35)-2-methoxytetrahydrofuran-3-yl]-L-leucine decylamine (intermediate 1.8), the reaction product was purified by chromatography on vermiculite Liquid: ethyl acetate / heptane, in a ratio of from 7/3 to 1:1, 228 mg of a yellow solid, m.p.: 164-165. Example 2: N-(10H-Phenothione-2-ylcarbonyl)-L-leucine-L-leucine-N,[(3S)-2-hydroxytetrahydrofuran-3-yl b - leucine amide: 228 mg (0.33 mmol) of the compound of Example 1 was dissolved in a flask containing 12 ml of acetone, and then 2 ml of a 2N aqueous solution of HCl was added dropwise at 20 ° C, and stirring was maintained for 6 hours and 30 minutes. The reaction vehicle was then concentrated to dryness and the residue was purified by chromatography on silica gel column chromatography (eluent: ethyl acetate / heptane 9). 49 mg of a yellow solid was obtained in a yield of 22%, m.p. The compounds of Examples 3 to 6 were prepared according to the same protocol as described in Example 1, starting from intermediates 1.4, 1.6 and 1.10 and a suitable commercially available protected amino acid. Example 3: N-(10H-Lymphidin-2-ylcarbonyl)glycine indenylmethoxytetrahydrofuran-3-yl]-L-leucine decylamine: yellow solid. Example 4: N-(10H-Lymphidin-2-ylcarbonyl)leucine--:^-[(33)-2-methoxytetrahydrofuran-3-yl]-L-leucine decylamine : -35- 1342311 Yellow solid 'Pet point: l80_180 5 〇c. Example 5: [(Benzyloxy)carbonyl]_N2_(1〇H_phthylthiophene-2-ylcarbonyl) lysyl methoxytetrahydrofuran-buquib leucine amide: yellow solid, melting point : 102-1031. EXAMPLES: i-dOH-Phenylthiazol-2-ylcarbonyl)-L-prolinyl-NMOS)-2-methoxytetrahydrofuran-3-yl b-L-leucine decylamine: yellow solid Training point: 243-243.5 1:. Example 7 '8, 9 and 1 oxime compounds were prepared according to the experimental procedure described for the compound of Example 2, starting from the compounds of Examples 3, 4, 5 and 6, respectively. Example 7: N-(i〇H-Phenothione-2-ylcarbonyl)glycidyl-;^-[(35)-2-hydroxytetrahydrofuran-3-yl]-L-leucine decylamine : Yellow solid 'melting point: 126-126.5. (: Example 8: Ν-(1〇Η-Phenothione-2-ylcarbonyl) leucine-Ni-[(3S)-2-hydroxytetrahydrofuran-3-yl]-L- leucine bismuth Amine: yellow-green solid, m.p.: 144 - 144.5. (:. Example 9: N6-[(benzyloxy)carbonyl]_n2_(10H_phthylthiophene-2-ylcarbonyl) lysyl group-!^- [(38)-2-Hydroxytetrahydrofuran-3-yl]-L-leucine decylamine: yellow solid, m.p.: 109 - 109.5 ° C. Example 1 〇: 1-U0H- thiophene-2-yl Carbonyl)-1^_valine-amino-1^-[(3 3)-2-hydroxytetrahydrofuran-3-yl]-L- leucine decylamine: pale yellow solid, m.p.: 144.5- 145. Example 1 1 : N-(l〇H-morphothion-2-ylcarbonyl)leucine-based-[(35)-2-(ethyloxy)tetrahydrofuran-3-yl]-L - leucine amide: -36- 1342311

Add 0.62 «1 丨 (10 ^.) of acetic anhydride and 40 | ^ (0.569,) of 4-dimethylaminopyridine to 366 mg (0.66 mmol) of the compound of Example 8 in 6 ml of dichloromethane, The mixture was stirred at 20 ° C for 4 hours, then diluted with 20 ml of dichloromethane and 20 ml of saturated NaHCO 3 solution. After stirring and pouring, the organic phase was washed with 20 ml of brine, then the organic solution was dried over sodium sulfate, filtered and evaporated. Concentrate to dryness and evaporate the residue on a silica gel column (washing solution: heptane / AcOEt: 4/6 to 0/1). The pure fractions were collected and concentrated in vacuo and crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -1 2 2 °C. Example 12: N2-(10H-morpholino-2-ylcarbonyl)-amino acid group -NMnS)"-hydroxytetrahydrofuran-3-yl]-L-leucine guanamine trifluoroacetic acid

0.5 g (0.7 mmole) of the compound of Example 9 was dissolved in 5 ml of acetic acid, cooled using an ice bath, 5 ml of a 33% aqueous solution of HBr was added dropwise, and stirred at 2 ° C for 4 hours, then the reaction mixture was concentrated to dryness. The residue was purified by preparative HPLC using EtOAc (EtOAc:EtOAc:EtOAc: After lyophilization, 100 mg of a gray ash solid was obtained in a yield of 21%. Example 13: N-(10H-Phenothione-2-ylethylindenyl)-leucine-based-(^-[(33)-2-methoxytetrahydrofuran-3-yl]-L-white Amidoxime: 13.1) 2-(2-oxin-4-yl-2-thioethyl)-1〇Η-morphothelazole: The experimental procedure for the preparation of this intermediate is subject to the German patent application DE 2 7 02 714 The revelation of the synthesis. 24.13g (0.1m〇l) of 2-ethenyl thiopyridinium, -37- 1342311 5.13g (1.6eq.) of sulfur and 39ml (4.5eq.) of morpholine were introduced into a thermometer, a condenser and The gas discharge port was continuously immersed in a three-necked flask of a 2N soda valve and a potassium permanganate concentrated solution valve. The reaction mixture was heated to reflux (internal temperature = 1 19 ° C) for 15 hours. After cooling, the brown solution was poured and stirred to 300 ml of absolute alcohol. The mixture was stored at 4 ° C for 1 hour to effect initial crystallization, then at -1 8 ° C overnight, after which the obtained solid was filtered and washed with cold ethanol and heptane, and after drying, 27 g of orange was obtained in 79% yield. solid. 13.2) 10H-Phenylthiazide-2-ylacetic acid: 31.23 g (91.2 mmol) of intermediate 13. Brake 36 g (6 eq.) of 85% potassium base and 350 ml of absolute ethanol were introduced into the three-necked flask previously described. . The reaction mixture was heated to reflux for 15 hours. After cooling, the mixture was concentrated in vacuo to half of its volume, then poured into 650 ml of water, and concentrated sulfuric acid was added to pH 1 with stirring, and then the mixture was brought to 80. After heating at ° C for 2 hours, the mixture was cooled, and the precipitate was filtered and washed 4 times with 40 ml of water. The solid thus obtained was dissolved in acetone and filtered to remove insoluble solids, and then the filtrate was concentrated to dryness in vacuo to give a pale yellow powder (15.67 g). C. 13.3) N-(10H-morphine-2-ylethylindenyl)-L-leucine methoxytetrahydrofuran-3-yl]-L-leucine guanamine is used in the same manner as in Example 1 Step 1. The experimental procedure described in 1:1, starting from intermediates 1.6 and 13·2, gave a tan solid, m.p.: 216-216.5. (: Example 14: 0-(Tertiary butyl)-N-(10H-phutthiam-2-ylethyl fluorenyl)-L-serine group-:^-[(33)-2- Methoxytetrahydrofuran-3-yl]-L-leucine decylamine: -38- 1342311 14.1) 〇-(t-butyl)-L-serine group-1^-[(35)-2 - Methoxytetrahydrofuran-3-yl]-L-leucine decylamine: The intermediate was prepared according to the intermediate steps 1.5 and 1.6. The intermediate was prepared from the intermediate 1-4 and the commercial Cbz-L-sodium amine. Starting with acid (tBu), a colorless oil was obtained. 