Derivatives of dolastatin 10

FIELD: organic chemistry of natural compounds, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): , wherein each R1, R2 and R3 means independently hydrogen atom or (C1-C4)-alkyl; R4 means (C1-C12)-alkyl optionally comprising from one to three substitutes chosen from group including hydroxy-group, (C1-C12)-alkoxycarbonyl, carbamoyl, (C2-C7)-alkenyl, (C6-C10)-aryl optionally comprising from one to three substitutes chosen from group including halogen atom, (C1-C12)-alkyl, (C1-C12)-alkoxy-, hydroxy-, (C1-C12)-alkylcarbonylamino-group, (C6-C10)-aryl-(C1-C12)-alkyl wherein aryl group comprises optionally from one to three substitutes chosen from group comprising halogen atom, (C1-C12)-alkyl, (C1-C12)-alkoxy-group, heterocyclyl-(C1-C12)-alkyl; R5 means hydroxy-, (C3-C7)-cycloalkylamino-group optionally substituted with phenyl, (C6-C10)-arylamino-, (C6-C10)-aryl-(C1-C4)-alkylamino-group optionally comprising from one to three substitutes chosen from group comprising sulfamoyl, (C1-C12)-alkyl, (C1-C12)-alkoxy-, hydroxy-group, heterocyclyl or benzyl, (C1-C4)-alkoxy-, benzhydrazino-group, heterocyclyl optionally comprising from one to three substitutes chosen from group including benzyl, benzhydryl, heterocyclylamino-group wherein heterocyclyl means saturated, unsaturated or aromatic monovalent cyclic radical comprising from 1 to 3 heteroatoms chosen from nitrogen (N), oxygen (O) and sulfur (S) atoms, or to their combination; n means a whole number 0, 1 or 2. Compounds of the formula (I) elicit anti-proliferative activity that allows their using in pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

30 cl, 1 tbl, 69 ex

 

The present invention relates to new compounds having antitumor activity, the use of these compounds in medicine, pharmaceutical compositions containing these compounds and to the method of preparation and intermediate compounds used in the preparation of these compounds.

It is known that microtubules are the main component of the mitotic spindle apparatus of eukaryotic cells and are involved in many basic and essential cellular functions. For many years the primary focus component of microtubules tubulin, which is a convenient molecular model for anticancer therapy (Exp. Opin. Ther. Patents, 9(8), 1069-1081 (1999). Indeed, the tubulin inhibitors such as taxanes and Vinca alkaloids from Madagascar, currently used as an important anticancer agents for the treatment of various types of solid tumors. However, their effectiveness is limited, as these inhibitors do not have a selective effect on tumor and however characterized by a rather high toxicity, such as myelotoxicity (bone marrow depression). It is known that effective antimitoticheskoy peptide is dolastatin 10, isolated from marine Mollusca Dolabella auricularia. The specified peptide inhibits the olymerization tubulin and belongs to a class of compounds, different in chemical structure from taxan and alkaloids from Vinca (Curr. Pharm. Des., 5, 139-162 (1999)). Preclinical trials of dolastatin 10 showed that it is active against a number of tumors in mouse and human, which was determined in cell culture and animal models. Currently dolastatin 10 and two synthetic derivatives of dolastatin, cemadotin and TZT-1027 (Drugs of the future, 24(4), 404-409 (1999))undergo phase I and phase II clinical trials. This new class of antitumor agents represents a new class of chemical compounds for clinical therapy in the near future, however, these agents still have shortcomings in terms of safety, such as myelotoxicity, neurotoxicity, and some other side effects.

Unexpectedly, it was found that some derivatives of dolastatin 10 containing various tighrope fragment of delaplaine, have a significantly higher antitumor activity and therapeutic index in the experiments on models of tumor xenograft human.

Therefore, the present invention relates to new compounds of formula I with antitumor activity

where

R1, R2and R3each independently mean hydrogen or C1-C4alkyl,

4means hydrogen;

alkyl, optionally containing from one to three substituents selected from the group comprising hydroxy, alkoxy, amino, mono - or dialkylamino, carboxy, alkoxycarbonyl, carbarnoyl, alkylcarboxylic, carbamoylated or halogen,

alkenyl,

quinil,

With3-C7cycloalkyl,

aryl, optionally containing from one to three substituents selected from the group comprising halogen, alkoxycarbonyl, sulfamoyl, alkylcarboxylic, cyano, mono - or dialkylamino, alkyl, alkoxy, phenyl, phenoxy, trifluoromethyl, triptoreline, alkylthio, hydroxy, alkylcarboxylic, heterocyclyl, 1,3-dioxolan, 1,4-dioxolan, amino or benzyl,

aralkyl, in which aryl group is optionally contains from one to three substituents selected from the group comprising halogen, alkoxycarbonyl, carbarnoyl, sulfamoyl, alkylcarboxylic, cyano, mono - or dialkylamino, alkyl, alkoxy, phenyl, phenoxy, trifluoromethyl, triptoreline, alkylthio, hydroxy, alkylcarboxylic, heterocyclyl, 1,3-dioxolan, 1,4-dioxolan, amino or benzyl; or geterotsiklicheskikh,

R5means C1-C6alkylamino, hydroxy, C3-C7cycloalkenyl, optionally substituted phenyl or benzyl, arylamino;

aralkylamines that contains1-C4alkylenes and aryl group, obazatelno containing from one to three substituents, selected from the group comprising halogen, alkoxycarbonyl, sulfamoyl, alkylcarboxylic, carbamoylated, cyano, mono - or dialkylamino, alkyl, alkoxy, phenyl, phenoxy, trifluoromethyl, triptoreline, alkylthio, hydroxy, alkylcarboxylic, heterocyclyl, 1,3-dioxolan, 1,4-dioxolan, amino or benzyl;

With1-C4alkoxy, benzhydrazide;

heterocyclyl, optionally containing from one to three substituents selected from the group comprising benzyl, benzhydryl, alkyl, hydroxy, alkoxy, alkylcarboxylic, amino, mono - or dialkylamino, acylamino, alkoxycarbonyl, phenyl or halogen;

heterocyclisation;

heterocyclochain, in which the group heterocyclyl optionally contains from one to three substituents selected from the group comprising benzyl, benzhydryl, alkyl, hydroxy, alkoxy, alkylcarboxylic, amino, dialkylamino, acylamino, alkoxycarbonyl or halogen;

aralkylated and aralkyl, both optionally containing from one to three substituents selected from the group comprising halogen, alkoxycarbonyl, sulfamoyl, alkylcarboxylic, cyano, mono - or dialkylamino, alkyl, alkoxy, phenyl, phenoxy, trifluoromethyl, triptoreline, alkylthio, hydroxy, alkylcarboxylic, heterocyclyl, 1,3-dioxolan, 1,4-dioxolan, amino, aminosulfonyl or benzyl;

and n is an integer num is 0, 1 or 2,

and their pharmaceutically acceptable salts.

These compounds possess anti-tumor activity and is used for treatment of malignant diseases, especially colorectal cancer, lung cancer, breast cancer, stomach cancer, cervical cancer and bladder cancer.

Unless otherwise stated, terms used in the description of the application to illustrate and define the extent and nature of the invention, have the following meanings.

The term "alkyl"used in the description of the application separately or in combination, means a hydrocarbon group with a straight or branched chain containing up to 12, preferably up to 6 carbon atoms, for example methyl, ethyl, n-propyl, 2-methylpropyl (isobutyl), 1-methylethyl (isopropyl), n-butyl and 1,1-dimethylethyl (tert-butyl), and more preferably up to 4 carbon atoms. The alkyl group is unsubstituted or substituted by one or more substituents, preferably contains from one to three substituents, more preferably one substituent. Substituents selected from the group comprising hydroxy, alkoxy, amino, mono - or dialkylamino, acetoxy, alkylcarboxylic, alkoxycarbonyl, carbamoylated, carbarnoyl, and halogen.

The term "alkenyl"used in the description of the application separately or in combination, means a hydrocarbon chain pointed to by the Yu for the alkyl groups, containing at least one olefinic double bond (including, for example, vinyl, allyl and butenyl), the General formulamH2m-1where m denotes an integer more than 2, preferably m means an integer from 2 to 7.

The term "quinil" means a hydrocarbon chain that is specified for alkyl groups containing at least one triple bond including, for example, PROPYNYL, butyn-1-yl and the like), the General formulamH2m-2where m denotes an integer more than 2, preferably m means an integer from 2 to 7.

The term "C3-C7cycloalkyl" means a saturated cyclic hydrocarbon group containing 3-7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, etc. Cycloalkyl group is unsubstituted or substituted by one or more substituents, preferably contains from one to three substituents, more preferably one substituent. Substituents chosen from the series alkyl, phenyl, amino, hydroxy or halogen, preferably phenyl.

The term "alkylene" means biradical branched or unbranched hydrocarbon chain containing from 1 to 4 carbon atoms, such as methylene (-CH2-), ethylene, propylene, isopropylene and butylene.

The term "aryl" means an aromatic carbocyclic radical, i.e. a 6 - or 10-membered aromatic or partially and ematichesky cycle, for example, phenyl (i.e. Ph), naphthyl or tetrahydronaphthyl, preferably phenyl or naphthyl, most preferably phenyl. Aryl fragment optionally substituted by one or more substituents, preferably contains from one to three substituents, most preferably by a Deputy selected from the group comprising halogen, preferably fluorine, chlorine, alkoxycarbonyl (for example, methoxycarbonyl), alkylcarboxylic (for example, acetoxy), cyano, alkyl, alkoxy, phenyl, phenoxy, trifluoromethyl, triptoreline, alkylthio, hydroxy, carbamoylated, alkylcarboxylic, heterocyclyl, sulfamoyl (i.e. H2NSO2-), amino, 1,3-dioxolan and 1,4-dioxole. Preferred substituents are primarily alkyl, alkoxy, hydroxy, halogen, amino, alkylamino, dialkylamino, alkylthio, sulfamoyl, benzyl or heterocyclyl.

The term "aralkyl" means an aryl group having values above associated with alkalinous group above. Aryl group of aralkyl may be substituted by one or more substituents, preferably contains from one to three substituents, more preferably one to two, most preferably one Deputy, selected from the series halogen, preferably fluorine, chlorine, alkoxycarbonyl (for example, methoxycarbonyl), alkylcarboxylic (e.g. the measures acetoxy), cyano, alkyl, alkoxy, phenyl, phenoxy, trifluoromethyl, triptoreline, alkylthio, hydroxy, carbamoylated, alkylcarboxylic, heterocyclyl, sulfamoyl, amino, 1,3-dioxolan and 1,4-dioxole. Preferred substituents are primarily aralkyl, alkoxy, hydroxy, halogen, amino, mono - or dialkylamino or alkylthio.

The term "heterocyclyl" means a saturated, unsaturated or aromatic monovalent cyclic radical containing from 1 to 3 heteroatoms selected from the series nitrogen, oxygen, or sulfur, or combinations thereof. Examples of the group heterocyclyl include furyl, piperidine (preferably piperidine-1-yl, piperidine-4-yl)piperazine (preferably piperazine-1-yl)pyridine, thiophene, thiadiazole, thiazole, benzthiazole, imidazole, tetrahydroisoquinoline etc. Heterocyclyl may be substituted by one or more substituents, preferably contains from one to three substituents, more preferably one to two, most preferably one Deputy, selected from the group comprising benzyl, benzhydryl, alkyl, hydroxy, alkoxy, alkylcarboxylic, amino, dialkylamino, acylamino, alkoxycarbonyl and halogen.

The term "heterocyclisation" means a heterocyclic group, the above attached through aminoacyl, i.e. heterocyclyl-NH-.

The term "geterotsiklicheskikh the Ino" means a heterocyclic group, the above attached through alkylenes group specified above, for aminouracil, i.e. heterocyclisation-NH-. Heterocyclisation may be substituted by one or more substituents, preferably contains from one to three substituents, more preferably one to two, most preferably one Deputy, selected from the group comprising benzyl, benzhydryl, alkyl, hydroxy, alkoxy, alkylcarboxylic, amino, mono - or dialkylamino, acylamino, alkoxycarbonyl and halogen. Preferred substituents are primarily alkyl, hydroxy, alkylcarboxylic, amino, dialkylamino, acylamino, alkylcarboxylic or halogen.

The term "amino" means a group-NH2and includes an amino group, which is additionally substituted by a group (or groups) (ness.)alkyl, or contain a protective group known in the art, such as menthoxycarbonyl, acetyl, alkoxycarbonyl or benzyl, etc.

The term "cycloalkenyl" means cycloalkyl group above, attached to the main fragment of the molecule through aminoacyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, etc. Cycloalkylation may be unsubstituted or substituted by one or more substituents, preferably contains from one to three substituents, more preferably is from one to two, most preferably one Deputy. Preferred substituents are phenyl or benzyl.

The term "arylamino" means aryl group mentioned above, attached to the main fragment of the molecule through aminoacyl, i.e. aryl-NH-.

The term "aralkylamines" means aryl group mentioned above, attached to the main fragment of the molecule through alkylenediamines, i.e. aralkyl-NH-. Aralkylamines optionally may be substituted (ness.)by alkyl, preferably by stands, i.e. it can mean aralkyl-NCH3.

The term "acetoxy" means-O-OC-CH3.

The term "carbarnoyl" means-CO-NH2and carbamoylated means-O-CO-NH.

The term "alkylcarboxylic" means an alkyl group defined above, attached to the main fragment of the molecule through carbamoyloximes, ie,- O-CO-NH-alkyl.

The term "alkylcarboxylic" means an alkyl group defined above, attached to the main fragment of the molecule through carbonoxygen, ie,- O-CO-alkyl.

The term "alkoxy" means the group R'-O-, where R' denotes the above alkyl group.

The term "aralkylated" means the group Y is-O-, where Y means the above aracelio group.

The term "alkylthio" means the group R-S-, where R denotes the above alkyl group.

The term "halogen" means fluorine, bromine, and the d and chlorine.

The term "optionally substituted"used in the description means that the substitution can occur at one or more positions, preferably by one to three provisions, and, unless otherwise specified, the substituents independently selected from the specified values.

"Pharmaceutically acceptable salt" means ordinary acid additive salts or basic additive salts, which possess the biological activity and properties of the compounds of formula I, and which is obtained from the corresponding non-toxic organic and inorganic acids or organic or inorganic bases. Examples of the acid additive salts include inorganic salts such as chloride-hydrogen acid, Hydrobromic acid, Modesto-hydrogen acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and salts of organic acids such as para-toluensulfonate, salicylic acid, methanesulfonate, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, etc. are Examples of basic additive salts include salts of potassium, sodium, ammonium and Quaternary ammonium hydroxide, such as a hydroxide of Tetramethylammonium.

"Pharmaceutically acceptable," such as pharmaceutically acceptable carrier, excipient the prodrug and the like, means pharmacologically acceptable and practically non-toxic in respect of the entity to which impose the specified connection.

"Pharmaceutically active metabolite" means a metabolic product of the compounds of formula I, which is pharmaceutically acceptable and effective.

The invention also relates to prodrugs of the above compounds. The term "prodrug" means a compound that can be transformed under physiological conditions or by solvolysis in any compound of formula I or pharmaceutically acceptable salt of the compounds of formula I. the Prodrug may be inactive when administered to a subject, but in vivo into the active compound of formula I.

The present invention preferably relates to compounds of the above formula (I), where R4means hydrogen, alkyl, optionally containing from one to three substituents selected from the group comprising hydroxy, amino, mono - or dialkylamino, carbarnoyl, carbamoylated, acetoxy and carboxy, alkenyl, quinil,3-C7cycloalkyl, aryl, optionally containing from one to three substituents selected from the group comprising alkyl, alkoxy, hydroxy, halogen, amino, mono - or dialkylamino, alkylthio, alkylcarboxylic, aralkyl, in which aryl group is optionally contains from one to three Zam is stitely, selected from the group comprising alkyl, alkoxy, hydroxy, halogen, amino, mono - or dialkylamino or alkylthio, or geterotsiklicheskikh.

More preferably the present invention relates to compounds of the above formula (I), where R4means phenyl, methyl, tert-butyl, 4-tert-butylphenyl, 4-methoxyphenyl, 2-amino-ethyl, 2-dimethylaminoethyl, ZHNCH2CH2- ("Z" means benzyloxycarbonyl), 4-methylthiophenyl, cyclohexyl, 2-, 3-, or 4-hydroxyphenyl, 4-acetamidophenyl, 4-forfinal, ethyl, isopropyl, benzyl, 2-acetoxyethyl, ethylcarboxylate, diethylcarbamoyl, phenylethyl, allyl, n-pentyl, 2-naphthyl, 4-tormentil, 2-furylmethyl or 2-hydroxyethyl.

Most preferably the present invention relates to compounds of the above formula (I), where R4means phenyl, 4-hydroxyphenyl (R), 4-acetamidophenyl, tert-butyl (R), ethyl, isopropyl, tert-butyl, benzyl, 3-hydroxyphenyl, 2-hydroxyphenyl, 2-acetoxyethyl, allyl, n-pentyl, 2-hydroxyethyl or methyl.

Preferably the present invention relates to compounds of the above formula (I), where R5means C1-C6alkylamino, hydroxy, C3-C7cycloalkenyl, optionally substituted phenyl or benzyl, arylamino, aralkylamines that contains1-C4alkylenes and aryl group, optionally containing o is one to three substituents, selected from the group comprising H2NSO2, hydroxy, alkyl, benzyl, alkoxy, carbamoylated or heterocyclyl; C1-C4alkoxy, benzhydrazide, heterocyclyl, optionally substituted, Barzilai or benzhydryl; heterocyclisation, heterocyclochain in which heterocyclyl optionally contains from one to three substituents selected from the group comprising alkyl, hydroxy, alkoxy, alkylcarboxylic, amino, dialkylamino, acylamino, alkoxycarbonyl or halogen; or Alcoxy and aralkyl both optionally contain from one to three substituents selected from the group comprising halogen, alkoxycarbonyl, sulfamoyl, alkylcarboxylic, cyano, mono - or dialkylamino, alkyl, alkoxy, phenyl, phenoxy, trifluoromethyl, triptoreline, alkylthio, hydroxy, alkylcarboxylic, heterocyclyl, 1,3-dioxolan, 1,4-dioxolan, amino, aminosulfonyl and benzyl.

More preferably the present invention relates to compounds of the above formula (I), where R5means phenylethylamine, venlafaxi, benzyloxy, 2-naphthylenediamine, benzylpiperazine, 1,2,3,4-tetrahydroisoquinoline, tert-butoxy, hydroxy, 4-H2NSO2PhCH2CH2, 2-, 3 - or 4-hydroxyphenylethylamine, 2-, 3 - or 4-hydroxyphenylethyl-N-methylamino, N-benzylpenicillin, 4-tert-butylbenzylamine, benzylamino, N-methylene is ylamino, 4 benzhydrylpiperazine, 2-phenylcyclopropane, titilation, 2-pyridinediamine, 5-aripirazole, a 4.3-dimethoxyphenylethylamine, benzylpiperazine, benzothiazole-2-ylmethylamino, 2-pyridine-4-ylamino, 3,4-dimethoxyphenylethylamine, benzothiazole-2-ylmethylamino, 2-pyridine-3-ylethylamine, pyridine-4-ylmethylamino, thiazol-2-ylamino, naphthalene-2-ylamino, 4-chlorophenylalanine, 4-methoxyphenylethylamine, 4-(1,2,3)thiadiazole-4-albesiano, 2-cyclohexylamino or 1-benzylpiperidine-4-ylamino.

Most preferably the present invention relates to compounds of the above formula (I), where R5means phenylethylamine, a 4.3-dimethoxyphenylethylamine, titilation, 2-pyridylmethylamine, 4-hydroxyphenylethylamine, N-methylpentylamino, 2-hydroxyphenylethylamine, 3 hydroxyphenylethylamine, 2-hydroxyphenylethyl-N-methylamino, 3-hydroxyphenylethyl-N-methylamino, 4-hydroxyphenylethyl-N-methylamino or benzylpiperazine.

Preferred compounds include the compounds of formula (I), where R1and R2means methyl, R3means hydrogen, and n is 0.

Examples of such compounds are:

a) N-[1-({1-sec-butyl-2-methoxy-4-oxo-4-[2-(2-phenetically-1-phenylsulfanyl)pyrrolidin-1-yl]butyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

b) N-[1-({1-sec-butyl-2-methoxy-4-[2-(1-methylsulfanyl-2-fenetilina olatile)pyrrolidin-1-yl]-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

C) N-[1-({1-sec-butyl-4-[2-(1-(S)-tert-butylsulfonyl-2-phenetically)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

g) N-{1-[(1-sec-butyl-4-{2-[1-(4-tert-butylphenylmethyl)-2-phenetically]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

e) N-{1-[(1-sec-butyl-2-methoxy-4-{2-[1-(4-methoxybenzenesulfonyl)-2-phenetically]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

e) finitely ester of 3-[1-(4-{[2-(2-dimethylamino-3-methylbutylamine)-3-methylbutyryl]methylamino}-3-methoxy-5-methylheptanoic)pyrrolidin-2-yl]-3-methylsulfinylpropyl acid,

W) benzyl ester of 3-[1-(4-{[2-(2-dimethylamino-3-methylbutylamine)-3-methylbutyryl]methylamino}-3-methoxy-5-methylheptanoic)pyrrolidin-2-yl]-3-methylsulfinylpropyl acid

C) N-(1-{[1-sec-butyl-2-methoxy-4-(2-{1-methylsulfanyl-2- [(naphthalene-2-ylmethyl)carbarnoyl]ethyl}pyrrolidin-1-yl)-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

and) N-{1-[(4-{2-[1-(2-aminomethanesulfonic)-2-phenetically]pyrrolidin-1-yl}-1-sec-butyl-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

K) N-{1-[(4-{2-[3-(4-benzylpiperazine-1-yl)-1-methylsulfanyl-3-oxopropyl]pyrrolidin-1-yl}-1-second-Boo the Il-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

l) N-{1-[(1-sec-butyl-4-{2-[3-(3,4-dihydro-1H-isoquinoline-2-yl)-1-methylsulfanyl-3-oxopropyl]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

m) N-{1-[(1-sec-butyl-4-{2-[1-(2-dimethylaminoethanol)-2-phenetically]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

n) benzyl ether (2-{1-[1-(4-{[2-(2-dimethylamino-3-methylbutylamine)-3-methylbutyryl]methylamino}-3-methoxy-5-methylheptanoic)pyrrolidin-2-yl]-2-phenethylnormorphine}ethyl) - carbamino acid,

o) N-{1-[(1-sec-butyl-2-methoxy-4-{2-[1-(4-methylsulfinylphenyl)-2-phenetically]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

p) N-[1-({1-sec-butyl-4-[2-(1-cyclohexylmethyl-2-phenetically-ethyl)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

p) N-{1-[(1-sec-butyl-4-{2-[1-(S)-(4-hydroxyphenylethyl)-2-phenetically]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

C) N-{1-[(1-sec-butyl-4-{2-[1-(R)-(4-hydroxyphenylethyl)-2-phenetically]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

t) N-{1-[(4-{2-[1-(4-acetylaminophenol the Anil)-2-phenetically]pyrrolidin-1-yl}-1-sec-butyl-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

u) N-{1-[(1-sec-butyl-4-{2-[1-(4-perpenicular)-2-phenetically]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

f) N-[1-[{1-sec-butyl-4-[2-(1-(R)-tert-butylsulfonyl-2-phenetically)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

x) N-[1-({1-sec-butyl-4-[2-(1-ethylsulfanyl-2-phenetically)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

C) N-[1-({1-sec-butyl-4-[2-(1-isopropylphenyl-2-phenetically)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

h) N-[1-({1-sec-butyl-4-[2-(1-tert-butylsulfonyl-2-phenetically)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

W) N-[1-({4-[2-(1-benzylmethyl-2-phenetically)pyrrolidin-1-yl]-1-sec-butyl-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

y) N-{1-[(1-sec-butyl-4-{2-[1-(2-hydroxyphenylethyl)-2-phenetically]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

e) N-{1-[(1-sec-butyl-4-{2-[1-(3-hydroxyphenylethyl)-2-phenetically]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)metalk rebamol]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

h) N-{1-[(1-sec-butyl-4-{2-[1-(2-hydroxyarylalkyl)-2-phenetically]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

