Amides of δ-amino-γ-hydroxy-ω-arylalcane acid

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to amide of δ-amino-γ-hydroxy-ω-arylalcane acid of formula and its pharmaceutically acceptable salts. Also described are pharmaceutical compositions, which include said compounds, and application of said compounds for preparation of medication, intended for treatment of pathological states, associated with renin activity, in particular for treatment of hypertension.

EFFECT: obtaining pharmaceutically acceptable salts, which possess rennin-inhibiting ability.

21 cl, 161 ex

 

The invention relates to new Amida δ-amino-γ-hydroxy-ω-arylalkenes acid of the formula (I)

in which

R1denotes hydrogen, halogen, optionally halogenated alkyl, cycloalkyl, the hydroxy-group, optionally halogenated alkoxygroup, cycloalkanes, NISS. alkoxy-ness. alkoxygroup or free or esterified or amidinophenoxy ness. alkoxygroup or nits. alkyl;

R2denotes hydrogen, halogen, optionally halogenated ness. alkyl, hydroxy-group, cycloalkyl, cycloalkanes, optionally halogenated ness. alkoxy-ness. alkyl, optionally substituted ness. alkoxy-ness. alkyl, cycloalkane-ness. alkyl; optional ness. alkanolamine, halogenated or sulfonylamino hydroxy-ness. alkoxygroup; amino-ness. alkyl, which is unsubstituted or contains as Vice ness. alkyl, NISS. alkanoyl and/or nits. alkoxycarbonyl, optionally hydrogenated heteroaryl-ness. alkyl, amino-ness. alkoxygroup, which is unsubstituted or contains as Vice ness. alkyl, NISS. alkanoyl and/or nits. alkoxycarbonyl; oxo-ness. alkoxygroup, NISS. alkoxygroup, NISS. alkenylacyl, cycloalkane-ness. alkoxygroup, NISS. alkoxy-ness. alkoxygroup the PU, ness. alkoxy-ness. alkenyl, NISS. alkenylacyl-ness. alkoxygroup, NISS. alkoxy-ness. alkenylacyl, NISS. alkenylacyl-ness. alkyl, NISS. alkanoyl ness. alkoxygroup, optionally S-oxidised ness. alkylthio-ness. alkoxygroup, NISS. alkylthio-(hydroxy)-ness. alkoxygroup, aryl-ness. alkoxygroup, aryl-ness. alkyl, aryl-ness. alkoxygroup, optional gidrirovannoe heteroaryl-ness. alkoxygroup, optionally hydrogenated heteroaryl-ness. alkyl, cyano-ness. alkoxygroup, cyano-ness. alkyl, free or esterified or amidinophenoxy carboxy-ness. alkoxygroup or free or esterified or aminirovanie carboxy-ness. alkyl;

R3and R4independently represent hydrogen, halogen, optionally halogenated ness. alkyl, hydroxy-group, optionally halogenated ness. alkoxygroup or cycloalkanes, NISS. alkoxy-ness. alkyl, cycloalkane-ness. alkyl, hydroxy-ness. alkyl, optionally S-oxidised ness. alkylthio-ness. alkyl, optionally hydrogenated, heteroaromatic-ness. alkyl, optionally hydrogenated heteroaryl-ness. alkyl; amino-ness. alkyl, which is unsubstituted or N-mono - or N,N-di-ness. alkilirovanny, N-ness. alkanolamines or N-ness. alkanolammonium or N,N-disubstituted ness. alkylene, unsubstituted or N ness. alkilirovanny or N'-ness. alkanolamines Aza-ness. alkylene, oxa-ness. alkylene or optionally S-oxidised thia-ness. alkylene, cyano-ness. the alkyl, free or esterified or emitirovannykh carboxy-ness. the alkyl, cycloalkyl, aryl, hydroxy-group, NISS. alkoxygroup, cycloalexie, NISS. alkoxy-ness. alkoxygroup, cycloalkane-ness. alkoxygroup, hydroxy-ness. alkoxygroup, aryl-ness. alkoxygroup, optionally halogenated ness. alkoxygroup, optionally S-oxidised ness. alkylthio-ness. alkoxygroup, optional gidrirovannoe heteroaryl-ness. alkoxygroup, optional gidrirovannoe heteroaromatic-ness. alkoxygroup; amino-ness. alkoxygroup, which is unsubstituted or N-mono - or N,N-di-ness. alkilirovanny, N-ness. alkanolamines or N-ness. alkanesulfonyl or substituted ness. alkylene, unsubstituted or N'-ness. alkilirovanny or N'-ness. alkanolamines Aza-ness. alkylene, oxa-ness. alkylene or optionally S-oxidised thia-ness. alkylene, cyano-ness. alkoxygroup or free or esterified or amidinophenoxy ness. alkoxygroup; or

R4together with R3means NISS. allinoneruby, NISS. alkylenedioxy or condensed aryl, optionally gidrirovanny the second heteroaryl or cycloalkyl ring;

X denotes methylene, hydroxymethylene, oxygen, optionally substituted ness. the alkyl nitrogen atom, optionally oxidized sulfur atom;

R5means NISS. alkyl or cycloalkyl;

R6denotes hydrogen, NISS. alkyl, hydroxy-group, alkoxygroup or halogen;

R7denotes unsubstituted or N-mono - or N,N-di-ness. alkilirovanny or N-ness. alkanolamine the amino group;

R8means NISS. alkyl, NISS. alkenyl, cycloalkyl or aryl-ness. alkyl;

R9denotes optionally substituted ness. alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, cycloalkylcarbonyl, N-mono or N,N-dialkylamino cycloalkylcarbonyl, optionally substituted arylalkyl, optionally substituted aryloxyalkyl, optionally substituted heteroepitaxial, free or formed aliphatic complex or a simple ester of hydroxy-ness. alkyl; amino-ness. alkyl, which is unsubstituted or N-ness. alkanolamines or N-mono - or N,N-di-ness. alkilirovanny or N,N-disubstituted ness. alkylene, hydroxy-, ness. alkoxy - or nits. alkanoyloxy-ness. alkylene, unsubstituted or N'-ness. alkanolamines or N'-ness. alkilirovanny Aza-ness. alkylene, oxa-ness. alkylene or optionally S-oxidised thia-ness. alkylene, with the rim or esterified or emitirovannykh carboxy-ness. the alkyl, free or esterified or emitirovannykh dicarboxy-ness. the alkyl, free or esterified or emitirovannykh carboxy-(hydroxy)-ness. the alkyl, free or esterified or emitirovannykh carboxylicacid-ness. the alkyl, cyano-ness. the alkyl, NISS. alkanesulfonyl-ness. the alkyl, unsubstituted or N-mono - or N,N-di-ness. alkilirovanny thiocarbamoyl-ness. the alkyl, unsubstituted or N-mono - or N,N-di-ness. alkilirovanny sulfamoyl-ness. the alkyl or heteroaryl radicals attached through a carbon atom and optionally gidrirovanny and/or oxazolidinyl, or nits. by alkyl, substituted heteroaryl radicals attached through a carbon atom and optionally gidrirovanny and/or oxazolidinyl;

and their pharmaceutically acceptable salts, a process for the production of compounds proposed in the present invention, to contain their pharmaceutical compositions and to their use as pharmaceutically active ingredients.

Connections proposed in the present invention, have the ability to inhibit the natural enzyme renin. Thus, the compounds of formula (I) can be used to treat hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, hypertrophy of the heart, fibrosis of the heart post-mi is cardiomyopathy, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, liver fibrosis, complications resulting from diabetes such as nephropathy, vasculopathies and neuropathy, diseases of the coronary vessels, restenosis after angioplasty, increased intraocular pressure, glaucoma, abnormal growth of blood vessels, hyperaldosteronism, disorders of cognition, Alzheimer's disease, dementia, anxiety States and cognitive disorders abilities.

Below are definitions of various terms used to describe the compounds proposed in the present invention. These definitions apply to terms when used throughout the description, if they are in specific cases is not specifically limited, either individually, or as part of a larger group.

Aryl and aryl in arylalkyl, aryl-ness. alkoxygroup, aryl-ness. the alkyl and the like, refers to, for example, phenyl or naphthyl, which is unsubstituted or mono-, di - or tizamidine ness. the alkyl, NISS. alkoxygroup, optionally substituted by halogen, a hydroxy-group, NISS. alkylaminocarbonyl, di-ness. alkylamino, halogen and/or trifluoromethyl.

Cycloalkanes and cycloalkanes in cycloalkane-ness. alkoxygroup means, for example, 3 - to 8-membered, preferably 3-, 5 - or 6-members of the ing, cycloalkanes, such as cyclopropylamino, cyclopentyloxy, cyclohexyloxy and cyclobutylamine, cycloheptylamine or cyclooctylamino.

Cycloalkyl and cycloalkyl in cycloalkenyl means, for example, optionally substituted monocyclic, bicyclic or tricyclic hydrocarbon group containing 3-12 carbon atoms, each of which optionally may be substituted by one or more substituents, such as alkenyl, quinil, halogen, hydroxy-group, alkoxygroup, alkoxyalkyl, allylthiourea, Aristocra, arielalexisxrp, carbarnoyl, sulfamoyl, sulfonyl, optionally substituted amino, cyano, carboxypropyl, alkoxycarbonyl, aryl, alloctype, heterocyclyl or alkyl, optionally substituted with amino, halogen, hydroxy-group, alkoxygroup, carboxypropyl, carbamoyl or heterocyclyl etc.

Typical monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl etc.

Typical bicyclic hydrocarbon group include bornyl, Intel, hexahydrobenzyl, tetrahydronaphthyl, decahydronaphthalene, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-d is methylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl etc.

Typical tricyclic hydrocarbon groups include substituted etc.

Optionally substituted amino group refers to a primary or secondary amino group, which optionally can be substituted, for example, acyl, sulfonyl, alkoxycarbonyl, cycloalkylcarbonyl, aryloxyalkyl, heteroarylboronic, arylethoxysilanes, heteroarylboronic, carbamoyl etc.

Carbarnoyl means, for example, H2NC(O)-, alkyl-NHC(O)-, (alkyl)2NC(O)-, aryl-NHC(O)-, alkyl(aryl)-NC(O)-, heteroaryl-NHC(O)-, alkyl(heteroaryl)-NC(O)-, arylalkyl-NHC(O)-, alkyl(arylalkyl)-NC(O) -, etc.

Sulfamoyl means, for example, H2NS(O)2-, alkyl-NHS(O)2-, (alkyl)2NS(O)2-, aryl-NHS(O)2-, alkyl(aryl)-NS(O)2-, (aryl)2NS(O)2-heteroaryl-NHS(O)2-arylalkyl-NHS(O)2-heteroaromatic-NHS(O)2and so on

Free or esterified or adaderana carboxy-ness. alkoxygroup means, for example, carboxy-ness. alkoxygroup, NISS. alkoxycarbonyl-ness. alkoxygroup, carbarnoyl-ness. alkoxygroup or N-mono - or N,N-di-ness. allylcarbamate-ness. alkoxygroup.

Optionally substituted ness. alkanolamine, halogenated or sulfonylurea hydroxy-ness. alkoxygroup oboznachaet is, for example, NISS. alkanoyloxy-ness. alkyl, hydroxy-ness. alkoxygroup, halogen-(hydroxy)-ness. alkoxygroup or nits. alkanesulfonyl-(hydroxy)-ness. alkoxygroup.

Amino-ness. alkyl, which is unsubstituted or substituted ness. the alkyl, NISS. alkanoyl and/or nits. alkoxycarbonyl indicates, for example, amino-ness. alkyl, NISS. alkylamino-ness. alkyl, di-ness. alkylamino-ness. alkyl, NISS. alkanolamine-ness. alkyl or nits. allyloxycarbonyl-ness. alkyl.

Amino-ness. alkoxygroup, which is unsubstituted or substituted ness. the alkyl, NISS. alkanoyl and/or nits. alkoxycarbonyl indicates, for example, amino-ness. alkoxygroup, NISS. alkylamino-ness. alkoxygroup, di-ness. alkylamino-ness. alkoxygroup, NISS. alkanolamine-ness. alkoxygroup or nits. allyloxycarbonyl-ness. alkoxygroup.

Optionally oxidized to S atom ness. alkylthio-ness. alkoxygroup means, for example, ness. alkylthio-ness. alkoxygroup or nits. alkanesulfonyl-ness. alkoxygroup.

Optional gidrirovanny heteroaryl-ness. alkoxygroup means, for example, optionally partially gidrirovannoe or oxidized by the N atom of the pyridyl-ness. alkoxygroup, thiazolyl-ness. alkoxygroup or, preferably, morpholino-ness. alkoxygroup.

Optional gidrirovanny is ethereality-ness. alkoxygroup means, for example, optionally partially or fully gidrirovannoe heteroaromatic-ness. alkoxygroup, such as thiazolino-ness. alkoxygroup or thiazolidine-ness. alkoxygroup, imidazolidin-ness. alkoxygroup, optionally oxidized to atom N pyridylthio-ness. alkoxygroup or pyramidally-ness. alkoxygroup.

Free or esterified or aminirovanie carboxy-ness. alkyl denotes, for example, carboxy-ness. alkyl, NISS. alkoxycarbonyl-ness. alkyl, carbarnoyl-ness. alkyl or N-mono - or N,N-di-ness. allylcarbamate-ness. alkyl.

Optionally halogenated ness. alkyl denotes, for example, ness. alkyl or polyhalogen-ness. alkyl.

Optionally halogenated ness. alkoxygroup means, for example, ness. alkoxygroup or polyhalogen-ness. alkoxygroup.

Optionally S-oxidised ness. alkylthio-ness. alkyl denotes, for example, ness. alkylthio-ness. alkyl or nits. alkanesulfonyl-ness. alkyl.

Optionally oxidized to S atom ness. alkylthio-ness. alkoxygroup means, for example, ness. alkylthio-ness. alkoxygroup or nits. alkanesulfonyl-ness. alkoxygroup.

Optional hydrogenated heteroaryl-ness. alkyl denotes, for example, optionally partially hydrogenated or oxidized by the N atom of the pyridyl-ness. alkyl.

<> Optionally hydrogenated, heteroaromatic-ness. alkyl denotes, for example, thiazolino-ness. alkyl or thiazolidine-ness. alkyl, imidazolidin-ness. alkyl, optionally oxidized to atom N pyridylthio-ness. alkyl or pyrimidinyl-ness. alkyl.

Amino-ness. alkyl, which is unsubstituted or N-mono - or N,N-di-ness. alkilirovanny, N-ness. alkanolamines or N-ness. alkanolammonium or N,N-disubstituted ness. alkylene, unsubstituted or N'-ness. alkilirovanny or N'-ness. alkanolamines Aza-ness. alkylene, oxa-ness. alkylene; or optionally S-oxidised thia-ness. alkylene means, for example, amino-ness. alkyl, NISS. alkylamino-ness. alkyl, di-ness. alkylamino-ness. alkyl, NISS. alkanolamine-ness. alkyl, NISS. alkanesulfonyl-ness. alkyl, polyhalogen-ness. alkanesulfonyl-ness. alkyl, pyrrolidino-ness. alkyl, piperidino-ness. alkyl, piperazine derivatives-, N'-ness. alkylpiperazine - or N'-ness. alkanolamine-ness. alkyl, morpholino-ness. alkyl, thiomorpholine-, S-oxathiolane - or S,S-dioxothiazolidine-ness. alkyl.

Optionally oxidized to S atom ness. alkylthio-ness. alkoxygroup means, for example, ness. alkylthio-ness. alkoxygroup or nits. alkanesulfonyl-ness. alkoxygroup.

Amino-ness. alkoxygroup, which is unsubstituted or N-mono - or N,N-di-bottom is. alkilirovanny, N-ness. alkanolamines or N-ness. alkanesulfonyl or N,N-disubstituted ness. alkylene, unsubstituted or N'-ness. alkilirovanny or N'-ness. alkanolamines Aza-ness. alkylene, oxa-ness. alkylene or optionally S-oxidised thia-ness. alkylene means, for example, amino-ness. alkoxygroup, NISS. alkylamino-ness. alkoxygroup, di-ness. alkylamino-ness. alkoxygroup, NISS. alkanolamine-ness. alkoxygroup, NISS. alkanesulfonyl-ness. alkoxygroup, polyhalogen-ness. alkanesulfonyl-ness. alkoxygroup, pyrrolidino-ness. alkoxygroup, piperidino-ness. alkoxygroup, piperazine derivatives-, N'-ness. alkylpiperazine - or N'-ness. alkanolamine-ness. alkoxygroup, morpholino-ness. alkoxygroup, thiomorpholine-, S-oxathiolane - or S,S-dioxothiazolidine-ness. alkoxygroup.

Unsubstituted or N-mono - or N,N-di-ness. alkilirovanny or N-ness. alkanolamine amino group denotes, for example, an amino group, NISS. the alkyl amino group, di-ness. the alkyl amino group or nits. alkanoyl the amino group.

Free or formed aliphatic complex or a simple ester of hydroxy-ness. alkyl denotes, for example, hydroxy-ness. alkyl, NISS. alkanoyloxy-ness. alkyl, NISS. alkoxy-ness. alkyl or nits. alkenylacyl-ness. alkyl.

Amino-ness. alkyl, which is resumes is authorized or N-ness. alkanolamines, N-mono - or N,N-di-ness. alkilirovanny or N,N-disubstituted ness. alkylene, hydroxy-, ness. alkoxy - or nits. alkanoyloxy-ness. alkylene, unsubstituted or N'-ness. alkanolamines Aza-ness. alkylene, oxa-ness. alkylene; or optionally S-oxidised thia-ness. alkylene indicates, for example, amino-ness. alkyl, NISS. alkanolamine-ness. alkyl, N-mono - or N,N-di-ness. alkylamino-ness. alkyl, optionally gidroksilirovanii or nits. alkoxycarbonyl piperidino-ness. alkyl, such as piperidino-ness. alkyl, hydroxypiperidine-ness. alkyl or nits. alkoxy-piperidino-ness. alkyl, piperazine derivatives-, W-ness. alkylpiperazine-; or N'-ness. alkanolamine-ness. alkyl, unsubstituted or nits. alkilirovanny morpholino-ness. alkyl, such as morpholino-ness. alkyl or dimethylmorpholine-ness. alkyl; or optionally S-oxidised, thiomorpholine-ness. alkyl, such as thiomorpholine-ness. alkyl or S,S-dioxothiazolidine-ness. alkyl.

Free or esterified or aminirovanie dicarboxy-ness. alkyl denotes, for example, dicarboxy-ness. alkyl, di-ness. alkoxycarbonyl-ness. alkyl, decarbamoyl-ness. alkyl or di-(N-mono - or N,N-di-ness. allylcarbamate)-ness. alkyl.

Free or esterified or aminirovanie carboxy-(hydroxy)-ness. alkyl denotes, for example, carboxy-(hydroxy)-n is ZS. alkyl, NISS. alkoxycarbonyl-(hydroxy)-ness. alkyl or carbarnoyl-(hydroxy)-ness. alkyl.

Free or esterified or aminirovanie carboxylicacid-ness. alkyl denotes, for example, 5 - or 6-membered carboxylicacid-ness. alkyl, NISS. alkoxycarbonylmethyl-ness. alkyl, carbamoylmethyl-ness. alkyl or N-mono - or N,N-di-ness. alkylcarboxylic-ness. alkyl.

