EP1060167A1 - Novel unsymmetrically substituted carboxylic acid derivatives, method for producing them, and their use as mixed et a?/et b?-receptor antagonists - Google Patents

Novel unsymmetrically substituted carboxylic acid derivatives, method for producing them, and their use as mixed et a?/et b?-receptor antagonists

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Publication number
EP1060167A1
EP1060167A1 EP99906251A EP99906251A EP1060167A1 EP 1060167 A1 EP1060167 A1 EP 1060167A1 EP 99906251 A EP99906251 A EP 99906251A EP 99906251 A EP99906251 A EP 99906251A EP 1060167 A1 EP1060167 A1 EP 1060167A1
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Prior art keywords
phenyl
cooh
ome
meüiyl
alkyl
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EP99906251A
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German (de)
French (fr)
Inventor
Wilhelm Amberg
Rolf Jansen
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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    • 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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • 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
    • C07C59/68—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 the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
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    • 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
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    • 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
    • C07D239/56—One oxygen atom and one sulfur 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
    • C07D239/60—Three or more oxygen or sulfur atoms

Definitions

  • New asymmetrically substituted carboxylic acid derivatives their preparation and use as mixed ET A / ET B receptor antagonists
  • 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. In the following, "endothelin” or “ET” denotes one or all isoforms of endochelin. 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, 2-11, 440-444, 1988 and Biochem. Biophys. Res. Commun., 151, 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 2-61, 2868 (1990), Nature 341, 114 (1990), N. Engl. J. Med. 32_2, 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 ü, 732 (1990)). Therefore substances that inhibit the binding of endothelin to both receptors and antagonize physiological effects of endothelin should be valuable pharmaceuticals.
  • the object of the present invention was to provide so-called mixed endothelin receptor antagonists.
  • Mixed endothelin receptor antagonists bind to the E A and ET B receptors with approximately the same affinity. There is approximately the same affinity for the receptors if the quotient of the affinities ET A : ET B is greater than 0.05, preferably greater than 0.1, and less than 20, preferably less than 10.
  • the invention relates to carboxylic acid derivatives of the formula I.
  • Hydrogen the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically acceptable organic ammonium ion such as C 1 -C 4 alkyl ammonium or the ammonium ion;
  • R 7 may furthermore be a phenyl radical which one to five halogen atoms and / or can carry one to three of the following radicals: nitro, cyano, C 4 -alkyl, C 4 haloalkyl, hydroxy, C ⁇ -C 4 - Alkoxy, mercapto, C 1 -C 4 -alkylthio, amino, NH (C 1 -C 4 -alkyl), N (C 1 -C 4 -alkyl) 2 ;
  • a 5-membered heteroaromatic linked via a nitrogen atom such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which can carry one or two halogen atoms, or one or two C 1 -C 4 -alkyl or one or two CC 4 -alkoxy groups.
  • C ⁇ -C 4 alkyl C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C ⁇ -C 4 -haloalkyl, where these radicals a C ⁇ -C 4 alkoxy, C ⁇ ⁇ C 4 alkylthio and / or a phenyl radical as mentioned under c) can wear;
  • R 13 and R 14 may be the same or different and have the following meaning:
  • Hydrogen, -CC 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl, benzyl, phenyl, the one to five halogen atoms and / or one to three of the following Residues can carry: nitro, cyano, C 1 -C 4 alkyl, -C-C 4 haloalkyl, hydroxy, C ⁇ -C 4 alkoxy, mercapto, C ⁇ -C 4 alkylthio, amino, NH (C ⁇ -C 4 - Alkyl), N (-CC 4 -alkyl) 2 ,
  • R 13 and R 14 together form a C 4 -C 7 alkylene chain which is closed to form a ring and which
  • alkylene group can be replaced by oxygen, sulfur or nitrogen
  • R 2 is hydrogen, hydroxy, NH 2 , H (-CC 4 alkyl), N (-C-C 4 alkyl) 2 , halogen, -C-alkyl, C 2 -C 4 alkenyl, C 2 -C -Alkinyl, -CC 4 -hydroxyalkyl, -C-C-haloalkyl, -C-C 4 alkoxy, C x -C 4 -haloalkoxy or -C-C 4 alkylthio, or CR 2 is with
  • Z is nitrogen or CR 10, wherein R 4 haloalkyl or C ⁇ -C 4 alkyl 10 is hydrogen, halogen, hydroxy, C ⁇ -C or CR 10 together with CR 2 or CR 3 a 5- or 6-membered alkylene or
  • Alkenylene ring which can be substituted by one or two -CC alkyl groups and in each case one or 5 several methylene groups can be replaced by oxygen, sulfur, -NH or N (-CC alkyl).
  • At least one of the ring members X, Y or Z is nitrogen.
  • R 3 is hydrogen, hydroxyl, NH 2 , H (C 1 -C 4 alkyl), N (C 1 -C alkyl) 2 , halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 -alkynyl, -C-C 4 -haloalkyl, -C-C 4 -alkoxy, C ⁇ -C 4 -haloalkoxy, C ⁇ -C 4 -hydroxyalkyl, C ⁇ -C 4 -alkylthio, or CR 3 is with CR 10 as above indicated linked to a 5- or 6-membered ring.
  • R 4 Ci-Q-alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl, which can be substituted by one or more of the following radicals: halogen, cyano, hydroxy, mercapto, C 1 -C 4 alkoxy , Phenoxy, carboxy, Cx ⁇ -haloalkoxy, -C-C-alkylthio, amino, NH (-C-C 4 alkyl), N (-C-C 4 alkyl) 2 or alkylcarbonyl.
  • R 5 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 alkenyl, C 1 -C 4 -hydroxyalkyl , C 2 -C alkynyl, -C-C 4 haloalkyl, C !
  • -C 4 -alkoxy phenoxy, carboxy, -C-C 4 -haloalkoxy, -C-C-alkylthio, amino, NH (-C-C-alkyl), N (-C-C 4 -alkyl) 2 or phenyl, the one or can be substituted several times, for example one to three times by halogen, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C ! -C 4 alkoxy, -C -C haloalkoxy or C 1 -C 4 alkylthio; or
  • Phenyl or naphthyl which is ortho-linked via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO 2 , NH or N-alkyl group with R 4 ;
  • R 6 is C 3 -C 8 -cycloalkyl, where these radicals in each case may be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, nitro, cyano, C 4 -alkoxy, C 4 alkyl, C -C 2 -alkenyl, C 2 -C alkynyl, C 3 -C 6 alkenyloxy, CC oxy 6 alkynyl, C ⁇ -C 4 alkylthio, C ⁇ -C4-haloalkoxy, C ⁇ -C-Alkylcar-carbonyl, C 1 -C 4 alkoxycarbonyl, C 3 -C 8 alkylcarbonylalkyl,
  • Phenyl or naphthyl each of which can carry one or more of the following radicals: halogen, R 15 , nitro, mercapto, carboxy, cyano, hydroxy, amino, C 1 -C 4 -alkyl, C 2 -C alkenyl, C 2 -C 4 -alkynyl, C 3 -C 6 -alkenyloxy, -C-C 4 haloalkyl, C 3 -C 6 -alkynyloxy, C ⁇ -C 4 -alkylcarbonyl, C ⁇ -C 4 -alkoxycarbonyl, C ⁇ -C-alkoxy, C ⁇ -C 4 -haloalkoxy, phenoxy, -C-alkylthio, NH (-C-C 4 alkyl), N (-C 4 -alkyl) 2; Dioxomethylene, dioxoethylene or phenyl, which can be substituted one or more times, for example one to three times by
  • 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: -CC 4 alkyl, C 2 - C 4 alkenyl, C 1 -C 6 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, phenyl or phenoxy, the phenyl radicals in turn having one to five halogen atoms and / or one to can carry three of the following radicals: -CC alkyl,
  • R 15 C 1 -C 4 alkyl, C 1 -C 4 alkylthio, C 1 -C alkoxy, which carry one of the following radicals: hydroxy, carboxy, amino, NH (C 1 -C 4 alkyl), N (C ⁇ -C 4 alkyl) 2 , carboxamide or CON (C 1 -C 4 alkyl) 2 ;
  • Q is a spacer that corresponds in length to a C 2 -C 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 correspond to the length of a C 2 -C 4 alkyl chain.
  • radicals for example with C 2 -C 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 -, -CO-N-CH 2 -CH 2 -, -CO-N (C 1 -C 4 alkyl) -CH 2 -CH 2 -, S0 2 -N (-C-alkyl) -CH 2 -CH 2 -, S0 2 -NH-CH 2 -CH 2 -, where these radicals can be substituted one or more times by: halogen, hydroxy, mercapto, Cx- C ⁇ alkyl, C 2 -C 4 alkenyl, C 2 -C alkynyl, carboxy, nitro, cyano, C 1 -C alkoxy, C 3 -C 6 alkenyl
  • C ⁇ -C4-haloalkoxy C ⁇ -C 4 alkylcarbonyl, C ⁇ -C 4 alkoxy carbonyl, C 3 -C 8 -Alkylcarbonylalkyl, NH (C ⁇ -C alkyl), N (C ⁇ -C alkyl) 2, phenyl which may be mono- or polysubstituted, for example mono- to trisubstituted by halogen, nitro, cyano, C 4 -alkyl, C haloalkyl, C ⁇ -C 4 -alkoxy, C 4 -haloalkoxy or -C-C-alkylthio;
  • the spacer Q is part of a 5-7 membered ring, heterocyclic or carbocyclic, to which R 6 is fused.
  • An alkali metal is e.g. Lithium, sodium, potassium;
  • alkaline earth metal is e.g. Calcium, magnesium, barium;
  • C 3 -C 8 cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;
  • -C-C 4 haloalkyl can be linear or branched, such as
  • C 1 -C 4 -Halogenalkoxy can be linear or branched such as difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2, 2-difluoroethoxy, 1, 1, 2, 2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy , 2-chloro-l, 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 -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 ⁇ ⁇ C 4 alkoxy can be linear or branched such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1, 1-dimethylethoxy; 8th
  • C 3 -C 6 alkenyloxy can be linear or branched, for example allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy;
  • C ⁇ -C 4 -hydroxyalkyl can be linear or branched, such as hydroxymethyl, l-hydroxyether-2-yl,
  • C 3 -C 6 alkynyloxy can be linear or branched, such as 2-propyn-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, methylthio, 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;
  • C 3 -C 8 -alkylcarbonylalkyl can be linear or branched, for example 2-oxo-prop-1-yl, 3-0xo-but-1-yl or 3-oxo-but-2-yl
  • C ! -C 8 alkyl can be linear or branched such as -CC 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, such as 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 or diastereomerically 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.
  • enantiomerically pure compounds of the formula IV can be obtained by carrying out a classic racemate resolution with suitable enantiomerically pure bases with racemic or diastereomeric compounds of the formula IV.
  • suitable bases are e.g. 4-chlorophenylethylamine and the bases mentioned in WO 96/11914.
  • R 11 is halogen or R 1 -S0 2 -, where R 12 can be C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or phenyl. 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, dirnethylformamide, dirnethylacetamide 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 an alkali amide such as lithium diisopropylamide or lithium amide.
  • 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 Imidazolide transferred and then reacted with a corresponding Hydroxy1 compound H ⁇ R 7 .
  • This reaction can be carried out in the usual solvents 11 and often requires the addition of a base, the above being considered.
  • These two steps can also be simplified, for example, by allowing the carboxylic acid to act on the hydroxyl compound in the presence of a water-releasing agent such as a carbodiimide.
  • 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 COR group and R is OM, where M is an alkali metal cation or the equivalent of one Alkaline earth metal cation can be.
  • These salts can be reacted with many compounds of the formula RA, where A is a customary 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.
  • A is a customary nucleofugic leaving group, for example halogen such as chlorine, bromine, iodine or aryl- or alkylsulfonyl optionally substituted by halogen, alkyl or hal
  • 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 ⁇ -C4 alkyl) 2, C ⁇ -C 4 -alkyl, C alkoxy, C ⁇ -C-alkylthio, C ⁇ -C4 haloalkyl, C ⁇ -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 1 -C 4 alkyl) 2, C ⁇ -C alkyl, C ⁇ -C 4 -alkoxy, C alkylthio, C ⁇ -C haloalkyl; -C-C 4 haloalkoxy, or CR 3 is linked to CR 10 as stated above to form a 5- or 6-membered ring;
  • R 4 -C 4 alkyl or C 2 -C 4 alkenyl which can be substituted by one or more of the following radicals: halogen, cyano, hydroxy, mercapto, -C 4 alkoxy, phenoxy, carboxy, C ⁇ - C 4 -haloalkoxy, -C-alkylthio, amino, NH (-C-C 4 alkyl), N (-C-alkyl) 2 or C 1 -C alkylcarbonyl.
  • R 5 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 alkenyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 -haloalkyl, -C-C 4 -haiogenalkoxy, -C-C-alkoxy, phenoxy, carboxy, C ⁇ -C 4 -alkylthio, amino,
  • NH C 1 -C 4 alkyl
  • N C ⁇ -C4 alkyl
  • phenyl which may be mono- or polysubstituted, for example mono- to trisubstituted by halogen, nitro, cyano, alkyl C , C ⁇ -C haloalkyl, C ⁇ ⁇ C 4 -alkoxy, C 4 -haloalkoxy or C ⁇ -C 4 alkylthio; or
  • R 6 is C 3 -C 8 cycloalkyl, where these radicals can each be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, nitro, cyano, C 1 -C 4 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 -alkynyl-oxy, -C-C 4 -alkylthio, -C-C 4 -haloalkoxy, -C-C 4 -Alkylcarbonyl, -CC 4 alkoxy-carbonyl, NH (-CC 4 alkyl), N (-C-alkyl) 2 or phenyl, which can be substituted one or more times, for example one to three times by halogen , Nitro, cyano, -CC alkyl, 13
  • Phenyl or naphthyl each of which can be substituted by one or more of the following radicals: halogen, ris,
  • a five- or six-membered heteroaromac 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 4 -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 1 -C 4 alkyl , -C-C 4 -haloalkyl, -C-C 4 alkoxy, -C-C-haloalkoxy and / or C 1. -C 4 alkylth.io;
  • R 15 is methyl, ethyl, methoxy or ethoxy, which carry one of the following radicals: hydroxy, carboxy, amino, NH (-CC 4 alkyl), N (-C-alkyl) 2 , carboxamide or C0N (-C-C 4 alkyl) 2 ;
  • the one C ⁇ C ⁇ -C-C may be or polysubstituted, for example mono- to trisubstituted by halogen, cyano, -C-alkyl, 4 haloalkyl, 4 alkoxy, CC 4 -haloalkoxy or C ⁇ -C -alkylthio 14 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,
  • R 2 trifluoromethyl, -CC 4 -alkyl, Cx-Cj-alkoxy, -C-C 4 alkylthio, or CR 2 is linked to CR 10 as stated below to form a 5- or 6-membered ring;
  • At least one of the ring members X, Y or Z is nitrogen
  • R3 trifluoromethyl, -CC 4 -alkyl, dC 4 -alkoxy, -C-C-alkylthio, or CR 3 is linked to CR 10 as stated above to form a 5- or 6-membered ring;
  • R 4 -CC alkyl which can be substituted by one or more of the following radicals: halogen, C ! -C 4 - lkoxy, -C-C 4 halo alkoxy.
  • R 5 is phenyl or naphthyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, mercapto, amino, C ⁇ -C4 ⁇ alkyl, C ⁇ -C4 halo-alkyl, C 1 -C -Halogenalkoxy, -CC 4 alkoxy, phenoxy, -C-alkyl thio, NH (-C 4 -alkyl), N (-C 4 -alkyl) 2 or phenyl, which can be substituted one or more times can, for example, one to three times 15 by halogen, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl,
  • Phenyl or naphthyl which is ortho-linked via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO 2 , NH or N-alkyl group with R 4 ;
  • R 6 cyclohexyl, which can be mono- or polysubstituted by: C 1 -C alkoxy, C 1 -C 4 -alkyl, halogen or phenyl, which can be mono- or polysubstituted, for example one to three times by halogen, C 1 -C C-alkyl, -CC 4 alkoxy;
  • R 15 methoxy or ethoxy, which carry one of the following radicals: hydroxy, carboxy, amino, NH (C 1 -C 4 -alkyl), N (-C-C 4 -alkyl) 2 , carboxamide or CON (-C-C-alkyl ) 2 ;
  • Phenyl which can be mono- or polysubstituted, for example one to three times by halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or Cx- 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, arrhythmia, acute / chronic kidney failure, renal failure, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhage, migraine, asthma, asthma endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty and by-pass surgery, 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 antagonistic effect on the neurokinin receptor.
  • NR R owns.
  • the invention further relates to combination preparations of endothelin receptor antagonists of the formula I and inhibitors of the renin-angiotensin system.
  • Inhibitors of the renin-angiotensin system are renin inhibitors, angiotensin II antagonists and, above all, angiotensin converting enzyme (ACE) inhibitors.
  • ACE angiotensin converting enzyme
  • Another object of the invention are combination preparations 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 presented in a single galenic form or in spatially separated forms.
  • the administration 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. 17
  • 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 streptomycin (Sigma No. P-0781). 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 x 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).
  • the membranes were incubated in incubation buffer (50 mM Tris-HCl, pH 7.4 with 5 mM MnCl, 40 mg / ml bacitracin and 0.2% BSA)
  • test animals were given the test compounds i.v. 30 min before the ETI administration. 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.
  • big endothelin (20 ⁇ g / kg, Appl. Vol. 0.5 ml / kg) or ETI (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 persistent changes in blood pressure are calculated as the area under the curve (AUC).
  • AUC area under the curve
  • the AUC of the substance-treated animals is compared with the AUC of the control animals.
  • 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 customary pharmaceutical application forms in solid or liquid form, for example as tablets, film-coated tablets, capsules, powders, granules, coated tablets, 19
  • Suppositories, solutions, ointments, creams or sprays are manufactured in the usual way.
  • the active ingredients 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, 1991).
  • the administration forms obtained in this way normally contain the active ingredient in an amount of 0.1 to 90% by weight.
  • the alkaline phase was adjusted to pH 2 with 2N HCl and then extracted with ether.
  • the combined organic phases were dried over MgSO 4 , filtered, then the solvent was distilled off and the residue (1.25 g of yellow foam) was stirred in diisopropyl ether (1.1 g of product, diasteromerically pure).

Abstract

The invention relates to carboxylic acid derivatives of formula (I), wherein R<1>-R<6>, Q, W, X, Y and Z have the meanings given in the description. The novel compounds are suitable for combating diseases.

Description

Neue unsymmetrisch substituierte Carbonsäurederivate, ihre Herstellung und Verwendung als gemischte ETA/ETB-RezeptorantagonistenNew asymmetrically substituted carboxylic acid derivatives, their preparation and use as mixed ET A / ET B 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 Endochelin. 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, 2-11, 440-444, 1988 und Biochem. Biophys. Res. Commun. , 151, 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. In the following, "endothelin" or "ET" denotes one or all isoforms of endochelin. 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, 2-11, 440-444, 1988 and Biochem. Biophys. Res. Commun., 151, 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 involviert. Dazu zählen: Hypertonie, akuter Myokard- infarkt, pulmonäre Hypertonie, Raynaud-Syndrom, zerebrale Vaso- spasmen, Schlaganfall, benigne Prostatahypertrophie, Athero- sklerose und Asthma (J. Vascular Med. Biology 2 , 207 (1990), J. Am. Med. Association 2-61, 2868 (1990), Nature 341, 114 (1990), N. Engl. J. Med. 32_2, 205 (1989), N. Engl . J. Med. 3_2_8, 1732 (1993), Nephron 66. 373 (1994), Stroke 25., 904 (1994), Nature 365, 759 (1993), J. Mol. Cell. Cardiol. 21, A234 (1995); Cancer Research 56, 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 2-61, 2868 (1990), Nature 341, 114 (1990), N. Engl. J. Med. 32_2, 205 (1989), N. Engl. J. Med. 3_2_8, 1732 (1993), Nephron 66, 373 (1994), Stroke 25, 904 (1994), Nature 365, 759 (1993), J. Mol. Cell. Cardiol. 21, A234 (1995); Cancer Research 56, 663 (1996)).
Mindestens zwei Endothelinrezeptorsubtypen, ETA- und ETB-Rezeptor, werden zur Zeit in der Literatur beschrieben (Nature 348, 730 (1990), Nature ü, 732 (1990)). Daher sollten Substanzen, die die Bindung von Endothelin an beide Rezeptoren inhibieren und physiologische Effekte von Endothelin antagonisieren 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 ü, 732 (1990)). Therefore substances that inhibit the binding of endothelin to both receptors and antagonize physiological effects of endothelin should be valuable pharmaceuticals.
In WO 95/26716 wurde bereits die Verbindung XX als Endothelin- rezeptorantagonist beschrieben. XXIn WO 95/26716, compound XX has already been described as an endothelin receptor antagonist. XX
Im Gegensatz dazu bestand in der vorliegenden Erfindung die Aufgabe sogenannte gemischte Endothelinrezeptorantagonisten bereitzustellen. Gemischte Endothelinrezeptorantagonisten binden mit ungefähr gleicher Affinität an den E A- und den ETB-Rezeptor. Ungefähr gleiche Affinität zu den Rezeptoren besteht, wenn der Quotient der Affinitäten ETA:ETB größer 0,05, bevorzugt größer 0,1, und kleiner 20, bevorzugt kleiner 10, ist.In contrast to this, the object of the present invention was to provide so-called mixed endothelin receptor antagonists. Mixed endothelin receptor antagonists bind to the E A and ET B receptors with approximately the same affinity. There is approximately the same affinity for the receptors if the quotient of the affinities ET A : ET B is greater than 0.05, preferably greater than 0.1, and less than 20, preferably less than 10.
In DE 196364046.3 wurden bereits Carbonsäurederivate beschrieben, die mit hoher Affinität an den ETA-Rezeptor, und an den ETB- Rezeptor binden. Ein Kennzeichen dieser Verbindungen ist z.B. die symmetrische Substitution mit zwei Phenylringen am ß-Zentrum. Völlig überraschend fanden wir nun, daß auch bei einer unsymmetrische Substitution am ß-Zentrum (z.B. Methyl/Phenyl) gemischte Rezeptorantagonisten erhalten werden können.DE 196364046.3 has already described carboxylic acid derivatives which bind with high affinity to the ET A receptor and to the ET B receptor. A characteristic of these compounds is, for example, the symmetrical substitution with two phenyl rings at the ß center. We have now found it completely surprising that mixed receptor antagonists can also be obtained with unsymmetrical substitution at the β center (eg methyl / phenyl).
Gegenstand der Erfindung sind Carbonsäurederivate der Formel IThe invention relates to carboxylic acid derivatives of the formula I.
HH
-Q— - C →y H 2-Q— - C → y H 2
RJ yR J y
wobei die Substituenten folgende Bedeutung haben:where the substituents have the following meaning:
R1 Tetrazol oder eine GruppeR 1 tetrazole or a group
RR
ein Rest OR7, worin R7 bedeutet:a radical OR 7 , in which R 7 denotes:
Wasserstoff, das Kation eines Alkalimetalls, das Kation eines Erdalkalimetalls, ein physiologisch verträgliches organisches Ammoniumion wie Cι-C-Alkylammonium oder das Ammoniumion; 3Hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically acceptable organic ammonium ion such as C 1 -C 4 alkyl ammonium or the ammonium ion; 3
C3-C8-Cycloalkyl, Ci-Cg-Alkyl, CH2-Phenyl, das durch einen oder mehrere der folgenden Reste substituiert sein kann: Halogen, Nitro, Cyano, Cι-C4-Alkyl, Cι-C4-Halogenalkyl, Hydroxy, Cι-C4-Alkoxy, Mercapto, Cι-C4-Alkylthio, A ino, Carboxy, NH(C1-C4-Alkyl) , N(C1-C4-Alkyl ) 2 ;C 3 -C 8 cycloalkyl, Ci-Cg-alkyl, CH 2 -phenyl, which can be substituted by one or more of the following radicals: halogen, nitro, cyano, C 4 -alkyl, C 4 -haloalkyl , Hydroxy, -C 4 alkoxy, mercapto, -C 4 alkylthio, A ino, carboxy, NH (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl) 2 ;
eine C3-C6-Alkenyl - oder eine C3-C6-Alkinylgruppe, wobei diese Gruppen ihrerseits ein bis fünf Halogenatome tragen können;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;
R7 kann weiterhin ein Phenylrest sein, welcher ein bis fünf Halogenatome und/oder ein bis drei der folgenden Reste tragen kann: Nitro, Cyano, Cι-C4-Alkyl, Cι-C4-Halogenalkyl, Hydroxy, Cι-C4-Alkoxy, Mercapto, Cι-C4-Alkylthio, Amino, NH(Cι-C4-Alkyl) , N(Cι-C4-Alkyl) 2 ;R 7 may furthermore be a phenyl radical which one to five halogen atoms and / or can carry one to three of the following radicals: nitro, cyano, C 4 -alkyl, C 4 haloalkyl, hydroxy, Cι-C 4 - Alkoxy, mercapto, C 1 -C 4 -alkylthio, amino, NH (C 1 -C 4 -alkyl), N (C 1 -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 Cι-C4-Alkyl oder eins bis zwei C-C4-Alkoxygruppen tragen kann.b) a 5-membered heteroaromatic linked via a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which can carry one or two halogen atoms, or one or two C 1 -C 4 -alkyl or one or two CC 4 -alkoxy groups.
c) eine Gruppec) a group
—0-(CH2)~S-R8 —0- (CH 2 ) ~ SR 8
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
Cι-C4-Alkyl, C3-C8-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, Cx-Cj-Alkyl, C1-C4-Halogenalkyl , Hydroxy, Cι-C4-Alkoxy, Cι-C4-Alkylthio, Mercapto, Amino, Carboxy, NH(Cι-C4-Alkyl) , N(Cι-C4-Alkyl )2.-C-C 4 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl or phenyl, which can be substituted by one or more, for example one to three of the following radicals : Halogen, nitro, cyano, Cx-Cj-alkyl, C 1 -C 4 -haloalkyl, hydroxy, Cι-C 4 -alkoxy, Cι-C 4 -alkylthio, mercapto, amino, carboxy, NH (Cι-C 4 - Alkyl), N (-CC 4 alkyl) 2nd
d) ein Restd) a rest
OO
" 9"9
—N—S—R—N — S — R
H ö worin R9 bedeutet: 4 H ö where R9 means: 4
Cι-C4-Alkyl, C3-C6-Alkenyl, C3-C6-Alkinyl, C3-C8-Cycloalkyl, Cι-C4-Halogenalkyl, wobei diese Reste einen Cι-C4-Alkoxy-, Cι~C4-Alkylthio- und/oder einen Phenylrest wie unter c) genannt tragen können;Cι-C 4 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C 8 cycloalkyl, Cι-C 4 -haloalkyl, where these radicals a Cι-C 4 alkoxy, C ~ ~ C 4 alkylthio and / or a phenyl radical as mentioned under c) can wear;
Phenyl , gegebenenfalls substituiert, insbesondere wie vorstehend genannt,Phenyl, optionally substituted, in particular as mentioned above,
e) eine Gruppee) a group
1313
RR
//
"N"N
1414
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-C8-Cycloalkyl, C3-C8-Alkenyl, C3-C8-Alkinyl, Benzyl, Phenyl, das ein bis fünf Halogenatome und/oder ein bis drei der folgenden Reste tragen kann: Nitro, Cyano, C1-C4-Alkyl, Cι-C4-Halogenalkyl , Hydroxy, Cι-C4-Alkoxy, Mercapto, Cι-C4-Alkylthio, Amino, NH(Cι-C4-Alkyl) , N(Cι-C4-Alkyl) 2 ,Hydrogen, -CC 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl, benzyl, phenyl, the one to five halogen atoms and / or one to three of the following Residues can carry: nitro, cyano, C 1 -C 4 alkyl, -C-C 4 haloalkyl, hydroxy, Cι-C 4 alkoxy, mercapto, Cι-C 4 alkylthio, amino, NH (Cι-C 4 - Alkyl), N (-CC 4 -alkyl) 2 ,
oder R13 und R14 bilden gemeinsam eine zu einem Ring geschlossene 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
Cι-C4-Alkyl substituiert und in der eine Alkylengruppe durch Sauerstoff, Schwefel oder Stickstoff ersetzt sein kann wie -(CH2)4-, -(CH2.5-. -(CH2)6-, -(CH2)2-0-(CH2)2-, -(CH2)7-, -CH2-S-(CH2)2-, -CH2-NH-(CH2)2-, - (CH2 ) 2-N- (CH2 ) 2-;-C-C 4 alkyl substituted and in which an alkylene group can be replaced by oxygen, sulfur or nitrogen such as - (CH 2 ) 4 -, - (CH2.5-. - (CH 2 ) 6 -, - (CH 2 ) 2 -0- (CH 2 ) 2 -, - (CH 2 ) 7 -, -CH 2 -S- (CH 2 ) 2 -, -CH 2 -NH- (CH 2 ) 2 -, - (CH 2 ) 2 -N- (CH 2 ) 2 -;
R2 Wasserstoff, Hydroxy, NH2, H(Cι-C4-Alkyl) , N(Cι-C4-Alkyl)2, Halogen, Cι-C-Alkyl, C2-C4-Alkenyl, C2-C-Alkinyl, Cι-C4-Hydroxyalkyl , Cι-C-Halogenalkyl, Cι-C4-Alkoxy, Cx-C4-Halogenalkoxy oder Cι-C4-Alkylthio, oder CR2 ist mitR 2 is hydrogen, hydroxy, NH 2 , H (-CC 4 alkyl), N (-C-C 4 alkyl) 2 , halogen, -C-alkyl, C 2 -C 4 alkenyl, C 2 -C -Alkinyl, -CC 4 -hydroxyalkyl, -C-C-haloalkyl, -C-C 4 alkoxy, C x -C 4 -haloalkoxy or -C-C 4 alkylthio, or CR 2 is with
CR10 wie unten angegeben zu einem 5- oder 6-gliedrigen Ring verknüpft.CR 10 linked 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, Halogen, Hydroxy, Cι-C4-Halogenalkyl oder Cι-C4-Alkyl bedeutet oder CR10 zusammen mit CR2 oder CR3 einen 5- oder 6-gliedrigen Alkylen- oderZ is nitrogen or CR 10, wherein R 4 haloalkyl or Cι-C 4 alkyl 10 is hydrogen, halogen, hydroxy, Cι-C or CR 10 together with CR 2 or CR 3 a 5- or 6-membered alkylene or
Alkenylenring bildet, der durch eine oder zwei Cι-C-Alkyl- gruppen substituiert sein kann und worin jeweils eine oder 5 mehrere Methylengruppen durch Sauerstoff, Schwefel, -NH oder N(Cι-C-Alkyl) ersetzt sein können.Alkenylene ring, which can be substituted by one or two -CC alkyl groups and in each case one or 5 several methylene groups can be replaced by oxygen, sulfur, -NH or N (-CC alkyl).
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, NH2, H(C1-C4-Alkyl) , N(C1-C-Alkyl)2, Halogen, Cι-C4-Alkyl, C2-C4-Alkenyl , C2-C4-Alkinyl, Cι-C4-Halogenalkyl, Cι-C4-Alkoxy, Cι-C4-Halogenalkoxy, Cι-C4-Hydroxyalkyl, Cι-C4-Alkylthio, oder CR3 ist mit CR10 wie oben angegeben zu einem 5- oder 6-gliedrigen Ring verknüpft.R 3 is hydrogen, hydroxyl, NH 2 , H (C 1 -C 4 alkyl), N (C 1 -C alkyl) 2 , halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 -alkynyl, -C-C 4 -haloalkyl, -C-C 4 -alkoxy, Cι-C 4 -haloalkoxy, Cι-C 4 -hydroxyalkyl, Cι-C 4 -alkylthio, or CR 3 is with CR 10 as above indicated linked to a 5- or 6-membered ring.
R4 Ci-Q-Alkyl, C2-C4-Alkenyl oder C2-C4-Alkinyl, das durch einen oder mehrere der folgenden Reste substituiert sein kann: Halogen, Cyano, Hydroxy, Mercapto, Cι-C4-Alkoxy, Phenoxy, Carboxy, Cx^-Halogenalkoxy, Cι-C-Alkylthio, Amino, NH(Cι-C4-Alkyl) , N(Cι-C4-Alkyl)2 oder Alkylcarbonyl .R 4 Ci-Q-alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl, which can be substituted by one or more of the following radicals: halogen, cyano, hydroxy, mercapto, C 1 -C 4 alkoxy , Phenoxy, carboxy, Cx ^ -haloalkoxy, -C-C-alkylthio, amino, NH (-C-C 4 alkyl), N (-C-C 4 alkyl) 2 or alkylcarbonyl.
