EP0929529A2 - Azinyloxy, and phenoxy-diaryl-carboxylic acid derivatives, their preparation and use as mixed et a?/et b? endothelin receptor antagonists - Google Patents

Azinyloxy, and phenoxy-diaryl-carboxylic acid derivatives, their preparation and use as mixed et a?/et b? endothelin receptor antagonists

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Publication number
EP0929529A2
EP0929529A2 EP97943819A EP97943819A EP0929529A2 EP 0929529 A2 EP0929529 A2 EP 0929529A2 EP 97943819 A EP97943819 A EP 97943819A EP 97943819 A EP97943819 A EP 97943819A EP 0929529 A2 EP0929529 A2 EP 0929529A2
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European Patent Office
Prior art keywords
phenyl
cooh
ome
alkyl
cnn
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EP97943819A
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German (de)
French (fr)
Inventor
Wilhelm Amberg
Rolf Jansen
Andreas Kling
Dagmar Klinge
Hartmut Riechers
Stefan Hergenröder
Manfred Raschack
Liliane Unger
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Abbott GmbH and Co KG
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BASF SE
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/734—Ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/60—Three or more oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the present invention relates to new carboxylic acid derivatives, their preparation and use.
  • Endothelin is a 21 amino acid peptide that is synthesized and released by vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3.
  • endothelin or "ET” means one or all isoforms of endothelin.
  • Endothelin is a potent vasoconstrictor and has a strong effect on vascular tone. This vasoconstriction is known to be caused by the binding of endothelin to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 211, 440-444, 1988 and Bioche. Biophys. Res. Commun., I, 868-875, 1988).
  • endothelin causes persistent vascular contraction in peripheral, renal, and cerebral blood vessels, which can lead to disease.
  • endothelin is involved in a number of diseases. These include: hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasm, stroke, benign prostatic hypertrophy, atherosclerosis and asthma (J. Vascular Med. Biology 2, 207 (1990), J. Am. Med. Association 264, 2868 (1990), Nature r 114 (1990), N. Engl. J. Med. 322. 205 (1989), N. Engl. J. Med.
  • ET A and ET B receptor At least two endothelin receptor subtypes, ET A and ET B receptor, are currently described in the literature (Nature 348, 730 (1990), Nature 3_J 732 (1990)). Accordingly, substances that inhibit the binding of endothelin to the two receptors should antagonize the physiological effects of endothelin and should therefore be valuable pharmaceuticals.
  • WO 96/11914 describes carboxylic acid derivatives which, however, bind with a high affinity to the ET A receptor and with a substantially lower affinity to the ET B receptor (so-called ET A -specific antagonists).
  • ET A -specific antagonists we refer here to those antagonists whose affinity for the ET A receptor is at least 20 times higher than their affinity for the ET B receptor.
  • the task was to provide endothelin receptor antagonists which bind to the ET A and ET B receptors with approximately the same affinity (so-called mixed antagonists).
  • the invention relates to carboxylic acid derivatives of the formula I.
  • R 1 stands for tetrazole or for a group
  • Hydrogen the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically compatible organic ammonium ion such as C1 . -C 4 alkyl ammonium or the ammonium ion;
  • R 7 can also be a phenyl radical which can carry one to five halogen atoms and / or one to three of the following radicals: nitro, cyano, C1.-C 4 -alkyl, C 1 -C 4 -haloalkyl, hydroxy, C 1 - C 4 alkoxy, mercapto, C 1 -C 4 alkylthio, amino, NH (C 1 -C 4 alkyl), N (Ci . -C 4 alkyl) 2 ;
  • a 5-membered heteroaromatic linked via a nitrogen atom such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which has one or two halogen atoms, or one or two C 1 -C 4 -alkyl or one or two C 1 -C 4 -alkoxy groups can carry.
  • R 9 means:
  • R 1 can also mean
  • R 13 and R 14 may be the same or different and have the following meaning:
  • R 13 and R 14 together form a C 4 -C 7 alkylene chain which is closed to form a ring and which can pass through
  • C ⁇ _C 4 alkyl substituted and in which an alkylene group can be replaced by oxygen, sulfur or nitrogen such as - (CH2.4-, - (CH 2 ) 5 -r - ( CH 2 ) 6 - ⁇ - ( CH 2 ) 2 - 0- ( CH 2 ) 2 -, - (CH 2 ) 7 -, 5 -CH 2 -S- (CH 2 ) 2 -, -CH 2 -NH- (CH 2 ) 2 -, - (CH 2 ) 2 -N- (CH 2 ) 2-
  • R 2 is hydrogen, hydroxy, NH 2 , NH (C1-C4-alkyl), (C 1 -C4 -alkyl) 2 , halogen, -C-C 4 -alkyl, C 2 C 4 alkenyl, C 2 C 4 alkynyl, C ⁇ -C 4 -hydroxyalkyl, C 1 -C 4 -haloalkyl, Ci -C 4 -alkoxy, 0 -C-C 4 -haloalkoxy or -C-C 4 -alkylthioo, or CR 2 is with CR 10 as stated below to a 5- or 6-membered ring linked.
  • Z is nitrogen or CR 10 , in which R 10 is hydrogen or C 3 -C 4 -alkyl or CR 10 together with CR 2 or CR J forms a 5- or - Q 6-membered alkylene or alkenylene ring which is replaced by one or two C 1 -C 4 alkyl groups can be substituted and in which one or more methylene groups can be replaced by oxygen, sulfur, -NH or N (C 1 -C 4 alkyl) 2 .
  • At least one of the ring members X, Y or Z is nitrogen.
  • R 3 is hydrogen, hydroxyl, NH 2 , NH (Ci -C 4 alkyl), N (-C-C 4 alkyl) 2 , halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 -alkynyl, -C-C 4 -haloalkyl, C 1 -C 4 -alkoxy, C ⁇ -C -haloalkoxy, C ⁇ -C 4 -hydroxyalkyl, C 1 -C 4 -alkylthio, or CR 3 is with CR 10 as linked above to form a 5- or 6-membered ring.
  • R 4 and R 5 (which may be the same or different):
  • Phenyl or naphthyl which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, mercapto, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, Ci -C 4 hydroxyalkyl, C 2 -C 4 alkynyl, Ci -C 4 - haloalkyl, C 1 -C 4 alkoxy, phenoxy, carboxy, C ⁇ -C 4 haloalkoxy, CJ-C, alkylthio, amino, H ⁇ C !
  • Bond a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an S0 2 -, NH or N-alkyl group are connected to one another;
  • R 6 C 3 -C 8 cycloalkyl where these radicals can each be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, nitro, cyano, C ⁇ -C 4 alkoxy, C ⁇ -C alkyl, C 2 -C 4 -alkenyl, C 2 -C -alkynyl, C 3 -C 6 -alkenyloxy, C 3 -C 6 -alkynyl-oxy, -C-C -alkylthio, C ⁇ -C 4 -haloalkoxy, -C-C -alkylcarbonyl, Ci -C 4 alkoxycarbonyl, C 3 -Cg alkylcarbonylalkyl, NH (C !
  • -C alkyl N (Ci -C 4 alkyl) 2 , or phenyl, which can be mono- or polysubstituted, eg mono- to trisubstituted by halogen, nitro, cyano, C 4 alkyl, C 1 -C 4 haloalkyl, C ⁇ -C 4 alkoxy, C 1 -C 4 -haloalkoxy or C ⁇ -C 4 alkylthio;
  • Phenyl or naphthyl each of which can be substituted by one or more of the following radicals: halogen, R 15 , nitro, mercapto, carboxy, cyano, hydroxy, amino, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 - C 4 -alkynyl, C 3 -C ⁇ -alkenyloxy, C 1 -C 4 -haloalkyl, C 3 -C 6 -alkynyloxy, -C-C 4 -alkylcarbonyl, C1 .
  • a five- or six-membered heteroaromatic containing one to three nitrogen atoms and / or a sulfur or oxygen atom which can carry one to four halogen atoms and / or one or two of the following radicals: C 1 -C 4 alkyl, C 2 -C 4 alkenyl, Ci -C 4 haloalkyl, C 1 -C 4 alkoxy, C ⁇ -C 4 haloalkoxy, C1 . -C 4 alkylthio, phenyl or phenoxy where the phenyl radicals can in turn carry one to five halogen atoms and / or one to 10 three of the following radicals: -C 1 -C 4 -alkyl,
  • R 15 C ⁇ _C 4 _alkyl, C 1 _C 4 _alkylthio, Cj.-C 4 alkoxy, which carry one of the following radicals: hydroxy, carboxy, amino, NH (C ⁇ _C 4 _alkyl), N (C ⁇ _C 4 alkyl) 2 , Carboxamide or CON (C 1 -C 4 alkyl) 2 ;
  • Q A spacer that corresponds in length to a C 2 -C 4 chain.
  • the function of Q is to produce a defined distance between the groups R 6 and W in the compounds of the formula I.
  • the distance should be the length of a C 2 -C 4 alkyl chain
  • 8- alkylcarbonylalkyl NH (C 1 -C 4 -alkyl), N (-C-C 4 -alkyl) 2 , phenyl, which can be mono- or polysubstituted, for example mono- to trisubstituted by halogen, nitro, Cyano, C ⁇ -C 4 -alkyl, C3.-C 4 -haloalkyl, C ⁇ -C 4 -alkoxy, C ⁇ -C -haloalkoxy or -CC 4 -alkylthio.
  • spacer Q is part of a 5-7 membered ring
  • An alkali metal is e.g. Lithium, sodium, potassium; 45
  • An alkaline earth metal is, for example, calcium, magnesium, barium;
  • C 3 -C 8 cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;
  • C 1 -C 4 haloalkyl can be linear or branched, such as, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl,
  • C 1 -C 4 haloalkoxy can be linear or branched, such as difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoro-ethoxy, 2, 2-difluoroethoxy, 1, 1, 2, 2-tetrafluoroethoxy, 2,2,2-tri- fluoroethoxy, 2 -chloro-1, 1,2-trifluoroethoxy, 2 -fluoroethoxy or pentafluoroethoxy;
  • C 1 -C 4 alkyl can be linear or branched, such as methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl or 2-butyl;
  • C 2 -C 4 alkenyl can be linear or branched, such as, for example, ethenyl, 1-propen-3-yl, 1-propen-2-yl, 1-propen-1-yl, 2-methyl-1-propenyl, 1- Butenyl or 2-butenyl;
  • C 2 -C 4 alkynyl can be linear or branched, such as, for example, ethynyl, 1-propyn-1-yl, 1-propyn-3-yl, 1-butyn-4-yl or 2-butyn-4-yl;
  • C 1 -C 4 -alkoxy can be linear or branched, such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1, 1 -dimethylethoxy;
  • C 3 -C 6 alkenyloxy can be linear or branched, such as, for example, allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy;
  • C 1 -C 4 -hydroxyalkyl can be linear or branched, such as hydroxymethyl, 1-hydroxyether-2 -yl,
  • C 6 -C 6 alkynyloxy can be linear or branched, such as 2-propin-1-yloxy, 2-butyn-1-yloxy or 3-butyn-2-yloxy;
  • C 1 -C 4 alkylthio can be linear or branched, such as, for example, methyl thio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio;
  • C 1 -C 4 -alkylcarbonyl can be linear or branched, such as acetyl, ethylcarbonyl or 2>-propylcarbonyl;
  • C 1 -C 4 alkoxycarbonyl can be linear or branched such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbonyl;
  • Cs-Ca alkylcarbonylalkyl can be linear or branched, e.g. 2-0xo-prop-l-yl, 3 -oxo-but-1 -yl or 3 -oxo-but-2 -yl
  • Ci-Ca alkyl can be linear or branched, such as Cj . -C 4 alkyl, pentyl, hexyl, heptyl or octyl;
  • Halogen is e.g. Fluorine, chlorine, bromine, iodine.
  • the invention further relates to those compounds from which the compounds of the formula I can be released (so-called prodrugs).
  • prodrugs in which the release takes place under conditions such as those in certain body compartments, e.g. in the stomach, intestines, bloodstream, liver, predominate.
  • the compounds and also the intermediates for their preparation can have one or more asymmetrically substituted carbon atoms.
  • Such compounds can exist as pure enantiomers or pure diastereomers or as a mixture thereof. Preference is given to using an enantiomerically pure compound as the active ingredient.
  • the invention further relates to the use of the abovementioned carboxylic acid derivatives for the production of medicaments, in particular for the production of inhibitors for ET A and ET B receptors.
  • the compounds according to the invention are particularly suitable as mixed antagonists as defined at the outset.
  • Compounds of general formula III are either known or can e.g. can be synthesized by reducing the corresponding carboxylic acids or their esters, or by other generally known methods.
  • Carboxylic acid derivatives of the general formula VI can be prepared by reacting a compound of the formula Via with an alcohol or thiol of the formula VII with acid catalysis.
  • R 1 has the meaning given under the general formula I.
  • R 16 and R 17 which may be the same or different, each optionally substituted, hydrogen or alkyl, alkenyl, alkynyl, phenyl, naphthyl, cycloalkyl,
  • R 18 is hydrogen or alkyl, alkenyl, alkynyl, phenyl, naphthyl, cycloalkyl, each optionally substituted
  • R 19 is hydrogen or alkyl, alkenyl, alkynyl, phenyl, naphthyl, cycloalkyl, each optionally substituted
  • radicals preferably have the following meaning:
  • R 16 and R 17 which may be the same or different,
  • R 18 alkyl, phenyl, cycloalkyl each optionally substituted
  • R 19 alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, each optionally substituted,
  • R 18 alkyl optionally substituted, especially methyl
  • the carboxylic acid derivatives of the general formula IV can be prepared by this process by reacting a compound of the formula IVa with an alcohol or thiol of the formula III with acid catalysis
  • the compounds IVa and III are mixed in bulk or in a solvent which is inert for this reaction and catalytic amounts of an acid such as, for example, p-toluenesulfonic acid are added.
  • inert solvents are methylene chloride, benzene or toluene.
  • inert solvents which form an azeotrope with the alcohol R 18 OH are also suitable.
  • R 11 is halogen or R 12 -S0 2 -, where R 12 is C ! -C 4 alkyl, -C-C 4 haloalkyl or phenyl can be. Furthermore, at least one of the ring members X or Y or Z is nitrogen.
  • the reaction preferably takes place in an inert solvent or diluent with the addition of a suitable base, ie a base which brings about a deprotonation of the intermediate IV, in a temperature range from room temperature to the boiling point of the solvent.
  • solvents or diluents are aliphatic, alicyclic and aromatic hydrocarbons, each of which may optionally be chlorinated, such as, for example, hexane, cyclohexane, petroleum ether, ligroin, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and trichlorethylene, Ethers, such as diisopropyl ether, dibutyl ether, methyl tert.
  • chlorinated such as, for example, hexane, cyclohexane, petroleum ether, ligroin, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and trichlorethylene
  • Ethers such as diisopropyl ether, dibutyl ether, methyl tert
  • nitriles such as, for example, acetonitrile and propionitrile
  • acid amides such as, for example, dimethylformamide, dimethylacetamide and N-methylpyrrolidone
  • sulfoxides and sulfones such as, for example, dimethyl sulfoxide and sulfolane.
  • an alkali or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride
  • a carbonate such as alkali metal carbonate, e.g. Sodium or potassium carbonate
  • an alkali or alkaline earth metal hydroxide such as sodium or potassium hydroxide
  • an organometallic compound such as butyllithium or a
  • Alkali amide such as lithium diisopropyl amide or lithium amide serve.
  • Compounds of the formula I can also be prepared by starting from the corresponding carboxylic acids, ie compounds of the formula I in which R 1 is COOH, and converting them first in the usual manner into an activated form such as an acid halide, an anhydride or Imidazolid transferred and then reacted with a corresponding hydroxyl compound H ⁇ R 7 . This reaction can be carried out in the customary solvents and often requires the addition of a base, the above-mentioned being possible. These two steps can also be simplified, for example, by adding the carboxylic acid to
  • compounds of the formula I can also be prepared by starting from the salts of the corresponding carboxylic acids, ie from compounds of the formula I in which R 1 is a group COR and R is OM, where M is an alkali metal cation or can be the equivalent of an alkaline earth metal cation.
  • R 1 is a group COR and R is OM
  • M is an alkali metal cation or can be the equivalent of an alkaline earth metal cation.
  • These salts can be reacted with many compounds of the formula RA, where A is a conventional nucleofugic leaving group, for example halogen such as chlorine, bromine, iodine or aryl or alkylsulfonyl optionally substituted by halogen, alkyl or haloalkyl, such as toluenesulfonyl and methylsulfonyl or one other equivalent leaving group.
  • the preparation of the compounds I according to the invention requires the use of generally known protecting group techniques.
  • R 6 is 4-hydroxyphenyl
  • the hydroxy group can first be protected as benzyl ether, which is then cleaved at a suitable stage in the reaction sequence.
  • carboxylic acid derivatives of the general formula I - both as pure enantiomers or pure diastereomers or as a mixture thereof - are preferred, in which the substituents have the following meaning:
  • R 2 is hydrogen, hydroxy, halogen, N (C ⁇ -C 4 alkyl) 2, C ! -C 4 -alkyl, C -alkoxy, C 4 alkylthio, Ci-C4 haloalkyl, C 1 -C 4 haloalkoxy, or CR 2 is linked to CR 10 to a 5- or 6-membered ring as indicated below;
  • At least one of the ring members X, Y or z is nitrogen.
  • R 3 is hydrogen, hydroxy, halogen, N (C ⁇ -C 4 -alkyl) 2 , -C-C 4 -alkyl, C ⁇ -C -alkoxy, C ⁇ -C -alkylthio, Ci -C 4 -haloalkyl,
  • C 1 -C 4 - haloalkoxy, or CR 3 is linked to CR 10 to give a 5- or 6-membered ring;
  • R 4 and R 5 (which may be the same or different):
  • Phenyl or naphthyl which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, mercapto, amino, C 1 -C 4 alkyl, Ci C 4 haloalkyl, carboxy, C 1 -C 4 alkoxy , -C -C haloalkoxy, phenoxy, C 1 -C 4 alkylthio, - NH (C 1 -C 4 alkyl) or N (C : -C 4 alkyl) 2 or
  • Phenyl which can be substituted one or more times, for example one to three times by halogen, nitro, cyano, C1 . -C 4 alkyl, -C.-C 4 haloalkyl, C 1 -C 4 alkoxy, C1.-C 4 haloalkoxy or C ⁇ -C 4 alkylthio; or
  • Phenyl or naphthyl which are ortho-linked via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an S0 2 , NH or N-alkyl group
  • R 6 C 3 -C 8 cycloalkyl where these radicals can each be mono- or polysubstituted by: halogen, hydroxyl, mercapto, carboxy, nitro, cyano, C ⁇ -C 4 alkoxy, C ⁇ -C alkyl,
  • Phenyl or naphthyl each of which can be substituted by one or more of the following radicals: halogen, R 15 , nitro, mercapto, carboxy, cyano, hydroxy, amino, C ⁇ -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 alkenyloxy, -C-C 4 haloalkyl, C 3 -C 6 alkynyloxy, C 1 -C alkylcarbonyl, C1 .
  • a five- or six-membered heteroaromatic containing one to three nitrogen atoms and / or a sulfur or acid atom which can carry one to four halogen atoms and / or one or two of the following radicals: C1 . -C 4 alkyl, Ci -C 4 haloalkyl, C 1 -C 4 alkoxy, Ci -C 4 haloalkoxy, C 1 -C 4 alkylthio, phenyl, phenoxy or phenylcarbonyl, the phenyl radicals in turn having one to five halogen atoms and / or can carry one to three of the following radicals: -CC 4 alkyl, C 1 -C haloalkyl, Ci-alkoxy, C 1 -C 4 haloalkoxy and / or C1.-C 4 alkylthio;
  • R i5 methyl, ethyl, methoxy or ethoxy which carry one of the following radicals: hydroxy, carboxy, amino, NH (-C 4 -alkyl), N (C 4 -C 4 -alkyl) 2 , carboxamide or CON (C ⁇ _C. Alkyl) 2 ;
  • radicals can each be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, Ci -C 4 alkyl thio, C 1 -C 4 haloalkoxy, Ci -C alkoxycarbonyl,
  • R 2 trif luormethyl, -C -C alkyl, -C -C 4 alkoxy, -C . -C 4 alkylthio, or CR 2 is linked to CR 10 to a 5- or 6-membered ring as indicated below;
  • At least one of the ring members X, Y or Z is nitrogen
  • R 3 trifluoromethyl, C ⁇ _-C 4 alkyl, C 1 -C 4 -alkoxy, C alkylthio, or CR 3 is linked with CR 10 as indicated above to form a 5- or 6-membered ring;
  • R 4 and R 5 (which may be the same or different):
  • Phenyl or naphthyl which can be substituted by one or more of the following radicals: halogen, nitro,
  • Phenyl or naphthyl which are linked to one another via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO 2 , NH or N-alkyl group
  • R 6 C 5 -C 7 cycloalkyl, where these radicals can each be mono- or polysubstituted by: -CC 4 alkoxy,
  • C ! -C 4 alkyl C 1 -C 4 alkylthio, halogen, hydroxy, carboxy, cyano, trifluoromethyl, acetyl or phenyl, which can be substituted one or more times, for example one to three times by halogen, cyano, C ⁇ - C 4 -alkyl, C ⁇ _-C 4 - haloalkyl, C ⁇ -C 4 -alkoxy, C J -C 4 - haloalkoxy or C ! -C 4 alkylthio;
  • Phenyl or naphthyl each of which can be substituted by one or more of the following radicals: halogen, R 15 , nitro, mercapto, carboxy, cyano, hydroxy, amino, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, acetyl , C ⁇ -C alkoxycarbonyl, C ⁇ -C 4 -alkoxy, C 4 haloalkoxy, phenoxy, C ⁇ . -C 4 alkylthio, NH (C1 . -C 4 alkyl), N (C 3.
  • -C 4 alkyl 2 , dioxomethylene, dioxoethylene or phenyl, which can be mono- or polysubstituted, for example one to three times by halogen, nitro, cyano, C1-C 4 alkyl, C 1 -C 4 haloalkyl, C ⁇ -C 4 -alkoxy, C haloalkoxy or C 1 -C 4 -alkylthio;
  • a five- or six-membered heteroaromatic containing one to three nitrogen atoms and / or a sulfur or oxygen atom which can carry one to four halogen atoms and / or one or two of the following radicals: ⁇ - C *, -alkyl, C ⁇ - C 4 - haloalkyl, C 1 -C 4 alkoxy, trifluoromethoxy, C 1 -C 4 alkyl thio, phenyl or phenoxy, where the phenyl radicals in turn can carry one to five halogen atoms and / or one to three of the following radicals: C ⁇ -C 4 -alkyl, halo-C 4 alkyl, Ci-Cj alkoxy, C ⁇ . -C 4 -haloalkoxy and / or -CC 4 alkyl thio;
  • R 15 methoxy or ethoxy which have one of the following radicals:
  • radicals in each case may be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, C 1 -C 4 - alkyl, C ⁇ -C 4 -alkoxy, C 4 -Alkylthio, or phenyl, which can be substituted one or more times, for example one to three times by halogen, nitro, cyano, C ⁇ -C 4 alkyl, C x -C 4 - haloalkyl, C 1 -C 4 alkoxy, C ⁇ -C - haloalkoxy or C ! -C 4 alkylthio
  • the compounds of the present invention offer new therapeutic potential for the treatment of hypertension, pulmonary hypertension, myocardial infarction, chronic heart failure, angina pectoris, acute / chronic renal failure, renal failure, cerebral vasospasm, cerebral ischemia, sub-arachnoid hemorrhage, migraine, asthma, Atherosclerosis, endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty, benign prostate hyperplasia, ischemic and intoxication-related kidney failure or hypertension, metastasis and growth of mesenchymal tumors, contrast agent-induced kidney failure , Pancreatitis, gastrointestinal ulcers.
  • the compounds according to the invention partly show. also antaganistic effect on the neurokinin receptor.
  • the invention further relates to combination preparations of endothelin receptor antagonists of the formula I and inhibitors of the renin-angiotensin system.
  • Inhibitors of renin angiotensin Systems are renin inhibitors, angiotensin II antagonists and especially angiotensin converting enzyme (ACE) inhibitors.
  • ACE angiotensin converting enzyme
  • Another object of the invention are combination preparation from ß-blockers and the above. Endothelin receptor antagonists and from mixed ACE-neutral endopeptidase (NEP) inhibitors and the above Endothelin receptor antagonists.
  • NEP mixed ACE-neutral endopeptidase
  • the combination preparations can be used in a single galenic. Form or be presented in spatially separate forms. The application can be carried out simultaneously or at different times.
  • the dosage in the combination can be up to the maximum amount of the respective single dose. However, it is also possible to use lower doses than with the individual therapy.
  • the ET A or ET B receptor-expressing CHO cells were in DMEM NUT MIX F ⁇ 2 medium (Gibco, No. 21331-020) with 10% fetal calf serum (PAA Laboratories GmbH, Linz, No. A15-022) , 1 mM glutamine (Gibco No. 25030-024), 100 U / ml penicillin and 100 ⁇ g / ml streptoycin (Gibco, Sig a No. P-0781) increased. After 48 hours. the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS for 5 minutes at 37 ° C. The mixture was then neutralized with medium and the cells were collected by centrifugation at 300 ⁇ g.
  • the cells were adjusted to a concentration of 10 8 cells / ml buffer (50 mM Tris-HCl buffer, pH 7.4) and then disintegrated by ultrasound (Branson Sonifier 250, 40-70 seconds / constant / output 20). Binding tests
  • the membranes were incubated in incubation buffer (50 mM Tris-HCl, pH 7.4 with 5 mM MnCl 2 , 40 ⁇ g / ml bacitracin and 0.2% BSA) in a concentration of 50 ⁇ g Protein suspended per test batch and incubated at 25 ° C with 25 pM 125 J-ET ⁇ (ET A receptor test) or 25 pM 125 J-ET 3 (ET B receptor test) in the presence and absence of test substance.
  • the non-specific binding was determined with 10 -7 M ET X.
  • test animals were given the test compounds i.v. 30 min before the administration of ET1. injected (1 ml / kg). To determine the ET antagonistic properties, the blood pressure changes in the test animals were compared with those in the control animals.
  • mice Male normotonic rats weighing 250-350 g (Sprague Dawley, Janvier) are orally pretreated with the test substances. 80 minutes later, the animals are anesthetized with urethane and the carotid artery (for measuring blood pressure) and the jugular vein (application of big endothelin / endothelin 1) are catheterized.
  • big endothelin (20 ⁇ g / kg, Appl. Vol. 0.5 ml / kg) or ET1 (0.3 ⁇ g / kg, Appl. Vol. 0.5 ml / kg) is given intravenously. Blood pressure and heart rate are continuously recorded over 30 minutes. The significant and long-lasting changes in blood pressure are calculated as the area under the curve (AUC). To determine the antagonistic effect of the test substances, the AUC of the substance-treated animals is compared with the AUC of control animals compared.
  • the compounds according to the invention can be administered in the usual way orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally). It can also be applied with vapors or sprays through the nasopharynx.
  • the dosage depends on the age, condition and weight of the patient and on the type of application.
  • the daily dose of active substance is between approximately 0.5 and 50 mg / kg body weight when administered orally and between approximately 0.1 and 10 mg / kg body weight when administered parenterally.
  • the new compounds can be used in the usual galenical 15 application forms solid or liquid, e.g. as tablets, film-coated tablets, capsules, powders, granules, dragees, suppositories, solutions, ointments, creams or sprays. These are manufactured in the usual way.
  • the active substances can be processed with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants (see H. Sucker et al .: Pharmaceutical Technology, Thieme -Verlag, Stuttgart, 25 1991).
  • the application forms thus obtained contain the following pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants (
  • Active ingredient usually in an amount of 0.1 to 90 wt .-%.

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Abstract

Carboxylic acid derivatives have the formula (I), in which R1 stands for tetrazole or a group (a); R2 stands for hydrogen, hydroxy, NH¿2?, NH(C1-c4-alkyl), N(C1-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkinyl, C1-C4-halogenalkyl, C1-C4-alkoxy, C1-C4-halogenalkoxy or C1-C4-alkylthio, or CR?2¿ is linked with CR10, as indicated below, into a 5- or 6-membered ring; X stands for nitrogen or methine; Y stands for nitrogen or methine; Z stands for nitrogen or CR10, wherein R10 is hydrogen or C¿1?-C4-alkyl or CR?10¿ forms together with CR?2 or CR3¿ an optionally substituted 5- or 6-membered alkylene or alkenylene ring, and wherein one or more methylene groups can be substituted by oxygen, sulphur, -NH or -N(C¿1?-C4-alkyl); R?3¿ stands for hydrogen, hydroxy, NH¿2?, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkinyl, C1-C4-hydroxyalkyl, C1-C4-halogenalkyl, C1-C4-alkoxy, C1-C4-halogenalkoxy, C1-C4-alkylthio; or CR?3¿ is linked to CR10 as indicated above into a 5- or 6-membered ring, R?4 and R5¿ (which may be identical or different) stand for optionally substituted phenyl or naphthyl, or for phenyl or naphthyl which are linked to each other at the ortho-position by a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulphur atom or an SO¿2?, NH or N-alkyl group; optionally substituted C3-C8-cycloalkyl; R?6¿ stands for optionally substituted C¿3?-C8-cycloalkyl; optionally substituted phenyl or naphthyl, a 5- or 6-membered, optionally substituted heteroaromatic compound containing one to three nitrogen atoms and/or one sulphur or oxygen atom; W stands for sulphur or oxygen; Q is a spacer with a length that corresponds to a C2-C4 chain. Also disclosed are the physiologically tolerable salts of these compounds, as well as their pure enantiomer and diastereoisomer forms, their preparation and use as mixed ETA/ETB-receptor antagonists.

Description

AZINYLOXY- UND PHENOXY-DIARYL-CARBONSÄURE DERIVATE, DEREN HERSTELLUNG UND DEREN VERWENDUNG ALS GEMISCHTE ETA ETB ENDOTHELIN-REZEPTORANTAGONISTENAZINYLOXY AND PHENOXY DIARYL CARBONIC ACID DERIVATIVES, THE PRODUCTION AND USE THEREOF AS MIXED ET A ET B ENDOTHELINE RECEPTOR ANTAGONISTS
Beschreibungdescription
Die vorliegende Erfindung betrifft neue Carbonsäurederivate, deren Herstellung und Verwendung.The present invention relates to new carboxylic acid derivatives, their preparation and use.
Endothelin ist ein aus 21 Aminosäuren aufgebautes Peptid, das von vaskulärem Endothel synthetisiert und freigesetzt wird. Endothelin existiert in drei Isoformen, ET-1, ET-2 und ET-3. Im Folgenden bezeichnet "Endothelin" oder "ET" eine oder alle Isoformen von Endothelin. Endothelin ist ein potenter Vasokon- striktor und hat einen starken Effekt auf den Gefäßtonus. Es ist bekannt, daß diese Vasokonstriktion von der Bindung von Endothelin an seinen Rezeptor verursacht wird (Nature, 332. 411-415, 1988; FEBS Letters, 211, 440-444, 1988 und Bioche . Biophys. Res. Commun., I , 868-875, 1988).Endothelin is a 21 amino acid peptide that is synthesized and released by vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. Hereinafter, "endothelin" or "ET" means one or all isoforms of endothelin. Endothelin is a potent vasoconstrictor and has a strong effect on vascular tone. This vasoconstriction is known to be caused by the binding of endothelin to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 211, 440-444, 1988 and Bioche. Biophys. Res. Commun., I, 868-875, 1988).
Erhöhte oder abnormale Freisetzung von Endothelin verursacht eine anhaltende Gefäßkontraktion in peripheren, renalen und zerebralen Blutgefäßen, die zu Krankheiten führen kann. Wie in der Literatur berichtet, ist Endothelin in einer Reihe von Krankheiten invol - viert. Dazu zählen: Hypertonie, akuter Myokardinfarkt, pulmonäre Hypertonie, Raynaud-Syndrom, zerebrale Vasospasmen, Schlaganfall, benigne Prostatahypertrophie, Atherosklerose und Asthma (J. Vascular Med. Biology 2, 207 (1990), J. Am. Med. Association 264, 2868 (1990), Nature r 114 (1990), N. Engl . J. Med. 322. 205 (1989), N. Engl. J. Med. 2L22~, 1732 (1993), Nephron ££r 373 (1994), Stroke 23., 904 (1994), Nature l, 759 (1993), J. Mol. Cell. Cardiol. 21, A234 (1995); Cancer Research £, 663 (1996)).Increased or abnormal release of endothelin causes persistent vascular contraction in peripheral, renal, and cerebral blood vessels, which can lead to disease. As reported in the literature, endothelin is involved in a number of diseases. These include: hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasm, stroke, benign prostatic hypertrophy, atherosclerosis and asthma (J. Vascular Med. Biology 2, 207 (1990), J. Am. Med. Association 264, 2868 (1990), Nature r 114 (1990), N. Engl. J. Med. 322. 205 (1989), N. Engl. J. Med. 2L22 ~, 1732 (1993), Nephron ££ r 373 (1994) , Stroke 23, 904 (1994), Nature l, 759 (1993), J. Mol. Cell. Cardiol. 21, A234 (1995); Cancer Research £, 663 (1996)).
Mindestens zwei Endothelinrezeptorsubtypen, ETA- und ETB-Rezeptor , werden zur Zeit in der Literatur beschrieben (Nature 348. 730 (1990), Nature 3_J 732 (1990)). Demnach sollten Substanzen, die die Bindung von Endothelin an die beiden Rezeptoren inhibieren, physiologische Effekte von Endothelin antagonisieren und daher wertvolle Pharmaka darstellen.At least two endothelin receptor subtypes, ET A and ET B receptor, are currently described in the literature (Nature 348, 730 (1990), Nature 3_J 732 (1990)). Accordingly, substances that inhibit the binding of endothelin to the two receptors should antagonize the physiological effects of endothelin and should therefore be valuable pharmaceuticals.
In WO 96/11914 wurden Carbonsäurederivate beschrieben, die jedoch mit hoher Affinität an den ETA-Rezeptor, und mit einer wesentlich geringeren Affinität an den ETB-Rezeptor binden (sog. ETA-spezifische Antagonisten) . Als ETA- spezifische Antagonisten bezeichnen wir hier solche Anta- gonisten, deren Affinität zum ETA-Rezeptor mindestens zwanzigfach höher ist als ihre Affinität zum ETB-Rezeptor .WO 96/11914 describes carboxylic acid derivatives which, however, bind with a high affinity to the ET A receptor and with a substantially lower affinity to the ET B receptor (so-called ET A -specific antagonists). As ET A -specific antagonists we refer here to those antagonists whose affinity for the ET A receptor is at least 20 times higher than their affinity for the ET B receptor.
Es bestand die Aufgabe, Endothelinrezeptorantagonisten bereitzustellen, die mit ungefähr gleicher Affinität an den ETA- und den ETB-Rezeptor binden (sog. gemischte Antagonisten).The task was to provide endothelin receptor antagonists which bind to the ET A and ET B receptors with approximately the same affinity (so-called mixed antagonists).
Ungefähr gleiche Affinität zu den Rezeptoren besteht, wenn der Quotient der Affinitäten ETA:ETB größer 0,1 und kleiner 20, bevorzugt kleiner 10, ist.There is approximately the same affinity for the receptors if the quotient of the affinities ET A : ET B is greater than 0.1 and less than 20, preferably less than 10.
Gegenstand der Erfindung sind Carbonsäurederivate der Formel IThe invention relates to carboxylic acid derivatives of the formula I.
wobei R1 steht für Tetrazol oder für eine Gruppewhere R 1 stands for tetrazole or for a group
00
C RC R
in der R folgende Bedeutung hat:in which R has the following meaning:
a) ein Rest OR7, worin R7 bedeutet:a) a radical OR 7 , in which R 7 denotes:
Wasserstoff, das Kation eines Alkalimetalls, das Kation eines Erdalkalimetalls, ein physiologisch verträgliches organisches Ammoniumion wie C1.-C4 -Alkylammonium oder das Ammoniumion;Hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically compatible organic ammonium ion such as C1 . -C 4 alkyl ammonium or the ammonium ion;
C3-C8-Cycloalkyl, Cι.-C8-Alkyl, CH2- Phenyl. das durch einen oder mehrere der folgenden Reste substituiert sein kann: Halogen, Nitro, Cyano, Ci -C -Alkyl, C1-C4-Halogenalkyl, Hydroxy, C1-C -Alkoxy, Mercapto, Cι-C4-Alkylthio, Amino, Carboxy, NH (Cχ-C4 -Alkyl) , N(Cχ -C4- Alkyl) 2;C 3 -C 8 cycloalkyl, Cι . -C 8 alkyl, CH 2 - phenyl. which can be substituted by one or more of the following radicals: halogen, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxy, C 1 -C 4 alkoxy, mercapto, C 1 -C 4 alkylthio, Amino, carboxy, NH (Cχ-C 4 alkyl), N (Cχ -C 4 alkyl) 2 ;
Eine C3-C6-Alkenyl - oder eine C3-C6-Alkinylgruppe, wobei diese Gruppen ihrerseits ein bis fünf Halogenatome tragen können; R7 kann weiterhin ein Phenylrest sein, welcher ein bis fünf Halogenatome und/oder ein bis drei der folgenden Reste tragen kann: Nitro, Cyano, C1.-C4 -Alkyl, C1-C4 -Halogenalkyl, Hydroxy, C1-C4 -Alkoxy, Mercapto, C1-C4 -Alkylthio, Amino, NH (C1-C4 -Alkyl ) , N (Ci. -C4 -Alkyl) 2 ;A C 3 -C 6 alkenyl or a C 3 -C 6 alkynyl group, these groups in turn being able to carry one to five halogen atoms; R 7 can also be a phenyl radical which can carry one to five halogen atoms and / or one to three of the following radicals: nitro, cyano, C1.-C 4 -alkyl, C 1 -C 4 -haloalkyl, hydroxy, C 1 - C 4 alkoxy, mercapto, C 1 -C 4 alkylthio, amino, NH (C 1 -C 4 alkyl), N (Ci . -C 4 alkyl) 2 ;
b) ein über ein Stickstoffatom verknüpfter 5-gliedriger Hetero- aromat wie Pyrrolyl, Pyrazolyl, Imidazolyl und Triazolyl, welcher ein bis zwei Halogenatome, oder eins bis zwei C1-C4 -Alkyl oder eins bis zwei C1-C4 -Alkoxygruppen tragen kann.b) a 5-membered heteroaromatic linked via a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which has one or two halogen atoms, or one or two C 1 -C 4 -alkyl or one or two C 1 -C 4 -alkoxy groups can carry.
c) eine Gruppec) a group
in der k die Werte 0, 1 und 2, p die Werte 1, 2, 3 und 4 annehmen und R8 fürwhere k is 0, 1 and 2, p is 1, 2, 3 and 4 and R 8 is
C1-C4-Alkyl.. C3-Ca-Cycloalkyl, C3-C6 -Alkenyl, C3 -C6 -Alkinyl oder Phenyl steht, das durch einen oder mehrere, z.B. ein bis drei der folgenden Reste substituiert sein kann: Halogen, Nitro, Cyano, Cι-C4-Alkyl, C1.-C4 -Halogenalkyl, Hydroxy, Cι-C4-Alkoxy, C1.-C4 -Alkylthio, Mercapto, Amino, Carboxy, NH (C1.-C4 -Alkyl) , N{Cι.-C4 -Alkyl) 2.C 1 -C 4 alkyl .. C 3 -C a cycloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl or phenyl, which is substituted by one or more, for example one to three, of the following radicals can be: halogen, nitro, cyano, -CC 4 alkyl, C1 . -C 4 haloalkyl, hydroxy, -C-C 4 alkoxy, C1 . -C 4 alkylthio, mercapto, amino, carboxy, NH (C1 . -C 4 alkyl), N {Cι . -C 4 alkyl) 2 .
d) ein Restd) a rest
worin R9 bedeutet:where R 9 means:
C1-C4 -Alkyl, C3-C6 -Alkenyl, C3-C6 -Alkinyl, C3-Cβ-Cycloalkyl , Ci -C4 -Halogenalkyl , wobei diese Reste einen Ci -C4 -Alkoxy - , Cι-C4-Alkylthio- und/oder einen Phenylrest wie unter c) genannt tragen können;C 1 -C 4 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C β cycloalkyl, Ci -C 4 haloalkyl, these radicals being a Ci -C 4 alkoxy - , C 1 -C 4 alkylthio and / or a phenyl radical as mentioned under c) can wear;
Phenyl, gegebenenfalls substituiert, insbesondere wie vor' stehend genannt, e) ferner kann R1 bedeutenPhenyl, optionally substituted, in particular as mentioned above, e) R 1 can also mean
R13 R 13
//
5 ~ N 5 ~ N
\ R14\ R 14
wobei R13 und R14 gleich oder verschieden sein können und folgende Bedeutung haben:where R 13 and R 14 may be the same or different and have the following meaning:
Wasserstoff, Cι-C8-Alkyl, C3-Cθ-.Cycloalkyl , C3_C8-Alkenyl,Hydrogen, -CC 8 alkyl, C 3 -C θ -.cycloalkyl, C 3 _C 8 alkenyl,
C-C8-Alkinyl, Benzyl, Phenyl, das ein bis fünf Halogenatome und/oder ein bis drei der folgenden Reste tragen kann: Nitro, 5 Cyano, C1_C4-Alkyl, C1_C4-Halogenalkyl , Hydroxy, C1-C.Alkoxy, Mercapto, Cι-C4-Alkylthio, Amino,CC 8 alkynyl, benzyl, phenyl, which can carry one to five halogen atoms and / or one to three of the following radicals: nitro, 5 cyano, C 1 _C 4 alkyl, C 1 _C 4 haloalkyl, hydroxy, C 1 - C. alkoxy, mercapto, C 1 -C 4 -alkylthio, amino,
NH(Cι-C4.Alkyl) , N (Cι-C4-Alkyl ) 2 ,NH (-C 4 -alkyl), N (-C 4 -alkyl) 2 ,
oder R13 und R14 bilden gemeinsam eine zu einem Ring geschlos0 sene C4-C7-Alkylenkette, die durchor R 13 and R 14 together form a C 4 -C 7 alkylene chain which is closed to form a ring and which can pass through
Cι_C4-Alkyl substituiert und in der eine Alkylengruppe durch Sauerstoff, Schwefel oder Stickstoff ersetzt sein kann wie -(CH2.4-, -(CH2)5-r -(CH2 ) 6-< -(CH2 ) 2-0-(CH2 ) 2-, -(CH2)7-, 5 -CH2-S-(CH2)2-, -CH2-NH-(CH2)2-, - (CH2) 2-N- (CH2) 2-Cι_C 4 alkyl substituted and in which an alkylene group can be replaced by oxygen, sulfur or nitrogen such as - (CH2.4-, - (CH 2 ) 5 -r - ( CH 2 ) 6 - <- ( CH 2 ) 2 - 0- ( CH 2 ) 2 -, - (CH 2 ) 7 -, 5 -CH 2 -S- (CH 2 ) 2 -, -CH 2 -NH- (CH 2 ) 2 -, - (CH 2 ) 2 -N- (CH 2 ) 2-
R2 Wasserstoff, Hydroxy, NH2, NH (C1-C4 -Alkyl ) , (C1-C4 -Alkyl) 2, Halogen, Cι-C4-Alkyl, C2 C4 Alkenyl, C2 C4 Alkinyl, Cι-C4-Hydroxyalkyl , C1-C4-Halogenalkyl, Ci -C4-Alkoxy, 0 Cι-C4-Halogenalkoxy oder Cι-C4-Alkylthιo, oder CR2 ist mit CR10 wie unten angegeben zu einem 5- oder 6-gliedrιgen Ring verknüpft .R 2 is hydrogen, hydroxy, NH 2 , NH (C1-C4-alkyl), (C 1 -C4 -alkyl) 2 , halogen, -C-C 4 -alkyl, C 2 C 4 alkenyl, C 2 C 4 alkynyl, Cι -C 4 -hydroxyalkyl, C 1 -C 4 -haloalkyl, Ci -C 4 -alkoxy, 0 -C-C 4 -haloalkoxy or -C-C 4 -alkylthioo, or CR 2 is with CR 10 as stated below to a 5- or 6-membered ring linked.
X Stickstoff oder Methin. 5X nitrogen or methine. 5
Y Stickstoff oder Methin.Y nitrogen or methine.
Z Stickstoff oder CR10, worin R10 Wasserstoff oder C3.-C4-Alkyl bedeutet oder CR10 zusammen mit CR2 oder CRJ einen 5- oder - Q 6-gliedrigen Alkylen- oder Alkenylenring bildet, der durch eine oder zwei Cι-C4-Alkylgruppen substituiert sein kann und worin jeweils eine oder mehrere Methylengruppen durch Sauerstoff, Schwefel, -NH oder N(Cι-C4 -Alkyl) 2 ersetzt sein können.Z is nitrogen or CR 10 , in which R 10 is hydrogen or C 3 -C 4 -alkyl or CR 10 together with CR 2 or CR J forms a 5- or - Q 6-membered alkylene or alkenylene ring which is replaced by one or two C 1 -C 4 alkyl groups can be substituted and in which one or more methylene groups can be replaced by oxygen, sulfur, -NH or N (C 1 -C 4 alkyl) 2 .
5 Mindestens eines der Ringglieder X, Y oder Z ist Stickstoff. R3 Wasserstoff, Hydroxy, NH2, NH (Ci -C4 -Alkyl) , N(Cι-C4 -Alkyl) 2, Halogen, C1-C4-Alkyl, C2-C4 -Alkenyl, C2-C4 -Alkinyl, Cι-C4-Halogenalkyl , C1-C4 -Alkoxy, Cι-C -Halogenalkoxy, Cι-C4-Hydroxyalkyl, C1-C4-Alkylthio, oder CR3 ist mit CR10 wie oben angegeben zu einem 5- oder 6-gliedrigen Ring verknüpft.5 At least one of the ring members X, Y or Z is nitrogen. R 3 is hydrogen, hydroxyl, NH 2 , NH (Ci -C 4 alkyl), N (-C-C 4 alkyl) 2 , halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 -alkynyl, -C-C 4 -haloalkyl, C 1 -C 4 -alkoxy, Cι-C -haloalkoxy, Cι-C 4 -hydroxyalkyl, C 1 -C 4 -alkylthio, or CR 3 is with CR 10 as linked above to form a 5- or 6-membered ring.
R4 und R5 (die gleich oder verschieden sein können) :R 4 and R 5 (which may be the same or different):
Phenyl oder Naphthyl, die durch einen oder mehrere der folgenden Reste substituiert sein können: Halogen, Nitro, Cyano, Hydroxy, Mercapto, C1-C4-Alkyl, C2-C4 -Alkenyl, Ci -C4 -Hydroxyalkyl , C2-C4-Alkinyl, Ci -C4- Halogenalkyl , C1-C4 -Alkoxy, Phenoxy, Carboxy, Cι-C4 -Halogenalkoxy, CJ-C, -Alkylthio, Amino, H{C!-C4 -Alkyl) , N (Cx -C4 -Alkyl ) 2 oder Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach durch Halogen, Nitro, Cyano, C1-C4 -Alkyl, C1-C4- Halogenalkyl, C1-C4 -Alkoxy, Ci -C4-Halogenalkoxy oder Cj.-C4-Alkylthio; oderPhenyl or naphthyl, which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, mercapto, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, Ci -C 4 hydroxyalkyl, C 2 -C 4 alkynyl, Ci -C 4 - haloalkyl, C 1 -C 4 alkoxy, phenoxy, carboxy, Cι-C 4 haloalkoxy, CJ-C, alkylthio, amino, H {C ! -C 4 alkyl), N (C x -C 4 alkyl) 2 or phenyl, which can be mono- or polysubstituted, for example one to three times by halogen, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, Ci -C 4 haloalkoxy or Cj . -C 4 alkylthio; or
Phenyl oder Naphthyl, die orthoständig über eine direktePhenyl or naphthyl, which is ortho-direct
Bindung, eine Methylen-, Ethylen- oder Ethenylengruppe, ein Sauerstoff- oder Schwefelatom oder eine S02-, NH- oder N-Alkyl -Gruppe miteinander verbunden sind;Bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an S0 2 -, NH or N-alkyl group are connected to one another;
C3-C8-Cycloalkyl.C 3 -C 8 cycloalkyl.
