DE3118191A1 - Amino acid derivatives, process for their preparation, compositions containing them, and their use - Google Patents

Amino acid derivatives, process for their preparation, compositions containing them, and their use

Info

Publication number
DE3118191A1
DE3118191A1 DE19813118191 DE3118191A DE3118191A1 DE 3118191 A1 DE3118191 A1 DE 3118191A1 DE 19813118191 DE19813118191 DE 19813118191 DE 3118191 A DE3118191 A DE 3118191A DE 3118191 A1 DE3118191 A1 DE 3118191A1
Authority
DE
Germany
Prior art keywords
compound
formula
och3
carboxylic acid
nmr
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
DE19813118191
Other languages
German (de)
Inventor
Rolf Prof. Dr. 6000 Frankfurt Geiger
Rainer Dr. 6300 Giessen Henning
Bernward Dr. 6233 Kelkheim Schölkens
Volker Dr. 6238 Hofheim Teetz
Hansjörg Dr. 6243 Kronberg Urbach
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hoechst AG
Original Assignee
Hoechst AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hoechst AG filed Critical Hoechst AG
Priority to DE19813118191 priority Critical patent/DE3118191A1/en
Priority to DE3177311T priority patent/DE3177311D1/en
Priority to EP81106535A priority patent/EP0046953B1/en
Priority to DE8181106535T priority patent/DE3177130D1/en
Priority to AT8989105371T priority patent/ATE105301T1/en
Priority to EP88102408A priority patent/EP0278530A3/en
Priority to EP89105371A priority patent/EP0328160B1/en
Priority to AT81106535T priority patent/ATE48415T1/en
Priority to ES504955A priority patent/ES504955A0/en
Priority to PT73584A priority patent/PT73584B/en
Priority to FI812652A priority patent/FI90072C/en
Priority to HU812478A priority patent/HU189531B/en
Priority to DK383581A priority patent/DK169382B1/en
Priority to AR286576A priority patent/AR240949A1/en
Priority to JP56134401A priority patent/JPS5777672A/en
Priority to KR1019810003193A priority patent/KR850001269B1/en
Priority to NZ198195A priority patent/NZ198195A/en
Priority to NO812933A priority patent/NO812933L/en
Priority to MX7581A priority patent/MX155680A/en
Priority to PH26117A priority patent/PH16812A/en
Priority to IE198681A priority patent/IE67438B1/en
Priority to AU74718/81A priority patent/AU544756C/en
Priority to GR65886A priority patent/GR75331B/el
Priority to ES505604A priority patent/ES505604A0/en
Priority to ES505605A priority patent/ES8301215A1/en
Priority to AR28982682A priority patent/AR240702A1/en
Publication of DE3118191A1 publication Critical patent/DE3118191A1/en
Priority to US06/565,887 priority patent/US5162362A/en
Priority to US06/565,900 priority patent/US5158959A/en
Priority to KR1019840005957A priority patent/KR850001270B1/en
Priority to KR1019840006028A priority patent/KR850001288B1/en
Priority to IL74857A priority patent/IL74857A0/en
Priority to AU79284/87A priority patent/AU599151B2/en
Priority to JP63209625A priority patent/JPH0678355B2/en
Priority to AU36625/89A priority patent/AU627741B2/en
Priority to JP3077208A priority patent/JPH07121955B2/en
Priority to FI914555A priority patent/FI90069C/en
Priority to FI914554A priority patent/FI90532C/en
Priority to CS914094A priority patent/CS409491A3/en
Priority to US08/208,443 priority patent/US5401766A/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention relates to compounds of the formula I <IMAGE> in which n denotes 0 or 1, R1 and R2, which can be identical or different and also can in turn be substituted, each denotes - alkyl or alkenyl, having up to 6 C-atoms, - cycloalkyl or cycloalkenyl each having 5-7 C-atoms, or aralkyl having 7-12 C-atoms, - aryl or partly hydrogenated aryl having 6-10 C-atoms, - aralkyl having 7-14 C-atoms, - a mono- or bicyclic heterocycle having 5-7 or 8-10 members respectively, of which 1-2 are -S- or -O- and/or up to 4 are -N- atoms, and COOR3 is a carboxyl or carboxylic acid ester group, which can be used as medicines, in particular as antihypertensives, a process for their preparation, compositions containing them, and their use.

Description

Aminosäurederivate, Verfahren zu ihrer Herstellung, dieseAmino acid derivatives, processes for their preparation, these

enthaltende Mittel und deren Verwendung Gegenstand der Erfindung ist eine Verbindung der Formel 1 in welcher bedeutet n 0 oder 1 R1 und R2, die gleich oder verschieden und auch ihrerseits substituiert sein können, je - Alkyl oder Alkenyl, mit bis zu 6 C-Atomen, - Cycloalkyl oder Cycloalkenyl mit je 5 - 7 C-Atomen, - Aryl oder teilhydriertes Aryl mit 6 -10 C-Atomen, - Aralkyl mit 7 - 14 C-Atomen - ein mono- oder bicyclischer Heterocyclus mit 5 - 7 bzw. 8 - 10 Gliedern, davon 1 - 2 -S- oder -0- und/oder bis zu 4 -N-Atomen, COOR3 eine Carboxyl- oder Carbonsäureestergruppe.Agents containing and their use The invention relates to a compound of the formula 1 in which n denotes 0 or 1 R1 and R2, which can be identical or different and also in turn substituted, each - alkyl or alkenyl, with up to 6 carbon atoms, - cycloalkyl or cycloalkenyl, each with 5 - 7 carbon atoms, - Aryl or partially hydrogenated aryl with 6-10 C atoms, - aralkyl with 7-14 C atoms - a mono- or bicyclic heterocycle with 5 - 7 or 8 - 10 members, of which 1 - 2 -S- or -0- and / or up to 4 -N atoms, COOR3 is a carboxyl or carboxylic acid ester group.

Als bevorzugte Beispiele für R¹ und R² seien insbesondere genannt Methyl, Ethyl, n-Propyl, Isopropyl, n-Butyl, Isobutyl, tert.-Butyl, sowie die gerädkettigen und verzweiaten Pentyle und Hexyle, ferner Cyclopentyl, Cyclohexyl, Cycloheptyl, Cyclopentenyl,Cyclohexenyl oder Cycloheptenyl, Phenyl, Naphthyl, Di- und Tetrahydronaphthyl, Benzyl, Phenethyl, p-Fluor-phenethyl, o-Methyl-phenethyl, p-Methoxyphenethyl, 2. 4-Dichlor-phenethyl.Preferred examples of R¹ and R² are particularly mentioned Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and the straight-chain ones and branched pentyls and hexyls, also cyclopentyl, cyclohexyl, cycloheptyl, Cyclopentenyl, cyclohexenyl or cycloheptenyl, phenyl, naphthyl, di- and tetrahydronaphthyl, Benzyl, phenethyl, p-fluorophenethyl, o-methyl-phenethyl, p-methoxyphenethyl, 2. 4-dichloro-phenethyl.

Die 5- bis 7-gliedrigen mono- oder 9-, 10-gliedrigen bicyclische Heterocyclen, können unsubstituiert sein, aber auch einen oder mehrere gleiche oder verschiedene Substituenten tragen wie Halogen, Sauerstoff (auch Sulfoxid oder Sulfon), Hydroxy, Carboxy, Carbonamido, Sulfonamido, Nitro, Alkyl und Aralkyl mit bis zu 9 C-Atomen, Methoxy oder Ethoxy. Im Falle einer Substitution ist Mono- oder Disubstitution bevorzugt.The 5- to 7-membered mono- or 9-, 10-membered bicyclic heterocycles, can be unsubstituted, but also one or more identical or different Carry substituents such as halogen, oxygen (also sulfoxide or sulfone), hydroxy, Carboxy, carbonamido, sulfonamido, Nitro, alkyl and aralkyl with up to 9 carbon atoms, methoxy or ethoxy. In the case of substitution, is mono- or Disubstitution preferred.

Die als R1 und R2 in Frage kommenden Alkyle oder Alkenyle können geradkettig oder verzweigt sein.The alkyls or alkenyls that come into consideration as R1 and R2 can be straight-chain or be branched.

Die Substituenten R1 und/oder R2 können einen oder mehrere gleiche oder verschiedene Substituenten tragen, insbesondere: Cycloalkyl oder Cycloalkenyl mit 5 - 7 C-Atomen, Hydroxy, Alkoxy mit 1 - 2 C-Atomen, Aryloxy, Aralkyloxy mit 1 - 2 C-Atomen im Alkylteil, wobei der Alkylteil durch Methoxy, Ethoxy, Carboxy, Carbonamido, Amino oder Alkylamino und der Arylteil durch die genannten Substituenten und zusätzlich durch Halogen oder Nitro substituiert sein kann, Amino, Mono-, Di- oder Trialkyl- oder -cycloalkyl-amino mit bis zu insgesamt 7 C-Atomen in den Alkyl- oder Cycloalkylgruppen, das gegebenenfalls durch Hydroxy, Carboxy, Carbonamido, Carbethoxy, Amino, Alkyl- oder Dialkylamino, Piperidino oder Morpholino im Alkylrest substituiert sein kann, Alkyl-, Aryl-, Aralkyl-oxycarbonylamino oder -ureido, Formyl, Alkanoyl-, Aroyl- oder Aralkancylamino mit bis zu 10 C-Atomen, Arylamino, Aralkylamino, in denen der Arylteil durch Alkyl oder Alkoxy mit 1 - 2 C-Atomen, Methylendioxy, Amino, Hydroxy, Acetoxy, Carboxy, Carbonamido, Carbethoxy, Halogen, oder Nitro mono- oder disubstituiert sein kann, Alkyl-, Aryl- oder Aralkylmercapto mit bis zu 7 C-Atomen, wobei der Alkylteil durch Methoxy, Ethoxy, Hydroxy, Carboxy, Carbonamido, Carbethoxy, Amino oder Alkylamino und der Arylteil durch die genannten Reste und zusätzlich durch Halogen, Nitro oder Sulfonamido substituiert sein kann, horner deren Sulfoxide und Sulfone, Carboxy, Carbethoxy, Carbonamido, Alkyl-, Cycloalkyl-, Cycloalkylen- oder Dialkylaminocarbonyl mit bis zu 6 C-Atomen, Aryl- oder Aralkylaminocarbonyl, Guanido, Phenyl, Naphthyl, Di- und Tetrahydronaphthyl, das durch Halogen, Hydroxy, Acetoxy, Carboxy, Carbonamido, Sulfonamido, Nitro, Methyl, Ethyl, Methoxy oder Ethoxy monodi- oder trisubstituiert sein kann, 5 - 7-gliedrige mono- oder 9- bis 10-gliedrige bicyclische Heterocyclen, gegebenenfalls 1 - 2 S- oder O-Atome und/oder bis 4 N-Atome pro Ring enthaltend, die gegebenenfalls wie oben substituiert sein können.The substituents R1 and / or R2 can be one or more identical or carry various substituents, in particular: cycloalkyl or cycloalkenyl with 5 - 7 carbon atoms, hydroxy, alkoxy with 1 - 2 carbon atoms, aryloxy, aralkyloxy with 1 - 2 carbon atoms in the alkyl part, the alkyl part being methoxy, ethoxy, carboxy, Carbonamido, amino or alkylamino and the aryl part by the substituents mentioned and can additionally be substituted by halogen or nitro, amino, mono-, di- or trialkyl- or -cycloalkyl-amino with up to a total of 7 carbon atoms in the alkyl or cycloalkyl groups, optionally substituted by hydroxy, carboxy, carbonamido, Carbethoxy, amino, alkyl or dialkylamino, piperidino or morpholino in the alkyl radical may be substituted, alkyl-, aryl-, aralkyl-oxycarbonylamino or -ureido, formyl, Alkanoyl, aroyl or aralkancylamino with up to 10 carbon atoms, arylamino, aralkylamino, in which the aryl part is replaced by alkyl or alkoxy with 1 - 2 carbon atoms, methylenedioxy, Amino, hydroxy, acetoxy, carboxy, carbonamido, carbethoxy, halogen, or nitro mono- or can be disubstituted, alkyl, aryl or aralkyl mercapto with up to 7 carbon atoms, where the alkyl part by methoxy, ethoxy, hydroxy, carboxy, carbonamido, carbethoxy, Amino or alkylamino and the aryl part through the radicals mentioned and in addition by Halogen, nitro or sulfonamido can be substituted, horner their sulfoxides and Sulfones, carboxy, carbethoxy, carbonamido, alkyl, cycloalkyl, cycloalkylene or Dialkylaminocarbonyl with up to 6 carbon atoms, aryl or aralkylaminocarbonyl, guanido, Phenyl, naphthyl, di- and tetrahydronaphthyl, which is replaced by halogen, hydroxy, acetoxy, Carboxy, carbonamido, sulfonamido, nitro, methyl, ethyl, methoxy or ethoxy monodi- or can be trisubstituted, 5-7-membered mono- or 9- to 10-membered bicyclic Heterocycles, optionally 1-2 S or O atoms and / or up to 4 N atoms per ring containing, which may optionally be substituted as above.

Unter Alkyl ist, falls im Einzelfall nichts anderes gesagt, vorzugsweise ein geradkettiges oder verzweigtes Alkyl mit 1 - 6 C-Atomen zu verstehen. Entsprechendes gilt für Alkanoyl, Alkylamino, Alkylmercapto.Unless otherwise stated in the individual case, alkyl is preferred to understand a straight-chain or branched alkyl with 1 - 6 carbon atoms. Corresponding applies to alkanoyl, alkylamino, alkylmercapto.

Aryl bedeutet bevorzugt Phenyl, Naphthyl, Biphenyl oder durch Halogen, Alkyl oder Alkoxy substituiertes Phenyl.Aryl preferably means phenyl, naphthyl, biphenyl or halogen, Alkyl or alkoxy substituted phenyl.

Entsprechendes gilt für Aroyl, Arylamino, Arylmercapto.The same applies to aroyl, arylamino, aryl mercapto.

Aralkyl umfaßt bevorzugt Benzyl, Phenethyl und die entsprechenden, im Phenylkern mit Halogen, Alkyl oder Alkoxy substituierten Verbindungen. Entsprechendes gilt für Aralkanoyl, Aralkylamino, Aralkylmercapto.Aralkyl preferably includes benzyl, phenethyl and the corresponding, compounds substituted in the phenyl nucleus by halogen, alkyl or alkoxy. Corresponding applies to aralkanoyl, aralkylamino, aralkylmercapto.

Verbindungen der allgemeinen Formel I, in der R1 die Seitenkette einer natürlich vorkommenden L-Aminosäure darstellt, z.B. Methyl, Isobutyl, Methylthioethyl, Carboxymethyl, Carboxyethyl, Amino-n-butyl, Guanido-n-propyl, Imidazole-4-ethyl, Benzyl, 4-Hydroxybenzyl oder 3-Indolylmethyl, sowie deren funktionelle Derivate wie Ether, Ester.Compounds of the general formula I in which R1 is the side chain of a represents naturally occurring L-amino acid, e.g. methyl, isobutyl, methylthioethyl, Carboxymethyl, carboxyethyl, amino-n-butyl, guanido-n-propyl, imidazole-4-ethyl, Benzyl, 4-hydroxybenzyl or 3-indolylmethyl, and their functional derivatives like ethers, esters.

oder Amide sind besonders bevorzugt. Der Rest R1 kann aber auch Teil von Aminosäuren sein, die nicht in der Natur vorkommen.or amides are particularly preferred. The remainder R1 can also be part of amino acids that are not in nature occurrence.

Gegenstand der Erfindung ist ferner ein Verfahren zur Herstellung der Verbindungen der Formel I, das dadurch gekennzeichnet ist, daß man (a) eine Verbindung der Formel II mit einer Verbindung der Formel III umsetzt in denen ein Q eine nucleofuge Gruppe und das andere Q - NH2 bedeutet und R4 für H, Methyl, Ethyl, Benzyl oder tert.-Butyl steht, und gegebenenfalls die Estergruppe R3 und/oder R4 abspaltet, oder (b) eine Verbindung der Formel IV worin P H bedeutet, eines der beiden P jedoch auch die Bedeutung von R4 haben kann, Y' -NW- ist und W entweder H oder eine Aminoschutzgruppe bedeutet, mit einer Verbindung der Formel V in Gegenwart eines Kondensationsmittels umsetzt und gegebenenfalls die Schutz gruppe abspaltet oder (c) eine Verbindung der Formel VI mit einer Verbindung der Formel VII umsetzt in denen ein T für eine NH2-Gruppe und das andere T für ein Sauerstoffatom steht, und die erhaltene Schiffsche Base reduziert.The invention also relates to a process for the preparation of the compounds of the formula I, which is characterized in that (a) a compound of the formula II is reacted with a compound of the formula III in which one Q denotes a nucleofugal group and the other Q denotes - NH2 and R4 denotes H, methyl, ethyl, benzyl or tert-butyl, and optionally splits off the ester group R3 and / or R4, or (b) a compound of the formula IV where PH is, but one of the two P can also have the meaning of R4, Y 'is -NW- and W is either H or an amino protecting group, with a compound of the formula V reacts in the presence of a condensing agent and optionally splits off the protective group or (c) reacts a compound of the formula VI with a compound of the formula VII in which one T stands for an NH2 group and the other T for an oxygen atom, and the resulting Schiff base is reduced.

Zur Herstellung der Verbindungen I kann man beispielsweise von 2-Halogencarbonsäurederivaten II oder III ausgehen, die mit Nucleophilen reagieren. Diese Reaktion wird bevorzugt in mit Wasser mischbaren organischen Lösungsmitteln, gegebenenfalls in Anwesenheit von Wasser, durchgeführt, wobei eine anorganische oder tertiäre oder quartäre organische Base zugegeben wird.The compounds I can be prepared, for example, from 2-halocarboxylic acid derivatives II or III that react with nucleophiles. This reaction is preferred in water-miscible organic solvents, optionally in the presence of water, being an inorganic or tertiary or quaternary organic Base is added.

Wenn die Reaktionspartner in aprotischen organischen Lösungsmitteln löslich sind, ist ein solches Lösungsmittel vorzuziehen, wobei als Base vorteilhaft ein Trialkylamin, Tetraalkylammoniumhydroxid oder Tetramethylguanidin oder eine Suspension eines Alkali-oder Erdalkalicarbonats zugesetzt werden.When the reactants in aprotic organic solvents are soluble, such a solvent is preferable, the base being advantageous a trialkylamine, tetraalkylammonium hydroxide or tetramethylguanidine or a Suspension of an alkali or alkaline earth carbonate can be added.

Die bevorzugten Ausgangsprodukte werden durch katalytische Hydrierung, bevorzugt an Rhodiumkatalysatoren, aus den literaturbekannten zugrunde liegenden Aromaten bzw. partiell hydrierten Aromaten hergestellt. Das Edukt von VIII kann nach Aust. J. Chem.The preferred starting products are prepared by catalytic hydrogenation, preferably over rhodium catalysts, from the aromatics or partially hydrogenated aromatics known from the literature. The starting material of VIII can according to Aust. J. Chem.

20 (1967), Seite 1935, das von IX nach J. Amer. Chem.20 (1967), page 1935, published by IX after J. Amer. Chem.

Soc. 70 (1948), Seite 182, hergestellt werden.Soc. 70 (1948), page 182.

Aus ihen erhält man die Ester mit R4 in bekannter Weise und kondensiert sie mit iialogencarbonsäuren zu den Verbindungen II (Q = Halogen) entweder über die Säurechloride, gemischte Anhydride, Aktivester oder andere Methoden, wie sie in Houben-Weyl, Methoden der Organischen Chemie, Band 15, ausführlich beschrieben sind. Bei R1 = CH3 kann man z.B. von der L-Milchsäure leicht zugänglichen D-2-Chlorpropionsäure ausgehen.The esters with R4 are obtained from them in a known manner and condensed they with iialogencarbonsäuren to the compounds II (Q = halogen) either over the acid chlorides, mixed anhydrides, active esters, or other methods like them in Houben-Weyl, Methods of Organic Chemistry, Volume 15, described in detail are. If R1 = CH3, for example, D-2-chloropropionic acid, which is easily accessible from L-lactic acid, can be obtained go out.

Die Zwischenprodukte der Formel II (Q = NH2) werden aus den Oktahydroindolin- oder Tetrahydroisochinolincarbonsäureestern durch Kondensation mit einer N-geschützten 2-Aminocarbonsäure erhalten. Die Schutzgruppe wird nach beendeter Kondensation wieder abgespalten. Als Schutzgruppe kommt z.B. Benzyloxycarbonyl in Frage.The intermediates of the formula II (Q = NH2) are made from the octahydroindoline or tetrahydroisoquinoline carboxylic acid esters by condensation with an N-protected one 2-aminocarboxylic acid obtained. The protective group is again after the condensation has ended cleaved. Benzyloxycarbonyl, for example, can be used as a protective group.

Die Kondensation kann nicht nur mit DCC/HOBt (Dicyclohexylcarbodiimid/1-Hydroxybenzotriazol) sondern auch mit einem anderen geeigneten Kondensationsmittel z.B. dem in Houben-Weyl, Band 15 beschriebenen, durchgeführt werden.The condensation can not only be carried out with DCC / HOBt (dicyclohexylcarbodiimide / 1-hydroxybenzotriazole) but also with another suitable condensing agent, e.g. the one in Houben-Weyl, Volume 15 described.

Die Verfahrensweise (b) geht von Verbindungen der Formel X aus. Procedure (b) is based on compounds of the formula X.

Sind R1 und R2 identisch, so können R5 und R6 Wasserstoff sein. Man kondensiert dann z.B. in Gegenwart von Dicyclohexylcarbodiimid, mit einem Äquivalent einer Verbindung der Formel V und spaltet R4 in bekannter Weise ab.If R1 and R2 are identical, then R5 and R6 can be hydrogen. Man then condenses, for example, in the presence of dicyclohexylcarbodiimide, with one equivalent a compound of the formula V and splits off R4 in a known manner.

W ist H oder eine N-Schutzgruppe. Als solche kommen die in der Peptidchemie gebräuchlichen Reste in Frage, z.B.W is H or an N-protecting group. As such come the in residues commonly used in peptide chemistry, e.g.

Benzyloxycarbonyl (falls kein Schwefel im Moleküi vorhanden ist, der die spätere Abspaltung durch katalytische Hydrierung stören würde), tert.-Butyloxycarbonyl, Formyl.Benzyloxycarbonyl (if there is no sulfur in the molecule, the the later cleavage by catalytic hydrogenation would interfere), tert-butyloxycarbonyl, Formyl.

Die Reaktion verläuft möglicherweise über das isolierbare Anhydrid XI, das anschließend mit einer Verbindung der Formel V geöffnet wird. The reaction possibly proceeds via the isolatable anhydride XI, which is then opened with a compound of the formula V.

Nötigenfalls gelangt man durch Abspalten der Schutzgruppen zu Verbindungen der Formel I.If necessary, compounds are obtained by splitting off the protective groups of formula I.

Sind die Reste R1 und R2 in der Verbindung X ungleich, so ist vorzugsweise nur einer der Reste R5 oder R6 Wasserstoff, der andere sollte vorzugsweise Ethyl, tert.-Butyl oder Benzyl sein. Man kondensiert dann in beschriebener Weise mit den Verbindungen der Formel V und spaltet gegebenenfalls die Schutzgruppen ab.If the radicals R1 and R2 in the compound X are not the same, then is preferred only one of the radicals R5 or R6 is hydrogen, the other should preferably be ethyl, be tert-butyl or benzyl. It is then condensed in the manner described with the Compounds of the formula V and, if appropriate, split off the protective groups.

Die für T=NH2 in den Formeln VI bzw. VII bedeutsame Kondensation mit 2-Ketocarbonsäure bzw. deren Estern gemäß (c) führt in an sich bekannter Weise über-Schiff' sche Basen z.B. nach Reduktion mit Natriumborhydrid oder Natriumcyanoborhydrid, durch katalytische Hydrierung oder elektrolytische Reduktion zu den entsprechenden Verbindungen der Formel I in guter Reinheit.The significant for T = NH2 in the formulas VI and VII with condensation 2-ketocarboxylic acid or its esters according to (c) leads in a manner known per se over-Schiff ' cal bases e.g. after reduction with sodium borohydride or sodium cyanoborohydride, by catalytic hydrogenation or electrolytic reduction to the corresponding Compounds of the formula I in good purity.

Die neuen Verbindungen besitzen unter anderem 3 chirale Zentren an O(-C-Atomen. Die Anordnung der Liganden entspricht bevorzugt der L-Konfiguration. Im allgemeinen können durch Kristallisation, speziell der Cyclohexylamin- oder Dicyclohexylaminsalze sterisch weitgehend ein- heitliche Verbindungen der Formel I erhalten werden. Auch Gegenstromverteilung in einem geeigneten, aus der Peptidchemie bekannten Lösungsmittelsystem oder präparative HPLC sind zur Anreicherung sterisch einheitlicher Formen geeignet.The new compounds have, among other things, 3 chiral centers O (-C atoms. The arrangement of the ligands preferably corresponds to the L configuration. In general, by crystallization, especially the cyclohexylamine or dicyclohexylamine salts largely sterically uniform compounds of formula I obtained will. Also countercurrent distribution in a suitable one known from peptide chemistry Solvent system or preparative HPLC are sterically more uniform for enrichment Forms suitable.

Auf der Stufe der Zwischenprodukte VIII und IX kann man gegebenenfalls Diastereomere durch Kristallisation oder präparative HPLC trennen, so daß nach dem oben beschriebenen Verfahren Produkte der Formel I erhalten werden können, die an allen 5 chiralen Zentren eine einheitliche sterische Anordnung besitzen.At the stage of the intermediates VIII and IX one can optionally Separate diastereomers by crystallization or preparative HPLC, so that after Processes described above, products of the formula I can be obtained which at all 5 chiral centers have a uniform steric arrangement.

Die neuen Verbindungen der Formel I besitzen eine langdauernde, intensive blutdrucksenkende Wirkung.The new compounds of the formula I have a long-lasting, intensive one antihypertensive effect.

Sie können zur Bekämpfung des Bluthochdrucks verschiedener Genese eingesetzt und für sich oder in Kombination mit anderen blutdrucksenkenden, gefäßerweiternden oder diuretisch wirksamen Verbindungen angewandt werden. Die Anwendung kann intravenös, subcutan oder peroral erfolgen.They can be used to combat high blood pressure of various origins used and used alone or in combination with other antihypertensive, vasodilator or diuretically active compounds are used. The application can be intravenous, be done subcutaneously or orally.

Typische Vertreter dieser Wirkklassen sind z.B. in Erhart-Ruschig, Arzneimittel, 2. Auflage, Weinheim 1972, beschrieben.Typical representatives of these active classes are e.g. in Erhart-Ruschig, Medicines, 2nd edition, Weinheim 1972, described.

Die Dosierung bei peroraler Gabe liegt bei 20 - 200 mg je Einzeldosis. Sie kann in schweren Fällen auch erhöht werden, da toxische Eigenschaften bisher nicht beobachtet wurden. Auch eine Herabsetzung der Dosis ist möglich und vor allem dann angebracht, wenn gleichzeitig Diuretika verabreicht werden. Bei intravenöser oder subcutaner Verabreichung sollte die Einzeldosis zwischen 0.01 und 10 mg liegen.The dosage for oral administration is 20-200 mg per single dose. In severe cases, it can also be increased, since it has previously had toxic properties were not observed. A lowering of the dose is also possible and above all Appropriate when concomitant diuretics are administered. With intravenous or subcutaneous administration, the single dose should be between 0.01 and 10 mg.

Die Verbindungen der Formel I liegen als innere Salze vor.The compounds of the formula I are present as internal salts.

Falls beide Carboxylgruppen frei sind, können zusätzlich Alkali- und Erdalkalisalze und solche mit physiologisch unbedenklichen Aminen gebildet werden. Ferner kann eine vorhandene freie Aminogruppe mit einer Mineralsäure oder organischen Säure zu einem Salz umgesetzt werden. Auch die anderen Verbindungen der Formel I können in freier Form oder als solche Salze angewandt werden.If both carboxyl groups are free, alkali and Alkaline earth salts and those with physiologically harmless amines are formed. Furthermore, a free amino group present with a mineral acid or organic acid can be converted to a salt. The other connections too of the formula I can be used in free form or as such salts.

Die nachfolgenden Beispiele sollen die erfindungsgemäßen Verfahrensweisen erläutern, ohne die Erfindung auf die hier stellvertretend genannten Substanzen zu beschränken.The following examples are intended to illustrate the procedures according to the invention explain without referring to the substances mentioned here as representative of the invention to restrict.

Beispiel 1 N- (1 -Carboxy- 3-phenvlpropyl) -L-alanyl-dekahydroisochinolin-3-carbonsäure A. L-Dekahydroisochinolin-3-carbonsäure (Dic) 250 g L-1 ,2,3,4-tetrahydroisochinolin-3-carbonsäure werden in 2 1 90-proz. Essigsäure suspendiert. Man gibt 10 g Rhodium auf Kohle zu und hydriert 24 Stunden bei 60-80"C und 120 bar. Die filtrierte Lösung wird eingeengt, der Rückstand in 200 ml Essigester aufgenommen und unter kräftigem Rühren in 2 1 Diisopropylether eingetropft. Man dekantiert vom harzigen Rückstand, engt die Lösung im Vakuum ein und wiederholt dieselbe Prozedur mit etwa 1/3 der vorher verwendeten Lösungsmittelmenge. Die harzigen Niederschläge werden vereinigt und mit heißem Essigester behandelt, wobei nur ein Teil in Lösung geht. Man läßt unter kräftigem Rühren in 3 l Diethylcther-Diisopropylestcr 1:1 einlaufen, wobei ein flockiger Niederschlag entsteht, der abfiltriert, mit Ether gewaschen und getrocknet wird.Example 1 N- (1-Carboxy-3-phenylpropyl) -L-alanyl-decahydroisoquinoline-3-carboxylic acid A. L-decahydroisoquinoline-3-carboxylic acid (Dic) 250 g of L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid are in 2 1 90 percent. Acetic acid suspended. 10 g of rhodium on charcoal are added and hydrogenated for 24 hours at 60-80 "C and 120 bar. The filtered solution is concentrated, the residue was taken up in 200 ml of ethyl acetate and, with vigorous stirring, in 2 l Added dropwise diisopropyl ether. The resinous residue is decanted and the solution is concentrated in vacuum one and repeat the same procedure with about 1/3 of the previously used Amount of solvent. The resinous precipitates are combined and washed with hot ethyl acetate treated, with only a part going into solution. It is left in with vigorous stirring 3 l of diethyl ether-diisopropyl ester 1: 1 run in, forming a fluffy precipitate arises, which is filtered off, washed with ether and dried.