Cι-C4-Alkyl, C2-C-Alkenyl oder C2-C-Alkinyl, das über eine direkte Bindung, eine Methylen-, Ethylen- oder Ethenylen- gruppe, ein Sauerstoff- oder Schwefelatom oder eine S02-, NH- oder N-Alkyl-Gruppe mit R5 verbunden ist;C 1 -C 4 alkyl, C 2 -C alkenyl or C 2 -C alkynyl, which has a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an S0 2 -, NH - or N-alkyl group is connected to R5;
R5 Phenyl oder Naphthyl, die durch einen oder mehrere der folgenden Reste substituiert sein können: Halogen, Nitro, Cyano, Hydroxy, Mercapto, Cι-C4-Alkyl, C2-C-Alkenyl, Cι-C4-Hydroxy- alkyl, C2-C-Alkinyl, Cι-C4-Halogenalkyl, C!-C4-Alkoxy, Phenoxy, Carboxy, Cι-C4-Halogenalkoxy, Cι-C-Alkylthio, Amino, NH(Cι-C-Alkyl) , N(Cι-C4-Alkyl)2 oder Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach durch Halogen, Nitro, Cyano, Cι-C4-Alkyl , Cι-C-Halogenalkyl, C!-C4-Alkoxy, Cι-C-Halogenalkoxy oder C1-C4-Alkylthio; oderR 5 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 alkenyl, C 1 -C 4 -hydroxyalkyl , C 2 -C alkynyl, -C-C 4 haloalkyl, C ! -C 4 -alkoxy, phenoxy, carboxy, -C-C 4 -haloalkoxy, -C-C-alkylthio, amino, NH (-C-C-alkyl), N (-C-C 4 -alkyl) 2 or phenyl, the one or can be substituted several times, for example one to three times by halogen, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C ! -C 4 alkoxy, -C -C haloalkoxy or C 1 -C 4 alkylthio; or
Phenyl oder Naphthyl, das orthoständig über eine direkte Bindung, eine Methylen-, Ethylen- oder Ethenylengruppe, ein Sauerstoff- oder Schwefelatom oder eine S02-, NH- oder N-Alkyl-Gruppe mit R4 verbunden ist;Phenyl or naphthyl, which is ortho-linked via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO 2 , NH or N-alkyl group with R 4 ;
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, Cι-C4-Alkoxy, Cι-C4-Alkyl, C2-C -Alkenyl, C2-C-Alkinyl, C3-C6-Alkenyloxy, C-C6-Alkinyl- oxy, Cι-C4-Alkylthio, Cι-C4-Halogenalkoxy, Cι-C-Alkylcar-bonyl, Cι-C4-Alkoxycarbonyl, C3-C8-Alkylcarbonylalkyl,R 6 is C 3 -C 8 -cycloalkyl, where these radicals in each case may be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, nitro, cyano, C 4 -alkoxy, C 4 alkyl, C -C 2 -alkenyl, C 2 -C alkynyl, C 3 -C 6 alkenyloxy, CC oxy 6 alkynyl, Cι-C 4 alkylthio, Cι-C4-haloalkoxy, Cι-C-Alkylcar-carbonyl, C 1 -C 4 alkoxycarbonyl, C 3 -C 8 alkylcarbonylalkyl,
NH(Cι-C4-Alkyl) , N(Cι-C4-Alkyl)2, oder Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach durch 6NH (-C 4 alkyl), N (-C 4 alkyl) 2 , or phenyl, which can be substituted one or more times, for example one to three times 6
Halogen, Nitro, Cyano, Cι-C-Alkyl, Cι-C4-Halogenalkyl , Cι-C4-Alkoxy, Cι-C-Halogenalkoxy oder Cι-C4-Alkylthio;Halogen, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C haloalkoxy or C 1 -C 4 alkylthio;
Phenyl oder Naphthyl, die jeweils einen oder mehrere der folgenden Reste tragen können: Halogen, R15, Nitro, Mercapto, Carboxy, Cyano, Hydroxy, Amino, Cι-C4-Alkyl, C2-C-Alkenyl, C2-C4-Alkinyl, C3-C6-Alkenyloxy, Cι-C4-Halogenalkyl, C3-C6-Alkinyloxy, Cι-C4-Alkylcarbonyl, Cι-C4-Alkoxycarbonyl , Cι-C-Alkoxy, Cι-C4-Halogenalkoxy, Phenoxy, Cι-C-Alkylthio, NH(Cι-C4-Alkyl) , N(Cι-C4-Alkyl)2; Dioxomethylen, Dioxoethylen oder Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach durch Halogen, Nitro, Cyano, Cι-C-Alkyl, Cι-C4-Halogenalkyl, Cι-C-Alkoxy, Cι-C4-Halogen- alkoxy oder Cι-C4-Alkylthio mit der Maßgabe, daß, falls R6 ein unsubstituierter Phenylrest ist, R2 und R3 nicht gleichzeitig OCH3 bedeuten dürfen;Phenyl or naphthyl, each of which can carry one or more of the following radicals: halogen, R 15 , nitro, mercapto, carboxy, cyano, hydroxy, amino, C 1 -C 4 -alkyl, C 2 -C alkenyl, C 2 -C 4 -alkynyl, C 3 -C 6 -alkenyloxy, -C-C 4 haloalkyl, C 3 -C 6 -alkynyloxy, Cι-C 4 -alkylcarbonyl, Cι-C 4 -alkoxycarbonyl, Cι-C-alkoxy, Cι-C 4 -haloalkoxy, phenoxy, -C-alkylthio, NH (-C-C 4 alkyl), N (-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 4 haloalkyl, C 1 -C alkoxy, C 1 -C 4 -Halogen- alkoxy or -CC 4 alkylthio with the proviso that if R 6 is an unsubstituted phenyl radical, R 2 and R 3 must not simultaneously mean OCH 3 ;
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: Cι-C4-Alkyl, C2-C4-Alkenyl, Cι-C-Halogenalkyl, Cι-C-Alkoxy, Cι-C4-Halogen- alkoxy, Cι-C-Alkylthio, Phenyl oder Phenoxy wobei die Phenyl- reste ihrerseits ein bis fünf Halogenatome und/oder einen bis 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: -CC 4 alkyl, C 2 - C 4 alkenyl, C 1 -C 6 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, phenyl or phenoxy, the phenyl radicals in turn having one to five halogen atoms and / or one to can carry three of the following radicals: -CC alkyl,
Cι-C4-Halogenalkyl, Cι~C4-Alkoxy, Cι-C4-Halogenalkoxy und/oder Cι-C4-Alkylthio; Cι-C4 haloalkyl, Cι ~ C 4 -alkoxy, C 4 -haloalkoxy and / or Cι-C 4 alkylthio;
R15 Cι-C4-Alkyl, Cι-C4-Alkylthio, Cι-C-Alkoxy, die einen der fol- genden Reste tragen: Hydroxy, Carboxy, Amino, NH(Cι-C4-Alkyl) , N(Cι-C4-Alkyl)2, Carboxamid oder CON(C1-C4-Alkyl)2;R 15 C 1 -C 4 alkyl, C 1 -C 4 alkylthio, C 1 -C alkoxy, which carry one of the following radicals: hydroxy, carboxy, amino, NH (C 1 -C 4 alkyl), N (Cι -C 4 alkyl) 2 , carboxamide or CON (C 1 -C 4 alkyl) 2 ;
W Schwefel oder Sauerstoff;W sulfur or oxygen;
Q ein Spacer, der in seiner Länge einer C2-C 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-Alkylkette 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-, -CO-N-CH2-CH2-, -CO-N(C1-C4-Alkyl ) -CH2-CH2-, S02-N(Cι-C-Alkyl)-CH2-CH2-, S02-NH-CH2-CH2-, wobei diese Reste jeweils ein- oder mehrfach substituiert sein können durch: Halogen, Hydroxy, Mercapto, Cx-C^-Alkyl, C2-C4-Alkenyl, C2-C -Alkinyl, Carboxy, Nitro, Cyano, Cι-C-Alkoxy, C3-C6-Alkenyloxy, C3-C6-Alkinyloxy, Cι-C-Alkylthio, 7Q is a spacer that corresponds in length to a C 2 -C 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 correspond to the length of a C 2 -C 4 alkyl chain. This can be achieved with a large number of chemical radicals, for example with C 2 -C 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 -, -CO-N-CH 2 -CH 2 -, -CO-N (C 1 -C 4 alkyl) -CH 2 -CH 2 -, S0 2 -N (-C-alkyl) -CH 2 -CH 2 -, S0 2 -NH-CH 2 -CH 2 -, where these radicals can be substituted one or more times by: halogen, hydroxy, mercapto, Cx- C ^ alkyl, C 2 -C 4 alkenyl, C 2 -C alkynyl, carboxy, nitro, cyano, C 1 -C alkoxy, C 3 -C 6 alkenyloxy, C 3 -C 6 alkynyloxy, Cι- C-alkylthio, 7
Cι-C4-Halogenalkoxy, Cι-C4-Alkylcarbonyl, Cι-C4-Alkoxy- carbonyl, C3-C8-Alkylcarbonylalkyl, NH(Cι-C-Alkyl) , N(Cι-C-Alkyl)2, Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach durch Halogen, Nitro, Cyano, Cι-C4-Alkyl, Cι-C-Halogenalkyl, Cι-C4-Alkoxy, Cι-C4-Halogenalkoxy oder Cι-C-Alkylthio; Cι-C4-haloalkoxy, Cι-C 4 alkylcarbonyl, Cι-C 4 alkoxy carbonyl, C 3 -C 8 -Alkylcarbonylalkyl, NH (Cι-C alkyl), N (Cι-C alkyl) 2, phenyl which may be mono- or polysubstituted, for example mono- to trisubstituted by halogen, nitro, cyano, C 4 -alkyl, C haloalkyl, Cι-C 4 -alkoxy, C 4 -haloalkoxy or -C-C-alkylthio;
oder der Spacer Q ist Teil eines 5-7 gliedrigen Ringes, hetero- oder carbocyclisch, an den R6 annelliert ist.or the spacer Q is part of a 5-7 membered ring, 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;An alkali metal is e.g. Lithium, sodium, potassium;
Ein Erdalkalimetall ist z.B. Calcium, Magnesium, Barium;An alkaline earth metal is e.g. Calcium, magnesium, barium;
C3-C8-Cycloalkyl ist z.B. Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Cycloheptyl oder Cyclooctyl;C 3 -C 8 cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;
Cι-C4-Halogenalkyl kann linear oder verzweigt sein wie z.B.-C-C 4 haloalkyl can be linear or branched, such as
Fluormethyl, Difluormethyl, Trifluormethyl, Chlordifluormethyl, Dichlorfluormethyl, 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;Fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 2, 2-difluoroethyl, 2, 2, 2-trifluoroethyl, 2-chloro-2, 2-difluoroethyl, 2, 2-dichloro- 2-fluoroethyl, 2, 2, 2-trichloroethyl or pentafluoroethyl;
Cι-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-l, 1, 2-trifluorethoxy, 2-Fluorethoxy oder Pentafluorethoxy;C 1 -C 4 -Halogenalkoxy can be linear or branched such as difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2, 2-difluoroethoxy, 1, 1, 2, 2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy , 2-chloro-l, 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-l-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-C-Alkenyl kann linear oder verzweigt sein wie z.B. Ethenyl, l-Propen-3-yl, l-Propen-2-yl, 1-Propen-l-yl, 2-Methyl-l-propenyl, 1-Butenyl oder 2-Butenyl;C 2 -C -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-l-yl, l-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; 8Cι ~ C 4 alkoxy can be linear or branched such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1, 1-dimethylethoxy; 8th
C3-C6-Alkenyloxy kann linear oder verzweigt sein wie z.B. Allyl- oxy, 2-Buten-l-yloxy oder 3-Buten-2-yloxy;C 3 -C 6 alkenyloxy can be linear or branched, for example allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy;
Cχ-C4-Hydroxyalkyl kann linear oder verzweigt sein wie z.B. Hydroxymethyl, l-Hydroxyether-2-yl,Cχ-C 4 -hydroxyalkyl can be linear or branched, such as hydroxymethyl, l-hydroxyether-2-yl,
C3-C6-Alkinyloxy kann linear oder verzweigt sein wie z.B. 2-Propin-l-yloxy, 2-Butin-l-yloxy oder 3-Butin-2-yloxy;C 3 -C 6 alkynyloxy can be linear or branched, such as 2-propyn-1-yloxy, 2-butyn-1-yloxy or 3-butyn-2-yloxy;
Cι-C4-Alkylthio kann linear oder verzweigt sein wie z.B. Methyl- thio, Ethylthio, Propylthio, 1-Methylethylthio, Butylthio, 1-Methylpropylthio, 2-Methylpropylthio oder 1, 1-Dimethylethyl- thio;C 1 -C 4 -Alkylthio can be linear or branched such as, for example, methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1, 1-dimethylethylthio;
Cι-C4-Alkylcarbonyl kann linear oder verzweigt sein wie z.B. Acetyl, Ethylcarbonyl oder 2-Propylcarbonyl;C 1 -C 4 -alkylcarbonyl can be linear or branched, such as acetyl, ethylcarbonyl or 2-propylcarbonyl;
Cι-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;
C3-C8-Alkylcarbonylalkyl kann linear oder verzweigt sein, z.B. 2-Oxo-prop-l-yl, 3-0xo-but-l-yl oder 3-Oxo-but-2-ylC 3 -C 8 -alkylcarbonylalkyl can be linear or branched, for example 2-oxo-prop-1-yl, 3-0xo-but-1-yl or 3-oxo-but-2-yl
C!-C8-Alkyl kann linear oder verzweigt sein wie z.B. Cι-C4-Alkyl, Pentyl , Hexyl , Heptyl oder Octyl ;C ! -C 8 alkyl can be linear or branched such as -CC 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 Körper- kompartimenten, 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 Her- Stellung, 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 Verwendung einer enantiomerenreinen oder diastereomerenreinen Verbindung als Wirkstoff. 9The compounds and also the intermediates for their preparation, such as 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 or diastereomerically pure compound as the active ingredient. 9
Die Herstellung solcher Verbindungen ist in den Beispielen beschrieben.The preparation of such compounds is described in the examples.
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 oder DE 19636046.3 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 or DE 19636046.3.
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.
O - R1 . 6 HO - R 1 . 6 H
+ R—Q- -H R Q— - •C—OH + R — Q- -HRQ— - • C — OH
II III IV R-II III IV R-
Weiterhin kann man enantiomerenreine Verbindungen der Formel IV erhalten, indem man mit racemischen bzw. diastereomeren Verbindungen der Formel IV eine klassische Racematspaltung mit geeigneten enantiomerenreinen Basen durchführt. Als solche Basen eignen sich z.B. 4-Chlorphenylethylamin und die Basen, die in WO 96/11914 genannt werden.Furthermore, enantiomerically pure compounds of the formula IV can be obtained by carrying out a classic racemate resolution with suitable enantiomerically pure bases with racemic or diastereomeric compounds of the formula IV. Suitable bases are e.g. 4-chlorophenylethylamine and the bases mentioned in WO 96/11914.
Die erfindungsgemäßen Verbindungen, in denen die Substituenten die unter der allgemeinen Formel I angegebene 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.
22
RR
11 W11 W.
IV ,τ x^IV, τ x ^
33
R 10R 10
In Formel V bedeutet R11 Halogen oder R1-S02-, wobei R12 Cι-C4-Alkyl, Cι-C-Halogenalkyl oder Phenyl sein kann. Ferner ist mindestens eines der Ringglieder X oder Y oder z Stickstoff. Die Reaktion findet bevorzugt in einem inerten Lösungs- 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 Lösungsmittels statt.In formula V, R 11 is halogen or R 1 -S0 2 -, where R 12 can be C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or phenyl. 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 Lösungsmittel und in einem Temperaturbereich von Raumtemperatur bis zum Siedepunkt des Lösungsmittels 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 Lösungsmittel beziehungsweise Verdünnungsmittel sind aliphatische, alicyclische und aromatische Kohlen- Wasserstoffe, 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 Dirnethylformamid, Dirnethylacetamid 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, dirnethylformamide, dirnethylacetamide 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 Natrium- hydrid, 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 ein Alkaliamid wie Lithiumdiisopropylamid oder Lithiumamid dienen.As the 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 an alkali amide such as lithium diisopropylamide or lithium amide.
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 Hydroxy1Verbindung HÖR7 umsetzt. Diese Umsetzung läßt sich in den üblichen Lösungsmitteln durchführen 11 und erfordert oft die Zugabe einer Base, wobei die oben genannten in Betracht kommen. Diese beiden Schritte lassen sich beispielsweise auch dadurch vereinfachen, daß man die Carbonsäure in Gegenwart eines wasserabspaltenden Mittels wie eines Carbodiimids auf die Hydroxylverbindung einwirken läßt.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 Imidazolide transferred and then reacted with a corresponding Hydroxy1 compound HÖR 7 . This reaction can be carried out in the usual solvents 11 and often requires the addition of a base, the above being considered. These two steps can also be simplified, for example, by allowing the carboxylic acid to act on the hydroxyl compound in the presence of a water-releasing agent such as a carbodiimide.
Außerdem können Verbindungen der Formel I auch dadurch hergestellt 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 Alkalimetallkation 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 Substituenten A sind bekannt oder mit dem allgemeinen Fachwissen leicht zu erhalten. Diese Umsetzung läßt sich in den üblichen Lösungsmitteln 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 COR group and R is OM, where M is an alkali metal cation or the equivalent of one Alkaline earth metal cation can be. These salts can be reacted with many compounds of the formula RA, where A is a customary 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 erfindungsgemäßenIn some cases, the preparation of the invention
Verbindungen I die Anwendung allgemein bekannter Schutzgruppentechniken erforderlich. Soll beispielsweise R6 = 4-Hydroxyphenyl bedeuten, so kann die Hydroxygruppe zunächst als Benzylether geschützt sein, der dann auf einer geeigneten Stufe in der Reaktionssequenz gespalten wird.Compounds I require the use of well-known protection 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(Cι-C4-Alkyl)2, Cι-C4-Alkyl, Cι-C-Alkoxy, Cι-C-Alkylthio, Cι-C4-Halogenalkyl , Cι-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 (Cι-C4 alkyl) 2, Cι-C 4 -alkyl, C alkoxy, Cι-C-alkylthio, Cι-C4 haloalkyl, Cι-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; 12X nitrogen or methine; 12
Y Stickstoff oder Methin;Y nitrogen or methine;
Z Stickstoff oder CR10, worin R10 Wasserstoff, Halogen,Z nitrogen or CR 10 , where R 10 is hydrogen, halogen,
Cι-C4-Halogenalkyl oder Cι-C4-Alkyl bedeutet oder CR10 zusammen mit CR2 oder CR3 einen 5- oder 6-gliedrigen Alkylen- oder Cι-C4-haloalkyl or Cι-C 4 alkyl, or CR 10 together with CR 2 or CR 3 a 5- or 6-membered alkylene or
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;Alkenylene ring forms, which can be substituted by one or two methyl groups and in which a 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 Stickstoff.At least one of the ring members X, Y or Z is nitrogen.
R3 Wasserstoff, Hydroxy, Halogen, N(C1-C4-Alkyl)2, Cι-C-Alkyl , Cι-C4-Alkoxy, Cι-C-Alkylthio, Cι-C-Halogenalkyl; Cι-C4-Halogenalkoxy, oder CR3 ist mit CR10 wie oben angegeben zu einem 5- oder 6-gliedrigen Ring verknüpft;R 3 is hydrogen, hydroxy, halogen, N (C 1 -C 4 alkyl) 2, Cι-C alkyl, Cι-C 4 -alkoxy, C alkylthio, Cι-C haloalkyl; -C-C 4 haloalkoxy, or CR 3 is linked to CR 10 as stated above to form a 5- or 6-membered ring;
R4 Cι-C4-Alkyl oder C2-C4-Alkenyl, das durch einen oder mehrere der folgenden Reste substituiert sein kann: Halogen, Cyano, Hydroxy, Mercapto, Cι-C4-Alkoxy, Phenoxy, Carboxy, Cι-C4-Halogenalkoxy, Cι-C-Alkylthio, Amino, NH (Cι-C4-Alkyl) , N(Cι-C-Alkyl)2 oder C1-C-Alkylcarbonyl .R 4 -C 4 alkyl or C 2 -C 4 alkenyl, which can be substituted by one or more of the following radicals: halogen, cyano, hydroxy, mercapto, -C 4 alkoxy, phenoxy, carboxy, Cι- C 4 -haloalkoxy, -C-alkylthio, amino, NH (-C-C 4 alkyl), N (-C-alkyl) 2 or C 1 -C alkylcarbonyl.
R5 Phenyl oder Naphthyl, die durch einen oder mehrere der folgenden Reste substituiert sein können: Halogen, Nitro, Cyano, Hydroxy, Mercapto, Cι-C-Alkyl, C2-C-Alkenyl, C1-C4-Hydroxyalkyl , Cι-C4-Halogenalkyl, Cι-C4-Haiogenalkoxy, Cι-C-Alkoxy, Phenoxy, Carboxy, Cι-C4-Alkylthio, Amino,R 5 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 alkenyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 -haloalkyl, -C-C 4 -haiogenalkoxy, -C-C-alkoxy, phenoxy, carboxy, Cι-C 4 -alkylthio, amino,
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, Cι-C-Alkyl, Cι-C-Halogenalkyl, Cι~C4-Alkoxy, Cι-C4-Halogenalkoxy oder Cι-C4-Alkylthio; oderNH (C 1 -C 4 alkyl), N (Cι-C4 alkyl) 2 or phenyl which may be mono- or polysubstituted, for example mono- to trisubstituted by halogen, nitro, cyano, alkyl C , Cι-C haloalkyl, Cι ~ C 4 -alkoxy, C 4 -haloalkoxy or Cι-C 4 alkylthio; or
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, Cι-C4-Alkoxy, Cι-C-Alkyl, C2-C4-Alkenyl, C2-C4-Alkinyl, C3-C6-Alkenyloxy, C3-C6-Alkinyl- oxy, Cι-C4-Alkylthio, Cι-C4-Halogenalkoxy, Cι-C4-Alkylcarbonyl, Cι-C4-Alkoxy-carbonyl, NH(Cι-C4-Alkyl) , N(Cι-C-Alkyl) 2 oder Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach durch Halogen, Nitro, Cyano, Cι-C-Alkyl, 13R 6 is C 3 -C 8 cycloalkyl, where these radicals can each be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, nitro, cyano, C 1 -C 4 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 -alkynyl-oxy, -C-C 4 -alkylthio, -C-C 4 -haloalkoxy, -C-C 4 -Alkylcarbonyl, -CC 4 alkoxy-carbonyl, NH (-CC 4 alkyl), N (-C-alkyl) 2 or phenyl, which can be substituted one or more times, for example one to three times by halogen , Nitro, cyano, -CC alkyl, 13
Cι-C4-Halogenalkyl, Cι-C4-Alkoxy, Cι-C-Halogenalkoxy oder Cι-C4-Alkylthio; Cι-C4-haloalkyl, Cι-C 4 -alkoxy, C haloalkoxy or Cι-C 4 alkylthio;
Phenyl oder Naphthyl, die jeweils durch einen oder mehrere der folgenden Reste substituiert sein können: Halogen, Ris,Phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, ris,
Nitro, Mercapto, Carboxy, Cyano, Hydroxy, Amino, Ci-C^-Alkyl, C2-C4-Alkenyl, C2-C-Alkinyl, C3-C6-Alkenyloxy, Cι-C4~Halogen- alkyl, C3-C6-Alkinyloxy, Cι-C-Alkylcarbonyl, Cι-C4-Alkoxy- carbonyl, Cχ-C4-Alkoxy, Cι-C4-Halogenalkoxy, Phenoxy, Cι-C-Alkylthio, NH(Cι-C-Alkyl) , N(Cι-C4-Alkyl)2, Dioxo- methylen, Dioxoethylen oder Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach durch Halogen, Nitro, Cyano, Cι-C4-Alkyl, Cι-C4-Halogenalkyl, Cι-C4-Alkoxy, Cι-C4-Halogenalkoxy oder Cι-C-Alkylthio, mit der Maßgabe, falls R6 ein unsubstituierter Phenylring ist, dann muß CR10 zusammen mit CR2 oder CR3 einen 5-gliedrigen Alkylenring bilden, worin eine oder zwei Methylengruppen durch 0 oder S ersetzt sein kann;Nitro, mercapto, carboxy, cyano, hydroxy, amino, Ci-C ^ alkyl, C 2 -C 4 alkenyl, C 2 -C alkynyl, C 3 -C 6 alkenyloxy, Cι-C 4 ~ halogeno-alkyl , C 3 -C 6 alkynyloxy, Cι-C alkyl-carbonyl, Cι-C 4 alkoxy carbonyl, Cχ-C 4 -alkoxy, C 4 haloalkoxy, phenoxy, Cι-C-alkylthio, NH (Cι- C-alkyl), N (-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, -CC 4 -haloalkyl, -C-C 4 -alkoxy, -C-C 4 -haloalkoxy or -C-C-alkylthio, with the proviso that if R 6 is an unsubstituted phenyl ring, then CR 10 together with CR 2 or CR 3 form a 5-membered alkylene ring, in which one or two methylene groups can be replaced by 0 or S;
ein fünf- oder sechsgliedriger Heteroaromac, enthaltend ein bis drei Stickstoffatome und/oder ein Schwefel- oder Sauerstoffatom, welcher ein bis vier Halogenatome und/oder einen bis zwei der folgenden Reste tragen kann: Cι-C4-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-Halogenalkyl, Cι-C4-Alkoxy, Cι-C-Halogenalkoxy und/oder C1.-C4-Alkylth.io;a five- or six-membered heteroaromac 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 4 -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: C 1 -C 4 alkyl , -C-C 4 -haloalkyl, -C-C 4 alkoxy, -C-C-haloalkoxy and / or C 1. -C 4 alkylth.io;
R15 Methyl, Ethyl, Methoxy oder Ethoxy, die einen der folgenden Reste tragen: Hydroxy, Carboxy, Amino, NH(Cι-C4-Alkyl) , N(Cι-C-Alkyl)2, Carboxamid oder C0N(Cι-C4-Alkyl)2;R 15 is methyl, ethyl, methoxy or ethoxy, which carry one of the following radicals: hydroxy, carboxy, amino, NH (-CC 4 alkyl), N (-C-alkyl) 2 , carboxamide or C0N (-C-C 4 alkyl) 2 ;
W Schwefel oder Sauerstoff;W sulfur or oxygen;
Q C-C3-Alkyl, C3-Alkenyl , -S-CH2-CH2-, -0-CH2-CH2-, wobei diese Reste jeweils ein- oder mehrfach substituiert sein können durch: Halogen, Hydroxy, Mercapto, Cyano, Cχ-C-Alkyl, C!-C4-Alkoxy, Cι-C-Alkylthio, Cι-C-Halogenalkoxy, Cι-C-Alkoxycarbonyl , NH (Cι-C4-Alkyl) , N(Cι-C4-Alkyl)2 oder Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach durch Halogen, Cyano, Cι,-C-Alkyl, Cι-C4-Halogenalkyl, Cι-C4-Alkoxy, C-C4-Halogenalkoxy oder Cι-C-Alkylthio 14 oder Q bildet zusammen mit R6 folgende Ringsysteme: Indan-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, Cι-C-Alkoxy, Cι-C4-Alkyl,Q CC 3 -alkyl, C 3 -alkenyl, -S-CH 2 -CH 2 -, -0-CH 2 -CH 2 -, where these radicals can be substituted one or more times by: halogen, hydroxy, mercapto, Cyano, Cχ-C-alkyl, C ! -C 4 -alkoxy, -C-C-alkylthio, -C-C-haloalkoxy, -C-C-alkoxycarbonyl, NH (-C-C 4 -alkyl), N (-C-C 4 -alkyl) 2 or phenyl, the one Cι Cι-C-C may be or polysubstituted, for example mono- to trisubstituted by halogen, cyano, -C-alkyl, 4 haloalkyl, 4 alkoxy, CC 4 -haloalkoxy or Cι-C -alkylthio 14 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,
C2-C-Alkenyl, C2-C4-Alkinyl, C3-C6-Alkenyloxy, C3-C6-Alkinyl- oxy, Cι-C4-Alkylthio, Cι-C-Halogenalkoxy, Cx^-Alkylcarbonyl, Cι-C4-Alkoxycarbonyl, Amino, NH (Cι-C4-Alkyl) , N(Cι-C-Alkyl)2 oder Phenyl .C 2 -C alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 alkenyloxy, C 3 -C 6 alkynyloxy, C 1 -C 4 alkylthio, C 1 -C 4 haloalkoxy, Cx ^ alkylcarbonyl , -C 4 -C alkoxycarbonyl, amino, NH (-C -C 4 alkyl), N (-C -C 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 Trifluormethyl, Cι-C4-Alkyl , Cx-Cj-Alkoxy, Cι-C4-Alkylthio, oder CR2 ist mit CR10 wie unten angegeben zu einem 5- oder 6-gliedrigen Ring verknüpft;R 2 trifluoromethyl, -CC 4 -alkyl, Cx-Cj-alkoxy, -C-C 4 alkylthio, or CR 2 is linked to CR 10 as stated below to form a 5- or 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, Fluor oder Methyl 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-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, fluorine or methyl 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 each case a 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 Trifluormethyl, Cι-C4-Alkyl, d-C4-Alkoxy, Cι-C-Alkylthio, oder CR3 ist mit CR10 wie oben angegeben zu einem 5- oder 6-gliedrigen Ring verknüpft;R3 trifluoromethyl, -CC 4 -alkyl, dC 4 -alkoxy, -C-C-alkylthio, or CR 3 is linked to CR 10 as stated above to form a 5- or 6-membered ring;
R4 Cι-C-Alkyl, das durch einen oder mehrere der folgenden Reste substituiert sein kann: Halogen, C!-C4- lkoxy, Cι-C4-Halogen- alkoxy.R 4 -CC alkyl, which can be substituted by one or more of the following radicals: halogen, C ! -C 4 - lkoxy, -C-C 4 halo alkoxy.
R5 Phenyl oder Naphthyl, die durch einen oder mehrere der folgenden Reste substituiert sein können: Halogen, Nitro, Cyano, Hydroxy, Mercapto, Amino, Cι-C4~Alkyl, Cι-C4-Halogen- alkyl, C1-C-Halogenalkoxy, Cι-C4-Alkoxy, Phenoxy, Cι-C-Alkyl- thio, NH(Cι-C4-Alkyl) , N(Cι-C4-Alkyl )2 oder Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach 15 durch Halogen, Nitro, Cyano, Cι-C-Alkyl , Cι-C4-Halogenalkyl,R 5 is phenyl or naphthyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, mercapto, amino, Cι-C4 ~ alkyl, Cι-C4 halo-alkyl, C 1 -C -Halogenalkoxy, -CC 4 alkoxy, phenoxy, -C-alkyl thio, NH (-C 4 -alkyl), N (-C 4 -alkyl) 2 or phenyl, which can be substituted one or more times can, for example, one to three times 15 by halogen, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl,
Ci-C-Alkoxy, Cι-C4-Halogenalkoxy oder Ci- -Alkylthio; oderCi-C-alkoxy, -C-C 4 haloalkoxy or Ci- alkylthio; or
Phenyl oder Naphthyl, das orthoständig über eine direkte Bindung, eine Methylen-, Ethylen- oder Ethenylengruppe, ein Sauerstoff- oder Schwefelatom oder eine S02-, NH- oder N-Alkyl-Gruppe mit R4 verbunden ist;Phenyl or naphthyl, which is ortho-linked via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO 2 , NH or N-alkyl group with R 4 ;
Cyclohexyl .Cyclohexyl.
R6 Cyclohexyl, das ein- oder mehrfach substituiert sein kann durch: C1-C-Alkoxy, Cι~C-Alkyl, Halogen oder Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach durch Halogen, Cι-C-Alkyl, Cι-C4-Alkoxy;R 6 cyclohexyl, which can be mono- or polysubstituted by: C 1 -C alkoxy, C 1 -C 4 -alkyl, halogen or phenyl, which can be mono- or polysubstituted, for example one to three times by halogen, C 1 -C C-alkyl, -CC 4 alkoxy;
Phenyl oder Naphthyl, die jeweils durch einen oder mehrere der folgenden Reste substituiert sein können: Halogen, R15, Cι-C4-Alkyl, Cι-C4-Halogenalkyl, Acetyl, Cι-C4-Alkoxycarbonyl , Cι-C4-Alkoxy, Phenoxy, Cι~C4-Alkylthio, NH (Cι-C-Alkyl) , N(Cι-C-Alkyl)2, Dioxomethylen, Dioxoethylen oder Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach durch Halogen, Cyano, Cι-C4-Alkyl, Cι-C4-Alkoxy, oder Cι-C4-Alkylthio, mit der Maßgabe, falls Q = -CH2-CH2- und W = 0 ist, dann muß der Phenylring mindestens einen von Wasserstoff verschiedenen Substituenten haben;Phenyl or naphthyl, each of which may be substituted by one or more of the following radicals: halogen, R 15, Cι-C 4 -alkyl, C 4 haloalkyl, acetyl, Cι-C 4 alkoxycarbonyl, Cι-C 4 - alkoxy, phenoxy, Cι ~ C 4 alkylthio, NH (Cι-C alkyl), N (Cι-C alkyl) 2, dioxomethylene, Dioxoethylen or phenyl which may be mono- or polysubstituted, for example mono- to trisubstituted by halogen, cyano, -CC 4 -alkyl, -C-C 4 -alkoxy, or -CC 4 -alkylthio, with the proviso that if Q = -CH 2 -CH 2 - and W = 0, then the Phenyl ring have at least one substituent other than hydrogen;
R15 Methoxy oder Ethoxy, die einen der folgenden Reste tragen: Hydroxy, Carboxy, Amino, NH(C1-C4-Alkyl) , N(Cι-C4-Alkyl )2, Carboxamid oder CON(Cι-C-Alkyl)2;R 15 methoxy or ethoxy, which carry one of the following radicals: hydroxy, carboxy, amino, NH (C 1 -C 4 -alkyl), N (-C-C 4 -alkyl) 2 , carboxamide or CON (-C-C-alkyl ) 2 ;
W Schwefel oder Sauerstoff;W sulfur or oxygen;
Q C2-C3-Alkyl, -S-CH2-CH2-, -0-CH2-CH2-, wobei diese Reste jeweils ein- oder mehrfach substituiert sein können durch: Halogen, C1-C4-Alkyl, C1-C4-Alkoxy, Cι-C4-Alkylthio, oderQC 2 -C 3 alkyl, -S-CH 2 -CH 2 -, -0-CH 2 -CH 2 -, where these radicals can be substituted one or more times by: halogen, C 1 -C 4 alkyl , C 1 -C 4 alkoxy, -C-C 4 alkylthio, or
Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach durch Halogen, Cι-C-Alkyl, Cι-C4-Alkoxy, oder Cx- -AlkylthioPhenyl which can be mono- or polysubstituted, for example one to three times by halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or Cx- alkylthio
oder Q bildet zusammen mit Rδ folgende Ringsysteme:or Q together with R δ 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, wobei die Phenylringe jeweils substituiert sein können durch: Halogen, Hydroxy, Mercapto, Carboxy, Cyano, Cι-C4-Alkoxy, C1-C4-Alkyl, C-C-Alkenyl, C2-C4-Alkinyl, C3-C6-Alkenyloxy, C3-C6-Alkinyloxy, C!-C4-Alkyl- thio, Cι-C4-Halogenalkoxy, Cι-C-Alkoxycarbonyl , NH (C1-C4-Alkyl ) , N (Cι-C4-Alkyl ) 2 oder Phenyl . 16Indan-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 -C 4 alkoxy, C 1 -C 4 alkyl, CC alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 alkenyloxy, C 3 -C 6 - Alkynyloxy, C ! -C 4 alkyl thio, Cι-C4-haloalkoxy, Cι-C alkoxycarbonyl, NH (C 1 -C 4 alkyl), N (Cι-C4 alkyl) 2 or phenyl. 16
Die Verbindungen der vorliegenden Erfindung bieten ein neues therapeutisches Potential für die Behandlung von Hypertonie, pulmonalem Hochdruck, Myokardinfarkt, chronischer Herzinsuffizienz, Angina Pectoris, Arrhythmie, akutem/chronischem Nierenversagen, Niereninsuffizienz, zerebralen vasospasmen, zerebraler Ischämie, Subarachnoidalblutungen, Migräne, Asthma, Atherosklerose, endotoxischem Schock, Endotoxin-induziertem Organversagen, intravaskulärer Koagulation, Restenose nach Angio- plastie und by-pass Operation, benigne Prostata-Hyperplasie, ischämisches und durch Intoxikation verursachtes Nierenversagen bzw. Hypertonie, Metastasierung und Wachstum mesenchymaler Tumoren, Kontrastmittel-induziertes Nierenversagen, 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, arrhythmia, acute / chronic kidney failure, renal failure, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhage, migraine, asthma, asthma endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty and by-pass surgery, 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 antagonistische Wirkung gegenüber dem Neurokinin- rezeptor .Surprisingly, the compounds according to the invention partly show. also antagonistic 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
OO
< 13 14<13 14
NR R besitzt.NR R 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 the renin-angiotensin system are renin inhibitors, angiotensin II antagonists and, above all, angiotensin converting enzyme (ACE) inhibitors.
Ein weiterer Gegenstand der Erfindung sind Kombinationspräparate 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 preparations 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 galenischen Form oder auch in räumlich getrennten Formen dargereicht werden. Die Verabreichung kann gleichzeitig oder zeitlich abgestuft vorgenommen werden.The combination preparations can be presented in a single galenic form or in spatially separated forms. The administration 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 ge- ringere Dosen als bei der jeweiligen Einzeltherapie einzusetzen. 17The 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. 17
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.
5 Die gute Wirkung der Verbindungen läßt sich in folgenden Versuchen zeigen:5 The good effects of the compounds can be demonstrated in the following experiments:
RezeptorbindungsStudienReceptor binding studies
10 Für Bindungsstudien wurden klonierte humane ETA- oder ETB- Rezeptor-exprimierende CHO-Zellen eingesetzt.10 Cloned human ET A or ET B receptor-expressing CHO cells were used for binding studies.
MembranpräparationMembrane preparation
15 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 Streptomycin (Sigma Nr P-0781) vermehrt. Nach 48 Stunden wurden15 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 streptomycin (Sigma No. P-0781). After 48 hours
20 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.20 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 x g.
25 Für die Membranpräparation 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).25 For 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).
30 Bindungstests30 binding tests
Für den ETA- und ETB-Rezeptorbindungstest wurden die Membranen in Inkubationspuffer (50 mM Tris-HCl, pH 7,4 mit 5 mM MnCl , 40 mg/ml Bacitracin und 0,2 % BSA) in einer Konzentration vonFor 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, 40 mg / ml bacitracin and 0.2% BSA)
35 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 10-7 M ETi bestimmt. Nach 30 min wurde der freie und der gebundene Radioligand durch Filtration35 50 μg protein per test batch suspended 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 ETi. After 30 min the free and the bound radioligand were removed by filtration
40 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.40 separated via GF / B glass fiber filter (Whatman, England) on a Skatron cell collector (Skatron, Lier, Norway) and the filters washed with ice-cold Tris-HCl buffer, pH 7.4 with 0.2% BSA. Radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.
45 1845 18th
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 katheteri- 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 ET-1 zu einem deutlichen Blutdruckanstieg, der über einen längeren Zeit- räum anhält.In control animals, intravenous administration of 1 μg / kg ET-1 leads to a significant increase in blood pressure that persists over a longer period of time.
Den Testtieren wurde 30 min vor der ETl 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 ETI administration. 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 pretreated orally 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. ETl (0.3 μg/kg, Appl. Vol. 0.5 ml/kg) intravenös gegeben. Blutdruck und Herzfrequenz werden kontinuierlich über 30 Minuten registriert. Die deutlichen und langanhaltenden Blutdruckänderungen werden als Fläche unter der Kurve (AUC) berechnet. Zur Bestimmung der antagoniscischenAfter a stabilization phase, big endothelin (20 μg / kg, Appl. Vol. 0.5 ml / kg) or ETI (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 persistent changes in blood pressure are calculated as the area under the curve (AUC). To determine the antagonistic
Wirkung der Testsubstanzen wird die AUC der Substanzbehandelten Tiere mit der AUC der Kontrolltiere verglichen.Effect of the test substances, the AUC of the substance-treated animals is compared with the AUC of the control animals.