R6 C3-C8-Cycloalkyl , wobei diese Reste jeweils ein- oder mehrfach substituiert sein können durch: Halogen, Hydroxy, Mercapto, Carboxy, Nitro, Cyano, Cχ-C4-Alkoxy, Cι-C -Alkyl, C2-C4 -Alkenyl, C2-C -Alkinyl, C3-C6-Alkenyloxy, C3-C6-Alkinyl - oxy, Cι-C -Alkylthio, Cχ-C4 -Halogenalkoxy, Cι-C -Alkylcarbonyl, Ci -C4 -Alkoxycarbonyl , C3 -Cg -Alkylcarbonylalkyl , NH (C!-C -Alkyl ) , N (Ci -C4 -Alkyl) 2, oder Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach durch Halogen, Nitro, Cyano, Cι-C4-Alkyl, C1-C4 -Halogenalkyl, Cι-C4-Alkoxy, C1-C4 -Halogenalkoxy oder Cι-C4-Alkylthio;R 6 C 3 -C 8 cycloalkyl, where these radicals can each be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, nitro, cyano, Cχ-C 4 alkoxy, Cι-C alkyl, C 2 -C 4 -alkenyl, C 2 -C -alkynyl, C 3 -C 6 -alkenyloxy, C 3 -C 6 -alkynyl-oxy, -C-C -alkylthio, Cχ-C 4 -haloalkoxy, -C-C -alkylcarbonyl, Ci -C 4 alkoxycarbonyl, C 3 -Cg alkylcarbonylalkyl, NH (C ! -C alkyl), N (Ci -C 4 alkyl) 2 , or phenyl, which can be mono- or polysubstituted, eg mono- to trisubstituted by halogen, nitro, cyano, C 4 alkyl, C 1 -C 4 haloalkyl, Cι-C 4 alkoxy, C 1 -C 4 -haloalkoxy or Cι-C 4 alkylthio;
Phenyl oder Naphthyl, die jeweils durch einen oder mehrere der folgenden Reste substituiert sein können: Halogen, R15, Nitro, Mercapto, Carboxy, Cyano, Hydroxy, Amino, Cι-C -Alkyl, C2-C -Alkenyl, C2-C4 -Alkinyl, C3-Cβ-Alkenyloxy , C1-C4 -Halogenalkyl, C3-C6-Alkinyloxy, Cι-C4-Alkylcarbonyl, C1.-C4 -Alkoxycarbonyl , Cι-C4 -Alkoxy, Cι-C4- Halogenalkoxy, Phenoxy, Cι-C4-Alkylthio, NH (C1-C4-Alkyl ) , N(Cι-C4 -Alkyl) 2 , Dioxomethy- len, Dioxoethylen oder Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach durch Halogen, Nitro, Cyano, Cι-C4-Alkyl, C1-C -Halogenalkyl , C1-C4 -Alkoxy, C1-C4- Halogenalkoxy oder Ci -C4 -Alkylthio;Phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, R 15 , nitro, mercapto, carboxy, cyano, hydroxy, amino, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 - C 4 -alkynyl, C 3 -Cβ-alkenyloxy, C 1 -C 4 -haloalkyl, C 3 -C 6 -alkynyloxy, -C-C 4 -alkylcarbonyl, C1 . -C 4 -alkoxycarbonyl, -C-C 4 alkoxy, -C-C 4 - haloalkoxy, phenoxy, Cι-C 4 -alkylthio, NH (C 1 -C 4 -alkyl), N (-C-C 4 -alkyl) 2 , Dioxomethylene, dioxoethylene or phenyl, which can be substituted one or more times, for example one to three times by halogen, nitro, cyano, C 1 -C 4 -alkyl, C 1 -C -haloalkyl, C 1 -C 4 - Alkoxy, C 1 -C 4 - haloalkoxy or Ci-C4 alkylthio;
ein fünf- oder sechsgliedriger Heteroaromat, enthaltend ein bis drei Stickstoffatome und/oder ein Schwefel- oder Sauer - 5 stoffatom, welcher ein bis vier Halogenatome und/oder einen bis zwei der folgenden Reste tragen kann: C1-C4 -Alkyl, C2-C4 -Alkenyl, Ci -C4 -Halogenalkyl, C1-C4 -Alkoxy, Cχ-C4 -Halogenalkoxy, C1.-C4 -Alkylthio, Phenyl oder Phenoxy wobei die Phenyl - reste ihrerseits ein bis fünf Halogenatome und/oder einen bis 10 drei der folgenden Reste tragen können: Cι-C -Alkyl,a five- or six-membered heteroaromatic containing one to three nitrogen atoms and / or a sulfur or oxygen atom which can carry one to four halogen atoms and / or one or two of the following radicals: C 1 -C 4 alkyl, C 2 -C 4 alkenyl, Ci -C 4 haloalkyl, C 1 -C 4 alkoxy, Cχ-C 4 haloalkoxy, C1 . -C 4 alkylthio, phenyl or phenoxy where the phenyl radicals can in turn carry one to five halogen atoms and / or one to 10 three of the following radicals: -C 1 -C 4 -alkyl,
C1-C4-Halogenalkyl, C1-C4 -Alkoxy, Ci -C4- Halogenalkoxy und/oder Ci -C4-Alkylthio;C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C -C 4 - haloalkoxy, and / or Ci-C4 alkylthio;
15 R15 Cι_C4_Alkyl, C1_C4_Alkylthio, Cj.-C4-Alkoxy, die einen der folgenden Reste tragen: Hydroxy, Carboxy, Amino, NH (Cι_C4_Alkyl) , N(Cι_C4-Alkyl)2, Carboxamid oder CON (C1-C4.Alkyl) 2; 15 R 15 Cι_C 4 _alkyl, C 1 _C 4 _alkylthio, Cj.-C 4 alkoxy, which carry one of the following radicals: hydroxy, carboxy, amino, NH (Cι_C 4 _alkyl), N (Cι_C 4 alkyl) 2 , Carboxamide or CON (C 1 -C 4 alkyl) 2 ;
W Schwefel oder Sauerstoff. 20W sulfur or oxygen. 20th
Q Ein Spacer, der in seiner Länge einer C2-C4 Kette entspricht. Die Funktion von Q ist, in den Verbindungen der Formel I einen definierten Abstand zwischen den Gruppen R6 und W herzustellen. Der Abstand soll der Länge einer C2-C4 -AlkylketteQ A spacer that corresponds in length to a C 2 -C 4 chain. The function of Q is to produce a defined distance between the groups R 6 and W in the compounds of the formula I. The distance should be the length of a C 2 -C 4 alkyl chain
" entsprechen. Dies kann mit einer Vielzahl von chemischen Resten erreicht werden, beispielsweise mit C2-C -Alkyl, C3-C4 -Alkenyl, C3 -C4 -Alkinyl, -S-CH2-CH2-, -0-CH2-CH2-, -N-CO-CH2-0- , wobei diese Reste jeweils ein- oder mehrfach substituiert sein können durch: Halogen, Hydroxy, Mercapto,This can be achieved with a large number of chemical residues, for example with C 2 -C 4 -alkyl, C 3 -C 4 -alkenyl, C 3 -C 4 -alkynyl, -S-CH 2 -CH 2 -, - 0-CH 2 -CH 2 -, -N-CO-CH 2 -0-, where these radicals can each be mono- or polysubstituted by: halogen, hydroxy, mercapto,
30 Cι-C4-Alkyl, C2-C4 -Alkenyl, C2-C4-Alkinyl, Carboxy, Nitro, Cyano, C1.-C4 -Alkoxy, C3-C6-Alkenyloxy, C3-C6-Alkinyloxy, Cι-C4-Alkylthio, C1-C4-Halogenalkoxy, C1-C4 -Alkylcarbonyl , Ci -C -Alkoxy- carbonyl , C3.8 -Alkylcarbonylalkyl , NH (C1-C4 -Alkyl ) , N (Cι-C4 -Alkyl) 2, Phenyl, das ein- oder mehr- ^ fach substituiert sein kann, z.B. ein- bis dreifach durch Halogen, Nitro, Cyano, Cχ-C4-Alkyl, C3.-C4 -Halogenalkyl , Cι-C4-Alkoxy, Cι-C -Halogenalkoxy oder Cι-C4-Alkylthio.30 -CC 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, carboxy, nitro, cyano, C1.-C 4 alkoxy, C 3 -C 6 alkenyloxy, C 3 -C 6 -alkynyloxy, -CC 4 -alkylthio, C 1 -C 4 -haloalkoxy, C 1 -C 4 -alkylcarbonyl, Ci -C -alkoxy-carbonyl, C 3 . 8- alkylcarbonylalkyl, NH (C 1 -C 4 -alkyl), N (-C-C 4 -alkyl) 2 , phenyl, which can be mono- or polysubstituted, for example mono- to trisubstituted by halogen, nitro, Cyano, Cχ-C 4 -alkyl, C3.-C 4 -haloalkyl, Cι-C 4 -alkoxy, Cι-C -haloalkoxy or -CC 4 -alkylthio.
Oder der Spacer Q ist Teil eines 5-7 gliedrigen Ringes,Or the spacer Q is part of a 5-7 membered ring,
40 hetero- oder carbocyclisch, an den R6 annelliert ist40 heterocyclic or carbocyclic to which R 6 is fused
Hierbei und im weiteren gelten folgende Definitionen:The following definitions apply here and below:
Ein Alkalimetall ist z.B. Lithium, Natrium, Kalium; 45An alkali metal is e.g. Lithium, sodium, potassium; 45
Ein Erdalkalimetall ist z.B. Calcium, Magnesium, Barium; C3-C8-Cycloalkyl ist z.B. Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Cycloheptyl oder Cyclooctyl;An alkaline earth metal is, for example, calcium, magnesium, barium; C 3 -C 8 cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;
C1-C4 -Halogenalkyl kann linear oder verzweigt sein wie z.B. Fluor- methyl, Difluormethyl , Trif luormethyl, Chlordif luormethyl ,C 1 -C 4 haloalkyl can be linear or branched, such as, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl,
Dichlorf luormethyl, Trichlormethyl , 1-Fluorethyl , 2 -Fluorethyl , 2, 2-Difluorethyl, 2,2, 2 -Trifluorethyl, 2 -Chlor -2 , 2 -difluorethyl, 2, 2-Dichlor-2-fluorethyl, 2, 2 , 2-Trichlorethyl oder Pentafluor- ethyl;Dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chlorine -2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2 , 2-trichloroethyl or pentafluoroethyl;
C1-C4 -Halogenalkoxy kann linear oder verzweigt sein wie z.B. Difluormethoxy, Trifluormethoxy, Chlordifluormethoxy, 1 -Fluor - ethoxy, 2, 2 -Difluorethoxy, 1, 1, 2 , 2 -Tetrafluorethoxy, 2,2,2-Tri- fluorethoxy, 2 -Chlor -1, 1, 2 -trifluorethoxy, 2 -Fluorethoxy oder Pentafluorethoxy;C 1 -C 4 haloalkoxy can be linear or branched, such as difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoro-ethoxy, 2, 2-difluoroethoxy, 1, 1, 2, 2-tetrafluoroethoxy, 2,2,2-tri- fluoroethoxy, 2 -chloro-1, 1,2-trifluoroethoxy, 2 -fluoroethoxy or pentafluoroethoxy;
Cι-C4-Alkyl kann linear oder verzweigt sein wie z.B. Methyl, Ethyl, 1-Propyl, 2-Propyl, 2 -Methyl -2 -propyl, 2 -Methyl - 1 -propyl, 1-Butyl oder 2-Butyl;C 1 -C 4 alkyl can be linear or branched, such as methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl or 2-butyl;
C2-C4 -Alkenyl kann linear oder verzweigt sein wie z.B. Ethenyl, 1 - Propen-3 -yl, 1 -Propen- 2 -yl , 1- Propen-1 -yl, 2 -Methyl -1 -propenyl, 1-Butenyl oder 2-Butenyl;C 2 -C 4 alkenyl can be linear or branched, such as, for example, ethenyl, 1-propen-3-yl, 1-propen-2-yl, 1-propen-1-yl, 2-methyl-1-propenyl, 1- Butenyl or 2-butenyl;
C2-C4 -Alkinyl kann linear oder verzweigt sein wie z.B. Ethinyl, 1 - Propin - 1 -yl, 1 -Propin- 3 -yl, l-Butin-4-yl oder 2 -Butin-4 -yl ;C 2 -C 4 alkynyl can be linear or branched, such as, for example, ethynyl, 1-propyn-1-yl, 1-propyn-3-yl, 1-butyn-4-yl or 2-butyn-4-yl;
Cι-C4-Alkoxy kann linear oder verzweigt sein wie z.B. Methoxy, Ethoxy, Propoxy, 1 -Methylethoxy, Butoxy, 1-Methylpropoxy, 2-Methylpropoxy oder 1 , 1 -Dimethylethoxy;C 1 -C 4 -alkoxy can be linear or branched, such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1, 1 -dimethylethoxy;
C3-C6-Alkenyloxy kann linear oder verzweigt sein wie z.B. Allyl- oxy, 2-Buten- 1-yloxy oder 3-Buten-2-yloxy;C 3 -C 6 alkenyloxy can be linear or branched, such as, for example, allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy;
Cι-C4-Hydroxyalkyl kann linear oder verzweigt sein wie z.B. Hydroxymethyl , 1 -Hydroxyether - 2 -yl ,C 1 -C 4 -hydroxyalkyl can be linear or branched, such as hydroxymethyl, 1-hydroxyether-2 -yl,
C -C6-Alkinyloxy kann linear oder verzweigt sein wie z.B. 2- Propin-1-yloxy, 2-Butin-l-yloxy oder 3-Butin-2-yloxy;C 6 -C 6 alkynyloxy can be linear or branched, such as 2-propin-1-yloxy, 2-butyn-1-yloxy or 3-butyn-2-yloxy;
C1-C4 -Alkylthio kann linear oder verzweigt sein wie z.B. Methyl thio, Ethylthio, Propylthio, 1 -Methylethylthio, Butylthio, 1-Methylpropylthio, 2-Methylpropylthio oder 1, l-Dimethylethyl - thio; Cι-C4-Alkylcarbonyl kann linear oder verzweigt sein wie z.B. Acetyl, Ethylcarbonyl oder 2>-Propylcarbonyl;C 1 -C 4 alkylthio can be linear or branched, such as, for example, methyl thio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio; C 1 -C 4 -alkylcarbonyl can be linear or branched, such as acetyl, ethylcarbonyl or 2>-propylcarbonyl;
C1-C4-Alkoxycarbonyl kann linear oder verzweigt sein wie z.B. Methoxycarbonyl, Ethoxycarbonyl, n-Propoxycarbonyl, i- Propoxy- carbonyl oder n-Butoxycarbonyl ;C 1 -C 4 alkoxycarbonyl can be linear or branched such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbonyl;
Cs-Ca-Alkylcarbonylalkyl kann linear oder verzweigt sein, z.B. 2-0xo-prop-l-yl, 3 -Oxo-but- 1 -yl oder 3 -Oxo-but- 2 -ylCs-Ca alkylcarbonylalkyl can be linear or branched, e.g. 2-0xo-prop-l-yl, 3 -oxo-but-1 -yl or 3 -oxo-but-2 -yl
Ci-Ca -Alkyl kann linear oder verzweigt sein wie z.B. Cj.-C4-Alkyl, Pentyl, Hexyl, Heptyl oder Octyl;Ci-Ca alkyl can be linear or branched, such as Cj . -C 4 alkyl, pentyl, hexyl, heptyl or octyl;
Halogen ist z.B. Fluor, Chlor, Brom, Jod.Halogen is e.g. Fluorine, chlorine, bromine, iodine.
Ein weiterer Gegenstand der Erfindung sind solche Verbindungen, aus denen sich die Verbindungen der Formel I freisetzen lassen (sog. Prodrugs) .The invention further relates to those compounds from which the compounds of the formula I can be released (so-called prodrugs).
Bevorzugt sind solche Prodrugs, bei denen die Freisetzung unter solchen Bedingungen abläuft, wie sie in bestimmten Körperkompar - timenten, z.B. im Magen, Darm, Blutkreislauf, Leber, vorherrschen.Preference is given to those prodrugs in which the release takes place under conditions such as those in certain body compartments, e.g. in the stomach, intestines, bloodstream, liver, predominate.
Die Verbindungen und auch die Zwischenprodukte zu ihrer Herstellung, wie z.B. II, III und IV, können ein oder mehrere asymmetrisch substituierte Kohlenstoffatome besitzen. Solche Verbindungen können als reine Enantiomere bzw. reine Diastereo - mere oder als deren Mischung vorliegen. Bevorzugt ist die Ver- wendung einer enantiomerenreinen Verbindung als Wirkstoff.The compounds and also the intermediates for their preparation, e.g. II, III and IV, can have one or more asymmetrically substituted carbon atoms. Such compounds can exist as pure enantiomers or pure diastereomers or as a mixture thereof. Preference is given to using an enantiomerically pure compound as the active ingredient.
Gegenstand der Erfindung ist weiter die Verwendung der oben genannten Carbonsäurederivate zur Herstellung von Arzneimitteln, insbesondere zur Herstellung von Hemmstoffen für ETA und ETB Rezeptoren. Die erfindungsgemäßen Verbindungen eignen sich besonders als gemischte Antagonisten, wie sie eingangs definiert wurden.The invention further relates to the use of the abovementioned carboxylic acid derivatives for the production of medicaments, in particular for the production of inhibitors for ET A and ET B receptors. The compounds according to the invention are particularly suitable as mixed antagonists as defined at the outset.
Die Herstellung der Verbindungen mit der allgemeinen Formel IV, in denen W Schwefel oder Sauerstoff ist, kann - auch in enantiomerenreiner Form - wie in WO 96/11914 beschrieben, erfolgen. The compounds of the general formula IV, in which W is sulfur or oxygen, can be prepared - also in enantiomerically pure form - as described in WO 96/11914.
II III IVII III IV
Verbindungen der allgemeinen Formel III sind entweder bekannt oder können z.B. durch Reduktion der entsprechenden Carbonsäuren bzw deren Ester, oder durch andere allgemein bekannte Methoden synthetisiert werden.Compounds of general formula III are either known or can e.g. can be synthesized by reducing the corresponding carboxylic acids or their esters, or by other generally known methods.
Carbonsäurederivate der allgemeinen Formel VI können hergestellt werden, indem eine Verbindung der Formel Via mit einem Alkohol oder Thiol der Formel VII unter Säurekatalyse zur Reaktion gebracht wird.Carboxylic acid derivatives of the general formula VI can be prepared by reacting a compound of the formula Via with an alcohol or thiol of the formula VII with acid catalysis.
R16 Ria 0.. £_ RI + Rl9_ w H -t-r, R 16 Ria 0 .. £ _ RI + Rl9 _ w H -t- r ,
R17 OHR 17 OH
Via VIIVia VII
R16 R 16
R19 -w C — R1 R 19 -w C - R 1
R K17 OHR K17 OH
VIVI
Die angegebenen Reste haben folgende Bedeutung:The radicals given have the following meaning:
R1 hat die unter der allgemeinen Formel I angegebene BedeutungR 1 has the meaning given under the general formula I.
R16 und R17, die gleich oder verschieden sein können, Wasserstoff oder Alkyl, Alkenyl, Alkinyl, Phenyl, Naphthyl, Cycloalkyl jeweils gegebenenfalls substituiert,R 16 and R 17 , which may be the same or different, each optionally substituted, hydrogen or alkyl, alkenyl, alkynyl, phenyl, naphthyl, cycloalkyl,
R18 Wasserstoff oder Alkyl, Alkenyl, Alkinyl, Phenyl, Naphthyl, Cycloalkyl jeweils gegebenenfalls substituiert, R19 Wasserstoff oder Alkyl, Alkenyl, Alkinyl, Phenyl, Naphthyl, Cycloalkyl jeweils gegebenenfalls substituiert,R 18 is hydrogen or alkyl, alkenyl, alkynyl, phenyl, naphthyl, cycloalkyl, each optionally substituted, R 19 is hydrogen or alkyl, alkenyl, alkynyl, phenyl, naphthyl, cycloalkyl, each optionally substituted,
bevorzugt haben die Reste folgende Bedeutung:the radicals preferably have the following meaning:
R1 COOR7 R 1 COOR 7
R16 und R17, die gleich oder verschieden sein können,R 16 and R 17 , which may be the same or different,
Alkyl, Phenyl, Naphthyl, Cycloalkyl jeweils gegebenenfalls substituiert,Alkyl, phenyl, naphthyl, cycloalkyl, each optionally substituted,
R18 Alkyl, Phenyl, Cycloalkyl jeweils gegebenenfalls substituiert,R 18 alkyl, phenyl, cycloalkyl each optionally substituted,
R19 Alkyl, Alkenyl, Alkinyl, Phenyl, Cycloalkyl, jeweils gegebenenfalls substituiert,R 19 alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, each optionally substituted,
besonders bevorzugt sind folgende Restethe following radicals are particularly preferred
R1 COOCH3 R 1 COOCH 3
R16 R4 R 16 R 4
Rl7 R5 R 17 R 5
R18 Alkyl gegebenenfalls substituiert, insbesondere MethylR 18 alkyl optionally substituted, especially methyl
R19 R6^3.R 19 R 6 ^ 3.
Die Carbonsäurederivate der allgemeinen Formel IV können nach diesem Verfahren hergestellt werden, indem eine Verbindung der Formel IVa mit einem Alkohol oder Thiol der Formel III unter Säurekatalyse zur Reaktion gebracht wird The carboxylic acid derivatives of the general formula IV can be prepared by this process by reacting a compound of the formula IVa with an alcohol or thiol of the formula III with acid catalysis
R4 R 4
HH
R18 _ - o - 1 C OH R6 - Q- W — H R 18 _ - o - 1 C OH R 6 - Q- W - H
11
R5 Rl IVa IIIR 5 Rl IVa III
R4 R 4
Hierzu werden die Verbindungen IVa und III in Substanz oder in einem für diese Reaktion inerten Lösungsmittel gemischt und kata- lytische Mengen einer Säure wie z.B. p-Toluolsulfonsäure zugegeben. Beispiele für inerte Lösungsmittel sind Methylenchlorid, Benzol oder Toluol. Geeignet sind auch solche inerte Lösungsmittel, die mit dem Alkohol R18OH ein Azeotrop bilden. Im Falle von Methanol (R18=CH ) sind dies zum Beispiel Chloroform oder Essigsäuremethylester.For this purpose, the compounds IVa and III are mixed in bulk or in a solvent which is inert for this reaction and catalytic amounts of an acid such as, for example, p-toluenesulfonic acid are added. Examples of inert solvents are methylene chloride, benzene or toluene. Inert solvents which form an azeotrope with the alcohol R 18 OH are also suitable. In the case of methanol (R 18 = CH), these are, for example, chloroform or methyl acetate.
Das Reaktionsgemisch wird anschließend zwischen Raumtemperatur und Siedetemperatur des Lösungsmittels gerührt. Der entstehende Alkohol R180H wird durch Abdestillieren oder Anlegen eines Vakuums entfernt. Diese Methode eignet sich auch zur Herstellung von enantiomerenreinem IV sofern von enantiomerenreinem IVa ausgegangen wird.The reaction mixture is then stirred between room temperature and the boiling point of the solvent. The resulting alcohol R 18 0H is removed by distilling off or applying a vacuum. This method is also suitable for the production of enantiomerically pure IV if it is assumed that enantiomerically pure IVa.
Verbindungen der Formel IVa sind bekannt und beispielsweise in WO 96/11914 beschrieben.Compounds of the formula IVa are known and are described, for example, in WO 96/11914.
Die erfindungsgemäßen Verbindungen, in denen die Substituenten die unter der allgemeinen Formel I angegebenen Bedeutung haben, können beispielsweise derart hergestellt werden, daß man die Carbonsäurederivate der allgemeinen Formel IV, in denen die Substituenten die angegebene Bedeutung haben, mit Verbindungen der allgemeinen Formel V zur Reaktion bringt. The compounds according to the invention in which the substituents have the meaning given under the general formula I can, for example, be prepared by reacting the carboxylic acid derivatives of the general formula IV in which the substituents have the meaning given with compounds of the general formula V. brings.
In Formel V bedeutet R11 Halogen oder R12-S02-, wobei R12 C!-C4-Alkyl, Cι-C4-Halogenalkyl oder Phenyl sein kann. Ferner ist mindestens eines der Ringglieder X oder Y oder Z Stickstoff. Die Reaktion findet bevorzugt in einem inerten Losungs- oder Verdünnungsmittel unter Zusatz einer geeigneten Base, d.h. einer Base, die eine Deprotonierung des Zwischenproduktes IV bewirkt, in einem Temperaturbereich von Raumtemperatur bis zum Siedepunkt des Losungsmittels statt.In formula V, R 11 is halogen or R 12 -S0 2 -, where R 12 is C ! -C 4 alkyl, -C-C 4 haloalkyl or phenyl can be. Furthermore, at least one of the ring members X or Y or Z is nitrogen. The reaction preferably takes place in an inert solvent or diluent with the addition of a suitable base, ie a base which brings about a deprotonation of the intermediate IV, in a temperature range from room temperature to the boiling point of the solvent.
Verbindungen des Typs I mit R1 = COOH lassen sich weiterhin direkt erhalten, wenn man das Zwischenprodukt IV, in dem R1 COOH bedeutet, mit zwei Equivalenten einer geeigneten Base deprotoniert und mit Verbindungen der allgemeinen Formel V zur Reaktion bringt. Auch hier findet die Reaktion in einem inerten Losungsmittel und in einem Temperaturbereich von Raumtemperatur bis zum Siedepunkt des Losungsmittels statt.Compounds of type I with R 1 = COOH can furthermore be obtained directly if the intermediate IV, in which R 1 is COOH, is deprotonated with two equivalents of a suitable base and reacted with compounds of the general formula V. Here too, the reaction takes place in an inert solvent and in a temperature range from room temperature to the boiling point of the solvent.
Beispiele für solche Losungsmittel beziehungsweise Verdünnungsmittel sind aliphatische, alicyclische und aromatische Kohlenwasserstoffe, die jeweils gegebenenfalls chloriert sein können, wie zum Beispiel Hexan, Cyclohexan, Petrolether, Ligroin, Benzol, Toluol, Xylol, Methylenchlorid, Chloroform, Kohlenstofftetra- chlorid, Ethylchlorid und Trichlorethylen, Ether, wie zum Beispiel Diisopropylether, Dibutylether, Methyl - tert. -Butylether, Propylenoxid, Dioxan und Tetrahydrofuran, Nitrile, wie zum Beispiel Acetonitril und Propionitril, Säureamide, wie zum Beispiel Dimethylformamid, Dimethylacetamid und N-Methylpyrrolidon, Sulfoxide und Sulfone, wie zum Beispiel Dimethylsulfoxid und Sulfolan.Examples of such solvents or diluents are aliphatic, alicyclic and aromatic hydrocarbons, each of which may optionally be chlorinated, such as, for example, hexane, cyclohexane, petroleum ether, ligroin, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and trichlorethylene, Ethers, such as diisopropyl ether, dibutyl ether, methyl tert. -Butyl ether, propylene oxide, dioxane and tetrahydrofuran, nitriles, such as, for example, acetonitrile and propionitrile, acid amides, such as, for example, dimethylformamide, dimethylacetamide and N-methylpyrrolidone, sulfoxides and sulfones, such as, for example, dimethyl sulfoxide and sulfolane.
Verbindungen der Formel V sind bekannt, teilweise käuflich oder können nach allgemein bekannter Weise hergestellt werden.Compounds of the formula V are known, some are commercially available or can be prepared in a generally known manner.
Als Base kann ein Alkali- oder Erdalkalimetallhydrid wie Natriumhydrid, Kaliumhydrid oder Calciumhydrid, ein Carbonat wie Alkali - metallcarbonat, z.B. Natrium- oder Kaliumcarbonat, ein Alkalioder Erdalkalimetallhydroxid wie Natrium- oder Kaliumhydroxid, eine metallorganische Verbindung wie Butyllithium oder einAs a base, an alkali or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as alkali metal carbonate, e.g. Sodium or potassium carbonate, an alkali or alkaline earth metal hydroxide such as sodium or potassium hydroxide, an organometallic compound such as butyllithium or a
Alkaliamid wie Lithiumdiisopropylarnid oder Lithiumamid dienen. Verbindungen der Formel I können auch dadurch hergestellt werden, daß man von den entsprechenden Carbonsäuren, d. h. Verbindungen der Formel I, in denen R1 COOH bedeutet, ausgeht und diese zunächst auf übliche Weise in eine aktivierte Form wie ein Säure - halogenid, ein Anhydrid oder Imidazolid überführt und dieses dann mit einer entsprechenden HydroxylVerbindung HÖR7 umsetzt. Diese Umsetzung läßt sich in den üblichen Lösungsmitteln durchführen und erfordert oft die Zugabe einer Base, wobei die oben genannten in Betracht kommen. Diese beiden Schritte lassen sich beispiels- weise auch dadurch vereinfachen, daß man die Carbonsäure inAlkali amide such as lithium diisopropyl amide or lithium amide serve. Compounds of the formula I can also be prepared by starting from the corresponding carboxylic acids, ie compounds of the formula I in which R 1 is COOH, and converting them first in the usual manner into an activated form such as an acid halide, an anhydride or Imidazolid transferred and then reacted with a corresponding hydroxyl compound HÖR 7 . This reaction can be carried out in the customary solvents and often requires the addition of a base, the above-mentioned being possible. These two steps can also be simplified, for example, by adding the carboxylic acid to
Gegenwart eines wasserabspaltenden Mittels wie eines Carbodiimids auf die HydroxylVerbindung einwirken läßt.Presence of a water releasing agent such as a carbodiimide on the hydroxyl compound.
Außerdem können Verbindungen der Formel I auch dadurch herge- stellt werden, daß man von den Salzen der entsprechenden Carbonsäuren ausgeht, d. h. von Verbindungen der Formel I, in denen R1 für eine Gruppe COR und R für OM stehen, wobei M ein Alkali - metallkation oder das Equivalent eines Erdalkalimetallkations sein kann. Diese Salze lassen sich mit vielen Verbindungen der Formel R-A zur Reaktion bringen, wobei A eine übliche nucleofuge Abgangsgruppe bedeutet, beispielsweise Halogen wie Chlor, Brom, Iod oder gegebenenfalls durch Halogen, Alkyl oder Halogenalkyl substituiertes Aryl - oder Alkylsulfonyl wie z.B. Toluolsulfonyl und Methylsulfonyl oder eine andere äquivalente Abgangsgruppe. Verbindungen der Formel R-A mit einem reaktionsfähigen Substi- tuenten A sind bekannt oder mit dem allgemeinen Fachwissen leicht zu erhalten. Diese Umsetzung läßt sich in den üblichen Losungsmitteln durchführen und wird vorteilhaft unter Zugabe einer Base, wobei die oben genannten in Betracht kommen, vorgenommen.In addition, compounds of the formula I can also be prepared by starting from the salts of the corresponding carboxylic acids, ie from compounds of the formula I in which R 1 is a group COR and R is OM, where M is an alkali metal cation or can be the equivalent of an alkaline earth metal cation. These salts can be reacted with many compounds of the formula RA, where A is a conventional nucleofugic leaving group, for example halogen such as chlorine, bromine, iodine or aryl or alkylsulfonyl optionally substituted by halogen, alkyl or haloalkyl, such as toluenesulfonyl and methylsulfonyl or one other equivalent leaving group. Compounds of the formula RA with a reactive substituent A are known or are easy to obtain with the general specialist knowledge. This reaction can be carried out in the customary solvents and is advantageously carried out with the addition of a base, the above-mentioned being suitable.
In einigen Fällen ist zur Herstellung der erfindungsgemäßen Verbindungen I die Anwendung allgemein bekannter Schutzgruppen- techniken erforderlich. Soll beispielsweise R6 = 4-Hydroxyphenyl bedeuten, so kann die Hydroxygruppe zunächst als Benzylether ge- schützt sein, der dann auf einer geeigneten Stufe in der Reaktionssequenz gespalten wird.In some cases the preparation of the compounds I according to the invention requires the use of generally known protecting group techniques. For example, if R 6 is 4-hydroxyphenyl, the hydroxy group can first be protected as benzyl ether, which is then cleaved at a suitable stage in the reaction sequence.
Verbindungen der Formel I in denen R1 Tetrazol bedeutet, können wie in WO 96/11914 beschrieben, hergestellt werden.Compounds of the formula I in which R 1 is tetrazole can be prepared as described in WO 96/11914.
Im Hinblick auf die biologische Wirkung sind Carbonsäurederivate der allgemeinen Formel I - sowohl als reine Enantiomere bzw. reine Diastereomere oder als deren Mischung - bevorzugt, in denen die Substituenten folgende Bedeutung haben:With regard to the biological action, carboxylic acid derivatives of the general formula I - both as pure enantiomers or pure diastereomers or as a mixture thereof - are preferred, in which the substituents have the following meaning:
R2 Wasserstoff, Hydroxy, Halogen, N(Cχ-C4 -Alkyl) 2, C!-C4 -Alkyl, Cι-C -Alkoxy, Cι-C4 -Alkylthio, Ci -C4-Halogenalkyl , C1-C4 -Halogenalkoxy, oder CR2 ist mit CR10 wie unten angegeben zu einem 5- oder 6-gliedrigen Ring verknüpft;R 2 is hydrogen, hydroxy, halogen, N (Cχ-C 4 alkyl) 2, C ! -C 4 -alkyl, C -alkoxy, C 4 alkylthio, Ci-C4 haloalkyl, C 1 -C 4 haloalkoxy, or CR 2 is linked to CR 10 to a 5- or 6-membered ring as indicated below;
X Stickstoff oder Methin;X nitrogen or methine;
Y Stickstoff oder Methin;Y nitrogen or methine;
Z Stickstoff oder CR10, worin R10 Wasserstoff oder C1..4 -Alkyl bedeutet oder CR10 zusammen mit CR2 oder CR3 einen 5- oder 6-gliedrigen Alkylen- oder Alkenylenring bildet, der durch eine oder zwei Methylgruppen substituiert sein kann und worin jeweils eine Methylengruppe durch Sauerstoff oder Schwefel ersetzt sein kann wie -CH2-CH2-0-, -CH2-CH2-CH -0- , -CH=CH-0-, -CH=CH-CH20-, -CH (CH3 ) -CH (CH3 ) -0- , -CH=C (CH3) -0- , -C(CH3)=C(CH3) -0-, oder -C (CH3) =C (CH3) -S;Z is nitrogen or CR 10 , in which R 10 is hydrogen or C1 .. 4 alkyl or CR 10 together with CR 2 or CR 3 forms a 5- or 6-membered alkylene or alkenylene ring which can be substituted by one or two methyl groups and in which in each case one methylene group can be replaced by oxygen or sulfur, such as -CH 2 -CH 2 -0-, -CH 2 -CH 2 -CH -0-, -CH = CH-0-, -CH = CH-CH 2 0-, -CH (CH 3 ) -CH (CH 3 ) -0-, -CH = C (CH 3 ) -0-, -C (CH 3 ) = C (CH 3 ) -0-, or -C (CH 3 ) = C (CH 3 ) -S;
Mindestens eines der Ringglieder X, Y oder z ist Stickstoff.At least one of the ring members X, Y or z is nitrogen.
R3 Wasserstoff, Hydroxy, Halogen, N (Cχ-C4 -Alkyl ) 2, Cι-C4-Alkyl, Cι-C -Alkoxy, Cι-C -Alkylthio, Ci -C4 -Halogenalkyl ,R 3 is hydrogen, hydroxy, halogen, N (Cχ-C 4 -alkyl) 2 , -C-C 4 -alkyl, Cι-C -alkoxy, Cι-C -alkylthio, Ci -C 4 -haloalkyl,
C1-C4- Halogenalkoxy, oder CR3 ist mit CR10 wie oben angegeben zu einem 5- oder 6-gliedrigen Ring verknüpft;C 1 -C 4 - haloalkoxy, or CR 3 is linked to CR 10 to give a 5- or 6-membered ring;
R4 und R5 (die gleich oder verschieden sein können) :R 4 and R 5 (which may be the same or different):
Phenyl oder Naphthyl, die durch einen oder mehrere der folgenden Reste substituiert sein können: Halogen, Nitro, Cyano, Hydroxy, Mercapto, Amino, C1-C4 -Alkyl, Ci C4 -Halogenalkyl , Carboxy, Cι-C4-Alkoxy, Cι-C -Halogenalkoxy, Phenoxy, C1-C4 -Alkylthio,- NH (C1-C4 -Alkyl) oder N (C: -C4-Alkyl) 2 oderPhenyl or naphthyl, which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, mercapto, amino, C 1 -C 4 alkyl, Ci C 4 haloalkyl, carboxy, C 1 -C 4 alkoxy , -C -C haloalkoxy, phenoxy, C 1 -C 4 alkylthio, - NH (C 1 -C 4 alkyl) or N (C : -C 4 alkyl) 2 or
Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach durch Halogen, Nitro, Cyano, C1.-C4 -Alkyl, Cι.-C4-Halogenalkyl, C1-C4-Alkoxy, C1.-C4 -Halogenalkoxy oder Cχ-C4 -Alkylthio; oderPhenyl, which can be substituted one or more times, for example one to three times by halogen, nitro, cyano, C1 . -C 4 alkyl, -C.-C 4 haloalkyl, C 1 -C 4 alkoxy, C1.-C 4 haloalkoxy or Cχ-C 4 alkylthio; or
Phenyl oder Naphthyl, die orthoständig über eine direkte Bindung, eine Methylen-, Ethylen- oder Ethenylengruppe, ein Sauerstoff- oder Schwefelatom oder eine S02-, NH- oder N-Alkyl -Gruppe miteinander verbunden sindPhenyl or naphthyl, which are ortho-linked via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an S0 2 , NH or N-alkyl group
C3 -Cβ- Cycloalkyl;C 3 -C 6 cycloalkyl;
R6 C3-C8-Cycloalkyl , wobei diese Reste jeweils ein- oder mehrfach substituiert sein können durch: Halogen, Hydroxy, Mercapto, Carboxy, Nitro, Cyano, Cχ-C4 -Alkoxy, Cι-C -Alkyl,R 6 C 3 -C 8 cycloalkyl, where these radicals can each be mono- or polysubstituted by: halogen, hydroxyl, mercapto, carboxy, nitro, cyano, Cχ-C 4 alkoxy, Cι-C alkyl,
C2-C -Alkenyl, C2-C -Alkinyl, C3-C6-Alkenyloxy, C3-C6-Alkinyl - oxy, Cι-C4-Alkylthio, Cι-C4 -Halogenalkoxy, Cι-C4-Alkylcarbonyl, C1-C4-Alkoxy-carbonyl, NH (Ci -C4 -Alkyl) , N (Ci -C4 -Alkyl) 2 oder Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach durch Halogen, Nitro, Cyano, C1-C4 -Alkyl, Cχ-C4-Halogenalkyl , Cι-C4-Alkoxy, C1.-C4-Halogenalkoxy oder C1-C4 -Alkylthio;C 2 -C alkenyl, C 2 -C alkynyl, C 3 -C 6 alkenyloxy, C 3 -C 6 -alkynyl - oxy, Cι-C 4 alkylthio, Cι-C4-haloalkoxy, Cι-C 4 -Alkylcarbonyl, C 1 -C 4 alkoxycarbonyl, NH (Ci -C 4 alkyl), N (Ci -C 4 alkyl) 2 or phenyl, which can be substituted one or more times, for example one to three times by halogen, Nitro, cyano, C 1 -C 4 alkyl, Cχ-C 4 haloalkyl, Cι-C 4 alkoxy, C1.-C 4 haloalkoxy or C 1 -C 4 alkylthio;
Phenyl oder Naphthyl, die jeweils durch einen oder mehrere der folgenden Reste substituiert sein können: Halogen, R15, Nitro, Mercapto, Carboxy, Cyano, Hydroxy, Amino, Cχ-C4 -Alkyl, C2-C4 -Alkenyl, C2 -C4 -Alkinyl, C3-C6-Alkenyloxy, Cι-C4 -Halogenalkyl, C3-C6-Alkinyloxy, C1-C -Alkylcarbonyl , C1.-C4 -Alkoxy- carbonyl, Cι-C4-Alkoxy, C1-C4-Halogenalkoxy, Phenoxy, Cι-C4-Alkylthio, NH (C1-C4 -Alkyl) , N (Ci -C4 -Alkyl) 2 , Dioxo- methylen, Dioxoethylen oder Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach durch Halogen, Nitro, Cyano, C1-C4 -Alkyl, C1.-C4 -Halogenalkyl, Cι_-C4 -Alkoxy, C1-C4 -Halogenalkoxy oder Cι-C4 -Alkylthio;Phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, R 15 , nitro, mercapto, carboxy, cyano, hydroxy, amino, Cχ-C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 alkenyloxy, -C-C 4 haloalkyl, C 3 -C 6 alkynyloxy, C 1 -C alkylcarbonyl, C1 . -C 4 alkoxy carbonyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, phenoxy, C 4 -C 4 alkylthio, NH (C 1 -C 4 alkyl), N (Ci -C 4 - Alkyl) 2 , dioxomethylene, dioxoethylene or phenyl, which can be substituted one or more times, for example one to three times by halogen, nitro, cyano, C 1 -C 4 alkyl, C1 . -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy or C 4 C 4 alkylthio;
ein fünf- oder sechsgliedriger Heteroaromat, enthaltend ein bis drei Stickstoffato e und/oder ein Schwefel- oder Sauer - Stoffatom, welcher ein bis vier Halogenatome und/oder einen bis zwei der folgenden Reste tragen kann: C1.-C4 -Alkyl, Ci -C4 -Halogenalkyl, C1-C4 -Alkoxy, Ci -C4 -Halogenalkoxy, C1-C4 -Alkylthio, Phenyl, Phenoxy oder Phenylcarbonyl , wobei die Phenylreste ihrerseits ein bis fünf Halogenatome und/oder einen bis drei der folgenden Reste tragen können: Cι-C4-Alkyl, C1-C -Halogenalkyl , Ci- j-Alkoxy, C1-C4 -Halogenalkoxy und/oder C1.-C4 -Alkylthio;a five- or six-membered heteroaromatic containing one to three nitrogen atoms and / or a sulfur or acid atom which can carry one to four halogen atoms and / or one or two of the following radicals: C1 . -C 4 alkyl, Ci -C 4 haloalkyl, C 1 -C 4 alkoxy, Ci -C 4 haloalkoxy, C 1 -C 4 alkylthio, phenyl, phenoxy or phenylcarbonyl, the phenyl radicals in turn having one to five halogen atoms and / or can carry one to three of the following radicals: -CC 4 alkyl, C 1 -C haloalkyl, Ci-alkoxy, C 1 -C 4 haloalkoxy and / or C1.-C 4 alkylthio;
Ri5 Methyl, Ethyl, Methoxy oder Ethoxy, die einen der folgenden Reste tragen: Hydroxy, Carboxy, Amino, NH (Cι-C4.Alkyl ) , N(Cι_C4-Alkyl)2, Carboxamid oder CON (Cι_C .Alkyl) 2; R i5 methyl, ethyl, methoxy or ethoxy, which carry one of the following radicals: hydroxy, carboxy, amino, NH (-C 4 -alkyl), N (C 4 -C 4 -alkyl) 2 , carboxamide or CON (Cι_C. Alkyl) 2 ;
W Schwefel oder Sauerstoff;W sulfur or oxygen;
Q C2-C4 -Alkyl, C3-C4 -Alkenyl, C3 -C4-Alkinyl , -S-CH2-CH2-,QC 2 -C 4 alkyl, C 3 -C 4 alkenyl, C 3 -C 4 alkynyl, -S-CH 2 -CH 2 -,
-0-CH2-CH2-, wobei diese Reste jeweils ein- oder mehrfach substituiert sein können durch: Halogen, Hydroxy, Mercapto, Carboxy, Nitro, Cyano, Cι-C4-Alkyl, Cι-C4-Alkoxy, Ci -C4 -Alkyl - thio, C1-C4- Halogenalkoxy, Ci -C -Alkoxycarbonyl ,-0-CH 2 -CH 2 -, where these radicals can each be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, Ci -C 4 alkyl thio, C 1 -C 4 haloalkoxy, Ci -C alkoxycarbonyl,
NH (C1-C4 -Alkyl ) , N(Cι-C4 -Alkyl) 2 oder Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach durch Halogen, Nitro, Cyano, C1-C -Alkyl, C1-C4-Halogenalkyl ,NH (C1-C 4 -alkyl), N (-C-C 4 -alkyl) 2 or phenyl, which can be substituted one or more times, for example one to three times by halogen, nitro, cyano, C 1 -C alkyl , C 1 -C 4 haloalkyl,
Cι-C4-Alkoxy, Cj.-C -Halogenalkoxy oder Cι-C4-Alkylthio oder Q bildet zusammen mit R6 folgende Ringsysteme: In- dan-2-yl, Indan-3-yl, 1 , 2 , 3, 4-Tetrahydronaphth-2-yl, 1, 2 , 3, 4-Tetrahydronaphth-3-yl , wobei die Phenylringe jeweils substituiert sein können durch: Halogen, Hydroxy, Mercapto, Carboxy, Nitro, Cyano, C1-C4_Alkoxy, C1.C4-Alkyl, C2.C -Alkenyl , C2-C4-Alkinyl, C3-C6-Alkenyloxy, C3-C6-Alkinyloxy, Cχ-C4-Alkyl- thio, Cι-C4-Halogenalkoxy, Cι-C .Alkylcarbonyl, Cι-C4-Alkoxycar- bonyl, Amino, NH(Cι-C -Alkyl) , N(Cι_C4-Alkyl) 2 oder Phenyl.C 1 -C 4 -alkoxy, C 1 -C -haloalkoxy or C 1 -C 4 -alkylthio or Q together with R 6 forms the following ring systems: indan-2-yl, indan-3-yl, 1, 2, 3, 4-tetrahydronaphth-2-yl, 1, 2, 3, 4-tetrahydronaphth-3- yl, where the phenyl rings can each be substituted by: halogen, hydroxy, mercapto, carboxy, nitro, cyano, C 1 -C 4 _alkoxy, C 1 .C 4 alkyl, C 2 .C alkenyl, C 2 -C 4 -Alkynyl, C 3 -C 6 -alkenyloxy, C 3 -C 6 -alkynyloxy, Cχ-C 4 -alkyl thio, -C-C 4 -haloalkoxy, Cι-C .alkylcarbonyl, Cι-C 4 -alkoxycarbonyl, Amino, NH (-CC alkyl), N (-C 4 alkyl) 2 or phenyl.