Ausbeute: 234 g; dünnschichtchromatographisch nicht einheitlich (Diastereoisomerengemisch). Nach UV-Spektrum und NMR kein Aromat mehr vorhanden, Elementaranalyse korrekt. Yield: 234 g; Not uniform by thin-layer chromatography (mixture of diastereoisomers). According to the UV spectrum and NMR, no more aromatic is present, elemental analysis correct.

Das Material wird ohne weitere Reinigung für die nächste Stufe eingesetzt. The material is used for the next stage without further purification.

B. N-Benzyloxycarbonyl-L-dekahydroisochinolin-3-carbonsäure (Z-Dic-OH) 58 g L-Dekahydroisochinolin-3-carbonsäure werden in 315 ml 1N NaOH gelöst. Unter kräftigem Rühren läßt man bei 0-50C gleichzeitig 48 ml Benzyloxycarbonylchlorid und 370 ml 1N NaOH innerhalb einer Stunde zutropfen.B. N-Benzyloxycarbonyl-L-decahydroisoquinoline-3-carboxylic acid (Z-Dic-OH) 58 g of L-decahydroisoquinoline-3-carboxylic acid are dissolved in 315 ml of 1N NaOH. Under While stirring vigorously, 48 ml of benzyloxycarbonyl chloride are left at 0-50C and 370 ml of 1N NaOH are added dropwise over the course of one hour.

Dabei fällt ein dicker Niederschlag aus. Man rührt nach beendeter Zugabe noch 2 Stdn. weiter, extrahiert dann mit Ether und filtriert den Niederschlag ab (=Natriumsalz eines Diastereoisomeren "A"; Ausbeute 43 g). A thick precipitate forms in the process. The mixture is then stirred finished Addition for a further 2 hours, then extracted with ether and filtered the precipitate from (= sodium salt of a diastereoisomer "A"; yield 43 g).

Das Filtrat wird mit konz. HCl auf pH 1,5 - 2 gebracht, wobei sich ein bl absetzt. Es wird in Essigester aufgenommen. Die Wasserphase wird mit Essigester extrahiert, die vereinigten Essigesterlösungen werden mit Wasser gewaschen, über Natriumsulfat getrocknet und auf ein kleines Volumen (ca. 200 ml) eingeengt. Bei Zugabe von 15-18 ml Cyclohexylamin (CA) fällt ein Niederschlag aus, der nach Kühlen mit Eiswasser abfiltriert und mit wenig kaltem Essigester gewaschen und dann getrocknet wird. Ausbeute: 48 g, (CA-Salz des Isomerengemisches B).The filtrate is concentrated with. HCl brought to pH 1.5-2, whereby a bl drops. It is taken up in ethyl acetate. The water phase is made with ethyl acetate extracted, the combined ethyl acetate solutions are washed with water, over Dried sodium sulfate and concentrated to a small volume (approx. 200 ml). at Addition of 15-18 ml of cyclohexylamine (CA), a precipitate separates out, which after cooling filtered off with ice water and washed with a little cold ethyl acetate and then dried will. Yield: 48 g (CA salt of the isomer mixture B).

Das Natriumsalz von "A" wird wie folgt in das CA-Salz übergeführt: Man suspendiert die Verbindung in 500 ml Wasser, überschichtet mit 200 ml Essigester und säuert mit konz. HCl bis pH 1,5 - 2 an. Nach Ausschütteln trennt man die Essigesterphase ab, wäscht mit etwas Wasser und trocknet über Natriumsulfat. Man engt wie oben ein und versetzt mit 16 ml Cyclohexylamin. Das CA-Salz wird wie oben isoliert.The sodium salt of "A" is converted into the CA salt as follows: The compound is suspended in 500 ml of water, covered with a layer of 200 ml of ethyl acetate and acidifies with conc. HCl up to pH 1.5 - 2. After shaking out, the ethyl acetate phase is separated off, wash with a little water and dry over sodium sulfate. You narrow as above and mixed with 16 ml of cyclohexylamine. The CA salt is isolated as above.

Zur Reinigung wird das CA-Salz von "A" aus der achtfachen Menge Essigester umkristallisiert. Schmelzpunkt: 197 - 198"C, /L-7D = 7,50 (c = 1, in Methanol). Elementaranalyse korrekt.For cleaning, the CA salt of "A" is made from eight times the amount of ethyl acetate recrystallized. Melting point: 197-198 "C, / L-7D = 7.50 (c = 1, in methanol). Elemental analysis correct.

Das CA-Salz von B wird aus der vierfachen Menge Essigester umkristallisiert. Schmp.: 1900 (sintert ab 187°) 1 /d /D = + 14,60 (c=1, in Methanol) Elementaranalyse korrekt.The CA salt of B is recrystallized from four times the amount of ethyl acetate. Mp .: 1900 (sinters from 187 °) 1 / d / D = + 14.60 (c = 1, in methanol) elemental analysis correctly.

Die freien Säuren werden in bekannter Weise durch Suspendieren der CA-Salze in Wasser/Essigester und Ansäuern mit Citronensäure erhalten. Die Essigesterphasen werden mit wenig Wasser gewaschen und eingeengt.The free acids are in a known manner by suspending the CA salts obtained in water / ethyl acetate and acidification with citric acid. The ethyl acetate phases are washed with a little water and concentrated.

Man erhält Z-Dic-OH als öligen Rückstand.Z-Dic-OH is obtained as an oily residue.

C. Benzyloxycarbonyl-L-dekahydroisochinolin-3-carbonsäuretert.-butylester (Z-Dic-OBut).C. Benzyloxycarbonyl-L-decahydroisoquinoline-3-carboxylic acid tert-butyl ester (Z-Dic-OBut).

41 g Z-Dic-OH (A) werden in 350 ml Methylenchlorid gelöst. Man gibt 52 ml t-Butanol und 1,3 g 4-Dimethylaminopyridin zu, kühlt auf O°C und tropft unter Rühren die Lösung von 29 g Dicyclohexylcarbodiimid (DCC) in 60 ml Methylenchlorid zu. Man rührt anschließend noch 20 min. bei OOC und 5 h bei Raumtemperatur und filtriert den ausgefallenen Dicyclohexylharnstoff ab. 41 g of Z-Dic-OH (A) are dissolved in 350 ml of methylene chloride. One gives Add 52 ml of t-butanol and 1.3 g of 4-dimethylaminopyridine, cool to 0 ° C. and drop in Stir the solution of 29 g of dicyclohexylcarbodiimide (DCC) in 60 ml of methylene chloride to. The mixture is then stirred for a further 20 minutes at OOC and 5 hours at room temperature and filtered the precipitated dicyclohexylurea.

Das Filtrat wird im Vakuum eingedampft, der Rückstand in Essigester aufgenommen, die Lösung nacheinander mit KHSO4/K2SO4-Lösung, Natriumhydrogencarbonat (nicht-umgesetztes Na-Salz von Z-Dic-OH fällt aus und wird abfiltriert) und Wasser gewaschen, getrocknet und im Vakuum zur Trockene gebracht. Öliger Rückstand. The filtrate is evaporated in vacuo, the residue in ethyl acetate added, the solution successively with KHSO4 / K2SO4 solution, sodium hydrogen carbonate (Unreacted sodium salt of Z-Dic-OH precipitates and is filtered off) and water washed, dried and brought to dryness in vacuo. Oily residue.

Ausbeute: 38,5 g -7D = -17,3" (c=1, in Methanol). Yield: 38.5 g -7D = -17.3 "(c = 1, in methanol).

Zur Gewinnung der analogen Verbindung von B geht man in derselben Weise vor. Ausbeute 38,1 g, + 6,70 (c=1, in Methanol). To obtain the analogous connection from B one proceeds in the same Way before. Yield 38.1g, + 6.70 (c = 1, in methanol).

D. L-Dekahydroisochinolin-3-carbonsäure-tert.butylestertosylat (H-Dic-OBut#TosOH) 27 g der nach Beispiel 1 C hergestellten Verbindung von A werden in 250 ml Methanol unter Zutropfen von 4N TosOH in Methanol an Pd/Kohle bei pH 4,5 (pH-Stat) katalytisch hydriert. Dann engt man die filtrierte Lösung im Vakuum ein, digeriert den kristallinen Rückstand mit Ether und trocknet. Ausbeute: 22,6 g Zur Analyse wird aus Essigester umkristallisiert.D. L-decahydroisoquinoline-3-carboxylic acid tert-butyl ester tosylate (H-Dic-OBut # TosOH) 27 g of the compound of A prepared according to Example 1 C are dissolved in 250 ml of methanol catalytically with the dropwise addition of 4N TosOH in methanol on Pd / charcoal at pH 4.5 (pH-Stat) hydrogenated. The filtered solution is then concentrated in vacuo and the crystalline solution is digested Residue with ether and dry. Yield: 22.6 g. For analysis, ethyl acetate is used recrystallized.

Schmp.: 159-1600C; [α]D = -6,5° (C=1, in Methanol). M.p .: 159-1600C; [α] D = -6.5 ° (C = 1, in methanol).

Elementaranalyse korrekt. Die Verbindung ist dünnschichtchromatographisch einheitlich. Elemental analysis correct. The compound is by thin layer chromatography uniformly.

Analog verfährt man mit der nach Beispiel 1 C hergestellten Verbindung des Isomerengemisches B. Dabei wird nach Umkristallisieren aus Essigester eine Substanz vom Schmp. 162-1640C, [ /7 = +4,40 (c=1, in Methanol) erhalten. Elementaranalyse korrekt. The procedure for the compound prepared according to Example 1C is analogous of the isomer mixture B. This becomes a substance after recrystallization from ethyl acetate from the M.p. 162-1640C, [/ 7 = +4.40 (c = 1, in methanol) obtained. Elemental analysis correct.

E. N-Benzyloxycarbonyl-L-alanyl-L-dekahydroisochinolin-3-carbonsäure-tert.-butylester (Z-Ala-Dic-OBut) 12,4 g H-Dic-OBut#TosOH, hergestellt nach Beispiel 1D mit Verbindung "A", werden in 250 ml Methylenchlorid gelöst. Man gibt 6,7 g Z-Ala-OH und 4,05 g 1-Hydroxybenzotriazol (HOBt) zu, versetzt mit 4,2 ml N-Ethylmorpholin und tropft unter Rühren bei O° bis 40C die Lösung von 6,6 g Dicyclohexylcarbodiimid (DCC) in 30 ml Methylenchlorid zu. Nach 5 filtriert man, engt das Filtrat zur Trockene ein, nimmt den Rückstand in Essigester auf und wäscht unterhalb 50C mit 10-prozentiger KHSO4/K2SO4 ( 1 : 2), 1M Natriumhydrogencarbonat und Wasser, trocknet über Natriumsulfat und destilliert das Lösungsmittel ab. Harz, leicht löslich in allen organischen Lösungsmitteln. Ausbeute: 15,2 g.E. N-Benzyloxycarbonyl-L-alanyl-L-decahydroisoquinoline-3-carboxylic acid tert-butyl ester (Z-Ala-Dic-OBut) 12.4 g of H-Dic-OBut # TosOH, prepared according to Example 1D with compound "A" are dissolved in 250 ml of methylene chloride. 6.7 g of Z-Ala-OH and 4.05 g are added 1-Hydroxybenzotriazole (HOBt) is added, 4.2 ml of N-ethylmorpholine are added and the mixture is added dropwise while stirring at 0 ° to 40 ° C., the solution of 6.6 g of dicyclohexylcarbodiimide (DCC) in 30 ml of methylene chloride. After 5 it is filtered, the filtrate is concentrated to dryness, takes up the residue in ethyl acetate and washes below 50C with 10 percent KHSO4 / K2SO4 (1: 2), 1M sodium hydrogen carbonate and water, dry over sodium sulfate and the solvent is distilled off. Resin, easily soluble in all organic Solvents. Yield: 15.2 g.

Analog verfährt man mit dem Isomerengemisch B, das auf dieser Stufe mittels präparativer HPLC an Silicagel im Laufmittel Chloroform/Cyclohexan (9:1) aufgetrennt werden kann. The procedure is analogous with isomer mixture B, which is at this stage by means of preparative HPLC on silica gel in the mobile phase chloroform / cyclohexane (9: 1) can be separated.

F. L-Alanyl-L-dekahydroisochinolin-3-carbonsäure-tert.-butylester-tosylat (H-Ala-Dic-OButTosOH) 8,5 g der Z-Verbindung werden analog Beispiel 1D katalytisch hydriert. Der nach dem Abdestillieren des Lösungsmittels zunächst harzige Rückstand kristallisiert nach einiger Zeit oder beim Verreiben mit Essigester und wird zur Analyse aus Essigester umkristallisiert. Schmp.: 151-1530 (Zers.), -i-7D = -28,8° (c=1, in Methanol). Elementaranalyse korrekt.F. L-Alanyl-L-decahydroisoquinoline-3-carboxylic acid tert-butyl ester tosylate (H-Ala-Dic-OButTosOH) 8.5 g of the Z compound are catalytically analogous to Example 1D hydrogenated. The initially resinous residue after the solvent has been distilled off crystallizes after a while or when rubbed with ethyl acetate and becomes Analysis recrystallized from ethyl acetate. M.p .: 151-1530 (dec.), -I-7D = -28.8 ° (c = 1, in methanol). Elemental analysis correct.

Analog wird mit dem Isomerengemisch B verfahren. Man erhält ein nichtkristallisierendes Harz; korrekte Elementaranalyse. The procedure for isomer mixture B is analogous. A non-crystallizing one is obtained Resin; correct elemental analysis.

Analog H-Ala-Dic-OBut werden Alanyl-oktahydroindol-2-2-carbonsäure-t-butylester (H-Ala-Dic-OBut) und die. Alanyl-octahydroindole-2-2-carboxylic acid t-butyl ester (H-Ala-Dic-OBut) and the.

folgenden Verbindungen dargestellt und bevorzugt als Tosylate isoliert -(NMR-Daten auf Base bezogen): 4,9 t (1H); 4,5 -3,0 m (2H); 1,4 s (9H); 1,2 d (3H); 2,0-1,0 m (11H), (H-Ala-Dict Die Ausgangsaminocarbonsäure Oktahydroindol-2-carbonsäure wird wie folgt hergestellt: 45 g Indol-2-carbonsäure werden in 500 ml 4-proz.the following compounds shown and preferably isolated as tosylates - (NMR data based on base): 4.9 t (1H); 4.5-3.0 m (2H); 1.4 s (9H); 1.2 d (3H); 2.0-1.0 m (11H), (H-Ala-Dict The starting aminocarboxylic acid, octahydroindole-2-carboxylic acid is prepared as follows: 45 g of indole-2-carboxylic acid are in 500 ml of 4 percent.

Natronlauge gelöst. Man setzt 20 g Raney-Nickel zu und hydriert 24 Stunden bei 400C. Man filtriert, säuert mit konz. HCl an, saugt von Ungelöstem ab und extrahiert die wässrige Phase mehrfach mit Butanol. Die organische Phase wird eingeengt und chromatographiert.Sodium hydroxide solution dissolved. 20 g of Raney nickel are added and the mixture is hydrogenated 24 Hours at 400C. It is filtered, acidified with conc. HCl on, sucks off undissolved material and the aqueous phase extracted several times with butanol. The organic phase will concentrated and chromatographed.

(CHCl3/Methanol/Eisessig 50:20:5) Ausbeute: 22 g Schmp.: 2600C.(CHCl3 / methanol / glacial acetic acid 50: 20: 5) Yield: 22 g m.p .: 2600C.

Analog werden folgende Verbindungen hergestellt. Die Verbindungen zeigen die folgenden NMR-Signale: 5,1-4,3 m (2H); 3,9-3,0 m (2H); 1,4 s (9H); 2,0-1,0m (12H) für R : H 3,9-3,0 m (4H) 13,1 s(1H); 7,5 s (1H); 6,8 s (1H); 2,8 m (2H) 1,0-2,0 m (15H); 0,9 d (6H) CH2F- 5,1-4,3 m (4H) 7,2 s (5H); 2,7-2,0 m (4H) 1,0-2,0 m (21H) 7,1 s (5H); 2,7 d (2H) 7,8-6,4 m (5H); 2,8 m (2H) HO-CH2- 3,7 d (2H) 7,1 s (5H); 5,0 s (2H); 2,4 m (2H); 2,0-1,0 m (18H) 7,1 s (5H); 5,0 s (2H); 2,4 m (2H); 2,0-1,0 m (20H) 7,1 s(5H); 5,0s (2H); 2,4 m (2H); 2,0-1,0 m (16H) 7,1 s (5H); 5,0 s (2H); 2,3 m (2H) 8,3-7,6 m (2H); 2,9-1,0 m (18H) 8,3-7,6 m (2H); 2,9-2,5 m (2H) 7,1 s (5H); 5,0 s (2H); 2,4 m (2H); 2,0-1,0 m(14H) 7,4 s(1H); 2,5 m (2H); 2,3 s (6H); 2,0-1,0 m (16H) 7,4 s(1H); 2,5 m (2H); 2,3 s (6H) 4,9 m (1H); 4,5-3,0 m (2H); 1,4 s (9H); 2,0-1,0 m (11H) für R : H 3,9-3,0 m (4H) 13,1 s (1H); 7,5 s (1H); 6,8 s (1H); 2,8 m (2H) 1,0-2,0 m (14H); 0,9 d (6H) CH2F- 5,1-4,3 m (4H) 7,2-7,0 m (5H); 2,7-2,0 m(4H) 1,0-2,0 m (20H) 7,1 s (5H); 2,7 d (2H) 7,8-6,4 m (5H); 2,8 m (2H) HO-CH2- 3,7 d (2H) 7,1 s (5H); 5,0 s (2H); 2,4 m (2H); 2,0-1,0 m (17H) 7,1 s (5H); 5,0 s (2H); 2,4 m (2H); 2,0-1,0 m (19H) 7,1 s (5H); 5,0 s (2H); 2,4 m (2H); 2,0-1,0 m (15H) 7,1 s (5H); 5,0 s (2H); 2,3 m (2H) 8,3-7,6 m (2H); 2,9-1,0 m (17H) 8,3-7,6 m (2H); 2,9-2,5 m (2H) 7,1 s (5H); 5,0 s (2H); 2,4 m (2H); 2,0-1,0 m (13H) 7,4 s(111); 2,5 m(2H); 2,3 s (6H); 2,0-1,0 m (15H) 7,4 s(111); 2,5 m (2H); 2,3 s (6H) G. N-(1-Carboxy-3-phenylpropyl)-L-alanyl-L-dekahydroisochinolin-3-carbonsäure-tert.-butylester 305 mg Alanyl-dekahydroisochinolin-3-carbonsäurebutylester (Ala-Dic-OBut) und 445 mg 4-Phenyl-2-oxo-buttersäure werden in 4 ml Methanol gelöst und mit wässriger 1n NaOH auf pH 7,5 gebracht. Man fügt 200 mg Natriumcyanoborhydrid hinzu und läßt 36 Stunden reagieren.The following connections are established analogously. The compounds show the following NMR signals: 5.1-4.3 m (2H); 3.9-3.0 m (2H); 1.4 s (9H); 2.0-1.0m (12H) for R: H 3.9-3.0 m (4H) 13.1 s (1H); 7.5 s (1H); 6.8 s (1H); 2.8 m (2H) 1.0-2.0 m (15H); 0.9 d (6H) CH2F- 5.1-4.3 m (4H) 7.2 s (5H); 2.7-2.0 m (4H) 1.0-2.0 m (21H) 7.1 s (5H); 2.7 d (2H) 7.8-6.4 m (5H); 2.8 m (2H) HO-CH2- 3.7 d (2H) 7.1 s (5H); 5.0 s (2H); 2.4 m (2H); 2.0-1.0 m (18H) 7.1 s (5H); 5.0 s (2H); 2.4 m (2H); 2.0-1.0 m (20H) 7.1 s (5H); 5.0s (2H); 2.4 m (2H); 2.0-1.0 m (16H) 7.1 s (5H); 5.0 s (2H); 2.3 m (2H) 8.3-7.6 m (2H); 2.9-1.0 m (18H) 8.3-7.6 m (2H); 2.9-2.5 m (2H) 7.1 s (5H); 5.0 s (2H); 2.4 m (2H); 2.0-1.0 m (14H) 7.4 s (1H); 2.5 m (2H); 2.3 s (6H); 2.0-1.0 m (16H) 7.4 s (1H); 2.5 m (2H); 2.3 s (6H) 4.9 m (1H); 4.5-3.0 m (2H); 1.4 s (9H); 2.0-1.0 m (11H) for R: H 3.9-3.0 m (4H) 13.1 s (1H); 7.5 s (1H); 6.8 s (1H); 2.8 m (2H) 1.0-2.0 m (14H); 0.9 d (6H) CH2F- 5.1-4.3 m (4H) 7.2-7.0 m (5H); 2.7-2.0 m (4H) 1.0-2.0 m (20H) 7.1 s (5H); 2.7 d (2H) 7.8-6.4 m (5H); 2.8 m (2H) HO-CH2- 3.7 d (2H) 7.1 s (5H); 5.0 s (2H); 2.4 m (2H); 2.0-1.0 m (17H) 7.1 s (5H); 5.0 s (2H); 2.4 m (2H); 2.0-1.0 m (19H) 7.1 s (5H); 5.0 s (2H); 2.4 m (2H); 2.0-1.0 m (15H) 7.1 s (5H); 5.0 s (2H); 2.3 m (2H) 8.3-7.6 m (2H); 2.9-1.0 m (17H) 8.3-7.6 m (2H); 2.9-2.5 m (2H) 7.1 s (5H); 5.0 s (2H); 2.4 m (2H); 2.0-1.0 m (13H) 7.4 s (111); 2.5 m (2H); 2.3 s (6H); 2.0-1.0 m (15H) 7.4 s (111); 2.5 m (2H); 2.3 s (6H) G. N- (1-Carboxy-3-phenylpropyl) -L-alanyl-L-decahydroisoquinoline-3-carboxylic acid tert-butyl ester 305 mg alanyl-decahydroisoquinoline-3-carboxylic acid butyl ester (Ala-Dic -OBut) and 445 mg of 4-phenyl-2-oxo-butyric acid are dissolved in 4 ml of methanol and brought to pH 7.5 with aqueous 1N NaOH. 200 mg of sodium cyanoborohydride are added and the mixture is left to react for 36 hours.

Man engt zur Trockne ein und gewinnt die Substanz durch Säulenchromatographie an Kieselgel (Laufmittelsystem: Chloroform/Methanol/Wasser/Eisessig 20+15+2+1). It is concentrated to dryness and the substance is recovered by column chromatography on silica gel (solvent system: chloroform / methanol / water / glacial acetic acid 20 + 15 + 2 + 1).

Ausbeute: 376 mg; Schmp.: ab 1230 Zers. Yield: 376 mg; M.p .: from 1230 dec.

H. N- (1 -Carboxy-3-phenylpropyl) -L-alanyl-L-dekahydroisochinolin-3-carbonsäure 350 mg N- (1 -Carboxy-3-phenylpropyl) -Ala-Dic-OBut werden in 3 ml wasserfreier Trifluoressigsäure gelöst und 30 Minuten bei Raumtemperatur belassen. Man engt im Vakuum ein und verreibt das hinterbleibende Cl mit kaltem Diisopropyläther und Petroläther.H. N- (1-Carboxy-3-phenylpropyl) -L-alanyl-L-decahydroisoquinoline-3-carboxylic acid 350 mg of N- (1-carboxy-3-phenylpropyl) -Ala-Dic-OBut become anhydrous in 3 ml Trifluoroacetic acid dissolved and left at room temperature for 30 minutes. One constricts in Vacuum and rub the remaining Cl with cold diisopropyl ether and petroleum ether.

Ausbeute: 226 mg amorphe Substanz NMR: 7,10 (s); 3,0-3,9 (m, breit); 1,23 und 1,15 (d); 2,0-1,0 (m, breit) Beispiel 2 N- (Carbethoxy- 3-phenyl-propyl) -L-alanyl-L-dekahydroisochinolin-3-carbonsäure Man löst 4,83 g H-Ala-Dic-OBut TosOH in 40 ml absol. Yield: 226 mg of amorphous substance NMR: 7.10 (s); 3.0-3.9 (m, broad); 1.23 and 1.15 (d); 2.0-1.0 (m, wide) Example 2 N- (Carbethoxy- 3-phenyl-propyl) -L-alanyl-L-decahydroisoquinoline-3-carboxylic acid Dissolve 4.83 g of H-Ala-Dic-OBut TosOH in 40 ml absolute

Ethanol, stellt mit KOH in Ethanol auf pH 7 und gibt 6,2 g 2-Oxo-4-phenylbuttersäure-ethylester zu und rührt in Anwesenheit von 9 g pulverisiertem Molekularsieb 4 i unter langsamer Zugabe von einer Lösung von 2 g Natriumcyanoborhydrid in 15 ml absol. Ethanol. Nach etwa 20 h wird filtriert und das Lösungsmittel im Vakuum abdestilliert. Der Rückstand wird zwischen Essigester und Wasser verteilt, die Essigesterphase abgetrennt und im Vakuum zur Trockene gebracht. Der Rückstand wird an Silicagel im Laufmittel Essigester/Cyclohexan (1:2 bis 1:4) chromatographiert.Ethanol, adjusts to pH 7 with KOH in ethanol and gives 6.2 g of ethyl 2-oxo-4-phenylbutyrate and stir in the presence of 9 g of pulverized molecular sieve 4 i under slower Addition of a solution of 2 g of sodium cyanoborohydride in 15 ml of absol. Ethanol. To It is filtered for about 20 hours and the solvent is distilled off in vacuo. The residue is distributed between ethyl acetate and water, the ethyl acetate phase is separated off and brought to dryness in vacuo. The residue is on silica gel in the mobile phase ethyl acetate / cyclohexane (1: 2 to 1: 4) chromatographed.

Das Produkt wird 30 min. in 20 ml Trifluoressigsäure gelöst. Man destilliert die Trifluoressigsäure im Vakuum ab, destilliert mit Toluol nach und chromatographiert über Silicagel in Methylenchlorid/Methanol (10:1).The product is dissolved in 20 ml of trifluoroacetic acid for 30 minutes. One distills the trifluoroacetic acid from in vacuo, distilled with toluene and chromatographed over silica gel in methylene chloride / methanol (10: 1).

Ausbeute: 1,8 g.Yield: 1.8 g.

Beispiel 3 a.) 2- (2-Oxo-propionyl) -L-dekahydroisochinolin-3-carbonsäure-tert.-butylester In eine auf -500C gekühlte Lösung von 700 mg Dic-OBut und 630 mg Dicyclohexylcarbodiimid in 15 ml wasserfreiem Chloroform wird eine gekühlte und frisch destillierte Lösung von 270 mg Brenztraubensäure in 5 ml Chloroform rasch eingerührt. Man beläßt 16 Stunden im Tiefkühlschrank (-200C) und filtriert den ausgefallenen DC-Harnstoff ab. Die Lösung wird mit KHSO4 - und anschließend mit KHCO3-Lösung gewaschen, über Na2SO4 getrocknet und im Vakuum eingeengt. Die Verbindung (öl) enthält etwas Dicyclohexylharnstoff; sie wurde zur Analyse über Kieselgel im System CHCl3/CH30H 15:1 chromatographiert.Example 3 a.) 2- (2-Oxo-propionyl) -L-decahydroisoquinoline-3-carboxylic acid tert-butyl ester In a solution of 700 mg Dic-OBut and 630 mg dicyclohexylcarbodiimide, cooled to -500C in 15 ml of anhydrous chloroform is a cooled and freshly distilled solution of 270 mg of pyruvic acid in 5 ml of chloroform quickly stirred. Leave 16 Hours in the freezer (-200C) and filtered the precipitated DC urea away. The solution is washed with KHSO4 - and then with KHCO3 solution, over Na2SO4 dried and concentrated in vacuo. The compound (oil) contains some dicyclohexylurea; it was chromatographed for analysis over silica gel in the system CHCl3 / CH30H 15: 1.

Analog der Kondensation Brenztraubensäure mit Dic-OBut werden folgende Kondensationsprodukte mit der entsprechenden « -Ketocarbonsäure dargestellt. Analogously to the condensation of pyruvic acid with Dic-OBut, the following condensation products with the corresponding -ketocarboxylic acid are prepared.