I) 2-{1-[1-(4-{[2-(2-dimethylamino-3-methylbutylamine)-3-methylbutyryl]methylamino}-3-methoxy-5-methylheptanoic)pyrrolidin-2-yl]-2-phenethylnormorphine}ethyl ester acetic acid,

AA) tert-butyl ether 3-[1-(4-{[2-(2-dimethylamino-3-methylbutylamine)-3-methylbutyryl]methylamino}-3-methoxy-5-methylheptanoic)pyrrolidin-2-yl]-3-methylsulfinylpropyl acid,

BB) 3-[1-(4-{[2-(2-dimethylamino-3-methylbutylamine)-3-methylbutyryl]methylamino}-3-methoxy-5-methylheptanoic)pyrrolidin-2-yl]-3-methylsulfinylpropyl acid,

C) N-(1-{[1-sec-butyl-2-methoxy-4-(2-{1-methylsulfanyl-2-[2-(4-sulfamoylbenzoyl)ethylcarbamate]ethyl}pyrrolidin-1-yl)-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

gg) N-(1-{[1-sec-butyl-4-(2-{2-[2-(4-hydroxyphenyl)ethylcarbamate]-1-methylsulfonylmethyl} pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

DD) N-{1-[(1-sec-butyl-2-methoxy-4-{2-[2-(methylphenylcarbinol)-1-methylsulfonylmethyl]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

it) N-{1-[(4-{2-[3-(4-benzhydrylpiperazine-1-yl)-1-methylsulfanyl-3-oxopropyl]Pirro is one-1-yl}-1-sec-butyl-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

LJ) N-(1-{[1-sec-butyl-4-(2-{2-[2-(2-hydroxyphenyl)ethylcarbamate]-1-methylsulfonylmethyl} pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

ZZ) N-(1-{[1-sec-butyl-4-(2-{2-[2-(3-hydroxyphenyl)ethylcarbamate]-1-methylsulfonylmethyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

AI) N-{1-[(4-{2-[2-(benzylpenicilloyl)-1-methylsulfonylmethyl]pyrrolidin-1-yl}-1-sec-butyl-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

QC) N-{1-[(1-sec-butyl-2-methoxy-4-{2-[1-methylsulfanyl-2-(2-phenylcyclopropanecarboxylic)ethyl]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

FL) N-{1-[(1-sec-butyl-4-{2-[2-(4-tert-butylbenzenesulfonyl)-1-methylsulfonylmethyl]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

mm) N-[1-({4-[2-(2-benzylcarbamoyl-1-methylsulfonylmethyl)pyrrolidin-1-yl]-1-sec-butyl-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

NN) N-{1-[(4-{2-[2-(N'-benzylaminocarbonyl)-1-methylsulfonylmethyl]pyrrolidin-1-yl}-1-sec-butyl-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

oo) N-[1-({1-sec-butyl-2-methoxy-4-oxo-4-[2-(2-phenetically-1-penetrant niatel)pyrrolidin-1-yl]butyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

PP) N-[1-({4-[2-(1-arylsulfonyl-2-phenetically)pyrrolidin-1-yl]-1-sec-butyl-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

pp) N-{1-[(1-sec-butyl-2-methoxy-4-{2-[1-methylsulfanyl-2-(2-pyridin-4-iletileri)ethyl]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

SS) N-(1-{[4-(2-{2-[(benzothiazole-2-ylmethyl)carbarnoyl]-1-methylsulfonylmethyl}pyrrolidin-1-yl)-1-sec-butyl-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

TT) N-{1-[(1-sec-butyl-2-methoxy-4-{2-[1-methylsulfanyl-2-(2-thiophene-2-iletileri)ethyl]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

su) N-{1-[(1-sec-butyl-2-methoxy-4-{2-[1-methylsulfanyl-2-(2-pyridin-3-iletileri)ethyl]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

FF) N-{1-[(1-sec-butyl-2-methoxy-4-{2-[1-methylsulfanyl-2-(2-pyridin-2-iletileri)ethyl]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

XX) N-(1-{[1-sec-butyl-2-methoxy-4-(2-{1-methylsulfanyl-2-[(pyridine-4-ylmethyl)carbarnoyl]ethyl}pyrrolidin-1-yl)-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

TP) N-(1-{[1-sec-butyl-4-(2-{2-[2-(3H-imidazol-4-yl)ethylcarbamate]-1-methylsulfanyl the l}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

HH) N-{1-[(1-sec-butyl-2-methoxy-4-{2-[1-methylsulfanyl-2-(thiazol-2-ylcarbonyl)ethyl]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

hush) N-{1-[(1-sec-butyl-2-methoxy-4-{2-[1-methylsulfanyl-2-(naphthalene-2-ylcarbonyl)ethyl]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

SS) N-[1-({1-sec-butyl-4-[2-(2-cyclohexylcarbonyl-1-methylsulfonylmethyl)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

EE) N-[1-({1-sec-butyl-2-methoxy-4-[2-(2-{[2-(3,4-acid)ethyl]methylcarbamoyl}-1-methylsulfonylmethyl)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

Yuyu) N-(1-{[1-sec-butyl-4-(2-{2-[2-(3,4-acid)ethylcarbamate]-1-methylsulfonylmethyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

Yaya) N-(1-{[1-sec-butyl-4-(2-{2-[2-(4-chlorophenyl)ethylcarbamate]-1-methylsulfonylmethyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

AAA) N-[1-({1-sec-butyl-2-methoxy-4-oxo-4-[2-(1-intercultural-2-phenetically)pyrrolidin-1-yl]butyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

BSCs) N-{1-[(1-sec-butyl-2-methoxy-4-{2-[1-(naphthalene-2-ylsulphonyl)-2-dryer is ylcarbamate]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

BBB) N-{1-[(1-sec-butyl-4-{2-[1-(4-perpenicular)-2-phenetically]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

GGG) N-{1-[(1-sec-butyl-4-(2-[1-(furan-2-elmersolver)-2-phenetically]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

DDD) N-(1-{[1-sec-butyl-2-methoxy-4-(2-{2-[2-(4-methoxyphenyl)ethylcarbamate]-1-methylsulfonylmethyl}pyrrolidin-1-yl)-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

Eee) N-{1-[(1-sec-butyl-2-methoxy-4-{2-[1-methylsulfanyl-2-(4-[1,2,3]thiadiazole-4-evensidemargin)ethyl]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

GGG) N-{1-[(4-{2-[2-(1-benzylpiperidine-4-ylcarbonyl)-1-methylsulfonylmethyl]pyrrolidin-1-yl}-1-sec-butyl-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

EPL) N-(1-{[1-sec-butyl-4-(2-{1-tert-butylsulfonyl-2-[2-(4-hydroxyphenyl)ethylcarbamate]ethyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

III) N-(1-{[1-sec-butyl-4-(2-{1-tert-butylsulfonyl-2-[2-(3-hydroxyphenyl)ethylcarbamate]ethyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

the KKK) N-(1-{[1-sec-butyl-4-(2-{1-tre is butylsulfonyl-2-[2-(2-hydroxyphenyl)ethylcarbamate]ethyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

LLL) N-(1-{[1-sec-butyl-4-(2-{1-dimethylcarbamoyl-2-[2-(3-hydroxyphenyl)ethylcarbamate]ethyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

mmm) N-[1-({1-sec-butyl-4-[2-(1-dimethylcarbamoyl-2-phenetically)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

IUU) 2-{1-[1-(4-{[2-(2-dimethylamino-3-methylbutylamine)-3-methylbutyryl]methylamino}-3-methoxy-5-methylheptanoic)pyrrolidin-2-yl]-2-phenethylnormorphine}ethyl ester ethylcarbamate acid.

If R1and R2means methyl, R3means hydrogen, and n is 0, preferred compounds of formula (I) are those compounds in which R4means phenyl, 4-hydroxyphenyl (R), 4-AcNHPh- (i.e. 4-acetamidophenyl), tert-butyl (R), ethyl, isopropyl, tert-butyl, benzyl, 3-hydroxyphenyl, 2-hydroxyphenyl, 2-hydroxyethyl, 2-acetoxyethyl, allyl or n-pentyl, and R5means phenylethylamine.

The present invention first of all preferred the following compounds of formula (I):

N-[1-({1-sec-butyl-2-methoxy-4-oxo-4-[2-(2-phenetically-1-phenylsulfanyl)pyrrolidin-1-yl]butyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

N-{1-[(1-sec-butyl-4-{2-[1-(R)-(4-hydroxyphenylethyl)-2-phenetically the Teal]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

N-{1-[(4-{2-[1-(4-acetylbenzenesulfonyl)-2-phenetically]pyrrolidin-1-yl}-1-sec-butyl-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

N-[1-({1-sec-butyl-4-[2-(1-(R)-tert-butylsulfonyl-2-phenetically)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

N-[1-({1-sec-butyl-4-[2-(1-ethylsulfanyl-2-phenetically)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

N-[1-({1-sec-butyl-4-[2-(1-isopropylphenyl-2-phenetically)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

N-[1-({1-sec-butyl-4-[2-(1-tert-butylsulfonyl-2-phenetically)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

N-[1-({4-[2-(1-benzylmethyl-2-phenetically)pyrrolidin-1-yl]-1-sec-butyl-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

N-{1-[(1-sec-butyl-4-{2-[1-(3-hydroxyphenylethyl)-2-phenetically]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

N-{1-[(1-sec-butyl-4-{2-[1-(2-hydroxyarylalkyl)-2-phenetically]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-ethylpropyl}-2-dimethylamino-Z-methylbutyric,

2-{1-[1-(4-{[2-(2-dimethylamino-3-methylbutylamine)-3-methylbutyryl]methylamino}-3-methoxy-5-methylheptanoic)pyrrolidin-2-yl]-2-phenethylnormorphine} ethyl ester acetic acid,

N-[1-({4-[2-(1-arylsulfonyl-2-phenetically)pyrrolidin-1-yl]-1-sec-butyl-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

N-[1-({1-sec-butyl-2-methoxy-4-oxo-4-[2-(1-intercultural-2-phenetically)pyrrolidin-1-yl]butyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate.

If R1and R2means methyl, R3means hydrogen, and n is 0, another group of preferred compounds of formula (I) are those compounds in which R4means methyl, R5means 4 hydroxyphenylethylamine, N-methylpentylamino, 2 - hydroxyphenylethylamine, 3 hydroxyphenylethylamine, benzylpiperazine, a 4.3-dimethoxyphenylethylamine, titilation, 2-pyridylmethylamine. The present invention first of all preferred the following compounds of formula (I):

N-(1-{[1-sec-butyl-4-(2-{2-[2-(4-hydroxyphenyl)ethylcarbamate]-1-methylsulfonylmethyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

N-{1-[(1-sec-butyl-2-methoxy-4-{2-[2-(methylphenylcarbinol)-1-methylsulfonylmethyl]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylprop the yl}-2-dimethylamino-3-methylbutyrate,

N-(1-{[1-sec-butyl-4-(2-{2-[2-(2-hydroxyphenyl)ethylcarbamate]-1-methylsulfonylmethyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

N-(1-{[1-sec-butyl-4-(2-{2-[2-(3-hydroxyphenyl)ethylcarbamate]-l-methylsulfonylmethyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

N-{1-[(4-{2-[2-(N'-benzylaminocarbonyl)-1-methylsulfonylmethyl]pyrrolidin-1-yl}-1-sec-butyl-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

N-{1-[(1-sec-butyl-2-methoxy-4-{2-[1-methylsulfanyl-2-(2-thiophene-2-iletileri)ethyl]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

N-{1-[(1-sec-butyl-2-methoxy-4-{2-[1-methylsulfanyl-2-(2-pyridin-3-iletileri)ethyl]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

N-{1-[(1-sec-butyl-2-methoxy-4-{2-[1-methylsulfanyl-2-(2-pyridin-2-iletileri)ethyl]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

N-(1-{[1-sec-butyl-4-(2-{2-[2-(3,4-acid)ethylcarbamate]-1-methylsulfonylmethyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate.

Another group of preferred compounds includes compounds of formula (I), g is e R 1and R2means methyl, R3means hydrogen, and n is 1, for example, the compound of the formula N-[1-({1-sec-butyl-4-[2-(1-methanesulfonyl-2-phenetically)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate.

Another group of preferred compounds includes compounds of formula (I), where R1and R2means methyl, R3means hydrogen, and n is 2. For example, the present invention relates to a compound of the formula N-[1-({1-sec-butyl-4-[2-(1-methanesulfonyl-2-phenetically)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl} methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate.

Another preferred variant of the present invention are the compounds of formula (I), where R1means methyl, R2and R3mean hydrogen, and n is 0.

Examples of such compounds are selected from the group including:

a) N-[1-({1-sec-butyl-4-[2-(1-ethylsulfanyl-2-phenetically)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-3-methyl-2-methylaminomethyl.

b) N-[1-({1-sec-butyl-2-methoxy-4-oxo-4-[2-(2-phenetically-1-phenylsulfanyl)pyrrolidin-1-yl]butyl}methylcarbamoyl)-2-methylpropyl]-3-methyl-2-methylaminomethyl,

C) N-[1-({1-sec-butyl-4-[2-(1-tert-butylsulfonyl-2-phenetically)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}metalk rebamol)-2-methylpropyl]-3-methyl-2-methylaminomethyl,

g) N-[1-({1-sec-butyl-2-methoxy-4-[2-(1-methylsulfanyl-2-phenetically)pyrrolidin-1-yl]-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-3-methyl-2-methylaminomethyl,

d) N-[1-({1-sec-butyl-4-[2-(1-isopropylphenyl-2-phenetically)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-3-methyl-2-methylaminomethyl,

e) N-{1-[(1-sec-butyl-2-methoxy-4-oxo-4-{2-[2-phenetically-1-(2-methylpropan-2-sulfonyl)ethyl]pyrrolidin-1-yl}butyl)methylcarbamoyl]-2-methylpropyl}-3-methyl-2-methylaminomethyl,

W) N-(1-{[1-sec-butyl-4-(2-{2-[2-(3-hydroxyphenyl)ethylcarbamate]-1-methylsulfonylmethyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-3-methyl-2-methylaminomethyl,

C) N-(1-{[1-sec-butyl-4-(2-{1-tert-butylsulfonyl-2-[2-(3-hydroxyphenyl)ethylcarbamate]ethyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-3-methyl-2-methylaminomethyl.

If R1means methyl, R2and R3mean hydrogen, and n is 0, preferred compounds of formula (I) are those compounds in which R4means ethyl, phenyl, tert-butyl, methyl, isopropyl, and R5means phenylethylamine, 3 hydroxyphenylethylamine. The present invention first of all preferred the following compounds of formula (I):

N-[1-({1-sec-butyl-4-[2-(1-ethylsulfanyl-2-phenetically)pyrrolidin the-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-3-methyl-2-methylaminomethyl,

N-[1-({1-sec-butyl-2-methoxy-4-oxo-4-[2-(2-phenetically-1-phenylsulfanyl)pyrrolidin-1-yl]butyl}methylcarbamoyl)-2-methylpropyl]-3-methyl-2-methylaminomethyl,

N-[1-({1-sec-butyl-2-methoxy-4-[2-(1-methylsulfanyl-2-phenetically)pyrrolidin-1-yl]-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-3-methyl-2-methylaminomethyl,

N-[1-({1-sec-butyl-4-[2-(1-isopropylphenyl-2-phenetically)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-3-methyl-2-methylaminomethyl,

N-(1-{[1-sec-butyl-4-(2-{2-[2-(3-hydroxyphenyl)ethylcarbamate]-1-methylsulfonylmethyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-3-methyl-2-methylaminomethyl.

Another preferred variant of the present invention are the compounds of formula (I), where R1means methyl, R2and R3mean hydrogen, and n is 2.

Examples of such compounds are selected from the group including:

a) N-[1-({1-sec-butyl-4-[2-(1-econsultancy-2-phenetically)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-3-methyl-2-methylaminomethyl,

b) N-[1-({4-[2-(1-benzazolyl-2-phenetically)pyrrolidin-1-yl]-1-sec-butyl-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-3-methyl-2-methylaminomethyl,

C) N-[1-({1-sec-butyl-4-[2-(1-methanesulfonyl-2-phenetically)pyrrolidin-1-yl]-2-labels and-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-3-methyl-2-methylaminomethyl,

g) N-{1-[(1-sec-butyl-2-methoxy-4-oxo-4-{2-[2-phenetically-1-(propane-2-sulfonyl)ethyl]pyrrolidin-1-yl}butyl)methylcarbamoyl]-2-methylpropyl}-3-methyl-2-methylaminomethyl.

If R1means methyl, R2and R3mean hydrogen, and n is 2, the preferred compounds of formula (I) are compounds in which

R4means methyl, and R5means phenylethylamine, for example a compound of the formula:

N-[1-({1-sec-butyl-4-[2-(1-methanesulfonyl-2-phenetically)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-3-methyl-2-methylaminomethyl.

Another preferred variant of the present invention are the compounds of formula (I), where R1and R3means methyl, R2means hydrogen, and n is 0. Examples of such compounds are selected from the group including

a) N-[1-({1-sec-butyl-2-methoxy-4-[2-(1-methylsulfanyl-2-ventilkappen)pyrrolidin-1-yl]-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-methylamino-3-methylbutyrate,

b) N-[1-((1-sec-butyl-4-[2-(1-tert-butylsulfonyl-2-ventilkappen)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-methylamino-3-methylbutyrate.

Another preferred variant of the present invention is a compound of formula (I), where R1, R2and R3mean methyl, and n is 0. Examples of the same, the compounds are selected from the group including:

a) N-[1-({1-sec-butyl-2-methoxy-4-[2-(1-methylsulfanyl-2-ventilkappen)pyrrolidin-1-yl]-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

b) N-[1-({1-sec-butyl-4-[2-(1-tert-butylsulfonyl-2-ventilkappen)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

C) N-{1-[(1-sec-butyl-4-{2-[1-(2-hydroxyarylalkyl)-2-ventilkappen]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

g) N-{1-[(1-sec-butyl-4-{2-[1-(4-hydroxyphenylethyl)-2-ventilkappen]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

e) N-{1-[(1-sec-butyl-4-{2-[1-(3-hydroxyphenylethyl)-2-ventilkappen]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

e) N-{1-[(1-sec-butyl-4-{2-[1-(2-hydroxyphenylethyl)-2-ventilkappen]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

W) N-(1-{[1-sec-butyl-4-(2-{2-[2-(4-hydroxyphenyl)ethylcarbamate]-1-tert-butylsulfonyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

C) N-(1-{[1-sec-butyl-4-(2-{2-[2-(3-hydroxyphenyl)ethylcarbamate is]-1-tert-butylsulfonyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

and) N-(1-{[1-sec-butyl-4-(2-{2-[2-(2-hydroxyphenyl)ethylcarbamate]-1-tert-butylsulfonyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

K) N-(1-{[1-sec-butyl-4-(2-{2-[2-(4-hydroxyphenyl)ethylcarbamate]-1-methylsulfinylpropyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

l) N-(1-{[1-sec-butyl-4-(2-{2-[2-(3-hydroxyphenyl)ethylcarbamate]-1-methylsulfinylpropyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

m) N-(1-{[1-sec-butyl-4-(2-{2-[2-(2-hydroxyphenyl)ethylcarbamate]-1-methylsulfinylpropyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

n) N-(1-{[1-sec-butyl-4-(2-{2-[2-(3-hydroxyphenyl)ethylcarbamate]-1-pencilsharpener}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

o) N-[1-({1-sec-butyl-4-[2-(2-{[2-(3-hydroxyphenyl)ethyl]methylcarbamoyl}-1-methylsulfinylpropyl)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

p) N-[1-({1-sec-butyl-4-[2-(1-ethylsulfanyl-2-{[2-(3-hydroxyphenyl)ethyl]methylcarbamoyl}propyl)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

R) N-(1-{[1-W is p-butyl 4-(2-{1-ethylsulfanyl-2-[2-(3-hydroxyphenyl)ethylcarbamate]propyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

C) 3-(2-{3-[1-(4-{[2-(2-dimethylamino-3-methylbutylamine)-3-methylbutyryl]methylamino}-3-methoxy-5-methylheptanoic)pyrrolidin-2-yl]-2-methyl-3-methylsulfinylpropyl}ethyl)phenyl ester ethylcarbamate acid.

If R1, R2and R3mean methyl, and n is 0, preferred compounds of formula (I) are compounds in which R4means methyl or ethyl, and R5means phenylethylamine, 3 hydroxyphenylethylamine or 3-hydroxyphenylethyl-N-methylamino, for example the compounds of formula

N-[1-({1-sec-butyl-2-methoxy-4-[2-(1-methylsulfanyl-2-ventilkappen)pyrrolidin-1-yl]-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

N-(1-{[1-sec-butyl-4-(2-{2-[2-(3-hydroxyphenyl)ethylcarbamate]-1-methylsulfinylpropyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

N-[1-({1-sec-butyl-4-[2-(2-{[2-(3-hydroxyphenyl)ethyl]methylcarbamoyl}-1-methylsulfinylpropyl)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl} methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

N-[1-({1-sec-butyl-4-[2-(1-ethylsulfanyl-2-{[2-(3-hydroxyphenyl)ethyl]methylcarbamoyl}propyl)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

N-(1-{[1-sec-butyl-4-(2-{1-ethylsulfanyl-2-[2-(3-hydroxyphenyl)ethylcarbamate]propyl}Pyrrhus is lidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate.

In the scope of the invention includes all stereoisomers of the compounds of formula (I), except in connection with spatial structure (I-1)

where R1, R2, R3, R4, R5and n have the meanings mentioned above, and pharmaceutically acceptable salts, prodrugs of the compounds of formula (I-1) or their salts.

The present invention primarily relates to compounds in which the group R4S(O)nis R-configuration, and R3is S-configuration are preferred because they possess antitumor activity.

These compounds are effective in suppressing or preventing tumor development of precancerous or cancerous cells and are used in the treatment of carcinomas, forming solid tumors, especially colorectal cancer, lung cancer, breast cancer, stomach cancer, cervical cancer and bladder cancer. Compounds according to the invention can be used in the treatment of these tumors with the aim to slow the progression of these tumors and to prevent the increase in the number of tumors (lesions).

Antitumor therapeutic activity of the compounds according to the invention it is possible to define various standard methods of analysis in vitro. It is known that described below and in the examples, the methods of analysis of ozbolat to determine the antitumor activity and are used to test anticancer therapeutics.

Compounds according to the invention have the structure indicated by formula I, and their antitumor activity determined by any standard method of analysis, especially the analysis of apoptosis. The connection is primarily effective as inducers of apoptosis in carcinoma cells, resulting in cell death. Thus, the connection has the necessary activity when exposed to cells causes cell death carcinoma. Carcinoma cells required for analysis (for example, cells in the breast, lung, colorectal cells and the like), can be obtained from the cell Bank, such as ATSS, or they can be obtained from cancer patients. The type of tumor, which is the most active particular connection, is determined by the type of cells used in this analysis.

Carcinoma cells growing in culture, can be incubated with a specific connection and to determine changes in cell viability, for example, when using dyes that selectively stained dead cells or in the measurement of optical density. If there is a loss of 10% of the cells, a compound is considered active inducer of apoptosis. Connections may not kill the cell directly (cell toxicity), and can modulate some inside/extracellular processes that cause apoptosis. Protivo the Holevo activity of the compounds according to the invention can also determine the effect of compounds on the growth and differentiation of cells. Inhibition of cell growth can be determined by adding the corresponding connection in the culture of carcinoma cells that contain dyes or radioactivedecay predecessors, and by the inclusion of the label under the microscope in a scintillation counter, or by determining the optical density, and thus to determine the increase in the number of cells during incubation. If the number of cells did not increase, this means that growth is suppressed, and the connection may have therapeutic activity. Similarly, after adding the analyzed compounds can be well-known methods to determine the fraction of differentiated cells (for example, measuring the rate of differentiation, i.e. oxidative burst in cells HL-60, the rate of differentiation, using reagent NBT). If there is differentiation 10% of cells or more, the compound may have therapeutic activity.

