DE3032709A1

DE3032709A1 - N-Amino:acyl-indoline and tetra:hydro-isoquinoline carboxylic acid(s) - which are aminoacid analogues with hypotensive activity

Info

Publication number: DE3032709A1
Application number: DE19803032709
Authority: DE
Inventors: Rolf Dipl.-Chem. Dr. 6000 Frankfurt Geiger; Bernward Dr. 6233 Kelkheim Schölkens; Volker Dipl.-Chem. Dr. 6238 Hofheim Teetz; Hansjörg Dipl.-Chem. Dr. 6243 Kronberg Urbach
Original assignee: Hoechst AG
Current assignee: Hoechst AG
Priority date: 1980-08-30
Filing date: 1980-08-30
Publication date: 1982-04-29
Also published as: MX9256A; ZA815988B; IL63683A; AR244241A1

Abstract

N-(Aminoacyl)-indoline-or -tetrahydro-isoquinoline-carboxylic acids (I) and their salts are new. n is 0 or 1; A is a fused on benzene or cyclohexane ring; R1 and R2 (both of which are opt. substd.) are 1-6C alkyl or alkenyl, 5-7C cycloalkyl or cycloalkenyl, 7-12C cycloalkyalkyl, 6-10C aryl or partially hydrogenated aryl, 7-14C aralkyl, or a mono-or bicyclic heterocycle with 5-7 or 8-10 ring members of which 1 or 2 may be S and/or O and/or up to 4 may be N; and R3 is H, 1-6C alkyl, 2-6C alkenyl or 7-14C aralkyl. The new cpds. have long-lasting intensive hypotensive activity and can be used for treating hypertenorin due to various causes. Dosages are 20-200 mg. orally or 0.01-10 mg. i.v. or s.c. for admin.

Description

Aminosäurederivate1 Verfahren zur ihrer Herstellung, dieseAmino acid derivatives1 process for their preparation, these

enthaltende Mittel und deren Verwendung Gegenstand der Erfindung ist eine Verbindung der Formel I n 0 oder 1 m 1 oder 2, aber m + n # 2 Y -S-, -0- oder -NH-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 't-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 I. n 0 or 1 m 1 or 2, but m + n # 2 Y -S-, -0- or -NH-R1 and R2, which can be identical or different and also in turn substituted, each - alkyl or alkenyl, with up to to 6 carbon atoms, - cycloalkyl or cycloalkenyl with 5 - 7 carbon atoms each, - aryl or partially hydrogenated aryl with 6 - 10 t 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 insbesorldere genannt Methyl, Ethyl, n-Propyl, Isopropyl, n-Butyl, Isobutyl, tert.-Butyl, sowie die geradkettigen und verzweigten Pentyl und Hexyle, ferner Cyclopentyl, Cyclohexyl, Cycloheptyl, Cyclopentenyl, Cyclohexenyl oder Cycloheptenyl, Phenyl, Naphthyl, Di- und Tetrahydronaphthyl.Particularly preferred examples of R1 and R2 are mentioned Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and the straight-chain ones and branched pentyl and hexyls, also cyclopentyl, cyclohexyl, cycloheptyl, Cyclopentenyl, cyclohexenyl or cycloheptenyl, phenyl, naphthyl, di- and tetrahydronaphthyl.

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 of the same or different ones Bearing 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 oder R² infragekommenden Alkyle oder Alkenyle können geradkettig oder verzweigt sein. Sie können einen oder mehrere gleiche oder verschiedene Substituenten tragen, insbesondere: Cycloalkenyl 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 -cyclalkyl-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 Aralkanoylamino 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, ferner deren Sulfoxide und Sulfone, Carboxy, Carbethoxy, Carbonamido, Alkyl-, Gycloalkyl-, Cycloalkylen- oder Dialkylaminocarbonyl mit bis zu 6 0-Atomen, Aryl- oder Aralkylaminocarbonyl, Guanido, Phenyl, Naphthyl, Di- und Tetrahydronaphthyl, das durch Halogen, Hydroxy, Acetoxy, Carboxy, Carbonamido, Sulfonamido, Nitro, Methyl, Ethyl, Methoxy oder Ethoxy mono- oder disubstituiert 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 alkyls or alkenyls which can be used as R¹ or R² can be straight-chain or be branched. They can have one or more identical or different substituents wear, in particular: cycloalkenyl 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, where the alkyl part by methoxy, ethoxy, carboxy, carbonamido, amino or alkylamino and the aryl part by the mentioned substituents and additionally by halogen or nitro can be substituted, amino, mono-, di- or trialkyl- or -cyclalkyl-amino with up to a total of 7 carbon atoms in the alkyl or cycloalkyl groups, which optionally by hydroxy, carboxy, carbonamido, carbethoxy, amino, alkyl or dialkylamino, Piperidino or morpholino can be substituted in the alkyl radical, alkyl-, aryl-, aralkyl-oxycarbonylamino or ureido, formyl, alkanoyl, aroyl or aralkanoylamino with up to 10 carbon atoms, Arylamino, aralkylamino, in which the aryl part is substituted by alkyl or alkoxy with 1-2 Carbon atoms, methylenedioxy, amino, hydroxy, acetoxy, carboxy, carbonamido, carbethoxy, Halogen or nitro can be mono- or disubstituted, alkyl, aryl or aralkyl mercapto with up to 7 carbon atoms, the alkyl part being methoxy, ethoxy, hydroxy, carboxy, Carbonamido, carbethoxy, amino or alkylamino and the aryl part by those mentioned Radicals and can additionally be substituted by halogen, nitro or sulfonamido, also their sulfoxides and sulfones, carboxy, carbethoxy, carbonamido, Alkyl, Gycloalkyl, cycloalkylene or dialkylaminocarbonyl with up to 6 0 atoms, aryl or aralkylaminocarbonyl, guanido, phenyl, naphthyl, di- and tetrahydronaphthyl, that by halogen, hydroxy, acetoxy, carboxy, carbonamido, sulfonamido, nitro, methyl, Ethyl, methoxy or ethoxy can be mono- or disubstituted, 5-7-membered mono- or 9- to 10-membered bicyclic heterocycles, optionally 1 - 2 S- or containing O atoms and / or up to 4 N atoms per ring, optionally such as may be substituted above.

Unter Alkyl ist, falls im Einzelfall nichts anderes gesagt, vorzugsweise ein geradkettiges oder verzweigtes Alkyl mit 1 - 6 C-Atomen zu verstehen. Gleiches 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. Same thing applies to alkanoyl, alkylamino, alkylmercapto.

Aryl bedeutet bevorzugt Phenyl, durch Halogen, Alkyl oder Alkoxy substituiertes Phenyl oder Naphthyl. Gleiches gilt für Aroyl, Arylamino, Arylmercapto.Aryl is preferably phenyl, substituted by halogen, alkyl or alkoxy Phenyl or naphthyl. 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. Gleiches gilt für Aralkanoyl, Aralkylamino, Aralkylmercapto.Aralkyl preferably includes benzyl, phenethyl and the corresponding, compounds substituted in the phenyl nucleus by halogen, alkyl or alkoxy. Same thing 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, Manino-n-butyl, Guanido-n-propyl, Imidazole-4-ethyl, Benzyl, 4-Hydroxybenzyl oder 3-Indolylmethyl, sowie deren funktionelle Derivate wie Ether, Ester oder Amide sind besonders bevorzugt. Der Rest R1 kann aber auch Teil von Mercapto-, Hydroxy- oder Aminosäuren sein, die nicht in der Natur vorkommen.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, manino-n-butyl, guanido-n-propyl, imidazole-4-ethyl, Benzyl, 4-hydroxybenzyl or 3-indolylmethyl, and their functional derivatives such as ethers, esters or amides are particularly preferred. The remainder R1 can also Be part of mercapto, hydroxy or amino acids that do not occur in nature.

Gegenstand der Erfindung ist ferner ein Verfahren zur Herstellung der Verbindungen der Formel I, das dadurch ge- kennzeichnet ist, daß man (a) eine Verbindung der Formel II mit einer Verbindung der Formel III umsetzt in der ein Q eine nucleofuge Gruppe und das andere Q -Y-H 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' -O-, -S- oder -NW-ist und W H oder eine Aminoschutzgruppe bedeutet, mit einer Verbindung der Formel V in Gegenwart eines Kondensationsmittels umsetzt und gegebenenfalls die Schutzgruppen abspaltet oder (c) sofern Y - -NH- ist, eine Verbindung der Formel VI mit einer Verbindung der Formel VII umsetzt in der ein T für ein Wasserstoffatom und eine NH2-Gruppe und das andere T für ein Sauerstoffatom steht, und die erhaltene Schiffsche Base reduziert oder (d) sofern Y -S- oder -NH- ist und R2 eine oC-Carbonylgruppe trägt, eine Verbindung der Formel VIII mit einer Verbindung der Formel IX umsetzt worin R8 eine Hydroxy, Alkoxy oder gegebenenfalls substituierte Aminogruppe darstellt.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 —YH 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 -O-, -S- or -NW- and WH or an amino protective group is, with a compound of the formula V reacts in the presence of a condensing agent and optionally splits off the protective groups or (c) if Y - is -NH-, 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 or (d) if Y is -S- or -NH- and R2 bears an oC-carbonyl group, a Reacts compound of formula VIII with a compound of formula IX wherein R8 represents a hydroxy, alkoxy or optionally substituted amino group.

Bevorzugt steht für R8 Amino, gesättigt oder ungesättigtes und/oder verzweigtes Alkyl-, Cyclalkyl- oder Dialkylamino mit bis zu 8 0-Atomen, wobei die beiden Alkylgruppen zum Ring geschlossen sein können, Aryl- oder aralkylamino mit bis zu 9 C-Atomerl steht, wobei Aryl wie oben substituiert sein kann.R8 is preferably amino, saturated or unsaturated and / or branched alkyl, cyclalkyl or dialkylamino with up to 8 0 atoms, the both alkyl groups can be closed to form a ring, with aryl or aralkylamino up to 9 carbon atoms, it being possible for aryl to be substituted as above.

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. 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. Auch flüssiges Ammoniak ist ein geeignetes Lösungsmittel, wobei Natrium als Base oder auch gegebenenfalls als Reduktionsmittel für Disulfide dient, die in Natriummercaptide übergehen und in dieser Form leicht mit den 2-Halogencarbonsäurederivaten reagieren. Die Reduktion der Disulfide ist selbstverständlich auch mit anderen bekannten Verwahren möglich.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. If the reactants are in aprotic organic Solvents are soluble, such a solvent is preferable, as Base advantageously a trialkylamine, tetraalkylammonium hydroxide or tetramethylguanidine or a suspension of an alkali metal or alkaline earth metal carbonate can be added. Even Liquid ammonia is a suitable solvent, using sodium as the base or also optionally serves as a reducing agent for disulfides, which are found in sodium mercaptides pass over and easily react in this form with the 2-halocarboxylic acid derivatives. The reduction of the disulfides is of course also possible with other known safeguards possible.

Die bevorzugten Ausgangsprodukte sind literaturbekannt, ihre spezifische pharmakologische Wirkung als Bestandteil der erfindungsgemäßen Verbindungen der Formel I wurde jedoch bisher nicht beschrieben. Die Verbindung X kann nach Aust.J.Chem. 20 (1967), Seite 1935, die Verbindung XI, nach Ber. 61 (1928), Seite 2377 und die Verbindung XII nach J.Amer.Chem.Soc. 70 (1948), Seite 182 hergestellt werden.The preferred starting products are known from the literature, but their specific pharmacological action as a constituent of the compounds of the formula I according to the invention has not yet been described. According to Aust.J.Chem. 20 (1967), page 1935, the compound XI, according to Ber. 61 (1928), page 2377 and the compound XII according to J.Amer.Chem.Soc. 70 (1948), page 182.

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

Die Zwischenprodukte der Formel II (Q = -YH) werden aus den lndolill-, Chillolln- oder Isochinolincarbonsäureestern durch Kondensation mit 2-Hydroxy-, 2-Mercapto- und 2-Aminocarbonsäuren erhalten. Die Hydroxygruppe kan als Acetyl- oder tert.-Butylverbindung vorübergehend geschützt werden, im allgemeinen ist aber kein besonderer Schutz erforderlich.The intermediates of the formula II (Q = -YH) are derived from the indolill, Chillolln or isoquinoline carboxylic acid esters condensation obtained with 2-hydroxy, 2-mercapto and 2-aminocarboxylic acids. The hydroxy group Can be temporarily protected as an acetyl or tert-butyl compound, in general however, no special protection is required.

Auch die Mercaptogruppe braucht nicht immer geschützt zu werden, da intermediär gebildete S-Acylverbindungen rasch Aminolyse erleiden und in die Verbindungen II mit Q = -SH übergehen. Auch der Schwefel kann aber vorübergehend durch Acetyl oder Benzoyl, Trityl, Diphenylmethyl, Acetamidomethyl oder andere S-Schutzgruppen, die in Houben-Weyl, Methoden der organischen Chemie, Band .15, beschrieben sind, geschützt sein. Eine spezielle Methode geht von den Disulfiden XIII aus, die z.B. nach folgendem Schema mit den Verbindungen der Formel V umgesetzt werden. Bevorzugt sind dabei Ausgangsverbindungen XIII, in denen R1 : R2 ist. The mercapto group does not always need to be protected either, since S-acyl compounds formed as intermediates quickly undergo aminolysis and convert to compounds II with Q = -SH. The sulfur can also be temporarily protected by acetyl or benzoyl, trityl, diphenylmethyl, acetamidomethyl or other S-protective groups, which are described in Houben-Weyl, Methods of Organic Chemistry, Volume 15. A special method is based on the disulfides XIII, which are reacted with the compounds of the formula V, for example, according to the following scheme. Starting compounds XIII in which R1 is R2 are preferred.

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. Auch ein anderes Reduktionsmittel anstelle Na/NH3 ist möglich, letzteres hat aber den Vorzug, die direkte weitere Umsetzung mit einer 2-Halogencarbonsäure zu ermöglichen.The condensation can not only be achieved with DCC / HOBt (dicyclohexylcarbodiimide / 1-hydroxybenzotriazole) but also with another suitable condensing agent, e.g. the one in Houben-Weyl, Volume 15 described. Also use another reducing agent instead Na / NH3 is possible, but the latter has the advantage of direct further conversion to allow with a 2-halocarboxylic acid.

Für die Reduktion des Disulfids mit Na/NH3 ist R4 vorteilhaft H oder tert.-Butyl.For the reduction of the disulfide with Na / NH3, R4 is advantageously H or tert-butyl.

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

Sind R1 und R2 identisch, so können R6 und R7 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. Ist Y = NH, so sollte auch der Stickstoff vorübergehend durch eine Schutzgruppe blockiert werden. Als solche kommen die in der Peptidchemie gebräuchlichen Reste in Frage, z.B.If R1 and R2 are identical, then R6 and R7 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. If Y = NH, so the nitrogen should also be temporarily blocked by a protective group. The radicals customary in peptide chemistry are suitable as such, e.g.

Benzyloxycarbonyl (falls kein Schwefel im Molekül 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 XV, das anschließend mit einer Verbindung der Formel V geöffnet wird. The reaction possibly proceeds via the isolable anhydride XV, 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 XIV ungleich, so ist vorzugsweise nur einer der Reste R6 oder R7 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 XIV are not the same, then is preferred only one of the radicals R6 or R7 is hydrogen, the other should preferably be ethyl, tert-Butyl or Benzyl sein.Man then condenses in the manner described with the Compounds of the formula V and, if appropriate, split off the protective groups.

Die für Y = NH bedeutsame Kondensation mit 2-Ketocarbonsäuren 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 condensation with 2-ketocarboxylic acids or their esters according to (c) lead in a manner known per se via Schiff's bases e.g. after reduction with sodium borohydride or sodium cyanoborohydride, by catalytic Hydrogenation or electrolytic reduction to the corresponding compounds of Formula I in good purity.

Die neuen Verbindungen besitzen 3 chiral Zentren. Die Anordnung der Liganden entspricht bevorzugt der L-Konfiguratio. Im allgemeinen können durch Kristallisation, speziell der Cyclohexylamin- oder Dicyclohexylaminsalze sterisch weitgehend einheitliche 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 3 chiral centers. The arrangement of the Ligand preferably corresponds to the L configuration. In general, through crystallization, especially the cyclohexylamine or dicyclohexylamine salts which are sterically largely uniform Compounds of formula I are obtained. Countercurrent distribution in a suitable, Solvent systems known from peptide chemistry or preparative HPLC are for Enrichment of sterically uniform forms suitable.

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

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, we 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 then appropriate when diuretics are administered concomitantly. With intravenous or subcutaneous administration, the single dose should be between 0.01 and 10 mg.

Die Verbindungen der Formel I mit Y = NH liegen als innere Salze vor. Falls beide Carboxylgruppen frei sind, können zusätzlich Alkali- und Erdalkalisalze und solche mit ph.ysiologisch unbedenklichen Aminen gebildet werden. Auch die anderen Verbindungen der Formel I können in freier Form oder als solche Salze angewandt werden.The compounds of the formula I where Y = NH are present as internal salts. If both carboxyl groups are free, alkali and alkaline earth salts can also be used and those with physiologically harmless amines are formed. The others too Compounds of the formula I can be used in free form or as such salts will.

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.

B e i s p i e l e Folgende Abkürzungen werden gebracht: 1.2.3.4-Tetrahydroisochinolin-3-carbonsäure Tic 1.2.3.4-Tetrahydrochinolin-2-carbonsäure Thc Indolin-2-carbonsäure Idc Benzyloxycarbonyl z tert-Butyloxycarbonyl Boc tert-Butyl tBu, But, tert-C4H9 4-Nitrobenzyl b Dicyclohexylcarbodiimid DCC Dimethylformamid DMF Dimethylacetamid DMA N-Ethylmorpholin MEM Cyclohexylamin CA Dicyclohexylamin DCA Soweit: kein anderes Verfahren angegeben ist, werden die in den folgenden Beispielen beschriebenen Verbindungen zur Analyse und biologischen Bestimmung einer HPLC-Reinigung unterworfen. Examples The following abbreviations are used: 1.2.3.4-Tetrahydroisoquinoline-3-carboxylic acid Tic 1.2.3.4-Tetrahydroquinoline-2-carboxylic acid Thc Indoline-2-carboxylic acid Idc Benzyloxycarbonyl z tert-Butyloxycarbonyl Boc tert-Butyl tBu, But, tert-C4H9 4-nitrobenzyl b dicyclohexylcarbodiimide DCC dimethylformamide DMF dimethylacetamide DMA N-ethylmorpholine MEM Cyclohexylamine CA Dicyclohexylamine DCA So far: no other Procedure given are the compounds described in the following examples subjected to HPLC purification for analysis and biological determination.

T. Verbindungen mit Y = 0 oder S Beispiel 1.T. Connections with Y = 0 or S Example 1.

2-(2,4-Dimethyl-3-oa-o-earhoxy-butyryl) isochinolin-3-carboensäure 2-Carbobenzoxy-3-carboxy-1,2,3,4-tetrahydroisochinolin (Z-Tic) 188 g (1,05 Mol) 3-Carboxy-1,2,4-tetrahydroisochinolin gibt man bei 0° zu 1050 ml 1 N-NaOH, und tropft dann bei dieser Temperatur unter Rühren gleichzeitig 160 ml Chlorkohlensäurebenzylester und weitere 1050 ml 1N-NaOH ein. Anschließend rührt man 2 Stunden bei Raumtemperatur. Man extrahiert dreimal mit Ather und säuert die alkalisch-wässrige Phase mit konz. HCl auf pH 1 an. Das ausgefallende Öl wird in Essigester extrahiert. Man wäscht die Essigesterlösung mit Wasser, bis die Wasserphase ein pH von 3,0 zeigt. 2- (2,4-Dimethyl-3-oa-o-earhoxy-butyryl) isoquinoline-3-carboenoic acid 2-carbobenzoxy-3-carboxy-1,2,3,4-tetrahydroisoquinoline (Z-Tic) 188 g (1.05 mol) 3-Carboxy-1,2,4-tetrahydroisoquinoline is added to 1050 ml of 1N NaOH at 0 ° and added dropwise then at this temperature while stirring at the same time 160 ml of benzyl chlorocarbonate and a further 1050 ml of 1N NaOH. The mixture is then stirred for 2 hours at room temperature. It is extracted three times with ether and the alkaline-aqueous phase is acidified with conc. HCl to pH 1. The precipitated oil is extracted into ethyl acetate. One washes the ethyl acetate solution with water until the water phase shows a pH of 3.0.

Nach Trocknung über Natriumsulfat kristallisiert das Produkt aus der Essigesterlösung nach Einengen und Anreiben. Man setzt 1,5 Liter Diisopropylather zu der Kristallsuspension und rührt eine Stunde bei Raumtemperatur, saugt ab, und trocknet das Produkt im Hochvakuum über Phosphorpentoxyd. After drying over sodium sulfate, the product crystallizes out the ethyl acetate solution after concentrating and rubbing. 1.5 liters of diisopropyl ether are used to the crystal suspension and stirred for one hour at room temperature, suctioned off, and dry the product in a high vacuum over phosphorus pentoxide.

Ausbeute: 256,7 g Schmp. 138-39 °C 2-Carbobenzoxy-3-carboxy-1,2t3,4-tetrahydroisochinolin-tert.-butylester Zur Lösung von 248,8 g (0,8 Mol) 2-Carbobenzoxy3-carboxy-1,2,3,4-tetrahydroisochinolin in 1600 ml Methylenchlorid gibt man 312 ml tert.Butanol und 3 g 4-Dimethylaminopyridin. Man kühlt auf -5 °C und setzt dann portionsweise die Lösung von 176 g icyclohexylcarbodiimid in 350 m Methylenchlorid zu. Man rührt 5 Stunden be Oo und laßt dann 16 Stunden bei Raumtemperatur stehen. Nach Absaugen vom Dicyclohexylharnstoff extrahiert man die Reaktionslösung dreimal mit gesättigter Natriumbicarbonatlösung. Man trocknet über Magnesiumsulfat, engt i.V. bei Raumtemperatur bis zur öligen Konsistenz ein, Es verbleiben 286 g produkt als gelbliches öl (97% d.Th.) NMP. 7,30 (55), 7,20 (4H), 5,17 3m (4H), 5,0s (2H): 1,46s (9H) c) 3-Carboxy-1 2,3, 4-tetrahydroisochinolin-tert-butylester-hydrochlorid 284 g 2-Carbobenzoxy-3-carboxy-1,2,3,4-tetrahydroisochinolin-te butylester (0,775 Mol) löst man in 3 Liter Methanol, gibt 15 g 10% Pd-Bariumsulfatkatalysator zu und hydriert mit Wasserstoff Normaldruck. Der pH-Wert der Lösung wird durch Zutropfen von 1 n methanolischer HCl auf pH 4,0 (Glaselektrode) gehalten. Man saugt vom Katalysator ab und dampft die Lösung im Vakuum bei Raumtemperatur zur Trockne ein. Das kristallisierte Produkt wird mit wasserfreiem Äther verrieben, abgesaugt und i.V. über Phosphorpentoxyd getrocknet. Yield: 256.7 g mp 138-39 ° C of 2-carbobenzoxy-3-carboxy-1,2t3,4-tetrahydroisoquinoline tert-butyl ester For the solution of 248.8 g (0.8 mol) of 2-carbobenzoxy-3-carboxy-1,2,3,4-tetrahydroisoquinoline 312 ml of tert-butanol and 3 g of 4-dimethylaminopyridine are added to 1600 ml of methylene chloride. The mixture is cooled to -5 ° C. and the solution of 176 g of cyclohexylcarbodiimide is then added in portions in 350 m of methylene chloride. The mixture is stirred for 5 hours at Oo and then left for 16 hours stand at room temperature. After the dicyclohexylurea has been filtered off with suction, it is extracted the reaction solution three times with saturated sodium bicarbonate solution. One dries over magnesium sulphate, concentrated i.V. at room temperature to an oily consistency, 286 g of product remain as a yellowish oil (97% of theory) of NMP. 7.30 (55), 7.20 (4H), 5.17 3m (4H), 5.0s (2H): 1.46s (9H) c) 3-carboxy-1,2,3,4-tetrahydroisoquinoline tert-butyl ester hydrochloride 284 g of 2-carbobenzoxy-3-carboxy-1,2,3,4-tetrahydroisoquinoline-te butyl ester (0.775 Mol) is dissolved in 3 liters of methanol, 15 g of 10% Pd-barium sulfate catalyst are added and hydrogenated with hydrogen at normal pressure. The pH of the solution is adjusted by dropping it kept at pH 4.0 (glass electrode) by 1N methanolic HCl. The catalyst is sucked off and the solution is evaporated to dryness in vacuo at room temperature. That crystallized The product is triturated with anhydrous ether, filtered off with suction and given over phosphorus pentoxide dried.

Ausbeute: 156 g Schmp. 180 ° (Zers.) Das Tosylat kann entweder durch Zugabe von methanolischer Toluolsulfosäure anstelle von methanolischer Salzsäure während der Hydrierung erhalten werden, oder man löst das Hydrochlorid in Wasser, versetzt mit der berechneten Menge Natriumtosylat und kühlt unter Animpfen und Rühren auf 4°C ab. Dabei fällt das Tosylat in kristalliner Form Die Kristalle werden abfiltriert, mit Wasser gewaschen und getrocknet. Yield: 156 g mp. 180 ° (decomp.) The tosylate can either through Addition of methanolic toluenesulphonic acid instead of methanolic hydrochloric acid obtained during the hydrogenation, or the hydrochloride is dissolved in water, mixed with the calculated amount of sodium tosylate and cooled with inoculation and stirring to 4 ° C. The tosylate falls in crystalline form. The crystals are filtered off, washed with water and dried.

Schmp. 139 - 140 ° (Zers.) 2-(2,4-Dimethyl-3-oxa-4-carboxy-butyryl)-1,2,3,4-tetrahydroisochinolin-3-carbonsäure 14.4 g L-Dilactylsäureanhydrid, hergestellt nach Bl. Soc. Chim. M.p. 139 - 140 ° (decomp.) 2- (2,4-Dimethyl-3-oxa-4-carboxy-butyryl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 14.4 g of L-dilactylic anhydride, produced according to Bl. Soc. Chim.

France £Q7 51(1932), Seite 589, werden in 300 ml Chloroform gelöst. Man gibt 40.4 g H-Tic-OBut, Tosylat und 13.9 ni Triethylamin zu, rührt 3 h bei-Raumtemperatur, extrahiert 2 mal mit je 50ml Wasser und trocknet über Natriumsulfat. Dann leitet man ca. - 4 g HCl-Gas ein, läßt 10 min stehen und destilliert das Lösungsmittel im Vakum ab. Die Verbindung wird über das Bisdicyclohexylaminsalz, CSchmp. 235 - 240 (Zers.)J gereinigt.France £ Q7 51 (1932), page 589, are dissolved in 300 ml of chloroform. 40.4 g of H-Tic-OBut, tosylate and 13.9 ni of triethylamine are added, and the mixture is stirred for 3 h at room temperature, extracted 2 times with 50ml of water each time and dried over sodium sulfate. Then forwards about -4 g of HCl gas are introduced, left to stand for 10 minutes and the solvent is distilled off in the vacuum. The compound is via the bisdicyclohexylamine salt, CSchmp. 235 - 240 (dec.) J cleaned.

Zum Freisetzen der Säure suspendiert man das Salz in 300 ml Essigester, versetzt mit 200 ml 1N H2S04 und rührt bis zur Auflösung der Suspension. Man trennt die Essigesterschicht ah, wäscht mit Wasser, trocknet über Natriumsulfat und destilliert das Lösungsmittel ab. Der harzige Rückstand wird beim Verreiben mit Petrolether fest.To release the acid, the salt is suspended in 300 ml of ethyl acetate, 200 ml of 1N H2S04 are added and the mixture is stirred until the suspension has dissolved. One separates the ethyl acetate layer ah, washed with water, dried over sodium sulfate and distilled the solvent off. The resinous residue becomes on trituration with petroleum ether fixed.

NMR: 7.4s (4H); 3.6 u. 4.m (5H); 3.8m (breit, 2H); 1.2 u. 1.5m (6H) Beispiel 2 2-£2-Methyl-3-oxa-4- (2' -phenylethyl) -4-carbethoxy-butyrylj-1 r 2,3,4-tetrahydroisochinolin-3-carbonsäure Aus 20.8 g 2-Hydroxy-4-phenylbuttersäure-ethylester und 2,3 g Natrium werden in 400 ml Ether das Natriumalkoholat hergestellt.NMR: 7.4s (4H); 3.6 & 4.m (5H); 3.8m (broad, 2H); 1.2 and 1.5m (6H) example 2 2- £ 2-methyl-3-oxa-4- (2 '-phenylethyl) -4-carbethoxy-butyrylj-1r 2,3,4-tetrahydroisoquinoline-3-carboxylic acid From 20.8 g of 2-hydroxy-4-phenylbutyric acid ethyl ester and 2.3 g of sodium are in 400 ml of ether produced the sodium alcoholate.

Zu der Suspension gibt man unter Rühren 17.6 g D-2-Brompropionsäure natriumsalz und rührt ca. 12 h. Dann versetzt man mit 120 ml 1N HCl, trennt die Etherschicht ab, wäscht sie mit 50 ml Wasser, trocknet über Natriumsulfat und destilliert den Ether ab. Der Rückstand kann durch Umkristallisieren des Cyclohexylaminsalzes aus Ethanol gereinigt werden. Freisetzen aus dem Salz wie unter Beispiel 1 beschrieben.17.6 g of D-2-bromopropionic acid are added to the suspension with stirring sodium salt and stir for about 12 h. Then 120 ml of 1N HCl are added and the Ether layer off, washed with 50 ml of water, dried over sodium sulfate and distilled the ether off. The residue can be obtained by recrystallizing the cyclohexylamine salt can be purified from ethanol. Release from the salt as described in Example 1.

Man löst die Verbindung in 200 ml Methylenchlorid, gibt 14.6 g H-Tic-OBut und 14 g DCC zu, rührt 2 h, läßt über Nacht stehen, filtriert anderntags vom Harnstoff ab und destilliert das Lösungsmittel im Vakuum ab. Man löst den Rückstand in 200 ml 2N HCl in Dioxan und destilliert nach 30 min Stehen das Lösungsmittel ab. Der Rückstand wird mit Ether/Petrolether (1 : 1) digeriert und im Vakuum über KOH und H2S04 getrocknet.The compound is dissolved in 200 ml of methylene chloride, and 14.6 g of H-Tic-OBut are added and 14 g of DCC are added, the mixture is stirred for 2 hours, left to stand overnight, and urea is filtered off the next day and the solvent is distilled off in vacuo. The residue is dissolved in 200 ml of 2N HCl in dioxane and, after standing for 30 minutes, the solvent is distilled off. Of the The residue is digested with ether / petroleum ether (1: 1) and in vacuo over KOH and H2S04 dried.

Durch alkalische Verseifung kann der Ethylester gespalten werden.The ethyl ester can be cleaved by alkaline saponification.

Isolieren der Säure durch Extraktion mit Essigester nach Ansäuern, Reinigung über Cyclohexylaminsalz und Freisetzen der Säure analog Beispiel 1 NMR: 7.08s; 1.34d (3H);- 6.84 u. 0.Isolation of the acid by extraction with ethyl acetate after acidification, Purification via cyclohexylamine salt and liberation of the acid analogous to Example 1 NMR: 7.08s; 1.34d (3H); -6.84 & 0.