4,9 m (1H); 4,2-3,5 m (1H); 3,0-1,2 m (11EI); 2,4 s (3H); 1,4 s (9H) bei nachstehenen Verbindungen werden einheitlich folgende Signale für das Grundgerüst beobachtet: 5,1-4,8m (1H); 3,9-3,0m (2H); 1,4 s (9H); 2,0-1,0m (12H) 13,1 s (1H); 7,5 s (1H); 6,8s (1H); 3,9-3,0 m (4H) 2,4-1,0 m (21H) 7,2-7,0 m (5H); 2,5 m (2H) CH2F- 4,4 s (2H) 7c15 (5H); 3,0 s (2H) 2,4-1,0 m (23H) 7,8-6,4 m (5H); 3,9-2,9 m(4H) b.) N- (1 -Carboxy-3-phenyl-3-thiapropyl) -alanyl-L-dekahydroisochinolin-3-carbonsäure-tert. -butylester 1,52 g Propyl-Dic-OBut und 394 mg S-Phenyl-cystein werden in 5 ml Methanol gelöst und mit 1n NaOH (wässrig) auf pH 7,0 gebracht. Man fügt 400 mg Natriumcyanoborhydrid zu und beläßt 24 Stunden bei Raumtemperatur. Man engt im Vakuum ein, nimmt in Chloroform auf, trocknet über Natriumsulfat und engt ein. Das Produkt wird durch Kieselgelchromatographie (System CHCl3/CH3OH/HAcO/H2O 50/20/5/1) rein erhalten.4.9 m (1H); 4.2-3.5 m (1H); 3.0-1.2 m (11EI); 2.4 s (3H); 1.4 s (9H) in the following compounds, the following signals are uniformly observed for the basic structure: 5.1-4.8m (1H); 3.9-3.0m (2H); 1.4 s (9H); 2.0-1.0m (12H) 13.1 s (1H); 7.5 s (1H); 6.8s (1H); 3.9-3.0 m (4H) 2.4-1.0 m (21H) 7.2-7.0 m (5H); 2.5 m (2H) CH2F- 4.4 s (2H) 7c15 (5H); 3.0 s (2H) 2.4-1.0 m (23H) 7.8-6.4 m (5H); 3.9-2.9 m (4H) b.) N- (1-Carboxy-3-phenyl-3-thiapropyl) -alanyl-L-decahydroisoquinoline-3-carboxylic acid tert. -butyl ester 1.52 g of propyl-Dic-OBut and 394 mg of S-phenyl-cysteine are dissolved in 5 ml of methanol and brought to pH 7.0 with 1N NaOH (aqueous). 400 mg of sodium cyanoborohydride are added and the mixture is left at room temperature for 24 hours. It is concentrated in vacuo, taken up in chloroform, dried over sodium sulfate and concentrated. The product is obtained in pure form by silica gel chromatography (system CHCl3 / CH3OH / HAcO / H2O 50/20/5/1).

NMR: 7,3 m (5H); 5,1-4,8 m (1H); 3,9-3,0 m (4H); 2,5 m (2H) c.) N- (1-Carboxy-3-phenyl-3-thiapropyl) -alanyl-L-dekahydroisochinolin- 3-carbonsäure 1 g Butylester aus Beispiel 21 wird in 5 ml Trifluoressigsäure gelöst. Man engt nach 30 Minuten im Vakuum ein, digeriert den Rückstand mit Diisopropyläther und trocknet über Kaliumhydroxyd. NMR: 7.3 m (5H); 5.1-4.8 m (1H); 3.9-3.0 m (4H); 2.5 m (2H) c.) N- (1-Carboxy-3-phenyl-3-thiapropyl) -alanyl-L-decahydroisoquinoline-3-carboxylic acid 1 g of butyl ester from Example 21 is dissolved in 5 ml of trifluoroacetic acid. One constricts after 30 minutes in vacuo, the residue digested with diisopropyl ether and dries over potassium hydroxide.

Ausbeute: 0,95 g Trifluoracetat (hygroskopisch) NMR: 7,3 m (5H); 5,2-4,8 m (1H); 3,9-3,0 m (4H); 2,5 m (2H); 1,25 m (3H) Beispiel 4 N- (1 -Carboxy-3-phenyl-propyl) -L-alanyl-L-dekahydroisochinolin- 3-carbonsäure 880 mg N- (1-Carbethoxy-3-phenyl-propyl) -L-alanyl-L-dekahydroisochinolin-3-carbonsäure werden in 20 ml Dioxan/ Wasser (9:1) gelöst und bei Raumtemperatur mit 4,5 ml in Natriumhydroxid-Lösung verseift. Nach einer Stunde wird die Lösung mit der äquivalenten Menge 1 n Salzsäure angesäuert und das Dioxan weitgehend abgedampft. Der Rückstand wird mehrfach mit Essigester extrahiert und die organische Phase nach Abziehen des Lösungsmittels über einen Kationenaustauscher (DOWEX 50) chromatographiert. Yield: 0.95 g trifluoroacetate (hygroscopic) NMR: 7.3 m (5H); 5.2-4.8 m (1H); 3.9-3.0 m (4H); 2.5 m (2H); 1.25 m (3H) Example 4 N- (1-Carboxy-3-phenyl-propyl) -L-alanyl-L-decahydroisoquinoline- 3-carboxylic acid 880 mg N- (1-carbethoxy-3-phenyl-propyl) -L-alanyl-L-decahydroisoquinoline-3-carboxylic acid are dissolved in 20 ml of dioxane / water (9: 1) dissolved and saponified at room temperature with 4.5 ml in sodium hydroxide solution. To one hour the solution is acidified with the equivalent amount of 1N hydrochloric acid and the dioxane largely evaporated. The residue is repeatedly washed with ethyl acetate extracted and the organic phase after stripping off the solvent on a Cation exchanger (DOWEX 50) chromatographed.

Ausbeute: 630 mg.Yield: 630 mg.

Beispiel 5 N- (1 -Carboxy-5-aminopentyl) -L-alanyl-L-dekahydroisochinolin- 3-carbonsäure 1,2 g N- (1-Carboxy-5-Boc-aminopentyl)-L-alanyl-L-dekahydroisochinolin-3-carbonsäure wurden mit 10 ml eiskalter Trifluoressigsäure übergossen und eine Stunde bei Raumtemperatur gerührt. Anschließend wird im Vakuum eingedampft.Example 5 N- (1 -Carboxy-5-aminopentyl) -L-alanyl-L-decahydroisoquinoline- 3-carboxylic acid 1.2 g of N- (1-carboxy-5-Boc-aminopentyl) -L-alanyl-L-decahydroisoquinoline-3-carboxylic acid were poured with 10 ml of ice-cold trifluoroacetic acid and one hour at room temperature touched. It is then evaporated in vacuo.

Der Rückstand wird in Wasser gelöst und einer Gefrier- trocknung unterworfen.The residue is dissolved in water and a freezer drying subject.

Ausbeute: 0,90 g.Yield: 0.90 g.

Beispiel 6 N-(1-Carbethoxy-3-amino-propyl)-L-alanyl-L-dekahydroisochinolin- 3-carbonsäure 1 , 1 g N- (1 -Carbethoxy-3-benzoxycarbonylamino-propyl) -L-alanyl-L-dekahydroisochinolin-3-carbonsäure werden in 150 ml Methanol gelöst und in Gegenwart von 100 mg Palladium - Aktivkohle (10 teig) bei 400C unter Normaldruck hydriert. Nach Beendigung der Reaktion wird vom Katalysator abfiltriert und das Lösungsmittel im Vakuum abgezogen.Example 6 N- (1-Carbethoxy-3-aminopropyl) -L-alanyl-L-decahydroisoquinoline- 3-carboxylic acid 1.1 g of N- (1-carbethoxy-3-benzoxycarbonylamino-propyl) -L-alanyl-L-decahydroisoquinoline-3-carboxylic acid are dissolved in 150 ml of methanol and in the presence of 100 mg of palladium - activated carbon (10 dough) hydrogenated at 400C under normal pressure. After completion of the reaction will the catalyst is filtered off and the solvent is stripped off in vacuo.

Ausbeute: 0,79 g.Yield: 0.79 g.

NMR: 5,1-4,8 m (1H); 3,9-2,5 m (6H); 2,0-1,0 m (14H); 1,2 d (3H).NMR: 5.1-4.8 m (1H); 3.9-2.5 m (6H); 2.0-1.0 m (14H); 1.2 d (3H).

Beispiel 7 N (1 -Carbethoxy-2-benzylsulfinylethyl) -L-alanyl-L-dekahydroisochinolin-3-carbonsäure Zu einer unter Eiskühlung gerührten Mischung von 0,64 g Natriumperjodat und 20 ml Wasser werden 1,3 g N-(1-Carbethoxy-2-benzyl-thio-ethyl) -L-alanyl-L-dekahydroisochinolin-3-carbonsäure gelöst in 20 ml Methanol gegeben.Example 7 N (1-carbethoxy-2-benzylsulfinylethyl) -L-alanyl-L-decahydroisoquinoline-3-carboxylic acid To a mixture of 0.64 g of sodium periodate and 20 ml, stirred while cooling with ice 1.3 g of N- (1-carbethoxy-2-benzyl-thio-ethyl) -L-alanyl-L-decahydroisoquinoline-3-carboxylic acid become water dissolved in 20 ml of methanol.

Man läßt die Reaktionsmischung für 24 Stunden bei OOC rühren und filtriert anschließend vom Natriumjodat ab.The reaction mixture is allowed to stir for 24 hours at OOC and filtered then from sodium iodate.

Das Filtrat wird mehrfach mit Methylenchlorid extrahiert.The filtrate is extracted several times with methylene chloride.

Nach Entfernen des Lösungsmittels erhält man 1,1 g des Sulfoxids. Im NMR-Spektrum werden folgende Signale beobachtet: 7,3 m (5H); 5,1-4,8 m (1H); 4,1 s (1H); 3,9-3,0 m (4H); 2,6 m (2H); 1,2 d (3H).After removing the solvent, 1.1 g of the sulfoxide are obtained. The following signals are observed in the NMR spectrum: 7.3 m (5H); 5.1-4.8 m (1H); 4.1 s (1H); 3.9-3.0 m (4H); 2.6 m (2H); 1.2 d (3H).

Beispiel 8 N-(1-Carbethoxy-3-phenylsulfonyl-propyl)-L-alanyl-L-dekahydroisochinolin-3-carbonsäure 260 mg N- (1-Carbethoxy-3-phenylthio-propyl) -L-alanyl-L-dekahydroisochinolin-3-carbonsäure und 20 mg Natriumwolframat Dihydrat werden in 50 ml Wasser gegeben und tropfenweise mit 1 ml Perhydrol (30 Zig) versetzt. Die Mischung wird für 30 min auf 80"C erwärmt und anschließend eine Stunde bei Raumtemperatur gerührt. Das überschüssige Peroxid wird sodann mit Palladium auf Bariumsulfat zerstört und nach Beendigung der Sauerstoffentwicklung wird die Lösung vom Palladium Katalysator abfiltriert und eingeengt. Das Rohprodukt wird durch Ionenaustauschchromatographie über DOWEX 50 H+-Form gereinigt.Example 8 N- (1-Carbethoxy-3-phenylsulfonyl-propyl) -L-alanyl-L-decahydroisoquinoline-3-carboxylic acid 260 mg of N- (1-carbethoxy-3-phenylthio-propyl) -L-alanyl-L-decahydroisoquinoline-3-carboxylic acid and 20 mg of sodium tungstate dihydrate are added to 50 ml of water and added dropwise with 1 ml of Perhydrol (30 Zig) added. The mixture is heated to 80 ° C. for 30 minutes and then stirred for one hour at room temperature. The excess peroxide is then destroyed with palladium on barium sulfate and after the evolution of oxygen has ceased the solution is filtered off from the palladium catalyst and concentrated. The raw product is purified by ion exchange chromatography over DOWEX 50 H + form.

Ausbeute: 220 mg NMR: 7,7 m (5H); 5,1-4,8 m (1H); 3,9-3,0 m (4H); 2,8 m (2H) 1,5 m (2H); 1,2 d (3H) Beispiel 9 N- (2-Amino-1-carboxypropyl) -L-alanyl-L-dekahydroisochinolin-3-carbonsäure ß 2,2 g N -Boc- 9,ß-Diaminobuttersäure, hergestellt nach Coll. czeck. chem. Commun. 31, 2955 (1966) analog der N -Boc-Verbindung, werden mit 2,4 g Pyruvyl-Dic-OBut, hergestellt nach Beispiel 3 a, in der in'Beispiel 3 b beschriebenen Weise umgesetzt. Die Boc-Schutzgruppe wird anschließend nach der in Beispiel 14 beschriebenen Weise abgespalten.Yield: 220 mg NMR: 7.7 m (5H); 5.1-4.8 m (1H); 3.9-3.0 m (4H); 2.8 m (2H) 1.5 m (2H); 1,2 d (3H) Example 9 N- (2-Amino-1-carboxypropyl) -L-alanyl-L-decahydroisoquinoline-3-carboxylic acid ß 2.2 g N -Boc- 9, ß-diaminobutyric acid, prepared according to Coll. czeck. chem. Commun. 31, 2955 (1966) analogous to the N -Boc compound, with 2.4 g of pyruvyl-Dic-OBut, prepared according to Example 3a, implemented in the manner described in Example 3b. The Boc protecting group is then added according to the manner described in Example 14 cleaved.

Ausbeute: 2,6 g.Yield: 2.6 g.

NMR: 5,1-4,8 m (1H); 3,9-3,0 m (5H); 2,0-1,0 m (15H) 1,2 d (3H).NMR: 5.1-4.8 m (1H); 3.9-3.0 m (5H); 2.0-1.0 m (15H) 1.2 d (3H).

Beispiel 10 L-N-(1-Carbethoxy-5-aminopentyl)--L-alanyl-L-dekahydroisochinolin- 3-carbonsäure t a) 35 g N -Benzyloxycarbonyl-L-lysin-ethylester-hydrochlorid und 30,6 g ol -Brompropionsäure werden in einer Mischung aus 350 ml Dioxan, 50 ml Ethanol und 75 ml 4N NaOH gelöst. Man rührt über Nacht bei Raumtemperatur unter Konstanthalten des pH bei 8.8-9 am Autotitrator, bringt dann mit wenig HCl auf pH 7-8 und destilliert das Lösungsmittel im Vakuum ab. Der Rückstand wird in möglichst wenig Wasser gelöst und die Lösung mit Salzsäure auf pH 5-6 gebracht. Man kühlt mit Eis und filtriert den Niederschlag nach kurzem Stehen ab, wäscht mit wenig eiskaltem Wasser und Ether und trocknet im Vakuum. Man kann die wässrige Lösung auch über schwach basischem Ionenaustauscher in das Zwitterion überführen und reinigen. Das Filtrat wird dann einfach lyophilisiert. Ausbeute: 12,9 g (52 %).Example 10 L-N- (1-Carbethoxy-5-aminopentyl) - L-alanyl-L-decahydroisoquinoline- 3-carboxylic acid t a) 35 g of N -benzyloxycarbonyl-L-lysine ethyl ester hydrochloride and 30.6 g of ol-bromopropionic acid are added to a mixture of 350 ml of dioxane and 50 ml of ethanol and 75 ml of 4N NaOH dissolved. The mixture is stirred overnight at room temperature while keeping constant the pH at 8.8-9 on the autotitrator, then brings it to pH 7-8 with a little HCl and distilled the solvent off in vacuo. The residue is dissolved in as little water as possible and the solution is brought to pH 5-6 with hydrochloric acid. It is cooled with ice and filtered the precipitate after standing for a short time, washed with a little ice-cold water and ether and dries in a vacuum. You can use the aqueous solution over weakly basic Transfer the ion exchanger into the zwitterion and clean it. The filtrate is then simply lyophilized. Yield: 12.9 g (52%).

b) Man löst die Verbindung in 100 ml Dimethylformamid und versetzt nacheinander bei Raumtemperatur mit 23 g H-Dic-OBzl; TosOH (in üblicher Weise aus der Aminosäure durch Kochen in Benzylalkohol-Toluol-Toluolsulfonsäure unter Rückfluß und Wasserabscheidung hergestellt), 6,5 ml N-Ethylmorpholin, 6,8 g 1-Hydroxybenzotriazol und 11 g Dicyclohexylcarbodiimid. Nach 4 h Rühren wird vom Harnstoff abfiltriert, das Lösungsmittel im Vakuum abdestilliert und der Rückstand in Cyclohexan-Essigester (4:1) an Silicagel chromatographiert. Dabei tritt Auftrennung der Diastereoisomeren ein. Die einheitlichen Fraktionen, welche die Titelverbindung enthalten, werden gesammtelt, das Lösungsmittel wird im Vakuum abdestilliert.b) The compound is dissolved in 100 ml of dimethylformamide and mixed one after the other at room temperature with 23 g of H-Dic-OBzl; TosOH (in the usual way from the amino acid by refluxing in benzyl alcohol-toluene-toluenesulfonic acid and water separation), 6.5 ml of N-ethylmorpholine, 6.8 g of 1-hydroxybenzotriazole and 11 g of dicyclohexylcarbodiimide. After stirring for 4 h, the urea is filtered off, the solvent is distilled off in vacuo and the residue is dissolved in cyclohexane-ethyl acetate Chromatographed (4: 1) on silica gel. Separation of the diastereoisomers occurs a. The uniform fractions containing the title compound are collected, the solvent is distilled off in vacuo.

c) Der Rückstand wird in Methanol aufgenommen, an Pd/Kohle katalytisch hydriert und ggfs. nach Abfiltrieren des Katalysators durch Einstellen des pH auf 3 in Hydrochlorid überführt. Abdestillieren des Lösungsmittels und Trocknen des Rückstandes im Vakuum.c) The residue is taken up in methanol on Pd / charcoal catalytic hydrogenated and, if necessary, after filtering off the catalyst by adjusting the pH 3 converted into hydrochloride. Distilling off the solvent and drying the Residue in vacuo.

Beispiel 11 L-N-(1-Carbethoxy-3-phenylpropsFl)-L-alanyl-L-oktahydroindolin-2-carbonsäure a) 55 g 2-Brom-4-phenyl-n-buttersäureäthylester, 14,5 g L-Alanin-t-butylester und 45 ml Triethylamin werden 24 h in Tetrahydrofuran aufbewahrt. Man destilliert das Lösungsmittel im Vakuum ab, verteilt den Rückstand zwischen Wasser und Essigester, trennt die Essigesterschicht ab, trocknet über Natriumsulfat und destilliert das Lösungsmittel im Vakuum ab. Der Rückstand wird in Cyclohexan-Essigester (4:1) über Silicagel chromatographiert, wobei neben der Reinigung auch Diastereoisomerentrennung eintritt. Nach Einengen der entsprechenden Fraktionen wird der t-Butylester durch 20 min. Aufbewahren der Verbindung in Trifluoressigsäure abgespalten. Man destilliert die Trifluoressigsäure im Vakuum ab und destilliert mit Toluol im Vakuum nach.Example 11 L-N- (1-Carbethoxy-3-phenylpropsFl) -L-alanyl-L-octahydroindoline-2-carboxylic acid a) 55 g of 2-bromo-4-phenyl-n-butyric acid ethyl ester, 14.5 g of L-alanine-t-butyl ester and 45 ml of triethylamine are stored in tetrahydrofuran for 24 hours. You distill that The solvent is removed in vacuo, the residue is distributed between water and ethyl acetate, separates the ethyl acetate layer, dries over sodium sulfate and distilled it Solvent in vacuo. The residue is dissolved in cyclohexane-ethyl acetate (4: 1) Chromatographed silica gel, with the addition of purification and separation of diastereoisomers entry. After concentration of the appropriate fractions, the t-butyl ester is through The compound is split off in trifluoroacetic acid for 20 min. One distills the trifluoroacetic acid from in vacuo and distilled with toluene in vacuo.

b) Nun setzt man analog Beispiel 10 b in Dimethylformamid mit 11 g Oktahydroindol-2-carbonsäure-benzylestertosylat, 3,2 ml N-Ethylmorpholin, 3,3. g 1-Hydroxybenzotriazol und 5,5 g Dicyclohexylcarbodiimid um, arbeitet wie dort beschrieben auf und trennt die Diastereomeren durch Chromatographie an Silicagel im System Cyclohexan:Essigester (4:1) auf. Von der chromatographisch einheitlichen Verbindung wird der Benzylester durch katalytische Hydrierung abgespalten.b) Now, as in Example 10b, 11 g are added to dimethylformamide Octahydroindole-2-carboxylic acid benzyl ester tosylate, 3.2 ml of N-ethylmorpholine, 3.3. G 1-Hydroxybenzotriazole and 5.5 g of dicyclohexylcarbodiimide work as described there and separates the diastereomers by chromatography on silica gel in the system cyclohexane: ethyl acetate (4: 1). The benzyl ester is obtained from the chromatographically uniform compound split off by catalytic hydrogenation.

Beispiel 12 L-N-W-Carbethoxy-4- (4, 6-dimethyl-pyrimidyl-2-amino)-butyl7-L-alanyl-L-dekahydroisochinolin-3-carbonsäure a) 15,3 g OL-Brompropionsäure und 41,1 g H-Dic-OBut TosOH werden in 300 ml Tetrahydrofuran in Anwesenheit von 12,8 ml N-Ethylmorpholin und 1,35 g 1-Hydroxybenzotriazol mittels 22 g Dicyclohexylcarbodiimid kondensiert. Nach 4 h wird der Harnstoff abfiltriert und das Lösungsmittel im Vakuum abdestilliert. Man nimmt den Rückstand in Essigester auf, wäscht die Lösung mit Natriumhydrogencarbonat- und Citronensäurelösung und mit Wasser, trocknet die Essigesterlösung über Natriumsulfat und destilliert das Lösungsmittel im Vakuum ab.Example 12 L-N-W-Carbethoxy-4- (4,6-dimethyl-pyrimidyl-2-amino) -butyl7-L-alanyl-L-decahydroisoquinoline-3-carboxylic acid a) 15.3 g of OL-bromopropionic acid and 41.1 g of H-Dic-OBut TosOH are in 300 ml of tetrahydrofuran in the presence of 12.8 ml of N-ethylmorpholine and 1.35 g of 1-hydroxybenzotriazole means 22 g of dicyclohexylcarbodiimide condensed. After 4 hours, the urea is filtered off and the solvent is distilled off in vacuo. The residue is taken in ethyl acetate on, washes the solution with sodium hydrogen carbonate and citric acid solution and with water, the ethyl acetate solution is dried over sodium sulfate and distilled Solvent in vacuo.

b) 3,75 g d -Brompropionyl-Dic-OBut werden in 20 ml Tetrahydrofuran mit 2,5 g N -(4,6-Dimethyl-pyrimidyl-2)-L-ornithin-ethylester unter Zusatz von 1 ml Diisopropylethylamin bei Raumtemperatur umgesetzt.b) 3.75 g of d -bromopropionyl-Dic-OBut are in 20 ml of tetrahydrofuran with 2.5 g of N - (4,6-dimethyl-pyrimidyl-2) -L-ornithine ethyl ester with the addition of 1 ml of diisopropylethylamine reacted at room temperature.

Nach 24 h wird das Lösungsmittel im Vakuum abdestilliert, der Rückstand in Essigester aufgenommen, die Lösung mit Wasser gewaschen, über Natriumsulfat getrocknet und im Vakuum eingeengt. Der Rückstand wird analog Beispiel (11b) unter Diastereoisomerentrennung chromatographiert. Der t-Butylester wird durch Lösen der Verbindung in Dioxan/HCl gespalten. Nach 10-1-5 min destilliert man das Lösungsmittel ab und trocknet den Rückstand scharf im Vakuum über KOH. Die Verbindung liegt als Hydrochlorid vor. After 24 h the solvent is distilled off in vacuo, the residue taken up in ethyl acetate, the solution washed with water and dried over sodium sulfate and concentrated in vacuo. The residue is prepared analogously to Example (11b) with separation of diastereoisomers chromatographed. The t-butyl ester is obtained by dissolving the compound in dioxane / HCl split. After 10-1-5 min, the solvent is distilled off and the The residue is sharp in vacuo over KOH. The compound is in the form of a hydrochloride.

Beispiel 13 N- (1-S-Carb ethoxy -3-phenyl-propyl) -S-alanyl-cisoctahydroindol-2-S-carbonsäure a) N (1 -S-Carb ethoxy -3-phenyl-propyl) -alanin-benzylester Durch Extraktion mit Essigester wird aus einer wässr.Example 13 N- (1-S-Carbethoxy -3-phenyl-propyl) -S-alanyl-cisoctahydroindole-2-S-carboxylic acid a) N (1 -S-Carbethoxy -3-phenyl-propyl) -alanine-benzyl ester By Extraction with ethyl acetate is carried out from an aq.

Sodalösung von 70 g Alanin-benzylester-Toluolsulfonat die freie Base gewonnen. Man versetzt die über wasserfreiem Natriumsu3fatgetrocknete organische Phase mit 200 ml Dimethylacetamid (DMA) und engt bei RT im Wasserstrahlvakuum ein. Nach Zugabe von 90 g Ct -Brom--phenyl-buttersäureethylester und 40 ml N-Äthylmorpholin wird die Lösung 4 Tage bei RT belassen. Die Reaktion wird dünnschichtchromatographisch auf Kieselgelplatten (System: Cyclohexan/Essigester 2:1) verfolgt. Man engt im Vakuum bis fast zur Trockne ein, stellt mit 2n methanolischer Salzsäure auf pH 3 und setzt 10 ml Wasser zu. Man extrahiert überschüssigen Bromester und lipophile Produkte in Petroläther, engt die methanolische Phase ein, fügt 3 % Sodalösung (250 ml) zu und extrahiert die Reaktionsprodukte in ein Essigester/Äther-Gemisch (1:1). Nach Trocknung über festem Natriumsulfat wird eingeengt und mit Hilfe einer Kieselgelchromatographie (System Cyclohexan/Essigester 4:1) eine Reinigung und Diastereomerentrennung vorgenommen. Die S,S-Verbindung weist einen niedrigeren Rf-Wert auf und fällt in überwiegender Menge an (48%). Soda solution of 70 g of alanine benzyl ester toluenesulfonate the free base won. The organic, dried over anhydrous sodium sulfate, is added Phase with 200 ml of dimethylacetamide (DMA) and concentrate at RT in a water-jet vacuum. After adding 90 g of Ct -Bromo-phenyl-butyric acid ethyl ester and 40 ml of N-Ethylmorpholine the solution is left at RT for 4 days. The reaction is carried out by thin layer chromatography followed on silica gel plates (system: cyclohexane / ethyl acetate 2: 1). It is concentrated in a vacuum almost to dryness, adjusts to pH 3 with 2N methanolic hydrochloric acid and sets Add 10 ml of water. Excess bromine ester and lipophilic products are extracted in petroleum ether, the methanolic phase is concentrated, 3% soda solution (250 ml) is added and extracted the reaction products into an ethyl acetate / ether mixture (1: 1). To Drying over solid sodium sulfate is concentrated and using silica gel chromatography (System cyclohexane / ethyl acetate 4: 1) carried out a purification and separation of diastereomers. The S, S link has a lower Rf value and falls predominantly Amount of (48%).

Die ölige Substanz wird sofort weiter verarbeitet. The oily substance is processed further immediately.

b) N(1-S-Carbethoxy -3-phenyl-propyl)-S-alanin 37 g des Benzylesters werden in 250 ml Ethanol aufgenommen und mit 1 g Pd/Kohle (10 % Pd) bei Normaldruck in 2 Stunden hydrogenolytisch entbenzyliert. Man filtriert den Katalysator ab, engt im Vakuum fast zur Trockene ein und fällt durch Zusatz von Petroläther.b) N (1-S-Carbethoxy -3-phenyl-propyl) -S-alanine 37 g of the benzyl ester are taken up in 250 ml of ethanol and treated with 1 g of Pd / charcoal (10% Pd) at normal pressure hydrogenolytically debenzylated in 2 hours. The catalyst is filtered off and concentrated almost to dryness in a vacuum and falls by adding petroleum ether.

Ausbeute: 33 g; amorph; NMR: 1,18 (d, 3H); 1,18 (t, 3H); 1,5-2,1 (m, 2H);-2,4-2,8 (m, 2H); 3,0-3,4 (2 m, je 1 H); 4,07 (q, 2H); 4,3-5,5 (b, 2H); 7,17 (s, 5H). DMSO-d6 c) N- (1-s- Carbethoxy -3-phenyl-propyl) -S-alanyl-cisoctahydroindol-2-R,S-carbonsäurebenzylester 5 g N-(1-S- Carbethoxy -3-phenyl-propyl)-S-alanin werden in 20 ml DMF gelöst. Man fügt 2,45 g 1-Hydroxybenzotriazol, 5,1 g cis-Octahydroindol-R,S-carbonsäurebenzylester-hydrochlorid, 2,5 ml N-Ethylmorpholin sowie 4 g Dicyclohexylcarbodiimid zu und rührt 3 Stunden bei Raumtemperatur. Man verdünnt mit 30 ml Essigester und saugt vom Harnstoff ab. Mach Einengen im Vakuum wird in 100 ml Äther aufgenommen und mit wässr. Bicarbonatlösung 2 x extrahiert. Die über Natriumsulfat getrocknete und zur Trockene eingeengte organische Phase wird an Kieselgel chromatographiert. Man eluiert mit Essigester/Petroläther 4:3 und erhält 2 Fraktionen, aus denen durch Einengen im Vakuum farblose Öle erhalten werden. Yield: 33 g; amorphous; NMR: 1.18 (d, 3H); 1.18 (t, 3H); 1.5-2.1 (m, 2H); - 2.4-2.8 (m, 2H); 3.0-3.4 (2 m, 1H each); 4.07 (q, 2H); 4.3-5.5 (b, 2H); 7.17 (s, 5H). DMSO-d6 c) N- (1-s-carbethoxy -3-phenyl-propyl) -S-alanyl-cisoctahydroindole-2-R, S-carboxylic acid benzyl ester 5 g of N- (1-S-carbethoxy -3-phenyl-propyl) -S-alanine are dissolved in 20 ml of DMF. 2.45 g of 1-hydroxybenzotriazole are added, 5.1 g of cis-octahydroindole-R, S-carboxylic acid benzyl ester hydrochloride, 2.5 ml of N-ethylmorpholine and 4 g of dicyclohexylcarbodiimide and stirred for 3 hours at room temperature. Man diluted with 30 ml of ethyl acetate and sucks off the urea. Do constricting in a vacuum is taken up in 100 ml of ether and washed with aq. Bicarbonate solution extracted 2 x. The organic phase, dried over sodium sulfate and concentrated to dryness is chromatographed on silica gel. It is eluted with ethyl acetate / petroleum ether 4: 3 and receives 2 fractions from which colorless oils are obtained by concentration in vacuo will.

Elementaranalyse: C 11 N ber. für C31H40N2°5 71.5 7.7 5.4 -Ausb. Elemental analysis: C 11 N calc. For C31H40N2 ° 5 71.5 7.7 5.4 -Ausb.