To determine the antitumor activity using the methods of analysis in vivo. Compounds according to the invention can reduce the size and/or number of tumors in laboratory animals such as mice with induced tumors. The type of tumor suggests, against any type of cancer can be active a particular connection. Individual tumors can be induced by exposure to specific fabric carcinogens, or in what under special types of carcinoma cells. These tests are given in the example of the Central Bank. Compounds of the present invention have significant preventive and therapeutic activity when exposed to rats with NMU induced breast tumors. Suddenly doses and schemes have proved effective and was not observed appreciable toxicity. Compounds were also effective in reducing the number of tumors in the course of the experiment (i.e. had chemoprophylactic action) at doses and schemes that are not associated with toxicity. In addition, the compounds proved to be therapeutically active, i.e. capable of causing regression of the identified primary tumors. Connections also had a preventive effect, i.e. were able to largely prevent the formation of new tumors.

Determination of the antiproliferative activity was carried out according to the following procedure. A suspension of tumor cells were made in 96-well microplates for serial dilution. Then the microplate was incubated in an atmosphere of 5% CO2at 37°C for 4 days (2-3×10 cells/well). The degree of cell growth in monolayer was measured using WST-8, Dojindo, Japan). The values of the IC50was calculated as the concentration of drug that causes 50% growth inhibition (results of measurement of optical density). the results are shown in table I.

The maximum tolerated dose (MTD) of typical compounds of the present invention, such as

N-[1-({1-sec-butyl-2-methoxy-4-[2-(1-methylsulfanyl-2-phenetically)pyrrolidin-1-yl]-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-3-methyl-2-methylaminomethyl,

N-[1-({1-sec-butyl-4-[2-(1-methanesulfonyl-2-phenetically)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl} methylcarbamoyl)-2-methylpropyl]-3-methyl-2-methylaminomethyl,

N-[1-((1-sec-butyl-4-[2-(1-isopropylphenyl-2-phenetically)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-3-methyl-2-methylaminomethyl,

N-[1-({1-sec-butyl-4-[2-(2-{[2-(3-hydroxyphenyl)ethyl]methylcarbamoyl}-1-methylsulfinylpropyl)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

N-[1-({1-sec-butyl-4-[2-(1-ethylsulfanyl-2-{[2-(3-hydroxyphenyl)ethyl]methylcarbamoyl}propyl)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

N-(1-{[1-sec-butyl-4-(2-{2-[2-(3-hydroxyphenyl)ethylcarbamate]-1-methylsulfinylpropyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

N-(1-{[1-sec-butyl-4-(2-{1-ethylsulfanyl-2-[2-(hydroxyphenyl)ethylcarbamate]propyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

determined when administered intravenously to mice. The corresponding MTD for these compounds are 14, 18 and 10, 8, 8, 2 and 2 mg/kg

Thus, the compounds according to the invention are therapeutically active, causing regression or remission of solid tumors.

The present invention relates also to the use of compounds of formula (I) to obtain medicines, preferably for obtaining a drug intended for the treatment of disorders of cell proliferation, more preferably to obtain funds intended for the treatment of cancer, and most preferably for the treatment of colorectal cancer, lung cancer, breast cancer, stomach cancer, cervical cancer and bladder cancer.

Another object of the present invention is a method of treatment of disorders of cell proliferation, comprising the administration to a patient in need of such treatment, a therapeutically effective amount of the compounds of formula (I).

According to the present invention the treatment of oncological diseases conduct systematic introduction of the compounds according to the invention to a patient in an amount effective for the treatment of such diseases. Growth suppression of tumor cells (carcinoma) means a stop of growth, induction of apoptosis or differentiation, or other changes in riroda cells, as a result of which the cell becomes harmless. The connection can be entered with the purpose of prevention, for example, a subject with a risk of tumor or entity that has already been subjected to effective therapy, usually with the introduction of a lower dose compared to the dose used in the treatment. The amount of coupling depends on the type of cancer, the number and size of lesions and the patient's needs. The usual daily dose is from about 0.1 mg/kg to about 100 mg/kg body weight, preferably from about 20 mg/kg to about 80 mg/kg, and the dose may be changed by the attending physician depending on evidence of the needs and condition of the patient. Therapy is usually carried out for about three months, but it depends on the condition of the patient and physician recommendations. Prophylactic administration duration of administration depends on the condition of the patient and doctor, but usually this term exceeds three months. For the above treatment of the compounds according to the invention is administered systemically in the form of a composition containing the compound according to the invention and a pharmaceutically acceptable carrier compatible with the specified connection. Upon receipt of such compositions can be used any conventional pharmaceutically acceptable carrier. Usually preferred Pho is my containing the standard dose, are tablets or capsules that can be taken once or twice a day depending on the weight and height of the patient. Compounds of the present invention can be entered separately or simultaneously with other types of chemical or biochemical treatment or radiation or surgical operation.

The pharmaceutical compositions according to the invention can be obtained in any conventional form, including: (a) solid forms for oral or rectal administration, such as tablets, capsules, pills, powders, granules and the like, (b) sterile, usually aqueous solutions or suspensions for intravenous or parenteral administration, and (C) topical preparations such as solutions, suspensions, ointments, creams, gels, finely ground powders, aerosols and the like, the Pharmaceutical compositions can be obtained sterile and/or they may contain adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, salts for modifying the osmotic pressure and/or buffer substances.

Compounds according to the invention is primarily used for the introduction of pharmaceutically acceptable oral way. These pharmaceutical compositions contain one or more compounds according to the invention or their pharmaceutical acceptable salts and their pharmaceutically acceptable erolzheim esters in a mixture with a compatible pharmaceutically acceptable material carrier. You can use any conventional materials carriers. Materials-carriers are organic or inorganic inert materials suitable for oral administration. Suitable carriers include water, gelatin, Arabic gum, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, vaseline, etc. in Addition, the pharmaceutical preparations can also contain other pharmaceutically active agents. In accordance with the existing practice, the compositions may include other additives, such as flavorings, preservatives, stabilizers, emulsifiers, buffering agents, etc.

The pharmaceutical preparations can be obtained in any conventional form for oral administration, including solid forms such as tablets, capsules, pills, powders, granules, etc. Preferred oral formulations include tablets, capsules made of hard or soft gelatin, methyl cellulose, or other suitable material, which easily dissolves in the gastrointestinal tract. The oral dose of the present invention modified in accordance with the needs of the individual patient and the physician's recommendation.

To a person skilled in the art it is obvious that the compounds of the present invention can be obtained by condensation of an acid of formula (II)

where R1and R2have the meanings indicated above, preferably R1and R2each independently mean alkyl, more preferably1-C6alkyl, most preferably1-C4alkyl,

with the compound of the formula (III)

where R3, R4, R5and n have the meanings specified above.

The compound (I) can be obtained by condensation of an acid of formula (II) with the compound of the formula (III) in the presence of a condensing agent, if necessary, followed by removal of the protective group (s) and/or, if necessary, to obtain salt.

In another embodiment, the compound of formula (I) can be obtained by condensation of an acid of formula (IV)

where R1means hydrogen or alkyl, preferably C1-C6alkyl, and most preferably1-C4alkyl, and R6means a protective group selected from a number tert-butoxycarbonyl, carbobenzoxy or 9-fluorenylmethoxycarbonyl (Fmoc),

with the compound of the formula (III)

where R3, R4, R5and n have the meanings specified above, optionally in the presence of a condensing agent, and if necessary, followed by removal of the protective group (s) and/or, if necessary, to obtain the salt. The condensing agent can mean, for example, dicyclohexylcarbodiimide (DCC), diphenylphosphoryl (DPPA), diethylphosphoramidite (DEPC), hexaflurophosphate benzotriazol-1 yloxy-Tris(dimethylamino)phosphonium (reagent THIEF), etc. and the reaction is carried out in an inert solvent, such as halogenated aliphatic hydrocarbons, such as chloform and dichloromethane, ethyl acetate, tetrahydrofuran (THF), dimethylformamide (DMF) or acetonitrile, optionally in the presence of an organic base, such as triethylamine or diisopropylethylamine (DIPEA).

Compounds of the present invention of formula (I), where R1or R2mean hydrogen, can be obtained by condensation Tripeptide fragment of the formula (IV)

where R1means hydrogen or alkyl, preferably C1-C6alkyl, and most preferably1-C4alkyl, and R6means a protective group chosen, for example, from a number tert-butoxycarbonyl (Boc), carbobenzoxy (Z) or 9-fluorenylmethoxycarbonyl (Fmoc),

with a fragment of the formula (III)

where R3, R4, R5and n have the meanings mentioned above, in the presence of a condensing agent.

The condensing agent can mean, for example, dicyclohexylcarbodiimide (DCC), diphenylphosphoryl is d (DPPA), diethylphosphoramidite (DEPC), the reagent THIEF, etc. and the reaction is carried out in an inert solvent, such as halogenated aliphatic hydrocarbons, such as chloform and dichloromethane, ethyl acetate, tetrahydrofuran (THF), dimethylformamide (DMF) or acetonitrile, optionally in the presence of an organic base, such as triethylamine or diisopropylethylamine (DIPEA), at a temperature of from -10°C to 50°C, preferably from 0°C to room temperature. Then the product of the condensation removing the protective group known in the art methods, for example, a basic or acidic hydrolysis, hydrogenolysis or by treatment with a fluorine anion.

Another variant of the present invention relates to the production of the compounds of formula (III).

The compounds of formula (III), where R3, R4, R5and n have the meanings indicated above, can be obtained according to scheme 1.

As shown in scheme 1, compounds of formula (III) are obtained from the compounds of formula (V), where R3means hydrogen or alkyl, preferably C1-C6alkyl, and most preferably1-C4alkyl, and R7means a protective group selected from a number tert-butoxycarbonyl, carbobenzoxy or 9-fluorenylmethoxycarbonyl (Fmoc), and soy is inania V is obtained from N-Boc-Proline known methods (see Heterocycles, 36(9), 2073-2080 (1993))by reaction with a compound of formula (VI), which is in the form of a salt of a commercial product or obtained from the appropriate mercaptan in the interaction with a base such as sodium hydroxide, sodium hydride, sodium carbonate or sodium bicarbonate, potassium hydroxide, hydride or potassium tert-piperonyl potassium, lithium hydroxide, lithium hydride, motility or n-utility, by conventional methods, typically in an inert organic solvent, such as tetrahydrofuran, acetonitrile, methanol, ethanol or DMF, at a temperature of from -40°C to the boiling point of the solvent, with the formation of the corresponding intermediate compounds of formula (VII), where R3and R4have the meanings specified in the description of the application, and R7means a protective group selected from a number tert-butoxycarbonyl, carbobenzoxy or Fmoc group. In another embodiment, in order to eliminate the use of gaseous mercaptan thiamethoxam sodium get in situ by the reaction of methylthiazole with ethoxide potassium.

Join dialkoxy potassium is carried out in the presence of a proton source, such as alcohol or phenol, preferably phenol at room temperature. This reaction takes place with high yield and high stereoselectivity with the education necessary stereoisomers against serondela the it group and the remainder R 3. For example, the interaction of the compounds of formula (V), where R3means methyl, and R7means tert-butoxycarbonyl group, and the Proline is in S-configuration at position 2, with thiamethoxam or toetaksid potassium in the presence of phenol leads to the formation of mainly tert-butyl ester (2S)-2-[(1R,2S)-2-etoxycarbonyl-1-methyl or ethylsulfanyl]pyrrolidin-1-carboxylic acid.

The intermediate compound of formula (VII), where R3, R4and R7have the meanings indicated above, if necessary, hydrolyzing the usual methods, and then injected into reaction with the alcohol or amine, usually using the above-mentioned condensing agent in an inert organic solvent such as a halogenated aliphatic hydrocarbon, tetrahydrofuran, acetonitrile or DMF, at a temperature of from -20°C to the boiling point of the solvent, preferably from 0°C to room temperature, with formation of the corresponding compounds of formula (IX), where R3, R4and R5have the meanings specified in the description of the application, and R7means a protective group selected from a number tert-butoxycarbonyl, carbobenzoxy or Fmoc, a n is 0.

The compound of formula (IX), where R3, R4and R5have the meanings specified above, n is 0 and R7means a protective group, fibrinous number tert-butoxycarbonyl, carbobenzoxy or Fmoc, it is not necessarily possible to oxidize meta-chlormadinone acid (mCPBA) by well-known methods, usually in an inert organic solvent such as a halogenated aliphatic hydrocarbon, at a temperature of from about -40°C to the boiling point of the solvent, with the formation of the corresponding sulfoxide or sulfone of the formula (IX), where R3, R4and R5have the meanings specified in the description of the application, n means an integer of 1 or 2, and R7means a protective group selected from a number tert-butoxycarbonyl, carbobenzoxy or Fmoc.

The compound of formula (I), where R1, R2, R3, R4and R5have the meanings given above and n is 0, you can also not necessary to oxidize using mCPBA by well-known methods, usually in an inert organic solvent such as a halogenated aliphatic hydrocarbon, at a temperature of from about -40°C to the boiling point of the solvent, with the formation of the corresponding sulfoxide or sulfone of the formula (I), where R1, R2, R3, R4and R5have the meanings specified above, and n means an integer of 1 or 2.

In another embodiment, the compound of formula (I), where R1, R2, R3, R4and R5have the meanings specified above, and n means an integer of 1 or 2, but R1R 2means hydrogen, can be obtained from the product of the condensation of the compound (IV), where R1means alkyl, R6means a protective group selected from a number tert-butoxycarbonyl, carbobenzoxy or Fmoc, with compound (III), where R3, R4and R5have the meanings specified above, n is 0, by oxidation using mCPBA, followed by removal of the protective group (s) with known methods, such as basic or acidic hydrolysis, hydrogenolysis or by treatment with fluoride.

In the compound of formula (IX), where R3, R4,R5and n have the meanings indicated above, and R7means a protective group selected from a number tert-butoxycarbonyl, carbobenzoxy or Fmoc protective group is removed by treatment triperoxonane acid (TFU) in an inert solvent such as a halogenated aliphatic hydrocarbon, or in the absence of a solvent at a temperature of from about -20°C to the boiling point of the solvent, preferably from 0°C to room temperature, with formation of the corresponding compounds of formula (III) in the form of triptoreline.

Examples

The invention is illustrated by the following examples without limiting its scope. Unless specified otherwise, the characteristics of the substances listed for trifurcation mixture of diastereoisomers relative to the chiral carbon atom linked to a sulfur atom (the ratio of R:S is from 4:1 to 10:1). The content of the stereoisomers were determined by NMR in the bicyclic lactam formed after removal of the BOC-group.

Unless otherwise stated, the retention time (dt) of each compound was determined by the method GHUR in the following conditions:

column: Interstil ODS-3/4,0×33 mm, GL Science Inc.),

mobile phase: 0.05% of TFU/water to 0.05% TFU/acetonitrile,

the flow rate of 1.0 ml/min

gradient: acetonitrile from 10% to 95% (0-4 min), acetonitrile 95% (4-5,5 min), acetonitrile 95% from 10% (5.5 to 6.0 min).

Obtaining input connections

Example 1

Obtaining 3-(N-tert-butoxycarbonyl-2'-pyrrolidinyl)-3-methylsulfinylpropyl acid

To a stirred solution of tert-butyl methyl ether (S)-2-(2-ethoxycarbonylphenyl)pyrrolidin-1-carboxylic acid (1 g, 3,71 mmole)obtained by a known method (Heterocycles, 36(9), 2073-2080 (1993)), in THF (10 ml) at 0°With added NaSMe (95%, 781 mg, 11.1 mmole), the mixture was heated to room temperature and was stirred for 16 hours the mixture is Then neutralized 1 N. HCl, and was extracted with AcOEt, dried (MgSO4) and concentrated in vacuum to receive the crude 3-(N-tert-butoxycarbonyl-2'-pyrrolidinyl)-3-methylsulfinylpropyl acid (1.13 g), which was used in the next stage without additional purification.

Example 2

Obtaining 3-(N-tert-butoxycarbonyl-2'-pyrrolidinyl)-3-methylsulfanyl-N-phenylethylenediamine

To the PE imasheva the solution of the crude 3-(N-tert-butoxycarbonyl-2'-pyrrolidinyl)-3-methylsulfinylpropyl acid (1.13 g), obtained as described above, and phenethylamine (and 0.61 ml of 4.83 mmole) in CH2Cl2(10 ml) at room temperature was added water soluble carbodiimide as monohydrochloride (WSCI monohydrochloride) (682 mg, of 4.46 mmole), HOBt monohydrate (682 mg, of 4.46 mmole) and diisopropylethylamine (1,94 ml, 11.1 mmole). The mixture was stirred at room temperature for 14 h, evaporated in vacuo, extracted with AcOEt, washed with 1 N. HCl and water, dried (MgSO4) and concentrated in vacuum. The remainder (approximately 2.0 g) was purified rapid chromatography on a column (eluent: hexane/AcOEt, 2:1), was obtained 3-(N-tert-butoxycarbonyl-2'-pyrrolidinyl)-3-methylsulfanyl-N-phenylethylamine in the form of oil (to 1.15 g, 79%), which according to the1H NMR was a mixture of two diastereomers in a ratio of 5:1 (R:S)formed due to the emergence of a new chiral center. LC-MS: 393 (MN+), IHVR: Wu 3,90 minutes

1H NMR (CDCl3, 270 MHz): δ 1,45 (s, N), 1,58-2,02 (m, 4H), 2,07 (s, 3H), 2,23-of 2.56 (m, 2H), 2,84 (t, J 6.9 Hz, 2H), 3,19-3,30 (m, 1H), 3,30 at 3.69 (m, 4H), 3,82-4,00 (m, 4/5H), a 4.03-to 4.14 (m, 1/4H), 6,32 (.s, 1H), 7,08-7,38 (m, 5H).

Example 3

Obtaining 3-(N-tert-butoxycarbonyl-2'-pyrrolidinyl)-3-ethylsulfanyl-N-phenylethylenediamine

To a stirred solution of tert-butyl methyl ether (S)-2-(2-ethoxycarbonylphenyl)pyrrolidin-1-carboxylic acid (103 mg, 0,382 mmole) in THF (2 ml) at 0°With added EtSH (85 μl, 1.15 mmole) NaH (60% in liquid paraffin, 46 mg, 1.15 mmole). The mixture was heated to room temperature and was stirred for 7 hours the mixture is Then neutralized 1 N. HCl, and was extracted with AcOEt, washed with saturated aqueous NaCl, dried (MgSO4) and concentrated in vacuum were obtained tert-butyl ester 2-(2-ethoxycarbonylphenyl)pyrrolidin-1-carboxylic acid (136 mg) as a crude oil which was used in the next stage without additional purification.

To a stirred suspension of tert-butyl methyl ether 2-(2-ethoxycarbonylphenyl)pyrrolidin-1-carboxylic acid (136 mg) in THF (1 ml) and N2O (1 ml) at room temperature was added LiOH·N2About (48 mg, 1,14 mmole). The mixture was stirred at room temperature for 17 h and was extracted with 1 N. NaOH and AcOEt. The aqueous layer was acidified using 1 N. HCl, and was extracted with AcOEt, washed with saturated aqueous NaCl, dried (MgSO4) and concentrated in vacuum were obtained tert-butyl ester 2-(2-carboxyvinyl)pyrrolidin-1-carboxylic acid in the form of crude oil (109 mg). To a stirred solution of the crude oil (105 mg) in CH3CN (2 ml) at 0°With added reagent THIEF (306 mg, 0,692 mmole), penicillin (87 μl, 0,693 mmole) and diisopropylethylamine (121 μl, 0,695 mmole). The mixture was heated to room temperature and was stirred for 12 hours Then the mixture was evaporated in vacuo, was dissolved in CH2Cl2 the solution was washed with 10% citric acid, saturated solution of NaHCO3saturated NaCl solution, dried (MgSO4) and concentrated in vacuum. The oily residue was purified preparative TLC (eluent: hexane/AcOEt, 1:1), was obtained 3-(N-tert-butoxycarbonyl-2'-pyrrolidinyl)-3-ethylsulfanyl-N-phenylethylamine (104 mg, 67%) as oil, which according to the1H NMR was a mixture of two diastereomers in a ratio of 5:1 (R:S), which were formed due to the emergence of a new chiral center. LC-MS: 407 (MN+), IHVR: Wu 3,90 minutes

1H NMR (CDCl3, 270 MHz): δ to 1.19 (t, J 7,6 Hz, 3H), 1,45 (s, 9H), 1.61 of-2,04 (m, 4H), 2,07 is 2.43 (m, 2H), 2,53 (q, J 7,6 Hz, 2H), 2,84 (t, J 6.9 Hz, 2H), 3,20-to 3.35 (m, 1H), 3,36-with 3.79 (m, 4H), 3,80-3,98 (m, 5/6H), 3,98-4,10 (m, 1/6H), 6,46 (.s, 1H), 7,15-7,38 (m, 5H).

Obtaining the compounds according to the invention

Example 1

N-[1-({1-sec-Butyl-2-methoxy-4-[2-(1-methylsulfanyl-2-phenetically-ethyl)pyrrolidin-1-yl]-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate

To a stirred solution of 3-(N-tert-butoxycarbonyl-2'-pyrrolidinyl)-3-methylsulfanyl-N-phenylethylenediamine (30,3 mg, 0,0772 mmole) in CH2Cl2(0.5 ml) at 0°With added TFU (0.5 ml). The mixture was heated to room temperature and was stirred for 4 h Then the mixture was evaporated in vacuum, thus received triptorelin 3-methylsulfanyl-N-phenethyl-3-pyrrolidin-2-ylpropyl is Yes in the form of crude oil.

The resulting triptorelin 3-methylsulfanyl-N-phenethyl-3-pyrrolidin-2-ylpropionic was dissolved in DMF (2 ml) and at 0° (C) was added to (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid is obtained from tert-butyl ether (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid (34 mg, 0,0700 mmole) when processing TFU in CH2Cl2by a known method (Chem. Pharm. Bull., 43(10), 1706-1718 (1995)). To the resulting solution at 0°C was added diethyl ether cyanophosphonate acid (95%: 12 ál, 0,0751 mmole) and triethylamine (49 μl, 0,352 mmole), was stirred at 0°C for 1 h, then was heated to room temperature and was stirred for 20 hours the Reaction was stopped by adding a saturated aqueous solution of NaHCO3the mixture was extracted with AcOEt, washed with saturated NaCl solution, dried (MgSO4) and concentrated in vacuum to receive the crude oil (90 mg), which was purified preparative GHUR (column: ODS-80Ts, eluent: N2O/acetonitrile., 39:31, +0.05% of TFU). The appropriate fractions were freeze-dried, thus received is listed in the title compound as an amorphous white powder (30 mg, 47%). LC-MS: 704 (MN+), IHVR: Wu 2,88 minutes

1H NMR (CDCl3, 270 MHz): δ 0,65-of 1.09 (m, 15H), of 1.12 (d, J 6.3 Hz, 3H), 1.30 and to 2.65 (m, 15H), to 2.06 (s, 3H), and 2.83 (t, J 7,6 Hz, 2H), 2.95 and (s, 6H), of 3.00 (s, 3H,), 3,30 (s, 3H) 3,35-3,90 (m, 4H), 3.95 to of 4.12 (m, 1H), 4,14-and 4.40 (m, 1H), 4,60-4,85 (m, 2H), 7,05-7,38 (m, 5H).

The following compounds (examples 2-45) was obtained in the same way as described in example 1.

Example 2

N-[1-({1-sec-Butyl-4-[2-(1-(S)-tert-butylsulfonyl-2-phenetically-ethyl)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-tert-butylsulfonyl-N-phenethyl-3-pyrrolidin-2-ylpropionic same way as described in example 1. LC-MS: 746 (MN+), IHVR: Wu 3,20 min (S-isomer).

1H NMR (CDCl3, 270 MHz): δ of 0.68 to 1.00 (m, 15H), of 1.07 (d, J 6.6 Hz, 3H), 1.27mm (s, N), 1,45 at 2.45 (m, 15H), a 2.75 (t, J 6.9 Hz, 2H), 2,88 (s, 6H), to 2.94 (s, 3H), 3,29 (s, 3H), 3,32-3,90 (m, 4H), 3,92-4,08 (m, 1H), 4,22-4,32 (m, 1H), 4,50-rate 4.79 (m, 2H), 7,05-to 7.32 (m, 5H).