Die erfindungsgemäßen Verbindungen können in üblicher Weise oral oder parenteral (subkutan, intravenös, intramuskulär, intra- peritoneal) 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 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 Applikationsformen fest oder flüssig angewendet werden, z.B. als Tabletten, Filmtabletten, Kapseln, Pulver, Granulate, Dragees, 19The new compounds can be used in the customary pharmaceutical application forms in solid or liquid form, for example as tablets, film-coated tablets, capsules, powders, granules, coated tablets, 19
Suppositorien, Lösungen, Salben, Cremes oder Sprays. Diese werden in üblicher Weise hergestellt. Die Wirkstoffe können dabei mit den üblichen galenischen Hilfsmitteln wie Tablettenbindern, Füllstoffen, Konservierungsmitteln, Tablettensprengmitteln, Fließ- reguliermitteln, Weichmachern, Netzmitteln, Dispergiermitteln, Emulgatoren, Lösungsmitteln, Retardierungsmitteln, Antioxidantien und/oder Treibgasen verarbeitet werden (vgl. H. Sucker et al . : Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991). Die so erhaltenen Applikationsformen enthalten den Wirkstoff normalerweise in einer Menge von 0,1 bis 90 Gew.-%.Suppositories, solutions, ointments, creams or sprays. These are manufactured in the usual way. The active ingredients 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, 1991). The administration forms obtained in this way normally contain the active ingredient in an amount of 0.1 to 90% by weight.
SynthesebeispieleSynthesis examples
Beispiel 1example 1
2-Hydroxy-3- (2- ( 4-chlorphenyl ) -ethoxy) -3-phenyl-buttersäure- methylester (Diastereomer I, verm. 2s, 3r)2-hydroxy-3- (2- (4-chlorophenyl) ethoxy) -3-phenylbutyric acid methyl ester (diastereomer I, verm. 2s, 3r)
Zu einem Gemisch aus 5 g (26 mmol) trans 2 , 3-Epoxy-3-phenyl- buttersäuremethylester und 4.0 g (26 mmol) 2- (4-Chlorphenyl) - ethanol wurden bei Raumtemperatur 8 Tropfen Bortrifluoridetherat gegeben und 2,5 Stunden bei 30-35°C gerührt (als Lösungsmittel kann optional Chloroform verwendet werden) . Zur Vervollständigung der Reaktion wurden dann nochmals 3 Tropfen Bortrifluoridetherat zugegeben und eine weitere Stunde bei 30-35°C gerührt. Das Gemisch wurde schließlich in Ether aufgenommen drei mal mit 2N NaOH extrahiert, die organische Phase über MgS04 getrocknet, filtriert und dann das Lösungsmittel abdestilliert. Rückstand: 8,7 g gelbliches Öl, das direkt weiter umgesetzt wurde.To a mixture of 5 g (26 mmol) of trans 2, 3-epoxy-3-phenylbutyric acid methyl ester and 4.0 g (26 mmol) of 2- (4-chlorophenyl) ethanol were added 8 drops of boron trifluoride etherate at room temperature and for 2.5 hours stirred at 30-35 ° C (optionally chloroform can be used as solvent). Another 3 drops of boron trifluoride etherate were then added to complete the reaction, and the mixture was stirred at 30-35 ° C. for a further hour. The mixture was finally taken up in ether, extracted three times with 2N NaOH, the organic phase was dried over MgSO 4 , filtered and then the solvent was distilled off. Residue: 8.7 g of yellowish oil, which was directly reacted further.
Beispiel 2Example 2
2-Hydroxy-3- (2- ( 4-chlorphenyl ) -ethoxy) -3 -phenylbuttersäure (Diastereomer I , verm. 2s , 3r)2-hydroxy-3- (2- (4-chlorophenyl) ethoxy) -3-phenylbutyric acid (diastereomer I, verm. 2s, 3r)
In 50 ml Dioxan wurden 8,7 g (2s, 3r) 2-Hydroxy-3- (2- (4-chlor- phenyl ) -ethoxy) -3-phenylbuttersäuremethylester (Rohprodukt aus Beispiel 1) gelöst mit 75 ml IM NaOH versetzt und drei Stunden bei Raumtemperatur gerührt. Anschließend wurde der Ansatz mit Wasser versetzt und die wäßrige Phase mit Ether extrahiert. Die wäßrige Phase wurde mit Salzsäure angesäuert, mit Essigester extrahiert und die organische Phase über Magnesiumsulfat getrocknet. Nach dem Abdestillieren des Lösungsmittels wurden 7,0 g Öl isoliert, welches direkt weiter eingesetzt wurde. (Diastereo- merengemisch (2s,3r/2s,3s 8o:20). 20In 50 ml of dioxane, 8.7 g (2s, 3r) of 2-hydroxy-3- (2- (4-chlorophenyl) ethoxy) -3-phenylbutyric acid methyl ester (crude product from Example 1) were mixed with 75 ml of 1M NaOH and stirred for three hours at room temperature. The mixture was then mixed with water and the aqueous phase extracted with ether. The aqueous phase was acidified with hydrochloric acid, extracted with ethyl acetate and the organic phase was dried over magnesium sulfate. After the solvent had been distilled off, 7.0 g of oil were isolated, which was used directly. (Diastereomer mixture (2s, 3r / 2s, 3s 8o: 20). 20th
Beispiel 3Example 3
2- (4, 6-Dimethyl-pyrimidin-2-yloxy)- 3- (2- (4-chlorphenyl) -ethoxy) - 3-phenylbuttersäure (Diastereomer I, verm. 2s, 3r)2- (4, 6-dimethyl-pyrimidin-2-yloxy) - 3- (2- (4-chlorophenyl) ethoxy) - 3-phenylbutyric acid (diastereomer I, verm. 2s, 3r)
In 10 ml DMF wurden unter Stickstoff 0,28 g NaH (9 mmol, 80% in Weißöl) vorgelegt, 1 g 2-Hydroxy-3- (2- (4-chlorphenyl) -ethoxy)-3- phenylbuttersäure (Rohprodukt aus Beispiel 2) gelöst in 5 ml DMF zugetropft und nach 10 Minuten 640 mg 2-Chlor-4, 6-dimethyl- pyrimidin zugegeben. Dann wurde 4 Tage bei Raumtemperatur gerührt. Das Gemisch wurde mit Wasser versetzt und mit 2N HC1 auf pH 2 gebracht. Die wäßrige Phase wurde mit Ether extrahiert. Die vereinigten organischen Phasen wurden drei mal mit 2N NaOH ausgeschüttelt und die organische Phase verworfen. Die alkalische Phase wurde mit 2N HC1 auf pH 2 gebracht und dann mit Ether extrahiert. Die vereinigten organischen Phasen wurden über MgS04 getrocknet, filtriert, dann das Lösungsmittel abdestilliert und der Rückstand (1,1 g gelber Schaum) chromatographisch (Methylenchlorid/Methanol 9:1) gereinigt. Zwei Fraktionen: 187 mg Gemisch aus zwei Diastereomeren (2s,3r/2s,3s 84:16); 400 mg Gemisch aus zwei Diastereomeren (2s,3r/2s,3s 75:25).0.28 g of NaH (9 mmol, 80% in white oil), 1 g of 2-hydroxy-3- (2- (4-chlorophenyl) ethoxy) -3-phenylbutyric acid (crude product from Example 2) dissolved in 5 ml of DMF, and after 10 minutes 640 mg of 2-chloro-4, 6-dimethyl-pyrimidine were added. Then the mixture was stirred at room temperature for 4 days. The mixture was mixed with water and brought to pH 2 with 2N HCl. The aqueous phase was extracted with ether. The combined organic phases were shaken three times with 2N NaOH and the organic phase was discarded. The alkaline phase was brought to pH 2 with 2N HCl and then extracted with ether. The combined organic phases were dried over MgSO 4 , filtered, then the solvent was distilled off and the residue (1.1 g of yellow foam) was purified by chromatography (methylene chloride / methanol 9: 1). Two fractions: 187 mg mixture of two diastereomers (2s, 3r / 2s, 3s 84:16); 400 mg mixture of two diastereomers (2s, 3r / 2s, 3s 75:25).
ESI-MS: M+ = 440ESI-MS: M + = 440
Beispiel 4Example 4
2-Hydroxy-3- (2- (4-chlorphenyl) -ethoxy) -3-phenyl-buttersäure- methylester (Diastereomer II, verm. 2s, 3s)2-hydroxy-3- (2- (4-chlorophenyl) ethoxy) -3-phenylbutyric acid methyl ester (diastereomer II, verm. 2s, 3s)
Zu einem Gemisch aus 5 g (26 mmol) eis 2 , 3-Epoxy-3-phenyl-butter- säuremethylester und 4.0 g (26 mmol) 2- (4-Chlorphenyl) -ethanol wurden bei Raumtemperatur 8 Tropfen Bortrifluoridetherat gegeben und 2,5 Stunden bei 30-35°C gerührt (als Lösungsmittel kann optional Chloroform verwendet werden) . Zur Vervollständigung der Reaktion wurden dann nochmals 9 Tropfen Bortrifluoridetherat gegeben und 3 Stunden bei 30-35°C gerührt. Das Gemisch wurde schließlich in Ether aufgenommen drei mal mit 2N NaOH extrahiert, die organische Phase über MgS04 getrocknet, filtriert und dann das Lösungsmittel abdestilliert. Rückstand: 8,1 g gelbliches Öl, das direkt weiter umgesetzt wurde. 21At room temperature, 8 drops of boron trifluoride etherate were added to a mixture of 5 g (26 mmol) of ice 2,3-epoxy-3-phenyl-butteric acid methyl ester and 4.0 g (26 mmol) of 2- (4-chlorophenyl) -ethanol, and 2. Stirred for 5 hours at 30-35 ° C (optionally chloroform can be used as a solvent). To complete the reaction, 9 drops of boron trifluoride etherate were then added and the mixture was stirred at 30-35 ° C. for 3 hours. The mixture was finally taken up in ether, extracted three times with 2N NaOH, the organic phase was dried over MgSO 4 , filtered and then the solvent was distilled off. Residue: 8.1 g of yellowish oil, which was directly reacted further. 21
Beispiel 5Example 5
2-Hydroxy-3- (2- (4-chlorphenyl) -ethoxy)- 3-phenylbuttersäure (Diastereomer II, verm. 2s, 3s)2-Hydroxy-3- (2- (4-chlorophenyl) ethoxy) -3-phenylbutyric acid (diastereomer II, verm. 2s, 3s)
In 50 ml Dioxan wurden 8,1 g (2s, 3r) 2-Hydroxy-3- (2- (4-chlor- phenyl ) -ethoxy) -3-phenylbuttersäuremethylester (Rohprodukt aus Beispiel 1) gelöst mit 69 ml IM NaOH versetzt und vier Stunden bei Raumtemperatur gerührt. Anschließend wurde der Ansatz mit Wasser versetzt und die wäßrige Phase mit Ether extrahiert. Die wäßrige Phase wurde mit Salzsäure angesäuert, mit Essigester extrahiert und die organische Phase über Magnesiumsulfat getrocknet. Nach dem Abdestillieren des Lösungsmittels wurden 5,8 g Öl isoliert (Diastereomerengemisch (2s,3s/2s,3r 87:13). Dieses Rohprodukt wurde in wenig Diisopropylether über Nacht aufgerührt. Der entstandene Niederschlag wurde abfiltriert, vom Lösungsmittel befreit (2,3 g weißer Feststoff, diastereomerenrein Smp. 94-95°C) und in Beispiel 6 weiter umgesetzt.In 50 ml of dioxane, 8.1 g (2s, 3r) of 2-hydroxy-3- (2- (4-chlorophenyl) ethoxy) -3-phenylbutyric acid methyl ester (crude product from Example 1) were dissolved with 69 ml of 1M NaOH and stirred for four hours at room temperature. The mixture was then mixed with water and the aqueous phase extracted with ether. The aqueous phase was acidified with hydrochloric acid, extracted with ethyl acetate and the organic phase was dried over magnesium sulfate. After the solvent had been distilled off, 5.8 g of oil were isolated (mixture of diastereomers (2s, 3s / 2s, 3r 87:13). This crude product was stirred in a little diisopropyl ether overnight. The resulting precipitate was filtered off and the solvent was removed (2.3 g white solid, diastereomerically pure mp. 94-95 ° C) and further implemented in Example 6.
Beispiel 6Example 6
2- (4, 6-Dimethyl-pyrimidin-2-yloxy) - 3- (2- (4-chlorphenyl) -ethoxy) - 3-phenylbuttersäure (Diastereomer II, verm. 2s, 3s)2- (4, 6-dimethyl-pyrimidin-2-yloxy) - 3- (2- (4-chlorophenyl) ethoxy) - 3-phenylbutyric acid (diastereomer II, verm. 2s, 3s)
In 10 ml DMF wurden unter Stickstoff 0,28 g NaH (9 mmol, 80% in Weißöl) vorgelegt, 1 g 2-Hydroxy-3- (2- (4-chlorphenyl) -ethoxy) -3- phenylbuttersäure (3 mmol aus Beispiel 5) gelöst in 5 ml DMF zugetropft und nach 10 Minuten 640 mg 2-Chlor-4, 6-dimethyl- pyrimidin zugegeben. Dann wurde über Nacht bei Raumtemperatur ge- rührt. Das Gemisch wurde mit Wasser versetzt und mit 2N HC1 auf pH 2 gebracht. Die wäßrige Phase wurde mit Ether extrahiert. Die vereinigten organischen Phasen wurden drei mal mit 2N NaOH ausgeschüttelt und die organische Phase verworfen. Die alkalische Phase wurde mit 2N HCl auf pH 2 eingestellt und dann mit Ether extrahiert. Die vereinigten organischen Phasen wurden über MgS04 getrocknet, filtriert, dann das Lösungsmittel abdestilliert und der Rückstand (1,25 g gelber Schaum) in Diisopropylether ausgerührt (1,1 g Produkt, diasteromerenrein) .0.28 g of NaH (9 mmol, 80% in white oil) were placed in 10 ml of DMF under nitrogen, 1 g of 2-hydroxy-3- (2- (4-chlorophenyl) ethoxy) -3-phenylbutyric acid (3 mmol from Example 5) dissolved in 5 ml of DMF, and after 10 minutes 640 mg of 2-chloro-4, 6-dimethylpyrimidine were added. The mixture was then stirred at room temperature overnight. The mixture was mixed with water and brought to pH 2 with 2N HCl. The aqueous phase was extracted with ether. The combined organic phases were shaken three times with 2N NaOH and the organic phase was discarded. The alkaline phase was adjusted to pH 2 with 2N HCl and then extracted with ether. The combined organic phases were dried over MgSO 4 , filtered, then the solvent was distilled off and the residue (1.25 g of yellow foam) was stirred in diisopropyl ether (1.1 g of product, diasteromerically pure).
IH-NMR (270 MHz, DMSO): 12,5-13,0 ppm (IH, br) ; 7,15-7,4 (9H, m) ; 6,85 (IH, s); 5,15 (IH, s) ; 3,50-3,65 (IH, m) ; 3,2-3,4 (IH, m) ; 2,7-2,85 (2H, m) , 2,25 (6H, s); 1,65 (3H, s).IH NMR (270 MHz, DMSO): 12.5-13.0 ppm (IH, br); 7.15-7.4 (9H, m); 6.85 (IH, s); 5.15 (IH, s); 3.50-3.65 (IH, m); 3.2-3.4 (IH, m); 2.7-2.85 (2H, m), 2.25 (6H, s); 1.65 (3H, s).
ESI-MS: M+ = 440 22ESI-MS: M + = 440 22
Die folgenden Verbindungen wurden analog zu den oben genannten Beispielen hergestelltThe following compounds were prepared analogously to the above examples
Beispiel 7Example 7
2- (4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3- (2- (4-methylphenyl) - ethoxy) -3-phenylbuttersäure (Diastereomer I, verm. 2s, 3r)2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3- (2- (4-methylphenyl) ethoxy) -3-phenylbutyric acid (diastereomer I, verm. 2s, 3r)
IH-NMR (200 MHz, CDCl3): 7,0-7,5 ppm (9 H, m) ; 6,25 (1 H, s); 5,3 (1 H, s); 3,9 (3 H, d) ; 3,65-3,8 (IH, m) ; 3,4-3,6 (IH, m) ; 2,8 3,0 (2H, m) 2,3 (3H, s), 1,8 (3H, m) .IH-NMR (200 MHz, CDCl 3 ): 7.0-7.5 ppm (9 H, m); 6.25 (1H, s); 5.3 (1H, s); 3.9 (3H, d); 3.65-3.8 (IH, m); 3.4-3.6 (IH, m); 2.8 3.0 (2H, m) 2.3 (3H, s), 1.8 (3H, m).
Beispiel 8Example 8
2- (4-Methoxy-6-methyl-pyrimidin-2-yloxy) -3- (2- (4-methylphenyl) - ethoxy) -3-phenylbuttersäure (Diastereomer II, verm. 2s, 3s)2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3- (2- (4-methylphenyl) ethoxy) -3-phenylbutyric acid (diastereomer II, verm. 2s, 3s)
IH-NMR (250 MHz, CDCI3): 7,0-7,5 ppm (9 H, m) ; 6,1 (1 H, s) ; 5,5 (1 H, s); 3,9 (3 H, d) ; 3,65-3,8 (IH, m) ; 3,4-3,6 (IH, m) ; 2,8 3,0 (2H, m) 2,3 (3H, s), 2,2 (6H, s); 1,8 (3H, m) .IH-NMR (250 MHz, CDCI 3 ): 7.0-7.5 ppm (9 H, m); 6.1 (1H, s); 5.5 (1H, s); 3.9 (3H, d); 3.65-3.8 (IH, m); 3.4-3.6 (IH, m); 2.8 3.0 (2H, m) 2.3 (3H, s), 2.2 (6H, s); 1.8 (3H, m).
Beispiel 9Example 9
2- (4, 6-Dimethyl-pyrimidin-2-yloxy) - 3- (2- (4-methylphenyl) - ethoxy) -3-phenylbuttersäure (Diastereomer I, verm. 2s, 3r)2- (4, 6-dimethyl-pyrimidin-2-yloxy) -3- (2- (4-methylphenyl) ethoxy) -3-phenylbutyric acid (diastereomer I, verm. 2s, 3r)
IH-NMR (200 MHz, DMSO): 12-13,5 ppm (IH, br) ; 7,0-7,3 (9H, m) ; 6,8 (IH, s); 5,3 (IH, s); 3,4-3,7 (2H, m) ; 2,7-2,9 (2H, m) ; 2,25 (6H, s); 2,2 (3H, s) ; 1,7 (3H, s) .IH NMR (200 MHz, DMSO): 12-13.5 ppm (IH, br); 7.0 - 7.3 (9H, m); 6.8 (IH, s); 5.3 (IH, s); 3.4-3.7 (2H, m); 2.7-2.9 (2H, m); 2.25 (6H, s); 2.2 (3H, s); 1.7 (3H, s).
ESI-MS: M+ = 420ESI-MS: M + = 420
Beispiel 10Example 10
2- (4, 6-Dimethyl-pyrimidin-2-yloxy)- 3- (3-phenylpropoxy) -3-phenylbuttersäure (Diastereomer I, verm. 2s, 3r)2- (4, 6-dimethyl-pyrimidin-2-yloxy) - 3- (3-phenylpropoxy) -3-phenylbutyric acid (diastereomer I, verm. 2s, 3r)
IH-NMR (200 MHz, DMSO): 12-13,5 ppm (IH, br) ; 7,1-7,4 (9H, m) ; 6,8 (IH, s); 5,3 (IH, s); 3,2-3,6 (2H, m) ; 2,5-2,7 (2H, m) ; 2,25 (6H, s); 1,7 (3H, s) ; 1,7-1,9 (2H, m) .IH NMR (200 MHz, DMSO): 12-13.5 ppm (IH, br); 7.1-7.4 (9H, m); 6.8 (IH, s); 5.3 (IH, s); 3.2-3.6 (2H, m); 2.5-2.7 (2H, m); 2.25 (6H, s); 1.7 (3H, s); 1.7-1.9 (2H, m).
ESI-MS: M+ = 420 23ESI-MS: M + = 420 23
Beispiel 11Example 11
2- (4 , 6-Dimethyl-pyrimidin-2-yloxy) - 3- (2- (naphth-2-yl ) -ethoxy) -3- phenylbuttersäure (Diastereomer I, verm. 2s, 3r)2- (4, 6-dimethyl-pyrimidin-2-yloxy) - 3- (2- (naphth-2-yl) -ethoxy) -3-phenylbutyric acid (diastereomer I, verm. 2s, 3r)
IH-NMR (250 MHz, DMSO): 12-13,5 ppm (IH, br) ; 7,7-7,9 (4H, m) ; 7,1-7,5 (8H, m) ; 6,9 (IH, s); 5,3 (IH, s ) ; 3,6-3,8 (IH, m) ; 3,4-3,6 (IH, m) ; 2,9-3,1 (2H, m) ; 2,3 (6H, s); 1,7 (3H, s).IH NMR (250 MHz, DMSO): 12-13.5 ppm (IH, br); 7.7-7.9 (4H, m); 7.1 - 7.5 (8H, m); 6.9 (IH, s); 5.3 (IH, s); 3.6-3.8 (IH, m); 3.4-3.6 (IH, m); 2.9-3.1 (2H, m); 2.3 (6H, s); 1.7 (3H, s).
ESI-MS: M+ = 456ESI-MS: M + = 456
Beispiel 12Example 12
2- (4, 6-Dimethyl-pyrimidin-2-yloxy) - 3- (3- (4-chlorphenyl)- propoxy) -3-phenylbuttersäure (Diastereomer I, verm. 2s, 3r)2- (4, 6-dimethyl-pyrimidin-2-yloxy) -3- (3- (4-chlorophenyl) propoxy) -3-phenylbutyric acid (diastereomer I, verm. 2s, 3r)
IH-NMR (270 MHz, DMSO): 12,5-13,0 ppm (IH, br) ; 7,15-7,5 (9H, m) ; 6,9 (IH, s); 5,2 (IH, s); 3,3-3,5 (IH, m) ; 3,1-3,3 (IH, m) ; 2,55-2,7 (2H, m) ; 2,3 (6H, s) ; 1,7 (3H, s); 1,65-1,9 (2H, m) .IH NMR (270 MHz, DMSO): 12.5-13.0 ppm (IH, br); 7.15-7.5 (9H, m); 6.9 (IH, s); 5.2 (IH, s); 3.3-3.5 (IH, m); 3.1-3.3 (IH, m); 2.55-2.7 (2H, m); 2.3 (6H, s); 1.7 (3H, s); 1.65-1.9 (2H, m).
ESI-MS: M+ = 454ESI-MS: M + = 454
Beispiel 13Example 13
2- (4, 6-Dimethyl-pyrimidin-2-yloxy) - 3- (2- (4-fluorphenyl) -ethoxy) - 3-phenylbuttersäure (Diastereomer I, verm. 2s, 3r)2- (4, 6-dimethyl-pyrimidin-2-yloxy) - 3- (2- (4-fluorophenyl) ethoxy) - 3-phenylbutyric acid (diastereomer I, verm. 2s, 3r)
IH-NMR (200 MHz, DMSO): 12,0-13,0 ppm (IH, br) ; 7,0-7,4 (9H, m) ; 6,8 (IH, S); 5,2 (IH, s); 3,5-3,7 (IH, m) ; 3,3-3,5 (IH, m) ; 2,7-2,85 (2H, m) ; 2,3 (6H, s) ; 1,7 (3H, s) .IH NMR (200 MHz, DMSO): 12.0-13.0 ppm (IH, br); 7.0-7.4 (9H, m); 6.8 (IH, S); 5.2 (IH, s); 3.5-3.7 (IH, m); 3.3-3.5 (IH, m); 2.7-2.85 (2H, m); 2.3 (6H, s); 1.7 (3H, s).
ESI-MS: M+ = 424ESI-MS: M + = 424
Beispiel 14Example 14
2- (4, 6-Dimethyl-pyrimidin-2-yloxy)- 3- (2- (4-fluorphenyl) -ethoxy) - 3-phenylbuttersäure (Diastereomer II, verm. 2s, 3s)2- (4, 6-dimethyl-pyrimidin-2-yloxy) - 3- (2- (4-fluorophenyl) ethoxy) - 3-phenylbutyric acid (diastereomer II, verm. 2s, 3s)
IH-NMR (200 MHz, DMSO): 12,5-13,0 ppm (IH, br) ; 7,0-7,4 (9H, m) ; 6,8 (IH, s); 5,1 (IH, s ) ; 3,5-3,7 (IH, m) ; 3,2-3,4 (IH, m) ; 2,7-2,85 (2H, m) ; 2,3 (6H, s) ; 1,65 (3H, s) .IH NMR (200 MHz, DMSO): 12.5-13.0 ppm (IH, br); 7.0-7.4 (9H, m); 6.8 (IH, s); 5.1 (IH, s); 3.5-3.7 (IH, m); 3.2-3.4 (IH, m); 2.7-2.85 (2H, m); 2.3 (6H, s); 1.65 (3H, s).
ESI-MS: M+ = 424 24ESI-MS: M + = 424 24
Beispiel 15Example 15
2- (4, 6-Dimethyl-pyrimidin-2-yloxy) - 3- (2- (4-methoxyphenyl)- ethoxy) -3-phenylbuttersäure (Diastereomer I, verm. 2s, 3r)2- (4, 6-dimethyl-pyrimidin-2-yloxy) - 3- (2- (4-methoxyphenyl) ethoxy) -3-phenylbutyric acid (diastereomer I, verm. 2s, 3r)
IH-NMR (200 MHz, DMSO): 12,0-13,0 ppm (IH, br) ; 7,2-7,4 (5H, m) ; 7,1 (2H, d) ; 6,9 (IH, s) ; 6,75 (2H, d) ; 5,2 (IH, s); 3,7 (3H, s); 3,4-3,6 (IH, m) ; 3,2-3,4 (IH, m) ; 2,7-2,85 (2H, m) ; 2,3 (6H, s ) ; 1,7 (3H, s).IH NMR (200 MHz, DMSO): 12.0-13.0 ppm (IH, br); 7.2-7.4 (5H, m); 7.1 (2H, d); 6.9 (IH, s); 6.75 (2H, d); 5.2 (IH, s); 3.7 (3H, s); 3.4-3.6 (IH, m); 3.2-3.4 (IH, m); 2.7-2.85 (2H, m); 2.3 (6H, s); 1.7 (3H, s).
ESI-MS: M+ = 436ESI-MS: M + = 436
Beispiel 16Example 16
2- (4, 6-Dimethyl-pyrimidin-2-yloxy) - 3- (3- (4-methoxyphenyl ) - propoxy) -3 -phenylbuttersäure (Diastereomer I, verm. 2s, 3r)2- (4, 6-dimethyl-pyrimidin-2-yloxy) -3- (3- (4-methoxyphenyl) propoxy) -3-phenylbutyric acid (diastereomer I, verm. 2s, 3r)
Smp: 153-156°C ESI-MS: M+ = 450M.p .: 153-156 ° C ESI-MS: M + = 450
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.
Tabelle 1 sβ sβTable 1 sβ sβ
*s v©* s v ©
∞∞
R— -Q— - -C.-J/ H 2R— -Q— - -C.-J / H 2
R R yR R y
Nr. R1 R5 R4 Q R6 R2 R3 Z X Y WNo. R 1 R 5 R 4 Q R6 R 2 R3 ZXYW
1-1 COOH Phenyl Methyl - CH2-CH2- Phenyl OMe Me CH N N s1-1 COOH phenyl methyl - CH 2 -CH 2 - phenyl OMe Me CH NN s
1-2 COOMe Phenyl Methyl - CH2-CH2- Phenyl CF3 Me CH N N 01-2 COOMe phenyl methyl - CH 2 -CH 2 - phenyl CF 3 Me CH NN 0
1-3 COOH 4-Br-Phenyl Methyl - CH2-CH2- Phenyl OMe OMe CH N N 01-3 COOH 4-Br-phenyl methyl - CH 2 -CH 2 - phenyl OMe OMe CH NN 0
1-4 COOH Phenyl Methyl - CH2-C(CH3)2- Phenyl OMe Me CH N N 01-4 COOH phenyl methyl - CH 2 -C (CH 3 ) 2 - phenyl OMe Me CH NN 0
UlUl
1-5 COOH 4-Cl-Phenyl CF3 - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl Me Me CH N N 01-5 COOH 4-Cl-Phenyl CF 3 - CH 2 -CH 2 - CH 2 - 3,4-Di-OMe-Phenyl Me Me CH NN 0
1-6 COOH 4-Cl-Phenyl Methyl - CH2-CH2- CH2- 3 ,4-Di-OMe-Phenyl Me Me N N N 01-6 COOH 4-Cl-Phenyl Methyl - CH 2 -CH 2 - CH 2 - 3, 4-Di-OMe-Phenyl Me Me NNN 0
1-7 COOH Phenyl Metliyl - CH2-CH2- 3,4-Di-Cl-Phenyl Me Me CH N N 01-7 COOH Phenyl Metliyl - CH 2 -CH 2 - 3,4-Di-Cl-Phenyl Me Me CH NN 0
1-8 COOH Phenyl EÜiyl - CH2-CH2- Phenyl Me Me N N CH 01-8 COOH Phenyl EÜiyl - CH2-CH2-Phenyl Me Me N N CH 0
1-9 COOH Phenyl Metliyl - CH2-CH2- Phenyl Ethyl Me N N N 01-9 COOH Phenyl Metliyl - CH 2 -CH 2 - Phenyl Ethyl Me NNN 0
1-10 COOH Phenyl Methyl - CH=CH- CH2- Phenyl Ethyl Me CH N N 01-10 COOH phenyl methyl - CH = CH- CH 2 - phenyl ethyl Me CH NN 0
I— 11 COOH Phenyl Bulyl - CH=CH- CH2- Phenyl OMe CH2- CH2-CH2-C N N 0I - 11 COOH phenyl bulyl - CH = CH- CH 2 - phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-12 COOH Phenyl Methyl - CH=CH- CH2- Phenyl OMe 0- CH2-CH2-C N N 01-12 COOH phenyl methyl - CH = CH- CH 2 - phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-13 COOH Phenyl Methyl - CH2-CH2- Phenyl OMe CH2- CH2-CH2-C N N s1-13 COOH phenyl methyl - CH 2 -CH 2 - phenyl OMe CH 2 - CH 2 -CH 2 -CNN s
1-14 COOEt Phenyl Methyl - CH2-CH2- Phenyl OMe 0- CH2-CH2-C N N 0 π 1-15 COOH 4-Et-Phenyl CF3 - CH2-CH2- 4-SMe-Phenyl Me Me CH N N 0 p. sO o1-14 COOEt Phenyl Methyl - CH 2 -CH 2 - Phenyl OMe 0- CH 2 -CH 2 -CNN 0 π 1-15 COOH 4-Et-Phenyl CF 3 - CH2-CH2- 4-SMe-Phenyl Me Me CH NN 0 p. so or not
00 00
Nr. R1 R5 R4 Q R6 R2 R3 Z X Y WNo. R 1 R 5 R 4 Q R6 R 2 R3 ZXYW
1-16 COOH 4-Et-Phenyl Ethyl - CH2-CH2- 4-SMe-Phenyl Me Me N N N 01-16 COOH 4-Et-Phenyl Ethyl - CH 2 -CH 2 - 4-SMe-Phenyl Me Me NNN 0
*-.* -.