Frakt. 1 71.3 7.8 5.3 3.3 g Frakt. 2 71.6 7.6 5.6 3.9 g d) N- (1-S-Carbethoxy -3-phenyl-propyl)-S-alanyl-cisoctahydroindol-2-S-carbonsäure 3 g des Benzylesters (Fraktion 2) werden in Ethanol gelöst und mit 200 mg 10 % Pd/Kohle bei Normaldruck hydrogenolytisch entbenzyliert. Nach beendeter Wasserstoffaufnahme (etwa 1 Stunde) wird vom Katalsator abfiltriert und die Lösung im Vakuum eingeengt. Man versetzt mit etwas Pentan, erwärmt auf etwa 450C und legt ein kräftiges Vakuum an. Es bildet sich ein amorpher, fester Schaum. Ausb,: 2,4 g. Fraction 1 71.3 7.8 5.3 3.3 g Fraction 2 71.6 7.6 5.6 3.9 g d) N- (1-S-carbethoxy -3-phenyl-propyl) -S-alanyl-cisoctahydroindole-2-S-carboxylic acid 3 g of the benzyl ester (Fraction 2) are dissolved in ethanol and mixed with 200 mg of 10% Pd / carbon at normal pressure hydrogenolytically debenzylated. After hydrogen uptake has ended (about 1 hour) is filtered off from the catalyst and the solution is concentrated in vacuo. One relocates with a little pentane, heated to about 450C and applies a strong vacuum. It educates an amorphous, solid foam. Yield: 2.4 g.

NMR (CDCl3): 1,20 (d, 3H); 1,23 (t, 3H); über Multiplett 1,0-2,9 (11H); 3,0-4,5 (m, 3H); 4,12 (q, 2H); 4,65 (b, 2H); 7,13 (S, 5H). NMR (CDCl3): 1.20 (d, 3H); 1.23 (t, 3H); over multiplet 1.0-2.9 (11H); 3.0-4.5 (m, 3H); 4.12 (q, 2H); 4.65 (b, 2H); 7.13 (S, 5H).

Beispiel 14 N- (1 -Car bethoxy - 3-phenyl-propyl) -alanyl-octahydro indo 1-2-carbonsäurebenzylester a) N-tertButyloxycarbonyl-alanyl- octahydroindol-2-carbonsäure-benzylester (Boc-Ala-Oic-OBzl) 19 g Boc-Ala-OH werden in 100 ml DMF gelöst und mit 13 ml N-Ethylmorpholin, 13,5 g HOBt sowie 29,6 g Octahydroindol-2-carbonsäurebenzylester-hydrochlorid versetzt. Man kühlt im Eisbad, fügt 21 g Dicyclohexylcarbodiimid zu und läßt 15 Stunden bei Raumtemperatur rühren. Der ausgefallene Harnstoff wird abgesaugt, das Filtrat im Vakuum eingeengt und in Essigester aufgenommen. Man extrahiert je 3 x mit wässriger KHSO4-, KHCO3 - und gesättigter NaCl-Lösung und engt die organische Phase im Vakuum ein. Ausbeute: 38.5 g.Example 14 N- (1-Carbethoxy-3-phenyl-propyl) -alanyl-octahydro indo 1-2-carboxylic acid benzyl ester a) N-tert-butyloxycarbonyl-alanyl-octahydroindole-2-carboxylic acid benzyl ester (Boc-Ala-Oic-OBzl) 19 g of Boc-Ala-OH are dissolved in 100 ml of DMF and mixed with 13 ml of N-ethylmorpholine, 13.5 g of HOBt and 29.6 g of octahydroindole-2-carboxylic acid benzyl ester hydrochloride were added. It is cooled in an ice bath, 21 g of dicyclohexylcarbodiimide are added and the mixture is left for 15 hours Stir at room temperature. The precipitated urea is suctioned off, the filtrate in Concentrated in vacuo and taken up in ethyl acetate. It is extracted 3 times with aqueous KHSO4, KHCO3 and saturated NaCl solution and the organic phase is concentrated in vacuo a. Yield: 38.5 g.

NMR: 1,26 (d, 3H); 1,40 (s, 9H); 1,1-2,4 (m, 12H); 3,2-3,9 (m, 2H); 5,28 (s, 2H); 7,31 (s, 5H). NMR: 1.26 (d, 3H); 1.40 (s, 9H); 1.1-2.4 (m, 12H); 3.2-3.9 (m, 2H); 5.28 (s, 2H); 7.31 (s, 5H).

b) Alanyl-octahydroindol-2-carbonsäurebenzylester-trifluoracetat 21,5 g Boc-Ala-Oic-OBzl werden in 50 ml Trifluoressigsäure gelöst. Man engt im Vakuum ein, digeriert den Rückstand mehrfach mit Diisopropyläther und trocknet im Vakuum. Ausbeute: 21 g. Im NMR fehlt das Protonensignal für die tert. Butylgruppe vollständig.b) Alanyl-octahydroindole-2-carboxylic acid benzyl ester trifluoroacetate 21.5 g of Boc-Ala-Oic-OBzl are dissolved in 50 ml of trifluoroacetic acid. It is concentrated in a vacuum one, the residue digested several times with diisopropyl ether and dried in vacuo. Yield: 21 g. In the NMR the proton signal for the tert. Butyl group completely.

c) N- (1-Carbethoxy -3-phenyl-propyl) -alanyl-octa'hydroindol-2-carbonsäurebenzylester 11,1 g Ala-Oic-OBzl.TFA, 7 g o(-Brom-phenylbuttersäureethylester und 3,3 ml N-Ethylmorpholin werden in 20 ml Dimethylacetamid 4 Tage bei Raumtemperatur gerührt.c) Benzyl N- (1-carbethoxy -3-phenyl-propyl) -alanyl-octa'hydroindole-2-carboxylate 11.1 g of Ala-Oic-OBzl.TFA, 7 g of ethyl o (-bromo-phenylbutyrate and 3.3 ml of N-ethylmorpholine) are stirred in 20 ml of dimethylacetamide for 4 days at room temperature.

Man engt im Vakuum weitgehend ein, löst den Rückstand in Methanol, stellt mit wässr. 2n HCl auf pH 2 und extrahiert lipophile Verbindungen mit Petroläther. Die methanolische Phase wird eingeengt, mit 5 % Sodalösung versetzt und das Reaktionsprodukt in Essigester extrahiert. Chromatographie über Kieselgel (System Essigester/Petroläther 5:3) liefert die Titelverbindung als farbloses Oel. It is largely concentrated in vacuo and the residue is dissolved in Methanol, represents with aq. 2N HCl to pH 2 and extracts lipophilic compounds with petroleum ether. The methanolic phase is concentrated and 5% soda solution is added and the reaction product extracted into ethyl acetate. Chromatography over silica gel (System ethyl acetate / petroleum ether 5: 3) gives the title compound as a colorless oil.

Die nachstehend aufgeführten Beispiele sind nach einer der folgenden Methoden A - F hergestellt, wobei die bezeichneten Methoden wie folgt charakterisiert werden: Methode A: Reduktive Aminierung eines Kondensationsproduktes aus Dic-OtC4Hg-Ester oder Benzylester bzw. Oic-OtC 4119 -Ester oder Benzylester und einer entsprechenden d -Ketocarbonsäure, dargestellt nach Beispiel (3a), mit einem entsprechenden Aminosäurederivat nach Beispiel (3b) Abspaltung der Schutzgruppen nach Beispiel (3c) bzw. (13d) und ggfs. Verseifung nach Beispiel (4).The examples listed below are after one of the following Methods A - F prepared, the designated methods being characterized as follows : Method A: Reductive amination of a condensation product from Dic-OtC4Hg ester or benzyl ester or Oic-OtC 4119 ester or benzyl ester and a corresponding one d -Ketocarboxylic acid, shown according to example (3a), with a corresponding amino acid derivative according to example (3b) splitting off of the protective groups according to example (3c) or (13d) and if necessary saponification according to example (4).

Methode B: Reduktive Aminierung eines Dipeptids-t-Butylesters, dargestellt nach Beispiel £1 E ,F)J mit einem entsprechenden Ot-Ketocarbonsäurederivat nach Beispiel (1G) und ggfs. Abspaltung der Schutzgruppen nach Beispiel (1H) und/oder ggfs.Method B: Reductive amination of a dipeptide t-butyl ester, shown according to Example £ 1 E, F) J with a corresponding Ot-ketocarboxylic acid derivative Example (1G) and, if necessary, splitting off of the protective groups according to Example (1H) and / or possibly

nach Beispiel 4. according to example 4.

Methode C: Reduktive Aminierung nach Methode A und mit einer # -geschützten bifunktionellen Aminosäure, Abspaltung einer Schutzgruppe aus dem eingesetzten Aminosäurederivat nach Beispiel 5.Method C: Reductive amination according to method A and with a # -protected bifunctional amino acid, splitting off of a protective group from the amino acid derivative used according to example 5.

Methode D: Oxidation der zugrunde liegenden Schwefel-Verbindung zum Sulfoxid nach Beispiel (7).Method D: Oxidation of the underlying sulfur compound to the Sulphoxide according to example (7).

Methode E: Oxidation der zugrunde liegenden Schwefel-Verbindung zum Sulfon nach Beispiel (8).Method E: Oxidation of the underlying sulfur compound to the Sulphone according to example (8).

Methode F: Kondensation einer entsprechenden N-alkylierten α -Aminosäure (dargestellt nach Beispiel 10a) t mit einem Aminosäureester (z.B. Dic-OBu oder Dic-OBzl bzw. Oic-OBu oder Oic-OBzl) nach Beispiel 10 b oder 13 c und Abspaltung der Schutzgruppe nach Beispiel 10 c oder 13 d.Method F: condensation of a corresponding N-alkylated α -Amino acid (shown according to Example 10a) t with an amino acid ester (e.g. Dic-OBu or Dic-OBzl or Oic-OBu or Oic-OBzl) according to Example 10 b or 13 c and cleavage the protective group according to Example 10 c or 13 d.

Methode G: Umsetzung eines N-acylierten Aminosäureesters, der im Acylteil in sol -Position zur Amidfunktion eine nucleofuge Gruppe trägt (wie z.B.Method G: Implementation of an N-acylated amino acid ester in the acyl part carries a nucleofugal group in the sol position to the amide function (e.g.

Halogen, Arylsulfonyl oder Alkylsulfonyl), dargestellt nach Beispiel 12 a, mit einer entsprechenden Aminosäure oder einem entsprechenden Aminosäureester nach Beispiel 12 b und Abspaltung der Schutzgruppen. Halogen, arylsulfonyl or alkylsulfonyl), shown according to the example 12 a, with a corresponding amino acid or a corresponding amino acid ester according to Example 12 b and splitting off of the protective groups.

Methode H: Umsetzung eines Dipeptid-benzylesters, dargestellt nach Beispiel 14a, 14b, mit einer entsprechend substituierten OG α-Arylsulfonyl- oder α-Alkylsulfonyl- oder α-Halogen-carbonsäure bzw. Carbonsäureester, dargestellt nach Beispiel 14 c und Spaltung des Benzylesters zu Verbindungen der Formel I, nach der in Beispiel 13 d angegebenen Weise.Method H: Implementation of a dipeptide benzyl ester, shown according to Example 14a, 14b, with an appropriately substituted OG α-arylsulfonyl or α-alkylsulfonyl or α-halocarboxylic acid or carboxylic acid ester, shown according to Example 14 c and cleavage of the benzyl ester to give compounds of Formula I, according to the manner given in Example 13d.

Falls nicht anders angegeben, gelten für die nachstehenden Verbindungen folgende NMR-Daten ( #-Werte in ppm; TMS als Standard): für n = 1 5.1-4.3m (2H); 3.9-3.0m (3H); 2,0-1,0m (12H); n = 0 4.9m (1H); 4.5-3.0m (3H); 2.0-1.0m (11H).Unless otherwise stated, apply to the following compounds the following NMR data (# values in ppm; TMS as standard): for n = 1 5.1-4.3m (2H); 3.9-3.0m (3H); 2.0-1.0m (12H); n = 0 4.9m (1H); 4.5-3.0m (3H); 2.0-1.0m (11H).