Analog werden beispielsweise hergestellt Z R1 R2 R3 Nt4R <charakteristische S grls Tic CH3 <CH3)2CH-CH2 C2R5 7.155 (4H'; 3 Em IZa) 3.8m (2H); 1 ,36m (3t,); 1.30t (3H); 0.90 u. 0.8M (oli', H 0 zu H 0.98 u. 0.91d t6H) Thc zu " H 7.10s (4H); 2,6t (2Hj; Thc 1 R 2.Qn (2Hj; 1 .25a i;I-:;; 1.02 u.0.95d (6H) 1 CH2-CHZ C2H5 7.3s iSH); 7.05s (6+: .2 2 2 2H5 T.2q (?H)i 1.5d (3:in; 1.3t (3Ei) H R R 7.35s ('zu); 1.4d (2H); 1.03d (6H .0.9; fac " 1 C2H5 7i4s (5H!;;.2 - S.5n ( a 3.35d (z); 1.sud r38); 13t jW] H i 7.2 j 13t - 6.5 >bLreit, H 7.2 - 6.5 Lit, 411) 7.ls 7.1s (5H); 1.2d (3E Tic " O 0-CH2 C2H5 7,4 6,7 6,7(brei=r 5n0 (2N) 1 1 1 R R " 4 - 6,7 - (breit, 5); 3,6d .2H) Idc w C2H5 7,2 - 6,5 (breit1 9H); 1.2-' (3H) ; .; 1,3Ct(3H) 1 1 1 R 7,5 - 6,8 Breit, 9K) Z R1 R2 Tic - CH3 HC.-CH H 7.5 - 6.7 (breit, 8H); 3\/2 2.8s (3H) 3Ce 1 H3CI)-CH2 C2R5 275s <3H);.1.3t <3H) Idc CH3 R3C>>)-CR2 H 7.2-6.8(breit, 8H); - j 1.48d (3F.? B3 e O CH2 c2g5 4.11q (2EI) C (3H)H 2 2 5 4.llq (); 1.3jt <3H) C1-o-CH, 1 COCH2 H 7.4 - 6.&n (811) Tic Cl 0CH2 C2H5 4.osq (2H); ; .33t !3H); 2 1.3O (3?I) 02N<O-CH2 " 02N\o-cR2 8.1 - 6.&ii (SI) i 4.1cm (2E); 1. 1.35t (3H) OçN t B OCH2 R 10.5s (in); 8.2 - 6.85;, () 1 1 H3CO O-CR2 H i 7.1 - 6.6m (4H); 3.TO !3ii e H3C0 2 C2H5 7.4-6.6 (8Ei;; 3.753 (8E;; 1.38t (3K) Idc 1 . : 7.2 - 6.6 (811?; 3.78s (3H); 1.34t (3H) 1 H 9.s (in); 7.2 - .6tu tE); 3.76s (3H) Tic H3C H 3. (IH); l.2d (6? s CH-O-CHZ- CH2- 1 C2n5 4.16q (2;<); 1.21d (6H); 1.31t (H) fdc I r I . 9 Beispiel 3 2-t2- (4' -Tert.butyloxycarbonylamino-n-butyl) -3-oxa-4- (2' -phemMnlethyl)-4-carboxy-butyryl]-1,2,3,4-tetrahydroisochinolin-2-carboensäure Man stellt analog Beispiel 2. aus 2-Hydroxy-4-phenylbuttersäureethylester und D-2-Brom-4-tert. -butyloxycarbonylamino-n-hexansäure (aus D-Lysin mit Nitrosylbromid, Veresterung mit Ethanol und Einführung der Boc-Gruppe in bekannter Weise erhalten) die 2-(4|-Tert.-butyloxycarbonylamino-n-butyl)-3-oxa-4-(2 -phenylethyl)-4-carbethoxy-buttersäure her und setzt sie analog Beispiel 2 mit H-Thc-OMe, hergestellt nach Chem. Ber. 61 (1928), Seite 2377, um. Man verseift die Ester mit 2N NaOH in Dioxan-Methanol-Wasser bei pH 13 - 14, säuert bei 2 - 4 ° C bis auf pH 2 an, extrahiert die Säure mit Essigester und fällt das Dicyclohexylaminsalz aus, das aus Acetonitril umkristallisiert und in bekannter Weise zerlegt wird.For example, they are produced analogously Z R1 R2 R3 Nt4R <characteristic S grls Tic CH3 <CH3) 2CH-CH2 C2R5 7.155 (4H '; 3 Em IZa) 3.8m (2H); 1.36m (3t,); 1.30t (3H); 0.90 and 0.8M (oli ', H 0 to H 0.98 and 0.91d t6H) Thc to "H 7.10s (4H); 2.6t (2Hj; Thc 1 R 2.Qn (2Hj; 1 .25a i; I -: ;; 1.02 and 0.95d (6H) 1 CH2-CH2 C2H5 7.3s iSH); 7.05s (6+: .2 2 2 2H5 T.2q (? H) i 1.5d (3: in; 1.3t (3Ei) HRR 7.35s ('to); 1.4d (2H); 1.03d (6H .0.9; fac "1 C2H5 7i4s (5H! ;;. 2 - p.5n ( a 3.35d (z); 1.sud r38); 13t jW] H i 7.2 j 13t - 6.5> wide, H 7.2 - 6.5 lit, 411) 7.ls 7.1s (5H); 1.2d (3E Tic "O 0 -CH2 C2H5 7.4 6.7 6.7 (mash = r 5n0 (2N) 1 1 1 RR "4 - 6.7 - (broad, 5); 3,6d .2H) Idc w C2H5 7.2-6.5 (broad1 9H); 1.2- ' (3H); .; 1.3Ct (3H) 1 1 1 R 7.5 - 6.8 wide, 9K) Z R1 R2 Tic - CH3 HC.-CH H 7.5-6.7 (broad, 8H); 3 \ / 2 2.8s (3H) 3Ce 1 H3CI) -CH2 C2R5 275s <3H);. 1.3t <3H) Idc CH3 R3C >>) - CR2 H 7.2-6.8 (broad, 8H); - j 1.48d (3F.? B3 e O CH2 c2g5 4.11q (2EI) C (3H) H 2 2 5 4.llq (); 1.3jt <3H) C1-o-CH, 1 COCH2 H 7.4 - 6. & n (811) Tic Cl OCH2 C2H5 4.osq (2H); ; .33t! 3H); 2 1.3O (3? I) 02N <O-CH2 "02N \ o-cR2 8.1 - 6. & ii (SI) i 4.1cm (2E); 1. 1.35t (3H) OçN t B OCH2 R 10.5s (in); 8.2 - 6.85 ;, () 11 H3CO O-CR2 H i 7.1-6.6m (4H); 3.TO! 3ii e H3C0 2 C2H5 7.4-6.6 (8Ei ;; 3.753 (8E ;; 1.38t (3K) Idc 1. : 7.2 - 6.6 (811 ?; 3.78s (3H); 1.34t (3H) 1 H 9.s (in); 7.2 - .6tu tE); 3.76s (3H) Tic H3C H3. (IH); l.2d (6? s CH-O-CHZ- CH2- 1 C2n5 4.16q (2; <); 1.21d (6H); 1.31t (H) fdc I r I. 9 Example 3 2-t2- (4 '-Tert.butyloxycarbonylamino-n-butyl) -3-oxa-4- (2' -phemMnlethyl) -4-carboxy-butyryl] -1,2,3,4-tetrahydroisoquinoline-2 carbonic acid is prepared analogously to Example 2. from ethyl 2-hydroxy-4-phenylbutyrate and D-2-bromo-4-tert. -butyloxycarbonylamino-n-hexanoic acid (obtained in a known manner from D-lysine with nitrosyl bromide, esterification with ethanol and introduction of the Boc group) the 2- (4 | -Tert.-butyloxycarbonylamino-n-butyl) -3-oxa-4 - (2-phenylethyl) -4-carbethoxy-butyric acid and sets it analogously to Example 2 with H-Thc-OMe, prepared according to Chem. Ber. 61 (1928), page 2377, at. The esters are saponified with 2N NaOH in dioxane-methanol-water at pH 13-14, acidified at 2-4 ° C. to pH 2, the acid is extracted with ethyl acetate and the dicyclohexylamine salt is precipitated, which is recrystallized from acetonitrile and converted into known substances Way is disassembled.

NMR: 7.3s (5H); 7.ls (4H); 4.5 -o.8m (2aR); 1.40s (9H) In analoger Weise werden die aus anderen Aminosäuren hergestellten 0-Bromverbindungen umgesetzt.NMR: 7.3s (5H); 7.ls (4H); 4.5-0.8m (2aR); 1.40s (9H) In analog The 0-bromine compounds produced from other amino acids are converted.

Analog werden z. B. hergestellt: Z R1 R2 Tic Boc-NH-(CHZ)q- 6-q,CH2-CH2- 1- 38s (5H); 7.15s (); .38s (9H) O-CH2- - CH2- 1 t.2 (breit, 14H) Idc w 1 23 - 6.6 (14H); 4.15t (2R) Tic H°°C-CH2-CiI2- r 9.8 (breit, 3H); 7.25s (4in;; 7.los (5EI) ; (CH3) 2CE CH2 ß 0.82 u. 0.76d (611) w BoC-NH- (511); l.35s (911) Boc-NH-(CH2)4- (SIi); " 1 -CH 2-O-CH 2 7~45s (5ein: S.ls (2F.) w HOOC-(CHZ) 9.5s ( (3H); 8.6; 8.0; 5.15s (211); (CH2) 3- (2H): 2.13t (2H) tO-CH2- 0-CH2- 7,4 - 6.7 (9H) 2.15t (2tIi I (411); 7.ls (511); 1 C112-C112 7. 1 s (2EI) Idc " w 9.5 - 8.0 (breit, (39'i; 7.15s (511); .i - 6.&n (4H) 2-71m (19); 2.lot (2H; Beispiel 4 2-[2-(4'-Amino-n-butyl)-3-oxa-4-(2'-phenylethyl)-4-carboxybutyryl]-1,2,3,4-tetrahydrochinolin-2-carboensäure Man löst die nach Beispiel 3 erhaltene Verbindung mit R1 = Boc-NH-(CH2)4- in der 5 fachen Menge Trifluoressigsäure, destilliert nach 30 min die Säure ab, löst den Rückstand in 50-proz Methanol, rührt mit schwach basischem Ionenaustauscher, bis pH 2.8 erreicht ist. Dann wird filtriert und das Filtrat im Vakuum zur Trockene gebracht. Der Rückstand wird mit Essigester digeriert und getrocknet.Analog are z. B. manufactured: Z R1 R2 Tic Boc-NH- (CH2) q- 6-q, CH2-CH2-1-38s (5H); 7.15s (); .38s (9H) O-CH2- - CH2- 1 t.2 (broad, 14H) Idc w 1 23-6.6 (14H); 4.15t (2R) Tic H ° C-CH2-CiI2- r 9.8 (broad, 3H); 7.25s (4in ;; 7th lot (5EI); (CH3) 2CE CH2 ß 0.82 and 0.76d (611) w BoC-NH- (511); l.35s (911) Boc-NH- (CH2) 4- (SIi); "1 -CH 2-O-CH 2 7 ~ 45s (5a: S.ls (2F.) w HOOC- (CHZ) 9.5s ((3H); 8.6; 8.0; 5.15s (211); (CH2) 3- (2H): 2.13t (2H) tO-CH2- 0-CH2- 7.4 - 6.7 (9H) 2.15t (2tIi I (411); 7.ls (511); 1 C112-C112 7. 1 s (2EI) Idc "w 9.5 - 8.0 (broad, (39'i; 7.15s (511); .i - 6. & n (4H) 2-71m (19); 2.lot (2H; Example 4 2- [2- (4'-Amino-n-butyl) -3-oxa-4- (2'-phenylethyl) -4-carboxybutyryl] -1,2,3,4-tetrahydroquinoline-2-carbonic acid Man the compound obtained according to Example 3 with R1 = Boc-NH- (CH2) 4- dissolves in 5 times the amount of trifluoroacetic acid, the acid is distilled off after 30 min, the residue is dissolved in 50 percent methanol, stirred with a weakly basic ion exchanger until pH 2.8 is reached. It is then filtered and the filtrate is brought to dryness in vacuo. The residue is digested with ethyl acetate and dried.

NMR: 9.8 (breit, 2H): 7.20 (5H); 7.11s (4H); 4.0 - 3.3s (3H); 2.7m (6H); 1.9 - 1.0m (1OH).NMR: 9.8 (broad, 2H): 7.20 (5H); 7.11s (4H); 4.0-3.3s (3H); 2.7m (6H); 1.9 - 1.0 m (1OH).

Analog werden z. B.' hergestellt: Z ta R2 NMR 7.25s NH2-(CH2)4CHZ-CH2- 7.25s (411); 7.11s (5) Tic NH2-(C112)4- 2 4 2 2 2.7m (breit, 6HJ Idc " w 7.2 - 6.5m (411); 7.15s (5H).. O O-CH2- 7.5 - 6.5m (9) Tic " " 7.4 - 6.8m (5H); 7.15s (4H) Bcisuiel S 2-(2.4-Dimethyl-4-carboxy-3-thia-butyryl)-1,2,3,4-tetrahydroi sochinol in-3 -carbonsäure Man stellt aus 2-D-Brompropionsäure und L-Thiomilchsäure analog J. pr. Chem.107 (1924), Seite 241, bzw. J. biol. Chem. 60 (1924), Seite 2, 2,4-Dimethyl-3-thia-glutarsäure her. Davon setzt man 17.8 g in 150 ml Methylenchlorid mit 22 g DCC um, filtriert den Harnstoff ab und gibt 23 g H-Tic-OBut zu. Nach 14 h Stehen destilliert man das Lösungsmittel im Vakuum ab, löst den Rückstand in 200ml 2N HCl in Dioxan und destilliert das Lösungsmittel nach weiteren 20 min im Vakuum ab. Der Rückstand wird mit Ether/Petrolether (1:1) und Petrolether digeriert. Reinigung durch Kristallisatjon des Bis-DCA-Salzes oder Bis-CA-Salzes aus Ethanol oder Isopropanol. Nach Freisetzen mit Säure und Aufarbeiten analog Beispiel 1 erhält man die Titelverbindung.Analog are z. B. ' manufactured: Z ta R2 NMR 7.25s NH2- (CH2) 4CHZ-CH2- 7.25s (411); 7.11s (5) Tic NH2- (C112) 4- 2 4 2 2 2.7m (wide, 6HJ Idc "w 7.2 - 6.5m (411); 7.15s (5H) .. O O-CH2- 7.5 - 6.5m (9) Tic "" 7.4-6.8m (5H); 7.15s (4H) Bcisuiel S 2- (2,4-dimethyl-4-carboxy-3-thia-butyryl) -1,2,3,4-tetrahydroi sochinol in-3 -carboxylic acid is prepared from 2-D-bromopropionic acid and L-thiolactic acid analogously to J. pr. Chem. 107 (1924), page 241, and J. biol. Chem. 60 (1924), page 2, 2,4-dimethyl-3-thia-glutaric acid. 17.8 g of this are reacted in 150 ml of methylene chloride with 22 g of DCC, the urea is filtered off and 23 g of H-Tic-OBut are added. After standing for 14 h, the solvent is distilled off in vacuo, the residue is dissolved in 200 ml of 2N HCl in dioxane and the solvent is distilled off in vacuo after a further 20 min. The residue is digested with ether / petroleum ether (1: 1) and petroleum ether. Purification by crystallizing the bis-DCA salt or bis-CA salt from ethanol or isopropanol. After liberation with acid and work-up as in Example 1, the title compound is obtained.

Durch Lösen in Ethanol, Versetzen mit der berechneten Menge Natriummethylat und Fällen mit Ether erhält man das Di-natriumsalz.By dissolving in ethanol, adding the calculated amount of sodium methylate and precipitation with ether gives the disodium salt.

NMR: 7,25s (4H); 1.51 u. 1.46d (6H) Nach diesem verfahren werden z. B hergestellt: s R1 2 NMR Tic CH3-CH2 7.25s (4H); 1.35 u. 1.30t !6EI) Idc 1 .7.2 - 6.5m (4H) TicCHZ-CHZ 7.35s.(lOFI); 7.26s (4H); 2.9t (4H) Idc 7.4O. (val); 7.3 - 6.-(rn (411) Tlic 1 7.35s (iCH); 7.14s (4E) Ti;c (3-o-CH2- ?.20s (4H);,.4 - 6.6nt (iCH); 3.5E1 (ÇH) fdc 7.5 - 6.6m (1411) Thc 7.155 (411); 7.lls.(loH) Tic H2N-(CH2)4 7;24s (4H); 2.6 - 2.Qn,(4H); 1.35n. (811) (über Boc-Verb.) 1.36s*(-1S) Boc7 Idc 7.3 - 6.6m.(4H); t1.37s (18H) Boc7 Tic 1L2N tCH2)2- 2.6 - 2.4ru (411); 1.35m (85);O.5-O.45ri (lir' (über Boc-Verb.) 5.39 u. 7.37s (18H)'für BocS Idc " 7.4 - 6.7 (4H); 2.6 - 2.4m (4H) Tic O2L0-CH2- 8.2 - 6.9m-.(8H); 7.31s (4H) Cl- O O-CH2- 8.0 - 7.1m'(8,H); 7.3s (4H) N3 CO-O-CH2- 7;2 O-CH2- 7 2 - 6.7m (8H); . 7.32st(4H); 3.. 2 3.84s (EH) Tic ge O-CH2- 7.5 - 8m (8H) ; 7.28s (4H) ; - 3.4Cm (4H) - - coo Tic C140-CH2 8.0 - W.7m (10H); 3.65m C4H) CONH2 Tic 5 O-CH2- 8.2 - 5.5(breit; 7,Qn (12H); 2 6.5 - 5.SCbreit, 4H) Tic H,CO-CH21 7.4 - 6.7u (12H) ; 3.61m (4H); Tic H3C zu O-CH2- 2 4 - 2.25s (12H); 3.6t (6H) Tic fl2NO0-CH2 8.3 - 7.1m (1ZH);. 6.4 (breit, 4H) Beispiel 6 2-{2-Methyl-4-chenoxvmethyl-4-carboxv-3-thiabutvrv')-1,2,3,4-tetrahydroisochinolin-3-carbonsäure Man setzt 10,6 g 2-Mercaptopropionsäure mit 23.2 g H-Tic-OBut (oder H-Thc-OBut bzw. 21.8 g H-Ido-OBut) und 22 g DCC in 200 mi Methylenchloridum filtriert, destilliert das Methylenchlorid ab, löst den Rückstand in 250 ml DMA, gibt 24.5 g 2-Brom-3-phenoxypropionsäure und langsam 23 g Tetramethylguanidin zu, rührt über Nacht und destilliert das Lösungsmittel im Vakuum ab. Aufarbeitung, Abspaltung des tert. -Butylesters und Reinigung analog Beispiel 1 Nach diesem Verfahren werden z. B. hergestellt: Z R2 NMR Tic cR2-cH2- 7.25s:(4H); 7.1s (5H); 2.7m (2H); 1.9m j2H); 1.3m.(3H) fdc " 7.1 - 6.7m (4H); 3.3m'(2H) Tic F<3CH2-CH2 7.35 (iN); 7.0 - 6.7m (4H) ldc 7.2 - 6.5Lfi (8H} Tic H3Cb*CH2-cH2- 7.3 - 6.7m (8Sj " P.2-CH2- 6.6 ei (311>; 5.85 (2'{) Z R2 NKR Tic OCH2-CH2 7.25s (breit, 9H) (CH3)2CH CH2 1.35m (3H); 0.95d (6H) - Idc 7.2-6.5m (4H), 1.3m(3ñ), 0.9d (6in) Thc 1 2.3 - 0.9 (11H); 1.3m (3H); 0.86d (6H) Tic (CH3)2CH-CH2-CH2- 2.3 - O.9.(9H);1.3m (3H); 0.82d (6H) Idc 1 7.3 - 6.6m (4H) Tic (3OCH2- 7.4 - 6.6m (5H); 3.n (2EI) Idc I 7,4 6.6m(9H); 4.15t (2H) 3.55m (20 Tic B3Ct)O-CH2- 2.24s (3H) 02NtO-CE2 8.2 - 6.9m (4H); 7.25s (4H); 3.85m (ZH) ClCH2 8.0 - 7.lm (4H) F1 ClvO-CH2 7.7 - 6.9 (2s, 6H); 3.5En (2H) cl " FOO-CH2 7.6 - 6.ihn (4H); 3.6mr(2H). Idc 7.5 - 6.6u'(8H); 4.16t (2H) 2 R2 NMR Idc (CH3)3C-NH-CO-CH2-CH2 1.27s C9H) Tic CH3-CO-NH-CH2- 1.90s (3H) Tic 9 CO-NH-CH2- 7.3 - 6.8m (5H); 7.20s (4H) Idc " 7.3 - 6.6m (9H) Tic H5C2NH-CO-NH-CH2 6.7 (breit, 1H); 1.18t (3H) Tic 9 NH-CO-NH-CH2- 8.1 (breit, 1H); 7.6 - 7.QP (6H); 7.15s d 7.155 (3H); 6.5 (breit, 1H) Idc r 2 7.6 - 6.4n (9H); 4.14t (2H) Tic H5C2-NH-CO-O-CH2- 7.25s (4H); 1.15t (3H) II C N-CO-CH2-CH2- 3.2 - 1.2n (12H) Idc fl 7.2 - 6.5m (4H); 3.4 - 2.2 (14H) Tic zuH-CO-CH2-CH2- 7.7 - 7.ohm (10H) Idc l 7.6 - 6.5m t loH); 4.15.t (2H). Tic zu(CH 2) 3 6.45.s (?EI); 2.0 s (breit, 6H) C113 Z 22 Idc H3CO-CH2 7.3 - 6.6 (811); 2.25s (3H) " Clt-cvi 8.0 - 6.6m (8H) Tic -CR2o-Co-NR-(cll2)4- 7.37s (5H); 7.2 (breit, 7H;; 5.lOs (2H); 5.3 - 4.7m (1H); 3.08m (2kl; 2.1 - 1.2m (6H) CH20-CO-NH-(CH2)2 7.38s (5H); 70, (breit, 1H); 5.08s (2u); 3.1m (2ä) Tic H2N-(CK2)4- 7.255 (4H); 2.70m (2E); 1.2d (3E) (ueber Boc-verb. ì Idc " 7.2 - 6.5m ;4R); 2,73m (2H) Tic H2N-(CH2)1- 7.23s C4H); 2.73tun (2u) (über Boc-Verb.i Idc " 7.3 - .6.55 (4H); 2.72m r2B) Tic HN C-NH- (ZH2) 3- 7.25 (breit, 7H davon 3H/D aus- / tauschbar); 7.93t (brett, 7H/D) H2N 4.5 - 3.81a (4H);3.2 - 1.6n (6:) 1.3m (211) !15C2-NH-CO-CH2-CH2 6.5 (breit, iP); 3.48q (2g); 1.05t .(3H) tdc 1 7.2 - 6.3m (5E) Tic (CH3)3C-NH-CO-CH2-CH2 1.26s (9ei) Beispiel 7 2-(2-Methyl-4-phenoxymethyl-4-carbethoxy-3-thiabutyryl)-1,2,3,4-tetrahvdroisochinolin-3-carbonsaure Man arbeitet nach Beispiel 6, gibt jedoch statt der 2-Bromphenoxypropionsäure 27.3 g von deren Ethylester zu.NMR: 7.25s (4H); 1.51 and 1.46d (6H) B made: s R1 2 NMR Tic CH3-CH2 7.25s (4H); 1.35 and 1.30t! 6EI) Idc 1 .7.2 - 6.5m (4H) TicCHZ-CHZ 7.35s. (LOFI); 7.26s (4H); 2.9t (4H) Idc 7.4O. (val); 7.3 - 6 .- (rn (411) Tlic 1 7.35s (iCH); 7.14s (4E) Ti; c (3-o-CH2-? .20s (4H);,. 4 - 6.6nt (iCH); 3.5E1 (ÇH) fdc 7.5 - 6.6m (1411) Thc 7,155 (411); 7.lls. (LoH) Tic H2N- (CH2) 4 7; 24s (4H); 2.6-2 Qn, (4H); 1.35n. (811) (via Boc conn.) 1.36s * (- 1S) Boc7 Idc 7.3-6.6m. (4H); t 1.37s (18H) Boc7 Tic 1L2N tCH2) 2 - 2.6 - 2.4ru (411); 1.35m (85); O.5-O.45ri (lir ' (via Boc conn.) 5.39 and 7.37s (18H) 'for BocS Idc "7.4 - 6.7 (4H); 2.6 - 2.4m (4H) Tic O2L0-CH2- 8.2-6.9m -. (8H); 7.31s (4H) Cl-O O-CH2- 8.0-7.1m '(8, H); 7.3s (4H) N3 CO-O-CH2-7; 2 O-CH2- 72-6.7m (8H); . 7.32st (4H); 3 .. 2 3.84s (EH) Tic ge O-CH2-7.5-8m (8H); 7.28s (4H); - 3.4cm (4H) - - coo Tic C140-CH2 8.0 - W.7m (10H); 3.65m C4H) CONH2 Tic 5 O-CH2- 8.2-5.5 (broad; 7, Qn (12H); 2 6.5 - 5.Sc wide, 4H) Tic H, CO-CH21 7.4-6.7u (12H); 3.61m (4H); Tic H3C to O-CH2-2 4-2.25s (12H); 3.6t (6H) Tic fl2NO0-CH2 8.3 - 7.1m (1ZH) ;. 6.4 (wide, 4H) Example 6 2- {2-Methyl-4-chenoxvmethyl-4-carboxy-3-thiabutvrv ') - 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 10.6 g of 2-mercaptopropionic acid are added to 23.2 g of H- Tic-OBut (or H-Thc-OBut or 21.8 g of H-Ido-OBut) and 22 g of DCC in 200 ml of methylene chloride are filtered, the methylene chloride is distilled off, the residue is dissolved in 250 ml of DMA, there are 24.5 g of 2-bromine 3-phenoxypropionic acid and slowly 23 g of tetramethylguanidine are added, the mixture is stirred overnight and the solvent is distilled off in vacuo. Work-up, splitting off of the tert. -Butyl ester and purification analogous to Example 1. B. manufactured: Z R2 NMR Tic cR2-cH2- 7.25s: (4H); 7.1s (5H); 2.7m (2H); 1.9m j2H); 1.3m. (3H) fdc "7.1 - 6.7m (4H); 3.3m '(2H) Tic F <3CH2-CH2 7.35 (iN); 7.0 - 6.7m (4H) ldc 7.2 - 6.5Lfi (8H} Tic H3Cb * CH2-cH2- 7.3 - 6.7m (8Sj "P.2-CH2- 6.6 ei (311>; 5.85 (2 '{) Z R2 NKR Tic OCH2-CH2 7.25s (wide, 9H) (CH3) 2CHCH2 1.35m (3H); 0.95d (6H) - Idc 7.2-6.5m (4H), 1.3m (3ñ), 0.9d (6in) Thc 1 2.3-0.9 (11H); 1.3m (3H); 0.86d (6H) Tic (CH3) 2CH-CH2-CH2-2.3-0.9. (9H); 1.3m (3H); 0.82d (6H) Idc 1 7.3 - 6.6m (4H) Tic (3OCH2- 7.4 - 6.6m (5H); 3.n (2EI) Idc I 7.4 6.6m (9H); 4.15t (2H) 3.55m (20th Tic B3Ct) O-CH2-2.24s (3H) 02NtO-CE2 8.2-6.9m (4H); 7.25s (4H); 3.85m (ZH) ClCH2 8.0 - 7.lm (4H) F1 ClvO-CH2 7.7-6.9 (2s, 6H); 3.5En (2H) cl "FOO-CH2 7.6-6th him (4H); 3.6mr (2H). Idc 7.5-6.6u '(8H); 4.16t (2H) 2 R2 NMR Idc (CH3) 3C-NH-CO-CH2-CH2 1.27s C9H) Tic CH3-CO-NH-CH2- 1.90s (3H) Tic 9 CO-NH-CH2- 7.3-6.8m (5H); 7.20s (4H) Idc "7.3 - 6.6m (9H) Tic H5C2NH-CO-NH-CH2 6.7 (broad, 1H); 1.18t (3H) Tic 9 NH-CO-NH-CH2-8.1 (broad, 1H); 7.6 - 7.QP (6H); 7.15sd 7.155 (3H); 6.5 (wide, 1H) Idc r 2 7.6-6.4n (9H); 4.14t (2H) Tic H5C2-NH-CO-O-CH2-7.25s (4H); 1.15t (3H) II C N-CO-CH2-CH2- 3.2 - 1.2n (12H) Idc fl 7.2-6.5m (4H); 3.4 - 2.2 (14H) Tic zuH-CO-CH2-CH2- 7.7 - 7.ohm (10H) Idc l 7.6 - 6.5mt loH); 4.15.t (2H). Tic to (CH 2) 3 6.45.s (? EI); 2.0 s (wide, 6H) C113 Z 22 Idc H3CO-CH2 7.3-6.6 (811); 2.25s (3H) "Clt-cvi 8.0 - 6.6m (8H) Tic -CR2o-Co-NR- (cl12) 4-7.37s (5H); 7.2 (broad, 7H ;; 5. 10s (2H); 5.3 - 4.7m (1H); 3.08m (2cl; 2.1 - 1.2m (6H) CH20-CO-NH- (CH2) 2 7.38s (5H); 70, (broad, 1H); 5.08s (2u); 3.1m (2ä) Tic H2N- (CK2) 4-7,255 (4H); 2.70m (2E); 1.2d (3E) (via Boc-verb. ì Idc "7.2 - 6.5m; 4R); 2.73m (2H) Tic H2N- (CH2) 1- 7.23s C4H); 2.73 do (2u) (via Boc-Verb.i Idc "7.3 - .6.55 (4H); 2.72m r2B) Tic HN C-NH- (ZH2) 3- 7.25 (broad, 7H of which 3H / D ex- / exchangeable); 7.93t (board, 7H / D) H2N 4.5 - 3.81a (4H); 3.2 - 1.6n (6 :) 1.3m (211) ! 15C2-NH-CO-CH2-CH2 6.5 (broad, iP); 3.48q (2g); 1.05t. (3H) tdc 1 7.2 - 6.3m (5E) Tic (CH3) 3C-NH-CO-CH2-CH2 1.26s (9ei) Example 7 2- (2-Methyl-4-phenoxymethyl-4-carbethoxy-3-thiabutyryl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid The procedure is as in Example 6, but instead of 2-bromophenoxypropionic acid, 27.3 g of their ethyl ester too.