Besonders bevorzugt sind Verbindungen der Formel I - sowohl als reine Enantiomere bzw. reine Diastereomere oder als deren Mischung - in denen die Substituenten folgende Bedeutung haben:Compounds of the formula I are particularly preferred - both as pure enantiomers or pure diastereomers or as a mixture thereof - in which the substituents have the following meaning:
R2 Trif luormethyl, Cι-C -Alkyl, Cι-C4 -Alkoxy , Cι.-C4-Alkylthio, oder CR2 ist mit CR10 wie unten angegeben zu einem 5- oder 6-gliedrigen Ring verknüpft;R 2 trif luormethyl, -C -C alkyl, -C -C 4 alkoxy, -C . -C 4 alkylthio, or CR 2 is linked to CR 10 to a 5- or 6-membered ring as indicated below;
X Stickstoff oder Methin;X nitrogen or methine;
Y Stickstoff oder Methin;Y nitrogen or methine;
Z Stickstoff oder CR10, worin R10 Wasserstoff oder Cχ-4-Alkyl bedeuten oder CR10 zusammen mit CR2 oder CR3 einen 5- oder 6-gliedrigen Alkylen- oder Alkenylenring bildet, der durch eine oder zwei Methylgruppen substituiert sein kann und worin jeweils eine Methylengruppe durch Sauerstoff oder Schwefel ersetzt sein kann wie -CH2-CH2-0-, -CH2-CH2-CH2-0- , -CH=CH-0-, -CH=CH-CH20-, -CH(CH3) -CH(CH3) -0- , -CH=C (CH3 ) -0- , -C(CH3)=C(CH3) -0-, oder -C (CH3) =C (CH3) -S;Z is nitrogen or CR 10 , in which R 10 is hydrogen or Cχ- 4 alkyl or CR 10 together with CR 2 or CR 3 forms a 5- or 6-membered alkylene or alkenylene ring which can be substituted by one or two methyl groups and where in each case one methylene group can be replaced by oxygen or sulfur such as -CH 2 -CH 2 -0-, -CH 2 -CH 2 -CH 2 -0-, -CH = CH-0-, -CH = CH-CH 2 0-, -CH (CH 3 ) -CH (CH 3 ) -0-, -CH = C (CH 3 ) -0-, -C (CH 3 ) = C (CH 3 ) -0-, or -C (CH 3 ) = C (CH 3 ) -S;
Mindestens eines der Ringglieder X, Y oder Z ist StickstoffAt least one of the ring members X, Y or Z is nitrogen
R3 Trif luormethyl, Cι_-C4-Alkyl, C1-C4-Alkoxy, Cι-C -Alkylthio, oder CR3 ist mit CR10 wie oben angegeben zu einem 5- oder 6-gliedrigen Ring verknüpft;R 3 trifluoromethyl, Cι_-C 4 alkyl, C 1 -C 4 -alkoxy, C alkylthio, or CR 3 is linked with CR 10 as indicated above to form a 5- or 6-membered ring;
R4 und R5 (die gleich oder verschieden sein können) :R 4 and R 5 (which may be the same or different):
Phenyl oder Naphthyl, die durch einen oder mehrere der folgenden Reste substituiert sein können: Halogen, Nitro,Phenyl or naphthyl, which can be substituted by one or more of the following radicals: halogen, nitro,
Cyano, Hydroxy, Mercapto, Amino, Cι-C4-Alkyl, Cι-C4 -Halogenalkyl, Cι-C4-Alkoxy, Cι-C4- Halogenalkoxy, Phenoxy, Cι_-C4-Alkyl thio, NH(Cι-C4 -Alkyl) oder N (C -C.3 -Alkyl) 2 oder Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bisCyano, hydroxy, mercapto, amino, Cι-C 4 -alkyl, C 4 haloalkyl, Cι-C 4 -alkoxy, C 4 - haloalkoxy, phenoxy, Cι_-C4 alkyl thio, NH (Cι- C 4 alkyl) or N (C -C. 3 alkyl) 2 or phenyl, which can be substituted one or more times, for example one to
dreifach durch Halogen, Nitro, Cyano, Cι-C4-Alkyl, Ci -C4- Halogenalkyl , Ci -C4 -Alkoxy, Cι-C -Halogenalkoxy oder Cι-C -Alkylthio; odertriple through halogen, nitro, cyano, C 1 -C 4 alkyl, Ci -C 4 - haloalkyl, Ci -C 4 alkoxy, -C -C haloalkoxy or -C -C alkylthio; or
Phenyl oder Naphthyl, die orthoständig über eine direkte Bin- düng, eine Methylen-, Ethylen- oder Ethenylengruppe, ein Sauerstoff- oder Schwefelatom oder eine S02 - , NH- oder N-Alkyl- Gruppe miteinander verbunden sindPhenyl or naphthyl, which are linked to one another via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO 2 , NH or N-alkyl group
C5-C7-Cycloalkyl;C 5 -C 7 cycloalkyl;
R6 C5 -C7 -Cycloalkyl , wobei diese Reste jeweils ein- oder mehrfach substituiert sein können durch: Cι-C4-Alkoxy,R 6 C 5 -C 7 cycloalkyl, where these radicals can each be mono- or polysubstituted by: -CC 4 alkoxy,
C!-C4-Alkyl, C1-C4-Alkylthio, Halogen, Hydroxy, Carboxy, Cyano, Trifluormethyl, Acetyl, oder Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach durch Halogen, Cyano, Cι-C4-Alkyl, Cι_-C4- Halogenalkyl , Cι-C4-Alkoxy, CJ-C4- Halogenalkoxy oder C!-C4 -Alkylthio;C ! -C 4 alkyl, C 1 -C 4 alkylthio, halogen, hydroxy, carboxy, cyano, trifluoromethyl, acetyl or phenyl, which can be substituted one or more times, for example one to three times by halogen, cyano, Cι- C 4 -alkyl, Cι_-C 4 - haloalkyl, Cι-C 4 -alkoxy, C J -C 4 - haloalkoxy or C ! -C 4 alkylthio;
Phenyl oder Naphthyl, die jeweils durch einen oder mehrere der folgenden Reste substituiert sein können: Halogen, R15, Nitro, Mercapto, Carboxy, Cyano, Hydroxy, Amino, C1-C -Alkyl, C1-C4-Halogenalkyl, Acetyl, Cι-C -Alkoxycarbonyl , Cι-C4 -Alkoxy , Cι-C4-Halogenalkoxy, Phenoxy, Cτ.-C4-Alkylthio, NH (C1.-C4 -Alkyl) , N (C3.-C4 -Alkyl) 2, Dioxomethylen, Dioxoethylen oder Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach durch Halogen, Nitro, Cyano, C1-C4 -Alkyl, C1-C4 -Halogenalkyl, Cι-C4-Alkoxy, Cι-C -Halogenalkoxy oder C1-C4 -Alkylthio;Phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, R 15 , nitro, mercapto, carboxy, cyano, hydroxy, amino, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, acetyl , Cι-C alkoxycarbonyl, Cι-C 4 -alkoxy, C 4 haloalkoxy, phenoxy, Cτ. -C 4 alkylthio, NH (C1 . -C 4 alkyl), N (C 3. -C 4 alkyl) 2 , dioxomethylene, dioxoethylene or phenyl, which can be mono- or polysubstituted, for example one to three times by halogen, nitro, cyano, C1-C 4 alkyl, C 1 -C 4 haloalkyl, Cι-C 4 -alkoxy, C haloalkoxy or C 1 -C 4 -alkylthio;
ein fünf- oder sechsgliedriger Heteroaromat, enthaltend ein bis drei Stickstoffatome und/oder ein Schwefel- oder Sauer - stoffatom, welcher ein bis vier Halogenatome und/oder einen bis zwei der folgenden Reste tragen kann: ^ - C*, -Alkyl, Cι-C4- Halogenalkyl, Cι-C4-Alkoxy, Trifluormethoxy, Cι-C4-Alkyl- thio, Phenyl oder Phenoxy, wobei die Phenylreste ihrerseits ein bis fünf Halogenatome und/oder einen bis drei der folgenden Reste tragen können: Cι-C4-Alkyl, Cι-C4-Halogen- alkyl, Ci-Cj -Alkoxy, Cι.-C4 -Halogenalkoxy und/oder Cι-C4-Alkyl- thio;a five- or six-membered heteroaromatic containing one to three nitrogen atoms and / or a sulfur or oxygen atom which can carry one to four halogen atoms and / or one or two of the following radicals: ^ - C *, -alkyl, Cι- C 4 - haloalkyl, C 1 -C 4 alkoxy, trifluoromethoxy, C 1 -C 4 alkyl thio, phenyl or phenoxy, where the phenyl radicals in turn can carry one to five halogen atoms and / or one to three of the following radicals: Cι-C 4 -alkyl, halo-C 4 alkyl, Ci-Cj alkoxy, Cι. -C 4 -haloalkoxy and / or -CC 4 alkyl thio;
R15 Methoxy oder Ethoxy, die einen der folgenden Reste tragen:R 15 methoxy or ethoxy which have one of the following radicals:
Hydroxy, Carboxy, Amino, NH(Cι-C4-Alkyl) , N(Cι-C4-Alkyl) 2, Car- boxamid oder CON(Cι-C4.Alkyl) 2;Hydroxy, carboxy, amino, NH (-C 4 alkyl), N (-C 4 alkyl) 2 , carboxamide or CON (-C 4 alkyl) 2 ;
W Schwefel oder Sauerstoff; Q ς2-C4 -Alkyl, C3-C4 -Alkenyl, C3 -C4 -Alkinyl , , -S-CH2-CH2-,W sulfur or oxygen; Q ς 2 -C 4 alkyl, C3-C 4 alkenyl, C 3 -C 4 alkynyl,, -S-CH 2 -CH 2 -,
-0-CH2-CH2-, wobei diese Reste jeweils ein- oder mehrfach substituiert sein können durch: Halogen, Hydroxy, Mercapto, Carboxy, C1-C4- Alkyl, Cι-C4-Alkoxy, Cι-C4-Alkylthio, oder Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach durch Halogen, Nitro, Cyano, Cχ-C4 -Alkyl, Cx -C4- Halogenalkyl , C1-C4 -Alkoxy, Cχ-C - Halogenalkoxy oder C!-C4-Alkylthio-0-CH 2 -CH 2 -, where these radicals in each case may be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, C 1 -C 4 - alkyl, Cι-C 4 -alkoxy, C 4 -Alkylthio, or phenyl, which can be substituted one or more times, for example one to three times by halogen, nitro, cyano, Cχ-C 4 alkyl, C x -C 4 - haloalkyl, C 1 -C 4 alkoxy, Cχ-C - haloalkoxy or C ! -C 4 alkylthio
oder Q bildet zusammen mit R6 folgende Ringsysteme: In- dan-2-yl, Indan-3-yl, 1, 2 , 3, 4-Tetrahydronaphth-2-yl, 1, 2 , 3, 4-Tetrahydronaphth-3-yl, wobei die Phenylringe jeweils substituiert sein können durch: Halogen, Hydroxy, Mercapto, Carboxy, Cyano, C1.C .Alkoxy, Cι-C4-Alkyl, C2-C4.Alkenyl, C2-C4-Alkinyl, C3-C6-Alkenyloxy, C3-C6-Alkinyloxy, Cι.-C4-Alkyl - thio, Cι-C4-Halogenalkoxy, Cι-C4-Alkoxycarbonyl , NH(Cι-C4-Al- kyl), N(Cι-C4-Alkyl)2 oder Phenyl.or Q together with R 6 forms the following ring systems: indan-2-yl, indan-3-yl, 1, 2, 3, 4-tetrahydronaphth-2-yl, 1, 2, 3, 4-tetrahydronaphth-3- yl, where the phenyl rings can each be substituted by: halogen, hydroxy, mercapto, carboxy, cyano, C 1 .C. alkoxy, C 1 -C 4 alkyl, C 2 -C 4. alkenyl, C 2 -C 4 alkynyl , C 3 -C 6 alkenyloxy, C 3 -C 6 alkynyloxy, Cι . -C 4 alkyl - thio, -C-C 4 haloalkoxy, -C-C 4 -alkoxycarbonyl, NH (-C-C 4 -alkyl), N (-C-C 4 alkyl) 2 or phenyl.
Die Verbindungen der vorliegenden Erfindung bieten ein neues therapeutisches Potential für die Behandlung von Hypertonie, pul - monalem Hochdruck, Myokardinfarkt, chronischer Herzinsuffizienz, Angina Pectoris, akutem/chronischem Nierenversagen, Niereninsuffizienz, zerebralen Vasospasmen, zerebraler Ischämie, Sub- arachnoidalblutungen, Migräne, Asthma, Atherosklerose, endo- toxischem Schock, Endotoxin- induziertem Organversagen, intravas- kulärer Koagulation, Restenose nach Angioplastie, benigne Pros- tata-Hyperplasie, ischämisches und durch Intoxikation verursachtes Nierenversagen bzw. Hypertonie, Metastasierung und Wachstum mesenchymaler Tumoren, Kontrastmittel- induziertes Nieren - versagen, Pankreatitis, gastrointestinale Ulcera.The compounds of the present invention offer new therapeutic potential for the treatment of hypertension, pulmonary hypertension, myocardial infarction, chronic heart failure, angina pectoris, acute / chronic renal failure, renal failure, cerebral vasospasm, cerebral ischemia, sub-arachnoid hemorrhage, migraine, asthma, Atherosclerosis, endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty, benign prostate hyperplasia, ischemic and intoxication-related kidney failure or hypertension, metastasis and growth of mesenchymal tumors, contrast agent-induced kidney failure , Pancreatitis, gastrointestinal ulcers.
Die erfindungsgemäßen Verbindungen zeigen überraschenderweise z.T. auch antaganistische Wirkung gegenüber dem Neurokinin- rezeptor .Surprisingly, the compounds according to the invention partly show. also antaganistic effect on the neurokinin receptor.
Insbesondere trifft dies für Verbindungen der Formel I zu, bei denen R1 die BedeutungThis applies in particular to compounds of the formula I in which R 1 has the meaning
.^ 0. ^ 0
•NR13R14 • NR13R14
besitzt.owns.
Ein weiterer Gegenstand der Erfindung sind Kombinationspräparate aus Endothelinrezeptorantagonisten der Formel I und Inhibitoren des Renin- Angiotensin Systems. Inhibitoren des Renin-Angiotensin- Systems sind Reninhemmer, Angiotensin- II -Antagonisten und vor allem Angiotensin-Converting- Enzyme (ACE) -Hemmer.The invention further relates to combination preparations of endothelin receptor antagonists of the formula I and inhibitors of the renin-angiotensin system. Inhibitors of renin angiotensin Systems are renin inhibitors, angiotensin II antagonists and especially angiotensin converting enzyme (ACE) inhibitors.
Ein weiterer Gegenstand der Erfindung sind Kombinationspräparace aus ß-Blockern und den o.g. Endothelinrezeptorantagonisten sowie aus gemischten ACE-Neutrale Endopeptidase (NEP) -Hemmern und den o.g. Endothelinrezeptorantagonisten .Another object of the invention are combination preparation from ß-blockers and the above. Endothelin receptor antagonists and from mixed ACE-neutral endopeptidase (NEP) inhibitors and the above Endothelin receptor antagonists.
Die Kombinationspräparate können in einer einzelnen galenischer. Form oder auch in räumlich getrennten Formen dargereicht werden. Die Verarbreichung kann gleichzeitig oder zeitlich abgestuft vorgenommen werden.The combination preparations can be used in a single galenic. Form or be presented in spatially separate forms. The application can be carried out simultaneously or at different times.
Die Dosierung bei der Kombination kann bis zu der Höchstmenge der jeweiligen Einzeldosis erfolgen. Jedoch ist es auch möglich geringere Dosen als bei der jeweiligen Einzeltherapie einzusetzen.The dosage in the combination can be up to the maximum amount of the respective single dose. However, it is also possible to use lower doses than with the individual therapy.
Diese Kombinationspräparate eigenen sich vor allem zur Behandlung und Verhütung von Hypertension und deren Folgeerkrankungen sowie zur Behandlung von Herzinsuffizienz.These combination products are particularly suitable for the treatment and prevention of hypertension and its complications as well as for the treatment of heart failure.
Die gute Wirkung der Verbindungen läßt sich in folgenden Versuchen zeigen:The good effects of the compounds can be shown in the following experiments:
RezeptorbindungsstudienReceptor binding studies
Für Bindungsstudien wurden klonierte humane ETA- oder ETB- Rezeptor-exprimierende CHO- Zellen eingesetzt.Cloned human ET A or ET B receptor-expressing CHO cells were used for binding studies.
MembranpräparationMembrane preparation
Die ETA- oder ETB-Rezeptor -exprimierenden CHO-Zellen wurden in DMEM NUT MIX Fι2-Medium (Gibco, Nr. 21331-020) mit 10 % fötalem Kälberserum (PAA Laboratories GmbH, Linz, Nr. A15-022), 1 mM Glutamin (Gibco Nr. 25030-024), 100 E/ml Penicillin und 100 μg/ml Strepto ycin (Gibco, Sig a Nr P-0781) vermehrt. Nach 48 Stunder. wurden die Zellen mit PBS gewaschen und mit 0,05 % trypsin- haltiger PBS 5 Minuten bei 37°C inkubiert. Danach wurde mit Medium neutralisiert und die Zellen durch Zentrifugation bei 300 x g gesammelt.The ET A or ET B receptor-expressing CHO cells were in DMEM NUT MIX Fι 2 medium (Gibco, No. 21331-020) with 10% fetal calf serum (PAA Laboratories GmbH, Linz, No. A15-022) , 1 mM glutamine (Gibco No. 25030-024), 100 U / ml penicillin and 100 μg / ml streptoycin (Gibco, Sig a No. P-0781) increased. After 48 hours. the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS for 5 minutes at 37 ° C. The mixture was then neutralized with medium and the cells were collected by centrifugation at 300 × g.
Für die Merrtbranpräparation wurden die Zellen auf eine Konzentration von 108 Zellen/ml Puffer (50 mM Tris-HCL Puffer, pH 7.4) eingestellt und danach durch Ultraschall desintegriert (Branson Sonifier 250, 40-70 Sekunden/constant/output 20). BindungstestsFor the membrane preparation, the cells were adjusted to a concentration of 10 8 cells / ml buffer (50 mM Tris-HCl buffer, pH 7.4) and then disintegrated by ultrasound (Branson Sonifier 250, 40-70 seconds / constant / output 20). Binding tests
Für den ETA- und ETB-Rezeptorbindungstest wurden die Membranen in Inkubationspuffer (50 mM Tris-HCl, pH 7,4 mit 5 mM MnCl2, 40 μg/ml Bacitracin und 0,2 % BSA) in einer Konzentration von 50 μg Protein pro Testansatz suspendiert und bei 25°C mit 25 pM 125J-ETι (ETA-Rezeptortest) oder 25 pM 125J-ET3 (ETB-Rezeptortest) in Anwesenheit und Abwesenheit von Testsubstanz inkubiert. Die unspezifische Bindung wurde mit lO-7 M ETX bestimmt. Nach 30 min wurde der freie und der gebundene Radioligand durch Filtration über GF/B Glasfaserfilter (Whatman, England) an einem Skatron- Zellsammler (Skatron, Lier, Norwegen) getrennt und die Filter mit eiskaltem Tris-HCl -Puffer, pH 7 , 4 mit 0,2 % BSA gewaschen. Die auf den Filtern gesammelte Radioaktivität wurde mit einem Packard 2200 CA Flüssigkeitsszintillationszähler quantifiziert.For the ET A and ET B receptor binding test, the membranes were incubated in incubation buffer (50 mM Tris-HCl, pH 7.4 with 5 mM MnCl 2 , 40 μg / ml bacitracin and 0.2% BSA) in a concentration of 50 μg Protein suspended per test batch and incubated at 25 ° C with 25 pM 125 J-ETι (ET A receptor test) or 25 pM 125 J-ET 3 (ET B receptor test) in the presence and absence of test substance. The non-specific binding was determined with 10 -7 M ET X. After 30 min, the free and bound radioligand were separated by filtration through GF / B glass fiber filters (Whatman, England) on a Skatron cell collector (Skatron, Lier, Norway) and the filters with ice-cold Tris-HCl buffer, pH 7.4 washed with 0.2% BSA. Radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.
Testung der ET-Antagonisten in vivo:Testing the ET antagonists in vivo:
Männliche 250 - 300 g schwere SD-Ratten wurden mit Amobarbital narkotisiert, künstlich beatmet, vagotomisiert und despinali- siert. Die Arteria carotis und Vena jugularis wurden kathete- siert .Male SD rats weighing 250-300 g were anesthetized with amobarbital, artificially ventilated, vagotomized and despinalized. The carotid artery and jugular vein were catheterized.
In Kontrolltieren führt die intravenöse Gabe von 1 μg/kg ET1 zu einem deutlichen Blutdruckanstieg, der über einen längeren Zeitraum anhält.In control animals, intravenous administration of 1 μg / kg ET1 leads to a significant increase in blood pressure that persists over a longer period of time.
Den Testtieren wurde 30 min vor der ET1 Gabe die Testverbindungen i.v. injiziert (1 ml/kg). Zur Bestimmung der ET-antagonistischen Eigenschaften wurden die Blutdruckänderungen in den Testtieren mit denen in den Kontrolltieren verglichen.The test animals were given the test compounds i.v. 30 min before the administration of ET1. injected (1 ml / kg). To determine the ET antagonistic properties, the blood pressure changes in the test animals were compared with those in the control animals.
p.o. - Testung der gemischten ETA- und ETB-Antagonisten:po - testing of mixed ET A and ET B antagonists:
Männliche 250- 350g schwere normotone Ratten (Sprague Dawley, Janvier) werden mit den Testsubstanzen oral vorbehandelt. 80 Minuten später werden die Tiere mit Urethan narkotisiert und die A. carotis (für Blutdruckmessung) sowie die V. jugularis (Applikation von big Endothelin/Endothelin 1) katheterisiert .Male normotonic rats weighing 250-350 g (Sprague Dawley, Janvier) are orally pretreated with the test substances. 80 minutes later, the animals are anesthetized with urethane and the carotid artery (for measuring blood pressure) and the jugular vein (application of big endothelin / endothelin 1) are catheterized.
Nach einer Stabilisierungsphase wird big Endothelin (20 μg/kg, Appl. Vol. 0.5 ml/kg) bzw. ET1 (0.3 μg/kg, Appl. Vol. 0.5 ml/kg) intravenös gegeben. Blutdruck und Herzfrequenz werden kontinuierlich über 30 Minuten registriert. Die deutlichen und langan- haltenden Blutdruckänderungen werden als Fläche unter der Kurve (AUC) berechnet. Zur Bestimmung der antagonistischen Wirkung der Testsubstanzen wird die AUC der Substanzbehandelten Tiere mit der AUC der Kontrolltiere verglichen.After a stabilization phase, big endothelin (20 μg / kg, Appl. Vol. 0.5 ml / kg) or ET1 (0.3 μg / kg, Appl. Vol. 0.5 ml / kg) is given intravenously. Blood pressure and heart rate are continuously recorded over 30 minutes. The significant and long-lasting changes in blood pressure are calculated as the area under the curve (AUC). To determine the antagonistic effect of the test substances, the AUC of the substance-treated animals is compared with the AUC of control animals compared.
Die erfindungsgemäßen Verbindungen können in üblicher Weise oral oder parenteral (subkutan, intravenös, intramuskulär, intraperit- 5 oneal) verabfolgt werden. Die Applikation kann auch mit Dämpfen oder Sprays durch den Nasen-Rachenraum erfolgen.The compounds according to the invention can be administered in the usual way orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally). It can also be applied with vapors or sprays through the nasopharynx.
Die Dosierung hängt vom Alter, Zustand und Gewicht des Patienten sowie von der Applikationsart ab. In der Regel beträgt die 10 tägliche Wirkstoffdosis zwischen etwa 0,5 und 50 mg/kg Körpergewicht bei oraler Gabe und zwischen etwa 0,1 und 10 mg/kg Körpergewicht bei parenteraler Gabe.The dosage depends on the age, condition and weight of the patient and on the type of application. As a rule, the daily dose of active substance is between approximately 0.5 and 50 mg / kg body weight when administered orally and between approximately 0.1 and 10 mg / kg body weight when administered parenterally.
Die neuen Verbindungen können in den gebräuchlichen galenischen 15 Applikationsformen fest oder flüssig angewendet werden, z.B. als Tabletten, Filmtabletten, Kapseln, Pulver, Granulate, Dragees, Suppositorien, Lösungen, Salben, Cremes oder Sprays. Diese werden in üblicher Weise hergestellt. Die Wirkstoffe können dabei mit den üblichen galenischen Hilfsmitteln wie Tablettenbindern, 20 Füllstoffen, Konservierungsmitteln, Tablettensprengmitteln, Fließreguliermitteln, Weichmachern, Netzmitteln, Dispergiermitteln, Emulgatoren, Lösungsmitteln, Retardierungsmitteln, Anti- oxidantien und/oder Treibgasen verarbeitet werden (vgl. H. Sucker et al.: Pharmazeutische Technologie, Thieme -Verlag, Stuttgart, 25 1991) . Die so erhaltenen Applikationsformen enthalten denThe new compounds can be used in the usual galenical 15 application forms solid or liquid, e.g. as tablets, film-coated tablets, capsules, powders, granules, dragees, suppositories, solutions, ointments, creams or sprays. These are manufactured in the usual way. The active substances can be processed with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants (see H. Sucker et al .: Pharmaceutical Technology, Thieme -Verlag, Stuttgart, 25 1991). The application forms thus obtained contain the
Wirkstoff normalerweise in einer Menge von 0,1 bis 90 Gew.-%.Active ingredient usually in an amount of 0.1 to 90 wt .-%.
SynthesebeispieleSynthesis examples
30 Beispiel 1:30 Example 1:
2 -Hydroxy- 3- (2- (3, 4 -dimethoxyphenyl) ethoxy) -3, 3 -diphenylpro- pionsäure ethylester2 -Hydroxy- 3- (2- (3, 4 -dimethoxyphenyl) ethoxy) -3, 3 -diphenylpropionic acid ethyl ester
35 7 g (27,5 mmol) 3, 3 -Diphenyl -2 , 3 -epoxypropionsäuremethylester und 5,5 g (30,2 mmol) 2- (3, 4 -Dimethoxyphenyl) ethanol wurden in 20 ml Dichlormethan gelöst und bei Raumtemperatur 5 Tropfen Bortri- fluorid-Etherat zugegeben. Die Lösung wurde zwei Stunden gerührt. Anschließend wurde das Lösungsmittel abdestilliert und der 0 Rückstand (10,7 g, 89 %) direkt weiter umgesetzt.35 7 g (27.5 mmol) of 3,3-diphenyl -2,3-epoxypropionic acid methyl ester and 5.5 g (30.2 mmol) of 2- (3,4-dimethoxyphenyl) ethanol were dissolved in 20 ml of dichloromethane and at room temperature 5 drops of boron trifluoride etherate are added. The solution was stirred for two hours. The solvent was then distilled off and the residue (10.7 g, 89%) was directly reacted further.
5 Beispiel 2 :5 Example 2:
2 -Hydroxy- 3- (2 - (3, 4 -dimethoxyphenyl) ethoxy) -3,3 -diphenylpropionsaure2 -hydroxy- 3- (2 - (3, 4 -dimethoxyphenyl) ethoxy) -3,3 -diphenylpropionic acid
12 g (27,5 mmol) 2 -Hydroxy- 3 - (2 - (3 , 4 -dimethoxyphenyl) - ethoxy) -3, 3-diphenylpropionsäuremethylester wurden in 110 ml Dioxan gelost und mit 55 ml 1 N NaOH-Losung versetzt. Das Gemisch wurde zwei Stunden bei 80°C gerührt. Zu dem Ansatz wurde Wasser gegeben und die wässrige Phase mit Ether zweimal extrahiert. Die wässrige Phase wurde mit 1 N wasssriger HCl angesäuert, mit Ether extrahiert, die organische Phase über Magnesiumsulfat getrocknet und das Losungsmittel abdestilliert. Der Ruckstand wurde in Ether/n-Hexan umkristallisiert und es konnten 10,2 g (87 %) farb- lose Kristalle isoliert werden.12 g (27.5 mmol) of 2-hydroxy-3 - (2 - (3, 4-dimethoxyphenyl) ethoxy) -3, 3-diphenylpropionic acid methyl ester were dissolved in 110 ml of dioxane and mixed with 55 ml of 1 N NaOH solution. The mixture was stirred at 80 ° C for two hours. Water was added to the mixture and the aqueous phase was extracted twice with ether. The aqueous phase was acidified with 1N aqueous HCl, extracted with ether, the organic phase was dried over magnesium sulfate and the solvent was distilled off. The residue was recrystallized from ether / n-hexane and 10.2 g (87%) of colorless crystals could be isolated.
Smp.: 133-135°CM.p .: 133-135 ° C
Beispiel 3:Example 3:
2- ( -Methoxy- 6 - ethyl-pyrimidin- 2 -yloxy) -3 - (2 - (3,4 -dimethoxyphenyl) ethoxy) -3, 3 -diphenylpropionsaure (1-482)2- (-Methoxy- 6 - ethyl-pyrimidine-2 -yloxy) -3 - (2 - (3,4 -dimethoxyphenyl) ethoxy) -3, 3 -diphenylpropionic acid (1-482)
1 g (2,3 mmol) 2 -Hydroxy-3- (2 - (3 , -dimethoxyphenyl) ethoxy) - 3, 3 -diphenylpropionsaure wurden in 10 ml DMF vorgelegt und 340 mg NaH (50 % Suspension) zugegeben. Nach 15 Minuten Ruhren wurde das Gemisch mit 526 mg 4 -Methoxy-6 -methyl - 2 -methylsulfonylpyrimidm versetzt und drei Stunden bei Raumtemperatur gerührt. Der Ansatz wurde mit Wasser versetzt und das Reaktionsgemisch mit Ether extrahiert. Die wässrige Phase wurde mit 1 N wassriger HCl angesäuert, mit Ether extrahiert und über Magnesiumsulfat getrocknet. Das Losungsmittel wurde abdestilliert, der Ruckstand mittels MPLC gereinigt und nach Umkristallisation in Ether/n-Hexan wurden 655 mg (52 %) farbloses Pulver isoliert.1 g (2.3 mmol) of 2-hydroxy-3- (2 - (3, -dimethoxyphenyl) ethoxy) - 3, 3 -diphenylpropionic acid were placed in 10 ml of DMF and 340 mg of NaH (50% suspension) were added. After stirring for 15 minutes, the mixture was mixed with 526 mg of 4-methoxy-6-methyl-2-methylsulfonylpyrimide and stirred for three hours at room temperature. Water was added to the mixture and the reaction mixture was extracted with ether. The aqueous phase was acidified with 1N aqueous HCl, extracted with ether and dried over magnesium sulfate. The solvent was distilled off, the residue was purified by MPLC and, after recrystallization from ether / n-hexane, 655 mg (52%) of colorless powder were isolated.
iH-NMR (200 MHz): 7.2 ppm (10 H, m) , 6.8 (3 H, m) , 6.2 (1 H, s) , 6.18 (1 H, s), 3.9 (9 H, m) , 3.8 (1 H, m) , 3.7 (1 H, m) , 2.85 (2 H, tr) , 2.2 (3 H, s) .iH-NMR (200 MHz): 7.2 ppm (10 H, m), 6.8 (3 H, m), 6.2 (1 H, s), 6.18 (1 H, s), 3.9 (9 H, m), 3.8 (1 H, m), 3.7 (1 H, m), 2.85 (2 H, tr), 2.2 (3 H, s).
ESI-MS: M+ = 544ESI-MS: M + = 544
Beispiel 4:Example 4:
3 , 3 -Di (4 -ethylphenyl) -2,3 -epoxypropionsäuremethylester3,3-di (4-ethylphenyl) -2,3-epoxypropionic acid methyl ester
Zu einer Suspension von 9.1 g (168 mmol) Natriummethanolat inTo a suspension of 9.1 g (168 mmol) sodium methoxide in
80 ml THF wurden bei -10°C eine Losung aus 15 ml (168 mmol) Chlor- essigsäuremethylester und 20 g (84 mmol) 4 , 4 ' -Diethylbenzophenon in 20 ml THF zugetropft. Das Gemisch wurde auf Raumtemperatur erwärmt und 2 Stunden gerührt. Der Ansatz wurde auf Wasser gegeben und mit Ether extrahiert. Die organische Phase wurde mit Natrium- 5 hydrogencarbonat -Lösung und Citronensäure-Lösung gewaschen, über Magnesiumsulfat getrocknetund das Losungsmittel abdestilliert. Es konnten 15.4 g eines Rohöls isoliert werden, welches direkt weiter eingesetzt wurde.80 ml THF was a solution of 15 ml (168 mmol) chlorine at -10 ° C methyl acetate and 20 g (84 mmol) of 4,4'-diethylbenzophenone in 20 ml of THF were added dropwise. The mixture was warmed to room temperature and stirred for 2 hours. The mixture was poured into water and extracted with ether. The organic phase was washed with sodium bicarbonate solution and citric acid solution, dried over magnesium sulfate and the solvent was distilled off. 15.4 g of a crude oil could be isolated, which was used directly.
10 Beispiel 5:10 Example 5:
2 -Hydroxy- - (2 - (3, 4 -dimethoxyphenyl) ethoxy) -3, 3-di (4 -ethyl -phenyl ) propionsäuremethylester2 -Hydroxy- - (2 - (3, 4 -dimethoxyphenyl) ethoxy) -3, 3-di (4 -ethyl-phenyl) propionic acid methyl ester
15 6 g (19,3 mmol) 3 , 3 -Di (4 -ethylphenyl) - 2 , 3 -epoxypropionsäuremethylester (roh) und 3,52 g (19,3 mmol) 2 - (3 , 4 -Dimethoxyphenyl) ethanol wurden in 20 ml Dichlormethan gelost und bei Raumtemperatur 5 Tropfen Bortrifluorid-Etherat zugegeben. Die Losung wurde 1,5 Stunden gerührt. Anschließend wurde das Losungsmittel15 6 g (19.3 mmol) of 3,3-di (4-ethylphenyl) -2,3-epoxypropionic acid methyl ester (crude) and 3.52 g (19.3 mmol) of 2 - (3,4-dimethoxyphenyl) ethanol were dissolved in 20 ml dichloromethane and 5 drops of boron trifluoride etherate added at room temperature. The solution was stirred for 1.5 hours. Then the solvent
20 abdestilliert und der Ruckstand, ein schwach gelbes 01 (8,66 g, 91 %) , direkt weiter umgesetzt.20 distilled off and the residue, a pale yellow 01 (8.66 g, 91%), directly implemented.
Beispiel 6:Example 6:
25 2 -Hydroxy- - (2- (3, 4 -dimethoxyphenyl) ethoxy) -3, 3-di (4 -ethylphenyl ) propionsäure25 2 -Hydroxy- - (2- (3,4-dimethoxyphenyl) ethoxy) -3,3-di (4-ethylphenyl) propionic acid
9,2 g (19,3 mmol) 2 -Hydroxy-3 - (2 - (3 , 4 -dimethoxyphenyl) - ethoxy) -3 , 3 -di ( -ethylphenyl) propionsäuremethylester wurden in9.2 g (19.3 mmol) of 2-hydroxy-3 - (2 - (3, 4-dimethoxyphenyl) ethoxy) -3, 3-di (-ethylphenyl) propionic acid methyl ester were in
30 26 ml Dioxan gelöst und mit 13 ml 3 N NaOH-Losung versetzt. Das Gemisch wurde drei Stunden bei 60°C gerührt. Zu dem Ansatz wurde Wasser gegeben und die wässrige Phase mit Ether zweimal extrahiert. Die wässrige Phase wurde mit 1 N wasssriger HCl angesäuert, mit Ether extrahiert, die organische Phase über30 26 ml of dioxane dissolved and mixed with 13 ml of 3 N NaOH solution. The mixture was stirred at 60 ° C for three hours. Water was added to the mixture and the aqueous phase was extracted twice with ether. The aqueous phase was acidified with 1 N aqueous HCl, extracted with ether, the organic phase over
35 Magnesiumsulfat getrocknet und das Lösungsmittel abdestilliert. Es wurden 6,5 g (71 %) eines eines gelblichen 01s isoliert, das direkt weiter umgesetzt wurde.35 dried magnesium sulfate and the solvent was distilled off. 6.5 g (71%) of a yellowish oil were isolated, which was directly reacted further.
Beispiel 7:Example 7:
4040
2 - (4 -Methoxy-6 -methyl-pyrimidin-2 -yloxy) -3 - (2- (3,4 -dimethoxyphenyl) ethoxy) -3 , 3 -di (4 -ethylphenyl) propionsäure (1-116)2 - (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3 - (2- (3,4-dimethoxyphenyl) ethoxy) -3, 3-di (4-ethylphenyl) propionic acid (1-116)
1,8 g (3,8 mmol) 2 -Hydroxy- 3 - (2 - (3 , 4 -dimethoxyphenyl) - 5 ethoxy) -3, 3-di (4 -ethylphenyl) ropionsäure wurden in 20 ml DMF vorgelegt und 554 mg NaH (50 % Suspension) zugegeben. Nach 15 Minuten Ruhren wurde das Gemisch mit 855 mg (4.2 mmol) 4 -Methoxy- 6 -methyl -2 -methylsulfonylpyrimidin versetzt und drei Stunden bei Raumtemperatur gerührt. Der Ansatz wurde mit Wasser versetzt und das Reaktionsgemisch mit Ether extrahiert. Die wässrige Phase wurde mit 1 N wässriger HCl angesäuert, mit Ether extrahiert und über Magnesiumsulfat getrocknet. Das Lösungsmittel wurde abdestilliert und nach Umkristallisation in Ether/n-Hexan wurden 540 mg (23 %) farbloses Pulver isoliert.1.8 g (3.8 mmol) of 2-hydroxy-3 - (2 - (3,4-dimethoxyphenyl) -5 ethoxy) -3, 3-di (4-ethylphenyl) ropionic acid were placed in 20 ml of DMF and 554 mg NaH (50% suspension) added. After stirring for 15 minutes, the mixture was treated with 855 mg (4.2 mmol) 4-methoxy-6-methyl -2-methylsulfonylpyrimidine were added and the mixture was stirred at room temperature for three hours. Water was added to the mixture and the reaction mixture was extracted with ether. The aqueous phase was acidified with 1N aqueous HCl, extracted with ether and dried over magnesium sulfate. The solvent was distilled off and, after recrystallization from ether / n-hexane, 540 mg (23%) of colorless powder were isolated.
iH-NMR (200 MHz): 7.0-7.4 ppm (10 H, m) , 6.8 (2 H, d) , 6.2 (1 H, s) , 6.15 (1 H, s) , 3.9 (3 H, s) , 3.8 (3 H, s) , 3.7 (1 H, m) , 3.5 (1 H, m) , 2.9 (2 H, tr) , 2.6 (4 H, m) , 2.3 (3 H, s), 1.2 (6 H, m) . i H-NMR (200 MHz): 7.0-7.4 ppm (10 H, m), 6.8 (2 H, d), 6.2 (1 H, s), 6.15 (1 H, s), 3.9 (3 H, s ), 3.8 (3 H, s), 3.7 (1 H, m), 3.5 (1 H, m), 2.9 (2 H, tr), 2.6 (4 H, m), 2.3 (3 H, s), 1.2 (6H, m).
ESI-MS: M+ = 600ESI-MS: M + = 600
Beispiel 8:Example 8:
2- (4 , 6 -Dimethyl-pyrimidin-2 -yloxy) -3- (3 -phenylprop- (2E) -en- oxy) -3, 3 -diphenylpropionsaure (1-27)2- (4,6-dimethyl-pyrimidin-2-yloxy) -3- (3-phenylprop- (2E) -en-oxy) -3,3-diphenylpropionic acid (1-27)
Zu einer Suspension von 432 mg (9 mmol, 50%) NaH in 20 ml DMF wurden 1.12 g (3 mmol) 2 -Hydroxy-3 - (3 -phenylprop- (2E) -en- oxy) -3 , 3 -diphenylpropionsaure zugegeben und 10 Minuten bei Raumtemperatur gerührt. Nach Zugabe von 614 mg (3.3 mmol) 4 , 6-Dimethyl -1 -methyl- sulfonylpyrimidin wurde 16 Stunden gerührt, anschließend mit 200 ml Wasser verdünnt, mit 1 N Salzsäure angesäuert und mit Ether extrahiert. Die Etherphase wurde mit 1 N Natronlauge extrahiert, die wässrige Phase wurde erneut angesäuert und das Produkt mit Ether extrahiert. Die organische Phase wurde über Magnesiumsulfat getrocknet, filtriert und das Lösungsmittel abdestilliert. Der Rückstand wurde aus Ether/Hexan umkristallisiert und es wurden 927 mg (65 %) Produkt kristallin isoliert .1.12 g (3 mmol) of 2-hydroxy-3 - (3 -phenylprop- (2E) -en- oxy) -3, 3 -diphenylpropionic acid were added to a suspension of 432 mg (9 mmol, 50%) NaH in 20 ml of DMF added and stirred for 10 minutes at room temperature. After addition of 614 mg (3.3 mmol) of 4, 6-dimethyl-1-methylsulfonylpyrimidine, the mixture was stirred for 16 hours, then diluted with 200 ml of water, acidified with 1N hydrochloric acid and extracted with ether. The ether phase was extracted with 1N sodium hydroxide solution, the aqueous phase was acidified again and the product extracted with ether. The organic phase was dried over magnesium sulfate, filtered and the solvent was distilled off. The residue was recrystallized from ether / hexane and 927 mg (65%) of product were isolated in crystalline form.
Smp. : 128-133°CM.p .: 128-133 ° C
*H-NMR (200 MHz): 7.3 ppm (15 H, m) , 6.74 (1 H, s) , 6.7 (1 H, d) , 6.3 (1 H,s), 6.2 (1 H, dtr, 4.3 (1 H, dd) , 4.1 (1 H, dd) , 2.3 (6 H, s) .* H-NMR (200 MHz): 7.3 ppm (15 H, m), 6.74 (1 H, s), 6.7 (1 H, d), 6.3 (1 H, s), 6.2 (1 H, dtr, 4.3 (1 H, dd), 4.1 (1 H, dd), 2.3 (6 H, s).
ESI-MS: M+ = 480 Beispiel :ESI-MS: M + = 480 For example:
4 , 6 -Di ethyl - 1 -methylthio-pyrimidin4, 6 -Di ethyl - 1 -methylthio-pyrimidine
15 g (107 mmol) 4, 6-Dimethyl - 1 -mercaptopyrimidin und 5,14 g NaOH wurden in 175 ml Wasser gelöst. Zu dieser Mischung wurden innerhalb von 10 Minuten bei Raumtemperatur 12 ml (128 mmol) Dimethyl - sulfat zugetropft. Nach einer Stunde wurde die wässrige Phase dreimal mit Ether extrahiert, über Magnesiumsulfat getrocknet und das Lösungsmittel abdestilliert. Es konnten 15,9 g (97 %) Rohprodukt isoliert werden.15 g (107 mmol) of 4, 6-dimethyl-1-mercaptopyrimidine and 5.14 g of NaOH were dissolved in 175 ml of water. 12 ml (128 mmol) of dimethyl sulfate were added dropwise to this mixture over the course of 10 minutes at room temperature. After an hour, the aqueous phase was extracted three times with ether, dried over magnesium sulfate and the solvent was distilled off. 15.9 g (97%) of crude product could be isolated.
iH-NMR (270 MHz): 6.7 ppm (1 H, s) , 2.5 (3 H,s), 2.3 (6 H,s). i H-NMR (270 MHz): 6.7 ppm (1 H, s), 2.5 (3 H, s), 2.3 (6 H, s).
Beispiel 10:Example 10:
4, 6 -Dimethyl -1 -methylsulfonyl-pyrimidin4,6-dimethyl-1-methylsulfonyl-pyrimidine
15,9 g (103 mmol) 4, 6 -Dimethyl-1 -methylthio-pyrimidin wurden in 120 ml Dichlormethan und 110 ml Wasser vorgelegt. Bei 0°C wurde Chlorgas bis zur Sättigung (Gelbfärbung) eingeleitet. Nach vollständigem Umsatz wurde überschüssiges Chlor mit Stickstoff ausgetrieben, die wässrige Phase mit Dichlormethan extrahiert und die gesammelten organischen Phasen über Magnesiumsulfat getrock- net. Die Lösung wurde eingeengt und durch Zugabe von Ether das Produkt (14 g, 73 %) auskristallisiert.15.9 g (103 mmol) of 4,6-dimethyl-1-methylthio-pyrimidine were placed in 120 ml of dichloromethane and 110 ml of water. At 0 ° C chlorine gas was introduced until saturation (yellow color). After conversion was complete, excess chlorine was driven off with nitrogen, the aqueous phase was extracted with dichloromethane and the collected organic phases were dried over magnesium sulfate. The solution was concentrated and the product (14 g, 73%) crystallized out by adding ether.
Smp.: 79-80°CM.p .: 79-80 ° C
iH-NMR (270 MHz): 7.2 ppm (1 H, s) , 3.4 (3 H, s) , 2.6 (6 H, s) .iH-NMR (270 MHz): 7.2 ppm (1 H, s), 3.4 (3 H, s), 2.6 (6 H, s).
Beispiel 11:Example 11:
(S) -2-Hydroxy-3-methoxy-3 , 3-diphenylpropionsäuremethylester(S) -2-Hydroxy-3-methoxy-3, 3-diphenylpropionic acid methyl ester
In 300 ml DMF wurden 54.4 g (200 mmol) (S) -2-Hydroxy-3-methoxy- 3, 3-diphenylpropionsaure mit 10.8 g (200rrιmol) Natriummethylat vorgelegt. Zu dieser Suspension wurden in 15 Minuten 21 ml (210 mmol) Dimethylsulfat zugetropft, wobei die Temperatur auf 50°C an- steigt und die Suspension dünnflüssiger wird. Das Gemisch wurde über Nacht nachgerührt und dann auf 1.5 1 Wasser und Eis gegeben. Die wässrige Phase wurde zweimal mit 500 ml Ether extrahiert und die Etherphase wiederum mit zweimal 200 ml Wasser gewaschen. Die organische Phase wurde über Magnesiumsulfat getrocknet, das Trockenmittel abfiltriert und das Lösungsmittel abdestilliert. Es wurden 55,8 g eines 01s isoliert, welches direkt weiterverarbeitet wurde.54.4 g (200 mmol) of (S) -2-hydroxy-3-methoxy-3, 3-diphenylpropionic acid with 10.8 g (200 mmol) of sodium methylate were placed in 300 ml of DMF. 21 ml (210 mmol) of dimethyl sulfate were added dropwise to this suspension in the course of 15 minutes, the temperature rising to 50 ° C. and the suspension becoming thinner. The mixture was stirred overnight and then added to 1.5 l of water and ice. The aqueous phase was extracted twice with 500 ml of ether and the ether phase was washed again with twice 200 ml of water. The organic phase was dried over magnesium sulfate, the drying agent was filtered off and the solvent was distilled off. It 55.8 g of a 01 were isolated, which was processed directly.
Beispiel 12:Example 12:
(S) -2-Hydroxy-3- (2- (3, 4-dimethoxyphenyl) ethoxy) -3, 3-diphenyl- propionsauremethylester(S) -2-Hydroxy-3- (2- (3,4-dimethoxyphenyl) ethoxy) -3, 3-diphenyl-propionic acid methyl ester
Variante A:Option A:
In einem Kolben wurden 27,9 g (S) -2-Hydroxy-3-methoxy-3, 3-diphe- nylpropionsäuremethylesters (100 mmol) mit 1 g p-Toluolsulfon- saure und 18,2 g 2- (3 , 4-Dimethoxyphenyl) ethanol (100 mmol) gemischt und auf 60°C erhitzt. An den Kolben wird ein Vakuum ange- legt, um entstehendes Methanol abzudestillieren, und weitere 5 Stunden bei 60°C gerührt. Zur Aufarbeitung wird das Gemisch abgekühlt, mit 300 ml Ether verdünnt und die organische Phase erst mit Natriumhydrogencarbonatlosung und dann mehrfach mit Wasser gewaschen. Anschließend wird mit Magnesiumsulfat getrocknet, das Trockenmittel abfiltriert und das Losungsmittel abdestilliert. Es wurde ein Ruckstand von 43 g 01 isoliert, der direkt in der weiteren Synthese eigesetzt werden konnte.27.9 g of (S) -2-hydroxy-3-methoxy-3, 3-diphenylpropionic acid methyl ester (100 mmol) with 1 g of p-toluenesulfonic acid and 18.2 g of 2- (3, 4 -Dimethoxyphenyl) ethanol (100 mmol) mixed and heated to 60 ° C. A vacuum is applied to the flask in order to distill off the methanol formed, and the mixture is stirred at 60 ° C. for a further 5 hours. For working up, the mixture is cooled, diluted with 300 ml of ether and the organic phase is washed first with sodium bicarbonate solution and then several times with water. It is then dried with magnesium sulfate, the drying agent is filtered off and the solvent is distilled off. A residue of 43 g 01 was isolated, which could be used directly in the further synthesis.