Im Falle der Ethylester treten noch folgende Signale auf: 4.2 q 7 Hz (2H) 1.2 t 7 Hz (3H). Nr. n R¹ R² R³ Methode NMR H # 1 1 CH3 CH2-N-CHO C2H5 A 8.3s (1H); 2,9 m ((2H); 1,2 d (3H) H # 2 1 CH3 CH2-N-COCH3 C2H5 A 2,9 m (2H); 2,1 s (3H); 1,2 d (3H) H # 3 1 CH3 CH2-N-CO-CH2-# C2H5 A 3,9-3,0 m (5H); 2,9 m (2H); 1,2 d (3H) H # 4 1 H CH2-N-CO-# C2H5 A 7,2-6,8 m (4H); 3,9-3,0m (4H); OH 2,9 m (2H) H # 5 1 H CH2-N-CO-# C2H5 A 7.9-7.4 m (4H); 3.9-3.0m (4H); COOH 2.9 m (2H) H # 6 1 CH3 CH2-N-CO-CH2-# C2H5 A 7.65-7.1m (4H); 3.9-3.0m (5H); Cl 2.9m (2H); 1.2 d (3H) H # 7 1 CH3 CH2-N-CO-CH2-# H A 7.65-7.1m (4H); 3.9-3.0m (5H); Cl 2.9m (2H); 1.2 d (3H) Nr. n R¹ R² R³ Methode NMR H # 8 1 CH3 CH2-N-CO-# C2H5 A 8.2-7.6m (4H); 2,9 m (2H); 1,2d (3H) NO2 H # 9 1 CH3 CH2-N-CO-# C2H5 A 7.2-6.8m (4H); 2.9m (2H); 1.2d (3H) NH2 H N CH2- # 10 1 # CH2-N-CO-#-OCH3 C2H5 A 13.0s (1H); 7.5-7.0m (6H); 3.9s (3H) HN 2.9-2.6m (4H) H # OCH3 11 1 CH3 CH2-N-CO-#-OCH3 C2H5 A 7.5-6.9m (3H); 3.9s (6H); 2.9m (2H); 1.2d (3H) H # OCH3 12 1 CH3 CH2-N-CO-#-OCH3 C2H5 A 7.3-6.8m (2H); 3.9s (9H); 2.9m (2H) OCH3 1.2d (3H) H # 13 1 CH3 CH2-N-CO-# C2H5 A 7.6-7.0m (4H); 2.9m (2H) CH3 2.4s (3H); 1.2d (3H) Nr. n R¹ R² R³ Methode NMR H # 14 1 CH3 CH2-N-CO-# C2H5 A 7.4-7.0m (4H); 2,9 m (2H); 2,4d CH3 (3H); 1.2d (3H) 15 1 CH3 CH2-CH2-N(CH3)2 C2H5 A 2.4m (2H); 2.2s (6H); 2.1-1.0m (14H) 1.2d (3H) H H # # 16 1 CH3 CH2-N-CO-N-# C2H5 A 7.3-7.0m (5H); 2.9m (2H); 1.2d (3H) H H # # 17 1 CH3 CH2-N-CO-N-#-Cl C2H5 A 8.0-7.0m (4H); 2.9m (2H); 1.2d (3H) H H # # 18 1 CH3 CH2-N-CO-N-# C2H5 A 8.3-7.1m (4H); 2.9m (2H); 1.2d (3H) NO2 H H # # 19 1 (CH3)2CH-CH2 CH2-N-CO-N-#-CH3 C2H5 A 7.4-7.0m (4H); 2.9m (2H); 2.3s (3H) 1.0d (6H) H H # # 20 1 CH3 CH2-N-CO-N-# C2H5 A 7.3-6.7m (4H); 3.8m (3H); 2.9m (2H); OCH3 1.2d (3H) Nr. n R¹ R² R³ Methode NMR H # 21 1 CH3 CH2-N-CO-# C2H5 A 7.3-6.7m (4H); 3.8m (3H); 2.9m (2H); OCH3 1.2d (3H) H H S # # 22 1 # CH2 CH2-N-CO-N-CH3 C2H5 A 7.3-7.0m (5H) 3.0-2.6m+s (7H) H H S # # 23 1 # CH2 CH2-N-CO-N-CH3 H A 7.3-7.0m (5H); 3.0-2.6 m+s (7H) H H # # 24 1 CH2F CH2-N-CO-N-#-C4H9 C2H5 A 5.1-4.3m (4H); 2.9m (2H); 1.0t (3H) H O H # # # 25 1 CH3 CH2-N-C-N-# C2H5 A 3.2-2.9m (3H); 2.4-1.0m (22H); 1.2d (3H) H O # # 26 1 CH3 CH2-N-C-O-CH2-# C2H5 A 7.1s (5H); 5.0s (2H); 2.9m (2H); 1.2d (3H) H O # # 27 1 CH3 CH2-N-C-O-C2H5 C2H5 A 4.2q (4H); 2.9m (2H); 1.2t+d (9H) H # 28 1 CH3 CH2-CH2-N-CHO C2H5 G 8.2-2s (1H); 2.9m (2H); 2.0-1.0m (14H) Nr. n R¹ R² R³ Methode NMR H # 29 1 H CH2-CH2-N-COCH3 C2H5 G 3.9-3.0m (5H); 2.9m (3H); 2.1s (3H); 1.5m (2H) H # 30 1 CH3 CH2-CH2-N-CO-# C2H5 G 7.6-7.0m (5H); 2.9m (2H); H 2.0-1.0m (14H) # 31 1 CH3 CH2-CH2-N-CO-# C2H5 G 7.2-6.8m (4H); 2.9m (2H) HO 2.0-1.0m (14H) H CH2 # 32 1 # CH2-CH2-N-CO-# C2H5 G 7.9-7.4m (9H); 2.9-2.7m (4H); COOH 2.0-1.0m (14H) H # 33 1 CH3 CH2-CH2-N-CO-#-Cl C2H5 G 8.0-7.1m (4H); 2.9m (2H); 2.0-1.0m (14H) H O # # 34 1 CH3 CH2-CH2-N-C-#-Cl H G 8.0-7.1m (4H); 2.9m (2H); 2.0-1.0m (14H) H O # # 35 1 CH3 CH2-CH2-N-C-# C2H5 G 8.3-7.6 (4H); 2.9m (2H) NO2 2.0-1.0m (14H) Nr. n R¹ R² R³ Methode NMR H O # # 36 1 CH3 CH2-CH2-N-C-# C2H5 G 7.2-6.8m (4H); 2.9m (2H); NH2 1.2d (3H); 2.0-1.0m (14H) H O # # 37 1 CH3 CH2-CH2-N-C-#-OCH3 C2H5 G 7.5-6.8m (4H); 3.8s (3H); 2.9m (2H); 1.2d (3H); 2.0-1.0m (14H) H O # # OCH3 38 1 CH3 CH2-CH2-N-C-#-OCH3 C2H5 G 7.5-6.9m (3H); 3.9m (6H) 2.9m (2H); 1.2d (3H); 2.0-1.0m (14H) H O # # OCH3 39 1 CH3-CH2-CH-CH2 CH2-CH2-N-C-#-OCH3 C2H5 G 7.2-6.8m (6H); 3.9s (9H); # OCH3 2.9m (2H); 2.0-1.0m (25H) CH3 H O # # 40 1 CH3 CH2-CH2-N-C-# C2H5 G 7.6-7.2m (4H); 2.9m (2H); CH3 2.3s (3H); 1.2d (3H); 2.0-1.0m (14H) n R¹ R² R³ Methode NMR H O # # 41 1 CH3 CH2-CH2-N-C-# H G 7.6-7.2m (4H); 2.9m (2H); CH3 2.3m (3H); 1.2d (3H) 2.0-1.0m (14H) 42 1 CH3 CH2-CH2-CH2-N(C2H5)2 C2H5 G 2.6-2.4m (6H); 2.0-1.0m (14H); 1.2d (3H); 0.9t (6H) H H # # 43 1 CH3 CH2-CH2-N-CO-N-#- C2H5 G 7.5-7.0m (5H); 2.9m (2H); 2.0-1.0m (14H); 1.2d (3H) H H # # 44 1 CH3 CH2-CH2-N-CO-N-#-Cl C2H5 G 7.5-7.0m (4H); 2.9m (2H); 2.0-1.0m (14H); 1.2d (3H) H H # # 45 1 CH3 CH2-CH2-N-CO-N-# C2H5 G 8.3-7.3m (4H); 2.9m (2H); NO2 2.2-1.0m (14H); 1.2d (3H) n R1 R2 R3 Methode NMR H H # # 46 1 CH3 CH2-CH2-N-CO-N-# C2H5 G 7.4-7.0m (4H); 2.9m (2H); # 2.3s (3H); 2.1-1.0m (14H) CH3 1.2d (3H) H H 47 1 CH3 CH2-CH2-N-CO-N-#-OCH3 C2H5 G 7.2-6.5m (4H); 3.9s (3H); 2.9m (2H); 2.0-1.0m (14h); 1.2d (3H) H H F 48 1 CH3 CH2-CH2-N-CO-N-#-CH3 C2H5 G 7.3-6.9m (3H); 2.9m (2H); 2.3s (3H); 2.0-1.0m (14H) 1.2d (3H) n R1 R2 R3 Methode NMR H H G 3.0-2.6m (5H); 2.0-1.0m 49 1 (CH3)2CH-CH2 CH2-CH2-N-CO-N-CH3 C2H5 (17H): 1.0d (6H) H H # # G 3.0-2.6m (4H); 2.0-1.0m 50 1 (CH3)2CH-CH2 CH2-CH2-N-CO-N-C4H9 C2H5 (21H); 0.9+t (9H) H H G 3.0-2.6m (4H); 2.0-1.0m 51 1 (CH3)2CH-CH2 CH2-CH2-N-CO-N-C4H9 H (21H); 0.9+t (9H) H H 52 1 CH2F CH2-CH2-N-CO-N-# C2H5 G 5.1-4.3m (4H); 2.9m (3H); 2.0-1.0m (24H) H G 7.1s (5H); 5.0s (2H); 53 1 CH3 CH2-CH2-N-CO-O-CH2-# C2H5 2.9m (2H); 2.0-1.0m (14H); 1.2d (3H) n R1 R2 R3 Methode NMR H 54 1 CH3 CH2-CH2-N-CO-O-C2H5 C2H5 A 4.2g (4H); 2.9m (2H); 2.0-1.0m (14H); 1.2+t (9H) H 2.4m (2H); 2.3s (3H); 55 1 CH3 CH2-CH2-N-CH3 C2H5 A 2.0-1.0m (14H); 1.2d (3H) 56 1 CH3 CH2-CH2-N# C2H5 A 2.4m (6H); 2.0-1.0m (20H); 1.2d (3H) H 7.0-6.5m (5H); 2.5 57 1 CH3 CH2-CH2-N-# C2H5 A 1.0m (16H); 1.2d (3H) Cl H # 7.2-6.6m (4H); 2.4 - 58 1 (CH3)2CH-CH2 CH2-CH2-N-# C2H5 A 1.0m (19H); 1.0d (6H) n R1 R2 R3 Methode NMR H 59 1 #S-CH2 CH2-CH2-N-#-OCH3 C2H5 A 7.3-6.4m (9H); 2.5-2.2m (4H); 2.0-1.0m (14H) H Cl 7.0-6.6m (3H); 5.1-4.3m 60 1 CH2F CH2-CH2-N-#CH3 C2H5 A (4H); 2.4m (2H); 2.3s (3H); 2.0-1.0m (14H) H COOCH3 7.0-6.5m (4H); 2.5-1.0m 61 1 CH3 CH2-N-#-OCOCH3 C2H5 A (14H); 2.1s (3H); 1.2d (3H) H NO2 7.7-7.0m (4H); 2.5m (2H) 62 1 CH3 CH2-N-# C2H5 A 1.2d (3H) H OH 7.6-6.7m (3H); 2.4m (2H) 63 1 CH3 CH2-N-#-CONH2 C2H5 A 1.2d (3H) n R1 R2 R3 Methode NMR H # 64 1 CH3 CH2-N-#-COOC2H5 C2H5 A 7.6-6.8m (4H); 4.2q (4H); 2.5m (2H); 1.2d+t (9H) H O 6.8-6.2 (3H); 5.0s (2H); 65 1 CH3 CH2-N-#-O C2H5 A 2.5m (2H); 1.2d (3H) H NH2 7.0-6.5m (8H); 2.5m (2H); 66 1 CH3 CH2-N-# C2H5 A 1.2d (3H) H 4.2q (4H); 2.6-2.3m (6H) 67 1 CH3 -CH2-N-CH2-CH2-COOC2H5 C2H5 A 1.2d+t (9H) 2.3m (2H); 2.0-1.0m (16H) 68 1 CH3 CH2-CH2-CH2-NH2 C2H5 A 1.2d (3H) n R1 R2 R3 Methode NMR H 2.6-1.0m (22H); 1.2d+t (9H) 69 1 CH3 CH2-N-CH2-CH2-N(C2H5)2 C2H5 A 70 1 CH3 CH2-N#O C2H5 A 3.9-3.0m (12H); 2.3m (2H); 1.2d (3H) 2.6-2.3m (6H); 2.1-1.0m 71 1 CH3 CH2-N# C2H5 A (16H); 1.2d (3H) H 72 1 CH3 CH2-N-CH2-CH2-CONH2 C2H5 A 2.6-2.2m (6H); 1.2d (3H) 2.4m (2H); 2.2s (6H); 2.0- 73 1 CH3 CH2-CH2-CH2-N(CH3)2 C2H5 A 1.0 (16H); 1.2d (3H) H 3.9-3.0m (5H); 2.4m (2H); 74 1 CH3 CH2-N-CH2-CONH2 C2H5 A 1.2d (3H) n R1 R2 R3 Methode NMR 75 1 CH3 (CH2)5-NH2 H C 2.3m (2H); 2.1-1.0m (20H); 1.2d (3H) 76 1 H2N-(CH2)4 (CH2)4-NH2 H C 2.4m (4H); 2.1-1.0m (24H) 77 1 CH3 CH2-CH2-NH-CH3 C2H5 A 2.4m (2H); 2.2s (3H); 2.0-1.0m (14H); 1.2d (3H) 78 1 CH3 CH2-NH-CH3 C2H5 A 2.4m (2H); 2.1s (3H);1.2d (3H) H # 7.0s (5H); 4.5-3.0m (5H); 79 0 CH3 CH2-N-CO-CH2# C2H5 A 2.9m (2H); 1.2d (3H) H # 7.8-7.3m (5H); 2.9m (2H); 80 0 CH3 CH2-N-CO-# C2H5 A 1.2d (3H) n R1 R2 R3 Methode NMR H # 81 O CH3 CH2-N-CO-#-Cl C2H5 A 7.8-7.2m (4H); 2.9m (2H); 1.2d (3H) H H # # 82 O CH3 CH2-N-CO-N-# C2H5 A 7.4-6.8m (5H); 2.9m (2H); 1.2d (3H) H H # # 83 O CH3 CH2-N-CO-N-#-Cl C2H5 A 7.7-6.5m (4H); 2.9m (2H); 1.2d (3H) H H # # 84 O CH3 CH2-N-CO-N-CH3 C2H5 A 3.0-2.6m + s (5H); 1.2d (3H) H O H # # # 85 O CH3 CH2-N-C-N-#H C2H5 A 4.5-2.9m (6H); 2.4-1.0m (21H); 1.2d (3H) H # 86 O CH3 CH2-CH2-N-CO-# C2H5 A 7.6-7.1m (5H); 2.9m (2H); 2.0-1.0m (13H); 1.2d (3H) n R1 R2 R3 Methode NMR H # 87 O CH3 CH3 CH2-CH2-N-CO-#-Cl C2H5 A 7.6-7.2m (4H); 2.9m (2H); H O # # 88 O CH3 CH2-CH2-N-C-#-Cl H A 7.6-7.2m (4H); 2.9m (2H); 2.0-1.0m (13H); 1.2d(3H) 2.6-2.4m (6H); 2.0 - 89 O CH3 CH2-CH2-CH2-N(C2H5)2 C2H5 A 1.0m (15H); 1.2d (3H); 1.0t (6H) H H # # 90 O CH3 CH2-CH2-N-CO-N-# C2H5 G 7.4-6.5m (5H); 2.9m (2H) 2.0-1.0m (13H); 1.2d (3H) H H # # 91 O CH3 CH2-CH2-N-CO-N-#-Cl C2H5 G 7.5-6.8m (4H); 2.9m (2H); 2.0-1.0m (13H); 1.2d (3H) n R1 R2 R3 Methode NMR H H # # 92 O CH3 CH2-CH2-N-CO-N-# C2H5 G 7.8-7.2m (4H); 2.9m (2H); 2.0- NO2 1.0m (13H); 1.2d (3H) H H # # 93 O CH3 CH2-CH2-N-CO-N-CH3 C2H5 G 3.0-2.6m+s (5H); 2.0-1.0m (13H); 1.2d (3H) 94 O CH3 CH2-CH2-N# C2H5 A 2.6-2.3m (6H); 2.0-1.0 m (19H) 1.2d (3H) H # 95 O CH3 CH2-CH2-N-# C2H5 A 6.9-6.5m (5H); 2.4m (2H); 2.0-1.0m (13H); 1.2d (3H) H Cl # # 96 O CH3 CH2-CH2-N-# C2H5 A 6.9-6.5m (4H); 2.4m (2H); 2.0-1.0m (13H); 1.2d (3H) n R1 R2 R3 Methode NMR H # 97 O CH3 CH2-CH2-N-#-OCH3 C2H5 A 7.0-6.4m (4H); 3.9s (3H); 2.4m (2H); 2.0-1.0m (13H) 1.2d (3H) 98 O CH3 (CH2)5-NH2 H C 2.4m (2H); 2.0-1.0m (19H) 1.2d (3H) 99 O CH3 (CH2)4-NH2 H C 2.4m (2H); 2.0-1.0m (17H); 1.2d (3H) 7.4-7.0m (5H); 2.7m (2H) 100 1 CH3 CH2-S-# C2H5 A 1.2d (3H) 7.3-6.8m (4H); 2.7m (2H) 101 1 CH3 CH2-S-#-F C2H5 A 1.2d (3H) n R1 R2 R3 Methode NMR 102 1 CH3 CH2-S-#-SO2NH2 C2H5 A 2.4m (2H); 1.2d (3H) OCH3 # 103 1 (CH3)2CH-CH2 CH2-S-# C2H5 A 8.1-7.1m (4H); 6.5bs (2H); 2.7m (2H); 1.3d (3H) CH2 CONH2 # # 7.0-6.7m (4H); 3.8s (3H); 104 1 N# CH2-S# C2H5 A 2.7m (2H); 2.0-1.0m (15H) N 1.0d (6H) H CH2 NO2 # # 13.0s (1H); 7.8-6.8m (6H) 105 1 #N# CH2-S-# C2H5 A 6.0bs (2H); 2.9-2.6m (4H) n R1 R2 R3 Methode NMR CH2 NH2 # # 106 1 #N# CH2-S-# C2H5 A 8.2m-6.4m (10H); 2.9- H 2.6m (4H) 107 1 (CH3)2CH-CH2 CH2-S-# C2H5 A 7.8-6.4m (10H);2.9- # 2.6m (4H) CH3 7.3-7.0m (4H); 2.7m (2H); 108 1 CH3 -CH2-S-CH2-# C2H5 A 2.3s (3H); 2.0-1.0m (15H) 1.0d (6H) CH2 109 1 # -CH2-S-CH(CH3)2 C2H5 A 7.3-7.0m (5H); 3.9-3.0+s (5H); 2.4m (2H); 1.2d(3H) n R1 R2 R3 Methode NMR 110 1 CH3 -CH2-S-CH2-CH2-N(CH3)2 C2H5 A 7.1s (5H); 2.6-2.3m (5H); 0.9d (6H) 111 1 CH2F -CH2-S-CH2-CH2-CONH2 C2H5 A 2.6-2.2m+s (12H); 1,2d (3H) 112 1 CH3 -CH2-S-CH2-CH2-COOC2H5 C2H5 A 5.1-4.3m (4H); 2.5-2.2m (6H) 113 1 CH3 -CH2-S-CH2-CH2-OC2H5 C2H5 A 4.2q (4H); 2.5-2.2m (6H) 1.2d+t (9H) 3.9-3.0q+m (7H); 2.4-2.2m 114 1 CH3 -CH2-CH2-S-# C2H5 A (4H); 1.2d+5 (6H) n R¹ R² R³ Methode NMR 71s (5H); 2.7m (2H); 115 1 CH3 -CH2-CH2-S-#-Cl C2H5 A 2.0-1.0m (14H); 1.2d (3H) 7.5-7.0m (4H); 2.7m (2H) 116 1 CH3 -CH2-CH2-S-#-COOH C2H5 A 2.0-1.0m (14H); 1.2d (3H) 7.9-6.9m (4H); 2.7m (2H) 117 1 CH3 -CH2-CH2-S-#-SO2NH2 C2H5 A 2.1-1.0m (14H); 1.2d (3H) 8.0-6.9m (4H); 6.5bs (2H) 118 1 CH3 -CH2-CH2-S-#-OCH3 C2H5 A 2.6m (2H); 2.0-1.0m (14H) 1.2d (3H) n R¹ R² R³ Methode NMR 6.9-6.4m (4H); 3.8s (3H); 119 1 CH3 CH2-CH2-S-#-CONH2 C2H5 A 2.7m (2H); 2.1-1.0m (14H): 1.2d (3H) 7.8-6.9m (4H); 6.0bs 120 1 CH3 CH2-ChH-S-#-NO2 C2H5 A (2H); 2.6m (2H); 2.0 - 1.0m (14H); 1.2d (3H) 8.1-6.9m (4H); 2.7m (2H) 121 1 H2N-(CH2)4 CH2-CH2-S-#-CH3 C2H5 A 2.0-1.0m(14H); 1.2d (3H) 7.0-6.8m (4H); 2.7-2.3 122 1 CH3 CH2-CH2-S-CH2-# C2H5 A m+s (7H); 2.0-1.0m (20H) n R¹ R² R³ Methode NMR 7.2s (5H); 3.9-3.0m+s 123 1 CH3 CH2-CH2-S-CH(CH3)2 C2H5 A (5H); 2.4m (2H); 2.0-1.0m 14H); 1.2d (3H) CH2 2.6-2.3m (3H); 2.1-1.0m 124 1 #N CH2-CH2-S-CH2-CH2-N(CH3)2 C2H5 A (14H); 1.2d (3H); H 1.0d (6H) 7.8-6.5m (6H); 2.8-2.3m 125 1 CH3 CH2-CH2-S-CH2-CH2-CONH2 C2H5 A (14H); 2.0-1.0m (14H) O # 6.0bs (2H); 2.5-2.2m (6H) 126 1 CH3 CH2-S-# C2H5 D 2.0-1.0m (14H); 1.2d (3H) n R¹ R² R³ Methode NMR O # 7.5-7.0m (5H); 2.6m (2H); 127 1 CH3 CH2-S-#-F C2H5 D 1.2d (3H) O # 7.4-6.9m (4H); 2.6m (2H); 128 1 CH3 -CH2-S-CH2-# C2H5 D 1.2d (3H) O # 7.1s (5H); 4.1s (2H); 129 1 CH3 -CH2-S-CH(CH3)2 C2H5 D 2.6m (2H); 1.2d (3H) O # 2.8-2.5m (3H); 1.2d (3H) 130 1 CH3 -CH2-CH2-S-# C2H5 D 1.0d (6H) O # 7.4-7.0m (5H); 2.6m (2H) 131 1 CH3 -CH2-CH2-S-#-Cl C2H5 D 2.0-1.0m (14H); 1.2d (3H) n R¹ R² R³ Methode NMR O # 7.5-6.9m (4H); 2.6m (2H); 132 1 CH3 CH2-CH2-S-#-CHH C2H5 D 2.0-1.0m (14H); 1.2d (3H) O # 7.6-6.9m (4H); 2.6m (2H); 133 1 CH3 CH2-CH2-S-CH2-# C2H5 D 2.3s (3H); 2.0-1.0m (14H); 1.2d (3H) O # 7.1s (5H); 4.1s (2H); 134 1 CH3 CH2-CH2-S-CH(CH3)2 C2H5 D 2.7m (2H); 2.0-1.0m (14H) 1.2d (3H) O # 2.8-2.5m (3H); 2.0-1.0m 135 1 CH3 CH2-CH2-S-CH2-CH2-N(CH3)2 C2H5 D (14H); 1.2d (3H); 0.9d (6H) O # 2.8-2.2m+s (12H); 2.0 136 1 CH2 CH2-S-# C2H5 E 1.0m (14H); 1.2d (3H) # O n R¹ R² R³ Methode NMR O # 7.8-7.1m (5H); 2.8m (2H); 137 1 CH3 CH2-S-#-F C2H5 E 1.2d (3H) # O O # 7.7-6.9m (4H); 2.0m (2H); 138 1 CH3 CH2-S-CH2-# C2H5 E 1.2d (3H) # O O # 7.2s (5H); 5.1-4.3m (4H); 139 1 CH3 CH2-S-CH(CH3)2 C2H5 E 2.8m (2H); 1.2d (3H) # O O # 3.0-2.7m (3H); 1.2d+5 (9H) 140 1 CH3 CH2-CH2-S-# C2H5 E # O O # 7.7-7.2m (5H); 2.8m (2H); 141 1 CH3 CH2-CH2-S-#-Cl C2H5 E 2.0-1.0m (14H); 1.2d (3H) # O n R¹ R² R³ Methode NMR 142 1 CH3 CH2-CH2-S-#-CH3 C2H5 E 8.0-7.1m (4H); 2,8m (2H); # 2.0-1.0m (14H); 1.2d (3H) O O # 7.6-6.9m (4H); 2.8m (2H); 143 1 CH3 CH2-CH2-S-CH2-# C2H5 E 2.3s (3H); 2.0-1.0m(14H); # 1.2d (3H) O O # 7.1s (5H); 4.2s (2H); 2.8m 144 1 CH3 CH2-CH2-S-CH(CH3)2 C2H5 E (2H); 2.0-1.0m (14H); # 1.2d (3H) O O # 3.0-2.7m (3H); 2.0-1.0m 145 1 CH3 CH2-CH2-S-CH2-CH2-N(CH3)2 C2H5 E (14H); 1.1d+5 (9H) 3.0-2.2m+s (12H); 2.0-1.0m 146 0 CH3 CH2-S-# C2H5 A (14H); 1.2d (3H) n R¹ R² R³ Methode NMR 147 O CH3 CH2-S-#-Cl C2H5 A 6.9s (5H); 2.5m (2H); 1.2d(3H) 7.4-6.8m (4H); 2.5m (2H); 148 O CH3 CH2-S-# C2H5 A 1.2d (3H) CH3 7.5-6.8m (4H); 2.5m (2H); 149 O CH3 -CH2-S-CH2-# C2H5 A 2.3s (3H); 1.2d (3H) 7.2s (5H); 3.7-3.0m+s 150 O CH3 -CH2-S-CH-(CH3)2 C2H5 A (5H); 2.4m (2H); 1.2d (3H) 2.7-2.3m (3H): 1.2d (3H) 151 O CH3 -CH2-CH2-S-# C2H5 A 0.9d (6H) n R1 R2 R3 Methode NMR 152 O CH3 -CH2-CH2-S-#-Cl C2H5 A 7.0s (5H); 2.7m (2H); 2.0-1.0m (13H); 1.2d(3H) 7.5-6.5m (4H); 2.7m (2H) 153 O CH3 CH2-CH2-S-#-CH3 C2H5 A 2.0-1.0m (13H); 1.2d (3H) 7.3-6.5m (4H); 2.7-2.3m+s 154 O CH3 CH2-CH2-S-CH2-# C2H5 A (5H); 2.0-1.0m (13H); 1.2d (3H) 4,5-3.0 m+s (5H); 2.4m 155 O CH3 CH2-CH2-S-CH(CH3)2 C2H5 A (2H); 2.0-1.0m (13H); 1.2d (3H) 2.6-2.3m (3H); 2.0-1.0m 156 O CH3 CH2-S-# C2H5 A (13H); 1.2d (3H), 1.0d (6H) n R1 R2 R3 Methode NMR O # 157 O CH3 CH2-S-#-Cl C2H5 D 7.5-7.0m (5H); 2.6m (2H) 1.2d (3H) O # 158 O CH3 -CH2-S-CH2-# C2H5 D 7.4-7.0m (4H); 2.6m (2H); 1.2d (3H) O # 159 O CH3 -CH2-S-CH(CH3)2 C2H5 D 7.1s (5H); 4.1s (2H); 2.6m (2H); 1.2d (3H) O # 160 O CH3 -CH2-CH2-S-# C2H5 D 2.8-2.5m (3H); 1.2d (3H) 1.0d (6H) O # 161 O CH3 -CH2-CH2-S-#-Cl C2H5 D 7.4-7.0m (5H); 2.6m (2H) 2.0-1.0m (13H); 1.2d (3H) n R1 R2 R3 Methode NMR O # 7.5-7.0m (4H); 2.6m (2H); 162 O CH3 CH2-CH2-S-#-CH3 C2H5 D 2.0-1.0m (13H); 1.2d (3H) O # 7.6-7.0 (4H); 2.6m (2H); 163 O CH3 CH2-CH2-S-CH2-# C2H5 D 2.3s (3H); 2.1-1.0m (13H); 1.2d (3H) O # 7.1s (5H); 4.1s (2H); 164 O CH3 CH2-CH2-S-CH(CH3)2 C2H5 D 2.7m (2H); 2.1-1.0m (13H); 1.2d (3H) O # 2.8-2.5m (3H); 2.0-1.0m 165 O CH3 CH2-S-# C2H5 E (13H); 1.2d (3H); 1.1d (6H) # O O # 7.8-7.3m (5H); 2.8m (2H); 166 O CH3 CH2-S-#-Cl C2H5 E 1.2d (3H) # O n R1 R2 R3 Methode NMR O # 7.7-7.2m (4H); 2.8m (2H); 167 O CH3 -CH2-S-CH2-# C2H5 E 1.2d (3H) # O O # 7.1s (5H); 4.3s (2H); 168 O CH3 -CH2-S-CH(CH3)2 C2H5 E 2.8m (2H); 1.2d (3H) # O O # 3.0-2.7m (3H); 1.2d+t (9H) 169 O CH3 -CH2-CH2-S-# C2H5 E # O O # 7.7-7.2m (5H); 2.8m (2H); 170 O CH3 -CH2-CH2-S-#-Cl C2H5 E 2.0-1.0m (13H); 1.2d (3H) # O O # 8.0-7.3m (4H); 2.8m (2H) 171 O CH3 -CH2-CH2-S-#-CH3 C2H5 E 2.0-1.0m (13H); 1.2d (3H) # O n R1 R2 R3 Methode NMR O # 7.1s (5H); 4.2s (2H) 172 O CH3 CH2-CH2-S-CH2-# C2H5 E 2.8m (2H); 2.1-1.0m # (13H) O O # 3.0-2.7m (3H); 2.0- 173 O CH3 CH2-S-CH(CH3)2 C2H5 E 1.0m (13H); 1.1d+t # (9H) O 174 1 CH3 -CH2-OH C2H5 A 3.9-3.0m (5H); 1.2d (3H) 175 1 CH3 -CH2-O-# C2H5 H 7.0s (5H); 3.9-3.0m (5H); 1.2d (3H) 7.3-6.6m (4H); 3.9-3.0m 176 1 CH3 -CH2-O-#-CH3 C2H5 H (5H); 2.3s (3H); 1.2d (3H) n R1 R2 R3 Methode NMR 7.3-6.7m (4H); 3.9-3.0m 177 1 CH3 -CH2-O-#-Cl C2H5 H (5H); 1.2d (3H) OCH2 # 6.8-6.3m (4H); 3.9-3.0 178 1 H2N-(CH2)4 -CH2-O-# C2H5 B m+s (8H); 2.4m (2H); 2.0-1.0m (18H) 8.2-6,8m (4H); 3.9-3.0m 179 1 H2N-(CH2)3 -CH2-O-#-NO2 C2H5 B (5H); 2.4m (2H); 2.0-1.0m (16H) 7.6-6.8m (4H); 4.2q(4H) 180 1 (CH3)2-CH-CH2- -CH2-O-#-COOC2H5 C2H5 A 3.9-3.0m (5H); 2.0 - 1.0m (15H); 1.2t (6H); 1.0d (6H) CH3 # 7.2-6.8m (3H); 3.9-3.0m 181 1 CH3 -CH2-O-#-Cl C2H5 A (5H); 2.3s (3H); 1.2d (3H) n R1 R2 R3 Methode NMR 7.0s (5H); 4.0s (2H); 182 1 CH3 -CH2-O-CH2-# C2H5 A 3.9-3.0m (5H); 1.3d (3H) 7.4-6.9m (4H); 4.0s (2H) 183 1 CH3 CH2-O-CH2-#-Cl C2H5 A 3.9-3.0m (5H); 1.2d (3H) CH3 # 7.4-7.0m (4H); 4.0s 184 1 H2N-(CH2)4 CH2-O-CH2-# C2H5 B (2H); 3.9-3.0m (5H); 2.5-2.2d+t (5H); 2.0-1.0m (18H) CH2 # 7.8-6.4m (10H); 4.0s 185 1 ##N CH2-O-CH2-# C2H5 A (2H); 3.8s (3H): 3.9-3.0 N # (5H); 2.7m (2H) H OCH3 7.8-7.0m (4H); 6.0bs (2H); 186 1 H CH2-O-CH2-#-CONH2 C2H5 A 4.0s (2H); 3.9-3.0m (6H) n R1 R2 R3 Methode NMR NO2 # 8.2-7.0m (4H); 4.0s (2H); 187 1 HS-CH2 CH2-O-CH2-# C2H5 B 3.9-3.0m (5H); 2.3m (2H) NO2 # 7.2-6.4m (4H); 4.0s (2H); 188 1 HS-CH2 CH2-O-CH2-# C2H5 B 3.9-3.0m (5H); 2.3m (2H) 3.9-3.0m (6H); 1.2d (3H); 189 1 CH3 CH2-O-CH(CH3)2 C2H5 H 0.9d (6H); 3.9-3.0m (7H); 2.4-2.1m+s. 190 1 CH3 CH2-O-CH2-CH2-N(CH3)2 C2H5 A (8H); 1.2d (3H) O # H 7.6-6.9m (5H); 4.0m (2H) 191 1 CH3 -CH2-O-C-N-# C2H5 A 1.2d (3H) n R1 R2 R3 Methode NMR 2.1-1.0m (14H); 192 1 CH3 CH2-CONH H A 1.2d (3H) 6.5bs (2H); 2.1-1.0m 193 1 CH3 CH2-CONH H A (14H); 1.2d (3H) 3.9-3.0m+2s (9H); 194 1 CH3 CH2-CON(CH3)2 H A 2.1-1.0m (14H); 1.2d (3H) CH2 # H 195 1 #N# CH2-CON-# H A 7.8-6.4m (11H); 2.8- H 1.0m (16H) CH3 # 7.3-6.9m (4H); 2.3s (3H) 196 1 CH3 Ch2-CON-# H A 2.2-1.0m (14H); 1.2d (3H) n R1 R2 R3 Methode NMR H 197 1 CH3 CH2-CON-#-Cl H F 7.7-6.9m (4H); 2.3m (2H); 1.2d (3H) CH2 # 13.0s (1H); 7.5-6.3m (6H) 198 1 N#N CH2-CO-NH-#-OCH3 H F 3.9s (3H); 2.7m (2H); H 2.1-1.0m (14H) 7.7-6.6m (4H); 2.1-1.0m 199 1 CH3 CH2-CO-NH-#-COOH H F (14H); 1.2d (3H) H 7.7-6.6m (4H); 2.1-1.0m 200 1 CH3 CH2-CON-#-CONH2 H F (14H); 1.2d (3H) H 7.7-6.6m (4H); 4.2q (2H) 201 1 CH3 CH2-CO-N-#-COOC2H5 H F 2.1-1.0m (14H); 1.2d+t (6H) n R1 R2 R3 Methode NMR H 7.3-6.4m (4H); 3.5q (2H); 202 1 CH3 CH2-CO-N-#-OC2H5 H F 2.1-1.0m (14H); 1.2d+t (6H) Cl H # 7.2-6.4m (3H); 3.9s (3H); 203 1 CH3 CH2-CO-N-# H F 2.1-1.0m (14H); 1.2d(3H) # CH3O OCH3 H # 7.1-6.3m (3H); 3.8s (6H); 204 1 CH3 CH2-CO-N-#-OCH3 H F 2.1-1.0m (14H); 1.2(3H) OCH3 H # 7.0-6.2m (2H); 3.9s (9H); 205 1 CH3 CH2-CO-N-#-OCH3 H F 2.1-1.0m (14H); 1.2d (3H) # OCH3 4.2q (2H); 2.0-1.0m (14H) 206 1 CH3 CH2-COOC2H5 H F 1.2d+t (6H) n R1 R2 R3 Methode NMR 4.8septett (1H); 2.1 - 207 1 CH3 CH2-CO-O-CH(CH3)2 H F 1.0m (14H); 1.2d (3H); 0.9d (6H) 7.2s (5H); 5.3s (2H); 208 1 CH3 CH2-CO-O-CH2-# H F 2.1-1.0m (14H); 1.2d (3H) 2.1-1.0m (16H); 1.2d 209 1 CH3 CH2-CH2-COOH C2H5 A (3H) 2.1-1.0m (16H); 1.2d 210 1 CH3 CH2-CH2-CONH2 C2H5 A (3H) 3.02s (6H); 2.0-1.0m (14H 211 1 CH3 CH2-CH2-CON(CH3)2 C2H5 A 1.2d (3H) n R1 R2 R3 Methode NMR H 7.1s (5H); 2.1-1.0m (16H) 212 1 CH3 CH2-CH2-CON-# C2H5 A 1.2d (3H) H 7.3-6.9m (4H); 2.1-1.0m 213 1 CH3 CH2-CH2-CON-#-F C2H5 A (16H); 1.2d (3H) H 7.3-6.8m (4H); 2.4-2.1m 214 1 H2N-(CH2)4 CH2-CH2-CON-#-F C2H5 B (4H); 2.0-1.0m (20H) 7.2-6.4m (4H); 3.9s (3H); 215 1 CH3 CH2-CH2-CONH-#-CH3 C2H5 A 2.1-1.0m (16H); 1.2d (3H) OH # 7.3-6.3m (4H); 2.1-1.0m 216 1 CH3 CH2-CH2-CONH-# C2H5 A (16H); 1.2d (3H) n R1 R2 R3 Methode NMR Cl H # 7.2-6.4m (3H); 3.9s (3H); 217 1 CH3 CH2-CH2-CON-# H A 2.1-1.0m (16H); 1.2d (3H) # CH3O O # H 7.7-7.0m (4H); 2.1-1.0m 218 1 CH3 CH2-CH2-C-N-#-CONH2 H A (16H); 1.2d (3H) H 7.6-7.0m (4H); 4.2q (2H); 219 1 CH3 CH2-CH2-CO-N-#-COOC2H5 H A 2.1-1.0m (16H); 1.2d+t (6H) O # H 7.3-6.4m (4H); 3.9-3.0m 220 1 CH3 CH2-CH2-C-N-#-OC2H5 H A m+q (5H); 2.1-1.0m (16H) 1.2d+t (6H) NO2 # 8.2-6.9m (4H); 2.1-1.0m 221 1 CH3 CH2-CH2-CON-# H A (16H); 1.2d (3H) n R1 R2 R3 Methode NMR OCH3 H # 7.1-6.3m (3H); 3.8s (6H); 222 1 CH3 CH2-CH2-CON-#-OCH3 C2H5 A 2.1-1.0m (16H); 1.2d (3H) OCH3 H # 7.0-6.2m (2H); 3.9s (9H); 223 1 CH3 CH2-CH2-CON-#-OCH3 C2H5 A 2.1-1.0m (16H); 1.2d # (3H) OCH3 H 2.8-2.2m (3H); 2.0-1.0m 224 1 CH3 CH2-CH2-CON-CH(CH3)2 C2H5 A (14H); 1.2d (3H); 1.0d (6H) H 7.2s (5H); 5.1-4.3m (4H); 225 1 CH3 CH2-CH2-CON-CH2-# C2H5 A 2.1-1.0m (16H); 1.2d (3H) OCH3 H # 7.1-6.3m (3H); 3.9s (6H); 226 1 CH3 CH2-CH2-CON-CH2-CH2-#-OCH3 C2H5 A 2.9-1.0m (20H); 1.2d (3H) n R1 R2 R3 Methode NMR 4.5-3.0m (5H); 1.2d (3H) 227 O CH3 CH2-OH C2H5 A 6.9s (5H); 4.5-3.0m 228 O CH3 -CH2-O-# C2H5 A (5H); 1.2d (3H) 7.2s (5H); 4.0s (2H); 229 O CH3 -CH2-O-CH2-# C2H5 A 4.5-3.0m (5H); 1.2d (3H) 7.4-6.5m (4H); 4.0s (2H) 230 O CH3 CH2-O-CH2-#-Cl C2H5 A 4.5-3.0m (5H); 1.2d (3H) 4.5-3.0m (6H); 1.2d (3H) 231 O CH3 CH2-O-CH(CH3)2 C2H5 A 0.9d (6H) n R¹ R² R³ Methode NMR 4.5-3.0m (7H); 2.4-2.1 232 O CH3 CH2-O-CH2-CH2-N(CH3)2 C2H5 A m+s (8H); 1.2d (3H) O H 7.3s (5H); 4.5-3.0m (5H) 233 O CH3 -CH2-O-C-N-# C2H5 A 1.2d (3H) 2.1-1.0m (13H); 1.2d 234 O CH3 CH2-COOH H A (3H) 6.5s (2H): 2.1-1.0m (13H) 235 O CH3 CH2-CONH2 H F 1.2d (3H) 4.5-3.0m+2s (9H); 2.1- 236 O CH3 CH2-CON(CH3)2 H F 1.0m (13H); 1.2d (3H) n R¹ R² R³ Methode NMR H 7.0s (5H); 2.1-1.0m(13H) 237 O CH3 CH2-CON-# H F 1.2d (3H) N CH3 7.3-6.5m (4H); 2.3s (3H); 238 O CH3 CH2-CON-# H F 2.2-1.0m (13H); 1.2d (3H) H 7.7-6.5m (4H); 2.3m (2H); 239 O CH3 CH2-CON-#-Cl H F 1.2d (3H) 4.2q (2H); 2.0-1.0m (13H) 240 O CH3 CH2-COOC2H5 H F 1.2d+t (6H) 241 O CH3 CH2-CH2-COOH C2H5 A 2.1-1.0m (15H); 1.2d (3H) n R¹ R² R³ Methode NMR 2.1-1.0m (15H); 1.2d 242 O CH3 CH2-CH2-CONH2 C2H5 A (3H) 3.02s (6H); 2.0-1.0m 243 O CH3 CH2-CH2-CON(CH3)2 C2H5 A (13H); 1.2d (3H) H 7.0s (5H); 2.1-1.0m 244 O CH3 CH2-CH2-CON-# C2H5 A (15H); 2.1d (3H) H 7.3-6.8m (4H); 2.1-1.0m 245 O CH3 CH2-CH2-CON-#-F H A (15H); 1.2d (3H) 7.3-6.4m (4H); 3.6q (2H) O H 2.1-1.0m (15H); 1.2 d+t 246 O CH3 CH2-CH2-C-N-#-OC2H5 C2H5 A (6H) n R¹ R² R³ Methode NMR H 2.8-2.2m (3H); 2.0-1.0m 247 O CH3 CH2-CH2-CON-CH(CH3)2 C2H5 A (13H); 1.2d (3H); 1.9d(6H) H 7.0s (5H); 5.1-4.3m+s (5H) 248 O CH3 CH2-CH2-CON-CH2-# C2H5 A 2.1-1.0m (15H); 1.2d (3H) H OCH3 7.0-6.2m (3H); 3.9s (6H); 249 O CH3 CH2-CH2-CON-CH2-CH2-#-OCH3 C2H5 A 2.9-1.0m (19H); 1.2d (3H) 7.2s (5H); 2.6m (2H); 250 1 CH3 CH2-CH2-# C2H5 B 2.0-1.0m (14H); 1.2d (3H) n R¹ R² R³ Methode NMR 7.2s (5H); 2.6m (2H); 251 1 CH3 CH2-CH2-# H B 2.0-1.0m (14H); 1.2d (3H) CH3 7.4-7.0m (4H); 2.6m 252 1 CH3 # C2H5 B (2H); 2.3s (3H); CH2-CH2 2.0-1.0m (14H); 1.2d (3H) 7.2s (5H); 2.8-2.5m (4H) 253 1 HO-CH2 CH2-CH2-# C2H5 B 2.0-1.0m (14H) # 7.2s (5H); 2.8-2.3m (4H) 254 1 H2C-(CH2)4- CH2-CH2 H 2.0-1.0m (20H) n R¹ R² R³ Methode NMR 255 1 H2N(CH2)3- # H B 8.2-7.1m (4H); 2.8-2.3m CH2-CH2- NO2 (4H); 2.0-1.0m (18H) Cl 7.5-6.9m (4H); 2.7m (2H) 256 1 CH3 # C2H5 B 2.0-1.0m (14H); 1.2d(3H) CH2-CH2- Cl 7.5-6.9m (4H); 2.7m 257 1 CH3 # H B (2H); 2.0-1.0m (14H); CH2-CH2- 1.2d (3H) COOH 7.8-7.m (4H); 2.7m (2H) 258 1 CH3 # H B 2.0-1.0m (14H); 1.2d(3H) CH2-CH2- HN Cl 7.5-7.0m (4H); 2.8-2.6m 259 1 C-NH-(CH2)1 # C2H5 B (4H); 2.0-1.0m (20H) H2N CH2-CH2- n R¹ R² R³ Methode NMR OH 7.2-6.5m (4H); 2.8-2.3m 260 1 H2N-(CH2)2 # H B (4H); 2.0-1.0m (16H) CH2-CH2- # 7.2bs (5H); 2.7-2.3m (4H) 261 1 H2N-(CH2)5 CH2-CH2- H B 2.0-1.0m (22H) CONH2 # 7.8-7.1m (4H); 2.7-2.3m 262 1 H2N-(CH2)4 CH2-CH2- H B (4H); 2.0-2.0m (20H) # 7.2bs (5H); 2.7-2.3m (4H) 263 1 H2N-CH2 CH2-CH2- H B 2.0-1.0m (14H) n R¹ R² R³ Methode NMR F 7.2-6.8m (4H); 2.7m (2H); 264 1 CH3 # C2H5 B 2.0-1.0m (14H); 1.2d(3H) CH2-CH2- OCH3 7.2-6.3m (3H); 3.9s 265 1 CH3 # C2H5 B (6H); 2.7m (2H); 2.0 - CH2-CH2- OCH3 1.0m (14H); 1.2d (3G) Cl 7.3-6.4m (3H); 3.8s(3H) 266 1 CH3 # C2H5 B 2.6m (2H); 2.0-.0m (14H) CH2-CH2 OCH3 Cl 7.4-6.8m (3H); 2.7m (2H); 267 1 CH3 # C2H5 B 2.0-1.0m (14H); 1.2d (3H). CH2-CH2- Cl n R¹ R² R³ Methode NMR H OCH3 CH2 OCH3 13.1s (1H); 7.5-6.2m (4H); 268 1 # # C2H5 B 3.9s (9H); 2.8-2.3m (4H); CH2-CH2- 2.0-1.0m (14H) 7.3-6.0m (3H); 2.8m (2H); 269 1 CH3 # C2H5 B 2.0-1.0m (14H); 1.2d CH2-CH2- H (3H) # 7.3-6.9m (3H); 2.9m (2H); 270 1 CH3 CH2-CH2- C2H5 B 2.0-1.0m (14H); 1.2d (3H) # 7.4-6.3m (3H); 2.8-2.3m 271 1 H2N-(CH2)4 CH2-CH2- H B (4H); 2.0-1.0m (20H) CH2-CH2- 8.6-7.1m (4H); 2.0m (2H); 272 1 CH3 # C2H5 B 2.0-1.0m (14H); 1.2d (3H) n R¹ R² R³ Methode NMR CH2-CH2 7.8-6.5m (H); 2.9m (2H); 273 1 CH3 ## C2H5 B 2.0-1.0m (14H); 1.2d (3H) H CH3 CH2-CH2 6.7s (1H); 3.9-3.0m+s (6H) 274 1 CH3 # C2H5 B 2.8m (2H); 2.0s (3H); CH3 2.0-1.0 (14H); 1.2d (3H) CH3 O 5.2s (1H); 3.2 2s (6H); 275 1 CH3 # C2H5 B 2.9m (2H); 2.0-1.0m (14H) O CH2-CH2 1.2d (3H) CH3 Cl 8.1s (1H), 3.2s (3H); 2.9m 276 1 CH3 # C2H5 B (2H); 2.0-1.0m (14H); 1.2d O CH2-CH2 (3H) CH3 n R¹ R² R³ Methode NMR 8.5-7.5m (6H); 3.9-3.0m 277 1 CH3 ## C2H5 B (5H); 2.0-1.0m (14H); CH2-CH2 1.2d (3H) CH2-CH2 8.8-7.4m (6H); 3.9-3.0m 278 1 CH3 ## C2H5 B (5H); 2.0-1.0m (14H); 1.2d (3H) 13.0s (1H); 3.9-2.9m (5H) 279 1 CH3 # C2H5 B 2.0-1.0m (14H); 1.2d CH2-CH2 (3H) CH2-CH2 7.9-7.4 2s (2H); 2.8m (2H) 280 1 CH3 # C2H5 B 2.0-1.0m (14H); 1.2d (3H) n R¹ R² R³ Methode NMR H2N CH2-CH2 8.0s (1H); 2.8m (2H); 281 1 CH3 # C2H5 B 2.0-1.0m (14H); 1.2d(3H) CH3 3.2 2s (6H); 3.9-3.0m O Cl (5H); 2.0-1.0m (14H); 282 1 CH3 # C2H5 B (5H); 2.0-1.0m (14H); CH3 CH2-CH2 1.2d (3H) CH3 7.2bs (5H); 2.7m (2H); 283 1 CH3 CHCH2-# C2H5 B 2.2-1.0, (13H); 1.2d (3H); 1.0d (3H) 7.4-7.0m (4H); 2.7-2.3m 284 1 H2N-(CH2)4 CH2-CH2-CH2-#-Cl H B (4H); 2.0-1.0m (22H) n R¹ R² R³ Methode NMR CH3 7.3-6.3m (4H); 3.9s 285 1 CH3 CH2-CH2-C-#-OCH3 C2H5 B (3H); 2.0-1.0m (16H); CH3 1.2d (3H); 1.0s (6H) HN H 7.2bs (5H); 2.9-2.6m 286 1 C-N-(CH2)3 CH2-# H B (4H); 2.0-1.0m (16H) H2N 7.4-6.9m (4H); 3.9- 287 1 H CH2-# H B 3.0m (4H); 2.7m (2H) F 7.8-7.0m (4H); 3.9- 288 1 H CH2-#-COOH H B 3.0m (4H); 2.7m (2H) n R¹ R² R³ Methode NMR OH 7.3-6.5m (4H); 3.9-3.0m 289 1 H -CH2-CH2-CH2-CH2-# H B (4H); 2.7m (2H); 2.0-1.0m (18H) 290 1 CH3 CH2-#-CONH2 H B 7.8-7.0m (4H); 2.8m (2H); 1.2d (3H) 291 1 CH3 CH2-#-NH2 H B 7.2-6.4m (4H); 2.7m (2H); 1.2d (3H) OCH3 7.2-6.3m (3H); 3.9s (6H); 292 1 CH3 -CH2-#-OCH3 H B 2.7m (2H); 1.2d (3H) n R¹ R² R³ Methode NMR OCH3 7.2-6.4m (3H); 3.8s (3H); 293 1 (CH3)2CH-CH2 CH2-CH-# C2H5 B 2.8m (2H) 2.0-1.0m (17H) Cl 0.9d (6H) 294 1 CH3 -CH2-## C2H5 B 7.8-6.5mn (6H); 2.9, H (2H); 1.2d (3H) OCH3 7.2-6.2m (3H); 3.9s 295 1 (CH3)2CH-CH2 CH2-CH2-#-OCH3 H B (9H); 2.7m (2H); 2.0 - OCH3 1.0m (17H); 0.9d (6H) 7.3-6.0m (3H); 2.8m (2H); 296 1 CH3 # H B 1.2d (3H) CH2 H CH2 7.3-6.9m (3H); 2.9m (2H); 297 1 CH3 # H B 1.2d (3H) n R¹ R² R³ Methode NMR 7.4-6.3m (3H); 2.8m (2H); 298 1 CH3 # H B 1.2d (3H) CH2 8.6-7.1m (4H); 2.9m (2H); 299 1 CH3 # H B 1.2d (3H) CH2 CH2 7.8-6.5m (6H); 2.9m (2H); 300 1 CH3 ## H B 1.12d 3H) H CH3 CH2- 6.5s (1H); 3.9-3.0m+s (6H) 301 1 (CH3)2CH-CH2 # C2H5 B 2.8m (2H); 2.0s (3H); CH3 2.0-1.0m (15H); 1.0d (6H) CH3 O 5.2s (1H); 3.2s (6H); 302 1 H # C2H5 B 3.9-2.9m (5H) O CH2 CH3 n R¹ R² R³ Methode NMR 303 1 CH3 ## H B 8.5-7.5m (6H); 3.9-3.0m CH2- (5H); 1.2d (3H) CH2- 8.8-7.4m (6H); 3.9- 304 1 CH3 ## H B 3.0m (5H); 1.2d (3H) 305 1 CH3 H2N-#-CH2- H B 8.0s (1H); 3.9-2.8m (5H) 1.2d (3H) O 8.1s (1H); 6.4s (1H); 306 1 CH3 CH3O- H B 8.1s (1H); 6.4s (1H); # 3.7s (3H); 3.9-2.9m(5H) CH2- 1.2s (3H) O 307 1 (CH3)2CH-CH2 CH3O- H B 8.1s (1H); 6.4s (1H);3.7 # (3H); 3.9-2.9m(5H); 2.0- CH2-CH2 1.0m (17H); 1.0d (6H) n R¹ R² R³ Methode NMR CH2-CH2 7.7-7.1m (2H); 3.9-2.9m 308 1 CH3 # C2H5 B (5H); 2.0-1.0m (14H) 1.2d (3H) CH2- 7.7-7.1m (2H); 3.9-2.9m 309 1 CH3 # C2H5 B (5H); 1.2d (3H) H 7.2-6.5m (5H); 2.7m (2H) 310 O CH3 # C2H5 B 2.0-1.0m (13H); 1.2d CH2-CH2 (3H) Cl 7.5-6.5m (4H); 2.7m (2H) 311 O CH3 # H B 2.0-1.0m (13H); 1.2d (3H) CH2-CH2 Cl 7.6-6.5m (3H); 4.5-2.8m 312 O CH3 # H B (5H); 2.0-1.0m (13H); CH2-CH2- 1.2d (3H) Cl n R¹ R² R³ Methode NMR 7.3-6.0m (3H); 2.8m (2H); 313 O CH3 # H B 2.0-1.0m (13H); 1.2d (3H) CH2-CH2 H 7.3-6.5m (3H); 4.5-2.9m 314 O CH3 # H B (5H); 2.0-1.0m (13H); CH2-CH2 1.2d (3H); CH2-CH2 8.6-6.5m (4H); 4.5-2.9m 315 O CH3 # H B 2.0-1.0m (13H); 1.2d (3H) CH2-CH2 7.8-6.5m (6H); 4.5-2.9m 316 O CH3 ## C2H5 B (5H; 2.0-1.0m (13H); 1.2d (3H) n R¹ R² R³ Methode NMR CH3 317 O CH3 CH-CH2-# C2H5 B 7.2-6.5m (5H)M; 4.5-2.9m (5H); 2.0-1.0m (12H); 1.2d (3H); 1.1d (3H) 7.4-6.5m (4H); 2.7-2.3m 318 O CH3 CH2-CH2-CH2-#-Cl C2H5 B (2H); 2.0-1.0m (15H); 1.2d (3H) CH3 7.3-6.3m (4H); 3.9s (3H); 319 O CH3 CH2-CH2C-#-OCH3 C2H5 B 2.0-1.0m (15H); 1.2d CH3 (3H); 1.0s (6H) OCH3 7.2-6.3m (3H); 3.0s (3H); 320 O CH3 CH2-CH2-# C2H5 B 2.7m (2H); 2.0-1.0m (13H) Cl 1.2d (3H) n R¹ R² R³ Methode NMR 7.8-6.5m (6H); 4.5-2.9m 321 O CH3 -CH2-## C2H5 B (5H); 1.2d (3H) 7.7-6.5m (2H); 4.5-2.9m 322 O CH3 CH2-CH2 C2H5 B (5H); 2.0-1.0m (13H); H 1.2d (3H) 7.7-6.5m (2H); 4.5-2.9m 323 O CH3 # C2H5 B (5H); .2d (3H) H 2.0-1.0m (19H); 1.2d 324 1 CH3 (CH3)2-CH-CH2-CH2-CH2 C2H5 A (3H); 0.9d (6H) n R¹ R² R³ Methode NMR 2.4m (2H); 2.0-1.0m 325 1 H2N-(CH)4 (CH3)2CH-CH2-CH2 C2H5 B (23H); 0.9d (6H) 2.0-1.0m (19H); 0.9d 326 1 H2N-(CH2)3 (CH3)2CH-CH2 C2H5 B (6H) 327 O FCH2 (CH3)2CH C2H5 B 4.3d (2H), 2.0-1.0m (12H); 0.9d (6H) 328 1 CH3-CH2-CH- CH2 H A 2.0-1.0m (28H); 1.0d+t CH3 # (6H) n R¹ R² R³ Methode NMR CH2-CH2 7.8-7.0m (7H); 2.7m (2H); 329 1 CH3 ## C2H5 A 2.0-1.0m (14H); 1.2d(3H) OH 330 1 CH3 # H B 7.3-6.5m (4H), 2.8m CH2 (2H); 1.2d (3H) OCH3 7.3-6.4m (4H); 3.9s (3H); 331 1 CH3 # H B 3.9-2.9m (5H); 1.2d (3H) CH2 332 1 CH3 # 7.6-6.4m (4H); 3.8s (3H); CH2 OCH3 C2H5 B 3.9-2.9m (5H); 1.2d (3H) n R¹ R² R³ Methode NMR Cl 7.6-7.0m (4H); 3.9-2.9m 333 1 CH3 # C2H5 B (5H); 1.2d (3H) CH2 Cl Cl 7.8-7.0m (3H); 3.9-2.9m 334 1 CH3 # H B (5H); 1.2d (3H) CH2 NO2 8.3-7.0m (4H); 3.9-2.9m 335 1 CH3 # H B (5H); 1.2d (3H) CH2 CH3 7.4-7.0m (4H); 3.9-2.9m 336 1 CH3 # C2H5 B (5H); 2.3s (3H); 1.2d (3H) CH2 n R¹ R² R³ Methode NMR 5.3m (1H); 2.3m (4H); 337 1 CH3 -# H A 2.0-1.0m (18H); 1.2d (3H) 5.4m (1H); 2.3m (4H); 338 1 CH3 -# H A 2,0-1.0m (16H); 1.2d (3H) 5.5m (1H); 3.9-3.0m (5H); 339 1 CH3 -# H A 2.5-1.0m (16H); 1.2d (3H) 5.9s (1H); 3.9-3.0m (7H); 340 1 CH3 -# H A 1.2d (3H) n R¹ R² R³ Methode NMR CH3 7.4s (1H); 2.5m (2H); 341 1 CH3 -#-NH(CH2)3- C2H5 A 2.3s (6H); 2.0-1.0m CH3 (16H) 342 1 CH3 ##-CH2CH2- C2H5 A 7.5-6.8m (4H); 2.8m (1H); 2.0-1.0m (14H); 343 1 CH3 ##-CH2-CH2- H A 7.5-6.8m (4H); 2.8m (2H); 2.0-2.0m (14H) n R¹ R² R³ Methode NMR 344 O CH3 CH2-CH2-#-Cl C2H5 B 7.5-6.5m (4H); 2.7m (2H; 2.0-1.0m (13H); 1.2d (3H) 345 O CH3 CH2-CH2-#-F C2H5 B 7.5-6.6m (4H); 2,7m (2H); 2.0-1.0m (13H); 1.2d (3H) 346 O CH3 CH2-CH2-# C2H5 B 7.4-7.0m (4H); 2.6m (2H); H3C 2.3s (3H); 2.0-1.0m (13H); 1.2d (3H) Cl 347 O CH3 CH2-CH2-# C2H5 B 7.6-6.5m (3H); 4.5-2.8m (5H); Cl 2.0-1.0m (13H); 1.2d (3H) 348 O CH3 CH2-CH2-#-Cl C2H5 B 7.5-6.5m (3H); 4.5-2.8m (5H); Cl 2.0-1.0m (13H); 1.2d (3H) 349 O CH3 CH2-CH2-#-OCH3 C2H5 B 7.3-6.4m (4H; 4.5-2.8m (8H); 2.0-1.0m (13H); 1.2d (3H) OCH3 7.2-6.3m (3H); 3.9s (6H); 350 O CH3 CH2-CH2-#-OCH3 C2H5 B 4.5-2.5m (5H); 2.0-1.0m (13H) 351 O CH3 CH2-CH2-# C2H5 B 7.3-6.5m (3H); 4.5-2.9m (5H); 2.0-1.0m (13H); 1.2d (3H) In the case of the ethyl esters, the following signals also occur: 4.2 q 7 Hz (2H) 1.2 t 7 Hz (3H). No. n R¹ R² R³ Method NMR H # 11 CH3 CH2-N-CHO C2H5 A 8.3s (1H); 2.9 m ((2H); 1.2 d (3H) H # 2 1 CH3 CH2-N-COCH3 C2H5 A 2.9 m (2H); 2.1 s (3H); 1.2 d (3H) H # 3 1 CH3 CH2-N-CO-CH2- # C2H5 A 3.9-3.0 m (5H); 2.9 m (2H); 1.2 d (3H) H # 4 1 H CH2 -N-CO- # C2H5 A 7.2-6.8 m (4H); 3.9-3.0m (4H); OH 2.9 m (2H) H # 5 1 H CH2-N-CO- # C2H5 A 7.9-7.4 m (4H); 3.9-3.0m (4H); COOH 2.9 m (2H) H # 6 1 CH3 CH2-N-CO-CH2- # C2H5 A 7.65-7.1m (4H); 3.9-3.0m (5H); Cl 2.9m (2H); 1.2 d (3H) H # 71 CH3 CH2-N-CO-CH2- # HA 7.65-7.1m (4H); 3.9-3.0m (5H); Cl 2.9m (2H); 1.2 d (3H) No. n R¹ R² R³ Method NMR H # 8 1 CH3 CH2-N-CO- # C2H5 A 8.2-7.6m (4H); 2.9 m (2H); 1.2d (3H) NO2 H # 91 CH3 CH2-N-CO- # C2H5 A 7.2-6.8m (4H); 2.9m (2H); 1.2d (3H) NH2 H N CH2- # 10 1 # CH2-N-CO - # - OCH3 C2H5 A 13.0s (1H); 7.5-7.0m (6H); 3.9s (3H) HN 2.9-2.6m (4H) H # OCH3 11 1 CH3 CH2-N-CO- # - OCH3 C2H5 A 7.5-6.9m (3H); 3.9s (6H); 2.9m (2H); 1.2d (3H) H # OCH3 12 1 CH3 CH2-N-CO - # - OCH3 C2H5 A 7.3-6.8m (2H); 3.9s (9H); 2.9m (2H) OCH3 1.2d (3H) H # 13 1 CH3 CH2-N-CO- # C2H5 A 7.6-7.0m (4H); 2.9m (2H) CH3 2.4s (3H); 1.2d (3H) No. n R¹ R² R³ Method NMR H # 14 1 CH3 CH2-N-CO- # C2H5 A 7.4-7.0m (4H); 2.9 m (2H); 2.4d CH3 (3H); 1.2d (3H) 15 1 CH3 CH2-CH2-N (CH3) 2 C2H5 A 2.4m (2H); 2.2s (6H); 2.1-1.0m (14H) 1.2d (3H) HH # # 16 1 CH3 CH2-N-CO-N- # C2H5 A 7.3-7.0m (5H); 2.9m (2H); 1.2d (3H) HH # # 17 1 CH3 CH2-N-CO-N - # - Cl C2H5 A 8.0-7.0m (4H); 2.9m (2H); 1.2d (3H) HH # # 18 1 CH3 CH2-N-CO-N- # C2H5 A 8.3-7.1m (4H); 2.9m (2H); 1.2d (3H) NO2 HH # # 19 1 (CH3) 2CH-CH2 CH2-N-CO-N - # - CH3 C2H5 A 7.4-7.0m (4H); 2.9m (2H); 2.3s (3H) 1.0d (6H) HH # # 20 1 CH3 CH2-N-CO-N- # C2H5 A 7.3-6.7m (4H); 3.8m (3H); 2.9m (2H); OCH3 1.2d (3H) No. n R¹ R² R³ Method NMR H # 21 1 CH3 CH2-N-CO- # C2H5 A 7.3-6.7m (4H); 3.8m (3H); 2.9m (2H); OCH3 1.2d (3H) HH S # # 22 1 # CH2 CH2-N-CO-N-CH3 C2H5 A 7.3-7.0m (5H) 3.0-2.6m + s (7H) HH S # # 23 1 # CH2 CH2-N-CO-N-CH3 HA 7.3-7.0m (5H); 3.0-2.6 m + s (7H) HH # # 24 1 CH2F CH2-N-CO-N - # - C4H9 C2H5 A 5.1-4.3m (4H); 2.9m (2H); 1.0t (3H) HIGH # # # 25 1 CH3 CH2-NCN- # C2H5 A 3.2-2.9m (3H); 2.4-1.0m (22H); 1.2d (3H) HO # # 26 1 CH3 CH2-NCO-CH2- # C2H5 A 7.1s (5H); 5.0s (2H); 2.9m (2H); 1.2d (3H) HO # # 27 1 CH3 CH2-NCO-C2H5 C2H5 A 4.2q (4H); 2.9m (2H); 1.2t + d (9H) H # 28 1 CH3 CH2-CH2-N-CHO C2H5 G 8.2-2s (1H); 2.9m (2H); 2.0-1.0m (14H) No. n R¹ R² R³ Method NMR H # 29 1H CH2-CH2-N-COCH3 C2H5 G 3.9-3.0m (5H); 2.9m (3H); 2.1s (3H); 1.5m (2H) H # 30 1 CH3 CH2-CH2-N-CO- # C2H5 G 7.6-7.0m (5H); 2.9m (2H); H 2.0-1.0m (14H) # 311 CH3 CH2-CH2-N-CO- # C2H5 G 7.2-6.8m (4H); 2.9m (2H) HO 2.0-1.0m (14H) H CH2 # 32 1 # CH2-CH2-N-CO- # C2H5 G 7.9-7.4m (9H); 2.9-2.7m (4H); COOH 2.0-1.0m (14H) H # 33 1 CH3 CH2-CH2-N-CO- # - Cl C2H5 G 8.0-7.1m (4H); 2.9m (2H); 2.0-1.0m (14H) HO # # 34 1 CH3 CH2-CH2-NC - # - Cl HG 8.0-7.1m (4H); 2.9m (2H); 2.0-1.0m (14H) HO # # 35 1 CH3 CH2-CH2-NC- # C2H5 G 8.3-7.6 (4H); 2.9m (2H) NO2 2.0-1.0m (14H) No. n R¹ R² R³ Method NMR HO # # 36 1 CH3 CH2-CH2-NC- # C2H5 G 7.2-6.8m (4H); 2.9m (2H); NH2 1.2d (3H); 2.0-1.0m (14H) HO # # 37 1 CH3 CH2-CH2-NC - # - OCH3 C2H5 G 7.5-6.8m (4H); 3.8s (3H); 2.9m (2H); 1.2d (3H); 2.0-1.0m (14H) HO # # OCH3 38 1 CH3 CH2-CH2-NC - # - OCH3 C2H5 G 7.5-6.9m (3H); 3.9m (6H) 2.9m (2H); 1.2d (3H); 2.0-1.0m (14H) HO # # OCH3 39 1 CH3-CH2-CH-CH2 CH2-CH2-NC - # - OCH3 C2H5 G 7.2-6.8m (6H); 3.9s (9H); # OCH3 2.9m (2H); 2.0-1.0m (25H) CH3 HO # # 40 1 CH3 CH2-CH2-NC- # C2H5 G 7.6-7.2m (4H); 2.9m (2H); CH3 2.3s (3H); 1.2d (3H); 2.0-1.0m (14H) n R¹ R² R³ method NMR HO # # 41 1 CH3 CH2-CH2-NC- # HG 7.6-7.2m (4H); 2.9m (2H); CH3 2.3m (3H); 1.2d (3H) 2.0-1.0m (14H) 42 1 CH3 CH2-CH2-CH2-N (C2H5) 2 C2H5 G 2.6-2.4m (6H); 2.0-1.0m (14H); 1.2d (3H); 0.9t (6H) HH # # 43 1 CH3 CH2-CH2-N-CO-N - # - C2H5 G 7.5-7.0m (5H); 2.9m (2H); 2.0-1.0m (14H); 1.2d (3H) HH # # 44 1 CH3 CH2-CH2-N-CO-N - # - Cl C2H5 G 7.5-7.0m (4H); 2.9m (2H); 2.0-1.0m (14H); 1.2d (3H) HH # # 45 1 CH3 CH2-CH2-N-CO-N- # C2H5 G 8.3-7.3m (4H); 2.9m (2H); NO2 2.2-1.0m (14H); 1.2d (3H) n R1 R2 R3 method NMR HH # # 46 1 CH3 CH2-CH2-N-CO-N- # C2H5 G 7.4-7.0m (4H); 2.9m (2H); # 2.3s (3H); 2.1-1.0m (14H) CH3 1.2d (3H) HH 471 CH3 CH2-CH2-N-CO-N - # - OCH3 C2H5 G 7.2-6.5m (4H); 3.9s (3H); 2.9m (2H); 2.0-1.0m (14h); 1.2d (3H) HHF 48 1 CH3 CH2-CH2-N-CO-N - # - CH3 C2H5 G 7.3-6.9m (3H); 2.9m (2H); 2.3s (3H); 2.0-1.0m (14H) 1.2d (3H) n R1 R2 R3 method NMR HHG 3.0-2.6m (5H); 2.0-1.0m 49 1 (CH3) 2CH-CH2 CH2-CH2-N-CO-N-CH3 C2H5 (17H): 1.0d (6H) HH # # G 3.0-2.6m (4H); 2.0-1.0m 50 1 (CH3) 2CH-CH2 CH2-CH2-N-CO-N-C4H9 C2H5 (21H); 0.9 + t (9H) HHG 3.0-2.6m (4H); 2.0-1.0m 51 1 (CH3) 2CH-CH2 CH2-CH2-N-CO-N-C4H9 H (21H); 0.9 + t (9H) HH 52 1 CH2F CH2-CH2-N-CO-N- # C2H5 G 5.1-4.3m (4H); 2.9m (3H); 2.0-1.0m (24H) HG 7.1s (5H); 5.0s (2H); 53 1 CH3 CH2-CH2-N-CO-O-CH2- # C2H5 2.9m (2H); 2.0-1.0m (14H); 1.2d (3H) n R1 R2 R3 method NMR H 54 1 CH3 CH2-CH2-N-CO-O-C2H5 C2H5 A 4.2g (4H); 2.9m (2H); 2.0-1.0m (14H); 1.2 + t (9H) H 2.4m (2H); 2.3s (3H); 55 1 CH3 CH2-CH2-N-CH3 C2H5 A 2.0-1.0m (14H); 1.2d (3H) 56 1 CH3 CH2-CH2-N # C2H5 A 2.4m (6H); 2.0-1.0m (20H); 1.2d (3H) H 7.0-6.5m (5H); 2.5 57 1 CH3 CH2-CH2-N- # C2H5 A 1.0m (16H); 1.2d (3H) Cl H # 7.2-6.6m (4H); 2.4 - 58 1 (CH3) 2CH-CH2 CH2-CH2-N- # C2H5 A 1.0m (19H); 1.0d (6H) n R1 R2 R3 method NMR H 59 1 # S-CH2 CH2-CH2-N - # - OCH3 C2H5 A 7.3-6.4m (9H); 2.5-2.2m (4H); 2.0-1.0m (14H) H Cl 7.0-6.6m (3H); 5.1-4.3m 60 1 CH2F CH2-CH2-N- # CH3 C2H5 A (4H); 2.4m (2H); 2.3s (3H); 2.0-1.0m (14H) H COOCH3 7.0-6.5m (4H); 2.5-1.0m 61 1 CH3 CH2-N - # - OCOCH3 C2H5 A (14H); 2.1s (3H); 1.2d (3H) H NO2 7.7-7.0m (4H); 2.5m (2H) 62 1 CH3 CH2-N- # C2H5 A 1.2d (3H) H OH 7.6-6.7m (3H); 2.4m (2H) 63 1 CH3 CH2-N - # - CONH2 C2H5 A 1.2d (3H) n R1 R2 R3 method NMR H # 64 1 CH3 CH2-N - # - COOC2H5 C2H5 A 7.6-6.8m (4H); 4.2q (4H); 2.5m (2H); 1.2d + t (9H) HO 6.8-6.2 (3H); 5.0s (2H); 65 1 CH3 CH2-N- # -O C2H5 A 2.5m (2H); 1.2d (3H) H NH2 7.0-6.5m (8H); 2.5m (2H); 66 1 CH3 CH2-N- # C2H5 A 1.2d (3H) H 4.2q (4H); 2.6-2.3m (6H) 67 1 CH3 -CH2-N-CH2-CH2-COOC2H5 C2H5 A 1.2d + t (9H) 2.3m (2H); 2.0-1.0m (16H) 68 1 CH3 CH2-CH2-CH2-NH2 C2H5 A 1.2d (3H) n R1 R2 R3 method NMR H 2.6-1.0m (22H); 1.2d + t (9H) 69 1 CH3 CH2-N-CH2-CH2-N (C2H5) 2 C2H5 A 70 1 CH3 CH2-N # O C2H5 A 3.9-3.0m (12H); 2.3m (2H); 1.2d (3H) 2.6-2.3m (6H); 2.1-1.0m 71 1 CH3 CH2-N # C2H5 A (16H); 1.2d (3H) H 72 1 CH3 CH2-N-CH2-CH2-CONH2 C2H5 A 2.6-2.2m (6H); 1.2d (3H) 2.4m (2H); 2.2s (6H); 2.0- 73 1 CH3 CH2-CH2-CH2-N (CH3) 2 C2H5 A 1.0 (16H); 1.2d (3H) H 3.9-3.0m (5H); 2.4m (2H); 74 1 CH3 CH2-N-CH2-CONH2 C2H5 A 1.2d (3H) n R1 R2 R3 method NMR 75 1 CH3 (CH2) 5-NH2 HC 2.3m (2H); 2.1-1.0m (20H); 1.2d (3H) 76 1 H2N- (CH2) 4 (CH2) 4-NH2 HC 2.4m (4H); 2.1-1.0m (24H) 77 1 CH3 CH2-CH2 -NH-CH3 C2H5 A 2.4m (2H); 2.2s (3H); 2.0-1.0m (14H); 1.2d (3H) 78 1 CH3 CH2-NH-CH3 C2H5 A 2.4m (2H); 2.1s (3H); 1.2d (3H) H # 7.0s (5H); 4.5-3.0m (5H); 79 0 CH3 CH2-N-CO-CH2 # C2H5 A 2.9m (2H); 1.2d (3H) H # 7.8-7.3m (5H); 2.9m (2H); 80 0 CH3 CH2-N-CO- # C2H5 A 1.2d (3H) n R1 R2 R3 method NMR H # 81 O CH3 CH2-N-CO- # -Cl C2H5 A 7.8-7.2m (4H); 2.9m (2H); 1.2d (3H) HH # # 82 O CH3 CH2-N-CO-N- # C2H5 A 7.4-6.8m (5H); 2.9m (2H); 1.2d (3H) HH # # 83 O CH3 CH2-N-CO-N - # - Cl C2H5 A 7.7-6.5m (4H); 2.9m (2H); 1.2d (3H) HH # # 84 O CH3 CH2-N-CO-N-CH3 C2H5 A 3.0-2.6m + s (5H); 1.2d (3H) HIGH # # # 85 O CH3 CH2-NCN- # H C2H5 A 4.5-2.9m (6H); 2.4-1.0m (21H); 1.2d (3H) H # 86 O CH3 CH2-CH2-N-CO- # C2H5 A 7.6-7.1m (5H); 2.9m (2H); 2.0-1.0m (13H); 1.2d (3H) n R1 R2 R3 method NMR H # 87 O CH3 CH3 CH2-CH2-N-CO - # - Cl C2H5 A 7.6-7.2m (4H); 2.9m (2H); HO # # 88 O CH3 CH2-CH2-NC - # - Cl HA 7.6-7.2m (4H); 2.9m (2H); 2.0-1.0m (13H); 1.2d (3H) 2.6-2.4m (6H); 2.0 - 89 O CH3 CH2-CH2-CH2-N (C2H5) 2 C2H5 A 1.0m (15H); 1.2d (3H); 1.0t (6H) HH # # 90 O CH3 CH2-CH2-N-CO-N- # C2H5 G 7.4-6.5m (5H); 2.9m (2H) 2.0-1.0m (13H); 1.2d (3H) HH # # 91 O CH3 CH2-CH2-N-CO-N - # - Cl C2H5 G 7.5-6.8m (4H); 2.9m (2H); 2.0-1.0m (13H); 1.2d (3H) n R1 R2 R3 method NMR HH # # 92 O CH3 CH2-CH2-N-CO-N- # C2H5 G 7.8-7.2m (4H); 2.9m (2H); 2.0- NO2 1.0m (13H); 1.2d (3H) HH # # 93 O CH3 CH2-CH2-N-CO-N-CH3 C2H5 G 3.0-2.6m + s (5H); 2.0-1.0m (13H); 1.2d (3H) 94 O CH3 CH2-CH2-N # C2H5 A 2.6-2.3m (6H); 2.0-1.0 m (19H) 1.2d (3H) H # 95 O CH3 CH2-CH2-N- # C2H5 A 6.9-6.5m (5H); 2.4m (2H); 2.0-1.0m (13H); 1.2d (3H) H Cl # # 96 O CH3 CH2-CH2-N- # C2H5 A 6.9-6.5m (4H); 2.4m (2H); 2.0-1.0m (13H); 1.2d (3H) n R1 R2 R3 method NMR H # 97 O CH3 CH2-CH2-N - # - OCH3 C2H5 A 7.0-6.4m (4H); 3.9s (3H); 2.4m (2H); 2.0-1.0m (13H) 1.2d (3H) 98 O CH3 (CH2) 5-NH2 HC 2.4m (2H); 2.0-1.0m (19H) 1.2d (3H) 99 O CH3 (CH2) 4-NH2 HC 2.4m (2H); 2.0-1.0m (17H); 1.2d (3H) 7.4-7.0m (5H); 2.7m (2H) 100 1 CH3 CH2-S- # C2H5 A 1.2d (3H) 7.3-6.8m (4H); 2.7m (2H) 101 1 CH3 CH2-S - # - F C2H5 A 1.2d (3H) n R1 R2 R3 method NMR 102 1 CH3 CH2 -S- # - SO2NH2 C2H5 A 2.4m (2H); 1.2d (3H) OCH3 # 103 1 (CH3) 2CH-CH2 CH2-S- # C2H5 A 8.1-7.1m (4H); 6.5bs (2H); 2.7m (2H); 1.3d (3H) CH2 CONH2 # # 7.0-6.7m (4H); 3.8s (3H); 104 1 N # CH2-S # C2H5 A 2.7m (2H); 2.0-1.0m (15H) N 1.0d (6H) H CH2 NO2 # # 13.0s (1H); 7.8-6.8m (6H) 105 1 # N # CH2-S- # C2H5 A 6.0bs (2H); 2.9-2.6m (4H) n R1 R2 R3 method NMR CH2 NH2 # # 106 1 # N # CH2-S- # C2H5 A 8.2m-6.4m (10H); 2.9- H 2.6m (4H) 107 1 (CH3) 2CH-CH2 CH2-S- # C2H5 A 7.8-6.4m (10H); 2.9- # 2.6m (4H) CH3 7.3-7.0m (4H); 2.7m (2H); 108 1 CH3 -CH2-S-CH2- # C2H5 A 2.3s (3H); 2.0-1.0m (15H) 1.0d (6H) CH2 109 1 # -CH2-S-CH (CH3) 2 C2H5 A 7.3-7.0m (5H); 3.9-3.0 + s (5H); 2.4m (2H); 1.2d (3H) n R1 R2 R3 method NMR 110 1 CH3 -CH2-S-CH2-CH2-N (CH3) 2 C2H5 A 7.1s (5H); 2.6-2.3m (5H); 0.9d (6H) 111 1 CH2F -CH2-S-CH2-CH2-CONH2 C2H5 A 2.6-2.2m + s (12H); 1.2d (3H) 112 1 CH3 -CH2-S-CH2-CH2-COOC2H5 C2H5 A 5.1-4.3m (4H); 2.5-2.2m (6H) 113 1 CH3 -CH2-S-CH2-CH2-OC2H5 C2H5 A 4.2q (4H); 2.5-2.2m (6H) 1.2d + t (9H) 3.9-3.0q + m (7H); 2.4-2.2m 114 1 CH3 -CH2-CH2-S- # C2H5 A (4H); 1.2d + 5 (6H) n R¹ R² R³ method NMR 71s (5H); 2.7m (2H); 115 1 CH3 -CH2-CH2-S - # - Cl C2H5 A 2.0-1.0m (14H); 1.2d (3H) 7.5-7.0m (4H); 2.7m (2H) 116 1 CH3 -CH2-CH2-S - # - COOH C2H5 A 2.0-1.0m (14H); 1.2d (3H) 7.9-6.9m (4H); 2.7m (2H) 117 1 CH3 -CH2-CH2-S - # - SO2NH2 C2H5 A 2.1-1.0m (14H); 1.2d (3H) 8.0-6.9m (4H); 6.5bs (2H) 118 1 CH3 -CH2-CH2-S - # - OCH3 C2H5 A 2.6m (2H); 2.0-1.0m (14H) 1.2d (3H) n R¹ R² R³ method NMR 6.9-6.4m (4H); 3.8s (3H); 119 1 CH3 CH2-CH2-S - # - CONH2 C2H5 A 2.7m (2H); 2.1-1.0m (14H): 1.2d (3H) 7.8-6.9m (4H); 6.0bs 120 1 CH3 CH2-ChH-S - # - NO2 C2H5 A (2H); 2.6m (2H); 2.0 - 1.0m (14H); 1.2d (3H) 8.1-6.9m (4H); 2.7m (2H) 121 1 H2N- (CH2) 4 CH2-CH2-S - # - CH3 C2H5 A 2.0-1.0m (14H); 1.2d (3H) 7.0-6.8m (4H); 2.7-2.3 122 1 CH3 CH2-CH2-S-CH2- # C2H5 A m + s (7H); 2.0-1.0m (20H) n R¹ R² R³ method NMR 7.2s (5H); 3.9-3.0m + s 123 1 CH3 CH2-CH2-S-CH (CH3) 2 C2H5 A (5H); 2.4m (2H); 2.0-1.0m 14H); 1.2d (3H) CH2 2.6-2.3m (3H); 2.1-1.0m 124 1 #N CH2-CH2-S-CH2-CH2-N (CH3) 2 C2H5 A (14H); 1.2d (3H); H 1.0d (6H) 7.8-6.5m (6H); 2.8-2.3m 125 1 CH3 CH2-CH2-S-CH2-CH2-CONH2 C2H5 A (14H); 2.0-1.0m (14H) O # 6.0bs (2H); 2.5-2.2m (6H) 126 1 CH3 CH2 -S- # C2H5 D 2.0-1.0m (14H); 1.2d (3H) n R¹ R² R³ method NMR O # 7.5-7.0m (5H); 2.6m (2H); 127 1 CH3 CH2-S - # - F C2H5 D 1.2d (3H) O # 7.4-6.9m (4H); 2.6m (2H); 128 1 CH3 -CH2-S-CH2- # C2H5 D 1.2d (3H) O # 7.1s (5H); 4.1s (2H); 129 1 CH3 -CH2-S-CH (CH3) 2 C2H5 D 2.6m (2H); 1.2d (3H) O # 2.8-2.5m (3H); 1.2d (3H) 130 1 CH3 -CH2-CH2-S- # C2H5 D 1.0d (6H) O # 7.4-7.0m (5H); 2.6m (2H) 131 1 CH3 -CH2-CH2-S - # - Cl C2H5 D 2.0-1.0m (14H); 1.2d (3H) n R¹ R² R³ method NMR O # 7.5-6.9m (4H); 2.6m (2H); 132 1 CH3 CH2-CH2-S - # - CHH C2H5 D 2.0-1.0m (14H); 1.2d (3H) O # 7.6-6.9m (4H); 2.6m (2H); 133 1 CH3 CH2-CH2-S-CH2- # C2H5 D 2.3s (3H); 2.0-1.0m (14H); 1.2d (3H) O # 7.1s (5H); 4.1s (2H); 134 1 CH3 CH2-CH2-S-CH (CH3) 2 C2H5 D 2.7m (2H); 2.0-1.0m (14H) 1.2d (3H) O # 2.8-2.5m (3H); 2.0-1.0m 135 1 CH3 CH2-CH2-S-CH2-CH2-N (CH3) 2 C2H5 D (14H); 1.2d (3H); 0.9d (6H) O # 2.8-2.2m + s (12H); 2.0 136 1 CH2 CH2 -S- # C2H5 E 1.0m (14H); 1.2d (3H) # O n R¹ R² R³ method NMR O # 7.8-7.1m (5H); 2.8m (2H); 137 1 CH3 CH2-S - # - F C2H5 E 1.2d (3H) # O O # 7.7-6.9m (4H); 2.0m (2H); 138 1 CH3 CH2-S-CH2- # C2H5 E 1.2d (3H) # O O # 7.2s (5H); 5.1-4.3m (4H); 139 1 CH3 CH2 -S-CH (CH3) 2 C2H5 E 2.8m (2H); 1.2d (3H) # O O # 3.0-2.7m (3H); 1.2d + 5 (9H) 140 1 CH3 CH2-CH2-S- # C2H5 E. # O O # 7.7-7.2m (5H); 2.8m (2H); 141 1 CH3 CH2-CH2-S - # - Cl C2H5 E 2.0-1.0m (14H); 1.2d (3H) # O n R¹ R² R³ method NMR 142 1 CH3 CH2-CH2-S - # - CH3 C2H5 E 8.0-7.1m (4H); 2.8m (2H); # 2.0-1.0m (14H); 1.2d (3H) O O # 7.6-6.9m (4H); 2.8m (2H); 143 1 CH3 CH2-CH2-S-CH2- # C2H5 E 2.3s (3H); 2.0-1.0m (14H); # 1.2d (3H) O O # 7.1s (5H); 4.2s (2H); 2.8m 144 1 CH3 CH2-CH2-S-CH (CH3) 2 C2H5 E (2H); 2.0-1.0m (14H); # 1.2d (3H) O O # 3.0-2.7m (3H); 2.0-1.0m 145 1 CH3 CH2-CH2-S-CH2-CH2-N (CH3) 2 C2H5 E (14H); 1.1d + 5 (9H) 3.0-2.2m + s (12H); 2.0-1.0m 146 0 CH3 CH2 -S- # C2H5 A (14H); 1.2d (3H) n R¹ R² R³ method NMR 147 O CH3 CH2-S - # - Cl C2H5 A 6.9s (5H); 2.5m (2H); 1.2d (3H) 7.4-6.8m (4H); 2.5m (2H); 148 O CH3 CH2-S- # C2H5 A 1.2d (3H) CH3 7.5-6.8m (4H); 2.5m (2H); 149 O CH3 -CH2-S-CH2- # C2H5 A 2.3s (3H); 1.2d (3H) 7.2s (5H); 3.7-3.0m + s 150 O CH3 -CH2-S-CH- (CH3) 2 C2H5 A (5H); 2.4m (2H); 1.2d (3H) 2.7-2.3m (3H): 1.2d (3H) 151 O CH3 -CH2-CH2-S- # C2H5 A 0.9d (6H) n R1 R2 R3 method NMR 152 O CH3 -CH2-CH2-S - # - Cl C2H5 A 7.0s (5H); 2.7m (2H); 2.0-1.0m (13H); 1.2d (3H) 7.5-6.5m (4H); 2.7m (2H) 153 O CH3 CH2-CH2-S - # - CH3 C2H5 A 2.0-1.0m (13H); 1.2d (3H) 7.3-6.5m (4H); 2.7-2.3m + s 154 O CH3 CH2-CH2-S-CH2- # C2H5 A (5H); 2.0-1.0m (13H); 1.2d (3H) 4.5-3.0 m + s (5H); 2.4m 155 O CH3 CH2-CH2-S-CH (CH3) 2 C2H5 A (2H); 2.0-1.0m (13H); 1.2d (3H) 2.6-2.3m (3H); 2.0-1.0m 156 O CH3 CH2 -S- # C2H5 A (13H); 1.2d (3H), 1.0d (6H) n R1 R2 R3 method NMR O # 157 O CH3 CH2 -S- # - Cl C2H5 D 7.5-7.0m (5H); 2.6m (2H) 1.2d (3H) O # 158 O CH3 -CH2-S-CH2- # C2H5 D 7.4-7.0m (4H); 2.6m (2H); 1.2d (3H) O # 159 O CH3 -CH2-S-CH (CH3) 2 C2H5 D 7.1s (5H); 4.1s (2H); 2.6m (2H); 1.2d (3H) O # 160 O CH3 -CH2-CH2-S- # C2H5 D 2.8-2.5m (3H); 1.2d (3H) 1.0d (6H) O # 161 O CH3 -CH2-CH2-S - # - Cl C2H5 D 7.4-7.0m (5H); 2.6m (2H) 2.0-1.0m (13H); 1.2d (3H) n R1 R2 R3 method NMR O # 7.5-7.0m (4H); 2.6m (2H); 162 O CH3 CH2-CH2-S - # - CH3 C2H5 D 2.0-1.0m (13H); 1.2d (3H) O # 7.6-7.0 (4H); 2.6m (2H); 163 O CH3 CH2-CH2-S-CH2- # C2H5 D 2.3s (3H); 2.1-1.0m (13H); 1.2d (3H) O # 7.1s (5H); 4.1s (2H); 164 O CH3 CH2-CH2-S-CH (CH3) 2 C2H5 D 2.7m (2H); 2.1-1.0m (13H); 1.2d (3H) O # 2.8-2.5m (3H); 2.0-1.0m 165 O CH3 CH2 -S- # C2H5 E (13H); 1.2d (3H); 1.1d (6H) # O O # 7.8-7.3m (5H); 2.8m (2H); 166 O CH3 CH2-S - # - Cl C2H5 E 1.2d (3H) # O n R1 R2 R3 method NMR O # 7.7-7.2m (4H); 2.8m (2H); 167 O CH3 -CH2-S-CH2- # C2H5 E 1.2d (3H) # O O # 7.1s (5H); 4.3s (2H); 168 O CH3 -CH2-S-CH (CH3) 2 C2H5 E 2.8m (2H); 1.2d (3H) # O O # 3.0-2.7m (3H); 1.2d + t (9H) 169 O CH3 -CH2-CH2-S- # C2H5 E. # O O # 7.7-7.2m (5H); 2.8m (2H); 170 O CH3 -CH2-CH2-S - # - Cl C2H5 E 2.0-1.0m (13H); 1.2d (3H) # O O # 8.0-7.3m (4H); 2.8m (2H) 171 O CH3 -CH2-CH2-S - # - CH3 C2H5 E 2.0-1.0m (13H); 1.2d (3H) # O n R1 R2 R3 method NMR O # 7.1s (5H); 4.2s (2H) 172 O CH3 CH2-CH2-S-CH2- # C2H5 E 2.8m (2H); 2.1-1.0m # (13H) O O # 3.0-2.7m (3H); 2.0- 173 O CH3 CH2-S-CH (CH3) 2 C2H5 E 1.0m (13H); 1.1d + t # (9H) O 174 1 CH3 -CH2-OH C2H5 A 3.9-3.0m (5H); 1.2d (3H) 175 1 CH3 -CH2-O- # C2H5 H7.0s (5H); 3.9-3.0m (5H); 1.2d (3H) 7.3-6.6m (4H); 3.9-3.0m 176 1 CH3 -CH2-O- # -CH3 C2H5 H (5H); 2.3s (3H); 1.2d (3H) n R1 R2 R3 method NMR 7.3-6.7m (4H); 3.9-3.0m 177 1 CH3 -CH2-O- # -Cl C2H5 H (5H); 1.2d (3H) OCH2 # 6.8-6.3m (4H); 3.9-3.0 178 1 H 2 N- (CH 2) 4 -CH 2 -O- # C2H5 B m + s (8H); 2.4m (2H); 2.0-1.0m (18H) 8.2-6.8m (4H); 3.9-3.0m 179 1 H2N- (CH2) 3 -CH2-O- # - NO2 C2H5 B (5H); 2.4m (2H); 2.0-1.0m (16H) 7.6-6.8m (4H); 4.2q (4H) 180 1 (CH3) 2-CH-CH2- -CH2-O- # - COOC2H5 C2H5 A 3.9-3.0m (5H); 2.0 - 1.0m (15H); 1.2t (6H); 1.0d (6H) CH3 # 7.2-6.8m (3H); 3.9-3.0m 181 1 CH3 -CH2-O- # -Cl C2H5 A (5H); 2.3s (3H); 1.2d (3H) n R1 R2 R3 method NMR 7.0s (5H); 4.0s (2H); 182 1 CH3 -CH2-O-CH2- # C2H5 A 3.9-3.0m (5H); 1.3d (3H) 7.4-6.9m (4H); 4.0s (2H) 183 1 CH3 CH2-O-CH2 - # - Cl C2H5 A 3.9-3.0m (5H); 1.2d (3H) CH3 # 7.4-7.0m (4H); 4.0s 184 1H2N- (CH2) 4 CH2-O-CH2- # C2H5 B (2H); 3.9-3.0m (5H); 2.5-2.2d + t (5H); 2.0-1.0m (18H) CH2 # 7.8-6.4m (10H); 4.0s 185 1 ## N CH2-O-CH2- # C2H5 A (2H); 3.8s (3H): 3.9-3.0 N # (5H); 2.7m (2H) H OCH3 7.8-7.0m (4H); 6.0bs (2H); 186 1H CH2-O-CH2 - # - CONH2 C2H5 A 4.0s (2H); 3.9-3.0m (6H) n R1 R2 R3 method NMR NO2 # 8.2-7.0m (4H); 4.0s (2H); 1871 HS-CH2 CH2-O-CH2- # C2H5 B 3.9-3.0m (5H); 2.3m (2H) NO2 # 7.2-6.4m (4H); 4.0s (2H); 188 1 HS-CH2 CH2-O-CH2- # C2H5 B 3.9-3.0m (5H); 2.3m (2H) 3.9-3.0m (6H); 1.2d (3H); 189 1 CH3 CH2-O-CH (CH3) 2 C2H5 H 0.9d (6H); 3.9-3.0m (7H); 2.4-2.1m + s. 1901 CH3 CH2-O-CH2-CH2-N (CH3) 2 C2H5 A (8H); 1.2d (3H) O # H 7.6-6.9m (5H); 4.0m (2H) 191 1 CH3 -CH2-OCN- # C2H5 A 1.2d (3H) n R1 R2 R3 method NMR 2.1-1.0m (14H); 192 1 CH3 CH2-CONH HA 1.2d (3H) 6.5bs (2H); 2.1-1.0m 193 1 CH3 CH2-CONH HA (14H); 1.2d (3H) 3.9-3.0m + 2s (9H); 194 1 CH3 CH2-CON (CH3) 2 HA 2.1-1.0m (14H); 1.2d (3H) CH2 # H 195 1 # N # CH2-CON- # HA 7.8-6.4m (11H); 2.8- H 1.0m (16H) CH3 # 7.3-6.9m (4H); 2.3s (3H) 196 1 CH3 Ch2-CON- # HA 2.2-1.0m (14H); 1.2d (3H) n R1 R2 R3 method NMR H 197 1 CH3 CH2-CON - # - Cl HF 7.7-6.9m (4H); 2.3m (2H); 1.2d (3H) CH2 # 13.0s (1H); 7.5-6.3m (6H) 198 1 N # N CH2-CO-NH- # -OCH3 HF 3.9s (3H); 2.7m (2H); H 2.1-1.0m (14H) 7.7-6.6m (4H); 2.1-1.0m 199 1 CH3 CH2-CO-NH - # - COOH HF (14H); 1.2d (3H) H 7.7-6.6m (4H); 2.1-1.0m 200 1 CH3 CH2-CON - # - CONH2 HF (14H); 1.2d (3H) H 7.7-6.6m (4H); 4.2q (2H) 201 1 CH3 CH2-CO-N - # - COOC2H5 HF 2.1-1.0m (14H); 1.2d + t (6H) n R1 R2 R3 method NMR H 7.3-6.4m (4H); 3.5q (2H); 202 1 CH3 CH2-CO-N - # - OC2H5 HF 2.1-1.0m (14H); 1.2d + t (6H) Cl H # 7.2-6.4m (3H); 3.9s (3H); 203 1 CH3 CH2-CO-N- # HF 2.1-1.0m (14H); 1.2d (3H) # CH3O OCH3 H # 7.1-6.3m (3H); 3.8s (6H); 204 1 CH3 CH2-CO-N - # - OCH3 HF 2.1-1.0m (14H); 1.2 (3H) OCH3 H # 7.0-6.2m (2H); 3.9s (9H); 205 1 CH3 CH2-CO-N - # - OCH3 HF 2.1-1.0m (14H); 1.2d (3H) # OCH3 4.2q (2H); 2.0-1.0m (14H) 206 1 CH3 CH2-COOC2H5 HF 1.2d + t (6H) n R1 R2 R3 method NMR 4.8 septet (1H); 2.1 - 207 1 CH3 CH2-CO-O-CH (CH3) 2 HF 1.0m (14H); 1.2d (3H); 0.9d (6H) 7.2s (5H); 5.3s (2H); 208 1 CH3 CH2-CO-O-CH2- # HF 2.1-1.0m (14H); 1.2d (3H) 2.1-1.0m (16H); 1.2d 209 1 CH3 CH2-CH2-COOH C2H5 A (3H) 2.1-1.0m (16H); 1.2d 210 1 CH3 CH2-CH2-CONH2 C2H5 A (3H) 3.02s (6H); 2.0-1.0m (14H 211 1 CH3 CH2-CH2-CON (CH3) 2 C2H5 A 1.2d (3H) n R1 R2 R3 method NMR H 7.1s (5H); 2.1-1.0m (16H) 212 1 CH3 CH2-CH2-CON- # C2H5 A 1.2d (3H) H 7.3-6.9m (4H); 2.1-1.0m 213 1 CH3 CH2-CH2-CON - # - F C2H5 A (16H); 1.2d (3H) H 7.3-6.8m (4H); 2.4-2.1m 214 1 H2N- (CH2) 4 CH2-CH2-CON - # - F C2H5 B (4H); 2.0-1.0m (20H) 7.2-6.4m (4H); 3.9s (3H); 215 1 CH3 CH2-CH2-CONH - # - CH3 C2H5 A 2.1-1.0m (16H); 1.2d (3H) OH # 7.3-6.3m (4H); 2.1-1.0m 216 1 CH3 CH2-CH2-CONH- # C2H5 A (16H); 1.2d (3H) n R1 R2 R3 method NMR Cl H # 7.2-6.4m (3H); 3.9s (3H); 217 1 CH3 CH2-CH2-CON- # HA 2.1-1.0m (16H); 1.2d (3H) # CH3O O # H 7.7-7.0m (4H); 2.1-1.0m 218 1 CH3 CH2-CH2-CN - # - CONH2 HA (16H); 1.2d (3H) H 7.6-7.0m (4H); 4.2q (2H); 219 1 CH3 CH2-CH2-CO-N - # - COOC2H5 HA 2.1-1.0m (16H); 1.2d + t (6H) O # H 7.3-6.4m (4H); 3.9-3.0m 220 1 CH3 CH2-CH2-CN - # - OC2H5 HA m + q (5H); 2.1-1.0m (16H) 1.2d + t (6H) NO2 # 8.2-6.9m (4H); 2.1-1.0m 221 1 CH3 CH2-CH2-CON- # HA (16H); 1.2d (3H) n R1 R2 R3 method NMR OCH3 H # 7.1-6.3m (3H); 3.8s (6H); 222 1 CH3 CH2-CH2-CON - # - OCH3 C2H5 A 2.1-1.0m (16H); 1.2d (3H) OCH3 H # 7.0-6.2m (2H); 3.9s (9H); 223 1 CH3 CH2-CH2-CON - # - OCH3 C2H5 A 2.1-1.0m (16H); 1.2d # (3H) OCH3 H 2.8-2.2m (3H); 2.0-1.0m 224 1 CH3 CH2-CH2-CON-CH (CH3) 2 C2H5 A (14H); 1.2d (3H); 1.0d (6H) H 7.2s (5H); 5.1-4.3m (4H); 225 1 CH3 CH2-CH2-CON-CH2- # C2H5 A 2.1-1.0m (16H); 1.2d (3H) OCH3 H # 7.1-6.3m (3H); 3.9s (6H); 226 1 CH3 CH2-CH2-CON-CH2-CH2 - # - OCH3 C2H5 A 2.9-1.0m (20H); 1.2d (3H) n R1 R2 R3 method NMR 4.5-3.0m (5H); 1.2d (3H) 227 O CH3 CH2-OH C2H5 A 6.9s (5H); 4.5-3.0m 228 O CH3 -CH2-O- # C2H5 A (5H); 1.2d (3H) 7.2s (5H); 4.0s (2H); 229 O CH3 -CH2-O-CH2- # C2H5 A 4.5-3.0m (5H); 1.2d (3H) 7.4-6.5m (4H); 4.0s (2H) 230 O CH3 CH2-O-CH2 - # - Cl C2H5 A 4.5-3.0m (5H); 1.2d (3H) 4.5-3.0m (6H); 1.2d (3H) 231 O CH3 CH2-O-CH (CH3) 2 C2H5 A 0.9d (6H) n R¹ R² R³ method NMR 4.5-3.0m (7H); 2.4-2.1 232 O CH3 CH2-O-CH2-CH2-N (CH3) 2 C2H5 A m + s (8H); 1.2d (3H) OH 7.3s (5H); 4.5-3.0m (5H) 233 O CH3 -CH2-OCN- # C2H5 A 1.2d (3H) 2.1-1.0m (13H); 1.2d 234 O CH3 CH2-COOH HA (3H) 6.5s (2H): 2.1-1.0m (13H) 235 O CH3 CH2-CONH2 HF 1.2d (3H) 4.5-3.0m + 2s (9H); 2.1- 236 O CH3 CH2-CON (CH3) 2 HF 1.0m (13H); 1.2d (3H) n R¹ R² R³ method NMR H 7.0s (5H); 2.1-1.0m (13H) 237 O CH3 CH2-CON- # HF 1.2d (3H) N, CH3 7.3-6.5m (4H); 2.3s (3H); 238 O CH3 CH2-CON- # HF 2.2-1.0m (13H); 1.2d (3H) H 7.7-6.5m (4H); 2.3m (2H); 239 O CH3 CH2-CON - # - Cl HF 1.2d (3H) 4.2q (2H); 2.0-1.0m (13H) 240 O CH3 CH2-COOC2H5 HF 1.2d + t (6H) 241 O CH3 CH2-CH2-COOH C2H5 A 2.1-1.0m (15H); 1.2d (3H) n R¹ R² R³ method NMR 2.1-1.0m (15H); 1.2d 242 O CH3 CH2-CH2-CONH2 C2H5 A (3H) 3.02s (6H); 2.0-1.0m 243 O CH3 CH2-CH2-CON (CH3) 2 C2H5 A (13H); 1.2d (3H) H 7.0s (5H); 2.1-1.0m 244 O CH3 CH2-CH2-CON- # C2H5 A (15H); 2.1d (3H) H 7.3-6.8m (4H); 2.1-1.0m 245 O CH3 CH2-CH2-CON - # - FHA (15H); 1.2d (3H) 7.3-6.4m (4H); 3.6q (2H) OH 2.1-1.0m (15H); 1.2 d + t 246 O CH3 CH2-CH2-CN - # - OC2H5 C2H5 A (6H) n R¹ R² R³ method NMR H 2.8-2.2m (3H); 2.0-1.0m 247 O CH3 CH2-CH2-CON-CH (CH3) 2 C2H5 A (13H); 1.2d (3H); 1.9d (6H) H 7.0s (5H); 5.1-4.3m + s (5H) 248 O CH3 CH2-CH2-CON-CH2- # C2H5 A 2.1-1.0m (15H); 1.2d (3H) H OCH3 7.0-6.2m (3H); 3.9s (6H); 249 O CH3 CH2-CH2-CON-CH2-CH2 - # - OCH3 C2H5 A 2.9-1.0m (19H); 1.2d (3H) 7.2s (5H); 2.6m (2H); 250 1 CH3 CH2-CH2- # C2H5 B 2.0-1.0m (14H); 1.2d (3H) n R¹ R² R³ method NMR 7.2s (5H); 2.6m (2H); 251 1 CH3 CH2-CH2- # HB 2.0-1.0m (14H); 1.2d (3H) CH3 7.4-7.0m (4H); 2.6m 2521 CH3 # C2H5 B (2H); 2.3s (3H); CH2-CH2 2.0-1.0m (14H); 1.2d (3H) 7.2s (5H); 2.8-2.5m (4H) 253 1 HO-CH2 CH2-CH2- # C2H5 B 2.0-1.0m (14H) # 7.2s (5H); 2.8-2.3m (4H) 254 1 H2C- (CH2) 4- CH2-CH2 H 2.0-1.0m (20H) n R¹ R² R³ method NMR 255 1 H2N (CH2) 3- # HB 8.2-7.1m (4H); 2.8-2.3m CH2-CH2-NO2 (4H); 2.0-1.0m (18H) Cl 7.5-6.9m (4H); 2.7m (2H) 256 1 CH3 # C2H5 B 2.0-1.0m (14H); 1.2d (3H) CH2-CH2- Cl 7.5-6.9m (4H); 2.7m 257 1 CH3 # HB (2H); 2.0-1.0m (14H); CH2-CH2- 1.2d (3H) COOH 7.8-7.m (4H); 2.7m (2H) 258 1 CH3 # HB 2.0-1.0m (14H); 1.2d (3H) CH2-CH2- HN Cl 7.5-7.0m (4H); 2.8-2.6m 2591 C-NH- (CH2) 1 # C2H5 B (4H); 2.0-1.0m (20H) H2N CH2-CH2- n R¹ R² R³ method NMR OH 7.2-6.5m (4H); 2.8-2.3m 260 1 H 2 N- (CH 2) 2 # HB (4H); 2.0-1.0m (16H) CH2-CH2- # 7.2bs (5H); 2.7-2.3m (4H) 261 1 H2N- (CH2) 5 CH2-CH2- HB 2.0-1.0m (22H) CONH2 # 7.8-7.1m (4H); 2.7-2.3m 262 1H2N- (CH2) 4 CH2-CH2-HB (4H); 2.0-2.0m (20H) # 7.2bs (5H); 2.7-2.3m (4H) 263 1 H2N-CH2 CH2-CH2- HB 2.0-1.0m (14H) n R¹ R² R³ method NMR F 7.2-6.8m (4H); 2.7m (2H); 264 1 CH3 # C2H5 B 2.0-1.0m (14H); 1.2d (3H) CH2-CH2- OCH3 7.2-6.3m (3H); 3.9s 265 1 CH3 # C2H5 B (6H); 2.7m (2H); 2.0 - CH2-CH2-OCH3 1.0m (14H); 1.2d (3G) Cl 7.3-6.4m (3H); 3.8s (3H) 266 1 CH3 # C2H5 B 2.6m (2H); 2.0-.0m (14H) CH2-CH2 OCH3 Cl 7.4-6.8m (3H); 2.7m (2H); 267 1 CH3 # C2H5 B 2.0-1.0m (14H); 1.2d (3H). CH2-CH2- Cl n R¹ R² R³ method NMR H OCH3 CH2 OCH3 13.1s (1H); 7.5-6.2m (4H); 268 1 # # C2H5 B 3.9s (9H); 2.8-2.3m (4H); CH2-CH2- 2.0-1.0m (14H) 7.3-6.0m (3H); 2.8m (2H); 269 1 CH3 # C2H5 B 2.0-1.0m (14H); 1.2d CH2-CH2- H (3H) # 7.3-6.9m (3H); 2.9m (2H); 270 1 CH3 CH2-CH2-C2H5 B 2.0-1.0m (14H); 1.2d (3H) # 7.4-6.3m (3H); 2.8-2.3m 2711 H2N- (CH2) 4 CH2-CH2-HB (4H); 2.0-1.0m (20H) CH2-CH2-8.6-7.1m (4H); 2.0m (2H); 272 1 CH3 # C2H5 B 2.0-1.0m (14H); 1.2d (3H) n R¹ R² R³ method NMR CH2-CH2 7.8-6.5m (H); 2.9m (2H); 273 1 CH3 ## C2H5 B 2.0-1.0m (14H); 1.2d (3H) H CH3 CH2-CH2 6.7s (1H); 3.9-3.0m + s (6H) 274 1 CH3 # C2H5 B 2.8m (2H); 2.0s (3H); CH3 2.0-1.0 (14H); 1.2d (3H) CH3 O 5.2s (1H); 3.2 2s (6H); 275 1 CH3 # C2H5 B 2.9m (2H); 2.0-1.0m (14H) O CH2-CH2 1.2d (3H) CH3 Cl 8.1s (1H), 3.2s (3H); 2.9m 276 1 CH3 # C2H5 B (2H); 2.0-1.0m (14H); 1.2d O CH2-CH2 (3H) CH3 n R¹ R² R³ method NMR 8.5-7.5m (6H); 3.9-3.0m 277 1 CH3 ## C2H5 B (5H); 2.0-1.0m (14H); CH2-CH2 1.2d (3H) CH2-CH2 8.8-7.4m (6H); 3.9-3.0m 278 1 CH3 ## C2H5 B (5H); 2.0-1.0m (14H); 1.2d (3H) 13.0s (1H); 3.9-2.9m (5H) 279 1 CH3 # C2H5 B 2.0-1.0m (14H); 1.2d CH2-CH2 (3H) CH2-CH2 7.9-7.4 2s (2H); 2.8m (2H) 280 1 CH3 # C2H5 B 2.0-1.0m (14H); 1.2d (3H) n R¹ R² R³ method NMR H2N CH2-CH2 8.0s (1H); 2.8m (2H); 2811 CH3 # C2H5 B 2.0-1.0m (14H); 1.2d (3H) CH3 3.2 2s (6H); 3.9-3.0m O Cl (5H); 2.0-1.0m (14H); 282 1 CH3 # C2H5 B (5H); 2.0-1.0m (14H); CH3 CH2-CH2 1.2d (3H) CH3 7.2bs (5H); 2.7m (2H); 283 1 CH3 CHCH2- # C2H5 B 2.2-1.0, (13H); 1.2d (3H); 1.0d (3H) 7.4-7.0m (4H); 2.7-2.3m 284 1 H 2 N- (CH 2) 4 CH 2 -CH 2 -CH 2 - # - Cl HB (4H); 2.0-1.0m (22H) n R¹ R² R³ method NMR CH3 7.3-6.3m (4H); 3.9s 285 1 CH3 CH2-CH2 -C- # - OCH3 C2H5 B (3H); 2.0-1.0m (16H); CH3 1.2d (3H); 1.0s (6H) HN H 7.2bs (5H); 2.9-2.6m 286 1 CN- (CH2) 3 CH2- # HB (4H); 2.0-1.0m (16H) H2N 7.4-6.9m (4H); 3.9- 287 1 H CH2- # HB 3.0m (4H); 2.7m (2H) F. 7.8-7.0m (4H); 3.9- 288 1 H CH2 - # - COOH HB 3.0m (4H); 2.7m (2H) n R¹ R² R³ method NMR OH 7.3-6.5m (4H); 3.9-3.0m 289 1 H -CH2-CH2-CH2-CH2- # HB (4H); 2.7m (2H); 2.0-1.0m (18H) 290 1 CH3 CH2 - # - CONH2 HB 7.8-7.0m (4H); 2.8m (2H); 1.2d (3H) 2911 CH3 CH2 - # - NH2 HB 7.2-6.4m (4H); 2.7m (2H); 1.2d (3H) OCH3 7.2-6.3m (3H); 3.9s (6H); 292 1 CH3 -CH2 - # - OCH3 HB 2.7m (2H); 1.2d (3H) n R¹ R² R³ method NMR OCH3 7.2-6.4m (3H); 3.8s (3H); 293 1 (CH3) 2CH-CH2 CH2-CH- # C2H5 B 2.8m (2H) 2.0-1.0m (17H) Cl 0.9d (6H) 294 1 CH3 -CH2 - ## C2H5 B 7.8-6.5mn (6H); 2.9, H (2H); 1.2d (3H) OCH3 7.2-6.2m (3H); 3.9s 295 1 (CH3) 2CH-CH2 CH2-CH2 - # - OCH3 HB (9H); 2.7m (2H); 2.0 - OCH3 1.0m (17H); 0.9d (6H) 7.3-6.0m (3H); 2.8m (2H); 296 1 CH3 # HB 1.2d (3H) CH2 H CH2 7.3-6.9m (3H); 2.9m (2H); 297 1 CH3 # HB 1.2d (3H) n R¹ R² R³ method NMR 7.4-6.3m (3H); 2.8m (2H); 298 1 CH3 # HB 1.2d (3H) CH2 8.6-7.1m (4H); 2.9m (2H); 299 1 CH3 # HB 1.2d (3H) CH2 CH2 7.8-6.5m (6H); 2.9m (2H); 300 1 CH3 ## HB 1.12d 3H) H CH3 CH2-6.5s (1H); 3.9-3.0m + s (6H) 301 1 (CH3) 2CH-CH2 # C2H5 B 2.8m (2H); 2.0s (3H); CH3 2.0-1.0m (15H); 1.0d (6H) CH3 O 5.2s (1H); 3.2s (6H); 302 1 H # C2H5 B 3.9-2.9m (5H) O CH2 CH3 n R¹ R² R³ method NMR 303 1 CH3 ## HB 8.5-7.5m (6H); 3.9-3.0m CH2- (5H); 1.2d (3H) CH2-8.8-7.4m (6H); 3.9- 304 1 CH3 ## HB 3.0m (5H); 1.2d (3H) 305 1 CH3 H2N - # - CH2-HB 8.0s (1H); 3.9-2.8m (5H) 1.2d (3H) O 8.1s (1H); 6.4s (1H); 306 1 CH3 CH3O-HB 8.1s (1H); 6.4s (1H); # 3.7s (3H); 3.9-2.9m (5H) CH2- 1.2s (3H) O 307 1 (CH3) 2CH-CH2 CH3O-HB 8.1s (1H); 6.4s (1H); 3.7 # (3H); 3.9-2.9m (5H); 2.0- CH2-CH2 1.0m (17H); 1.0d (6H) n R¹ R² R³ method NMR CH2-CH2 7.7-7.1m (2H); 3.9-2.9m 308 1 CH3 # C2H5 B (5H); 2.0-1.0m (14H) 1.2d (3H) CH2- 7.7-7.1m (2H); 3.9-2.9m 309 1 CH3 # C2H5 B (5H); 1.2d (3H) H 7.2-6.5m (5H); 2.7m (2H) 310 O CH3 # C2H5 B 2.0-1.0m (13H); 1.2d CH2-CH2 (3H) Cl 7.5-6.5m (4H); 2.7m (2H) 311 O CH3 # HB 2.0-1.0m (13H); 1.2d (3H) CH2-CH2 Cl 7.6-6.5m (3H); 4.5-2.8m 312 O CH3 # HB (5H); 2.0-1.0m (13H); CH2-CH2- 1.2d (3H) Cl n R¹ R² R³ method NMR 7.3-6.0m (3H); 2.8m (2H); 313 O CH3 # HB 2.0-1.0m (13H); 1.2d (3H) CH2-CH2 H 7.3-6.5m (3H); 4.5-2.9m 314 O CH3 # HB (5H); 2.0-1.0m (13H); CH2-CH2 1.2d (3H); CH2-CH2 8.6-6.5m (4H); 4.5-2.9m 315 O CH3 # HB 2.0-1.0m (13H); 1.2d (3H) CH2-CH2 7.8-6.5m (6H); 4.5-2.9m 316 O CH3 ## C2H5 B (5H; 2.0-1.0m (13H); 1.2d (3H) n R¹ R² R³ method NMR CH3 317 O CH3 CH-CH2- # C2H5 B 7.2-6.5m (5H) M; 4.5-2.9m (5H); 2.0-1.0m (12H); 1.2d (3H); 1.1d (3H) 7.4-6.5m (4H); 2.7-2.3m 318 O CH3 CH2-CH2-CH2 - # - Cl C2H5 B (2H); 2.0-1.0m (15H); 1.2d (3H) CH3 7.3-6.3m (4H); 3.9s (3H); 319 O CH3 CH2-CH2C - # - OCH3 C2H5 B 2.0-1.0m (15H); 1.2d CH3 (3H); 1.0s (6H) OCH3 7.2-6.3m (3H); 3.0s (3H); 320 O CH3 CH2-CH2- # C2H5 B 2.7m (2H); 2.0-1.0m (13H) Cl 1.2d (3H) n R¹ R² R³ method NMR 7.8-6.5m (6H); 4.5-2.9m 321 O CH3 -CH2 - ## C2H5 B (5H); 1.2d (3H) 7.7-6.5m (2H); 4.5-2.9m 322 O CH3 CH2-CH2 C2H5 B (5H); 2.0-1.0m (13H); H 1.2d (3H) 7.7-6.5m (2H); 4.5-2.9m 323 O CH3 # C2H5 B (5H); .2d (3H) H 2.0-1.0m (19H); 1.2d 324 1 CH3 (CH3) 2-CH-CH2-CH2-CH2 C2H5 A (3H); 0.9d (6H) n R¹ R² R³ method NMR 2.4m (2H); 2.0-1.0m 325 1 H 2 N- (CH) 4 (CH 3) 2 CH-CH 2 -CH 2 C 2 H 5 B (23H); 0.9d (6H) 2.0-1.0m (19H); 0.9d 326 1 H2N- (CH2) 3 (CH3) 2CH-CH2 C2H5 B (6H) 327 O FCH2 (CH3) 2CH C2H5 B 4.3d (2H), 2.0-1.0m (12H); 0.9d (6H) 328 1 CH3-CH2-CH2 HA 2.0-1.0m (28H); 1.0d + t CH3 # (6H) n R¹ R² R³ method NMR CH2-CH2 7.8-7.0m (7H); 2.7m (2H); 329 1 CH3 ## C2H5 A 2.0-1.0m (14H); 1.2d (3H) OH 330 1 CH3 # HB 7.3-6.5m (4H), 2.8m CH2 (2H); 1.2d (3H) OCH3 7.3-6.4m (4H); 3.9s (3H); 3311 CH3 # HB 3.9-2.9m (5H); 1.2d (3H) CH2 332 1 CH3 # 7.6-6.4m (4H); 3.8s (3H); CH2 OCH3 C2H5 B 3.9-2.9m (5H); 1.2d (3H) n R¹ R² R³ method NMR Cl 7.6-7.0m (4H); 3.9-2.9m 333 1 CH3 # C2H5 B (5H); 1.2d (3H) CH2 Cl Cl 7.8-7.0m (3H); 3.9-2.9m 334 1 CH3 # HB (5H); 1.2d (3H) CH2 NO2 8.3-7.0m (4H); 3.9-2.9m 335 1 CH3 # HB (5H); 1.2d (3H) CH2 CH3 7.4-7.0m (4H); 3.9-2.9m 336 1 CH3 # C2H5 B (5H); 2.3s (3H); 1.2d (3H) CH2 n R¹ R² R³ method NMR 5.3m (1H); 2.3m (4H); 337 1 CH3- # HA 2.0-1.0m (18H); 1.2d (3H) 5.4m (1H); 2.3m (4H); 338 1 CH3 - # HA 2.0-1.0m (16H); 1.2d (3H) 5.5m (1H); 3.9-3.0m (5H); 339 1 CH3 - # HA 2.5-1.0m (16H); 1.2d (3H) 5.9s (1H); 3.9-3.0m (7H); 340 1 CH3 - # HA 1.2d (3H) n R¹ R² R³ method NMR CH3 7.4s (1H); 2.5m (2H); 3411 CH3- # - NH (CH2) 3-C2H5 A 2.3s (6H); 2.0-1.0m CH3 (16H) 342 1 CH3 ## -CH2CH2-C2H5 A 7.5-6.8m (4H); 2.8m (1H); 2.0-1.0m (14H); 343 1 CH3 ## - CH2-CH2-HA 7.5-6.8m (4H); 2.8m (2H); 2.0-2.0m (14H) n R¹ R² R³ method NMR 344 O CH3 CH2-CH2 - # - Cl C2H5 B 7.5-6.5m (4H); 2.7m (2H; 2.0-1.0m (13H); 1.2d (3H) 345 O CH3 CH2-CH2 - # - F C2H5 B 7.5-6.6m (4H); 2.7m (2H); 2.0-1.0m (13H); 1.2d (3H) 346 O CH3 CH2-CH2- # C2H5 B 7.4-7.0m (4H); 2.6m (2H); H3C 2.3s (3H); 2.0-1.0m (13H); 1.2d (3H) Cl 347 O CH3 CH2-CH2- # C2H5 B 7.6-6.5m (3H); 4.5-2.8m (5H); Cl 2.0-1.0m (13H); 1.2d (3H) 348 O CH3 CH2-CH2 - # - Cl C2H5 B 7.5-6.5m (3H); 4.5-2.8m (5H); Cl 2.0-1.0m (13H); 1.2d (3H) 349 O CH3 CH2-CH2 - # - OCH3 C2H5 B 7.3-6.4m (4H; 4.5-2.8m (8H); 2.0-1.0m (13H); 1.2d (3H) OCH3 7.2-6.3m (3H); 3.9s (6H); 350 O CH3 CH2-CH2 - # - OCH3 C2H5 B 4.5-2.5m (5H); 2.0-1.0m (13H) 351 O CH3 CH2-CH2- # C2H5 B 7.3-6.5m (3H); 4.5-2.9m (5H); 2.0-1.0m (13H); 1.2d (3H)