Unsubstituted or N-mono - or N,N-di-ness. alkilirovanny sulfamoyl-ness. alkyl denotes, for example, sulfamoyl-ness. alkyl, NISS. alkylsulfanyl-ness. alkyl or di-ness. alkylsulfanyl-ness. alkyl.

Unsubstituted or N-mono - or N,N-di-ness. alkilirovanny thiocarbamoyl-ness. alkyl denotes, for example, thiocarbamoyl-ness. alkyl, NISS. alkylthiomethyl-ness. alkyl; or di-ness. alkylthiomethyl-ness. alkyl, such as N,N-dimethylthiocarbamate.

Above and below in the present invention, NISS. radicals and compounds should be understood as meaning, for example, those which contain up to and including 7 carbon atoms, preferably up to and including 4 carbon atoms.

Five - or 6-membered carboxylicacid-ness. alkyl, NISS. alkoxycarbonylmethyl-ness. alkyl, carbamoylmethyl-ness. alkyl, N-mono - or N,N-di-ness. alkylcarboxylic-ness. alkyl denotes, for example, ω-(1-carboxylicacid)-C1 -C4alkyl, ω-(1-ness. alkoxycarbonylmethyl)-C1-C4alkyl, ω-(1-carbamoylmethyl)-C1-C4alkyl, ω-(1-ness. alkylcarboxylic)-C1-C4alkyl or ω-(1-di-ness. alkylcarboxylic)-C1-C4alkyl, where cycloalkyl means, for example, cyclopentyl or cyclohexyl; ness. alkoxycarbonyl means, for example, With1-C4alkoxycarbonyl, such as methoxy - or etoxycarbonyl; ness. allylcarbamate means, for example, With1-C4allylcarbamate, such as methylcarbamoyl; di-ness. allylcarbamate means, for example, di-C1-C4allylcarbamate, such as dimethylcarbamoyl; and NISS. alkyl denotes, for example, With1-C4alkyl, such as methyl, ethyl, propyl or butyl, preferably - (1-carboxylatomethyl)methyl.

Five - or 6-membered, cycloalkane-ness. alkoxygroup means, for example, cyclopentyloxy or cyclohexyloxy-C1-C4alkoxygroup, such as cyclopentyloxy or cyclohexylmethoxy, 2-cyclopentyloxy - or 2-cyclohexylacetate, 2 - or 3-cyclopentyloxy - or 2 - or 3-cyclohexylpropionic or 4 cyclopentyloxy - or 4-cyclohexyloxycarbonyloxy, preferably, cyclopentyloxy or cyclohexylmethoxy.

Five - or 6-membered, cycloalkane-nissalke means, for example, cyclopentyloxy or cyclohexyloxy-C1-C4alkyl, such as cyclopentyloxy or cyclohexyloxy, 2-cyclopentyloxy - or 2-cyclohexylethyl, 2 - or 3-cyclopentyloxy - or 2 - or 3-cyclohexanediol, 2-cyclopentyloxy - or 2-cyclohexyloxy-2-methylpropyl, 2-cyclopentyloxy - or 2-cyclohexyloxy-2-ethylbutyl or 4 cyclopentyloxy - or 4-cyclohexylacetate, preferably, cyclopentyloxy or cyclohexyloxy.

Amino-ness. alkoxygroup means, for example, amino-C1-C4alkoxygroup, such as 2-aminoethoxy or 5-aminophenylacetate and 3-aminopropoxy or 4-aminobutoxy.

Amino-ness. alkyl denotes, for example, amino-C1-C4alkyl, such as 2-amino-ethyl, 3-aminopropyl or 4-aminobutyl.

Carbarnoyl-(hydroxy)-ness. alkyl denotes, for example, carbarnoyl-C1-C7(hydroxy)alkyl, such as 1-carbarnoyl-2-hydrocity.

Carbarnoyl-ness. alkoxygroup means, for example, carbarnoyl-C1-C4alkoxygroup, such as carbamoylmethyl, 2-carbamoylethyl, 3-carbamoylphenoxy or 4-carbamoylphenoxy, preferably carbamoylmethyl.

Carbarnoyl-ness. alkyl denotes, for example, carbarnoyl-C1-C7alkyl, such as carbamoylmethyl, 2-carbamoyl is ethyl, 3-carbamoylethyl, 2-(3-carbarnoyl)propyl, 2-carbamoylethyl, 3-(1-carbarnoyl)propyl, 2-(2-carbarnoyl)propyl, 2-(carbarnoyl-2-methyl)propyl, 4-carbamoylmethyl, 1-carbamoylethyl, 1-(1-carbarnoyl-2-methyl)butyl, or 3-(4-carbarnoyl-2-methyl)butyl.

Carboxy-(hydroxy)-ness. alkyl denotes, for example, carboxy-C1-C7(hydroxy)alkyl, such as 1-carboxy-2-hydroxyethyl.

Carboxy-ness. alkoxygroup means, for example, carboxy-C1-C4alkoxygroup, such as carboxymethoxy, 2-carboxitherapy,

2 - or 3-carboxyphenoxypropane or 4-carboxymethyloxime, preferably, carboxymethoxy.

Carboxy-ness. alkyl denotes, for example, carboxy-C1-C4alkyl, such as carboxymethyl, 2-carboxyethyl, 2 - or 3-carboxypropyl, 2-carboxy-2-methylpropyl, 2-carboxy-2-ethylbutyl or 4-carboxybutyl, preferably carboxymethyl.

Cyano-ness. alkoxygroup means, for example, cyano-C1-C4alkoxygroup, such as cinematograph, 2-cyanoethoxy, 2 - or 3-cyanopropionic or 4-cyanoborohydride, preferably cinematograph.

Cyano-ness. alkyl denotes, for example, cyano-C1-C4alkyl, such as cyanomethyl, 2-cyanoethyl, 2 - or 3-cyanopropyl, 2-cyano-2-methylpropyl, 2-cyano-2-ethylbutyl or 4-cyanomethyl, preferably lanemate is.

di-(N-mono - or N,N-di-ness. allylcarbamate)-ness. alkyl denotes, for example, di-(N-mono - or N,N-di-C1-C4allylcarbamate)-C1-C4alkyl, such as 1,2-di-(N-mono - or N,N-di-C1-C4allylcarbamate)ethyl or 1,3-di-(N-mono - or N,N-di-C1-C4allylcarbamate)propyl.

Decarbamoyl-ness. alkyl denotes, for example, decarbamoyl-C1-C4alkyl, such as 1,2-decarbamylated or 1,3-dicarbonitrile.

Dicarboxy-ness. alkyl denotes, for example, dicarboxy-C1-C4alkyl, such as 1,2-dicarboxyethyl or 1,3-dicarboxylate.

Dimethylmorpholine-ness. alkoxygroup can be oxidized by atom N and denotes, for example, 2,6-dimethylmorpholine - or 3,5-dimethylmorpholine-C1-C4alkoxygroup, such as 2,6-dimethylmorpholine - or 3,5-dimethylmorpholine-methoxy, 2-(2,6-dimethylmorpholine - or 3,5-dimethylmorpholine)-ethoxypropan, 3-(2,6-dimethylmorpholine - or 3,5-dimethylmorpholine)-propyloxy, 2-(2,6-dimethylmorpholine - or 3,5-dimethylmorpholine-3-methyl)propyloxy, or 1 - or 2-[4-(2,6-dimethylmorpholine - or 3,5-dimethylmorpholine)]-butylacrylate.

Dimethylmorpholine-ness. the alkyl can be oxidized by atom N and denotes, for example, 2,6-dimethylmorpholine - or 3,5-dimethylmorpholine-C1-C4alkyl, such as 2,6-dimethylmorpholine - or 3,5-dimethylmorpholine-methoxy, 2-(2,6-dimethy is morpholino - or 3,5-dimethylmorpholine)-ethoxypropan, 3-(2,6-dimethylmorpholine - or 3,5-dimethylmorpholine)-propyl, 2-(2,6-dimethylmorpholine - or 3,5-dimethylmorpholine-3-methyl)-propyl, or 1 - or 2-[4-(2,6-dimethylmorpholine - or 3,5-dimethylmorpholine)]-butyl.

Di-ness. alkoxycarbonyl-ness. alkyl denotes, for example, di-ness. alkoxycarbonyl-C1-C4alkyl, such as 1,2-diethoxycarbonyl, 1,3-diethoxycarbonyl, 1,2-diethoxycarbonyl or 1,3-diethoxycarbonyl.

Di-ness. alkylamino means, for example, di-C1-C4alkylamino, such as dimethylaminopropyl, N-methyl-N-ethylamino, diethylaminopropyl, N-methyl-N-propylamino or N-butyl-N-methylaminopropyl.

Di-ness. alkylamino-ness. alkoxygroup means, for example, N,N-di-C1-C4alkylamino-C1-C4alkoxygroup, such as 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 4-dimethylaminoethoxy, 2-diethylaminoethoxy, 2-(N-methyl-N-ethylamino)ethoxypropan or 2-(N-butyl-N-methylamino)ethoxypropan.

Di-ness. alkylamino-ness. alkyl denotes, for example, N,N-di-C1-C4alkylamino-C1-C4alkyl, such as 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminomethyl, 2-diethylaminoethyl, 2-(N-methyl-N-ethylamino)ethyl or 2-(N-butyl-N-methylamino)ethyl.

Di-ness. allylcarbamate-ness. alkoxygroup means, for example ,N-di-C 1-C4allylcarbamate-C1-C4alkoxygroup, such as methyl - or dimethylcarbamoyl-C1-C4alkoxygroup, such as N-methyl, N-butyl - or N,N-dimethylcarbamoyl, 2-(N-methylcarbamoyl)ethoxypropan, 2-(N-butylcarbamoyl)ethoxypropan, 2-(N,N-dimethylcarbamoyl)ethoxypropan, 3-(N-methylcarbamoyl)propyloxy, 3-(N-butylcarbamoyl)propyloxy, 3-(N,N-dimethylcarbamoyl)propyloxy or 4-(N-methylcarbamoyl)butylacrylate, 4-(N-butylcarbamoyl)butylacrylate or 4-(N N-dimethylcarbamoyl)butylacrylate, preferably N-methyl-N-butyl - or N,N-dimethylcarbamodithioato.

Di-ness. allylcarbamate-ness. alkyl denotes, for example, N,N-di-C1-C4allylcarbamate-C1-C4alkyl, such as 2-dimethylcarbamoyl, 3-dimethylcarbamoyl, 2-dimethylcarbamoyl, 2-(dimethylcarbamoyl-2-methyl)propyl or 2-(1-dimethylcarbamoyl-3-methyl)butyl.

Di-ness. alkylsulfanyl-ness. alkyl denotes, for example, N,N-di-C1-C4alkylsulfanyl-C1-C4alkyl, N,N-dimethylsulphamoyl-C1-C4alkyl, such as N,N-dimethylaminomethyl, 2-(N,N-dimethylcarbamoyl)ethyl, 3-(N,N-dimethylcarbamoyl)propyl or 4-(N,N-dimethylcarbamoyl)butyl, preferably N,N-dimethylcarbamoyl.

Unsubstituted or N-ness. alkanolamines piperidyl-ness. alkyl, oboznachaet is, for example, 1-C1-C7-ness. alkanolamides-4-yl-C1-C4alkyl, such as 1-acetylpiperidine or 2-(1-acetylpiperidine)ethyl.

Optional partially gidrirovanny or oxidized by the N atom of the pyridyl-ness. alkoxygroup means, for example, optionally partially gidrirovannoe pyridyl - or N-oxidability-C1-C4alkoxygroup, such as pyridyl - or N-oxidability-methoxy, 2-pyridylacetate, 2 - or 3-pyridylmethylamine or 4-pyridylmethylamine, preferably 3 - or 4-pyridylmethyl.

Optionally partially hydrogenated or oxidized by the N atom of the pyridyl-ness. alkyl denotes, for example, optionally partially hydrogenated pyridyl - or N-oxidability-C1-C4alkyl, such as pyridyl - or N-oxidability-methyl, 2-pyridylethyl, 2 - or 3-pyridylmethyl or 4-pyridylmethyl, preferably 3 - or 4-pyridylmethyl.

Halogen-(hydroxy)-ness. alkoxygroup means, for example, halogen-C2-C7(hydroxy)alkoxygroup, preferably halogen-C2-C4(hydroxy)alkoxygroup, such as 3-halogen, such as 3-chloro-2-hydroxypropylamino.

Hydroxy-ness. alkoxygroup means, for example, hydroxy-C2-C7alkoxygroup, preferably hydroxy-C2-C4alkoxygroup, such as 2-guide is oxybutyninum, 3-hydroxypropylamino or 4-hydroxyethyloxy.

Hydroxy-ness. alkyl denotes, for example, hydroxy-C2-C7alkyl, preferably hydroxy-C2-C4alkyl, such as 2-hydroxyethyl, 3-hydroxypropyl or 4-hydroxybutyl.

Hydroxypiperidine-ness. alkyl denotes, for example, 3 - or 4-hydroxypiperidine-C1-C4alkoxygroup, such as 3 - or 4-hydroxypiperidine, 2-(3 - or 4-hydroxypiperidine)ethoxypropan, 3-(3 - or 4-hydroxypiperidine)propyloxy or 4-(3 - or 4-hydroxypiperidine)butylacrylate.

Imidazolyl-ness. alkyl denotes, for example, imidazolyl-C1-C4alkyl, such as imidazol-4-yl-methyl, 2-(imidazol-4-yl)ethyl, 3-(imidazol-4-yl)propyl or 4-(imidazol-4-yl)butyl.

Imidazolyl-ness. alkoxygroup means, for example, imidazolyl-C1-C4alkoxygroup, such as imidazol-4-yl-methoxy, 2-(imidazol-4-yl)ethoxypropan, 3-(imidazol-4-yl)propyloxy or 4-(imidazol-4-yl)butylacrylate.

Imidazolyl-ness. alkyl denotes, for example, imidazolyl-C1-C4alkyl, such as imidazol-4-yl-methyl, 2-(imidazol-4-yl)ethyl, 3-(imidazol-4-yl)propyl or 4-(imidazol-4-yl)butyl.

Morpholinoethyl-ness. alkyl denotes, for example, morpholinomethyl-C1-C4alkyl, such as 1-morpholinoethyl, 3-morpholinopropan propyl or 1 -(morpholinomethyl-2-methyl)propyl.

Morpholino-ness. alkoxygroup can be oxidized by atom N and denotes, for example, morpholino-C1-C4alkoxygroup, such as 1-morpholinoethoxy, 3-morpholinopropan or 1-(morpholino-2-methyl)propyloxy.

Morpholino-ness. the alkyl can be oxidized by atom N and denotes, for example, morpholino-C1-C4alkyl, such as morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropan or 1 - or 2-(4-morpholino)butyl.

Ness. alkanoyl means, for example, With1-C7alkanoyl, preferably-C2-C6alkanoyl, such as acetyl, propionyl, butyryl, isobutyryl or pivaloyl.

Ness. alkanolamine means, for example, N-C1-C7alkanolamines, such as acetylamino or evaluieringsrapport.

Ness. alkanolamine means, for example, N-C1-C7alkanolamines, such as acetylamino or evaluieringsrapport.

Ness. alkanolamine-ness. alkyl denotes, for example, N-C1-C4alkanolamine-C1-C4alkyl, such as 2-acetoxyacetyl.

Ness. alkanolamine-ness. alkyl denotes, for example, N-C1-C4alkanolamine-C1-C4alkyl, such as 2-acetoxyacetyl.

Ness. alkanoyl-ness. alkoxygroup (oxo-ness. alkoxygroup) contains NISS. alkanoyloxy group floor in the terms hereinafter, than the α-position and denotes, for example, With1-C7alkanoyl-C1-C4alkoxygroup, such as 4-acetylbutyrate.

Ness. alkanoyloxy-ness. alkyl contains NISS. alkanoyloxy in a position further than the α-position and denotes, for example, With1-C7alkanoyloxy-C1-C4alkyl, such as 4-acetoxymethyl.

Ness. alkanesulfonyl-(hydroxy)-ness. alkoxygroup means, for example, With1-C7alkanesulfonyl-C1-C4(hydroxy)alkoxygroup, such as 3-methanesulfonyl-2-hydroxypropylamino.

Ness. alkanesulfonyl-ness. alkoxygroup means, for example, C1-C7alkanesulfonyl-C1-C4alkoxygroup, such as methysulfonylmethane or 3-methanesulfonyl-2-hydroxypropylamino.

Ness. alkanesulfonyl-ness. alkoxygroup means, for example, With1-C7alkanesulfonyl-C1-C4alkoxygroup, such as ethanolammonium, 2-econsultantresources.com, 3-econsultantresources.com or 3-(1,1-dimethylethanolamine)propyloxy.

Ness. alkanesulfonyl-ness. alkyl denotes, for example, C1-C7alkanesulfonyl-C1-C4alkyl, such as ethanolamine, 2-ethanolamines, 3-ethanolgasoline the yl or 3-(1,1-dimethylethanolamine)propyl.

Ness. alkanesulfonyl-ness. alkyl denotes, for example, C1-C7alkanesulfonyl-C1-C4alkyl, such as ethanallenhotel, 2-econsultancy, 3-acanaloniidae or 3-(1,1-dimethylaminophenyl)propyl.

Ness. alkenyl means, for example, With1-C7alkenyl, such as vinyl or allyl.

Ness. alkenylacyl means, for example, C1-alkenylacyl, such as alliancegroup.

Ness. alkenylacyl-ness. alkoxygroup means, for example, C1-C7alkenylacyl-C1-C4alkoxygroup, such as allyloxymethyl.

Ness. alkenylacyl-ness. alkyl denotes, for example, With1-C7alkenylacyl-C1-C4alkyl, such as allyloxymethyl.

Ness. alkoxygroup means, for example, With1-C7alkoxygroup, preferably - C1-C5alkoxygroup, such as a methoxy group, ethoxypropan, propyloxy, isopropylacetate, butylacrylate, isobutylacetate, sec-butylacrylate, tert-butylacrylate, pentyloxy or hexyloxy or heptyloxy.

Ness. alkoxycarbonyl means, for example, With1-C7alkoxycarbonyl, preferably - C1-C5alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl, propylenecarbonate, isopropoxycarbonyl, BU is jocstarbunny, isobutylketone, second-butyloxycarbonyl, tert-butylacrylate, pentyloxybenzoyl or hexyloxybenzoyl or heptyloxybiphenyl.

Ness. alkoxycarbonyl-(hydroxy)-ness. alkyl denotes, for example, With1-C4alkoxycarbonyl-C1-C7(hydroxy)alkyl, such as 1-methoxycarbonyl - or 1-etoxycarbonyl-2-hydroxyethyl.

Ness. allyloxycarbonyl-ness. alkoxygroup means, for example, With1-C7alkoxycarbonyl-C2-C7alkoxygroup, preferably - C2-C5alkoxycarbonyl-C2-C7alkoxygroup, such as methoxycarbonylamino-C2-C7alkoxygroup, ethoxycarbonylethyl-C2-C7alkoxygroup, propylenecarbonate-C2-C7alkoxygroup, isobutylacetophenone-C2-C7alkoxygroup, butyloxycarbonyl-C2-C7alkoxygroup, isobutylacetophenone-C2-C7alkoxygroup, sec-butyloxycarbonyl-C2-C7alkoxygroup or tert-butylacetamide-C2-C7alkoxygroup, where C2-C7alkoxygroup means, for example, methoxy, ethoxypropan, propyloxy, butylacrylate, pentyloxy or hexyloxy.