Nach dieser Verfahrensweise werden z.B. hergestellt: z R NMR Tic >2 7.4-6.Em (5H); 7.4 - 6.4m (9H); 7.le t4}I); 4.2q (2sps); 1.26t (3in) Iac Tlc FtO-CEI2- 7.2-6.5m (4H) ; 7.15s, (4R) Idc FOO-CH2- 7.25-6.5m (8H) Thc 1 7.2-6.5rU- (4H) ; 7.08s,(4H) Tic CH3O-O-CH2- 7.1-6.7m (4E) ; 3.75s (3H) Idc 1 7.3-6.Sm (8H) ; 3.70s (3H) Thc 1 7.2-6.6m (8H).; 3.78s..(3H) 7.23s (4H); 2.7om (2H); Tic X2N-(CH2)4- 1.6-0.8m (6H) ; - (über Boc-Verb.) 1.34mit (3H) Idc " 7,2-6.5, (4H) ; 1.6-O.Rn (6H) Thc 1 2.7m (2H) ; 1.36rn'(3H) 2 R2 NMR 2 Tic H2N-(CEI2)2- 1.15so (breit 2 H/D) titer Boc-Verb.) Idd w 1.16s (breit, 2H/D) Thc " 1.2s .(breit 2 H/D) Tic H5C2-NH-CO-CH2-cH2- 2.3t (2Hj; 1.05t (3H) Idc « 2.8 - 2.3m (4H) ; 1.06t (3H) Tic -CO-CH2-CH2- 3.2 - 2.2m (6H),- 1.8 - 1.cm (9) Idc w 7.2 - 6.5m (4H) 2.8 - 2.2m.(6H); 1.3 - 1.3m (6H) Tic ONE-CO-CH2-CH2 7.6 - 7.ti (5H) : 7.25s (4H) Idc 1 7.5 - 6.5m((gH) 7 7.9m'(iH) Thc Z 7.6 - 7.1m'(6H) , 7-13s (4H) Tic (CH3)3C-NH-CO (CH2)2 6.lm (1H) ; 1.26s (9H) Idc " 6.3m (1H); 1.25s (9H) Tic CEI-CEI2-CO-NH-CH~-CH2- 3.7m (2H); 2.26 (2H)i; 1.13t (3h) Tic CH3-CO-NH-CH2-CH2- 7.28s (4H>) 3.2m.(2H); 2.los (3ist Z R2' NMR Idc CH3-CO-NH-CH2-CH2- 7.2 - 6.5m (4H) ; 3.25m (2H) 2.12s (3H) Thc " 7.15s (4H) ; 2.1s (3H) Tic co-NH-cH2-cH2 8.0 - 7.«a (5H);21.9m 8.0 - 7.3Ta (5H»;2.9m (2:I);,15m Idc " 8.0 - 7.?s!1 (5H); 2.9ion (211); 1.55in (2H) Thc " 8.0 - 7.3m (5H); 2.9m (2H); 1.5Sm (2H) Tic Orco-N- (C2)4- 8.0 - 7,. (SH) Ide " 8.0 - 7.3n .(5B) ic NH-CO-O4H2 7.65 - 7.0i (sah) Idc " 7.65 - 7.- (5H) Tic H5C2-NH-CO-NH-CH -CH 6.5 (breit; 2H);;3.2 - 2.ohm (4H); 1.55m (zu); o.94,t (3K) Tic R5C2-NH-CO-O-CH2- 4.20m (2H); 3.0m (2kl; 0.94t (3) Tic OCH2~CH2~ 7.24s (breit, 9H): 2.8t (2H) Idc w 7.259. (5H); 2.75t (2H) Thc 1 7.24s (5H); 7.15s (4H) Z R2 NMR Tic F Tic F CH2-CH2- 7.2 - 6.7m (4H), 2.70t (2lI) Idc F e CH2-CH2- 7*3 - 6.7m (9H); 2.73t (2H) Thc "* 7.3 - 6.8m (4H); 2.71t (2H) Beispiel .8 2-(2-Methyl-4-phenylethyl-4-carboxy-3-thiabutyryl)-1,2,3,4-tetrahydroisochinolin-3-carbonsäure 21 g 2,5-Dimethyl-3,4-dithia-adipinsäure (Dithiodilactylsäure) hergestellt nach Ark. Kemi 13 (1937), Seite 12 und 45 g H-Tic-OBut werden in 700 ml Methylenchlorid mit 44 g DCC umgesetzt.: Nach 6 h filtriert man Dicyclohexylharnstoff ab, dampft ein und lost den Rückstand in flüssigem Ammoniak (ca.This procedure is used to produce, for example: z R NMR Tic> 2 7.4-6. Em (5H); 7.4 - 6.4m (9H); 7.le t4} I); 4.2q (2sps); 1.26t (3in) Iac Tlc FtO-CEI2-7.2-6.5m (4H); 7.15s, (4R) Idc FOO-CH2- 7.25-6.5m (8H) Thc 1 7.2-6.5rU- (4H); 7.08s, (4H) Tic CH3O-O-CH2-7.1-6.7m (4E); 3.75s (3H) Idc 1 7.3-6.Sm (8H); 3.70s (3H) Thc 1 7.2-6.6m (8H) .; 3.78s .. (3H) 7.23s (4H); 2.7om (2H); Tic X2N- (CH2) 4- 1.6-0.8m (6H); - (via Boc connection) 1.34 with (3H) Idc "7.2-6.5, (4H); 1.6-O.Rn (6H) Thc 1 2.7m (2H); 1.36rn '(3H) 2 R2 NMR 2 Tic H2N- (CEI2) 2- 1.15so (wide 2 H / D) titer Boc-Verb.) Idd w 1.16s (wide, 2H / D) Thc "1.2s. (Broad 2 H / D) Tic H5C2-NH-CO-CH2-cH2- 2.3t (2Hj; 1.05t (3H) Idc «2.8-2.3m (4H); 1.06t (3H) Tic -CO-CH2-CH2- 3.2 - 2.2m (6H), - 1.8 - 1.cm (9) Idc w 7.2 - 6.5m (4H) 2.8-2.2m. (6H); 1.3 - 1.3m (6H) Tic ONE-CO-CH2-CH2 7.6 - 7.ti (5H): 7.25s (4H) Idc 1 7.5 - 6.5m ((gH) 7 7.9m '(iH) Thc Z 7.6 - 7.1m '(6H), 7-13s (4H) Tic (CH3) 3C-NH-CO (CH2) 2 6.lm (1H); 1.26s (9H) Idc "6.3m (1H); 1.25s (9H) Tic CEI-CEI2-CO-NH-CH ~ -CH2- 3.7m (2H); 2.26 (2H) i; 1.13t (3h) Tic CH3-CO-NH-CH2-CH2- 7.28s (4H>) 3.2m. (2H); 2. lot (3ist Z R2 'NMR Idc CH3-CO-NH-CH2-CH2-7.2-6.5m (4H); 3.25m (2H) 2.12s (3H) Thc "7.15s (4H); 2.1s (3H) Tic co-NH-cH2-cH2 8.0 - 7th «a (5H); 21.9m 8.0 - 7.3 Ta (5H »; 2.9m (2: I) ;, 15m Idc "8.0 - 7.?s!1 (5H); 2.9ion (211); 1.55in (2H) Thc "8.0-7.3m (5H); 2.9m (2H); 1.5Sm (2H) Tic Orco-N- (C2) 4- 8.0 - 7 ,. (SH) Ide "8.0 - 7.3n. (5B) ic NH-CO-O4H2 7.65 - 7.0i (saw) Idc "7.65 - 7.- (5H) Tic H5C2-NH-CO-NH-CH-CH 6.5 (broad; 2H) ;; 3.2 - 2.ohm (4H); 1.55m (to); o.94, t (3K) Tic R5C2-NH-CO-O-CH2-4.20m (2H); 3.0m (2cl; 0.94t (3) Tic OCH2 ~ CH2 ~ 7.24s (broad, 9H): 2.8t (2H) Idc w 7,259. (5H); 2.75t (2H) Thc 1 7.24s (5H); 7.15s (4H) Z R2 NMR Tic F Tic F CH2-CH2- 7.2 - 6.7m (4H), 2.70t (2lI) Idc Fe CH2-CH2-7 * 3-6.7m (9H); 2.73t (2H) Thc "* 7.3 - 6.8m (4H); 2.71t (2H) Example .8 2- (2-Methyl-4-phenylethyl-4-carboxy-3-thiabutyryl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 21 g of 2,5-dimethyl-3,4-dithia- adipic acid (dithiodilactylic acid) manufactured according to Ark. Kemi 13 (1937), page 12 and 45 g of H-Tic-OBut are reacted in 700 ml of methylene chloride with 44 g of DCC .: After 6 h, dicyclohexylurea is filtered off, evaporated and the residue is dissolved in liquid ammonia (approx.

700 ml). Bei 400 gibt man Natrium jis zur bestehenden Blaufärbung zu und trägt langsam 64.4 g Natriumsalz der 2-Brom-4-phenylbuttersäure, hergestellt nach Chem. Ber. 39, (1906), Seite 2213, ein. Man rührt einige Stunden (im allgemeinen ist die Reaktion schon nach 1 h beendet) bei -30° und destilliert das Ammoniak durch Erhöhen der Badtemperatur ab. Der Rückstand wird zwischen 250 ml iN H2S04 und 400 ml Essigester verteilt, der Essigester mit wenig Wasser gewaschen, über Natriumsulfat getrocknet und abdestilliert. Die zurückbleibende Verbindung wird nach Spalten des tert.-Butylesters analog Beispiel 1 durch Umkristallisieren des CA-Salzes aus Isoprepanol/Acetonitril gereinigt. Freisetzen der Säure analog Beispiel 11 NMR: 8.30s (5H); 7.20s (4EI); ; 3.8 - 3.3 (4H) Beispiel 9 2-(2-Methyl-4.5-diethyloxycarbonyl-3-thiaveleryl)-1,2,3,4-tetrahdroisochinolin-3-carbonsä Man setzt 15.3 g 2-Brompropionsäure mit 23.2 g H-Tic-OBu und 22 g DCC in 250 ml Methylenchlorid um, filtriert, destilliert das Lösungsmittel im Vakuum ab. Man gibt 27.8 g 2-Mercaptobernsteinsäure-diethylester in 200 ml DMF zum Rückstand und tropft langsam unter Rühren 11.5 g Tetramethylguanidin zu.700 ml). At 400, add sodium jis to the existing blue color and slowly contributes 64.4 g of the sodium salt of 2-bromo-4-phenylbutyric acid, prepared according to Chem. Ber. 39, (1906), p. 2213. It is stirred for a few hours (generally the reaction is already over after 1 h) at -30 ° and the ammonia distills through Increase the bath temperature. The residue is between 250 ml in H2S04 and 400 ml of ethyl acetate distributed, the ethyl acetate washed with a little water over sodium sulfate dried and distilled off. The remaining connection is after splitting the tert-butyl ester analogous to Example 1 by recrystallizing the CA salt from isoprepanol / acetonitrile cleaned. Release of the acid analogously to Example 11 NMR: 8.30s (5H); 7.20s (4EI); ; 3.8 - 3.3 (4H) Example 9 2- (2-Methyl-4,5-diethyloxycarbonyl-3-thiaveleryl) -1,2,3,4-tetrahdroisoquinoline-3-carboxylic acid 15.3 g of 2-bromopropionic acid are added with 23.2 g of H-Tic-OBu and 22 g of DCC in 250 ml Methylene chloride, filtered, the solvent is distilled off in vacuo. One gives Add 27.8 g of diethyl 2-mercaptosuccinate in 200 ml of DMF to the residue and add dropwise 11.5 g of tetramethylguanidine are slowly added with stirring.

Nach Stehen über Nacht destilliert man das Lösungsmittel im Vakuum ah und verteilt den Rückstand zwischen 250 ml Essigester und 150 ml 1N H2S04. Die Essigesterphase wird abgetrennt und über Natriumsulfat getrocknet. Nach Abdestillieren des Lösungsmittels spaltet man den tert.-Butylester mit 2N HCl in Dioxan, destilliert das Dioxan nach 15 min Stehen ab, digeriert den Rückstand mit Ether/Petrolether (1 : 1) und reinigt die Verbindung analog Beispiel 1 über das CA-Salz.After standing overnight, the solvent is distilled in vacuo ah and distribute the residue between 250 ml of ethyl acetate and 150 ml of 1N H2S04. the The ethyl acetate phase is separated off and dried over sodium sulfate. After distilling off of the solvent, the tert-butyl ester is cleaved with 2N HCl in dioxane, and the mixture is distilled the dioxane is removed after standing for 15 minutes, and the residue is digested with ether / petroleum ether (1: 1) and purifies the compound analogously to Example 1 using the CA salt.

NMR: 4.25u. 4.14q (2H); 3.28 (breit, 2H); 1.36m (3H); 1.30 u. 1.23t (311).NMR: 4.25u. 4.14q (2H); 3.28 (broad, 2H); 1.36m (3H); 1.30 and 1.23t (311).

Beispiel 10 2-(2-Methyl-4-tert.-butyloxymethyl-4-carboxy-3-thiabutyryl)-1,2,3,4-tetrahydroisochinolin-3-carbonsäure 32 g 2-Mercaptopropionyl-Tic-OBut werden 30 min in 150 ml Trifluoressigsäure @ stehen gelassen. Man destilliert die Trifluoressigsäure im Vakuum ab, verteilt den Rückstand zwischen 250 ml Chloroform und 150-ml Wasser, trennt die Chloroformschicht ab, wäscht sie mit wenig Wasser, trocknet über Natriumsulfat und destilliert das Chloroform ab.Example 10 2- (2-Methyl-4-tert-butyloxymethyl-4-carboxy-3-thiabutyryl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 32 g of 2-mercaptopropionyl-Tic-OBut are left to stand in 150 ml of trifluoroacetic acid for 30 minutes calmly. The trifluoroacetic acid is distilled off in vacuo and the residue is distributed between 250 ml of chloroform and 150 ml of water, separates the chloroform layer, washes them with a little water, dry over sodium sulfate and distill the chloroform away.

Der Rückstand wird in 250 ml Dimethylformamid gelöst. Man gibt 22 g 2-Brom-3-tert.-butyloxypropionsäure und 34 g Tetraraethylguanidin (cder 42 ml Triethylamin) zu und rührt über Nacht.The residue is dissolved in 250 ml of dimethylformamide. One gives 22 g 2-bromo-3-tert-butyloxypropionic acid and 34 g tetraraethylguanidine (or 42 ml Triethylamine) and stir overnight.

Man destilliert das Lösungsmittel im Vakuum ab, verteilt den Rückstand zwischen 8300 ml Essigester und 250 ml 1N H2S04, trennt die Essigesterschicht ab, wäscht sie mit wenig Wasser, trocknet über Natriumsulfat und destilliert den Essigester ab.The solvent is distilled off in vacuo and the residue is distributed between 8300 ml of ethyl acetate and 250 ml of 1N H2S04, separates the ethyl acetate layer, washes them with a little water, dried over sodium sulfate and distilled the ethyl acetate away.

Der Rückstand wird analog Beispiel 1 über das Dicyclohexylammoniumsalz gereinigt.The residue is analogous to Example 1 via the dicyclohexylammonium salt cleaned.

NMR: 3.55 m (2H); 1.30s (9H); 1.2 (3H) Nach diesem Beispiel werden u. a. hergestellt: Z R2 NMR Tic Bos-NH-(CH2)4- 3.08 (breit, 2H); 2.0 - 1.5m (9H) 1.37s (9H) Bos-NH-(CH2)2- 3.15 (breit, 2H); 2.0 - 1.5 (5h): 1.38s (9H) Idc n 3.10 (breitt2Hì; 2.0 - 1.5m (5H); 1.40s (9H) " Boc-NH-(CH2)- 2.1 - 1.5m (9H); 1.37m (9H) Beispiel 11 2-(2-Methyl-4-tert.-butyloxymethyl-4-carbethoxy-3-thiabutyryl)-1,2,3,4-tetrahydroisochinolin-3-carbonsäure Man arbeitet nach Beispiel n 1 setzt jedoch 25 g 2-Brom-3-tert.-butyloxypropionsäure-ethylester und 23 g Tetramethylguanidin (bzw. 28 ml Triethylamin) ein.NMR: 3.55 m (2H); 1.30s (9H); 1.2 (3H) According to this example the following are produced: Z R2 NMR Tic Bos -NH- (CH2) 4- 3.08 (broad, 2H); 2.0-1.5m (9H) 1.37s (9H) Bos-NH- (CH2) 2- 3.15 (broad, 2H); 2.0-1.5 (5h): 1.38s (9H) Idc n 3.10 (broad2Hì; 2.0-1.5m (5H); 1.40s (9H) "Boc-NH- (CH2) - 2.1-1.5m (9H); 1.37m (9H) Example 11 2- (2-methyl-4-tert-butyloxymethyl-4-carbethoxy-3-thiabutyryl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid g of ethyl 2-bromo-3-tert-butyloxypropionate and 23 g of tetramethylguanidine (or 28 ml of triethylamine).

Nach diesem Beispiel werden u. a. hergestellt: Z R2 NMR Tic Boc-NH-(CH2)4- 4.10q (2H); 1.30t (3H); 1.28s (9H) 1.20d (3H) Idc " 7.2 - 6.5m (4H); 4.11q (2H);2.1 -(5H); 1,30 t (3H); 1.29s (9H), " Boc-NH-(CH2)2- 2.0 - 1.3m (5H); 1.31s (9H) Tic " 7.20s (4H); 1.31s (9H); 1.21m (3H Thc MM 7.15s (4H); i.30s (9H); 1.20m (3H Z R2 NMR Idc -N}3 7.S-6.5m (4H) Tic -NJ 7.3-7.Otn t4H) Idc . 7.4-6.5m (4H) Tic -N(CH3)2 7.2bs (4H); 2.ls (6H) Tic N(C2E5)2 7.2bs (J4H); 1.0t (6ei) 7.4-6.5m (4H); 1.0t (6F) Thc 1 7.3-7.0m (4H); 1.0t (6H) Tic -EHQ 7.2bs (4H) Idc 7.4-6.5m (4H) Thc CONH2 7.3-7.Om (411) Tic -NHt Q 7.8-6.9m (8B) Tic -NHCCOC2H5 7.8-6.3m (8H); 4.2g :2H): 1.2ddt (6H) Tic -NH-F 7.2-6.3m (89:; 1.2,,:, (311) Tic -NBt9 7.2-6.3m (8); 1.2d (3E) Tlc -NHt3Cl 7.3-6.5m (8in); 1.2d (3I1) Tic -NHt3CH3 7.3-6.4m (8H); 2.2s (3H); 1.2d (311) Tic -NH-CH2 t3No2 8.2-7.0m (8H); 3.8s (2H) 1.2d (3H) Idc " 8.2-6.5m (8H); 3.8s (211) Thc " 8.2-6.9m (8H); 3.8s (2H) Tic -NH-CH243 7.4-6.9m (8H); 3.5s (2H) F 1-2d (3H) Idc 7.4-6.5m (8in); 3.5s (2H) 1.2d (311) Thc t 7.4-7.0m (8); 3.5s (2H) 1.2d (3}1) Z R2 NMR 3032709 Tic -NH t °C2H5 7.3-6.4m (8H); 3.4q (2H); 1.2ddt C6H) Idc I 7.3-6.4m (8H); 3.4 q (2H); 1.2d+t (6H) Thc n 7.3-6.4m (8H); 3.4q (2H); 1.2ddt C6H) Beispiel 12 2-(2-Methyl-3-thia-4-carboxy-6-benzylamidoadipoyl)-1,2,3,4-tetrahydroisochinolin-3-carbonsäure Man stellt nach J. Amer. Chem. Soc. 75 (1953), Seite 330, das Benzylamidsalz des Maleinsäure-monobenzylamids her und macht die Säure analog Beispiel 1 aus dem Salz frei.According to this example the following are produced: Z R2 NMR Tic Boc-NH- (CH2) 4-4.10q (2H); 1.30t (3H); 1.28s (9H) 1.20d (3H) Idc "7.2 - 6.5m (4H); 4.11q (2H); 2.1 - (5H); 1.30 t (3H); 1.29s (9H)," Boc-NH - (CH2) 2-2.0-1.3m (5H); 1.31s (9H) Tic "7.20s (4H); 1.31s (9H); 1.21m (3H Thc MM 7.15s (4H); i.30s (9H); 1.20m (3H Z R2 NMR Idc -N} 3 7.S-6.5m (4H) Tic -NJ 7.3-7.Otn t4H) Idc. 7.4-6.5m (4H) Tic -N (CH3) 2 7.2bs (4H); 2.ls (6H) Tic N (C2E5) 2 7.2bs (J4H); 1.0t (6ei) 7.4-6.5m (4H); 1.0t (6F) Thc 1 7.3-7.0m (4H); 1.0t (6H) Tic -EHQ 7.2bs (4H) Idc 7.4-6.5m (4H) Thc CONH2 7.3-7.Om (411) Tic -NHt Q 7.8-6.9m (8B) Tic -NHCCOC2H5 7.8-6.3m (8H); 4.2g: 2H): 1.2ddt (6H) Tic -NH-F 7.2-6.3m (89 :; 1.2 ,,:, (311) Tic -NBt9 7.2-6.3m (8); 1.2d (3E) Tlc -NHt3Cl 7.3-6.5m (8in); 1.2d (3I1) Tic -NHt3CH3 7.3-6.4m (8H); 2.2s (3H); 1.2d (311) Tic -NH-CH2 t3No2 8.2-7.0m (8H); 3.8s (2H) 1.2d (3H) Idc "8.2-6.5m (8H); 3.8s (211) Thc "8.2-6.9m (8H); 3.8s (2H) Tic -NH-CH243 7.4-6.9m (8H); 3.5s (2H) F 1-2d (3H) Idc 7.4-6.5m (8in); 3.5s (2H) 1.2d (311) Thc t 7.4-7.0m (8); 3.5s (2H) 1.2d (3} 1) Z R2 NMR 3032709 Tic -NH t ° C2H5 7.3-6.4m (8H); 3.4q (2H); 1.2ddt C6H) Idc I 7.3-6.4m (8H); 3.4 q (2H); 1.2d + t (6H) Thc n 7.3-6.4m (8H); 3.4q (2H); 1.2ddt C6H) Example 12 2- (2-Methyl-3-thia-4-carboxy-6-benzylamidoadipoyl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Prepared according to J. Amer. Chem. Soc. 75 (1953), page 330, the benzylamide salt of maleic acid monobenzylamide and releases the acid from the salt analogously to Example 1.

20.5 g des Monoamids werden in 200 ml DMF mit 32g 2-Mercaptopropionyl-Tic-CBu in Anwesenheit den 28 ml Triethylamin während 24h bei 60-700C umgesetzt. Aufarbeitung, Abspaltung des tert.-Butylesters und Reinigung analog Beispiel 1.20.5 g of the monoamide are dissolved in 200 ml of DMF with 32 g of 2-mercaptopropionyl-Tic-CBu reacted in the presence of the 28 ml of triethylamine for 24 hours at 60-700C. Reconditioning, Cleavage of the tert-butyl ester and purification as in Example 1.

Nach diesem Verfahren werden z.B. hergestellt Z R2 N}IR Tho -NH-CH2<3 7.4-7.Cm (9H); 5.C-4.5 (iN); 3.9-3.0m (4H); 2.5-1.7m (6H:; 1.2d (3H). Idc 1 7.4-6.Sra (9H); 4.4t i1H); 3.9-3.Cm (ES); -NH-CHZ (cg]; 2.5-1.7m (4H); 1.2d (3E). Tic -NH-CH2eF 7.5-7.0m (8H); 5.1-4.3 (3K); 3.9-3.0m-(6If); 2.3m (2H); 1.2d (31i Idc -NH-CH2-F 7.4-6.5m (ob); 4.4t (1H); 3.3-3. Cn (bs); 1.2d (3H). Tic -NH-C2N5 7.4-7.0m (45); 1.1 t+d (6E) Idc " 7.4-6.Sm (45); 1.It+d (6H) Thc " 7.4-7.1m (4H); 1.1t+d (6H) Tic -NH-CH3 7.4-7.0m (4H); 2.los (3X) Idc -flH-cH3 7.4-6.5m (45); 2.1s (3H) Thc -NH-CH3' 7.2bs (4H); 2.ls (3H) Tic NH-CH-(CH3)2 7.2bs t4E); 1.0d (65) Idc 1 7.4-6.5m (4H); 1.od (65) Tic -NH-C(c53)3 7.2bs (45); O.9s (99) Idc " 7.4-6.5m (4EI); 0.95s (9) Thc ^ 7.2bs (4H); 0.9s (9d) Tic -ND 7.3-7.1m (45) II. Verbindungen mit Y = Beispiel el a). Carbobenzoxy-L-alanyl-3-carboxyl-1,2,3,4-tetrahydroisochinolintert.-butylester Man suspendiert 27 g (0,15 Mol) 3-Carboxy-1,2,3,4-tetra-hydroisochinolin-tert.-butylesterhydroichlorid in 200 ml Dimethyllformamid, kühlt unter Rühren und Feuchttigkeitsausschluß auf -5°C, und gibt 19 ml (0,15 Mol) N-Rthylmorpholin sowie die Lösung von 33,4 g Carbobenzoxyalanin und 20 g N-Hydroxybenzotriazol in 100 ml Dimethylformamid zu. Man rührt eine Stunde bei O OC, läßt über Nacht bei +4 °C stehen und arbeitet dann nach einstündigem Rühren bei Raumtemperatur auf. Man saugt vom ausgeschiedenen Dicyclohexylharnstoff ab und bringt die Reaktionslösung im Hochvakuum bei Raumtemperatur zur Trockne. Das verbliebene öl nimmt man in 1 1 Essigester auf und wäscht dreimal mit je 150 ml gesättigter Natriumcarbonatlösung, 5 % Kaliumbisulfatlösung und einmal mit Wasser. Nach Trocknung über wasseXfreiem Natriumsulfat wird das Lösungsmittel i.V. bei Raumtemperatur abdestilliert.This process is used to produce, for example Z R2 N} IR Tho -NH-CH2 <3 7.4-7.cm (9H); 5.C-4.5 (iN); 3.9-3.0m (4H); 2.5-1.7m (6H :; 1.2d (3H). Idc 1 7.4-6.Sra (9H); 4.4t i1H); 3.9-3.cm (IT); -NH-CHZ (cg); 2.5-1.7m (4H); 1.2d (3E). Tic -NH-CH2eF 7.5-7.0m (8H); 5.1-4.3 (3K); 3.9-3.0m- (6If); 2.3m (2H); 1.2d (31i Idc -NH-CH2-F 7.4-6.5m (ob); 4.4t (1H); 3.3-3. Cn (bs); 1.2d (3H). Tic -NH-C2N5 7.4-7.0m (45); 1.1 t + d (6E) Idc "7.4-6.Sm (45); 1.It + d (6H) Thc "7.4-7.1m (4H); 1.1t + d (6H) Tic -NH-CH3 7.4-7.0m (4H); 2. lot (3X) Idc -flH-cH3 7.4-6.5m (45); 2.1s (3H) Thc -NH-CH3 '7.2bs (4H); 2.ls (3H) Tic NH-CH- (CH3) 2 7.2bs t4E); 1.0d (65) Idc 1 7.4-6.5m (4H); 1.od (65) Tic -NH-C (c53) 3 7.2bs (45); O.9s (99) Idc "7.4-6.5m (4EI); 0.95s (9) Thc ^ 7.2bs (4H); 0.9s (9d) Tic -ND 7.3-7.1m (45) II. Connections with Y = example el a). Carbobenzoxy-L-alanyl-3-carboxyl-1,2,3,4-tetrahydroisoquinoline-tert.-butyl ester 27 g (0.15 mol) of 3-carboxy-1,2,3,4-tetra-hydroisoquinoline-tert. -butylesterhydroichlorid in 200 ml of dimethylformamide, cools with stirring and exclusion of moisture to -5 ° C, and gives 19 ml (0.15 mol) of N-rthylmorpholine and the solution of 33.4 g of carbobenzoxyalanine and 20 g of N-hydroxybenzotriazole in 100 ml of dimethylformamide to. The mixture is stirred for one hour at OC, left to stand overnight at +4 ° C. and then worked up at room temperature after stirring for one hour. The dicyclohexylurea which has separated out is suctioned off and the reaction solution is brought to dryness in a high vacuum at room temperature. The remaining oil is taken up in 1 l of ethyl acetate and washed three times with 150 ml of saturated sodium carbonate solution, 5% potassium bisulfate solution and once with water. After drying over anhydrous sodium sulfate, the solvent is distilled off in vacuo at room temperature.

Ausbeute: 59g Oel L-Alanyl-3-carboxy-1,2,3,4-tetrahydroisochinolin- tert.-butylesterhydrochlorid Man hydriert 15 g Carbobenzoxy-alanyl-3-carboxy-1,Z,3,-tetrahydroisochinolin-tert.-butylester in 4CO ml Methanol mit 8 g 10 % Pd/ bariumsulfatkatalysator. Der scheinbare pH der Lösung (Glasselektrode) wird durch Zugabe von 1 n methanolischer Salzsäure bei 4,0 gehalten. Yield: 59 g of oil L-Alanyl-3-carboxy-1,2,3,4-tetrahydroisoquinoline- tert-butyl ester hydrochloride 15 g of carbobenzoxy-alanyl-3-carboxy-1, Z, 3-tetrahydroisoquinoline tert-butyl ester are hydrogenated in 4CO ml of methanol with 8 g of 10% Pd / barium sulfate catalyst. The apparent pH of the Solution (glass electrode) is by adding 1 N methanolic hydrochloric acid at 4.0 held.

Nach 8 Stunden saugt man vom Katalysator ab und dampft die Lösung i.V. bei Raumtemperatur zur Trockne. Den festen Rückstand digeriert man mit Diisopropyläther und trocknet i.V..After 8 hours, the catalyst is filtered off with suction and the solution is evaporated i.V. to dryness at room temperature. The solid residue is digested with diisopropyl ether and dries i.V ..

Schmp. 1100 (Zers.) Analog Ala-Tic-OBut werden dargestellt: 7.3-6.5m (4H); 4,4t (1); 3,8-3,0 m+d (3H); 1,4s (9H); 1,2d (3H) 7,2s (4H); 5,0-4,5m (1H); 3,8-3,0m (1H); 2,5-1,7m (4H); 1,4s (9H); 1,2d (3H) nachstehenden Verbindungcn sind folgende Signale gemeinsam: 7,2s (4H); 5,1-4,3m (3H); 3,9-3,0m (4H); 1,4s (9H) 7,2s (4H); 3,9-3,0m (5H) 13,1s (1H); 7,5s (1H); 6,8s (1H) 2,8m (2H) 1,5m (3H); 0,9d (6H) 5,1-4,3m (5H) 7,2-7,0m (9H); 2,7-2,0m (4H) 1,5-1,0m (9H) 7,ls (5H); 2,7d (2H) 7,6-6,4m (9H) 3,7d (2H) 7,1s (5H); 5,0s (2H); 2.4m (2H); 1,8-1,3m (6H) 7,1s (5H); 5,0s (2H); 2,4m (2H); 1,8-1,3m (8H) 7,1s (5H); 5,0s (2H); 2,4m (2H); 1,8-1,3m (4H) 7,1s (5H); 5,0s (2H); 2,3m (2H) 8,3-7,6m (2H); 2,9-1,6m (6H) 7,1s (5H); 5,0s (2H); 2,4m (2H); 1,7-1,4m (2H) c.) N-(1-Carboxy-3-phenylpropyl)-L-alanyl-1,2,3,4-tetrahydroisochinolin-3-carbonsäure-tert.-butylester 305 mg Alanyl-1,2,3,4-tetrahydroisoçhinolin-3-carbonsäurebutylester (Ala-Tic-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 Std. reagieren.Melting point 1100 (decomp.) Analogous to Ala-Tic-OBut are shown: 7.3-6.5m (4H); 4.4t (1); 3.8-3.0 m + d (3H); 1.4s (9H); 1.2d (3H) 7.2s (4H); 5.0-4.5m (1H); 3.8-3.0m (1H); 2.5-1.7m (4H); 1.4s (9H); 1.2d (3H) The following compounds have the following signals in common: 7.2s (4H); 5.1-4.3m (3H); 3.9-3.0m (4H); 1.4s (9H) 7.2s (4H); 3.9-3.0m (5H) 13.1s (1H); 7.5s (1H); 6.8s (1H) 2.8m (2H) 1.5m (3H); 0.9d (6H) 5.1-4.3m (5H) 7.2-7.0m (9H); 2.7-2.0m (4H) 1.5-1.0m (9H) 7, ls (5H); 2.7d (2H) 7.6-6.4m (9H) 3.7d (2H) 7.1s (5H); 5.0s (2H); 2.4m (2H); 1.8-1.3m (6H) 7.1s (5H); 5.0s (2H); 2.4m (2H); 1.8-1.3m (8H) 7.1s (5H); 5.0s (2H); 2.4m (2H); 1.8-1.3m (4H) 7.1s (5H); 5.0s (2H); 2.3m (2H) 8.3-7.6m (2H); 2.9-1.6m (6H) 7.1s (5H); 5.0s (2H); 2.4m (2H); 1,7-1,4m (2H) c.) N- (1-Carboxy-3-phenylpropyl) -L-alanyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid tert-butyl ester 305 mg alanyl Butyl -1,2,3,4-tetrahydroisoçhinoline-3-carboxylate (Ala-Tic-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/Methanolj 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: 382 mg; Schmp. ab 1200 Zers. Yield: 382 mg; From 1200 dec.

N-(1-Carboxy-3-phenylpropyl)-L-alanyl-1,2,3,4-tetrahydroisochinolin-3-carbonsäure 350 mg N-(l-Carboxy-3-phenylpropyl)-Ala-Tic-OBut werden in 3 ml wasserfreier Trifluoressigsäure gelöst und 30 Min. bei Raumtemperatur belassen. Man engt i.Vak. ein und verreibt das hinterbleibende öl mit kaltem Diisopropyläther und Petroläther.N- (1-Carboxy-3-phenylpropyl) -L-alanyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 350 mg of N- (l-carboxy-3-phenylpropyl) -Ala-Tic-OBut are dissolved in 3 ml of anhydrous trifluoroacetic acid dissolved and left at room temperature for 30 minutes. One constricts in vacuo. one and grinds the remaining oil with cold diisopropyl ether and petroleum ether.