Claims (5)

PATENTANSPRÜCHE: 1. Verbindungen der Formel I in welcher bedeutet n 0 oder 1 R1 und R2 t die gleich oder verschieden und auch ihrerseits substituiert sein können, je - Alkyl oder Alkenyl, mit bis zu 6 C-Atomen, - Cycloalkyl oder Cycloalkenyl mit je 5 - 7 C-Atomen, Aralkyl mit 7 - 12 C-Atomen - Aryl oder teilhydriertes Aryl mit 6-10 C-Atomen, - Aralkyl mit 7-14 C-Atomen, - ein mono- oder bicyclischer Heterocyclus mit 5 - 7 bzw. 8 - 10 Gliedern, davon 1 - 2 -S-oder -0- und/oder bis zu 4 -N-Atomen, COOR3 eine Carboxyl- oder Carbonsäureestergruppe.PATENT CLAIMS: 1. Compounds of the formula I in which n denotes 0 or 1 R1 and R2 t, which can be identical or different and also in turn substituted, each - alkyl or alkenyl, with up to 6 carbon atoms, - cycloalkyl or cycloalkenyl, each with 5-7 carbon atoms, aralkyl with 7-12 carbon atoms - aryl or partially hydrogenated aryl with 6-10 carbon atoms, - aralkyl with 7-14 carbon atoms, - a mono- or bicyclic heterocycle with 5-7 or 8-10 members, of which 1 - 2 -S- or -0- and / or up to 4 -N atoms, COOR3 a carboxyl or carboxylic acid ester group. 2. Verfahren zur Herstellung einer Verbindung der Formel I dadurch gekennzeichnet, daß man (a) eine Verbindung der Formel II mit einer Verbindung der Formel III umsetzt in denen ein Q eine nucleofuge Gruppe und das andere Q -NH2 bedeutet und R4 für H, Methyl, Ethyl, Benzyl oder tert.-Butyl steht, und gegebenenfalls die Estergruppe R3 und/oder R4 abspaltet, oder (b) eine Verbindung der Formel IV worin P H bedeutet, eines der beiden P jedoch auch die Bedeutung von R4 haben kann, yr -NW-ist und W entweder H oder eine Aminoschutzgruppe bedeutet, mit einer Verbindung der Formel V in Gegenwart eines Kondensationsmittels umsetzt und gegebenenfalls die Schutz gruppen abspaltet oder (c) eine Verbindung der Formel VI mit einer Verbindung der Formel VII umsetzt in denen ein T für ein Wasserstoffatom und eine NH2-Gruppe und das andere T für ein Sauerstoffatom steht, und die erhaltene Schiffsche Base reduziert.2. Process for the preparation of a compound of the formula I, characterized in that (a) a compound of the formula II is reacted with a compound of the formula III in which one Q denotes a nucleofugal group and the other Q denotes —NH2 and R4 denotes H, methyl, ethyl, benzyl or tert-butyl, and optionally splits off the ester group R3 and / or R4, or (b) a compound of the formula IV where PH is, but one of the two P can also have the meaning of R4, yr is -NW- and W is either H or an amino protecting group, with a compound of the formula V reacts in the presence of a condensing agent and optionally splits off the protective groups or (c) reacts a compound of the formula VI with a compound of the formula VII in which one T stands for a hydrogen atom and an NH2 group and the other T stands for an oxygen atom, and the resulting Schiff base is reduced. 3. Mittel, enthaltend eine Verbindung gemäß Anspruch 1.3. Agent containing a compound according to claim 1. 4. Verwendung einer Verbindung gemäß Anspruch 1 als Heilmittel.4. Use of a compound according to claim 1 as a medicament. 5.Verbindungen nach Anspruch 1, in denen R¹ Methyl und R² Phenethyl oder durch Halogen, Methyl oder Methoxy substituiertes Phenethyl ist.5.Verbindungen according to claim 1, in which R¹ is methyl and R² is phenethyl or phenethyl substituted by halogen, methyl or methoxy.
DE19813118191 1980-08-30 1981-05-08 Amino acid derivatives, process for their preparation, compositions containing them, and their use Withdrawn DE3118191A1 (en)