14.2) 0-(Tertiary butyl)-N-(10H-morphin-2-ylethenyl)-L-serinyl---[(33)-2-methoxytetrahydrohydrate喃-3-yl]-L- leucine guanamine: using the same experimental procedure as described in Step 1.1.1 of Example 1, starting from intermediates 14.1 and 13.2, white solid, melting point: 179-180° C. Example 15: N-(10H-Phenothione-2-ylethylindenyl)-L-alanine-3-cyclohexyl-NM(3S)-2-methoxytetrahydrofuran-3-yl]-L - Amidyl propylamine: 15.1) 3-Cyclohexyl-Nl-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-alanine decylamine: This intermediate was prepared according to the procedure 1.1 to 1.4 of Example 1. Starting from (S)-2-amino-4-butyrolactone hydrobromide and commercial Cbz-3-cyclohexyl-L-alanine, a colorless oil was obtained. 15.2) L-alanine-3-cyclohexyl-1^-[(35)-2-methoxytetrahydrofuran-3-yl]-L-alanine decylamine: the same according to the synthesis of intermediates 1.5 and 1.6 Experimental Procedure This intermediate was synthesized in 2 steps starting from intermediate 15.1 and Cbz-L-alanine. 15.3) N-(10H-Brothidin-2-ylethyl)-L-alanine-3-cyclohexyl-heart-[(3 5)-2-methoxytetrahydrofuran-3-yl]- 1 丙 丙 丙 : : : : : : : : : : : 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 -39- 1342311 According to the experimental plan described in Example 2, the preparation of Examples 1, 6 and 18 compounds 'started from Examples 13, 3 and 14 respectively. Example 16: Ν-(1〇Η-Phenyl-2-ylethylidene)-L-leucine-NMUS)-2·Perfluorotetrahydrofuran-3·yl]-L- leucine Amine: Grayish brown solid, m.p.: 168-168.5. (: Example 17: 〇-(t-butyl)-N-(10H-morphin-2-ylethyl)-L-serinyl-N 1 [(3 S )- 2 - Hydroxytetrahydrofuran-3-yl]-L- leucine decylamine: pale gray-brown solid, m.p.: 1 3 5 - 1 3 6 t. Example 18: N-(l〇H-ph- thiophene-2-yl Ethyl)-L-alaninyl-3-cyclohexyl-p-[(35)-2-hydroxytetrahydrofuran-3-yl]-L-alanine decylamine: white solid, m.p.: 215-217. Example 19: Ν·[3-(1〇Η-Phenothione-2-yl)propanyl]-L-leucine methoxytetrahydrofuran-3-yl]-L-leucine decylamine : 19.1) 10 -Ethyl-10H-morphine trap: After 20 g (0.1 m〇l) of the morphine trap, I4.3 ml (2 eq) of ethyl chloride was added to a 500 ml flask containing 200 ml of toluene. The heterologous reaction mixture was stirred at 50 ° C for 1 hour, concentrated to dryness, and the precipitate was taken up in a small amount of isopentane and filtered, and dried to give a quantitative yield of 24 g of a beige solid, melting point: 2 1 0 - 2 1 1 〇C. 19.2) 1-(10-Ethyl-10H-morphothi-2-yl)propan-1-one: 150 ml of CS2 was introduced into a mechanical stirrer, argon-filled, multi-necked flask Condensation Additional flask and the flask, followed by addition of 24g of Intermediate 19.1. 10.4 ml (1.2 eq.) of propyl chlorohydrin was added dropwise to a vigorously stirred suspension of -40-1342311. A portion of 50 g (4 eq.) of A1C13 was then added, using a solid additional funnel. Rinse the funnel immediately with an additional 50 ml of CS2. While stirring vigorously, the mixture was heated at 55 ° C for 2 hours, then the mixture was cooled in an ice bath and CS 2 was removed using a catheter. The reaction mixture was initially hydrolyzed by slowly adding a small amount of ice and reacted less vigorously when hydrolyzed using cold water. The mixture was diluted with 300 ml of ethyl acetate and transferred to a sep. funnel. The organic solution was poured, washed twice with 100 ml of water and 100 ml of brine, dried over sodium sulfate, filtered and evaporated to dryness The residue obtained was honed in an alkane, then the solid was filtered and washed with a small amount of isopentane to obtain a yield of 45% of I3.2 g of white solid, melting point: 146.5-147 °C» 19.3) 3-(10H-Brown Thiazin-2-yl)propionic acid: using the same experimental procedure as described for the synthesis of these intermediates 13.1 and 13.2, 2 g of brown solid was obtained from 6 g of intermediate 19.2, 33% of total yield (2 steps), using this The compound (80% purity) was used in the following procedure. 19.4) Ν-[3·(10Η-morphothionate-2-yl)propanyl]-L-leucine-based-[(3 5)-2-methoxytetrahydrofuran-3-yl]- 1^-Acetylamine amide: This example was prepared according to the same synthetic procedure as described in Example 1. Step 1. Starting from intermediates 1.6 and 19.3, yellow solid, melting: 21 5-21 6 °C. Example 20: N-[3-(10H-morphinoth-2-yl)propanyl]-L-leucine--:^-[(35)-2-hydroxytetrahydrofuran-3-yl]- L-Leucinate decylamine: Starting from the same procedure as the compound of Example 2, starting from the compound of Example 19, pale brown solid, m.p.: 212-213. Example 21: N-[(10H-Phenylthiam-2-yloxy)ethenyl]-L-leucine-based-heart-1(35)-2-methoxytetrahydrofuran-3-yl] -1^- leucine decylamine: • 41- 1342311 21.1) 10H-morphic guanine-2-ol: heated at 1701 for 25g (109mm〇l) 2-methoxymorphine and 60g (4.8eq.) chlorine The mixture of the pyridine key was stirred for 15 hours, and after cooling to a temperature of about 80 ° C, the obtained brown solution was diluted with 200 ml of ethyl acetate. After the reaction mixture was poured into 200 ml of water, stirring was continued for 30 minutes, stirred and poured out. The organic phase was dried over sodium sulfate and concentrated in vacuo to dry. Recrystallization from 7 ml of boiling toluene gave a pale green solid. The insoluble solid was removed by filtration, and the filtrate was automatically crystallized overnight, and crystals were collected by filtration and washed with isopentane. After drying, 12.43 g of a gray solid was obtained in 53% yield, m.p.: 207-208. 