Variante B:Variant B:
In einem Kolben wurden 27,9 g (S) -2-Hydroxy-3-methoxy-3 , 3- diphenylpropionsäuremethylester (100 mmol), 1 g p-Toluolsulfonsäure und 18,2 g (100 mmol) 2- (3, 4-Dιmethoxyphenyl) ethanol in 75 ml Dichlormethan gelost. Die Losung wurde erhitzt und das Dichlormethan abdestilliert unter gleichzeitigem Zutropfen von Dichlormethan, um entstehendes Methanol abzudestillieren, und weitere 5 Stunden bei 60°C gerührt. Zur Aufarbeitung wird das Gemisch abgekühlt, mit 300 ml Ether verdünnt und die organische Phase erst mit Natriumhydrogencarbonatlosung und dann mehrfach mit Wasser gewaschen. Anschließend wird mit Magnesiumsulfat getrocknet, das Trockenmittel abfiltriert und das Losungsmittel abdestilliert. Es wurde ein Rückstand von 43 g 01 isoliert, der direkt in der weiteren Synthese eigesetzt werden konnte.27.9 g of (S) -2-hydroxy-3-methoxy-3, 3-diphenylpropionic acid methyl ester (100 mmol), 1 g of p-toluenesulfonic acid and 18.2 g (100 mmol) of 2- (3, 4 -Dιmethoxyphenyl) ethanol dissolved in 75 ml dichloromethane. The solution was heated and the dichloromethane was distilled off while simultaneously dropping dichloromethane to distill off the methanol formed, and the mixture was stirred at 60 ° C. for a further 5 hours. For working up, the mixture is cooled, diluted with 300 ml of ether and the organic phase is washed first with sodium bicarbonate solution and then several times with water. It is then dried with magnesium sulfate, the drying agent is filtered off and the solvent is distilled off. A residue of 43 g 01 was isolated, which could be used directly in the further synthesis.
Beispiel 13:Example 13:
(S) -2-Hydroxy-3- (2- (3 , 4-dimethoxyphenyl) ethoxy) -3 , 3-diphenylpro- pionsäure(S) -2-Hydroxy-3- (2- (3,4-dimethoxyphenyl) ethoxy) -3, 3-diphenylpropionic acid
Zu einer Lösung aus 74 g (170 mmol) (S) -2-Hydroxy-3- (2- (3, 4- di ethoxyphenyl) ethoxy) -3, 3-diphenylpropionsauremethylester in 510 ml Dioxan wurden 255 ml 1 N Natronlauge gegeben und die Suspension bei 50°C zwei Stunden gerührt. Das Gemisch wurde mit255 ml of 1N sodium hydroxide solution were added to a solution of 74 g (170 mmol) of (S) -2-hydroxy-3- (2- (3,4-diethoxyphenyl) ethoxy) -3, 3-diphenylpropionic acid methyl ester in 510 ml of dioxane and the Suspension stirred at 50 ° C for two hours. The mixture was mixed with
2.5 1 Wasser verdünnt und mit Zitronensaure neutralisiert. Die wässrige Phase wurde zweimal mit 500 ml Ether extrahiert. Anschließend wurde die organische Phase mit Wasser gewaschen, über Magnesiumsulfat getrocknet und nach dem Abfiltrieren der Ether abdestilliert. Der Rückstand wurde durch Kristallisation aus Ether/n-Hexan gereinigt und es wurden 70 g Kristalle isoliert.2.5 1 water diluted and neutralized with citric acid. The aqueous phase was extracted twice with 500 ml of ether. The organic phase was then washed with water, dried over magnesium sulfate and, after the ethers had been filtered off, distilled off. The residue was purified by crystallization from ether / n-hexane and 70 g of crystals were isolated.
iH-NMR (200 MHz): 7.3 ppm (10 H, m) , 6.8 (1 H, dbr) , 6.7 (1 H, dbr), 6.6 (1 H, sbr) , 5.0 (1 H, s) , 3.9 (3 H, s) , 3.85 (3 H, s) ,iH-NMR (200 MHz): 7.3 ppm (10 H, m), 6.8 (1 H, dbr), 6.7 (1 H, dbr), 6.6 (1 H, sbr), 5.0 (1 H, s), 3.9 (3 H, s), 3.85 (3 H, s),
3.6 (1 H, dt), 3.4 (1 H, OH), 3.2 (1 H, dt), 2.8 (2 H, t) .3.6 (1 H, dt), 3.4 (1 H, OH), 3.2 (1 H, dt), 2.8 (2 H, t).
[α] 20 = 8 . 3 ( 1 ; Ethanol )[α] 20 = 8. 3 (1; ethanol)
Beispiel 14 :Example 14:
2- (4 , 6-Dimethyl-pyrimidin-2-yloxy) -3- (2- (3 , 4-dimethoxyphenyl) ethoxy) -3, 3-diphenylpropionsaure (1-445) und (S) -2- (4, 6-Dimethyl-pyrimidin-2-yloxy) -3- (2- (3 , 4-dιmethoxy- phenyl) ethoxy) -3, 3-diphenylpropionsaure (1-445 (S) -Enantiomeres)2- (4, 6-Dimethyl-pyrimidin-2-yloxy) -3- (2- (3, 4-dimethoxyphenyl) ethoxy) -3, 3-diphenylpropionic acid (1-445) and (S) -2- (4 , 6-Dimethyl-pyrimidin-2-yloxy) -3- (2- (3, 4-dimethoxyphenyl) ethoxy) -3, 3-diphenylpropionic acid (1-445 (S) -enantiomer)
Zu einer Vorlage aus 9 g (390 mmol) Lithiumamid in 35 ml DMF wurden 55 g (130 mmol) 2-Hydroxy-3- (2- (3 , 4-dimethoxyphenyl ) eth - oxy) -3 , 3-diphenylpropionsäure, gelost in 150 ml DMF, über55 g (130 mmol) of 2-hydroxy-3- (2- (3, 4-dimethoxyphenyl) eth - oxy) -3, 3-diphenylpropionic acid were dissolved in an initial charge of 9 g (390 mmol) of lithium amide in 35 ml of DMF in 150 ml DMF, about
15 Minuten zugegeben. Hierzu wurden langsam 25 g (137 mmol) 2-Me- thylsulfon-4 , 6-dimethylpyrimidin, gelost in 75 ml DMF, zugetropft und 18 Stunden bei Raumtemperatur gerührt. Zur Aufarbeitung wurde das Gemisch auf 2 1 Eiswasser und Zitronensäure zur Neutrali - sation gegeben. Die ausgefallenen Kristalle wurden abgesaugt und mit Wasser gewaschen. Die feuchten Kristalle wurden in Dichlormethan gelost, die Losung über Magnesiumsulfat getrocknet, filtriert und das Losungsmittel abdestilliert. Der ölige Ruckstand wurde in Ether aufgenommen, mit 130 ml 1 N Natronlauge extrahiert und die wässrige Phase mit 130 ml 1 N Salzsäure neutralisiert, wobei Kristalle ausfielen. Nach der Trocknung wurden 64 g Produkt isoliert.Added 15 minutes. 25 g (137 mmol) of 2-methylsulfone-4, 6-dimethylpyrimidine, dissolved in 75 ml of DMF, were slowly added dropwise and the mixture was stirred at room temperature for 18 hours. For working up, the mixture was added to 2 l of ice water and citric acid for neutralization. The precipitated crystals were filtered off and washed with water. The moist crystals were dissolved in dichloromethane, the solution was dried over magnesium sulfate, filtered and the solvent was distilled off. The oily residue was taken up in ether, extracted with 130 ml of 1N sodium hydroxide solution and the aqueous phase was neutralized with 130 ml of 1N hydrochloric acid, crystals precipitating out. After drying, 64 g of product were isolated.
l-H-NMR (200 MHz): 7.3 ppm (10 H, m) , 6.7 (4 H, m) , 6.3 (1 H, s) , 3.9 (3 H, s) , 3.85 (3 H, s) , 3.7 (1 H, dt), 3.6 (1 H, dt), 2.8 (2 H, t) , 2.3 (6 H, s) . 1 H NMR (200 MHz): 7.3 ppm (10 H, m), 6.7 (4 H, m), 6.3 (1 H, s), 3.9 (3 H, s), 3.85 (3 H, s) , 3.7 (1 H, dt), 3.6 (1 H, dt), 2.8 (2 H, t), 2.3 (6 H, s).
Smp . : 125- 130°C Zers . ESI-MS : M+ = 528 Analog wurde aus (S) -2-Hydroxy-3- (2- (3 , 4-dιmethoxy- phenyl) ethoxy) -3, 3-diphenylpropionsaure und 2-Methylsul- fon-4, 6-dιmethylpyrιmιdιn m Gegenwart von LithiumamidM.p. : 125-130 ° C dec. ESI-MS: M + = 528 Analogously, (S) -2-hydroxy-3- (2- (3, 4-dιmethoxy-phenyl) ethoxy) -3, 3-diphenylpropionic acid and 2-methylsulfone-4, 6-dimethylpyrιmιdιn in the presence of lithium amide
(S) -2- (4, 6-Dimethyl-pynmιdιn-2-yloxy) -3- (2- (3, 4-dιmethoxy- phenyl) ethoxy) -3, 3-diphenylpropionsaure hergestellt.(S) -2- (4, 6-Dimethyl-pynmιdιn-2-yloxy) -3- (2- (3, 4-dιmethoxy-phenyl) ethoxy) -3, 3-diphenylpropionic acid.
[α]20 = 111 (1; Ethanol)[α] 20 = 111 (1; ethanol)
Beispiel 15:Example 15:
Die folgenden Verbindungen wurden analog zu Beispiel 8 hergestelltThe following compounds were prepared analogously to Example 8
2- (4 -Methoxy-6 -methyl -pyπmιdιn-2 -yloxy) -3- (2- (4-methoxy- phenyl) ethoxy) -3, 3 -di (4 -ethylphenyl) propions ure (1-147)2- (4-methoxy-6-methyl -pyπmιdιn-2 -yloxy) -3- (2- (4-methoxy-phenyl) ethoxy) -3, 3 -di (4 -ethylphenyl) propionic acid (1-147)
Smp.: 150-155°C ESI-MS: M+ = 570M.p .: 150-155 ° C ESI-MS: M + = 570
2 - (4 -Methoxy-5, 6 -dihydrofuro- (2, 3d) -pyπmιdιn-2 -yloxy) -3 - (2- (4 -chlorophenyl) ethoxy) -3 , 3 -diphenylpropionsaure (1-651)2 - (4-methoxy-5, 6 -dihydrofuro- (2, 3d) -pyπmιdιn-2 -yloxy) -3 - (2- (4-chlorophenyl) ethoxy) -3, 3 -diphenylpropionic acid (1-651)
Smp.: 150-152°C ESI-MS: M+ = 546M.p .: 150-152 ° C ESI-MS: M + = 546
2 - (4,6 -Dimethyl -pyrimidm- 2 -yloxy) -3 - (2 - (4 -chlorophenyl) ethoxy) - 3, 3 -diphenylpropionsaure (1-713)2 - (4,6 -dimethyl-pyrimidm- 2 -yloxy) -3 - (2 - (4 -chlorophenyl) ethoxy) - 3, 3 -diphenylpropionic acid (1-713)
Smp. : 108°C Zers. ESI-MS: M+ = 502M.p .: 108 ° C dec. ESI-MS: M + = 502
2 - (4, 6 -Dimethoxy-pyrimιdιn-2-yloxy) -3- (2 - (4 -chlorophenyl) ethoxy) 3,3- diphenylpropionsaure2 - (4, 6 -Dimethoxy-pyrimιdιn-2-yloxy) -3- (2 - (4-chlorophenyl) ethoxy) 3,3-diphenylpropionic acid
Smp. : 165-167°C ESI-MS: M+ = 534M.p .: 165-167 ° C ESI-MS: M + = 534
2- (4 -Methoxy-6 -methyl -pyrimidm- 2 -yloxy) -3- (2- (4 -chloro-phenyl) - ethoxy) -3, 3 -diphenylpropionsaure (1-746)2- (4-methoxy-6-methyl-pyrimidm-2-yloxy) -3- (2- (4-chlorophenyl) ethoxy) -3, 3 -diphenylpropionic acid (1-746)
Smp. : 93-98°C ESI-MS: M+ = 518 2- (4, 6 -Dimethyl -pyrimidin- 2 -yloxy) -3 - (2 - (4 -methoxyphenyl) ethoxy) 3, 3 -di (4 -ethylphenyl) propionsäure (1-148)M.p .: 93-98 ° C ESI-MS: M + = 518 2- (4, 6-dimethyl-pyrimidine-2-yloxy) -3 - (2 - (4-methoxyphenyl) ethoxy) 3, 3-di (4-ethylphenyl) propionic acid (1-148)
Smp. : 130-133°C ESI-MS: M+ = 554M.p .: 130-133 ° C ESI-MS: M + = 554
2 - (4 -Methoxy- 6 -methyl -pyrimidin- 2 -yloxy) -3 - (2- (4 -methylphenyl) - ethoxy) -3, 3-di (4 -chlorophenyl) propionsäure (1-710)2 - (4-methoxy-6-methyl-pyrimidine-2-yloxy) -3 - (2- (4-methylphenyl) -ethoxy) -3, 3-di (4-chlorophenyl) propionic acid (1-710)
Smp. : 90-100°C ESI-MS: M+ = 566M.p .: 90-100 ° C ESI-MS: M + = 566
2 - (4 -Methoxy- 6 -methyl -pyrimidin- 2 -yloxy) -3 - (3,3 -diphenylpropoxy) 3 , 3-di (4 -chlorophenyl) propionsäure2 - (4-methoxy-6-methyl-pyrimidine-2-yloxy) -3 - (3,3-diphenylpropoxy) 3,3-di (4-chlorophenyl) propionic acid
XH-NMR(200 MHz): 7.3 ppm (18 H, m) , 6.25 (1 H, s) , 6.0 (1 H, s) , 4.0 (1 H, tr), 3.8 (3 H, s) , 3.4 (2 H, m) , 2.2 (5 H, m) . X H-NMR (200 MHz): 7.3 ppm (18 H, m), 6.25 (1 H, s), 6.0 (1 H, s), 4.0 (1 H, tr), 3.8 (3 H, s), 3.4 (2 H, m), 2.2 (5 H, m).
ESI-MS: M+ = 642ESI-MS: M + = 642
2 - (4 -Methoxy- 6 -methyl -pyrimidin- 2 -yloxy) -3 - (2- (3,4 -dimethoxyphenyl) ethoxy) -3 , 3 -di (4 -chlorophenyl (propionsäure (1-699)2 - (4-methoxy-6-methyl-pyrimidine-2-yloxy) -3 - (2- (3,4-dimethoxyphenyl) ethoxy) -3, 3 -di (4-chlorophenyl (propionic acid (1-699)
Smp. : 100-110°C ESI-MS: M+ = 612M.p .: 100-110 ° C ESI-MS: M + = 612
2- (4 -Methoxy-6 -methyl-pyrimidin-2-yloxy) -3- (2- (2 -methoxy -phenyl) ■ ethoxy) -3 , 3-di (4 -chlorophenyl) propionsäure (1-487)2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3- (2- (2-methoxy-phenyl) ■ ethoxy) -3, 3-di (4-chlorophenyl) propionic acid (1-487)
Smp. : 85-90°CM.p .: 85-90 ° C
ESI-MS: M+ = 582ESI-MS: M + = 582
2 - (4 -Methoxy- 5, 6 -dihydrofuro- (2, 3d) -pyrimidin-2 -yloxy) -3 - (2 - (3 -methoxyphenyl) ethoxy) -3, 3-di (4 -chlorophenyl) propionsäure (1-486)2 - (4-Methoxy- 5, 6 -dihydrofuro- (2, 3d) -pyrimidin-2-yloxy) -3 - (2 - (3-methoxyphenyl) ethoxy) -3, 3-di (4-chlorophenyl) propionic acid (1-486)
Smp. : 190-195°C ESI-MS: M+ = 610M.p .: 190-195 ° C ESI-MS: M + = 610
2- (4 -Methoxy-5, 6 -dihydrofuro- (2,3d) -pyrimidin- 2 -yloxy) -3- (2-phenylethylthio) -3, 3-di (4 -chlorophenyl) propionsäure2- (4-methoxy-5, 6 -dihydrofuro- (2,3d) pyrimidine-2-yloxy) -3- (2-phenylethylthio) -3, 3-di (4-chlorophenyl) propionic acid
Smp.: 173-175°CM.p .: 173-175 ° C
iH-NMR (200): 7.0-7.4 ppm (13 H, m) , 6.0 (1 H, s) , 4.7 (2 H, tr) , 3.8 (3 H, s) , 3.1 (2 H, tr) , 2.5 (4 H, m) 2- (4 -Methoxy- 5, 6 -dihydrofuro- (2, 3d) -pyrimidin- 2 -yloxy) -3 - (2 - (3, 4 -dimethoxyphenyl) ethoxy) -3, 3-di (4 -chlorophenyl) propionsäure (1-635)iH-NMR (200): 7.0-7.4 ppm (13 H, m), 6.0 (1 H, s), 4.7 (2 H, tr), 3.8 (3 H, s), 3.1 (2 H, tr), 2.5 (4 H, m) 2- (4-methoxy-5, 6 -dihydrofuro- (2, 3d) -pyrimidine-2-yloxy) -3 - (2 - (3,4-dimethoxyphenyl) ethoxy) -3, 3-di (4-chlorophenyl ) propionic acid (1-635)
Smp. : 100-110°C ESI-MS: M+ = 640M.p .: 100-110 ° C ESI-MS: M + = 640
2 - (4 -Methoxy- 5, 6 -dihydrofuro- (2, 3d) -pyrimidin- 2 -yloxy) -3 - (2 - (3, 5 -dimethoxyphenyl) ethoxy) -3, 3-di (4 -chlorophenyl) propion- säure (1-593)2 - (4 -Methoxy- 5, 6 -dihydrofuro- (2, 3d) -pyrimidine-2 -yloxy) -3 - (2 - (3, 5 -dimethoxyphenyl) ethoxy) -3, 3-di (4-chlorophenyl ) propionic acid (1-593)
Smp. : 90-100°CM.p .: 90-100 ° C
ESI-MS: M+ = 640ESI-MS: M + = 640
2 - (4 -Methoxy-5, 6 -dihydrofuro- (2 , 3d) -pyrimidin- 2 -yloxy) -3 -2 - (4-methoxy-5, 6 -dihydrofuro- (2, 3d) -pyrimidine- 2 -yloxy) -3 -
(2 - (2 -methoxyphenyl) ethoxy) -3 , 3 -di (4 -chlorophenyl) propionsäure (1-164)(2 - (2-methoxyphenyl) ethoxy) -3, 3 -di (4-chlorophenyl) propionic acid (1-164)
Smp.: 135-145°C ESI-MS: M+ = 610M.p .: 135-145 ° C ESI-MS: M + = 610
2- (4 -Methoxy- 5, 6 -dihydrofuro- (2, 3d) -pyrimidin- 2 -yloxy) -3 - (3, 3 -diphenylpropoxy) -3 , 3 -di (4 -chlorophenyl ) propionsäure2- (4-methoxy- 5, 6 -dihydrofuro- (2, 3d) -pyrimidine-2-yloxy) -3 - (3, 3 -diphenylpropoxy) -3, 3 -di (4-chlorophenyl) propionic acid
Smp. : 125-127°CM.p .: 125-127 ° C
ESI-MS: M+ = 670ESI-MS: M + = 670
2- (4 -Methoxy-6 , 7 -dihydro-5H-cyclopentapyrimidin- 2 -yloxy) -3- (3,3 -diphenylpropoxy) -3, 3-di (4 -chlorophenyl) ropionsäure2- (4-methoxy-6,7-dihydro-5H-cyclopentapyrimidine-2-yloxy) -3- (3,3-diphenylpropoxy) -3,3-di (4-chlorophenyl) ropionic acid
Smp.: 135-140°C ESI-MS: M+ = 668M.p .: 135-140 ° C ESI-MS: M + = 668
2- ( -Methoxy-6 , 7 -dihydro-5H-cyclopentapyrimidin-2 -yloxy) -3- (2 -phenylethylthio) -3, 3-di (4 -chlorophenyl) propionsäure2- (-Methoxy-6, 7-dihydro-5H-cyclopentapyrimidin-2-yloxy) -3- (2-phenylethylthio) -3, 3-di (4-chlorophenyl) propionic acid
Smp.: 135-140°CM.p .: 135-140 ° C
iH-NMR (200): 7.0-7.5 ppm (13 H, m) , 5.9 (1 H, s) , 3.9 (3 H, s) , 2.6-2.8 (8 H, m) , 2.1 (2 H, m) .iH-NMR (200): 7.0-7.5 ppm (13 H, m), 5.9 (1 H, s), 3.9 (3 H, s), 2.6-2.8 (8 H, m), 2.1 (2 H, m) ).
2 - (4 -Methoxy-6 , 7 -dihydro-5H-cyclopentapyrimidin-2 -yloxy) -3 - (2 - (2 -methoxyphenyl) ethoxy) -3, 3-di (4 -chlorophenyl) propionsäure2 - (4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy) -3 - (2 - (2-methoxyphenyl) ethoxy) -3, 3-di (4-chlorophenyl) propionic acid
Smp. : 105-115°C ESI-MS: M+ = 608 2- (4 -Methoxy-6, 7 -dihydro-5H-cyclopentapyrimidin-2 -yloxy) -3-M.p .: 105-115 ° C ESI-MS: M + = 608 2- (4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy) -3-
(2 - (3 -methoxyphenyl) ethoxy) - 3 , 3-di (4 -chlorophenyl) propionsäure(2 - (3-Methoxyphenyl) ethoxy) -3,3-di (4-chlorophenyl) propionic acid
Smp.: 110-120°C ESI-MS: M+ = 608M.p .: 110-120 ° C ESI-MS: M + = 608
2 - (4 -Methoxy- 6 , 7 -dihydro- 5H-cyclopentapyrimidin- 2 -yloxy) -3 - (2 - (4 -dimethylaminophenyl) ethoxy) -3, 3-di (4 -chlorophenyl) propionsäure2 - (4-methoxy-6,7-dihydro-5H-cyclopentapyrimidine-2-yloxy) -3 - (2 - (4-dimethylaminophenyl) ethoxy) -3,3-di (4-chlorophenyl) propionic acid
Smp.: 135-140°C ESI-MS: M+ = 621M.p .: 135-140 ° C ESI-MS: M + = 621
2 - (4 -Methoxy-6 , 7 -dihydro- 5H-cyclopentapyrimidin- 2 -yl- oxy) -3- (2- (3, -dimethoxyphenyl) ethoxy) -3 , 3 -di (4 -chlorophenyl) - propionsäure2 - (4-methoxy-6,7-dihydro-5H-cyclopentapyrimidine-2-yloxy) -3- (2- (3, -dimethoxyphenyl) ethoxy) -3,3-di (4-chlorophenyl) propionic acid
Smp. : 125-130°C ESI-MS: M+ = 638M.p .: 125-130 ° C ESI-MS: M + = 638
2 - (4 -Methoxy- 6, 7 -dihydro-5H-cyclopentapyrimidin- 2 -yloxy) - 3 - (2 - (3,5-dimethoxyphenyl ) ethoxy) - 3 , 3 -di ( 4 -chlorophenyl ) - propionsäure2 - (4-methoxy-6, 7-dihydro-5H-cyclopentapyrimidine-2-yloxy) - 3 - (2 - (3,5-dimethoxyphenyl) ethoxy) - 3, 3-di (4-chlorophenyl) -propionic acid
Smp. : 125-130°C ESI-MS: M+ = 638M.p .: 125-130 ° C ESI-MS: M + = 638
2 - (4 -Methoxy- 5, 6 -dihydrofuro- (2, 3d) -pyrimidin- 2 -yloxy) -3 - (2- (4 -methylphenyl) ethoxy) -3, 3 -diphenylpropionsaure (1-370)2 - (4-methoxy- 5, 6 -dihydrofuro- (2, 3d) -pyrimidine- 2 -yloxy) -3 - (2- (4 -methylphenyl) ethoxy) -3, 3 -diphenylpropionic acid (1-370)
Smp. : 128-130°C ESI-MS: M+ = 526M.p .: 128-130 ° C ESI-MS: M + = 526
2- (4 -Methoxy- 6 -methyl -pyrimidin-2 -yloxy) -3- (2 -phenylethoxy) - 3, 3 -diphenylpropions ure (1-719)2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3- (2-phenylethoxy) - 3,3-diphenylpropionic acid (1-719)
Smp. : 155°C Zers.M.p .: 155 ° C dec.
ESI-MS: M+ = 484ESI-MS: M + = 484
2- (4, 6-Dimethoxy-pyrimidin-2 -yloxy) -3- (2 -phenylethoxy) -3, 3 -diphenylpropionsaure2- (4, 6-Dimethoxypyrimidin-2-yloxy) -3- (2-phenylethoxy) -3, 3 -diphenylpropionic acid
Smp. : 203°C Zers. ESI-MS: M+ = 500 2- (4, 6 -Dimethyl-pyrimidin-2 -yloxy) -3 - (2 -phenylethoxy) -3 , 3 -diphenylpropionsaure (1-720)M.p .: 203 ° C dec. ESI-MS: M + = 500 2- (4, 6-dimethyl-pyrimidin-2-yloxy) -3 - (2-phenylethoxy) -3, 3 -diphenylpropionic acid (1-720)
Smp . : 130 - 133°C ES I - MS : M+ = 468M.p. : 130 - 133 ° C ES I - MS: M + = 468
2- (4 -Methoxy- 5, 6 -dihydrofuro- (2, 3d) -pyrimidin- 2 -yloxy) -3 - (2 -phenylethoxy) -3 , 3 -diphenylpropions ure (1-657)2- (4-methoxy- 5, 6 -dihydrofuro- (2, 3d) -pyrimidine- 2 -yloxy) -3 - (2 -phenylethoxy) -3, 3 -diphenylpropionic acid (1-657)
Smp . : 138 - 142°C ESI -MS : M+ = 512M.p. : 138 - 142 ° C ESI -MS: M + = 512
2 - (4,6 -Dirnethoxy-pyrimidin-2 -yloxy) -3 - (2 - (4 -methylphenyl) - ethoxy) -3,3-diphenylpropionsaure2 - (4,6 -Dirnethoxy-pyrimidin-2-yloxy) -3 - (2 - (4 -methylphenyl) - ethoxy) -3,3-diphenylpropionic acid
Smp . : 155 - 158°C ESI -MS : M+ = 514M.p. : 155-158 ° C ESI -MS: M + = 514
2 - (4 -Methoxy-6 -methyl -pyrimidin- 2 -yloxy) -3 - (2 - (4 -methylphenyl) - ethoxy) -3 , 3 -diphenylpropionsaure (1-465)2 - (4-methoxy-6-methyl-pyrimidine-2-yloxy) -3 - (2 - (4-methylphenyl) -ethoxy) -3, 3 -diphenylpropionic acid (1-465)
Smp. : 145-147°C ESI-MS: M+ = 498M.p .: 145-147 ° C ESI-MS: M + = 498
2 - (4 -Methoxy-6 -methyl -pyrimidin- 2 -yloxy) -3 - (3 - (4 -methoxyphenyl) • propoxy) -3 , 3 -diphenylpropionsaure (1-554)2 - (4-methoxy-6-methyl-pyrimidine-2-yloxy) -3 - (3 - (4-methoxyphenyl) • propoxy) -3, 3 -diphenylpropionic acid (1-554)
Smp. : 160-165°C ESI-MS: M+ = 528M.p .: 160-165 ° C ESI-MS: M + = 528
2 - (4,6 -Dimethyl -pyrimidin-2 -yloxy) -3 - (3 - (4 -methoxyphenyl) propoxy) -3, -diphenylpropionsaure (1-555)2 - (4,6-dimethyl-pyrimidin-2-yloxy) -3 - (3 - (4-methoxyphenyl) propoxy) -3, -diphenylpropionic acid (1-555)
Smp. : 165-170°C ESI-MS: M+ = 512M.p .: 165-170 ° C ESI-MS: M + = 512
2- (4 -Methoxy- 6 -methyl -pyrimidin-2 -yloxy) -3- (3- (3,4 , 5- trimethoxy- phenyl) propoxy) -3, 3 -diphenylpropionsaure (1-335)2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3- (3- (3,4, 5-trimethoxy-phenyl) propoxy) -3, 3 -diphenylpropionic acid (1-335)
XH-NMR (200): 7.2-7.4 ppm (10 H, m) , 6.3 (2 H, s) , 6.2 (2 H, s) , 3.8 (3 H, S) , 3.75 (10 H, s) , 3.4 (2 H, m) , 2.6 (2 H, m) , 2.25 (3 H, s) , 1.9 (2 H, m) . X H-NMR (200): 7.2-7.4 ppm (10 H, m), 6.3 (2 H, s), 6.2 (2 H, s), 3.8 (3 H, S), 3.75 (10 H, s) , 3.4 (2 H, m), 2.6 (2 H, m), 2.25 (3 H, s), 1.9 (2 H, m).
ESI-MS: M+ = 588 2 - (4,6 -Dimethyl -pyrimidin-2 -yloxy) - 3 - (3- (3,4, 5-trime hoxyphenyl) - propoxy) -3 , 3 -diphenylpropionsaure (1-336)ESI-MS: M + = 588 2 - (4,6-dimethyl-pyrimidin-2-yloxy) - 3 - (3- (3,4, 5-trime hoxyphenyl) propoxy) -3, 3 -diphenylpropionic acid (1-336)
l-H-NMR (200): 7.2-7.5 ppm (10 H, m) , 6.6 (1 H, s) , 6.3 (3 H, s), 3.8 (9 H, s), 3.4 (2 H, m) , 2.6 (2 H, m) , 2.3 (6 H, s) , 1.9 (2 H, m) .1 H-NMR (200): 7.2-7.5 ppm (10 H, m), 6.6 (1 H, s), 6.3 (3 H, s), 3.8 (9 H, s), 3.4 (2 H, m), 2.6 (2 H, m), 2.3 (6 H, s), 1.9 (2 H, m).
ESI-MS: M+ = 572ESI-MS: M + = 572
2- (4 -Methoxy-6 -methyl -pyrimidin- 2 -yloxy) -3- (3- (2 -chlorophenyl) - propoxy) -3,3-diphenylpropionsaure (1-383)2- (4-methoxy-6-methyl-pyrimidine-2-yloxy) -3- (3- (2-chlorophenyl) propoxy) -3,3-diphenylpropionic acid (1-383)
iH-NMR (200): 7.1-7.5 ppm (14 H, m) , 6.24 (1 H, s) , 6.23 (1 H, s) , 3.8 (3 H, s), 3.4 (2 H, ) , 2.75 (2 H, m) , 2.25 (3 H, s) , 1.9 (2 H, m) . i H-NMR (200): 7.1-7.5 ppm (14 H, m), 6.24 (1 H, s), 6.23 (1 H, s), 3.8 (3 H, s), 3.4 (2 H,), 2.75 (2 H, m), 2.25 (3 H, s), 1.9 (2 H, m).
ESI-MS: M+ = 532ESI-MS: M + = 532
2 - (4,6 -Dimethyl -pyrimidin- 2 -yloxy) -3 - (3- (2 -chlorophenyl) - propoxy) -3, 3 -diphenylpropionsaure (1-384)2 - (4,6-dimethyl-pyrimidine-2-yloxy) -3 - (3- (2-chlorophenyl) -propoxy) -3, 3 -diphenylpropionic acid (1-384)
Smp.: 172-178°C ESI-MS: M+ = 516M.p .: 172-178 ° C ESI-MS: M + = 516
2- (4 , 6 -Dimethyl -pyrimidin- 2 -yloxy) -3- (3- ( -chlorophenyl) - propoxy) -3 , 3 -diphenylpropionsaure (1-251)2- (4,6-dimethyl-pyrimidine-2-yloxy) -3- (3- (-chlorophenyl) -propoxy) -3,3-diphenylpropionic acid (1-251)
iH-NMR (200): 7.0-7.4 ppm (14 H, m) , 6.6 (1 H, s) , 6.3 (1 H, s) , 3.5 (2 H, m) , 2.7 (2 H, m) , 2.3 (6 H, s) , 1.9 (2 H, m) . ESI-MS: M+ = 516 i H-NMR (200): 7.0-7.4 ppm (14 H, m), 6.6 (1 H, s), 6.3 (1 H, s), 3.5 (2 H, m), 2.7 (2 H, m) , 2.3 (6 H, s), 1.9 (2 H, m). ESI-MS: M + = 516
2 - (4,6 -Dimethyl-pyrimidin- 2 -yloxy) -3 - (3- (3,4 -dimethoxyphenyl ) - propoxy) - , -diphenylpropionsaure (1-490))2 - (4,6-dimethyl-pyrimidine-2-yloxy) -3 - (3- (3,4-dimethoxyphenyl) propoxy) -, -diphenylpropionic acid (1-490))
iH-NMR (200): 7.1-7.5 ppm (10 H, m) , 6.74 (1 H, s) , 6.7 (3 H, s) , 6.3 (1 H, s), 3.8 (6 H, s) , 3.5 (2 H, m) , 2.7 (2 H, m) , 2.3 (6 H, s) , 1.9 (2 H, m) . i H-NMR (200): 7.1-7.5 ppm (10 H, m), 6.74 (1 H, s), 6.7 (3 H, s), 6.3 (1 H, s), 3.8 (6 H, s) , 3.5 (2 H, m), 2.7 (2 H, m), 2.3 (6 H, s), 1.9 (2 H, m).
ESI-MS: M+ = 542ESI-MS: M + = 542
2- (4 -Methoxy-6 -methyl -pyrimidin-2 -yloxy) -3- (2- (4 -propoxyphenyl) - ethoxy) -3, 3 -diphenylpropionsaure (1-69)2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3- (2- (4-propoxyphenyl) ethoxy) -3, 3 -diphenylpropionic acid (1-69)
Smp.: 115-119°C ESI-MS: M+ = 542 2- (4 -Methoxy-6 -methyl-pyrimidin-2 -yloxy) -3- (2- (4 -butoxyphenyl) ethoxy) -3,3 -diphenylpropionsaure (1-71)M.p .: 115-119 ° C ESI-MS: M + = 542 2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3- (2- (4-butoxyphenyl) ethoxy) -3,3 -diphenylpropionic acid (1-71)
Smp. : 118-122°C ESI-MS: M+ = 556M.p .: 118-122 ° C ESI-MS: M + = 556
2- (4,6 -Dimethyl -pyrimidin- 2 -yloxy) -3 - (2- (4 -butoxyphenyl) - ethoxy) -3, 3 -diphenylpropionsaure (1-70)2- (4,6-dimethyl-pyrimidine-2-yloxy) -3 - (2- (4-butoxyphenyl) -ethoxy) -3, 3 -diphenylpropionic acid (1-70)
Smp . : 122 - 125°C ES I - MS : M+ = 540M.p. : 122 - 125 ° C ES I - MS: M + = 540
2- (4 -Methoxy-6 -methyl -pyrimidin- 2 -yloxy) -3 - (3 -phenylprop- (2E) - enoxy) -3 , 3 -diphenylpropionsaure (1-44)2- (4-methoxy-6-methyl-pyrimidine-2-yloxy) -3 - (3 -phenylprop- (2E) - enoxy) -3, 3 -diphenylpropionic acid (1-44)
Smp. : 171-174°C ESI-MS: M+ = 496M.p .: 171-174 ° C ESI-MS: M + = 496
2- (4 -Methoxy-6 -methyl -pyrimidin- 2 -yloxy) -3- (3- (2 -methylphenyl) propoxy) -3 , 3 -diphenylpropionsaure (1-107)2- (4-methoxy-6-methyl-pyrimidine-2-yloxy) -3- (3- (2-methylphenyl) propoxy) -3, 3 -diphenylpropionic acid (1-107)
Zersetzung: 144-146°C ESI-MS: M+ = 512Decomposition: 144-146 ° C ESI-MS: M + = 512
2- (4,6-Dimethyl-pyrimidin-2-yloxy) - 3 - (3 - (2 -methylphenyl) - propoxy) -3,3 -diphenylpropionsaure (1-90)2- (4,6-dimethyl-pyrimidin-2-yloxy) - 3 - (3 - (2-methylphenyl) propoxy) -3,3 -diphenylpropionic acid (1-90)
Zersetzung: 173-176°C ESI-MS: M+ = 496Decomposition: 173-176 ° C ESI-MS: M + = 496
2- (4-Methoxy-6 -methyl -pyrimidin- 2 -yloxy) -3- (3- (4 -methylphenyl) ■ propoxy) -3 , 3 -diphenylpropionsaure (1-363)2- (4-methoxy-6-methyl-pyrimidine-2-yloxy) -3- (3- (4-methylphenyl) ■ propoxy) -3, 3 -diphenylpropionic acid (1-363)
Zersetzung: 158-161°C ESI-MS: M+ = 512Decomposition: 158-161 ° C ESI-MS: M + = 512
2- (4,6 -Dimethyl-pyrimidin- 2-yloxy) - 3- (3- (4 -methylphenyl) - propoxy) -3, 3 -diphenylpropionsaure (1-346)2- (4,6-dimethyl-pyrimidin-2-yloxy) -3- (3- (4-methylphenyl) propoxy) -3,3-diphenylpropionic acid (1-346)
Zersetzung: 163-167°C ESI-MS: M+ = 496Decomposition: 163-167 ° C ESI-MS: M + = 496
2- (4 -Methoxy-6-methyl-pyrimidin-2-yloxy) -3- (2- (4 -methylthio- phenyl) ethoxy) -3 , 3 -diphenylpropionsaure (1-246)2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3- (2- (4-methylthiophenyl) ethoxy) -3, 3 -diphenylpropionic acid (1-246)
Zersetzung: 136-138°C ES I - MS : M+ = 530Decomposition: 136-138 ° C ES I - MS: M + = 530
2 - (4,6 -Dimethyl -pyrimidin- 2 -yloxy) - 3- (2 - (4 -methyl thiophenyl ) - ethoxy) -3,3- diphenylpropions ure ( I - 217 )2 - (4,6-dimethyl-pyrimidine-2-yloxy) - 3- (2 - (4-methyl-thiophenyl) -ethoxy) -3,3-diphenylpropionic acid (I - 217)
Zersetzung: 166-169°C ESI-MS: M+ = 514Decomposition: 166-169 ° C ESI-MS: M + = 514
2 - (4 -Methoxy- 6 -methyl -pyrimidin- 2 -yloxy) -3 - (2 - (4 -ethoxy- 3 -meth- oxyphenyl) ethoxy) -3, 3 -diphenylpropionsaure (1-145)2 - (4-methoxy-6-methyl-pyrimidine-2-yloxy) -3 - (2 - (4 -ethoxy-3-meth-oxyphenyl) ethoxy) -3, 3 -diphenylpropionic acid (1-145)
Zersetzung: 141-145°C ESI-MS: M+ = 558Decomposition: 141-145 ° C ESI-MS: M + = 558
2- (4 -Methoxy-6 -methyl-pyrimidin-2 -yloxy) -3- (2- (4 -ethoxyphenyl) ethoxy) -3,3 -diphenylpropionsaure (I- 510)2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3- (2- (4-ethoxyphenyl) ethoxy) -3,3 -diphenylpropionic acid (I- 510)
Zersetzung: 131-135°C ESI-MS: M+ = 528Decomposition: 131-135 ° C ESI-MS: M + = 528
2 - (4 -Methoxy-6 -methyl -pyrimidin- 2 -yloxy) -3 - (2 - (4 -i -propylphenyl) ethoxy) -3,3 -diphenylpropionsaure (I -705)2 - (4-methoxy-6-methyl-pyrimidine-2-yloxy) -3 - (2 - (4-i-propylphenyl) ethoxy) -3,3 -diphenylpropionic acid (I -705)
iH-NMR (200 MHz, DMSO): 7.0-7.35 ppm (14 H, m) , 6.35 (1 H, s) , 6.1 (1 H, s), 4.0 (1 H, m) , 3.9 (3 H, s) , 3.8 (3 H, s) , 3.7 (1 H, m) , 2.9 (3 H, m) , 2.2 (3 H, s) , 1.1 (6 H, d) . i H-NMR (200 MHz, DMSO): 7.0-7.35 ppm (14 H, m), 6.35 (1 H, s), 6.1 (1 H, s), 4.0 (1 H, m), 3.9 (3 H , s), 3.8 (3 H, s), 3.7 (1 H, m), 2.9 (3 H, m), 2.2 (3 H, s), 1.1 (6 H, d).
ESI-MS: M+ = 526ESI-MS: M + = 526
2 - (4 -Methoxy-6 -methyl -pyrimidin- 2 -yloxy) -3 - (2- (3,4 -methylendioxy- phenyl) ethoxy) -3 , 3 -diphenylpropionsaure (1-568)2 - (4-methoxy-6-methyl-pyrimidine-2-yloxy) -3 - (2- (3,4-methylenedioxy-phenyl) ethoxy) -3, 3 -diphenylpropionic acid (1-568)
Zersetzung: 146-148°C ESI-MS: M+ = 528Decomposition: 146-148 ° C ESI-MS: M + = 528
2- (4 -Methoxy- 5, 6 -dihydrofuro- (2, 3d) -pyrimidin- 2 -yloxy) -3-2- (4-methoxy- 5, 6 -dihydrofuro- (2, 3d) -pyrimidine- 2 -yloxy) -3-
(2 - (3,4 -methylendioxyphenyl) ethoxy) -3,3 -diphenylpropionsaure(2 - (3,4-methylenedioxyphenyl) ethoxy) -3,3 -diphenylpropionic acid
(1-501)(1-501)
Zersetzung: 145-149°C ESI-MS: M+ = 556 2 - (4 -Methoxy- 5, 6 -dihydrofuro- (2 , 3d) -pyrimidin-2 -yloxy) -3 - (2 - (4 -ethoxy-3 -methoxyphenyl) ethoxy) -3,3 -diphenylpropionsaure (1-735)Decomposition: 145-149 ° C ESI-MS: M + = 556 2 - (4-methoxy-5, 6 -dihydrofuro- (2, 3d) -pyrimidin-2-yloxy) -3 - (2 - (4 -ethoxy-3-methoxyphenyl) ethoxy) -3,3 -diphenylpropionic acid (1 -735)
XH-NMR (270 MHz, DMSO): 7.1-7.4 ppm (10 H, m) , 6.85 (2 H, ) , 6.7 (1 H, d) , 6.1 (1 H, s) , 4.6 (2 H, tr) , 4.0 (3 H, ) , 3.85 (3 H, s) , 3.75 (3 H, s) , 3.65 (1 H, m) , 3.05 (2 H, tr) , 2.8 (2 H, m) , 1.25 (3 H, m) . X H-NMR (270 MHz, DMSO): 7.1-7.4 ppm (10 H, m), 6.85 (2 H,), 6.7 (1 H, d), 6.1 (1 H, s), 4.6 (2 H, tr), 4.0 (3 H,), 3.85 (3 H, s), 3.75 (3 H, s), 3.65 (1 H, m), 3.05 (2 H, tr), 2.8 (2 H, m), 1.25 (3H, m).
ESI-MS: M+ = 586ESI-MS: M + = 586
2 - (4 -Methoxy- 5, 6 -dihydrofuro- (2, 3d) -pyrimidin- 2 -yloxy) -3 - (2- (4 -ethoxyphenyl) ethoxy) -3,3 -diphenylpropionsaure (1-407)2 - (4-methoxy- 5, 6 -dihydrofuro- (2, 3d) -pyrimidine- 2 -yloxy) -3 - (2- (4 -ethoxyphenyl) ethoxy) -3,3 -diphenylpropionic acid (1-407)
!H-NMR (270 MHz, DMSO): 7.1-7.4 ppm (12 H, m) , 6.8 (2 H, d) , 6.1 (1 H, s), 4.65 (2 H, tr) , 3.95 (3 H, m) , 3.8 (3 H, s), 3.65 (1 H, m) , 3.05 (2 H, tr) , 2.8 (2 H, m) , 1.25 (3 H, m) . ! H-NMR (270 MHz, DMSO): 7.1-7.4 ppm (12 H, m), 6.8 (2 H, d), 6.1 (1 H, s), 4.65 (2 H, tr), 3.95 (3 H, m), 3.8 (3 H, s), 3.65 (1 H, m), 3.05 (2 H, tr), 2.8 (2 H, m), 1.25 (3 H, m).
ESI-MS: M+ = 556ESI-MS: M + = 556
2 - (4,6 -Dimethyl -pyrimidin- 2 -yloxy) - 3- (2 - (4 -ethoxy- 3 -methoxyphenyl ) ethoxy) -3 , 3 -diphenylpropions ure (1-146)2 - (4,6-dimethyl-pyrimidine-2-yloxy) - 3- (2 - (4 -ethoxy-3-methoxyphenyl) ethoxy) -3, 3 -diphenylpropionic acid (1-146)
Zersetzung: 129-134°C ESI-MS: M+ = 542Decomposition: 129-134 ° C ESI-MS: M + = 542
2 - (4,6 -Dimethyl -pyrimidin- 2 -yloxy) -3 - (2 - (3,4 -methylendioxyphe- nyl) -ethoxy) -3 , 3 -diphenylpropions ure (1-569)2 - (4,6-dimethyl-pyrimidine-2-yloxy) -3 - (2 - (3,4-methylenedioxyphenyl) -ethoxy) -3, 3 -diphenylpropionic acid (1-569)
iH- MR (270 MHz, DMSO): 7.1-7.4 ppm (10 H, m) , 6.9 (1 H, s) , 6.8 (2 H, m) , 6.7 (1 H, d) , 6.2 (1 H, s) , 6.0 (2 H, s) , 3.95 (3 H, m) , 3.65 (1 H, m) , 2.8 (2 H, m) , 2.3 (6 H, s) .iH- MR (270 MHz, DMSO): 7.1-7.4 ppm (10 H, m), 6.9 (1 H, s), 6.8 (2 H, m), 6.7 (1 H, d), 6.2 (1 H, s), 6.0 (2 H, s), 3.95 (3 H, m), 3.65 (1 H, m), 2.8 (2 H, m), 2.3 (6 H, s).