1-17 COOMe Phenyl Methyl - CH2-CH2- 4-OMe-Phenyl OMe Me CH N N 0 ve1-17 COOMe phenyl methyl - CH 2 -CH 2 - 4-OMe-phenyl OMe Me CH NN 0 ve
1-18 COOEt Phenyl Methyl - CH2-CH2- 4-OMe-Phenyl Me Me CH N N s1-18 COOEt Phenyl Methyl - CH 2 -CH 2 - 4-OMe-Phenyl Me Me CH NN s
1-19 Tetrazol Phenyl Metliyl - CH2-CH2- 4-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-19 Tetrazole Phenyl Metliyl - CH 2 -CH 2 - 4-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-20 COOH Phenyl Methyl - C(CH3)2-CH2- 4-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-20 COOH phenyl methyl - C (CH 3 ) 2 -CH 2 - 4-OMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-21 COOH Phenyl Ethyl - CH2- C(CH3)2- 4-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-21 COOH Phenyl Ethyl - CH 2 - C (CH 3 ) 2 - 4-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-22 COOH 4-Cl-Phenyl CF3 - CH2-CH2- CH2- 4-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-22 COOH 4-Cl-Phenyl CF 3 - CH 2 -CH 2 - CH 2 - 4-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-23 COOH 4-Cl-Phenyl Metliyl - CH2-CH2- CH2— 3,4-Di-OMe-Phenyl OMe Me CH N N 01-23 COOH 4-Cl-Phenyl Metliyl - CH 2 -CH 2 - CH 2 - 3,4-Di-OMe-Phenyl OMe Me CH NN 0
1-24 COOH 4-Br-Phenyl Methyl - CH2-CH2- 4-OMe-Phenyl OMe OMe CH N N 01-24 COOH 4-Br-phenyl methyl - CH2-CH2- 4-OMe-phenyl OMe OMe CH N N 0
1-25 COOH Phenyl Methyl - CH2-CH2- 4-OMe-Phenyl OMe Me N N N 01-25 COOH phenyl methyl - CH 2 -CH 2 - 4-OMe-phenyl OMe Me NNN 0
1-26 COOH Phenyl Methyl - CH2-CH2- 4-OMe-Phenyl Me Me N N CH 01-26 COOH phenyl methyl - CH 2 -CH 2 - 4-OMe-phenyl Me Me NN CH 0
-sj-sj
1-27 COOH Phenyl Metliyl - CH=CH- CH2- Phenyl Me Me CH N N 0 σ-1-27 COOH Phenyl Metliyl - CH = CH- CH 2 - Phenyl Me Me CH NN 0 σ-
1-28 COOH Phenyl Metliyl - CH=CH- CH2- Phenyl Me Me N N N 01-28 COOH Phenyl Metliyl - CH = CH- CH 2 - Phenyl Me Me NNN 0
1-29 COOH Phenyl Metliyl - CH2-CH2- 4-OMe-Phenyl Ethyl Me N N N 01-29 COOH Phenyl Metliyl - CH 2 -CH 2 - 4-OMe-Phenyl Ethyl Me NNN 0
1-30 COOH Phenyl Methyl - CH2-CH2- 4-OMe-Phenyl OMe CH2- CH2-CH2-C N N s1-30 COOH phenyl methyl - CH 2 -CH 2 - 4-OMe-phenyl OMe CH 2 - CH 2 -CH 2 -CNN s
1-31 COOH 4-Et-Phenyl Methyl - CH2-CH2- 3-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-31 COOH 4-Et-Phenyl Methyl - CH 2 -CH 2 - 3-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-32 COOH 4-Et-Phenyl Meüiyl - CH2-CH2- 4-SMe-Phenyl OMe Me CH N N 01-32 COOH 4-Et-Phenyl Meüiyl - CH 2 -CH 2 - 4-SMe-Phenyl OMe Me CH NN 0
1-33 COOEt Phenyl Methyl - CH2-CH2- 4-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-33 COOEt Phenyl Methyl - CH2-CH2- 4-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-34 COOH Phenyl Propyl - CH2-CH2- 3,4-Di-OMe-Phenyl OMe O- CH2-CH2-C N N s1-34 COOH phenyl propyl - CH2-CH2- 3,4-di-OMe-phenyl OMe O-CH2-CH2-C N N s
1-35 COOMe Phenyl Methyl - C(CH3)2-CH2- 3,4-Di-OMe-Phcnyl OMe Me N N CH s1-35 COOMe Phenyl Methyl - C (CH 3 ) 2 -CH 2 - 3,4-Di-OMe-Phcnyl OMe Me NN CH s
1-36 COOH Phenyl Metliyl - C(CH3)2-CH2- 3,4-Di-OMe-Phenyl Ethyl Me CH N N 01-36 COOH Phenyl Metliyl - C (CH 3 ) 2 -CH 2 - 3,4-Di-OMe-Phenyl Ethyl Me CH NN 0
OO
1-37 COOH 4-Br-Phenyl Meüiyl - CH2-CH2- 3,4-Di-OMe-Phenyl CF3 Me CH N N 0 H1-37 COOH 4-Br-Phenyl Meüiyl - CH2-CH2- 3,4-Di-OMe-Phenyl CF 3 Me CH NN 0 H
MM
1-38 COOH 4-Cl-Phenyl Methyl — CH2— CH2— CH2— 4-OMe-Phenyl Me Me N N *Ü N 0 v© vo o1-38 COOH 4-Cl-Phenyl Methyl - CH2-CH2-CH2-4-OMe-Phenyl Me Me NN * Ü N 0 v © vo o
0 o0 0 o0
Nr. R1 R5 R4 Q R6 R2 R3 Z X Y WNo. R 1 R 5 R 4 Q R6 R 2 R 3 ZXYW
1-39 COOH 4-Cl-Phenyl Methyl - CH2-CH2- CH2- 4-OMe-Phenyl Ethyl Me CH N N 0 sβ sβ1-39 COOH 4-Cl-Phenyl Methyl - CH 2 -CH 2 - CH 2 - 4-OMe-Phenyl Ethyl Me CH NN 0 sβ sβ
1-40 COOH Phenyl Methyl - CH2-CH2- 3,4-Di-Me-Phenyl OMe Me CH N N 01-40 COOH phenyl methyl - CH 2 -CH 2 - 3,4-di-Me-phenyl OMe Me CH NN 0
1-41 COOH Phenyl Ethyl - CH2-CH2- 3,4-Di-OMe-Phenyl SMe Me CH N N 0 sβ s1-41 COOH phenyl ethyl - CH 2 -CH 2 - 3,4-di-OMe-phenyl SMe Me CH NN 0 sβ s
1-42 COOH Phenyl Metliyl - CH2-CH2- 3,4-Di-OMe-Phenyl Me Me N N CH 01-42 COOH Phenyl Metliyl - CH 2 -CH 2 - 3,4-Di-OMe-Phenyl Me Me NN CH 0
1-43 COOH Phenyl Metliyl - CH=CH- CH2- Phenyl CF3 Me CH N N 01-43 COOH Phenyl Metliyl - CH = CH- CH 2 - Phenyl CF 3 Me CH NN 0
1-44 COOH Phenyl Butyl - CH=CH- CH2- Phenyl OMe Me CH N N 01-44 COOH phenyl butyl - CH = CH - CH 2 - phenyl OMe Me CH NN 0
1^.5 COOH Phenyl Metliyl - CH2-CH2- 3,4-Di-OMe-Phenyl Ethyl Me CH N N s1 ^ .5 COOH Phenyl Metliyl - CH 2 -CH 2 - 3,4-Di-OMe-Phenyl Ethyl Me CH NN s
1-46 COOBzl Phenyl Methyl - CH2-CH2- 3,4-Di-OMe-Phenyl OMe CH2- CH2-CH2-C N N 01-46 COOBzl phenyl methyl - CH 2 -CH 2 - 3,4-di-OMe-phenyl OMe CH2-CH2-CH 2 -CNN 0
1-47 COOH 4-Et-Phenyl Methyl - CH2-CH2- 3-OMe-Phenyl Me Me N N N 01-47 COOH 4-Et-Phenyl Methyl - CH2-CH 2 - 3-OMe-Phenyl Me Me NNN 0
1-48 COOH 4-Et-Phenyl CF3 - CH2-CH2- 3-OMe-Phenyl Ethyl Me CH N N 01-48 COOH 4-Et-Phenyl CF 3 - CH 2 -CH 2 - 3-OMe-Phenyl Ethyl Me CH NN 0
1-49 COOH 4-F-Phenyl Ethyl - CH2-CH2- 3,4-Di-OMe-Phenyl OMe 0- CH2-CH2-C N N 0 t1-49 COOH 4-F-phenyl ethyl - CH 2 -CH 2 - 3,4-di-OMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0 t
1-50 COOH Phenyl Methyl - C(CH3)2-CH2- 3,4,5-Tri-OMe-Phenyl CF3 Me CH N N 01-50 COOH phenyl methyl - C (CH 3 ) 2 -CH 2 - 3,4,5-tri-OMe-phenyl CF 3 Me CH NN 0
1-51 COOH Phenyl Ethyl - CH2-CH2- 3-Me-4-Et-Phenyl OMe CF3 CH N N 01-51 COOH phenyl ethyl - CH 2 -CH 2 - 3-Me-4-Et-phenyl OMe CF 3 CH NN 0
1-52 COOH Phenyl Metliyl - CH2-CH2- 3-Me-4-Et-Phenyl OMe Me CH N N 01-52 COOH Phenyl Metliyl - CH 2 -CH 2 - 3-Me-4-Et-Phenyl OMe Me CH NN 0
1-53 COOH 4-F-Phenyl Methyl - CH2-CH2- 4-Br-Phenyl Me Me N N N 01-53 COOH 4-F-phenyl methyl - CH2-CH2- 4-Br-phenyl Me Me N N N 0
1-54 COOH 4-Cl-Phenyl Butyl - CH2-CH2- CH2- 4-OMe-Phenyl OMe Me CH N N 01-54 COOH 4-Cl-Phenyl Butyl - CH2-CH2-CH2- 4-OMe-Phenyl OMe Me CH N N 0
1-55 COOH 4-Cl-Phenyl Methyl - CH2-CH2- CH2- 4-OMe-Phenyl Me Me CH N N 01-55 COOH 4-Cl-Phenyl Methyl - CH 2 -CH 2 - CH 2 - 4-OMe-Phenyl Me Me CH NN 0
1-56 COOH Phenyl Methyl - CH2-CH2- 4-Br-Phαιyl Me Me N N CH 01-56 COOH phenyl methyl - CH 2 -CH 2 - 4-Br-Phαιyl Me Me NN CH 0
1-57 COOH Phenyl Methyl - CH2-CH2- 3-Br-Phenyl Ethyl Me CH N N s1-57 COOH phenyl methyl - CH 2 -CH 2 - 3-Br-phenyl ethyl Me CH NN s
1-58 COOH Phenyl CF3 - CH2-CH2- 2-Me-Phenyl OMe CH2-CH2-CH2-C N N 01-58 COOH Phenyl CF 3 - CH 2 -CH 2 - 2-Me-Phenyl OMe CH 2 -CH 2 -CH 2 -CNN 0
1-59 COOH Phenyl Ethyl - CH=CH- CH2- 4-Me-Phenyl OMe CH2- CH2-CH2-C N N 01-59 COOH phenyl ethyl - CH = CH- CH 2 - 4-Me-phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-60 COOH Phenyl Methyl - CH=CH- CH2- 4-Mc-Phenyl OMe 0- CH2-CH2-C N N 0 O1-60 COOH phenyl methyl - CH = CH- CH 2 - 4-Mc-phenyl OMe 0- CH 2 -CH 2 -CNN 0 O
HH
1-61 COOH 4-F-Phenyl Metliyl - CH2-CH2- 3-Me-Phenyl OMe 0- CH2-CH2-C N N 0 P.1-61 COOH 4-F-Phenyl Metliyl - CH 2 -CH 2 - 3-Me-Phenyl OMe 0- CH 2 -CH 2 -CNN 0 P.
• sβv vβ• sβv vβ
Kl o 00 Kl o 00
Nr. R1 R5 R4 Q R6 R2 R3 Z X Y WNo. R 1 R 5 R 4 Q R6 R 2 R 3 ZXYW
1-62 COOH Phenyl Methyl - CH2-CH2- 3-Me-4-SMe-Phenyl CF3 Me CH N N 01-62 COOH phenyl methyl - CH 2 -CH 2 - 3-Me-4-SMe-phenyl CF 3 Me CH NN 0
--
1-63 COOH 4-Et-Phenyl Ethyl - CH2-CH2- 3-OMe-Phenyl OMe Me CH N N 0 sO-- sβ1-63 COOH 4-Et-Phenyl Ethyl - CH 2 -CH 2 - 3-OMe-Phenyl OMe Me CH NN 0 sO-- sβ
0000
1-64 COOH 4-Et-Phenyl Methyl - CH2-CH2- 3-OMe-Phenyl Me Me CH N N 01-64 COOH 4-Et-Phenyl Methyl - CH 2 -CH 2 - 3-OMe-Phenyl Me Me CH NN 0
1-65 Tetrazol Phenyl Meüiyl - CH2-CH2- 4-SMe-Phenyl Me OMe CH N N 01-65 Tetrazole Phenyl Meüiyl - CH 2 -CH 2 - 4-SMe-Phenyl Me OMe CH NN 0
1-66 COOH 3-OMe-Phenyl Butyl - CH2-CH2- 4-SMe-Phenyl OMe Me CH N N 01-66 COOH 3-OMe-Phenyl Butyl - CH 2 -CH 2 - 4-SMe-Phenyl OMe Me CH NN 0
1-67 COOH Phenyl Methyl -0- CH2-CH2- 4-SMe-Phenyl Me Me CH N N 01-67 COOH phenyl methyl -0- CH 2 -CH 2 - 4-SMe-phenyl Me Me CH NN 0
1-68 COOH Phenyl Methyl - CH2-CH2- 4-ιι-Propoxy-Phenyl Me Me CH N N 01-68 COOH phenyl methyl - CH 2 -CH 2 - 4-ιι-propoxy-phenyl Me Me CH NN 0
1-69 COOH Phenyl Methyl - CH2-CH2- 4-n-Propoxy-Phenyl OMe Me CH N N 01-69 COOH phenyl methyl - CH 2 -CH 2 - 4-n-propoxy-phenyl OMe Me CH NN 0
1-70 COOH Phenyl CF3 - CH2-CH2- 4-n-Butoxy-Phenyl Me Me CH N N 01-70 COOH phenyl CF 3 - CH 2 -CH 2 - 4-n-butoxy-phenyl Me Me CH NN 0
1-71 COOH Phenyl Ethyl - CH2-CH2- 4-n-Butoxy-Phenyl OMe Me CH N N 01-71 COOH phenyl ethyl - CH 2 -CH 2 - 4-n-butoxy-phenyl OMe Me CH NN 0
1-72 COOH Phenyl Methyl -0- CH2-CH2- 4-SMe-Phenyl Me Me CH N CH 01-72 COOH phenyl methyl -0- CH 2 -CH 2 - 4-SMe-phenyl Me Me CH N CH 0
1-73 COOH Phenyl Meüiyl -0- CH2-CH2- l Me CH N N s tυ1-73 COOH Phenyl Meüiyl -0- CH 2 -CH 2 - l Me CH NN s tυ
4-SMe-Ph ιyl Ethy 004-SMe-Ph ιyl Ethy 00
1-74 COOH Phenyl Meüiyl - CH2-CH2- CH2- 2-Me-Phenyl Ethyl Me CH N N 01-74 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 2-Me-Phenyl Ethyl Me CH NN 0
1-75 COOH Phenyl Meüiyl — CH2— CH2— CH2— 2-Me-Phenyl OMe CH2- CH2-CH2-C N N 01-75 COOH Phenyl Meüiyl - CH 2 - CH 2 - CH2-2-Me-Phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-76 COOH Phenyl Methyl - CH2-CH2- 2-Me-4-SMe-Phenyl OMe CH2- CH2-CH2-C N N 01-76 COOH phenyl methyl - CH 2 -CH 2 - 2-Me-4-SMe-phenyl OMe CH2-CH2-CH2-C NN 0
1-77 COOH Phenyl Meüiyl - C(CH3)2-CH2- 4-SMe-Phenyl OMe 0- CH2-CH2-C N N 01-77 COOH Phenyl Meüiyl - C (CH 3 ) 2 -CH 2 - 4-SMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-78 COOMe Phenyl Meüiyl - CH2-CH2- 4-OEt-3-OMe-Phenyl CF3 Me CH N N 01-78 COOMe Phenyl Meüiyl - CH2-CH2- 4-OEt-3-OMe-Phenyl CF 3 Me CH NN 0
1-79 COOH Phenyl Meüiyl - CH=CH- CH2- 4-Me-Phenyl Me Me N N N 01-79 COOH Phenyl Meüiyl - CH = CH- CH 2 - 4-Me-Phenyl Me Me NNN 0
1-80 COOH Phenyl Methyl - CH=CH- CH2- 4-Me-Phenyl Ethyl Me CH N N 01-80 COOH phenyl methyl - CH = CH- CH 2 - 4-Me-phenyl ethyl Me CH NN 0
1-81 COOH Phenyl Meüiyl - CH2-CH2- 4-(Di-Me-Aιnino)-Phenyl OMe O- CH2-CH2-C N N 01-81 COOH Phenyl Meüiyl - CH 2 -CH 2 - 4- (Di-Me-Aιnino) -phenyl OMe O- CH2-CH 2 -CNN 0
1-82 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 4-OMe-Phenyl OMe Me CH N N 01-82 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - 4-OMe-Phenyl OMe Me CH NN 0
1-83 COOH 4-Et-Phenyl Meüiyl - CH2-CH2- 3,4-Di-OMe-Phenyl Ethyl Me CH N N 0 O1-83 COOH 4-Et-Phenyl Meüiyl - CH2-CH2- 3,4-Di-OMe-Phenyl Ethyl Me CH N N 0 O
HH
1-84 COOH 4-Et-Phenyl Meüiyl - CH2-CH2- 3,4-Di-OMe-Phenyl OMe 0- CH2-CH2-C N N 0 M s 1-84 COOH 4-Et-Phenyl Meüiyl - CH2-CH2- 3,4-Di-OMe-Phenyl OMe 0- CH 2 -CH2-C NN 0 M s
^ vβ o-.^ vβ o-.
K> oK> o
OS OS
Nr. R1 R5 R4 Q R6 R2 R3 Z X Y WNo. R 1 R5 R 4 Q R6 R 2 R 3 ZXYW
1-85 COOH 3-OMe-Phenyl Methyl - CH2-CH2- 4-OEt-3-OMe-Phenyl OMe Me CH N N O sβ SO1-85 COOH 3-OMe-Phenyl Methyl - CH 2 -CH 2 - 4-OEt-3-OMe-Phenyl OMe Me CH NNO sβ SO
1-86 COOH Phenyl Meüiyl -0- CH2-CH2- 4-OEt-3-OMe-Phenyl Me Me CH N N 0 *- sβ1-86 COOH Phenyl Meüiyl -0- CH 2 -CH 2 - 4-OEt-3-OMe-Phenyl Me Me CH NN 0 * - sβ
1-87 COOH Phenyl Methyl -S- CH2-CH2- 3-OMe-4-Cl-Phenyl Me Me CH N N 0 sβ1-87 COOH phenyl methyl -S- CH 2 -CH 2 - 3-OMe-4-Cl-phenyl Me Me CH NN 0 sβ
0000
1-88 COOH Phenyl Methyl - CH2-CH2- 3-OMe-4-Cl-Phenyl Ethyl Me CH N N 01-88 COOH phenyl methyl - CH 2 -CH 2 - 3-OMe-4-Cl-phenyl ethyl Me CH NN 0
1-89 COOH 3-Me-Phenyl Meüiyl - CH2-CH2- 3-OMe-4-Cl-Phenyl OMe CH2- CH2-CH2-C N N 01-89 COOH 3-Me-Phenyl Meüiyl - CH 2 -CH 2 - 3-OMe-4-Cl-Phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-90 COOH Phenyl Meüiyl - CH2-CH2- CH2- 2-Me-Phenyl Me Me CH N N 01-90 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 2-Me-Phenyl Me Me CH NN 0
1-91 COOH Phenyl Meüiyl - CH2-CH2- CH2- 2-Me-Phenyl Me Me N N N 01-91 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 2-Me-Phenyl Me Me NNN 0
1-92 COOH Phenyl Methyl - CH2-CH2- 4-OEt-3-OMe-Phenyl OMe O- CH2-CH2-C N N s1-92 COOH phenyl methyl - CH 2 -CH 2 - 4-OEt-3-OMe-phenyl OMe O-CH 2 -CH 2 -CNN s
1-93 COOMe Phenyl Butyl - CH2-CH2- 4-iPr-Phenyl CF3 Me CH N N 01-93 COOMe Phenyl Butyl - CH 2 -CH 2 - 4-iPr-Phenyl CF 3 Me CH NN 0
1-94 COOH 2-Me-Phenyl Meüiyl - CH2-CH2- 4-F-Phenyl OMe Me CH N N 01-94 COOH 2-Me-Phenyl Meüiyl - CH 2 -CH 2 - 4-F-Phenyl OMe Me CH NN 0
1-95 COOH Phenyl Meüiyl - CH=CH- CH2- 4-Me-Phenyl OMe Me CH N N 0 )1-95 COOH Phenyl Meüiyl - CH = CH- CH 2 - 4-Me-Phenyl OMe Me CH NN 0)
1-96 COOH Phenyl Meüiyl - CH=CH- CH2- 4-Me-Phenyl Me Me CH N N 0 so1-96 COOH Phenyl Meüiyl - CH = CH- CH 2 - 4-Me-Phenyl Me Me CH NN 0 see above
1-97 COOH 2-Me-Phenyl CF3 - CH2-CH2- 4-iPr-Phenyl Me Me CH N N 01-97 COOH 2-Me-Phenyl CF 3 - CH 2 -CH 2 - 4-iPr-Phenyl Me Me CH NN 0
1-98 COOH Phenyl Meüiyl -O- CH2-CH2- Phenyl Me Me N N N 01-98 COOH Phenyl Meüiyl -O- CH 2 -CH 2 - Phenyl Me Me NNN 0
1-99 COOH 4~Et-Phenyl Butyl - CH2-CH2- 3,4-Di-OMe-Phenyl Me Me CH N N 01-99 COOH 4 ~ Et-phenyl butyl - CH 2 -CH 2 - 3,4-di-OMe-phenyl Me Me CH NN 0
1-100 COOH 4-Et-Phenyl Methyl - CH2-CH2- 3 ,4-Di-OMc-Phenyl Me Me N N N 01-100 COOH 4-Et-Phenyl Methyl - CH 2 -CH 2 - 3, 4-Di-OMc-Phenyl Me Me NNN 0
I— 101 COOH Phenyl Meüiyl - CH2-CH2- 4-{Di-Me-Aιnino)-Plιenyl Me Me N N N 0I-101 COOH Phenyl Meüiyl - CH 2 -CH 2 - 4- {Di-Me-Aιnino) -Plιenyl Me Me NNN 0
1-102 COOH Phenyl Methyl - CH2-CH2- 4-(Di-Me-Aιnino)-Phenyl Ethyl Me CH N N 01-102 COOH Phenyl Methyl - CH 2 -CH 2 - 4- (Di-Me-Aιnino) -phenyl Ethyl Me CH NN 0
1-103 COOH 2-Me-Phenyl CF3 - CH2-CH2- 4-Cl-Phenyl Ethyl Me CH N N 01-103 COOH 2-Me-Phenyl CF 3 - CH 2 -CH 2 - 4-Cl-Phenyl Ethyl Me CH NN 0
1-104 COOH 4-F-Phenyl Meüiyl ~ CH2-CH2- 4-OMe-Phenyl OMe CH2- CH2-CH2-C N N 01-104 COOH 4-F-Phenyl Meüiyl ~ CH 2 -CH 2 - 4-OMe-Phenyl OMe CH2-CH 2 -CH2-C NN 0
1-105 COOH Phenyl Butyl - C(CH3)2-CH2- 3-Cl-Phenyl OMe O- CH2-CH2-C N N 01-105 COOH phenyl butyl - C (CH 3 ) 2 -CH 2 - 3-Cl-phenyl OMe O-CH2-CH 2 -CNN 0
1-106 COOH Phenyl Meüiyl - CH2-CH2- CH2- 2-Me-Phenyl CF3 Me CH N N 0 "0 o 1-107 COOH Phenyl Meüiyl - CH2-CH2- CH2- 2-Me-Phenyl OMe Me CH N N 0 H Ό so β ts- o 1-106 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 2-Me-Phenyl CF 3 Me CH NN 0 "0 o 1-107 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 2-Me-Phenyl OMe Me CH NN 0 H Ό so β ts- o
Nr. R1 R5 R4 Q R6 R2 R3 Z X Y WR 1 R5 R 4 QR 6 R 2 R 3 ZXYW
1-108 COOH Phenyl Methyl - CH2-CH2- 3 ,4-Methylendioxyphenyl Me Me N N CH 0 vβ ve1-108 COOH phenyl methyl - CH 2 -CH 2 - 3, 4-methylenedioxyphenyl Me Me NN CH 0 vβ ve
1-109 COOMe Phenyl Methyl - CH2-CH2- 3,4-Methylendioxyphenyl OMe Me CH N N O sβ1-109 COOMe phenyl methyl - CH 2 -CH 2 - 3,4-methylenedioxyphenyl OMe Me CH NNO sβ
1-110 COOH Phenyl Methyl - CH2-CH2- 3,4-Methylendioxyphenyl Me Me CH N N s sβ1-110 COOH phenyl methyl - CH 2 -CH 2 - 3,4-methylenedioxyphenyl Me Me CH NN s sβ
I— 111 COOH Phenyl Methyl - CH=CH- CH2- 4-iPr-Phenyl OMe O- CH2-CH2-C N N 0I- 111 COOH phenyl methyl - CH = CH- CH 2 - 4-iPr-phenyl OMe O- CH 2 -CH 2 -CNN 0
1-112 COOH Phenyl Butyl - CH=CH- CH2- 4-Me-Phenyl CF3 Me CH N N 01-112 COOH phenyl butyl - CH = CH- CH 2 - 4-Me-phenyl CF 3 Me CH NN 0
1-113 COOH Phenyl Meüiyl - CH2-CH2- 3,4-Di-Me-Phenyl Me Me CH N N 01-113 COOH Phenyl Meüiyl - CH 2 -CH 2 - 3,4-Di-Me-Phenyl Me Me CH NN 0
1-114 COOH Phenyl Meüiyl -0- CH2-CH2- 3,4-Di-Me-Phenyl Ethyl Me CH N N 01-114 COOH Phenyl Meüiyl -0- CH 2 -CH 2 - 3,4-Di-Me-Phenyl Ethyl Me CH NN 0
1-115 COOH 4-Et-Phenyl Meüiyl - CH2-CH2- 4-OMe-Phenyl OMe O- CH2-CH2-C N N 01-115 COOH 4-Et-Phenyl Meüiyl - CH 2 -CH 2 - 4-OMe-Phenyl OMe O-CH 2 -CH 2 -CNN 0
1-116 COOH 4-Et-Phenyl CF3 - CH2-CH2- 3 ,4-Di-OMe-Phenyl OMe Me CH N N 01-116 COOH 4-Et-Phenyl CF 3 - CH 2 -CH 2 - 3, 4-Di-OMe-Phenyl OMe Me CH NN 0
1-117 COOProp Phenyl Meüiyl - CH2-CH2- 3 ,4-Methylendioxyphenyl OMe CH2- CH2-CH2-C N N 01-117 COOProp Phenyl Meüiyl - CH 2 -CH 2 - 3, 4-Methylenedioxyphenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-118 COOH Phenyl Butyl - CH2-CH2- 3,4-Di-Me-Phenyl OMe O- CH2-CH2-C N N 0 ω1-118 COOH phenyl butyl - CH 2 -CH 2 - 3,4-di-Me-phenyl OMe O-CH 2 -CH 2 -CNN 0 ω
1-119 COOH Phenyl Meüiyl - CH2-CH2- 4-(Di-Me-Amino)-Phenyl OMe Me CH N N 0 o1-119 COOH Phenyl Meüiyl - CH 2 -CH 2 - 4- (Di-Me-Amino) -phenyl OMe Me CH NN 0 o
1-120 COOH Phenyl Meüiyl - CH2-CH2- 4-(Di-Me-Anιino)-Phenyl Me Me CH N N 01-120 COOH Phenyl Meüiyl - CH 2 -CH 2 - 4- (Di-Me-Anιino) -phenyl Me Me CH NN 0
1-121 COOH 4-F-Phenyl Methyl - CH2-CH2- 4-Me-Phenyl CF3 Me CH N N 01-121 COOH 4-F-phenyl methyl - CH 2 -CH 2 - 4-Me-phenyl CF 3 Me CH NN 0
1-122 COOH Phenyl CF3 - CH2-CH2- CH2- 3-OMe-Phenyl Ethyl Me CH N N 01-122 COOH Phenyl CF 3 - CH 2 -CH 2 - CH 2 - 3-OMe-Phenyl Ethyl Me CH NN 0
1-123 COOH Phenyl Meüiyl — CH2-CH2— CH2- 3-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-123 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 3-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-124 COOH Phenyl Butyl -S- CH2-CH2- 4-Me-Phenyl OMe Me CH N N 01-124 COOH phenyl butyl -S- CH 2 -CH 2 - 4-Me-phenyl OMe Me CH NN 0
1-125 COOH Phenyl Meüiyl - CH(OH)-CH2- 4-Me-Phenyl Me Me CH N N 01-125 COOH Phenyl Meüiyl - CH (OH) -CH 2 - 4-Me-Phenyl Me Me CH NN 0
1-126 COOH Phenyl Meüiyl - CH2-CH2- 3-OMe-4-Me-Phenyl Me Me CH N N 01-126 COOH Phenyl Meüiyl - CH 2 -CH 2 - 3-OMe-4-Me-Phenyl Me Me CH NN 0
1-127 COOH Phenyl Methyl - CH=CH- CH2- 4-iPr-Phenyl Ethyl Me CH N N 01-127 COOH Phenyl Methyl - CH = CH- CH 2 - 4-iPr-Phenyl Ethyl Me CH NN 0
1-128 COOH Phenyl CF3 - CH=CH- CH2- 4-iPr-Phenyl OMe Me CH N N 01-128 COOH Phenyl CF 3 - CH = CH- CH 2 - 4-iPr-Phenyl OMe Me CH NN 0
1-129 COOH Phenyl Meüiyl - CH2-CH2- 4-Me-Phenyl Ethyl Me N N CH 0 *0 o 1-130 COOH Phenyl Butyl - CH2-CH2- 3-OMe-4-Me-Phenyl OMe CH2- CH2-CH2-C N N 0 sβ vβ ts- o1-129 COOH Phenyl Meüiyl - CH 2 -CH 2 - 4-Me-Phenyl Ethyl Me NN CH 0 * 0 o 1-130 COOH phenyl butyl - CH 2 -CH 2 - 3-OMe-4-Me-phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0 sβ vβ ts- o
00 00
Nr. R1 R5 R4 Q R6 R2 R3 Z X Y WR 1 R5 R 4 QR 6 R 2 R 3 ZXYW
1-131 COOH 4-Et-Phenyl Methyl - CH2-CH2- 4-OMe-Phenyl Me Me N N N 0 sβ s©1-131 COOH 4-Et-Phenyl Methyl - CH 2 -CH 2 - 4-OMe-Phenyl Me Me NNN 0 sβ s ©
1-132 COOH 4-Et-Phenyl Meüiyl - CH2-CH2- 4-OMe-Phenyl Ethyl Me CH N N 0 sβ sβ1-132 COOH 4-Et-Phenyl Meüiyl - CH 2 -CH 2 - 4-OMe-Phenyl Ethyl Me CH NN 0 sβ sβ
1-133 COOH Phenyl Meüiyl - CH2-CH2- 4-Me-Phenyl OMe 0- CH2-CH2-C N N s1-133 COOH Phenyl Meüiyl - CH 2 -CH 2 - 4-Me-Phenyl OMe 0- CH 2 -CH 2 -CNN s
1-134 COOButyl Phenyl CF3 - CH2-CH2- 4-Et-Phenyl CF3 Me CH N N 01-134 COOButyl Phenyl CF 3 - CH 2 -CH 2 - 4-Et-Phenyl CF 3 Me CH NN 0
1-135 COOH 4-I-Phenyl Meüiyl - CH2-CH2- 4-Et-Phenyl OMe Me CH N N 01-135 COOH 4-I-Phenyl Meüiyl - CH 2 -CH 2 - 4-Et-Phenyl OMe Me CH NN 0
1-136 COOH Phenyl Butyl - CH(OH)-CH2- 4-Et-Phenyl Me Me CH N N 01-136 COOH Phenyl Butyl - CH (OH) -CH 2 - 4-Et-Phenyl Me Me CH NN 0
1-137 COOH Phenyl Methyl - CH2-CH2- 2-OMe-Phenyl OMe CH2- CH2-CH2-C N N 01-137 COOH phenyl methyl - CH 2 -CH 2 - 2-OMe-phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-138 COOH Phenyl Methyl — CH2""~Cr--2 — CH.2" 3-OMe-Phenyl Me Me CH N N 01-138 COOH phenyl methyl - CH 2 "" ~ Cr-- 2 - CH. 2 "3-OMe-Phenyl Me Me CH NN 0
1-139 COOH Phenyl Meüiyl - CH2-CH2- CH2- 3-OMe-Phenyl Me Me N N N 01-139 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 3-OMe-Phenyl Me Me NNN 0
1-140 COOH Phenyl CF3 - CH2-CH2- 2-OMe-Phenyl OMe O- CH2-CH2-C N N 01-140 COOH Phenyl CF 3 - CH 2 -CH 2 - 2-OMe-Phenyl OMe O-CH2-CH2-C NN 0
1-141 COOH Phenyl Methyl - CH2-CH2- 3-OMe-4-Et-Phenyl Me Me N N N 0 ω1-141 COOH phenyl methyl - CH 2 -CH 2 - 3-OMe-4-Et-phenyl Me Me NNN 0 ω
1-142 COOH Phenyl Butyl - CH2-CH2- 4-Et-Phenyl Ethyl Me N N N 0 H1-142 COOH Phenyl Butyl - CH 2 -CH 2 - 4-Et-Phenyl Ethyl Me NNN 0 H
1-143 COOH Phenyl Meüiyl - CH=CH- CH2- 4-Cl-Phenyl Ethyl Me CH N N 01-143 COOH Phenyl Meüiyl - CH = CH- CH 2 - 4-Cl-Phenyl Ethyl Me CH NN 0
1-144 COOH Phenyl Meüiyl - CH=CH- CH2- 4-Cl-Phenyl OMe CH2- CH2-CH2-C N N 01-144 COOH Phenyl Meüiyl - CH = CH- CH 2 - 4-Cl-Phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-145 COOH Phenyl Meüiyl - CH2-CH2- 4-OEt-3-OMe-Phenyl OMe Me CH N N 01-145 COOH Phenyl Meüiyl - CH 2 -CH 2 - 4-OEt-3-OMe-Phenyl OMe Me CH NN 0
1-146 COOH Phenyl CF3 - CH2-CH2- 4-OEt-3-OMe-Phenyl Me Me CH N N 01-146 COOH Phenyl CF 3 - CH 2 -CH 2 - 4-OEt-3-OMe-Phenyl Me Me CH NN 0
1-147 COOH 4-Et-Phenyl Butyl - CH2-CH2- 4-OMe-Phenyl OMe Me CH N N 01-147 COOH 4-Et-Phenyl Butyl - CH 2 -CH 2 - 4-OMe-Phenyl OMe Me CH NN 0
1-148 COOH 4-Et-Phenyl Methyl - CH2-CH2- 4-OMe-Phenyl Me Me CH N N 01-148 COOH 4-Et-Phenyl Methyl - CH 2 -CH 2 - 4-OMe-Phenyl Me Me CH NN 0
1-149 COOH Phenyl Methyl - CH2-CH2- 3-OMe-4-Et-Phenyl OMe 0- CH=CH-C N N 01-149 COOH phenyl methyl - CH 2 -CH 2 - 3-OMe-4-Et-phenyl OMe 0- CH = CH-C NN 0
1-150 COOH Phenyl Methyl - CH2-CH2- 3-OMe-4-Et-Phenyl OMe O- CH2-CH2-C N N 01-150 COOH phenyl methyl - CH 2 -CH 2 - 3-OMe-4-Et-phenyl OMe O-CH 2 -CH 2 -CNN 0
1-151 COOH 4—Me-Phenyl Meüiyl - CH2-CH2- Cyclohexyl CF3 Me CH N N 01-151 COOH 4-Me-Phenyl Meüiyl - CH 2 -CH 2 - Cyclohexyl CF 3 Me CH NN 0
1-152 COOH Phenyl Meüiyl - CH2-CH2- Cyclohexyl OMe EÜiyl CH N N 0 n1-152 COOH Phenyl Meüiyl - CH 2 -CH 2 - Cyclohexyl OMe EÜiyl CH NN 0 n
H 1-153 COOMe Phenyl Meüiyl - CH2-CH2- Cyclohexyl OMe Me CH N N 0 wH 1-153 COOMe Phenyl Meüiyl - CH 2 -CH 2 - Cyclohexyl OMe Me CH NN 0 w
-0 sβ vβ-0 sβ vβ
© l o 00 © lo 00
Nr. R1 R5 R4 Q R6 R2 R3 Z X Y WNo. R 1 R 5 R 4 QR 6 R 2 R 3 ZXYW
1-154 COOH Phenyl CF3 — CH2-CH2- CH2— 3-OMe-Phenyl CF3 Me CH N N 0 v© sO1-154 COOH Phenyl CF 3 - CH 2 -CH 2 - CH 2 - 3-OMe-Phenyl CF 3 Me CH NN 0 v © sO
1-155 -≥1-155 -≥
COOH Phenyl Butyl - CH2-CH2- CH2- 3-OMe-Phenyl OMe Me CH N N 0COOH phenyl butyl - CH 2 -CH 2 - CH 2 - 3-OMe-phenyl OMe Me CH NN 0
1-156 COOH Phenyl Methyl - CH2-CH2- Cyclohexyl Me Me CH N CH 01-156 COOH phenyl methyl - CH 2 -CH 2 - cyclohexyl Me Me CH N CH 0
1-157 COOH Phenyl Methyl - CH2-CH2- Cyclohexyl Me Me N N CH 01-157 COOH phenyl methyl - CH 2 -CH 2 - cyclohexyl Me Me NN CH 0
1-158 COOH 4-Cl-Phenyl Methyl - CH2-CH2- Cyclohexyl Ethyl Me CH N N 01-158 COOH 4-Cl-Phenyl Methyl - CH 2 -CH 2 - Cyclohexyl Ethyl Me CH NN 0
1-159 COOH Phenyl Meüiyl - CH=CH- CH2- 4-Cl-Phenyl Me Me CH N N 01-159 COOH Phenyl Meüiyl - CH = CH- CH 2 - 4-Cl-Phenyl Me Me CH NN 0
1-160 COOH Phenyl Methyl - CH=CH- CH2- 4-Cl-Phenyl Me Me N N N 01-160 COOH phenyl methyl - CH = CH- CH 2 - 4-Cl-phenyl Me Me NNN 0
1-161 COOH Phenyl Meüiyl — G-C12- Cr 2~ 2-OMe-Phenyl Me Me N N N 01-161 COOH Phenyl Meüiyl - G-C12-Cr 2 ~ 2-OMe-Phenyl Me Me N N N 0
1-162 COOH Phenyl CF3 - CH2-CH2- 2-OMe-Phenyl Ethyl Me CH N N 01-162 COOH Phenyl CF 3 - CH 2 -CH 2 - 2-OMe-Phenyl Ethyl Me CH NN 0
1-163 COOH 4-Cl-Phenyl Methyl - CH2-CH2- 2-OMe-Phenyl Ethyl Me CH N N 01-163 COOH 4-Cl-Phenyl Methyl - CH 2 -CH 2 - 2-OMe-Phenyl Ethyl Me CH NN 0
1-164 COOH 4-Cl-Phenyl Methyl - CH2-CH2- 2-OMe-Phenyl OMe 0- CH2-CH2-C N N 0 u>1-164 COOH 4-Cl-Phenyl Methyl - CH 2 -CH 2 - 2-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0 u>
1-165 COOH 4-Et-Phenyl Methyl - CH2-CH2- Cyclohexyl OMe CH2- CH2-CH2-C N N 01-165 COOH 4-Et-Phenyl Methyl - CH 2 -CH 2 - Cyclohexyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-166 COOH Phenyl Methyl - CH2-CH2- Cyclohexyl OMe 0- CH2-CH2-C N N s1-166 COOH phenyl methyl - CH 2 -CH 2 - cyclohexyl OMe 0- CH 2 -CH 2 -CNN s
1-167 COOH Phenyl Meüiyl - CH2-CH2- 4-SMe-Phenyl OMe 0- CH2-CH2-C N N 01-167 COOH Phenyl Meüiyl - CH 2 -CH 2 - 4-SMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-168 COOH Phenyl Methyl - CH2-CH2- 4-OEt-3-OMe-Phenyl CF3 Me CH N N 01-168 COOH phenyl methyl - CH 2 -CH 2 - 4-OEt-3-OMe-phenyl CF 3 Me CH NN 0
1-169 COOH Plicnyl CF3 - CH2-CH2- 3-Me-4-Cl-Phenyl CF3 Me CH N N 01-169 COOH Plicnyl CF 3 - CH 2 -CH 2 - 3-Me-4-Cl-Phenyl CF 3 Me CH NN 0
1-170 COOH Phenyl Meüiyl - CH2-CH2- CH2- 4-OEt-Phenyl Ethyl Me CH N N 01-170 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-OEt-Phenyl Ethyl Me CH NN 0
1-171 COOH Phenyl Meüiyl - CH2-CH2- CH2- 4-OEl-Phenyl OMe CH2- CH2-CH2-C N N 01-171 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-OEl-Phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-172 COOH Phenyl Meüiyl - CH2-CH2- 4-Cl-Phenyl OMe Me CH N N s1-172 COOH Phenyl Meüiyl - CH 2 -CH 2 - 4-Cl-Phenyl OMe Me CH NN s
1-173 COOH 3-Me-Phenyl Meüiyl - CH2-CH2- 4-Cl-Phenyl Me Me CH N N 01-173 COOH 3-Me-Phenyl Meüiyl - CH 2 -CH 2 - 4-Cl-Phenyl Me Me CH NN 0