Ausbeute 276 mg amorphe Substanz NMR: 7.20 u. 7,10 (s); 4,3 (s, breit); 3,0-3,9 (m, breit); 1,23 u. 1,15 (d) Beispiel 14 N-(1-Carboxy-5-aminopentyl)-L-alanyl-1,2,3,4-tetrahydroisochinolin-3-carbonsäure 1,2 g N-(1-Carboxy-5-Boc-aminopentyl)-L-alanyl-1,2,3,4-tetrahydrosochinolin-3-carbonsäure wurden mit 10 ml eiskalter Trifluoressigsäure übergossen und eine Stunde bei Raumtemperatur gerührt. Anschließend wird im Vakuum eingedampft. Der Rückstand wird in Wasser gelöst und einer Gefriertrocknung unterworfen.Yield 276 mg of amorphous substance NMR: 7.20 and 7.10 (s); 4.3 (s, broad); 3.0-3.9 (m, broad); 1.23 and 1.15 (d) Example 14 N- (1-Carboxy-5-aminopentyl) -L-alanyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 1.2 g of N- (1-carboxy-5-Boc-aminopentyl) -L-alanyl-1,2,3,4-tetrahydrosoquinoline-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. The residue is dissolved in water and subjected to freeze-drying.

Ausbeute: 0.95 g Beispiel 15 a.) 2-(2-Oxo-propyl)-1,2,3,4-tetrahydroisochinolin-3-carbonsäuretert -butylester In eine auf -50 °C gekühlte Lösung von 700 mg Tic-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 Std. im Tiefkühischrank (-20 °C und filtriert den ausgefallenen DC-Harnstoff ab. Die Lösung wird mit KHS04- und anschließend mit KHC03-Lösung gewaschen, über Na2S04 getrocknet und i.Vak. eingeengt. Die Verbindung (Ö1) enthält etwas Dicyclohexylharnstoff; sie wurde zur Analyse über Kieselgel im System CHCl3/CH3oH 15:1 chromatographiert.Yield: 0.95 g Example 15 a.) 2- (2-Oxo-propyl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid tert -butylester In a solution, cooled to -50 ° C, of 700 mg Tic-OBut and 630 mg dicyclohexylcarbodiimide 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 (-20 ° C and filtered off the precipitated DC urea. The solution is washed with KHS04 and then with KHCO3 solution over Na2S04 dried and in vacuo constricted. The compound (Ö1) contains some dicyclohexylurea; it was chromatographed for analysis over silica gel in the system CHCl3 / CH3oH 15: 1.

Analog der Kondensation Brenztraubensäure mit Tic-OBut werden.. Analogous to the condensation of pyruvic acid with Tic-OBut ..

folgende Kondensationsprodu1'te aus Tic, Idc, Thc und der entsprechenden α-Kotocarbonsäure dargestellt. The following condensation products from Tic, Idc, Thc and the corresponding α-cotocarboxylic acid are shown.

7,3-6,5m (4H); 2,4s (3H); 1,4s (3H) 7,2s (4H); 5'0-4,Sm (1H); 2,5-1,7 m+s (7H), 1,4s (9H) bei nachstehenden Verbindungen werden einheitlich folgende Signale für das Grundgerüst beobachtet 7,2s (4H); 5,1-4,3m (3H); 3,9-3,0rn (2H); 1,4s (9H) 13,1s (1H); 7,5s (1H); 6,8s (1H); 3,9-3,Om (4H) 2,4-1,0m+d (9H) 7,2-7,0m (9H); 2,5m (2H) 4,4s (2H) 7,15s (5H); 3,0s (2H) 2.4-1,9m (3H); 1,5-1,Om (8H) 7,8-6,4m (9H); 3,9-2,9m (4H) N-(1-Carboxy-3-phenyl-3-thiapropyl)-alanyl-1,2,3,4-tetrahydroisochinolin-3-carbonsäure-tert. -butylester 1,52 g Pyrbvyl-Tic-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 Stdn. bei Raumtemperatur. Man engt i.Vak. ein, nimmt in Chloroform auf, trocknet über Natriumsulfat und engt ein. Das Produkt wird durch Kieselgelchromatographie (System CHCl3/CH30H/HAcO/H20 50/20/5/1) rein erhalten.7.3-6.5m (4H); 2.4s (3H); 1.4s (3H) 7.2s (4H); 5'0-4, Sm (1H); 2.5-1.7 m + s (7H), 1.4s (9H) in the following compounds, the following signals are uniformly observed for the basic structure: 7.2s (4H); 5.1-4.3m (3H); 3.9-3.0 mn (2H); 1.4s (9H) 13.1s (1H); 7.5s (1H); 6.8s (1H); 3.9-3, Om (4H) 2.4-1.0m + d (9H) 7.2-7.0m (9H); 2.5m (2H) 4.4s (2H) 7.15s (5H); 3.0s (2H) 2.4-1.9m (3H); 1.5-1, Om (8H) 7.8-6.4m (9H); 3.9-2.9m (4H) N- (1-carboxy-3-phenyl-3-thiapropyl) -alanyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid tert. butyl ester 1.52 g of Pyrbvyl-Tic-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. One constricts in vacuo. a, taken up in chloroform, dried over sodium sulfate and concentrated. The product is obtained in pure form by silica gel chromatography (system CHCl3 / CH30H / HAcO / H20 50/20/5/1).

NMR: . 7,3-7,0M(9H); 5,1-4,3m (3H); 3,9-3,0m (4H); 2,5m (2H) c.) N-(1-Carboxy-3-phenyl-3-thiapropyl)-alanyl-1,2,3,4-tetrahydroisochinolin-3-carbonsäure 1 g Butylester aus Beispiel 21 wird in 5 ml Trifluoressigsäure gelöst. Man engt nach 30 Min. i.Vak. ein, digeriert den Rückstand mit Diisopropyläther und trocknet über Kaliumhydroxyd.NMR:. 7.3-7.0M (9H); 5.1-4.3m (3H); 3.9-3.0m (4H); 2.5m (2H) c.) N- (1-Carboxy-3-phenyl-3-thiapropyl) -alanyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 1 g of butyl ester from Example 21 is dissolved in 5 ml of trifluoroacetic acid. One constricts after 30 min. in vacuo one, digests the residue with diisopropyl ether and dries about potassium hydroxide.

Ausbeute 0,95 g Trifluoracetat (hygroskopisch) NMR: 7,4-7,1M(9H); 5,2-4,4m (3H); 3,9-3,0m (4H); 2,5m (2H); 1,25m (3H) Beispiel 16 N-(1-Carboxy-3-phenyl-propyl)-L-alanyl-1,2,3,4-tetrahydroisochinolin-3-carbonsäure 880 mg N-(1-Carbethoxy-3-phenyl-propyl)-L-alanyl-1,2,3,4-tetrahydroisochinolin-3-carbonsäure werden in 20 ml Dioxan / Wasser (9 : 1) gelöst und bei Raumtemperatur mit 4.5..ml 1 n Natrunlhydroxid-Lösung verseift. Nach einer Stunde wird die Lösung mit der Nquivalenten 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: 7.4-7.1M (9H); 5.2-4.4m (3H); 3.9-3.0m (4H); 2.5m (2H); 1.25m (3H) Example 16 N- (1-Carboxy-3-phenyl-propyl) -L-alanyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 880 mg of N- (1-carbethoxy-3-phenyl-propyl) -L-alanyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid are dissolved in 20 ml of dioxane / water (9: 1) and at room temperature with 4.5..ml 1 n sodium hydroxide solution saponified. After one hour the solution with the equivalents Amount of 1N hydrochloric acid acidified and the dioxane largely evaporated. The residue is extracted several times with ethyl acetate and the organic phase after removing the Solvent chromatographed over a cation exchanger (DOWEX 50).

Ausbeute: 630 mg Bcispie 17 N(1-CarbethOxy-2-benzylsulfinylethyl)-L-alanyl-L-1,2,3,4-tetrahydroisochinolin-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-benzylthio-ethyl)-L-alanyl-L-1,2,3,4-tetrahydroisochinolin-3-carbonsäure gelöst in 20 ml Methanol gegeben. Man läßt die Reaktionsmischung für 24 Stunden bei 0°C rühren und filtriert anschließend vom Natriumjodat ab. Das Filtrat wird mehrfach mit Methylenchlorid extrahiert. Nach Entfernen des Lösungsmittels erhält man 1,1 g des Sulfoxids. Im NMR-Spektrum werden folgende Signale beobachtet: 7,3-7.0m (9H); 5,1-4,3m (3H); 4,1s (2H); 3,9-3,0m (4H); 2,6m (2H); 1,2d (3H) ispiel 18 (1-Carbethoxy-3-phenylsulfonyl-propyl)-L-alanyl-1,2,3,4-tetradrois-ochinolin-3-carbonsäure 0 mg N-(1-Carbethoxy-3-phenylthio-propyl)-L-alanyl-1,2,3,4-tetratdroisochinolin-3-carbonsäure und 20 mg Natriumwolframat Dihydrat erden in 50 ml Wasser gegeben und tropfenweise mit 1 ml Perhydrol 10 %ig) versetzt. Die Mischung wird für 30 min auf 80 C erwärmt id anschließend eine Stunde bei Raumtemperatur gerührt. Das über hüssige Peroxid wird sodann mit Palladium auf Bariumsulfat zerstört ad nach Beendigung der Sauerstoffentwicklung wird die Lösung vom alladium Katalysator abfiltriert und eingeengt. Das Rohprodukt ird durch Ionenaustauschchromatographie über DOWEX 50 H+-Form ereinigt.Yield: 630 mg Example 17 N (1-carbethoxy-2-benzylsulfinylethyl) -L-alanyl-L-1,2,3,4-tetrahydroisoquinoline-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-benzylthio-ethyl) -L-alanyl-L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid become water dissolved in 20 ml of methanol. The reaction mixture is left for 24 hours stir at 0 ° C and then filtered off from the sodium iodate. The filtrate will extracted several times with methylene chloride. Obtained after removal of the solvent 1.1 g of the sulfoxide. The following signals are observed in the NMR spectrum: 7.3-7.0m (9H); 5.1-4.3m (3H); 4.1s (2H); 3.9-3.0m (4H); 2.6m (2H); 1.2d (3H) ispiel 18 (1-Carbethoxy-3-phenylsulfonyl-propyl) -L-alanyl-1,2,3,4-tetradrois-oquinoline-3-carboxylic acid 0 mg of N- (1-carbethoxy-3-phenylthio-propyl) -L-alanyl-1,2,3,4-tetratdroisoquinoline-3-carboxylic acid and 20 mg of sodium tungstate dihydrate ground in 50 ml of water and added dropwise with 1 ml of Perhydrol 10%). The mixture is heated to 80 ° C. for 30 minutes id then stirred for one hour at room temperature. The excess peroxide is then destroyed with palladium on barium sulfate ad after the evolution of oxygen has ceased the solution is filtered off from the alladium catalyst and concentrated. The raw product ird is purified by ion exchange chromatography on DOWEX 50 H + form.

usbeute: 220 mg MR: 7,7m (9H); 5,1-4,3m (3H); 3,9-3,0m (4H); 2,8m (2H); 1,5m (2H); ,2d (3H) Beispiel 19 l 2-Carbamoyl-1-carbethcxyethyr)-L-alanyl-1,2,3,4-tetrahydroisochinolin-3-carbonsäure 1.2 g Maleinsäuremonoamid und 3.1 g Ala-Tic-OBut werden in 20 ml trockenem Dioxan unter Erwärmen gelöst. Nach 10 min gibt man 2 ml Triethylamin zu und kocht 15 min unter Rückfluß. Man läßt abkühlen, zieht das Lösungsmittel im Vakuum ab und reinigt das Produkt durch Ionenaustausch-Chromatographit.us yield: 220 mg MR: 7.7m (9H); 5.1-4.3m (3H); 3.9-3.0m (4H); 2.8m (2H); 1.5m (2H); , 2d (3H) Example 19 l 2-carbamoyl-1-carbethoxyethyr) -L-alanyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 1.2 g of maleic acid monoamide and 3.1 g of Ala-Tic-OBut are dissolved in 20 ml of dry dioxane dissolved with warming. After 10 minutes, 2 ml of triethylamine are added and the mixture is boiled for 15 minutes under reflux. It is allowed to cool, the solvent is stripped off in vacuo and the product is purified the product by ion exchange chromatographite.

Ausbeute: 1.05 g (24 % d. Th.) Im NMR-Cpektrum werden folgende Signale beobachtet: 7,3bs (4H); 6,5bs (2H); 5, 1 - 4, 3m (5H); 3,9 - 3,0m (4H); 2,1m (2H); 1,4s (9H); 1,2d (3H) Beispiel 20 N-(1-Carbetoxy-3-amino-propyl)-L-alanyl-1,2,3,4-tetrahydroisochinolin-3-carbonsäure 1.1 g N-(1-Carbetoxy-3-benzoxycarbonylamino-propyl)-L-alanyl 1, 2, 3, 4-tetrahydroisochinolin-3-carbonsäure werden in 150 ml Methanol gelöst und in Gegenwart von 100 mg Palladium - ARtivkohle (10 %ig) bei 400 C unter Normaldruck hydriert. Nach Beendigung der Reaktion wird vom Katalysator abfiltriert und das Lösungsmittel im Vakuum abgezogen.Yield: 1.05 g (24% of theory) The following signals are shown in the NMR spectrum observed: 7.3bs (4H); 6.5bs (2H); 5.1-4.3m (5H); 3.9-3.0m (4H); 2.1m (2H); 1.4s (9H); 1.2d (3H) Example 20 N- (1-Carbetoxy-3-aminopropyl) -L-alanyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 1.1 g of N- (1-carbetoxy-3-benzoxycarbonylamino-propyl) -L-alanyl 1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid are dissolved in 150 ml of methanol and in the presence of 100 mg of palladium activated carbon (10%) hydrogenated at 400 ° C. 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 Beispiel 21 N-(2-Amino-1-carboxylpropyl)-L-alanyl-1,2,3,4-tetrahydroisochinolin-3-carbonsäure 2.2 g N -Boc-a,ß-Diaminobuttersäure, hergestellt nach Coll. czech. chem. Commun. 31, 2955 (1966) analog der NY-Boc-Verbindung, werden mit 2.4 g Pyruvyl-Tic-OBut, hergestellt nach Beispiel 15 a), in der in Beispiel 15 b) beschriebenen Weise umgesetzt. Die Boc-Schutzgruppe wird anschließend auf die in Beispiel 14 beschriebene Weise abgespalten.Yield: 0.79 g Example 21 N- (2-Amino-1-carboxylpropyl) -L-alanyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2.2 g of N -Boc-a, ß-diaminobutyric acid, prepared according to Coll. czech. chem. Commun. 31, 2955 (1966) analogous to the NY-Boc compound, with 2.4 g of pyruvyl-Tic-OBut, prepared according to Example 15 a), implemented in the manner described in Example 15 b). The Boc protecting group is then applied in the manner described in Example 14 cleaved.

Ausbeute: 2.6 g Die nachstehend aufgeführten Beispiele sind nach einer der Methoden A - F hergestellt, wobei die bezeichneten Methoden wie folgt charakterisiert werden: Methode A: Reduktive Aminierung eines Kondensationsproduktes aus Tio-OtC4H9-Estor und einer entsprechenden α-Ketocarbonsäure, dargestellt in Beispiel(15 a) mit einem entsprechenden Aminosäurederivat nach Beispiel (1ts Abspaltung der Schutzgruppen nach Beispiel (15 c)und ggf. Verseifung nach Beispiel 06 ).Yield: 2.6 g The examples listed below are based on one of the Methods A - F produced, whereby the designated methods are characterized as follows: Method A: Reductive amination of a condensation product of Tio-OtC4H9-Estor and a corresponding α-ketocarboxylic acid, shown in example (15 a) with a corresponding amino acid derivative according to example (1ts Cleavage of the protective groups according to example (15c) and optionally saponification according to example 06).

Methode B: Reduktive Aminierung eines Dipeptids-t-Butylesters, d-argestellt nach Beispiel(13 b)mit einem entsprechenden α-Ketocarbonsäurerivat nach Beispiel(13 c)und ggf. Abspaltung der Schutzgruppen nach Beispiel(13 d) und / oder ggf. nach Beispiel 16. Method B: Reductive amination of a dipeptide t-butyl ester, shown in the diagram according to example (13 b) with a corresponding α-ketocarboxylic acid derivative according to example (13 c) and if necessary splitting off of the protective groups according to example (13 d) and / or if necessary after Example 16.

Methode C: Reduktive Aminierung nach Methode A und mit einer #-geschützten bifunktionellen Aminosäure, Abspaltung einer Schutzgruppe aus dem eingesetzten Aminosäurederivat nach Beispiel(14).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 (14).

Methode D: Oxidation der zugrunde liegenden Schwefel-Verbindung zum Sulfoxid nach Beispiel (j7.).Method D: Oxidation of the underlying sulfur compound to the Sulphoxide according to example (j7.).

Methode E: Oxidation der zugrunde liegenden- Schwefel-Verbindung zum Sulfon nach Beispiel (18).Method E: Oxidation of the underlying sulfur compound to the Sulfone according to example (18).