ESI-MS: M+ = 512ESI-MS: M + = 512
2 - (4,6 -Dimethyl -pyrimidin- 2 -yloxy) -3 - (2 - (4 -ethoxyphenyl) ethoxy) - 3, -diphenylpropionsaure (1-473)2 - (4,6-dimethyl-pyrimidine-2-yloxy) -3 - (2 - (4 -ethoxyphenyl) ethoxy) - 3, -diphenylpropionic acid (1-473)
Zersetzung: 145-148°C ESI-MS: M+ = 512 2- (4 -Methoxy- 5, 6 -dihydrofuro- (2, 3d) -pyrimidin- 2 -yloxy) -3 -Decomposition: 145-148 ° C ESI-MS: M + = 512 2- (4-methoxy- 5, 6 -dihydrofuro- (2, 3d) -pyrimidine- 2 -yloxy) -3 -
( 2 - ( 4 - i -propylphenyl ) ethoxy) -3,3- diphenylpropionsaure (1-604)(2 - (4 - i-propylphenyl) ethoxy) -3,3-diphenylpropionic acid (1-604)
iH- MR (270 MHz, DMSO): 7.1-7.4 ppm (14 H, m) , 6.1 (1 H, s) , 4.6 (2 H, tr) , 3.9 (1 H, m) , 3.8 (3 H, s) , 3.6 (1 H, m) , 3.0 (2 H, tr) , 2.8 (3 H, m) , 1.1 (6 H, d) . i H-MR (270 MHz, DMSO): 7.1-7.4 ppm (14 H, m), 6.1 (1 H, s), 4.6 (2 H, tr), 3.9 (1 H, m), 3.8 (3 H , s), 3.6 (1 H, m), 3.0 (2 H, tr), 2.8 (3 H, m), 1.1 (6 H, d).
ESI-MS: M+ = 554ESI-MS: M + = 554
2 - (4 , 6 -Dimethyl -pyrimidin- 2 -yloxy) -3 - (2 - (4 -i -propylphenyl ) - ethoxy) -3 , 3 -diphenylpropionsaure (1-672)2 - (4, 6-dimethyl-pyrimidine-2-yloxy) -3 - (2 - (4-i-propylphenyl) -ethoxy) -3, 3 -diphenylpropionic acid (1-672)
Zersetzung: 156-160°C ESI-MS: M+ = 510Decomposition: 156-160 ° C ESI-MS: M + = 510
2 - (4 -Methoxy- 5, 6 -dihydrofuro- (2, 3d) -pyrimidin -2 -yloxy) -3 - (2 - (4 -methoxyphenyl) ethoxy) -3 , 3 -di (4 -methylphenyl ) - propionsäure (1-517)2 - (4-methoxy-5, 6 -dihydrofuro- (2, 3d) -pyrimidine -2 -yloxy) -3 - (2 - (4-methoxyphenyl) ethoxy) -3, 3 -di (4 -methylphenyl) - propionic acid (1-517)
iH-NMR (200 MHz, DMSO): 7.0-7.3 ppm (10 H, m) , 6.8 (2 H, d) , 6.0 (1 H, s), 4.6 (2 H, tr), 3.85 (3 H, s), 3.8 (1 H, m) , 3.7 (3 H, s) , 3.6 (1 H, m) , 3.0 (2 H, tr) , 2.8 (2 H, tr), 1.1 (6 H, d) . i H-NMR (200 MHz, DMSO): 7.0-7.3 ppm (10 H, m), 6.8 (2 H, d), 6.0 (1 H, s), 4.6 (2 H, tr), 3.85 (3 H , s), 3.8 (1 H, m), 3.7 (3 H, s), 3.6 (1 H, m), 3.0 (2 H, tr), 2.8 (2 H, tr), 1.1 (6 H, d ).
ESI-MS: M+ = 570ESI-MS: M + = 570
2 - (4 -Methoxy -6 -methyl -pyrimidin- 2 -yloxy) -3 - (2 - (4 -methoxyphenyl ) - ethoxy) -3,3- diphenylpropionsaure ( I - 622 )2 - (4-methoxy -6-methyl-pyrimidine-2-yloxy) -3 - (2 - (4-methoxyphenyl) - ethoxy) -3,3-diphenylpropionic acid (I - 622)
XH-NMR (270 MHz, DMSO): 7.1-7.4 ppm (12 H, m) , 6.8 (2 H, d) , 6.4 (1 H, s), 6.1 (1 H, s), 4.0 (1 H, m) , 3.7 (3 H, s) , 3.7 (1 H, m) , 2.8 (2 H, tr) , 2.3 (3 H, s) . X H-NMR (270 MHz, DMSO): 7.1-7.4 ppm (12 H, m), 6.8 (2 H, d), 6.4 (1 H, s), 6.1 (1 H, s), 4.0 (1 H , m), 3.7 (3 H, s), 3.7 (1 H, m), 2.8 (2 H, tr), 2.3 (3 H, s).
ESI-MS: M+ = 514ESI-MS: M + = 514
2 - (4 , 6 -Dimethyl -pyrimidin- 2 -yloxy) -3 - (2 - (4 -methoxyphenyl) - ethoxy) -3, 3 -diphenylpropionsaure (1-585)2 - (4, 6-dimethyl-pyrimidine-2-yloxy) -3 - (2 - (4-methoxyphenyl) -ethoxy) -3, 3 -diphenylpropionic acid (1-585)
iH-NMR (200 MHz, DMSO): 7.1-7.4 ppm (12 H, m) , 6.8 (3 H, m) , 6.1 (1 H, s), 4.0 (1 H, m) , 3.7 (3 H, s) , 3.6 (1 H, m) , 2.8 (2 H, tr) , 2.3 (6 H, s) . i H-NMR (200 MHz, DMSO): 7.1-7.4 ppm (12 H, m), 6.8 (3 H, m), 6.1 (1 H, s), 4.0 (1 H, m), 3.7 (3 H , s), 3.6 (1 H, m), 2.8 (2 H, tr), 2.3 (6 H, s).
ESI-MS: M+ = 498ESI-MS: M + = 498
2- (4 -Methoxy-6 -methyl -pyrimidin- 2 -yloxy) -3- (3 -phenylpropoxy) - 3, 3 -diphenylpropionsaure (1-499)2- (4-methoxy-6-methyl-pyrimidine-2-yloxy) -3- (3-phenylpropoxy) - 3,3-diphenylpropionic acid (1-499)
Zersetzung: 153-155°C ESI-MS: M+ = 498Decomposition: 153-155 ° C ESI-MS: M + = 498
2 - (4,6 -Dimethyl -pyrimidin-2 -yloxy) - 3 - (3 -phenylpropoxy) -3 , 3 -di - phenylpropionsäure (1-500)2 - (4,6-dimethyl-pyrimidin-2-yloxy) - 3 - (3-phenylpropoxy) -3, 3 -di - phenylpropionic acid (1-500)
Zersetzung: 148-151°C ESI-MS: M+ = 482Decomposition: 148-151 ° C ESI-MS: M + = 482
Analog oder wie im allgemeinen Teil beschrieben lassen sich die in Tabelle 1 aufgeführten Verbindungen herstellen. The compounds listed in Table 1 can be prepared analogously or as described in the general part.
Tabel le ITabel le I
Nr. R1 R4, R5 Q R6 R2 R3 Z X Y WR 1 R 4 , R 5 QR 6 R 2 R 3 ZXYW
1-1 COOH Phenyl - CH2-CH2- Phenyl OMe Me CH N N s1-1 COOH phenyl - CH2-CH2-phenyl OMe Me CH N N s
1-2 COOMe Phenyl - CH2-CH2- Phenyl CF3 Me CH N N 01-2 COOMe phenyl - CH2-CH2-phenyl CF 3 Me CH NN 0
1-3 COOH 4-Br-Phenyl - CH2-CH2- Phenyl OMe OMe CH N N 01-3 COOH 4-Br-phenyl - CH2-CH2-phenyl OMe OMe CH N N 0
1-4 COOH Phenyl - CH2-C(CH3)2- Phenyl OMe Me CH N N 01-4 COOH phenyl - CH 2 -C (CH 3 ) 2 - phenyl OMe Me CH NN 0
1-5 COOH 4-Cl-Phenyl - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl Me Me CH N N 01-5 COOH 4-Cl-phenyl-CH2-CH2-CH2-3,4-di-OMe-phenyl Me Me CH N N 0
1-6 COOH 4-Cl-Phenyl - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl Me Me N N N 01-6 COOH 4-Cl-Phenyl-CH2-CH2-CH 2 - 3,4-Di-OMe-Phenyl Me Me NNN 0
1-7 COOH Phenyl - CH2-CH2- 3,4-Di-C!-Phenyl Me Me CH N N 01-7 COOH phenyl - CH2-CH2-3,4-di-C! -Phenyl Me Me CH N N 0
1-8 COOH Phenyl - CH2-CH2- Phenyl Me Me N N CH 01-8 COOH phenyl - CH 2 -CH 2 - phenyl Me Me NN CH 0
1-9 COOH Phenyl - CH2-CH2- Phenyl Ethyl Me N N N 01-9 COOH phenyl - CH 2 -CH 2 - phenyl ethyl Me NNN 0
1-10 COOH Phenyl - CH=CH- CH2- Phenyl Ethyl Me CH N N 01-10 COOH phenyl - CH = CH- CH 2 - phenyl ethyl Me CH NN 0
1-11 COOH Phenyl - CH=CH- CH2- Phenyl OMe CH2- CH 2-CH2-C N N 01-11 COOH phenyl - CH = CH- CH 2 - phenyl OMe CH 2 - CH 2-CH 2 -CNN 0
1-12 COOH Phenyl - CH=CH- CH2- Phenyl OMe 0- CH2 -CH2-C N N 01-12 COOH phenyl - CH = CH- CH 2 - phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-13 COOH Phenyl - CH2-CH2- Phenyl OMe CH2- CH -CH2-C N N s1-13 COOH phenyl - CH2-CH2-phenyl OMe CH 2 - CH -CH 2 -CNN s
1-14 COOEt Phenyl - CH2-CH2- Phenyl OMe 0- CH2 -CH2-C N N 01-14 COOEt Phenyl - CH 2 -CH 2 - Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-15 COOH 4-Et-Phenyl - CH2-CH2- 14-SMe-Phenyl Me Me CH N N 0 1-15 COOH 4-Et-Phenyl - CH2-CH 2 - 14-SMe-Phenyl Me Me CH NN 0
Nr. R1 R4, R5 Q R6 R2 R3 Z X Y WR 1 R 4 , R 5 QR 6 R 2 R 3 ZXYW
1-16 COOH 4-Et-Phenyl - CH2-CH2- 4-SMe-Phenyl Me Me N N N 01-16 COOH 4-Et-Phenyl - CH 2 -CH 2 - 4-SMe-Phenyl Me Me NNN 0
1-17 COOMe Phenyl - CH2-CH2- 4-OMe-Phenyl OMe Me CH N N 01-17 COOMe Phenyl - CH2-CH2- 4-OMe-Phenyl OMe Me CH N N 0
1-18 COOEt Phenyl - CH2-CH2- 4-OMe-Phenyl Me Me CH N N s1-18 COOEt Phenyl - CH2-CH2- 4-OMe-Phenyl Me Me CH N N s
1-19 Tetrazol Phenyl - CH2-CH2- 4-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-19 tetrazole phenyl - CH 2 -CH 2 - 4-OMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-20 COOH Phenyl - C(CH3)2-CH2- 4-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-20 COOH phenyl - C (CH 3 ) 2 -CH 2 - 4-OMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-21 COOH Phenyl - CH2- C(CH3)2- 4-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-21 COOH phenyl - CH 2 - C (CH 3 ) 2 - 4-OMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-22 COOH 4-Cl-Phenyl - CH2-CH2- CH2- 4-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-22 COOH 4-Cl-Phenyl - CH 2 -CH 2 - CH 2 - 4-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-23 COOH 4-Cl-Phenyl - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl OMe Me CH N N 01-23 COOH 4-Cl-phenyl - CH 2 -CH 2 - CH 2 - 3,4-di-OMe-phenyl OMe Me CH NN 0
1-24 COOH 4-Br-Phenyl - CH2-CH2- 4-OMe-Phenyl OMe OMe CH N N 01-24 COOH 4-Br-phenyl - CH2-CH2- 4-OMe-phenyl OMe OMe CH N N 0
1-25 COOH Phenyl - CH2-CH2- 4-OMe-Phenyl OMe Me N N N 01-25 COOH phenyl - CH2-CH2- 4-OMe-phenyl OMe Me N N N 0
1-26 COOH Phenyl - CH2-CH2- 4- Me-Phenyl Me Me N N CH 01-26 COOH phenyl - CH 2 -CH2- 4- Me-phenyl Me Me NN CH 0
1-27 COOH Phenyl - CH=CH- CH2- Phenyl Me Me CH N N 01-27 COOH phenyl - CH = CH- CH 2 - phenyl Me Me CH NN 0
1-28 COOH Phenyl - CH=CH- CH2- Phenyl Me Me N N N 01-28 COOH phenyl - CH = CH- CH 2 - phenyl Me Me NNN 0
1-29 COOH Phenyl - CH2-CH1- 4-OMe-Phenyl Ethyl Me N N N 01-29 COOH phenyl - CH 2 -CH1- 4-OMe-phenyl ethyl Me NNN 0
1-30 COOH Phenyl - CH2-CH2- 4-OMe-Phenyl OMe CH2- CH2-CH2-C N N s1-30 COOH phenyl - CH 2 -CH 2 - 4-OMe-phenyl OMe CH 2 - CH 2 -CH 2 -CNN s
1-31 COOH 4-Et-Phenyl - CH2-CH2- 3- Me-Phenyl OMe 0- CH2-CH2-C N N 01-31 COOH 4-Et-Phenyl - CH 2 -CH 2 - 3- Me-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-32 COOH 4-£t-Phenyl - CH2-CH2- 4-SMe-Phenyl OMe Me | CH N N 01-32 COOH 4- £ t-phenyl - CH 2 -CH 2 - 4-SMe-phenyl OMe Me | CH NN 0
1-33 COOEt Phenyl - CH2-CH2- 4-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-33 COOEt Phenyl - CH2-CH2- 4-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-34 COOH Phenyl - CH2-CH2- 3,4-Di-OMe-Phenyl OMe 0- CH2-CH2-C N N s1-34 COOH phenyl - CH2-CH2- 3,4-di-OMe-phenyl OMe 0- CH 2 -CH 2 -CNN see
1-35 COOMe Phenyl - C(CH3)2-CH2- 3,4-Di-OMe-Phenyl OMe Me N N CH s1-35 COOMe phenyl - C (CH 3 ) 2 -CH 2 - 3,4-di-OMe-phenyl OMe Me NN CH s
1-36 COOH Phenyl - C(CH3)2-CH2- 3,4-Di-OMe-Phenyl Ethyl Me CH N N 01-36 COOH phenyl - C (CH 3 ) 2 -CH 2 - 3,4-di-OMe-phenyl ethyl Me CH NN 0
1-37 COOH 4-Br-Phenyl - CH2-CH2- 3,4-Di- Me-Phenyl CF3 Me CH N N 01-37 COOH 4-Br-phenyl-CH 2 -CH2- 3,4-di-Me-phenyl CF 3 Me CH NN 0
1-38 COOH 4-Cl-Phenyl - CH2-CH2- CH2- 4-OMe-Phenyl Me Me N N N 01-38 COOH 4-Cl-Phenyl - CH2-CH2-CH 2 - 4-OMe-Phenyl Me Me NNN 0
1-39 COOH 4-CI-Phenyl - CH1-CH2- CH2- 4-OMe-Phenyl Ethyl Me CH N N 01-39 COOH 4-CI-Phenyl - CH1-CH2-CH 2 - 4-OMe-Phenyl Ethyl Me CH NN 0
1 1—40 COOH Phenyl - CH2-CH2- 3,4-Di-Me-Phenyl OMe Me CH N N 0 1 1-40 COOH phenyl - CH2-CH2- 3,4-di-Me-phenyl OMe Me CH NN 0
r. R1 R4, R5 Q R6 R2 R3 Z X Y Wr. R 1 R 4 , R 5 QR 6 R 2 R 3 ZXYW
1-41 COOH Phenyl - CH2-CH2- 3,4-Di-OMe-Phenyl SMe Me CH N N 01-41 COOH phenyl - CH 2 -CH 2 - 3,4-di-OMe-phenyl SMe Me CH NN 0
1-42 COOH Phenyl - CH2-CH2- 3,4-Di-OMe-Phenyl Me Me N N CH 01-42 COOH phenyl - CH 2 -CH 2 - 3,4-di-OMe-phenyl Me Me NN CH 0
1-43 COOH Phenyl - CH=CH- CH2- Phenyl CF3 Me CH N N 01-43 COOH phenyl - CH = CH- CH 2 - phenyl CF 3 Me CH NN 0
1-44 COOH Phenyl - CH=CH- CH2- Phenyl OMe Me CH N N 01-44 COOH phenyl - CH = CH- CH 2 - phenyl OMe Me CH NN 0
1-45 COOH Phenyl - CH2-CH2- 3,4-Di- Me-Phenyl Ethyl Me CH N N s1-45 COOH phenyl - CH 2 -CH 2 - 3,4-di-Me-phenyl ethyl Me CH NN s
1-46 COOBzl Phenyl - CH2-CH2- 3,4-Di-OMe-Phenyl OMe CH2- CH2-CH2-C N N 01-46 COOBzl phenyl - CH 2 -CH 2 - 3,4-di-OMe-phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-47 COOH 4-Et-Phenyl - CH2-CH2- 3-OMe-Phenyl Me Me N N N 01-47 COOH 4-Et-Phenyl - CH 2 -CH 2 - 3-OMe-Phenyl Me Me NNN 0
1-48 COOH 4-Et-Phenyl - CH2-CH2- 3-OMe-Phenyl Ethyl Me CH N N 01-48 COOH 4-Et-Phenyl - CH2-CH2-3-OMe-Phenyl Ethyl Me CH N N 0
1-49 COOH 4-FπPhenyl - CH2-CH7- 3,4-^)i-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-49 COOH 4-FπPhenyl - CH2-CH7- 3,4 - ^) i-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-50 COOH Phenyl - C(CH3)2-CH2- 3,4,5-Tri-OMe-Phenyl CF3 Me CH N N 01-50 COOH phenyl - C (CH 3 ) 2 -CH 2 - 3,4,5-tri-OMe-phenyl CF 3 Me CH NN 0
1-51 COOH Phenyl - CH2-CH2- 3-Me-4-Et-Phenyl OMe CF3 CH N N 01-51 COOH phenyl - CH 2 -CH 2 - 3-Me-4-Et-phenyl OMe CF 3 CH NN 0
1-52 COOH Phenyl - CH2-CH2- 3-Me4-El-Phenyl OMe Me CH N N 01-52 COOH Phenyl - CH 2 -CH 2 - 3-Me4-El-Phenyl OMe Me CH NN 0
1-53 COOH 4-F-Phenyl - CH2-CH2- 4-Br-Phenyl Me Me N N N 01-53 COOH 4-F-phenyl - CH 2 -CH 2 - 4-Br-phenyl Me Me NNN 0
1-54 COOH 4-Cl-Phenyl - CH2-CH2- CH2- 4-OMe-Phenyl OMe Me CH N N 01-54 COOH 4-Cl-Phenyl-CH2-CH2-CH 2 - 4-OMe-Phenyl OMe Me CH NN 0
1-55 COOH 4-Cl-Phenyl - CH2-CH2- CH2- 4-OMe-Phenyl Me Me CH N N 01-55 COOH 4-Cl-Phenyl - CH2-CH2-CH 2 - 4-OMe-Phenyl Me Me CH NN 0
1-56 COOH Phenyl - CH2-CH2- 4-Br-Phenyl Me Me N N CH 01-56 COOH phenyl - CH2-CH2- 4-Br-phenyl Me Me N N CH 0
1-57 COOH Phenyl - CH2-CH2- 3-Br-Phenyl Ethyl Me CH N N s1-57 COOH phenyl - CH 2 -CH 2 - 3-Br-phenyl ethyl Me CH NN s
1-58 COOH Phenyl - CH2-CH2- 2-Me-Phenyl OMe CH2- CH2-CH2-C N N 01-58 COOH phenyl - CH2-CH2- 2-Me-phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-59 COOH Phenyl - CH=CH- CH2- 4— Me— Phenyl OMe CH2- CH2-CH2-C N N 01-59 COOH phenyl - CH = CH- CH 2 - 4-OMe Me Phenyl CH 2 - CH 2 -CH 2 -CNN 0
1-60 COOH Phenyl - CH=CH- CH2- 4— Me— Phenyl OMe 0- CH2-CH -C N N 01-60 COOH phenyl - CH = CH - CH 2 - 4 - Me - phenyl OMe 0 - CH 2 --CH - CNN 0
1-61 COOH 4-F-Phenyl - CH2-CH2- 3-Me-Phenyl OMe 0- CH2-CH2-C N N 01-61 COOH 4-F-phenyl-CH2-CH2-3-Me-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-62 COOH Phenyl - CH2-CH2- 3-Me4-SMe-Phenyl CF3 Me CH N N 01-62 COOH phenyl - CH2-CH2- 3-Me4-SMe-phenyl CF 3 Me CH NN 0
1-63 COOH 4-Et-Phenyl - CH2-CH2- 3- Me-Phenyl OMe Me CH N N 0 1-63 COOH 4-Et-Phenyl - CH 2 -CH 2 - 3- Me-Phenyl OMe Me CH NN 0
1-64 COOH 4-Et-Phenyl - CH2-CH2- 3-OMe-Phenyl Me Me CH N N 01-64 COOH 4-Et-Phenyl-CH2-CH2-3-OMe-Phenyl Me Me CH N N 0
1-65 Tetrazol Phenyl - CH2-CH2- 4-SMe-Phenyl Me OMe CH N N 0 1-65 tetrazole phenyl - CH2-CH2- 4-SMe-phenyl Me OMe CH NN 0
Nr. R1 R4, R5 0 R6 R2 R3 Z X Y WNo. R 1 R 4 , R 5 0 R 6 R 2 R 3 ZXYW
1-66 COOH 3-OMe-Phenyl - CH2-CH2- 4-SMe-Phenyl OMe Me CH N N 01-66 COOH 3-OMe-Phenyl - CH2-CH2- 4-SMe-Phenyl OMe Me CH N N 0
1-67 COOH Phenyl -0- CH2-CH2- 4-SMe-Phenyl Me Me CH N N O1-67 COOH phenyl -0- CH 2 -CH 2 - 4-SMe-phenyl Me Me CH NNO
1-68 COOH Phenyl - CH2-CH2- 4—n-Propoxy-Phenyl Me Me CH N N O1-68 COOH phenyl - CH 2 -CH2- 4-n-propoxy-phenyl Me Me CH NNO
1-69 COOH Phenyl - CH2-CH2- 4—n— Propoxy-Phenyl OMe Me CH N N 01-69 COOH phenyl - CH2-CH2- 4-n-propoxy-phenyl OMe Me CH N N 0
1-70 COOH Phenyl - CH2-CH2- 4-n—Butoxy-Phenyl Me Me CH N N 01-70 COOH phenyl - CH2-CH2- 4-n-butoxy-phenyl Me Me CH N N 0
1-71 COOH Phenyl - CH2-CH2- 4-n-Butoxy-Phenyl OMe Me CH N N 01-71 COOH phenyl - CH 2 -CH 2 - 4-n-butoxy-phenyl OMe Me CH NN 0
1-72 COOH Phenyl -O- CH2-CH2- 4-SMe-Phenyl Me Me CH N CH 01-72 COOH phenyl -O- CH2-CH2- 4-SMe-phenyl Me Me CH N CH 0
1-73 COOH Phenyl -0- CH2-CH2- 4-SMe-Phenyl Ethyl Me CH N N s1-73 COOH phenyl -0- CH 2 -CH 2 - 4-SMe-phenyl ethyl Me CH NN s
1-74 COOH Phenyl - CH2-CH2- CH2- 2-Me— Phenyl Ethyl Me CH N N 01-74 COOH phenyl - CH2-CH 2 - CH2-2-Me - phenyl ethyl Me CH NN 0
1-75 COOH Phenyl - CH2-CH2- CH - 2-Me-Phenyl OMe CH2- CH2-CH2-C N N 01-75 COOH phenyl - CH2-CH2-CH - 2-Me-phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-76 COOH Phenyl - CH2-CH2- 2-Me-4-SMe-Phenyl OMe CH2- CH2-CH2-C N N 01-76 COOH phenyl - CH2-CH2- 2-Me-4-SMe-phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-77 COOH Phenyl - C(CH3)2-CH2- 4-SMe- >henyl OMe O- CH2-CH2-C N N 01-77 COOH phenyl - C (CH 3 ) 2 -CH 2 - 4-SM- > henyl OMe O- CH 2 -CH 2 -CNN 0
1-78 COOMe Phenyl - CH2-CH2- 4-0Et-3-0Me-Phenyl CF3 Me CH N N 01-78 COOMe Phenyl - CH2-CH2- 4-0Et-3-0Me-Phenyl CF 3 Me CH NN 0
1-79 COOH Phenyl - CH=CH- CH2- 4— Me— Phenyl Me Me N N N 01-79 COOH phenyl - CH = CH - CH 2 - 4 - Me - phenyl Me Me NNN 0
I-S0 COOH Phenyl - CH=CH- CH2- 4-Me— Phenyl Ethyl Me CH N N 0I-S0 COOH phenyl - CH = CH- CH 2 - 4-Me - phenyl ethyl Me CH NN 0
1-81 COOH Phenyl - CH2-CH2- 4-(Di- e-Aπιino)-Phenyl OMe O CH2-CH2-C N N 01-81 COOH Phenyl - CH2-CH2- 4- (Di- e-Aπιino) -phenyl OMe O CH 2 -CH 2 -CNN 0
1-82 COOH 4-Cl-Phenyl - CH2-CH2- 4-OMe-Phenyl OMe Me CH N N 01-82 COOH 4-Cl-Phenyl - CH 2 -CH 2 - 4-OMe-Phenyl OMe Me CH NN 0
1-83 COOH 4-Et-Phenyl - CH2-CH2- 3,4-Oi-OMe-Phenyl Ethyl Me CH N N 01-83 COOH 4-Et-Phenyl - CH2-CH 2 - 3,4-Oi-OMe-Phenyl Ethyl Me CH NN 0
1-84 COOH 4-Et-Phcnyl - CH2-CH2- 3,4-Di-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-84 COOH 4-Et-Phenyl-CH2-CH2-3,4-Di-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-85 COOH 3-OMe-Phenyl - CH2-CH2- 4-OEt-3-OMe-Phenyl OMe Me CH N N 01-85 COOH 3-OMe-Phenyl - CH2-CH2- 4-OEt-3-OMe-Phenyl OMe Me CH N N 0
1-86 COOH Phenyl -0- CH2-CH2- 4-OEt-3-OMe-Phenyl Me Me CH N N 01-86 COOH phenyl -0- CH2-CH2- 4-OEt-3-OMe-phenyl Me Me CH N N 0
1-87 COOH Phenyl -S- CH2-CH2- 3-OMe-4-Cl-Phenyl Me Me CH N N 01-87 COOH phenyl -S- CH2-CH2- 3-OMe-4-Cl-phenyl Me Me CH N N 0
I-S8 COOH Phenyl - CH2-CH2- 3-OMe-4-Cl-Phenyl Ethyl Me CH N N 0 l-£9 COOH 3-Me-Phenyl - CH2-CH2- 3-OMe-4-Cl-Phcnyl OMe CH2- CH2-CH2-C N N 0I-S8 COOH Phenyl - CH2-CH2- 3-OMe-4-Cl-Phenyl Ethyl Me CH NN 0 l- £ 9 COOH 3-Me-Phenyl - CH2-CH2- 3-OMe-4-Cl-Phcnyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-90 COOH Phenyl - CH2-CH2- CH2- 2-Me-Phenyl Me Me CH N N 0 1-90 COOH phenyl - CH2-CH2-CH 2 - 2-Me-phenyl Me Me CH NN 0
Nr. R1 R , R5 Q R6 R2 R3 Z X Y WR 1 R, R 5 QR 6 R 2 R 3 ZXYW
1-91 COOH Phenyl - CH2-CH2- CH2- 2-Me-Phenyl Me Me N N N O1-91 COOH phenyl - CH 2 -CH 2 - CH 2 - 2-Me-phenyl Me Me NNNO
1-92 COOH Phenyl - CH2-CH2- 4-OEt-3-OMe-Phenyl OMe 0- CH2-CH2-C N N s1-92 COOH phenyl - CH2-CH2- 4-OEt-3-OMe-phenyl OMe 0-CH 2 -CH 2 -CNN s
1-93 COOMe Phenyl - CH2-CH2- 4-iPr-Phenyl CF3 Me CH N N 01-93 COOMe Phenyl - CH2-CH2- 4-iPr-Phenyl CF 3 Me CH NN 0
1-94 COOH 2-Mc-Phenyl - CH2-CH2- 4—F-Phenyl OMe Me CH N N 01-94 COOH 2-Mc-phenyl-CH 2 -CH2- 4-F-phenyl OMe Me CH NN 0
1-95 COOH Phenyl - CH=CH- CH2- 4-Me— Phenyl OMe Me CH N N 01-95 COOH phenyl - CH = CH- CH 2 - 4-Me- phenyl OMe Me CH NN 0
1-96 COOH Phenyl - CH=CH- CH2- 4— Me— henyl Me Me CH N N 01-96 COOH phenyl - CH = CH - CH 2 - 4- methenyl Me Me CH NN 0
1-97 COOH 2— Me-Phenyl - CH2-CH2- 4-iPr-Phenyl Me Me CH N N 01-97 COOH 2- Me phenyl - CH 2 -CH2- 4-iPr-phenyl Me Me CH NN 0
1-98 COOH Phenyl -O- CH2-CH2- Phenyl Me Me N N N 01-98 COOH phenyl -O- CH 2 -CH2- phenyl Me Me NNN 0
1-99 COOH 4-Et-Phenyl - CH2-CH2- 3,4-Di-OMe-Phenyl Me Me CH N N 0 l-I 00 COOH 4-Et-Phenyl - CH2-CH2- 3,4-4>i-OMe-Phenyl Me Me N N N 01-99 COOH 4-Et-Phenyl - CH2-CH2- 3,4-Di-OMe-Phenyl Me Me CH NN 0 lI 00 COOH 4-Et-Phenyl - CH2-CH2- 3,4-4> i-OMe -Phenyl Me Me NNN 0
1-101 COOH Phenyl - CH2-CH2- 4—( Di-M e— Amino)-Phenyl Me Me N N N 01-101 COOH Phenyl - CH2-CH2- 4- (Di-M e-Amino) -phenyl Me Me N N N 0
I-I02 COOH Phenyl - CH2-CH2- 4-(Di-Me-Anιino)-Phenyl Ethyl Me CH N N 0I-I02 COOH phenyl - CH2-CH2- 4- (Di-Me-Anιino) -phenyl ethyl Me CH N N 0
1-103 COOH 2-Me— Phenyl - CH2-CH2- 4-Cl-Phenyl Ethyl Me CH N N 01-103 COOH 2-Me-Phenyl - CH2-CH2- 4-Cl-Phenyl Ethyl Me CH N N 0
1-104 COOH 4-4"-Phenyl - CH2-CH2- 4-OMe-Phenyl OMe CH2- CH2-CH2-C N N 01-104 COOH 4-4 " -phenyl - CH2-CH2- 4-OMe-Phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
[-105 COOH Phenyl - C(CH3)2-CH2- 3-Cl-Phenyl OMe 0- CH2-CH2-C N N 0[-105 COOH phenyl - C (CH 3) 2 -CH 2 - 3-Cl-phenyl OMe CH 2 -CH 2 0- 0 -CNN
1-106 COOH Phenyl - CH2-CH2- CH2- 2— Me— Phenyl CF3 Me CH N N 01-106 COOH phenyl - CH 2 -CH2- CH2- 2-Me-phenyl CF 3 Me CH NN 0
1-107 COOH Phenyl - CH2-CH2- CH;,- 2-Me-Phenyl OMe Me CH N N 01-107 COOH phenyl - CH2-CH2-CH;, - 2-Me-phenyl OMe Me CH N N 0
1-108 COOH Phenyl - CH2-CH2- 3 ,4— Methylendioxyphenyl Me Me N N CH 01-108 COOH phenyl - CH2-CH2-3,4- methylenedioxyphenyl Me Me N N CH 0
1-109 COOMe Phenyl - CH2-CH2- 3,4— Methylendioxyphenyl OMe Me CH N N 01-109 COOMe phenyl - CH2-CH2- 3,4- methylenedioxyphenyl OMe Me CH N N 0
1-110 COOH Phenyl - CH2-CH2- 3 ,4— ethylendioxyphenyl Me Me CH N N s1-110 COOH phenyl - CH2-CH2-3,4- ethylenedioxyphenyl Me Me CH N N s
1-111 COOH Phenyl - CH=CH- CH2- 4-iPr-Phenyl OMe 0- CH2-CH2-C N N 01-111 COOH phenyl - CH = CH- CH 2 - 4-iPr-phenyl OMe 0- CH 2 -CH 2 -CNN 0
[-1 12 COOH Phenyl - CH=CH- CH2- 4— Me-Phenyl CF3 Me CH N N 0[-1 12 COOH phenyl - CH = CH - CH 2 - 4- Me phenyl CF 3 Me CH NN 0
1-1 13 COOH Phenyl - CH-.-CH2- 3,4-Di-Me-Phenyl Me Me CH N N 01-1 13 COOH Phenyl - CH -.- CH2- 3,4-Di-Me-Phenyl Me Me CH N N 0
1-1 14 COOH Phenyl -0- CH2-CH2 3,4-Di~Mc-Phenyl Ethyl Me CH N N 01-1 14 COOH phenyl -0- CH2-CH 2 3,4-di ~ Mc-phenyl ethyl Me CH NN 0
1-1 15 COOH 4-Et-Pheny] - CH2-CH2- 4-OMe-Phenyl OMe 0- CH2-CH2-C N N 0 1-1 15 COOH 4-Et-Pheny] - CH2-CH2- 4-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
Nr. R1 R4, R5 0 R6 R2 R3 Z X Y WNo. R 1 R 4 , R 5 0 R 6 R 2 R 3 ZXYW
1-116 COOH 4-El-Phenyl - CH2-CH2- 3,4-Di-OMe-Phenyl OMe Me CH N N 01-116 COOH 4-El-Phenyl - CH 2 -CH2- 3,4-Di-OMe-Phenyl OMe Me CH NN 0
1-1 17 COO- Phenyl - CH2-CH2- 3 ,4-Methylendioxyphenyl OMe CH2- CH2-CH2-C N N 0 i— Propyl1-1 17 COO- phenyl - CH2-CH2- 3, 4-methylenedioxyphenyl OMe CH 2 - CH 2 -CH 2 -CNN 0 i-propyl
1-1 18 COOH Phenyl - CH2-CH2- 3,4-Di-Me-Phenyl OMe 0- CH2-CH2-C N N 01-1 18 COOH phenyl - CH2-CH2-3,4-di-Me-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-119 COOH Phenyl - CH2-CH2- 4-<Di-Me-Amino)-Phenyl OMe Me CH N N 01-119 COOH phenyl - CH2-CH2- 4- <di-Me-amino) -phenyl OMe Me CH N N 0
1-120 COOH Phenyl - CH2-CH2- 4-(Di-Me-Amino>-Phenyl Me Me CH N N 01-120 COOH phenyl - CH2-CH2- 4- (Di-Me-Amino> -phenyl Me Me CH N N 0
1-121 COOH 4— F-Phenyl - CH2-CH2- 4—Me-Phenyl CF3 Me CH N N 01-121 COOH 4- F-phenyl-CH2-CH2-4-Me-phenyl CF 3 Me CH NN 0
1-122 COOH Phenyl - CH2-CH2- CH2- 3-OMe-Phenyl Ethyl Me CH N N 01-122 COOH phenyl - CH2-CH2-CH 2 - 3-OMe-phenyl ethyl Me CH NN 0
1-123 COOH Phenyl - CH2-CH2- CH2- 3-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-123 COOH phenyl - CH2-CH 2 - CH 2 - 3-OMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-124 COOH Phenyl -S- CH2-CH2- 4—Me-Phenyl OMe Me CH N N 0COOH 1-124 phenyl -S- CH 2 -CH 2 - 4-Me-phenyl OMe Me CH NN 0
1—125 COOH Phenyl - CH(OH)-CH2- 4—Me-Phenyl Me Me CH N N 0COOH 1-125 phenyl - CH (OH) -CH 2 - 4-Me-phenyl Me Me CH NN 0
1-126 COOH Phenyl - CH -CH2- 3-OMe-4-Me-Phenyl Me Me CH N N 01-126 COOH phenyl - CH -CH2- 3-OMe-4-Me-phenyl Me Me CH N N 0
1-127 COOH Phenyl - CH=CH- CH2- 4-iPr-Phenyl Ethyl Me CH N N 0 1-127 COOH Phenyl - CH = CH- CH 2 - 4-iPr-Phenyl Ethyl Me CH NN 0
1-128 COOH Phenyl - CH=CH- CH2- 4-iPr-Phenyl OMe Me CH N N 01-128 COOH phenyl - CH = CH- CH 2 - 4-iPr-phenyl OMe Me CH NN 0
1-129 COOH Phenyl - CH2-CH2- 4— Me-Phenyl Ethyl Me N N CH 0COOH 1-129 phenyl - CH 2 CH 2 - 4-Me-phenyl ethyl Me CH NN 0
1-130 COOH Phenyl - CH2-CH2- 3- Me-4-Me-Phenyl OMe CH2- CH2-CH2-C N N 01-130 COOH phenyl - CH2-CH 2 - 3- Me-4-Me-phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-131 COOH 4-Et-Phenyl - CH2-CH2- 4-OMe-Phenyl Me Me N N N 01-131 COOH 4-Et-Phenyl - CH2-CH2- 4-OMe-Phenyl Me Me N N N 0
1-132 COOH 4-Et-Phenyl - CH2-CH2- 4-OMe-Phenyl Ethyl Me CH N N 01-132 COOH 4-Et-Phenyl - CH2-CH2- 4-OMe-Phenyl Ethyl Me CH N N 0
1-133 COOH Phenyl - CH2-CH2- 4-Me-Phenyl OMe θ CH2-CH2-C N N s1-133 COOH phenyl - CH2-CH2- 4-Me-phenyl OMe θ CH 2 -CH 2 -CNN s
1-134 COOBulyl Phenyl - CH2-CH2- 4-Et-Phenyl CF3 Me CH N N 01-134 COOBulyl Phenyl - CH 2 -CH 2 - 4-Et-Phenyl CF 3 Me CH NN 0
1-135 COOH 4-1-Phenyl - CH2-CH2- 4-Et-Phenyl OMe Me CH N N 01-135 COOH 4-1-phenyl - CH2-CH2- 4-Et-phenyl OMe Me CH N N 0
[-136 COOH Phenyl - CH(OH)-CH2- 4-Et-Phenyl Me Me CH N N 0[-136 COOH phenyl - CH (OH) -CH 2 - 4-Et-phenyl Me Me CH NN 0
1-137 COOH Phenyl - CH2-CH2- 2-OMe-Phenyl OMe CH2- CH2-CH2-C N N 01-137 COOH phenyl - CH 2 -CH 2 - 2-OMe-phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-138 COOH Phenyl - CH2-CH2- CH2- 3- Me-Phenyl Me Me CH N N 01-138 COOH Phenyl - CH2-CH 2 - CH2- 3- Me-Phenyl Me Me CH NN 0
1-139 | COOH Phenyl - CH2-CH2- CH2- 3-OMe-Phenyl Me Me N N N 0 1-139 | COOH phenyl - CH2-CH2-CH 2 - 3-OMe-phenyl Me Me NNN 0
Nr. R1 R4, R5 Q R6 R2 R3 Z X Y WR 1 R 4 , R 5 QR 6 R 2 R 3 ZXYW
1-140 COOH Phenyl - CH2-CH2- 2-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-140 COOH phenyl - CH 2 -CH 2 - 2-OMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-141 COOH Phenyl - CH2-CH2- 3-OMe-4-Et-Phenyl Me Me N N N 01-141 COOH phenyl - CH 2 -CH 2 - 3-OMe-4-Et-phenyl Me Me NNN 0
1-142 COOH Phenyl - CH2-CH2- 4-Et-Phenyl Ethyl Me N N N 01-142 COOH Phenyl - CH2-CH2- 4-Et-Phenyl Ethyl Me N N N 0
1-143 COOH Phenyl - CH=CH- CH2- 4-Cl-Phenyl Ethyl Me CH N N 01-143 COOH Phenyl - CH = CH- CH 2 - 4-Cl-Phenyl Ethyl Me CH NN 0
1-144 COOH Phenyl - CH=CH- CH2- 4-Cl-Phenyl OMe CH2- CH2-CH2-C N N 01-144 COOH phenyl - CH = CH- CH 2 - 4-Cl-phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-145 COOH Phenyl - CH2-CH2- 4-OEt-3-OMe-Phenyl OMe Me CH N N 01-145 COOH phenyl - CH2-CH2- 4-OEt-3-OMe-phenyl OMe Me CH N N 0
1-146 COOH Phenyl - CH2-CH2- 4-OEt-3-OMe-Phenyl Me Me CH N N 01-146 COOH phenyl - CH2-CH2- 4-OEt-3-OMe-phenyl Me Me CH N N 0
1-147 COOH 4-Et-Phenyl - CH2-CH2- 4-OMe-Phenyl OMe Me CH N N 01-147 COOH 4-Et-Phenyl - CH2-CH2- 4-OMe-Phenyl OMe Me CH N N 0
1-148 COOH 4-^t-Phenyl - CH2-CH2- 4-OMe-Phenyl Me Me CH N N 01-148 COOH 4- ^ t-phenyl - CH2-CH2- 4-OMe-phenyl Me Me CH N N 0
1-149 COOH Phenyl - CH2-CH2- 3-OMe-4-Et-Phenyl OMe 0- CH=CH-C N N 01-149 COOH phenyl - CH2-CH2- 3-OMe-4-Et-phenyl OMe 0- CH = CH-C N N 0
1-150 COOH Phenyl - CH2-CH7- 3-OMe -Et-Phenyl OMe O CH2-CH2-C N N 01-150 COOH phenyl - CH2-CH7- 3-OMe -Et-phenyl OMe O CH 2 -CH 2 -CNN 0
1-151 COOH 4-Me-Phenyl - CH2-CH2- Cyclohexyl CF3 Me CH N N 01-151 COOH 4-Me-Phenyl - CH 2 -CH 2 - Cyclohexyl CF 3 Me CH NN 0
1-152 COOH Phenyl - CH2-CH2- Cyclohexyl OMe Ethyl CH N N 01-152 COOH phenyl - CH 2 -CH 2 - cyclohexyl OMe ethyl CH NN 0
1-153 COOMe Phenyl - CH2-CH2- Cyclohexyl OMe Me CH N N 01-153 COOMe Phenyl - CH2-CH2-Cyclohexyl OMe Me CH N N 0
1-154 COOH Phenyl - CH2-CH2- CH2- 3-OMe-Phenyl CF3 Me CH N N 01-154 COOH phenyl - CH 2 -CH2- CH 2 - 3-OMe-phenyl CF 3 Me CH NN 0
1-155 COOH Phenyl - CH2-CH2- CH2- 3- Me-Phenyl OMe Me CH N N 01-155 COOH phenyl - CH2-CH2-CH 2 - 3- Me-phenyl OMe Me CH NN 0
1-156 COOH Phenyl - CH2-CH2- Cyclohexyl Me Me CH N CH 01-156 COOH phenyl - CH 2 -CH 2 - cyclohexyl Me Me CH N CH 0
1-157 COOH Phenyl - CH2-CH2- Cyclohexyl Me Me N N CH 01-157 COOH phenyl - CH2-CH2-cyclohexyl Me Me N N CH 0
1-158 COOH 4-Cl-Phenyl - CH2-CH2- Cyclohexyl Ethyl Me CH N N 01-158 COOH 4-Cl-Phenyl-CH2-CH2-Cyclohexyl Ethyl Me CH N N 0
1-159 COOH Phenyl - CH=CH- CH2- 4-Cl-Phenyl Me Me CH N N 01-159 COOH phenyl - CH = CH- CH 2 - 4-Cl-phenyl Me Me CH NN 0
1-160 COOH Phenyl - CH=CH- CH2- 4-CI-Phenyl Me Me N N N 01-160 COOH phenyl - CH = CH- CH 2 - 4-CI-phenyl Me Me NNN 0
1—161 COOH Phenyl - CH2-CH2- 2-OMe-Phenyl Me Me N N N 01-161 COOH phenyl - CH2-CH 2 - 2-OMe-phenyl Me Me NNN 0
1-162 COOH Phenyl - CH2-CH2- 2- Me-Phenyl Ethyl Me CH N N 01-162 COOH phenyl - CH2-CH2- 2 Me phenyl ethyl Me CH N N 0
1-163 COOH 4-Cl-Phcnyl - CH2-CH2- 2-OMe-Phenyl Ethyl Me CH N N 01-163 COOH 4-Cl-Phenyl-CH2-CH2-2-OMe-Phenyl Ethyl Me CH N N 0
1-164 COOH 4-Cl-Phenyl - CH7-CH2- 2-OMe-Phenyl OMe 0- CH2-CH2-C N N 0 1-164 COOH 4-Cl-Phenyl-CH7-CH2- 2-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
Nr. R ' R4, R5 Q R6 R2 R3 Z X Y WNo. R 'R 4 , R 5 QR 6 R 2 R 3 ZXYW
1-189 COOH 2-Me-Phenyl - CH7-CH2- Naphth-2-yl OMe Me CH N N 01-189 COOH 2-Me-Phenyl-CH7-CH2-Naphth-2-yl OMe Me CH N N 0
1-190 COOH Phenyl - CH2-CH2- Naphth-2-yl Me Me CH N N s1-190 COOH phenyl - CH2-CH2-naphth-2-yl Me Me CH N N s
1-191 COOH Phenyl - CH=CH- CH2- 4-C -Phenyl OMe 0- CH2-CH2-C N N 01-191 COOH phenyl - CH = CH- CH 2 - 4-C -phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-192 COOH Phenyl - CH=CH- CH2- 4-iPr-Phenyl Me Me CH N N 01-192 COOH phenyl - CH = CH- CH 2 - 4-iPr-phenyl Me Me CH NN 0
1-193 COOH Phenyl - CH2-CH2- 4-SMe-Phenyl Ethyl Me CH N N 01-193 COOH phenyl - CH2-CH2- 4-SMe-phenyl ethyl Me CH N N 0
1-194 COOH Phenyl - CH2-CH2- 4-SMe-Phenyl OMe CH2- CH2-CH2-C N N 01-194 COOH phenyl - CH2-CH2- 4-SMe-phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-195 COOH 4-CF3-Phenyl - CH2-CH2- 3 ,4-4)i-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-195 COOH 4-CF 3 -phenyl - CH 2 -CH 2 - 3, 4-4) i-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-196 COOH 4-CF3-Phenyl - CH2-CH2- 3-OMe-Phenyl OMe Me CH N N 01-196 COOH 4-CF 3 -phenyl - CH 2 -CH 2 - 3-OMe-Phenyl OMe Me CH NN 0
1-197 COOH Phenyl - CH2-CH2- Naphth-2-yl Me Me N N CH 01-197 COOH phenyl - CH2-CH2-naphth-2-yl Me Me N N CH 0
1-198 COOH Phenyl - CH2-CH2- l-Me-Naphth-2- rl Ethyl Me CH N N 01-198 COOH Phenyl - CH2-CH 2 - l-Me-Naphth-2-rl Ethyl Me CH NN 0
1-199 COOH Phenyl - CH2-CH2- l-Me-Naphth-2-yl OMe CH2- CH2-CH2-C N N 01-199 COOH phenyl - CH 2 -CH2- l-Me-Naphth-2-yl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-200 COOMe Phenyl - CH2-CH2- Naphlh-2-yl OMe 0- CH2-CH2-C N N 01-200 COOMe phenyl - CH2-CH2-Naphlh-2-yl OMe 0- CH 2 -CH 2 -CNN 0