1-174 COOH Phenyl Meüiyl -0- CH2-CH2- 4-Cl-Phenyl Ethyl Me N N N 01-174 COOH Phenyl Meüiyl -0- CH 2 -CH 2 - 4-Cl-Phenyl Ethyl Me NNN 0
1-175 COOH Phenyl Meüiyl - CH=CH- CH2- 4-Cl-Phenyl CF3 Me CH N N 0 O 1-176 COOH Phenyl CF3 - CH=CH- CH2- 4-Cl-Phenyl OMe Me CH N N 0 s© s© o 00 1-175 COOH Phenyl Meüiyl - CH = CH- CH 2 - 4-Cl-Phenyl CF 3 Me CH NN 0 O 1-176 COOH Phenyl CF 3 - CH = CH- CH 2 - 4-Cl-Phenyl OMe Me CH NN 0 s © s © o 00
Nr. R1 R5 R4 Q R6 R2 R3 Z X Y WNo. R 1 R 5 R 4 QR 6 R 2 R 3 ZXYW
1-177 COOH Phenyl Propyl - CH2-CH2- 2-Me-4-Cl-Phenyl SMe Me CH N N 0 so1-177 COOH phenyl propyl - CH 2 -CH 2 - 2-Me-4-Cl-phenyl SMe Me CH NN 0 see above
1-178 COOH Phenyl Meüiyl - CH2-CH2- Cyclohexyl OMe CH2- CH2-CH2-C N N 01-178 COOH Phenyl Meüiyl - CH 2 -CH 2 - Cyclohexyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-179 COOH 4- CF3-Phenyl Meüiyl - CH2-CH2- 3-OMc-Phenyl Me Me CH N N 01-179 COOH 4- CF 3 -phenyl Meüiyl - CH 2 -CH 2 - 3-OMc-Phenyl Me Me CH NN 0
1-180 COOH 4- CF3-Phenyl Meüiyl - CH2-CH2- 3-OMe-Phenyl Me Me N N N 01-180 COOH 4- CF 3 -phenyl Meüiyl - CH 2 -CH 2 - 3-OMe-Phenyl Me Me NNN 0
1-181 COOH Phenyl Meüiyl - CH2-CH2- Cyclohexyl OMe 0- CH2-CH2-C N N 01-181 COOH Phenyl Meüiyl - CH 2 -CH 2 - Cyclohexyl OMe 0- CH 2 -CH 2 -CNN 0
1-182 COOBzl Phenyl Meüiyl - CH2-CH2- 4-Cl-Phenyl OMe CH2- CH2-CH2-C N N 01-182 COOBzl Phenyl Meüiyl - CH 2 -CH 2 - 4-Cl-Phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-183 COOH Phenyl Meüiyl - CH2-CH2- 2-Me-4-Cl-Phenyl OMe 0- CH2-CH2-C N N 01-183 COOH Phenyl Meüiyl - CH 2 -CH 2 - 2-Me-4-Cl-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-184 COOH Phenyl Methyl - CH(OH)-CH2- Naphth-2-yl CF3 Me CH N N 01-184 COOH phenyl methyl - CH (OH) -CH 2 - naphth-2-yl CF3 Me CH NN 0
1-185 COOH Phenyl Meüiyl - CH2-CH2- 2-OMe-Phenyl OMe Me CH N N 01-185 COOH Phenyl Meüiyl - CH 2 -CH 2 - 2-OMe-Phenyl OMe Me CH NN 0
1-186 COOH Phenyl Meüiyl - CH2-CH2- CH2- 4-OEt-Phenyl Me Me CH N N 01-186 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-OEt-Phenyl Me Me CH NN 0
1-187 COOH Phenyl -CH2-CH2-CF3 - CH2-CH2- CH2- 4-OEt-Phenyl Me Me N N N 0 ω1-187 COOH phenyl -CH 2 -CH 2 -CF 3 - CH 2 -CH 2 - CH 2 - 4-OEt-phenyl Me Me NNN 0 ω
1-188 COOH Phenyl Methyl - CH2-CH2- 2-OMe-Phenyl Me Me CH N N 0 ω1-188 COOH phenyl methyl - CH 2 -CH 2 - 2-OMe-phenyl Me Me CH NN 0 ω
1-189 COOH 2-Me-Phenyl Meüiyl - CH2-CH2- NaphÜι-2-yl OMe Me CH N N 01-189 COOH 2-Me-Phenyl Meüiyl - CH2-CH2-NaphÜι-2-yl OMe Me CH N N 0
1-190 COOH Phenyl Meüiyl - CH2-CH2- Naphth-2-yl Me Me CH N N s1-190 COOH Phenyl Meüiyl - CH 2 -CH 2 - Naphth-2-yl Me Me CH NN s
1-191 COOH Phenyl Methyl - CH=CH- CH2- 4-Cl-Phenyl OMe 0- CH2-CH2-C N N 01-191 COOH phenyl methyl - CH = CH- CH 2 - 4-Cl-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-192 COOH Phenyl Meüiyl - CH=CH- CH2- 4-iPr-Phenyl Me Me CH N N 01-192 COOH Phenyl Meüiyl - CH = CH- CH 2 - 4-iPr-Phenyl Me Me CH NN 0
1-193 COOH Phenyl -CH2-CH2-CF3 - CH2-CH2- 4-SMe-Phenyl Ethyl Me CH N N 01-193 COOH phenyl -CH 2 -CH 2 -CF 3 - CH 2 -CH 2 - 4-SMe-phenyl ethyl Me CH NN 0
1-194 COOH Phenyl Meüiyl - CH2-CH2- 4-SMe-Phenyl OMe CH2- CH2-CH2-C N N 01-194 COOH Phenyl Meüiyl - CH 2 -CH 2 - 4-SMe-Phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-195 COOH 4-CF3-Phenyl Meüiyl - CH2-CH2- 3,4-Di-OMe-Phenyl OMe O- CH2-CH2-C N N 01-195 COOH 4-CF 3 -phenyl Meüiyl - CH 2 -CH 2 - 3,4-Di-OMe-Phenyl OMe O-CH2-CH2-C NN 0
1-196 COOH 4-CF3-Phenyl Methyl - CH2-CH2- 3-OMe-Phenyl OMe Me CH N N 01-196 COOH 4-CF 3 -phenyl methyl - CH 2 -CH 2 - 3-OMe-Phenyl OMe Me CH NN 0
1-197 COOH Phenyl Methyl - CH2-CH2- Naphth-2-yl Me Me N N CH 01-197 COOH phenyl methyl - CH 2 -CH 2 - naphth-2-yl Me Me NN CH 0
1-198 COOH Phenyl CF3 - CH2-CH2- l-Me-Naphth-2-yl Ethyl Me CH N N 0 o 131-198 COOH Phenyl CF 3 - CH 2 -CH 2 - l-Me-Naphth-2-yl Ethyl Me CH NN 0 o 13
1-199 COOH Phenyl Propyl - CH2-CH2- l-Me-Naphth-2-yl OMe CH2- CH2-CH2-C N N 0 Pi "Ö sβ1-199 COOH Phenyl propyl - CH 2 -CH 2 - l-Me-Naphth-2-yl OMe CH2-CH 2 -CH2-C NN 0 Pi "Ö sβ
;β o ts. o 00 ; β o ts. o 00
Nr. R1 R5 R4 Q R6 R2 R3 Z X YNo. R 1 R 5 R 4 QR 6 R 2 R 3 ZXY
1-200 COOMe Phenyl sβ1-200 COOMe phenyl s β
Meüiyl - CH2-CH2- Naphth-2-yl OMe 0- CH2-CH2-C N N O βMeüiyl - CH 2 -CH 2 - naphth-2-yl OMe 0-CH 2 -CH 2 -CNNO β
1-201 COOEt Phenyl Meüiyl - CH2-CH2- 4-OEt-Phenyl CF3 Me CH N N 0 \ s©o1-201 COOEt Phenyl Meüiyl - CH 2 -CH 2 - 4-OEt-Phenyl CF 3 Me CH NN 0 \ s © o
1-202 COOH Phenyl Meüiyl - CH2-CH2- CH2- 4-OEt-Phenyl CF3 Me CH N N 01-202 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-OEt-Phenyl CF 3 Me CH NN 0
1-203 COOH Phenyl Meüiyl - CH2-CH2- CH2- 4-OEt-Phenyl OMe Me CH N N 01-203 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-OEt-Phenyl OMe Me CH NN 0
1-204 COOH Phenyl Methyl - CH2-CH2- Cyclohexyl Me Me N N N 01-204 COOH phenyl methyl - CH 2 -CH 2 - cyclohexyl Me Me NNN 0
1-205 COOH Phenyl Meüiyl - CH2-CH2- Cyclohexyl Ethyl Me CH N N 01-205 COOH Phenyl Meüiyl - CH 2 -CH 2 - Cyclohexyl Ethyl Me CH NN 0
1-206 Tetra zol Phenyl -CH2-CH2-CF3 - CH2-CH2- 4-OEt-Phenyl OMe Me CH N N 01-206 tetra zene phenyl -CH 2 -CH 2 -CF 3 - CH 2 -CH 2 - 4-OEt-phenyl OMe Me CH NN 0
1-207 COOH Phenyl Meüiyl - CH=CH- CH2- 3,4-Di-OMe-Phenyl Ethyl Me CH N N 01-207 COOH Phenyl Meüiyl - CH = CH- CH 2 - 3,4-Di-OMe-Phenyl Ethyl Me CH NN 0
1-208 COOH Phenyl Methyl - CH=CH- CH2- 3,4-Di-OMe-Phenyl OMe O- CH2-CH2-C N N 01-208 COOH phenyl methyl - CH = CH- CH 2 - 3,4-di-OMe-phenyl OMe O-CH 2 -CH 2 -CNN 0
1-209 COOH Phenyl Meüiyl - CH2-CH2- 4-OH-Phenyl Me Me CH N N 01-209 COOH Phenyl Meüiyl - CH 2 -CH 2 - 4-OH-Phenyl Me Me CH NN 0
1-210 COOH Phenyl Methyl - CH2-CH2- 4-OH-Phenyl Ethyl Me N N CH 01-210 COOH phenyl methyl - CH 2 -CH 2 - 4-OH-phenyl ethyl Me NN CH 0
1-211 COOH 4-CF3-Phenyl CF3 - CH2-CH2- 3,4-Di-OMc-Phenyl Me Me N N N 01-211 COOH 4-CF 3 -phenyl CF 3 - CH 2 -CH 2 - 3,4-di-OMc-phenyl Me Me NNN 0
1-212 COOH 4-CF3-Phenyl Propyl - CH2-CH2- 3,4-Di-OMe-Phenyl Ethyl Me CH N N 01-212 COOH 4-CF 3 -phenyl propyl - CH2-CH 2 - 3,4-di-OMe-phenyl ethyl Me CH NN 0
1-213 COOH Phenyl Butyl - CH2-CH2- 3-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-213 COOH phenyl butyl - CH 2 -CH 2 - 3-OMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-214 COOH Phenyl CH2-0-CH2-C - CH2-CH2- 2-OMe-Phαιyl CF3 Me CH N N 0 H3 1-214 COOH phenyl CH 2 -0-CH 2 -C - CH 2 -CH 2 - 2-OMe-Phαιyl CF 3 Me CH NN 0 H 3
1-215 COOH Phenyl Meüiyl - CH2-CH2- 4-OEt-Phenyl EÜiyl Me CH N N s1-215 COOH Phenyl Meüiyl - CH 2 -CH 2 - 4-OEt-Phenyl EÜiyl Me CH NN s
1-216 COOH Phenyl Methyl - C(CH3)2-CH2- 4-OEt-Phenyl OMe CH2- CH2-CH2-C N N 01-216 COOH phenyl methyl - C (CH 3 ) 2 -CH 2 - 4-OEt-phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-217 COOH Phenyl -CH2-CH2-CF3 - CH2-CH2- 4-SMe-Phenyl Me Me CH N N 01-217 COOH phenyl -CH 2 -CH 2 -CF 3 - CH 2 -CH 2 - 4-SMe-phenyl Me Me CH NN 0
1-218 COOH Phenyl Meüiyl - CH2-CH2- CH2- 4-Cl-Phenyl OMe CH2- CH2-CH2-C N N 01-218 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-Cl-Phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-219 COOH Phenyl Meüiyl - CH2-CH2- CH2- 4-Cl-Phenyl OMe O- CH2-CH2-C N N 01-219 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-Cl-Phenyl OMe O- CH 2 -CH 2 -CNN 0
1-220 COOH Phenyl Meüiyl - CH2-CH2- 4-SMe-Phenyl Me Me N N N 0 n1-220 COOH Phenyl Meüiyl - CH 2 -CH 2 - 4-SMe-Phenyl Me Me NNN 0 n
1-221 COOH Phenyl Meüiyl - O-CH2-CH2- 4-OEt-Phenyl OMe O- CH2-CH2-C N N 0 ä s© s© o 1-221 COOH Phenyl Meüiyl - O-CH 2 -CH 2 - 4-OEt-Phenyl OMe O- CH 2 -CH 2 -CNN 0 ä s © s © o
Nr. R1 R5 R4 Q R6 R2 R3 Z X Y WNo. R 1 R 5 R 4 QR 6 R 2 R 3 ZXYW
1-222 COOH 4-Br-Phenyl CF3 - CH2-CH2- 3 , 5-Di-OMe-Phenyl CF3 Me N N CH 01-222 COOH 4-Br-Phenyl CF 3 - CH 2 -CH 2 - 3, 5-Di-OMe-Phenyl CF 3 Me NN CH 0
1-223 COOH Phenyl Methyl - CH=CH- CH2- 3 ,4-Di-OMe-Phenyl Me Me CH N N 01-223 COOH Phenyl Methyl - CH = CH- CH 2 - 3, 4-Di-OMe-Phenyl Me Me CH NN 0
1-224 COOH Phenyl Methyl - CH=CH- CH2- 3,4-Di-OMe-Phenyl Me Me N N N 01-224 COOH phenyl methyl - CH = CH- CH 2 - 3,4-di-OMe-phenyl Me Me NNN 0
1-225 COOH 4-I-Phenyl Methyl - CH2-CH2- 3,5-Di-OMe-Phenyl OMe Me CH N N 01-225 COOH 4-I-phenyl methyl - CH 2 -CH 2 - 3,5-di-OMe-phenyl OMe Me CH NN 0
1-226 COOH Phenyl Methyl - CH2-CH2- 3,5-Di-OMe-Phenyl Me Me CH N CH 01-226 COOH phenyl methyl - CH 2 -CH 2 - 3,5-di-OMe-phenyl Me Me CH N CH 0
1-227 COOH 4-CF3-Phenyl Meüiyl - CH2-CH2- 3,4-Di-OMe-Phenyl OMe Me CH N N 01-227 COOH 4-CF 3 -phenyl Meüiyl - CH 2 -CH 2 - 3,4-Di-OMe-Phenyl OMe Me CH NN 0
1-228 COOH 4-CF3-Phenyl Meüiyl - CH2-CH2- 3,4-Di-OMe-Phenyl Me Me CH N N 01-228 COOH 4-CF 3 -phenyl Meüiyl - CH 2 -CH 2 - 3,4-Di-OMe-Phenyl Me Me CH NN 0
1-229 COOH Phenyl Methyl - CH2-CH2- 3,5-Di-OMe-Phenyl Ethyl Me N N N 01-229 COOH Phenyl Methyl - CH 2 -CH 2 - 3,5-Di-OMe-Phenyl Ethyl Me NNN 0
1-230 COOH Phenyl Methyl - CH2-CH2- Cyclohexyl OMe Me CH N N 01-230 COOH phenyl methyl - CH 2 -CH 2 - cyclohexyl OMe Me CH NN 0
1-231 COOH Phenyl CH2-0-CH2-1-231 COOH phenyl CH 2 -0-CH 2 -
- CH -CH2- Cyclohexyl Me Me CH N N 0 CH3 - CH -CH 2 - cyclohexyl Me Me CH NN 0 CH 3
1-232 COOH Phaiyl Meüiyl - CH(OH)-CH2- 3,5-Di~OMc-Phenyl Ethyl Me CH N N 0 ω 1/11-232 COOH Phaiyl Meüiyl - CH (OH) -CH 2 - 3,5-Di ~ OMc-Phenyl Ethyl Me CH NN 0 ω 1/1
1-233 COOH Phenyl Meüiyl - CH2-CH2- 3,5-Di-OMe-4-Cl-Phenyl OMe CH2- CH2-CH2-C N N 01-233 COOH Phenyl Meüiyl - CH 2 -CH 2 - 3,5-Di-OMe-4-Cl-Phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-234 COOH Phenyl Meüiyl - CH2-CH2- CH2- 4-Cl-Phenyl Me Me N N N 01-234 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-Cl-Phenyl Me Me NNN 0
1-235 COOH Phenyl Methyl - CH2-CH2- CH2- 4-Cl-Phenyl Ethyl Me CH N N 01-235 COOH phenyl methyl - CH 2 -CH 2 - CH 2 - 4-Cl-phenyl ethyl Me CH NN 0
1-236 COOMe Phenyl Methyl - CH2-CH2- 3,5-Di-OMe-Phenyl OMe O- CH2-CH2-C N N 01-236 COOMe phenyl methyl - CH 2 -CH 2 - 3,5-di-OMe-phenyl OMe O-CH 2 -CH 2 -CNN 0
1-237 COOH Phenyl Meüiyl - CH2-CH2- 3-OMe-Phenyl Ethyl Me CH N N 01-237 COOH Phenyl Meüiyl - CH 2 -CH 2 - 3-OMe-Phenyl Ethyl Me CH NN 0
1-238 COOH Phenyl Methyl - CH2-CH2- 3-OMe-Phenyl OMe CH2- CH2-CH2-C N N 01-238 COOH phenyl methyl - CH 2 -CH 2 - 3-OMe-phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-239 COOH Phenyl Methyl - CH=CH- CH2- 3,4-Di-OMe-Phenyl CF3 Me CH N N 01-239 COOH phenyl methyl - CH = CH- CH 2 - 3,4-di-OMe-phenyl CF 3 Me CH NN 0
1-240 COOH Phenyl Methyl - CH=CH- CH2- 3,4-Di-OMe-Phenyl OMe Me CH N N 01-240 COOH phenyl methyl - CH = CH- CH 2 - 3,4-di-OMe-phenyl OMe Me CH NN 0
1-241 COOH Phenyl Meüiyl - CH2-CH2- 2-Me-3-OMe-Phenyl CF3 Me CH N N 01-241 COOH Phenyl Meüiyl - CH 2 -CH 2 - 2-Me-3-OMe-Phenyl CF 3 Me CH NN 0
1-242 COOH Phenyl CH2-0-CH2-1-242 COOH phenyl CH 2 -0-CH 2 -
- CH2-CH2- 3-OMe-Phenyl OMe Me N N N 0 CH3 n H- CH 2 -CH 2 - 3-OMe-Phenyl OMe Me NNN 0 CH 3 n H
M -0 so v©M -0 so v ©
Kl oLoo
00 00
Nr. R1 R5 R4 Q R6 R2 R3 Z X Y WNo. R 1 R5 R 4 Q R6 R 2 R 3 ZXYW
1-243 COOH 4-CF3-Phenyl Meüiyl - CH2-CH2- 4-OMe-Phenyl Ethyl Me CH N N 0 sβ1-243 COOH 4-CF 3 -phenyl Meüiyl - CH 2 -CH 2 - 4-OMe-Phenyl Ethyl Me CH NN 0 sβ
1-244 COOH 4-CF3-Phenyl Meüiyl - CH2-CH2- 4-OMe-Phenyl OMe O- CH2-CH2-C N N 01-244 COOH 4-CF 3 -phenyl Meüiyl - CH 2 -CH 2 - 4-OMe-Phenyl OMe O-CH 2 -CH 2 -CNN 0
1-245 COOH Phenyl Meüiyl - CH2-CH2- 4-SMe-Phenyl OMe OMe CH N N 01-245 COOH Phenyl Meüiyl - CH 2 -CH 2 - 4-SMe-Phenyl OMe OMe CH NN 0
1-246 COOH Phenyl Meüiyl - CH2-CH2- 4-SMe-Phenyl OMe Me CH N N 01-246 COOH Phenyl Meüiyl - CH 2 -CH 2 - 4-SMe-Phenyl OMe Me CH NN 0
1-247 COOH Phenyl CF3 - CH2-CH2- 3-OMe-Phenyl Me Me CH N CH 01-247 COOH Phenyl CF 3 - CH 2 -CH 2 - 3-OMe-Phenyl Me Me CH N CH 0
1-248 COOH Phenyl Meüiyl - CH2-CH2- 3-OMe-Phenyl Me Me N N CH 01-248 COOH Phenyl Meüiyl - CH 2 -CH 2 - 3-OMe-Phenyl Me Me NN CH 0
1-249 COOH Phenyl Meüiyl - CH2-CH2- 3-OMe-Ph ιyl Ethyl Me CH N N s1-249 COOH Phenyl Meüiyl - CH 2 -CH 2 - 3-OMe-Ph ιyl Ethyl Me CH NN s
1-250 COOH Phenyl Meüiyl - CH2-CH2- CH2- 4-Cl-Phenyl OMe Me CH N N 01-250 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-Cl-Phenyl OMe Me CH NN 0
1-251 COOH Phenyl Meüiyl - CH2-CH2- CH2- 4-Cl-Phenyl Me Me CH N N 01-251 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-Cl-Phenyl Me Me CH NN 0
1-252 COOH 4-F-Phenyl Meüiyl - CH2-CH2- 3-OMe-Phenyl OMe CH2- CH2-CH2-C N N 01-252 COOH 4-F-Phenyl Meüiyl - CH 2 -CH 2 - 3-OMe-Phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-253 COOH Phenyl Meüiyl - CH2-CH(CH3)- 3-OMe-Phenyl OMe O- CH2-CH2-C N N 01-253 COOH Phenyl Meüiyl - CH 2 -CH (CH 3 ) - 3-OMe-Phenyl OMe O- CH 2 -CH 2 -CNN 0
1-254 COOH Phenyl Meüiyl - CH2-CH2- Cyclohexyl CF3 Me CH N N 0 r.1-254 COOH Phenyl Meüiyl - CH 2 -CH 2 - Cyclohexyl CF 3 Me CH NN 0 r.
1-255 COOH Phenyl Butyl ~ CH=CH- CH2- 4-OMe-Phenyl OMe CH2- CH2-CH2-C N N 01-255 COOH phenyl butyl ~ CH = CH- CH 2 - 4-OMe-phenyl OMe CH 2 - CH2-CH2-C NN 0
1-256 COOH Phenyl Methyl - CH=CH- CH2- 4-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-256 COOH phenyl methyl - CH = CH- CH 2 - 4-OMe-phenyl OMe 0- CH 2 -CH2-C NN 0
1-257 COOH Phenyl Meüiyl - CH2-CH2- Cyclohexyl OMe OMe CH N N 01-257 COOH Phenyl Meüiyl - CH 2 -CH 2 - Cyclohexyl OMe OMe CH NN 0
1-258 Tetrazol Phenyl Meüiyl - CH2-CH2- 2-OMe-Phenyl CF3 Me CH N N 01-258 Tetrazole Phenyl Meüiyl - CH 2 -CH 2 - 2-OMe-Phenyl CF 3 Me CH NN 0
1-259 COOH 4-CF3-Phenyl Meüiyl - CH2-CH2- 4-OMe-Phenyl Me Me CH N N 01-259 COOH 4-CF 3 -phenyl Meüiyl - CH 2 -CH 2 - 4-OMe-Phenyl Me Me CH NN 0
1-260 COOH 4-CF3-Phenyl Meüiyl - CH2-CH2- 4-OMe-Phenyl Me Me N N N 01-260 COOH 4-CF 3 -phenyl Meüiyl - CH 2 -CH 2 - 4-OMe-Phenyl Me Me NNN 0
1-261 COOH Phenyl CH2-0-CH2- - CH(2-OMe- 2-OMe-Phenyl OMe Me CH N N 0 CH3 Phenyl)-CH2-1-261 COOH Phenyl CH 2 -0-CH 2 - - CH (2-OMe- 2-OMe-Phenyl OMe Me CH NN 0 CH 3 Phenyl) -CH 2 -
1-262 COOH Phenyl Meüiyl - CH2-CH2- 2-0Me-4-Br-Phenyl Me Mc CH N N 01-262 COOH Phenyl Meüiyl - CH 2 -CH 2 - 2-0Me-4-Br-Phenyl Me Mc CH NN 0
1-263 COOH Phenyl Methyl - CH2-CH2- 3-OMe-Phcnyl Me Me CH N N 0 o 1-264 COOH Phenyl Meüiyl - CH2-CH2- 3-OMe-Phenyl Me Me N N N 0 s© s© 1-263 COOH Phenyl Methyl - CH 2 -CH 2 - 3-OMe-Phcnyl Me Me CH NN 0 o 1-264 COOH Phenyl Meüiyl - CH 2 -CH 2 - 3-OMe-Phenyl Me Me NNN 0 s © s ©
Nr. R1 R5 R4 Q R6 R2 R3 Z X Y WNo. R 1 R 5 R 4 Q R6 R 2 R 3 ZXYW
1-265 COOH Phenyl Meüiyl N CH 0 s©1-265 COOH Phenyl Meüiyl N CH 0 s ©
- CH2-CH2- 2-OMe-Phenyl Me Me N SO- CH 2 -CH2- 2-OMe-phenyl Me Me N SO
1-266 COOH Phenyl CF3 - CH2-CH2- CH2- 4-Et-Phenyl OMe 0- CH2-CH2-C N N 0 V©1-266 COOH Phenyl CF 3 - CH 2 -CH 2 - CH 2 - 4-Et-Phenyl OMe 0- CH 2 -CH 2 -CNN 0 V ©
1-267 COOH Phenyl CH N N 0 001-267 COOH phenyl CH N N 0 00
Meüiyl - CH2-CH2- CH2- 4-Cl-Phenyl CF3 MeMeüiyl - CH 2 -CH 2 - CH 2 - 4-Cl-Phenyl CF 3 Me
1-268 COOH Phenyl Methyl - CH2-CH2- 2-OMe-Phenyl Ethyl Me CH N N s1-268 COOH phenyl methyl - CH 2 -CH 2 - 2-OMe-phenyl ethyl Me CH NN s
1-269 COOH Phenyl Meüiyl - CH2-CH2- 3,4,5-Tri-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-269 COOH Phenyl Meüiyl - CH 2 -CH 2 - 3,4,5-Tri-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-270 COOH Phenyl Meüiyl - CH2-CH2- 4-SMe-Phenyl CF3 Me CH N N 01-270 COOH Phenyl Meüiyl - CH 2 -CH 2 - 4-SMe-Phenyl CF 3 Me CH NN 0
1-271 COOH Phenyl Methyl - CH=CH- CH2- 4-OMe-Phenyl Me Me N N N 01-271 COOH Phenyl Methyl - CH = CH- CH 2 - 4-OMe-Phenyl Me Me NNN 0
1-272 COOH Phenyl Meüiyl - CH=CH- CH2- 4-OMe-Phenyl Ethyl Me CH N N 01-272 COOH Phenyl Meüiyl - CH = CH- CH 2 - 4-OMe-Phenyl Ethyl Me CH NN 0
1-273 COOH 4-Br-Phenyl CH2-0-CH2- CH3 - CH2-CH2- 2-OMe-Phenyl OMe CH2- CH2-CH2-C N N 01-273 COOH 4-Br-Phenyl CH 2 -0-CH 2 - CH 3 - CH 2 -CH 2 - 2-OMe-Phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-274 COOH Phenyl Meüiyl - CH(OH)-CH2- 2-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-274 COOH Phenyl Meüiyl - CH (OH) -CH 2 - 2-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-275 COOH 4-Et-Phenyl Methyl - CH2-CH2- 4-Me-Phenyl OMe 0- CH2-CH2-C N N 01-275 COOH 4-Et-Phenyl Methyl - CH 2 -CH 2 - 4-Me-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-276 COOH 4-CF3-Phenyl Meüiyl - CH2-CH2- 4-OMe-Phenyl OMe Me CH N N 01-276 COOH 4-CF 3 -phenyl Meüiyl - CH 2 -CH 2 - 4-OMe-Phenyl OMe Me CH NN 0
1-277 COOH - CH(4-0Me-1-277 COOH - CH (4-0Me-
4-Cl-Phenyl Meüiyl 4-OMe-Phenyl OMe Me CH N N 0 Phenyl)-CH2-4-Cl-Phenyl Meüiyl 4-OMe-Phenyl OMe Me CH NN 0 Phenyl) -CH 2 -
1-278 COOH 4-Cl-Phenyl CF3 - CH2-CH2- 3-Me-4-OMe-Phenyl Me Me CH N N 01-278 COOH 4-Cl-Phenyl CF 3 - CH 2 -CH 2 - 3-Me-4-OMe-Phenyl Me Me CH NN 0
1-279 COOH 4-Cl-Phenyl Methyl - CH2-CH2- 3,4-Methylendioxyphenyl Me Me CH N N 01-279 COOH 4-Cl-Phenyl Methyl - CH 2 -CH 2 - 3,4-Methylenedioxyphenyl Me Me CH NN 0
1-280 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 3 ,4-Methylendioxyphenyl Me Me N N N 01-280 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - 3, 4-Methylenedioxyphenyl Me Me NNN 0
1-281 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 4-OMe-Phenyl Ethyl Me N N N 01-281 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - 4-OMe-Phenyl Ethyl Me NNN 0
1-282 COOH Phenyl Meüiyl - CH2-CH2- CH2- 4-Et-Phenyl EÜiyl Me CH N N 01-282 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-Et-Phenyl EÜiyl Me CH NN 0
1-283 COOH Phenyl Methyl - CH2-CH2- CH2- 4-Et-Phenyl OMe CH2- CH2-CH2-C N N 01-283 COOH phenyl methyl - CH 2 -CH 2 - CH 2 - 4-Et-phenyl OMe CH2-CH 2 -CH 2 -CNN 0
1-284 COOH Phenyl Meüiyl - CH2-CH2- 4-Et-Phenyl OMe CH2- CH2-CH2-C N N 01-284 COOH Phenyl Meüiyl - CH 2 -CH 2 - 4-Et-Phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
OO
1-285 COOH Phenyl Methyl - CH2-CH2- 4-Et-Phenyl OMe 0- CH2-CH2-C N N 0 H1-285 COOH phenyl methyl - CH 2 -CH 2 - 4-Et-phenyl OMe 0-CH 2 -CH 2 -CNN 0 H
■0 o s© o ■ 0 os © o
(-) e 00 (-) e 00
Nr. R1 R5 R4 Q R6 R2 R3 Z X Y WNo. R 1 R 5 R 4 Q R6 R 2 R 3 ZXYW
CH2-0-CH2- SOCH 2 -0-CH 2 - SO
1-286 COOH 4-Cl-Phenyl - CH2-CH2- 4-OMe-Phenyl Ethyl Me CH N N CH3 s s© s©1-286 COOH 4-Cl-Phenyl - CH 2 -CH 2 - 4-OMe-Phenyl Ethyl Me CH NN CH 3 ss © s ©
1-287 COOH Phenyl Methyl - CH=CH- CH2- 4-OMe-Phenyl OMe Me CH N N 01-287 COOH Phenyl Methyl - CH = CH- CH 2 - 4-OMe-Phenyl OMe Me CH NN 0
1-288 COOH Phenyl Meüiyl - CH=CH- CH2- 4-OMe-Phenyl Me Me CH N N 01-288 COOH Phenyl Meüiyl - CH = CH- CH 2 - 4-OMe-Phenyl Me Me CH NN 0
1-289 COOH 3,4-Di-Cl-Phenyl Meüiyl - CH2-CH2- 4-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-289 COOH 3,4-Di-Cl-Phenyl Meüiyl - CH 2 -CH 2 - 4-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-290 COOEt 4-Cl-Phenyl Methyl - CH(OH)-CH2- 3,4-Di-OMe-Phenyl OMe Me CH N N 01-290 COOEt 4-Cl-Phenyl Methyl - CH (OH) -CH 2 - 3,4-Di-OMe-Phenyl OMe Me CH NN 0
1-291 COOH 4-Et-Phenyl Meüiyl — CH2—CH2— 4-Me-Phenyl Me Me N N N 01-291 COOH 4-Et-Phenyl Meüiyl - CH 2 -CH 2 - 4-Me-Phenyl Me Me NNN 0
1-292 COOH 4-Et-Phenyl Meüiyl - CH2-CH2- 4-Me-Phenyl Ethyl Me CH N N 01-292 COOH 4-Et-Phenyl Meüiyl - CH 2 -CH 2 - 4-Me-Phenyl Ethyl Me CH NN 0
1-293 COOH Phenyl Meüiyl - CH2-CH2- 3-OMe-Phenyl CF3 Me CH N N 01-293 COOH Phenyl Meüiyl - CH2-CH2- 3-OMe-Phenyl CF 3 Me CH NN 0
1-294 COOH Phenyl Meüiyl - CH2-CH2- 3-OMe-Phenyl OMe Me CH N N 01-294 COOH Phenyl Meüiyl - CH2-CH2-3-OMe-Phenyl OMe Me CH N N 0
CH2-0-CH2-CH 2 -0-CH 2 -
1-295 COOH 4-Cl-Phenyl - CH2-CH2- 34-Di-OMe-Phenyl Me Me CH N CH 0 CH3 ω1-295 COOH 4-Cl-phenyl - CH2-CH2- 34-di-OMe-phenyl Me Me CH N CH 0 CH 3 ω
1-296 COOH 4-Cl-Phenyl Meüiyl - C(CH3)2-CH2- 3,4-Di-OMe-Phenyl Me Me N N N 0 001-296 COOH 4-Cl-Phenyl Meüiyl - C (CH 3 ) 2 -CH 2 - 3,4-Di-OMe-Phenyl Me Me NNN 0 00
1-297 COOH Phenyl Meüiyl - CH2-CH2- 3,4,5-Tri-OMe-Phenyl Ethyl Me CH N N 01-297 COOH Phenyl Meüiyl - CH 2 -CH 2 - 3,4,5-Tri-OMe-Phenyl Ethyl Me CH NN 0
1-298 COOH Phenyl Meüiyl - CH2-CH2- CH2- 4-Et-Phenyl Me Me CH M N 01-298 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-Et-Phenyl Me Me CH MN 0
1-299 COOH Phenyl Meüiyl - CH2-CH2- CH2- 4-Et-Phenyl Me Me N N N 01-299 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-Et-Phenyl Me Me NNN 0
1-300 COOH Phenyl CF3 - CH2-CH2- 3 ,4,5-Tri-OMe-Phenyl OMe CH2- CH2-CH2-C N N 01-300 COOH phenyl CF 3 - CH 2 -CH 2 - 3, 4,5-tri-OMe-phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-301 COOH 4-Cl-Phenyl Methyl - CH2-CH2- 3,4-Di-OMe-Phenyl Ethyl Me N N N 01-301 COOH 4-Cl-Phenyl Methyl - CH 2 -CH 2 - 3,4-Di-OMe-Phenyl Ethyl Me NNN 0
1-302 COOH 3,4-Di-Cl-Phenyl Methyl - CH2-CH2- 3,4-Di-OMe-Phenyl OMe O- CH2-CH2-C N N 01-302 COOH 3,4-di-Cl-phenyl methyl - CH 2 -CH 2 - 3,4-di-OMe-phenyl OMe O-CH 2 -CH2-C NN 0
1-303 COOH Phenyl Meüiyl - CH2-CH2- CH2- 3,4,5-Tri-OMe-Phenyl OMe CH2- CH2-CH2-C N N 01-303 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 3,4,5-Tri-OMe-Phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-304 COOH Phenyl Propyl - CH=CH- CH2- 4-OMe-Phenyl CF3 Me CH N N 01-304 COOH phenyl propyl - CH = CH - CH 2 - 4-OMe-phenyl CF 3 Me CH NN 0
1-305 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 3-Me-4-Et-Phenyl OMe Me CH N N 0 o1-305 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 3-Me-4-Et-Phenyl OMe Me CH N N 0 o
1-306 COOH 4-Cl-Phenyl Methyl - CH2-CH2- 3-Me-4-Et-Phenyl SMe Me CH N N 0 H 1-307 COOH 4-Et-Plιenyl CF3 - CH2-CH2- 4-Me-Phenyl OMe Me CH N N 0 SO s© o 1-306 COOH 4-Cl-Phenyl Methyl - CH2-CH2-3-Me-4-Et-Phenyl SMe Me CH NN 0 H 1-307 COOH 4-Et-Plιenyl CF 3 - CH2-CH2- 4-Me-Phenyl OMe Me CH NN 0 SO s © o
Nr. R1 R5 R4 Q R6 R2 R3 Z X Y WNo. R 1 R5 R 4 Q R6 R 2 R 3 ZXYW
1-308 COOH 4-Et-Phenyl Methyl - CH2-CH2- 4-Me-Phenyl Me Me CH N N 01-308 COOH 4-Et-Phenyl Methyl - CH 2 -CH 2 - 4-Me-Phenyl Me Me CH NN 0
4≥4≥
1-309 COOH 4~C1-Phenyl Meüiyl - CH2-CH2- 4-iPr-Phenyl OMe 0- CH2-CH2-C N N O β1-309 COOH 4 ~ C1-Phenyl Meüiyl - CH 2 -CH 2 - 4-iPr-Phenyl OMe 0- CH 2 -CH 2 -CNNO β
1-310 COOH 4~C1-Phenyl Meüiyl - CH2-CH2- ,4-Methylendioxyphenyl OMe Me CH N N 0 001-310 COOH 4 ~ C1-Phenyl Meüiyl - CH 2 -CH 2 -, 4-methylenedioxyphenyl OMe Me CH NN 0 00
1-311 COOH 4~C1-Phenyl Butyl - CH2-CH2- 4-Br-Phenyl Me Me N N N 01-311 COOH 4 ~ C1-phenyl butyl - CH 2 -CH 2 - 4-Br-phenyl Me Me NNN 0
1-312 COOH Phenyl Methyl - CH2-CH2- 4-Et-Phenyl Me Me N N N 01-312 COOH Phenyl Methyl - CH 2 -CH 2 - 4-Et-Phenyl Me Me NNN 0
1-313 COOH Phenyl Meüiyl - CH2-CH2- 4-Et-Phenyl Ethyl Me CH N N 01-313 COOH Phenyl Meüiyl - CH 2 -CH 2 - 4-Et-Phenyl Ethyl Me CH NN 0
1-314 COOH Phenyl CF3 - CH2-CH2- CH2- 4-Et-Phenyl CF3 Me CH N N 01-314 COOH Phenyl CF 3 - CH2-CH2-CH 2 - 4-Et-Phenyl CF 3 Me CH NN 0
1-315 COOH Phenyl Meüiyl — CH2— CH2— CH2— 4-Et-Phenyl OMe Me CH N N 01-315 COOH Phenyl Meüiyl - CH 2 - CH 2 - CH 2 - 4-Et-Phenyl OMe Me CH NN 0
1-316 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 4-Br-Phenyl Ethyl Me N N N 01-316 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 4-Br-Phenyl Ethyl Me N N N 0
1-317 COOH - CH(4-Br-Phαιyl>-1-317 COOH - CH (4-Br-Phαιyl> -
4-Cl-Phenyl Meüiyl 4-Br-Phenyl OMe 0- CH2-CH2-C N N 0 CH2-4-Cl-Phenyl Meüiyl 4-Br-Phenyl OMe 0- CH 2 -CH 2 -CNN 0 CH 2 -
1-318 COOH 4-Cl-Phenyl Methyl - CH(OH)-CH2- 4-SMe-Phenyl OMe Me CH N N 0 ω so1-318 COOH 4-Cl-phenyl methyl - CH (OH) -CH 2 - 4-SMe-phenyl OMe Me CH NN 0 ω see above
1-319 COOH Phenyl Propyl - CH2-CH2- CH2- 3 ,4,5-Tri-OMe-Phenyl Me Me N N N 01-319 COOH phenyl propyl - CH 2 -CH 2 - CH 2 - 3, 4,5-tri-OMe-phenyl Me Me NNN 0
1-320 COOH Phenyl Meüiyl - CH2-CH2- CH2- 3,4,5-Tri-OMe-Phenyl Ethyl Me CH N N 01-320 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 3,4,5-Tri-OMe-Phenyl Ethyl Me CH NN 0
1-321 COOH Phenyl Meüiyl - CH2-CH2- 3,5-Di-OMe-Phenyl OMe CH2- CH2-CH2-C N N 01-321 COOH Phenyl Meüiyl - CH 2 -CH 2 - 3,5-Di-OMe-Phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-322 COOH Phenyl CF3 - CH2-CH2- 3,5-Di-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-322 COOH phenyl CF 3 - CH 2 -CH 2 - 3,5-di-OMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-323 COOH 4-Et-Phenyl Methyl - CH2-CH2- 4-SMe-Phenyl Ethyl Me CH N N 01-323 COOH 4-Et-Phenyl Methyl - CH 2 -CH 2 - 4-SMe-Phenyl Ethyl Me CH NN 0
1-324 COOH 4-Et-Phenyl Methyl - CH2-CH2- 4-SMe-Phenyl OMe O- CH2-CH2-C N N 01-324 COOH 4-Et-Phenyl Methyl - CH 2 -CH 2 - 4-SMe-Phenyl OMe O-CH2-CH2-C NN 0
1-325 COOH 4-Cl-Phenyl Meüiyl - C(CH3)2-CH2- 4-SMe-Phenyl Me Me CH N CH 01-325 COOH 4-Cl-Phenyl Meüiyl - C (CH 3 ) 2 -CH 2 - 4-SMe-Phenyl Me Me CH N CH 0