2·2) tert-butyl (10H-morphothin-2-yloxy) acetate: lg (4.6 mmol) of intermediate 21.1 and 1.40 ml (2 eq·) of tert-butyl in a 100 ml flask Bromobromoacetate was dissolved in 25 m of THF, 1.93 g (3 eq.) of K2C03 was added to the solution and the reaction mixture was heated to reflux for 15 hours. After cooling, 50 m 1 of water and 5 0 m 1 of 2 were added. The organic phase was decanted, washed with 50 ml of water and 50 ml of brine, dried over sodium sulfate, filtered, and concentrated in vacuo, and the residue was purified on a silica gel column. Heptane (2/8). 940 mg of a cream solid was obtained in 70% yield. 21.3) (10H-Phenylthio-2-yloxy)acetic acid: 935 mg (2.8 mmol) of the intermediate 21.2 was dissolved in 9 ml of dichloromethane, and 2.19 ml (10 eq.) of trifluoroacetic acid was added dropwise. The mixture was cooled to 〇 ° C. At the end of the addition, the temperature was returned to 20 t and stirring was maintained for 3 hours, then the reaction mixture was concentrated to dryness in vacuo and the residue was diluted with 50 ml of ethyl acetate. The organic solution was washed twice with 25 ml of water, then washed with brine (25 ml - 42 - 1342311), dried over sodium sulfate, filtered, and concentrated on a rotary evaporator to yield 540 mg of y. -181 ° C. 21·4)Ν-[(10Η-Phenothione-2-yloxy)ethenyl]-L-leucine-NyOS)-]-methoxytetrahydrofuran-3-yl]-L-white Ammonium Amine: This example was prepared according to the same synthetic strategy as described in Step 1.U of Example 1, from Intermediates 1.6 and 21.3. Gray-brown solid, melting point: 21 1.5-212 ° C. The compounds of Examples 22 to 35 were prepared according to the same synthetic strategy as described for the compound of Example 1 and were initiated by intermediates 1.4, 21.3 and the appropriate commercially available protected amino acids. Example 22: Ν-[(1〇Η-Phenothione-2-yloxy)ethenyl]-glycine-yl-1--[(35)-2-methoxytetrahydrofuran_3_yl ] L_Linate amide: Grayish brown solid, melting point: 181-182. !:. Example 23: N-[(i〇H_phlethiat_2_yloxy)ethenyl]_L_alanine 4|-[(38)-2-methoxytetrahydrofuran-3-yl] _[_Acetylamine amide: white solid 'melting point: 195-1961. Example 24: N-[(] 〇h_morphothionioxy)ethinyl]_L_proline group -N^LPS). -Methoxytetrahydrofuran_3_yl]_L_ leucine amide: white solid ‘melting point: 24〇_241t:. Example 25: N-[(10H-Phenylthiazol-2-yloxy)ethenyl]-D-alanine base&gt;^-[(35)-2-methoxytetrahydrofuran-3•yl]L • leucine amide: brown solid 'melting point: 155-157. (3. Example 26: N-methyl-indole-[(1〇Η-morphindol-2-yloxy)ethylglycosyl-amino-N-[(3S)-2-methoxy Tetrahydrofuran-3yl]_L_ leucine decylamine: pale pink solid 'melting point: 9 2 - 9 5 ° C. -43- 1342311 Example 27: Ν-[(1〇Η-phthyridin-2- Ethyloxy)ethinyl]-D-proline-U3S)-2-methoxyhydrotetrahydrofuran·3·kib L-leucine decylamine: light gray-brown solid, melting point: 204-206 T: . Example 28: 3-Methyl-N-[(10H-Phenylthiopyridin-2-yloxy)ethenyl]-L-co-aminol-1--[(38)-2-methoxy Tetrahydrofuran-3-yl]-L-leucine decylamine: beige solid, m.p.: 1 52 - 1 53. (: Example 29: &gt;^-[(38)-2-methoxytetrahydrofuran-3-yl]-N2-((2S)-2-U(10H-morphothen-2-yloxy) )-Ethyl]amino} 醯 醯 ) 白 白 : : : : : : : : : : : 164 164 164 164 164 164 164 164 164 164 164 164 164 164 164 164 164 164 164 164 164 164 164 164 164 164 164 164 164 Ethyl hydrazide]-L-n-decylamino-NL[(3S)-2-methoxytetrahydrofuran-3.yl]-L- leucine decylamine: beige solid <melting point: 225-226. Example 31: N-[(l〇H-Phenyl-2-yloxy)ethinyl]-L-serinyl---[(35)-2-methoxytetrahydrofuran- 3_yl]-L- leucine decylamine: gray solid. Example 32: Ν·[(ι〇Η-morpholino-2-yloxy)ethenyl]-L-cylamine thiol- Ni-[(3S)-2-methoxytetrahydrofuran-3-yl]-L- leucine decylamine: pale yellow solid 'melting point: 92-93. (:. Example 33: &amp;-[(33 _2-methoxytetrahydrofuran-3-yl]-N2-((2S)-2-{[(iOH_phthylphen-2-yloxy)ethinyl]amino}-2-phenylethyl Mercapto)-L- leucine decylamine: pale yellow solid 'melting point: 2 1 5 - 2 1 7. (: -44- 1342311 Example 34: :^-[(35)-2 -methoxy Tetrahydrofuran-3-yl ]-N2-((2S)-2-{[(10H-Phenyl-4-yloxy)ethinyl]amino}8〇3丨-3-enyl)-L-leucine Guanidine: a pale pink solid. Example 35: 2-Methyl-N-[(10H-phrothiam-2-yloxy)ethenyl]alanine-&gt;^-[(35)- 2-Methoxytetrahydrofuran-3-yl]-L-leucine decylamine: pale pink solid, m.p.: 1 19-12 (TC). Example 36: N-[(10H - thiophene-2- Ethyloxy)glycolyl]-glycine

Methoxytetrahydrofuran-3-yl]-L-proline decylamine: 36.1) 1^-[(35)-2-methoxytetrahydrofuran-3-yl]-L-proline amide: according to the implementation The experimental procedure described in Steps 1.1 to 1.4 of Example 1 was carried out in 4 steps using (S)-2-amino-4-butyrolactone hydrobromide and Cbz-L-proline. A colorless oil was obtained. 36.2) N-[(10H-Phenothione-2-yloxy)ethenyl]-glycine-yl-&gt;^-[(35)-2-methoxytetrahydrofuran-3-yl]-L - valine amide amine: The experimental procedure described in steps 1.5, 1.6 and 1.11 of Example 1 was carried out in 3 steps using Cbz-glycine and intermediates 36.1 and 21.3 to give a brown solid. Example 37: N-[(10H-Phenyloxy-2-yloxy)ethinyl]-glycine-yl-3-cyclohexyl-1^-[(35)-2-methoxytetrahydrofuran- 3-yl]-L-alanine decylamine: Using Cbz-glycine and intermediates 15.1 and 2丨_3, using the same synthetic strategy as described in Example 6.2, step 6.2, to obtain a pale pink solid' Melting point: 1 7 9 - 1 8 0. (: ° -45 - 1342311 Example 38: N-[(10H-Phenyl-2-yloxy)ethinyl-glycine-N-[(3S)-2-methoxytetrahydrofuran- 3-yl]-L-phenylalanine decylamine: 38.1) N-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-phenylalanine decylamine: according to Example 1. Step 1 · 1 to 1 · 4 The experimental procedure was carried out in 4 steps to prepare