Ness. allyloxycarbonyl-ness. alkyl denotes, for example, With1-C7al is oxcarbazepine-C 2-C7alkyl, preferably - C2-C5alkoxycarbonyl-C2-C7alkyl, such as methoxycarbonyl-C2-C7alkyl, ethoxycarbonylethyl-C2-C7alkyl, propylenecarbonate-C2-C7alkyl, isopropoxycarbonyl-C2-C7alkyl, butyloxycarbonyl-C2-C7alkyl, isobutylacetophenone-C2-C7alkyl, sec-butyloxycarbonyl-C2-C7alkyl or tert-butylacetamide-C2-C7alkyl, where C2-C7alkyl denotes, for example, methyl, ethyl, propyl, butyl, pentyl or hexyl.

Ness. alkoxycarbonyl-ness. alkoxygroup means, for example, C1-C4alkoxycarbonyl-C1-C4alkoxygroup, such as methoxycarbonyl or etoxycarbonyl-methoxy, 2-methoxycarbonyl - or 2-ethoxycarbonylethyl, 2 - or 3-methoxycarbonyl - or 2 - or 3-ethoxycarbonylmethoxy or 4-methoxycarbonyl - or 4-ethoxycarbonylmethoxy, preferably methoxycarbonyl or ethoxycarbonylmethoxy or 3-methoxycarbonyl - or 3-ethoxycarbonylmethoxy.

Ness. alkoxycarbonyl-ness. alkyl denotes, for example, C1-C4alkoxycarbonyl-C1-C4alkyl, such as methoxycarbonyl or ethoxycarbonylmethoxy, 2-methoxycarbonyl - or 2-ethoxy is arboreteum, 3-methoxycarbonyl - or 3-ethoxycarbonylmethoxy or 4-ethoxycarbonylmethoxy.

Ness. alkoxy-ness. alkenyl means, for example, With1-C4alkoxy-C2-C4alkenyl, such as 4-methoxybutyl-2-enyl.

Ness. alkoxy-ness. alkoxygroup means, for example, With1-C4alkoxy-C2-C4alkoxygroup, such as 2-methoxy-, 2-ethoxy - or 2-propylacetate, 3-methoxy - or 3-ethoxypropylamine or 4-methoxybenzyloxy, preferably 3-methoxypropylacetate or 4-methoxybenzyloxy.

Ness. alkoxy-ness. alkoxy-ness. alkyl denotes, for example, C1-C4alkoxy-C1-C4alkoxy-C1-C4alkyl, such as 2-methoxy-, 2-ethoxy - or 2-propyloxy-ethoxymethyl, 2-(2-methoxy-, 2-ethoxy - or 2-propyloxy-ethoxy)ethyl, 3-(3-methoxy - or 3-ethoxypropionate)propyl or 4-(2-methoxybenzyloxy)butyl, preferably 2-(3-methoxyphenoxy)ethyl or 2-(4-methoxybenzyloxy)ethyl.

Ness. alkoxy-ness. alkyl denotes, for example, With1-C4alkoxy-C1-C4alkyl, such as ethoxymethyl, propylacetate, butylacetate, 2-methoxy-, 2-ethoxy - or 2-propylacetate, 3-methoxy - or 3-ethoxypropan or 4-methoxybutyl, preferably 3-methoxypropyl or 4-methoxybutyl.

Ness. alkoxyimino-ness. alkyl denotes, for example piperidino-, hydroxypiperidine or nits. alkoxyimino-C1-C4alkyl, such as piperidinomethyl, 4-hydroxypiperidine or 4-C1-C4alkoxy-, such as 4-methoxy-piperidinomethyl.

Ness. alkoxyimino-ness. alkyl denotes, for example, C1-C4alkoxyimino-C1-C4alkyl, such as 4-C1-C4alkoxyphenyl, preferably 4-methoxypiperidine.

Ness. the alkyl can be linear or branched and/or cyclic, and denotes, for example, corresponding With1-C7alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, or pentyl, hexyl or heptyl. Ness. alkyl R2or R3preferably stands With2-C7alkyl, NISS. alkyl R5or R7and preferably branched C3-C7alkyl and NISS. alkyl R8or R3means, for example, linear, branched or bridge With3-C7alkyl.

Ness. alkylamino means, for example, With1-C4alkylamino, such as methylaminopropyl, ethylamino, propylamino, butylamino, isobutylamino, sec-butylamino or tert-butylamino.

Ness. alkylamino-ness. alkoxygroup means, for example, With1-C4alkylamino-C1With 4alkoxygroup, such as propylaminoethyl, 2-methylamino-, 2-ethylamino-, 2-propylamino - or 2-butylaminoethyl, 3 ethylamino - or 3-propylimidazolium or 4-methylaminorex.

Ness. alkylamino-ness. alkyl denotes, for example, With1-C4alkylamino-C1-C4alkyl, such as propylaminoethyl, 2-methylamino-, 2-ethylamino-, 2-propylamino - or 2-butylaminoethyl, 3 ethylamino - or 3-propylaminoethyl or 4-methylaminomethyl.

Ness. allylcarbamate-ness. alkoxygroup means, for example, N-C1-C7allylcarbamate-C1-C4alkoxygroup, such as methyl - or dimethylcarbamoyl-C1-C4alkoxygroup, for example, methylcarbamoylmethyl, 2-methylcarbamoylmethyl or 3-methylcarbamoylmethyl.

Ness. alkylenedioxy means, for example, methylenedioxy or Ethylenedioxy, but may designate and 1,3 - or 1,2-propyleneoxide.

Ness. alkylsulfanyl-ness. alkyl denotes, for example, N-C1-C7alkylsulfanyl-C1-C4alkyl, such as N-methyl, N-ethyl-, N-propyl or N-butylsulfonyl-C1-C4alkyl, such as N-methyl, N-ethyl-, N-propyl or N-butylsulfonyl, 2-(N-methylcarbamoyl)ethyl, 2-(N-butylsulfonyl)ethyl, 3-(N-methylsulfonyl)propyl, 3-(N-butylsulfonyl)propyl or 4-(N-methyls livemail)butyl, 4-(N-butylsulfonyl)butyl or 4-(N,N-dimethylsulphamoyl)butyl, preferably N-methyl-N-butyl - or N,N-dimethylsulphamoyl.

Ness. alkylthio-(hydroxy)-ness. alkoxygroup means, for example, N-C1-C4alkylthio-C1-C4(hydroxy)alkoxygroup, such as 2-hydroxy-3-methylthiopropionate.

Oxazolyl-ness. alkyl denotes, for example, oxazolyl-C1-C4alkyl, such as 2-(1,2,4-oxadiazol-5-yl)ethyl, 3-(1,2,4-oxadiazol-5-yl)propyl or 4-(1,2,4-oxadiazol-5-yl)butyl.

Ness. alkylthio-ness. alkoxygroup means, for example, N-C1-C4alkylthio-C1-C4alkoxygroup, such as methylthio-C1-C4alkoxygroup, for example, methylthiomethyl, 2-methylthioethyl or 3-methylthiopropionate.

Ness. alkylthio-ness. alkyl denotes, for example, N-C1-C4alkylthio-C1-C4alkyl, such as methylthio-C1-C4alkyl, for example, methylthiomethyl, 2-methylthioethyl or 3-metaltipped.

N'-Ness. alkanolamine-ness. alkoxygroup means, for example, N'-ness. alkanolamine-C1-C4alkoxygroup, such as 4-acetylpiperidine.

N'-Ness. alkanolamine-ness. alkyl denotes, for example, N'-C2-C7-ness. alkanolamine-C1-C4alkyl, such as 4-acetylpiperidine the L.

N'-Ness. alkylpiperazine-ness. alkyl denotes, for example, N'-C1-C4alkylpiperazine-C1-C4alkyl, such as 4-methylpiperazine.

Oxo-ness. alkoxygroup means, for example, oxo-C1-C4alkoxygroup, such as 3,3-dimethyl-2-oxobutyraldehyde.

The piperazine derivatives-ness. alkyl denotes, for example, the piperazine derivatives-C1-C4alkyl, such as piperidinomethyl, 2-piperidinoethyl or 3-piperazinediones.

Piperidino-ness. alkoxygroup means, for example, piperidino-C1-C4alkoxygroup, such as piperidinomethyl, 2-piperidinoethyl or 3-piperidinecarboxylate.

Piperidino-ness. alkyl denotes, for example, piperidino-C1-C4alkyl, such as piperidinomethyl, 2-piperidinoethyl or 3-piperidinophenyl.

Polyhalogen-ness. alkanesulfonyl-ness. alkoxygroup means, for example, trifter-C1-C7alkanesulfonyl-C1-C4alkoxygroup, such as triftormetilfullerenov.

Polyhalogen-ness. alkanesulfonyl-ness. alkyl denotes, for example, trifter-C1-C7alkanesulfonyl-C1-C4alkyl, such as triftormetilfullerenov.

Pyrimidinyl-ness. alkoxygroup means, for example, pyrimidinyl-C1-C4alkoxygroup, such cekilmeyecegi, 2-pyrimidinylidene or 3-pyrimidinylpiperazine.

Pyrimidinyl-ness. alkyl denotes, for example, pyrimidinyl-C1-C4alkyl, such as pyrimidinyl, 2-pyrimidinyl or 3-pyrimidinediamine.

Pyrrolidino-ness. alkoxygroup means, for example, pyrrolidino-C2-C4alkoxygroup, such as 2-pyrrolidinecarboxamido or 3-pyrrolidinyloxy.

Pyrrolidino-ness. alkyl denotes, for example, pyrrolidino-C1-C4alkyl, such as pyrrolidinyl, 2-pyrrolidinyl or 3-pyrrolidinedione.

S,S-Dioxothiazolidine-ness. alkyl denotes, for example, S,S, diocletianopolis-C1-C4alkyl, such as S,S-dioxothiazolidine or 2-(S,S-dioxo)thiomorpholine.

S-Oxathiolane-ness. alkyl denotes, for example, S-oxathiolane-C1-C4alkyl, such as S-occatioinally or 2-(S-oxo)thiomorpholine.

Sulfamoyl-ness. alkyl denotes, for example, sulfamoyl-C1-C4alkyl, such as sulfamoyl-C1-C4alkyl, such as sulfamoyl, 2-sulphatoethyl, 3-sulfamoylbenzoyl or 4-sulfamoylbenzoyl.

Tetrazolyl-ness. alkyl denotes, for example, tetrazolyl-C1-C4alkyl, such as tetrazol-5-ylmethyl, 2-(tetrazol-5-yl)ethyl, 3-(tetrazol-5-yl)propyl or 4-(tetrazol-4-yl)butyl.

Tosolini the-ness. alkoxygroup means, for example, tosolini-C1-C4alkoxygroup, such as disainiklassiku, 2-disainiklassiku or 3-disainiprojektiks.

Tosolini-ness. alkyl denotes, for example, tosolini-C1-C4alkyl, such as titelnummer, 2-disaineritel or 3-isolinear.

Thiazolyl-ness. alkoxygroup means, for example, thiazolyl-C1-C4alkoxygroup, such as triazolylmethyl, 2-thiazoleacetate or 3-thiazolidinediones.

Thiazolyl-ness. alkyl denotes, for example, thiazolyl-C1-C4alkyl, such as triazolylmethyl, 2-thiazoleacetic or 3-triazolylmethyl.

Thiomorpholine-ness. alkyl or S,S-dioxothiazolidine-ness. alkyl denotes, for example, thiomorpholine-C1-C4alkyl, such as-methyl or-ethyl, or S,S-dioxothiazolidine-C1-C4alkyl, such as-methyl or-ethyl.

Depending on the presence of asymmetric carbon atoms of the compounds proposed in the present invention may be in the form of mixtures of isomers, preferably in the form of racemates or in the form of pure isomers, preferably the optical antipodes.

Salts of compounds containing soleobrazutaya group, preferred are salts with acids, salts with bases or, if contains several sleebraty the groups, they can also be mixed salts or internal salts.

Salts preferably are pharmaceutically acceptable or non-toxic salts of the compounds of formula (I).

Such salts are formed, for example, compounds of formula (I)having an acidic group, for example, carboxypropyl or sulfopropyl, and represents, for example, their salts with suitable bases, such as non-toxic salts of the metals of groups Ia, Ib, IIa and IIb of the Periodic system of elements, for example, alkali metal salts, preferably salts of lithium, sodium or potassium; or salts of alkaline earth metals such as magnesium or calcium; and also zinc salts or ammonium salts, and salts formed with organic amines, such as unsubstituted or replacement mono-, di - or trialkylamine, preferably mono-, di - or tri-ness. the bonds alkylamines; or with Quaternary ammonium bases, for example, methyl-, ethyl-, diethyl - or triethyl-amine; mono-, bis - or Tris-(2-hydroxy-ness. alkyl)-amines, such as ethanol-, diethanol - or triethanolamines; Tris(hydroxymethyl)methylamine or 2-hydroxy-tert-butylamine, N,N-di-ness. alkyl-N-(hydroxy-ness. alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)-amine or N-methyl-D-glucamine; or Quaternary ammonium hydroxides, such as tetrabutylammonium. The connection form is s (I), containing a basic group such as amino group, can form molecular salts with acids, for example, with suitable inorganic acids, for example, halogen acids such as hydrochloric acid and Hydrobromic acid, or sulfuric acid with replacement of one or both protons; phosphoric acid with replacement of one or more protons, for example, orthophosphoric acid or metaphosphoric acid; or pyrophosphoryl acid substitution, for example, one or more protons; or with organic carboxylic, sulfonic, sulfo - or phosphonic acids or N-substituted sulfamic acids, for example, acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleimide acid, methylmaleimide acid, fumaric acid, malic acid, tartaric acid, gluconic acid, glutaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, almond acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, monowai acid, nicotinic acid and isonicotinic acid, and also amino acids, such as α-amino acids mentioned above in the present invention; and with methanesulfonic acid, econsultancy acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzosulfimide acid, 4-toluensulfonate acid, naphthalene-2-sulfonic acid, 2 - or 3-phosphoglyceric acid, glucose-6-phosphoric acid or N-cyclohexylsulfamic acid (with the formation of cyclamates); or with other acid organic compounds, such as ascorbic acid. The compounds of formula (I)containing acidic or basic groups can form internal salts.

For isolation and purification it is also possible to use pharmaceutically unacceptable salts.

Connections proposed in the present invention, have the ability to inhibit the enzymes. In particular, they inhibit the action of the natural enzyme renin. The last of the kidney into the blood, where it affects the cleavage of angiotensin, highlighting Decapeptide angiotensin I, which is then cleaved in the lungs, kidneys and other organs with the release of oktapeptid of angiotensin II. This oktapeptid increases blood pressure and directly by narrowing of the arteries, and indirectly through the release of adrenal retaining sodium ions of the hormone aldosterone, which is accompanied by increase in the volume of extracellular fluid. This increase can be attributed to the impact and is of giotensin II. Inhibitors of the enzymatic effects of renin reduce the formation of angiotensin I. as a Consequence, a smaller quantity of angiotensin II. The decrease in the concentration of this active peptide hormone is the direct cause of the hypotensive effect of inhibitors of renin.

Thus, the compounds proposed in the present invention, can be used for the treatment of hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, hypertrophy of the heart, fibrosis of the heart, cardiomyopathy postinfarction, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, liver fibrosis, complications resulting from diabetes such as nephropathy, vasculopathies and neuropathy, diseases of the coronary vessels, restenosis after angioplasty, increased intraocular pressure, glaucoma, abnormal growth of blood vessels, hyperaldosteronism, disorders of cognition, Alzheimer's disease, dementia, anxiety States and cognitive disorders abilities.

The group of compounds listed below should not be regarded as unique; on the contrary, for example, to replace General definitions with more specific definitions of these groups of compounds in the above definitions can vzaimozamenjat or replacing the e l e C or exclude depending on what is better.

Preferred are the compounds of formula (I), designated as group a, in which

R9means NISS. alkyl, optionally substituted cycloalkyl (alkyl, HE alkoxygroup, alkoxyalkyl, halogen), optionally substituted cycloalkenyl (HE, alkoxygroup, alkoxyalkyl, halogen-free at cycloalkyl), cycloalkylcarbonyl, N-mono or N,N-dialkylamino cycloalkylcarbonyl, optionally substituted arylalkyl, free or formed aliphatic complex or a simple ester of hydroxy-ness. alkyl; amino-ness. alkyl, which is unsubstituted or N-ness. alkanolamines or N-mono - or N,N-di-ness. alkilirovanny or N,N-disubstituted ness. alkylene, hydroxy-, ness. alkoxy - or nits. alkanoyloxy-ness. alkylene, unsubstituted or N'-ness. alkanolamines or N'-ness. alkilirovanny Aza-ness. alkylene, oxa-ness. alkylene or optionally S-oxidised thia-ness. alkylene, free or esterified or emitirovannykh carboxy-ness. the alkyl, free or esterified or emitirovannykh dicarboxy-ness. the alkyl, free or esterified or emitirovannykh carboxy-(hydroxy)-ness. the alkyl, free or esterified or emitirovannykh carboxylicacid-ness. the alkyl, cyano-ness. the alkyl, n is ZS. alkanesulfonyl-ness. the alkyl, unsubstituted or N-mono - or N,N-di-ness. alkilirovanny thiocarbamoyl-ness. the alkyl, unsubstituted or N-mono - or N,N-di-ness. alkilirovanny sulfamoyl-ness. the alkyl or heteroaryl radicals attached through a carbon atom and optionally gidrirovanny and/or oxazolidinyl, or nits. by alkyl, substituted heteroaryl radicals attached through a carbon atom and optionally gidrirovanny and/or oxazolidinyl;

or their pharmaceutically acceptable salt.

Preferred are compounds in group a, in which

R1and R4represent hydrogen;

R2means NISS. alkoxy-ness. alkoxygroup;

R3denotes halogen or mono-, di - or trihalomethanes alkyl;

or their pharmaceutically acceptable salt.

Other preferred are compounds in group a, in which the halogen denotes fluorine or chlorine;

or their pharmaceutically acceptable salt.

More preferred are compounds in group a, in which R3denotes fluorine or trifluoromethyl;

or their pharmaceutically acceptable salt.

Most preferred are compounds in group a, in which R2located in the meta-position and R3located in the para-position;

or their pharmaceutically acceptable salt.

Most predpochtitelnye are compounds in group a, in which R3located in the ortho-position;

or their pharmaceutically acceptable salt.

Most preferred are also the compounds in group a, in which R3located in the meta-position;

or their pharmaceutically acceptable salt.

Preferred are also the compounds in group a, designated as group b, in which R2located in the meta-position and denotes ness. alkoxy-ness. alkoxygroup, optionally substituted with halogen (halogen);

or their pharmaceutically acceptable salt.

Other preferred are compounds in group b, in which halogen(s) denotes fluorine or chlorine;

or their pharmaceutically acceptable salt.

More preferred are compounds in group b, in which halogen(s) denotes fluorine;

or their pharmaceutically acceptable salt.