1-326 COOH 4-Cl-Phenyl Butyl - CH2-CH2- 4-SMe-Phenyl Me Me N N N s1-326 COOH 4-Cl-Phenyl Butyl - CH2-CH2- 4-SMe-Phenyl Me Me N N N s
1-327 COOH Phenyl Methyl - CH2-CH2- 3,4,5-Tri-OMe-Phcnyl Me Me CH N N 01-327 COOH Phenyl Methyl - CH2-CH2- 3,4,5-Tri-OMe-Phcnyl Me Me CH N N 0
1-328 COOH Phenyl Methyl - CH2-CH2- 3,4,5-Tri-OMe-Phenyl Me Me N N N 0 -*3 1-329 COOH n1-328 COOH Phenyl Methyl - CH2-CH2- 3,4,5-Tri-OMe-Phenyl Me Me NNN 0 - * 3 1-329 COOH n
4-Cl-Phenyl CF3 - O-CH2-CH2- 4-SMe-Phenyl Ethyl Me CH N N 0 H w4-Cl-Phenyl CF 3 - O-CH2-CH2- 4-SMe-Phenyl Ethyl Me CH NN 0 H w
1313
o 00 o 00
Nr. R1 R5 R4 Q R6 R2 R3 Z X Y WNo. R 1 R 5 R 4 Q R6 R 2 R 3 ZXYW
1-330 COOH Phenyl Meüiyl - CH2-CH2- CH2- 4-Me-Phenyl Ethyl Me CH N N 0 se1-330 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-Me-Phenyl Ethyl Me CH NN 0 se
1-331 COOH Phenyl Propyl - CH2-CH2- CH2- 4-Me-Phenyl OMe O- CH2-CH2-C N N 0 s© s©1-331 COOH Phenyl Propyl - CH2-CH2-CH2- 4-Me-Phenyl OMe O- CH 2 -CH 2 -CNN 0 s © s ©
1-332 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 4-SMe-Phenyl OMe 0- CH=CH-C N N 0 001-332 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - 4-SMe-Phenyl OMe 0- CH = CH-C NN 0 00
1-333 COOH 4-Cl-Phenyl Methyl - CH(OH)-CH2- 4-OEt-3-OMe-Phenyl OMe Me CH N N 01-333 COOH 4-Cl-Phenyl Methyl - CH (OH) -CH 2 - 4-OEt-3-OMe-Phenyl OMe Me CH NN 0
1-334 COOH 4-Cl-Phenyl CF3 - CH(4-SMe- 4-SMe-Phenyl Me Me CH N N 0 Phenyl)-CH2-1-334 COOH 4-Cl-Phenyl CF 3 - CH (4-SMe-4-SMe-Phenyl Me Me CH NN 0 phenyl) -CH 2 -
1-335 COOH Phenyl Meüiyl - CH2-CH2- - CH2- 3 ,4,5-Tri-OMe-Phenyl OMe Me CH N N 01-335 COOH Phenyl Meüiyl - CH 2 -CH 2 - - CH 2 - 3, 4,5-Tri-OMe-Phenyl OMe Me CH NN 0
1-336 COOH Phenyl Meüiyl - CH2-CH2- CH2- 3,4,5-Tri-OMe-Pheιιyl Me Me CH N N 01-336 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 3,4,5-Tri-OMe-Pheιιyl Me Me CH NN 0
1-337 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 4-iPr-Phenyl Me Me N N N 01-337 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - 4-iPr-Phenyl Me Me NNN 0
1-338 COOH 4-Cl-Phenyl Butyl - CH2-CH2- 4-iPr-Phenyl Ethyl Me CH N N 01-338 COOH 4-Cl-Phenyl Butyl - CH2-CH2- 4-iPr-Phenyl Ethyl Me CH N N 0
1-339 COOH 4-Me-Phenyl Meüiyl - CH2-CH2- 3,4-Di-OMe-Phenyl Me Me CH N N 01-339 COOH 4-Me-Phenyl Meüiyl - CH 2 -CH 2 - 3,4-Di-OMe-Phenyl Me Me CH NN 0
1-340 COOH 4-Me-Phenyl Methyl - CH2-CH2- 3 ,4-Di-OMe-Phenyl Me Me N N N 0 o1-340 COOH 4-Me-Phenyl Methyl - CH 2 -CH 2 - 3, 4-Di-OMe-Phenyl Me Me NNN 0 o
1-341 COOH 3,4-Di-Cl-Phenyl CF3 - CH2-CH2- 4-OEt-3-OMe-Phenyl Me Me N N N 01-341 COOH 3,4-Di-Cl-Phenyl CF 3 - CH 2 -CH 2 - 4-OEt-3-OMe-Phenyl Me Me NNN 0
1-342 COOH Phenyl Meüiyl - CH2-CH2- 4-Et-Phenyl OMe Me CH N N 01-342 COOH Phenyl Meüiyl - CH2-CH2- 4-Et-Phenyl OMe Me CH N N 0
1-343 COOH Phenyl Propyl - CH2-CH2- 4-Et-Phenyl Me Me CH N N 01-343 COOH Phenyl Propyl - CH2-CH2- 4-Et-Phenyl Me Me CH N N 0
1-344 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 4-OEt-3-OMe-Phenyl Ethyl Me CH N N s1-344 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - 4-OEt-3-OMe-Phenyl Ethyl Me CH NN s
1-345 COOH 4-Cl-Phenyl Methyl - CH(4-Me-Phenyl)-1-345 COOH 4-Cl-Phenyl Methyl - CH (4-Me-Phenyl) -
4-Me-Phenyl OMe Me CH N N 0 CH2-4-Me-Phenyl OMe Me CH NN 0 CH 2 -
1-346 COOH Phenyl CF3 ~ CH2-CH2- CH2- 4-Me-Phenyl Me Me CH N N 01-346 COOH Phenyl CF 3 ~ CH 2 -CH 2 - CH 2 - 4-Me-Phenyl Me Me CH NN 0
1-347 COOH Phenyl Meüiyl - CH2-CH2- CH2- 4-Me-Phenyl Me Me N N N 01-347 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-Me-Phenyl Me Me NNN 0
1-348 COOMe 4-Cl-Phenyl Meüiyl - CH2-CH2- 4-Mc-Phenyl Me Me CH N CH 01-348 COOMe 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - 4-Mc-Phenyl Me Me CH N CH 0
1-349 COOH Phenyl Meüiyl - CH2-CH2- 3,5 -Di-OMe -Phenyl Me Me N N N 01-349 COOH Phenyl Meüiyl - CH 2 -CH 2 - 3,5 -Di-OMe -Phenyl Me Me NNN 0
1-350 COOH -01-350 COOH -0
Phenyl Butyl - CH2-CH2- 3,5-Di-OMe-Phenyl Ethyl Me CH N N 0Phenyl butyl - CH 2 -CH 2 - 3,5-di-OMe-phenyl ethyl Me CH NN 0
H nH n
1-351 COOH Phenyl Methyl - CH2-CH2- CH2- 2-Cl-Phenyl OMe CH2- CH2-CH2-C N N 0 1-351 COOH phenyl methyl - CH 2 -CH 2 - CH 2 - 2-Cl-phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
o 00 o 00
Nr. R1 R5 R4 Q R6 R2 R3 Z X Y WNo. R 1 R 5 R 4 QR 6 R 2 R 3 ZXYW
1-352 COOH Phenyl e CH N N 0 so1-352 COOH phenyl e CH N N 0 so
Meüiyl — CH2— CH2— CH2— 3,4,5-Tri-OMe-Phenyl CF3 M SOMeüiyl - CH 2 - CH 2 - CH 2 - 3,4,5-Tri-OMe-Phenyl CF 3 M SO
1-353 COOH 4-Cl-Phenyl CF3 - CH(OH)-CH2- 4-Me-Phenyl Me Me N N N 0 Sβ SO1-353 COOH 4-Cl-Phenyl CF 3 - CH (OH) -CH 2 - 4-Me-Phenyl Me Me NNN 0 Sβ SO
1-354 COOH 4-Cl-Phenyl Methyl - CH2-CH2- 3,4-Di-Me-Phenyl Ethyl Me CH N N 01-354 COOH 4-Cl-Phenyl Methyl - CH 2 -CH 2 - 3,4-Di-Me-Phenyl Ethyl Me CH NN 0
1-355 COOH 4-Me-Phenyl Propyl - CH2-CH2- 4-OMe-Phenyl OMe 0- CH2 -CH2-C N N 01-355 COOH 4-Me-Phenyl Propyl - CH 2 -CH 2 - 4-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-356 COOH 4-Me-Phenyl Meüiyl - CH2-CH2- 3,4-Di-OMe-Phenyl OMe Me CH N N 01-356 COOH 4-Me-Phenyl Meüiyl - CH 2 -CH 2 - 3,4-Di-OMe-Phenyl OMe Me CH NN 0
1-357 COOH Phenyl Meüiyl - CH2-CH2- ,4,5-Tri-OMe-Phenyl OMe OMe CH N N 01-357 COOH Phenyl Meüiyl - CH 2 -CH 2 -, 4,5-Tri-OMe-Phenyl OMe OMe CH NN 0
1-358 COOH Phenyl Meüiyl - CH2-CH2- 3,4,5-Tri-OMe-Phenyl OMe Me CH N N 01-358 COOH Phenyl Meüiyl - CH 2 -CH 2 - 3,4,5-Tri-OMe-Phenyl OMe Me CH NN 0
1-359 COOH 4-Cl-Phenyl Methyl - CH2-CH2- 4-Me-Phenyl OMe O- CH2 -CH2-C N N s1-359 COOH 4-Cl-Phenyl Methyl - CH 2 -CH 2 - 4-Me-Phenyl OMe O-CH2 -CH 2 -CNN s
1-360 COOH 4-Cl-Phenyl Methyl - CH2-CH2- 4-Et-Phenyl OMe Me CH N N s1-360 COOH 4-Cl-Phenyl Methyl - CH 2 -CH 2 - 4-Et-Phenyl OMe Me CH NN s
1-361 COOH 4-Cl-Phenyl Butyl - CH2-CH2- 4-Et-Phenyl Me Me CH N CH 01-361 COOH 4-Cl-Phenyl Butyl - CH 2 -CH 2 - 4-Et-Phenyl Me Me CH N CH 0
1-362 COOH Phenyl Methyl - CH2-CH2- CH2- 4-Me-Phenyl CF3 Me CH N N 01-362 COOH phenyl methyl - CH2-CH2-CH 2 - 4-Me-phenyl CF 3 Me CH NN 0
1-363 COOH Phenyl Meüiyl - CH2-CH2- CH2- 4-Me-Phenyl OMe Me CH N N 01-363 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-Me-Phenyl OMe Me CH NN 0
1-364 COOH 4-Cl-Phenyl Methyl - CH2-CH2- 4-Et-Phenyl Ethyl Me _j N N N 01-364 COOH 4-Cl-Phenyl Methyl - CH 2 -CH 2 - 4-Et-Phenyl Ethyl Me _j NNN 0
1-365 COOH 4-Cl-Phenyl CF3 - CH2-CH2- 4-iPr-Phenyl OMe Me CH N N 01-365 COOH 4-Cl-Phenyl CF 3 - CH2-CH2- 4-iPr-Phenyl OMe Me CH NN 0
1-366 COOH 4-Cl-Phenyl Ethyl - CH2-CH2- 4-iPr-Phenyl Me Me CH N N 01-366 COOH 4-Cl-Phenyl Ethyl - CH 2 -CH 2 - 4-iPr-Phenyl Me Me CH NN 0
1-367 COOH Phenyl Meüiyl - CH2-CH2- CH2- 2-Cl-Phenyl Me Me N N N 01-367 COOH Phenyl Meüiyl - CH 2 -CH2- CH 2 - 2-Cl-Phenyl Me Me NNN 0
1-368 COOH Phenyl Methyl - CH2-CH2- CH2- 2-Cl-Phenyl Ethyl Me CH N N 01-368 COOH phenyl methyl - CH 2 -CH 2 - CH 2 - 2-Cl-phenyl ethyl Me CH NN 0
1-369 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 4-Et-Phenyl SMe Me CH N N 01-369 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 4-Et-Phenyl SMe Me CH N N 0
1-370 COOH Phenyl Meüiyl - CH2-CH2- 4-Me-Phenyl OMe O- CH2- -CH2-C N N 01-370 COOH Phenyl Meüiyl - CH2-CH2- 4-Me-Phenyl OMe O- CH2- -CH 2 -CNN 0
1-371 COOH 4-Me-Phenyl Ethyl - CH2-CH2- 4-OMe-Phenyl Me Me N N N 01-371 COOH 4-Me-Phenyl Ethyl - CH2-CH2- 4-OMe-Phenyl Me Me N N N 0
1-372 COOH 4-Me-Phenyl CF3 - CH2-CH2- 4-OMe-Phenyl EUiyl Me CH N N 01-372 COOH 4-Me-Phenyl CF 3 - CH2-CH2- 4-OMe-Phenyl EUiyl Me CH NN 0
T3T3
1-373 COOH Phenyl Methyl - CH2-CH2- 4-Et-Phenyl CF3 Me CH N N 0 O H1-373 COOH phenyl methyl - CH2-CH2- 4-Et-phenyl CF 3 Me CH NN 0 OH
1-374 COOH 4-Cl-Phenyl Meüiyl - C(CH3)2-CH2- 4-Et-Phenyl OMe O- CH2-CH2-C N N 0 M 13 o o 1-374 COOH 4-Cl-Phenyl Meüiyl - C (CH 3 ) 2 -CH 2 - 4-Et-Phenyl OMe O-CH 2 -CH 2 -CNN 0 M 13 oo
Nr. R1 R5 R4 Q R6 R2 R3 Z X Y W oNo.R 1 R 5 R 4 Q R6 R 2 R 3 ZXYW o
1-375 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 4-Cl-Phenyl OMe Me CH N N s so1-375 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - 4-Cl-Phenyl OMe Me CH NN s so
**
1-376 COOH 4-Cl-Phenyl *--1-376 COOH 4-Cl-Phenyl * -
Meüiyl - CH2-CH2- l-Me-NaphÜι-2-yl OMe Me CH N N 0 s© so 00Meüiyl - CH2-CH 2 - l-Me-NaphÜι-2-yl OMe Me CH NN 0 s © so 00
1-377 COOH Phenyl Meüiyl - CH2-CH2- 3,5-Di-OMe-Phenyl OMe Me CH N N 01-377 COOH Phenyl Meüiyl - CH 2 -CH 2 - 3,5-Di-OMe-Phenyl OMe Me CH NN 0
1-378 COOH Phenyl Meüiyl - CH2-CH2- CH2- 3,4-Methylendioxyphenyl Ethyl Me CH N N 01-378 COOH Phenyl Meüiyl - CH2-CH2-CH2- 3,4-Methylenedioxyphenyl Ethyl Me CH N N 0
1-379 COOH Phenyl Meüiyl - CH2-CH2- CH2- 3,4-Methylendioxyphenyl OMe 0- CH2-CH2-C N N 01-379 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 3,4-methylenedioxyphenyl OMe 0- CH 2 -CH 2 -CNN 0
1-380 COOH Phenyl Methyl - CH2-CH2- 3,5-Di-OMe-Phenyl Me Me CH N N 01-380 COOH phenyl methyl - CH2-CH 2 - 3,5-di-OMe-phenyl Me Me CH NN 0
1-381 COOH 4-Cl-Phenyl Butyl - CH(4-OEt-Phenyl)- 4-OEt-Phenyl OMe Me CH N N 0 CH2-1-381 COOH 4-Cl-Phenyl Butyl - CH (4-OEt-Phenyl) - 4-OEt-Phenyl OMe Me CH NN 0 CH 2 -
1-382 COOH 4-Cl-Phenyl Meüiyl - CH(OH)-CH2- 4-OEt-Phenyl Me Me CH N N 01-382 COOH 4-Cl-Phenyl Meüiyl - CH (OH) -CH 2 - 4-OEt-Phenyl Me Me CH NN 0
1-383 COOH Phenyl Meüiyl - CH2-CH2- CH2- 2-Cl-Phenyl OMe Me CH N N 01-383 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 2-Cl-Phenyl OMe Me CH NN 0
1-384 COOH Phenyl Methyl - CH2-CH2- CH2- 2-Cl-Phenyl Me Me CH N N 01-384 COOH phenyl methyl - CH 2 -CH 2 - CH 2 - 2-Cl-phenyl Me Me CH NN 0
1-385 COOH Phenyl CF3 - CH2-CH2- 3,4-Di-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-385 COOH phenyl CF 3 - CH2-CH2- 3,4-di-OMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-386 COOH Phenyl EÜiyl - CH2-CH2- 3 ,4,5-Tri-OMe-Phenyl CF3 Me CH N N 01-386 COOH Phenyl EÜiyl - CH 2 -CH 2 - 3, 4,5-Tri-OMe-Phenyl CF 3 Me CH NN 0
1-387 COOH 4-Me-Phenyl Meüiyl - CH2-CH2- 4-OMe-Phenyl OMe Me CH N N 01-387 COOH 4-Me-Phenyl Meüiyl - CH 2 -CH 2 - 4-OMe-Phenyl OMe Me CH NN 0
1-388 COOH 4-Me-Phenyl Metiiyl - CH2-CH2- 4-OMe-Phenyl Me Me CH N N 01-388 COOH 4-Me-Phenyl Metiiyl - CH2-CH 2 - 4-OMe-Phenyl Me Me CH NN 0
1-389 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 4-OEt-Phenyl Ethyl Me N N CH 01-389 COOH 4-Cl-Phenyl Meüiyl - CH2-CH 2 - 4-OEt-Phenyl Ethyl Me NN CH 0
1-390 COOH 3,4-Di-Cl-Phenyl Meüiyl - CH2-CH2- 3,5-Di-OMe-Phenyl OMe Me CH N N ' 01-390 COOH 3,4-Di-Cl-Phenyl Meüiyl - CH2-CH 2 - 3,5-Di-OMe-Phenyl OMe Me CH NN '0
1-391 COOH 4-Cl-Phenyl Ethyl - CH2-CH2- 3,5-Di-OMe-4-Cl-Phenyl Me Me CH N N 01-391 COOH 4-Cl-Phenyl Ethyl - CH2-CH2-3,5-Di-OMe-4-Cl-Phenyl Me Me CH N N 0
1-392 COOH 4-Cl-Phenyl CF3 - CH2-CH2- 3,5-Di-OMe-Phenyl Me Me N N CH 01-392 COOH 4-Cl-Phenyl CF 3 - CH2-CH 2 - 3,5-Di-OMe-Phenyl Me Me NN CH 0
1-393 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 4-OEt-3-OMe-Phenyl Ethyl Me CH N N 01-393 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - 4-OEt-3-OMe-Phenyl Ethyl Me CH NN 0
1-394 COOH Phenyl Meüiyl - CH2-CH2- CH2- 3,4-Methylendioxyphenyl Me Me CH N N 01-394 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 3,4-methylenedioxyphenyl Me Me CH NN 0
1-395 COOH Phenyl Methyl - CH2-CH2- CH2- 3 ,4-MethyIendioxyphenyl Me Me N N N 01-395 COOH phenyl methyl - CH 2 -CH 2 - CH 2 - 3, 4-methylenedioxyphenyl Me Me NNN 0
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1-396 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 4-OEt-3-OMe-Phenyl OMe 0- CH2-CH2-C N N 0 H 1-396 COOH 4-Cl-Phenyl Meüiyl - CH2-CH 2 - 4-OEt-3-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0 H
* SO*a SO* SO * a SO
© 00 © 00
Nr. R1 R5 R4 Q R6 R2 R3 Z X Y WNo. R 1 R 5 R 4 QR 6 R 2 R 3 ZXYW
1-397 COOH 4-Cl-Phenyl Methyl - C(CH3)2-CH2- 3-OMe-Phenyl CF3 Me CH N N O1-397 COOH 4-Cl-phenyl methyl - C (CH 3 ) 2 -CH 2 - 3-OMe-phenyl CF 3 Me CH NNO
1-398 COOH Phenyl Methyl - CH2-CH2- 4— Me-P enyl Ethyl Me CH N N 0 β1-398 COOH phenyl methyl - CH 2 -CH 2 - 4- Me-P enyl ethyl Me CH NN 0 β
1-399 COOH 4-Me-Phenyl Meüiyl - CH2-CH2- CH2- 4-Me-Phenyl Ethyl Me CH N N 01-399 COOH 4-Me-Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-Me-Phenyl Ethyl Me CH NN 0
1^100 COOH Phenyl Meüiyl - CH2-CH2- CH2- 2-Cl-Phenyl CF3 Me CH N N 01 ^ 100 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 2-Cl-Phenyl CF 3 Me CH NN 0
1-401 COOH Phenyl Butyl - CH2-CH2- 4-Me-Phenyl OMe CH2- CH2-CH2-C N N 01-401 COOH phenyl butyl - CH 2 -CH 2 - 4-Me-phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-402 COOH 4-Cl-Phenyl Methyl - C(CH3)2-CH2- 3-OMe-Phenyl Me Me CH N N 01-402 COOH 4-Cl-Phenyl Methyl - C (CH 3 ) 2 -CH 2 - 3-OMe-Phenyl Me Me CH NN 0
1-403 COOH 4-CF3-Phenyl Meüiyl - CH2-CH2- 4-Me-Phenyl Ethyl Me CH N N 01-403 COOH 4-CF 3 -phenylmeiyl - CH 2 -CH 2 - 4-Me-phenyl ethyl Me CH NN 0
1-404 COOH 4-CF3-Phenyl Meüiyl - CH2-CH2- 4-Me-Phenyl OMe O- CH2-CH2-C N N 01-404 COOH 4-CF 3 -phenylmeiyl - CH 2 -CH 2 - 4-Me-phenyl OMe O- CH 2 -CH 2 -CNN 0
1-405 COOH 4-Et-Phenyl CF3 - CH2-CH2- 4-OMe-Phenyl OMe Me CH N N s1-405 COOH 4-Et-Phenyl CF 3 - CH2-CH2- 4-OMe-Phenyl OMe Me CH NN s
1-406 COOH 4-Et-Phenyl Ethyl - CH2-CH2- 3-Me-4-OMe-Phenyl Me Me CH N N 01-406 COOH 4-Et-Phenyl Ethyl - CH 2 -CH 2 - 3-Me-4-OMe-Phenyl Me Me CH NN 0
1-407 COOH Phenyl Meüiyl - CH2-CH2- 4-OEt-Phenyl OMe O- CH2-CH2-C N N 01-407 COOH Phenyl Meüiyl - CH2-CH2- 4-OEt-Phenyl OMe O- CH 2 -CH 2 -CNN 0
1-408 COOH Phenyl Methyl - CH2-CH2- 3,5-Di-OMe-Phenyl CF3 Me CH N N 0 ω1-408 COOH phenyl methyl - CH 2 -CH 2 - 3,5-di-OMe-phenyl CF 3 Me CH NN 0 ω
1-409 COOH 4-Et-Phenyl Methyl - CH2-CH2- 3-Me-4-OMe-Phenyl Me Me N N CH 01-409 COOH 4-Et-Phenyl Methyl - CH 2 -CH 2 - 3-Me-4-OMe-Phenyl Me Me NN CH 0
1-410 COOH Phenyl Meüiyl - CH2-CH2- CH2- 3 ,4-Methylendioxyphenyl CF3 Me CH N N 01-410 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 3, 4-Methylenedioxyphenyl CF 3 Me CH NN 0
1-411 COOH Phenyl Ethyl - CH2-CH2- CH2- 3,4-Methylendioxyphenyl OMe Me CH N N 01-411 COOH phenyl ethyl - CH2-CH 2 - CH 2 - 3,4-methylenedioxyphenyl OMe Me CH NN 0
1-412 COOH 4-Et-Phenyl CF3 - CH2-CH2- 4-OMe-Phenyl Ethyl Me CH CH N 01-412 COOH 4-Et-Phenyl CF 3 - CH 2 -CH 2 - 4-OMe-Phenyl Ethyl Me CH CH N 0
1-413 COOH Phenyl Methyl - CH2-CH2- 3,4-Di-OMe-Phenyl Ethyl Me CH N N 01-413 COOH phenyl methyl - CH2-CH2- 3,4-di-OMe-phenyl ethyl Me CH N N 0
1-414 COOH Phenyl Methyl - CH2-CH2- 3,4-Di-OMe-Phenyl OMe CH2- CH2-CH2-C N N 01-414 COOH phenyl methyl - CH 2 -CH 2 - 3,4-di-OMe-phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-415 COOH 4-Me-Phenyl Methyl - CH2-CH2- CH2- 4-Me-Phenyl Me Me CH N N 01-415 COOH 4-Me-Phenyl Methyl - CH 2 -CH 2 - CH 2 - 4-Me-Phenyl Me Me CH NN 0
1-416 COOH 4-Me-Phenyl Meüiyl - CH2-CH2- CH2- 4-Me-Phenyl Me Me N N N 01-416 COOH 4-Me-Phenyl Meüiyl - CH2-CH 2 - CH 2 - 4-Me-Phenyl Me Me NNN 0
1-417 COOH 4-Et-Phenyl Mctiiyl - CH2-CH2- 3,4-Di-OMe-Phenyl SMc Me CH N N 01-417 COOH 4-Et-Phenyl Mctiiyl - CH 2 -CH 2 - 3,4-Di-OMe-Phenyl SMc Me CH NN 0
1-418 COOMe 4-El-Phenyl Meüiyl - CH2-CH2- 3,4-Di-OMe-Phenyl Me Me CH N N 0 O1-418 COOMe 4-El-Phenyl Meüiyl - CH2-CH2- 3,4-Di-OMe-Phenyl Me Me CH N N 0 O
HH
1-419 COOH 4-CF3-Phenyl Methyl - CH2-CH2- 4-Me-Phenyl Me Me CH N N 0 W -0 so 1-419 COOH 4-CF 3 -phenyl methyl - CH 2 -CH 2 - 4-Me-Phenyl Me Me CH NN 0 W -0 so
Nr. R1 R5 R4 Q R6 R2 R3 Z X Y WNo. R 1 R 5 R 4 QR 6 R 2 R 3 ZXYW
1-420 COOH 4-CF3-Phenyl Meüiyl - CH2-CH2- 4-Me-Phenyl Me Me N N N 01-420 COOH 4-CF 3 -phenylmeiyl - CH 2 -CH 2 - 4-Me-Phenyl Me Me NNN 0
1-421 COOH 4-Et-Phenyl Butyl - CH2-CH2- 3,4-Di-OMe-Phenyl Me Me N N N s *s1-421 COOH 4-Et-Phenyl Butyl - CH 2 -CH 2 - 3,4-Di-OMe-Phenyl Me Me NNN s * s
1-422 COOH 4-Et-Phenyl Meüiyl - CH2-CH2- 3 ,4-Di-OMe-Phenyl Ethyl Me CH CH N 01-422 COOH 4-Et-Phenyl Meüiyl - CH 2 -CH 2 - 3, 4-Di-OMe-Phenyl Ethyl Me CH CH N 0
1-423 COOH 4-Cl-Phenyl Methyl - CH2-CH2- 4-OEt-3-OMe-Phenyl Me Me CH N N 01-423 COOH 4-Cl-Phenyl Methyl - CH 2 -CH 2 - 4-OEt-3-OMe-Phenyl Me Me CH NN 0
1-Λ2A COOH 4-Cl-Phenyl Methyl - CH2-CH2- 4-OEt-3-OMe-Phenyl Me Me N N N 01-Λ2A COOH 4-Cl-phenyl methyl - CH2-CH 2 - 4-OEt-3-OMe-phenyl Me Me NNN 0
1-425 COOH 4-Et-Phenyl CF3 - CH2-CH2- 3,4-Di-OMe-Phenyl OMe 0- CH=CH-C N N 01-425 COOH 4-Et-Phenyl CF 3 - CH 2 -CH 2 - 3,4-Di-OMe-Phenyl OMe 0- CH = CH-C NN 0
1-426 COOH Phenyl EÜiyl - CH2-CH2- CH2- 4-SMe-Phenyl Ethyl Me CH N N 01-426 COOH Phenyl EÜiyl - CH 2 -CH 2 - CH 2 - 4-SMe-Phenyl Ethyl Me CH NN 0
1-427 COOH Phenyl Meüiyl - CH2-CH2- CH2- 4-SMe-Phenyl OMe 0- CH2-CH2-C N N 01-427 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-SMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-428 COOH Phenyl Meüiyl - CH2-CH2- 4-Me-Phenyl Me Me CH N N 01-428 COOH Phenyl Meüiyl - CH 2 -CH 2 - 4-Me-Phenyl Me Me CH NN 0
1-429 COOH Phenyl Meüiyl - CH2-CH2- 4-Me-Phenyl Me Me N N N 01-429 COOH Phenyl Meüiyl - CH 2 -CH 2 - 4-Me-Phenyl Me Me NNN 0
1-430 COOH 4-Et-Phenyl Meüiyl - CH2-CH2- 3-OMe-Phenyl OMe CF3 CH N N 01-430 COOH 4-Et-Phenyl Meüiyl - CH 2 -CH 2 - 3-OMe-Phenyl OMe CF 3 CH NN 0
1-431 COOH 4-Me-Phenyl Ethyl - CH2-CH2- CH2- 4-SMe-Phenyl OMe Me CH N N 01-431 COOH 4-Me-Phenyl Ethyl - CH2-CH2-CH2- 4-SMe-Phenyl OMe Me CH N N 0
1-432 COOH 4-Me-Phenyl CF3 - CH2-CH2- CH2- 4-SMe-Phenyl OMe O- CH2-CH2-C N N 01-432 COOH 4-Me-Phenyl CF 3 - CH 2 -CH 2 - CH 2 - 4-SMe-Phenyl OMe O-CH 2 -CH 2 -CNN 0
1-433 COOH 4-Et-Phenyl Methyl - CH(3-OMe- 3-OMe-Phenyl Me Me CH N N 0 Phenyl)-CH2-1-433 COOH 4-Et-Phenyl Methyl - CH (3-OMe- 3-OMe-Phenyl Me Me CH NN 0 Phenyl) -CH 2 -
1-434 COOH 4-Cl-Phenyl Methyl - CH2-CH2- Naphtiι-2-yl Me Me CH N N 01-434 COOH 4-Cl-Phenyl Methyl - CH2-CH2-Naphtiι-2-yl Me Me CH N N 0
1^135 COOH 4-CF3-Phenyl Meüiyl - CH2-CH2- 4-SMe-Phenyl OMe 0- CH2-CH2-C N N 01 ^ 135 COOH 4-CF 3 -phenyl Meüiyl - CH 2 -CH 2 - 4-SMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-436 COOH 4-CF3-Phenyl Meüiyl - CH2-CH2- 4-Me-Phenyl OMe Me CH N N 01-436 COOH 4-CF 3 -phenylmeiyl - CH2-CH2- 4-Me-phenyl OMe Me CH NN 0
1^437 COOH 4-Cl-Phenyl Methyl - CH2-CH2- NaphÜι-2-yl Me Me N N N 01 ^ 437 COOH 4-Cl-phenyl methyl - CH 2 -CH 2 - NaphÜι-2-yl Me Me NNN 0
1-438 COOH 4-Et-Phenyl Methyl - CH(OH)-CH2- 3-OMe-Phenyl Me Me N N N 01-438 COOH 4-Et-Phenyl Methyl - CH (OH) -CH 2 - 3-OMe-Phenyl Me Me NNN 0
1-439 COOH Phenyl Meüiyl - CH2-CH2- 4-OEt-Phenyl Ethyl Me CH N N 01-439 COOH Phenyl Meüiyl - CH2-CH 2 - 4-OEt-Phenyl Ethyl Me CH NN 0
1-440 COOH Phenyl Meüiyl - CH2-CH2- 4-OEt-Phenyl OMe CH2- CH2-CH2-C N N 01-440 COOH Phenyl Meüiyl - CH 2 -CH 2 - 4-OEt-Phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
O 1-441 COOH 4-Et-Phenyl Methyl ~ CH2-CH2- 3-OMe-Phenyl Me Me CH N CH 0 HO 1-441 COOH 4-Et-Phenyl Methyl ~ CH 2 -CH 2 - 3-OMe-Phenyl Me Me CH N CH 0 H
13 so13 so
o 00 o 00
Nr. R1 R5 R4 Q R6 R2 R3 Z X Y WNo. R 1 R 5 R 4 Q R6 R 2 R 3 ZXYW
1-442 COOH Phenyl -CH2-CH2-CF3 - CH2-CH2- CH2- 4-SMe-Phenyl Me Me CH N N 01-442 COOH phenyl -CH 2 -CH 2 -CF 3 - CH 2 -CH2- CH 2 - 4-SMe-phenyl Me Me CH NN 0
1-443 COOH Phenyl Methyl - CH2-CH2- CH2- 4-SMe-Phenyl Me Me N N N 01-443 COOH phenyl methyl - CH2-CH2-CH2- 4-SMe-phenyl Me Me N N N 0
1-444 COOH 4-Et-Phenyl Meüiyl - C(CH3)2-CH2- 3-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-444 COOH 4-Et-Phenyl Meüiyl - C (CH 3 ) 2 -CH 2 - 3-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1^445 COOH Phenyl Methyl - CH2-CH2- 3,4-Di-OMe-Phenyl Me Me CH N N 01 ^ 445 COOH phenyl methyl - CH 2 -CH 2 - 3,4-di-OMe-phenyl Me Me CH NN 0
1-446 COOH Phenyl Methyl - CH2-CH2- 3,4-Di-OMe-Phenyl Me Me N N N 01-446 COOH phenyl methyl - CH 2 -CH2- 3,4-di-OMe-phenyl Me Me NNN 0
1-447 COOH 4— Me-Phenyl CF3 — CH2— CH2- CH2— 3,4-Di-OMe-Phenyl Ethyl Me CH N N 01-447 4- COOH-phenyl Me CF 3 - CH 2 - CH 2 - CH 2 - 3,4-di-OMe-phenyl ethyl Me CH NN 0
1^448 COOH 4-Me-Phenyl Meüiyl - CH2-CH2- CH2- 3-OMe-Phenyl OMe 0- CH2-CH2-C N N 01 ^ 448 COOH 4-Me-Phenyl Meüiyl - CH 2 -CH2- CH 2 - 3-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1^149 COOH 4-Et-Phenyl Meüiyl - CH2-CH2- 4-SMe-Phenyl OMe Me CH N N s1 ^ 149 COOH 4-Et-Phenyl Meüiyl - CH 2 -CH 2 - 4-SMe-Phenyl OMe Me CH NN s
1^150 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 2-OMe-Phenyl Me Me CH N N 01 ^ 150 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH2- 2-OMe-Phenyl Me Me CH NN 0
1-451 COOH 4-CF3-Phenyl Meüiyl - CH2-CH2- 4-SMe-Phenyl Me Me N N N 01-451 COOH 4-CF 3 -phenyl Meüiyl - CH 2 -CH 2 - 4-SMe-Phenyl Me Me NNN 0
1-452 COOH 4-CF3-Phenyl Methyl - CH2-CH2- 4-SMe-Phenyl Ethyl Me CH N N 01-452 COOH 4-CF 3 -phenyl methyl - CH 2 -CH 2 - 4-SMe-phenyl ethyl Me CH NN 0
1-453 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 2-OMe-Phenyl Me Me N N N 0 011-453 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - 2-OMe-Phenyl Me Me NNN 0 01
1-454 COOBzl 4-Et-Phenyl Meüiyl - CH2-CH2- 4-SMe-Phenyl Me Me CH N N 01-454 COOBzl 4-Et-Phenyl Meüiyl - CH 2 -CH 2 - 4-SMe-Phenyl Me Me CH NN 0
1-455 COOH 4-Et-Phenyl Methyl - CH2-CH2- 4-SMe-Phenyl Ethyl Me CH CH N 01-455 COOH 4-Et-Phenyl Methyl - CH 2 -CH 2 - 4-SMe-Phenyl Ethyl Me CH CH N 0
1-456 COOH 4-Et-Phenyl CH2-0-CH2- - CH2-CH2- 4-Me-Phαιyl OMe Me N N N 0 CH3 1-456 COOH 4-Et-Phenyl CH 2 -0-CH 2 - - CH 2 -CH 2 - 4-Me-Phαιyl OMe Me NNN 0 CH 3
1-457 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 4-SMe-Phenyl OMe 0- CH2-CH2-C N N 01-457 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - 4-SMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-458 COOH Phenyl Methyl - CH2-CH2- CH2- 4-S Me-Phenyl CF3 Me CH N N 01-458 COOH phenyl methyl - CH 2 -CH 2 - CH 2 - 4-S Me-phenyl CF 3 Me CH NN 0
1-459 COOH Phenyl Meüiyl - CH2-CH2- CH2- 4-SMe-Phenyl OMe Me CH N N 01-459 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-SMe-Phenyl OMe Me CH NN 0
1-460 COOH 4-Cl-Phenyl Methyl - CH2-CH2- 4-OEt-3-OMe-Phenyl OMe Me CH N N 01-460 COOH 4-Cl-Phenyl Methyl - CH 2 -CH 2 - 4-OEt-3-OMe-Phenyl OMe Me CH NN 0
1^461 COOH 4-CF3-Phenyl Meüiyl - CH2-CH2- 4-OMe-Phenyl Me Me N CH N 01 ^ 461 COOH 4-CF 3 -phenyl Meüiyl - CH2-CH2- 4-OMe-Phenyl Me Me N CH N 0
1-462 COOH Phenyl Meüiyl - CH2-CH2- 4-Me-Phenyl CF3 Me CH N N 0 o1-462 COOH Phenyl Meüiyl - CH 2 -CH 2 - 4-Me-Phenyl CF 3 Me CH NN 0 o
H 1-463 COOH 4—Me-Phenyl -CH2-CH2-CF3 - CH2-CH2- CH2- 3,4-Di-OMe-Pheny] OMe Me CH N N 0 M -0 so H COOH 1-463 4-Me-phenyl -CH 2 -CH 2 -CF 3 - CH 2 -CH 2 - CH 2 - 3,4-di-OMe-phenyl] OMe Me CH NN 0 M -0 so
Nr. R1 R5 R4 Q R6 R2 R3 Z X Y W soNo.R 1 R5 R 4 QR 6 R 2 R 3 ZXYW see above
1-464 COOH 4-Me-Phenyl Meüiyl - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl Me Me CH N N 0 so1-464 COOH 4-Me-Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 3,4-Di-OMe-Phenyl Me Me CH NN 0 see above
*s* s
1—465 COOH Phenyl Meüiyl - CH2-CH2- 4-Me-Phenyl OMe Me CH N N 0 sβ1-465 COOH Phenyl Meüiyl - CH 2 -CH 2 - 4-Me-Phenyl OMe Me CH NN 0 sβ
SO 00SO 00
1-466 COOH 4-CF3-Phenyl Meüiyl - C(CH3)2-CH2- 4-OMe-Phenyl Ethyl Me CH N N 01-466 COOH 4-CF 3 -phenylmeiyl - C (CH 3 ) 2 -CH 2 - 4-OMe-phenylethyl Me CH NN 0
1-467 COOH 4-CF3-Phenyl Meüiyl - CH2-CH2- 4-SMe-Phenyl OMe Me CH N N 01-467 COOH 4-CF 3 -phenyl Meüiyl - CH2-CH2- 4-SMe-Phenyl OMe Me CH NN 0
1-468 COOH 4-CF3-Phenyl CF3 - CH2-CH2- 4-SMe-Phenyl Me Me CH N N 01-468 COOH 4-CF 3 -phenyl CF 3 - CH 2 -CH 2 - 4-SMe-Phenyl Me Me CH NN 0
1-469 COOH 4-CF3-Phenyl Meüiyl - CH2-CH2- 3,4-Di-OMe-Phenyl Ethyl Me CH CH N 01-469 COOH 4-CF 3 -phenylmeuyl - CH2-CH 2 - 3,4-di-OMe-phenyl ethyl Me CH CH N 0
1-470 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 4-Cl-Phenyl OMe 0- CH2-CH2-C N N 01-470 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - 4-Cl-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-471 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- NaphÜι-2-yl OMe Me CH N N 01-471 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2-NaphÜι-2-yl OMe Me CH N N 0
1-472 COOH 4-CF3-Phenyl Meüiyl - CH2-CH2- 3,4-Di-OMe-Phenyl OMe O- CH2-CH2-C N N s1-472 COOH 4-CF 3 -phenyl Meüiyl - CH 2 -CH 2 - 3,4-Di-OMe-Phenyl OMe O-CH 2 -CH 2 -CNN s
1-473 COOH Phenyl Methyl - CH2-CH2- 4-OEt-Phenyl Me Me CH N N 01-473 COOH phenyl methyl - CH 2 -CH 2 - 4-OEt-phenyl Me Me CH NN 0
1-474 COOH Phenyl Methyl - CH2-CH2- CH2- 3,4-Di-OMe-Phcnyl Ethyl Me CH N N 01-474 COOH Phenyl Methyl - CH 2 -CH 2 - CH 2 - 3,4-Di-OMe-Phcnyl Ethyl Me CH NN 0
1-475 COOH Phenyl Meüiyl — CH2— CH2— CH2— 3,4-Di-OMe-Phenyl OMe 0- CH2-CH2-C N N 0 σ.1-475 COOH Phenyl Meüiyl - CH2 - CH2 - CH2 - 3,4-Di-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0 σ.