the intermediate ' using (S)-2-amino-4-butyrolactone hydrobromide and Cbz-L-phenylalanine. Yellow oil. 38.2) Ν-[(1〇Η-morphines-2-yloxy)ethinyl]-glycine-yl-N-[(3S)-2-methoxytetrahydrofuran-3-yl]-L -Phenylalanine decylamine: Using Cbz-glycine and intermediates 38.1 and 21.3, identical to the synthesis strategy described in Example 36, step 36.2, to give a brown solid, m.p. Example 39: N-[(10H-Phenylthiam-2-yloxy)ethinyl]glycidyl-N2-isobutyl-N^tOS)-2-methoxytetrahydrofuran-3-yl ]Glyceramide: 39.1) N2-isobutyl-1^-[(33)-2-methoxytetrahydrofuran-3-yl]glycine amide: according to steps 1.1 to 1.4 of Example 1. Experimental Procedure 4 The intermediate was prepared using (s)-2-amino-4-butyrolactone hydrobromide and Boc-N-isobutylglycine (J. Med. Chem. (2000), 43 (15), 2805-28 13), obtained a colorless oil. 39.2) N-[(10H-Phenyl-2-methyloxy)ethinyl]glycidyl-N2-isobutyl-1^-[(33)-2-methoxytetrahydrofuran-3- Glycolate: The same synthetic strategy as described in Example 36.2 was used, using Cbz-glycine and an intermediate. The compounds of Examples 40 to 58 were started according to the experimental procedures described in the compound of Example 2, starting from the compounds of Examples 21 to 39, respectively. -46- 1342311 Example 4〇: N-[(10H-Phenyl-4-yloxy)ethinyl]-L-leucine-NMpS)-2-hydroxytetrahydrofuran-3-yl]- L-Acetylamine: Light grayish brown solid, melting point: 141.5-142 °C. Example 41: N-[(10H-Phenothione-2-yloxy)ethenyl]-glycine hydrazino-&gt;^-[(35)-2-hydroxytetrahydrofuran-3-yl]- L-leucine decylamine: light pink solid, melting point: 1 8 4 - 1 8 6. (: Example 42: Ν-[(1〇Η-Phenyl-2-yloxy)ethinyl]-L-alanine 蕋-heart-[(35)-2-hydroxytetrahydrofuran -3_yl]_L_ leucine decylamine: a beige solid, m.p.: 1 4 4 - 1 4 6 t:. Example 43: N-[(l〇H-ph-thiophen-2-yloxy) Ethyl)-L-proline-NMPS)-2-hydroxytetrahydrofuran-3-yl]-L- leucine decylamine: white solid, m.p.: 205-206 °C. Example 44: NL(l〇H-morphothion-2-yloxy)ethinyl]-P-alanine^^[(38)-2-hydroxytetrahydrofuran-buquib lysine Amine: Light pink solid, melting point: 1 6 1 -1 6 2 . (: Example 45: N-methyl-N_[(1〇H_morphindol-2-yloxy)ethyl)glycidyl-nI_L(3S)-2-hydroxytetrahydrofuran-3- ]]-L- leucine decylamine: pale gray-brown solid 'melting point: 137-138. (:. Example 40: N-[(i0H_morphin-2-yloxy)ethinyl]_D - 缬 酸 - - - - - - - - - - - - - - - - - - - - - - _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ N_[(1〇H-morphothion-2-yloxy)ethenyl b-L-leucine-N1·[(3 S )-2-hydroxytetrahydrofuran-3-yl]-L-leucine Guanidine: White solid 'melting point: 1 5 7 - 1 5 9 (: -47- 1342311 Example 48: Taking -[(33)-2-hydroxytetrahydrofuran-3-yl]-N2-((2S -2{[(l〇H-Brothidene-2-yloxy)ethinyl]amino}butanyl)-L-leucine decylamine: gray-brown solid. Melting point: 160-161 °C Example 49: Ν-[(1〇Η-Phenothione-2-yloxy)ethenyl]-L-n-decylamino-N Μ (3 S)-2·hydroxytetrahydrofuran_3_ Base]_L·Acetylamine leucine: Grayish brown solid, m.p.: 195-196 ° C. Example 50: Ν-[(1〇Η-phthylphen-2-yloxy)acetamidine ]-L-Lesylamino-N1-[(3S)-2-hydroxytetrahydrofuran-3.yl]-L·Acetylamine amide: Gray solid, m.p.: 1 2 8 - 1 30 ° C. Example 51: Ν_[(1〇Η-Phenothione-2-yloxy)ethenyl]-L-succinylamino 41-[(38)-2-hydroxytetrahydrofuran-3-yl]-1 ^Acetylamine amide · White solid, melting point: 195-1961: Example 52: N, [(3S)-2-hydroxytetrahydrofuran-3-yl]-&gt;12-((25)-2 -{[(1〇^1_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ - 2 : : : : : : : 7 - 1 3 8 (: Example 53: -hydroxytetrahydrofuran-3-yl)-N2-((2S)-2-{[(丨0H_phthymphidin-2-yloxy)_acetamidine Amino]((indol-3-ylindenyl)-L- leucine decylamine: pale pink solid, melting point: 1 5 9 - 1 6 1 t: Example 54: 2 -Methyl-N - [(10H-Phenothione-2-yloxy)ethinyl]alanine-1^-[(33)-2-hydroxytetrahydrofuran-3_yl]_^ leucine amide: beige Solid 'melting point: 138-140 °C. -48- 1342311 Example 55: n_[(1〇H-Phenyl-2-yloxy)ethinyl]glycidyl]N-[(3S)·2-Pheptyltetrahydrofuran-3_yl ]_L_Glutamine: Light grayish brown solid, melting point: 2 〇〇 _ 2 0 1 °C. Example 56: N-[(10H-Phenylindole-2-yloxy)ethenyl]glycidyl-3-cyclohexyl-1^-[(35)-2-hydroxytetrahydrofuran-3_ Base]-L_Alanine decylamine: Light pink solid 'melting point: 2丨2 _ 2丨5芄. Example 57: ^[(1〇!1-Phenylthiazol-2-yloxy)ethenyl]glycidyl-&gt;^-[(33)-2-hydroxytetrahydrofuran-3_yl]_1 _Phenylalanine decylamine: light yellow solid, melting point: 2 0 7 - 2 0 8. (:. Example 58: Ν·[(1〇Η·Phenothione-2-yloxy)ethinyl]glycidyl-N'tOS)-]-hydroxytetrahydrofuran-3_yl]_Ν2- Isobutylglycine decylamine: pink solid, melting point: 1 22-1 24. (:. Example 59: N-[2-methyl-2-(10H-physino-2-yloxy)propanyl]glycine---^-[(33)_2-methoxy Tetrahydrofuran-3-yl]-L-leucine decylamine: 59.1) tert-butyl 2-methyl-2-(10H-morphothion-2-yloxy)propionate 1.93 g (3 eq .) K2C03 was added to a solution of lg (4.6 mmol) of intermediate 21.1 in 10 ml of DMF, and the reaction mixture was heated to 60 ° C before adding 1.73 ml (2 eq.) of tert-butyl 2-bromoisobutyrate. The mixture was allowed to reach ll ° ° C and maintained at this temperature for 6 hours. After returning to 20 ° C, the mixture was poured into 1 ml of water and the product was extracted twice with 100 ml of ethyl acetate. The organic solution was washed with EtOAc (EtOAc m. The evaporation residue was purified on a silica gel column eluting with ethyl acetate &lt;RTI ID=0.0&gt;&gt; 45 0 mg of a pale pink solid was obtained in 28% yield, m.p.: 1 3 - 1 40 T:. 59.2) 2-Methyl-2-(10H-Phenylthiam-2-yloxy)propanoic acid: The intermediate step 21.2 was replaced with the intermediate 5 9 · 1 using the same experimental procedure as the intermediate 2 1 · 3 Obtaining 254 mg of a purple solid in a yield of 67%, melting point: 1 7 7 - 1 8 0 〇C ° 59.3) Ν-[2·methyl-2-(10H-morphothion-2-yloxy)propanthene Glycosyl-glycine-heart-[(3 3)-2-methoxytetrahydrofuran-3-yl]-L-leucine guanamine: The synthesis strategy was synthesized using the same Example 22 compound using glycine Mercapto-?^-[(33)-2-methoxytetrahydrofuran-3-yl]-L- leucine decylamine (prepared by a similar method of intermediate 1.6) and intermediate 5 9 · 2, light Yellow solid, melting point: 1 00- 1 04. . ° Example 60: N-[2-methyl-2-(10H-Phenylthio-2-yloxy)propanyl]glycidyl-1^-[(35)-2-hydroxytetrahydrofuran- 3-yl]-L- leucine decylamine: This experimental procedure was identical to the compound of Example 2, starting with the compound of Example 59 in place of the compound of Example 1 to give a beige solid, m.p. 28〇C ° Example 61 ··Ga-5H-dibenzo[b,f]azhen-3-ylidene)-L-lysine methoxytetrahydrofuran-3_yl]_L-白amine Acid amide: 61.1) 5-Ethyl-10,11-dihydro-5H-dibenzo[b,f]azepin-3-carboxylic acid: The same experimental scheme was synthesized using the same intermediate 1.1. Use 1 _(5 _ acetamino-10,11-dihydro-511-dibenzo[1),1*]azepine-3-yl)ethanone (](:1^111. -50- 1342311