Preferred are also the compounds in the group designated as group C, in which R denotes ness. alkoxygroup, substituted with halogen (halogen);

or their pharmaceutically acceptable salt.

Preferred are compounds in group C, in which halogen(s) denotes fluorine or chlorine;

or their pharmaceutically acceptable salt.

Other preferred are compounds in group C, in which halogen(s) denotes fluorine;

or their pharmaceutical is acceptable salt.

Preferred are also the compounds in the group designated as group D, in which R3located in the para-position;

or their pharmaceutically acceptable salt.

Other preferred are compounds in group D, in which R3denotes a methoxy group;

or their pharmaceutically acceptable salt.

Other preferred are also the compounds in group D, in which R3denotes cryptometer;

or their pharmaceutically acceptable salt.

Preferred are also the compounds of formula (I)in which R3located in the para-position and denotes halogen;

or their pharmaceutically acceptable salt.

Preferred amides are also δ-amino-γ-hydroxy-ω-arylalkenes acid of the formula (I), denoted as group E, having the formula (Ia)

in which

R1denotes hydrogen, halogen, optionally halogenated alkyl, cycloalkyl, the hydroxy-group, optionally halogenated alkoxygroup, cycloalkanes, NISS. alkoxy-ness. alkoxygroup or free or esterified or amidinophenoxy ness. alkoxygroup or nits. alkyl;

R2denotes hydrogen, halogen, optionally halogenated ness. alkyl, hydroxy-group, cycloalkyl, cycloalkanes, it is certainly halogenated ness. alkoxy-ness. alkyl, optionally substituted ness. alkoxy-ness. alkoxygroup, cycloalkane-ness. alkyl; optional ness. alkanolamine, halogenated or sulfonylamino hydroxy-ness. alkoxygroup; amino-ness. alkyl, which is unsubstituted or contains as Vice ness. alkyl, NISS. alkanoyl and/or nits. alkoxycarbonyl; optional hydrogenated heteroaryl-ness. alkyl; amino-ness. alkoxygroup, which is unsubstituted or contains as Vice ness. alkyl, NISS. alkanoyl and/or nits. alkoxycarbonyl; oxo-ness. alkoxygroup, NISS. alkoxygroup, cycloalkanes, NISS. alkenylacyl, cycloalkane-ness. alkoxygroup, NISS. alkoxy-ness. alkenyl, NISS. alkenylacyl-ness. alkoxygroup, NISS. alkoxy-ness. alkenylacyl, NISS. alkenylacyl-ness. alkyl, NISS. alkanoyl-ness. alkoxygroup, optionally S-oxidised ness. alkylthio-ness. alkoxygroup, NISS. alkylthio-(hydroxy)-ness. alkoxygroup, aryl-ness. alkoxygroup, aryl-ness. alkyl, aryl-ness. alkoxygroup, optional gidrirovannoe heteroaryl-ness. alkoxygroup, optionally hydrogenated heteroaryl-ness. alkyl, cyano-ness. alkoxygroup, cyano-ness. alkyl, free or esterified or amidinophenoxy carboxy-ness. alkoxygroup or free or atrificial the config or aminirovanie carboxy-ness. alkyl;

R3and R4independently represent hydrogen, halogen, optionally halogenated ness. alkyl, hydroxy-group, optionally halogenated ness. alkoxygroup or cycloalkanes, NISS. alkoxy-ness. alkyl, cycloalkane-ness. alkyl, hydroxy-ness. alkyl, optionally S-oxidised ness. alkylthio-ness. alkyl, optionally hydrogenated, heteroaromatic-ness. alkyl, optionally hydrogenated heteroaryl-ness. alkyl; amino-ness. alkyl, which is unsubstituted or N-mono - or N,N-di-ness. alkilirovanny, N-ness. alkanolamines or N-ness. alkanolammonium or N,N-disubstituted ness. alkylene, unsubstituted or N'-ness. alkilirovanny or N'-ness. alkanolamines Aza-ness. alkylene, oxa-ness. alkylene or optionally S-oxidised thia-ness. alkylene; cyano-ness. alkyl, free or esterified or aminirovanie carboxy-ness. alkyl, cycloalkyl, aryl, hydroxy-group, NISS. alkoxygroup, cycloalkanes, NISS. alkoxy-ness. alkoxygroup, cycloalkane-ness. alkoxygroup, hydroxy-ness. alkoxygroup, aryl-ness. alkoxygroup, optionally halogenated ness. alkoxygroup, optionally S-oxidised ness. alkylthio-ness. alkoxygroup, optional gidrirovannoe heteroaryl-ness. alkoxygroup, optional gidrirovannoe heteroaromatic-n is ZS. alkoxygroup; amino-ness. amino-ness. alkoxygroup, which is unsubstituted or N-mono - or N,N-di-ness. alkilirovanny, N-ness. alkanolamines or N-ness. alkanesulfonyl or substituted ness. alkylene, unsubstituted or N'-ness. alkilirovanny or N'-ness. alkanolamines Aza-ness. alkylene, oxa-ness. alkylene or optionally S-oxidised thia-ness. alkylene; cyano-ness. alkoxygroup or free or esterified or amidinophenoxy carboxy-ness. alkoxygroup; or

R4together with R3means NISS. allinoneruby, NISS. alkylenedioxy or condensed aryl, optionally gidrirovannoe heteroaryl or cycloalkyl ring;

X denotes methylene, hydroxymethylene, oxygen, optionally substituted ness. the alkyl nitrogen atom or an optionally oxidized sulfur atom;

R5means NISS. alkyl or cycloalkyl;

R6denotes hydrogen, NISS. alkyl, hydroxy-group, alkoxygroup or halogen;

R7denotes unsubstituted or N-mono - or N,N-di-ness. alkilirovanny or N-ness. alkanolamine the amino group;

R8means NISS. alkyl, NISS. alkenyl, cycloalkyl or aryl-ness. alkyl;

R9denotes optionally substituted ness. alkyl, optionally substituted cycloalkyl, not necessarily samewe the hydrated cycloalkenyl, cycloalkylcarbonyl, N-mono or N,N-dialkylamino cycloalkylcarbonyl, optionally substituted arylalkyl, optionally substituted aryloxyalkyl, optionally substituted heteroepitaxial, free or formed aliphatic complex or a simple ester of hydroxy-ness. alkyl; amino-ness. alkyl, which is unsubstituted or N-ness. alkanolamines or N-mono - or N,N-di-ness. alkilirovanny or N,N-disubstituted ness. alkylene, hydroxy-, ness. alkoxy - or nits. alkanoyloxy-ness. alkylene, unsubstituted or N'-ness. alkanolamines or N'-ness. alkilirovanny Aza-ness. alkylene, oxa-ness. alkylene or optionally S-oxidised thia-ness. alkylene, free or esterified or emitirovannykh carboxy-ness. the alkyl, free or esterified or emitirovannykh dicarboxy-ness. the alkyl, free or esterified or emitirovannykh carboxy-(hydroxy)-ness. the alkyl, free or esterified or emitirovannykh carboxylicacid-ness. the alkyl, cyano-ness. the alkyl, NISS. alkanesulfonyl-ness. the alkyl, unsubstituted or N-mono - or N,N-di-ness. alkilirovanny thiocarbamoyl-ness. the alkyl, unsubstituted or N-mono - or N,N-di-ness. alkilirovanny sulfamoyl-ness. the alkyl or heteroaryl radicals attached through a carbon atom and optionally selective the data and/or oxazolidinyl, or nits. by alkyl, substituted heteroaryl radicals attached through a carbon atom and optionally gidrirovanny and/or oxazolidinyl;

or their pharmaceutically acceptable salt.

Preferred are compounds in group E, in which

R9denotes cycloalkyl containing as substituents alkyl, hydroxy-group, alkoxygroup, alkoxyalkyl or halogen; cycloalkyl, optionally containing as substituents alkyl, hydroxy-group, alkoxygroup, alkoxyalkyl or halogen at cycloalkyl or halogen in the alkyl or halogen at alkoxygroup; cycloalkylcarbonyl; N-mono or N,N-dialkylamino cycloalkylcarbonyl; or optionally substituted arylalkyl; or their pharmaceutically acceptable salt.

Preferred are also the compounds in the group of E, denoted as group F, in which

R9denotes hydrogen; halogenated alkyl; optionally substituted arylalkyl, optionally substituted aryloxyalkyl, cycloalkyl that contains 1-3 substituent selected from the group consisting of alkenyl, quinil, halogen, a hydroxy-group, alkoxygroup, alkoxyalkyl, allylthiourea, killigrew, arielalexisxrp, carbarnoyl, sulfamoyl, sulfonyl, optionally substituted by an amino, a cyano, carboxylate is, alkoxycarbonyl, aryl, alloctype, heterocyclyl or alkyl, optionally containing as substituents of the amino group, halogen, a hydroxy-group, alkoxygroup, carboxypropyl, alkoxycarbonyl, carbarnoyl or heterocyclyl;

or optionally substituted cycloalkenyl;

or their pharmaceutically acceptable salt.

Preferred are compounds in group F, in which

R1denotes hydrogen;

R2stands With1-C4alkoxy-C1-C4alkoxygroup or1-C4alkoxy-C1-C4alkyl;

R3stands With1-C4alkyl or C1-C4alkoxygroup;

R4denotes hydrogen;

X represents methylene;

R5means NISS. alkyl;

R6denotes hydrogen;

R7represents the unsubstituted amino group;

R8denotes branched C3-C4alkyl;

R9denotes optionally substituted cycloalkenyl;

or their pharmaceutically acceptable salt.

Other preferred are compounds in group F, in which

R2denotes 3-methoxypropylamine;

R3denotes a methoxy group;

R5means isopropyl;

R8means isopropyl;

or their pharmaceutically acceptable salt.

Preferred is also are compounds in group F, marked as group G, in which

R1denotes hydrogen;

R2stands With1-C4alkoxy-C1-C4alkoxygroup or1-C4alkoxy-C1-C4alkyl;

R3stands With1-C4alkyl or C1-C4alkoxygroup;

R4denotes hydrogen;

X represents methylene;

R5means NISS. alkyl;

R6denotes hydrogen;

R7represents the unsubstituted amino group;

R8denotes branched C3-C4alkyl;

R9denotes an unsubstituted arylalkyl;

or their pharmaceutically acceptable salt.

Preferred are compounds in group G, in which

R2denotes 3-methoxypropylamine;

R3denotes a methoxy group;

R5means isopropyl;

R8means isopropyl;

or their pharmaceutically acceptable salt.

Preferred are also the compounds in the group G, in which arylalkyl refers to alkyl substituted by phenyl;

or their pharmaceutically acceptable salt.

Other preferred are compounds in group G, in which arylalkyl represents methyl substituted by phenyl.

More preferred are compounds in group G, in which

R2denotes 3-methoxypropylacetate

R3denotes a methoxy group;

R5means isopropyl;

R8means isopropyl;

or their pharmaceutically acceptable salt.

Due to the high affinity of the new compounds in free form and in the form of their salts above and below in the present invention any reference to the free compounds and their salts should be understood as including also the corresponding salts or free compounds, respectively, if it is appropriate and expedient.

Connections proposed in the present invention, can usually be obtained by the techniques disclosed in U.S. patent No. 5559111, which is included in the present invention in its entirety by reference, as if he was fully included.

The present invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of pharmacologically active compounds proposed in the present invention, one or in combination with one or more pharmaceutically acceptable carriers.

The pharmaceutical composition proposed in the present invention are those suitable for enteral, such as oral or rectal, transdermal and parenteral administration to mammals, including humans, for the inhibition of renin activity, and dedicated to superior quality products is obtained for the treatment of pathological States, related renin activity. Such pathological conditions include hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, fibrosis of the heart, postinfarct cardiomyopathy, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, hepatic fibrosis, complications resulting from diabetes such as nephropathy, vasculopathies and neuropathy, diseases of the coronary vessels, restenosis after angioplasty, increased intraocular pressure, glaucoma, abnormal growth of blood vessels, giperaldosteronizm, disorders of cognition, Alzheimer's disease, dementia, anxiety disorders cognitive abilities.

Thus, pharmacologically active compounds proposed in the present invention can be applied in the manufacture of pharmaceutical compositions comprising effective amounts together or in a mixture with inert excipients or carriers suitable for enteral or parenteral application. Preferred are tablets and gelatin capsules comprising the active ingredient together with:

a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine;

(b) lubricating agents, for example, dioxi the Ohm silicon, talc, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also with

c) binders, e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth gum, methylcellulose, sodium salt of carboxymethylcellulose and/or polyvinylpyrrolidone; if necessary

d) substances that provide raspadaemost, for example, starches, agar-agar, alginic acid or its salt, or effervescent mixtures; and/or

e) absorbents, colorants, flavors and sweeteners.

Compositions for injection are preferably an aqueous isotonic solutions or suspensions, and emulsions or suspensions based on fat successfully prepare suppositories.

These compositions can be sterilized and/or contain auxiliary substances, such as preserving, stabilizing or emulsifying agents, contributing to the dissolved substances, salts for regulating osmotic pressure and/or buffers. In addition, they can also contain other therapeutically useful substances. These compositions are obtained by conventional methods of mixing, granulating or coating, respectively, and contain about 0.1 to 75%, preferably about 1-50% of the active ingredient.

Compositions suitable for the Czech Republic is sonogo introduction, include a therapeutically effective amount of the compounds proposed in the present invention, with the carrier. Preferred carriers include absorbable pharmacologically acceptable solvents, designed to facilitate the passage through the patient's skin. Usually percutaneous devices represent a bandage that includes a back layer, a reservoir containing the compound optionally with carriers, optionally regulating the speed barrier element for the delivery of compounds into the skin of the patient with controlled and predetermined rate over a prolonged period of time and means for fastening the device on the skin.

Accordingly, the present invention relates to pharmaceutical compositions described above, intended for the treatment of pathological conditions mediated by effects of renin, preferably hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, hypertrophy of the heart, fibrosis of the heart, cardiomyopathy postinfarction, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, liver fibrosis, complications resulting from diabetes such as nephropathy, vasculopathies and neuropathy, diseases of the coronary vessels, restenosis after angioplasty, increased nutrigenie pressure, glaucoma, abnormal growth of blood vessels, hyperaldosteronism, disorders of cognition, Alzheimer's disease, dementia, anxiety States and cognitive disorders abilities.

The pharmaceutical compositions may contain a therapeutically effective amount of the compounds proposed in the present invention described above, one or in combination with another therapeutic agent, for example, containing each of them in a therapeutically effective dose, as indicated in the art. Such therapeutic agents include:

a) anti-diabetic agents such as insulin derivatives and mimetics of insulin; a means of enhancing insulin secretion, such as sulfonylureas, such as glipizide, gliburid and amaryl; ligands insulinotropic sulfonylurea receptor, such as meglitinide, for example, nateglinide and Repaglinide; ligand activated receptor peroxisome proliferation (appd); inhibitors patientinitiated-1B (PTP-1B), such as PTP-112; GSK3 inhibitors (glikogensintetazy-3), such as SB-517955, SB-4195052, SB-216763, NN-57-05441 and NN-57-05445; RXR ligands such as GW-0791 and AGN-194204; inhibitors retrieveimage of superelastic glucose, such as T-1095; glycogen phosphorylase inhibitors And such as BAY R3401; biguanides such as Metformin; alpha inhibitors-glucoside is SHL, such as acarbose; GLP-1 (like peptide-1), analogues of GLP-1, such as on the basis of 4, and mimetics of GLP-1; and inhibitors IV (dipeptidylpeptidase IV), such as LAF237;

b) lipid-lowering agents such as inhibitors of the reductase 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA), for example, lovastatin, pitavastatin, simvastatin, pravastatin, tseriwastatina, mevastatin, vasostatin, fluvastatin, dalvastatin, Rothstein, rosuvastatin and mevastatin; inhibitors stvalentines; FXR ligands (farnesoid X receptor) and LXR (X receptor liver); cholestyramine; fibrates; nicotinic acid and aspirin;

c) anti-obesity, such as orlistat;

d) antihypertensives, for example, loop diuretics such as ethacrynic acid, furosemide and torsemide; inhibitors angiotenzinkonvertiruyuschego enzyme (ACE), such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril; inhibitors of membrane pump Na-K-ATPase, such as digoxin; inhibitors of neutral endopeptidase (NEP); inhibitors ACF/NEP, such as omapatrilat, sampatrilat and fasidotril; antagonists of angiotensin II, such candesartan, eprosartan, irbesartan, losartan, telmisartan and valsartan, preferably valsartan; blockers β-adrenergic receptor, such as acebutolol, ateno the ol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol and timolol; inotropic agents such as digoxin, dobutamine, milrinone; calcium channel blockers such as amlodipine, bepridil, diltiazem, felodipine, nicardipine, nimodipine, nifedipine, nisoldipine and verapamil; aldosterone antagonists of the receptor; and inhibitors aldosteroneinduced.

Other specific antidiabetic compounds described in the publication Mona Patel in Expert Opin Investig Drugs, 2003, 12(4), 623-633, figures 1 to 7, which are included in the present invention as a reference. The connection proposed in the present invention, can be administered simultaneously, before or after an active ingredient, are individually the same or different routes of administration or together in the same pharmaceutical composition.

The structure of therapeutic agents that have code numbers, generic or trade names that are listed in the latest edition of "The Merck Index", and databases, for example, Patents International (e.g. IMS World Publications). Corresponding to the content included in the present invention by reference.

Accordingly, the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of the compounds proposed in the present invention, in combination with a therapeutically effective amount of the other therapeutic agent, preferably selected from the group comprising antidiabetics, lipid-lowering means, means against obesity and antihypertensives, most preferably from the group comprising antidiabetics, antihypertensives and lipid-lowering means described above.

The present invention also relates to pharmaceutical compositions described above, intended for use as a medicine.

The present invention also relates to use of pharmaceutical compositions or combinations as described above, for preparing a medicinal product intended for the treatment of pathological conditions mediated by effects of renin, preferably hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, hypertrophy of the heart, fibrosis of the heart, cardiomyopathy postinfarction, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, liver fibrosis, complications resulting from diabetes such as nephropathy, vasculopathies and neuropathy, diseases of the coronary vessels, restenosis after angioplasty, increased intraocular pressure, glaucoma, abnormal growth of blood vessels, hyperaldosteronism, violations cognitive SPO is oblasti, Alzheimer's, dementia, anxiety States and cognitive disorders abilities.

Thus, the present invention also relates to the compound of formula (I), intended for use as a drug, to the use of compounds of formula (I) for the preparation of pharmaceutical compositions intended for the prevention and/or treatment of pathological conditions mediated by effects of renin, and to pharmaceutical compositions intended for use in pathological conditions mediated by effects of renin, comprising the compound of formula (I)or its pharmaceutically acceptable salt, together with its pharmaceutically acceptable diluent or carrier.

The present invention also relates to a method for prevention and/or treatment of pathological conditions mediated by effects of renin, which includes the introduction of a therapeutically effective amount of the compounds proposed in the present invention.

Single dose for a mammal weighing about 50 to 70 kg may contain from about 1 to 1000 mg, preferably about 5-600m mg of the active ingredient. A therapeutically effective dose of the active compound depends on the species of warm-blooded animal (mammal), body weight, age and individual condition, from HUF is s introduced and used for the connection.