Example 3

N-{1-[(1-sec-Butyl-4-{2-[1-(4-tert-butylphenylmethyl)-2-phenetically]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl)-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-(4-tert-butylphenylmethyl)-N-phenethyl-3-pyrrolidin-2-ylpropionic same way as described in example 1. LC-MS: 822 (MN+), IHVR: Wu of 3.64 min (R-isomer).

1H NMR (CDCl3, 270 MHz): 4 0,70-1,08 (m, 15H), of 1.13 (d, J 6.6 Hz, 3H), 1.28 (in s, N), 1,20-to 2.55 (m, 15H), and 2.79 (t, J 7,3 Hz, 2H), 2.95 and (s, 6H), to 2.99 (s, 3H), 3,26 (s, 3H), 3,30-3,82 (m, 4H), 3,92-4,10 (m, 1H), 4,25-to 4.38 (m, 1H), br4.61-4,82 (m, 2H), 7,08-7,33 (m, 5H).

Example 4

N-{1-[(1-sec-Butyl-2-methoxy-4-{2-[1-(4-methoxybenzenesulfonyl)-2-phenetically]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-(4-methoxybenzenesulfonyl)-N-phenethyl-3-pyrrolidin-2-ylpropionic same way as described in example 1. LC-MS: 796 (MN+), IHVR: Wu 3,14 min (R-isomer).

1H NMR (CDCl3, 270 MHz,): δ 0,70-1,08 (m, 15H), of 1.13 (d, J 6.6 Hz, 3H), 1,20-to 2.55 (m, 15H), and 2.79 (t, J 7,3 Hz, 2H), 2.95 and (s, 6H), to 2.99 (s, 3H), of 3.27 (s, 3H), 3,30-3,90 (m, 4H), of 3.77 (s, 3H), 3,90-4,18 (m, 1H), 4,20-4,35 (m, 1H), 4,60-4,85 (m, 2H), 6,79 (d, J a 8.9 Hz, 2H), 7,32 (d, J 8.5 Hz, 2H), 7,10-7,40 (m, 5H).

Example 5

N-{1-[(1-sec-Butyl-4-{2-[1-(S)-(4-hydroxyphenylethyl)-2-phenetically]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-(4-hydroxyphenylethyl)-N-phenethyl-3-pyrrolidin-2-ylpropionic same way as described in example 1. LC-MS: 782 (MN+), IHVR: Wu 2,87 min (S-isomer).

p> 1H NMR (CDCl3, 270 MHz): δ 0,65-of 1.18 (m, 18H), 1,20-1,40 (m, 2H), 1,50-2,90 (m, 15H), 2,95 (s, 6H), 3,01 (s, 3H), 3,25 (s, 1H), 3,32 (s, 2H), 3,35-4,10 (m, 5H), 4,12-4,30 (m, 1H), 4,50-4,78 (m, 2H), 6.75 in (d, J 8.6 Hz, 2/3 N), PC 6.82 (d, J 8.6 Hz, 4/3 N), 7,08-7,35 (m, 7H).

Example 6

N-{1-[(1-sec-Butyl-4-{2-[1-(R)-(4-hydroxyphenylethyl)-2-phenetically]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl)-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-(4-hydroxyphenylethyl)-N-phenethyl-3-pyrrolidin-2-ylpropionic same way as described in example 1. LC-MS: 782 (MN+), IHVR: Wu 2,88 min (R-isomer).

1H NMR (CDCl3, 270 MHz): δ 0,68 is 1.20 (m, 18H), 1,21-of 1.40 (m, 2H), 1,50-2,90 (m, 15H), 2,96 (s, 6H), 3,03 (s, 3H), 3,26 (s, 3H), 3,32-3,70 (m, 4H), 3.72 points-of 4.00 (m, 1H), 4,15-of 4.35 (m, 1H), 4,68-4,78 (m, 2H), 6.75 in (d, J 8.6 Hz, 2H), 7,08-7,35 (m, 7H).

Example 7

N-{1-[(4-{2-[1-(4-Acetylbenzenesulfonyl)-2-phenetically]-pyrrolidin-1-yl}-1-sec-butyl-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-(4-acetylbenzenesulfonyl)-N-phenethyl-3-pyrrolidin-2-ylpropionic same way as described in example 1. LC-MS: 823 (MN+), IHVR: Wu 2,82 min (R ' from the EP).

1H NMR (CDCl3, 270 MHz): δ 0,70-1,20 (m, 18H), 1,21-2,95 (m, 15H), of 2.16 (s, 3H), and 2.79 (t, J 7,3 Hz, 2H), 2,96 (s, 6H), of 3.00 (s, 3H), of 3.25 (s, 3H), 3,30-4,08 (m, 5H), 4,20 is 4.35 (m, 1H), 4,50-4,80 (m, 2H), 7,08-7,40 (m, 7H), the 7.43 (d, J 8.2 Hz, 2H).

Example 8

N-{1-[(1-sec-Butyl-4-{2-[1-(4-perpenicular)-2-phenetically-ethyl]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-(4-perpenicular)-N-phenethyl-3-pyrrolidin-2-ylpropionic same way as described in example 1. LC-MS: 784 (MN+), IHVR: Wu 3,17 min (R-isomer).

1H NMR (CDCl3, 270 MHz): δ 0,67-of 1.09 (m, 15H), of 1.13 (d, J 6.6 Hz, 3H), 1,20-1,40 (m, 2H), 1,42-2,62 (m, 13H), 2,80 (t, J 6.9 Hz, 2H), 2,96 (s, 6H), 2,98 (s, 3H), 3,26 (s, 3H), 3.27 to 4,08 (m, 5H), 4,20 is 4.35 (m, 1H), 4,60-4,80 (m, 2H), 6,95 (t, J 8.6 Hz, 2H), 7,08-7,30 (m, 5H), was 7.36 (dd, J 5,3, a 8.9 Hz, 2H).

Example 9

N-[1-({1-sec-Butyl-4-[2-(1-(R)-tert-butylsulfonyl-2-phenetically-ethyl)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl)methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-tert-butylsulfonyl-N-phenethyl-3-pyrrolidin-2-ylpropionic same way as described in example 1. LC-MS: 746 (MN+), IHVR: Wu, and 3.16 min (R-isomer).

1H NMR (CDCl3, 270 MHz): δ of 0.65 to 1.00 (m, 15H), of 1.06 (d, J 6.4 Hz, 3H), of 1.17 (s, 9H), 1,35 is 2.55 (m, 15H), and 2.79 (t, J 6.9 Hz, 2H), 2,88 (s, 6H), to 2.94 (s, 3H), 3,21 (s, 3H), 3,22-3,82 (m, 4H), 3,92-of 4.05 (m, 2H), 4,55-4,80 m, 2H), 6,95-7,30 (m, 5H).

Example 10

N-{1-[(1-sec-Butyl-4-{2-[1-(2-hydroxyarylalkyl)-2-phenethyl-carbamoylethyl]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-(N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-(2-hydroxyarylalkyl)-N-phenethyl-3-pyrrolidin-2-ylpropionic same way as described in example 1. LC-MS: 734 (MN+), IHVR: Wu 2,70 minutes

1H NMR (CDCl3, 270 MHz): δ 0,57-to 1.21 (m, 18H), 1,20-of 1.55 (m, 2H), 1,55-of 2.30 (m, 10H), 2,30-2,77 (m, 5H), by 2.73 (t, J 6,59 Hz, 2H), 2,96 (s, 6H), was 3.05 (s, 3H), at 3.35 (s, 3H), 3,40-to 3.92 (m, 6H), 3.95 to to 4.46 (m, 2H), 4,56-4,90 m, 2H), 6,55 (.s, 1H), 7,08-7,39 (m, 5H), 7,92 (user, 1H).

Example 11

2-{1-[1-(4-{[2-(2-Dimethylamino-3-methylbutylamine)-3-methylbutyryl]-methylamino}-3-methoxy-5-methylheptanoic)pyrrolidin-2-yl]-2-phenethylnormorphine}ethyl ester of acetic acid

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 2-(2-phenetically-1-pyrrolidin-2-reticular)ethyl ester of acetic acid in the same way as described in example 1. LC-MS: 776 (MN+, GHUR: Wu 2,86 minutes

1H NMR (CDCl3, 270 MHz): δ 0,57 is 1.20 (m, 18H), 1,20-of 1.45 (m, 2H), 1,55-2,31 (m, 10H), 2,02 (s, 3H), 2,30-to 2.67 (m, 3H), by 2.73 (t, J 6,11 Hz, 2H), and 2.83 (t, J 6,93 Hz, 2H), 2,96 (s, 6H), 3,03 (s, 3H), and 3.31 (s, 3H), 3,40-3,95 (m, 4H), 3.95 to and 4.40 (m, 4H), to 4.52-4,88 (m, 2H), 6,45 (.s, 1H), 7,08-7,39 (m, 5H), 7,79 (.s, 1H).

Example 12

tert-Butyl ester 3-[1-(4-{[2-(2-dimethylamino-3-methylbutylamine)-3-methylbutyryl]methylamino}-3-methoxy-5-methylheptanoic)pyrrolidin-2-yl]-3-methylsulfinylpropyl acid

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid tert-butyl ester 3-methylsulfanyl-3-pyrrolidin-2-ylpropionic acid in the same way as described in example 1. LC-MS: 657 (MN+), IHVR: Wu 3,10 minutes

1H NMR (CDCl3, 270 MHz): δ 0,68 is 1.20 (m, 18H), 1,20-of 1.42 (m, 2H), 1,45 (s, 9H), 1,55-to 2.29 (m, 10H), 2,10 (s, 3H), 2,30-of 2.58 (m, 3H), 2,96 (s, 6H), 3,01 (s, 3H), of 3.33 (s, 3H), 3,40-3,90 (m, 2H), 4,01-4,39 (m, 2H), 4,59-4,89 (m, 2H), 7,50 (user s, 1H).

Example 13

3-[1-(4-{[2-(2-Dimethylamino-3-methylbutylamine)-3-methylbutyryl]-methylamino}-3-methoxy-5-methylheptanoic)pyrrolidin-2-yl]-3-methylsulfinylpropyl acid

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-methylsulfanyl-3-pyrrolidin-2-ylpropionic acid in the same way as described in example 1. LC-MS: 601 (MN+), JHW is: vu of 2.51 minutes

1H NMR (DMSO-d6, 270 MHz): δ 0,76 (m, 3H), 0,81-of 1.07 (m, 15H), 1,12-of 1.40 (m, 2H), 1,55-to 2.18 (m, 10H), a 2.01 (s, 3H), 2,20-of 2.66 (m, 3H), 2,67-2,84 (m, 6H), 3,01 (s, 3H), 3,20 (s, 3H), 3,24-of 3.80 (m, 2H), 3,80-4,37 (m, 2H), 4,49-rate 4.79 (m, 2H), 8,93 (d, J a 7.92 Hz, 1H), 9,50 (.s, 1H).

Example 14

N-(1-{[1-sec-Butyl-2-methoxy-4-(2-{1-methylsulfanyl-2-[2-(4-sulfamoylbenzoyl)ethylcarbamate]ethyl}pyrrolidin-1-yl)-4-oxobutyl]-methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-methylsulfanyl-3-pyrrolidin-2-yl-N-[2-(4-sulfamoylbenzoyl)ethyl]propionamide same way as described in example 1. LC-MS: 783 (MN+), IHVR: Wu 2,42 minutes

1H NMR (CDCl3, 270 MHz): δ 0,81 (t, J 6,59 Hz, 3H), 0,85-1,19 (m, 15H), 1,20-of 1.42 (m, 2H), 1,62-of 2.30 (m, 10H), 2,04 (s, 3H), 2,30 2.63 in (m, 3H), 2,78-to 2.99 (m, 2H), 2,99 (s, 6H), 3,06 (s, 3H), of 3.12 (s, 3H), 3,23-with 3.79 (m, 4H), 3,80-of 4.25 (m, 4H), 4.53-in-to 4.81 (m, 2H), 7,12 (.s, 1H), 7,32 (d, J a 7.92 Hz, 2H), 7,79 (d, J a 7.92 Hz, 2H), 7,65-of 7.82 (m, 3H).

Example 15

N-(1-{[1-sec-Butyl-4-(2-{2-[2-(4-hydroxyphenyl)ethylcarbamate]-1-methylsulfonylmethyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methyl-carbarnoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and N-[2-(4-hydroxyphenyl)ethyl]-3-methylsulfanyl-3-pyrrolidin-2-ylpropionic analogy is ichno to as described in example 1. LC-MS: 720 (MN+), IHVR: Wu 2,50 minutes

1H NMR (CDCl3, 270 MHz): δ 0,81 (t, J 6,92 Hz, 3H), 0,89-1,19 (m, 15H), 1,20-of 1.42 (m, 2H), 1,59 is 2.33 (m, 10H), 2,03 (s, 3H), 2,30-2,60 (m, 3H), 2,60-2,82 (m, 2H), 2,98 (s, 6H), of 3.07 (s, 3H), 3,23 (s, 3H), 3,30-3,70 (m, 4H), 3,70-4,32 (m, 4H), 4,57-to 4.81 (m, 2H), 6.75 in (d, J to 8.57 Hz, 2H), 7,00 (.s, 1H), 7,01 (d, J to 8.57 Hz, 2H), 7,30 at 8.60 (m, 2H).

Example 16

N-{1-[(1-sec-Butyl-2-methoxy-4-{2-[2-(methylphenylcarbinol)-1-methylsulfonylmethyl]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and N-methyl-3-methylsulfanyl-N-phenethyl-3-pyrrolidin-2-ylpropionic same way as described in example 1. LC-MS: 718 (MN+), IHVR: Wu 2,92 minutes

'H NMR (CDCl3, 270 MHz): δ 0,51-1,19 (m, 18H), 1,20-1,40 (m, 2H), 1,55-of 2.30 (m, 10H), a 2.01 (s, 3H), 2,30-a 2.71 (m, 3H), 2.71 to 3,10 (m, 14H), 3,10-3,88 (m, 4H), and 3.31 (s, 3H), 3.95 to and 4.40 (m, 2H), 4,47-4,91 (m, 2H), 6,99-7,38 (m, 5H), 7,56 (.s, 1H).

Example 17

N-{1-[(4-{2-[3-(4-Benzhydrylpiperazine-1-yl)-1-methylsulfanyl-3-oxopropyl]pyrrolidin-1-yl)-1-sec-butyl-2-methoxy-4-oxobutyl)-methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 1-(4-benzhydrylpiperazine-1-yl)-3-methylsulfanyl-3-pyrrolidin-2-propen-1-she just as described in example 1. LC-MS: 835 (MN+), IHVR: Wu to 2.57 minutes

1H NMR (CDCl3, 270 MHz): δ 0,51-1,19 (m, 18H), 1,20-of 1.41 (m, 2H), 1,55-of 2.20 (m, 10H), of 1.99 (s, 3H), 2,20-of 2.75 (m, 3H), 2,75-4,55 (m, 12H), to 3.02 (s, 6H), and 3.16 (s, 3H), 3,34 (s, 3H), 4,55-5,02 (m, 2H), 5,09-of 5.26 (m, 1H), 7,30-of 7.48 (m, 6H), 7,50-to 7.77 (m, 4H).

Example 18

N-(1-{[1-sec-Butyl-4-(2-{2-[2-(2-hydroxyphenyl)ethylcarbamate]-1-methylsulfonylmethyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]-methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and N-[2-(2-hydroxyphenyl)ethyl]-3-methylsulfanyl-3-pyrrolidin-2-ylpropionic same way as described in example 1. LC-MS: 720 (MN+), IHVR: Wu 2,67 minutes

1H NMR (CDCl3, 270 MHz): δ of 0.82 (t, J 6,59 Hz, 3H), 0,87 is 1.20 (m, 15H), 1,20-of 1.42 (m, 2H), 1,59-of 2.34 (m, 10H), from 2.00 (s, 3H), 2,34-to 2.65 (m, 3H), 2,65 (t, J 6,60 Hz, 2H), 2,97 (s, 6H), of 3.07 (s, 3H), of 3.32 (s, 3H), 3,37-3,91 (m, 4H), 3,91 is 4.35 (m, 2H), 4,57-4,88 (m, 2H), 6,10-of 8.15 (m, 3H), 6,55-7,17 (m, 4H).

Example 19

N-(1-{[1-sec-Butyl-4-(2-{2-[2-(3-hydroxyphenyl)ethylcarbamate]-1-methylsulfonylmethyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and N-[2-(3-hydroxyphenyl)ethyl]-3-methylsulfanyl-3-pyrrolidin-2-Elpro is ionamine same as described in example 1. LC-MS: 720 (MN+), IHVR: Wu 2,58 minutes

1H NMR (CDCl3, 270 MHz): δ 0,81 (t, J 6,59 Hz, 3H), 0,87 is 1.20 (m, 15H), 1,20-1,40 (m, 2H), 1,65-2,31 (m, 10H), 2,04 (s, 3H), 2,31 of 2.68 (m, 3H), 2,78 (t, J 6,60 Hz, 2H), 2,96 (s, 6H), to 3.09 (s, 3H), of 3.33 (s, 3H), 3,41-3,79 (m, 4H), 3,79-to 4.28 (m, 2H), 4,35-4,88 (m, 2H), 6,50-7,21 (m, 4H), 7,78 (.s, 1H).

Example 20

N-{1-[(4-{2-[2-(Benzylpenicilloyl)-1-methylsulfonylmethyl]-pyrrolidin-yl}-1-sec-butyl-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and N-benzyl-3-methylsulfanyl-N-phenethyl-3-pyrrolidin-2-ylpropionic same way as described in example 1. LC-MS: 794 (MN+), IHVR: Wu 3,43 minutes

1H NMR (CDCl3, 270 MHz): δ 0,81 (t, J 6,93 Hz, 3H), 0,87-1,17 (m, 15H), 1,17-of 1.40 (m, 2H), 150-2,31 (m, 10H), of 2.08 (s, 3H), 2,31 was 2.76 (m, 3H), 2,75-2,89 (m, 2H), 2,98 (s, 6H), 3,06 (s, 3H), of 3.32 (s, 3H), 3,38-4.09 to (m, 5H), 4,13-4,56 (m, 3H), 4,56-4,82 (m, 2H), 6,85-7,41 (m, 4H), 7,81 (.s, 1H).

Example 21

N-{1-[(1-sec-Butyl-2-methoxy-4-{2-[1-methylsulfanyl-2-(2-paneltitle-propellerblades)ethyl]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-methylsulfanyl-N-(2-vinylcyclopropyl)-3-pyrrolidin the-2-ylpropionic same as described in example 1. LC-MS: 716 (MN+), IHVR: Wu min 2,90

1H NMR (CDCl3, 270 MHz): δ 0,50-of 1.18 (m, 18H), 1.18 to a 1.45 (m, 2H), 155-2,31 (m, 10H), 2,11 (s, 3H), 2,31-of 2.72 (m, 3H), 2,72-2,95 (m, 1H), 2,97 (s, 6H), 3,03 (s, 3H), of 3.32 (s, 3H), 3,35-4.09 to (m, 4H), 4,10-4,43 (m, 1H), 4,50 of 4.83 (m, 2H), 6,88-7,40 (m, 4H), 7,68 (.s. 1H).

Example 22

N-{1-[(1-sec-Butyl-4-{2-[2-(4-tert-butylbenzenesulfonyl)-1-methylsulfonylmethyl]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and N-(4-tert-butylbenzyl)-3-methylsulfanyl-3-pyrrolidin-2-ylpropionic same way as described in example 1. LC-MS: 746 (MN+), IHVR: Wu 3,41 minutes

1H NMR (CDCl3, 270 MHz): δ 0,50-1,20 (m, 18H), 1,20-of 2.24 (m, 12H), of 1.30 (s, 9H), is 2.09 (s, 3H), 2,25-a 2.71 (m, 3H), 2.95 and (s, 6H), 3,01 (s, 3H), and 3.31 (s, 3H), 3.33 and-4,18 (m, 3H), 4,19-4,60 (m, 3H), with 4.64 of 4.83 (m, 2H), 6,63 (.s, 1H), 7.23 percent (d, J of 8.25 Hz, 2H), 7,34 (d, J of 8.25 Hz, 2H), 7,56 (.s, 1H).

Example 23

N-[1-({4-[2-(2-Benzylcarbamoyl-1-methylsulfonylmethyl)pyrrolidin-1-yl]-1-sec-butyl-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and N-benzyl-3-methylsulfanyl-3-pyrrolidin-2-ylpropionic similar to the AK described in example 1. LC-MS: 690 (MN+), IHVR: Wu was 2.76 minutes

1H NMR (CDCl3, 270 MHz): δ 0,50-1,20 (m, 18H), 1,20-of 1.39 (m, 2H), 1,45-2,31 (m, 10H), of 2.08 (s, 3H), 2,31 of 2.68 (m, 3H), 2,96 (s, 6H), to 3.02 (s, 3H), 3,30 (s, 3H), 3.33 and-4,12 (m, 3H), 4,18-to 4.62 (m, 3H), 4,62 of 4.83 (m, 2H), 6,79 (.s, 1H), 7,02-7,39 (m, 5H), 7,52 (.s, 1H).

Example 24

N-{1-[(4-{2-[2-(N-benzylaminocarbonyl)-1-methylsulfonylmethyl]-pyrrolidin-1-yl}-1-sec-butyl-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl)-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and N'-benzylpiperazine 3-methylsulfanyl-3-pyrrolidin-2-ylpropionic acid in the same way as described in example 1. LC-MS: 705 (MN+), IHVR: Wu 2,52 minutes

1H NMR (CD3OD, 270 MHz): δ 0,76 (t, J 7,02 Hz, 3H), 0,82-1,10 (m, 15H), 1,15-of 1.42 (m, 2H), 1,55-to 2.18 (m, 10H), to 1.98 (s, 3H), 2,18 at 2.59 (m, 3H), 2,80 (s, 6H), was 3.05 (s, 3H), up 3.22 (s, 3H), 3,34-to 3.73 (m, 3H), 3,80-to 4.38 (m, 2H), 4,51-4,78 (m, 2H), 7,25-7,47 (m, 5H).

Example 25

N-[1-({1-sec-Butyl-2-methoxy-4-oxo-4-[2-(2-geneticalgorithm)-pyrrolidin-1-yl]butyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and N-phenethyl-3-penicillanic-3-pyrrolidin-2-ylpropionic same way as described in example 1. LC-MS: 794 (MN+), IHVR: Wu 3,25 is in.

1H NMR (CDCl3, 270 MHz): δ 0,80-1,10 (m, 18H), 1,19-of 1.35 (m, 2H), 1,79-of 2.50 (m, 14H), 2,72-2,82 (m, 4H), 2.95 and (s, 6H), 3,01 (s, 3H), up 3.22 (s, 3H), 3,26-3,63 (m, 4H), 3,70-3,82 (m, 1H), 4,03 (.s, 1H), 4,20 (.s, 1H), 4,73 (.s, 2H), 6,41 (.s, 1H), 7,14-7,30 (m, 10H), 7,66 (.s, 1H).

Example 26

N-[1-({4-[2-(1-Arylsulfonyl-2-phenetically)pyrrolidin-1-yl]-1-sec-butyl-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-arylsulfonyl-N-phenethyl-3-pyrrolidin-2-ylpropionic same way as described in example 1. LC-MS: 730 (MN+), IHVR: Wu 2,96 minutes

1H NMR (CDCl3, 270 MHz): δ 0,79-of 1.15 (m, 18H), to 1.22 to 1.34 (m, 2H), 1,66 of $ 2.53 (m, 14H), and 2.83 (t, J 7.9 Hz, 2H), 2.95 and (s, 6H), 3,01 (s, 3H), 3,30 (s, 3H), 3,35-3,82 (m, 5H), 4,06-4,20 (m, 2H), 4,73 (t, J 7.4 Hz, 2H), 5,03 (d, J 9.6 Hz, 1H), 5,10 (d, J a 16.8 Hz, 1H), 5,62-5,80 (m, 1H), 6,58 (.s, 1H), 7,19-7,31 (m, 5H), 7,60 (.s, 1H).