Soc. 1 973, 859-863) As a starting product, a pale yellow solid (yield: 189-189.5). (3. 61.2) 10,11-Dihydro-5H-dibenzo[b,f]azep-3-carboxylic acid:

A mixture of 3.06 g (10.88 mmol) of intermediate 61.1 and 3 g (45 mmol) of KOH in 35 ml of ethanol was heated to reflux for 15 hours, and after cooling to 〇 ° C, the reaction medium was acidified to pH = 1 using 2N HCl. The mixture was extracted with EtOAc then EtOAc (EtOAc)EtOAc. Mass spectrometry indicated 20% of the expected compound and 7 % by weight of the oxiranylation product (intermediate 61.1), using this mixture in the following procedure: 61. 3) Ν-(10,11-dihydro-5H-dibenzo [b,f]azet-3-ylcarbonyl)-L-leucine-l^-[(33)-2-methoxytetrahydrofuran-3-yl]-L-leucine amide: basis The same procedure as described in the synthesis of the compound of Example 1 was used to prepare this compound using intermediates 1.6 and 6 1.2 as starting materials. Example 62: N-(10,l 1-dihydro-5H-dibenzo[b,f]azhen-3-yl forging)-L-leucine-1--[(33)- 2-Hydroxytetrahydrofuran-3-yl]-L-leucine decylamine = This experimental procedure was identical to that of the compound of Example 2, using the compound of Example 6 as the starting material' to obtain a pale gray-brown solid, melting point: 142-143t. Example 63: N-[(5·Ethyl-indenyl, 丨1-dihydro-5H-dibenzo[b,f]azhen-3-yl)carbonyl]-L-leucine- &amp;-[(35)-2-Methoxytetrahydrofuran_3_yl]-L-leucine amide: This compound was prepared according to the same synthetic strategy as described for the compound of Example 1, using intermediates 1.6 and 61.1 as a starting point. material. -5 1- 1342311 Example 64: 2-Methyl-N-[(10H-cyanosin-2-yloxy)ethenyl]alanine---[(38)-2-hydroxytetrahydrofuran- 3-yl]-L- leucine amide: This experimental procedure was identical to that described in Example 2, substituting the compound of Example 163 for the compound of Example 1 to give a white solid, m.p.: 16 6 - 1 6 7 ° c. Example 65: N-[(3S)-2-methoxytetrahydrofuran-3-yl]-4-methyl-2-(3-{[(10H-morphothion-2-yloxy)acetamidine (amino) propyl) amylamine: 65.1) tert-butyl 2-(diethoxyphosphonyl)-4·methylvalerate): 1.74 g (43.61 mmol) of one part 60% NaH was added to 10 g (39.64 mmol) of tert-butyl(diethoxyphosphonyl) acetate (J. Amer. Chem. Soc. (1987), 109 (15), 4755-6) in 14 ml of anhydrous DMF. In the solution, cool to -10 °C. Before adding 4.48 ml (41.23 mmol) of isobutyl bromide dropwise, the reaction mixture was stirred at -10 ° C for 35 minutes, maintained at 20 ° C for another 15 hours, and the resulting precipitate was filtered and washed with a minimum amount of DMF. The filtrate was concentrated in vacuo to dryness. EtOAc was evaporated. mjjjjjjjjjjjjjjj The material was purified by chromatography on a silica gel column (eluent: ethyl acetate / heptane: 1/1). A very colorless colorless oil was obtained with a yield of 46%. 65.2) Tert-butyl(2Z)-5-([(benzyloxy)carbonyl]amino}-2-isobutylpent-2-enoate: 0.73 g (18.26 mmol) of one part 60 %NaH was added to 5.63 g (18.26 mmol) of intermediate 65.1 in 40 ml of anhydrous 1,2-dimethoxyethane solution, cooled to 0 ° C. Then 3.78 g (18.26 mm 〇l) benzyl was added dropwise. The 3-ketopropylamine carbamate was previously stirred at 20 ° C for 1 - 52 - 1342311 hours (J. Med. Chem. (2002), 45 (23), 5098 - 5 1 1 1 ) - Diluted with 20 ml of anhydrous 1,2-dimethoxyethane. After stirring at 20 ° C for 30 minutes, the mixture was evaporated to dryness in vacuo and the residue was partitioned between 150 ml of ethyl acetate and 100 ml of NaHC03 saturated solution. After pouring, the organic phase was washed successively with 50 ml of brine, 50 ml of a 1 M solution of KHS04 and finally 50 ml of brine, dried over sodium sulfate, filtered and concentrated in vacuo, and the oily residue was chromatographed on a silica gel column. (washing solution: heptane / ethyl acetate: 8 0/20). A colorless oil was obtained in 44% yield. 65.3) (2Z)-5-{[(benzyloxy)carbonyl]amino}-2- Isobutylpent-2-enoic acid: Intermediate 65.2 (100 mg; 0.28 mmol) It was dissolved in 1 ml of anhydrous methylene chloride, and the solution was cooled to 0 ° C before adding 〇. 2 ml (2.8 mm 〇l) of trifluoroacetic acid. Stirring was continued for 3 hours and 30 minutes at 20 ° C, and then the reaction mixture was diluted with 20 ml of dichloromethane and 1 ml of water. After stirring and pouring, the organic phase was washed with EtOAc EtOAc EtOAc EtOAc EtOAc 7 1 °C. 65.4) Benzyl (3Z)-4-({[(3S)-2-methoxytetrahydrofuran-3-yl]amino}carbonyl)-6-methylhept-3-enylaminecarboxylate: Intermediate 65.3 and (S)-2-amino-4-butyrolactone hydrobromide salt were synthesized according to intermediate 1.3. The intermediate step was prepared in 3 steps and purified on a silica gel column (washing solution, Heptane / ethyl acetate: 70 / 30 to 60 / 40) ' Obtained 41 mg of a colorless oil. 65.5) 2-(3-Aminopropyl)-N-[(3S)-2-methoxytetrahydrofuran-3-yl]-4-methylpentamidine: -53- 1342311 40 mg of 10% Pd/C 404 mg (1 mmol) of the intermediate 65.4 was hydrogenated (2 bar) in 20 ml of ethanol for 3 hours. The catalyst was filtered and concentrated in vacuo to dryness. Oily.