In accordance with the foregoing the present invention also relates to therapeutic combinations, for example, the set, the set of components, for example, for use in any method described in the present invention, including the compound of formula (I) or its pharmaceutically acceptable salt, intended for use, simultaneous or sequential, together with at least one pharmaceutical composition comprising at least another therapeutic agent, preferably selected from the group comprising antidiabetics, lipid-lowering means, means against obesity and antihypertensives. The kit may include instructions for its implementation.

Similarly, the present invention relates to a set of components, including: (i) a pharmaceutical composition proposed in the present invention, and (ii) a pharmaceutical composition comprising a compound selected from the group including antidiabetic agent, a hypolipidemic agent, an anti-obesity, anti-hypertensive agent or its pharmaceutically acceptable salt in the form of two separate forms of components (i) and (ii).

Similarly, the present invention relates to method described above comprising co-administration, e.g., simultaneous sludge is consistent, therapeutically effective amounts of compounds of formula (I)or its pharmaceutically acceptable salt and a second drug, the specified second drug is an anti-diabetic agent, a hypolipidemic agent, anti-obesity or anti-hypertensive agent, such as described above.

Preferably, if the connection is proposed in the present invention, is introduced needs it the mammal.

Preferably, if the connection is proposed in the present invention, is used for treatment of diseases that respond to modulation of renin activity.

Preferably, if a pathological condition associated with the renin activity, selected from the group including hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, fibrosis of the heart, postinfarct cardiomyopathy, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, hepatic fibrosis, complications resulting from diabetes such as nephropathy, vasculopathies and neuropathy, diseases of the coronary vessels, restenosis after angioplasty, increased intraocular pressure, glaucoma, abnormal growth of blood vessels, giperaldosteronizm, disorders of cognitive abilities, booleanalgebra, dementia, anxiety disorders cognitive abilities.

Finally, the present invention relates to a method or application, which includes the introduction of the compounds of formula (I) in combination with a therapeutically effective amount of antidiabetics, lipid-lowering means, means anti-obesity or anti-hypertensive tools.

Ultimately, the present invention relates to a method or application, which includes the introduction of the compounds of formula (I) in the form of pharmaceutical compositions described in this invention.

When used in the present description and the claims, the term "treatment" includes all the various forms and modes of treatment, known to experts in the art and, in particular, includes preventive, healing, delaying the beginning and/or progression and palliative treatment.

The above characteristics can be demonstrated through the ongoing in vitro and in vivo studies, preferably using mammals, such as mice, rats, rabbits, dogs, monkeys, or isolated organs, tissues and cooked them drugs. These compounds can be applied in vitro in the form of solutions, for example, preferably aqueous solutions, and in vivo enterline, parenteral, predpochtite the flax - intravenously, for example, in the form of a suspension or aqueous solution. The dosage in vitro may be in a concentration range of from about 10-3up to 10-10M Therapeutically effective amount in vivo may vary depending on route of administration and amounts from about 0.001 to 500 mg/kg, preferably from about 0.1 to 100 mg/kg

As indicated above, the compounds proposed in the present invention, have the ability to inhibit the enzymes. In particular, they inhibit the action of the natural enzyme renin. Renin from the kidney into the blood, where it affects the cleavage of angiotensin, highlighting Decapeptide angiotensin I, which is then cleaved in the lungs, kidneys and other organs with the formation of oktapeptid of angiotensin II. This oktapeptid increases blood pressure and directly by narrowing of the arteries, and indirectly through the release of adrenal retaining sodium ions of the hormone aldosterone, which is accompanied by increase in the volume of extracellular fluid, which increase can be attributed to the effects of angiotensin II. Inhibitors of the enzymatic effects of renin reduce the formation of angiotensin I and consequently a smaller quantity of angiotensin II. The decrease in the concentration of this active peptide hormone is the direct cause hypotensive e is the action of renin inhibitors.

Effects of renin inhibitors can be demonstrated and experimentally using in vitro, reduce the formation of angiotensin I was measured in different systems (human plasma, purified human renin together with synthetic or natural renin substrate).

In particular, you can use the following in vitro tests:

Extract of human renin from the kidney (0,5 Meg [millidynes Goldblatt]/ml) incubated for 1 h at 37°C and pH 7.2 in 1 M aqueous buffer solution of 2-N-(Tris-hydroxymethylamino)-aminoethanesulfonic acid with 23 μg/ml of synthetic renin substrate, tetradecapeptide H-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Leu-Val-Tyr-Ser-OH. The amount of angiotensin I formed was determined by radioimmunoassay analysis. Each of the inhibitors proposed in the present invention, added to the incubation mixture at different concentrations. The value of the IC50is defined as the concentration of a specific inhibitor, which reduces the formation of angiotensin I by 50%.

Recombinant human renin (expressed in ovary cells Chinese hamster and purified by standard methods) at a concentration of 4 nm incubated with the test compound at various concentrations for 1 h at RT in 0.1 M buffer Tris-HCl [Tris = Tris(hydroxyethylaminomethyl)], pH of 7.4, containing 0.05 M NCl, 0.5 mm add (ethylenediaminetetraacetic acid) and 0.05% FLAPS [3-((3-cholamidopropyl)dimethylammonio)-1-propanesulfonic acid]. Synthetic peptide substrate Arg-Glu(EDANS)-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Thr-Lys(DABCYL)-Arg9 added at a final concentration of 2 μm and register increased fluorescence at the wavelength of excitation equal to 340 nm, and the wavelength of emission equal to 485 nm, for an microplate. The values of the IC50rely on expressed in percent inhibition of renin activity as a function of the concentration of tested compound (analysis of energy transfer resonance fluorescence, PERF).

Recombinant human renin (expressed in ovary cells Chinese hamster and purified by standard methods) at a concentration of 1 nm incubated with the test compound at various concentrations for 1.5 h at 37°C in 0.1 M Tris/HCl, pH 7,4, containing 0.05 M NaCl, 0.5 mm etc and 0.025% (wt./about.) FLAPS. Synthetic peptide substrate Ac-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Asn-Lys-[DY-505-X5] added at a final concentration of 5 μm. The enzymatic reaction is stopped by addition of 6 μl of 1.0% TFA (triperoxonane acid). The reaction product is separated using HPLC (high performance liquid chromatography) and quantitatively determined by spectrophotometric measurement at a wavelength of equal to 505 nm. EIT is possible IC 50rely on expressed in percent inhibition of renin activity, as a function of the concentrations of the studied compounds.

Recombinant human renin (expressed in ovary cells Chinese hamster and purified by standard methods) at a concentration of 3.3 nm 125I-NVP-AJI891-NX-1 (0,27 µci/ml) and granules streptavidin-PAN (polyacrylonitrile sodium) (0,67 mg/ml) incubated with the test compound at various concentrations for 20 h at RT in 0.1 M Tris/HCl, pH 7,4, containing 0.5 M NaCl and 0.5% (wt./about.) Brij35. After a time of incubation tablets centrifuged (55 g, 60) and the radioactivity is measured using a counter Wallac MicroBeta. The values of the IC50rely on expressed in percent substitution associated with the renin of radioligand, as a function of the concentrations of the studied compounds.

In animals in which there is a lack of salt, renin inhibitors lower blood pressure. Renin person may differ from the renin individuals of other species. For studies of inhibitors of human renin, you can use primates, such as monkeys (Callithrix jacchus), because the human renin and renin primates substantially homologous at the enzymatic active site. In particular, you can use the following in vivo studies:

The compounds studied on with normal artery is determined as being the pressure of the monkeys of both sexes with body weight, approximately 350 g, which are in the mind, which give the possibility to move freely and keep in their cells. Blood pressure and heart rate is measured via a catheter inserted in the descending aorta, and measured radiometrically. Endogenous secretion of renin simulate using a combination of weekly diet with low salt content and a single intramuscular injection of furosemide (5-(aminosulfonyl)-4-chloro-2-[(2-furylmethyl)amino]benzoic acid) (5 mg/kg). After 16 h after injection of furosemide study compound is injected either directly into the femoral artery with a needle for injection or in the form of a suspension or solution through the esophageal tube directly into the stomach and evaluate their impact on blood pressure and heart rate. In the studies described in vivo of the compounds proposed in the present invention exert a hypotensive effect in doses equal to from about 0.003 to about 1 mg/kg when administered intravenously, at doses equal to from about 0.3 to about 100 mg/kg by oral administration.

Alternative inhibitors of renin can be investigated with normal blood pressure male monkeys with weight equal to from 250 to 500 g, which are in the mind, which give the possibility to freely move the rotated and kept in their cells. Blood pressure and heart rate is measured via a catheter inserted in the descending aorta, and measured radiometrically. Electrocardiogram (ECG) is removed by placing the electrodes in lead II. Endogenous secretion of renin mimic with two intramuscular injections of furosemide (5-(aminosulfonyl)-4-chloro-2-[(2-furylmethyl)amino]benzoic acid) (10 mg/kg), 43 and 19 h before the introduction of the connection. The compounds injected either directly into the femoral artery with a needle for injection or in the form of a suspension or solution through the esophageal tube directly into the stomach and evaluate their impact on blood pressure, heart rate and ECG. In the studies described in vivo of the compounds proposed in the present invention exert a hypotensive effect in doses equal to from about 0.003 to about 0.3 mg/kg when administered intravenously, at doses equal to from about 0.31 to about 30 mg/kg by oral administration.

Connections proposed in the present invention, also have the ability to regulate, in particular to reduce intraocular pressure.

The degree of intraocular pressure reduction after the introduction of the pharmaceutically active ingredient of the formula (I), proposed in the present invention, it is possible to determine, for example, animal is, for example, rabbits or monkeys. Two typical experimental method, which illustrate the present invention but does not limit it, as described below.

In vivo on rabbits breed "Fauve de Bourgogne" to measure the ability of the applied topically composition to reduce the intraocular pressure can be carried out, for example, as follows: Intraocular pressure (IOP) measured by Atlanticheskogo tonometer before the experiment and then at regular intervals of time. After local anesthesia of the appropriate composition of the investigated compounds at a specific concentration (e.g., 0,000001-5 wt.%) applied topically to one eye of the laboratory animal. The second eye is treated, for example, saline solution. Thus obtained data is subjected to statistical processing.

In vivo studies on monkeys of the species Macaca Fascicularis to determine the ability of the applied topically composition to reduce the intraocular pressure can be carried out, for example, as follows: the Appropriate composition of the investigated compounds at a specific concentration (e.g., 0,000001-5 wt.%) applied topically to one eye of each monkey, the Second monkey eyes treated, for example, saline solution. Before the study animals anaesthetize with nutrimetics injection, for example, ketamine. At equal intervals of time measured intraocular pressure (IOP). The study was conducted and evaluated in accordance with standards established laboratory practice" (GLP).

Illustrating the present invention the compound of example 29 inhibits renin activity with the value of the IC50approximately 0.3 nm in the analysis PART.

The following examples are intended to illustrate the present invention and are not considered to impose on a limit. If not stated otherwise, the evaporation is always carried out under reduced pressure, preferably about 10 to 100 mm Hg (=20-133 mbar). The structure of final products, intermediates and starting compounds was confirmed using standard analytical methods, e.g., microanalysis, melting point and spectroscopic characteristics, for example, MS (mass spectrometry), LC/MS (liquid chromatography - mass spectroscopy), IR spectroscopy, NMR. Commonly used abbreviations are common to this area of technology.

Example 1. General methodology (I)

Boc: tert-butoxycarbonyl; TBDM - tert-butultimately.

Obtaining initial acid:

a) (2S,4S,5S,7S)-5-tert-Butoxycarbonylamino-4-(tert-butyldimethylsilyloxy)-2-isopropyl-7-[4-meth is XI-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The triethylamine (NEt3) (7.2 ml, 51.6 mmol, 3.0 equiv.) and then dimethylaminopyridine (DMAP) (640 mg, 5.2 mmol, 0.3 EQ.) added to a solution of (2S,4S,5S,7S)-5-tert-butoxycarbonylamino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid (at 9.53 g, and 17.2 mmol, 1.0 EQ.) and TBDMSCl (10.3 g, of 68.7 mmol, 4.0 EQ.) in dimethylformamide (DMF) (100 ml) at room temperature (RT). The reaction mixture was stirred at RT for 16 h, and then added water (H2About). Extraction with ethyl acetate (EtOAc), drying [over sodium sulfate (Na2SO4)] and evaporation of the solvent gives the crude product. Flash chromatography on a column of [600 g of silicon dioxide (SiO2), hexane: EtOAc 5:1] gives a product with two protective TBDMS groups in the form of a colorless oil.

His portion (904 mg, 1,24 mmol, 1.0 EQ.) dissolved in methyl alcohol (Meon) (20 ml) and added 1 M HCl (2 ml, 2 mmol, 1.6 EQ.). The mixture is stirred at RT for 10 min, and then to process added 1 M solution of sodium hydroxide (NaOH) (2 ml), then N2Oh and 10% citric acid solution. Extraction with EtOAc, drying (Na2SO4) the combined organic extracts and evaporation of the solvent gives the crude product, which was purified using flash chromatography on a column of [50 g of SiO2CH2Cl2:Meon (9:1)] and obtain the desired product of the t in the form of a colorless oil. MS (LC-MS): 691,3 [M+Na]+; tR(HPLC, C8 column, 5-95% CH3CN/N2O/6,5 min, 95% CH3CN/H2O/1 min, flow: 0.5 ml/min): 7,63 minutes

b) tert-Butyl ether ((1S,2S,4S)-4-benzylcarbamoyl-2-(tert-butyldimethylsilyloxy)-1-{(S)-2-[4-methoxy-3-(3-methoxypropane)-benzyl]-3-methylbutyl}-5-etylhexyl)-carbamino acid

BTU (O-benzotriazole-N,N,N',N'-tetramethylpropylenediamine) (400 mg, 1,03 mmol, 1.2 EQ.) added to a solution of (2S,4S,5S,7S)-5-tert-butoxycarbonylamino-4-(tert-butyldimethylsilyloxy)-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid (575 mg, 0.86 mmol, 1.0 EQ.) in acetonitrile (CH3CN) (15 ml) and DMF (1 ml) at 0°C. After 5 min add the solution benzylamine (94 μl, 0.86 mmol, 1.0 EQ.) and Net3(1.2 ml, 8.6 mmol, 10 EQ.) in CH3CN (3 ml) and the reaction mixture was stirred at room temperature for 5 minutes To process added EtOAc and the organic layer is washed with 1 N. HCl, saturated solution of sodium bicarbonate (NaHCO3) and brine. Drying (Na2SO4) the organic phase and evaporation of the solvent gives the crude product, which was purified using flash chromatography on a column of [50 g of SiO2, hexane: EtOAc (4:1)] and obtain the desired product as a colourless foam substance. MS (LC-MS): 780,4 [M+Na]+; Rf[hexane: EtOAc (1:1)]: 0,65 minutes

(C) tert-Butyl ether ((1S,2S,4S)-4-benzylcarbamoyl-2-hydroxy-1-{(S)-2-[4-methoxy-3-(3-methoxypropane)-benzyl]-3-methylbutyl}-5-etylhexyl)-carbamino acid

TBAF·3 H2On (TBAF - tetrabutylammonium) (302 mg, 0.96 mmol, 1.5 EQ.) added to a solution of tert-butyl methyl ether ((1S,2S,4S)-4-benzylcarbamoyl-2-(tert-butyldimethylsilyloxy)-1-{(S)-2-[4-methoxy-3-(3-methoxypropane)-benzyl]-3-methylbutyl}-5-etylhexyl)-carbamino acid (485 mg, 0.64 mmol, 1.0 EQ.) in tetrahydrofuran (THF) (6 ml) at RT. After 1 h add H2Oh and the mixture extracted with EtOAc. The combined extracts are dried (Na2SO4) and the solvent is evaporated. Flash chromatography on a column of [50 g of SiO2, hexane: EtOAc (3:1)] to give the desired product as a colourless foam substance. MS (LC-MS): 665,3 [M+Na]+; Rf[hexane: EtOAc (1:1)]: 0,33 minutes

d) Benzylamine (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

At 0°C 4 N. HCl/dioxane (7 ml, 28 mmol) was added to tert-butyl ether ((1S,2S,4S)-4-benzylcarbamoyl-2-hydroxy-1 - {(S)-2-[4-methoxy-3-(3-methoxypropane)-benzyl]-3-methylbutyl}-5-etylhexyl)-carbamino acid (214 mg, 0.34 mmol, 1.0 EQ.). The resulting solution was stirred at RT for 15 min, and then gently add a saturated solution of NaHCO3. The mixture is extracted with EtOAc, the combined extracts dried (Na2SO4) and the solvent is evaporated. Flash chromatography on columns is e [20 g of SiO 2from CH2Cl2:MeOH (9:1) to CH2Cl2:MeOH (9:1)+1% NEt3] gives the product as colorless oil. MS (LC-MS): TO 544.3 [M+H]+; Rf[CH2Cl2:MeOH (9:1)]: 0,19 minutes

a) (2S,4S,5S,7S)-5-Azido-4-(tert-butyldimethylsilyloxy)-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The lithium hydroxide (LiOH)·H2O (2,18 g, with 52.0 mmol) was added to a solution of (3S,5S)-5-{(1S,3S)-1-azido-3-[4-methoxy-3-(3-methoxypropane)-benzyl]-4-methylpentyl}-3-isopropylpyridine-2-it (20,0 g, a 43.3 mmol) in dimethoxyethane (DME) (400 ml) and N2O (200 ml) and the resulting solution was stirred at RT for 2 h the Solvent is evaporated with toluene and the obtained solid is dried in a high vacuum.