1-476 COOH Phenyl Meüiyl - CH2-CH2- 4-OEt-Phenyl Me Me N N N 01-476 COOH Phenyl Meüiyl - CH 2 -CH 2 - 4-OEt-Phenyl Me Me NNN 0
1-477 COOH CH2-0-CH2-1-477 COOH CH 2 -0-CH 2 -
4-CF3-Phenyl CH3 - CH2-CH2- 3-OMe-Phenyl Ethyl Me N N N 04-CF 3 -phenyl CH 3 - CH2-CH2- 3-OMe-phenyl ethyl Me NNN 0
1-478 COOH 4-CF3-Phenyl Meüiyl - CH2-CH2- 2-Me-3-OMe-Phenyl OMe O- CH2-CH2-C N N 01-478 COOH 4-CF 3 -phenylmeiyl - CH 2 -CH 2 - 2-Me-3-OMe-Phenyl OMe O-CH2-CH2-C NN 0
1-479 COOH 4-Me-PhenyI Meüiyl - CH2-CH2- CH2- 4-OMe-Phenyl Ethyl Me CH N N 01-479 COOH 4-Me-PhenyI Meüiyl - CH2-CH2-CH2- 4-OMe-Phenyl Ethyl Me CH N N 0
1-480 COOH 4-Me-Phenyl Meüiyl - CH2-CH2- CH2- 4-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-480 COOH 4-Me-Phenyl Meüiyl - CH2-CH2-CH2- 4-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-481 COOH Phenyl Meüiyl - CH2-CH2- 3,4-Di-OMe-Phenyl OMe OMe CH N N 01-481 COOH Phenyl Meüiyl - CH2-CH2- 3,4-Di-OMe-Phenyl OMe OMe CH N N 0
1-482 COOH Phenyl Meüiyl - CH2-CH2- 3,4-Di-OMe-Phenyl OMe Me CH N N 01-482 COOH Phenyl Meüiyl - CH 2 -CH 2 - 3,4-Di-OMe-Phenyl OMe Me CH NN 0
1-483 COOH 4-CF3-Phenyl Methyl - CH2-CH2- 3-OMe-Phenyl Ethyl Me CH N N 01-483 COOH 4-CF 3 -phenyl methyl - CH 2 -CH 2 - 3-OMe-phenyl ethyl Me CH NN 0
1-484 COOH 4-CF3-Phenyl -CH2-CH2-CF3 - CH2-CH2- 3-OMe-Phenyl OMe O- CH2-CH2-C N N 0 o1-484 COOH 4-CF 3 -phenyl -CH 2 -CH 2 -CF 3 - CH2-CH2- 3-OMe-Phenyl OMe O- CH 2 -CH2-C NN 0 o
HH
1-485 COOH 4-CF3-Phenyl Methyl - CH2-CH2- 3-Me-4-SMe-Phenyl OMe Me CH N N 0 M so so 1-485 COOH 4-CF 3 -phenyl methyl - CH2-CH2- 3-Me-4-SMe-phenyl OMe Me CH NN 0 M so so
Nr. R1 R5 R4 Q R6 R2 R3 Z X Y WNo. R 1 R 5 R 4 QR 6 R 2 R 3 ZXYW
1-486 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 3-OMe-Phenyl OMe 0- CH2-CH2-C N N O1-486 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - 3-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNNO
*-* -
1-487 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 2-OMe-Phenyl OMe Me CH N N 01-487 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - 2-OMe-Phenyl OMe Me CH NN 0
1-488 COOH 4-CF3-Phenyl Methyl - CH2-CH2- Cyclohexyl OMe Me CH N N 01-488 COOH 4-CF 3 -phenyl methyl - CH 2 -CH 2 - cyclohexyl OMe Me CH NN 0
1-489 COOH 4-CF3-Phenyl CF3 - CH2-CH2- 4-Me-Phenyl Me Me CH N N s1-489 COOH 4-CF 3 -phenyl CF 3 - CH 2 -CH 2 - 4-Me-Phenyl Me Me CH NN s
1-490 COOH Phenyl Meüiyl - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl Me Me CH N N 01-490 COOH Phenyl Meüiyl - CH2-CH 2 - CH 2 - 3,4-Di-OMe-Phenyl Me Me CH NN 0
1^.91 COOH Phenyl Methyl - CH2-CH2- CH2- 3 ,4-Di-OMe-Phenyl Me Me N N N 01 ^ .91 COOH Phenyl Methyl - CH 2 -CH 2 - CH 2 - 3, 4-Di-OMe-Phenyl Me Me NNN 0
1-492 COOH 4-Me-Phenyl Methyl - CH2-CH2- Cyclohexyl OMe Me CH N N 01-492 COOH 4-Me-Phenyl Methyl - CH 2 -CH 2 - Cyclohexyl OMe Me CH NN 0
1^193 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 4-SMe-Phenyl Me Me N N N 01 ^ 193 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - 4-SMe-Phenyl Me Me NNN 0
1-494 COOH 4-Cl-Phenyl Methyl - CH2-CH2- 4-SMe-Phenyl Ethyl Me CH N N 01-494 COOH 4-Cl-Phenyl Methyl - CH2-CH 2 - 4-SMe-Phenyl Ethyl Me CH NN 0
1-495 COOH 4-CF3-Phenyl Meüiyl - CH2-CH2- CH2- 4-Me-Phenyl OMe O- CH2-CH2-C N N 01-495 COOH 4-CF 3 -phenylmeiyl - CH 2 -CH 2 - CH 2 - 4-Me-phenyl OMe O- CH 2 -CH 2 -CNN 0
1-496 COOH 4-Me-Phenyl Meüiyl - CH2-CH2- CH2- 4-OMe-Phenyl OMe Me CH N N 01-496 COOH 4-Me-Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-OMe-Phenyl OMe Me CH NN 0
1-497 COOH 4-Me-Phenyl Meüiyl - CH2-CH2- 4-OMe-Phenyl Me Me CH N N s1-497 COOH 4-Me-Phenyl Meüiyl - CH 2 -CH 2 - 4-OMe-Phenyl Me Me CH NN s
1-498 COOH Phenyl CH2-0-CH2- - CH2-CH2- 3 ,4-Methylendioxyphenyl OMe CH2- CH2-CH2-C N N 0 CH3 1-498 COOH phenyl CH 2 -0-CH 2 - - CH 2 -CH 2 - 3, 4-methylenedioxyphenyl OMe CH 2 - CH 2 -CH 2 -CNN 0 CH 3
1-499 COOH Phenyl Methyl - CH2-CH2- CH2- Phenyl OMe Me CH N N 01-499 COOH phenyl methyl - CH 2 -CH 2 - CH 2 - phenyl OMe Me CH NN 0
1-500 COOH Phenyl Meüiyl - CH2-CH2- CH2- Phenyl Me Me CH N N 01-500 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - Phenyl Me Me CH NN 0
1-501 COOH Phenyl Methyl - CH2-CH2- 3,4-Methylendioxyphenyl OMe O- CH2-CH2-C N N 01-501 COOH phenyl methyl - CH 2 -CH 2 - 3,4-methylenedioxyphenyl OMe O- CH 2 -CH 2 -CNN 0
1-502 COOH 4-Me-Phenyl Meüiyl - CH2-CH2- 3,4-Di-OMe-Phenyl Me Me N CH N 01-502 COOH 4-Me-Phenyl Meüiyl - CH 2 -CH 2 - 3,4-Di-OMe-Phenyl Me Me N CH N 0
1-503 COOH 4-Me-Phenyl Meüiyl - CH2-CH2- 3,4-Di-OMe-Phenyl Ethyl Me CH N N s1-503 COOH 4-Me-Phenyl Meüiyl - CH 2 -CH 2 - 3,4-Di-OMe-Phenyl Ethyl Me CH NN s
1-504 COOH 4-Cl-Phenyl Methyl - CH2-CH2- 4-Cl-Phenyl Me Me N N N 01-504 COOH 4-Cl-Phenyl Methyl - CH 2 -CH 2 - 4-Cl-Phenyl Me Me NNN 0
1-505 COOH 4-Cl-Phenyl -CH2-CH2-CF3 - CH2-CH2- 4-Cl-Phenyl Ethyl Me CH N N 01-505 COOH 4-Cl-phenyl -CH 2 -CH 2 -CF 3 - CH 2 -CH 2 - 4-Cl-phenyl ethyl Me CH NN 0
1-506 COOH Phenyl Meüiyl - CH -CH2— CH2- 3,4-Di-OMe-PhenyI CF3 Me CH N N 0 n H 1-507 COOH Phenyl Methyl - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl OMe Me CH N N 0 so so 1-506 COOH Phenyl Meüiyl - CH -CH 2 - CH 2 - 3,4-Di-OMe-PhenyI CF 3 Me CH NN 0 n H 1-507 COOH phenyl methyl - CH2-CH 2 - CH 2 - 3,4-di-OMe-phenyl OMe Me CH NN 0 so so
Nr. R1 R5 R4 Q R6 R2 R3 Z X Y WR 1 R5 R 4 QR 6 R 2 R 3 ZXYW
1-508 COOH 4-Me-Phenyl SO1-508 COOH 4-Me-Phenyl SO
Methyl - CH2-CH2- Cyclopentyl OMe Me CH N N 0 SOMethyl - CH 2 -CH 2 - cyclopentyl OMe Me CH NN 0 SO
J≥J≥
1-509 COOH Phenyl Meüiyl - CH2-CH2- 4-OEt-Phenyl CF3 Me CH N N 0 SO SS1-509 COOH Phenyl Meüiyl - CH 2 -CH 2 - 4-OEt-Phenyl CF 3 Me CH NN 0 SO SS
1-510 COOH Phenyl CF3 CH N N 0 001-510 COOH phenyl CF 3 CH NN 0 00
- CH2-CH2- 4-OEt-Phenyl OMe Me- CH 2 -CH 2 - 4-OEt-phenyl OMe Me
1-511 COOH 4-CF3-Phenyl Meüiyl - CH2-CH2- CH2- 4-Me-Phenyl Me Me N N N 01-511 COOH 4-CF 3 -phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-Me-Phenyl Me Me NNN 0
1-512 COOH 4-CF3-Phenyl Meüiyl - CH2-CH2- CH2- 4-Me-Phenyl Ethyl Me CH N N 01-512 COOH 4-CF 3 -phenylmeiyl - CH 2 -CH 2 - CH 2 - 4-Me-phenyl ethyl Me CH NN 0
1-513 COOH 4-Me-Phenyl Meüiyl - CH2-CH2- 4-SMe-Phenyl OMe Me CH N N s1-513 COOH 4-Me-Phenyl Meüiyl - CH 2 -CH 2 - 4-SMe-Phenyl OMe Me CH NN s
1-514 COOH 4-Me-Phenyl Methyl - CH2-CH2- 4-SMe-Phenyl Ethyl Mc N N N 01-514 COOH 4-Me-Phenyl Methyl - CH 2 -CH 2 - 4-SMe-Phenyl Ethyl McNNN 0
1-515 COOH 4-Me-Phenyl Methyl - CH2-CH2- 4-Me-Phenyl OMe 0- CH2-CH2-C N N 01-515 COOH 4-Me-Phenyl Methyl - CH 2 -CH 2 - 4-Me-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-516 COOH Phenyl Meüiyl - CH2-CH2- CH2- Phenyl CF3 Me CH N N 01-516 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - Phenyl CF 3 Me CH NN 0
1-517 COOH Phenyl Methyl - CH2-CH2- 4-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-517 COOH phenyl methyl - CH 2 -CH 2 - 4-OMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-518 COOH Phenyl Methyl - CH2-CH2- 3,4-Di-OMe-Phenyl CF3 Me CH N N 0 2- 001-518 COOH phenyl methyl - CH 2 -CH 2 - 3,4-di-OMe-phenyl CF 3 Me CH NN 0 2 - 00
1-519 COOH CH2-0-CH1-519 COOH CH 2 -0-CH
4-Me-Phenyl - CH2-CH2- 4-SMe-Phenyl Ethyl Me CH CH N 0 CH3 4-Me-Phenyl - CH 2 -CH 2 - 4-SMe-Phenyl Ethyl Me CH CH N 0 CH 3
1-520 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 3-OMe-Phenyl Me Me N N N 01-520 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - 3-OMe-Phenyl Me Me NNN 0
1-521 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 3-OMe-Phenyl Ethyl Me CH N N 01-521 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - 3-OMe-Phenyl Ethyl Me CH NN 0
1-522 COOH Phenyl Meüiyl - CH2-CH2- CH2- 4-OMe-Phenyl OMe CH2- CH2-CH2-C N N 01-522 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-OMe-Phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-523 COOH Phenyl Methyl — Cri2— Cri2— Cri2~~ 4-OMe-Phenyl OMe O- CH2-CH2-C N N 01-523 COOH Phenyl Methyl - Cri2 - Cri2 - Cri2 ~~ 4-OMe-Phenyl OMe O- CH 2 -CH 2 -CNN 0
1-524 COOMe 4-Me-Phenyl Meüiyl - CH2-CH2- 4-Me-Phenyl OMe O- CH2-CH2-C N N 01-524 COOMe 4-Me-Phenyl Meüiyl - CH 2 -CH 2 - 4-Me-Phenyl OMe O-CH 2 -CH 2 -CNN 0
1-525 COOMe Phenyl Methyl - CH2-CH2- CH2- Phenyl CF3 Me CH N N 01-525 COOMe Phenyl Methyl - CH 2 -CH 2 - CH 2 - Phenyl CF 3 Me CH NN 0
1-526 COOH Phenyl Meüiyl - CH2-CH2- CH2- Phenyl OMe Me CH N N s1-526 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - Phenyl OMe Me CH NN s
1-527 COOH 4-CF3-Phenyl Meüiyl - CH2-CH2- CH2- 4-SMe-Phenyl Ethyl Me CH N N 01-527 COOH 4-CF 3 -phenylmeiyl - CH 2 -CH 2 - CH 2 - 4-SMe-phenyl ethyl Me CH NN 0
*<3* <3
1-528 COOH 4-CF3-Phenyl Meüiyl - CH2-CH2- CH2- 4-SMe-Phenyl OMe 0- CH2-CH2-C N N 0 o1-528 COOH 4-CF 3 -phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-SMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0 o
H 1-529 COOH 4-Cl-Phenyl Methyl - CH2-CH2- 4-SMe-Phenyl OMe Me CH N N 0 "0 so soH 1-529 COOH 4-Cl-Phenyl Methyl - CH 2 -CH 2 - 4-SMe-Phenyl OMe Me CH NN 0 "0 so so
© 00 © 00
Nr. R1 R5 R4 Q R6 R2 R3 Z X Y W gNo.R 1 R 5 R 4 QR 6 R 2 R 3 ZXYW g
1-530 COOH 4-Cl-Phenyl Methyl - CH2-CH2- 4-SMe-Phenyl Me Me CH N N 0 •fe -≥.1-530 COOH 4-Cl-Phenyl Methyl - CH 2 -CH 2 - 4-SMe-Phenyl Me Me CH NN 0 • fe -≥.
1-531 COOH 4-Me-Phenyl Methyl - CH2-CH2- 4—Me-Phenyl Me Me N N N 01-531 COOH 4-Me-Phenyl Methyl - CH2-CH2- 4-Me-Phenyl Me Me N N N 0
1-532 COOH 4-Me-Phenyl Methyl - CH2-CH2- 4-Me-Phenyl Ethyl Me CH N N 01-532 COOH 4-Me-Phenyl Methyl - CH 2 -CH2- 4-Me-Phenyl Ethyl Me CH NN 0
1-533 COOH Phenyl Meüiyl - CH2-CH2- CH2- 4-F-Phenyl Me Me CH N N 01-533 COOH Phenyl Meüiyl - CH 2 -CH2- CH2- 4-F-Phenyl Me Me CH NN 0
1-534 COOH Phenyl Meüiyl - CH2-CH2- 3 ,4-Methylendioxyphenyl Me Me N N N 01-534 COOH Phenyl Meüiyl - CH 2 -CH2- 3, 4-methylenedioxyphenyl Me Me NNN 0
1-535 COOH Phenyl Meüiyl - CH2-CH2- 3,4— Methylendioxyphenyl Ethyl Me CH N N 01-535 COOH Phenyl Meüiyl - CH 2 -CH2- 3,4-methylenedioxyphenyl Ethyl Me CH NN 0
1-536 COOH Phenyl Meüiyl - CH2-CH2- CH2- Phenyl Me Me N N CH 01-536 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - Phenyl Me Me NN CH 0
1-537 COOH 4-Br-Phenyl Meüiyl - CH2-CH2- CH2- Phenyl Ethyl Me CH N N 01-537 COOH 4-Br-Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - Phenyl Ethyl Me CH NN 0
1-538 COOH Phenyl Meüiyl - CH2-CH2- CH2- 4-OMe-Phenyl Me Me N N N 01-538 COOH Phenyl Meüiyl - CH 2 -CH2- CH2- 4-OMe-Phenyl Me Me NNN 0
1-539 COOH Phenyl Meüiyl - CH2-CH2- CH2- 4-OMe-Phenyl Ethyl Me CH N N 01-539 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-OMe-Phenyl Ethyl Me CH NN 0
1-540 COOH 4-Cl-Phenyl Methyl - CH2-CH2- 4-Cl-Phenyl OMe Me CH N N 01-540 COOH 4-Cl-Phenyl Methyl - CH 2 -CH2- 4-Cl-Phenyl OMe Me CH NN 0
1-541 COOH 4-Cl-Phenyl Methyl - CH2-CH2- 4-Cl-Phenyl Me Me CH N N 0 -s1-541 COOH 4-Cl-Phenyl Methyl - CH 2 -CH2- 4-Cl-Phenyl Me Me CH NN 0 -s
1-542 COOH 4-F-Phenyl Meüiyl - CH2-CH2- CH2- Phenyl OMe 0- CH2-CH2-C N N 01-542 COOH 4-F-Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-543 COOH 4-CF3-Phenyl Methyl - CH2-CH2- CH2- 3-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-543 COOH 4-CF 3 -phenyl methyl - CH 2 -CH 2 - CH 2 - 3-OMe-Phenyl OMe 0- CH 2 -CH2-C NN 0
1-544 COOH 4-CF3-Phenyl Meüiyl - CH2-CH2- CH2- 4-SMe-Phenyl OMe Me CH N N 01-544 COOH 4-CF 3 -phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-SMe-Phenyl OMe Me CH NN 0
1-545 COOH Phenyl Meüiyl - CH2-CH2- Naphth-2-yl OMe CH2- CH2-CH2-C N N 01-545 COOH Phenyl Meüiyl - CH 2 -CH 2 - Naphth-2-yl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-546 COOH Phenyl Meüiyl - CH2-CH2- NaphÜι-2-yl OMe 0- CH2-CH2-C N N 01-546 COOH Phenyl Meüiyl - CH 2 -CH2- NaphÜι-2-yl OMe 0- CH 2 -CH 2 -CNN 0
1-547 COOH 4-Me-Phcnyl Meüiyl - CH2-CH2- 4-Me-Phenyl OMe Me CH N N 01-547 COOH 4-Me-Phenyl Meüiyl - CH 2 -CH 2 - 4-Me-Phenyl OMe Me CH NN 0
1-548 COOH 4-Me-Phenyl Methyl - CH2-CH2- 4-Me-Phenyl Me Me CH N N 01-548 COOH 4-Me-Phenyl Methyl - CH 2 -CH 2 - 4-Me-Phenyl Me Me CH NN 0
1-549 COOMe Phenyl Meüiyl - CH(Phenyl)-CH2- Phenyl CF3 Me CH N N 0 CH2-1-549 COOMe Phenyl Meüiyl - CH (Phenyl) -CH 2 - Phenyl CF 3 Me CH NN 0 CH 2 -
1-550 COOH 4-F-Phenyl Meüiyl - CH(Plιenyl)-CH2- Phenyl OMe Me CH N N 0 o CH2- H 1-551 COOH Phenyl Methyl - CH2-CH2- 4-OMe-Phenyl Ethyl Me CH N N 0 1-550 COOH 4-F-Phenyl Meüiyl - CH (Plιenyl) -CH 2 - Phenyl OMe Me CH NN 0 o CH 2 - H 1-551 COOH phenyl methyl - CH 2 -CH 2 - 4-OMe-phenyl ethyl Me CH NN 0
Nr. R1 R5 R4 Q R6 R2 R3 Z X Y W soNo. R 1 R5 R 4 Q R6 R 2 R 3 ZXYW see above
1-552 COOH Phenyl Meüiyl — CH2— CH2— 4-OMe-Phenyl OMe CH2- CH2-CH2-C N N 0 o (Phenyl)-CH2- SO1-552 COOH Phenyl Meüiyl - CH 2 - CH2 - 4-OMe-Phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0 o (phenyl) -CH 2 - SO
1-553 COOH Phenyl Meüiyl - CH Phenyl Me Me CH CH N 0 SO CH2- 001-553 COOH Phenyl Meüiyl - CH Phenyl Me Me CH CH N 0 SO CH 2 - 00
1-554 COOH Phenyl Meüiyl - CH2-CH2- CH2- 4-OMe-Phenyl OMe Me CH N N 01-554 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-OMe-Phenyl OMe Me CH NN 0
1-555 COOH Phenyl Methyl - CH2-CH2- CH2- 4-OMe-Phenyl Me Me CH N N 01-555 COOH phenyl methyl - CH 2 -CH 2 - CH 2 - 4-OMe-phenyl Me Me CH NN 0
1-556 COOH 4-Cl-Phenyl Methyl - CH2-CH2- 3-OMe-Phenyl OMe Me CH N N 01-556 COOH 4-Cl-phenyl methyl - CH2-CH2-3-OMe-phenyl OMe Me CH N N 0
1-557 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 3-OMe-Phenyl Me Me CH N N 01-557 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - 3-OMe-Phenyl Me Me CH NN 0
1-558 COOH Phenyl - CH(Phenyl)-CH2-1-558 COOH phenyl - CH (phenyl) -CH 2 -
Meüiyl Phenyl OMe Me N N N 0 CH2-Meüiyl Phenyl OMe Me NNN 0 CH 2 -
1-559 COOH 4~CF3-Phenyl Meüiyl - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-559 COOH 4 ~ CF 3 -phenylmeuyl - CH 2 -CH 2 - CH 2 - 3,4-di-OMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-560 COOH 4-CF3-Phenyl Meüiyl - CH2-CH2- CH2- 3-OMe-Phenyl Ethyl Me CH N N 01-560 COOH 4-CF 3 -phenylmeiyl - CH 2 -CH 2 - CH 2 - 3-OMe-phenyl ethyl Me CH NN 0
- CH(Phenyl)-CH2-- CH (phenyl) -CH 2 -
1-561 COOH Phenyl Meüiyl Phenyl Ethyl Me N N N 0 m CH2- o1-561 COOH Phenyl Meüiyl Phenyl Ethyl Me NNN 0 m CH 2 - o
1-562 COOMe Phenyl Meüiyl - CH2-CH2- CH2- 4-OMe-Phenyl CF3 Me CH N N 01-562 COOMe Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-OMe-Phenyl CF 3 Me CH NN 0
1-563 COOH 4-Me-Phenyl Meüiyl - CH2-CH2- 4-SMe-Phenyl EÜiyl Me CH N N 01-563 COOH 4-Me-Phenyl Meüiyl - CH 2 -CH 2 - 4-SMe-Phenyl EÜiyl Me CH NN 0
1-564 COOH 4-Me-Phenyl Meüiyl - CH2-CH2- 4-SMe-Phenyl OMe 0- CH2-CH2-C N N 01-564 COOH 4-Me-Phenyl Meüiyl - CH 2 -CH 2 - 4-SMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-565 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 3,4,5-Tri-OMe-Phenyl Etiiyl Me CH N N 01-565 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - 3,4,5-Tri-OMe-Phenyl Etiiyl Me CH NN 0
1-566 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 3 ,4,5-Tri-OMe-Phenyl OMe O- CH2-CH2-C N N 01-566 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - 3, 4,5-Tri-OMe-Phenyl OMe O-CH2-CH 2 -CNN 0
1-567 COOH Phenyl Meüiyl - CH2-CH2- CH2- 4-OMe-Phenyl OMe Me CH N N s1-567 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-OMe-Phenyl OMe Me CH NN s
1-568 COOH Phenyl — CH2— CH2— CF3 - CH2-CH2- 3 ,4—Methylendioxyphenyl OMe Me CH N N 01-568 COOH phenyl - CH 2 - CH 2 - CF 3 - CH 2 -CH 2 - 3, 4-methylenedioxyphenyl OMe Me CH NN 0
1-569 COOH Phenyl Meüiyl - CH2-CH2- 3,4-Methylendioxyphenyl Me Me CH N N 01-569 COOH Phenyl Meüiyl - CH 2 -CH 2 - 3,4-methylenedioxyphenyl Me Me CH NN 0
1-570 COOH Phenyl - CH(Phenyl)-CH2-1-570 COOH phenyl - CH (phenyl) -CH 2 -
Meüiyl Phenyl OMe O- CH2-CH2-C N N 0 *0 CH2- r>Meüiyl Phenyl OMe O- CH 2 -CH2-C NN 0 * 0 CH 2 - r>
1-571 COOH Phenyl Meüiyl - CH2-CH2- CH2- 4-OMe-Phenyl CF3 Me CH N N 0 ps1-571 COOH Phenyl Meüiyl - CH2-CH2-CH2- 4-OMe-Phenyl CF 3 Me CH NN 0 ps
13 so so o13 so so o
00 00
Nr. R1 R5 R4 Q R6 R2 R3 Z X Y W soNo. R 1 R 5 R 4 Q R6 R 2 R 3 ZXYW see above
1-572 COOH Phenyl Methyl - CH2-CH2- CH2- 4-OMe-Phenyl Me Me CH N CH 0 o1-572 COOH phenyl methyl - CH 2 -CH 2 - CH 2 - 4-OMe-phenyl Me Me CH N CH 0 o
1-573 COOH Phenyl CF3 - CH2-CH2- CH2- 4-OMe-Phenyl Ethyl Me N N N O1-573 COOH Phenyl CF 3 - CH 2 -CH 2 - CH 2 - 4-OMe-Phenyl Ethyl Me NNNO
1-574 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 4-Et-Phenyl Ethyl Me CH N N 01-574 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - 4-Et-Phenyl Ethyl Me CH NN 0
1-575 COOH 4-CF3-Phenyl Meüiyl - CH2-CH2- CH2- 3 ,4-Di-OMe-Phenyl OMe Me CH N N 01-575 COOH 4-CF 3 -phenylmeuyl - CH2-CH2-CH2- 3,4,4-di-OMe-phenyl OMe Me CH NN 0
1-576 COOH 4-CF3-Phenyl Meüiyl - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl Ethyl Me CH N N 01-576 COOH 4-CF 3 -phenylmeiyl - CH2-CH2-CH2- 3,4-di-OMe-phenyl ethyl Me CH NN 0
1-577 COOH 4-Cl-Phenyl Methyl - CH2-CH2- 4-Et-Phenyl OMe O- CH2-CH2-C N N 01-577 COOH 4-Cl-Phenyl Methyl - CH2-CH2- 4-Et-Phenyl OMe O-CH 2 -CH 2 -CNN 0
1-578 COOH Phenyl Meüiyl - CH2-CH2- CH2- 3-Cl-4-OMe-Phenyl Ethyl Me CH N N 01-578 COOH Phenyl Meüiyl - CH2-CH2-CH2- 3-Cl-4-OMe-Phenyl Ethyl Me CH N N 0
1-579 COOH 4-Me-Phenyl Meüiyl - CH2-CH2- 4-SMe-Phenyl Me Me CH N N 01-579 COOH 4-Me-Phenyl Meüiyl - CH2-CH2- 4-SMe-Phenyl Me Me CH N N 0
1-580 COOH 4-Me-Phenyl Methyl - CH2-CH2- 4-SMe-Phenyl Me Me N N N 01-580 COOH 4-Me-Phenyl Methyl - CH2-CH2- 4-SMe-Phenyl Me Me N N N 0
1-581 COOH Phenyl Meüiyl - CH2-CH2- Naphth-2-yl Me Me N N N 01-581 COOH Phenyl Meüiyl - CH 2 -CH 2 - Naphth-2-yl Me Me NNN 0
1-582 COOH - CH(Phenyl)-CH2-1-582 COOH - CH (phenyl) -CH 2 -
Phenyl Meüiyl Phenyl Me Me N N N 0 CH2- υiPhenyl Meüiyl Phenyl Me Me NNN 0 CH 2 - υi
1-583 COOH Phenyl CH2-0-CH2-C1-583 COOH phenyl CH 2 -0-CH 2 -C
- CH2-CH2- Naphth-2-yl Ethyl Me CH N N 0 H3 - CH2-CH2-naphth-2-yl ethyl Me CH NN 0 H 3
1-584 COOH 4-F-Phenyl Meüiyl - CH2-CH2- CH2- 4-OMe-Phenyl OMe CH2-CH2-CH2-C N N 01-584 COOH 4-F-Phenyl Meüiyl - CH2-CH2-CH2- 4-OMe-Phenyl OMe CH 2 -CH 2 -CH 2 -CNN 0
1-585 COOH 4-F-Phenyl Meüiyl - CH2-CH2- CH2- 4-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-585 COOH 4-F-Phenyl Meüiyl - CH2-CH2-CH2- 4-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-586 COOH Phenyl Meüiyl - CH2-CH2- 4-OMe-Phenyl Me Me CH N N 01-586 COOH Phenyl Meüiyl - CH2-CH2- 4-OMe-Phenyl Me Me CH N N 0
1-587 COOH Phenyl Butyl - CH(Phenyl)-CH2- Phenyl Ethyl Me CH N N 0 CH2-1-587 COOH phenyl butyl - CH (phenyl) -CH 2 - phenyl ethyl Me CH NN 0 CH 2 -
1-588 COOH Phenyl Methyl - CH2-CH2- 4-OMe-Phenyl Me Me N N N 01-588 COOH phenyl methyl - CH 2 -CH 2 - 4-OMe-phenyl Me Me NNN 0
1-589 COOH 4-F-Phenyl Methyl - CH2-CH2- CH2- 3 ,4-Di-OMc-Phenyl CF3 Me CH N N 01-589 COOH 4-F-phenyl methyl - CH 2 -CH 2 - CH 2 - 3, 4-di-OMc-phenyl CF 3 Me CH NN 0
1-590 COOH 4-Cl-Phenyl — CH2— CH2— CF3 - CH2-CH2- 3,5-Di-OMe-Phenyl Ethyl Me CH N N 01-590 COOH 4-Cl-Phenyl - CH 2 - CH 2 - CF 3 - CH2-CH2- 3,5-Di-OMe-Phenyl Ethyl Me CH NN 0
1-591 COOH 4-Et-Phenyl Meüiyl - CH2-CH2- CH2- 4-Me-Phenyl OMe 0- CH2-CH2-C N N 0 o1-591 COOH 4-Et-Phenyl Meüiyl - CH2-CH2-CH 2 - 4-Me-Phenyl OMe 0- CH 2 -CH 2 -CNN 0 o
HH
1-592 COOH 4- CF3-Phenyl Meüiyl — CH2— CH2— CH2— 4-OMe-Phenyl OMe 0- CH2-CH2-C N N 0 "V1-592 COOH 4- CF 3 -phenylmeüyl - CH2-CH2-CH 2 - 4-OMe-phenyl OMe-CH 2 -CH 2 -CNN 0 "V
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Nr. R1 R5 R4 Q R6 R2 R3 Z X Y W soNo.R 1 R 5 R 4 QR 6 R 2 R 3 ZXYW see above
1-593 COOH 4-Cl-Phenyl Methyl - CH2-CH2- 3,5-Di-OMe-Phenyl OMe O- CH2-CH2-C N N 0 SO1-593 COOH 4-Cl-phenyl methyl - CH 2 -CH 2 - 3,5-di-OMe-phenyl OMe O-CH 2 -CH 2 -CNN 0 SO
44
S---- O-S ---- O-
1-594 COOH Phenyl - CH(OH)-CH(OH)-1-594 COOH phenyl - CH (OH) -CH (OH) -
Meüiyl 3,4-Di-OMe-Phenyl OMe Me CH N N 0 SO CH2- 00Meüiyl 3,4-Di-OMe-Phenyl OMe Me CH NN 0 SO CH 2 - 00