Example 27

N-{1-[(1-sec-Butyl-2-methoxy-4-{2-[1-methylsulfanyl-2-(2-pyridin-4-iletileri)ethyl]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-methylsulfanyl-N-(2-pyridin-4-retil)-3-pyrrolidin-2-ylpropionic just as described, the example1. LC-MS: 705 (MH+), IHVR: Wu 2,01 minutes

1H NMR (CDCl3, 270 MHz): δ 0,82-of 1.10 (m, 18H), 1,23 is 1.48 (m, 2H), 1,86 was 2.25 (m, 5H), was 2.05 (s, 3H), 2.91 in-3,0 (m, 2H), 2,97 (s, 6H), 3,06 (s, 3H), 3,30 (s, 3H), 3,10-4,07 (m, 7H), 4,73 (.s, 2H), 7,79 (.s, 2H), 8,75 (.s, 2H).

Example 28

N-(1-{[4-(2-{2-[(Benzothiazole-2-ylmethyl)carbamoyl-1-methylsulfonylmethyl}-pyrrolidin-1-yl)-1-sec-butyl-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and N-benzothiazol-2-ylmethyl-3-methylsulfanyl-3-pyrrolidin-2-yl-propionamide same way as described in example 1. LC-MS: 747 (MN+), IHVR: Wu 2,73 minutes

1H NMR (CDCl3, 270 MHz): δ 0,74-1,14 (m, 18H), 1,20-to 1.38 (m, 2H), 1,80-2,20 (m, 7H), to 2.13 (s, 3H), 2,32 is 2.75 (m, 5H), 2,94 (.s, 6H), to 3.33 (s, 3H), 3,22-to 3.58 (m, 2H), 3,65-6,79 (m, 1H), 3,90-4,11 (m, 1H), 4,36 (.s, 1H), 4,78 to 4.92 (m, 4H), 7,34-7,51 (m, 2H), 7,82-of 8.00 (m, 2H).

Example 29

N-{1-[(1-sec-Butyl-2-methoxy-4-{2-[1-methylsulfanyl-2-(2-thiophene-2-iletileri)ethyl]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-methylsulfanyl-3-pyrrolidin-2-yl-N-(2-thiophene-2-retil)propionamide same way as described in example 1. LC-MS: 70 (MN +), IHVR: Wu 2,74 minutes

1H NMR (CDCl3, 270 MHz): δ 0,79 is 1.13 (m, 18H), of 1.20 and 1.33 (m, 2H), 1.85 to 2,58 (m, 14H), 2,07 (s, 3H), 2,97 (.s, 6H), 3,03 (s, 3H), and 3.31 (s, 3H), 3,36 at 3.69 (m, 4H), 4,18-4,32 (m, 1H), 4,66-4,80 (m, 2H), 6,68 (.s, 1H), 6,83-to 6.88 (m, 1H), 6,91-6,94 (m, 1H), 7,13-to 7.15 (m, 1H), 7,56 (.s 1H).

Example 30

N-{1-[(1-sec-Butyl-2-methoxy-4-(2-[1-methylsulfanyl-2-(2-pyridin-3-iletileri)ethyl]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-methylsulfanyl-N-(2-pyridin-3-retil)-3-pyrrolidin-2-ylpropionic same way as described in example 1. LC-MS: 705 (MH+), IHVR: Wu 1,99 minutes

1H NMR (CDCl3, 270 MHz): δ 0,82-1,11 (m, 18H), 1,20-1,40 (m, 2H), 1.85 to of 2.56 (m, 12H), 2,04 (s, 3H), 2,98 (s, 6H), 2,89-to 3.02 (m, 2H), is 3.08 (s, 3H), of 3.32 (s, 3H), 3,40-3,55 (m, 4H), 3,80-4,50 (m, 3H), 4,66-4,80 (m, 2H), to 7.67-7,88 (.s, 2H), compared to 8.26 is 8.38 (m, 1H), 8,67 (.s, 1H).

Example 31

N-{1-[(1-sec-Butyl-2-methoxy-4-{2-[1-methylsulfanyl-2-(2-pyridin-2-iletileri)ethyl]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-methylsulfanyl-N-(2-pyridin-2-retil)-3-pyrrolidin-2-ylpropionic same way as described in note the re 1. LC-MS: 705 (MN+), IHVR: Wu 2,00 minutes

1H NMR (CDCl3, 270 MHz): δ 0,81-of 1.09 (m, 18H), 1,20-1,50 (m, 2H), 1,70-2,70 (m, 12H), of 1.97 (s, 3H), 2,85-of 3.12 (m, 2H), 3.00 and (s, 6H), of 3.07 (s, 3H), 3,29 (s, 3H), 3,36-3,86 (m, 6H), 4,21 (.s, 1H), 4,71 (.s, 2H), 7,76 (, .s, 1H), 7,89 (.s, 1H), 8,03 (.s, 1H), 8.34 per (.s, 1H), 8,68 (.s, 1H).

Example 32

N-(1-{[1-sec-Butyl-2-methoxy-4-(2-{1-methylsulfanyl-2-[(pyridine-4-ylmethyl)carbarnoyl]ethyl}pyrrolidin-1-yl)-4-oxobutyl] methylcarbamoyl)-2-methylpropyl)-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-methylsulfanyl-N-pyridin-4-ylmethyl-3-pyrrolidin-2-ylpropionic same way as described in example 1. LC-MS: 691 (MN+), IHVR: Wu 2,00 minutes

1H NMR (CDCl3, 270 MHz): δ 0,82-of 1.40 (m, 20H), 1,73-of 2.27 (m, 7H), 2,12 (s, 3H), 2,35-2,70 (m, 5H), 2,96 (.s, 6H), is 3.08 (s, 3H), of 3.33 (s, 3H), 3,42-4,06 (m, 6H), 4,30 (.s, 1H), 4,42-of 4.57 (m, 1H), 4,62-4,88 (m, 3H), 7,88 (.s, 2H), 8,80 (.s, 2H).

Example 33

N-(1-{[1-sec-Butyl-4-(2-{2-[2-(3H-imidazol-4-yl)ethylcarbamate]-1-methylsulfonylmethyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and N-[2-(3H-imidazol-4-yl)ethyl]-3-methylsulfanyl-3-pyrrolidin-2-improvingdebugging to as described in example 1. LC-MS: 694 (MN+), IHVR: Wu to 2.06 minutes

1H NMR (DMSO-d6, 270 MHz): δ 0,74-a 1.01 (m, 18H), 1.25 or of 1.28 (m, 2H), 1,63-of 1.88 (m, 7H), of 1.95 (s, 3H), 1,95 is 2.33 (m, 7H), 2,77 (s, 6H), 3,01 (s, 3H), 3,21 (s, 3H), 3,23-4,12 (m, 7H), 4,50-4,71 (m, 2H), 7,42 (.s, 1H), 8,06 (.s, 1H), 8,92-8,99 (m, 1H), 9,70 (.s, 1H), 14,36 (.s, 1H).

Example 34

N-{1-[(1-sec-Butyl-2-methoxy-4-{2-[1-methylsulfanyl-2-(thiazol-2-ylcarbonyl)ethyl]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-methylsulfanyl-3-pyrrolidin-2-yl-N-thiazol-2-ylpropionic same way as described in example 1. LC-MS: 683 (MN+), IHVR: Wu 2,67 minutes

1H NMR (CDCl3, 270 MHz): δ 0,79 by 1.12 (m, 18H), 1,20-1,50 (m, 2H), 1,60-2,50 (m, 12H), and 2.14 (s, 3H), 2,97 (.s, 6H), 3,11 (s, 3H), and 3.31 (s, 3H), 3,40-of 3.80 (m, 3H), 4,01 (.s, 1H), to 4.38 (.s, 1H), 4,67-4,78 (m, 2H), 7,07 (.s, 1H), of 7.48 (.s, 1H), 7,65 (.s, 1H), 8,62 (.s, 1H).

Example 35

N-{1-[(1-sec-Butyl-2-methoxy-4-{2-[1-methylsulfanyl-2-(naphthalene-2-ylcarbonyl)ethyl]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl)-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-methylsulfanyl-N-naphthalene-2-yl-3-pyrrolidin-2-ylpropionic analogy is ichno to as described in example 1. LC-MS: 726 (MN+), IHVR: Wu 3,13 minutes

1H NMR (CDCl3, 270 MHz): δ 0,52 of 1.50 (m, 20H), 1,95 is 2.43 (m, 12H), 2,17 (s, 3H), 2,78 (s, 3H), 2.95 and (s, 3H), of 3.27 (s, 3H), 3,45-4,08 (m, 4H), 4,42 (.s, 1H), 4.72 in (.s, 2H), 7,41 to 7.75 (m, 7H), 8,33 (.s, 1H), 8,93 (.s, 1H).

Example 36

N-[1-({1-sec-Butyl-4-[2-(2-cyclohexylcarbonyl-1-methylsulfonylmethyl)-pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and N-cyclohexyl-3-methylsulfanyl-3-pyrrolidin-2-ylpropionic same way as described in example 1. LC-MS: 682 (MN+), IHVR: Wu 2,85 minutes

1H NMR (CDCl3, 270 MHz): δ 0,82-of 1.33 (m, 20H), 1,60-2,00 (m,15H), 2,10 (s, 3H), 2,40-2,60 (m, 5H), to 2.99 (s, 6H), of 3.07 (s, 3H), of 3.32 (s, 3H), 3,50-3,98 (m, 7H), 4,29 (.s, 1H), 4,73 (.s, 2H), between 6.08 (.s, 1H), to 7.77 (.s, 1H).

Example 37

N-[1-({1-sec-Butyl-4-[2-(2-{[2-(3,4-acid)ethyl]methyl-carbarnoyl}-1-methylsulfonylmethyl)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}-methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and N-[2-(3,4-acid)ethyl]-N-methyl-3-methylsulfanyl-3-pyrrolidin-2-ylpropionic same way as described in the example 1. LC-MS: 778 (MN+), IHVR: Wu 2,80 minutes

1H NMR (CDCl3, 270 MHz): δ 0,81-1,11 (m, 18H), 1,20-1,40 (m, 2H), 1,65-of 1.94 (m, 7H), 2,10 (s, 3H), 2,02 is 2.51 (m, 5H), 2,81 (.s, 2H), 2,98 (.s, 9H), of 3.07 (s, 3H), and 3.31 (s, 3H), 3,40-4,00 (m, 6H), a 3.87, of 3.85 (2s, 6H), or 4.31 (m, 1H), 4,73 (.s, 2H), 6,03 is 6.67 (m, 3H), 7,71 (.s, 1H).

Example 38

N-(1-{[1-sec-Butyl-4-(2-{2-[2-(3,4-acid)ethylcarbamate]-1-methylsulfonylmethyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]-methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and N-[2-(3,4-acid)ethyl]-3-methylsulfanyl-3-pyrrolidin-2-ylpropionic same way as described in example 1. LC-MS: 764 (MN+), IHVR: Wu 2,69 minutes

1H NMR (CDCl3, 270 MHz): δ 0,78-of 1.15 (m, 18H), 1,20-1,40 (m, 2H), 1,62-2,48 (m, 12H), to 2.06 (s, 3H), 2,78 (t, J 7,6 Hz, 2H), 2,96 (s, 6H), 3,01 (s, 3H), and 3.31 (s, 3H), 3,35 is 3.76 (m, 5H), 3,86 (s, 6H), 3,92-4,10 (m, 1H), 4,15-4,30 (m, 1H), 4,68-4,80 (m, 1H), 6,40 (.s, 1H), 6,72-for 6.81 (m, 3H), 7,42 (.s, 1H).

Example 39

N-[1-({1-sec-Butyl-2-methoxy-4-oxo-4-[2-(1-intercultural-2-phenetically)pyrrolidin-1-yl]butyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-intercultural-N-phenethyl-3-pyrrolidin-2-ylpropionic Academy of Sciences of the logical volume, as described in example 1. MS-LC: 760 (M+), IHVR: Wu 3,71 min (system firm Waters).

1H NMR (CDCl3, 270 MHz): δ 0,81-of 1.62 (m, 27H), 1,72-to 2.40 (m, 12H), 2,44 at 2.59 (m, 5H), 2,73-2,90 (m, 2H), 2.95 and (s, 6H), to 3.02 (s, 3H), 3,30 (s, 3H), 3,30-3,86 (m, 4H), 4,01-4,20 (m, 2H), 4,73 (.s, 2H), 7.18 in-7,28 (m, 5H).

Example 40

N-{1-[(1-sec-Butyl-2-methoxy-4-{2-[1-(naphthalene-2-ylsulphonyl)-2-phenetically]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-(naphthalene-2-ylsulphonyl)-N-phenethyl-3-pyrrolidin-2-ylpropionic same way as described in example 1. LC-MS: 816 (M+), 817 (M+N+), IHVR: Wu 3,90 min (system firm Waters).

1H NMR (CDCl3, 270 MHz): δ 0,70-1,20 (m, 18H), 1,40-2,60 (m, 15H), 2,77 (t, J 5.0 Hz, 2H), equal to 2.94 (s, 6H), 2,96 (s, 3H), at 3.35 (s, 3H), 3,50-of 3.80 (m, 4H), 4,30-and 4.40 (m, 2H)and 4.65-4.75 in (m, 2H), 7,05-7,80 (m, 12H).

Example 41

N-{1-[(1-sec-Butyl-4-{2-[1-(4-perpenicular)-2-phenetically]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)-methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-(4-perpenicular)-N-phenethyl-3-pyrrolidin-2-ylpropionic same way as described in example 1. LC-is From: 798 (M +), 799 (M+N+), IHVR: Wu 3,21 minutes

1H NMR (CDCl3, 270 MHz): δ 0,80-1,20 (m, 18H), 1.30 and of 2.20 (m, 12H), 2,30-2,70 (m, 5H), is 2.88 (m, 2H), 2,96 (s, 6H), 3,01 (s, 3H), of 3.27 (s, 3H), 3,30-of 4.90 (m, 4H), 4,00-of 4.25 (m, 2H), 4,74 (m, 2H), 6,92-to 7.32 (m, 9H).

Example 42

N-{1-[(1-sec-butyl-4-{2-[1-(furan-2-elmersolver)-2-phenetically]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)-methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-(furan-2-elmersolver)-N-phenethyl-3-pyrrolidin-2-ylpropionic same way as described in example 1. LC-MS: 770 (M), 771 (M+N+), IHVR: Wu 3,42 min (system firm Waters).

1H NMR (CDCl3, 270 MHz): δ 0,70-1,20 (m, 18H), 1,20-1,90 (m, 12H), 1,90-to 2.55 (m, 5H), 2,82 (t, J 6.9 Hz, 2H), 2,96 (s, 6H), is 3.08 (s, 3H), 3,26 (s, 3H), 3,31-a-3.84 (m, 4H), 4,05-4,27 (m, 2H), 4,62-4,74 (m, 2H), 6,18-6,55 (m, 3H), 7,19-7,31 (m, 5H).

Example 43

N-(1-{[1-sec-Butyl-2-methoxy-4-(2-{2-[2-(4-methoxyphenyl)-ethylcarboxyl]-1-methylsulfonylmethyl}pyrrolidin-1-yl)-4-oxobutyl]-methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and N-[2-(4-methoxyphenyl)ethyl]-3-methylsulfanyl-3-pyrrolidin-2-ylpropionic same way as described in example 1. LC-MS: 734 (M+), 735(M+N +), IHVR: Wu 2,88 minutes

1H NMR (CDCl3, 270 MHz): δ 0,70-1,20 (m, 18H), 1,20-1,90 (m, 12H), 2,07 (s, 3H), 2,30-2,70 (t, J 7,3 Hz, 3H), 2.95 and (s, 6H), 3,01 (s, 3H), 3,30 (s, 3H), 3,40-3,70 (m, 4H), of 3.78 (s, 3H), 4,00-4,30 (m, 2H), and 4.75 (m, 2H), PC 6.82 (d, J 8.6 Hz, 2H), 7,11 (d, J 8.6 Hz, 2H).

Example 44

N-{1-[(1-sec-Butyl-2-methoxy-4-{2-[1-methylsulfanyl-2-(4-[1,2,3]thiadiazole-4-evensidemargin)ethyl]pyrrolidin-1-yl}-4-oxobutyl)-methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-methylsulfanyl-3-pyrrolidin-2-yl-N-(4-[1,2,3]thiadiazole-4-ylbenzyl)propionamide same way as described in example 1. LC-MS: 774 (M+), 775 (M+N+), IHVR: Wu 2,92 minutes

1H NMR (CDCl3, 270 MHz): δ 0,70-of 1.10 (m, 18H), 1,20-2,00 (m, 12H), 2,10 (s, 3H), 2,30-2,70 (m, 3H), 2.95 and (s, 6H), 3,01 (s, 3H), and 3.31 (s, 3H), of 3.54 (m, 2H), 3,70-4,20 (m, 2H), 4,30-4,80 (m, 4H), 7,43 (d, J 7.9 Hz, 2H), 7,98 (d, J 7.9 Hz, 2H), 8,69 (d, J 5.3 Hz, 1H).

Example 45

N-{1-[(4-{2-[2-(1-Benzylpiperidine-4-ylcarbonyl)-1-methylsulfonylmethyl]pyrrolidin-1-yl}-1-sec-butyl-2-methoxy-4-oxobutyl)-methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and N-(1-benzylpiperidine-4-yl)-3-methylsulfanyl-3-pyrrolidin-2-ylpropionic similar to how the op is Sano in example 1. LC-MS: 773 (M+), IHVR: Wu 2,33 minutes

1H NMR (CDCl3, 270 MHz): δ 0,70-1,20 (m, 22H), 1,70 is 2.80 (m, 15H), to 2.06 (s, 3H), 2,96 (s, 9H), to 3.33 (s, 3H), 3,40-of 4.05 (m, 6H), 4,20-and 4.40 (m, 5H), 4,70 (.s, 2H), 7,44 (m, 5H).

Example 46

N-[1-({1-sec-Butyl-4-[2-(1-methanesulfonyl-2-phenetically)-pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}-methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate

Obtain tert-butyl ester 2-(methanesulfonyl-2-phenethyl-carbamoylethyl)pyrrolidin-1-carboxylic acid.

To a stirred solution of tert-butyl methyl ether 2-(methanesulfonyl-2-phenetically)pyrrolidin-1-carboxylic acid (62 mg, 0,158 mmole) in CH2Cl2(2 ml) at 0°C was added mCPBA (30 mg, 0,174 mmole) and the reaction mixture was stirred at 0°C for 1 h the Reaction was stopped by adding 1 N. NaOH, and was extracted with AcOEt, the extract was washed with saturated NaCl solution, dried (MgSO4) and concentrated in vacuum. The obtained residue was purified preparative TLC (eluent: CH2Cl2/Meon, 95:5), was obtained tert-butyl ester 2-(methanesulfonyl-2-phenetically)pyrrolidin-1-carboxylic acid as a colourless oil (39 mg, 61%). LC-MS: 409 (MH+), IHVR: Wu 2,99 minutes

1H NMR (CDCl3, 270 MHz): δ of 1.46 (s, 9H), 1,20-of 1.39 (m, 2H), 1,62-to 2.40 (m, 6H), 2,47 (s, 3H), and 2.83 (t, J 6.9 Hz, 2H), 3,13-to 3.33 (m, 1H), 3,35-3,70 (m, 3H), 3.75 to 3,95 (m, 1H), 3.95 to to 4.15 (m, 1H), 7,10-7,38 (m, 5H).

Specified in the header with the unity was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-methanesulfonyl-N-phenethyl-3-pyrrolidin-2-ylpropionic same as described in example 1. LC-MS: 720 (MN+), IHVR: Wu 2,50 minutes

1H NMR (CDCl3, 270 MHz): δ 0,65-of 1.09 (m, 15H), of 1.12 (d, J 6.0 Hz, 3H), 1,27-of 2.72 (m, 15H), of 2.53 (s, 3H), 2,82 (t, J 6.9 Hz, 2H), equal to 2.94 (s, 6H), 3,03 (s, 3H), 3,29 (s, 3H), 3.25 to the 3.65 (m, 4H), 3,70-of 4.05 (m, 1H), 4,30-4,50 m, 1H), 4,60-4,85 (m, 2H), 6,95-7,37 (m, 5H).

Example 47

N-[1-({1-sec-Butyl-4-[2-(1-methanesulfonyl-2-phenetically)-pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}-methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate

Obtain tert-butyl ester 2-(methanesulfonyl-2-phenetically-ethyl)pyrrolidin-1-carboxylic acid

To a stirred solution of tert-butyl methyl ether 2-(methanesulfonyl-2-phenetically)pyrrolidin-1-carboxylic acid (130 mg, 0,331 mmole) in CH2Cl2(4 ml) at 0°C was added mCPBA (286 mg, of 1.66 mmole) and the reaction mixture was stirred at RT for 2 h the Reaction was stopped by adding 1 N. NaOH, and was extracted with AcOEt, the extract was washed with saturated NaCl solution, dried (MgSO4) and concentrated in vacuum. The obtained residue was purified preparative TLC (eluent: n-hexane/AcOEt, 1:3), was obtained tert-butyl ester 2-(methanesulfonyl-2-phenetically)pyrrolidin-1-carboxylic acid (140 mg, yield quantitative) as a colorless oil. LC-MS: 425 (MN+), IHVR: Wu 3,45 minutes

1H NMR (CDCl3, 270 MHz): δ the 1.44 (s, N), 1,65 is 2.80 (m, 6H), 2,82 (t, J 6.9 Hz, 2H), 2,90 (s, 3H), 3,00-4,00 (m, 5H), 4,20-and 4.40(m, 1H), 5.40 to-5,74 (m, 1H), 7,05-7,40 (m, 5H).

Specified in the title compound was obtained by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-methanesulfonyl-N-phenethyl-3-pyrrolidin-2-ylpropionic same way as described in example 1. LC-MS: 736 (MN+), IHVR: Wu 2,67 minutes

1H NMR (CDCl3, 270 MHz): δ 0,65-of 1.09 (m, 15H), to 1.14 (d, J 6.3 Hz, 3H), 1,25-to 2.85 (m, 17H), to 2.94 (s, 6H), 2,96 (s, 3H), 2,99 (s, 3H), 3,30 (s, 3H), 3.25 to to 3.92 (m, 5H), 4,00-of 4.25 (m, 1H), 4,50-4,80 (m, 2H), 7,05-7,38 (m, 5H).

Example 48

N-[1-({1-sec-Butyl-2-methoxy-4-[2-(1-methylsulfanyl-2-phenetically)pyrrolidin-1-yl]-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-3-methyl-2-methylaminomethyl

To a stirred solution of tert-butyl methyl ether 2-(1-methylsulfanyl-2-phenetically)pyrrolidin-1-carboxylic acid (1,15 g of 2.93 mmole) in CH2Cl2(3 ml) at 0°With added TFU, the mixture was stirred at 0°C for 30 min and evaporated in vacuum, thus received triptorelin 3-methylsulfanyl-N-phenethyl-3-pyrrolidin-2-ylpropionic in the form of crude oil (1,87 g), which was used in the next stage without additional purification (diastereomers were separated preparative GHUR (column ODS-80TS, eluent: N2O/acetonitrile, 79:21, +0.05% of TFU)).