1-201 COOEt Phenyl - CH2-CH2- 4-OEt-Phenyl CF3 Me CH N N 01-201 COOEt Phenyl - CH2-CH2- 4-OEt-Phenyl CF 3 Me CH NN 0
1-202 COOH Phenyl - CH2-CH2- CH2- 4-OEt-Phenyl CF3 Me CH N N 01-202 COOH phenyl - CH2-CH2-CH 2 - 4-OEt-phenyl CF 3 Me CH NN 0
1-203 COOH Phenyl - CH2-CH2- CH2- 4-OEt-Phenyl OMe Me CH N N 01-203 COOH phenyl - CH2-CH2-CH 2 - 4-OEt-phenyl OMe Me CH NN 0
1-204 COOH Phenyl - CH2-CH2- Cyclohexyl Me Me N N N 01-204 COOH phenyl - CH2-CH2-cyclohexyl Me Me N N N 0
1-205 COOH Phenyl - CH2-CH2- Cyclohexyl Ethyl Me CH N N 01-205 COOH phenyl - CH2-CH2-cyclohexyl ethyl Me CH N N 0
1-206 Tetrazol Phenyl - CH2-CH2- 4-OEt-Phenyl OMe Me CH N N 01-206 tetrazole phenyl - CH2-CH2- 4-OEt-phenyl OMe Me CH N N 0
1-207 COOH Phenyl - CH=CH- CH2- 3,4-Di-OMe-Phenyl Ethyl Me CH N N 01-207 COOH phenyl - CH = CH- CH 2 - 3,4-di-OMe-phenyl ethyl Me CH NN 0
1-208 COOH Phenyl - CH=CH- CH2- 3,4-Di-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-208 COOH phenyl - CH = CH- CH 2 - 3,4-di-OMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-209 COOH Phenyl - CH7-CH2- 4-OH-Phenyl Me Me CH N N 01-209 COOH phenyl - CH7-CH2- 4-OH-phenyl Me Me CH N N 0
1-210 COOH Phenyl - CH7-CH2- 4- H-Phenyl Ethy! Me N N CH 01-210 COOH phenyl - CH7-CH2- 4- H-phenyl ethyl! Me N N CH 0
1-211 COOH 4-CF3-Phenyl - CH7-CH2- 3,4-4)i-OMe-Phenyl Me Me N N N 01-211 COOH 4-CF 3 -phenyl - CH7-CH2- 3,4-4) i-OMe-Phenyl Me Me NNN 0
1-212 COOH 4-CF3-Phcnyl - CH7-CH2- 3,4-Di-OMe-Phenyl Ethyl Me CH N N 0 1-212 COOH 4-CF 3 -Phcnyl - CH7-CH2- 3,4-Di-OMe-Phenyl Ethyl Me CH NN 0
Nr. R1 R4, R5 Q R6 R2 R3 Z X Y WR 1 R 4 , R 5 QR 6 R 2 R 3 ZXYW
1-213 COOH Phenyl - CH2-CH2- 3-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-213 COOH phenyl - CH 2 -CH 2 - 3-OMe-phenyl OMe 0-CH 2 -CH 2 -CNN 0
1-214 COOH Phenyl - CH2-CH2- 2-OMe-Phenyl CF3 Me CH N N 01-214 COOH phenyl - CH2-CH2-2-OMe-phenyl CF 3 Me CH NN 0
1-215 COOH Phenyl - CH2-CH2- 4-OEt-Phenyl Ethyl Me CH N N s1-215 COOH phenyl - CH2-CH2- 4-OEt-phenyl ethyl Me CH N N s
1-216 COOH Phenyl - C(CH3)2-CH2- 4-OEt-Phenyl OMe CH2- CH2-CH2-C N N 01-216 COOH phenyl - C (CH 3 ) 2-CH 2 - 4-OEt-phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-217 COOH Phenyl - CH2-CH2- 4-SMe-Phenyl Me Me | CH N N 01-217 COOH phenyl - CH2-CH2- 4-SMe-phenyl Me Me | CH N N 0
1-218 COOH Phenyl - CH2-CH2- CH2- 4-Cl-Phenyl OMe CH2- CH2-CH2-C N N 01-218 COOH phenyl - CH2-CH2-CH 2 - 4-Cl-phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-219 COOH Phenyl - CH-2-CH2- CH2- 4-Cl-Phenyl OMe 0- CH2-CH2-C N N 01-219 COOH phenyl - CH-2-CH2-CH 2 - 4-Cl-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-220 COOH Phenyl - CH2-CH2- 4-SMe-Phenyl Me Me N N N 01-220 COOH phenyl - CH 2 -CH 2 - 4-SMe-phenyl Me Me NNN 0
1-221 COOH Phenyl - O-CH2-CH2- 4-OEt-Phenyl OMe 0- CH2-CH2-C N N 01-221 COOH phenyl - O-CH2-CH2- 4-OEt-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-222 COOH 4-Br-Phenyl - CH2-CH2- 3,5- i-OMe-Phenyl CF3 Me N N CH 01-222 COOH 4-Br-phenyl-CH2-CH2-3,5-i-OMe-phenyl CF 3 Me NN CH 0
1-223 COOH Phenyl - CH=CH- CH2- 3,4-Di-OMe-Phenyl Me Me CH N N 01-223 COOH phenyl - CH = CH- CH 2 - 3,4-di-OMe-phenyl Me Me CH NN 0
1-224 COOH Phenyl - CH=CH- CH2- 3,4-Di-OMe-Phenyl Me Me N N N 01-224 COOH phenyl - CH = CH- CH 2 - 3,4-di-OMe-phenyl Me Me NNN 0
1-225 COOH 4-I-Phenyl - CH2-CH2- 3,5-Di-OMe-Phenyl OMe Me CH N N 01-225 COOH 4-I-phenyl-CH2-CH2-3,5-di-OMe-phenyl OMe Me CH N N 0
1-226 COOH Phenyl - CH2-CH2- 3,5-Di-OMe-Phenyl Me Me CH N CH 01-226 COOH phenyl - CH 2 -CH 2 - 3,5-di-OMe-phenyl Me Me CH N CH 0
1-227 COOH 4-CF3-Phcnyl - CH2-CH2- 3,4-4)i-OMe-Phenyl OMe Me CH N N 01-227 COOH 4-CF 3 -Phcnyl - CH 2 -CH 2 - 3,4-4) i-OMe-Phenyl OMe Me CH NN 0
1-228 COOH 4-CF3-Phenyl - CH2-CH2- 3,4-Di-OMe-Phenyl Me Me CH N N 01-228 COOH 4-CF 3 -phenyl-CH2-CH2-3,4-di-OMe-phenyl Me Me CH NN 0
1-229 COOH Phenyl - CH7-CH2- 3,5-Di-OMe-Phenyl Ethyl Me N N N 01-229 COOH phenyl - CH7-CH2- 3,5-di-OMe-phenyl ethyl Me N N N 0
1-230 COOH Phenyl - CH2-CH2- Cyclohexyl OMe Me CH N N 01-230 COOH phenyl - CH2-CH2-cyclohexyl OMe Me CH N N 0
1-231 COOH Phenyl - CH2-CH2- Cyclohexyl Me Me CH N N 01-231 COOH phenyl - CH2-CH 2 - cyclohexyl Me Me CH NN 0
1-232 COOH Phenyl - CH(OH)-CH2- 3,5-4)i-OMe-Phenyl Ethyl Me CH N N 01-232 COOH phenyl - CH (OH) -CH 2 - 3.5-4) i-OMe-phenyl ethyl Me CH NN 0
1-233 COOH Phenyl - CH2-CH2- 3 ,5-4)i-OMe^-Cl-Phenyl OMe CH2- CH2-CH2-C N N 0COOH 1-233 phenyl - CH2-CH2- 3, 5-4) i-OMe ^ -Cl-phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-234 COOH Phenyl - CH2-CH2- CH2- 4-Cl-Phenyl Me Me N N N 01-234 COOH phenyl - CH2-CH2-CH 2 - 4-Cl-phenyl Me Me NNN 0
1-235 COOH Phenyl - CH2-CH2- CH2- 4-Cl-Phenyl Ethyl Me CH N N 01-235 COOH phenyl - CH2-CH2-CH 2 - 4-Cl-phenyl ethyl Me CH NN 0
1-236 COOMe Phenyl - CH2-CH7- 3,5-Di-OMe-Phenyl OMe 0- CH2-CH2-C N N 0 1-236 COOMe phenyl - CH 2 -CH7- 3,5-di-OMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0
Nr. R1 R4, Rs Q R6 R2 R3 Z X Y WR 1 R 4 , R s QR 6 R 2 R 3 ZXYW
1-261 COOH Phenyl - CH(2-OMe-Phenyl)-CH2- 2-OMe-Phenyl OMe Me CH N N O1-261 COOH phenyl - CH (2-OMe-phenyl) -CH 2 - 2-OMe-phenyl OMe Me CH NNO
1-262 COOH Phenyl - CH2-CH2- 2-OMe-4-Br-Phenyl Me Me CH N N 01-262 COOH phenyl - CH 2 -CH 2 - 2-OMe-4-Br-phenyl Me Me CH NN 0
1-263 COOH Phenyl - CH2-CH2- 3-OMe-Phenyl Me Me CH N N 01-263 COOH phenyl - CH2-CH2- 3-OMe-phenyl Me Me CH N N 0
1-264 COOH Phenyl - CH2-CH2- 3-OMe-Phenyl Me Me N N N 01-264 COOH phenyl - CH2-CH2- 3-OMe-phenyl Me Me N N N 0
1-265 COOH Phenyl - CH2-CH2- 2-OMe-Phenyl Me Me N N CH 01-265 COOH phenyl - CH2-CH2-2-OMe-phenyl Me Me N N CH 0
1-266 COOH Phenyl - CH2-CH2- CH2- 4-Et-Phenyl OMe 0- CH2-CH2-C N N 01-266 COOH Phenyl - CH2-CH 2 - CH 2 - 4-Et-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-267 COOH Phenyl - CH2-CH2- CH2- 4-Cl-Phenyl CF3 Me CH N N 01-267 COOH phenyl - CH2-CH 2 - CH 2 - 4-Cl-phenyl CF 3 Me CH NN 0
1-268 COOH Phenyl - CH2-CH2- 2-OMe-Phenyl Ethyl Me CH N N s1-268 COOH phenyl - CH 2 -CH 2 - 2-OMe-phenyl ethyl Me CH NN s
1-269 COOH Phenyl - CH2-CH7- 3 ,4,5-Tri-OMe-Phenyl OMe 0- CH2-CH2-C N N 0COOH 1-269 phenyl - CH2-CH7- 3, 4,5-tri-OMe-phenyl OMe CH 2 -CH 2 0- 0 -CNN
1-270 COOH Phenyl - CH2-CH2- 4-SMe-Phenyl CF3 Me CH N N 01-270 COOH phenyl - CH 2 -CH 2 - 4-SMe-phenyl CF 3 Me CH NN 0
1-271 COOH Phenyl - CH=CH- CH2- 4-OMe-Phenyl Me Me N N N 01-271 COOH phenyl - CH = CH - CH 2 - 4-OMe-phenyl Me Me NNN 0
1-272 COOH Phenyl - CH=CH- CH2- 4~OMe-Phenyl Ethyl Me CH N N 01-272 COOH Phenyl - CH = CH- CH 2 - 4 ~ OMe-Phenyl Ethyl Me CH NN 0
1-273 COOH 4-Br-Phenyl - CH2-CH2- 2-OMe-Phenyl OMe CH2- CH2-CH2-C N N 0COOH 1-273 4-Br-phenyl - CH2-CH2 2-OMe-phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-274 COOH Phenyl - CH(OH)-CH2- 2-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-274 COOH phenyl - CH (OH) -CH 2 - 2-OMe-phenyl OMe 0-CH 2 -CH 2 -CNN 0
1-275 COOH 4-Et-Phenyl - CH2-CH2- 4— Me-Phenyl OMe 0- CH2-CH2-C N N 01-275 COOH 4-Et-Phenyl-CH2-CH2- 4- Me-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-276 COOH 4-CF3-Phenyl - CH2-CH2- 4~OMe-Phenyl OMe Me CH N N 01-276 COOH 4-CF 3 -phenyl - CH2-CH2- 4 ~ OMe-Phenyl OMe Me CH NN 0
1-277 COOH 4-Cl-Phenyl - CH(4-OMe-Phenyl)-CH2- 4-OMe-Phenyl OMe Me CH N N 01-277 COOH 4-Cl-phenyl-CH (4-OMe-phenyl) -CH 2 - 4-OMe-phenyl OMe Me CH NN 0
1-278 COOH 4-Cl-Phenyl - CH2-CH7- 3-Me^4-OMe-Phenyl Me Me CH N N 01-278 COOH 4-Cl-Phenyl-CH2-CH7-3-Me ^ 4-OMe-Phenyl Me Me CH N N 0
1-279 COOH 4-Cl-Phenyl - CH2-CH2- 3 ,4-Met ylendioxypheny 1 Me Me CH N N 01-279 COOH 4-Cl-phenyl-CH2-CH2-3, 4-methylenedioxypheny 1 Me Me CH N N 0
1-280 COOH 4-Cl-Phenyl - CH2-CH2- 3,4-Methylendioxyphenyl Me Me N N N 01-280 COOH 4-Cl-phenyl-CH 2 -CH 2 - 3,4-methylenedioxyphenyl Me Me NNN 0
1-281 COOH 4-Cl-Phenyl - CH2-CH2- 4-OMe-Phenyl Ethyl Me N N N 01-281 COOH 4-Cl-Phenyl - CH2-CH2- 4-OMe-Phenyl Ethyl Me N N N 0
1-282 COOH Phenyl - CH2-CH2- CH2- 4-Et-Phenyl Ethyl Me CH N N 01-282 COOH Phenyl - CH2-CH2-CH 2 - 4-Et-Phenyl Ethyl Me CH NN 0
1-283 COOH Phenyl - CH2-CH2- CH2- 4-Et-Phenyl OMe CH2- CH2-CH2-C N N 01-283 COOH phenyl - CH2-CH2-CH 2 - 4-Et-phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-284 COOH Phenyl - CH2-CH2- 4-Et-Phcnyl OMe CH2- CH2-CH2-C N N 0 1-284 COOH Phenyl - CH2-CH2- 4-Et-Phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
Nr. R 1 R4, R5 Q R6 R2 R3 Z X Y WR 1 R 4 , R 5 QR 6 R 2 R 3 ZXYW
1-285 COOH Phenyl - CH2-CH2- 4-Et-Phenyl OMe 0- CH2-CH2-C N N O1-285 COOH phenyl - CH2-CH2- 4-Et-phenyl OMe 0- CH 2 -CH 2 -CNNO
1-286 COOH 4-Cl-Phenyl - CH2-CH2- 4- Me-Phcnyl Ethyl Me CH N N s1-286 COOH 4-Cl-Phenyl - CH2-CH2- 4- Me-Phcnyl Ethyl Me CH N N s
1-287 COOH Phenyl - CH=CH- CH2- 4- Me-Phenyl OMe Me CH N N 01-287 COOH Phenyl - CH = CH- CH 2 - 4- Me-Phenyl OMe Me CH NN 0
1-288 COOH Phenyl - CH=CH- CH2- 4-OMe-Phenyl Me Me CH N N 01-288 COOH phenyl - CH = CH- CH 2 - 4-OMe-phenyl Me Me CH NN 0
1-289 COOH 3,4-DHCl-Phenyl - CH2-CH2- 4-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-289 COOH 3,4-DHCl-phenyl - CH2-CH2- 4-OMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-290 COOEt 4-Cl-Phenyl - CH(OH)-CH2- 3,4-Di-OMe-Phenyl OMe Me CH N N 01-290 COOEt 4-Cl-Phenyl - CH (OH) -CH 2 - 3,4-Di-OMe-Phenyl OMe Me CH NN 0
1-291 COOH 4-^t-Phenyl - CH-2-CH2- 4-Me-Phenyl Me Me N N N 01-291 COOH 4- ^ t-phenyl - CH-2-CH2- 4-Me-phenyl Me Me N N N 0
1-292 COOH 4-^t-Phenyl - CH2-CH2- 4-Me-Phenyl Ethyl Me CH N N 01-292 COOH 4- ^ t-phenyl - CH 2 -CH 2 - 4-Me-phenyl ethyl Me CH NN 0
1-293 COOH Phenyl - CH7-CH2- 3-OMe-Phenyl CF3 Me CH N N 01-293 COOH phenyl - CH7-CH2- 3-OMe-phenyl CF 3 Me CH NN 0
1-294 COOH Phenyl - CH7-CH2- 3-OMe-Phenyl OMe Me CH N N 01-294 COOH phenyl - CH7-CH2- 3-OMe-phenyl OMe Me CH N N 0
1-295 COOH 4-Cl-Phenyl - CH7-CH2- 3,4-Di-OMe-Phenyl Me Me CH N CH 01-295 COOH 4-Cl-phenyl-CH7-CH2-3,4-di-OMe-phenyl Me Me CH N CH 0
1-296 COOH 4- l-Phenyl - C(CH3)2-CH2- 3 ,4-Di-OMe-Phenyl Me Me N N N 01-296 COOH 4- l-phenyl - C (CH 3) 2 -CH 2 - 3, 4-di-OMe-phenyl Me Me NNN 0
1-297 COOH Phenyl - CH2-CH2- 3 ,4,5-Tri-OMe-Phenyl Ethyl Me CH N N 01-297 COOH phenyl - CH2-CH2-3, 4,5-tri-OMe-phenyl ethyl Me CH N N 0
1-298 COOH Phenyl - CH2-CH2- CH2- 4-Et-Phenyl Me Me CH N N 01-298 COOH Phenyl - CH 2 -CH 2 - CH 2 - 4-Et-Phenyl Me Me CH NN 0
1-299 COOH Phenyl - CH2-CH2- CH2- 4-El-Phenyl Me Me N N N 01-299 COOH phenyl - CH2-CH2-CH 2 - 4-el-phenyl Me Me NNN 0
1-300 COOH Phenyl - CH2-CH2- 3,4,5-Tri-OMe-Phenyl OMe CH2- CH2-CH2-C N N 01-300 COOH phenyl - CH2-CH2-3,4,5-tri-OMe-phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-301 COOH 4-Cl-Phenyl - CH2-CH2- 3,4-Di-OMe-Phenyl Ethyl Me | N N N 01-301 COOH 4-Cl-Phenyl - CH 2 -CH 2 - 3,4-Di-OMe-Phenyl Ethyl Me | NNN 0
1-302 COOH 3,4-Oi-Cl-Phenyl - CH2-CH2- 3,4-Di-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-302 COOH 3,4-Oi-Cl-phenyl-CH2-CH2-3,4-di-OMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-303 COOH Phenyl - CH7-CH2- CH2- 3,4,5-Tri-OMe-Phenyl OMe CH2- CH2-CH2-C N N 01-303 COOH Phenyl - CH7-CH2-CH 2 - 3,4,5-Tri-OMe-Phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-304 COOH Phenyl - CH=CH- CH2- 4-OMe-Phenyl CF3 Me CH N N 01-304 COOH phenyl - CH = CH- CH 2 - 4-OMe-phenyl CF 3 Me CH NN 0
1-305 COOH 4-CI-Phenyl - CH2-CH2- 3-Me-4-Et-PhenyI OMe Me CH N N 01-305 COOH 4-CI-Phenyl - CH 2 -CH 2 - 3-Me-4-Et-PhenyI OMe Me CH NN 0
1-306 COOH 4-Cl-Phenyl - CH2-CH2- 3-Me-4-Et-Phenyl SMe Me CH N N 01-306 COOH 4-Cl-Phenyl - CH2-CH2-3-Me-4-Et-Phenyl SMe Me CH N N 0
1-307 COOH 4-Et-Phenyl - CH2-CH2- 4-Me-Phenyl OMe Me CH N N 01-307 COOH 4-Et-Phenyl - CH2-CH2- 4-Me-Phenyl OMe Me CH N N 0
1-308 COOH 4-El-Phenyl - CH7-CH2- 4-Me-Plιenyl Me Me CH N N 01-308 COOH 4-El-Phenyl - CH7-CH2- 4-Me-Plιenyl Me Me CH N N 0
1-309 COOH 4-Cl-Phenyl | - CH2-CH2- 4-iPr-Phenyl OMe 0- CH2-CH2-C N N 0 1-309 COOH 4-Cl-Phenyl | - CH 2 -CH 2 - 4-iPr-phenyl OMe 0- CH 2 -CH 2 -CNN 0
Nr. R1 R4, R5 Q R6 R2 R3 Z X Y WR 1 R 4 , R 5 QR 6 R 2 R 3 ZXYW
1-310 COOH 4-Cl-Phenyl - CH -CH2- 3,4-Methylendioxyphenyl OMe Me CH N N 01-310 COOH 4-Cl-phenyl - CH -CH 2 - 3,4-methylenedioxyphenyl OMe Me CH NN 0
1-311 COOH 4-Cl-Phenyl - CH2-CH2- 4-Br-Phenyl Me Me N N N 01-311 COOH 4-Cl-phenyl - CH2-CH2- 4-Br-phenyl Me Me N N N 0
1-312 COOH Phenyl - CH2-CH2- 4-Et-Phenyl Me Me N N N 01-312 COOH phenyl - CH2-CH2- 4-Et-phenyl Me Me N N N 0
1-313 COOH Phenyl - CH2-CH2- 4-El-Phenyl Ethyl Me CH N N 01-313 COOH phenyl - CH2-CH2- 4-el-phenyl ethyl Me CH N N 0
1-314 COOH Phenyl - CH2-CH2- CH2- 4-Et-Phenyl CF3 Me CH N N 01-314 COOH phenyl - CH2-CH2-CH 2 - 4-Et-phenyl CF 3 Me CH NN 0
1-315 COOH Phenyl - CH2-CH2- CH2- 4-Et-Phenyl OMe Me CH N N 01-315 COOH phenyl - CH2-CH2-CH 2 - 4-Et-phenyl OMe Me CH NN 0
1-316 COOH 4-Cl-Phenyl - CH2-CH2- 4-Br-Phenyl Ethyl Me N N N 01-316 COOH 4-Cl-phenyl - CH2-CH2- 4-Br-phenyl ethyl Me N N N 0
1-317 COOH 4-Cl-Phenyl - CH(4-Br-Phenyl)-CH2- 4-Br-Phenyl OMe 0- CH2-CH2-C N N 01-317 COOH 4-Cl-phenyl-CH (4-Br-phenyl) -CH 2 - 4-Br-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-318 COOH 4-Cl-Phenyl - CH(OH)-CH2- 4-SMe-Phenyl OMe Me CH N N 01-318 COOH 4-Cl-phenyl-CH (OH) -CH 2 - 4-SMe-phenyl OMe Me CH NN 0
1-319 COOH Phenyl - CH2-CH2- CH2- 3,4,5-Tri-OMe-Phenyl Me Me N N N 01-319 COOH phenyl - CH2-CH2-CH 2 - 3,4,5-tri-OMe-phenyl Me Me NNN 0
1-320 COOH Phenyl - CH2-CH7- CH2- 3,4,5-Tri-OMe-Phenyl Ethyl Me CH N N 01-320 COOH phenyl - CH2-CH7-CH 2 - 3,4,5-tri-OMe-phenyl ethyl Me CH NN 0
1-321 COOH Phenyl - CH2-CH2- 3,5-Di-OMe-Phenyl OMe CH2- CH2-CH2-C N N 01-321 COOH phenyl - CH2-CH2- 3,5-di-OMe-phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-322 COOH Phenyl - CH2-CH2- 3,5-Di-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-322 COOH phenyl - CH 2 -CH 2 - 3,5-di-OMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-323 COOH 4-Et-Phenyl - CH2-CH2- 4-SMe-Phenyl Ethyl Me | CH N N 01-323 COOH 4-Et-Phenyl - CH 2 -CH 2 - 4-SMe-Phenyl Ethyl Me | CH NN 0
1-324 COOH 4-Et-Phenyl - CH2-CH2- 4-SMe-Phenyl OMe 0- CH2-CH2-C N N 01-324 COOH 4-Et-Phenyl - CH2-CH2- 4-SMe-Phenyl OMe 0-CH 2 -CH 2 -CNN 0
1-325 COOH 4-Cl-Phenyl - C(CH3)2-CH2- 4-SMe-Phenyl Me Me CH N CH 01-325 COOH 4-Cl-phenyl - C (CH 3 ) 2 -CH 2 - 4-SMe-phenyl Me Me CH N CH 0
1-326 COOH 4-Cl-Phenyl - CH2-CH2- 4-SMe-Phenyl Me Me N N N s1-326 COOH 4-Cl-Phenyl - CH 2 -CH 2 - 4-SMe-Phenyl Me Me NNN s
1-327 COOH Phenyl - CH2-CH2- 3,4,5-Tri-OMe-Phenyl Me Me CH N N 01-327 COOH phenyl - CH2-CH2-3,4,5-tri-OMe-phenyl Me Me CH N N 0
1-328 COOH Phenyl - CH2-CH7- 3,4,5-Tri-OMe-Phenyl Me Me N N N 01-328 COOH Phenyl - CH 2 -CH7- 3,4,5-Tri-OMe-Phenyl Me Me NNN 0
1-329 COOH 4-Cl-Phenyl - O-CH7-CH2- 4-SMe-Phenyl Ethyl Me CH N N 01-329 COOH 4-Cl-Phenyl - O-CH7-CH2- 4-SMe-Phenyl Ethyl Me CH N N 0
1-330 COOH Phenyl - CH2-CH2- CH2- 4-Me-Phenyl Ethyl Me CH N N 01-330 COOH phenyl - CH2-CH2-CH 2 - 4-Me-phenyl ethyl Me CH NN 0
1-331 COOH Phenyl - CH2-CH2- CH7- 4— Me— Phenyl OMe 0- CH2-CH2-C N N 01-331 COOH phenyl - CH2-CH 2 - CH7- 4- Me phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-332 COOH 4-CI-Phenyl - CH2-CH7- 4-SMe-Phenyl OMe 0- CH=CH-C N N 01-332 COOH 4-CI-Phenyl - CH2-CH7- 4-SMe-Phenyl OMe 0-CH = CH-C N N 0
1-333 COOH 4-C1 -Phenyl - CH(OH)-CH2- 4- El-3-OMe-Plιcnyl OMe Me CH N N 01-333 COOH 4-C1-phenyl-CH (OH) -CH 2 - 4- El-3-OMe-Plιcnyl OMe Me CH NN 0
1-334 COOH 4-Cl-Phenyl - CH(4-SMe-Phenyl)-CH2- 4-SMe-Phenyl Me Me CH N N 0 1-334 COOH 4-Cl-phenyl - CH (4-SMe-phenyl) -CH 2 - 4-SMe-phenyl Me Me CH NN 0
Nr. R1 R4, R5 Q R6 R2 R3 Z X Y WNo. R 1 R 4 , R 5 Q R6 R 2 R 3 ZXYW
1-335 COOH Phenyl - CH2-CH2- CH2- 3 ,4,5-Tri-OMe-Phenyl OMe Me CH N N 01-335 COOH phenyl - CH2-CH2-CH2- 3,4,5-tri-OMe-phenyl OMe Me CH N N 0
1-336 COOH Phenyl - CH2-CH2- CH2- 3,4,5-Tri-OMe-Phenyl Me Me CH N N O1-336 COOH phenyl - CH2-CH2-CH 2 - 3,4,5-tri-OMe-phenyl Me Me CH NNO
1-337 COOH 4-Cl-Phenyl - CH2-CH7- 4-iPr-Phenyl Me Me N N N O1-337 COOH 4-Cl-Phenyl - CH2-CH7- 4-iPr-Phenyl Me Me N N N O
1-338 COOH 4-Cl-Phenyl - CH2-CH2- 4-iPr-Phenyl Ethyl Me CH N N O1-338 COOH 4-Cl-Phenyl - CH2-CH2- 4-iPr-Phenyl Ethyl Me CH N N O
1-339 COOH 4-Me-Phenyl - CH2-CH2- 3,4-Di-OMe-Phenyl Me Me CH N N O1-339 COOH 4-Me-Phenyl - CH2-CH2-3,4-Di-OMe-Phenyl Me Me CH N N O
1-340 COOH 4-Me-Phenyl - CH2-CH2- 3,4-Di-OMe-Phenyl Me Me N N N O1-340 COOH 4-Me-Phenyl - CH 2 -CH 2 - 3,4-Di-OMe-Phenyl Me Me NNNO
1-341 COOH 3,4-Di-Cl-Phenyl - CH2-CH2- 4-OEl-3-OMe-Phenyl Me Me N N N 01-341 COOH 3,4-di-Cl-phenyl - CH2-CH2- 4-OEl-3-OMe-phenyl Me Me N N N 0
1-342 COOH Phenyl - CH2-CH7- 4-Et-Phenyl OMe Me CH N N 01-342 COOH phenyl - CH2-CH7- 4-Et-phenyl OMe Me CH N N 0
1-343 COOH Phenyl - CH2-CH7- 4-Et-Phenyl Me Me CH N N 01-343 COOH Phenyl - CH2-CH7- 4-Et-Phenyl Me Me CH N N 0
1-344 COOH 4-Cl-Phenyl - CH2-CH2- 4-OEt-3-OMe-Phenyl Ethyl Me CH N N s1-344 COOH 4-Cl-Phenyl - CH 2 -CH 2 - 4-OEt-3-OMe-Phenyl Ethyl Me CH NN s
1-345 COOH 4-Cl-Phenyl - CH(4-Me-Phenyl)-CH2- 4-Me-Phenyl OMe Me CH N N 01-345 COOH 4-Cl-Phenyl-CH (4-Me-Phenyl) -CH 2 - 4-Me-Phenyl OMe Me CH NN 0
1-346 COOH Phenyl - CH2-CH2- CH2- 4— Me-Phenyl Me Me CH N N 01-346 COOH phenyl - CH 2 -CH 2 - CH 2 - 4- Me phenyl Me Me CH NN 0
1-347 COOH Phenyl - CH2-CH2- CH2- 4-Me-Phenyl Me Me N N N 0 1-347 COOH Phenyl - CH 2 -CH 2 - CH 2 - 4-Me-Phenyl Me Me NNN 0
1-348 COOMe 4-Cl-Phenyl - CH7-CH2- 4— Me-Phenyl Me Me CH N CH 01-348 COOMe 4-Cl-phenyl-CH7-CH2- 4- Me-phenyl Me Me CH N CH 0
1-349 COOH Phenyl - CH2-CH2- 3,5-Di-OMe-Phenyl Me Me N N N 01-349 COOH phenyl - CH2-CH2-3,5-di-OMe-phenyl Me Me N N N 0
1-350 COOH Phenyl - CH2-CH2- 3,5-4">i-OMe-Phenyl Ethyl Me CH N N 01-350 COOH phenyl - CH2-CH2-3.5-4 " > i-OMe-phenyl ethyl Me CH NN 0
1-351 COOH Phenyl - CH2-CH2- CH2- 2-Cl-Phenyl OMe CH2- CH2-CH2-C N N 01-351 COOH phenyl - CH2-CH2-CH 2 - 2-Cl-phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-352 COOH Phenyl - CH2-CH2- CH2- 3 ,4,5-Tri-OMe-Phenyl CF3 Me CH N N 01-352 COOH phenyl - CH2-CH2-CH2- 3,4,5-tri-OMe-phenyl CF 3 Me CH NN 0
1-353 COOH 4-Cl-Phenyl - CH(OH)-CH2- 4-Me-Phenyl Me Me N N N 01-353 COOH 4-Cl-Phenyl - CH (OH) -CH 2 - 4-Me-Phenyl Me Me NNN 0
1-354 COOH 4-Cl-Phenyl - CH2-CH2- 3,4-Di-Me-Phenyl Ethyl Me CH N N 01-354 COOH 4-Cl-phenyl-CH2-CH2-3,4-di-Me-phenyl ethyl Me CH N N 0
1-355 COOH 4-Me-Phenyl - CH2-CH2- 4-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-355 COOH 4-Me-Phenyl - CH2-CH2- 4-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-356 COOH 4-Me-Phenyl - CH7-CH2- 3,4-Di-OMe-Phenyl OMe Me CH N N 01-356 COOH 4-Me-Phenyl - CH7-CH2- 3,4-Di-OMe-Phenyl OMe Me CH N N 0
1-357 COOH Phenyl - CH7-CH2- 3,4,5-Tri-OMe-Phenyl OMe OMe CH N N 01-357 COOH Phenyl - CH7-CH2- 3,4,5-Tri-OMe-Phenyl OMe OMe CH N N 0
1-358 COOH Phenyl - CH2-CH7- 3 ,4,5-Tri- Me-Phenyl OMe Me CH N N 01-358 COOH phenyl - CH2-CH7-3, 4,5-tri-Me-phenyl OMe Me CH N N 0
1-359 COOH 4-Cl-Phenyl - CH7-CH2- 4-Me-Phenyl OMe 0- CH2-CH2-C N N s 1-359 COOH 4-Cl-Phenyl - CH7-CH2- 4-Me-Phenyl OMe 0- CH 2 -CH 2 -CNN s
Nr. R1 R4, R5 Q R6 R2 R3 Z X Y WR 1 R 4 , R 5 QR 6 R 2 R 3 ZXYW
1-360 COOH 4-Cl-Phenyl - CH2-CH - 4-Et-Phenyl OMe Me CH N N S1-360 COOH 4-Cl-phenyl - CH 2 -CH - 4-Et-phenyl OMe Me CH NNS
1-361 COOH 4-Cl-Phenyl - CH2-CH2- 4-Et-Phenyl Me Me CH N CH 01-361 COOH 4-Cl-Phenyl - CH2-CH2- 4-Et-Phenyl Me Me CH N CH 0
1-362 COOH Phenyl - CH2-CH2- CH2- 4-Me-Phenyl CF3 Me CH N N 01-362 COOH phenyl - CH2-CH2-CH 2 - 4-Me-phenyl CF 3 Me CH NN 0
1-363 COOH Phenyl - CH2-CH2- CH2- 4-Me-Phenyl OMe Me CH N N 01-363 COOH phenyl - CH 2 -CH 2 - CH 2 - 4-Me-phenyl OMe Me CH NN 0
1-364 COOH 4-Cl-Phenyl - CH2-CH2- 4-Et-Phenyl Ethyl Me N N N 01-364 COOH 4-Cl-Phenyl - CH2-CH2- 4-Et-Phenyl Ethyl Me N N N 0
1-365 COOH 4-Cl-Phenyl - CH2-CH2- 4-iPr-Phenyl OMe Me CH N N 01-365 COOH 4-Cl-phenyl - CH 2 -CH 2 - 4-iPr-phenyl OMe Me CH NN 0
1-366 COOH 4-Cl-Phenyl - CH2-CH2- 4-iPr-Phenyl Me Me CH N N 01-366 COOH 4-Cl-Phenyl - CH2-CH2- 4-iPr-Phenyl Me Me CH N N 0
1-367 COOH Phenyl - CH2-CH2- CH2- 2-Cl-Phenyl Me Me N N N 01-367 COOH phenyl - CH 2 -CH 2 - CH 2 - 2-Cl-phenyl Me Me NNN 0
1-368 COOH Phenyl - CH2-CH2- CH2- 2- l-Phenyl Ethyl Me CH N N 01-368 COOH phenyl - CH2-CH2-CH 2 - 2- l-phenyl ethyl Me CH NN 0
1-369 COOH 4-Cl-Phenyl - CH2-CH2- 4-Et-Phenyl SMe Me CH N N 01-369 COOH 4-Cl-Phenyl - CH2-CH2- 4-Et-Phenyl SMe Me CH N N 0
1-370 COOH Phenyl - CH2-CH2- 4-Me-Phenyl OMe 0- CH2-CH2-C N N 01-370 COOH phenyl - CH2-CH2- 4-Me-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-371 COOH 4—Me- Phenyl - CH2-CH2- 4-OMe-Phenyl Me Me N N N 01-371 COOH 4-Me-Phenyl-CH 2 -CH 2 - 4-OMe-Phenyl Me Me NNN 0
1-372 COOH 4-Me— Phenyl - CH2-CH2- 4-OMe-Phenyl Ethyl Me CH N N 01-372 COOH 4-Me-Phenyl - CH2-CH2- 4-OMe-Phenyl Ethyl Me CH N N 0
1-373 COOH Phenyl - CH2-CH2- 4-Et-Phenyl CF3 Me CH N N 01-373 COOH Phenyl - CH 2 -CH 2 - 4-Et-Phenyl CF 3 Me CH NN 0
1-374 COOH 4-Cl-Phenyl - C(CH3)2-CH2- 4-Et-Phenyl OMe θ CH2-CH2-C N N 01-374 COOH 4-Cl-phenyl - C (CH 3 ) 2 -CH 2 - 4-Et-phenyl OMe θ CH 2 -CH 2 -CNN 0
1-375 COOH 4-Cl-Phenyl - CH .-CH2- 4-Cl-Phenyl OMe Me CH N N s1-375 COOH 4-Cl-phenyl - CH. -CH2- 4-Cl-phenyl OMe Me CH N N s
1-376 COOH 4-Cl-Phenyl - CH2-CH2- l-Me-Naphth-2-yl OMe Me CH N N 01-376 COOH 4-Cl-phenyl-CH2-CH2-l-Me-Naphth-2-yl OMe Me CH N N 0
1-377 COOH Phenyl - CH2-CH2- 3,5-Di-OMe-Phenyl OMe Me CH N N 01-377 COOH phenyl - CH2-CH2- 3,5-di-OMe-phenyl OMe Me CH N N 0
1-378 COOH Phenyl - CH7-CH2- CH2- 3,4— Methylendioxyphenyl EÜiyl Me CH N N 01-378 COOH phenyl - CH7-CH2-CH 2 - 3,4- methylenedioxyphenyl EÜiyl Me CH NN 0
1-379 COOH Phenyl - CH2-CH2- CH2- 3,4— Methylendioxyphenyl OMe 0- CH2-CH2-C N N 01-379 COOH phenyl - CH2-CH2-CH 2 - 3,4-methylenedioxyphenyl OMe 0-CH 2 -CH 2 -CNN 0
1-380 COOH Phenyl - CH2-CH2- 3,5-Di-OMe-Phenyl Me Me CH N N 01-380 COOH phenyl - CH2-CH2-3,5-di-OMe-phenyl Me Me CH N N 0
1-381 COOH 4-Cl-Phenyl - CH(4-OEt-Phcnyl)-CH2- 4-OEt-Phenyl OMe Me CH N N 01-381 COOH 4-Cl-phenyl-CH (4-OEt-phenyl) -CH 2 - 4-OEt-phenyl OMe Me CH NN 0
1-382 COOH 4-Cl-Phenyl - CH(OH)-CH2- 4-OEt-Phenyl Me Me CH N N 01-382 COOH 4-Cl-phenyl-CH (OH) -CH 2 - 4-OEt-phenyl Me Me CH NN 0
1-383 COOH Phenyl - CΗ2-CH2- CH7- 2-Cl-Pheπyl OMe Me CH N N 01-383 COOH phenyl - CΗ 2 -CH 2 - CH7- 2-Cl-phenyl OMe Me CH NN 0
1-384 | COOH Phenyl - CH7-CH7- CH-i- 2-Cl-Phenyl Me Me CH N N 0 1-384 | COOH phenyl - CH7-CH7-CH-i- 2-Cl-phenyl Me Me CH NN 0
Nr. R1 R4, Rs Q R6 R2 R3 Z X Y WR 1 R 4 , R s QR 6 R 2 R 3 ZXYW
1-410 COOH Phenyl - CH2-CH2- CH2- 3 ,4— Methy lendioxypheny 1 CF3 Me CH N N 01-410 COOH phenyl - CH 2 -CH 2 - CH 2 - 3, 4 - methylenedioxypheny 1 CF 3 Me CH NN 0
1-411 COOH Phenyl - CH2-CH2- CH2- 3 ,4— Methy lendioxypheny 1 OMe Me CH N N 0COOH 1-411 phenyl - CH2-CH2-CH 2 - 3, 4-Methyl-1 lendioxypheny OMe Me CH NN 0
1-412 COOH 4-^t-Phenyl - CH2-CH2- 4-OMe-Phenyl Ethyl Me CH CH N 01-412 COOH 4- ^ t-phenyl - CH 2 -CH 2 - 4-OMe-phenyl ethyl Me CH CH N 0
1-413 COOH Phenyl - CH2-CH2- 3,4-Di-OMe-Phenyl Ethyl Me CH N N 01-413 COOH phenyl - CH 2 -CH 2 - 3,4-di-OMe-phenyl ethyl Me CH NN 0
1-414 COOH Phenyl - CH2-CH2- 3,4-Di-OMe-Phenyl OMe CH2- CH2-CH2-C N N 01-414 COOH phenyl - CH2-CH2-3,4-di-OMe-phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-415 COOH 4-Me-Phenyl - CH2-CH2- CH2- 4-Me-Phenyl Me Me CH N N 01-415 COOH 4-Me-Phenyl - CH2-CH2-CH 2 - 4-Me-Phenyl Me Me CH NN 0
1^116 COOH 4-Me- Phenyl - CH2-CH2- CH2- 4-Me-Phenyl Me Me N N N 01 ^ 116 COOH 4-Me-Phenyl - CH 2 -CH 2 - CH 2 - 4-Me-Phenyl Me Me NNN 0
1-417 COOH 4-^t-Phenyl - CH7-CH2- 3,4-Di-OMe-Phenyl SMe Me CH N N 01-417 COOH 4- ^ t-phenyl - CH7-CH2- 3,4-di-OMe-phenyl SMe Me CH N N 0
1-418 COOMe 4-Et-Phenyl - CH2-CH2- 3,4-Di-OMe-Phenyl Me Me CH N N 01-418 COOMe 4-Et-Phenyl-CH2-CH2-3,4-Di-OMe-Phenyl Me Me CH N N 0
1-419 COOH 4-CF3-Phenyl - CH2-CH2- 4-Me— Phenyl Me Me CH N N 01-419 COOH 4-CF 3 -phenyl - CH 2 -CH 2 - 4-Me - phenyl Me Me CH NN 0
1-420 COOH 4-CF3-Phenyl - CH2-CH2- 4-Me-Phenyl Me Me N N N 01-420 COOH 4-CF 3 -phenyl - CH2-CH2- 4-Me-Phenyl Me Me NNN 0
1-421 COOH 4-Et-Phenyl - CH2-CH2- 3,4-Di-OMe-Phenyl Me Me N N N s 1-421 COOH 4-Et-Phenyl - CH 2 -CH 2 - 3,4-Di-OMe-Phenyl Me Me NNN s
1-422 COOH 4-Et-Phenyl - CH2-CH7- 3,4-Di-OMe-Phenyl Ethyl Me CH CH N 01-422 COOH 4-Et-Phenyl - CH2-CH7-3,4-Di-OMe-Phenyl Ethyl Me CH CH N 0
1-423 COOH 4-Cl-Phenyl - CH7-CH2- 4-OEt-3-OMe-Phenyl Me Me CH N N 01-423 COOH 4-Cl-Phenyl - CH7-CH 2 - 4-OEt-3-OMe-Phenyl Me Me CH NN 0
M24 COOH 4-Cl-Phenyl - CH2-CH2- 4- Et-3-OMe-Phenyl Me Me N N N 0M24 COOH 4-Cl-phenyl - CH2-CH2- 4-Et-3-OMe-phenyl Me Me N N N 0
1-425 COOH 4— Et— Phenyl - CH2-CH2- 3,4-Di-OMe-Phenyl OMe O CH=CH-C N N 01-425 COOH 4- Et-phenyl-CH 2 -CH2- 3,4-di-OMe-phenyl OMe O CH = CH-C NN 0
1- 26 COOH Phenyl - CH2-CH2- CH2- 4-SMe-Phenyl Ethyl Me CH N N 01- 26 COOH phenyl - CH 2 -CH 2 - CH 2 - 4-SMe-phenyl ethyl Me CH NN 0
1-427 COOH Phenyl - CH2-CH2- CH2- 4-SMe-Phenyl OMe 0- CH2-CH2-C N N 01-427 COOH phenyl - CH2-CH2-CH 2 - 4-SMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-128 COOH Phenyl - CH2-CH2- 4-Mc-Phenyl Me Me CH N N 01-128 COOH phenyl - CH2-CH2- 4-Mc-phenyl Me Me CH N N 0
1-429 COOH Phenyl - CH7-CH2- 4-Me-Phenyl Me Me N N N 01-429 COOH phenyl - CH7-CH2- 4-Me-phenyl Me Me N N N 0
1-430 COOH 4-Et~Phenyl - CH2-CH2- 3-OMe-Phenyl OMe CF3 CH N N 01-430 COOH 4-Et ~ phenyl - CH2-CH2- 3-OMe-Phenyl OMe CF 3 CH NN 0
1-431 COOH 4-Me-Phenyl - CH2-CH2- CH2- 4-S Me-Phenyl OMe Me CH N N 01-431 COOH 4-Me-Phenyl - CH2-CH2-CH 2 - 4-S Me-Phenyl OMe Me CH NN 0
1-432 COOH 4-Me-Phenyl - CH7-CH2- CH2- 4-SMe-Phenyl OMe 0- CH2-CH2-C N N 01-432 COOH 4-Me-Phenyl - CH7-CH 2 - CH 2 - 4-SMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-433 COOH 4-Et-Phenyl - CH(3-OMe-Phcnyl)-CH2- 3-OMe-Phenyl Me Me CH N N 01-433 COOH 4-Et-Phenyl - CH (3-OMe-Phenyl) -CH 2 - 3-OMe-Phenyl Me Me CH NN 0
1-434 COOH 4-Cl-Phenyl - CH2-CH2- Naphth-2-yl Me Me CH N N 0 1-434 COOH 4-Cl-phenyl-CH2-CH2-naphth-2-yl Me Me CH NN 0
Nr. R1 R4, R5 Q R6 R2 R3 Z X Y WR 1 R 4 , R 5 QR 6 R 2 R 3 ZXYW
1-435 COOH 4-CF3-Phenyl - CH2-CH2- 4-SMe-Phenyl OMe 0- CH2-CH2-C N N 01-435 COOH 4-CF 3 -phenyl - CH 2 -CH 2 - 4-SMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-436 COOH 4-CF3-Phenyl - CH2-CH2- 4— Me-Phenyl OMe Me CH N N 01-436 COOH 4-CF 3 -phenyl-CH2-CH2- 4- Me-phenyl OMe Me CH NN 0
1-437 COOH 4-Cl-Phenyl CH2-CH2- Naphth-2-yl Me Me N N N 01-437 COOH 4-Cl-Phenyl CH2-CH2-Naphth-2-yl Me Me N N N 0
1-138 COOH 4-Et-Phenyl - CH(OH)-CH2- 3-OMe-Phenyl Me Me N N N 01-138 COOH 4-Et-Phenyl - CH (OH) -CH 2 - 3-OMe-Phenyl Me Me NNN 0
1-439 COOH Phenyl - CH2-CH2- 4- Et-Phenyl Ethyl Me CH N N 01-439 COOH Phenyl - CH2-CH2- 4- Et-Phenyl Ethyl Me CH N N 0
1-440 COOH Phenyl - CH2-CH2- 4-OEt-Phenyl OMe CH2- CH2-CH2-C N N 01-440 COOH phenyl - CH2-CH2- 4-OEt-phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-441 COOH 4-Et-Phenyl - CH2-CH2- 3-OMe-Pheny! Me Me CH N CH O1-441 COOH 4-Et-Phenyl - CH 2 -CH 2 - 3-OMe-Pheny! Me Me CH N CH O
1-442 COOH Phenyl - CH2-CH2- CH2- 4-SMe-Phenyl Me Me CH N N 01-442 COOH phenyl - CH 2 -CH 2 - CH 2 - 4-SMe-phenyl Me Me CH NN 0
1-443 COOH Phenyl - CH2-CH2- CH2- 4-SMe-Phenyl Me Me N N N 01-443 COOH phenyl - CH 2 -CH 2 - CH 2 - 4-SMe-phenyl Me Me NNN 0
1-444 COOH 4-Et-Phenyl - C(CH3)2-CH2- 3-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-444 COOH 4-Et-Phenyl - C (CH 3 ) 2 -CH 2 - 3-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-445 COOH Phenyl - CH2-CH2- 3,4-Di-OMe-Phenyl Me Me CH N N 01-445 COOH phenyl - CH 2 -CH 2 - 3,4-di-OMe-phenyl Me Me CH NN 0
[-446 COOH Phenyl - CH2-CH2- 3,4-Di-OMe-Phenyl Me Me N N N 0[-446 COOH phenyl - CH 2 -CH 2 - 3,4-di-OMe-phenyl Me Me NNN 0
1-447 COOH 4-Me-Phenyl - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl Ethyl Me CH N N 01-447 COOH 4-Me-Phenyl - CH2-CH2-CH 2 - 3,4-Di-OMe-Phenyl Ethyl Me CH NN 0
1-448 COOH 4-Me— Phenyl - CH2-CH2- CH2- 3-OMe-Phenyl OMe O- CH2-CH2-C N N 0COOH 1-448 4-Me-phenyl - CH 2 -CH 2 - CH 2 - 3-OMe-phenyl OMe O CH 2 CH 2 0 -CNN
1-449 COOH 4-Et-Phenyl - CH2-CH2- 4-SMe-Phenyl OMe Me CH N N s1-449 COOH 4-Et-Phenyl - CH 2 -CH 2 - 4-SMe-Phenyl OMe Me CH NN s