This residue is dissolved in DMF (160 ml) and successively add NEt3(32 ml, 227,6 mmol), TBDMSOTf (41,8 ml, 182,1 mmol) and DMAP (556 mg, 4.6 mmol). The mixture is stirred at RT for 16 hours To process added EtOAc and the reaction is stopped by adding a saturated solution of NaHCO3. The organic phase is separated and the aqueous phase extracted with EtOAc. Evaporation of the solvent from the combined organic extracts yields a product with two protective groups TBDMS (32,4 g), and acidification of the alkaline layer with 1 N. HCl, followed by extraction with EtOAc and n is rivane solvent gives the corresponding monochlorophenol free acid (8.8 g). Both of the selected product are combined and subjected to flash chromatography on a column [hexane: EtOAc (4:1) to hexane: EtOAc (1:1)] and get the desired monochlorophenol acid as a viscous oil (during the chromatography is full disilylgermane acid containing silyl protective group). MS (LC-MS): 616,0 [M+Na]+; tR(HPLC, C8 column, 20-95% CH3CN/H2O/a 3.5 min, 95% CH3CN/1 min, flow: 0.8 ml/min): 3,93 minutes

b) (2-piperidine-1-retil)-amide (2S,4S,5S,7S)-5-azido-4-(tert-butyldimethylsilyloxy)-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

BTU (1.20 g, 3.0 mmol) was added to a solution of (2S,4S,5S,7S)-5-azido-4-(tert-butyldimethylsilyloxy)-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid (1.50 g, 2.5 mmol) in CH3CN (50 ml). Then add 2-AMINOETHYLPIPERAZINE (324 mg, 2.5 mmol) and NEt3(3.9 ml) and the resulting solution was stirred at RT for 2.5 hours To process added EtOAc and the organic phase is washed with 1 N. HCl, a saturated solution of NaHCO3and brine. Drying of the organic phase (Na2SO4) and evaporation of the solvent gives the crude product, which was purified using flash chromatography on a column of [CH2Cl2:Meon (95:5)] and obtain the desired product as a colorless oil. MS (LC-MS): 705,1 [M+H] +; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 6,82 minutes

c) (2-piperidine-1-retil)-amide (2S,4S,5S,7S)-5-azido-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

TBAF·3 H2O (1.73 g, 5.5 mmol) was added to a solution of (2-piperidine-1-retil)-amide(2S,4S,5S,7S)-5-azido-4-(tert-butyldimethylsilyloxy)-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid (1.54 g, 2.2 mmol) in THF (15 ml). The reaction mixture was stirred at RT for 72 h For handle add H2Oh and the mixture extracted with CH2Cl2. The combined organic extracts dried (Na2SO4) and the solvent is evaporated. Flash chromatography on a column of [CH2Cl2:Meon (9:1)] to give the desired product as a yellowish oil. MS (LC-MS): 590,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,24 minutes

d) (2-piperidine-1-retil)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

Palladium on coal (Pd/C 10% (200 mg) was added to a solution of (2-piperidine-1-retil)-amide (2S,4S,5S,7S)-5-azido-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(methoxypropane)-benzyl]-8-methylnonanoic acid (780 mg, of 1.32 mmol) in Meon (40 ml) in an atmosphere of Ar. Then the reaction suspension is stirred in an atmosphere of hydrogen (H2within 8 hours the Catalyst is filtered off through celite and washed with Meon. Evaporation of the solvent gives the crude product, which according to the analysis is pure and used without further purification. MS (LC-MS): 564,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): or 4.31 minutes

Example 3. The General procedure (III)

Cyclopropylamine (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

A solution of (3S,5S)-5-{(1S,3S)-1-azido-3-[4-methoxy-3-(3-methoxypropane)-benzyl]-4-methylpentyl}-3-isopropylpyridine-2-she (2.00 g, 4.3 mmol) and cyclopropanemethylamine (1.9 ml, and 21.7 mmol) in acetic acid (0,78 ml) for 30 min heated at 100°C in a sealed tube. Add water and the mixture extracted with CH2Cl2. Drying (Na2SO4) of the combined extracts and evaporation of the solvent gives the crude product which is used without further purification.

Pd/C 10% (1.10 g, 1.0 mmol) was added to a solution of the crude product (2.58 g) in the Meon (16 ml) and the reaction mixture was stirred in an atmosphere of H2 during the 9 hours the Catalyst is filtered off through celite and the solvent is evaporated. Purification of the crude product by flash chromatography on a column of [CH2Cl2until CH2Cl2:Meon (8:2)] gives the desired product as a colourless foam substance. MS (LC-MS): 508,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 4,91 minutes

Example 4. The General procedure (IV)

a) 4-Bromo-1-fluoro-2-(3-methoxypropane)-benzene

Diisopropyl ester of azodicarboxylic acid is added to a solution of 4-bromo-1-fluoro-2-hydroxybenzoyl [see Maleczak, Jr., Shi, Holmes and Smith, J Am Chem Soc, Vol.125, No. 26, pp.7792-7793 (2003)] (5,52 g of 28.9 mmol, 1 EQ.), triphenylphosphine (8,4 g of 31.8 mmol, 1.1 EQ.) in THF (20 ml) and 3-methoxypropanol (3 ml, of 31.8 mmol, 1.1 EQ.) in THF at RT and the solution stirred for 16 h and then the solvent is evaporated. Flash chromatography on a column [hexane: EtOAc (9:1) to hexane: EtOAc (4:1)] to give the product as a pale yellow oil. MS (LC-MS): 264,9 [M+H]+; Rf[hexane: EtOAc (4:1)]: 0,6 minutes

b) (3S,5S)-5-((1S,3S)-1-Azido-3-{[4-fluoro-3-(3-methoxypropane)-phenyl]-hydroxymethyl}-4-methylpentyl)-3-isopropylpyridine-2-he

To a solution of 4-bromo-1-fluoro-2-(3-methoxypropane)-benzene (1,94 g, 13.3 mmol, 1.4 EQ.) and N is ethylmorpholine (1.6 ml, 14.7 mmol, 3 EQ.) in THF (20 ml) at -78°C. are added dropwise N-utility in hexane (1.6 M, 5.5 ml, 8,8 mmol, 1.8 EQ.). The solution was stirred at -78°C for 1 h, and then at -78°C is added dropwise a solution of MgBr2(14.7 mmol) in THF (50 ml), freshly prepared from magnesium (0.36 g, 14.7 mmol, 3 EQ.) and 1,2-dibromethane (1.3 ml, 14.7 mmol, 3 EQ.). The reaction mixture was stirred at the same temperature for 45 min, and then at -78°C is added dropwise (S)-2-[(S)-2-azido-2-((2S,4S)-4-isopropyl-5-oxitetraciclina-2-yl)-ethyl]-3-methylmalonyl aldehyde (1.4 g, 4.9 mmol, 1 EQ.) in THF (14 ml). The reaction mixture is stirred for another 1 h at the same temperature, and then the reaction is stopped by adding a saturated solution of NH4Cl (20 ml) and heated to CT. The mixture is extracted with EtOAc, the combined extracts washed with brine, dried over Na2SO4and the solvent is evaporated. Flash chromatography on a column of [CH2Cl2until CH2Cl2:acetone (9:1)] to give the product as a pale yellow oil. MS (LC-MS): 488[M+Na]+; Rf[CH2Cl2:acetone (98:2)]: 0,25 minutes

Starting material, (S)-2-[(S)-2-azido-2-((2S,4S)-4-isopropyl-5-oxitetraciclina-2-yl)-ethyl]-3-methylmalonyl aldehyde receive according to the methods described in EP 0678503 B1 and EP 0678514 A1.

c) (3S,5S)-5-{(1S,3S)-1-Amino-3-[4-fluoro-3-(3-methoxypropane)-benzyl]-4-methylpentyl}-3-isopropylthio is furan-2-he

A solution of (S)-2-[(S)-2-azido-2-((2S,4S)-4-isopropyl-5-oxitetraciclina-2-yl)-ethyl]-1-[4-fluoro-3-(3-methoxypropane)-phenyl]-3-methylbutylamine ether somaclonal acid (1.45 g, 2.7 mmol, 1 EQ.), Pd/C (10%, 2.9 g) and ethanolamine (0.17 ml, 2.7 mmol, 1 EQ.) in ethanol (135 ml) is shaken in an atmosphere of H2(1 ATM) for 24 h, the Reaction mixture was filtered, then the solvent is evaporated and receive the product in the form of a light grey resin. MS (LC-MS): 424 [M+H]+

(d) tert-Butyl ether [(1S,3S)-3-[4-Fluoro-3-(3-methoxypropane)-benzyl]-1-((2S,4S)-4-isopropyl-5-oxitetraciclina-2-yl)-4-methylpentyl]-carbamino acid

A solution of (3S,5S)-5-{(1S,3S)-1-amino-3-[4-fluoro-3-(3-methoxypropane)-benzyl]-4-methylpentyl}-3-isopropylpyridine-2-she (1.13 g, 2.7 mmol, 1 EQ.), di-tert-BUTYLCARBAMATE (2.1 g, 9.4 mmol) and diisopropylethylamine (1,83 ml and 10.7 mmol, 4 equiv.) in CH2Cl2(20 ml) is stirred at RT for 164 hours the Solution was washed with aqueous solution of HCl (1 M), saturated aqueous NaHCO3and brine, dried over Na2SO4and solvents byprivate-chromatography on a column of [CH2Cl2until CH2Cl2:acetone (95:5)] gives the product as a pale yellow oil. MS (LC-MS): 546 [M+Na]+; Rf(CH2Cl2:acetone (95:5)]: 0,71 minutes

(e) tert-Butyl ester {(1S,2S,4S)-1-{(S)-2-[4-fluoro-3-(3-methoxypropane)-ensil]-3-methylbutyl}-2-hydroxy-4-[(1-hydroxymethylpropane)-carbarnoyl]-5-methylhexan}-carbamino acid

tert-Butyl ether [(1S,3S)-3-[4-Fluoro-3-(3-methoxypropane)-benzyl]-1-((2S,4S)-4-isopropyl-5-oxitetraciclina-2-yl)-4-methylpentyl]-carbamino acid (100 g, 0,19 mmol, 1 EQ.), 3-amino-2,2-DIMETHYLPROPANE (0.3 g, 2.8 mmol, 15 EQ.) and acetic acid (0,11 μl, 0.002 mmol, 0.01 EQ.) stirred at 60°C for 24 h and then the solvent is evaporated. Flash chromatography on a column (CH2Cl2/Meon 95:5 to CH2Cl2/Meon 9:1) gives the product as a pale yellow solid. MS (LC-MS): 627 [M+H]+; Rf(CH2Cl2/MeOH 9:1): 0,25.

f) (1-Hydroxymethylpropane)-amide (2S,4S,5S,7S)-5-amino-7-[4-fluoro-3-(3-methoxypropane)-benzyl]-4-hydroxy-2-isopropyl-8-methylnonanoic acid

At 5°4 N. HCl/dioxane (0,97 ml) was added to tert-butyl ether ((1S,2S,4S)-4-cyclopropanecarbonyl-1-{(S)-2-[4-fluoro-3-(3-methoxypropane)-benzyl]-3-methylbutyl}-2-hydroxy-5-methylhexan)-carbamino acid (89 mg, 0.14 mmol, 1.0 EQ.) in dioxane (0.8 ml). The resulting solution was stirred at 5°C for 1 h, and then lyophilizer. Flash chromatography on a column (CH2Cl2/MeOH(10% NH4OH) 95:5 to CH2Cl2/MeOH(10% NH4OH) 9:1) gives the product as a pale yellow solid. MS (LC-MS): 527,1 [M+H]+; Rf(CH2Cl2/MeOH (10% NH4OH) 9:1): 0.16 minutes

Example 5 (3-Hydrox the -2,2-dimethylpropyl)-amide (2S,4S,5S,7S)-5-amino-7-[4-fluoro-3-(3-methoxypropane)-benzyl]-4-hydroxy-2-isopropyl-8-methylnonanoic acid

The desired connection receive General method (IV).

MS (LC-MS): 527,1 [M+H]+; Rf[CH2Cl2:Meon (10% NH3) (9:1)]: 0,16 minutes

Example 6. (3-Hydroxy-2,2-dimethylpropyl)-amide (2S,4S,5S,7S)-5-amino-7-[4-fluoro-3-(3-methoxypropane)-benzyl]-4-hydroxy-2-isopropyl-8-methylnonanoic acid

The desired connection receive General method (IV).

MS (LC-MS): 606,1 [M+H]+; Rf[CH2Cl2:MeOH (9:1)]: 0,16 minutes

Example 7. [1-({(2S,4S,5S,7S)-5-Amino-7-[4-fluoro-3-(3-methoxypropane)-benzyl]-4-hydroxy-2-isopropyl-8-methylnonanoic}-methyl)-cyclopropyl]-amide cyclopropanecarbonyl acid

The desired connection receive General method (II).

MS (LC-MS): 590,1 [M+H]+; Rf[CH2Cl2:MeOH (10% NH3) (9:1)]: 0,16 minutes

Example 8. (1-Ethoxymethylenemalonic)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General method (II).

MS (LC-MS): 551 [M+H]+; Rf[CH2Cl2:MeOH (9:1): 0,16 minutes

Example 9. (1-Hydroxymethylpropane)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General the second method (II).

MS (LC-MS): 537 [M+H]+; Rf[CH2Cl2:MeOH (9:1): 0,15 minutes

Example 10. (2-Foradil)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General method (II).

MS (LC-MS): 499,1 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/N2O/6,5 min, 95% CH3CN/H2O/1 min, flow: 0.5 ml/min): 4,63 minutes

Example 11. (2.2-Dottorati)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 518,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/N2O/3 min, flow: 1.5 ml/min): 4,75 minutes

Example 12. (2,2,2-Triptorelin)amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General method (II).

MS (LC-MS): 535,1 [M+H]; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6,5 min, 95% CH3CN/N2On/1 min, flow: 0.5 ml/min): 4,9 minutes

Example 13. Cyclopropylamine (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonane the howling acid

The desired connection receive General method (III).

MS (LC-MS): 508,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 4,91 minutes

Example 14. (1-Cyclopropyl-1-methylethyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 536,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/N2O/3 min, flow: 1.5 ml/min): to 5.21 minutes

Example 15. ((R)-1-Cyclopropylethyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 522,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/N2O/3 min, flow: 1.5 ml/min): 4,95 minutes

Example 16. ((S)-1-Cyclopropylethyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 522,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3 CN/N2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 4,93 minutes

Example 17. (2.2-Dimethylcyclopropene)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 536,1 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/N2O/6,5 min, 95% CH3CN/N2On/1 min, flow: 0.5 ml/min): 4,81 minutes

Example 18. [(1R,3S)-2,2-Dimethyl-3-(2-methyl-propenyl)-cyclopropylmethyl]-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 590,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/N2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,70 minutes

Example 19. ((R)-1-Cyclobutylmethyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 536,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/N2O/3 min, flow: 1.5 ml/min): 5,12 minutes

Example 20. ((S)-1-Cyclobutylmethyl)-amide (2S,4S,5S,7S)-5-AMI is about-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 536,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/N2O/3 min, flow: 1.5 ml/min): 5,15 min

Example 21. Cyclopentylamine (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MC (LC-MS): 535,4 [M]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,15 min

Example 22. ((S)-1-Cyclopentylmethyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MC (LC-MS): 550,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,25 minutes

Example 23. ((R)-1-Cyclopentylmethyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 550,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/N2the/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,24 minutes

Example 24. ((R)-2,2-Dimethylcyclobutyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 550,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,27 minutes

Example 25. ((S)-2,2-Dimethylcyclobutyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 550,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,25 minutes

Example 26. (1-Methylcyclopentene)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General method (II).

MS (LC-MS): 535,1 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/N2O/6,5 min, 95% CH3CN/N2On/1 min, flow: 0.5 ml/min): 5,08 minutes

Example 27. (2S,4S,5S,7S)-5-amino-N-((1-forticlient)methyl)-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy what repossi)-benzyl]-8-methylnonane amide

The desired connection receive General method (II).

MS (LC-MS): 554 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/N2O/6,5 min, 95% CH3CN/H2O/1 min, flow: 0.5 ml/min): 5,42 minutes

Example 28. Cyclohexylethylamine (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 549,3 [M]+; tR(HPLC, C8 column, 5-95% CH3CN/N2O/6,5 min, 95% CH3CN/H2O/1 min, flow: 0.5 ml/min): a 3.87 min

Example 29. ((S)-1-Cyclohexylethyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 564,0 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/N2O/3 min, flow: 1.5 ml/min): are 5.36 minutes

Example 30. ((R)-1-Cyclohexylethyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 564,0 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3C/H 2O/3 min, flow: 1.5 ml/min): 5,38 minutes

Example 31. Cycloheptylamine (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 563,2 [M]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,62 minutes

Example 32. (1,7,7-Trimethylbicyclo[2.2.1]hept-2-yl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 590,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,71 minutes

Example 33. Methyl ester 1-({(2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic}-methyl)-cyclopropanecarboxylic acid

The desired connection receive General methodology (I).

MS (LC-MS): 566,0 [M+H]+; tR(HPLC, C8 column, 20-95% CH3CN/N2O/a 3.5 min, 95% CH3CN/1 min, flow: 0.8 ml/min): 2,44 minutes

Example 34. Methyl ester 1-({(2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic the Mino}-methyl)-cyclobutanecarbonyl acid

The desired connection receive General methodology (I).

MS (LC-MS): 580,0 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,11 minutes

Example 35. Methyl ester 1-{(2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic}-cyclopentanecarboxylic acid

The desired connection receive General methodology (I).

MS (LC-MS): 580,0 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,02 minutes

Example 36. Methyl ester 1-({(2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic}-methyl)-cyclopentanecarbonyl acid

The desired connection receive General methodology (I).

MS (LC-MS): 594,0 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/N2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,19 minutes

Example 37. Methyl ester 1- {(2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic}-cyclohexanecarbonyl acid

The desired connection receive General methodology (I).

MS (THE X-MS): 594.1 nm [M+H] +; tR(HPLC, C18 column, 10-100% CH3CN/N2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,13 minutes

Example 38. Methyl ester 1-({(2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic}-methyl)-cyclohexanecarbonyl acid

The desired connection receive General methodology (I).

MC (LC-MS): 608,0 [M+H]+; tR(HPLC, C8 column, 20-95% CH3CN/H2O/a 3.5 min, 95% CH3CN/1 min, flow: 0.8 ml/min): 2,74 minutes

Example 39. Methyl ester of (S)-{(2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic}-cyclohexyloxy acid

The desired connection receive General methodology (I).

MC (LC-MS): 608,0 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,26 minutes

Example 40. Methyl ester of (1S,3R)-3-{(2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic}-cyclopentanecarboxylic acid

The desired connection receive General methodology (I)

MS (LC-MS): 580,0 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/N2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/mi is): 5,10 minutes

Example 41. Methyl ester of (1S,3R)-3-{(2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic}-cyclopentanecarboxylic acid

The desired connection receive General methodology (I).

MS (LC-MS): 580,0 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/N2O/6,5 min, 95% CH3CN/H2O/1 min, flow: 0.5 ml/min): 4,36 minutes

Example 42. Methyl ester of 4-{(2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic}-cyclohexanecarbonyl acid

The desired connection receive General methodology (I).

MS (LC-MS): 594,0 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/N2O/3 min, flow: 1.5 ml/min): 5,08 minutes

Example 43. Methyl ester of 4-{(2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic}-cyclohexanecarbonyl acid

The desired connection receive General methodology (I).

MS (LC-MS): 594,0 [M+H]+; tR(HPLC, column 18, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,01 minutes

Example 44. 1-({(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic}-mate is)-cyclopentanecarbonyl acid

The desired connection receive General methodology (I).

MS (LC-MS): 579,1 [M+H]+; tR(HPLC. column C8, 20-95% CH3CN/H2O/a 3.5 min, 95% CH3CN/1 min, flow: 0.8 ml/min): 2,48 minutes

Example 45. Amide of (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 453,1 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/N2O/6,5 min, 95% CH3CN/H2O/1 min, flow: 0.5 ml/min)to 4.41 min

Example 46. Amide 1-({(2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic}-methyl)-cyclopropanecarboxylic acid

The desired connection receive General methodology (I).

MS (LC-MS): 550,1 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6,5 min, 95% CH3CN/N2On/1 min, flow: 0.5 ml/min): of 5.05 min

Example 47. Amide 1-({(2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic}-methyl)-cyclobutanecarbonyl acid

The desired connection receive General methodology (I).

MS (LC-MS): 564,1 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6,5 min, 95% CH3CN/N2On/1 min, flow: 0.5 ml/min): 4,54 min

Example 48. Amide 1-({(2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic}-methyl)- cyclopentanecarbonyl acid

The desired connection receive General methodology (I).