Methode F: Michaeladdition eines Dipeptid -t-C4Hg-Esters, dargestellt nach Beispiel (134an ein entsprechendes Maleinsäurderivat nach Beispiel(19) Falls nicht anderes angegeben, gelten für die nachstehenden Verbindungen folgende NMR-Daten (#-Werte in ppm; TMS als Standard): für m = n = 1 7.3s (4H), 5.1-4.3m (3H) 3.9-3.Om C4H) m = 2, n = 0 7.2s (4H); 5.0-4.5m (1H); 3.9-3.0m (2H); 2.5-1.7m (4H) m = 1, n = 0 7.2-6.5m (4H);- 4.9t 7Hz (1H); 3.6-3.0m (4H) Im Falle der Ethylester treten noch folgende Signale auf: 4.2q 7Hz (2H) 1.2t 7Hz (3H) Nr. m n R¹ R² R³ Methode NMR H # 1 1 1 CH3 CH2-N-CHO C2H5 A 8.3 2s (1H); 2.9 (2H); 1.2d (3H) H # 2 1 1 CH3 CH2-N-COCH3 C2H5 A 2.9 (2H); 2.1s (3H)'; 1.2d (3H) H # 3 1 1 CH3 CH2-N-CO-CH2# C2H5 A 3.9-3.Om (6H); 2.9 (2H); 1.2d (3H) H # 4 1 1 H CH2-N-CO# C2H5 A 7.2-6.8 (8H); 3.9-3.Om (5H) OH 2.9m (2H) E # 5 1 1 CH3 CH2-N-CO# C2H5 A 7.9-7.Om (8H); 3.9-3.Om (5H) COOH 2.9m (2H) H # 6 1 1 CH3 CH2-N-CO-CH2# C2H5 A 7.65-7.1m (8H); 3.9-3.Om (6H) Cl 2.9m (2H); 1.2d (3H) H # 7 1 1 CH3 CH2-N-CO-CH2# H A 7.65-7.1m (8H); 3.9-3.Om (6H) Cl 2.9m (2H); 1.2d (3H) Nr. m n R¹ R² R³ Methode NMR H # 8 1 1 CH3 CH2-N-CO# C2H5 A 8.2-7.1m (8H); 2.9 (2H); NO2 1.2d (3H) H # 9 1 1 CH3 CH2-N-CO-# C2H5 A 7.2-6.8m (8H); 2.9s (2H); 1.2d (3H) NH2 H N-CH2- # 10 1 1 # CH2-N-CO-#OCH3 C2H5 A 13.Os (1H); 7.5-6.8m (10H); 3.9s (3H) HN 2.9-2.6m (4H) H # OCH3 11 1 1 CH3 CH2-N-CO#OCH3 C2H5 A 7.5-6.9m (7H); 3.9s (6H); 2.9m (2H); H 1.2d (3H) # OCH3 12 1 1 CH3 CH2-N-CO#OCH3 C2H5 A 7.3-6.8m (6H); 3.9s (9H); 2.9m (2H) OCH3 1.2m (3H) H # 13 1 1 CH3 CH2N-CO# C2H5 A 7.4-7.Om (8H); 2.9m (2H) CH3 2.4s (3H); 1.2d (3H) Nr. m n R¹ R² R³ Methode NMR H # 14 1 1 CH3 CH2-N-CO-# C2H5 A 7.4-7.Om (8H); 2.9m (2H); 2.4m (3H) CH3 1.2d (3H) 15 1 1 CH3 CH2-CH2-N(CH3)2 C2H5 A 2.4m (2H); 2.2s (6H); 1.7m (2H); H H 1.2d (3H) # # 16 1 1 CH3 CH2-N-CO-N# C2H5 A 7.3-7.Om (9H); 2.9m (2H); 1.2d (3H) H H # # 17 1 1 CH3 CH2-N-CO-N#Cl C2H5 A 8.0-7.1m (8H); 2.9m (2H); 1.2d (3H) H H # # 18 1 1 CH3 CH2-N-CO-N# C2H5 A 8.3-7.1m (8H); 2.9m (2H); 2.3s (3H) NO2 H H # # 19 1 1 (CH3)CH-CH2 CH2-N-CO-N#CH3 C2H5 A 7.4-7.Om (8H); 2.9m (2H); 2.3s (3H) 1.Od (6H) Nr. m n R¹ R² R³ Methode NMR H H # # 20 1 1 CH3 CH2-N-CO-N# C2H5 A 7.3-6.7m (8H); 3.8s (3H); OCH3 2.9m (2H); 1.2d (3H) H H # #Cl 21 1 1 CH3 CH2-N-CO-N#CH3 C2H5 A 7.6-6.9m (7H); 2.9m (2H); H H 2.4s (3H); 1.2d (3H) # # 22 1 1 #S-CH2 CH2-N-CO-N-CH3 C2H5 A 7.3-7.Om (9H); 3.0-2.6m+s H H (7H) # # 23 1 1 #S-CH2 CH2-N-CO-N-CH3 H A 7.3-7.Om (9H); 3.0-2.6m+s H H (7H) # # 24 1 1 C2F CH2-N-CO-N-C4H9 C2H5 A 5.1-4.3m (5H); 2.9m (2H); 1.Ot (3H) Nr. m n R¹ R² R³ Methode NMR H O H # # # 25 1 1 CH3 CH2-N-C-O-N#H C2H5 A 3.2-2.9m (3H); 2.4-1.Om (10H); 1.2d (3H) H H # # 26 1 1 CH3 CH2-N-C-O-CH2# C2H5 A 7.1s (5H); 5.Os (2H); H O 2.9m (2H); 1.2d (3H) # # 27 1 1 CH3 CH2-N-C-O-C2H5 C2H5 A 4.2q (4H); 2.9m (2H); 1.2ct+d (9H) H # 28 1 1 CH3 CH2-CH2-N-CHO C2H5 A 8.2 2s (1H); 2.9m (2H); 1.5m (2H); 1.2d (3H) H # 29 1 1 H CH2-CH2-N-COOH C2H5 A 3.9-3.Om (9H); 2.9m (2H) 2.1s (3H); 1.5m (2H) H # 30 1 1 CH3 CH2-CH2-N-CO# C2H5 A 7.6-7.Om (9H); 2.9m (2H) 1.5m (2H); 1.2d (3H) Nr. m n R¹ R² R³ Methode NMR H # 31 1 1 CH3 CH2-CH2-N-CO# C2H5 A 7.2-6.8m (8H); 2.9m (2H). HO 1.5m (2H); 1.2d (3H) H # 32 1 1 #CH2 CH2-CH2-N-CO#COOH C2H5 A 7.9-7.Om (13H); 2.9-2.7m (4H); 1.5m (2H) H # 33 1 1 CH3 CH2-CH2-N-CO#Cl C2H5 A 8.0-7.1m (8H); 2.9m (2H); 1.5m (2H); 1.2d (3H) H O # # 34 1 1 CH3 CH2-CH2-N-C#Cl H A 8.0-7.1m (8H); 2.9m (2H) 1.5m (2H); 1.2d (3H) H H # # 35 1 1 CH3 CH2-CH2-N-C#NO2 C2H5 A 8.3-7.Om (8H); 2.9m (2H); 1.5m (2H); 1.2d (3H) Nr. m n R¹ R² R³ Methode NMR H O # # 36 1 1 CH3 CH2-CH2-N-C#NH2 C2H5 A 7.2-6.8m (8H); 2.9m (2H); 1.5m (2H); 1.2d (3H) H O # # 37 1 1 CH3 CH2-CH2-N-C#OCH3 C2H5 A 7.5-6.8m (8H); 3.8s (3H); 2.9 (2H); 1.5m (2H); 1.2d (3H) H O # #OCH3 38 1 1 CH3 CH2-CH2-N-C#OCH3 C2H5 A 7.5-6.9m (7H); 3.9s (6H); 2.9m (2H); 1.5m (2H); 1.2d (3H) H O # #OCH3 39 1 1 CH3-CH2-CH-CH2 CH2-CH2-N-C#OCH3 C2H5 A 7.2-6.8m (6H); 3.9s (9H); 2.9m # OCH3 (2H); 1.5m (2H); 1.Om (13H) CH3 H H # # 40 1 1 CH3 CH2-CH2-N-C#CH3 C2H5 A 7.4-7.Om (8H); 2.9m (2H); 2.3s (3H); 1.5m (2H); 1.2d (3H) Nr. m n R¹ R² R³ Methode NMR H O # # 41 1 1 CH3 CH2-CH2-N-C# C2H5 A 7.4-7.Om (8H); 2.9m (2H); 2.3s CH3 (3H); 1.5m (2H); 1.2d (3H) 42 1 1 CH3 CH2-CH2-CH2-N(C2H5)2 C2H5 A 2.6-2.4m (6H); 1.5m (4H); 1.2d (3H 0.9t (6H) H H # # 43 1 1 CH3 CH2-CH2-N-CO-N# C2H5 A 7.5-7.Om (9H); 2.9m (2H); 1.5m (2H); 1.2d (3H) H H # # 44 1 1 CH3 CH2-CH2-N-CO-N#Cl C2HE A 7.5-7.Om (8H); 2.9m (2H); 1.5m (2H 1.2d (3H) H H # # 45 1 1 CH3 CH2-CH2-N-CO-N#NO2 C2H5 A 8.3-7.1m (8H); 2.9m (2H); 1.5m (2H 1.2d (3H) H H # # 46 1 1 CH3 CH2-CH2-N-CO-N# C2H5 A 7.4-7.Om (8H); 2.9m (2H); 2.3m (3H CH3 1.5m (2H); 1.2d (3H) Nr. m n R¹ R² R³ Methode NMR H H 47 1 1 CH3 CH2-CH2-N-CO-N#OCH3 C2H5 A 7.2-6.5m (8H); 3.9s (3H); 2.9m (2H); 1.5m (2H); 1.2d (3H) H HF 48 1 1 CH3 CH2-CH2-N-CO-N#CH3 C2H5 A 7.3-6.9m (7H);2.9m (2H); 2.3s (3H); 1.5m (4H); 1.2d (3H Nr. m n R¹ R² R³ Methode NMR H 49 1 1 (CH3)2CH-CH2 CH2-CH2-N-CO-N-CH3 C2H5 A 3.0-2.6m (5H); 1.7-1,3m (5H); 1.Od (6H) H H # # 50 1 1 (CH3)2CH-CH2 CH2-CH2-N-CO-N-C4H9 C2H5 A 3.0-2.6m (4H); 1.7-1,2m (9H); 0.9d+t (9H) H H 51 1 1 (CH3)2CH-CH2 CH2-CH2-N-CO-N-C4H9 H A 3.0-2.6m (4H); 1.7-1,2m (9H); 0.9d+d (9H) H H 52 1 1 CH2F CH2-CH2-N-CO-N#H C2HE A 5.1-4.3m (5H); 2.9m (3H); 2.0-1,0m (12H) H 53 1 1 CH3 CH2-CH2-N-CO-O-CH2# C2H5 A 7.1s (5H); 5,0s (2H); 2.9m (2H); 1.5m (2H); 1.2d (3H) Nr. m n R¹ R² R³ Methode NMR H 54 1 1 CH3 CH2-CH2-N-CO-O-C2H5 C2H5 A 4.2q (4H); 2.9m (2H); 1.5m (2H) 1.2d+t (9H) H 55 1 1 CH3 CH2-CH2-N-CH3 C2H5 A 2.4m (2H); 2.3s (3H); 1.5m (2H); 1.2d (3H) 56 1 1 CH3 CH2-CH2-N# C2H5 A 2.4m (6H); 1.8-1.2m (8H); 1.2d (3H) H 57 1 1 CH3 CH2-CH2-N# C2HE A 7.2-6.5m (9H); 2.5m (2H); 1.5m (2H 1.2d (3H) H 58 1 1 (CH3)2CH-CH2 CH2-CH2-N#Cl C2H5 A 7.2-6.6m (8H); 2.4m (2H); 1.5m (5H) 1.0d (6H) Nr. m n R¹ R² R³ Methode NMR H 59 1 1 #S-CH2 CH2-CH2-N#OCH3 C2H5 A 7.3-6.4m (13H); 3.8m (3H); 2.5-2.2m HCl (4H); 1.5m (2H) 60 1 1 CH2F CH2-CH2-N#CH3 C2H5 A 7.2-6.6m (7H); 5.1-4.3m (5H); 2.4m (2H); 2.3s (3H); 1.5m (2H) H 61 1 1 CH3 CH2-N#CCOCH C2H5 A 7.3-6.5m (8H); 2.5m (2H); 1.1s (3H); 1.2d (3H) H 62 1 1 CH3 CH2-N#NO2 C2HE A 7.7-7.Om (8H); 2.5m (2H); 1.2d (3H) HOH 63 1 1 CH3 CH2-N#CONH2 C2H5 A 7.6-6.7m (7H); 2.4m (2H); 1.2d (3H) Nr. m n R¹ R² R³ Methode NMR H # 64 1 1 CH3 CH2-N#COOCH2H5 C2H5 A 7.6-6.8m (8H); 4.2q (4H); 2.5m (2H) 1.2d+t (9H) H 65 1 1 CH3 CH2-N# C2H5 A 7.2-6.2m (7H); 5.0s (2H); 2.5m (2H) 1.2d (3H) H 66 1 1 CH3 CH2-N#NH2 C2H5 A 7.2-6.7m (8H); 2.5m (2H); 1.2d (3H) H 67 1 1 CH3 CH2-N-CH2-CH2-COOC2H5 C2HE A 4.2q (4H); 2.6-2.3m (6H); 1.2d+t (9H) 68 1 1 CH3 CH2-CH2-CH2-NH2 C2H5 A 2.3m (2H); 1.5m (4H); 1.2d (3H) Nr. m n R¹ R² R³ Methode NMR H 69 1 1 CH3 CH2-N-CH2-CH2-N(C2H5) C2H5 A 2.6-2.4m (10H); 1.2d+t (9H) 70 1 1 CH3 CH2-N#O C2H5 A 3.9-3.Om (12H); 2.3m (2H); 1.2d (3H) 71 1 1 CH3 CH2-N# C2H5 A 2.6-2.3m (6H); 1.6-1.4m (4H); 1.2d (3H) H 72 1 1 CH3 CH2-N-CH2-CH2-CONH2 C2HE A 2.6-2.2m (6H); 1.2d (3H) 73 1 1 CH3 CH2-CH2-CH2-N(CH3)2 C2H5 A 2.4m (2H); 2.2s (6H); 1.5m (4H); 1.2d (3H) H 74 1 1 CH3 CH2-N-CH2-CONH2 C2H5 A 3.9-3.Om (6H); 2.4m (2H); 1.2d (3H) 75 1 1 CH3 (CH2)5-NH2 H C 2.3m (2H); 1.6-1.2m (8H); 1.2d (3H) Nr. m n R¹ R² R³ Methode NMR 76 1 1 H2N-(CH2)4 (CH2)4-NH2 H A 2.4m (4H); 1.6-1.2m (12H) 77 1 1 CH3 CH2-CH2-NH-CH3 C2H5 A 2.4m (2H); 2.2s (3H); 1.5m (2H); 1.2d (3H) 78 1 1 CH3 CH2-NH-CH3 C2H5 A 2.4m (2H); 2.1s (3H); 1.2d (3H) H 79 1 0 CH3 CH2-N-CO-CH2# C2HE A 7.2-6.5m (9H); 3.8-3.Om (6H); 2.9m (2H); 1.2d (3H) H # 80 1 0 CH3 CH2-N-CO# C2H5 A 7.8-6.5m (9H); 2.9m (2H); 1.2d (3H) H # 81 1 0 CH3 CH2-N-CH2-CONH2 C2H5 A 7.8-6.5m (8H); 2.9m (2H); 1.2d (3H) H H # # 82 1 0 CH3 CH2-N-CO-N-# C2H5 A 7.4-6.5m (9H); 2.9m (2H); 1.2d (3H) m n R¹ R² R³ Methode NMR H H 83 1 0 CH3 CH2-N-CO-N-#-Cl C2H5 A 7.7-6.5m (8H); 2.9m (2H); 1.2d (3H) H H 84 1 0 CH3 CH2-N-CO-N-CH3 C2H5 A 3.0 - 3.6m + s (5H); 1.2d (3H) H O H 85 1 0 CH3 CH2-N-C-N-# C2H5 A 3.2 - 2.9m (3H); 2.4 - 1.2m (10H) 1.2d (3H) H 86 1 0 CH3 CH2-CH2-N-CO-# C2H5 A 7.6 - 6.5m (9H); 2.9m (2H); 1.5m (2H); 1.2d (3H) H 87 1 0 CH3 CH2-CH2-N-CO-# C2H5 A 7.6 - 6.5m (8H); 2,9m (2H); 1.5m (2H); 1.2d (3H) H O 88 1 0 CH3 CH2-CH2-N-C-#-Cl C2H5 A 7.6 - 6.5m (8H); 2.9m (2H); 1.5m (2H); 1.2d (3H) 89 1 0 CH3 CH2-CH2-CH2-N(C2H5)2 C2H5 A 2.6 - 2.4m (6H); 1.5m (4H); 1.2d (3H); 1.0 t (6H) m n R¹ R² R³ Methode NMR H H 90 1 0 CH3 CH2-CH2-N-CO-N-# C2H5 A 7.4 - 6.5m (9H); 2.9m (2H); 1.5m (2H); 1.2d (3H) H H 91 1 0 CH3 CH2-CH2-N-CO-N-#-Cl C2H5 A 7.5 - 6.5m (8H); 2.9m (2H); 1.5m (2H); 1.2d (3H) H H 92 1 0 CH3 CH2-CH2-N-CO-N-# C2H5 A 7.8 - 6.5m (8H); 2.9m (2H); \ 1.5m (2H); 1.2d (3H) NO2 H H 93 1 0 CH3 CH2-CH2-N-CO-N-CH3 C2H5 A 3.0 - 2.6m + n (5H); 1.5m (2H); 1.2d (3H) 94 1 0 CH3 CH2-CH2-# C2H5 A 2.6 - 2.3m (6H); 1.8 - 1.2 (8e 1.2d (3H) H 95 1 0 CH3 CH2-CH2-N-# C2H5 A 7.2 - 6.5m (9H); 2.4m (2H); 1.5m (2H); 1.2d (3H) m n R¹ R² R³ Methode NMR H /Cl 96 1 0 CH3 CH2-CH2-N-# C2H5 A 7.6 - 6.5m (8H); 2.4m (2H); 1.5m (2H); 1.2d (3H) H 97 1 0 CH3 CH2-CH2-N-#-OCH3 C2H5 A 7.2 - 6.5m (8H); 2.9m (2H); 1.5m (2H); 1.2d (3H) 98 1 0 CH3 (CH2)5-NH2 C2H5 A 2.4m (2H); 1.8 - 1.2m (8H); 1.2d (3H) H 99 1 0 CH3 (CH2)4-NH2 C2H5 A 2.4m (2H); 1.8 - 1.2m (6H); 1.2d (3H) m n R¹ R² R³ Methode NMR H 100 2 0 CH3 CH2-N-COCH3 C2H5 A 2.9m (2H); 2,3s (3H); 1.2d (3H) H 101 2 0 CH3 CH2-N-CO-CH2-# C2H5 A 3,9 - 3,0 m+s (4H); 2,9m (2H) 1.2d (3H) H O H 102 2 0 CH3 CH2-N-C-N-#-Cl C2H5 A 7,5 - 7,0m (8H); 2.9m (2H); 1,2d (3H) H H 103 2 0 CH3 CH2-N-CO-N-C4H9 C2H5 A 2,9m (4H): 1,7 - 1,3m (4H); 1.2d (3H); 0,9 t (3H) 104 2 0 CH3 CH2-N-CO-N-C4H9 C2H5 A 4,2q (4H); 2,9m (2H); 1,2 d+t (9H) m n R¹ R² R³ Methode NMR H 105 2 0 CH3 CH2-CH2-N-CO-# C2H5 A 7,8 - 7.0m (9H); 2.9m (2H); 1.5m (2H); 1.2d (3H) H 106 2 0 CH3 CH2-CH2-N-CO-#-Cl C2H5 A 7,9 - 7,0m (8H); 2.9m (2H); 1.5m (2H); 1.2d (3H) H 107 2 0 CH3 CH2-CH2-N-C-#-Cl C2H5 A 7,9 - 7,0m (8H); 2.9m (2H); 1.5m (2H); 1.2d (3H) H O 108 2 0 CH3 CH2-CH2-N-C-# C2H5 A 7,8 - 7,0m (8H); 2,9m (2H); / 2,3s (3H); 1,5m (2H); 1,2d (3H) CH3 109 2 0 CH3 CH2-CH2-N-C-# H A 7,6 - 7,0m (8H); 2,9m (2H); 2,3s / (3H); 1,5m (2H); 1,2d (3H) CH3 m n R¹ R² R³ Methode NMR H O H 110 2 0 CH3 CH2-CH2-N-C-N-# C2H5 A 7.4 - 7,0m (9H); 2.9m (2H); 1.5m (2H); 1.2d (3H) H O H 111 2 0 CH3 CH2-CH2-N-C-N-#-Cl C2H5 A 7,7 - 6,9m (8H); 2.9m (2H); 1.5m (2H); 1.2d (3H) H H 112 2 0 CH3 CH2-CH2-N-C-N-#-Cl C2H5 A 7,5 - 6,8m (8H); 2.9m (2H); / 2,3s (3H); 1.5m (2H); 1.2d (3H) CH3 H O H 113 2 0 CH3 CH2-CH2-N-C-N-C4H9 C2H5 A 2,9 - 2.6m (4H); 1,7 - 1,3m (6H); 1.2d (3H); 0,9t (3H) H /Cl 114 2 0 CH3 CH2-CH2-N-# C2H5 A 7,5 - 6,5m (8H); 2,4m (2H); 1,5m (2H); 1.2d (3H) m n R¹ R² R³ Methode NMR 115 2 0 CH3 (CH2)5-NH2 H C 2,4m (2H); 1,8 - 1,2m (8H); 1.2d (3H) 116 2 0 CH3 (CH2)4-NH2 H C 2,4m (2H); 1,8 - 1,3m (6H); 1.2d (3H) 117 1 1 CH3 CH2-S-# C2H5 A 7,4 - 7,0m (9H); 2,7m (2H); 1.2d (3H) 118 1 1 CH3 CH2-S-#-F C2H5 A 7,3 - 6,8m (8H); 2,7m (2H); 1.2d (3H) 119 1 1 CH3 CH2-SH C2H5 A 2,4m (2H); 1,2d (3H) m n R¹ R² R³ Methode NMR 120 1 1 CH3 CH2-S-#-SO2NH2 C2H5 A 8,1 - 7,1m (8H); 6,5bs (2H); 2,7m (2H); 1,3d (3H) OCH3 / 121 1 1 (CH3)2CH-CH2 CH2-S-# C2H5 A 7,2 - 6.7m (8H); 3,8s (3H); 2,7m (2H); 1,6 - 1,2m (3H); 1,06 (6H) CH2 CONH2 122 1 1 # CH2-S-# C2H5 A 13,0s (1H); 7,8 - 6,8m (10H); 6,0 bs (2H); 2,9 - 2,6m (4H) CH2 NO2 / / 123 1 1 ## CH2-S-# C2H5 A 8,2 - 6,4m (14H); 2,9 - 2,6m (4H) CH2 NH2 / / 124 1 1 ## CH2-S-# C2H5 A 7,8 - 6,4m (14H); 2,9 - 2,6m (4H) m n R¹ R² R³ Methode NMR 125 1 1 (CH3)2CH-CH2 CH2-S-# C2H5 A 7,3 - 7,0m (8H); 2,7m (2H); 2,3s / (3H); 1,9 - 1,4m (3H): 1,0d (6H) CH3 126 1 1 CH3 -CH2-S-CH2-# C2H5 A 7,3 - 7,0m (9H); 3,9 3,0 m+s (6H); 2,4m (2H); 1.2d (3H) CH2 / 127 1 1 # -CH2-S-CH(CH3)2 C2H5 A 7,3 - 6,9m (9H); 2,6 - 2,3m (5H); 0,9d (6H) 128 1 1 CH3 -CH2-S-CH2-CH2-N(CH3)2 C2H5 A 2,6 - 2,2 m+s (12H); 1,2d (3H); 129 1 1 CH2F -CH2-S-CH2-CH2-CONH2 C2H5 A 5,1 - 4,3m (5H); 2,5 - 2,2 (6H) m n R¹ R² R³ Methode NMR 130 1 1 CH3 -CH2-S-CH2-CH2-COOC2H5 C2H5 A 4,2q (4H); 2,5 - 2,2m (6H); 1,2 d+t (9H) 131 1 1 CH3 -CH2-S-CH2-CH2-OC2H5 C2H5 A 3,9 - 3,0 q+m (8H); 2,4 - 2,2m (4H); 1,2 d+t (6H) 132 1 1 CH3 -CH2-CH2-S-# C2H5 A 7,3 - 7,0m (9H); 2,7m (2H); 1,5m (2H); 1.2d (3H) 133 1 1 CH3 -CH2-CH2-S-#-Cl C2H5 A 7,5 - 7,0m (8H); 2,7m (2H); 1,5m (2H); 1.2d (3H) 134 1 1 CH3 -CH2-CH2-S-#-COOH C2H5 A 7,9 - 6,9m (8H); 2,7m (2H); 1,5m (2H); 1.2d (3H) m n R¹ R² R³ Methode NMR 135 1 1 CH3 CH2-CH2-S-#-SO2NH2 C2H5 A 8,0 - 6,9m (8H); 6,5bs (2H); 2,6m (2H); 1,5m (2H); 1,2d (3H) 136 1 1 CH3 CH2-CH2-S-#-OCH3 C2H5 A 7,3 - 6,4m (8H); 3,8s (3H); 2,7m (2H); 1,5m ("H); 1,2d (3H) CONH2 / 137 1 1 CH3 CH2-CH2-S-# C2H5 A 7,8 - 6,9m (8H); 6,0bs (2H); 2,6m (2H); 1.5m (2H); 1.2d (3H) NO2 / 138 1 1 CH3 CH2-CH2-S-# C2H5 A 8,1 - 6,9m (8H); 2,7m (2H); 1,5m (2H); 1.2d (3H) 139 1 1 H2N-(CH2)4 CH2-CH2-S-#-CH3 C2H5 B 7,3 - 6,8m (8H); 2,7 - 2,3 m+s (7H); 1,7 - 1,3m (8H) m n R¹ R² R³ Methode NMR 140 1 1 CH3 CH2-CH2-S-CH2-# C2H5 A 7,4 - 7,0m (9H); 3,9 - 3,0 m+s (6H); 2,4m (2H); 1,5m (2H); 1.2d (3H) 141 1 1 CH3 CH2-CH2-S-CH(CH3)2 C2H5 A 2,6 - 2,3m (3H); 1,5m (2H); 1,2d (3H); 1.0d (6H) CH2 / 142 1 1 ## CH2-CH2-S-CH2-CH2-N(CH3)2 C2H5 A 7.8 - 6.5m (10H); 2,8 - 2,3m (14H); 1.5m (2H) 143 1 1 CH3 CH2-CH2-S-CH2-CH2-CONH2 C2H5 A 6,0 bs (2H); 2,5 - 2,2m (6H); 1,5, (2H); 1.2d (3H) O 144 1 1 CH3 CH2-S-# C2H5 D 7,5 - 7,0m (9H); 2,6m (2H); 1.2d (3H) m n R1 R² R³ Methode NMR O 145 1 1 CH3 CH2-S-#-F C2H5 D 7,4-6,9m (8H); 2,6m (2H); 1,2d (3H) O 146 1 1 CH3 -CH2-S-CH2-# C2H5 D 7,3-7,0m (9H); 4,1m (2H); 2,6m (2H); 1,2 (3H) O 147 1 1 CH3 -CH2-S-CH(CH3)2 C2H5 D 2,8-2,5m (3H); 1,2m (3H); 1,0d (6H) O 148 1 1 CH3 -CH2-CH2-S-# C2H5 D 7,4-7,0m (9H); 2,6m (2H); 1,5m (2H); 1,2 (3H) O 149 1 1 CH3 -CH2-CH2-S-#-Cl C2H5 D 7,5-6,9m (8H); 2,6m (2H); 1,5m (2H); 1,2d (3H) m n R1 R² R³ Methode NMR O 150 1 1 CH3 CH2-CH2-S-#-CH3 C2H5 D 7,4-6,9m (8H); 2,6m (2H); 2,3s (3H); 1,5m (2H); 1,2d (3H) O 151 1 1 CH3 CH2-CH2-S-CH2-# C2H5 D 7,3-7,0m (9H); 4,1s (2H); 2,7m (2H); 1,5m (2H); 1,2d (3H) O 152 1 1 CH3 CH2-CH2-S-CH(CH3)2 C2H5 D 2,8-2,5m (3H); 1,5m (2H); 1,2d (3H); 0,9d (6H) O 153 1 1 CH3 CH2-CH2-S-CH2-CH2-N(CH3)2 C2H5 D 7,4-6,9m (8H); 2,6m (2H); 2,3s (3H); 1,5m (2H); 1,2d (3H) O 154 1 1 CH2 CH2-S-# C2H5 E 7,8-7,1m (9H); 2,8m (2H) 1,2d (3H) m n R1 R² R³ Methode NMR O 155 1 1 CH3 CH2-S-#-F C2H5 E 7,7-6,9m (8H); 2,8m (2H); O 1,2d (3H) O 156 1 1 CH3 -CH2-S-CH2-# C2H5 E 7,6-7,0m (9H); 5,0-4,3m (5H); O 2,8m (2H); 1,2d (3H) O 157 1 1 CH3 -CH2-S-CH(CH3)2 C2H5 E 3,0-2,7m (3H); 1,2 d+t (9H) O O 158 1 1 CH3 -CH2-CH2-S-# C2H5 E 7,7-7,2m (9H); 2,8m (2H); O 1,5m (2H); 1,2d (3H) O 159 1 1 CH3 -CH2-CH2-S-#-Cl C2H5 E 8,0-7,1m (8H); 2,8m (2H); O 1,5m (2H); 1,2d (3H) m n R1 R² R³ Methode NMR O 160 1 1 CH3 CH2-CH2-S-#-CH3 C2H5 E 7,6-6,9m (8H); 2,8m (2H); 2,3s (3H); 1,5m (2H); 1,2d (3H) O 161 1 1 CH3 CH2-CH2-S-CH2-# C2H5 E 7,2-6,9m (9H); 4,2s (2H); 2,8m O (2H); 1,5m (2H); 1,2d (3H) O 162 1 1 CH3 CH2-CH2-S-CH(CH3)2 C2H5 E 3,0-2,7m (3H); 1,5m (2H); O 1,1 d+t (9H) O 163 1 1 CH3 CH2-CH2-S-CH2-CH2-N(CH3)2 C2H5 E 3,0-2,2 m+s (12H); 1,5m (2H); O 1,2d (3H) 164 1 0 CH2 CH2-S-# C2H5 E 7,4-6,5m (9H); 2,5m (2H); 1,2d (3H) m n R1 R² R³ Methode NMR 165 1 0 CH3 CH2-S-#-Cl C2H5 A 7,4-6,4m (8H); 2,5m (2H); 1,2d (3H) 166 1 0 CH3 CH2-S-# C2H5 A 7,5-6,5m (8H); 2,5m (2H); CH3 2,3s (3H); 1,2d (3H) 167 1 0 CH3 -CH2-S-CH2-# C2H5 A 7,3-6,5m (9H); 3,6-3,0 m+s (6H); 2,4m (2H); 1,2d (3H) 168 1 0 CH3 -CH2-S-CH-(CH3)2 C2H5 A 2,7-2,3m (3H); 1,2d (3H); 0,9d (6H) 169 1 0 CH3 -CH2-S-Cl C2H5 A 7,3-6,5m (9H); 2,7m (2H); 1,5m (2H); 1,2d (3H) m n R1 R² R³ Methode NMR 170 1 0 CH3 -CH2-CH2-S-#-Cl C2H5 A 7,5-6,5m (8H); 2,7m (2H); 1,5m (2H); 1,2d (3H) 171 1 0 CH3 CH2-CH2-S-#-CH3 C2H5 A 7,3-6,5m (8H); 2,7-2,3m+s (5H); 1,5m (2H); 1,2d (3H) 172 1 0 CH3 CH2-CH2-S-CH2-# C2H5 A 3,9-3,0m+s (6H); 2,4m (2H); 1,5m (2H); 1,2d (3H) 173 1 0 CH3 CH2-CH2-S-CH(CH3)2 C2H5 A 2,6-2,3m (3H); 1,5m (2H); 1,2d (3H); 1,0d (6H) O 174 1 0 CH3 CH2-S-# C2H5 D 7,5-6,5m (9H); 2,6m (2H); 1,2d (3H) m n R1 R² R³ Methode NMR O 175 1 0 CH3 CH2-S-#-Cl C2H5 D 7,4-6,5m (8H); 2,6m (2H); 1,2d (3H) O 176 1 0 CH3 -CH2-S-CH2-# C2H5 D 7,3-6,5m (9H); 4,1m (2H); 2,6m (2H); 1,2d (3H) O 177 1 0 CH3 -CH2-S-CH(CH3)2 C2H5 D 2,8-2,5m (3H); 1,2d (3H); 1,0d (6H) O 178 1 0 CH3 -CH2-CH2-S-# C2H5 D 7,4-6,5m (9H); 2,6m (2H); 1,5m (2H); 1,2d (6H) O 179 1 0 CH3 -CH2-CH2-S-#-Cl C2H5 D 7,5-6,5m (8H); 2,6m (2H); 1,5m (2H); 1,2d (6H) m n R1 R² R³ Methode NMR O 180 1 0 CH3 CH2-CH2-S-#-CH3 C2H5 D 7.6-6.5m (8H); 2.6m (2H); 2.3s (3H); 1.5m (2H); 1.2d (3H) O 181 1 0 CH3 CH2-CH2-S-CH2-# C2H5 D 7.3-6.5m (8H); 4.1s (2H); 2.7s (3H); 1.5m (2H); 1.2d (3H) O 182 1 0 CH3 CH2-CH2-S-CH(CH3)2 C2H5 D 2.8-2.5m (3H); 1.5s (2H); 1.2d (3H); 1.2d (6H) O 183 1 0 CH3 CH2-S-# C2H5 E 7.8-6.5m (9H); 2.8m (2H); 1.2d O (3H) O 184 1 0 CH3 CH2-S-#-Cl C2H5 E 7.7-6.5m (8H); 2.8m (2H); 1.2d (3H) O m n R1 R² R³ Methode NMR O 185 1 0 CH3 -CH2-S-CH2-# C2H5 E 7.6-6.5m (9H); 4.3s (2H); 2.8m (2H); O 1.2d (3H) O 186 1 0 CH3 -CH2-S-CH2-# C2H5 E 3.0-2.7m (3H); 1.2d+t (9H) O O 187 1 0 CH3 -CH2-CH2-S-# C2H5 E 7.7-6.5m (9H); 2.8m (2H); 1.5m (2H); O 1.2d (3H) O 188 1 0 CH3 -CH2-CH2-S-#-Cl C2H5 E 8.0-6.5m (8H); 2.8m (2H); 1.5m (2H); O 1.2d (3H) O 189 1 0 CH3 CH2-CH2-S-#-CH3 C2H5 E 7.7-6.5m (8H); 2.8m (2H); 1.5m (2H); 2.3s (3H); O 1.5m (2H); 1.2d (3H) m n R1 R² R³ Methode NMR O 190 1 0 CH3 CH2-CH2-S-CH2-# C2H5 E 7.2-6.5m (9H); 4.2s (2H); 2.8m (2H); O 1.5m (2H); 1.2d (3H) O 191 1 0 CH3 CH2-CH2-S-CH(CH3)2 C2H5 E 3.0-2.7m (3H); 1.5m (2H); O 1.1d+t (9H) 192 2 0 CH3 CH2-S-# C2H5 A 7.4-7.0m (9H); 2.7m (2H); 1.2d (3H) 193 2 0 CH3 -CH2-S-CH2-# C2H5 A 7.3-7.0m (9H); 3.9-3.0m+s (4H) 2.5-1.7m (6H); 1.2d (3H) 194 2 0 CH3 -CH2-CH2-S-#-Cl C2H5 A 7.5-7.0m (8H); 2.7 (2H); 2.5- 1.7m (4H); 1.2d (3H) m n R1 R² R³ Methode NMR 195 2 0 CH3 CH2-CH2-S-CH2-# C2H5 A 7.4-7.0m (9H); 3.9-3.0 m+s (4H); 2.5.1.7m (6H); 1.2d (3H) 196 2 0 CH3 CH2-CH2-S-CH(CH3)2 C2H5 A 2.6-1.7m (7H); 1.5m (2H); O 1.2d (3H); 1.0d (6H) 197 2 0 CH3 CH2-S-#-F C2H5 D 7.5-7.0m (8H); 2.6-1.7m (6H) 1.2d (3H) O 198 2 0 CH3 -CH2-S-CH2-# C2H5 D 7.3-7.0m (9H); 4.1s (2H); 2.6-1.7 m(6H); 1.2d (3H) O 199 2 0 CH3 -CH2-CH2-S-#-Cl C2H5 D 7.5-6.9m (8H); 2.7-1.7m (6H); 1.5m (2H); 1.2d (3H) m n R1 R² R³ Methode NMR O 200 2 0 CH3 CH2-CH2-S-CH2-# C2H5 D 7.3-7.0m (9H); 4.1s (2H); 2.8-1.7 m (6H); 1.5m (2H); 1.2d (3H) O 201 2 0 CH3 CH2-CH2-S-CH(CH3)2 C2H5 D 2.8-2.5m (3H); 1.5m (2H); 1.2d (3R); 0.9d (6H) O 202 2 0 CH3 CH2-S-#-F C2H5 E 7.8-7.1m (8H); 2.8m (2H); 1.2 O d (3H) O 203 2 0 CH3 -CH2-S-CH2-# C2H5 E 7.6-7.0m (9H); 4.3s (2H); 2.8m O O 204 2 0 CH3 -CH2-CH2-S-#-Cl C2H5 E 8.0-7.1m (8H); 2.8 (2H); 1.5m O (2H); 1.2d (3H) m n R1 R² R³ Methode NMR O 205 2 0 CH3 CH2-CH2-S-CH2-# C2H5 E 7.2-6.9m (9H); 4.2s (2H); O 2.8m (2H); 1.5m (2H); 1.2d (3H) O 206 2 0 CH3 CH2-CH2-S-CH(CH3)2 C2H5 E 3.0-2.7m (3H); 1.5m (2H); O 1.1 d+t (9H) 207 1 1 CH3 -CH2-OH C2H5 A 3.9-3.0m (6H); 1.2m (3H); 208 1 1 CH3 -CH2-O-# C2H5 A 7.8-6.7m (9H); 3.9-3.0m (6H) 1.2d (3H) 209 1 1 CH3 -CH2-O-#-CH3 C2H5 A 7.3-6.6m (8H); 3.9-3.0m (6H); 2.3s (3H); 1.2d (3H) m n R1 R² R³ Methode NMR 210 1 1 CH3 -CH2-O-#-Cl C2H5 A 7.3-6.7m (8H); 3.9-3.0m (6H); 1.2d (3H) OCH3 211 1 1 H2N-(CH2)4 -CH2-O-# C2H5 B 7.2-6.4m (8H); 3.9-3.0m (9H); 2.4m (2H); 1.7-1.3m (6H) 212 1 1 H2N-(CH2)3 -CH2-O-#-NO2 C2H5 B 8.2-6.8m (8H); 3.9-3.0m (6H); 2.4m (2H); 1.7-1.3m (4H) 213 1 1 (CH3)2-CH-CH2- -CH2-O-#-COOC2H5 C2H5 A 7.6-6.8m (8H); 4.2q (4H); 3.9-3.0 m (6H); 1.9-1.3m (3H); 1.2t (6H) 1.0d (6H) CH3 214 1 1 CH3 -CH2-O-#-Cl C2H5 A 7.2-6.0m (7H); 3.9-3.0m (6H); 2.3m (3H); 1.2d (3H) m n R1 R² R³ Methode NMR 215 1 1 CH3 -CH2-O-#-CH2-# C2H5 A 7.2-6.9m (9H); 4.0s (2H); 3.9-3.0m (6H); 1.3d (3H) 216 1 1 CH3 CH2-O-CH2-#-Cl C2H5 A 7.4-6.9m (8H); 4.0s (2H); 3.9-3.0m (6H); 1.2d (3H) CH3 217 1 1 H2N-(CH2)4 CH2-O-CH2-# C2H5 B 7.4-7.0m (8H); 4.0s (2H); 3.9-3.0 CH2 m (6H); 2.5-2.2 d+t (5H); 1.7-1.3m 218 1 1 ## CH2-O-CH2-# C2H5 A 7.8-6.4m (14H); 4.0s (2H); 3.8s (3H) N 3.9-3.0m (6H); 2.7m (2H) H OCH3 219 1 1 H CH2-O-#-CH2-# C2H5 A 7.8-7.0m (8H); 6.0bs (2H); 4.0 s (2H); 3.9-3.0m (7H) m n R1 R² R³ Methode NMR NO2 220 1 1 HS-CH2 CH2-O-#-CH2-# C2H5 B 8.2-7.0m (8H); 4.0s (2H); 3.9-3.0m (6H); 2.3d (2H) NH2 221 1 1 HS-CH2 CH2-O-#-CH2-# C2H5 B 7.2-6.4m (8H); 4.0s (2H); 3.9-3.0m (6H); 2.3d (2H) 222 1 1 CH3 CH2-O-CH(CH3)2 C2H5 A 3.9-3.0m (7H); 1.2d (3H); 0.9d (6H) 223 1 1 CH3 CH2-O-CH2-CH2-N(CH3)2 C2H5 A 3.9-3.0m (8H); 2.4-2.1 m+s (8H); 1.2d (3H) O H 224 1 1 CH3 -CH2-O-C-N-# C2H5 A 7.6-6.9m (9H); 4.0m (2H); 1.2d (3H) m n R1 R² R³ Methode NMR 225 1 1 CH3 CH2-COOH H A 2,1m (2H); 1,2d (3H) 226 1 1 CH3 CH2-CONH2 H F 6,5bs (2H); 2,1m (2H); 1,2d (3H) 227 1 1 CH3 CH2-CON(CH3)2 H F 3,9-3.0m+2s (10H); 2,1m (2H); 1,2d (3H) CH2 H 228 1 1 ## CH2-CON-# H F 7,8-6,4m (15H); 2,8-2,0m (4H) N H CH3 229 1 1 CH3 CH2-CON-# H F 7,3-6,9m (8H); 2,3s (3H); 2,2m (2H); 1,2d (3H) m n R1 R2 R3 Methode NMR H 230 1 1 CH3 CH2-CON-#-Cl H F 7,7-6,9m (8H); 2,3m (2H); 1,2d (3H) N CH2 H 231 1 1 # CH2-CO-NH-#-OCH3 H F 13,0s (1H); 7,5-6,3m (10H); N 3,9s (3H); 2,7m (2H); 2,1m (2H) H 232 1 1 CH3 CH2-CO-NH-#-COOH H F 7,7-6,6m (8H); 2,1m (2H); 1,2d (3H) H 233 1 1 CH3 CH2-CON-#-CONH2 H F 7,7-6,6m (8H); 2,1m (2H); 1,2d (3H) H 234 1 1 CH3 CH2-CO-N-#-COOC2H5 H F 7,7-6,6m (8H); 4,2q (2H); 2,1m (2H); 1,2d+t (6H) m n R1 R2 R3 Methode NMR H 235 1 1 CH3 CH2-CO-N-#-OC2H5 H F 7,2-6,2m (8H); 3,5q (2H); 2,1m (2H); 1,2d+t (6H) Cl H 236 1 1 CH3 CH2-CO-N-#- H F 7,2-6,4m (7H); 3,9s (3H); CH3O 2,1m (2H); 1,2d+t (6H) OCH3 H 237 1 1 CH3 CH2-CO-N-#-OCH3 H F 7,2-6,4m (7H); 3,8s (3H); 2,1m (2H); 1,2d (3H) OCH3 H 238 1 1 CH3 CH2-CO-N-#-OCH3 H F 7,2-6,2m (7H); 3,9s (9H); OCH3 2,1m (2H); 1,2d (3H) 239 1 1 CH3 CH2-COOC2H5 H F 4,2q (2H); 2,0m (2H); 1,2d+t (6H) m n R1 R2 R3 Methode NMR 240 1 1 CH3 CH2-CO-CH(CH3)2 H F 4,8septet (1H); 2,1m (2H); 1,2d (3H); 0,9d (6H) 241 1 1 CH3 CH2-CO-CH2-# H F 7,3-7,0m (9H); 5,3s (2H);; 2,1m (2H); 1,2d (3H); 242 1 1 CH3 CH2-CH2-COOH C2H5 A 2,1m (2H); 1,5m (2H); 1,2d (3H); 243 1 1 CH3 CH2-CH2-CONH2 C2H5 A 2,1m (2H); 1,5m (2H); 1,2d (3H); 244 1 1 CH3 CH2-CH2-CON(CH3)2 C2H5 A 3,02s (6H); 1,5m (2H); 1,2d (3H); m n R1 R2 R3 Methode NMR H 245 1 1 CH3 CH2-CH2-CON-# C2H5 A 7,4-7,0m (9H); 2,1m (2H); 1,5m (2H); 1,2d (3H) H 246 1 1 CH3 CH2-CH2-CON-#-F C2H5 A 7,3-6,9m (8H); 2,1m (2H); 1,5m (2H); 1,2d (3H) H 247 1 1 H2N-(CH2)4 CH2-CH2-CON-#-F C2H5 B 7,3-6,8m (8H); 2,4-2,1m (4H); 1,7-1,3m (8H) 248 1 1 CH3 CH2-CH2-CONH-#-CH3 C2H5 A 7,2-6,4m (8H); 3,9s (3H); 2,1m (2H); 1,5m (2H); 1,2d (3H) 249 1 1 CH3 CH2-CH2-CON-# H A 7,3-6,3m (8H); 2,1m (2H); 1,5m (2H); 1,2d (3H) m n R1 R2 R3 Methode NMR Cl 250 1 1 CH3 CH2-CH2-CON-# H A 7,3-6,4m (7H); 3,9s (3H); 2,1m (2H); 1,5m (2H); 1,2d (2H) CH3O O H 251 1 1 CH3 CH2-CH2-C-N-#-CONH2 H A 7,7-7,0m (8H); 2,1m (2H); 1,5m (2H); 1,2d (3H) H 252 1 1 CH3 CH2-CH2-CO-N-#-COOC2H5 H A 7,6-7,0m (8H); 4,2q (2H); 2,1m (2H); 1,5m (2H); 1,2d+t (6H) O H 253 1 1 CH3 CH2-CH2-C-N-#-OC2H5 H A 7,3-6,4m (8H); 3,9-3,0 m+q (6H); 2,1m (2H); 1,5m (2H); 1,2 d+t (6H) 254 1 1 CH3 CH2-CH2-CON-# H A 8,2-6,9m (8H); 2,1m (2H); 1,5m (2H); 1,2d (3H) m n R1 R2 R3 Methode NMR OCH3 H 255 1 1 CH3 CH2-CH2-CON-#-OCH3 C2H5 A 7,3-6,3m (7H); 3,8s (6H); 2,1m (2H); 1,5m (2H); 1,2d (3H) OCH3 H 256 1 1 CH3 CH2-CH2-CON-#-OCH3 C2H5 A 7,3-6,2m (6H); 3,9s (9H); 2,1m (2H); 1,5m (2H); 1,2d (3H) OCH3 H 257 1 1 CH3 CH2-CH2-CON-CH(CH3)2 H A 2,8-2,2m (3H); 1,5m (2H); 1,2d (3H); 1,0d (6H) H 258 1 1 CH3 CH2-CH2-CON-CH2-# H A 7,4-7,0m (9H); 5,1-4,3 m+s (5H); 2,1m (2H); 1,5m (2H); 1,2d (3H) H 259 1 1 CH3 CH2-CH2-CON-CH2-#-OCH3 C2H5 A 7,3-6,2m (7H); 3,9s (6H); 2,9- 2,1m (6H), 1,5m (2H); 1,2d (3H) m n R1 R2 R3 Methode NMR 260 1 0 CH3 CH2-OH C2H5 A 3,6-3,0m (6H); 1,2d (3H) 261 1 0 CH3 -CH2-O-# C2H5 A 7,3-6,5m (9H); 3,9-3,0m (6H); 1,2d (3H) 262 1 0 CH3 -CH2-O-CH2-# C2H5 A 7,2-6,5m (9H); 4,0s (2H); 3,9-3,0m (6H); 1,2d (3H) 263 1 0 CH3 CH2-O-CH2-#-Cl C2H5 A 7,4-6,5m (8H); 4,0s (2H); 3,9-3,0m (6H); 1,2d (3H) 264 1 0 CH3 CH2-O-CH(CH3)2 C2H5 A 3,9-3,0m (7H); 1,2d (3H); 0,6d (6H) m n R1 R2 R3 Methode NMR 265 1 0 CH3 CH2-O-CH2-CH2-N(CH3)2 C2H5 A 3,9-3,0m (8H); 2,4-2,1 m+s (8H); 1,2d (2H) O H 266 1 0 CH3 -CH2-O-C-N-# C2H5 A 7,6-6,5m (9H); 4,0m (2H); 1,2d (3H) 267 1 0 CH3 CH2-COOH H A 2,1m (2H); 1,2d (3H) 268 1 0 CH3 CH2-CONH2 H F 6,5bs (2H); 2,1m (2H); 1,2d (3H) 269 1 0 CH3 CH2-CON(CH3)2 H F 3,9-3,0 m+2s (10H); 2.1m (2H); 1,2d (3H) m n R1 R2 R3 Methode NMR H 270 1 0 CH3 CH2-CON-# H F 7,3-6,5m (9H); 2,1m (2H); 1,2d (3H) CH3 H 271 1 0 CH3 CH2-CON-# H F 7,3-6,5m (9H); 2,3m (2H); 2,2m (2H); 1,2d (3H) H 272 1 0 CH3 CH2-CON-#-Cl H F 7,7-6,5m (8H); 2,3m (2H); 1,2d (3H) 273 1 0 CH3 CH2-COOC2H5 H F 4,2q (2H); 2,0m (2H); 1,2 d+t (6H) 274 1 0 CH3 CH2-CH2-COOH C2H5 A 2,1m (2H); 1,5m (2H); 1,2d (3H) m n R1 R2 R3 Methode NMR 275 1 0 CH3 CH2-CH2-CONH2 C2H5 A 2,1m (2H); 1,5m (2H); 1,2d (3H) 276 1 0 CH3 CH2-CH2-CON(CH3)2 C2H5 A 3,0 2s (6H); 1,5m (2H); 1,2d (3H) H 277 1 0 CH3 CH2-CH2-CON-# C2H5 A 7,4-6,5 (9H); 2,1m (2H); 1,5m (2H); 1,2d (3H) 278 1 0 CH3 CH2-CH2-CON-#-F H A 7,3-6,5 (8H); 2,1m (2H); 1,5m (2H); 1,2d (3H) 279 1 0 CH3 CH2-CH2-C-N-#-OC2H5 C2H5 A 7.3-6.4 (8H); 3.6q (3H); 2.1m (2H); 1.5m (2H); 1.2 d+t (6H) m n R1 R2 R3 Methode NMR H 280 1 0 CH3 CH2-CH2-CON-CH(CH3)2 C2H5 A 2,8-2,2m (3H); 1,5m (2H);d 1,2d (3H); 1,0d (6H) H 281 1 0 CH3 CH2-CH2-CON-CH2-# C2H5 A 7,4-6,5m (9H); 5,1-4,3 m+s (5H); 2,1m (2H); 1,5m (2H); 1,2d (3H) OCH3 H 282 1 0 CH3 CH2-CH2-CON-CH2-CH2-#-OCH3 C2H5 A 7,3-6,2m (7H); 3,9s (6H); 2,9- C2H5 2,1m (6H); 1,5m (2H); 1,2d (3H) 283 2 0 CH3 -CH2-OH C2H5 A 3,9-3,0m (4H); 1,2d (3H) 284 2 0 CH3 -CH2-O-# C2H5 A 7,3-6,7m (9H); 3,9-3,0m (4H); 1,2d (3H) m n R1 R2 R3 Methode NMR 285 2 0 CH3 -CH2-O-CH2-#- C2H5 A 7,2-6,9m (9H); 4,0s (2H); 3,9- 3,0m (4H); 1,2d (3H); 286 2 0 CH3 CH2-O-CH2-#-Cl C2H5 A 7,4-6,9m (8H); 4,0s (2H); 3,9- 3,0m (4H); 1,2d (3H); 287 2 0 CH3 CH2-O-CH(CH3)2 C2H5 A 3,9-3,0m (5H); 1,2s (3H); 0,9d (6H) 288 2 0 CH3 CH2-O-CH2-CH2-N(CH3)2 C2H5 A 3,9-3,0m (6H); 2,4-2,1 m+s (8H); 1,2d (3H) O H 289 2 0 CH3 -CH2-O-C-N-# C2H5 A 7,6-6,9m (9H); 4,0s (2H); 1,2d (3H) m n R1 R2 R3 Methode NMR 290 2 0 CH3 CH2-COOH H A 2.5-1.7m (6H); 1.2d (3H) 291 2 0 CH3 CH2-CONH2 H F 6.5bs (2H); 2.5-1.7m (6H); 1.2d (3H) 292 2 0 CH3 CH2-CON(CH3)2 H F 3.9-3.0 m+2S (8H); 2.5-1.7m (6H); 1.2d (3H) 293 2 0 CH3 CH2-CON-# H F 7.8-7.0m (9H); 2.8-1.7 (6H) 1.2d (3H) Cl 294 2 0 CH3 CH2-CON-# H F 7.3-6.9 (8H); 2.5-1.7m (6H); 1.2d (3H) m n R¹ R² R³ Methode NMR H 295 2 0 CH3 CH2-CON-#-CH3 H F 7.3-6.9m (BH); 2.5-1.7m+s (9H); 1.2d (3H) 296 2 0 CH3 CH2-CO-OC2H5 H F 4.2q 2(H); 2.5-1.7m (6H); 1.2 d+t (6H) 297 2 0 CH3 CH2-CH2-COOH C2H5 A 2.5-1.7m (6H); 1.5m (2H); 1.2d (3H) 298 2 0 CH3 CH2-CH2-CONH2 C2H5 A 6.0 bs (2H); 2.5-1.7m (6H); 1.5m (2H); 1.2d (3H) 299 2 0 CH3 CH2-CH2-CON(CH3)2 C2H5 A 3.0 2s (6H); 1.5m (2H); 1.2d (3H) m n R¹ R² R³ Methode NMR H 300 2 0 CH3 CH2-CH2-CON# C2H5 A 7.4-7.0m (9H); 2.5-1.7m (6H); 1.5m (2H); 1.2d (3H) H 301 2 0 CH3 CH2-CH2-CON#F C2H5 A 7.3-6.9m (8H), 2.5-1.7m (6H); 1.5 (2H); 1.2d (3H) 302 1 1 CH3 CH2-CH2# C2H5 B 7.2bs (9H); 2.6m (2H); 1.7m (2H); 1.2d (3H) 303 1 1 CH3 CH2-CH2# H B 7.2bs (9H); 2.6m (2H); 1.7m (2H) CH3 304 1 1 CH3 # C2H5 B 7.4-7.0m (8H); 2.6m (2H); 2.3s CH2-CH2 (3H); 1.7m (2H); 1.2d (3H) m n R¹ R² R³ Methode NMR # 305 1 1 HO-CH2 CH2-CH2 C2H5 B 7.2bs (9H); 2.8-2.5m (4H); 1.7m (2H) # 306 1 1 H2N-(CH2)4- CH2-CH2 H B 7.2bs (9H); 2.8-2.3m (4H9; 1.8-1.3m (8H) 307 1 1 2N(CH2)3- CH2-CH2-#-NO2 H B 8.2-7.1m (8H); 2.8-2.3, (4H) 1.8-1.3m (6H) Cl 308 1 1 CH3 CH2-CH2# C2H5 B 7.5-6.9m (8H); 2.7m (2H); 1.7m (2H); 1.2d (3H) Cl 309 1 1 CH3 CH2-CH2# H B 7.5-6.9m (8H); 2.7m (2H); 1.7m (2H); 1.2d (3H) m n R¹ R² R³ Methode NMR COOH 310 1 1 CH3 CH2-CH2# H B 7.8-7.1m (8H); 2.7m (2H); 1.7m (2H); 1.2d (3H) HN Cl 311 1 1 C-NH-(CH2)4 CH2-CH2# C2H5 B 7.5-7.0m (8H); 2.8-2.6m (4H); H2N 1.7-1.3m (6H) OH 312 1 1 H2N-(CH2)2 CH2-CH2 H B 7.2-6.5m(8H); 2.8-2.3m (4H); 1.7-1.3m (4H) 313 1 1 H2N-(CH2)5 CH2-CH2# H B 7.2bs (9H); 2.7-2.3m (4H); 1.7-1.2m (10H) COONH2 314 1 1 H2N-(CH2)4 CH2-CH2# H B 7.8-7.1m (8H); 2.7-2.3m (4H); 1.8-1.3m (8H) m n R¹ R² R³ Methode NMR 315 1 1 H2N-CH2 CH2-CH2# H B 7.2bs (9H); 2.7-2.3m (4H); 1.7m (2H) F 316 1 1 CH3 CH2-CH2# C2H5 B 7.2-6.8m (8H); 2.7m (2H); 1.7m (2H); 1.2d (3H) OCH3 317 1 1 CH3 CH2-CH2# C2H5 B 7.2-6.3m (7H); 3.9s (6H); 2.7m (2H) OCH3 1.7m (2H); 1.2d (3H) CL 318 1 1 CH3 CH2-CH2# C2H5 B 7.3-6.4m (7H); 3.8s (3H); 2.6m (2H) OCH3 1.7m (2H); 1.2d (3H) Cl 319 1 1 CH3 CH2-CH2# B 7.4-6.8m (7H); 2.7m (2H); 1.7m (2H) Cl C2H5 1.2d (3H) m n R¹ R² R³ Methode NMR H OCH3 N CH2 OCH3 320 1 1 # CH2-CH2#OCH3 C2H5 B 13.1s (1H); 7.5-6.2m(8H); 3.9s (9H) 2.8-2.3m (4H); 1.7m (2H) # N 321 1 1 CH3 CH2-CH2-H C2H5 B 7.3-7.0m (7H); 2.8m (2H); 1.7m (2H); 1.2d (3H) # 322 1 1 CH3 CH2-CH2-S C2H5 B 7.3-6.9m (7H); 2.9m (2H); 1.7m (2H) 1.2d (3H) # 323 1 1 H2N-(CH2)4 CH2-CH2-O H B 7.4-6.3m (7H); 2.8-2.3m (4H);1.8- 1.3m (8H) 324 1 1 CH3 CH2-CH2# C2H5 B 8.6-7.1m (8H); 2.9m (2H); 1.7m (2H); 1.2d (3H) m n R¹ R² R³ Methode NMR 325 1 1 CH3 ##CH2-CH2 C2H5 B 7.8-6.5m (10H); 2.9m (2H); 1.7m N (2H); 1.2d (3H) H CH3 CH2-CH2 326 1 1 CH3 N# C2H5 B 7.4-7.0m (5H); 3.9-3.0m+s (7H); N 2.8m (2H); 2.0s (3H); 1.7 (2H); CH3 1.2d (3H) O 327 1 1 CH3 CH3-N# C2H5 B 5.2s (1H); 3.2 2s (6H); 2.9m (2H); O N CH2-CH2 1.7m (2H); 1.2d (3H) CH3 N Cl 328 1 1 CH3 # C2H5 B 8.1m (1H); 3.2s (3H); 2.9m (2H); O N CH2-CH2 1.7m (2H); 1.2d (3H) CH3 329 1 1 CH3 ## C2H5 B 8.5-7.5m (6H); 3.1m (2H); 1.8m N (2H); 1.2d (3H); CH2-CH2 m n R¹ R² R³ Mehtode NMR CH2-CH2 330 1 1 CH3 ## C2H5 B 8.8-7.4m (6H); 3.0m (2H); 1.7m N (2H); 1.2d (3H) N 331 1 1 CH3 HN#N C2H5 B 13.0 (1H); 2.9m (2H); 1.8m (2H); CH2-CH2 N 1.2d (3H) N CH2-CH2 332 1 1 CH3 # C2H5 B 7.9-7.4m 2s (2H); 2.8m (2H); O 1.7m (2H); 1.2d (3H) H2N N CH2-CH2 333 1 1 CH3 # C2H5 B 8.0s (1H); 2.8m (2H); 1.7m (2H); S 1.2d (3H) CH3 O N Cl 334 1 1 CH3 # C2H5 B 3.2 2s (1H); 3.1m (2H); 1.8 (2H) CH3 N CH2-CH2 1.2d (3H) m n R¹ R² R³ Methode NMR CH3 335 1 1 CH3 CHCH2# C2H5 B 7.2bs (9H); 2.7m (2H); 2.2m (1H); 1.2s (3H); 1.0d (3H) 336 1 1 H2N-(CH2)4 CH2-CH2-CH2#Cl H B 7.4-7.0m (8H); 2.7-2.3m (4H); 1.8- 1.3m (10H) CH3 337 1 1 CH3 CH2-CH2-C#OCH3 C2H5 B 7.3-6.3m(8H); 3.9m (3H); 1.9- CH3 1.2m (4H); 1.2d (3H); 1.0s (6H) HN H 338 1 1 C-N-(CH2)3 CH2# H B 7.2bs (9H); 2.9-2.6m (4H); 1.7-1.3 H2N m (4H); 339 1 1 H CH2# H B 7.4-6.9m (8H); 3.9-3.0m (5H); F 2.7m (2H) m n R¹ R² R³ Methode NMR 340 1 1 H CH2#COOH H B 7.8-7.0m (8H); 3.9-3.0m (5H); 2.7m (2H) OH 341 1 1 H -CH2-CH2-CH2-CH2# H B 7.3-6.5m(8H); 3.9-3.0, (5H); 2.7m (2H); 1.8-1.3m (6H) 342 1 1 CH3 CH2#CONH2 H B 7.8-7.0m (8H); 2.8m (2H); 1.2d (3H) 343 1 1 CH3 CH2#NH2 H B 7.2-6.4m (8H); 2.7m (2H); 1.2d (3H) OCH3 344 1 1 CH3 -CH2#OCH3 H B 7.2-6.3m (7H); 3.9s (6H); 2.7m (2H); 1.2d (3H) m n R¹ R² R³ Methode NMR OCH3 345 1 1 (CH3)2CH-CH2 CH2-CH2# C2H5 B 7.2-6.4m (7H); 3.8s (3H); 2.8m (2H); Cl 2.0-1.5m (5H); 0.9d (6H) 346 1 1 CH3 -CH2## C2H5 B 7.8-6.5m (10H); 2.9m (2H); 1.2d (3H) N H OCH3 347 1 1 (CH3)2CH-CH2 CH2-CH2#OCH3 H B 7.2-6.2m (6H); 3.9s (9H); OCH3 2.7m (2H); 1.9-1.3m (5H); 0.9d (6H) 348 1 1 CH3 # H B 7.3-6.0m (7H); 2.8m (2H); 1.2d (3H) CH2 N H CH2 349 1 1 CH3 # H B 7.3-6.9m (7H); 2.9m (2H); 1.2d (3H) m n R¹ R² R³ Methode NMR 350 1 1 CH3 # H B 7.4-6.3m(7H); 2.8m (2H); 1.2d (3H) CH2 O 351 1 1 CH3 # H B 8.6-7.1m (8H); 2.9m (2H); 1.2d (3H) N CH2 CH2 352 1 1 CH3 ## H B 7.8-6.5m (10h); 2.9m (2H); 1.2d (3H) N CH3 H CH2- 353 1 1 (CH3)2CH-CH2 N# C2H5 B 7.4-7.0m (5H); 3.9-3.0m+s (7H); N 2.8-m (2H); 2.0s (3H); 1.8-1.3m (3H); CH3 1.0d (6H) CH3 O 354 1 1 H N# C2H5 B 5.2s (1H); 3.2s (6H); 2.9m (2H) O N CH2 CH3 m n R¹ R² R³ Methode NMR 355 1 1 CH3 ## H B 8.5-7.5m (6H); 3.1m (2H); 1.2d (3H) N CH2- CH2 356 1 1 CH3 ## H B 8,8-7.4m (6H); 3.0m (2H); 1.2d (3H) N H2N N CH2- 357 1 1 CH3 S# H B 8.0s (1H); 2.8m (2H); 1.2d (3H) CH3O O 358 1 1 CH3 # H B 8.1s (1H); 6.4s (1H); 3.7s (3H); O CH2- CH3O O 359 1 1 (CH3)2CH-CH2 # H B 8.1s (1H); 6.4s (1H); 3.7s (3h); O CH2-CH2 2.9m (2H); 1.8-1.3m (5H); 1.0d (6H) m n R¹ R² R³ Methode NMR CH2-CH2 360 1 1 CH3 N# C2H5 B 7.7-7.1m (6H); 2.9m (2H); 1.7m (2H) N 1.2d (3H) H CH2- 361 1 1 CH3 N# C2H5 B 7.7-7.1m (6); 2.9m (2H); 1.2d (3H) N H 362 1 0 CH3 CH2-CH2# C2H5 B 7.2-6.5m(9H); 2.7m (2H); 1.7m (2H); 1.2d (3H) Cl 363 1 0 CH3 CH2-CH2 H B 7.5-6.5m (8H); 1.7m(2H); 1.7m (2H); 1.2d (3H) Cl 364 1 0 CH3 CH2-CH2# H B 7.6-6.5m (7H); 2.8m (2H); 1.7m (2H); Cl 1.2d (3H) m n R¹ R² R³ Methode NMR # 365 1 0 CH3 CH2-CH2 N H B 7.3-6.0m (7H); 2.8m (2H); 1.7m (2H); H 1.2d (3H) # 366 1 0 CH3 CH2-CH2 S H B 7.3-6.5m (7H); 2.9m (2H); 1.7m (2H); 1.2d (3H) CH2-CH2 367 1 0 CH3 # H B 8.6-6.5m (8H); 2.9m (2H); 1,7m (2H); N 1.2d (3H) CH2-CH2 368 1 0 CH3 ## C2H5 B 7.8-6.5m (10H); 2.9m (2H); 1.7m (2H); N 1.2d (3H) H CH3 369 1 0 CH3 CH-CH2# C2H5 B 7.2-6.5m (9H); 2.9m (2H); 1.8m (1H); 1.2d (3H); 1.1d (3H) m n R¹ R² R³ Methode NMR 370 1 0 CH3 CH2-CH2-CH2#Cl C2H5 B 7.4-6.5m (8H); 2.7-2.3m (2H); 1.8- 1.3m (4H); 1.2d (3H) CH3 371 1 0 CH3 CH2-CH2-C#OCH3 C2H5 B 7.3-6.3m (8H); 3.9s (3H); 1.9-1.2m (4H); CH3 1.2d (3H); 1.0s (6H) OCH3 372 1 0 CH3 CH2-CH2# C2H5 B 7.2-6.3m (7H); 3.9m (3H); 2.7m (2H); Cl 1.8m (2H); 1.2d (3H) 373 1 0 CH3 -CH2## C2H5 B 7.8-6.5m (10H); 2.9m (2H); 1.2d (3H) N H N CH2-CH2 374 1 0 CH3 # C2H5 B 7.7-6.5m (6H); 2.9m (2H); 1.7m (2H); N 1.2d (3H) H m n R¹ R² R³ Methode NMR CH2- 375 1 0 CH3 N# C2H5 B 7.7-6.5m (6H); 2.9m (2H); 1.2d (3H) N H 376 2 0 CH3 # C2H5 B 7.2bs (9H); 2.8-1.6m (8H); CH2-CH2 CH2-CH2 1.2d (3H) CH3 377 2 0 CH3 # C2H5 B 7.4-7.0m (8H); 2.6-1.7m (1H); CH2-CH2 1.2d (3H) OCH3 378 2 0 CH3 # C2H5 B 7.2-6.4m (8H); 3.8m (3H); 2.7-1.6m CH2-CH2 (8H); 1.2d (3H) Cl 379 2 0 CH3 # C2H5 B 7.4-7.0m (8H); 2.8-1.6m (8H); CH2-CH2 1.2d (3H) m n R¹ R² R³ Methode NMR Cl 380 2 0 CH3 # C2H5 B 7.6-7.0m (7H); 2.9-1.7m (8H); CH2-CH2 1.2d (3H) Cl # 381 2 0 CH3 CH2-CH2 S C2H5 B 7.3-6.5m (7H); 2.9-1.7m (8H); 1.2d (3H) CH2-CH2 382 2 0 CH3 # C2H5 B 8.6-7.0m (8H); 2.9-1.7m (8H); N 1.2d (3H) CH2-CH2 383 2 0 CH3 ## C2H5 B 7.8-6.5m (10H); 2.9-1.7m (8H); N 1.2d (3H) H 384 2 0 CH3 (CH3)2-CH-CH2-CH2-CH2 C2H5 A 1.9-1.3m (7H); 1.2d (3H); 0.9d (6H) m n R¹ R² R³ Methode NMR 385 1 1 H2N-(CH2)4 (CH3)2CH-CH2-CH2 C2H5 B 2.4m (2H); 1.9-1.3m (11H); 0.9d (6H) 386 1 1 H2N-(CH2)3 (CH3)2CH-CH2 C2H5 B 2.4m (2H); 1.9-1.3m (7H); 0.9d (6H) 387 1 0 FCH2 (CH3)2CH C2H5 B 4.3dd (2H); 1.9m (1H); 0.9d (6H) CH2 388 2 0 # CH3 C2H5 A 7.2bs (9H); 3.0m (2H); 1.0d (3H) CH2 389 1 1 CH3-CH2-CH H# H A 1.9-1.2m (16H); 1.0d+t (6H) m n R¹ R² R³ Methode NMR 390 2 0 HO-CH2 H H B 3.9-3.0m (3H); 2.5m (2H) CH2-CH2 391 1 1 CH3 ## C2H5 A 7.8-7.0m (11H); 2.7m (2H); 1.5m (2H); 1.2d (3H) OH 392 1 1 CH3 # H B 7.3-6.5m (8H); 2.8m (2H); 1.2d (3H) CH2 OCH3 393 1 1 CH3 # H B 7.3-6.4m (8H); 3.9m (3H); 2.9m (2H); CH2 1.2d (3H) 394 1 1 CH3 # C2H5 B 7.6-6.4m (8H); 3.8s (3H); 2.9m (2H); CH2 OCH3 1.2d (3H) m n R¹ R² R³ Methode NMR 395 1 1 CH3 CH2-#-Cl C2H5 B 7.6-7.0m (8H); 2.9m (2H); 1.2d (3H) Cl 396 1 1 CH3 CH2-#-Cl H B 7.8-7.0m (7H); 2.9m (2H) 1.2d (3H) 397 1 1 CH3 CH2-#-NO2 H B 8.3-7.0m (8H); 2.9m (2H); 1.2d (3H) 398 1 1 CH3 CH2-#-CH3 C2H5 B 7.4-7.0m (8H); 2.9m (2H); 2.3s (3H); 1.2d (3H) 399 1 1 CH3 -# H A 5.3m (1H); 2.3m (4H); 1.8-1.3m (6H); 1.2d (3H) m n R¹ R² R³ Methode NMR 400 1 1 CH3 -#- C2H5 B 5.4m (1H); 2.3m (4H); 1.8-1.4m (4H); 1.2d (3H) 401 1 1 CH3 -#- H B 5.5m (1H); 3.9m-3.0 (6H); 2.5-2.1m (3H) 1.2d (3H) 402 1 1 CH3 -#- H B 5.9s (1H); 3.9-3.0m (8H); 1.2d (3H) CH3 403 1 1 CH3 -#-NH(CH2)3- C2H5 B 7.4s (1H); 2.5m (2H); 2.3s (6H); CH3 1.8-1.2d (4H) m n R¹ R² R³ Methode NMR 404 1 1 CH3 #-#-CH2CH2- C2H5 A 7.5-6.8m (8H); 2.8m (2H); 1.5m (2H) Cl 405 1 1 CH3 #-#-CH2-CH2- H A 7.5-6.8m (8H); 2.8m (2H); 1.5m (2H) Method F: Michael addition of a dipeptide -t-C4Hg ester, shown according to example (134 to a corresponding maleic acid derivative according to example (19)) Unless otherwise stated, the following NMR data apply to the compounds below (# values in ppm; TMS as standard ): for m = n = 1 7.3s (4H), 5.1-4.3m (3H) 3.9-3.Om C4H) m = 2, n = 0 7.2s (4H); 5.0-4.5m (1H); 3.9-3.0m (2H); 2.5-1.7m (4H) m = 1, n = 0 7.2-6.5m (4H); -4.9t 7Hz (1H); 3.6-3.0m (4H) In the case of ethyl esters, the following signals also occur: 4.2q 7Hz (2H) 1.2t 7Hz (3H) No. mn R¹ R² R³ Method NMR H # 1 1 1 