65.6) N-[(3S)-2-Methoxytetrahydrofuran-3-yl]-4-methyl-2-(3-{[(10H-morphothiono 2-yloxy)ethenyl]amine Base propyl) pentamidine: The experimental procedure used was the same as in Example 1, step 1.1.1, using intermediates 65.5 and 21.3 as starting reagents, and purifying the product on a ruthenium tube column (washing solution: g Alkyl/ethyl acetate: 20/80 to 0/100%, mp. Example 66: N-[(3S)-2-Hydroxytetrahydrofuran-3-yl]-4-methyl-2-(3-{[(10H-morpholino-2-yloxy)ethenyl] Amino}propyl)pentanylamine: This procedure was identical to that described in Example 2, substituting the compound of Example 65 for the compound of Example 1 to afford a white solid, 44% yield, m. . . Example 67: N-(10H-Phenyl oxime-2-ylcarbonyl)-L-leucine--:^-[(33)-2-methoxytetrahydrofuran-3-yl]-L-leamine The acid amide: The experimental procedure used is the same as the intermediate 1. The synthesis is carried out starting with 10H-Brownin-2-carboxylic acid (J. Org. Chem. 1 960, 25, 747 -7 5 3) and L-leucine methoxytetrahydrofuran-3-yl]-L-leucine decylamine (intermediate 1. 6). The concentrated product was chromatographed on a silica gel column (eluent: heptane / ethyl acetate: 3/7) to afford a brown solid of &lt;RTI ID=0.0&gt;&gt; -54- 1342311 Example 68: N-(l〇H-peptidin-2-ylcarbonyl)-L-leucine--^-[(35)-2-trans-tetrahydrofuran·3·yl ]-L - leucine amine: This experimental procedure was identical to that described in Example 2, substituting the compound of Example 67 for the compound of Example 1 to give a pale yellow solid, m.p. 1 45〇C. Pharmacological study of the compound of the present invention: effect on human calcineurin I. This test consists of measuring enzyme activity (enzyme purified from human red blood cells). It is cultured in the presence of a binding fluorescent dye (amino group). - methyl dye, AMC) and calcium peptide receptor buffer, this enzyme is activated by calcium to decompose the substrate and release the AMC fragment. The AMC released at 380 nm excitation emits fluorescence at 4 60 nm. Therefore, the activity of this enzyme is proportional to the amount of fluorescence, that is, the free 八1^40 fragment. Use a porous fluorimeter (\^(^〇『2,\¥3113〇) to measure Dengguang (380/460 // m). Perform this test in a 96-well microplate with a transparent bottom layer and black holes. One well was placed in each well to determine the substrate, and in 1% DMSO, the 45/1 reaction mixture contained human calcium activin I at 2.2 U/ml (Calbiochem, ref: 2087 1 3) &gt; Sue Leu Tyr-AMC receptor (Bachem, ref: 1-1355) in 1.1 mM buffer (110 mM Tris-HCl; 110 mM NaCl; 2.2 mM EDTA; 2.2 mM EGTA; 1.1 mM hydrazine ethanol). Add 45 &quot;1 of 22 mM CaCl2. To determine background noise, add calcium-free control wells to a flat plate (1 0 // 110% DMSO + 45y 1 enzyme-containing buffer and substrate + 45μ 1 H20) In order to determine the total activity of the enzyme, the control-free wells of the product-free were added to the flat plate (1 〇# 1 1 〇% -55-1342311 DMSO + 45 μl of the enzyme-containing buffer and the substrate +45 μl of 22 mM CaCl2) Repeat the concentration of each well of the test product (〇' InM to 10 μ Μ), shake the plate and incubate in the dark at 25 °C for 1 hour, read at 380/460 nm using a fluorometer. Fluorescent oximes. Compounds of Examples 2, 7 to 12, 16 to 18, 20, 40 to 53, 55 to 57, 60, 62 and 64 have an IC 5Q of less than or equal to 5 #M in this test. The in situ effect of calcinein activity in rat (C6) glial cells was inoculated into 96-well plates in 25,000 cells of C6 glial cells per well in DMEM 10% FBS. The next day, the attached cells were washed 3 times in serum-free and 40 mM Hepes DMEM medium. 100 μl of calcium activin inhibitor was placed in the well and incubated at 37 ° C 5% CO 2 atmosphere. After the hour, in order to obtain a final concentration of 1 00 β Μ and lnM per well, 10#1 containing fluorescin calcium activator substrate (Suc-Leu-Tyr-AMC) and scorpion toxin (maitotoxin) (Sigma) , ref : M-9 1 59). To determine the total activity of the cytogene, add the product-free well to the flat plate (1 00 // 1 DMSO 100th plus 10 1 MTX and substrate). Background noise is added Determined without the MTX control well, repeat the test for each concentration of inhibitors (0.01/z Μ to 100//M), shake the plate, use Victo r Fluorescent krypton was read at 380/460 nm of T0, and C6 cells were left in the dark at 30 ° C for 1 hour and 30 minutes. Examples 8' 9, 11, 16, 20, 40, 43 and 47 to 53 have IC5 少于 less than or equal to 1 〇 β 于此 in this test. -56- 1342311 Effect of lipid peroxidation on rat cerebral cortex The inhibitory activity of the product of the present invention is determined by measuring its effect on the degree of lipid peroxidation, measured by malonate dialdehyde (MDA) concentration, MDA produced from peroxidation of unsaturated fatty acids is a good indicator (H Esterbauer and KH Cheeseman, Meth. Enzymol. (1990), 186, 407-421). Male Sprague Dawley rats weighing 200 to 250 g (Charles River) via

Broken head sacrifice, remove the cerebral cortex, then use Thomas pottery in 20 mM Tris-HCl buffer, pH = 7.4. Centrifuge twice at 50,000g for 10 minutes at 4t and store the small nine at -80 °C. On the day of the experiment, the small nine pieces were placed in a suspension at a concentration of lg/15 ml and centrifuged at 515 g at 4 ° C for 10 minutes. The supernatant was immediately assayed for lipid peroxidation, and the rat cortical homogenate (500//1) was incubated at 37 ° C for 15 minutes with the test compound or solvent (1 〇 / / 1). The peroxidation reaction was initiated by the addition of 5 0 &quot; 1 mM FeCl2, 1 mM EDTA and 4 mM ascorbic acid, after incubation at 37 ° C for 30 minutes, via the addition of 50 μl of bis-tert-butylhydroxytoluene (BHT, 0.2%) The solution is terminated. The colorimetric test was used to quantify MDA, and the reaction chromogenic reagent (R), Ν-methyl-2-phenyl hydrazine (650/zl) contained 200//1 homogenate at 45 ° C for 1 hour, containing 2 molecules. The condensation of MD A molecules of reagent R produces a stable chromophore,

The maximum absorption wavelength is equal to 586 nm (Caldwell et al., European I

Pharmacol. (1 99 5), 285, 203-206) ° Compounds of Examples 2, 7 to 9, 11, 12, 16, 17, 20, 40 to 45, 56, 57, 60 and 62 in this test Has an IC50 少于 less than or equal to 5//M. -57-

Claims (1)