MS (LC-MS): 578,1 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6,5 min, 95% CH3CN/N2On/1 min, flow: 0.5 ml/min): 4,2 minutes

Example 49. Amide 1-({(2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic}-methyl)-cyclohexanecarbonyl acid

The desired connection receive General methodology (I).

MS (LC-MS): 592,2 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/N2O/6,5 min, 95% CH3CN/N2On/1 min, flow: 0.5 ml/min): 5,02 minutes

Example 50. Amide 1-{(2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic}-cyclopentanecarboxylic acid

The desired connection receive General method (II).

MS (LC-MS): 564,2 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6,5 min, 95% CH3CN/N2On/1 min, flow: 0.5 ml/min): 4,66 min,

Example 51. Amide 2-{(2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic}-cyclopentanecarboxylic acid

The desired connection recip who have common methodology (I).

MS (LC-MS): made 564.3 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6,5 min, 95% CH3CN/H2O/1 min, flow: 0.5 ml/min): 4,3 minutes

Example 52. Amide 2-{(2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic}-cyclohexanecarbonyl acid

The desired connection receive General methodology (I).

MS (LC-MS): 578,1 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/N2O/6,5 min, 95% CH3CN/H2O/1 min, flow: 0.5 ml/min): 4,84 minutes

Example 53. Methylamide 1-({(2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic}-methyl)-cyclopentanecarbonyl acid

The desired connection receive General methodology (I).

MS (LC-MS): 592,1 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6,5 min, 95% CH3CN/N2On/1 min, flow: 0.5 ml/min): 4,51 minutes

Example 54. (1-Formelementname)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General method (II).

MS (LC-MS): 551 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6,5 min, 95% CH3CN/H2O/1 min, flow: 0.5 ml/min)to 4.41 min

Example 55. (-Acetylaminophenol)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General method (II).

MC (LC-MS): 565,1 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6,5 min, 95% CH3CN/H2O/1 min, flow: 0.5 ml/min): 4,46 minutes

Example 56. (1-Formalininactivated)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (II)

MC (LC-MS): 579,1 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6,5 min, 95% CH3CN/N2On/1 min, flow: 0.5 ml/min): 4,7 minutes

Example 57. (1-Acetylaminophenol)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General method (II).

MC (LC-MS): 592,1 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6,5 min, 95% CH3CN/H2O/1 min, flow: 0.5 ml/min): 4,68 minutes

Example 58. [1-(2,2-Dimethylpropylene)-cyclopentylmethyl]-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3 - methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General method (II).

MC (LC-MS): 634,2 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6,5 min, 95% CH CN/H2O/1 min, flow: 0.5 ml/min): 5,18 minutes

Example 59. {1-[(2,2-Dimethyl-propionamide)-methyl]-cyclopentyl}-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General method (II).

MC (LC-MS): 635,1 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6,5 min, 95% CH3CN/N2On/1 min, flow: 0.5 ml/min): 5,34 minutes

Example 60. [1-({(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic}-methyl)-cyclopentyl]-amide cyclopropanecarbonyl acid

The desired connection receive General method (II).

MS (LC-MS): [M+H]+; Rf[CH2Cl2:MeOH (9:1)]: 0,18 minutes

Example 61. Tert-butyl ether [1-({(2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic}-methyl)-cyclopropyl]-carbamino acid

The desired connection receive General method (II).

MS (LC-MS): 623,1 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6,5 min, 95% CH3CN/N2On/1 min, flow: 0.5 ml/min): 5,22 minutes

Example 62. Tert-butyl ether [1-({(2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic}-methyl)-cyclopentyl]-to raminosoa acid

The desired connection receive General method (II).

MS (LC-MS): 650,1 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6,5 min, 95% CH3CN/H2O/1 min, flow: 0.5 ml/min): 5,43 minutes

Example 63. (1-Aminocyclopropane)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General method (II).

MS (LC-MS): 523,1 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6,5 min, 95% CH3CN/N2On/1 min, flow: 0.5 ml/min): 4,33 minutes

Example 64. (1-Aminocyclopentane)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 550,1 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/N2O/6,5 min, 95% CH3CN/N2On/1 min, flow: 0.5 ml/min): or 4.31 minutes

Example 65. (4-Aminocyclohexane)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MC (LC-MS): 550,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/N2O/3 min, flow: 1.5 ml/min): 4,18 minutes

Example 66. (4-Aminocyclohexane)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MC (LC-MS): 550,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/N2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/N2O/3 min, flow: 1.5 ml/min): 4,14 minutes

Example 67. (1-Dimethylaminoisopropyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General method (II).

MS (LC-MS): 551,1 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6,5 min, 95% CH3CN/N2On/1 min, flow: 0.5 ml/min): 4,36 minutes

Example 68. (1-Dimethylaminocarbonylmethyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General method (II).

MS (LC-MS): 578,2 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6,5 min, 95% CH3CN/N2On/1 min, flow: 0.5 ml/min): 4,29 minutes

Example 69. (1-Methoxyethylamine)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

p> The desired connection receive General method (II).

MS (LC-MS): 565,1 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6,5 min, 95% CH3CN/H2O/1 min, flow: 0.5 ml/min): 5,11 minutes

Example 70. (1-Methoxycarbonylethyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General method (II).

MS (LC-MS): 566 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6,5 min, 95% CH3CN/N2On/1 min, flow: 0.5 ml/min): 5,01 minutes

Example 71. (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid ((1S,2S)-2-benzyloxycarbonyl)-amide

The desired connection receive General methodology (I).

MS (LC-MS): 628,0 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,38 minutes

Example 72. ((1R,2R)-2-Benzyloxycarbonyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MC (LC-MS): 628,0 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/N2O/3 min, flow: 1.5 ml/min): 5,42 minutes

Example 73. (4-Methoxycyclohexyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General method (II).

MC (LC-MS): 565,1 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6,5 min, 95% CH3CN/N2On/1 min, flow: 0.5 ml/min): 4,59 minutes

Example 74. (4-Methoxycyclohexyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General method (II).

MS (LC-MS): 565,1 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6,5 min, 95% CH3CN/N2On/1 min, flow: 0.5 ml/min): 4,67 minutes

Example 75. ((1S,2S)-2-Benzyloxycarbonyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 641,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/N2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 6,10 minutes

Example 76. ((1R,2R)-2-Benzyloxycarbonyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-metile anovas acid

The desired connection receive General methodology (I).

MS (LC-MS): 641,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/N2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/N2O/3 min, flow: 1.5 ml/min): 6,00 minutes

Example 77. (1-Hydroxycarbonylmethyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General method (II).

MS (LC-MS): 523,1 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6,5 min, 95% CH3CN/H2O/1 min, flow: 0.5 ml/min)to 4.52 min

Example 78. ((1R,2R)-2-Hydroxycyclopent)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 538,0 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/N2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 4,74 minutes

Example 79. ((1S,2S)-2-Hydroxycyclopent)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MC (LC-MS): 537,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H 2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): lower than the 5.37 minutes

Example 80. (1-Hydroxymethylglutaryl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General method (II).

MC (LC-MS): 551,1 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6,5 min, 95% CH3CN/H2O/1 min, flow: 0.5 ml/min): 4,77 minutes

Example 81. (1-Hydroxycarbonylmethyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General method (II).

MS (LC-MS): 552 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6,5 min, 95% CH3CN/H2O/1 min, flow: 0.5 ml/min): 4.72 in minutes

Example 82. ((1R,2R)-2-Hydroxycyclohexyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 551,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/N2O/3 min, flow: 1.5 ml/min): 4,62 minutes

Example 83. ((1S,2S)-2-Hydroxycyclohexyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-m is oxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 551,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/N2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min)to 4.41 min

Example 84. (4-Hydroxycyclohexyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): of 551.3 [M]+; Rf[CH2Cl2:MeOH (9:1)]: 0,61 minutes

Example 85. (4-Hydroxycyclohexyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MC (LC-MS): 552,0 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,81 minutes

Example 86. (1-Hydroxycyclohexyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General method (III).

MC (LC-MS): 565,2 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6,5 min, 95% CH3CN/N2On/1 min, flow: 0.5 ml/min): 5,07 minutes

Example 8. ((R)-1-Phenylethyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MC (LC-MS): 558,3 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6,5 min, 95% CH3CN/N2On/1 min, flow: 0.5 ml/min): 4,63 minutes

Example 88. ((S)-1-Phenylethyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 558,3 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6,5 min, 95% CH3CN/H2O/1 min, flow: 0.5 ml/min): 4,69 minutes

Example 89. (1-Methyl-1-phenylethyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 572,0 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6,5 min, 95% CH3CN/N2On/1 min, flow: 0.5 ml/min): 3,85 minutes

Example 90. (Naphthalene-1-ylmethyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): of 594.5 [M+H]+ ; Rf[CH2Cl2:MeOH (9:1)]: 0,21 minutes

Example 91. Indan-2-alamid (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 569,1 [M]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/N2O/3 min, flow: 1.5 ml/min): 5,16 minutes

Example 92. 2-Methylbenzylamine (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 558,3 [M+H]+; Rf[CH2Cl2:Meon (9:1)]: 0,17 minutes

Example 93. 3-Methylbenzylamine (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 558,3 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,28 minutes

Example 94. 4-Methylbenzylamine (2S,4S,5S,7S))-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-is): 558,3 [M+H] +; tR(HPLC, C8 column, 5-95% CH3CN/N2O/6,5 min, 95% CH3CN/N2On/1 min, flow: 0.5 ml/min): 3,76 minutes

Example 95. ((R)-1-p-Triletal)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 571,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/N2O/3 min, flow: 1.5 ml/min): 5,24 minutes

Example 96. ((S)-1-p-Triletal)-amide (2S,4S,5S,7S))-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 571,2 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/N2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,25 minutes

Example 97. 4-Isopropylbenzylamine (2S,4S,5S,7S))-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 586,3 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/N2O/3 min, flow: 1.5 ml/min): 4.26 deaths / min

Example 98. 2-Methoxybenzylamine (2S,4S,5S,7S)-5-amino-4-hydroc and-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 573,3 [M]+; Rf[CH2Cl2:MeOH (9:1)]: 0,15 minutes

Example 99. 3-Methoxybenzylamine (2S,4S,5S,7S))-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS(LC-MS): 573,3 [M]+; Rf[CH2Cl2:(9:1)]: 0,17 minutes

Example 100. 4-Methoxybenzylamine (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 573,3 [M]+; Rf[CH2Cl2:MeOH (9:1)]: 0,14 minutes

Example 101. [(S)-1-(3-Methoxyphenyl)-ethyl]-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 587,2 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min: 5,10 minutes

Example 102. [(R)-1-(3-Methoxyphenyl)-ethyl]-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General met the dick (I).

MC (LC-MS): 587,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,10 minutes

Example 103. [(S)-1-(4-Methoxyphenyl)-ethyl]-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MC (LC-MS): 587,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,07 minutes

Example 104. [(R)-1-(4-Methoxyphenyl)-ethyl]-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 587,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,09 minutes

Example 105. 2-Methylsulfonylbenzoyl (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 589,3 [M]+; Rf[CH2Cl2:MeOH (9:1)]: 0,10 minutes

Example 106. 4-Methylsulfonylbenzoyl (2S,4S,5S,7S)-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 589,0 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/N2O/3 min, flow: 1.5 ml/min): 5,12 minutes

Example 107. 2.5-Dimethoxybenzene (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 603,3 [M]+; Rf[CH2Cl2:MeOH (9:1)]: 0,13 minutes

Example 108. 2,3-Dimethoxybenzamide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 603,3 [M]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,03 minutes

Example 109. 2,4-Dimethoxybenzamide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 603,3 [M]+; Rf[CH2Cl2:MeOH (9:1)]: 0,23 minutes

Example 110. 3,4-Dimethoxybenzamide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxyp is hydroxy)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 603,3 [M]+; Rf[CH2Cl2:MeOH (9:1)]: 0,18 minutes

Example 111. 2,6-Dimethoxybenzamide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 603,3 [M]+; Rf[CH2Cl2:MeOH (9:1)]: 0,24 minutes

Example 112. 3,5-Dimethoxybenzamide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 603,3 [M]+; tR(HPLC, C18 column, 10-100% CH3CN/N2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,04 minutes

Example 113. 2-Cryptomaterial (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 627,3 [M]+; Rf[CH2Cl2:MeOH (9:1)]: 0,31 minutes

Example 114. 3-Cryptomaterial (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive about is her methodology (I).

MS (LC-MS): 627,2 [M]+; Rf[CH2Cl2:MeOH (9:1)]: 0,17 minutes

Example 115. 4-Cryptomaterial (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 627,3 [M]+; Rf[CH2Cl2:MeOH (9:1)]: 0,26 minutes

Example 116. 2-Forbindelse (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 561,3 [M]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,03 minutes

Example 117. 3-Forbindelse (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 561,3 [M]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,09 minutes

Example 118. 4-Forbindelse (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection paluchato General methodology (I).

MS (LC-MS): 561,3 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/N2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,08 minutes

Example 119. [(R)-1-(4-Forfinal)-ethyl]-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 575,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/N2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min flow: 1.5 ml/min): 5,11 minutes

Example 120. [(S)-1-(4-Forfinal)-ethyl]-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 575,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,09 minutes

Example 121. 2-Chlorobenzilate (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MC (LC-MS): 577,3 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, is OK: 1.5 ml/min): 5,15 min

Example 122. 3-Chlorobenzilate (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MC (LC-MS): 577,3 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,18 minutes

Example 123. 4-Chlorobenzilate (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MC (LC-MS): 577,3 [M]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/N2O/3 min, flow: 1.5 ml/min): 5,14 minutes

Example 124. 2.5-Differentiated (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MC (LC-MS): 579,1 [M]+; tR(HPLC, C18 column, 10-100% CH3CN/N2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,13 minutes

Example 125. 2,4-Differentiated (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I.

MS (LC-MS): 579,1 [M]+; tR(HPLC, C18 column, 10-100% CH3CN/N2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/N2O/3 min, flow: 1.5 ml/min): 5,07 minutes

Example 126. 2,6-Differentiated (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 579,0 [M]+; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6,5 min, 95% CH3CN/H2O/1 min, flow: 0.5 ml/min): 4,63 minutes

Example 127. 3,4-Differentiated (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 579,0 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,11 minutes

Example 128. 3,5-Differentiated (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 579,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,12 minutes

Prima is 129. 2-Triptoreline (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 611,1 [M]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/N2O/3 min, flow: 1.5 ml/min): 5,43 minutes

Example 130. 3-Triptoreline (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 611,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,59 minutes

Example 131. 4-Triptoreline (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 611,0 [M]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/N2O/3 min, flow: 1.5 ml/min): 5,43 minutes

Example 132. 4-Cyanobenzene (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection get total the method (I).

MC (LC-MS): 568,3 [M]+; Rf[CH2Cl2:MeOH (9:1)]: 0,25 minutes

Example 133. 4-Dimethylaminobenzene (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 586,3 [M]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 4.26 deaths / min

Example 134. (2,3-Dihydrobenzo[1,4]dioxin-6-ylmethyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 601,3 [M]+; Rf[CH2Cl2:MeOH (9:1)]: 0,25 minutes

Example 135. (2,3-Dihydrobenzo[1,4]dioxin-5-ylmethyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 601,3 [M]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,07 minutes

Example 136. (3,4-Dihydro-2H-benzo [b] [1,4]doxepin-7-ylmethyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-labels is propoxy)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 615,3 [M]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/N2O/3 min, flow: 1.5 ml/min): 5,07 minutes

Example 137. (2,3-Dihydrobenzofuran-5-ylmethyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 585,3 [M]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/N2O/3 min, flow: 1.5 ml/min): 5,07 minutes

Example 138. (Benzofuran-4-ylmethyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 583,3 [M]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,11 minutes

Example 139. 2-piperidine-1-ylbenzene (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MC (LC-MS): 626,4 [M+H]+; tR(HPLC, C18 column, 10-100% CH3 CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 4,58 minutes

Example 140. 3-piperidine-1-ylbenzene (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MC (LC-MS): 626,3 [M]+; tR(HPLC, C18 column, 10-100% CH3CN/N2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/N2O/3 min, flow: 1.5 ml/min): 4,35 minutes

Example 141. 4-piperidine-1-ylbenzene (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 626,4 [M]+; Rf[CH2Cl2:MeOH (9:1)]: 0,35 minutes

Example 142. 2-Morpholine-4-ylbenzene (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 628,4 [M]+; tR(HPLC, C18 column, 10-100% CH3CN/N2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 4,58 minutes

Example 143. 3-Morpholine-4-ylbenzene (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection is of get a General methodology (I).

MS (LC-MS): 628,3 [M]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): br4.61 minutes

Example 144. 4-Morpholine-4-ylbenzene (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 628,4 [M]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 4,55 minutes

Example 145. 2-Pyrrolidin-1-ylbenzene (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MC (LC-MS): 612,4 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 4,46 minutes

Example 146. 3-Pyrrolidin-1-ylbenzene (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MC (LC-MS): 612,3 [M]+; tR(HPLC, C18 column, 10-100% CH3CN/N2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 mi the, flow: 1.5 ml/min): 4,66 minutes

Example 147. 4-Pyrrolidin-1-ylbenzene (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MC (LC-MS): 612,4 [M]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/N2O/3 min, flow: 1.5 ml/min): 4,37 minutes

Example 148. 3-Pyrrol-1-ylbenzene (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 608,3 [M]+; Rf[CH2Cl2:MeOH (9:1)]: 0,37 minutes

Example 149. 4-Pyrrol-1-ylbenzene (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 608,3 [M]+; Rf[CH2Cl2:MeOH (9:1)]: 0,35 minutes

Example 150. 4-Thiophene-3-ylbenzene (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 625,3 [M]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH CN/3 min, 100-10% CH3CN/N2O/3 min, flow: 1.5 ml/min): the 5.45 minutes

Example 151. Penetrated (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MC (LC-MS): 557,1 [M]+; tR(HPLC, C18 column, 10-100% CH3CN/N2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,18 minutes

Example 152. [1-Methyl-1-(1-vinylcyclopropyl)-ethyl]-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General method (II).

MC (LC-MS): 611,1 [M+H]+; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6,5 min, 95% CH3CN/N2On/1 min, flow: 0.5 ml/min): 5,6 minutes

Example 153. [2-(2-Forfinal)-ethyl]-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MC (LC-MS): 575,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,12 minutes

Example 154. [2-(3-Forfinal)-ethyl]-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methyl is nanoway acid

The desired connection receive General methodology (I).

MS (LC-MS): 575,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/N2O/3 min, flow: 1.5 ml/min): 5,11 minutes

Example 155. [2-(4-Forfinal)-ethyl]-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 575,0 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,06 minutes

Example 156. (2-Phenoxyethyl)-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 573,3 [M]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,08 minutes

Example 157. [2-(4-Methoxyphenoxy)-ethyl]-amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)-benzyl]-8-methylnonanoic acid

The desired connection receive General methodology (I).