CH3 CH2-N-CHO C2H5 A 8.3 2s (1H); 2.9 (2H); 1.2d (3H) H # 2 1 1 CH3 CH2-N-COCH3 C2H5 A2.9 (2H); 2.1s (3H) '; 1.2d (3H) H # 3 1 1 CH3 CH2-N-CO-CH2 # C2H5 A 3.9-3.0m (6H); 2.9 (2H); 1.2d (3H) H # 411 H CH2-N-CO # C2H5 A 7.2-6.8 (8H); 3.9-3.Om (5H) OH 2.9m (2H) E. # 511 CH3 CH2-N-CO # C2H5 A 7.9-7.0m (8H); 3.9-3.Om (5H) COOH 2.9m (2H) H # 611 CH3 CH2-N-CO-CH2 # C2H5 A 7.65-7.1m (8H); 3.9-3.Om (6H) Cl 2.9m (2H); 1.2d (3H) H # 711 CH3 CH2-N-CO-CH2 # HA 7.65-7.1m (8H); 3.9-3.Om (6H) Cl 2.9m (2H); 1.2d (3H) No. mn R¹ R² R³ Method NMR H # 8 11 CH3 CH2-N-CO # C2H5 A 8.2-7.1m (8H); 2.9 (2H); NO2 1.2d (3H) H # 911 CH3 CH2-N-CO- # C2H5 A 7.2-6.8m (8H); 2.9s (2H); 1.2d (3H) NH2 H N-CH2- # 10 1 1 # CH2-N-CO- # OCH3 C2H5 A 13.Os (1H); 7.5-6.8m (10H); 3.9s (3H) HN 2.9-2.6m (4H) H # OCH3 11 11 CH3 CH2-N-CO # OCH3 C2H5 A 7.5-6.9m (7H); 3.9s (6H); 2.9m (2H); H 1.2d (3H) # OCH3 12 1 1 CH3 CH2-N-CO # OCH3 C2H5 A 7.3-6.8m (6H); 3.9s (9H); 2.9m (2H) OCH3 1.2m (3H) H # 13 11 CH3 CH2N-CO # C2H5 A 7.4-7.0m (8H); 2.9m (2H) CH3 2.4s (3H); 1.2d (3H) No. mn R¹ R² R³ Method NMR H # 14 11 CH3 CH2-N-CO- # C2H5 A 7.4-7.0m (8H); 2.9m (2H); 2.4m (3H) CH3 1.2d (3H) 15 1 1 CH3 CH2-CH2-N (CH3) 2 C2H5 A 2.4m (2H); 2.2s (6H); 1.7m (2H); HH 1.2d (3H) # # 16 11 CH3 CH2-N-CO-N # C2H5 A 7.3-7.0m (9H); 2.9m (2H); 1.2d (3H) HH # # 1711 CH3 CH2-N-CO-N # Cl C2H5 A 8.0-7.1m (8H); 2.9m (2H); 1.2d (3H) HH # # 1811 CH3 CH2-N-CO-N # C2H5 A 8.3-7.1m (8H); 2.9m (2H); 2.3s (3H) NO2 HH # # 1911 (CH3) CH-CH2 CH2-N-CO-N # CH3 C2H5 A 7.4-7.0m (8H); 2.9m (2H); 2.3s (3H) 1.Od (6H) No. mn R¹ R² R³ Method NMR HH # # 2011 CH3 CH2-N-CO-N # C2H5 A 7.3-6.7m (8H); 3.8s (3H); OCH3 2.9m (2H); 1.2d (3H) HH # #Cl 2111 CH3 CH2-N-CO-N # CH3 C2H5 A 7.6-6.9m (7H); 2.9m (2H); HH 2.4s (3H); 1.2d (3H) # # 22 1 1 # S-CH2 CH2-N-CO-N-CH3 C2H5 A 7.3-7.0m (9H); 3.0-2.6m + s HH (7H) # # 23 11 # S-CH2 CH2-N-CO-N-CH3 HA 7.3-7.0m (9H); 3.0-2.6m + s HH (7H) # # 24 1 1 C2F CH2-N-CO-N-C4H9 C2H5 A 5.1-4.3m (5H); 2.9m (2H); 1.Ot (3H) No. mn R¹ R² R³ Method NMR HIGH # # # 2511 CH3 CH2-NCON # H C2H5 A 3.2-2.9m (3H); 2.4-1.Om (10H); 1.2d (3H) HH # # 2611 CH3 CH2-NCO-CH2 # C2H5 A 7.1s (5H); 5. Os (2H); HO 2.9m (2H); 1.2d (3H) # # 27 1 1 CH3 CH2-NCO-C2H5 C2H5 A 4.2q (4H); 2.9m (2H); 1.2ct + d (9H) H # 28 1 1 CH3 CH2-CH2-N-CHO C2H5 A 8.2 2s (1H); 2.9m (2H); 1.5m (2H); 1.2d (3H) H # 2911 H CH2-CH2-N-COOH C2H5 A 3.9-3.0m (9H); 2.9m (2H) 2.1s (3H); 1.5m (2H) H # 3011 CH3 CH2-CH2-N-CO # C2H5 A 7.6-7.0m (9H); 2.9m (2H) 1.5m (2H); 1.2d (3H) No. mn R¹ R² R³ Method NMR H # 3111 CH3 CH2-CH2-N-CO # C2H5 A 7.2-6.8m (8H); 2.9m (2H). HO 1.5m (2H); 1.2d (3H) H # 32 1 1 # CH2 CH2-CH2-N-CO # COOH C2H5 A 7.9-7.0m (13H); 2.9-2.7m (4H); 1.5m (2H) H # 3311 CH3 CH2-CH2-N-CO # Cl C2H5 A 8.0-7.1m (8H); 2.9m (2H); 1.5m (2H); 1.2d (3H) HO # # 3411 CH3 CH2-CH2-NC # Cl HA 8.0-7.1m (8H); 2.9m (2H) 1.5m (2H); 1.2d (3H) HH # # 3511 CH3 CH2-CH2-NC # NO2 C2H5 A 8.3-7.0m (8H); 2.9m (2H); 1.5m (2H); 1.2d (3H) No. mn R¹ R² R³ Method NMR HO # # 3611 CH3 CH2-CH2-NC # NH2 C2H5 A 7.2-6.8m (8H); 2.9m (2H); 1.5m (2H); 1.2d (3H) HO # # 3711 CH3 CH2-CH2-NC # OCH3 C2H5 A 7.5-6.8m (8H); 3.8s (3H); 2.9 (2H); 1.5m (2H); 1.2d (3H) HO # # OCH3 3811 CH3 CH2-CH2-NC # OCH3 C2H5 A 7.5-6.9m (7H); 3.9s (6H); 2.9m (2H); 1.5m (2H); 1.2d (3H) HO # # OCH3 3911 CH3-CH2-CH-CH2 CH2-CH2-NC # OCH3 C2H5 A 7.2-6.8m (6H); 3.9s (9H); 2.9m # OCH3 (2H); 1.5m (2H); 1. Om (13H) CH3 HH # # 4011 CH3 CH2-CH2-NC # CH3 C2H5 A 7.4-7.0m (8H); 2.9m (2H); 2.3s (3H); 1.5m (2H); 1.2d (3H) No. mn R¹ R² R³ Method NMR HO # # 4111 CH3 CH2-CH2-NC # C2H5 A 7.4-7.0m (8H); 2.9m (2H); 2.3s CH3 (3H); 1.5m (2H); 1.2d (3H) 42 1 1 CH3 CH2-CH2-CH2-N (C2H5) 2 C2H5 A 2.6-2.4m (6H); 1.5m (4H); 1.2d (3H 0.9t (6H) HH # # 4311 CH3 CH2-CH2-N-CO-N # C2H5 A 7.5-7.0m (9H); 2.9m (2H); 1.5m (2H); 1.2d (3H) HH # # 4411 CH3 CH2-CH2-N-CO-N # Cl C2HE A 7.5-7.0m (8H); 2.9m (2H); 1.5m (2H 1.2d (3H) HH # # 4511 CH3 CH2-CH2-N-CO-N # NO2 C2H5 A 8.3-7.1m (8H); 2.9m (2H); 1.5m (2H 1.2d (3H) HH # # 46 11 CH3 CH2-CH2-N-CO-N # C2H5 A 7.4-7.0m (8H); 2.9m (2H); 2.3m (3H CH3 1.5m (2H); 1.2d (3H) No. mn R¹ R² R³ Method NMR HH 4711 CH3 CH2-CH2-N-CO-N # OCH3 C2H5 A 7.2-6.5m (8H); 3.9s (3H); 2.9m (2H); 1.5m (2H); 1.2d (3H) H HF 48 1 1 CH3 CH2-CH2-N-CO-N # CH3 C2H5 A 7.3-6.9m (7H); 2.9m (2H); 2.3s (3H); 1.5m (4H); 1.2d (3H No. mn R¹ R² R³ Method NMR H 4911 (CH3) 2CH-CH2 CH2-CH2-N-CO-N-CH3 C2H5 A 3.0-2.6m (5H); 1.7-1.3m (5H); 1.Od (6H) HH # # 50 1 1 (CH3) 2CH-CH2 CH2-CH2-N-CO-N-C4H9 C2H5 A 3.0-2.6m (4H); 1.7-1.2m (9H); 0.9d + t (9H) HH 5111 (CH3) 2CH-CH2 CH2-CH2-N-CO-N-C4H9 HA 3.0-2.6m (4H); 1.7-1.2m (9H); 0.9d + d (9H) HH 5211 CH2F CH2-CH2-N-CO-N # H C2HE A 5.1-4.3m (5H); 2.9m (3H); 2.0-1.0m (12H) H 5311 CH3 CH2-CH2-N-CO-O-CH2 # C2H5 A 7.1s (5H); 5.0s (2H); 2.9m (2H); 1.5m (2H); 1.2d (3H) No. mn R¹ R² R³ Method NMR H 5411 CH3 CH2-CH2-N-CO-O-C2H5 C2H5 A 4.2q (4H); 2.9m (2H); 1.5m (2H) 1.2d + t (9H) H 55 1 1 CH3 CH2-CH2-N-CH3 C2H5 A 2.4m (2H); 2.3s (3H); 1.5m (2H); 1.2d (3H) 5611 CH3 CH2-CH2-N # C2H5 A 2.4m (6H); 1.8-1.2m (8H); 1.2d (3H) H 5711 CH3 CH2-CH2-N # C2HE A 7.2-6.5m (9H); 2.5m (2H); 1.5m (2H 1.2d (3H) H 58 1 1 (CH3) 2 CH-CH2 CH2-CH2-N # Cl C2H5 A 7.2-6.6m (8H); 2.4m (2H); 1.5m (5H) 1.0d (6H) No. mn R¹ R² R³ Method NMR H 59 1 1 # S-CH2 CH2-CH2-N # OCH3 C2H5 A 7.3-6.4m (13H); 3.8m (3H); 2.5-2.2m HCl (4H); 1.5m (2H) 6011 CH2F CH2-CH2-N # CH3 C2H5 A 7.2-6.6m (7H); 5.1-4.3m (5H); 2.4m (2H); 2.3s (3H); 1.5m (2H) H 6111 CH3 CH2-N # CCOCH C2H5 A 7.3-6.5m (8H); 2.5m (2H); 1.1s (3H); 1.2d (3H) H 6211 CH3 CH2-N # NO2 C2HE A 7.7-7.0m (8H); 2.5m (2H); 1.2d (3H) HIGH 63 11 CH3 CH2-N # CONH2 C2H5 A 7.6-6.7m (7H); 2.4m (2H); 1.2d (3H) No. mn R¹ R² R³ Method NMR H # 6411 CH3 CH2-N # COOCH2H5 C2H5 A 7.6-6.8m (8H); 4.2q (4H); 2.5m (2H) 1.2d + t (9H) H 6511 CH3 CH2-N # C2H5 A 7.2-6.2m (7H); 5.0s (2H); 2.5m (2H) 1.2d (3H) H 66 11 CH3 CH2- N # NH2 C2H5 A 7.2-6.7m (8H); 2.5m (2H); 1.2d (3H) H 67 1 1 CH3 CH2-N-CH2-CH2-COOC2H5 C2HE A 4.2q (4H); 2.6-2.3m (6H); 1.2d + t (9H) 68 1 1 CH3 CH2-CH2-CH2-NH2 C2H5 A 2.3m (2H); 1.5m (4H); 1.2d (3H) No. mn R¹ R² R³ Method NMR H 69 1 1 CH3 CH2-N-CH2-CH2-N (C2H5) C2H5 A 2.6-2.4m (10H); 1.2d + t (9H) 7011 CH3 CH2-N # O C2H5 A 3.9-3.0m (12H); 2.3m (2H); 1.2d (3H) 7111 CH3 CH2-N # C2H5 A 2.6-2.3m (6H); 1.6-1.4m (4H); 1.2d (3H) H 72 1 1 CH3 CH2-N-CH2-CH2-CONH2 C2HE A 2.6-2.2m (6H); 1.2d (3H) 73 1 1 CH3 CH2-CH2-CH2-N (CH3) 2 C2H5 A 2.4m (2H); 2.2s (6H); 1.5m (4H); 1.2d (3H) H 74 1 1 CH3 CH2-N-CH2-CONH2 C2H5 A 3.9-3.0m (6H); 2.4m (2H); 1.2d (3H) 75 1 CH3 (CH2) 5-NH2 HC 2.3m (2H); 1.6-1.2m (8H); 1.2d (3H) No. mn R¹ R² R³ Method NMR 76 lH2N- (CH2) 4 (CH2) 4-NH2 HA 2.4m (4H); 1.6-1.2m (12H) 77 1 1 CH3 CH2-CH2-NH-CH3 C2H5 A 2.4m (2H); 2.2s (3H); 1.5m (2H); 1.2d (3H) 78 1 1 CH3 CH2-NH-CH3 C2H5 A 2.4m (2H); 2.1s (3H); 1.2d (3H) H 7910 CH3 CH2-N-CO-CH2 # C2HE A 7.2-6.5m (9H); 3.8-3.0m (6H); 2.9m (2H); 1.2d (3H) H # 80 10 CH3 CH2-N-CO # C2H5 A 7.8-6.5m (9H); 2.9m (2H); 1.2d (3H) H # 8110 CH3 CH2-N-CH2-CONH2 C2H5 A 7.8-6.5m (8H); 2.9m (2H); 1.2d (3H) HH # # 8210 CH3 CH2-N-CO-N- # C2H5 A 7.4-6.5m (9H); 2.9m (2H); 1.2d (3H) mn R¹ R² R³ method NMR HH 8310 CH3 CH2-N-CO-N - # - Cl C2H5 A 7.7-6.5m (8H); 2.9m (2H); 1.2d (3H) HH 8410 CH3 CH2-N-CO-N-CH3 C2H5 A 3.0-3.6m + s (5H); 1.2d (3H) HIGH 85 10 CH3 CH2-NCN- # C2H5 A 3.2-2.9m (3H); 2.4 - 1.2m (10H) 1.2d (3H) H 86 10 CH3 CH2-CH2-N-CO- # C2H5 A 7.6-6.5m (9H); 2.9m (2H); 1.5m (2H); 1.2d (3H) H 87 10 CH3 CH2-CH2-N-CO- # C2H5 A 7.6-6.5m (8H); 2.9m (2H); 1.5m (2H); 1.2d (3H) HO 88 10 CH3 CH2-CH2-NC - # - Cl C2H5 A 7.6-6.5m (8H); 2.9m (2H); 1.5m (2H); 1.2d (3H) 89 10 CH3 CH2-CH2-CH2-N (C2H5) 2 C2H5 A 2.6-2.4m (6H); 1.5m (4H); 1.2d (3H); 1.0 t (6H) mn R¹ R² R³ method NMR HH 90 10 CH3 CH2-CH2-N-CO-N- # C2H5 A 7.4-6.5m (9H); 2.9m (2H); 1.5m (2H); 1.2d (3H) HH 9110 CH3 CH2-CH2-N-CO-N - # - Cl C2H5 A 7.5-6.5m (8H); 2.9m (2H); 1.5m (2H); 1.2d (3H) HH 9210 CH3 CH2-CH2-N-CO-N- # C2H5 A 7.8-6.5m (8H); 2.9m (2H); \ 1.5m (2H); 1.2d (3H) NO2 HH 93 10 CH3 CH2-CH2-N-CO-N-CH3 C2H5 A 3.0-2.6m + n (5H); 1.5m (2H); 1.2d (3H) 9410 CH3 CH2-CH2- # C2H5 A 2.6-2.3m (6H); 1.8 - 1.2 (8e 1.2d (3H) H 95 10 CH3 CH2-CH2-N- # C2H5 A 7.2-6.5m (9H); 2.4m (2H); 1.5m (2H); 1.2d (3H) mn R¹ R² R³ method NMR H / Cl 9610 CH3 CH2-CH2-N- # C2H5 A 7.6-6.5m (8H); 2.4m (2H); 1.5m (2H); 1.2d (3H) H 97 10 CH3 CH2-CH2-N- # - OCH3 C2H5 A 7.2-6.5m (8H); 2.9m (2H); 1.5m (2H); 1.2d (3H) 9810 CH3 (CH2) 5-NH2 C2H5 A 2.4m (2H); 1.8 - 1.2m (8H); 1.2d (3H) H 99 10 CH3 (CH2) 4-NH2 C2H5 A 2.4m (2H); 1.8 - 1.2m (6H); 1.2d (3H) mn R¹ R² R³ method NMR H 100 2 0 CH3 CH2-N-COCH3 C2H5 A 2.9m (2H); 2.3s (3H); 1.2d (3H) H 101 2 0 CH3 CH2-N-CO-CH2- # C2H5 A 3.9-3.0 m + s (4H); 2.9m (2H) 1.2d (3H) HIGH 102 2 0 CH3 CH2-NCN - # - Cl C2H5 A 7.5-7.0 m (8H); 2.9m (2H); 1.2d (3H) HH 10320 CH3 CH2-N-CO-N-C4H9 C2H5 A 2.9m (4H): 1.7-1.3m (4H); 1.2d (3H); 0.9 t (3H) 10420 CH3 CH2-N-CO-N-C4H9 C2H5 A 4.2q (4H); 2.9m (2H); 1.2 d + t (9H) mn R¹ R² R³ method NMR H 10520 CH3 CH2-CH2-N-CO- # C2H5 A 7.8-7.0m (9H); 2.9m (2H); 1.5m (2H); 1.2d (3H) H 10620 CH3 CH2-CH2-N-CO- # -Cl C2H5 A 7.9-7.0m (8H); 2.9m (2H); 1.5m (2H); 1.2d (3H) H 10720 CH3 CH2-CH2-NC- # -Cl C2H5 A 7.9-7.0m (8H); 2.9m (2H); 1.5m (2H); 1.2d (3H) HO 10820 CH3 CH2-CH2-NC- # C2H5 A 7.8-7.0m (8H); 2.9m (2H); / 2.3s (3H); 1.5m (2H); 1.2d (3H) CH3 10920 CH3 CH2-CH2-NC- # HA 7.6-7.0m (8H); 2.9m (2H); 2.3s / (3H); 1.5m (2H); 1.2d (3H) CH3 mn R¹ R² R³ method NMR HIGH 110 2 0 CH3 CH2-CH2-NCN- # C2H5 A 7.4-7.0m (9H); 2.9m (2H); 1.5m (2H); 1.2d (3H) HIGH 111 2 0 CH3 CH2-CH2-NCN - # - Cl C2H5 A 7.7-6.9m (8H); 2.9m (2H); 1.5m (2H); 1.2d (3H) HH 11220 CH3 CH2-CH2-NCN - # - Cl C2H5 A 7.5-6.8 m (8H); 2.9m (2H); / 2.3s (3H); 1.5m (2H); 1.2d (3H) CH3 HIGH 113 2 0 CH3 CH2-CH2-NCN-C4H9 C2H5 A 2.9-2.6m (4H); 1.7-1.3m (6H); 1.2d (3H); 0.9t (3H) H / Cl 11420 CH3 CH2-CH2-N- # C2H5 A 7.5-6.5m (8H); 2.4m (2H); 1.5m (2H); 1.2d (3H) mn R¹ R² R³ method NMR 115 2 0 CH3 (CH2) 5-NH2 HC 2.4m (2H); 1.8-1.2m (8H); 1.2d (3H) 116 2 0 CH3 (CH2) 4-NH2 HC 2.4m (2H); 1.8-1.3m (6H); 1.2d (3H) 117 11 CH3 CH2 -S- # C2H5 A 7.4-7.0 m (9H); 2.7m (2H); 1.2d (3H) 118 1 1 CH3 CH2 -S- # -F C2H5 A 7.3-6.8 m (8H); 2.7m (2H); 1.2d (3H) 119 1 1 CH3 CH2-SH C2H5 A 2.4m (2H); 1.2d (3H) mn R¹ R² R³ method NMR 120 11 CH3 CH2 -S- # - SO2NH2 C2H5 A 8.1-7.1 m (8H); 6.5bs (2H); 2.7m (2H); 1.3d (3H) OCH3 / 121 1 1 (CH3) 2CH-CH2 CH2-S- # C2H5 A 7.2-6.7m (8H); 3.8s (3H); 2.7m (2H); 1.6-1.2m (3H); 1.06 (6H) CH2 CONH2 122 1 1 # CH2-S- # C2H5 A 13.0s (1H); 7.8-6.8 m (10H); 6.0 bs (2H); 2.9 - 2.6m (4H) CH2 NO2 / / 123 1 1 ## CH2-S- # C2H5 A 8.2-6.4m (14H); 2.9 - 2.6m (4H) CH2 NH2 / / 124 1 1 ## CH2-S- # C2H5 A 7.8-6.4 m (14H); 2.9 - 2.6m (4H) mn R¹ R² R³ method NMR 125 1 1 (CH3) 2CH-CH2 CH2-S- # C2H5 A 7.3-7.0m (8H); 2.7m (2H); 2.3s / (3H); 1.9 - 1.4m (3H): 1.0d (6H) CH3 126 1 1 CH3 -CH2-S-CH2- # C2H5 A 7.3-7.0m (9H); 3.9 3.0 m + s (6H); 2.4m (2H); 1.2d (3H) CH2 / 127 1 1 # -CH2-S-CH (CH3) 2 C2H5 A 7.3-6.9m (9H); 2.6-2.3m (5H); 0.9d (6H) 128 1 1 CH3 -CH2-S-CH2-CH2-N (CH3) 2 C2H5 A 2.6-2.2 m + s (12H); 1.2d (3H); 129 1 1 CH2F-CH2-S-CH2-CH2-CONH2 C2H5 A 5.1-4.3m (5H); 2.5 - 2.2 (6H) mn R¹ R² R³ method NMR 130 1 1 CH3 -CH2-S-CH2-CH2-COOC2H5 C2H5 A 4.2q (4H); 2.5-2.2m (6H); 1.2 d + t (9H) 131 1 1 CH3 -CH2-S-CH2-CH2-OC2H5 C2H5 A 3.9-3.0 q + m (8H); 2.4-2.2m (4H); 1.2 d + t (6H) 132 11 CH3 -CH2-CH2-S- # C2H5 A 7.3-7.0m (9H); 2.7m (2H); 1.5m (2H); 1.2d (3H) 133 11 CH3 -CH2-CH2-S - # - Cl C2H5 A 7.5-7.0 m (8H); 2.7m (2H); 1.5m (2H); 1.2d (3H) 134 11 CH3 -CH2-CH2-S - # - COOH C2H5 A 7.9-6.9m (8H); 2.7m (2H); 1.5m (2H); 1.2d (3H) mn R¹ R² R³ method NMR 135 1 1 CH3 CH2-CH2-S - # - SO2NH2 C2H5 A 8.0-6.9m (8H); 6.5bs (2H); 2.6m (2H); 1.5m (2H); 1.2d (3H) 136 11 CH3 CH2-CH2-S - # - OCH3 C2H5 A 7.3-6.4 m (8H); 3.8s (3H); 2.7m (2H); 1.5m ("H); 1.2d (3H) CONH2 / 137 1 1 CH3 CH2-CH2-S- # C2H5 A 7.8-6.9m (8H); 6.0bs (2H); 2.6m (2H); 1.5m (2H); 1.2d (3H) NO2 / 13811 CH3 CH2-CH2-S- # C2H5 A 8.1-6.9m (8H); 2.7m (2H); 1.5m (2H); 1.2d (3H) 139 liters of H2N- (CH2) 4 CH2-CH2-S - # - CH3 C2H5 B 7.3-6.8 m (8H); 2.7-2.3 m + s (7H); 1.7 - 1.3m (8H) mn R¹ R² R³ method NMR 14011 CH3 CH2-CH2-S-CH2- # C2H5 A 7.4-7.0 m (9H); 3.9-3.0 m + s (6H); 2.4m (2H); 1.5m (2H); 1.2d (3H) 141 1 1 CH3 CH2-CH2-S-CH (CH3) 2 C2H5 A 2.6-2.3m (3H); 1.5m (2H); 1.2d (3H); 1.0d (6H) CH2 / 142 1 1 ## CH2-CH2-S-CH2-CH2-N (CH3) 2 C2H5 A 7.8-6.5m (10H); 2.8-2.3m (14H); 1.5m (2H) 143 1 1 CH3 CH2-CH2-S-CH2-CH2-CONH2 C2H5 A 6.0 bs (2H); 2.5-2.2m (6H); 1.5, (2H); 1.2d (3H) O 144 1 1 CH3 CH2 -S- # C2H5 D 7.5-7.0 m (9H); 2.6m (2H); 1.2d (3H) mn R1 R² R³ method NMR O 145 "1" CH3 CH2-S - # - F C2H5 D 7.4-6.9m (8H); 2.6m (2H); 1.2d (3H) O 146 "1" CH3 -CH2-S-CH2- # C2H5 D 7.3-7.0m (9H); 4.1m (2H); 2.6m (2H); 1.2 (3H) O 147 1 1 CH3 -CH2-S-CH (CH3) 2 C2H5 D 2.8-2.5m (3H); 1.2m (3H); 1.0d (6H) O 148 "1" CH3 -CH2-CH2-S- # C2H5 D 7.4-7.0m (9H); 2.6m (2H); 1.5m (2H); 1.2 (3H) O 149 1 1 CH3 -CH2-CH2-S - # - Cl C2H5 D 7.5-6.9m (8H); 2.6m (2H); 1.5m (2H); 1.2d (3H) mn R1 R² R³ method NMR O 15011 CH3 CH2-CH2-S - # - CH3 C2H5 D 7.4-6.9m (8H); 2.6m (2H); 2.3s (3H); 1.5m (2H); 1.2d (3H) O 151 1 1 CH3 CH2-CH2-S-CH2- # C2H5 D 7.3-7.0m (9H); 4.1s (2H); 2.7m (2H); 1.5m (2H); 1.2d (3H) O 152 1 1 CH3 CH2-CH2-S-CH (CH3) 2 C2H5 D 2.8-2.5m (3H); 1.5m (2H); 1.2d (3H); 0.9d (6H) O 153 1 1 CH3 CH2-CH2-S-CH2-CH2-N (CH3) 2 C2H5 D 7.4-6.9m (8H); 2.6m (2H); 2.3s (3H); 1.5m (2H); 1.2d (3H) O 154 11 CH2 CH2 -S- # C2H5 E 7.8-7.1m (9H); 2.8m (2H) 1.2d (3H) mn R1 R² R³ method NMR O 155-1 "CH3 CH2-S - # - F C2H5 E 7.7-6.9m (8H);" 2.8m (2H); O 1.2d (3H) O 156 1 1 CH3 -CH2-S-CH2- # C2H5 E 7.6-7.0m (9H); 5.0-4.3m (5H); O 2.8m (2H); 1.2d (3H) O 157 1 1 CH3 -CH2-S-CH (CH3) 2 C2H5 E 3.0-2.7m (3H); 1.2 d + t (9H) O O 158 1 1 CH3 -CH2-CH2-S- # C2H5 E 7.7-7.2m (9H); 2.8m (2H); O 1.5m (2H); 1.2d (3H) O 159 1 CH3 -CH2-CH2-S - # - Cl C2H5 E 8.0-7.1m (8H); 2.8m (2H); O 1.5m (2H); 1.2d (3H) mn R1 R² R³ method NMR O 160 1 CH3 CH2-CH2-S - # - CH3 C2H5 E 7.6-6.9m (8H); 2.8m (2H); 2.3s (3H); 1.5m (2H); 1.2d (3H) O 161-1 CH3 CH2-CH2-S-CH2- # C2H5 E 7.2-6.9m (9H); 4.2s (2H); 2.8m O (2H); 1.5m (2H); 1.2d (3H) O 162 1 1 CH3 CH2-CH2-S-CH (CH3) 2 C2H5 E 3.0-2.7m (3H); 1.5m (2H); O 1.1 d + t (9H) O 163 1 1 CH3 CH2-CH2-S-CH2-CH2-N (CH3) 2 C2H5 E 3.0-2.2 m + s (12H); 1.5m (2H); O 1.2d (3H) 164 10 CH2 CH2 -S- # C2H5 E 7.4-6.5m (9H); 2.5m (2H); 1.2d (3H) mn R1 R² R³ method NMR 165 10 CH3 CH2 -S- # - Cl C2H5 A 7.4-6.4m (8H); 2.5m (2H); 1.2d (3H) 166 10 CH3 CH2 -S- # C2H5 A 7.5-6.5m (8H); 2.5m (2H); CH3 2.3s (3H); 1.2d (3H) 167 10 CH3 -CH2-S-CH2- # C2H5 A 7.3-6.5m (9H); 3.6-3.0 m + s (6H); 2.4m (2H); 1.2d (3H) 168 10 CH3 -CH2-S-CH- (CH3) 2 C2H5 A 2.7-2.3m (3H); 1.2d (3H); 0.9d (6H) 169 10 CH3 -CH2-S-Cl C2H5 A 7.3-6.5m (9H); 2.7m (2H); 1.5m (2H); 1.2d (3H) mn R1 R² R³ method NMR 170 10 CH3 -CH2-CH2-S - # - Cl C2H5 A 7.5-6.5m (8H); 2.7m (2H); 1.5m (2H); 1.2d (3H) 171 10 CH3 CH2-CH2 -S- # - CH3 C2H5 A 7.3-6.5m (8H); 2.7-2.3m + s (5H); 1.5m (2H); 1.2d (3H) 172 10 CH3 CH2-CH2-S-CH2- # C2H5 A 3.9-3.0m + s (6H); 2.4m (2H); 1.5m (2H); 1.2d (3H) 173 10 CH3 CH2-CH2-S-CH (CH3) 2 C2H5 A 2.6-2.3m (3H); 1.5m (2H); 1.2d (3H); 1.0d (6H) O 174 10 CH3 CH2 -S- # C2H5 D 7.5-6.5m (9H); 2.6m (2H); 1.2d (3H) mn R1 R² R³ method NMR O 175 10 CH3 CH2 -S- # -Cl C2H5 D 7.4-6.5m (8H); 2.6m (2H); 1.2d (3H) O 176 10 CH3 -CH2-S-CH2- # C2H5 D 7.3-6.5m (9H); 4.1m (2H); 2.6m (2H); 1.2d (3H) O 177 10 CH3 -CH2-S-CH (CH3) 2 C2H5 D 2.8-2.5m (3H); 1.2d (3H); 1.0d (6H) O 178 10 CH3 -CH2-CH2-S- # C2H5 D 7.4-6.5m (9H); 2.6m (2H); 1.5m (2H); 1.2d (6H) O 179 10 CH3 -CH2-CH2-S - # - Cl C2H5 D 7.5-6.5m (8H); 2.6m (2H); 1.5m (2H); 1.2d (6H) mn R1 R² R³ method NMR O 180 10 CH3 CH2-CH2-S - # - CH3 C2H5 D 7.6-6.5m (8H); 2.6m (2H); 2.3s (3H); 1.5m (2H); 1.2d (3H) O 181 1 0 CH3 CH2-CH2-S-CH2- # C2H5 D 7.3-6.5m (8H); 4.1s (2H); 2.7s (3H); 1.5m (2H); 1.2d (3H) O 182 1 0 CH3 CH2-CH2-S-CH (CH3) 2 C2H5 D 2.8-2.5m (3H); 1.5s (2H); 1.2d (3H); 1.2d (6H) O 183 10 CH3 CH2 -S- # C2H5 E 7.8-6.5m (9H); 2.8m (2H); 1.2d O (3H) O 184 10 CH3 CH2 -S- # - Cl C2H5 E 7.7-6.5m (8H); 2.8m (2H); 1.2d (3H) O mn R1 R² R³ method NMR O 185 1 0 CH3 -CH2-S-CH2- # C2H5 E 7.6-6.5m (9H); 4.3s (2H); 2.8m (2H); O 1.2d (3H) O 186 10 CH3 -CH2-S-CH2- # C2H5 E 3.0-2.7m (3H); 1.2d + t (9H) O O 187 10 CH3 -CH2-CH2-S- # C2H5 E 7.7-6.5m (9H); 2.8m (2H); 1.5m (2H); O 1.2d (3H) O 188 1 0 CH3 -CH2-CH2-S - # - Cl C2H5 E 8.0-6.5m (8H); 2.8m (2H); 1.5m (2H); O 1.2d (3H) O 189 10 CH3 CH2-CH2-S - # - CH3 C2H5 E 7.7-6.5m (8H); 2.8m (2H); 1.5m (2H); 2.3s (3H); O 1.5m (2H); 1.2d (3H) mn R1 R² R³ method NMR O 190 10 CH3 CH2-CH2-S-CH2- # C2H5 E 7.2-6.5m (9H); 4.2s (2H); 2.8m (2H); O 1.5m (2H); 1.2d (3H) O 191 10 CH3 CH2-CH2-S-CH (CH3) 2 C2H5 E 3.0-2.7m (3H); 1.5m (2H); O 1.1d + t (9H) 192 2 0 CH3 CH2 -S- # C2H5 A 7.4-7.0m (9H); 2.7m (2H); 1.2d (3H) 193 2 0 CH3 -CH2-S-CH2- # C2H5 A 7.3-7.0m (9H); 3.9-3.0m + s (4H) 2.5-1.7m (6H); 1.2d (3H) 19420 CH3 -CH2-CH2-S - # - Cl C2H5 A 7.5-7.0m (8H); 2.7 (2H); 2.5- 1.7m (4H); 1.2d (3H) mn R1 R² R³ method NMR 195 2 0 CH3 CH2-CH2-S-CH2- # C2H5 A 7.4-7.0m (9H); 3.9-3.0 m + s (4H); 2.5.1.7m (6H); 1.2d (3H) 196 2 0 CH3 CH2-CH2-S-CH (CH3) 2 C2H5 A 2.6-1.7m (7H); 1.5m (2H); O 1.2d (3H); 1.0d (6H) 197 2 0 CH3 CH2 -S- # - F C2H5 D 7.5-7.0m (8H); 2.6-1.7m (6H) 1.2d (3H) O 198 2 0 CH3 -CH2-S-CH2- # C2H5 D 7.3-7.0m (9H); 4.1s (2H); 2.6-1.7 m (6H); 1.2d (3H) O 199 2 0 CH3 -CH2-CH2-S - # - Cl C2H5 D 7.5-6.9m (8H); 2.7-1.7m (6H); 1.5m (2H); 1.2d (3H) mn R1 R² R³ method NMR O 200 2 0 CH3 CH2-CH2-S-CH2- # C2H5 D 7.3-7.0m (9H); 4.1s (2H); 2.8-1.7 m (6H); 1.5m (2H); 1.2d (3H) O 201 2 0 CH3 CH2-CH2-S-CH (CH3) 2 C2H5 D 2.8-2.5m (3H); 1.5m (2H); 1.2d (3R); 0.9d (6H) O 202 2 0 CH 3 CH 2 -S- # - F C2H5 E 7.8-7.1m (8H); 2.8m (2H); 1.2 O d (3H) O 20320 CH3 -CH2-S-CH2- # C2H5 E 7.6-7.0m (9H); 4.3s (2H); 2.8m O O 204 2 0 CH3 -CH2-CH2-S - # - Cl C2H5 E 8.0-7.1m (8H); 2.8 (2H); 1.5m O (2H); 1.2d (3H) mn R1 R² R³ method NMR O 205 2 0 CH3 CH2-CH2-S-CH2- # C2H5 E 7.2-6.9m (9H); 4.2s (2H); O 2.8m (2H); 1.5m (2H); 1.2d (3H) O 206 2 0 CH3 CH2-CH2-S-CH (CH3) 2 C2H5 E 3.0-2.7m (3H); 1.5m (2H); O 1.1 d + t (9H) 207 11 CH3 -CH2-OH C2H5 A 3.9-3.0m (6H); 1.2m (3H); 208 11 CH3 -CH2-O- # C2H5 A 7.8-6.7m (9H); 3.9-3.0m (6H) 1.2d (3H) 209 11 CH3 -CH2-O- # - CH3 C2H5 A 7.3-6.6m (8H); 3.9-3.0m (6H); 2.3s (3H); 1.2d (3H) mn R1 R² R³ method NMR 210 11 CH3 -CH2-O- # - Cl C2H5 A 7.3-6.7m (8H); 3.9-3.0m (6H); 1.2d (3H) OCH3 211-1 H 2 N- (CH2) 4 -CH2-O- # C2H5 B 7.2-6.4m (8H); 3.9-3.0m (9H); 2.4m (2H); 1.7-1.3m (6H) 212 lH2N- (CH2) 3 -CH2-O- # - NO2 C2H5 B 8.2-6.8m (8H); 3.9-3.0m (6H); 2.4m (2H); 1.7-1.3m (4H) 213 1 1 (CH3) 2-CH-CH2- -CH2-O- # - COOC2H5 C2H5 A 7.6-6.8m (8H); 4.2q (4H); 3.9-3.0 m (6H); 1.9-1.3m (3H); 1.2t (6H) 1.0d (6H) CH3 214 11 CH3 -CH2-O- # -Cl C2H5 A 7.2-6.0m (7H); 3.9-3.0m (6H); 2.3m (3H); 1.2d (3H) mn R1 R² R³ method NMR 215 11 CH3 -CH2-O- # - CH2- # C2H5 A 7.2-6.9m (9H); 4.0s (2H); 3.9-3.0m (6H); 1.3d (3H) 216 11 CH3 CH2-O-CH2 - # - Cl C2H5 A 7.4-6.9m (8H); 4.0s (2H); 3.9-3.0m (6H); 1.2d (3H) CH3 217-1 H 2 N- (CH2) 4 CH2-O-CH2- # C2H5 B 7.4-7.0m (8H); 4.0s (2H); 3.9-3.0 CH2 m (6H); 2.5-2.2 d + t (5H); 1.7-1.3m 218 1 1 ## CH2-O-CH2- # C2H5 A 7.8-6.4m (14H); 4.0s (2H); 3.8s (3H) N 3.9-3.0m (6H); 2.7m (2H) H OCH3 219 1 "H" CH2-O- # - CH2- # C2H5 A 7.8-7.0m (8H); 6.0bs (2H); 4.0 s (2H); 3.9-3.0m (7H) mn R1 R² R³ method NMR NO2 220 1 1 HS-CH2 CH2-O- # - CH2- # C2H5 B 8.2-7.0m (8H); 4.0s (2H); 3.9-3.0m (6H); 2.3d (2H) NH2 221 11 HS-CH2 CH2-O- # - CH2- # C2H5 B 7.2-6.4m (8H); 4.0s (2H); 3.9-3.0m (6H); 2.3d (2H) 222 1 1 CH3 CH2-O-CH (CH3) 2 C2H5 A 3.9-3.0m (7H); 1.2d (3H); 0.9d (6H) 223 1 1 CH3 CH2-O-CH2-CH2-N (CH3) 2 C2H5 A 3.9-3.0m (8H); 2.4-2.1 m + s (8H); 1.2d (3H) OH 224 11 CH3 -CH2-OCN- # C2H5 A 7.6-6.9m (9H); 4.0m (2H); 1.2d (3H) mn R1 R² R³ method NMR 225 1 1 CH3 CH2-COOH HA 2.1m (2H); 1.2d (3H) 226 1 1 CH3 CH2-CONH2 HF 6.5bs (2H); 2.1m (2H); 1.2d (3H) 227 1 1 CH3 CH2-CON (CH3) 2 HF 3.9-3.0m + 2s (10H); 2.1m (2H); 1.2d (3H) CH2 H 228 11 ## CH2-CON- # HF 7.8-6.4m (15H); 2.8-2.0m (4H) N H CH3 22911 CH3 CH2-CON- # HF 7.3-6.9m (8H); 2.3s (3H); 2.2m (2H); 1.2d (3H) mn R1 R2 R3 method NMR H 230 11 CH3 CH2-CON - # - Cl HF 7.7-6.9m (8H); 2.3m (2H); 1.2d (3H) N CH2 H 231 1 1 # CH2-CO-NH - # - OCH3 HF 13.0s (1H); 7.5-6.3m (10H); N 3.9s (3H); 2.7m (2H); 2.1m (2H) H 232 11 CH3 CH2-CO-NH- # -COOH HF 7.7-6.6m (8H); 2.1m (2H); 1.2d (3H) H 233 11 CH3 CH2-CON - # - CONH2 HF 7.7-6.6m (8H); 2.1m (2H); 1.2d (3H) H 234 11 CH3 CH2-CO-N - # - COOC2H5 HF 7.7-6.6m (8H); 4.2q (2H); 2.1m (2H); 1.2d + t (6H) mn R1 R2 R3 method NMR H 23511 CH3 CH2-CO-N- # -OC2H5 HF 7.2-6.2m (8H); 3.5q (2H); 2.1m (2H); 1.2d + t (6H) Cl H 236 11 CH3 CH2-CO-N - # - HF 7.2-6.4m (7H); 3.9s (3H); CH3O 2.1m (2H); 1.2d + t (6H) OCH3 H 237-1 CH3 CH2-CO-N - # - OCH3 HF 7.2-6.4m (7H); 3.8s (3H); 2.1m (2H); 1.2d (3H) OCH3 H 23811 CH3 CH2-CO-N - # - OCH3 HF 7.2-6.2m (7H); 3.9s (9H); OCH3 2.1m (2H); 1.2d (3H) 239 11 CH3 CH2-COOC2H5 HF 4.2q (2H); 2.0m (2H); 1.2d + t (6H) mn R1 R2 R3 method NMR 240 1 1 CH3 CH2-CO-CH (CH3) 2 HF 4.8septet (1H); 2.1m (2H); 1.2d (3H); 0.9d (6H) 2411-1 CH3 CH2-CO-CH2- # HF 7.3-7.0m (9H); 5.3s (2H) ;; 2.1m (2H); 1.2d (3H); 242 1 1 CH3 CH2-CH2-COOH C2H5 A 2.1m (2H); 1.5m (2H); 1.2d (3H); 243 1 1 CH3 CH2-CH2-CONH2 C2H5 A 2.1m (2H); 1.5m (2H); 1.2d (3H); 244 11 CH3 CH2-CH2-CON (CH3) 2 C2H5 A 3.02s (6H); 1.5m (2H); 1.2d (3H); mn R1 R2 R3 method NMR H 245 11 CH3 CH2-CH2-CON- # C2H5 A 7.4-7.0m (9H); 2.1m (2H); 1.5m (2H); 1.2d (3H) H 246 11 CH3 CH2-CH2-CON - # - F C2H5 A 7.3-6.9m (8H); 2.1m (2H); 1.5m (2H); 1.2d (3H) H 247 liters of H2N- (CH2) 4 CH2-CH2-CON - # - F C2H5 B 7.3-6.8m (8H); 2.4-2.1m (4H); 1.7-1.3m (8H) 248-1 CH3 CH2-CH2-CONH - # - CH3 C2H5 A 7.2-6.4m (8H); 3.9s (3H); 2.1m (2H); 1.5m (2H); 1.2d (3H) 24911 CH3 CH2-CH2-CON- # HA 7.3-6.3m (8H); 2.1m (2H); 1.5m (2H); 1.2d (3H) mn R1 R2 R3 method NMR Cl 250 1 1 CH3 CH2-CH2-CON- # HA 7.3-6.4m (7H); 3.9s (3H); 2.1m (2H); 1.5m (2H); 1.2d (2H) CH3O OH 2511-1 CH3 CH2-CH2-CN - # -CONH2 HA 7.7-7.0m (8H); 2.1m (2H); 1.5m (2H); 1.2d (3H) H 252 1 1 CH3 CH2-CH2-CO-N - # - COOC2H5 HA 7.6-7.0m (8H); 4.2q (2H); 2.1m (2H); 1.5m (2H); 1.2d + t (6H) OH 253 11 CH3 CH2-CH2-CN - # - OC2H5 HA 7.3-6.4m (8H); 3.9-3.0 m + q (6H); 2.1m (2H); 1.5m (2H); 1.2 d + t (6H) 254-1 CH3 CH2-CH2-CON- # HA 8.2-6.9m (8H); 2.1m (2H); 1.5m (2H); 1.2d (3H) mn R1 R2 R3 method NMR OCH3 H 255 1 1 CH3 CH2-CH2-CON - # - OCH3 C2H5 A 7.3-6.3m (7H); 3.8s (6H); 2.1m (2H); 1.5m (2H); 1.2d (3H) OCH3 H 256 1 CH3 CH2-CH2-CON - # - OCH3 C2H5 A 7.3-6.2 m (6H); 3.9s (9H); 2.1m (2H); 1.5m (2H); 1.2d (3H) OCH3 H 257-1 CH3 CH2-CH2-CON-CH (CH3) 2 HA 2.8-2.2m (3H); 1.5m (2H); 1.2d (3H); 1.0d (6H) H 258 11 CH3 CH2-CH2-CON-CH2- # HA 7.4-7.0m (9H); 5.1-4.3 m + s (5H); 2.1m (2H); 1.5m (2H); 1.2d (3H) H 2591-1 CH3 CH2-CH2-CON-CH2 - # - OCH3 C2H5 A 7.3-6.2m (7H); 3.9s (6H); 2.9- 2.1m (6H), 1.5m (2H); 1.2d (3H) mn R1 R2 R3 method NMR 260 10 CH3 CH2-OH C2H5 A 3.6-3.0m (6H); 1.2d (3H) 261 10 CH3 -CH2-O- # C2H5 A 7.3-6.5m (9H); 3.9-3.0m (6H); 1.2d (3H) 262 1 0 CH3 -CH2-O-CH2- # C2H5 A 7.2-6.5m (9H); 4.0s (2H); 3.9-3.0m (6H); 1.2d (3H) 263 10 CH3 CH2-O-CH2 - # - Cl C2H5 A 7.4-6.5m (8H); 4.0s (2H); 3.9-3.0m (6H); 1.2d (3H) 264 10 CH3 CH2-O-CH (CH3) 2 C2H5 A 3.9-3.0m (7H); 1.2d (3H); 0.6d (6H) mn R1 R2 R3 method NMR 265 10 CH3 CH2-O-CH2-CH2-N (CH3) 2 C2H5 A 3.9-3.0m (8H); 2.4-2.1 m + s (8H); 1.2d (2H) OH 266 10 CH3 -CH2-OCN- # C2H5 A 7.6-6.5m (9H); 4.0m (2H); 1.2d (3H) 267 10 CH3 CH2-COOH HA 2.1m (2H); 1.2d (3H) 268 10 CH3 CH2-CONH2 HF 6.5bs (2H); 2.1m (2H); 1.2d (3H) 269 10 CH3 CH2-CON (CH3) 2 HF 3.9-3.0 m + 2s (10H); 2.1m (2H); 1.2d (3H) mn R1 R2 R3 method NMR H 270 10 CH3 CH2-CON- # HF 7.3-6.5m (9H); 2.1m (2H); 1.2d (3H) CH3 H 271 10 CH3 CH2-CON- # HF 7.3-6.5m (9H); 2.3m (2H); 2.2m (2H); 1.2d (3H) H 272 10 CH3 CH2-CON - # - Cl HF 7.7-6.5m (8H); 2.3m (2H); 1.2d (3H) 273 10 CH3 CH2-COOC2H5 HF 4.2q (2H); 2.0m (2H); 1.2 d + t (6H) 274 10 CH3 CH2-CH2-COOH C2H5 A 2.1m (2H); 1.5m (2H); 1.2d (3H) mn R1 R2 R3 method NMR 275 10 CH3 CH2-CH2-CONH2 C2H5 A 2.1m (2H); 1.5m (2H); 1.2d (3H) 276 10 CH3 CH2-CH2-CON (CH3) 2 C2H5 A 3.0 2s (6H); 1.5m (2H); 1.2d (3H) H 277 10 CH3 CH2-CH2-CON- # C2H5 A 7.4-6.5 (9H); 2.1m (2H); 1.5m (2H); 1.2d (3H) 278 10 CH3 CH2-CH2-CON - # - FHA 7.3-6.5 (8H); 2.1m (2H); 1.5m (2H); 1.2d (3H) 279 10 CH3 CH2-CH2-CN - # - OC2H5 C2H5 A 7.3-6.4 (8H); 3.6q (3H); 2.1m (2H); 1.5m (2H); 1.2 d + t (6H) mn R1 R2 R3 method NMR H 280 10 CH3 CH2-CH2-CON-CH (CH3) 2 C2H5 A 2.8-2.2m (3H); 1.5m (2H); d 1.2d (3H); 1.0d (6H) H 281 10 CH3 CH2-CH2-CON-CH2- # C2H5 A 7.4-6.5m (9H); 5.1-4.3 m + s (5H); 2.1m (2H); 1.5m (2H); 1.2d (3H) OCH3 H 282 1 0 CH3 CH2-CH2-CON-CH2-CH2 - # - OCH3 C2H5 A 7.3-6.2m (7H); 3.9s (6H); 2.9- C2H5 2.1m (6H); 1.5m (2H); 1.2d (3H) 28320 CH3 -CH2-OH C2H5 A 3.9-3.0m (4H); 1.2d (3H) 28420 CH3 -CH2-O- # C2H5 A 7.3-6.7m (9H); 3.9-3.0m (4H); 1.2d (3H) mn R1 R2 R3 method NMR 28520 CH3 -CH2-O-CH2- # - C2H5 A 7.2-6.9m (9H); 4.0s (2H); 3.9- 3.0m (4H); 1.2d (3H); 286 20 CH3 CH2-O-CH2 - # - Cl C2H5 A 7.4-6.9m (8H); 4.0s (2H); 3.9- 3.0m (4H); 1.2d (3H); 28720 CH3 CH2-O-CH (CH3) 2 C2H5 A 3.9-3.0m (5H); 1.2s (3H); 0.9d (6H) 28820 CH3 CH2-O-CH2-CH2-N (CH3) 2 C2H5 A 3.9-3.0m (6H); 2.4-2.1 m + s (8H); 1.2d (3H) OH 28920 CH3 -CH2-OCN- # C2H5 A 7.6-6.9m (9H); 4.0s (2H); 1.2d (3H) mn R1 R2 R3 method NMR 290 2 0 CH 3 CH 2 -COOH HA 2.5-1.7m (6H); 1.2d (3H) 291 2 0 CH3 CH2-CONH2 HF 6.5bs (2H); 2.5-1.7m (6H); 1.2d (3H) 292 2 0 CH3 CH2-CON (CH3) 2 HF 3.9-3.0 m + 2S (8H); 2.5-1.7m (6H); 1.2d (3H) 29320 CH3 CH2-CON- # HF 7.8-7.0m (9H); 2.8-1.7 (6H) 1.2d (3H) Cl 29420 CH3 CH2-CON- # HF 7.3-6.9 (8H); 2.5-1.7m (6H); 1.2d (3H) mn R¹ R² R³ method NMR H 295 2 0 CH3 CH2-CON - # - CH3 HF 7.3-6.9m (BH); 2.5-1.7m + s (9H); 1.2d (3H) 296 2 0 CH3 CH2-CO-OC2H5 HF 4.2q 2 (H); 2.5-1.7m (6H); 1.2 d + t (6H) 297 2 0 CH3 CH2-CH2-COOH C2H5 A 2.5-1.7m (6H); 1.5m (2H); 1.2d (3H) 298 20 CH3 CH2-CH2-CONH2 C2H5 A 6.0 bs (2H); 2.5-1.7m (6H); 1.5m (2H); 1.2d (3H) 299 20 CH3 CH2-CH2-CON (CH3) 2 C2H5 A 3.0 2s (6H); 1.5m (2H); 1.2d (3H) mn R¹ R² R³ method NMR H 300 20 CH3 CH2-CH2-CON # C2H5 A 7.4-7.0m (9H); 2.5-1.7m (6H); 1.5m (2H); 1.2d (3H) H 301 2 0 CH3 CH2-CH2-CON # F C2H5 A 7.3-6.9m (8H), 2.5-1.7m (6H); 1.5 (2H); 1.2d (3H) 30211 CH3 CH2-CH2 # C2H5 B 7.2bs (9H); 2.6m (2H); 1.7m (2H); 1.2d (3H) 303 1 1 CH3 CH2-CH2 # HB 7.2bs (9H); 2.6m (2H); 1.7m (2H) CH3 30411 CH3 # C2H5 B 7.4-7.0m (8H); 2.6m (2H); 2.3s CH2-CH2 (3H); 1.7m (2H); 1.2d (3H) mn R¹ R² R³ method NMR # 305 1 1 HO-CH2 CH2-CH2 C2H5 B 7.2bs (9H); 2.8-2.5m (4H); 1.7m (2H) # 306 11 H2N- (CH2) 4-CH2-CH2 HB 7.2bs (9H); 2.8-2.3m (4H9; 1.8-1.3m (8H) 307 1 1 2N (CH2) 3-CH2-CH2 - # - NO2 HB 8.2-7.1m (8H); 2.8-2.3, (4H) 1.8-1.3m (6H) Cl 30811 CH3 CH2-CH2 # C2H5 B 7.5-6.9m (8H); 2.7m (2H); 1.7m (2H); 1.2d (3H) Cl 309 11 CH3 CH2-CH2 # HB 7.5-6.9m (8H); 2.7m (2H); 1.7m (2H); 1.2d (3H) mn R¹ R² R³ method NMR COOH 310 1 1 CH3 CH2-CH2 # HB 7.8-7.1m (8H); 2.7m (2H); 1.7m (2H); 1.2d (3H) HN Cl 3111-1 C-NH- (CH2) 4 CH2-CH2 # C2H5 B 7.5-7.0m (8H); 2.8-2.6m (4H); H2N 1.7-1.3m (6H) OH 312 1 1 H2N- (CH2) 2 CH2-CH2 HB 7.2-6.5m (8H); 2.8-2.3m (4H); 1.7-1.3m (4H) 313 1 1 H 2 N- (CH 2) 5 CH 2 -CH 2 # HB 7.2bs (9H); 2.7-2.3m (4H); 1.7-1.2m (10H) COONH2 314 1 1 H 2 N- (CH 2) 4 CH 2 -CH 2 # HB 7.8-7.1m (8H); 2.7-2.3m (4H); 1.8-1.3m (8H) mn R¹ R² R³ method NMR 315 1 1 H 2 N-CH2 CH2-CH2 # HB 7.2bs (9H); 2.7-2.3m (4H); 1.7m (2H) F. 316 11 CH3 CH2-CH2 # C2H5 B 7.2-6.8m (8H); 2.7m (2H); 1.7m (2H); 1.2d (3H) OCH3 317 11 CH3 CH2-CH2 # C2H5 B 7.2-6.3m (7H); 3.9s (6H); 2.7m (2H) OCH3 1.7m (2H); 1.2d (3H) CL 318 11 CH3 CH2-CH2 # C2H5 B 7.3-6.4m (7H); 3.8s (3H); 2.6m (2H) OCH3 1.7m (2H); 1.2d (3H) Cl 319 11 CH3 CH2-CH2 # B 7.4-6.8m (7H); 2.7m (2H); 1.7m (2H) Cl C2H5 1.2d (3H) mn R¹ R² R³ method NMR H OCH3 N CH2 OCH3 320 1 1 # CH2-CH2 # OCH3 C2H5 B 13.1s (1H); 7.5-6.2m (8H); 3.9s (9H) 2.8-2.3m (4H); 1.7m (2H) # N 321 1 1 CH3 CH2-CH2-H C2H5 B 7.3-7.0m (7H); 2.8m (2H); 1.7m (2H); 1.2d (3H) # 322 1 1 CH3 CH2-CH2-S C2H5 B 7.3-6.9m (7H); 2.9m (2H); 1.7m (2H) 1.2d (3H) # 323 1 1 H 2 N- (CH 2) 4 CH 2 -CH 2 -O HB 7.4-6.3m (7H); 2.8-2.3m (4H); 1.8- 1.3m (8H) 324 11 CH3 CH2-CH2 # C2H5 B 8.6-7.1m (8H); 2.9m (2H); 1.7m (2H); 1.2d (3H) mn R¹ R² R³ method NMR 325 1 1 CH3 ## CH2-CH2 C2H5 B 7.8-6.5m (10H); 2.9m (2H); 1.7m N (2H); 1.2d (3H) H CH3 CH2-CH2 326 11 CH3 N # C2H5 B 7.4-7.0m (5H); 3.9-3.0m + s (7H); N 2.8m (2H); 2.0s (3H); 1.7 (2H); CH3 1.2d (3H) O 327 11 CH3 CH3-N # C2H5 B 5.2s (1H); 3.2 2s (6H); 2.9m (2H); ON CH2-CH2 1.7m (2H); 1.2d (3H) CH3 N Cl 328 11 CH3 # C2H5 B 8.1m (1H); 3.2s (3H); 2.9m (2H); ON CH2-CH2 1.7m (2H); 1.2d (3H) CH3 329 11 CH3 ## C2H5 B 8.5-7.5m (6H); 3.1m (2H); 1.8m N (2H); 1.2d (3H); CH2-CH2 mn R¹ R² R³ Method NMR CH2-CH2 330 1 1 CH3 ## C2H5 B 8.8-7.4m (6H); 3.0m (2H); 1.7m N (2H); 1.2d (3H) N 3311-1 CH3 HN # N C2H5 B 13.0 (1H); 2.9m (2H); 1.8m (2H); CH2-CH2 N 1.2d (3H) N CH2-CH2 332 1 1 CH3 # C2H5 B 7.9-7.4m 2s (2H); 2.8m (2H); O 1.7m (2H); 1.2d (3H) H2N N CH2-CH2 333 11 CH3 # C2H5 B 8.0s (1H); 2.8m (2H); 1.7m (2H); S 1.2d (3H) CH3 ON Cl 334 11 CH3 # C2H5 B 3.2 2s (1H); 3.1m (2H); 1.8 (2H) CH3 N CH2-CH2 1.2d (3H) mn R¹ R² R³ method NMR CH3 335 11 CH3 CHCH2 # C2H5 B 7.2bs (9H); 2.7m (2H); 2.2m (1H); 1.2s (3H); 1.0d (3H) 336 11 H2N- (CH2) 4 CH2-CH2-CH2 # Cl HB 7.4-7.0m (8H); 2.7-2.3m (4H); 1.8- 1.3m (10H) CH3 337 11 CH3 CH2-CH2 -C # OCH3 C2H5 B 7.3-6.3m (8H); 3.9m (3H); 1.9- CH3 1.2m (4H); 1.2d (3H); 1.0s (6H) HN H 338 1 1 CN- (CH2) 3 CH2 # HB 7.2bs (9H); 2.9-2.6m (4H); 1.7-1.3 H2N m (4H); 339 1 1 H CH2 # HB 7.4-6.9m (8H); 3.9-3.0m (5H); F 2.7m (2H) mn R¹ R² R³ method NMR 340 1 1 H CH2 # COOH HB 7.8-7.0m (8H); 3.9-3.0m (5H); 2.7m (2H) OH 341 1 1 H -CH2-CH2-CH2-CH2 # HB 7.3-6.5m (8H); 3.9-3.0, (5H); 2.7m (2H); 1.8-1.3m (6H) 342 11 CH3 CH2 # CONH2 HB 7.8-7.0m (8H); 2.8m (2H); 1.2d (3H) 343 11 CH3 CH2 # NH2 HB 7.2-6.4m (8H); 2.7m (2H); 1.2d (3H) OCH3 344 11 CH3 -CH2 # OCH3 HB 7.2-6.3m (7H); 3.9s (6H); 2.7m (2H); 1.2d (3H) mn R¹ R² R³ method NMR OCH3 345 11 (CH3) 2 CH-CH2 CH2-CH2 # C2H5 B 7.2-6.4m (7H); 3.8s (3H); 2.8m (2H); Cl 2.0-1.5m (5H); 0.9d (6H) 346 1 1 CH3 -CH2 ## C2H5 B 7.8-6.5m (10H); 2.9m (2H); 1.2d (3H) N H OCH3 347 1 1 (CH3) 2CH-CH2 CH2-CH2 # OCH3 HB 7.2-6.2m (6H); 3.9s (9H); OCH3 2.7m (2H); 1.9-1.3m (5H); 0.9d (6H) 348 11 CH3 # HB 7.3-6.0m (7H); 2.8m (2H); 1.2d (3H) CH2 N H CH2 349 11 CH3 # HB 7.3-6.9m (7H); 2.9m (2H); 1.2d (3H) mn R¹ R² R³ method NMR 350 11 CH3 # HB 7.4-6.3m (7H); 2.8m (2H); 1.2d (3H) CH2 O 351 11 CH3 # HB 8.6-7.1m (8H); 2.9m (2H); 1.2d (3H) N CH2 CH2 352 1 1 CH3 ## HB 7.8-6.5m (10h); 2.9m (2H); 1.2d (3H) N CH3 H CH2- 353 11 (CH3) 2 CH-CH2 N # C2H5 B 7.4-7.0m (5H); 3.9-3.0m + s (7H); N 2.8-m (2H); 2.0s (3H); 1.8-1.3m (3H); CH3 1.0d (6H) CH3 O 354 11 HN # C2H5 B 5.2s (1H); 3.2s (6H); 2.9m (2H) ON CH2 CH3 mn R¹ R² R³ method NMR 355 1 1 CH3 ## HB 8.5-7.5m (6H); 3.1m (2H); 1.2d (3H) N CH2- CH2 356 11 CH3 ## HB 8.8-7.4m (6H); 3.0m (2H); 1.2d (3H) N H2N N CH2- 357 11 CH3 S # HB 8.0s (1H); 2.8m (2H); 1.2d (3H) CH3O O 358 1 1 CH3 # HB 8.1s (1H); 6.4s (1H); 3.7s (3H); O CH2- CH3O O 359 11 (CH3) 2CH-CH2 # HB 8.1s (1H); 6.4s (1H); 3.7s (3h); O CH2-CH2 2.9m (2H); 1.8-1.3m (5H); 1.0d (6H) mn R¹ R² R³ method NMR CH2-CH2 36011 CH3 N # C2H5 B 7.7-7.1m (6H); 2.9m (2H); 1.7m (2H) N 1.2d (3H) H CH2- 361 11 CH3 N # C2H5 B 7.7-7.1m (6); 2.9m (2H); 1.2d (3H) N H 362 1 0 CH3 CH2-CH2 # C2H5 B 7.2-6.5m (9H); 2.7m (2H); 1.7m (2H); 1.2d (3H) Cl 363 10 CH3 CH2-CH2 HB 7.5-6.5m (8H); 1.7m (2H); 1.7m (2H); 1.2d (3H) Cl 364 10 CH3 CH2-CH2 # HB 7.6-6.5m (7H); 2.8m (2H); 1.7m (2H); Cl 1.2d (3H) mn R¹ R² R³ method NMR # 365 10 CH3 CH2-CH2 NHB 7.3-6.0m (7H); 2.8m (2H); 1.7m (2H); H 1.2d (3H) # 366 10 CH3 CH2-CH2 SHB 7.3-6.5m (7H); 2.9m (2H); 1.7m (2H); 1.2d (3H) CH2-CH2 367 10 CH3 # HB 8.6-6.5m (8H); 2.9m (2H); 1.7m (2H); N 1.2d (3H) CH2-CH2 368 10 CH3 ## C2H5 B 7.8-6.5m (10H); 2.9m (2H); 1.7m (2H); N 1.2d (3H) H CH3 369 10 CH3 CH-CH2 # C2H5 B 7.2-6.5m (9H); 2.9m (2H); 1.8m (1H); 1.2d (3H); 1.1d (3H) mn R¹ R² R³ method NMR 370 10 CH3 CH2-CH2-CH2 # Cl C2H5 B 7.4-6.5m (8H); 2.7-2.3m (2H); 1.8- 1.3m (4H); 1.2d (3H) CH3 371 10 CH3 CH2-CH2 -C # OCH3 C2H5 B 7.3-6.3m (8H); 3.9s (3H); 1.9-1.2m (4H); CH3 1.2d (3H); 1.0s (6H) OCH3 372 10 CH3 CH2-CH2 # C2H5 B 7.2-6.3m (7H); 3.9m (3H); 2.7m (2H); Cl 1.8m (2H); 1.2d (3H) 373 10 CH3 -CH2 ## C2H5 B 7.8-6.5m (10H); 2.9m (2H); 1.2d (3H) N H N CH2-CH2 374 10 CH3 # C2H5 B 7.7-6.5m (6H); 2.9m (2H); 1.7m (2H); N 1.2d (3H) H mn R¹ R² R³ method NMR CH2- 375 10 CH3 N # C2H5 B 7.7-6.5m (6H); 2.9m (2H); 1.2d (3H) N H 376 2 0 CH3 # C2H5 B 7.2bs (9H); 2.8-1.6m (8H); CH2-CH2 CH2-CH2 1.2d (3H) CH3 377 2 0 CH3 # C2H5 B 7.4-7.0m (8H); 2.6-1.7m (1H); CH2-CH2 1.2d (3H) OCH3 37820 CH3 # C2H5 B 7.2-6.4m (8H); 3.8m (3H); 2.7-1.6m CH2-CH2 (8H); 1.2d (3H) Cl 379 20 CH3 # C2H5 B 7.4-7.0m (8H); 2.8-1.6m (8H); CH2-CH2 1.2d (3H) mn R¹ R² R³ method NMR Cl 380 2 0 CH3 # C2H5 B 7.6-7.0m (7H); 2.9-1.7m (8H); CH2-CH2 1.2d (3H) Cl # 381 2 0 CH3 CH2-CH2 S C2H5 B 7.3-6.5m (7H); 2.9-1.7m (8H); 1.2d (3H) CH2-CH2 382 2 0 CH3 # C2H5 B 8.6-7.0m (8H); 2.9-1.7m (8H); N 1.2d (3H) CH2-CH2 383 2 0 CH3 ## C2H5 B 7.8-6.5m (10H); 2.9-1.7m (8H); N 1.2d (3H) H 38420 CH3 (CH3) 2-CH-CH2-CH2-CH2 C2H5 A 1.9-1.3m (7H); 1.2d (3H); 0.9d (6H) mn R¹ R² R³ method NMR 385-1H2N- (CH2) 4 (CH3) 2CH-CH2-CH2 C2H5 B 2.4m (2H); 1.9-1.3m (11H); 0.9d (6H) 386 1 1 H 2 N- (CH 2) 3 (CH 3) 2 CH-CH 2 C 2 H 5 B 2.4m (2H); 1.9-1.3m (7H); 0.9d (6H) 387 10 FCH2 (CH3) 2CH C2H5 B 4.3dd (2H); 1.9m (1H); 0.9d (6H) CH2 388 2 0 # CH3 C2H5 A 7.2bs (9H); 3.0m (2H); 1.0d (3H) CH2 38911 CH3-CH2-CH H # HA 1.9-1.2m (16H); 1.0d + t (6H) mn R¹ R² R³ method NMR 390 2 0 HO-CH 2 HHB 3.9-3.0m (3H); 2.5m (2H) CH2-CH2 391 1 1 CH3 ## C2H5 A 7.8-7.0m (11H); 2.7m (2H); 1.5m (2H); 1.2d (3H) OH 392 1 1 CH3 # HB 7.3-6.5m (8H); 2.8m (2H); 1.2d (3H) CH2 OCH3 393 1 1 CH3 # HB 7.3-6.4m (8H); 3.9m (3H); 2.9m (2H); CH2 1.2d (3H) 394 11 CH3 # C2H5 B 7.6-6.4m (8H); 3.8s (3H); 2.9m (2H); CH2 OCH3 1.2d (3H) mn R¹ R² R³ method NMR 395 11 CH3 CH2 - # - Cl C2H5 B 7.6-7.0m (8H); 2.9m (2H); 1.2d (3H) Cl 396 11 CH3 CH2 - # - Cl HB 7.8-7.0m (7H); 2.9m (2H) 1.2d (3H) 397 11 CH3 CH2 - # - NO2 HB 8.3-7.0m (8H); 2.9m (2H); 1.2d (3H) 398 11 CH3 CH2 - # - CH3 C2H5 B 7.4-7.0m (8H); 2.9m (2H); 2.3s (3H); 1.2d (3H) 399 11 CH3 - # HA 5.3m (1H); 2.3m (4H); 1.8-1.3m (6H); 1.2d (3H) mn R¹ R² R³ method NMR 400 11 CH3 - # - C2H5 B 5.4m (1H); 2.3m (4H); 1.8-1.4m (4H); 1.2d (3H) 401 1 1 CH3 - # - HB 5.5m (1H); 3.9m-3.0 (6H); 2.5-2.1m (3H) 1.2d (3H) 402 1 1 CH3 - # - HB 5.9s (1H); 3.9-3.0m (8H); 1.2d (3H) CH3 403 11 CH3 - # - NH (CH2) 3 - C2H5 B 7.4s (1H); 2.5m (2H); 2.3s (6H); CH3 1.8-1.2d (4H) mn R¹ R² R³ method NMR 404 1 1 CH3 # - # - CH2CH2- C2H5 A 7.5-6.8m (8H); 2.8m (2H); 1.5m (2H) Cl 405 11 CH3 # - # - CH2-CH2-HA 7.5-6.8m (8H); 2.8m (2H); 1.5m (2H)

Claims

Claims: 1. Compounds of the formula I in which n denotes 0 or 1 m 1 or 2, but m + n, 2 Y -S-, -0- or -NH-R1 and R2, which can be identical or different and also in turn substituted, each - alkyl or alkenyl, with up to 6 0 atoms, - cycloalkyl or cycloalkenyl with 5 - 7 0 atoms each, - aryl or partially hydrogenated aryl with 6 - 10 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 is a carboxyl or carboxylic acid ester group.

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 —YH 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 -O-, -S- or -NW- and WH or an amino protective group is, with a compound of the formula V reacts in the presence of a condensing agent and optionally splits off the protective groups or (c) if Y = -NH-, 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 or (d) if Y is -S- or -NH- and R2 bears an α-carbonyl group, a Reacts compound of formula VIII with a compound of formula IX wherein R8 is hydroxy, alkoxy or an optionally substituted amino group.

3. Agent containing a compound according to claim 1.

4. Use of a compound according to claim 1 as a medicament.