Priority Applications (39)

Application Number Priority Date Filing Date Title
DE19813118191 DE3118191A1 (en) 1981-05-08 1981-05-08 Amino acid derivatives, process for their preparation, compositions containing them, and their use
DE3177311T DE3177311D1 (en) 1980-08-30 1981-08-22 Amino acid derivatives, processes for their preparation, compositions containing them and their use.
EP81106535A EP0046953B1 (en) 1980-08-30 1981-08-22 Amino acid derivatives, processes for their preparation, compositions containing them and their use
DE8181106535T DE3177130D1 (en) 1980-08-30 1981-08-22 AMINO ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, MEANS CONTAINING THEM AND THE USE THEREOF.
AT8989105371T ATE105301T1 (en) 1980-08-30 1981-08-22 AMINO ACID DERIVATIVES, PROCESS FOR THEIR PRODUCTION, AGENTS CONTAINING THEM AND THEIR USE.
EP88102408A EP0278530A3 (en) 1980-08-30 1981-08-22 Amino acid derivatives, process for their preparation, agents containing them and their use
EP89105371A EP0328160B1 (en) 1980-08-30 1981-08-22 Amino acid derivatives, process to prepare them, composition containing them and their use
AT81106535T ATE48415T1 (en) 1980-08-30 1981-08-22 AMINO ACID DERIVATIVES, PROCESS FOR THEIR PRODUCTION, AGENTS CONTAINING THEM AND THEIR USE.
ES504955A ES504955A0 (en) 1980-08-30 1981-08-25 PROCEDURE FOR THE PREPARATION OF AMINO ACID DERIVATIVES
PT73584A PT73584B (en) 1980-08-30 1981-08-27 AMINOSAUTE DERIVATIVES PROCESS FOR THEIR MANUFACTURE THESE AGENTS AND THEIR USE
FI812652A FI90072C (en) 1980-08-30 1981-08-27 Process for the preparation of therapeutically useful tetrahydroisoc inoline derivatives
HU812478A HU189531B (en) 1980-08-30 1981-08-27 Process for producing alanin derivatives
AR286576A AR240949A1 (en) 1980-08-30 1981-08-28 PROCEDURE TO PREPARE ACID DERIVATIVES N- (AMINOALCANOIL) -AZA-BICICLOCARBOXILICO
PH26117A PH16812A (en) 1980-08-30 1981-08-28 Amino acid derivatives,agent containing these compounds,and the use thereof
JP56134401A JPS5777672A (en) 1980-08-30 1981-08-28 Amino acid derivative and manufacture
KR1019810003193A KR850001269B1 (en) 1980-08-30 1981-08-28 Process for preparing aminoacid derivatives
NZ198195A NZ198195A (en) 1980-08-30 1981-08-28 Heterocyclic amino acid derivatives and pharmaceutical compositions containing such
NO812933A NO812933L (en) 1980-08-30 1981-08-28 AMINO ACID DERIVATIVES, PROCEDURES FOR THEIR PREPARATION, MENTALS CONTAINING THE COMPOUNDS AND THEIR USE
MX7581A MX155680A (en) 1980-08-30 1981-08-28 PROCEDURE FOR PREPARING ACIDIC DERIVATIVES 1,2,3,4-TETRAHIDROISOQUINOLEIN-3-CARBOXILICO, CAHIDROISOQUINOLEIN-3-CARBOXILICO, INDOLIN-2-CARBOXILICO AND / OR OCTAHIDROINDOL-2-CARBOXILICO
DK383581A DK169382B1 (en) 1980-08-30 1981-08-28 Analogous process for the preparation of alanyl derivatives of isoquinoline derivatives
IE198681A IE67438B1 (en) 1980-08-30 1981-08-28 Aminoacid derivatives a process for their preparation agents containing these compounds and the use thereof
AU74718/81A AU544756C (en) 1980-08-30 1981-08-28 Aminoacid derivatives, a process for their preparation, agents containing these compounds, and the use thereof
GR65886A GR75331B (en) 1980-08-30 1981-08-28
ES505604A ES505604A0 (en) 1980-08-30 1981-09-18 PROCEDURE FOR THE PREPARATION OF AMINO ACID DERIVATIVES
ES505605A ES8301215A1 (en) 1980-08-30 1981-09-18 Amino acid derivatives, processes for their preparation, compositions containing them and their use.
AR28982682A AR240702A1 (en) 1980-08-30 1982-06-29 Process for the preparation of n-(aminoalkanoyl)-aza bicyclic carboxylic derivatives
US06/565,900 US5158959A (en) 1980-08-30 1983-12-27 Decahydroisoquinoline carboxylic acids
US06/565,887 US5162362A (en) 1980-08-30 1983-12-27 Octahydroindole-2-carboxylic acids
KR1019840006028A KR850001288B1 (en) 1980-08-30 1984-09-27 Process for preparing aminoacid derivatives
KR1019840005957A KR850001270B1 (en) 1980-08-30 1984-09-27 Process for preparing aminoacid derivatives
IL74857A IL74857A0 (en) 1980-08-30 1985-04-10 Aminoacid derivatives of perhydro-indole(perhydroisoquinoline)carboxylic acids,process for their preparation,and pharmaceutical compositions containing them
AU79284/87A AU599151B2 (en) 1980-08-30 1987-10-01 Aminoacid derivatives, a process for their preparation, agents containing these compounds, and the use thereof
JP63209625A JPH0678355B2 (en) 1980-08-30 1988-08-25 Amino acid derivative and production method thereof
AU36625/89A AU627741B2 (en) 1980-08-30 1989-06-20 Aminoacid derivatives, a process for their preparation, agents containing these compounds, and the use thereof
JP3077208A JPH07121955B2 (en) 1980-08-30 1991-03-18 Amino acid derivative and method for producing the same
FI914554A FI90532C (en) 1980-08-30 1991-09-27 A process for the preparation of new therapeutically useful octahydroindole derivatives
FI914555A FI90069C (en) 1980-08-30 1991-09-27 Process for the preparation of novel therapeutically useful dihydroindra derivatives
CS914094A CS409491A3 (en) 1980-08-30 1991-12-27 Derivatives of amino acids, process of their preparation, agents comprising said compounds and their application
US08/208,443 US5401766A (en) 1980-08-30 1994-03-09 Aminoacid derivatives, a process for their preparation, agents containing these compounds, and the use thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE19813118191 DE3118191A1 (en) 1981-05-08 1981-05-08 Amino acid derivatives, process for their preparation, compositions containing them, and their use

Publications (1)

Publication Number Publication Date
DE3118191A1 true DE3118191A1 (en) 1982-11-25

Family

ID=6131744

Family Applications (1)

Application Number Title Priority Date Filing Date
DE19813118191 Withdrawn DE3118191A1 (en) 1980-08-30 1981-05-08 Amino acid derivatives, process for their preparation, compositions containing them, and their use

Country Status (1)

Country Link
DE (1) DE3118191A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4511504A (en) * 1983-04-26 1985-04-16 G.D. Searle & Co. Carboxyalkyl peptide derivatives
US4558065A (en) * 1982-11-13 1985-12-10 Hoechst Aktiengesellschaft Derivatives of tricyclic aminoacids, processes for their preparation, agents containing these compounds and their use, and new bicyclic aminoacids as intermediates and processes for their preparation

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4558065A (en) * 1982-11-13 1985-12-10 Hoechst Aktiengesellschaft Derivatives of tricyclic aminoacids, processes for their preparation, agents containing these compounds and their use, and new bicyclic aminoacids as intermediates and processes for their preparation
US4511504A (en) * 1983-04-26 1985-04-16 G.D. Searle & Co. Carboxyalkyl peptide derivatives

Similar Documents

Publication Publication Date Title
EP0046953B1 (en) Amino acid derivatives, processes for their preparation, compositions containing them and their use
EP0610487B1 (en) New aminoacid derivates, process for producing the same and pharmaceutical compositions containing these compounds
EP0119161B1 (en) Benzazocinone and benzazoninone derivatives, process for their preparation, pharmaceutical preparations containing these compounds, and their therapeutical use
EP0111873B1 (en) Derivatives of cis, endo-2-azabicyclo-(5.3.0)-decane-3-carboxylic acid, process for their preparation, compositions containing them and their use
DE3242151A1 (en) NEW DERIVATIVES OF TRICYCLIC AMINO ACIDS, METHOD FOR THE PRODUCTION THEREOF, THEIR SUBSTANCES AND THE USE THEREOF, AND NEW BICYCLIC AMINO ACIDS AS INTERMEDIATE STAGES AND METHOD FOR THE PRODUCTION THEREOF
DE3210496A1 (en) NEW DERIVATIVES OF BICYCLIC AMINO ACIDS, METHOD FOR THE PRODUCTION THEREOF, THE MEANS CONTAINING THEM AND THE USE THEREOF, AND NEW BICYCLIC AMINO ACIDS AS INTERMEDIATE STAGES AND METHOD FOR THE PRODUCTION THEREOF
DE2946909A1 (en) NEW TETRAHYDROISOCHINOLINE DERIVATIVES
DE1184770C2 (en) Process for the production of antibacterially active peptides
EP0052870A1 (en) Amino acid derivatives and processes for their preparation
DE2740699C2 (en)
DE2730549A1 (en) PEPTIDE DERIVATIVES AND THEIR PRODUCTION
EP1117642A1 (en) Substituted 1,3-diaryl-2-pyridine-2-yl-3-(pyridine-2-ylamino)-propanol derivatives, methods for their production, pharmaceutical compositions containing the same and their use
DE3340208C2 (en)
DE1916481C3 (en) Hydroxylamine derivatives and drugs containing these compounds
DE1518133B1 (en) Process for the production of a new hypotensive acting hecapeptide
DE3118191A1 (en) Amino acid derivatives, process for their preparation, compositions containing them, and their use
DE2633976A1 (en) TRIPEPTIDE DERIVATIVES, PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THESE
EP0013891B1 (en) Dipeptides for use in the treatment of diseases, some compounds of this class, medicaments containing dipeptides and their manufacture
DE2819277A1 (en) NEW POLYPEPTIDE DERIVATIVES, THEIR PRODUCTION AND USE
DE3024369A1 (en) NEW TRIPEPTIDES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THEM
EP0203450B1 (en) Derivatives of bicyclic amino acids process for their preparation, agents containing them and their use
EP0328160B1 (en) Amino acid derivatives, process to prepare them, composition containing them and their use
CH672315A5 (en)
DE2730524A1 (en) PEPTIDE DERIVATIVES AND THEIR PRODUCTION
DE3032709A1 (en) N-Amino:acyl-indoline and tetra:hydro-isoquinoline carboxylic acid(s) - which are aminoacid analogues with hypotensive activity

Legal Events

Date Code Title Description
8139 Disposal/non-payment of the annual fee