MS (LC-MS): 603,1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H23CN/3 min, 100-10% CH3CN/H2O/3 min, flow: 1.5 ml/min): 5,09 minutes

Example 158. A solution of gelatin

Sterile-filtered aqueous solution containing 20% cyclodextrins as a solubilizer, one of the compounds of formula (I), noted in the previous examples, as the active ingredient, when heated and in aseptic conditions mixed with a sterile solution of gelatin containing phenol as preservative, so as to obtain 1.0 ml of a solution having the following composition:

The active ingredient3 mg
Gelatin150,0 mg
Phenol4,7 mg
Distilled water containing 20%1.0 ml
The active ingredient3 mg
cyclodextrins as a solubilizer

Example 159. Sterile dry connection for injection

Five (5) mg of one of the compounds of formula (I), noted in the previous examples, as the active ingredient, dissolved in 1 ml of an aqueous solution containing 20 mg of mannitol and 20% of the CEC is dextrine as a solubilizer. The solution is sterile filtered and aseptically injected into a vial with a volume of 2 ml, deep freeze and lyophilizers. Before use, the lyophilisate is dissolved in 1 ml of distilled water or 1 ml of saline. The solution is injected intramuscularly or intravenously. The composition also can be placed in a dual chamber disposable syringes.

Example 160. Preparation for nasal spray

Five hundred (500) mg pulverized (<5.0 g) powder of one of the compounds of formula (I), mentioned in the preceding examples, suspended as an active ingredient in a mixture of 3.5 ml of "Myglyol 8 12" and 0.08 g of benzyl alcohol. The suspension is placed in a container with a metering valve. Five (5,0) g "Freon 12" through the valve under pressure is introduced into the container. "Freon" when shaken dissolved in a mixture of miglyol/benzyl alcohol. A container for spray contains approximately 100 single doses, which can be entered separately.

Example 161. Tablets film coated

The following components are processed for preparation of 10,000 tablets, each containing 100 mg of active ingredient:

The active ingredient1000 g
Corn starch680 g
Colloidal silicic acid200 g
Magnesium stearate20 g
Stearic acid50 g
Sodium salt of carboxymethyl amylum250 g
Wateras needed

A mixture of one of the compounds of formula (I), noted in the previous examples, as the active ingredient, 50 g of corn starch and the colloidal silicic acid is processed in wet weight with a paste of starch obtained from 250 g of corn starch and 2.2 kg of demineralised water. The mass is forced through a sieve with a mesh size of 3 mm and dried at 45°C for 30 min in a fluidized bed dryer. The dried granules are forced through a sieve with mesh size of 1 mm, mixed with a previously sieved mixture (a sieve with mesh size 1 mm) 330 g of corn starch, magnesium stearate, stearic acid and sodium salt of carboxymethyl amylum and pressed with getting slightly biconvex tablets.

Although the present invention is described in detail using the preferred variants of its implementation, without deviating from the essence and scope described preferred VA is intov its implementation possible other options for its implementation. All references and patents (U.S. and others)in their entirety are included in the present invention by reference as if they were fully described in this invention.

1. Amide δ-amino-γ-hydroxy-ω-arylalkenes acid of the formula (I)

in which R1denotes hydrogen;
R2stands With1-C4alkoxy-C1-C4alkoxy or1-C4alkoxy-C1-C4alkyl;
R3stands With1-C4alkyl or C1-C4alkoxy;
R4denotes hydrogen;
X represents methylene;
R5denotes lower alkyl;
R6denotes hydrogen;
R7represents the unsubstituted amino group;
R8denotes branched C3-C4alkyl;
R9stands With3-C12cycloalkyl, substituted lower alkyl, hydroxy-group, the lower alkoxygroup, lower alkoxy-alkoxygroup, halogen or lower alkoxycarbonyl, where the lower alkyl may be optionally substituted by a hydroxy-group; C3- C12cycloalkyl-lower alkyl, where cycloalkyl optionally substituted lower alkyl, hydroxy-group, the lower alkoxygroup, lower alkoxy-alkoxygroup or halogen, or alkyl may be substituted by halogen, or alkoxygroup may be replaced by halogen; With 3- C12cycloalkylcarbonyl; N-mono or N,N-di(lower alkyl)substituted C3-C12cycloalkylcarbonyl; or optionally substituted aryl-lower alkyl, where the aryl may be optionally substituted lower alkyl, lower alkoxygroup, optionally substituted by halogen, a hydroxy-group, the lower alkylamino, di(lower alkyl)amino group, halogen and/or cryptomeria; or its pharmaceutically acceptable salt.

2. The compound according to claim 1, in which R9stands With3-C12cycloalkyl, substituted lower alkyl, HE, the lowest alkoxygroup, lower alkoxy-alkoxygroup, halogen, or its pharmaceutically acceptable salt.

3. The compound according to claim 2, in which
R1and R4represent hydrogen;
R2stands With1-C4alkoxy-C1-C4alkoxy;
R3stands With1-C4alkoxy;
or its pharmaceutically acceptable salt.

4. The compound according to claim 2, in which the halogen denotes fluorine or chlorine, or its pharmaceutically acceptable salt.

5. The compound according to claim 4, in which R3denotes methoxy, or its pharmaceutically acceptable salt.

6. The compound according to claim 5, in which R2located in the meta-position, and R3located in the para-position, or its pharmaceutically acceptable salt.

7. The compound according to claim 5, in which R3n is located in the ortho-position, or its pharmaceutically acceptable salt.

8. The compound according to claim 5, in which R3located in the meta-position, or its pharmaceutically acceptable salt.

9. The compound according to claim 2, in which R2located in the meta-position and denotes1-C4alkoxy-C1-C4alkoxy, or its pharmaceutically acceptable salt.

10. Amide δ-amino-γ-hydroxy-ω-arylalkenes acid according to claim 1 of formula (Ia)

in which R1denotes hydrogen;
R2stands With1-C4alkoxy-C1-C4alkoxy or1-C4alkoxy-C1-C4alkyl;
R3stands With1-C4alkyl or C1-C4alkoxy;
R4denotes hydrogen;
X represents methylene;
R5denotes lower alkyl;
R6denotes hydrogen;
R7represents the unsubstituted amino group;
R8denotes branched C3-C4alkyl;
R9stands With3-C12cycloalkyl, substituted lower alkyl, hydroxy-group, the lower alkoxygroup, lower alkoxy-alkoxygroup or halogen; C3-C12cycloalkyl-lower alkyl, where cycloalkyl optionally substituted lower alkyl, hydroxy-group, the lower alkoxygroup, lower alkoxy-alkoxygroup or halogen, or alkyl may be substituted by the halogen is, or alkoxygroup may be replaced by halogen; C3-C12cycloalkylcarbonyl; N-mono or N,N-di(lower alkyl)substituted C3-C12cycloalkylcarbonyl; or optionally substituted aryl-lower alkyl, where the aryl may be optionally substituted lower alkyl, lower alkoxygroup, optionally substituted by halogen, a hydroxy-group, the lower alkylamino, di(lower alkyl)amino group, halogen and/or cryptomeria; or its pharmaceutically acceptable salt.

11. The connection of claim 10, in which R9stands With3-C12cycloalkyl, substituted lower alkyl, hydroxy-group, the lower alkoxygroup, lower alkoxy-alkoxygroup or halogen, or its pharmaceutically acceptable salt.

12. The connection of claim 10, in which
R2denotes 3-methoxypropylamine;
R3denotes methoxy;
R5means isopropyl;
R8means isopropyl;
or its pharmaceutically acceptable salt.

13. The compound according to claim 1, which represents a (1-hydroxymethylglutaryl)amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)benzyl]-8-methylnonanoic acid, or its pharmaceutically acceptable salt.

14. The compound according to claim 1, which represents a methyl ester 1-{(2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)Ben who yl]-8-methylnonanoic}cyclohexanecarboxylic acid, or its pharmaceutically acceptable salt.

15. The compound according to claim 1, which represents the ((1S,2S)-2-hydroxycyclopent)amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)benzyl]-8-methylnonanoic acid, or its pharmaceutically acceptable salt.

16. The compound according to claim 1, which represents the ((R)-2,2-dimethylcyclobutyl)amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)benzyl]-8-methylnonanoic acid, or its pharmaceutically acceptable salt.

17. Pharmaceutical composition having inhibitory activity against renin, comprising a therapeutically effective amount of a compound according to claims 1-16, and one or more pharmaceutically acceptable inert filler(s).

18. The use of the pharmaceutical composition according to 17 for the preparation of medicines intended for the treatment of pathological conditions associated with renin activity.

19. Use p, in which a pathological condition associated with the activity of renin, is a hypertension.

20. The use of compounds according to claims 1 to 16 for preparing a medicinal product intended for the treatment of pathological conditions associated with renin activity.

21. The application of claim 20, in which the pathological condition associated with the activity of renin, is the th hypertension.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new 2-phenylethylaminosubstituted derivatives of carboxamides of formula (I) where J, J, W, R, R0, R1, R2, R3 and R4 have values, such as specified in cl. 1 of the patent claim, and to their pharmaceutically acceptable salts, pharmaceutical compositions containing them as sodium and/or calcium channel modulators for prevention, relief and treatment of a broad range of pathologies including neurological, mental, cardiovascular, inflammatory, ophthalmologic, urological and gastrointestinal diseases.

EFFECT: preparation of new 2-phenylethylaminosubstituted derivatives of carboxamides.

22 cl, 1 dwg, 10 tbl, 117 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, specifically to a method of producing 2,3,4,5-tetraalkylthiophenes, which can be used as an intermediate product during synthesis of dyes, biologically active compounds, as well as components of flavour boosters in food, additives to oil and hydraulic fluids. A method is described for producing 2,3,4,5-tetraalkylthiophenes, involving reaction of disubstituted acetylenes with n-BuMgCl in the presence of a zirconocene dichloride catalyst in an argon atmosphere at room temperature in diethyl ether for 2-4 hours with subsequent addition of elemental sulphur S8 in equimolar amount with respect to BuMgCl and boiling in benzene for 5 hours.

EFFECT: obtaining end product with high selectivity using simple technique due to exclusion of difficult to access 1,4-butadiene diiodide, highly pyrophoric n-butylithium and highly toxic carbon disulphide.

1 cl, 1 tbl, 9 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 2,3,4,5-tetraalkylthiophenes. Method involves interaction of disubstituted acetylenes with R'-AlCl2 and SOCl2 in the presence of metallic Mg and zirconacene dichloride as a catalyst in argon atmosphere in tetrahydrofuran medium for 11-15 h. Proposed method shows the simplified technology and uses easily available and nontoxic raw and provides preparing the end product with the yield about 47-54%. Synthesized compounds can be used in food industry, as biologically active compounds, dyes, addition agents to oils and hydraulic liquids.

EFFECT: improved method of synthesis, valuable properties of compounds.

1 tbl, 10 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 2,3,4,5-tetraalkylthiophenols. Method involves interaction of disubstituted acelylenes with n-BuMgCl and sulfur monochloride (S2Cl2) in the presence of zirconacene dichloride as a catalyst, in argon atmosphere, at room temperature in diethyl ether medium for 6-10 h. Proposed method provides preparing the end product with the yield 40-54% by simplified technology and with using easily available and nontoxic raw. Synthesized compounds can be used in food processing industry, as biologically active compounds, dyes, addition agents to oils and hydraulic liquids.

EFFECT: improved method of synthesis.

1 tbl, 9 ex

FIELD: organic chemistry.

SUBSTANCE: claimed method includes interaction of disubstituted acetylenes with n-BuMgCl and thionyl chloride SOCl2 in presence of zircon acetyl dichloride in argon atmosphere at room temperature in diethyl ether for 6-10 hours. Yield of target product is 48-58 %. Compounds of present invention are useful in food processing industry, as biologically active compounds, colorants, additives for oils and hydraulic liquids.

EFFECT: simplified method with increased yield; accessible and non-toxic raw materials.

1 tbl, 9 ex

The invention relates to a method for producing TRANS-3,4-dialkylacrylamide

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a novel method for synthesis of compound of the formula (VII) , formula (VIII) and formula (IX) that effect on 5-HT-receptors of the central nervous system. In compound of the formula (VII) R represents (C1-C3)-alkyl; Y represents fragment chosen from group comprising (C1-C6)-alkoxy-group, (C1-C6)-alkyl; Ar represents 2,3-dihydrobenzodioxin-5-yl. In compound of the formula (VIII) R represents (C1-C3)-alkyl; Ar represents 2,3-dihydrobenzodioxin-5-yl, and * indicated the chiral center. In compound of the formula (IX) R and Ar are given above; Aryl represents (C6-C12)-aromatic group substituted optionally and comprising up to three substitutes chosen independently from group comprising halogen atoms, alkyl, alkoxy-group, alkoxycarbonyl, nitro-, amino-, alkylamino-, dialkylamino-group, halogenalkyl, dihalogenalkyl, trihalogenalkyl, nitrile and amido-substitutes wherein each comprises six carbon atoms, not above.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds.

11 cl, 9 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to intermediates compounds of formulae (II) , (III) and (IV) wherein each R and R' represents independently of one another (C1-C3)-lower alkyl, and its optical isomers and salt; or each R and R' means independently of one another (C1-C3)-lower alkyl; Ar represents dihydrobenzodioxinyl, benzodioxinyl or phenyl optionally substituted with substitutes up to three-fold and chosen independently from halogen atom, methoxy-group, halogenmethyl, dihalogenmethyl and trihalogenmethyl, and its optical isomers; or Ar represents dihydrobenzodioxinyl or benzodioxinyl, or phenyl optionally substituted with substitutes up to three-fold chosen from halogen atom, methoxy-group, halogenmethyl, dihalogenmethyl and trihalogenmethyl, and its optical isomers. Also, invention relates to a method for synthesis of compounds of formulae (III), (IV) and compound of the formula (V) given in the invention description, and these compounds are intermediates substances used in synthesis of agent binding 5-HT1A receptors and can be used in treatment of disorders of the central nervous system. Invention provides simplifying the process and preparing optically preferable piperazines.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds.

13 cl, 7 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to 6-(4'-chlorobenzoyl)-7-(N-4''-nitrobenzoyl)amino-1,4-benzodioxane and its analogs of the general formula (I) possessing with an anticonvulsant activity wherein R' represents (C3-C4)-alkyl; Ar-X wherein X means hydrogen atom (H), p-CH3, ortho-, p-Hal; R'' represents -CH2Cl, Ar-X wherein X means p-CH3, meta-, p-OCH, p-NO2, 2-thiophenyl, 6-benzo-1,4-dioxanyl. Invention provides preparing new compounds that can be used in pharmacology.

EFFECT: valuable medicinal properties of compounds.

1 cl, 3 tbl, 2 ex

The invention relates to new derivatives of N, S-substituted N'-1-[(hetero)aryl] -N'-[(hetero)aryl] methylisothiazoline General formula I or their salts with pharmacologically acceptable acids HX in the form of a racemic mixture or in the form of a mixture of stereoisomers, which can be used for the treatment and prevention of diseases associated with dysfunction glutamatergic nanoperiodic

The invention relates to piperazine derivatives and methods for their preparation

The invention relates to chemical means of protection of plants, particularly to the new connection formulas

CH3OOCOOHH2Nhave a weed-killing activity

The invention relates to a process for the preparation of new derivatives of 1-aryl-2-aryloxides General formula

Ar-H--O-Ar< / BR>
(I) in which

Ar1the aromatic ring of the formula

_and Ar is an aromatic ring of the formula

in which p, n is 1 or 2;

Z is hydrogen, lower alkyl, lower alkoxyl, halogen atom, hydroxyl, lower acyloxy, lower alkenylacyl, phenoxy, phenyl or (lower alkyl) oxycarbonyl or chain(CH2)2Oh or CH CH-CH= CH, forming with the benzene ring more condensed cycle;

Y is H, lower alkyl, lower alkoxyl or lower acyloxy;

X is hydroxyl, lower alkoxyl, lower acyloxy, the group in which Ar' have the above meanings, in the presence of an acid catalyst to obtain diarylethene General formula

r--CH2-O-A the latter being in engagement with the lower alkylhalogenide, then subjected to repair using a borohydride of an alkali metal to obtain diarylethene General formula

r-CHOH-CH2O-Ar< / BR>
(V) in which Ar, Ar' have the above meanings, X is hydroxyl, which is subjected to alkylation using an alkylating agent in a basic environment or subjected to acylation using a derivative of carboxylic or phosphonic, or sulfuric or sulfonic acid

The invention relates to a new connection, 6-aminobenzoic-1,4(2,4-dichlorophenoxy)acetate formula

ClOCH2COOHH2Nwhich can find application in agricultural practice as a herbicide and as a stimulator of plant growth

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method for making a new compound 4-benzoyl-1H-benzo[c] oxepin-3-one of formula: consisting in the fact that 2-benzoyl-3-(2-bromomethylphenyl)propenic ethyl ether prepared by bromination of 2-benzoyl-3-(2-methylphenyl)propenic ethyl ethyl ether with N-bromsuccinimide, heated at temperature 230-260°C with simultaneous ethyl bromide distillation for 15-45 minutes. 4-Benzoyl-1H-benzo[c]oxepin-3-one shows analgesic activity.

EFFECT: preparation of the new compound showing analgesic activity.

1 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of a therapeutic agent which is an α-amino-amide compound of formula (I):

, in which R is a phenyl ring which is optionally substituted with one or two substitutes independently selected from halogen, hydroxy, cyano, C1-C6-alkyl, C1-C6-alkoxy or trifluoromethyl; R1 is hydrogen or C1-C6-alkyl; R2 and R3 are independently selected from hydrogen, C1-C4-alkyl; R4 and R5 independently denote hydrogen, C1-C6-alkyl; X is O or S; Y and Z, taken together with X and a phenyl ring bonded to Y and X, form a 5-7-member saturated heterocycle containing O or S atoms, or Y and Z denote hydrogen; or its isomers, mixtures and pharmaceutically acceptable salts for preparing a medicinal agent for treating lower urinary tract disorders.

EFFECT: obtaining a pharmaceutical composition based on the said compounds.

8 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of novel alkyl esters of 3-oxo-1,3-dihydrobenzo[c]oxepin-4-carboxylic acid of general formula , where R is methyl, ethyl, propyl, isopropyl, butyl, isopentyl, involving heating dialkyl esters of 2-(2-bromomethylbenzylidene)malonic acid, obtained through bromation of dialkyl esters of 2-(2-methylbenzylidene)malonic acid with N-bromosuccinimide to temperature of 190-220°C with simultaneous distillation of alkylbromide for 1-5 hours.

EFFECT: compounds can be used as intermediate products for synthesis of different organic compounds, particularly biologically active compounds.

1 cl, 6 ex

FIELD: medicine, cosmetology, organic chemistry.

SUBSTANCE: invention relates to a biologically active compound used for preparing agents promoting to hair growth. Compound is represented by the formula (I): wherein R1 and R2 are similar or different and each represents hydrogen atom, (C1-C6)-alkyl group or (C2-C6)-alkanoyl group; X represents hydrogen atom or halogen atom; R3a and R3b are different and each represents hydrogen atom or hydroxyl group; R4, R5, R6, R7 R8 and R9 are similar or different and each represents hydrogen atom, hydroxyl group, halogen atom or (C2-C6)-alkanoyloxy-group, or indicated group that are to be adjacent form in common π-bond or ester bond, or R5 and R8 or R5 and R9 form in common ester bond. Invention provides expanding assortment of chemical compounds possessing activity for inhibition of production of WNT-5A and stimulating growth of derma papilla cells.

EFFECT: valuable properties of tonic.

2 tbl, 8 dwg, 41 ex

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