To a stirred solution of (3R*,4S*,5S*)-4-[N-benzyloxycarbonyl-N-methyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic key is lots of (1.12 g, is 2.05 mmole)obtained in a known manner (see Chem.Pharm.Bull, 43 (10), 1706-1718, 1995), and the crude trifenatate 3-methyl-effect-free remedy N-phenethyl-3-pyrrolidin-2-ylpropionic (1.31 g, is 2.05 mmole), obtained as described above, in CH2Cl2(3 ml) at 0°With added diisopropylethylamine (to 3.58 ml of 20.5 mmole), WSCI monohydrochloride (511 mg, to 2.67 mmole) and HOBt monohydrate (408 mg, to 2.67 mmole). The mixture was stirred at room temperature for 16 h and evaporated in vacuo, the residue was dried in vacuum, to receive benzyl ether {1-[1-({1-sec-butyl-2-methoxy-4-[2-(1-methylsulfanyl-2-phenetically)pyrrolidin-1-yl]-4-oxobutyl}-methylcarbamoyl)-2-methylpropionyl]-2-methylpropyl}methylcarbamate acid (2,19 g) in the form of crude oil, which was used in the next stage without additional purification. To a stirred solution of benzyl ether {1-[1-({1-sec-butyl-2-methoxy-4-[2-(1-methylsulfanyl-2-phenetically)pyrrolidin-1-yl]-4-oxobutyl}methylcarbamoyl)-2-methylpropionyl]-2-methylpropyl}-methylcarbamyl acid (1.1 g), obtained as described above, in tBuOH (36 ml) and H2O (4 ml) at room temperature was added Pd(OH)2coal (approximately 20 wt.%, 1 g) and the mixture was first made in an atmosphere of H2under stirring at room temperature for 14 hours Then the mixture was filtered through a layer of celite, celite washed EON. The filtrate and washing were combined and concentrated in vacuum to receive the crude resin (1.01 g), which was purified preparative GHUR (column ODS-80Ts, eluent: N2O/acetonitrile, 57:43, +0.05% of TFU). The appropriate fractions were freeze-dried, thus received is listed in the title compound as an amorphous white powder (388 mg, 47%). LC-MS: 690 (MN+), IHVR: Wu was 2.76 min (R-isomer).

1H NMR (CDCl3, 270 MHz): δ 0,81 (t, J 6,93 Hz, 3H), 0,85-of 1.13 (m, 15H), 1,22-of 1.42 (m, 2H), 1,51-to 2.18 (m, 10H), 2,02 (s, 3H), 2,2-2,49 (m, 3H), 2,71 (s, 3H), of 2.81 (t, J 6.6 Hz, 2H), 2,92 (s, 3H), 3,29 (s, 3H), 3.33 and-3,95 (m, 4H), was 4.02-4,16 (m, 1H), 4,16-4,32 (m, 1H), 4,56 is equal to 4.97 (m, 2H), 6,59 (.s, 1H), 7,07-7,38 (m, 5H), 7,6 (.s, 1H).

The following compounds (examples 49-53) was obtained in the same way as described in example 48.

Example 49

N-[1-({1-sec-Butyl-4-[2-(1-ethylsulfanyl-2-phenetically)-pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-3-methyl-2-methylaminomethyl

Specified in the title compound was obtained from (3R*,4S*,5S*)-4-[N-benzyloxycarbonyl-N-methyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-ethylsulfanyl-N-phenethyl-3-pyrrolidin-2-yl-propionamide same way as described in example 48. LC-MS: 704 (MN+), IHVR: Wu 2,87 min (R-isomer).

1H NMR (CDCl3, 270 MHz): δ 0,68-of 1.10 (m, 18H), of 1.16 (t, J 7,3 Hz, 3H), 1,20-of 1.42 (m, 2H), 1,55-to 2.18 (m, 10H), 2,18-2,60 (m, 3H), 2.49 USD (t, J 7.2 Hz, 2H), 2,71 (s, 3H), and 2.83 (t, J 6.9 Hz, 2H), 3,03 (s, 3H, 3,29 (s, 3H), 3,20-of 3.78 (m, 4H), 3,97-4,12 (m, 1H), 4,12-to 4.28 (m, 1H), 4,65-of 4.90 (m, 2H), 7,08-to 7.32 (m, 5H).

Example 50

N-[1-({1-sec-Butyl-2-methoxy-4-oxo-4-[2-(2-phenetically-1-phenylsulfanyl)pyrrolidin-1-yl]butyl}methylcarbamoyl)-2-methylpropyl]-3-methyl-2-methylaminomethyl

Specified in the title compound was obtained from (3R*,4S*,5S*)-4-[N-benzyloxycarbonyl-N-methyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and N-phenethyl-3-phenylsulfanyl-3-pyrrolidin-2-yl-propionamide same way as described in example 48. LC-MS: 752 (MH+), IHVR: Wu is 3.08 min (R-isomer).

1H NMR (CDCl3, 270 MHz): δ 0,65-of 1.15 (m, 18H), 1.18 to 2,58 (m, 15H), a 2.71 (s, 3H), 2,60-to 2.85 (m, 2H), 3,03 (s, 3H), 3,21 (s, 3H), 3,22-3,95 (m, 4H), 3,98 was 4.42 (m, 2H), 4,50-4,85 (m, 2H), 7,05-7,42 (m, 10H).

Example 51

N-[1-({1-sec-Butyl-4-[2-(1-tert-butylsulfonyl-2-phenetically-ethyl)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}-methylcarbamoyl)-2-methylpropyl]-3-methyl-2-methylaminomethyl

Specified in the title compound was obtained from (3R*,4S*,5S*)-4-[N-benzyloxycarbonyl-N-methyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-tert-butylsulfonyl-N-phenethyl-3-pyrrolidin-2-ylpropionic same way as described in example 48. LC-MS: 732 (MN+), IHVR: Wu 3,25 min (R-isomer).

1H NMR (CDCl3, 270 MHz): δ 0,65-of 1.40 (m, 18H), 1,25 (s, 9H), 1,50-to 2.65 (m, 15H), of 2.72 (s, 3H), of 2,75 2,95 (m, 2H), 3.04 from (s, 3H), of 3.28 (s, 3H), 3,29-of 3.80 (m, 4H), 3,92-4,22 (m, 2H), 4,60-of 4.95 (m, 2H), 7,00-7,40 (m, 5H).

Example 52

N-[1-({1-sec-Butyl-4-[2-(1-isopropylphenyl-2-phenetically-ethyl)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}-methylcarbamoyl)-2-methylpropyl]-3-methyl-2-methylaminomethyl

Specified in the title compound was obtained from (3R*,4S*,5S*)-4-[N-benzyloxycarbonyl-N-methyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-isopropylphenyl-N-phenethyl-3-pyrrolidin-2-ylpropionic same way as described in example 48. LC-MS: 718 (MN+), IHVR: Wu 2,97 min (R-isomer).

1H NMR (CDCl3, 270 MHz): δ 0,81 (t, J 6,92 Hz, 3H), from 0.88 to 1.11 (m, 15H), 1,11-of 1.45 (m, 8H), 1,50-of 2.21 (m, 11N), 2.21 are 2,60 (m, 3H), 2,71 (s, 3H), 2,84 (t, J 6,93 Hz, 3H), 3,03 (s, 3H), of 3.32 (s, 3H), 3,39-of 3.78 (m, 4H), 3,93-4,29 (m, 2H), 4.63 to-the 4.90 (m, 2H), 6,70 (.s, 1H), 7,07 and 7.36 (m, 5H), to 7.64 (.s, 1H).

Example 53

N-{1-[(1-sec-Butyl-2-methoxy-4-oxo-4-{2-[2-phenetically-1-(2-methylpropan-2-sulfonyl)ethyl]pyrrolidin-1-yl}butyl)methylcarbamoyl]-2-methylpropyl}-3-methyl-2-methylaminomethyl

Specified in the title compound was obtained from (3R*,4S*,5S*)-4-[N-benzyloxycarbonyl-N-methyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-(2-methylpropan-2-sulfonyl)-N-phenethyl-3-pyrrolidin-2-ylpropionic same way as described in example 48. LC-MS: 764 (MN+), IHVR: Wu 2,81 min (R-isomer).

1H NMR (CDCl3, 270 MHz): δ 0,81 (t, J 6,93 Hz, 3H), 0,85-1,17 (m, 15H), 1,17-of 1.52 (m, 2H), of 1.18 (s, 9H), 1,52 at 2.59 (m, 13H), a 2.71 (s, 3H), and 2.79 (t, J 6,93 Hz, 2H), 2,92 (s, 3H), 3,10 is 3.76 (m, 4H), 3,29 (s, 3H), 3,85-to 4.41 (m, 2), to 4.52-of 4.90 (m, 2H), 6,41 (.s, 1H), 7,00 was 7.36 (m, 5H), 7,51 (.s, 1H).

Example 54

N-[1-({1-sec-Butyl-4-[2-(1-methanesulfonyl-2-phenetically)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-3-methyl-2-methylaminomethyl

To a stirred solution of benzyl ether {1-[1-({1-sec-butyl-2-methoxy-4-[2-(1-methylsulfanyl-2-phenetically)pyrrolidin-1-yl]-4-oxobutyl}methylcarbamoyl)-2-methylpropionyl]-2-methylpropyl}methylcarbamate acid (0.35 g) in CH2Cl2(3 ml) at room temperature was added mCPBA (80%, 356 mg, 1.65 mmole). After stirring at room temperature for 4 h the reaction was stopped by adding 5 N. NaOH (10 ml), the mixture was extracted with AcOEt, the extract washed with N2Oh, dried (MgSO4) and concentrated in vacuum to receive benzyl ether {1-[1-({1-sec-butyl-2-methoxy-4-[2-(1-methylsulphonyl-2-phenetically)pyrrolidin-1-yl]-4-oxobutyl}methylcarbamoyl)-2-methylpropionyl]-2-methylpropyl}methylcarbamate acid (311 mg) as a crude oil which was used in the next stage without additional purification.

To a stirred solution of benzyl ether {1-[1-({1-sec-butyl-2-methoxy-4-[2-(1-methylsulphonyl-2-phenetically)pyrrolidin-1-yl]-4-oxobutyl}methylcarbamoyl)-2-methylpropionyl]-2-methylpropyl}methylcarbamate acid (311 mg), poluchennogo is, as described above, in tBuOH (9 ml) and N2O (1 ml) at room temperature was added Pd(OH)2coal (approximately 20 wt.%, 1 g) and the mixture was first made in an atmosphere of H2under stirring at room temperature for 13.5 hours Then the mixture was filtered through a layer of celite, celite was washed Meon. The filtrate and washing were combined and concentrated in vacuum to receive the crude resin (285 mg), which was purified preparative GHUR (column ODS-80Ts, eluent N2About+/acetonitrile, 40:30, +0.05% of TFU). The appropriate fractions were freeze-dried, thus received is listed in the title compound as an amorphous white powder (160 mg, 58%). LC-MS: 722 (MN+), IHVR: Wu 2,61 min (R-isomer).

1H NMR (CDCl3, 270 MHz): δ 0,49-1,14 (m, 18H), 1,20-of 1.39 (m, 2H), 1,48 at 2.59 (m, 13H), a 2.71 (s, 3H), 2,77 (d, J 6.6 Hz, 2H), 2.95 and (s, 3H), 3,01 (s, 3H), 3,02-3,98 (m, 4H), of 3.28 (s, 3H), was 4.02-to 4.38 (m, 2H), 4,42-of 4.95 (m, 2H,), 6,27 (.s, 1H), 7,02-7,40 (m, 5H), 7,81 (.s, 1H).

The following compounds (examples 55-57) was obtained in the same way as described in example 54.

Example 55

N-[1-({1-sec-Butyl-4-[2-(1-econsultancy-2-phenetically)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-3-methyl-2-methylaminomethyl

Specified in the title compound was obtained by oxidation of benzyl ether {1-[1-({1-sec-butyl-4-[2-(1-ethylsulfanyl-2-phenetically)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}metalk rebamol)-2-methylpropionyl]-2-methylpropyl}methylcarbamate acid in the presence of mCPBA and the subsequent hydrogenation of the resulting product in the same way as described in example 54. LC-MS: 736 (MN+), IHVR: Wu 2,68 min (R-isomer).

1H NMR (CDCl3, 270 MHz): δ 0,70-of 1.18 (m, 18H), to 1.38 (t, J 7,3 Hz, 3H), 1,20 was 1.43 (m, 2H), 1,55-of 2.86 (m, 13H), a 2.71 (s, 3H), 2,78 (t, J 7,3 Hz, 2H), 3.00 and (s, 3H), 3,29 (s, 3H), 3,02-3,81 (m, 6H), 3,81-of 3.97 (m, 1H), 4,10-4,22 (m, 1H), 4,55-4,88 (m, 2H), 7,08-7,39 (m, 5H).

Example 56

N-[1-({4-[2-(1-Benzazolyl-2-phenetically)pyrrolidin-1-yl]-1-sec-butyl-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-3-methyl-2-methylaminomethyl

Specified in the title compound was obtained in the same way as described in example 54 by oxidation of benzyl ether {1-[1-({1-sec-butyl-2-methoxy-4-oxo-4-[2-(2-phenetically-1-phenylsulfanyl)pyrrolidin-1-yl]butyl}-methylcarbamoyl)-2-methylpropionyl]-2-methylpropyl}methylcarbamate acid in the presence of m-SRVA and subsequent hydrogenation. LC-MS: 784 (MN+), IHVR: Wu 2,92 min (R-isomer).

1H-NMR (CDCl3, 270 MHz): δ 0,65-of 1.18 (m, 18H), 1.30 and 2,60 (m, 15 NM), a 2.71 (s, 3H), 2,60 is 2.80 (m, 2H), 2,99 (s, 3H), 3,29 (s, 3H), 3,10-of 3.75 (m, 4H), 3,88-4,17 (m, 2H), 4,60-4,88 (m, 2H), 7,00-to 7.32 (m, 5H), 7,40 to 7.75 (m, 3H), 7,89 (d, J 7,3 Hz, 1H).

Example 57

N-{1-[(1-sec-Butyl-2-methoxy-4-oxo-4-{2-[2-phenetically-1-(propane-2-sulfonyl)ethyl]pyrrolidin-1-yl}butyl)methylcarbamoyl]-2-methylpropyl}-3-methyl-2-methylaminomethyl

Specified in the title compound was obtained in the same way as described in example 54 by oxidation of benzyl ether {1-[1-({1-sec-butyl-4-[2-(1-ISO-propyl who sulfanyl-2-phenetically)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropionyl]-2-methylpropyl}methylcarbamate acid in the presence of m-SRVA and subsequent hydrogenation. LC-MS: 750 (MN+), IHVR: Wu 2,72 min (R-isomer).

1H-NMR (CDCl3, 270 MHz): δ 0,81 (t, J 6,93 Hz, 3H), 0,85-1,15 (m, 15 NM), 1,15-for 1.49 (m, 8H), 1,50-to 2.67 (m, 13H), a 2.71 (s, 3H), 2,78 (t, J 6,92 Hz, 2H), 3.00 and (s, 3H), 3,10-with 3.79 (m, 4H), of 3.28 (s, 3H), 3.95 to 4,37 (m, 2H), 4,45-to 4.98 (m, 2H), of 6.31 (.s, 1H), 7,02-7,38 (m, 5H), 7,54 (.s, 1H).

Example 58

N-[1-({1-sec-Butyl-2-methoxy-4-[2-(1-methylsulfanyl-2-phenethyl-carbamoylmethyl)pyrrolidin-1-yl]-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate

Obtain tert-butyl ester 2-(1-methylsulfanyl-2-phenethyl-carbamoylmethyl)pyrrolidin-1-carboxylic acid

To a stirred solution of tert-butyl methyl ether (S)-2-(2-methoxy-carbonylethyl)pyrrolidin-1-carboxylic acid (200 mg, of 0.71 mmole) in THF (3 ml) at room temperature was added NaSMe (95%, 156 mg, 2.12 mmole). Then the mixture was stirred in a sealed vial at 150°C for 14 h, cooled to room temperature, neutralized by adding 1 N. HCl (20 ml), was extracted with AcOEt, dried (MgSO4) and concentrated in vacuum were obtained tert-butyl ester 2-(2-carboxy-1-methylsulfinylpropyl)-pyrrolidin-1-carboxylic acid (223 mg) as a crude oil which was used in the next stage without additional purification.

To a stirred solution of the crude tert-butyl ether 2-(2-carboxy-1-methylsulfinylpropyl)pyrrolidin-1-carboxylic acid (223 mg), receive the frame, as described above, in CH2Cl2(3 ml) at room temperature was added phenethylamine (of 0.18 ml of 1.41 mmole), WSCI monohydrochloride (203 mg, of 1.06 mmole), HOBt monohydrate (162 mg, of 1.06 mmole) and diisopropylethylamine (0,37 ml, 2.12 mmole). The mixture was stirred at room temperature for 4.5 hours, neutralized by adding 1 N. HCl (20 ml), was extracted with AcOEt, dried (MgSO4) and concentrated in vacuum to receive the crude oil, which was purified rapid chromatography on a column (eluent: hexane/AcOEt, 3:1), was obtained tert-butyl ester 2-(1-methylsulfanyl-2-phenethyl-carbamoylmethyl)pyrrolidin-1-carboxylic acid in the form of oil (123 mg, 43%).

Specified in the title compound was obtained in the same way as described in example 1 by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 2-methyl-3-methyl-effect-free remedy N-phenethyl-3-pyrrolidin-2-ylpropionic obtained from N-Boc-derivative, as described above. LC-MS: 407 (MN+), IHVR: Wu 4,06 minutes

1H-NMR (CDCl3270 MHz): δ of 1.27 (d, J 7,6 Hz, 6N), 1,45 (s, 9H), 1,58 was 2.25 (m, 4H), 2.26 and at 2.45 (m, 4H), 2,84 (t, J 6,93 Hz, 2H), 3,13-of 3.75 (m, 5H), 3,83-Android 4.04 (m, 1H), 6,03 (.s, 1H), 7,08-7,40 (m, 5H).

Example 59

N-[1-({1-sec-Butyl-2-methoxy-4-[2-(1-methylsulfanyl-2-phenethyl-carbamoylmethyl)pyrrolidin-1-yl]-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-methylamino-3-methylbutyrate

Specified in reception is e compound was obtained from (3R*,4S*,5S*)-4-[N-benzyloxycarbonyl-N-methyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid and 3-methylsulfanyl-N-phenethyl-3-pyrrolidin-2-ylpropionic same as described in example 48. LC-MS: 704 (MN+), IHVR: Wu 2,88 minutes

1H-NMR (CDCl3, 270 MHz): δ 0,60-of 1.16 (m, 18H), 1,16-of 1.42 (m, 5H), 1,50 is 2.10 (m, 9H), 2,07 (s, 3H), 2,15-2,52 (m, 3H), of 2.72 (s, 3H), 2,69-is 2.88 (m, 2H), 3,01 (s, 3H), and 3.31 (s, 3H), 3,26-of 3.77 (m, 4H), 3,99-4,18 (m, 1H), 4,18-4,30 (m, 1H), 4,59-of 5.89 (m, 2H), 7,02 and 7.36 (m, 4H).

Example 60

N-(1-{[1-sec-Butyl-4-(2-{2-[2-(3-hydroxyphenyl)ethylcarbamate]-1-methyl-sulfanilyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate

Obtain tert-butyl ester (2S)-2-[(1R,2S)-2-benzyloxycarbonyl-1-matilal anistropy] pyrrolidin-1-carboxylic acid

To mix the solution AcSMe (24.4 g, of 0.27 mol) in THF (580 ml), cooled in an ice bath, was added KOEt (of 22.8 g of 0.27 mol) and the resulting mixture was stirred at room temperature for 3.5 hours and Then the mixture was sequentially added phenol (11.9 ml, of 0.14 mol) and a solution of tert-butyl ester (2S)-2-(2-benzyloxycarbonylamino)pyrrolidin-1-carboxylic acid (15.6 g, of 0.045 mol) in THF (50 ml). After 45 min the mixture was added a saturated solution of NH4Cl and concentrated in vacuum. The residue was diluted with EtOAc (600 ml), washed with 1 N. NaOH (3×300 ml) and brine (200 ml). The organic layer was dried over anhydrous Na2SO4and concentrated in vacuum. The residue was purified by chromatography on a column of silica gel (eluent: hexane/EtOAc, 9:1), was obtained tert-butyl EF the R (2S)-2-[(1R,2S)-2-benzyloxycarbonyl-1-methylsulfinylpropyl]pyrrolidin-1-carboxylic acid, which contained a mixture of phenol. Removal of phenol fractions containing tert-butyl ester (2S)-2-[(1R,2S)-2-benzyloxycarbonyl-1-methylsulfinylpropyl]pyrrolidin-1-carboxylic acid, washed with 5 N. NaOH (300 ml), N2O (300 ml) and dried over anhydrous MgSO4. The organic layer was concentrated in vacuum and obtained tert-butyl ester (2S)-2-[(1R,2S)-2-benzyloxycarbonyl-1-methylsulfinylpropyl]pyrrolidin-1-carboxylic acid (12.5 g, 70%). MS (ES): m/z 416 (M++Na), IHVR: Wu is 3.08 min

1H-NMR (CDCl3, 400 MHz): δ 1,10-of 1.39 (m, 3H), of 1.46 (s, 9H), 1,64 to 1.76 (m, 1H), 1,81-of 1.97 (m, 3H), of 2.06 (s, 3H), 2,52 of 2.68 (m, 1H), 3,12-of 3.25 (m, 1H+5/9H), 3,34-3,62 (m, 1H+4/9H), 3,82-Android 4.04 (m, 1H), 5,04-of 5.26 (m, 2H), 7,26-7,40 (m, 5H) (mixture of two rotamers).

Obtain tert-butyl ester (2S)-2-[(1R,2S)-2-carboxy-1-methyl-sulfanilyl]pyrrolidin-1-carboxylic acid

A mixture of tert-butyl ester (2S)-2-[(1R,2S)-2-benzyloxycarbonyl-1-methylsulfinylpropyl]pyrrolidin-1-carboxylic acid (4.4 g, 11.2 mmole) and Pd(OH)2coal (approximately 20 wt.%, 2.0 g) in EtOH (50 ml) was stirred at room temperature in a hydrogen atmosphere for 14 hours Then the mixture was filtered through a layer of celite, celite was washed Meon. The filtrate and washing were combined and concentrated in vacuum to receive the crude resin, which was purified Express chromatography (eluent: hexane/EtOAc, 1:1), was obtained tert-butyl ester (2S)-2-[(1R,2S)-2-carboxy-1-METI sulfanilyl]-pyrrolidin-1-carboxylic acid resin (3,39 g, 98%). LC-MS: 304 (MN+), IHVR: Wu 3,45 minutes

1H-NMR (CDCl3, 270 MHz): δ of 1.39 (d, J 5,94 Hz, 3H), 1,45 (s, 9H), 1,58 is 2.01 (m, 5H), 2,12 (s, 3H), 2,47-2,69 (m, 1H), 3,11-of 3.75 (m, 2H), 3,92-4,16 (m, 1H).

Obtain tert-butyl ester (2S)-2-{(1R,2S)-2-[2-(3-hydroxyphenyl)-ethylcarboxyl]-1-methylsulfinylpropyl} pyrrolidin-1-carboxylic acid

To a stirred solution of tert-butyl ester (2S)-2-[(1R,2S)-2-carboxy-1-methylsulfinylpropyl]pyrrolidin-1-carboxylic acid (1.7 g, 5.6 mmole) in CH2Cl2(20 ml) at room temperature was added hydrogen bromide 3-hydroxytyramine (2,44 g, 11.2 mmole), THIEF (and 3.72 g, 8.4 mmole), NOT (1.29 g, 8.4 mmole) and diisopropylethylamine (4,88 ml of 28.0 mmole). Then the mixture was stirred at room temperature for 2 h, neutralized by adding 1 N. HCl (80 ml ×3), was extracted with AcOEt, dried (MgSO4) and concentrated in vacuum to receive the crude oil, which was purified Express chromatography (eluent: hexane/EtOAc, 1:1), was obtained tert-butyl ester (2S)-2-{(1R,2S)-2-[2-(3-hydroxyphenyl)ethylcarbamate]-1-methylsulfinylpropyl}pyrrolidin-1-carboxylic acid resin (2,07 g, 87%). MS (ES): m/z 423 (M++1), IHVR: Wu 3,57 minutes

1H-NMR (CDCl3, 270 MHz): δ of 1.26 and 1.35 (m, 3H), 1,49 (s, 9H), 1.70 to of 1.97 (m, 1H), 2,12 (s, 3H), 2,24-to 2.41 (m, 1H), 2,67-and 2.83 (m, 2H), is 3.08-to 3.36 (m, 2H), 3,45-3,66 (m, 2H), of 3.77-3,91 (m, 1H), 3,98-4,10 (m, 1H), 5,80 (.s, 1H), 6,65-to 6.80 (m, 2H), 6,92 (.s, 1H), 7,18 (t, J 7.8 Hz, 1H), 7,86 (.s, 1H).