1-450 COOH 4-Cl-Phenyl - CH2-CH2- 2-OMe-Phenyl Me Me CH N N 01-450 COOH 4-Cl-Phenyl - CH 2 -CH 2 - 2-OMe-Phenyl Me Me CH NN 0
1-451 COOH 4-CF3-Phenyl - CH2-CH2- 4-SMe-Phenyl Me Me N N N 01-451 COOH 4-CF 3 -phenyl-CH 2 -CH2- 4-SMe-phenyl Me Me NNN 0
1-452 COOH 4-CF3-Phenyl - CH2-CH2- 4-SMe-Phenyl Ethyl Me CH N N 01-452 COOH 4-CF 3 -phenyl - CH2-CH2- 4-SMe-phenyl ethyl Me CH NN 0
1-453 COOH 4-Cl-Phenyl - CH7-CH7- 2-OMe-Phenyl Me Me N N N 01-453 COOH 4-Cl-Phenyl - CH7-CH7-2-OMe-Phenyl Me Me N N N 0
1-454 COOBzl 4-Et-Phenyl - CH2-CH2- 4-SMe-Phenyl Me Me CH N N 01-454 COOBzl 4-Et-Phenyl - CH2-CH2- 4-SMe-Phenyl Me Me CH N N 0
1-455 COOH 4-Et-Phenyl - CH2-CH2- 4-SMe-Phenyl Ethyl Me CH CH N 01-455 COOH 4-Et-Phenyl - CH2-CH2- 4-SMe-Phenyl Ethyl Me CH CH N 0
1-156 COOH 4-Et-Phenyl - CH2-CH2- 4-Me-Phenyl OMe Me N N N 01-156 COOH 4-Et-Phenyl - CH2-CH2- 4-Me-Phenyl OMe Me N N N 0
1-157 COOH 4-Cl-Phcnyl - CH2-CH7- 4-SMe-Phcnyl OMe 0- CH2-CH2-C N N 01-157 COOH 4-Cl-Phcnyl - CH2-CH7- 4-SMe-Phcnyl OMe 0- CH 2 -CH 2 -CNN 0
1-458 COOH Phenyl - CH7-CH2- CH2- 4-SMe-Pheπyl CF3 Me CH N N 01-458 COOH Phenyl - CH7-CH2-CH 2 - 4-SMe-Phenyl CF 3 Me CH NN 0
1-159 COOH Phenyl - CH2-CH7- CH2- 4-SMe-Phenyl OMe Me CH N N 0 1-159 COOH phenyl - CH2-CH7-CH 2 - 4-SMe-phenyl OMe Me CH NN 0
Nr. R1 R4, R5 Q R6 R2 R3 Z X Y WR 1 R 4 , R 5 QR 6 R 2 R 3 ZXYW
1-460 COOH 4-Cl-Phenyl - CH2-CH2- 4-OEt-3-OMe-Phenyl OMe Me CH N N 01-460 COOH 4-Cl-Phenyl - CH 2 -CH 2 - 4-OEt-3-OMe-Phenyl OMe Me CH NN 0
1-461 COOH 4-CF3-Phenyl - CH2-CH2- 4-OMe-Phenyl Me Me N CH N 01-461 COOH 4-CF 3 -phenyl - CH 2 -CH 2 - 4-OMe-Phenyl Me Me N CH N 0
\-A62 COOH Phenyl - CH2-CH2- 4-Me-Phenyl CF3 Me CH N N 0\ -A62 COOH phenyl - CH 2 -CH 2 - 4-Me-phenyl CF 3 Me CH NN 0
1-463 COOH 4-Me-Phcnyl - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl OMe Me CH N N 01-463 COOH 4-Me-Phcnyl - CH 2 -CH 2 - CH 2 - 3,4-Di-OMe-Phenyl OMe Me CH NN 0
1-464 COOH 4-Me— Phenyl - CH2-CH2- CH2- 3,443i-OMe-Phenyl Me Me CH N N 0COOH 1-464 4-Me-phenyl - CH 2 -CH 2 - CH 2 - 3,443i-OMe-phenyl Me Me CH NN 0
1-465 COOH Phenyl - CH7-CH2- 4— Me-Phenyl OMe Me CH N N 01-465 COOH phenyl - CH7-CH2- 4- Me phenyl OMe Me CH N N 0
1-466 COOH 4-CF3-Phenyl - C(CH3)2-CH2- 4~OMe-Phenyl Ethyl Me CH N N 01-466 COOH 4-CF 3 -phenyl - C (CH 3 ) 2 -CH 2 - 4 ~ OMe-phenyl ethyl Me CH NN 0
1-467 COOH 4-CF3-Phenyl - CH2-CH2- 4-SMe-Phenyl OMe Me CH N N 01-467 COOH 4-CF 3 -phenyl - CH 2 -CH 2 - 4-SMe-phenyl OMe Me CH NN 0
1-468 COOH 4-CF3-Phenyl - CH2-CH2- 4-SMe-Phenyl Me Me CH N N 01-468 COOH 4-CF 3 -phenyl - CH2-CH2- 4-SMe-phenyl Me Me CH NN 0
1-469 COOH 4-CF3-Phenyl - CH2-CH2- 3,4-4>i-OMe-PhenyI Ethyl Me CH CH N 01-469 COOH 4-CF 3 -phenyl - CH2-CH2- 3,4-4> i-OMe-PhenyI ethyl Me CH CH N 0
1-470 COOH 4-Cl-Phenyl - CH2-CH2- 4-Cl-Phenyl OMe 0- CH2-CH2-C N N 01-470 COOH 4-Cl-phenyl - CH2-CH2- 4-Cl-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-471 COOH 4-CI-Phenyl - CH2-CH2- Naphth-2-yl OMe Me | CH N N 0 1-471 COOH 4-CI-Phenyl - CH2-CH2-Naphth-2-yl OMe Me | CH NN 0
1-472 COOH 4-CF3-Phenyl - CH2-CH2- 3 ,4-Di-OMe-Pheny 1 OMe 0- CH2-CH2-C N N s1-472 COOH 4-CF 3 -phenyl - CH 2 -CH 2 - 3, 4-di-OMe-Pheny 1 OMe 0- CH 2 -CH 2 -CNN see
1-473 COOH Phenyl - CH2-CH2- 4-OEt-Phenyl Me Me CH N N 01-473 COOH phenyl - CH 2 -CH 2 - 4-OEt-phenyl Me Me CH NN 0
1-474 COOH Phenyl - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl Ethyl Me CH N N 01-474 COOH phenyl - CH2-CH2-CH 2 - 3,4-di-OMe-phenyl ethyl Me CH NN 0
1-475 COOH Phenyl - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-475 COOH phenyl - CH2-CH 2 - CH 2 - 3,4-di-OMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-476 COOH Phenyl - CH2-CH2- 4~ Et-Phenyl Me Me N N N 01-476 COOH phenyl - CH2-CH2- 4 ~ Et-phenyl Me Me N N N 0
1-477 COOH 4-CF3-Phenyl - CH2-CH2- 3-OMe-Phenyl Ethyl Me N N N 01-477 COOH 4-CF 3 -phenyl-CH2-CH2-3-OMe-phenyl ethyl Me NNN 0
1-478 COOH 4-CF3-Phenyl - CH7-CH2- 2-Me-3- Me-Phenyl OMe 0- CH2-CH2-C N N 01-478 COOH 4-CF 3 -phenyl - CH7-CH2- 2-Me-3-Me-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-479 COOH 4-Me— Phenyl - CH2-CH2- CH2- 4-OMe-Phenyl Ethyl Me CH N N 01-479 COOH 4-Me-Phenyl - CH2-CH2-CH 2 - 4-OMe-Phenyl Ethyl Me CH NN 0
1-480 COOH 4-^Me-Phenyl - CH2-CH2- CH2- 4-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-480 COOH 4- ^ Me-phenyl - CH2-CH2-CH 2 - 4-OMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-181 COOH Phenyl - CH2-CH2- 3,4-Di-OMe-Phenyl OMe OMe CH N N 0 82 COOH Phenyl - CH7-CH2- 3,4-Di-OMe-Phenyl OMe Me CH N N 01-181 COOH phenyl - CH2-CH2- 3,4-di-OMe-phenyl OMe OMe CH N N 0 82 COOH phenyl - CH7-CH2-3,4-di-OMe-phenyl OMe Me CH N N 0
1-483 COOH 4-CF3-Phenyl - CH7-CH2- 3-OMe-Phenyl Ethyl Me CH N N 0 1-483 COOH 4-CF 3 -phenyl - CH7-CH2- 3-OMe-phenyl ethyl Me CH NN 0
Nr. R' R4, R5 Q R6 R2 R3 Z X | Y | WNo. R 'R 4 , R 5 QR 6 R 2 R 3 ZX | Y | W
1-484 COOH 4-CF3-Phenyl - CH2-CH2- 3-OMe-Phenyl OMe O- CH2-CH2-C N N O1-484 COOH 4-CF 3 -phenyl - CH 2 -CH 2 - 3-OMe-Phenyl OMe O-CH 2 -CH 2 -CNNO
1-485 COOH 4-CF3-Phenyl - CH2-CH2- 3-Me4-SMe-Phenyl OMe Me CH N N O1-485 COOH 4-CF 3 -phenyl-CH2-CH2-3-Me4-SMe-phenyl OMe Me CH NNO
1-486 COOH 4-Cl-Phenyl - CH2-CH2- 3-OMe-Phenyl OMe O- CH2-CH2-C N N O1-486 COOH 4-Cl-phenyl-CH2-CH2-3-OMe-phenyl OMe O-CH 2 -CH 2 -CNNO
1-487 COOH 4-Cl-Phenyl - CH2-CH2- 2-OMe-Phenyl OMe Me CH N N O1-487 COOH 4-Cl-Phenyl - CH2-CH2-2-OMe-Phenyl OMe Me CH N N O
1-488 COOH 4-CF3-Phenyl - CH2-CH2- Cyclohexyl OMe Me CH N N 01-488 COOH 4-CF 3 -phenyl-CH2-CH2-cyclohexyl OMe Me CH NN 0
1-489 COOH 4-CF3-Phenyl - CH2-CH2- 4—Me-Phenyl Me Me CH N N s1-489 COOH 4-CF 3 -phenyl-CH2-CH2- 4-Me-Phenyl Me Me CH NN see
1-490 COOH Phenyl - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl Me Me CH N N 01-490 COOH phenyl - CH2-CH 2 - CH 2 - 3,4-di-OMe-phenyl Me Me CH NN 0
1-491 COOH Phenyl - CH2-CH7- CH2- 3,4-Di-OMe-Phenyl Me Me N N N 01-491 COOH phenyl - CH2-CH7-CH 2 - 3,4-di-OMe-phenyl Me Me NNN 0
1-492 COOH 4— Me— Phenyl - CH2-CH2- Cyclohexyl OMe Me CH N N 01-492 COOH 4- Me phenyl CH2 CH2 cyclohexyl OMe Me CH N N 0
1-493 COOH 4-Cl-Phenyl - CH2-CH2- 4-SMe-Phenyl Me Me N N N 01-493 COOH 4-Cl-Phenyl - CH2-CH2- 4-SMe-Phenyl Me Me N N N 0
1-494 COOH 4-Cl-Phenyl - CH2-CH2- 4-S Me-Phenyl Ethyl Me CH N N 01-494 COOH 4-Cl-Phenyl - CH2-CH2- 4-S Me-Phenyl Ethyl Me CH N N 0
1-495 COOH 4-CF3-Phenyl - CH2-CH2- CH2- 4-Me-^Phenyl OMe 0- CH2-CH2-C N N 01-495 COOH 4-CF 3 -phenyl - CH2-CH2-CH 2 - 4-Me- ^ phenyl OMe 0- CH 2 -CH 2 -CNN 0
[-496 COOH 4-Me— Phenyl - CH7-CH7- CH2- 4-OMe-Phenyl OMe Me CH N N 0[-496 COOH 4-Me-Phenyl-CH7-CH7-CH 2 - 4-OMe-Phenyl OMe Me CH NN 0
1-497 COOH 4-Me-Phenyl - CH2-CH2- 4-OMe-Phenyl Me Me CH N N s1-497 COOH 4-Me-Phenyl - CH 2 -CH 2 - 4-OMe-Phenyl Me Me CH NN s
1-498 COOH Phenyl - CH2-CH7- 3,4- ethylendioxyphenyl OMe CH2- CH2-CH2-C N N 01-498 COOH phenyl - CH2-CH7-3,4-ethylenedioxyphenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-499 COOH Phenyl - CH2-CH2- CH2- Phenyl OMe Me CH N N 01-499 COOH phenyl - CH2-CH2-CH2-phenyl OMe Me CH N N 0
1-500 COOH Phenyl - CH2-CH2- CH2- Phenyl Me Me CH N N 01-500 COOH phenyl - CH 2 -CH 2 - CH 2 - phenyl Me Me CH NN 0
1-501 COOH Phenyl - CH2-CH2- 3,4-Methylendioxyphenyl OMe O- CH2-CH2-C N N 01-501 COOH phenyl-CH2-CH2-3,4-methylenedioxyphenyl OMe O-CH 2 -CH 2 -CNN 0
1-502 COOH 4-Me-Phenyl - CH2-CH2- 3,4-Di-OMe-Phenyl Me Me N CH N 01-502 COOH 4-Me-Phenyl - CH2-CH2-3,4-Di-OMe-Phenyl Me Me N CH N 0
1-503 COOH 4— Me— Phenyl - CH2-CH2- 3,4-Di-OMe-Phenyl Ethyl Me CH N N s1-503 COOH 4- Me phenyl CH 2 CH 2 3,4-di-OMe phenyl ethyl Me CH NN see
1-504 COOH 4-Cl-Phenyl - CH2-CH2- 4-Cl-Phenyl Me Me N N N 01-504 COOH 4-Cl-Phenyl - CH 2 -CH 2 - 4-Cl-Phenyl Me Me NNN 0
1-505 COOH 4-CI-Phenyl - CH2-CH2- 4-Cl-Phenyl Ethyl Me CH N N 01-505 COOH 4-CI-Phenyl - CH 2 -CH 2 - 4-Cl-Phenyl Ethyl Me CH NN 0
1-506 COOH Phenyl - CH2-CH7- CH2- 3,4-Oi-OMe-Phenyl CF3 Me CH N N 01-506 COOH Phenyl - CH 2 -CH7- CH2- 3,4-Oi-OMe-Phenyl CF 3 Me CH NN 0
1-507 COOH Phenyl - CH2-CH2- CH2- 3,4-Di-OMc-Phenyl OMe Me CH N N 01-507 COOH phenyl - CH2-CH2-CH2-3,4-di-OMc-phenyl OMe Me CH N N 0
1-508 COOH 4-Me-Phenyl - CH7-CH2- Cyclopentyl OMe Me CH N N 0 1-508 COOH 4-Me-Phenyl - CH7-CH2-Cyclopentyl OMe Me CH NN 0
Nr. R1 R4, R5 Q R6 R2 R3 Z X Y WR 1 R 4 , R 5 QR 6 R 2 R 3 ZXYW
1-509 COOH Phenyl - CH2-CH2- 4-OEl-Phenyl CF3 Me CH N N O1-509 COOH phenyl - CH2-CH2- 4-OEl-phenyl CF 3 Me CH NNO
[-510 COOH Phenyl - CH2-CH2- 4-OEt-Phenyl OMe Me CH N N 0[-510 COOH phenyl - CH2-CH2- 4-OEt-phenyl OMe Me CH N N 0
1-511 COOH 4-CF3-Phenyl - CH2-CH2- CH2- 4-Me- >henyl Me Me N N N 01-511 COOH 4-CF 3 -phenyl - CH2-CH2-CH 2 - 4-Me- > henyl Me Me NNN 0
1-512 COOH 4-CF3-Phenyl - CH2-CH2- CH7- 4-Me-Phenyl Ethyl Me CH N N 01-512 COOH 4-CF 3 -phenyl - CH2-CH2-CH7- 4-Me-phenyl ethyl Me CH NN 0
[-513 COOH 4-Me-Phenyl - CH2-CH2- 4-SMe-Phenyl OMe Me CH N N s[-513 COOH 4-Me-Phenyl - CH 2 -CH 2 - 4-SMe-Phenyl OMe Me CH NN s
1-514 COOH 4-Me-Phenyl - CH2-CH2- 4-SMe-Phenyl Ethyl Me N N N 01-514 COOH 4-Me-Phenyl - CH 2 -CH 2 - 4-SMe-Phenyl Ethyl Me NNN 0
1-515 COOH 4-Me- Phenyl - CH2-CH2- 4— Me— Phenyl OMe 0- CH2-CH2-C N N 0COOH 1-515 4-Me-phenyl - CH 2 -CH 2 - 4-OMe Me Phenyl CH 2 -CH 2 0- 0 -CNN
1-516 COOH Phenyl - CH2-CH2- CH2- Phenyl CF3 Me CH N N 01-516 COOH phenyl - CH 2 -CH 2 - CH 2 - phenyl CF 3 Me CH NN 0
1-517 COOH Phenyl - CH2-CH2- 4-OMe-Phenyl OMe 0- CH2-CH -C N N 01-517 COOH phenyl - CH 2 -CH 2 - 4-OMe-phenyl OMe 0- CH 2 -CH -CNN 0
1-518 COOH Phenyl - CH2-CH2- 3,4-Di-OMe-Phenyl CF3 Me CH N N 01-518 COOH phenyl - CH2-CH2-3,4-di-OMe-phenyl CF 3 Me CH NN 0
1-519 COOH 4-^1 e— Phenyl - CH2-CH2- 4-SMe-Phenyl Ethyl Me CH CH N 01-519 COOH 4- ^ 1 e - phenyl - CH2-CH2- 4-SMe-phenyl ethyl Me CH CH N 0
1-520 COOH 4-Cl-Phenyl - CH2-CH2- 3-OMe-Phenyl Me Me N N N 01-520 COOH 4-Cl-phenyl-CH2-CH2-3-OMe-phenyl Me Me N N N 0
1-521 COOH 4-Cl-Phenyl - CH2-CH2- 3-OMe-Phenyl Ethyl Me CH N N 01-521 COOH 4-Cl-Phenyl - CH 2 -CH 2 - 3-OMe-Phenyl Ethyl Me CH NN 0
1-522 COOH Phenyl - CH2-CH2- CH2- "4-OMe-Phenyl OMe CH2- CH2-CH2-C N N 01-522 COOH phenyl - CH2-CH 2 - CH 2 - " 4-OMe-phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-523 COOH Phenyl - CH2-CH2- CH2- 4-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-523 COOH phenyl - CH2-CH2-CH 2 - 4-OMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-524 COOMe 4-Me-Phenyl - CH2-CH2- 4-Me-Phenyl OMe 0- CH2-CH2-C N N 01-524 COOMe 4-Me-Phenyl - CH2-CH2- 4-Me-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-525 COOMe Phenyl - CH2-CH2- CH2- Phenyl CF3 Me CH N N 01-525 COOMe phenyl - CH2-CH2-CH2-phenyl CF 3 Me CH NN 0
1-526 COOH Phenyl - CH2-CH2- CH2- Phenyl OMe Me CH N N s1-526 COOH phenyl - CH 2 -CH2- CH 2 - phenyl OMe Me CH NN s
1-527 COOH 4-CF3-Phenyl - CH7-CH7- CH2- 4-SMe-Phenyl Ethyl Me CH N N 01-527 COOH 4-CF 3 -phenyl - CH7-CH7-CH 2 - 4-SMe-phenyl ethyl Me CH NN 0
1-528 COOH 4-CF3-Phenyl - CH2-CH2- CH2- 4-SMe-Phenyl OMe 0- CH2-CH2-C N N 01-528 COOH 4-CF 3 -phenyl - CH2-CH2-CH 2 - 4-SMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-529 COOH 4-CI-Phenyl - CH2-CH2- 4-SMe-Phenyl OMe Me CH N N 01-529 COOH 4-CI-Phenyl - CH2-CH 2 - 4-SMe-Phenyl OMe Me CH NN 0
1-530 COOH 4-Cl-Phenyl - CH2-CH2- 4-SMe-Phenyl Me Me CH N N 01-530 COOH 4-Cl-Phenyl - CH2-CH2- 4-SMe-Phenyl Me Me CH N N 0
1-531 COOH 4-Me-Phenyl - CH2-CH2- 4-Me-Phenyl Me Me N N N 01-531 COOH 4-Me-Phenyl - CH2-CH2- 4-Me-Phenyl Me Me N N N 0
1-532 COOH 4— Me-Phenyl - CH2-CH2- 4-Me-Phenyl Ethyl Me CH N N 0 1-532 COOH 4- Me phenyl - CH2-CH2 -4-Me phenyl ethyl Me CH NN 0
Nr. R1 R4, R5 Q R6 R2 R3 Z X Y WR 1 R 4 , R 5 QR 6 R 2 R 3 ZXYW
1-533 COOH Phenyl - CH2-CH2- CH2- 4-F-Phenyl Me Me CH N N 01-533 COOH phenyl - CH 2 -CH 2 - CH 2 - 4-F-phenyl Me Me CH NN 0
1-534 COOH Phenyl - CH2-CH2- 3 ,4-Methy lendioxypheny 1 Me Me N N N 01-534 COOH phenyl - CH2-CH2-3,4-methylenedioxypheny 1 Me Me N N N 0
1-535 COOH Phenyl - CH2-CH2- 3 ,4-Methylendioxypheny 1 Ethyl Me CH N N 01-535 COOH phenyl - CH2-CH2-3,4-methylenedioxypheny 1 ethyl Me CH N N 0
1-536 COOH Phenyl - CH2-CH2- CH2- Phenyl Me Me N N CH 01-536 COOH phenyl - CH2-CH2-CH 2 - phenyl Me Me NN CH 0
1-537 COOH 4-Br-Phenyl - CH2-CH2- CH2- Phenyl Ethyl Me CH N N 01-537 COOH 4-Br-phenyl - CH 2 -CH 2 - CH 2 - phenyl ethyl Me CH NN 0
1-538 COOH Phenyl - CH2-CH2- CH2- 4-OMe-Phenyl Me Me N N N 01-538 COOH phenyl - CH 2 -CH 2 - CH 2 - 4-OMe-phenyl Me Me NNN 0
1-539 COOH Phenyl - CH2-CH2- CH2- 4-OMe-Phenyl Ethyl Me CH N N 01-539 COOH phenyl - CH 2 -CH 2 - CH 2 - 4-OMe-phenyl ethyl Me CH NN 0
1-540 COOH 4-CI-Phenyl - CH2-CH2- 4-Cl-Phenyl OMe Me CH N N 01-540 COOH 4-CI-Phenyl - CH2-CH2- 4-Cl-Phenyl OMe Me CH N N 0
1-541 COOH 4-Cl-PhenyI - CH2-CH2- 4-Cl-Phenyl Me Me CH N N 01-541 COOH 4-Cl-PhenyI - CH2-CH 2 - 4-Cl-Phenyl Me Me CH NN 0
1-542 COOH 4-F-Phenyl - CH2-CH2- CH2- Phenyl OMe 0- CH2-CH2-C N N 0COOH 1-542 4-F-phenyl - CH 2 -CH 2 - CH 2 - phenyl OMe CH 2 -CH 2 0- 0 -CNN
1-543 COOH 4-CF3-Phenyl - CH2-CΗ2- CH2- 3-OMe-Phcnyl OMe 0- CH2-CH2-C N N 01-543 COOH 4-CF 3 -phenyl - CH2-CΗ2- CH 2 - 3-OMe-Phcnyl OMe 0- CH 2 -CH 2 -CNN 0
1-544 COOH 4-CF3-Phenyl - CH2-CH2- CH2- 4-SMe-Phenyl OMe Me CH N N 01-544 COOH 4-CF 3 -phenyl - CH2-CH2-CH 2 - 4-SMe-phenyl OMe Me CH NN 0
1-545 COOH Phenyl - CH2-CH2- Naphth-2-yl OMe CH2- CH2-CH2-C N N 01-545 COOH phenyl - CH2-CH2-naphth-2-yl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-546 COOH Phenyl - CH2-CH2- Naphth-2-yl OMe O CH2-CH2-C N N 01-546 COOH phenyl - CH2-CH2-naphth-2-yl OMe O CH 2 -CH 2 -CNN 0
1-547 COOH 4~Me— Phenyl - CH2-CH2- 4—Me-Phenyl OMe Me CH N N 01-547 COOH 4 ~ Me-phenyl-CH 2 -CH 2 - 4-Me-phenyl OMe Me CH NN 0
1-548 COOH 4-Me— Phenyl - CH2-CH2- 4— Me-Phenyl Me Me CH N N 01-548 COOH 4-Me- phenyl - CH2-CH2- 4- Me-phenyl Me Me CH N N 0
1-549 COOMe Phenyl - CH(Phenyl)-CH2- CH2- Phenyl CF3 Me CH N N 01-549 COOMe phenyl - CH (phenyl) -CH 2 - CH 2 - phenyl CF 3 Me CH NN 0
1-550 COOH 4— F-Phenyl - CH(Phenyl)-CH2- CH2- Phenyl OMe Me CH N N 01-550 COOH 4- F-phenyl - CH (phenyl) -CH 2 - CH 2 - phenyl CH OMe Me NN 0
1-551 COOH Phenyl - CH2-CH2- 4-OMe-Phenyl Ethyl Me CH N N 01-551 COOH phenyl - CH2-CH2- 4-OMe-phenyl ethyl Me CH N N 0
1-552 COOH Phenyl - CH2-CH2- 4-OMe-Pheny! OMe CH2- CH2-CH2-C N N 01-552 COOH Phenyl - CH2-CH2- 4-OMe-Pheny! OMe CH 2 - CH 2 -CH 2 -CNN 0
1-553 COOH Phenyl - CH(Phenyl)-CH2- CH2- Phenyl Me Me CH CH N 01-553 COOH phenyl - CH (phenyl) -CH 2 - CH 2 - phenyl Me Me CH CH N 0
1-554 COOH Phenyl - CH7-CH7- CH2- 4-OMe-Phenyl OMe Me CH N N 01-554 COOH phenyl - CH7-CH7-CH 2 - 4-OMe-phenyl OMe Me CH NN 0
1-555 COOH Phenyl - CH2-CH2- CH2- 4-OMe-Phenyl Me Me CH N N 01-555 COOH phenyl - CH2-CH2-CH 2 - 4-OMe-phenyl Me Me CH NN 0
1-556 COOH 4-Cl-Phenyl - CH2-CH2- 3-OMe-Phenyl OMe Me H N N 01-556 COOH 4-Cl-Phenyl - CH2-CH2-3-OMe-Phenyl OMe Me H N N 0
1-557 COOH 4-Cl-Phenyl - CH2-CH2- 3-OMe-Phenyl Me Me CH N N 0 1-557 COOH 4-Cl-phenyl-CH2-CH2-3-OMe-phenyl Me Me CH NN 0
Nr. R1 R4, R5 Q R6 R2 R3 Z X Y WR 1 R 4 , R 5 QR 6 R 2 R 3 ZXYW
1-558 COOH Phenyl - CH(Phenyl)-CH2- CH2- Phenyl OMe Me N N N 01-558 COOH phenyl - CH (phenyl) -CH 2 - CH 2 - phenyl OMe Me NNN 0
1-559 COOH 4-CF3-Phenyl - CH2-CH7- CH7- 3,4-^)i-OMe-Phenyl OMe 0- CH2-CH2-C N N O1-559 COOH 4-CF 3 -phenyl - CH2-CH7-CH7- 3,4 - ^) i-OMe-phenyl OMe 0- CH 2 -CH 2 -CNNO
1-560 COOH 4-CF3-Phenyl - CH2-CH2- CH2- 3-OMe-Phenyl Ethyl Me CH N N 01-560 COOH 4-CF 3 -phenyl - CH 2 -CH 2 - CH 2 - 3-OMe-Phenyl Ethyl Me CH NN 0
1-561 COOH Phenyl - CH(Phenyl)-CH2- CH2- Phenyl Ethyl Me N N N 01-561 COOH phenyl - CH (phenyl) -CH 2 - CH 2 - phenyl ethyl Me NNN 0
1-562 COOMe Phenyl - CH2-CH2- CH7- 4-OMe-Phenyl CF3 Me CH N N 01-562 COOMe phenyl - CH2-CH2-CH7- 4-OMe-phenyl CF 3 Me CH NN 0
1-563 COOH 4-Me— Phenyl - CH2-CH2- 4-SMe-Phenyl Ethyl Me CH N N 01-563 COOH 4-Me-phenyl-CH 2 -CH 2 - 4-SMe-phenyl-ethyl Me CH NN 0
1-564 COOH 4-Me-Phenyl - CH2-CH2- 4-SMe-Phenyl OMe 0- CH2-CH2-C N N 01-564 COOH 4-Me-Phenyl - CH 2 -CH 2 - 4-SMe-Phenyl OMe 0-CH 2 -CH 2 -CNN 0
1-565 COOH 4-Cl-Phenyl - CH2-CH2- 3,4,5-Tri-OMe-Phenyl Ethyl Me | CH N N 01-565 COOH 4-Cl-Phenyl - CH 2 -CH 2 - 3,4,5-Tri-OMe-Phenyl Ethyl Me | CH NN 0
1-566 COOH 4-Cl-Phenyl - CH2-CH2- 3 ,4,5-Tri-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-566 COOH 4-Cl-phenyl - CH 2 -CH 2 - 3, 4,5-tri-OMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-567 COOH Phenyl - CH2-CH2- CH2- 4-OMe-Phenyl OMe Me CH N N s1-567 COOH phenyl - CH 2 -CH 2 - CH 2 - 4-OMe-phenyl OMe Me CH NN s
1-568 COOH Phenyl - CH2-CH2- 3 ,4-Methylendioxypheny 1 OMe Me CH N N 01-568 COOH phenyl - CH 2 -CH 2 - 3, 4-methylenedioxypheny 1 OMe Me CH NN 0
1-569 COOH Phenyl - CH2-CH2- 3 ,4-Methylendioxypheny 1 Me Me CH N N 01-569 COOH phenyl - CH 2 -CH 2 - 3, 4-methylenedioxypheny 1 Me Me CH NN 0
1-570 COOH Phenyl - CH(Phenyl)-CH2- CH2- Phenyl OMe 0- CH2-CH2-C N N 01-570 COOH phenyl - CH (phenyl) -CH 2 - CH 2 - phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-571 COOH Phenyl - CH2-CH2- CH2- 4-OMe-Phenyl CF3 Me CH N N 01-571 COOH phenyl - CH2-CH 2 - CH 2 - 4-OMe-phenyl CF 3 Me CH NN 0
1-572 COOH Phenyl - CH2-CH7- CH2- 4-OMe-Phenyl Me Me CH N CH 01-572 COOH phenyl - CH2-CH7-CH 2 - 4-OMe-phenyl Me Me CH N CH 0
1-573 COOH Phenyl - CH2-CH2- CH2- 4-OMe-Phenyl Ethyl Me N N N 01-573 COOH phenyl - CH 2 -CH 2 - CH 2 - 4-OMe-phenyl ethyl Me NNN 0
1-574 COOH 4-Cl-Phenyl - CH2-CH2- 4-Et-Phenyl Ethyl Me CH N N 01-574 COOH 4-Cl-Phenyl - CH2-CH2- 4-Et-Phenyl Ethyl Me CH N N 0
1-575 COOH 4-CF3-Phenyl - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl OMe Me CH N N 01-575 COOH 4-CF 3 -phenyl-CH2-CH2-CH 2 - 3,4-di-OMe-phenyl OMe Me CH NN 0
1-576 COOH 4~CF3-Phcnyl - CH7-CH7- CH7- 3,4-Di-OMe-Phenyl Ethyl Me CH N N 01-576 COOH 4 ~ CF 3 -Phcnyl - CH7-CH7-CH7- 3,4-Di-OMe-Phenyl Ethyl Me CH NN 0
1-577 COOH 4-Cl-Phenyl - CH2-CH2- 4-Et-Phenyl OMe 0- CH2-CH2-C N N 01-577 COOH 4-Cl-phenyl-CH 2 -CH 2 - 4-Et-phenyl OMe 0-CH 2 -CH 2 -CNN 0
1-578 COOH Phenyl - CH2-CH2- CH2- 3-Cl-4-OMe-PhenyI Ethyl Me CH N N 01-578 COOH Phenyl - CH2-CH2-CH 2 - 3-Cl-4-OMe-PhenyI Ethyl Me CH NN 0
1-579 COOH 4-Mc-Phenyl - CH2-CH2- 4-SMe-Phenyl Me Me CH N N 01-579 COOH 4-Mc-Phenyl - CH 2 -CH 2 - 4-SMe-Phenyl Me Me CH NN 0
1-580 COOH 4-Me-Phenyl - CH7-CH2- 4-SMe-Phcnyl Me Me N N N 01-580 COOH 4-Me-Phenyl - CH7-CH2- 4-SMe-Phcnyl Me Me N N N 0
1-581 COOH Phenyl - CH2-CH2- Naphlh-2-yl Me Me N N N 01-581 COOH phenyl - CH2-CH2-Naphlh-2-yl Me Me N N N 0
1-582 COOH Phenyl - CH7-CH7- Naphth-2-yl Ethyl Me CH N N 0 1-582 COOH phenyl - CH7-CH7-naphth-2-yl ethyl Me CH NN 0
Nr. R' R4, R5 Q R6 R2 R3 Z X Y wNo. R 'R 4 , R 5 QR 6 R 2 R 3 ZXY w
1-583 COOH 4— F-Phenyl - CH2-CH2- CH2- 4-OMe-Phenyl OMe CH2- CH2-CH2-C N N O1-583 COOH 4- F-phenyl - CH 2 -CH 2 - CH 2 - 4-OMe-phenyl OMe CH 2 - CH 2 -CH 2 -CNNO
1-584 COOH 4-F-Phenyl - CH2-CH2- CH2- 4- Me-Phenyl OMe 0- CH2-CH2-C N N 01-584 COOH 4-F-phenyl - CH 2 -CH 2 - CH 2 - 4- Me-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-585 COOH Phenyl - CH2-CH2- 4-OMe-Phenyl Me Me CH N N 01-585 COOH phenyl - CH2-CH2- 4-OMe-phenyl Me Me CH N N 0
1-586 COOH Phenyl - CH(Phenyl)-CH2- CH2- Phenyl Me Me N N N 01-586 COOH phenyl - CH (phenyl) -CH 2 - CH 2 - phenyl Me Me NNN 0
1-587 COOH Phenyl - CH(Phenyl)-CH2- CH2- Phenyl Ethyl Me CH N N 01-587 COOH phenyl - CH (phenyl) -CH 2 - CH 2 - phenyl ethyl Me CH NN 0
1-588 COOH Phenyl - CH2-CH2- 4-OMe-Phenyl Me Me N N N 01-588 COOH phenyl - CH 2 -CH 2 - 4-OMe-phenyl Me Me NNN 0
1-589 COOH 4—F-Phenyl - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl CF3 Me CH N N 0COOH 1-589 4-F-phenyl - CH 2 -CH 2 - CH 2 - 3,4-di-OMe-phenyl CF 3 Me CH NN 0
1-590 COOH 4-Cl-Phenyl - CH2-CH2- 3,5- Di-OMe-Phenyl Ethyl Me CH N N 01-590 COOH 4-Cl-Phenyl - CH2-CH2- 3,5-Di-OMe-Phenyl Ethyl Me CH N N 0
1-591 COOH 4-Et-Phenyl - CH2-CH2- CH2- 4— Me-Phenyl OMe 0- CH2-CH2-C N N 0COOH 1-591 4-Et-phenyl - CH 2 -CH 2 - CH 2 - 4-Me-phenyl OMe CH 2 -CH 2 0- 0 -CNN
1-592 COOH 4-CF3-Phenyl - CH2-CH2- CH2- 4-OMe-Phenyl OMe O- CH2-CH2-C N N 01-592 COOH 4-CF 3 -phenyl - CH 2 -CH 2 - CH 2 - 4-OMe-Phenyl OMe O-CH 2 -CH 2 -CNN 0
1-593 COOH 4-Cl-Phenyl - CH2-CH2- 3,5-^Di-OMe-Phenyl OMe O CH2-CH2-C N N 01-593 COOH 4-Cl-Phenyl - CH 2 -CH 2 - 3.5- ^ Di-OMe-Phenyl OMe O CH 2 -CH 2 -CNN 0
1-594 COOH Phenyl - CH(OH)-CH(OH)- CH2- 3,4-Di-OMe-Phenyl OMe Me | CH N N 01-594 COOH phenyl - CH (OH) -CH (OH) - CH 2 - 3,4-di-OMe-phenyl OMe Me | CH NN 0
1-595 COOH 4-Me— Phenyl - CH2-CH2- 3-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-595 COOH 4-Me-phenyl-CH2-CH2-3-OMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-596 COOH 4— Me— Phenyl - CH2-CH2- 4-SMe-Phenyl OMe Me CH N N 01-596 COOH 4- Me phenyl CH2-CH2 4- SMe phenyl OMe Me CH N N 0
1-597 COOH Phenyl - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl Me Me CH N N s1-597 COOH phenyl - CH 2 -CH 2 - CH 2 - 3,4-di-OMe-phenyl Me Me CH NN s
1-598 COOH Phenyl - CH2-CH2- CH2- 3,4-Üi-OMe-Phenyl Me Me N CH N 01-598 COOH phenyl - CH2-CH2-CH2-3,4-Üi-OMe-phenyl Me Me N CH N 0
1-599 COOH 4-Cl-Phenyl - CH2-CH2- 3,4,5-Tri-OMe-Phenyl Me Me CH N N 01-599 COOH 4-Cl-Phenyl-CH2-CH2-3,4,5-Tri-OMe-Phenyl Me Me CH N N 0
1-600 COOH 4-Cl-Phenyl - CH2-CH2- 3 ,4,5-Tri-OMe-Phenyl Me Me N N N 01-600 COOH 4-Cl-Phenyl - CH2-CH2-3, 4,5-Tri-OMe-Phenyl Me Me N N N 0
1-601 COOEt Phenyl - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl Ethyl Me CH N N 01-601 COOEt Phenyl - CH 2 -CH 2 - CH 2 - 3,4-Di-OMe-Phenyl Ethyl Me CH NN 0
1-602 COOH Phenyl - CH(Phenyl)-CH2- CH2- Phenyl OMe Me CH N N 01-602 COOH phenyl - CH (phenyl) -CH 2 - CH 2 - phenyl OMe Me CH NN 0
1-603 COOH Phenyl - CH(Phenyl)-CH2- CH2- Phenyl Me Me CH N N 01-603 COOH phenyl - CH (phenyl) -CH 2 - CH 2 - phenyl Me Me CH NN 0
1-604 COOH Phenyl - CH2-CH2- 4-iPr-Phenyl OMe 0- CH2-CH2-C N N 01-604 COOH phenyl - CH2-CH2- 4-iPr-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-605 COOH Phenyl - CH2-CH2- 3 ,4— Methy lendioxypheny 1 CF3 Me CH N N 01-605 COOH phenyl - CH2-CH2-3,4- methylenedioxypheny 1 CF 3 Me CH NN 0
1-606 COOH Phenyl - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl OMe O- CH2-CH2-C N N s 1-606 COOH phenyl - CH2-CH 2 - CH 2 - 3,4-di-OMe-phenyl OMe O-CH 2 -CH 2 -CNN s
Nr. R1 R4, R5 Q R6 R2 R3 Z X Y WR 1 R 4 , R 5 QR 6 R 2 R 3 ZXYW
1-607 COOH 4-Et-Phenyl - CH2-CH7- CH7- 4-SMe-Phenyl OMe 0- CH2-CH2-C N N O1-607 COOH 4-Et-Phenyl-CH2-CH7-CH7- 4-SMe-Phenyl OMe 0- CH 2 -CH 2 -CNNO
1-608 COOH 4-Et-Phenyl - CH2-CH2- CH2- 4— Me-Phenyl OMe Me CH N N O1-608 COOH 4-Et-Phenyl-CH2-CH2-CH2- 4- Me-Phenyl OMe Me CH N N O
1-609 COOH 4-Br-Phenyl - CH2-CH7- CH2- 4-SMe-Phenyl OMe Me CH N N 01-609 COOH 4-Br-phenyl - CH2-CH7-CH2- 4-SMe-phenyl OMe Me CH N N 0
1-610 COOH 4-Cl-Phenyl - CH2-CH2- 4-Et-Phenyl Me Me CH N N 01-610 COOH 4-Cl-Phenyl - CH 2 -CH 2 - 4-Et-Phenyl Me Me CH NN 0
1-611 COOH 4~Me-Phenyl - CH2-CH2- 3-OMe-Phenyl Me Me N N N 01-611 COOH 4 ~ Me-Phenyl - CH2-CH2-3-OMe-Phenyl Me Me N N N 0
1-612 COOH 4-Me-Phenyl - CH2-CH2- 3-OMe-Phenyl Ethyl Me CH N N 01-612 COOH 4-Me-Phenyl - CH 2 -CH 2 - 3-OMe-Phenyl Ethyl Me CH NN 0
1-613 COOH 4-Cl-Phenyl - CH2-CH2- 4-Et-Phenyl Me Me N N N 01-613 COOH 4-Cl-Phenyl - CH 2 -CH 2 - 4-Et-Phenyl Me Me NNN 0
1-614 COOH Phenyl - CH2-CH2- CH2- 4-SMe-Phenyl Ethyl Me N CH N 01-614 COOH phenyl - CH2-CH2-CH2- 4-SMe-phenyl ethyl Me N CH N 0
1-615 COOH Phenyl - CH7-CH2- Naphth-2-yl OMe Me CH N N 01-615 COOH phenyl - CH7-CH2-naphth-2-yl OMe Me CH N N 0
1-616 COOH Phenyl - CH2-CH2- Naphth-2-yl Me Me CH N N 01-616 COOH phenyl - CH2-CH2-naphth-2-yl Me Me CH N N 0
1-617 COOH Phenyl - CH(OH)-CH(OH)- CH2- 4-SMe-Phenyl OMe O- CH2-CH2-C N N 01-617 COOH phenyl - CH (OH) -CH (OH) - CH 2 - 4-SMe-phenyl OMe O-CH 2 -CH 2 -CNN 0
1-618 COOH Phenyl - CH7-CH2- CH2- Phenyl OMe O- CH2-CH2-C N N 01-618 COOH phenyl - CH7-CH2-CH2-phenyl OMe O-CH 2 -CH 2 -CNN 0
1-619 COOH Phenyl - CH(Phenyl)-CH2- CH2- Phenyl CF3 Me CH N N 01-619 COOH phenyl - CH (phenyl) -CH 2 - CH 2 - phenyl CF 3 Me CH NN 0
1-620 COOH Phenyl - CH2-CH2- CH2- 4-Me-Phenyl Me Me N N CH 01-620 COOH Phenyl - CH 2 -CH 2 - CH 2 - 4-Me-Phenyl Me Me NN CH 0
1-621 COOH Phenyl - CH2-CH2- 4-OMe-Phenyl OMe OMe CH N N 01-621 COOH phenyl - CH2-CH2- 4-OMe-phenyl OMe OMe CH N N 0
1-622 COOH Phenyl - CH2-CH2- 4-OMe-Phenyl OMe Me CH N N 01-622 COOH phenyl - CH2-CH2- 4-OMe-phenyl OMe Me CH N N 0
1-623 COOH 4-Et-Phenyl - CH7-CH2- CH2- 4-SMe-Phenyl Me Me CH N N 01-623 COOH 4-Et-Phenyl - CH7-CH2-CH2- 4-SMe-Phenyl Me Me CH N N 0
1-624 COOH 4-Et-Phenyl - CH2-CH2- CH2- 4-SMe-Phenyl Elhyl Me CH N N 01-624 COOH 4-Et-Phenyl - CH2-CH2-CH2- 4-SMe-Phenyl Elhyl Me CH N N 0
1-625 COOH Phenyl - CH2-CH2- CH2- 4—Me-Phenyl CF3 Me CH N N sCOOH 1-625 phenyl - CH2-CH2-CH 2 - 4-Me-phenyl CF 3 Me CH NN s
1-626 COOH 4-Cl-Phenyl - CH2-CH2- 3,5-Di-OMe-Phenyl Me Me CH N N 01-626 COOH 4-Cl-phenyl-CH2-CH2-3,5-di-OMe-phenyl Me Me CH N N 0
1-627 COOH 4— Me— Phenyl - CH7-CH2- 3-OMe-Phenyl OMe Me CH N N 01-627 COOH 4- Me phenyl-CH7-CH2 -3-OMe-phenyl OMe Me CH N N 0
1-628 COOH 4- le— Phenyl - CH7-CH2- 3-OMe-Phenyl Me Me CH N N 01-628 COOH 4- le- phenyl - CH7-CH2- 3-OMe-phenyl Me Me CH N N 0
1-629 COOH 4-Cl-Phcnyl - CH2-CH7- 3,5-Di-OMe-Phenyl Me Me N N N 01-629 COOH 4-Cl-Phenyl-CH2-CH7-3,5-Di-OMe-Phenyl Me Me N N N 0
1-630 COOH Phenyl - CH2-CH2- CH2- 4— Me-Phenyl OMe Me N N N 01-630 COOH phenyl - CH2-CH2-CH2- 4- Me-phenyl OMe Me N N N 0
1-631 COOH Phenyl - CH(OH)-CH(OH)- CH2- 4-Me-Phenyl Me Me CH N N 0 1-631 COOH Phenyl - CH (OH) -CH (OH) - CH 2 - 4-Me-Phenyl Me Me CH NN 0
Nr. R> R4, R5 Q R6 R2 R3 Z X Y WNo. R> R 4 , R 5 QR 6 R 2 R 3 ZXYW
1-632 COOH 4-Cl-Phenyl - CH2-CH2- CH2- 4-Et-Phcnyl Ethyl Me CH N N 01-632 COOH 4-Cl-Phenyl - CH2-CH2-CH2- 4-Et-Phcnyl Ethyl Me CH N N 0
1-633 COOH 4-Cl-Phenyl - CH2-CH2- CH2- 4-Et-Phenyl OMe 0- CH2-CH2-C N N 01-633 COOH 4-Cl-Phenyl-CH2-CH2-CH 2 - 4-Et-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-634 COOH 4-F-Phenyl - CH2-CH2- CH2- 4-Me-Phenyl Me Me | N N N 01-634 COOH 4-F-Phenyl - CH2-CH2-CH 2 - 4-Me-Phenyl Me Me | NNN 0
1-635 COOH 4-Cl-Phenyl - CH2-CH2- 3,4-Di-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-635 COOH 4-Cl-phenyl-CH2-CH2-3,4-di-OMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-636 COOH Phenyl - CH2-CH2- CH2- Phenyl Me Me N N N 01-636 COOH phenyl - CH 2 -CH 2 - CH 2 - phenyl Me Me NNN 0
1-637 COOH Phenyl - CH2-CH2- CH2- Phenyl Ethyl Me CH N N 01-637 COOH phenyl - CH 2 -CH 2 - CH 2 - phenyl ethyl Me CH NN 0
1-638 COOH 4-Cl-Phenyl - CH2-CH2- 3,4,5-Tri-OMe-Phenyl OMe Me CH N N 01-638 COOH 4-Cl-Phenyl-CH2-CH2-3,4,5-Tri-OMe-Phenyl OMe Me CH N N 0
1-639 COOH 4-F-Phenyl - CH2-CH2- CH2- 4-Me-Phenyl Ethyl Me CH N N 01-639 COOH 4-F-Phenyl - CH2-CH2-CH 2 - 4-Me-Phenyl Ethyl Me CH NN 0
1-640 COOH Phenyl - CH7-CH2- 4-iPr-Phenyl Ethyl Me CH N N 01-640 COOH phenyl - CH7-CH2- 4-iPr-phenyl ethyl Me CH N N 0
1-641 COOH 4-Et-Phenyl - CH2-CH2- CH2- 3-OMe-Phenyl Ethyl Me CH N N 01-641 COOH 4-Et-Phenyl - CH2-CH2-CH 2 - 3-OMe-Phenyl Ethyl Me CH NN 0
1-642 COOH 4-£t-Phenyl - CH7-CH2- CH2- 3-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-642 COOH 4- £ t-phenyl - CH7-CH 2 - CH 2 - 3-OMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-643 COOH Phenyl - CH2-CH2- 4-iPr-Phenyl OMe CH2- CH2-CH2-C N N 01-643 COOH phenyl - CH 2 -CH2- 4-iPr-phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-644 COOH 4-F-Phenyl - CH2-CH2- CH2- 4— Me-Phenyl OMe O CH2-CH2-C N N 01-644 COOH 4-F-phenyl-CH2-CH2-CH 2 - 4- Me-phenyl OMe O CH 2 -CH 2 -CNN 0
1-645 COOH 4-JMe-Phenyl - CH2-CH2- 3 ,4-Di-OMe-Phenyl Ethyl Me | CH N N 01-645 COOH 4- J Me-Phenyl - CH 2 -CH 2 - 3, 4-Di-OMe-Phenyl Ethyl Me | CH NN 0
1-646 COOH 4-^vle- Phenyl - CH2-CH2- 3,4-Di-OMe-Phenyl OMe 0- CH -CH2-C N N 01-646 COOH 4- ^ vle-phenyl - CH 2 -CH 2 - 3,4-di-OMe-phenyl OMe 0- CH -CH 2 -CNN 0
1-647 COOH 4-F-Phenyl - CH2-CH2- CH2- 4-Et-Phenyl CF3 Me CH N N 01-647 COOH 4-F-phenyl - CH 2 -CH 2 - CH 2 - 4-Et-phenyl CF 3 Me CH NN 0
1-648 COOH 4-Cl-Phenyl - CH2-CH2- 4-Me-Phenyl OMe 0- CH2-CH2-C N N 01-648 COOH 4-Cl-phenyl-CH 2 -CH 2 - 4-Me-phenyl OMe 0-CH 2 -CH 2 -CNN 0