1342311 No. 09 3 1 3 6 8 7 8 "Application" Ε Ε-------- | Novel derivative of 2-hydroxytetrahydrofuran and its medicine (as amended on December 29, 2010) X. Patent application scope : 1. A compound of the formula (I) Α~Χ—(AA)—N I Η Ο) where: A represents Base, where R1! ^2, R4, R5 and R6 independently represent a hydrogen atom, a halogen atom, a hydrazine H group, an alkyl group, an alkoxy group, a cyano group, a nitro group or a NR7R* group, and R7 and R8 independently represent a hydrogen atom, an alkyl group or _ c〇R9 group, R9 represents a hydrogen atom, an alkyl group or an alkoxy group, R3 represents a hydrogen atom, an alkyl group or a -c〇r1q group, R1() represents a hydrogen atom or an alkyl group or an alkoxy group, and W represents a bond Or - CHyCHy'-CHsCH-'-O-'-S-.-NR11-, wherein R11 represents a hydrogen atom or an alkyl group: X represents -CO-, -Y-CO-, -0-Y-C0 - or - NR12-Y-CO·, 1342311 4 γ represents an alkyl or haloalkyl group, R12 represents a hydrogen atom, an alkyl group or a -cor13 group, and R13 represents a hydrogen atom, an alkyl group, a haloalkyl group or an alkoxy group, When mentioned, it represents a natural amino acid, a natural amino acid with a reactive chemical functional side chain selected from a carboxylic acid, an amine, an alcohol or a thiol group, the side chain being an alkyl or aralkyl ester (for an acid) Protected by an alkyl group, an aralkyl carbamate, or an alkyl or aralkyl carboxamide (for an amine functional group), an alkyl or aralkyl ether or an alkyl or aralkyl group Thioether type or alkyl or aralkyl ester type (for alcohol and mercapto functional groups) protection, or the final formula is -NR14-(CH2)p-CR15R16-CO-type amino acid, where ρ represents 0 or 1, R14 represents a hydrogen atom or an alkyl group, R15 Represents a hydrogen atom or an alkyl group and R16 is a hydrogen atom, an alkyl group, a haloalkyl group, a phenyl 'cycloalkyl group, a cycloalkylalkyl group or an alkenyl group, or R15 and R16 form a carbon atom with 3 to 7 carbon atoms attached thereto A saturated carbon ring of an atom, -(AA)2-yl can also represent a carbonyl peptide of the formula -NR17-(CH2)3-CH(R18)-CO-, wherein R17 represents a hydrogen atom or an alkyl group and R18 represents hydrogen. Atom or alkyl; η represents 2 or 3; and finally R represents a hydrogen atom or an alkyl group or a -CO-R19 group, wherein R19 represents an alkyl group: or a salt of such a compound. 2. A compound of the formula (I) according to claim 1 wherein R15 and R16 of the amino acid of the formula -NR14-(CH2)P-RI5R16-CO- form 3 to 6 with the carbon atom to which it is attached A saturated carbon ring of carbon atoms. 3. A compound of the formula (I) according to claim 1 wherein: -2- 1342311 R1, R2, R4, R5 and R6 independently represent a hydrogen atom, a halogen atom or an alkyl group, an alkoxy group or an NR7R8 group; R3 represents a hydrogen atom, a methyl group or a -COR9 group, wherein R9 represents a methyl group or a third butoxy group; w represents a bond or -CH2-CH2-, -CH=CH-, -0- or -S-; X represents -C0·, -γ-co - or - O- Y-CO-; -(AA)n-containing independently selected from natural amino acids, 3-methylproline, n-decylamine, phenylglycine An amino acid composed of an acid, a vinyl glycine, and a 2-aminobutyric acid; η represents 2; and R represents a hydrogen atom or a methyl group; or a salt of the compound. 4. A compound of the formula (1) according to the scope of the patent application, wherein: R1, R2, R4, R5 and R6 independently represent a hydrogen atom or a methyl group; R3 represents a hydrogen atom or a methyl group; W represents or -S- X represents - Y- C0 -or- 0- Y- C0-; - (eight eight) „- stands for - (AAMjAA1)- 'where ΑΑ1 represents Leu and ΑΑ2 represents a natural amino acid selected from 3, methyl hydrazine An amino acid consisting of aminic acid, n-proline, phenylglycine, vinyl glycine, and 2-aminobutyric acid; R represents a hydrogen atom; or a salt of the compound. A compound of the formula (I), which is selected from the group consisting of the following compounds: 1342311 -N-(10H-phutthiam-2-ylcarbonyl)-L-leucine-L-leucine-NMOS -]-methoxytetrahydrofuran-3-yl]-L-leucine guanamine; -Ν-(10Η·phenothiazole-2-ylcarbonyl)-L-leucine-L-leucine -&gt;^-[(33)-2-hydroxytetrahydrofuran-3-yl]-[- leucine decylamine; -N-(10H-phithylthiam-2-ylcarbonyl)glycine thiol-"- [(33)-2-methoxytetrahydrofuran-3-yl]-L-leucine decylamine; -N-(10H-morphothion-2-ylcarbonyl) leucine methoxytetrahydrofuran-3 -基]-L- Amidoxime; -N6-[(benzyloxy)carbonyl]-N2-(10H-morphothion-2-ylcarbonyl)-amino acid-Ni-[(3S)-2-methoxytetrahydrofuran- 3-yl]-L-leucine decylamine; -1-(10H-morphothion-2-ylcarbonyl)-L-prolinyl-N,[(3S)-2-methoxytetrahydrofuran- 3-yl]-L-leucine decylamine; -N-(10H-morphothion-2-ylcarbonyl)glycine hydroxy hydroxytetrahydrofuran-3-yl]-L-leucine amide; -N -(10H-morphothion-2-ylcarbonyl)leucine-&gt;^-{(33)-2-hydroxytetrahydrofuran, 3-yl}-1^ leucine amide; -N6-{( Benzyloxy)carbonyl}-N2-(10H-phrolyl trap-2-ylcarbonyl)-amino acid group-:^-[(38)-2-hydroxytetrahydrofuran-3-yl]-L-leucine Amine; -1-U0H-morpholino-2-ylcarbonyl)-L-prolinyl-:^-[(33)-2-hydroxytetrahydrofuran-3-yl]-L-leucine amide; -N-(10H-Lymphidin-2-ylcarbonyl) leucine-based-[(33)-2-(ethyloxy)-tetrahydrofuran-3-yl]-L-leucine decylamine -N2-(10H-morpholino-2-ylcarbonyl)-amino acid-!^-[(38)-2-hydroxytetrahydrofuran-3-yl]-L-leucine amide; -4 * -N-(10H-morphin-2-ylethyl)-L-leucine--^-[(3 5)-2-methoxytetrahydrofuran-3-yl]-L-leucine decylamine; -〇-(t-butyl)-N-(10H-cyanosin-2-ylethyl)- L-Lesylamino-1^-[(33)-2-methoxytetrahydrofuran-3-yl]-L-leucine decylamine: -N-(10H-phrothiaphen-2-ylethyl hydrazine -L-alanine-3-cyclohexyl•&gt;^-[(3 5)-2-methoxytetrahydrofuran-3-yl]-L-alanine decylamine; -N-(10H-morphine Thiophene 2-ylethyl fluorenyl)-L-leucine--"-[(35)-2-hydroxytetrahydrofuran-3-yl]-L-leucine amide; -〇-(t-butyl -N-(10H-Phenothione-2-ylethylindenyl)-L-serminyl S)-2-hydroxytetrahydrofuran-3-yl]-L-leucine amide; -N-( 10H-morphin-2-ylethylindenyl)-L-alaninyl-3-cyclohexyl-:^-[(33)-2-hydroxytetrahydrofuran-3-yl]-L-alanine decylamine; -N-[3-(10H-Phenylthiazol-2-yl)propanyl]-L-leucine-yl-[(33)-2-methoxytetrahydrofuran-3-yl]-L - leucine decylamine; -N-[3-(10H-morphothion-2-yl)propanyl]-L-leucine-1--[(33)-2-hydroxytetrahydrofuran-3 -yl]-L-leucine guanamine; -N-K10H-morphothion-2-yloxy)ethinyl]-L-leucine-based-[(3 8)-2-A Oxygen four Hydrogenfuran-3-yl]-L-leucine guanamine; -N-[(10H-cyanosin-2-yloxy)ethenyl]-glycine-l--[(38 --2-methoxytetrahydrofuran-3-yl]-L-leucine decylamine; -N-[(10H-phthathiam-2-yloxy)ethinyl]-L-alanine- !