Specified in the title compound was obtained in the form of an individual stereoisomer by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid tert-butyl ester (2S)-2-{(1R,2S)-2-[2-(3-hydroxyphenyl)ethylcarbamate]-1-methylsulfinylpropyl}pyrrolidin-1-carboxylic acid in the same way as described in example 1. The product remained the stereochemical configuration specified for each component. LC-MS: 734 (MN+), IHVR: Wu 2,62 minutes

1H-NMR (CDCl3, 270 MHz): δ of 0.82 (d, J 6,92 Hz, 3H), 0,81-1,17 (m, 15H), 1,17-of 1.41 (m, 8H), 1,50 is 2.10 (m, 9H), was 2.05 (s, 3H), 2,10-to 2.65 (m, 3H), 2,65-2,84 (m, 2H), 2,99 (s, 6H), 3,11 (s, 3H), of 3.32 (s, 3H), 3,22-of 3.60 (m, 4H), 3,62-to 3.92 (m, 1H), 3,92-4,11 (m, 1H), 4,55-to 4.81 (m, 2H), 6,60-6,85 (m, 3H), 7,14 (t, J to 7.59 Hz, 1H).

Example 61

N-[1-({1-sec-Butyl-4-[2-(2-{[2-(3-hydroxyphenyl)ethyl]methylcarbamoyl}-1-methylsulfinylpropyl)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate

Obtain tert-butyl ester (2S)-2-((1R,2S)-2-{[2-(3-hydroxyphenyl)-ethyl]methylcarbamoyl}-1-methylsulfinylpropyl)pyrrolidin-1-carboxylic acid

To a stirred solution of tert-butyl ester (2S)-2-[(1R,2S)-2-carboxy-1-methylsulfinylpropyl]pyrrolidin-1-carboxylic acid (1.70 g, 5.6 mmole) in CH2Cl2(20 ml) at room temperature was added hydrogen bromide N-methyl-3-hydroxytyramine (2,44 g, 11.2 mmole), THIEF (and 3.72 g, 8.4 mmole), HOBt (1.9 grams, 8.4 mmole) and diisopropylethylamine (4,88 ml of 28.0 mmole). The mixture was stirred at room temperature for 2 h, neutralized by adding 1 N. HCl (80 ml ×3), was extracted with AcOEt, dried (MgSO4) and concentrated in vacuum to receive the crude oil (3,83 g)which was purified by the method of rapid chromatography on a column (eluent:hexane/AcOEt, 1:1), was obtained tert-butyl ester (2S)-2-((1R,2S)-2-{[2-(3-hydroxyphenyl)-ethyl]methylcarbamoyl}-1-methyl sulfanilyl)pyrrolidin-1-carboxylic acid resin (1,38 g, 56%). LC-MS: 437 (MH+), IHVR: Wu 3,90 minutes

1H-NMR (CDCl3, 270 MHz): δ of 1.27 (d, J 7,26 Hz, 3H), 1.30 and of 1.56 (m, 9H), of 1.5-2.1 (m, 5H), 1,99 is 2.33 (m, 3H), 2.49 USD is 2.80 (m, 1H), 1,90-is 2.88 (m, 2H), 2,88 of 3.56 (m, 3H), 3,56-to 4.15 (m, 1H), 6,52-6,89 (m, 3H), 7,00-7,21 (m, 1H).

Obtaining specified in the connection header

Specified in the title compound was obtained in the form of an individual stereoisomer by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid tert-butyl ester (2S)-2-((1R,2S)-2-{[2-(3-hydroxyphenyl)ethyl]methylcarbamoyl}-1-methylsulfinylpropyl)pyrrolidin-1-carboxylic acid in the same way as described in example 1. The product remained the stereochemical configuration specified for each component. LC-MS: 748 (MN+), IHVR: Wu 2,78 minutes

1H-NMR (CDCl3, 270 MHz): δ 0,62-of 1.17 (m, 18H), 1,17-of 1.42 (m, 5H), 1,45 is 2.10 (m, 9H), 1.91 a-2,11 (m, 3H), 2.1 to 2,62 (m, 3H), 2,70-2,84 (m, 2H), 2,99 (s, 6H), 3,06 (s, 3H), 3,30 (s, 3H), 3,38 (s, 3H), 3,20-the 3.65 (m, 4H), of 3.77-of 4.25 (m, 2H), 4,40-of 4.95 (m, 2H), 6,83 (m, 3H), 6,92-to 7.18 (m, 1H).

Example 62

N-[1-({1-sec-Butyl-4-[2-(1-ethylsulfanyl-2-{[2-(3-hydroxyphenyl)ethyl]-methylcarbamoyl}propyl)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate

Obtain tert-butyl ester (2S)-2-[(1R,2S)-2-benzyloxycarbonyl-1-ethylsulfanyl]pyrrolidin-1-carboxylic acid

To a stirred suspension of t-BuOK (609 mg, 5,43 mmole) in THF (90 ml) was added EtSH (8,04 ml of 0.11 mol) and the mixture was stirred at room temperature for 30 minutes Then to the mixture was added a solution of tert-butyl ester (2S)-2-(2-benzyloxycarbonylamino)pyrrolidin-1-carboxylic acid (3.75 g, 10.8 mmole) in THF (75 ml). After 2.5 h the mixture was added a saturated solution of NH4Cl and concentrated in vacuum. The residue was diluted with EtOAc (400 ml), washed with saturated solution of NH4Cl (150 ml), a saturated solution of NaHCO3(150 ml) and water (150 ml). The organic layer was dried over anhydrous Na2SO4and concentrated in vacuum. The residue was purified by chromatography on a column of silica gel (eluent: hexane/EtOAc, 12:1 to 8:1), was obtained tert-butyl ester (2S)-2-[(1R,2S)-2-benzyloxycarbonyl-1-ethylsulfanyl]pyrrolidin-1-carboxylic acid (3,66 g, 83%). MS (ES): m/z 430 (M++Na), IHVR: Wu 3,20 minutes

1H-NMR (CDCl3, 400MHz): δ to 1.19 (t, J 7.4 Hz, 3H), 1,28-of 1.40 (m, 3H), of 1.50 (s, 9H), 1.60-to 1,72 (m, 1H), 1,78 is 2.00 (m, 3H), 2,41-of 2.64 (m, 3H), 3,16 of 3.28 (m, 1H), 3,32-the 3.65 (m, 2H), 3,76-4,00 (m, 1H), 5,04-5,23 (m, 2H), 7,26-7,41 (m, 5H) (mixture of two rotamers).

Obtain tert-butyl ester (2S)-2-((1R,2S)-1-ethylsulfanyl-2-{[2-(3-hydroxyphenyl)ethyl]methylcarbamoyl}propyl)pyrrolidin-1-carboxylic acid

tert-Butyl ester (2S)-2-((1R,2S)-1-ethylsulfanyl-2-{[2-(3-hydroxyphenyl)ethyl]methylcarbamoyl}propyl)pyrrolidin-1-carboxylic acid was obtained in the same way as described in example 61, from tert-butyl ether (2S)-2-[(1R,2S)-2-benzyloxycarbonyl-1-ethylsulfanyl]pyrrolidin-1-carboxylic acid by hydrogenation and subsequent amidation of the hydrobromide of N-methyl-3-hydroxytyramine. LC-MS: 451 (MH+), IHVR: Wu 4,12 minutes

1H-NMR (CDCl3, 270 MHz): δ of 1.05 to 1.55 (m, 15H), 1.55V to 2.35 (m, 5H), 2,38-2,70 (m, 2H), 2.70 height is 3.00 (m, 5H), 3,05-to 4.28 (m, 6H), 6,50-of 6.90 (m, 3H), 7,00-of 7.23 (m, 1H).

Obtaining specified in the connection header

Specified in the title compound was obtained in the form of an individual stereoisomer by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid tert-butyl ester (2S)-2-((1R,2S)-1-ethyl-effect-free remedy 2-{[2-(3-hydroxyphenyl)ethyl]methylcarbamoyl}propyl)-pyrrolidine-1-carboxylic acid analogously to that described in example 1. The product remained the stereochemical configuration specified for each component. LC-MS: 762 (THE N +), IHVR: Wu 2,94 minutes

1H-NMR (CD3OD, 270 MHz): δ 0,75-1,50 (m, 26H), 1,55-to 2.85 (m, 13H), 2,85-3,20 (m, 12H), 3.25 to 4.25 in (m, 10H), 4,55 to 4.92 (m, 2H), 6.48 in-is 6.78 (m, 3H), 6,92-to 7.18 (m, 1H).

Example 63

N-(1-{[1-sec-Butyl-4-(2-{1-ethylsulfanyl-2-[2-(3-hydroxyphenyl)ethyl-carbarnoyl]propyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate

Obtain tert-butyl ester (2S)-2-{(1R,2S)-1-ethylsulfanyl-2-[2-(3-hydroxyphenyl)ethylcarbamate]propyl}pyrrolidin-1-carboxylic acid

tert-Butyl ester (2S)-2-{(1R,2S)-1-ethylsulfanyl-2-[2-(3-hydroxy-phenyl)ethylcarbamate]propyl}pyrrolidin-1-carboxylic acid was obtained from tert-butyl ether (2S)-2-[(1R,2S)-2-benzyloxycarbonyl-1-ethylsulfanyl]pyrrolidin-1-carboxylic acid with the using hydrogenation and subsequent amidation of the hydrobromide 3-hydroxytyramine same way as described in example 62. LC-MS: 437 (MH+), IHVR: Wu of 3.77 min

1H-NMR (CDCl3, 270 MHz): δ of 1.20 (t, J 7,3 Hz, 3H), of 1.31 (d, J 6.9 Hz, 3H), of 1.48 (s, 9H), 1,55-to 2.40 (m, 5H), 2,42-to 2.65 (m, 2H), 2,67-to 2.85 (m, 2H), 3,18 is 3.40 (m, 2H), 3.45 points-of 3.85 (m, 3H), 3,90-of 4.05 (m, 1H), 5,99 (.s, 1H), 6,62-to 6.80 (m, 2H), 6.90 to (.s, 1H), 7,17 (t, J 7,6 Hz, 1H).

Obtaining specified in the connection header

Specified in the title compound was obtained in the form of an individual stereoisomer by condensation of (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid, and require the-butyl ester (2S)-2-{(1R,2S)-1-ethylsulfanyl-2-[2-(3-hydroxyphenyl)ethylcarbamate]propyl}pyrrolidin-1-carboxylic acid analogously to as described in example 1. The product remained the stereochemical configuration specified for each component. LC-MS: 748 (MN+), IHVR: Wu 2,72 minutes

1H-NMR (CDCl3, 270 MHz): δ 0,57 is 1.60 (m, 26H), 1,60-of 2.30 (m, 8H), 2,30-to 2.85 (m, 7H), 2.95 and (s, 6H), 3,00-3,20 (m, 3H), of 3.27 (s, 3H), 3,30-3,95 (m, 5H), 3.95 to 4,30 (m, 2H), 4,30-of 4.90 (m, 2H), 6,40 (.s, 1H), 6,58-of 6.78 (m, 2H,), 6,93 (s, 1H), 7,12 (t, J 7,6 Hz, 1H), 7,79 (.s, 1H).

Example 64

N-(1-{[1-sec-Butyl-4-(2-{1-dimethylcarbamoyl-2-[2-(3-hydroxyphenyl)ethylcarbamate]ethyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]-methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate

Specified in the title compound was obtained from (3R*,4S*,5S*)-4-[N,N-dimethyl-L-felled(N-methyl-L-valinamide)]-3-methoxy-5-methylheptanoic acid tert-butyl ester 2-{1-dimethylcarbamoyl-2-[2-(3-hydroxyphenyl)ethylcarbamate]ethyl}pyrrolidin-1-carboxylic acid in the same way as described in example 1. LC-MS: 748 (MN+), IHVR: Wu 2,41 minutes

1H-NMR (CD3OD, 270 MHz): δ 0,75-of 1.18 (m, 18H), 1.18 to of 2.20 (m, 11H), 2.21 are of 2.81 (m, 5H), 2,90 (s, 6H), 3,00-3,20 (m, 6H), 3,30 (s, 3H), 3.25 to 3,90 (m, 7H), 4,00-4,30 (m, 2H), 4,60-5,00 (m, 2H), 6,50 to 6.75 (m, 3H), 6,98-7,15 (m, 1H).

Example 65

2-{1-[1-(4-{[2-Dimethylamino-3-methylbutylamine)-3-methylbutyryl]-methylamino}-3-methoxy-5-methylheptanoic)pyrrolidin-2-yl]-2-phenethyl-carbamoylethyl}ethyl ester ethylcarbamate acid

To a stirred solution of N-{1-[(1-sec-butyl-4-{2-[1-(2-hydroxyethyl lpanel)-2-phenetically]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutylamine (50 mg, 0,067 mmole) in CH2Cl2(1 ml) at 0°With added N,N'-carbonyldiimidazole (33 mg, 0,204 mmole) and pyridine (0,020 ml, 0,202 mmole). The mixture was stirred at room temperature for 24 h and concentrated in vacuum. The crude oil was dissolved in CH2CN (1 ml) and to the solution at 0°With added ethylamine hydrochloride (55 mg, 0,674 mmole) and pyridine (0,067 ml, 0,676 mmole). The mixture was stirred at room temperature for 15 h and concentrated in vacuum to receive the crude oil, which was purified preparative GHUR (column ODS-80TS, eluent N2O/CH3CN, 38:32, +0.05% OF TFU). The appropriate fractions were freeze-dried, thus received is listed in the title compound as an amorphous white powder (46 mg, 84%). LC-MS: 805 (MN+), IHVR: Wu 2,73 minutes

1H-NMR (CD3OD, 270 MHz): δ 0,57-of 1.18 (m, 21H), 1,25-1,50 (m, 2H), 1.60-to of 2.21 (m, 9H), 2.23 to-2,85 (m, 9H), of 2.86 (s, 6H), is 3.08 (q, 2H), 3,14 (s, 3H), and 3.31 (s, 3H), 3,30-3,95 (m, 5H), 3.95 to of 4.25 (m, 2H), 4,60-of 4.95 (m, 2H), 7,10-to 7.35 (m, 5H).

Example 66

3-(2-{3-[1-(4-{[2-(2-Dimethylamino-3-methylbutylamine)-3-methylbutyryl]-methylamino}-3-methoxy-5-methylheptanoic)pyrrolidin-2-yl]-2-methyl-3-methylsulfinylpropyl}ethyl)phenyl ester ethylcarbamate acid

To a stirred solution of N-(1-{[1-sec-butyl-4-(2-{2-[2-(3-hydroxy-phenyl)ethylcarbamate]-1-methylsulfinylpropyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-METI is propyl)-2-dimethylamino-3-methylbutylamine (30 mg, 0.035 mmole) in CH2Cl2(0.5 ml) at room temperature was added utilizationa (0,042 ml of 0.53 mmole) and diisopropylethylamine (0,062 ml, 0.35 mmole). The mixture was stirred at room temperature for 13 h and then concentrated in vacuo, to receive the crude oil (58 mg), which was purified preparative GHUR (column ODS-80Ts, eluent N2O/CH3CN, 35:35, +0.05% OF TFU). The appropriate fractions were freeze-dried, thus received is listed in the title compound as an amorphous white powder (13 mg, 39%). LC-MS: 805 (MN+), IHVR: Wu 2,70 minutes

1H-NMR (CDCl3, 270 MHz): δ 0,68-1,19 (m, 18H), 1,15-of 1.46 (m, 8H), 1,50 is 2.10 (m, 9H), 2,07 (s, 3H), 2,10 of 2.68 (m, 3H), of 2,75 2,90 (m, 2H), equal to 2.94 (s, 6H), 3,03 (s, 3H), of 3.32 (s, 3H), 3,30-of 3.78 (m, 4H), of 3.95 (q, J 6,93 Hz, 2H,), 3,80-4,08 (m, 1H), 4,08-4,37 (m, 1H), 4,59 and 5.86 (m, 2H), for 6.81-to 7.09 (m, 3H), 7,12-7,29 (m, 1H).

The following examples describe pharmaceutical preparations containing compounds of the present invention.

Example 67

The tablet formulation

Gelatin capsules, stamped in blister card and contains the following ingredients that have been known method.

Example 68

Example 69

Obtaining a solution/emulsion for injection

1. The compound of formula (I)

where R1, R2and R3 1-C4alkyl;

R4means1-C12alkyl, optionally containing from one to three substituents selected from the group comprising hydroxy, C1-C12alkoxycarbonyl, carbarnoyl; C2-C7alkenyl; C6-C10aryl, optionally containing from one to three substituents selected from the group comprising halogen, C1-C12alkyl, C1-C12alkoxy, hydroxy, C1-C12alkylcarboxylic; C6-C10aryl With1-C12alkyl, in which aryl group is optionally contains from one to three substituents selected from the group comprising halogen, C1-C12alkyl, C1-C12alkoxy; or heterocyclyl1-C12alkyl;

R5means hydroxy, C3-C7cyclooctylamino, optionally substituted by phenyl; C6-C10arylamino; aralkylamines that contains1-C4alkylenes and C6-C10aryl group, optionally containing from one to three substituents selected from the group including sulfamoyl,1-C12alkyl, C1-C12alkoxy, hydroxy, heterocyclyl or benzyl; With1-C4alkoxy, benzhydrazide; heterocyclyl, optionally containing from one to three substituents selected from the group consisting of gasoline is, benzhydryl; heterocyclisation;

where heterocyclyl means a saturated, unsaturated or aromatic monovalent cyclic radical containing from 1 to 3 heteroatoms selected from nitrogen, oxygen, or sulfur, or combinations thereof;

and n is an integer 0, 1 or 2,

and its pharmaceutically acceptable salts.

2. The compound according to claim 1, where R1means1-C4alkyl.

3. The compound according to claim 2, where R1means methyl.

4. The compound according to claim 1, where R2means1-C4alkyl.

5. The compound according to claim 4, where R2means methyl.

6. The compound according to claim 1, where R3means hydrogen or methyl.

7. The compound according to claim 1, where R4means1-C12alkyl, optionally containing from one to three substituents selected from the group comprising hydroxy, carbarnoyl,2-C7alkenyl; C6-C10aryl, optionally containing from one to three substituents selected from the group comprising From1-C12alkyl, C1-C12alkoxy, hydroxy, halogen or1-C12alkylcarboxylic,6-C10arils1-C12alkyl, where aryl group optionally contains from one to three substituents selected from the group comprising From1-C12alkyl, C1-C12alkoxy or halogen, or heterocyclic 1-C12alkyl.

8. The compound according to claim 1, where R4means phenyl, methyl, tert-butyl, 4-tert-butylphenyl, 4-methoxyphenyl, 2-, 3 - or 4-hydroxyphenyl, 4-acetamidophenyl, 4-forfinal, ethyl, isopropyl, benzyl, 2-acetoxyethyl, phenylethyl, allyl, n-pentyl, 2-naphthyl, 4-tormentil, 2-furylmethyl or 2-hydroxyethyl.

9. The compound according to claim 1, where R5means hydroxy, C3-C7cycloalkenyl, optionally substituted phenyl,

aralkylamines that contains1-C4alkylenes and C6-C10aryl group, optionally containing from one to three substituents selected from the group comprising H2NSO2, hydroxy, C1-C12alkyl, benzyl,1-C12alkoxy or heterocyclyl,1-C4alkoxy, benzhydrazide; heterocyclyl, optionally substituted benzyl or benzhydryl, heterocyclisation.

10. The compound according to claim 1, where R5means phenylethylamine, 2-naphthylenediamine, benzylpiperazine, 1,2,3,4-tetrahydroisoquinoline, tert-butoxy, hydroxy, 2-, 3 - or 4-hydroxyphenylethylamine, N-benzylpenicillin, 4-tert-butylbenzylamine, benzylamino, N-methylpentylamino, 2-, 3 - or 4-hydroxyphenylethyl-N-methylamino, 4-benzhydrylpiperazine, 2-phenylcyclopropane, a 4.3-dimethoxyphenylethylamine, benzylpiperazine, 2-pyridine-4-ylamino, 3,4-dimethoxyphenylethylamine ti is evil-2-ylamino, naphthalene-2-ylamino, 4-methoxyphenylethylamine, 4-(1,2,3)thiadiazole-4-albesiano, 2-cyclohexylamino.

11. The compound according to claim 1, where n is equal to 0.

12. The compound according to claim 1, where R1and R2means methyl, R3means hydrogen, and n is 0.

13. The connection section 12, selected from the group including

a) N-[1-({1-sec-butyl-2-methoxy-4-oxo-4-[2-(2-phenetically-1-phenylsulfanyl)pyrrolidin-1-yl]butyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

b) N-[1-({1-sec-butyl-2-methoxy-4-[2-(1-methylsulfanyl-2-phenethyl-carbamoylethyl)pyrrolidin-1-yl]-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

C) N-[1-({1-sec-butyl-4-[2-(1-(S)-tert-butylsulfonyl-2-phenethyl-carbamoylethyl)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

g) N-{1-[(1-sec-butyl-4-{2-[1-(4-tert-butylphenylmethyl)-2-phenetically]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

e) N-{1-[(1-sec-butyl-2-methoxy-4-{2-[1-(4-methoxybenzenesulfonyl)-2-phenetically]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

C) N-(1-{[1-sec-butyl-2-methoxy-4-(2-{1-methylsulfanyl-2-[(naphthalene-2-ylmethyl)carbarnoyl]ethyl}pyrrolidin-1-yl)-4-oxobutyl]methylcarbamoyl}--methylpropyl)-2-dimethylamino-3-methylbutyrate,

K) N-{1-[(4-{2-[3-(4-benzylpiperazine-1-yl)-1-methylsulfanyl-3-oxopropyl]pyrrolidin-1-yl}-1-sec-butyl-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

l) N-{1-[(1-sec-butyl-4-{2-[3-(3,4-dihydro-1H-isoquinoline-2-yl)-1-methylsulfanyl-3-oxopropyl]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

p) N-{1-[(1-sec-butyl-4-{2-[1-(S)-(4-hydroxyphenylethyl)-2-phenetically]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

C) N-{1-[(1-sec-butyl-4-{2-[1-(R)-(4-hydroxyphenylethyl)-2-phenetically]pyrrolidin-1-yl})-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

t) N-{1-[(4-{2-[1-(4-acetylbenzenesulfonyl)-2-phenetically]pyrrolidin-1-yl}-1-sec-butyl-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

u) N-{1-[(1-sec-butyl-4-{2-[1-(4-perpenicular)-2-phenetically]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

f) N-[1-[{1-sec-butyl-4-[2-(1-(R)-tert-butylsulfonyl-2-phenethyl-carbamoylethyl)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

x) N-[1-({1-sec-butyl-4-2-(1-ethylsulfanyl-2-phenetically)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

C) N-[1-({1-sec-butyl-4-[2-(1-isopropylphenyl-2-phenethyl-carbamoylethyl)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

h) N-[1-({1-sec-butyl-4-[2-(1-tert-butylsulfonyl-2-fenetilina-mailutil)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

y) N-{1-[(1-sec-butyl-4-{2-[1-(2-hydroxyphenylethyl)-2-phenetically]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

e) N-{1-[(1-sec-butyl-4-{2-[1-(3-hydroxyphenylethyl)-2-phenetically]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

h) N-{1-[(1-sec-butyl-4-{2-[1-(2-hydroxyarylalkyl)-2-phenethyl-carbamoylethyl]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

I) 2-{1-[1-(4-{[2-(2-dimethylamino-3-methylbutylamine)-3-methyl-butyryl]methylamino}-3-methoxy-5-methylheptanoic)pyrrolidin-2-yl]-2-phenethylnormorphine}ethyl ester acetic acid,

BB) 3-[1-(4-{[2-(2-dimethylamino-3-methylbutylamine)-3-methyl-butyryl]methylamino}-3-methoxy-5-methylheptanoic)pyrrolidin-2-yl]-3-methylsulfinylpropyl acid,

C) N-(1-{[1-sec-butyl-2-methoxy-4-(2-{1-methylsulfanyl-2-[2-4-sulfamoylbenzoyl)ethylcarbamate]ethyl}pyrrolidin-1-yl)-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

gg) N-(1-{[1-sec-butyl-4-(2-{2-[2-(4-hydroxyphenyl)ethylcarbamate]-1-methylsulfonylmethyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