1-649 COOH 4-Cl-Phenyl - CH2-CH2- 4-Et-Phenyl OMe Me CH N N 01-649 COOH 4-Cl-Phenyl - CH 2 -CH 2 - 4-Et-Phenyl OMe Me CH NN 0
1-650 COOMe Phenyl - CH2-CH2- CH2- 4-Et-Phenyl OMe Me CH N N 01-650 COOMe Phenyl - CH 2 -CH 2 - CH 2 - 4-Et-Phenyl OMe Me CH NN 0
1-651 COOH Phenyl - CH7-CH2- 4-Cl-Phenyl OMe 0- CH2-CH2-C N N 01-651 COOH phenyl - CH7-CH2- 4-Cl-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-652 COOH 4-Cl-Phenyl - CH2-CH2- CH2- 4—Me-Phenyl Ethyl Me CH N N 01-652 COOH 4-Cl-Phenyl-CH2-CH2-CH2- 4-Me-Phenyl Ethyl Me CH N N 0
1-653 COOH 4-Cl-Phenyl - CH2-CH7- CH2- 4-Et-Phenyl OMe Me CH N N 01-653 COOH 4-Cl-Phenyl-CH 2 -CH7-CH 2 - 4-Et-Phenyl OMe Me CH NN 0
1-654 COOH Phenyl - CH7-CH7- Naphllι-2-yl CF3 Me CH N N 01-654 COOH Phenyl - CH7-CH7-Naphllι-2-yl CF 3 Me CH NN 0
1-655 COOH Phenyl - CH7-CH7- CH2- 3,4-Di-CVPhenyl Me Me N N N 01-655 COOH phenyl - CH7-CH7-CH2- 3,4-di-CVPhenyl Me Me N N N 0
1-656 COOH 4-F-Phenyl - CH2-CH7- CH2- 4-Cl-Phenyl Ethyl Me CH N N 0 1-656 COOH 4-F-Phenyl - CH2-CH7-CH 2 - 4-Cl-Phenyl Ethyl Me CH NN 0
Nr. R1 R4, R5 Q R6 R2 R3 Z X Y WR 1 R 4 , R 5 QR 6 R 2 R 3 ZXYW
1-657 COOH Phenyl - CH2-CH2- Phenyl OMe 0- CH2-CH2-C N N 01-657 COOH phenyl - CH2-CH2-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-658 COOH Phenyl - CH2-CH2- 4- Me-Phenyl CF3 Me CH N N 01-658 COOH phenyl - CH2-CH2- 4- Me-phenyl CF 3 Me CH NN 0
1-659 COOH 4-Et-Phenyl - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-659 COOH 4-Et-Phenyl - CH2-CH2-CH 2 - 3,4-Di-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-660 COOH 4-Et-Phenyl - CH2-CH2- CH2- 3-OMe-Phenyl OMe Me | CH N N 01-660 COOH 4-Et-Phenyl - CH2-CH2-CH2- 3-OMe-Phenyl OMe Me | CH N N 0
1-661 COOH Phenyl - CH2-CH2- CH2- 4-Cl-Phenyl OMe CH2- CH2-CH2-C N N s1-661 COOH phenyl - CH 2 -CH 2 - CH 2 - 4-Cl-phenyl OMe CH 2 - CH 2 -CH 2 -CNN s
1-662 COOH 4-Cl-Phenyl - CH7.-CH2- 4-OEt-Phenyl OMe 0- CH2-CH2-C N N 01-662 COOH 4-Cl-phenyl-CH7.-CH2- 4-OEt-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-663 COOH 4-Cl-Phenyl - CH2-CH2- 3,5- Di-OMe-Phenyl OMe Me CH N N 01-663 COOH 4-Cl-phenyl - CH2-CH2- 3,5-di-OMe-phenyl OMe Me CH N N 0
1-664 COOH Phenyl - CH2-CH2- CH2- 3-OMe-Phenyl Ethyl Me N CH N 01-664 COOH phenyl - CH 2 -CH 2 - CH 2 - 3-OMe-phenyl ethyl Me N CH N 0
1-665 COOH Phenyl - CH2-CH2- CH2- 3-OMe-Phenyl OMe Me N N N 01-665 COOH phenyl - CH 2 -CH 2 - CH 2 - 3-OMe-phenyl OMe Me NNN 0
1-666 COOH 4-Cl-Phenyl - CH2-CH2- CH2- 4-Me— Phenyl OMe Me CH N N 01-666 COOH 4-Cl-phenyl-CH2-CH2-CH 2 - 4-Me-phenyl OMe Me CH NN 0
1-667 COOH 4-Cl-Phenyl - CH2-CH2- CH2- 4— Me-Phenyl Me Me N N N 01-667 COOH 4-Cl-phenyl-CH2-CH2-CH 2 - 4- Me-phenyl Me Me NNN 0
1-668 COOH Phenyl - CH2-CH2- CH2- 2,3-Di-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-668 COOH phenyl - CH2-CH2-CH 2 - 2,3-di-OMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-669 COOH 4-Cl-Phenyl - CH2-CH7- 3,4-Di-OMe-Phenyl Me Me N N N 01-669 COOH 4-Cl-phenyl-CH2-CH7-3,4-di-OMe-phenyl Me Me N N N 0
1-670 COOH 4-Cl-Phenyl - CH2-CH2- 3,4-Oi-OMe-Phenyl Ethyl Me CH N N 01-670 COOH 4-Cl-Phenyl-CH2-CH2-3,4-Oi-OMe-Phenyl Ethyl Me CH N N 0
1-671 COOH 3,4-Di-Cl-Phenyl - CH2-CH2- CH2- 4-OMe-Phenyl OMe Me CH N N 01-671 COOH 3,4-di-Cl-phenyl-CH2-CH2-CH 2 - 4-OMe-phenyl OMe Me CH NN 0
1-672 COOH Phenyl - CH2-CH2- 4-iPτ-Phenyl Me Me CH N N 01-672 COOH phenyl - CH 2 -CH 2 - 4-iPτ-phenyl Me Me CH NN 0
1-673 COOH 4-Et-Phenyl - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl Me Me CH N N 01-673 COOH 4-Et-Phenyl - CH 2 -CH 2 - CH 2 - 3,4-Di-OMe-Phenyl Me Me CH NN 0
1-674 COOH 4-Et-Pheny! - CH2-CH2- CH2- 3,4-^i-OMe-Phenyl Ethyl Me CH N N 01-674 COOH 4-Et-Pheny! - CH2-CH2-CH 2 - 3,4- ^ i-OMe-Phenyl Ethyl Me CH NN 0
1-675 COOH Phenyl - CH2-CH2- 4-iPr-Phenyl Me Me N N N 01-675 COOH phenyl - CH 2 -CH 2 - 4-iPr-phenyl Me Me NNN 0
1-676 COOH 3,4-Di-Cl-Phenyl - CH2-CH2- CH2- 4-OMe-Phenyl Me Me CH N N 01-676 COOH 3,4-di-Cl-phenyl - CH 2 -CH 2 - CH 2 - 4-OMe-phenyl Me Me CH NN 0
1-677 COOH 3,4-Di-Cl-Phenyl - CH2-CH2- CH2- 4-OMe-Phenyl Ethyl Me CH N N 01-677 COOH 3,4-di-Cl-phenyl - CH 2 -CH 2 - CH 2 - 4-OMe-phenyl ethyl Me CH NN 0
1-678 COOH 4-Cl-Phenyl - CH2-CH2- 4-Me— Phenyl Me Me N N N 01-678 COOH 4-Cl-Phenyl-CH2-CH2- 4-Me-Phenyl Me Me N N N 0
1-679 COOH 4-Cl-Phenyl - CH2-CH2- 4— Me-Phenyl Ethyl Me CH N N 0COOH 1-679 4-Cl-phenyl - CH 2 -CH 2 - 4-Me-phenyl ethyl Me CH NN 0
1-680 COOH 4-CI-Phenyl - CH2-CH2- CH2- 3 ,4-Methylendioxypheny 1 Me Me CH N N 01-680 COOH 4-CI-Phenyl - CH2-CH2-CH 2 - 3, 4-methylenedioxypheny 1 Me Me CH NN 0
1-681 COOH 4-Cl-Phenyl - CH2-CH2- CH2- 3 ,4-Methy lendioxyphenyl OMe 0- CH2-CH2-C N N 0 COOH 1-681 4-Cl-phenyl - CH2-CH2-CH 2 - 3, 4-methyl lendioxyphenyl OMe CH 2 -CH 2 0- 0 -CNN
Nr. R1 R4, R5 Q R6 R2 R3 Z X Y WR 1 R 4 , R 5 QR 6 R 2 R 3 ZXYW
1-682 COOH 3,4-Di-Cl-Phenyl - CH2-CH2- CH2- 4-OMe-Phenyl OMe 0-CH2-CH2-C N N O1-682 COOH 3,4-di-Cl-phenyl - CH 2 -CH 2 - CH 2 - 4-OMe-phenyl OMe 0-CH 2 -CH 2 -CNNO
1-683 COOH Phenyl -CH2-CH2- 4-Cl-Phenyl Ethyl Me |CH N N O1-683 COOH phenyl -CH2-CH2- 4-Cl-phenyl ethyl Me | CH N N O
1-684 COOH Phenyl -CH2-CH2- 4-CI-Phenyl OMe CH2-CH2-CH2-C N N O1-684 COOH phenyl -CH2-CH2- 4-CI-phenyl OMe CH 2 -CH 2 -CH 2 -CNNO
1-685 COOH Phenyl -CH(OH)-CH(OH)-CH2- 2-Cl-Phenyl OMe Me CH N N O1-685 COOH phenyl -CH (OH) -CH (OH) -CH 2 - 2-Cl-phenyl OMe Me CH NNO
1-686 COOH Phenyl -CH2-CH2-CH2- 2-Cl-Phenyl Me Me CH CH N 01-686 COOH phenyl -CH2-CH2-CH 2 - 2-Cl-phenyl Me Me CH CH N 0
1-687 COOH 4-Et-Phenyl -CH2-CH2-CH2- 4-OMe-Phenyl OMe 0-CH2-CH2-C N N 01-687 COOH 4-Et-Phenyl -CH 2 -CH 2 -CH 2 - 4-OMe-Phenyl OMe 0-CH 2 -CH 2 -CNN 0
1-688 COOH 4-Et-Phenyl - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl OMe Me CH N N 01-688 COOH 4-Et-Phenyl - CH2-CH2-CH 2 - 3,4-Di-OMe-Phenyl OMe Me CH NN 0
1-689 COOH Phenyl - CH2-CH2- Phenyl Me Me N N N 01-689 COOH phenyl - CH 2 -CH 2 - phenyl Me Me NNN 0
1-690 COOH Phenyl -CH2-CH2- Phenyl Ethyl Me CH N N 01-690 COOH phenyl -CH 2 -CH 2 - phenyl ethyl Me CH NN 0
1-691 COOH Phenyl -CH2-CH7-CH2- 2-Cl-Phenyl Me Me N N N s1-691 COOH phenyl -CH 2 -CH7-CH 2 - 2-Cl-phenyl Me Me NNN s
1-692 COOH 4-Cl-Phenyl -CH2-CH2- 4-OEt-Phenyl Me Me N N N 01-692 COOH 4-Cl-Phenyl -CH2-CH2- 4-OEt-Phenyl Me Me N N N 0
1-693 COOH 4-CI-Phenyl -CH2-CH2- 4-OEt-Phenyl Ethyl Me CH N N 01-693 COOH 4-CI-Phenyl -CH 2 -CH 2 - 4-OEt-Phenyl Ethyl Me CH NN 0
1-694 COOH 4-Cl-Phenyl - CH2-CH2- CH2- 4-iPr-Phenyl Ethyl Me CH N N 01-694 COOH 4-Cl-Phenyl - CH 2 -CH 2 - CH 2 - 4-iPr-Phenyl Ethyl Me CH NN 0
1-695 COOH 4-Cl-Phenyl - CH2-CH2- CH2- 3 ,4— Methy lendioxypheny 1 OMe Me CH N N 0COOH 1-695 4-Cl-phenyl - CH 2 -CH 2 - CH 2 - 3, 4-Methyl-1 lendioxypheny OMe Me CH NN 0
1-696 COOH Phenyl -CH2-CH2-CH2- 2-Cl-Phenyl Ethyl Me CH N N s1-696 COOH phenyl -CH 2 -CH 2 -CH 2 - 2-Cl-phenyl ethyl Me CH NN s
1-697 COOMe Phenyl -CH2-CH2-CH2- 2-C!-Phenyl OMe CH2-CH2-CH2-C N N 0.1-697 COOMe phenyl -CH2-CH2-CH 2 - 2-C! -Phenyl OMe CH 2 -CH 2 -CH 2 -CNN 0.
1-698 COOH Phenyl -CH2-CH2-CH2- 3 ,5-Di-OMe-4-Cl-Phenyl OMe Me CH N N o„1-698 COOH phenyl -CH2-CH2-CH2- 3,5-di-OMe-4-Cl-phenyl OMe Me CH N N o „
1-699 COOH 4-Cl-Phenyl -CH2-CH2- 3,4-Di-OMe-Phenyl OMe Me CH N N 01-699 COOH 4-Cl-phenyl -CH2-CH2- 3,4-di-OMe-phenyl OMe Me CH N N 0
1-700 COOH 4-CI-Phenyl -CH2-CH7- 3,4-Di-OMe-Phenyl Me Me CH N N 01-700 COOH 4-CI-Phenyl -CH2-CH7- 3,4-Di-OMe-Phenyl Me Me CH N N 0
1-701 COOH 4-Cl-Phenyl -CH2-CH2-CH2- 3-OMc-Phenyl OMe 0-CH2-CH2-C N N 01-701 COOH 4-Cl-phenyl -CH 2 -CH2-CH2- 3-OMc-phenyl OMe 0-CH 2 -CH 2 -CNN 0
1-702 COOH 4-Et-Phenyl - CH2-CH2- CH2- 4-OMe-Phenyl Ethyl Me CH N N 01-702 COOH 4-Et-Phenyl - CH2-CH2-CH 2 - 4-OMe-Phenyl Ethyl Me CH NN 0
1-703 COOH Phenyl -CH2-CH2-CH2- 3,5-Di-OMe-4-Cl-Phenyl Me Me CH N N 01-703 COOH phenyl -CH2-CH 2 -CH 2 - 3,5-di-OMe-4-Cl-phenyl Me Me CH NN 0
1-704 COOH Phenyl -CH2-CH2- 4-iPr-Phenyl CF3 Me CH N N 01-704 COOH phenyl -CH2-CH2- 4-iPr-phenyl CF 3 Me CH NN 0
1-705 COOH Phenyl -CH2-CH2- 4-iPr-Phenyl OMe Me CH N N 01-705 COOH phenyl -CH2-CH2- 4-iPr-phenyl OMe Me CH N N 0
1-706 COOH Phenyl -CH=CH-CH2- 4-OMe-Phenyl OMe Me CH N N s 1-706 COOH phenyl -CH = CH-CH 2 - 4-OMe-phenyl OMe Me CH NN s
Nr. R' R4, R5 Q R* R2 R3 Z X Y WNo. R 'R 4 , R 5 QR * R 2 R 3 ZXYW
1-707 COOMe Phenyl - CH=CH- CH2- 4- Me-Phenyl Me Me CH N N O 1-707 COOMe Phenyl - CH = CH- CH 2 - 4- Me-Phenyl Me Me CH NNO
1-708 COOH 4-Cl-Phenyl - CH2-CH2- CH2- 4-OEt, 3-OMe-Phenyl OMe O- CH2-CH2-C N N O1-708 COOH 4-Cl-phenyl-CH2-CH2-CH2- 4-OEt, 3-OMe-phenyl OMe O-CH 2 -CH 2 -CNNO
1-709 COOH 4-Cl-Phenyl - CH2-CH2- CH2- 4-iPr-Phenyl Me Me N N N O1-709 COOH 4-Cl-phenyl - CH2-CH2-CH 2 - 4-iPr-phenyl Me Me NNNO
1-710 COOH 4-Cl-Phenyl - CH2-CH2- 4-Me— henyl OMe Me CH N N O1-710 COOH 4-Cl-phenyl-CH2-CH2- 4-methenyl OMe Me CH N N O
1-711 COOH 4-Cl-Phenyl - CH2-CH2- 4-Me-Phenyl Me Me CH N N 01-711 COOH 4-Cl-Phenyl - CH 2 -CH 2 - 4-Me-Phenyl Me Me CH NN 0
1-712 COOH Phenyl - CH=CH- CH2- 4-OMe-Phenyl Me Me N CH N 01-712 COOH phenyl - CH = CH- CH 2 - 4-OMe-phenyl Me Me N CH N 0
1-713 COOH Phenyl - CH2-CH2- 4-Cl-Phenyl Me Me CH N N 01-713 COOH phenyl - CH 2 -CH 2 - 4-Cl-phenyl Me Me CH NN 0
1-714 COOH Phenyl - CH2-CH2- 4-Cl-Phenyl Me Me N N N 01-714 COOH phenyl - CH2-CH2- 4-Cl-phenyl Me Me N N N 0
1-715 COOH 4-Cl-Phenyl - CH2-CH2- CH2- 3- Me-Phenyl Me Me N N N 01-715 COOH 4-Cl-Phenyl-CH2-CH2-CH 2 - 3-Me-Phenyl Me Me NNN 0
1-716 COOH 4-Cl- >henyl - CH2-CH2- CH2- 3-OMe-Phenyl Ethyl Me CH N N 01-716 COOH 4-Cl- > henyl - CH 2 -CH 2 - CH 2 - 3-OMe-Phenyl Ethyl Me CH NN 0
1-717 COOH Phenyl - CH=CH- CH2- 3-Cl-4-OMe-Phenyl Ethyl Me CH N N 01-717 COOH Phenyl - CH = CH- CH 2 - 3-Cl-4-OMe-Phenyl Ethyl Me CH NN 0
1-718 COOH Phenyl - CH=CH- CH2- 3-Cl-4-0Me-Phenyl OMe 0- CH2-CH2-C N N 01-718 COOH phenyl - CH = CH- CH 2 - 3-Cl-4-0Me-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-719 COOH Phenyl - CH2-CH2- Phenyl OMe Me CH N N 01-719 COOH phenyl - CH 2 -CH 2 - phenyl OMe Me CH NN 0
1-720 COOH Phenyl - CH2-CH2- Phenyl Me Me CH N N 01-720 COOH phenyl - CH 2 -CH 2 - phenyl Me Me CH NN 0
1-721 COOH 4-F -Phenyl - CH=CH- CH2- 3,4-Di-OMe-Phenyl OMe Me CH N N 01-721 COOH 4-F -phenyl-CH = CH-CH 2 - 3,4-di-OMe-phenyl OMe Me CH NN 0
1-722 COOH 4-Cl-Phenyl - CH2-CH2- CH2- 4-SMe-Phenyl OMe 0- CH2-CH2-C N N 01-722 COOH 4-Cl-phenyl - CH 2 -CH 2 - CH 2 - 4-SMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-723 COOH 4-Cl-Phenyl - CH2-CH2- CH2- 4-OEt, 3- Me-Phenyl OMe Me CH N N 01-723 COOH 4-Cl-Phenyl-CH2-CH2-CH 2 - 4-OEt, 3-Me-Phenyl OMe Me CH NN 0
1-724 COOH 4-Cl-Phenyl - CH2-CH2- 4-OEt-Phenyl OMe Me CH N N 01-724 COOH 4-Cl-Phenyl - CH2-CH2- 4-OEt-Phenyl OMe Me CH N N 0
1-725 COOH 4-Cl-Phenyl - CH2-CH2- 4-OEt-Phenyl Me Me CH N N 01-725 COOH 4-Cl-Phenyl - CH2-CH2- 4-OEt-Phenyl Me Me CH N N 0
1-726 COOMe Phenyl - CH=CH- CH2- 3,4-Di-OMe-Phenyl Me Me CH N N 01-726 COOMe Phenyl - CH = CH- CH 2 - 3,4-Di-OMe-Phenyl Me Me CH NN 0
1-727 COOH Phenyl - CH=CH- CH2- 3,4-Di-OMe-Phenyl Me Me N CH N 01-727 COOH phenyl - CH = CH- CH 2 - 3,4-di-OMe-phenyl Me Me N CH N 0
1-728 COOH Phenyl - CH=CH- CH2- 3,4-Oi-OMe-Phenyl OMe 0- CH2-CH2-C N N s1-728 COOH phenyl - CH = CH - CH 2 - 3,4-Oi-OMe-phenyl OMe 0-CH 2 -CH 2 -CNN s
1-729 COOH 4-Cl-Phenyl - CH2-CH7- CH2- 3-OMe-Phenyl OMe Me CH N N 01-729 COOH 4-Cl-Phenyl - CH2-CH7-CH2- 3-OMe-Phenyl OMe Me CH N N 0
1-730 COOH 4-Cl-Phenyl - CH2-CH2- CH2- 3-OMe-Phenyl Me Me CH N N 01-730 COOH 4-Cl-Phenyl - CH2-CH 2 - CH 2 - 3-OMe-Phenyl Me Me CH NN 0
1-731 COOH 4-Cl-Phenyl - CH2-CH2- 4-OMe-Phenyl Ethyl Me CH N N 0 1-731 COOH 4-Cl-Phenyl - CH2-CH2- 4-OMe-Phenyl Ethyl Me CH NN 0
Nr. R1 R4, R5 Q | R6 R2 R3 Z X | Y WNo. R 1 R 4 , R 5 Q | R 6 R 2 R 3 ZX | YW
1-732 COOH 4-CI-Phenyl - CH2-CH2- 4-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-732 COOH 4-CI-Phenyl - CH 2 -CH 2 - 4-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-733 COOH Phenyl - CH=CH- CH2- Cyclohexyl OMe Me CH N N O1-733 COOH phenyl - CH = CH- CH 2 - cyclohexyl OMe Me CH NNO
1-734 COOH Phenyl - CH2-CH7- 4-OEt-3-OMe-Phenyl OMe CH2- CH2-CH2-C N N O1-734 COOH phenyl - CH2-CH7- 4-OEt-3-OMe-phenyl OMe CH 2 - CH 2 -CH 2 -CNNO
1-735 COOH Phenyl - CH2-CH2- 4-OEt-3-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-735 COOH phenyl - CH2-CH2- 4-OEt-3-OMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-736 COOH 4-Cl-Phenyl - CH2-CH2- CH2- 4-SMe-Phenyl Me Me N N N 01-736 COOH 4-Cl-Phenyl - CH2-CH 2 - CH 2 - 4-SMe-Phenyl Me Me NNN 0
1-737 COOH 4-Cl-Phenyl - CH2-CH2- CH2- 4-SMe-Phenyl Ethyl Me CH N N 01-737 COOH 4-Cl-Phenyl - CH 2 -CH 2 - CH 2 - 4-SMe-Phenyl Ethyl Me CH NN 0
1-738 COOH Phenyl - CH=CH- CH2- Cyclohexyl Me Me CH N N 01-738 COOH Phenyl - CH = CH- CH 2 - Cyclohexyl Me Me CH NN 0
1-739 COOH Phenyl - CH=CH- CH2- 4— Me-Phenyl Me Me N N N s1-739 COOH phenyl - CH = CH - CH 2 - 4- Me phenyl Me Me NNN see
1-740 COOH 4-Cl-Phenyl - CH7-CH7- 3,4— Methylendioxyphenyl Ethyl Me CH N N 01-740 COOH 4-Cl-phenyl - CH7-CH7- 3,4- methylenedioxyphenyl ethyl Me CH N N 0
1-741 COOH 4-Cl-Phenyl - CH2-CH2- 3 ,4-Methylendioxyphenyl OMe 0- CH2-CH2-C N N 01-741 COOH 4-Cl-phenyl - CH 2 -CH 2 - 3, 4-methylenedioxyphenyl OMe 0- CH 2 -CH 2 -CNN 0
1-742 COOH Phenyl - C(Phenyl)=CH- CH2- Phenyl OMe Me CH N N 01-742 COOH phenyl - C (phenyl) = CH- CH 2 - phenyl OMe Me CH NN 0
1-743 COOH 4-Cl-Phenyl - CH2-CH2- CH2- 3,5-Oi-OMe-Phenyl OMe Me CH N N 01-743 COOH 4-Cl-Phenyl-CH2-CH2-CH 2 - 3,5-Oi-OMe-Phenyl OMe Me CH NN 0
1-744 COOH 4-Cl-Phenyl - CH2-CH2- CH2- 3,5-Di-OMe-Phenyl Me Me CH N N 01-744 COOH 4-Cl-Phenyl - CH 2 -CH 2 - CH 2 - 3,5-Di-OMe-Phenyl Me Me CH NN 0
1-745 COOH Phenyl - CH2-CH2- 4-Cl-Phenyl CF3 Me CH N N 01-745 COOH phenyl - CH2-CH 2 - 4-Cl-phenyl CF 3 Me CH NN 0
1-746 COOH Phenyl - CH2-CH2- 4-Cl-Phenyl OMe Me CH N N 01-746 COOH phenyl - CH2-CH2- 4-Cl-phenyl OMe Me CH N N 0
1-747 COOH 4-F-Phenyl - CH=CH- CH2- Phenyl Me Me CH N N 01-747 COOH 4-F-phenyl-CH = CH-CH 2 -phenyl Me Me CH NN 0
1-748 COOH 4-F-^henyl - CH=CH- CH2- Phenyl Me Me N N N 01-748 COOH 4-F- ^ henyl - CH = CH- CH 2 - phenyl Me Me NNN 0
1-749 COOH Phenyl - CH2-CH2- 4-OEt-3-OMe-Phenyl Me Me N N N 01-749 COOH phenyl - CH2-CH2- 4-OEt-3-OMe-phenyl Me Me N N N 0
1-750 COOH 4-Cl-Phcnyl - CH2-CH2- CH2- 4-SMe-Phenyl OMe Me CH N N 01-750 COOH 4-Cl-Phenyl-CH2-CH2-CH2- 4-SMe-Phenyl OMe Me CH N N 0
1-751 COOH 4-Cl-Phenyl - CH2-CH2- CH2- 4-SMe-Phenyl Me Me CH N N 01-751 COOH 4-Cl-phenyl - CH 2 -CH 2 - CH 2 - 4-SMe-phenyl Me Me CH NN 0
1-752 COOH Phenyl - CH2-CH2- 4-OEt-3-OMe-Phenyl Ethyl Me CH N N 01-752 COOH Phenyl - CH 2 -CH 2 - 4-OEt-3-OMe-Phenyl Ethyl Me CH NN 0
1-753 COOH Phenyl - C(PhenyD=CH- CH2- Phenyl Ethyl Me CH N N 01-753 COOH Phenyl - C (PhenyD = CH- CH 2 - Phenyl Ethyl Me CH NN 0
1-754 COOH 4-Cl-Phenyl - CH2-CH2- Naphth-2-yl Ethyl Me CH N N 01-754 COOH 4-Cl-phenyl-CH2-CH2-naphth-2-yl ethyl Me CH N N 0
1-755 COOH 4-CI-Phenyl - CH2-CH2- Naphth-2-yl OMe 0- CH2-CH2-C N N 01-755 COOH 4-CI-Phenyl-CH2-CH2-Naphth-2-yl OMe 0- CH 2 -CH 2 -CNN 0
1-756 COOH Phenyl - CH=CH- CH2- Phenyl OMe 0- CH2-CH2-C N N s 1-756 COOH phenyl - CH = CH- CH 2 - phenyl OMe 0- CH 2 -CH 2 -CNN see
Nr. R1 R4, R5 Q R6 R2 R3 Z X Y WR 1 R 4 , R 5 QR 6 R 2 R 3 ZXYW
1-757 COOH 4-Cl-Phenyl - CH2-CH2- CH2- 4-OEt-Phenyl Me Me CH N N 01-757 COOH 4-Cl-phenyl - CH 2 -CH 2 - CH 2 - 4-OEt-phenyl Me Me CH NN 0
1-758 COOH 4-Cl-Phenyl - CH2-CH2- CH2- 4-OEt-Phenyl Ethyl Me CH N N O1-758 COOH 4-Cl-Phenyl - CH2-CH2-CH2- 4-OEt-Phenyl Ethyl Me CH N N O
1-759 COOH Phenyl - CH2-CH2- CH2- 4-OEt-Phenyl CF3 Me CH N N 01-759 COOH phenyl - CH2-CH2-CH 2 - 4-OEt-phenyl CF 3 Me CH NN 0
1-760 COOH Phenyl - CH2-CH2- CH2- 4-OEl-Phenyl OMe Me CH N N 01-760 COOH phenyl - CH 2 -CH 2 - CH 2 - 4-OEl-phenyl OMe Me CH NN 0
1-761 COOH 4-Cl-Phenyl - CH2-CH2- 4-OMe-Phenyl Me Me CH N N 01-761 COOH 4-Cl-Phenyl - CH 2 -CH 2 - 4-OMe-Phenyl Me Me CH NN 0
1-762 COOH 4-CI-Phenyl - CH2-CH2- 4-OMe-Phenyl Me Me N N N 01-762 COOH 4-CI-Phenyl - CH2-CH2- 4-OMe-Phenyl Me Me N N N 0
1-763 COOH 4-Cl-Phenyl - CH2-CH2- CH2- 3 ,4-Di-OMe-Pheny l Ethyl Me CH N N 0COOH 1-763 4-Cl-phenyl - CH2-CH2-CH 2 - 3, 4-di-OMe-phenyl-l ethyl Me CH NN 0
1-764 COOH 4-Cl-Phenyl - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-764 COOH 4-Cl-phenyl-CH2-CH2-CH2-3,4-di-OMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-765 COOH Phenyl - CH2-CH2- CH2- 4-OEt-Phenyl Me Me | CH N N 0 1-765 COOH Phenyl - CH2-CH2-CH 2 - 4-OEt-Phenyl Me Me | CH NN 0
Beispiel 16Example 16
Gemäß dem oben beschriebenen Bindungstest wurden für die nachfol gend aufgeführten Verbindungen Rezeptorbindungsdaten gemessen.According to the binding test described above, receptor binding data were measured for the compounds listed below.
Die Ergebnisse sind in Tabelle 2 dargestellt.The results are shown in Table 2.
Tabelle 2Table 2
Rezeptorbindungsdaten (Ki -Werte)Receptor binding data (Ki values)
Verbindung ETA [nM/1] ETB [nM/1]Connection ET A [nM / 1] ET B [nM / 1]
1-116 35 351-116 35 35
1-140 575 4601-140 575 460
1-146 4 291-146 4 29
1-321 340 2901-321 340 290
1-355 132 821-355 132 82
1-370 11 541-370 11 54
1-445 3,5 7,21-445 3.5 7.2
1-445 (S) -Enantio- 1,3 4,1 eres1-445 (S) -Enantio- 1.3 4.1 eres
1-445 (R)-Enantio- 65 140 eres1-445 (R) -Enantio- 65 140 eres
1-482 2 141-482 2 14
1-499 31 1351-499 31 135
1-585 6 231-585 6 23
1-593 300 1601-593 300 160
1-622 3 231-622 3 23
1-635 210 1261-635 210 126
1-672 60 1851-672 60 185
1-699 230 1301-699 230 130
1-713 20 96 1-713 20 96

Claims

Patentansprüche claims
1. Carbonsäurederivate der Formel I1. Carboxylic acid derivatives of the formula I.
wobei R1 Tetrazol oder eine Gruppewhere R 1 is tetrazole or a group
0 c~R0 c ~ R
in der R folgende Bedeutung hat:in which R has the following meaning:
a) ein Rest OR7, worin R7 bedeutet:a) a radical OR 7 , in which R 7 denotes:
Wasserstoff, das Kation eines Alkalimetalls, das Kation eines Erdalkalimetalls oder ein physiologisch verträgliches organisches Ammoniumion;Hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal or a physiologically acceptable organic ammonium ion;
C3-C8-Cycloalkyl, d-C8-Alkyl,C 3 -C 8 cycloalkyl, dC 8 alkyl,
CH2- Phenyl gegebenenfalls substituiert,CH 2 - phenyl optionally substituted,
C3-C6-Alkenyl- oder eine C3-C6-Alkinylgruppe gegebenfalls sub- stituiert oderC 3 -C 6 alkenyl or a C 3 -C6 alkynyl group optionally substituted or
Phenyl gegebenfalls substituiert.Phenyl optionally substituted.
b) ein über ein Stickstoffatom verknüpfter 5-gliedriger Hetero- aromat .b) a 5-membered heteroaromatic linked via a nitrogen atom.
c) eine Gruppec) a group
in der k die Werte 0, 1 und 2, p die Werte 1, 2, 3 und 4 annehmen kann und R8 für Cι - C4 -Alkyl , C3 -C8 -Cycloalkyl , C3 - C6 -Alkenyl , C3 - C6 -Alkinyl oder gegebenenf alls substituiertes Phenyl steht .in which k can assume the values 0, 1 and 2, p the values 1, 2, 3 and 4 and R 8 for -C - C 4 alkyl, C 3 -C 8 cycloalkyl, C 3 - C 6 alkenyl, C 3 - C 6 alkynyl or optionally substituted phenyl.
d) ein Rest 0 NH S R9 d) a residue 0 NH SR 9
00
worin R9 bedeutet:where R 9 means:
Cx-C -Alkyl, C3-C6 -Alkenyl, C3 -C6 -Alkinyl, C3-C8-Cycloalkyl, wobei diese Reste einen Ci -C4 -Alkoxy- , C1-C4 -Alkylthio- und/oder einen Phenylrest tragen können;C x -C alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C 8 cycloalkyl, these radicals being a Ci -C 4 alkoxy, C 1 -C 4 alkylthio - and / or can carry a phenyl radical;
Phenyl, gegebenenfalls substituiert.Phenyl, optionally substituted.
e) ein Reste) a rest
/R13 / R 13
— N- N
\ R14\ R 14
wobei R13 und R14 gleich oder verschieden sein können und folgende Bedeutung haben:where R 13 and R 14 may be the same or different and have the following meaning:
Wasserstoff, Cι-C8-Alkyl, C3-CB-Cycloalkyl, C3_C8-Alkenyl, C3_C8-Alkinyl, Benzyl, Phenyl, gegebenenfalls substituiert,Hydrogen, -CC 8 alkyl, C 3 -C B cycloalkyl, C 3 _C 8 alkenyl, C 3 _C 8 alkynyl, benzyl, phenyl, optionally substituted,
oder R13 und R14 bilden gemeinsam eine zu einem Ring geschlossene, gegebenenfalls substituierte C4-C-Alkylenkette, die ein Heteroatom enthalten kann.or R 13 and R 14 together form an optionally substituted C 4 -C alkylene chain which is closed and which may contain a hetero atom.
R2 Wasserstoff, Hydroxy, NH2, NH (Ci -C4-Alkyl ) , N (Cχ-C4 -Alkyl) 2, Halogen, C1-C4 -Alkyl, C2-C4 -Alkenyl, C2-C4 -Alkinyl, Cχ-C4-Halogenalkyl, C1.-C4 -Alkoxy, C1-C4-Halogenalkoxy oder Cι-C4-Alkylthio, oder CR2 ist mit CR10 wie unten angegeben zu einem 5- oder 6-gliedrigen Ring verknüpft;R 2 is hydrogen, hydroxy, NH 2 , NH (Ci -C 4 alkyl), N (Cχ-C 4 alkyl) 2 , halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 -alkynyl, Cχ-C 4 -haloalkyl, C1.-C 4 -alkoxy, C 1 -C 4 -haloalkoxy or -C-C 4 -alkylthio, or CR 2 is with CR 10 as specified below to a 5- or linked 6-membered ring;
X Stickstoff oder Methin;X nitrogen or methine;
Y Stickstoff oder Methin;Y nitrogen or methine;
Z Stickstoff oder CR10, worin R10 Wasserstoff oder Cι-4 -Alkyl bedeutet oder CR10 zusammen mit CR2 oder CR3 einen 5- oder 6-gliedrigen Alkylen- oder Alkenylenring bildet, der gegebenenfalls substituiert sein kann, und worin jeweils eine oder mehrere Methylengruppen durch Sauerstoff, Schwefel, -NH oder -N (C1-C4 -Alkyl) , ersetzt sein können;Z is nitrogen or CR 10 , where R 10 is hydrogen or C 4 alkyl or CR 10 together with CR 2 or CR 3 is a 5- or Forms 6-membered alkylene or alkenylene ring, which may be optionally substituted, and in which one or more methylene groups can be replaced by oxygen, sulfur, -NH or -N (C 1 -C 4 alkyl);
R3 Wasserstoff, Hydroxy, NH , NH (Ci -C4 -Alkyl ) , N (C: -C -Alkyl ) 2, Halogen, C1-C4 -Alkyl, C2-C4-Alkenyl, C2-C4 -Alkinyl, Cι-C4-Hydroxyalkyl, C1-C4-Halogenalkyl, Ci -C4 -Alkoxy, C1-C4 -Halogenalkoxy, Cχ-C4 -Alkylthio; oder CR3 ist mit CR10 wie oben angegeben zu einem 5- oder 6-gliedrigen Ring verknüpft;R 3 is hydrogen, hydroxy, NH, NH (Ci -C 4 alkyl), N (C : -C alkyl) 2 , halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 - C 4 -alkynyl, C 1 -C 4 -hydroxyalkyl, C 1 -C 4 -haloalkyl, Ci -C 4 -alkoxy, C 1 -C4 -haloalkoxy, Cχ-C 4 -alkylthio; or CR 3 is linked to CR 10 to a 5- or 6-membered ring as stated above;
R4 und R5 (die gleich oder verschieden sein können) :R 4 and R 5 (which may be the same or different):
Phenyl oder Naphthyl, gegebenenfalls substituiert, oderPhenyl or naphthyl, optionally substituted, or
Phenyl oder Naphthyl, die orthoständig über eine direkte Bindung, eine Methylen-, Ethylen- oder Ethenylengruppe, ein Sauerstoff- oder Schwefelatom oder eine S0 -, NH- oder N-Alkyl- Gruppe miteinander verbunden sindPhenyl or naphthyl, which are ortho-linked via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO, NH or N-alkyl group
C3 -Cβ-Cycloalkyl gegebenenfalls substituiert;C 3 -C 6 cycloalkyl optionally substituted;
R6 gegebenenfalls substituiertes C3 -C8-Cycloalkyl ;R 6 optionally substituted C 3 -C 8 cycloalkyl;
Phenyl oder Naphthyl, gegebenenfalls substituiert; ein fünf- oder sechsgliedriger Heteroaromat, enthaltend ein bis drei Stickstoffatome und/oder ein Schwefel- oder Sauer - Stoffatom, und welcher gegebenenfalls substituiert sein kann;Phenyl or naphthyl, optionally substituted; a five- or six-membered heteroaromatic containing one to three nitrogen atoms and / or a sulfur or acid atom, and which may optionally be substituted;
W Schwefel oder Sauerstoff;W sulfur or oxygen;
Q ein Spacer, der in seiner Länge einer C2-C4-Kette entspricht,Q is a spacer which corresponds in length to a C 2 -C 4 chain,
bedeuten, sowie die physiologisch verträglichen Salze, und die enantiomerenreinen sowie diastereoisomerenreinen Formen.mean, as well as the physiologically acceptable salts, and the enantiomerically pure and diastereoisomerically pure forms.
2. Arzneimittelzubereitungen zur peroralen, parenteralen und in- traperenteralen Anwendung, enthaltend neben den üblichen Arzneimittelhilfsstoffen, mindestens ein Carbonsäurederivat I gemäß Anspruch 1.2. Pharmaceutical preparations for oral, parenteral and intra-oral use, containing, in addition to the usual pharmaceutical excipients, at least one carboxylic acid derivative I according to claim 1.
3. Verwendung der Carbonsäurederivate gemäß Anspruch 1 zur Behandlung von Krankheiten.3. Use of the carboxylic acid derivatives according to claim 1 for the treatment of diseases.
4. Verwendung der Verbindungen I gemäß Anspruch 3 als Endothe- lin-Rezeptorantagonisten. 4. Use of the compounds I according to claim 3 as endothelin receptor antagonists.
5. Verwendung der Carbonsäurederivate I gemäß Anspruch 1 zur5. Use of the carboxylic acid derivatives I according to claim 1 for
Herstellung von Arzneimitteln zur Behandlung von Krankheiten, bei denen erhöhte Endothelinspiegel auftreten.Manufacture of medicines for the treatment of diseases in which increased endothelin levels occur.
6. Verwendung der Carbonsäurederivate I gemäß Anspruch 1 zur Behandlung von chronischer Herzinsuffizienz, Restenose, Bluthochdruck, pulmonalem Hochdruck, akutem/chronischen Nierenversagen, zerebraler Ischämie, Asthma, benigne Prostatahyper- plasie und Prostatakrebs.6. Use of the carboxylic acid derivatives I according to claim 1 for the treatment of chronic heart failure, restenosis, high blood pressure, pulmonary high pressure, acute / chronic kidney failure, cerebral ischemia, asthma, benign prostatic hyperplasia and prostate cancer.
7. Verwendung der Carbonsäurederivate I gemäß Anspruch 1 in Kombination mit Inhibitoren des Renin-Angiotensin Systems gemischten ACE/Neutrale Endopeptidase (NEP) -Hemmern; ß-Blok- kern.7. Use of the carboxylic acid derivatives I according to claim 1 in combination with inhibitors of the renin-angiotensin system mixed ACE / neutral endopeptidase (NEP) inhibitors; ß block.
8. Verwendung von Verbindungen der Formel IV8. Use of compounds of formula IV
R4 R 4
R6 R 6
worin die Reste R1, R4, R5, R6, Q und W die in Anspruch 1 angegebene Bedeutung haben, als Ausgangsmaterial zur Synthese von gemischten ERA/ETs-Rezeptorantagonisten.wherein the radicals R 1 , R 4 , R 5 , R 6 , Q and W have the meaning given in claim 1, as starting material for the synthesis of mixed ER A / ETs receptor antagonists.
9. Ein strukturelles Fragment der Formel9. A structural fragment of the formula
R4 R 4
worin die Reste R1, R4, R5, R6, Q und W die in Anspruch 1 an- gegebene Bedeutung haben, als strukturelles Element in einem gemischten ET)\./ETB-Rezeptorantagonisten.wherein the radicals R 1 , R 4 , R 5 , R 6 , Q and W have the meaning given in claim 1, as a structural element in a mixed ET) \ ./ ET B receptor antagonist.
10. Verfahren zur Herstellung von Carbonsäurederivaten der allgemeinen Formel IV R4 10. Process for the preparation of carboxylic acid derivatives of the general formula IV R 4
II.
! H R6— Q-W 1 C OH IV! H R6-Q-W 1 C OH IV
*5 Rl indem man Verbindungen der Formel IVa* 5 R l by using compounds of the formula IVa
R4R4
: H: H
R18 _ o ■ C OH IVa i R 1 8 _ o ■ C OH IVa i
R5 RiR 5 Ri
mit einem Alkohol oder Thiol der Formel III R6 Q-W-H inwith an alcohol or thiol of the formula III R 6 QWH in
worin die Reste R' , R4, R5, R6, Q, W die in Anspruch 1 angegebene Bedeutung besitzen und R18 für offenkettiges oder cycli - sches Alkyl oder Phenyl, das gegebenenfalls substituiert sein kann, steht,in which the radicals R ', R 4 , R 5 , R 6 , Q, W have the meaning given in claim 1 and R 18 represents open-chain or cyclic alkyl or phenyl which may be substituted,
unter Säurekatalyse umsetzt, implemented under acid catalysis,
EP97943819A 1996-09-05 1997-09-02 Azinyloxy, and phenoxy-diaryl-carboxylic acid derivatives, their preparation and use as mixed et a?/et b? endothelin receptor antagonists Withdrawn EP0929529A2 (en)

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CO4900070A1 (en) 2000-03-27
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PL331998A1 (en) 1999-08-16
WO1998009953A3 (en) 1998-10-29
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WO1998009953A2 (en) 1998-03-12
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AU4552497A (en) 1998-03-26
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