^-[(38)-2-Methoxytetrahydrofuran-3-yl]-L-leucine decylamine; N-[(10H-morphothion-2-yloxy)ethenyl]-L -proline-yl-p-amine-[(38)-2-methoxytetrahydrofuran-3-yl]-L-leucine; 1342311 -Ν-[(1〇Η-phetidyl-2-yl) Oxy)ethinyl]-β-alaninyl-methoxytetrahydrofuran_3_yl]-L· leucine amide; -N-methyl-N-K10H-morphothel-2-yloxy Ethylamino]glycine-yl-1--[(38)-2-methoxytetrahydrofuran_3_yl b-L-leucine guanamine; N-[(10H-morphothelin-2 Benzyloxy)ethinyl]-D-proline-yl-&gt;^-[(38)-2-methoxytetrahydrofuran-3-yl]-L-leucine amide; -3 -methyl -Ν-[(1〇Η-Phenothione-2-yloxy)ethinyl]-L-proline methoxytetrahydrofuran-3-yl]-L· leucine amide; -N !-[(3S)-2-Methoxytetraaminopyran-3-yl]-&gt;12-((2 5)-2-{[(1〇11-morphine) -2-yloxy)-ethinyl]amino}butanyl)-L-leucine guanamine; -N-[(10H-cyanosin-2-yloxy)ethenyl]-L - Orthodecanoic acid-:^-[(35)-2-methoxytetrahydrofuran-3-yl]-L- leucine guanamine; -N-[(10H-phthathiam-2-yloxy) Ethyl]-L-serinate-!^-[(33)-2-methoxytetrahydrofuran-3-yl]-L-leucine amide; • N-[(10H-morphine -2-yloxy)ethinyl]-L-milamine-indenyl-^-[(33)-2-methoxytetrahydrofuran-3-yl]-L-leucine amide; ^^[(38 )-2-methoxytetrahydrofuran-3-yl]-N2-((2S)-2-{[(10H-morphothion-2-yloxy)ethinyl]amino}-2-phenylethyl醯-)-L-leucine amide; -N'-[(3S)-2-methoxytetrahydrofuran-3-yl]-N2-((2S)-2-{[(10H-morphine 2-yloxy)ethinyl]amino}butan-3-enylamino)-L-leucine guanamine; -2 -methyl-N-[(10H-morpholine-2-yloxy) Ethyl ethionyl]alanine---^-[(33)-2-methoxytetrahydrofuran-3-yl]-L-leucine amide; -Ν-[(10Η·啡噻耕-2 -yloxy)ethinyl]-glycine-yl-:^-[(33)-2-methoxytetrahydrofuran-3-yl]-L-valerate : -Ν-[(10Η-Phenyl-2-yloxy)ethinyl]-glycidyl-3-cyclohexylmethoxytetrahydrofuran-3-yl]-L-alanine decylamine; Ν-[(1〇Η-Phenyl-2-yloxy)ethinyl]-glycine-N-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-benzene丙 丙 ; ; Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ ; -Ν·[(1〇Η-Phenothione-2-yloxy)ethinyl]-L-lysyl-1--[(33)-2-hydroxytetrahydrofuran-3-yl]- L-Leucinate decylamine: -Ν-[(1〇Η-Phenothione-2-yloxy)ethenyl]-glycine indolyl-1^-[(33)-2-hydroxytetrahydrofuran- 3-yl]-L-leucine amide; -N-U10H-morpholino-2-yloxy)ethinyl]-L-alanine-based NMOS)-]-hydroxytetrahydrofuran-3-yl ]-L-Acetamine amide; -N-[(l〇H-morpholino-2-yloxy)ethenyl]-L-proline----[(33)-2- Hydroxytetrahydrofuran-3-yl]-L-leucine guanamine; -N-[(l〇H-morpholino-2-yloxy)ethenyl]-cold-alanine-^^-1 (38)-2-hydroxytetrahydrofuran-3-yl]-L-leucine guanamine '· • N-A _n-[(10H-Phenothione-2-yloxy)ethinyl]glycidyl-NMos)-]-hydroxytetrahydrofuran-3-yl]-L-leucine amide; -Ν-[ (1〇Η-Phenothione-2-yloxy)ethinyl]-D-proline hydroxytetrahydrofuran-3-yl]-L-leucine amide; 1342311 -3-methyl-N -[(10H-Phenylthiazol-2-yloxy)ethinyl]-L-proline--[^-[(38)-2-hydroxytetrahydrofuran-3-yl]-L-白amine Acid guanamine; -&gt;1丨-[(35)-2-hydroxytetrahydrofuran-3-yl]-N2-((2S)-2-{[(10H-morphothein 2-yloxy)acetamidine (amino) butyl hydrazide)-L- leucine decylamine; -N-U10H-morphine-t-butyl-2-yloxy)ethinyl]-L-n-decylamine-1^-[(35 -2-hydroxytetrahydrofuran-3-yl]-1^ leucine guanamine; -Ν-[(1〇Η-phthathiam-2-yloxy)ethenyl]-L-serinate -1^-[(38)-2-hydroxytetrahydrofuran-3-yl]-1^- leucine decylamine; -Ν-[(1〇Η-ph-thiophen-2-yloxy)ethenyl ]-L-Crustamine-yl-:^-[(3 3)-2-hydroxytetrahydrofuran-3-yl]-L-leucine guanamine; -1^-[(33)-2-hydroxytetrahydrofuran- 3-yl]-N2-((2S)-2-{[(10H-morphothionion 2-yloxy)ethenyl]amino}-2-phenylethenyl)-L- Indoleamine leucine; -N^tOS)-]-hydroxytetrahydrofuran-3-yl]-N2-((2S)-2-{[(10H-morphothen-2-yloxy)·ethinyl Amino}but-3-enylamino)-L-leucine amide; _· -2-methyl-N-[(10H-phthathiam-2-yloxy)ethenyl]propylamine Acid group-:^-[(33)-2-hydroxytetrahydrofuran-3-yl]-L-leucine decylamine; -N-[(10H-morpholino-2-yloxy)ethenyl] Glycosyl 41-[(35)-2-hydroxytetrahydrofuran-3-yl]-1^ decyl decylamine; -N-U10H-morpholino-2-yloxy)ethinyl]glycine Mercapto-3-cyclohexyl-&gt;^-[(3 5)-2-hydroxytetrahydrofuran-3-yl]-L-alanine decylamine; -N-[(10H-morphothion-2-yloxy) Ethylamino]glycine-N-[(3 S )-2-hydroxytetrahydrofuran-3-yl-L-phenylalanine decylamine; •N-U10H-morpholino-2-yloxy Ethyl)glycolyl]glycidyl-&gt;^-[(38)-2-hydroxytetrahydrofuran-3-yl]-N2-isobutylglycine decylamine; -Ν-[2·methyl- 2-(ι〇Η-phetathiam-2-yloxy)propanyl]glycidyl•1^-[(33)-2-methoxytetrahydrofuran-3-yl]-L-leucine醯 醯 amine; -N-[2-methyl-2-(1〇Η-phthathiam-2-yloxy)propanyl]glycine •&gt;^-[(33)-2-hydroxytetrahydrofuran-3-yl] leucine amide; -Ν·(10,11-dihydro-5H-dibenzo[b,f]azepine-3 -ylcarbonyl)-L-lysine-&gt;^-[(35)-2-methoxytetrahydrofuran-3-yl]-L-leucine amide; -N-(l〇,l 1 _Dihydro_5Η·dibenzo[b,f]azhen-3-ylcarbonyl)_L_leucine-1--[(38)-2-hydroxytetrahydrofuran-3-yl]-L-white Amidoxime; _&gt;^-[(5-Ethyl-1〇,11-dihydro-51^-dibenzo[13, guanidin-3-yl)carbonyl]-L-leucine Base-&gt;^-[(35)-2.methoxytetrahydrofuran-3-yl]-L-leucine decylamine; -2-methyl-N-[(10H-morphothel-2-yl) Oxy)ethinyl]alanine--^-[(35)-2-hydroxytetrahydrofuran-3-yl]-L-leucine amide; -N-[(3S)-2-methoxy Tetrahydrofuran-3-+-yl]-4-methyl-2-(3-{[(10H-morpholino-2-yloxy)ethenyl]amino}propyl)pentanylamine; -N- [(3S)-2-hydroxytetrahydrofuran-3-yl]-4-methyl-2-(3-{[(10H-morphothionion 2-yloxy)ethinyl]amino}propyl) pentyl Indoleamine; -N-(10H-peptone-2-ylcarbonyl)-L-leucine-1^4(38)-2-methoxytetrahydrofuran-3-yl]-L-leucine Guanamine -N-(10H-peptone-2-ylcarbonyl)-L-leucine-1^-[(33)-2-hydroxytetrahydrofuran-3-yl]-L-leucine decylamine: 1342311 Or a salt of such a compound. 6. The compound of the formula (1) or the pharmaceutically acceptable salt of the compound of the first aspect of the patent application is as a medicament. 7. A pharmaceutical composition comprising a compound of the formula (I) according to item 1 of the patent application as an active ingredient or a pharmaceutically acceptable salt of the compound and at least one pharmaceutically acceptable excipient. 8. The use of a compound of the formula (I) or a pharmaceutically acceptable salt of the compound of claim 1 for use in the preparation of a medicament intended to inhibit calcium-activated proteinase. 9. A use of a compound of the formula (1) or a pharmaceutically acceptable salt of the compound according to the first aspect of the invention, which is for the preparation of a medicament intended to inhibit lipid peroxidation. 1 . The use of a compound of the formula (I) or a pharmaceutically acceptable salt of the compound of claim 1 for the preparation of a medicament intended to inhibit calcium-activated proteinase and lipid peroxidation. 1 1. A use of a compound of the formula (I) or a pharmaceutically acceptable salt of the compound of claim 1 for the preparation of a medicament intended to treat a disorder or disease, wherein the disorder or disease is selected from inflammation and Immune diseases 'cardiovascular and cerebrovascular diseases, central or peripheral nervous system disorders, cachexia' osteoporosis, muscular dystrophy, proliferative diseases, cataracts, organ transplants and rejection after autoimmunity and viral diseases.