DD) N-{1-[(1-sec-butyl-2-methoxy-4-{2-[2-(methylphenylcarbinol)-1-methylsulfonylmethyl]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

it) N-{1-[(4-{2-[3-(4-benzhydrylpiperazine-1-yl)-1-methylsulfanyl-3-oxopropyl]pyrrolidin-1-yl}-1-sec-butyl-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

LJ) N-(1-{[1-sec-butyl-4-(2-{2-[2-(2-hydroxyphenyl)ethylcarbamate]-1-methylsulfonylmethyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

ZZ) N-(1-{[1-sec-butyl-4-(2-{2-[2-(3-hydroxyphenyl)ethylcarbamate]-1-methylsulfonylmethyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

AI) N-{1-[(4-{2-[2-(benzylpenicilloyl)-1-methylsulfonylmethyl]pyrrolidin-1-yl}-1-sec-butyl-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

QC) N-{1-[(1-sec-butyl-2-methoxy-4-{2-[1-methylsulfanyl-2-(2-phenylcyclopropanecarboxylic)ethyl]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

FL) N-{1-[(1-the top-butyl-4-{2-[2-(4-tert-butylbenzenesulfonyl)-1-methylsulfonylmethyl]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

mm) N-[1-({4-[2-(2-benzylcarbamoyl-1-methylsulfonylmethyl)pyrrolidin-1-yl]-1-sec-butyl-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

NN) N-[1-({1-sec-butyl-2-methoxy-4-oxo-4-[2-(2-phenetically-1-geneticalgorithm)pyrrolidin-1-yl]butyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

OO) N-[1-({4-[2-(1-arylsulfonyl-2-phenetically)pyrrolidin-1-yl]-1-sec-butyl-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

PP) N-{1-[(4-{2-[2-(N'-benzylaminocarbonyl)-1-methylsulfanyl-ethyl]pyrrolidin-1-yl}-1-sec-butyl-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

RR) N-{1-[(1-sec-butyl-2-methoxy-4-{2-[1-methylsulfanyl-2-(2-pyridin-4-iletileri)ethyl]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

cc) N-(1-{[4-(2-{2-[(benzothiazole-2-ylmethyl)carbarnoyl]-1-methyl-sulfanilate}pyrrolidin-1-yl)-1-sec-butyl-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

TT) N-{1-[(1-sec-butyl-2-methoxy-4-{2-[1-methylsulfanyl-2-(2-thiophene-2-iletileri)ethyl]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

su) N-{1-[(1-sec-butyl-2-methoxy-4-{2-[1-methylsulfanyl-2-(2-what iridin-3-iletileri)ethyl]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

FF) N-{1-[(1-sec-butyl-2-methoxy-4-{2-[1-methylsulfanyl-2-(2-pyridin-2-iletileri)ethyl]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

XX) N-(1-{[1-sec-butyl-2-methoxy-4-(2-{1-methylsulfanyl-2-[(pyridine-4-ylmethyl)carbarnoyl]ethyl}pyrrolidin-1-yl)-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

TP) N-(1-{[1-sec-butyl-4-(2-{2-[2-(3H-imidazol-4-yl)ethylcarbamate]-1-methylsulfonylmethyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

HH) N-{1-[(1-sec-butyl-2-methoxy-4-{2-[1-methylsulfanyl-2-(thiazol-2-ylcarbonyl)ethyl]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

hush) N-{1-[(1-sec-butyl-2-methoxy-4-{2-[1-methylsulfanyl-2-(naphthalene-2-ylcarbonyl)ethyl]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

SS) N-[1-({1-sec-butyl-4-[2-(2-cyclohexylcarbonyl-1-methylsulfonylmethyl)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

EE) N-[1-({1-sec-butyl-4-[2-(2-{[2-(3,4-acid)ethyl]methylcarbamoyl}-1-methylsulfonylmethyl)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

Yuyu) N-(1-{[1-sec-butyl-4-(2-{2-2-(3,4-acid)ethylcarbamate]-1-methylsulfonylmethyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

AAA) N-[1-({1-sec-butyl-2-methoxy-4-oxo-4-[2-(1-intercultural-2-phenetically)pyrrolidin-1-yl]butyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

BSCs) N-{1-[(1-sec-butyl-2-methoxy-4-{2-[1-(naphthalene-2-ylsulphonyl)-2-phenetically]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

BBB) N-{1-[(1-sec-butyl-4-{2-[1-(4-perpenicular)-2-phenethyl-carbamoylethyl]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

GGG) N-{1-[(1-sec-butyl-4-{2-[1-(furan-2-elmersolver)-2-phenetically]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

DDD) N-(1-{[1-sec-butyl-2-methoxy-4-(2-{2-[2-(4-methoxyphenyl)ethylcarbamate]-1-methylsulfonylmethyl}pyrrolidin-1-yl)-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

Eee) N-{1-[(1-sec-butyl-2-methoxy-4-{2-[1-methylsulfanyl-2-(4-[1,2,3]thiadiazole-4-evensidemargin)ethyl]pyrrolidin-1-yl}-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

EPL) N-(1-{[1-sec-butyl-4-(2-{1-tert-butylsulfonyl-2-[2-(4-hydroxyphenyl)ethylcarbamate]ethyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

III) N-(1-{[1-the top-butyl-4-(2-{1-tert-butylsulfonyl-2-[2-(3-hydroxyphenyl)ethylcarbamate]ethyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

the KKK) N-(1-{[1-sec-butyl-4-(2-{1-tert-butylsulfonyl-2-[2-(2-hydroxyphenyl)ethylcarbamate]ethyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

LLL) N-(1-{[1-sec-butyl-4-(2-{1-dimethylcarbamoyl-2-[2-(3-hydroxyphenyl)ethylcarbamate]ethyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

mmm) N-[1-({1-sec-butyl-4-[2-(1-dimethylcarbamoyl-2-phenetically)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate.

14. The compound according to claim 1, where R1and R2means methyl, R3means hydrogen, and n is 1.

15. The connection 14, which is N-[1-({1-sec-butyl-4-[2-(1-methanesulfonyl-2-phenetically)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate.

16. The compound according to claim 1, where R1and R2means methyl, R3means hydrogen, and n is 2.

17. Connection P16, which is N-[1-({1-sec-butyl-4-[2-(1-methanesulfonyl-2-phenetically)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate.

18. The compound according to claim 1, where R1means methyl, R2and R3mean hydrogen, and n is 0.

19. Connection p selected from the group including

a) N-[1-({1-sec-butyl-4-[2-(1-ethylsulfanyl-2-phenetically)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-3-methyl-2-methylaminomethyl,

b) N-[1-({1-sec-butyl-2-methoxy-4-oxo-4-[2-(2-phenetically-1-phenylsulfanyl)pyrrolidin-1-yl]butyl}methylcarbamoyl)-2-methylpropyl]-3-methyl-2-methylaminomethyl,

C) N-[1-({1-sec-butyl-4-[2-(1-tert-butylsulfonyl-2-fenetilina-mailutil)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-3-methyl-2-methylaminomethyl,

g) N-[1-({1-sec-butyl-2-methoxy-4-[2-(1-methylsulfanyl-2-phenethyl-carbamoylethyl)pyrrolidin-1-yl]-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-3-methyl-2-methylaminomethyl,

d) N-[1-({1-sec-butyl-4-[2-(1-isopropylphenyl-2-fenetilina-mailutil)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-3-methyl-2-methylaminomethyl,

W) N-(1-{[1-sec-butyl-4-(2-{2-[2-(3-hydroxyphenyl)ethylcarbamate]-1-methylsulfonylmethyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-3-methyl-2-methylaminomethyl,

C) N-(1-{[1-sec-butyl-4-(2-{1-tert-butylsulfonyl-2-[2-(3-hydroxy-phenyl)ethylcarbamate]ethyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-3-methyl-2-methylaminomethyl.

20. The compound according to claim 1, where R 1means methyl, R2and R3mean hydrogen, and n is 2.

21. Connection claim 20, selected from the group including

a) N-[1-({1-sec-butyl-4-[2-(1-econsultancy-2-phenetically)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-3-methyl-2-methylaminomethyl,

b) N-[1-({4-[2-(1-benzazolyl-2-phenetically)pyrrolidin-1-yl]-1-sec-butyl-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-3-methyl-2-methylaminomethyl,

C) N-[1-({1-sec-butyl-4-[2-(1-methanesulfonyl-2-phenetically-ethyl)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-3-methyl-2-methylaminomethyl,

g) N-{1-[(1-sec-butyl-2-methoxy-4-oxo-4-{2-[2-phenetically-1-(propane-2-sulfonyl)ethyl]pyrrolidin-1-yl}butyl)methylcarbamoyl]-2-methylpropyl}-3-methyl-2-methylaminomethyl,

e) N-{1-[(1-sec-butyl-2-methoxy-4-oxo-4-{2-[2-phenetically-1-(2-methylpropan-2-sulfonyl)ethyl]pyrrolidin-1-yl}butyl)methylcarbamoyl]-2-methylpropyl}-3-methyl-2-methylaminomethyl.

22. The compound according to claim 1, where R1and R3means methyl, R2means hydrogen, and n is 0.

23. Connection p.22 selected from the group including

a) N-[1-({1-sec-butyl-2-methoxy-4-[2-(1-methylsulfanyl-2-phenethyl-carbamoylmethyl)pyrrolidin-1-yl]-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-methylamino-3-methylbutyrate the

b) N-[1-({1-sec-butyl-4-[2-(1-tert-butylsulfonyl-2-ventilkappen)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-methylamino-3-methylbutyrate.

24. The compound according to claim 1, where R1, R2and R3mean methyl, and n is 0.

25. The connection point 24, selected from the group including

a) N-[1-({1-sec-butyl-2-methoxy-4-[2-(1-methylsulfanyl-2-ventilkappen)pyrrolidin-1-yl]-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

b) N-[1-({1-sec-butyl-4-[2-(1-tert-butylsulfonyl-2-ventilkappen)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

C) N-{1-[(1-sec-butyl-4-{2-[1-(2-hydroxyarylalkyl)-2-ventilkappen]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

g) N-{1-[(1-sec-butyl-4-{2-[1-(4-hydroxyphenylethyl)-2-ventilkappen]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

e) N-{1-[(1-sec-butyl-4-{2-[1-(3-hydroxyphenylethyl)-2-ventilkappen]pyrrolidin-1-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

e) N-{1-[(1-sec-butyl-4-{2-[1-(2-hydroxyphenylethyl)-2-ventilkappen]pyrrolidin-yl}-2-methoxy-4-oxobutyl)methylcarbamoyl]-2-methylpropyl}-2-dimethylamino-3-methylbutyrate,

W) N-(1-{[1-sec-butyl-4-(2-{2-[2-(4-hydroxyphenyl)ethylcarbamate]-1-tert-butylsulfonyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

C) N-(1-{[1-sec-butyl-4-(2-{2-[2-(3-hydroxyphenyl)ethylcarbamate]-1-tert-butylsulfonyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

and) N-(1-{[1-sec-butyl-4-(2-{2-[2-(2-hydroxyphenyl)ethylcarbamate]-1-tert-butylsulfonyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

K) N-(1-{[1-sec-butyl-4-(2-{2-[2-(4-hydroxyphenyl)ethylcarbamate]-1-methylsulfinylpropyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

l) N-(1-{[1-sec-butyl-4-(2-{2-[2-(3-hydroxyphenyl)ethylcarbamate]-1-methylsulfinylpropyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

m) N-(1-{[1-sec-butyl-4-(2-{2-[2-(2-hydroxyphenyl)ethylcarbamate]-1-methylsulfinylpropyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate,

n) N-(1-{[1-sec-butyl-4-(2-{2-[2-(3-hydroxyphenyl)ethylcarbamate]-1-pencilsharpener}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimetil the Ino-3-methylbutyrate,

o) N-[1-({1-sec-butyl-4-[2-(2-{[2-(3-hydroxyphenyl)ethyl]methylcarbamoyl}-1-methylsulfinylpropyl)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

p) N-[1-({1-sec-butyl-4-[2-(1-ethylsulfanyl-2-{[2-(3-hydroxyphenyl)ethyl]methylcarbamoyl}propyl)pyrrolidin-1-yl]-2-methoxy-4-oxobutyl}methylcarbamoyl)-2-methylpropyl]-2-dimethylamino-3-methylbutyrate,

R) N-(1-{[1-sec-butyl-4-(2-{1-ethylsulfanyl-2-[2-(3-hydroxyphenyl)ethylcarbamate]propyl}pyrrolidin-1-yl)-2-methoxy-4-oxobutyl]methylcarbamoyl}-2-methylpropyl)-2-dimethylamino-3-methylbutyrate.

26. The compound according to claim 1 of formula (I-1)

where R1, R2, R3, R4, R5and n have the meanings indicated in claim 1,

and their pharmaceutically acceptable salts.

27. Compounds according to one of claims 1 to 26, with antiproliferative activity.

28. The pharmaceutical composition exhibiting anti-proliferative activity, comprising a compound according to one of claims 1 to 26, and a pharmaceutically acceptable carrier.

29. The pharmaceutical composition according to item 27, which is suitable for oral and parenteral administration.

30. The compounds of formula (III)

where R3, R4, R5and n have the meanings indicated in claim 1.



 

Same patents:

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to novel substituted derivatives of cyclohexane of the formula (I): wherein U means a free electron pair; V means a simple bond, -CH2-, -CH=CH-, -CH=CH-CH2-O-, -C≡C-; W means -COO, -CSO or -SO2; m and n mean independently of one another numbers from 0 to 4; m + n = 0-7; A1 means hydrogen atom (H), lower alkyl, hydroxy-(lower)-alkyl or lower alkenyl; A2 means pyrrolyl, pyrimidinyl, optionally substituted (lower)-alkyl or lower alkyl optionally substituted with R2; or A1 and A2 are bound to form ring; -A1-A2- means lower alkylene optionally substituted with R2 wherein one group -CH2- in -A1-A2- can be optionally replaced for -NR3 or oxygen atom (O); A3, A4, A5, A6, A7 and A8 mean H; R9 means H, lower alkyl; R10 means (lower)-alkyl, phenyl wherein phenyl can be substituted with 1-3 substitutes chosen independently from the group comprising halogen atom, -CF3, (lower)-alkyl; p means 0, 1; R2 means H; R3 means H, lower alkyl, and their pharmaceutically acceptable salts. Compounds of the formula (I) possess the inhibitory effect on activity of enzyme oxidosqualene lanosterol cyclase and can be used in pharmaceutical composition. Also, method relates to a method for treatment and/or prophylaxis of hyperlipemia, artheriosclerosis, hypercholesterolemia and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

27 cl, 9 sch, 10 tbl, 43 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 2-(1-methyl-2-(3,4-fullero[60]pyrrolidinyl)phenol of the formula (1): Method involves interaction of fullerene[60] with 2-[(dimethylamino)methyl]phenol of the general formula: (R-CH2-N(CH3)2) wherein R means in taken in the mole ratio C60 : R-CH2-N-(CH3)2 = 0.01:(0.01-0.011) in the presence of Cp2TiCl2 as catalyst taken in the amount 15-25 mole% relatively to fullerene[60] in argon atmosphere, in toluene medium as a solvent, at temperature 140-160°C for 2-4 h. Method provides preparing the novel compound with the yield 78-86%. Compound of the formula (1) can be used as a chelating agent, sorbent and biologically active substance.

EFFECT: improved method of synthesis.

1 tbl, 1 ex

The invention relates to agriculture and veterinary medicine

The invention relates to an improved process for the preparation of CIS-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl] ethyl} pyrrolidine, which is a substance to obtain the (-)CIS-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl-5,6,7,8-tetrahydronaphthalen-2-ol, which is used in the treatment of osteoporosis, as well as to intermediate compounds for this method

The invention relates to new niftystories compounds of formula I, where R1and R2- H, -OH, -O(C1-C4alkyl), -OCOC6H5, -OCO(C1-C6alkyl), -OSO2(C4-C6alkyl); R3- 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, 1 hexamethyleneimino; intermediate compounds, which are suitable for easing symptoms of postmenopausal syndrome, including osteoporosis, hyperlipemia and estrogenzawisimy cancer, and inhibition of uterine fibroids, endometriosis and proliferation of aortic smooth muscle cells

The invention relates to therapeutic tools, specifically setidentityproviderid N-substituted nitrogenous heterocyclic compounds and methods of producing such compounds, intermediate products used in obtaining, compositions containing such compounds and the use of such heterocycles

FIELD: medicine.

SUBSTANCE: method involves carrying out 5-10 sessions of general magnetotherapy beginning from 3-rd day after surgical intervention in static mode: magnetic field rotation frequency is equal to 100 Hz, magnetic field intensity of 30 oersted, magnetic field shape is sinusoid half-cycle, raising time being equal to 30 s, time of recession 30 s; the number of procedures is equal to 15. Then, remote radiation therapy is administered 4 weeks later after surgical intervention. The treatment is applied to removed kidney bed and lymphatic collectors in single stage in classical fractioning mode at a doze of 2 Gy 5 times a week within 5 weeks up to reach total doze of 50 Gy with general magnetotherapy being concurrently applied in 1 session per day mode, the number of procedures being equal to 25. The first biotherapy course with recombinant human alpha tumor necrosis factor (TNF-α) is given at a dose of 2 mln units 2 weeks later after the radiation therapy being done. Total З biotherapy courses are to be given with 21 days long pause available between the courses.

EFFECT: enhanced effectiveness of treatment; reduced risk of postoperative complications; increased immune activity.

FIELD: medicine.

SUBSTANCE: method involves excising basic tumor as one-stage operation by means of high-energy СО2 laser or cytoreduction operation is carried out (basic tumor component removal) using laser output power of 20-40 W at the first stage. Remote photodynamic therapy is applied by irradiating the whole vulva surface with radiation dose of 100-150 J/cm2, power density of 50-70 mW/cm2 and irradiating tumor localization zone with radiation dose of 200-300 J/cm, power density of 150-200 mW/cm at the second stage. Additional interstitial laser irradiation with radiation dose of 200-300 J is optionally carried out at radiation power of 200-300 mW in tumor invasion zone.

EFFECT: enhanced effectiveness of organ-retaining and sparing treatment; accelerated treatment course; reduced risk of postoperative complications.

2 cl

FIELD: medicine, oncology.

SUBSTANCE: during the first day of therapy it is necessary to affect the lesion focus with alternating magnetic field at induction being 5-160 mTl, frequency of 50-100 Hz for about 7-10 min. Out of peripheral vein one should sample blood into two vials with hemoconservant per 100 ml/each; one vial should be supplemented with doxorubicin at the dosage of 50 mg/sq. m, the second vial - with 5-fluorouracil 750 mg/sq. m. Both vials should be incubated. Then it is necessary to inject intravenously by drops the content of the first, and then of the second vial for a patient. During the period since the first day up to the seventh one it is necessary to introduce cyclophosphan intramuscularly per 200 mg/sq. m. Since the first up to the tenth day of therapy one should affect with alternating and direct magnetic field. On the eighth day after seances of magnetic therapy one should repeatedly introduce anti-tumor chemopreparations at the same dosages and sequence. In two weeks it is necessary to repeat the above-mentioned curative impacts. In two weeks after the last introduction of chemopreparations one should fulfill surgical removal of lesion focus. The innovation enables to avoid side toxic manifestations of chemopreparations and notching of sutures and, also, healing due to secondary tension.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: pharmaceutical industry, in particular agent having cytostatic and apoptosis-inducing activity.

SUBSTANCE: claimed agent represents β-Asparagine, obtained by extraction of ground burdock roots having specific particle size with heated water in specific raw materials/extractant ratio; decoction, extract separation, concentration up to dry residue in concentrate, filtering, and double recrystallization.

EFFECT: agent with high cytostatic and apoptosis-inducing (anti-tumor) activity.

5 dwg, 2 tbl

FIELD: medicine, oncology.

SUBSTANCE: method involves carrying out lumbal puncture to a patient in post-operative period, subarachnoid space is catheterized, and 5 ml of liquor is removed followed by incubation of liquor with nimustine taken in the dose 5 mg in vitro at temperature 38°C for 30 min, and liquor is administrated into subarachnoid space through catheter. Procedure is carried out 2 times with interval for 7 days. Since the second day after onset of this procedure distant gamma-therapy on bed of removed tumor is carried out up to the total focus dose 60 Gr. Method provides stable remission, decreasing toxicity of chemopreparation, frequency of adverse by-side effects and significant reducing the cost of chemotherapy. Invention can be used in carrying out the adjuvant chemoradiation therapy of brain malignant glial tumors.

EFFECT: improved method of chemoradiation therapy, enhanced effectiveness of method.

1 ex

FIELD: medicine, oncology, gynecology.

SUBSTANCE: method involves trepanopuncture of flank bone wing, aspiration of bone marrow suspension in the amount 150-200 ml followed by incubation of suspension with chemopreparations cisplatin and cyclophosphan at temperature 37°C for 40 min in doses above therapeutic ones. Doxorubicin is not incubated with bone marrow suspension and chemopreparations are administrated separately by intravenous route, by drops in indicated order in day when the bone marrow suspension has been taken, and this procedure is repeated with interval for 3-4 weeks but totally 4 times per one treatment course. Proposed method provides attaining the stable anti-tumor effect up to the complete tumor regression in this category of patients showing high tolerance to chemotherapy, and in practical absence of adverse toxic responses. Invention can be used in treatment of patients with relapses of ovary and uterus body cancer in case absence effectiveness of other methods of treatment or in case of their low effectiveness.

EFFECT: improved method of treatment.

2 ex

FIELD: medicine, oncology.

SUBSTANCE: method involves administration of bleomycin and erythropoietin simultaneously in patients. Invention can be used for decreasing pulmonary cytotoxicity in patients treated with bleomycin. Invention provides improving functioning lung in patients of this category.

EFFECT: valuable medicinal properties of erythropoietin.

4 cl, 2 dwg, 2 ex

FIELD: medicine, oncology, pharmacology, pharmacy.

SUBSTANCE: invention relates to methods and medicinal formulations used in antitumor treatment and enhancing oral biological availability of taxanes. Method involves administration of taxane in combination with agent enhancing biological availability of taxane in oral administration in subject wherein concentrations of taxane attain levels of therapeutic activity in subject. Ketoconazol representing inhibitor of cytochrome P-450 is used as agent enhancing oral biological availability of taxane. Invention provides enhancing bioavailability of taxane in its oral administration in subject in subtherapeutic doses that results to decreasing toxicity of treatment.

EFFECT: improved and valuable medicinal properties of drug.

33 cl, 42 dwg, 10 tbl, 12 ex

FIELD: chemistry, medicine.

SUBSTANCE: invention relates to hemin-peptide of general formula I , wherein R1 is ArgTrpHisArgLeuLysGlu(OMe)OH; R2 is -OH; Y is Cl; Me is Fe, or pharmaceutically acceptable salts thereof having virulicidal and anti-viral activity, including activity against herpes virus and HIV, and capability for destroying of λ fag, herpes and HIV DNA. Hemin-peptide fragment also is disclosed.

EFFECT: new anti-viral agent.

2 cl, 5 tbl, 5 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention relates to derivatives of 2-aminonicotine amide of the formula (I): , to methods of their synthesis and a pharmaceutical composition based on thereof inhibiting activity of receptor tyrosine kinase vessel endothelial growth factor (VEGF) and to corresponding method for inhibition of activity of VEGF-receptor tyrosine kinase. It is suggested that this activity will allow offering the curative effect in proliferative diseases associated with angiogenesis, in particular, in treatment of tumors, retinopathy or age degeneration of yellow (corneal) spot.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

9 cl, 42 ex

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition comprising the medicinal preparation "Noopept" as an active component. Pharmaceutical composition for preparing solid medicinal formulations of the preparation comprises "Noopept", microcrystalline cellulose, polyvinylpyrrolidone, stearic acid or stearate as tablets. The medicinal preparation "Noopept" representing N-phenylacetyl-L-prolylglycine ethyl ester elicits the nootropic and neuroprotective activity in broad ranges of doses. The composition comprises small amounts of special additives, tablet release active component easily and invention provides its high bioavailability. Tablets satisfy all requirements of the State Pharmacopoeia of XI edition.

EFFECT: improved and valuable pharmaceutical and medicinal properties of pharmaceutical composition.

7 cl, 1 tbl, 3 ex

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