1-595 COOH 4-Me-Phenyl CF3 - CH2-CH2- 3-OMe-Phenyl OMe O- CH2-CH2-C N N 01-595 COOH 4-Me-Phenyl CF 3 - CH 2 -CH 2 - 3-OMe-Phenyl OMe O-CH 2 -CH2-C NN 0
1-596 COOH 4-Me-Phenyl Meüiyl - CH2-CH2- 4-SMe-Phenyl OMe Me CH N N 01-596 COOH 4-Me-Phenyl Meüiyl - CH 2 -CH 2 - 4-SMe-Phenyl OMe Me CH NN 0
1-597 COOH Phenyl Meüiyl - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl Me Me CH N N s1-597 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 3,4-Di-OMe-Phenyl Me Me CH NN s
1-598 COOH Phenyl Methyl - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl Me Me N CH N 01-598 COOH phenyl methyl - CH 2 -CH 2 - CH 2 - 3,4-di-OMe-phenyl Me Me N CH N 0
1-599 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 3,4,5-Tri-OMe-Phenyl Me Me CH N N 01-599 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - 3,4,5-Tri-OMe-Phenyl Me Me CH NN 0
1-600 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 3 ,4,5-Tri-OMe-Phenyl Me Me N N N 01-600 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - 3, 4,5-Tri-OMe-Phenyl Me Me NNN 0
1-601 COOEt Phenyl Methyl - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl Ethyl Me CH N N 01-601 COOEt Phenyl Methyl - CH 2 -CH 2 - CH 2 - 3,4-Di-OMe-Phenyl Ethyl Me CH NN 0
1-602 COOH Phenyl Meüiyl - CH(Phenyl)-CH2- Phenyl OMe Me CH N N 0 CH2- υi to1-602 COOH Phenyl Meüiyl - CH (Phenyl) -CH 2 - Phenyl OMe Me CH NN 0 CH 2 - υi to
1-603 COOH Phenyl Meüiyl - CH(Phenyl)-CH2- Phenyl Me Me CH N N 0 CH2-1-603 COOH Phenyl Meüiyl - CH (Phenyl) -CH 2 - Phenyl Me Me CH NN 0 CH 2 -
1-604 COOH Phenyl CH2-0-CH2-C H3 - CH2-CH2- 4-iPr-Phenyl OMe O- CH2-CH2-C N N 01-604 COOH phenyl CH 2 -0-CH 2 -CH 3 - CH 2 -CH 2 - 4-iPr-phenyl OMe O-CH 2 -CH 2 -CNN 0
1-605 COOH Phenyl Meüiyl - CH2-CH2- 3 ,4-Methylendioxyphenyl CF3 Me CH N N 01-605 COOH Phenyl Meüiyl - CH 2 -CH 2 - 3, 4-methylenedioxyphenyl CF 3 Me CH NN 0
1-606 COOH Phenyl Methyl - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl OMe O- CH2-CH2-C N N s1-606 COOH phenyl methyl - CH2-CH2-CH2- 3,4-di-OMe-phenyl OMe O-CH 2 -CH 2 -CNN s
1-607 COOH 4-Et-Phenyl Meüiyl - CH2-CH2- CH2- 4-SMe-Phenyl OMe O- CH2-CH2-C N N 01-607 COOH 4-Et-Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-SMe-Phenyl OMe O- CH 2 -CH 2 -CNN 0
1-608 COOH 4-Et-Phenyl Meüiyl - CH2-CH2- CH2- 4-Me-Phenyl OMe Me CH N N 01-608 COOH 4-Et-Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-Me-Phenyl OMe Me CH NN 0
1-609 COOH 4-Br-Phenyl Propyl - CH2-CH2- CH2- 4-SMe-Phenyl OMe Me CH N N 01-609 COOH 4-Br-Phenyl Propyl - CH 2 -CH 2 - CH 2 - 4-SMe-Phenyl OMe Me CH NN 0
1-610 COOH 4-Cl-Phenyl Methyl - CH2-CH2- 4-Et-Phenyl Me Me CH N N 01-610 COOH 4-Cl-Phenyl Methyl - CH 2 -CH 2 - 4-Et-Phenyl Me Me CH NN 0
1-611 COOH 4—Me-Phenyl Methyl - CH2-CH2- 3-OMe-Phenyl Me Me N N N 0 o !H 1-612 COOH 4-Me-Phenyl -CH2-CH2-CF3 - CH2-CH2- 3-OMe-Phenyl Ethyl Me CH N N 0 M so1-611 COOH 4-Me-Phenyl Methyl - CH 2 -CH 2 - 3-OMe-Phenyl Me Me NNN 0 o! H 1-612 COOH 4-Me-Phenyl -CH 2 -CH 2 -CF 3 - CH 2 -CH 2 - 3-OMe-Phenyl Ethyl Me CH NN 0 M so
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Nr. R1 R5 R4 Q R6 R2 R3 Z X Y W oNo.R 1 R5 R 4 QR 6 R 2 R 3 ZXYW o
1-613 COOH 4-Cl-Phenyl Methyl - CH2-CH2- 4-Et-Phenyl Me Me N N N 0 o1-613 COOH 4-Cl-Phenyl Methyl - CH 2 -CH 2 - 4-Et-Phenyl Me Me NNN 0 o
≤:≤:
1-614 COOH Phenyl Meüiyl - CH2-CH2- CH2- 4-SMe-Phenyl Ethyl Me N CH N 0 so1-614 COOH Phenyl Meüiyl - CH2-CH2-CH 2 - 4-SMe-Phenyl Ethyl Me N CH N 0 so
SO 00SO 00
1-615 COOH Phenyl Meüiyl - CH2-CH2- NaphÜι-2-yl OMe Me CH N N 01-615 COOH Phenyl Meüiyl - CH 2 -CH 2 - NaphÜι-2-yl OMe Me CH NN 0
1-616 COOH Phenyl Meüiyl - CH2-CH2- Naphth-2-yl Me Me CH N N 01-616 COOH Phenyl Meüiyl - CH 2 -CH2- Naphth-2-yl Me Me CH NN 0
1-617 COOH Phenyl CF3 - CH(OH)-CH(OH)- 4-SMe-Phenyl OMe O- CH2-CH2-C N N 0 CH2-1-617 COOH Phenyl CF 3 - CH (OH) -CH (OH) - 4-SMe-Phenyl OMe O- CH 2 -CH2-C NN 0 CH 2 -
1-618 COOH Phenyl Methyl - CH2-CH2- CH2- Phenyl OMe 0- CH2-CH2-C N N 01-618 COOH phenyl methyl - CH 2 -CH 2 - CH 2 - phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-619 COOH Phenyl Meüiyl - CH(Phenyl)-CH2- Phenyl CF3 Me CH N N 0 CH2-1-619 COOH Phenyl Meüiyl - CH (Phenyl) -CH 2 - Phenyl CF 3 Me CH NN 0 CH 2 -
1-620 COOH Phenyl Meüiyl - CH2-CH2- CH2- 4-Me-Phenyl Me Me N N CH 01-620 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-Me-Phenyl Me Me NN CH 0
1-621 COOH Phenyl Methyl - CH2-CH2- 4-OMe-Phenyl OMe OMe CH N N 01-621 COOH phenyl methyl - CH 2 -CH 2 - 4-OMe-phenyl OMe OMe CH NN 0
1-622 COOH Phenyl Meüiyl - CH2-CH2- 4-OMe-Phenyl OMe Me CH N N 0 υi1-622 COOH Phenyl Meüiyl - CH 2 -CH 2 - 4-OMe-Phenyl OMe Me CH NN 0 υi
1-623 COOH 4-Et-Phenyl Meüiyl - CH2-CH2- CH2- 4-SMe-Phenyl Me Me CH N N 0 ω1-623 COOH 4-Et-Phenyl Meüiyl - CH2-CH2-CH 2 - 4-SMe-Phenyl Me Me CH NN 0 ω
1-624 COOH 4-Et-Phenyl Meüiyl - CH2-CH2- CH2- 4-SMe-Phenyl Ethyl Me CH N N 01-624 COOH 4-Et-Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-SMe-Phenyl Ethyl Me CH NN 0
1-625 COOH Phenyl Methyl - CH2-CH2- CH2- 4-Me-Phenyl CF3 Me CH N N s1-625 COOH phenyl methyl - CH 2 -CH 2 - CH 2 - 4-Me-phenyl CF 3 Me CH NN s
1-626 COOH 4-Cl-Phenyl CH2-0-CH2- CH3 - CH2-CH2- 3,5-Di-OMe-Phenyl Me Me CH N N 01-626 COOH 4-Cl-Phenyl CH 2 -0-CH 2 - CH 3 - CH 2 -CH 2 - 3,5-Di-OMe-Phenyl Me Me CH NN 0
1-627 COOH 4-Me-Phenyl Methyl - CH2-CH2- 3-OMe-Phenyl OMe Me CH N N 01-627 COOH 4-Me-Phenyl Methyl - CH 2 -CH 2 - 3-OMe-Phenyl OMe Me CH NN 0
1-628 COOH 4— Me-Phenyl Meüiyl - CH2-CH2- 3-OMe-Phcnyl Me Me CH N N 01-628 COOH 4- Me-Phenyl Meiyl - CH 2 -CH2- 3-OMe-Phcnyl Me Me CH NN 0
1-629 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 3,5-Di-OMe-Phenyl Me Me N N N 01-629 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - 3,5-Di-OMe-Phenyl Me Me NNN 0
1-630 COOH Phenyl Methyl - CH2-CH2- CH2- 4-Me-Phenyl OMe Me N N N 01-630 COOH Phenyl Methyl - CH 2 -CH 2 - CH 2 - 4-Me-Phenyl OMe Me NNN 0
1-631 COOH Phenyl CF3 - CH(OH)-CH(OH)- 4-Me-PhenyI Me Me CH N N 0 CH2- n 1-632 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- CH2- 4-Et-Phenyl Ethyl Me CH N N 0 H1-631 COOH Phenyl CF 3 - CH (OH) -CH (OH) - 4-Me-PhenyI Me Me CH NN 0 CH 2 - n 1-632 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-Et-Phenyl Ethyl Me CH NN 0 H
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Nr. R1 R5 R4 Q R6 R2 R3 Z X Y W oNo.R 1 R 5 R 4 QR 6 R 2 R 3 ZXYW o
1-633 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- CH2- 4-Et-Phenyl OMe O- CH2-CH2-C N N 0 SO1-633 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-Et-Phenyl OMe O-CH 2 -CH2-C NN 0 SO
*-* -
1-634 COOH 4-F-Phenyl -CH2-CH2-CF3 - CH2-CH2- CH2- 4-Me-Phenyl Me Me N N N 0 ©1-634 COOH 4-F-Phenyl -CH 2 -CH 2 -CF 3 - CH 2 -CH 2 - CH 2 - 4-Me-Phenyl Me Me NNN 0 ©
SO 00SO 00
1-635 COOH 4-Cl-Phenyl Methyl - CH2-CH2- 3,4-Di-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-635 COOH 4-Cl-Phenyl Methyl - CH 2 -CH 2 - 3,4-Di-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-636 COOH Phenyl Meüiyl - CH2-CH2- CH2- Phenyl Me Me N N N 01-636 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - Phenyl Me Me NNN 0
1-637 COOH Phenyl Meüiyl - CH2-CH2- CH2- Phenyl Ethyl Me CH N N 01-637 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - Phenyl Ethyl Me CH NN 0
1-638 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 3,4,5-Tri-OMe-Phenyl OMe Me CH N N 01-638 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - 3,4,5-Tri-OMe-Phenyl OMe Me CH NN 0
1-639 COOH 4-F-Phenyl CF3 - CH2-CH2- CH2- 4-Me-Phenyl Ethyl Me CH N N 01-639 COOH 4-F-Phenyl CF 3 - CH 2 -CH 2 - CH 2 - 4-Me-Phenyl Ethyl Me CH NN 0
1-640 COOH Phenyl Methyl - CH2-CH2- 4-iPr-Phenyl Ethyl Me CH N N 01-640 COOH phenyl methyl - CH 2 -CH 2 - 4-iPr-phenyl ethyl Me CH NN 0
1-641 COOH 4-Et-Phenyl Methyl - CH2-CH2- CH2- 3-OMe-Phenyl Ethyl Me CH N N 01-641 COOH 4-Et-Phenyl Methyl - CH2-CH2-CH2- 3-OMe-Phenyl Ethyl Me CH N N 0
1-642 COOH 4-Et-Phenyl Meüiyl - CH2-CH2— CH2— 3-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-642 COOH 4-Et-Phenyl Meüiyl - CH2-CH2-CH 2 - 3-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-643 COOH Phenyl Meüiyl - CH2-CH2- 4-iPr-Phenyl OMe CH2- CH2-CH2-C N N 01-643 COOH Phenyl Meüiyl - CH2-CH2- 4-iPr-Phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-644 COOH 4-F-Phenyl Meüiyl — CH2— CH2— CH2— 4-Me-Phenyl OMe 0- CH2-CH2-C N N 01-644 COOH 4-F-Phenyl Meüyl - CH2-CH2-CH2-4-Me-Phenyl OMe 0- CH2-CH 2 -CNN 0
1-645 COOH 4-Me-Phenyl Meüiyl - CH2-CH2- 3,4-Di-OMe-Phenyl Ethyl Me CH N N 01-645 COOH 4-Me-Phenyl Meüiyl - CH2-CH2- 3,4-Di-OMe-Phenyl Ethyl Me CH N N 0
1-646 COOH 4-Me-Phenyl Methyl - CH2-CH2- 3,4-Di-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-646 COOH 4-Me-Phenyl Methyl - CH2-CH2-3,4-Di-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-647 COOH 4-F-Phenyl Methyl - CH2-CH2- CH2- 4-Et-Phenyl CF3 Me CH N N 01-647 COOH 4-F-phenyl methyl - CH2-CH2-CH2- 4-Et-phenyl CF 3 Me CH NN 0
1-648 COOH CH2-0-CH2-1-648 COOH CH 2 -0-CH 2 -
4-Cl-Phenyl - CH2-CH2- 4-Me-Phenyl OMe 0- CH2-CH2-C N N 0 CH3 4-Cl-phenyl - CH 2 -CH 2 - 4-Me-phenyl OMe 0- CH 2 -CH 2 -CNN 0 CH 3
1-649 COOH 4-Cl-Phenyl Methyl - CH2— CH2- 4-Et-Phenyl OMe Me CH N N 01-649 COOH 4-Cl-Phenyl Methyl - CH2-CH2- 4-Et-Phenyl OMe Me CH N N 0
1-650 COOMe Phenyl Methyl - CH2-CH2- CH2- 4-Et-Phenyl OMe Me CH N N 01-650 COOMe Phenyl Methyl - CH2-CH2-CH2- 4-Et-Phenyl OMe Me CH N N 0
1-651 COOH Phenyl Meüiyl - CH2-CH2- 4-Cl-Phenyl OMe O- CH2-CH2-C N N 01-651 COOH Phenyl Meüiyl - CH2-CH2- 4-Cl-Phenyl OMe O-CH 2 -CH2-C NN 0
1-652 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- CH2- 4-Me-Phenyl Ethyl Me CH N N 01-652 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2-CH2- 4-Me-Phenyl Ethyl Me CH N N 0
1-653 COOH 4-Cl-Phenyl Butyl — C 2— Cr 2~" Cri2— 4-Et-Phenyl OMe Me CH N N 0 o1-653 COOH 4-Cl-Phenyl Butyl - C 2 - Cr 2 ~ "Cri2 - 4-Et-Phenyl OMe Me CH NN 0 o
HH
1-654 COOH Phenyl Methyl - CH2-CH2- Naphth-2-yl CF3 Me CH N N 0 M •0 so1-654 COOH Phenyl methyl - CH2-CH2-naphth-2-yl CF 3 Me CH NN 0 M • 0 so
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Nr. R1 R5 R4 Q R6 R2 R3 Z X Y WNo. R 1 R 5 R 4 Q R6 R 2 R 3 ZXYW
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1-655 COOH Phenyl Methyl - CH2-CH2- CH - 3,4-Di-Cl-Phenyl Me Me N N N 0 SO1-655 COOH phenyl methyl - CH 2 -CH 2 - CH - 3,4-di-Cl-phenyl Me Me NNN 0 SO
1-656 COOH 4-F-Phenyl 4-s1-656 COOH 4-F-phenyl 4-s
-CH2-CH2-CF3 - CH2-CH2- CH2- 4-Cl-Phenyl Ethyl Me CH N N O SO © OO-CH 2 -CH 2 -CF 3 - CH 2 -CH 2 - CH 2 - 4-Cl-Phenyl Ethyl Me CH NNO SO © OO
1-657 COOH Phenyl Meüiyl - CH2-CH2- Phenyl OMe 0- CH2-CH2-C N N 01-657 COOH Phenyl Meüiyl - CH 2 -CH 2 - Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-658 COOH Phenyl Meüiyl - CH2-CH2- 4-OMe-Phenyl CF3 Me CH N N 01-658 COOH Phenyl Meüiyl - CH 2 -CH 2 - 4-OMe-Phenyl CF 3 Me CH NN 0
1-659 COOH 4-Et-Phenyl Methyl - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl OMe O- CH2-CH2-C N N 01-659 COOH 4-Et-Phenyl Methyl - CH 2 -CH 2 - CH 2 - 3,4-Di-OMe-Phenyl OMe O-CH2-CH 2 -CNN 0
1-660 COOH 4-Et-Phenyl Meüiyl - CH2-CH2- CH2- 3-OMe-Phenyl OMe Me CH N N 01-660 COOH 4-Et-Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 3-OMe-Phenyl OMe Me CH NN 0
1-661 COOH Phenyl CF3 - CH2-CH2- CH2- 4-Cl-Phenyl OMe CH2- CH2-CH2-C N N s1-661 COOH phenyl CF 3 - CH 2 -CH 2 - CH 2 - 4-Cl-phenyl OMe CH 2 - CH 2 -CH 2 -CNN s
1-662 COOH 4-Cl-Phenyl Methyl - CH2-CH2- 4-OEt-Phenyl OMe O- CH2-CH2-C N N 01-662 COOH 4-Cl-phenyl methyl - CH 2 -CH 2 - 4-OEt-phenyl OMe O-CH 2 -CH 2 -CNN 0
1-663 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 3,5-Di-OMe-Phenyl OMe Me CH N N 01-663 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - 3,5-Di-OMe-Phenyl OMe Me CH NN 0
1-664 COOH Phenyl Meüiyl - CH2-CH2- CH2- 3-OMe-Phenyl Ethyl Me N CH N 01-664 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 3-OMe-Phenyl Ethyl Me N CH N 0
1-665 COOH Phenyl Methyl - CH2-CH2- CH2- 3-OMe-Phenyl OMe Me N N N 0 in1-665 COOH Phenyl Methyl - CH 2 -CH 2 - CH 2 - 3-OMe-Phenyl OMe Me NNN 0 in
1-666 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- CH2- 4-Me-Phenyl OMe Me CH N N 0 ui1-666 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-Me-Phenyl OMe Me CH NN 0 ui
1-667 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- CH2- 4-Me-Phenyl Me Me N N N 01-667 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-Me-Phenyl Me Me NNN 0
1-668 COOH Phenyl Meüiyl — CH-2- ■ C 2-" CrΪ2~ 2,3-Di-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-668 COOH Phenyl Meüiyl - CH-2 - ■ C 2- "CrΪ2 ~ 2,3-Di-OMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-669 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 3,4-Di-OMe-Phenyl Me Me N N N 01-669 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - 3,4-Di-OMe-Phenyl Me Me NNN 0
1-670 COOH 4-Cl-Phenyl CH2-0-CH2- CH3 - CH2-CH2- 3,4-Di-OMe-Phenyl Ethyl Me CH N N 01-670 COOH 4-Cl-Phenyl CH 2 -0-CH 2 - CH 3 - CH2-CH2- 3,4-Di-OMe-Phenyl Ethyl Me CH NN 0
1-671 COOH 3,4-Di-Cl-Phenyl Meüiyl - CH2-CH2- CH2- 4-OMe-Phenyl OMe Me CH N N 01-671 COOH 3,4-Di-Cl-Phenyl Meüiyl - CH2-CH2-CH 2 - 4-OMe-Phenyl OMe Me CH NN 0
1-672 COOH Phenyl Meüiyl - CH2-CH2- 4-iPr-Phenyl Me Me CH N N 01-672 COOH Phenyl Meüiyl - CH2-CH2- 4-iPr-Phenyl Me Me CH N N 0
1-673 COOH 4-Et-Phenyl Meüiyl — CH2— CH2— CH2— 3,4-Di-OMe-Plιenyl Me Me CH N N 01-673 COOH 4-Et-Phenyl Meüiyl - CH2-CH2-CH 2 - 3,4-Di-OMe-Plenyl Me Me CH NN 0
1-674 COOH 4-Et-Phenyl Methyl - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl Ethyl Me CH N N 01-674 COOH 4-Et-Phenyl Methyl - CH2-CH2-CH 2 - 3,4-Di-OMe-Phenyl Ethyl Me CH NN 0
1-675 COOH Phenyl Propyl - CH2-CH2- 4-iPr-Phenyl Me Me N N N 0 n 1-676 COOH 3,4-Di-Cl-Phenyl Meüiyl - CH2-CH2- CH2- 4-OMe-Phenyl Me Me CH N N 01-675 COOH phenyl propyl - CH 2 -CH 2 - 4-iPr-phenyl Me Me NNN 0 n 1-676 COOH 3,4-Di-Cl-Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-OMe-Phenyl Me Me CH NN 0
SO o > sSO o> s
OO OO
Nr. R1 R5 R4 Q R6 R2 R3 Z X Y WR 1 R5 R 4 QR 6 R 2 R 3 ZXYW
SOSO
1-677 COOH 3,4-Di-Cl-Phenyl Meüiyl - CH2-CH2- CH2- 4-OMe-Phenyl Ethyl Me CH N N 0 so1-677 COOH 3,4-Di-Cl-Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-OMe-Phenyl Ethyl Me CH NN 0 see above
1-678 COOH 4-Cl-Phenyl -CH2-CH2-CF3 - CH2-CH2- 4-Me-Phenyl Me Me N N N 0 so so 001-678 COOH 4-Cl-Phenyl -CH 2 -CH 2 -CF 3 - CH2-CH2- 4-Me-Phenyl Me Me NNN 0 so so 00
1-679 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 4-Me-Phenyl Ethyl Me CH N N 01-679 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - 4-Me-Phenyl Ethyl Me CH NN 0
1-680 COOH 4-Cl-Phenyl Methyl - CH2-CH2- CH2- 3,4— Methylendioxyphenyl Me Me CH N N 0COOH 1-680 4-Cl-phenyl methyl - CH 2 -CH 2 - CH 2 - 3,4-methylenedioxyphenyl Me Me CH NN 0
1-681 COOH 4-Cl-Phenyl Methyl - CH2-CH2- CH2- 3,4-Methylendioxyphenyl OMe 0- CH2-CH2-C N N 01-681 COOH 4-Cl-phenyl methyl - CH 2 -CH 2 - CH 2 - 3,4-methylenedioxyphenyl OMe 0- CH 2 -CH 2 -CNN 0
1-682 COOH 3,4-Di-Cl-Phenyl Methyl - CH2-CH2- CH2- 4-OMe-Phenyl OMe 0- CH2-CH2-C N N 01-682 COOH 3,4-di-Cl-phenyl methyl - CH 2 -CH 2 - CH 2 - 4-OMe-phenyl OMe 0- CH 2 -CH 2 -CNN 0
1-683 COOH Phenyl CF3 - CH2-CH2- 4-Cl-Phenyl Ethyl Me CH N N 01-683 COOH Phenyl CF 3 - CH2-CH2- 4-Cl-Phenyl Ethyl Me CH NN 0
1-684 COOH Phenyl Methyl - CH2-CH2- 4-Cl-Phenyl OMe CH2- CH2-CH2-C N N 01-684 COOH phenyl methyl - CH2-CH2- 4-Cl-phenyl OMe CH 2 - CH 2 -CH 2 -CNN 0
1-685 COOH - CH(OH)-CH(OH)-1-685 COOH - CH (OH) -CH (OH) -
Phenyl Methyl 2-Cl-Phenyl OMe Me CH N N 0 CH2-Phenyl methyl 2-Cl-phenyl OMe Me CH NN 0 CH 2 -
1-686 COOH Phenyl Methyl - CH2-CH2- CH2- 2-Cl-Phenyl Me Me CH CH N 01-686 COOH phenyl methyl - CH 2 -CH 2 - CH 2 - 2-Cl-phenyl Me Me CH CH N 0
1-687 COOH 4-Et-Phenyl Methyl - CH2-CH2- CH2- 4-OMe-Phenyl OMe 0- CH2-CH2-C N N 0 in1-687 COOH 4-Et-Phenyl Methyl - CH2-CH2-CH 2 - 4-OMe-Phenyl OMe 0- CH2-CH2-C NN 0 in
1-688 COOH 4-Et-Phenyl Meüiyl - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl OMe Me CH N N 01-688 COOH 4-Et-Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 3,4-Di-OMe-Phenyl OMe Me CH NN 0
1-689 COOH Phenyl Methyl - CH2-CH2- Phenyl Me Me N N N 01-689 COOH phenyl methyl - CH2-CH2-phenyl Me Me N N N 0
1-690 COOH Phenyl Meüiyl - CH2-CH2- Phenyl Ethyl Me CH N N 01-690 COOH Phenyl Meüiyl - CH2-CH2-Phenyl Ethyl Me CH N N 0
1-691 COOH Phenyl Meüiyl - CH2-CH2- CH2- 2-Cl-Phenyl Me Me N N N s1-691 COOH Phenyl Meüiyl - CH2-CH2-CH2- 2-Cl-Phenyl Me Me N N N s
1-692 COOH CH2-0-CH2-1-692 COOH CH 2 -0-CH 2 -
4-Cl-Phenyl - CH2-CH2- 4-OEt-Phenyl Me Me N N N 0 CH3 4-Cl-phenyl - CH 2 -CH 2 - 4-OEt-phenyl Me Me NNN 0 CH 3
1-693 COOH 4-Cl-Phenyl Methyl - CH2-CH2- 4-OEt-Phenyl Ethyl Me CH N N 01-693 COOH 4-Cl-Phenyl Methyl - CH 2 -CH 2 - 4-OEt-Phenyl Ethyl Me CH NN 0
1-694 COOH 4-Cl~Phenyl Meüiyl - CH2-CH2- CH2- 4-iPr-Phenyl EÜiyl Me CH N N 01-694 COOH 4-Cl ~ Phenyl Meüiyl - CH2-CH2-CH2- 4-iPr-Phenyl EÜiyl Me CH N N 0
1-695 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- CH2- 3,4-Methylendioxyphenyl OMe Me CH N N 01-695 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 3,4-methylenedioxyphenyl OMe Me CH NN 0
1-696 COOH Phenyl Meüiyl - CH2-CH2- CH2- 2-Cl-Phenyl Ethyl Me CH N N s o1-696 COOH Phenyl Meüiyl - CH2-CH2-CH2- 2-Cl-Phenyl Ethyl Me CH N N s o
1-697 COOMe Phenyl Methyl — CH2— CH2— CH2— 2-Cl-Phenyl OMe CH2- CH2-CH2-C N N 0 H M 1-698 COOH Phenyl Methyl - CH2-CH2- CH - 3 ,5-Di-OMe-4-Cl-Phenyl OMe Me CH N N 0 SO SO1-697 COOMe phenyl methyl - CH2-CH2-CH2-2-Cl-phenyl OMe CH2-CH2-CH2-C NN 0 HM 1-698 COOH phenyl methyl - CH 2 -CH 2 - CH - 3,5-di-OMe-4-Cl-phenyl OMe Me CH NN 0 SO SO
© 00 © 00
Nr. R1 R5 R4 Q R6 R2 R3 Z X Y W soNo.R 1 R 5 R 4 QR 6 R 2 R 3 ZXYW see above
1-699 COOH 4-Cl-Phenyl -CH2-CH2-CF3 - CH2-CH2- 3,4-Di-OMe-Phenyl OMe Me CH N N 0 so1-699 COOH 4-Cl-Phenyl -CH 2 -CH 2 -CF 3 - CH2-CH 2 - 3,4-Di-OMe-Phenyl OMe Me CH NN 0 see above
Ji.Ji.
1-700 COOH 4-Cl-Phenyl Methyl - CH2-CH2- 3,4-Di-OMe-Phenyl Me Me CH N N 0 SO s©1-700 COOH 4-Cl-Phenyl Methyl - CH 2 -CH 2 - 3,4-Di-OMe-Phenyl Me Me CH NN 0 SO s ©
1-701 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- CH2- 3-OMe-Phenyl OMe O- CH2-CH2-C N N 01-701 COOH 4-Cl-Phenyl Meüiyl - CH2-CH 2 - CH 2 - 3-OMe-Phenyl OMe O-CH2-CH2-C NN 0
1-702 COOH 4-Et-Phenyl Meüiyl - CH2-CH2- CH2- 4-OMe-Phenyl Ethyl Me CH N N 01-702 COOH 4-Et-Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-OMe-Phenyl Ethyl Me CH NN 0
1-703 COOH Phenyl Meüiyl - CH2-CH2- CH2- 3,5-Di-OMe-4-Cl-Phenyl Me Me CH N N 01-703 COOH Phenyl Meüiyl - CH2-CH 2 - CH 2 - 3,5-Di-OMe-4-Cl-Phenyl Me Me CH NN 0
1-704 COOH Phenyl CF3 - CH2-CH2- 4-iPr-Phenyl CF3 Me CH N N 01-704 COOH Phenyl CF 3 - CH2-CH2- 4-iPr-Phenyl CF 3 Me CH NN 0
1-705 COOH Phenyl Methyl - CH2-CH2- 4-iPr-Phenyl OMe Me CH N N 01-705 COOH phenyl methyl - CH2-CH 2 - 4-iPr-phenyl OMe Me CH NN 0
1-706 COOH Phenyl Meüiyl - CH=CH- CH2- 4-OMe-Phenyl OMe Me CH N N s1-706 COOH Phenyl Meüiyl - CH = CH- CH 2 - 4-OMe-Phenyl OMe Me CH NN s
1-707 COOMe Phenyl Meüiyl - CH=CH- CH2- 4-OMe-Phenyl Me Me CH N N 01-707 COOMe Phenyl Meüiyl - CH = CH- CH 2 - 4-OMe-Phenyl Me Me CH NN 0
1-708 COOH 4-Cl-Phenyl Methyl - CH2-CH2- CH2- 4-OEt, 3-OMe-Phenyl OMe O- CH2-CH2-C N N 01-708 COOH 4-Cl-phenyl methyl - CH 2 -CH 2 - CH 2 - 4-OEt, 3-OMe-phenyl OMe O-CH 2 -CH 2 -CNN 0
1-709 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- CH2- 4-iPr-Phenyl Me Me N N N 0 υi1-709 COOH 4-Cl-Phenyl Meüiyl - CH2-CH 2 - CH 2 - 4-iPr-Phenyl Me Me NNN 0 υi
1-710 COOH 4-Cl-Phenyl Methyl - CH2-CH2- 4-Me-Phenyl OMe Me CH N N 01-710 COOH 4-Cl-Phenyl Methyl - CH2-CH 2 - 4-Me-Phenyl OMe Me CH NN 0
1-711 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- 4-Me-Phenyl Me Me CH N N 01-711 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - 4-Me-Phenyl Me Me CH NN 0
1-712 COOH Phenyl Meüiyl - CH=CH- CH2- 4-OMe-Phenyl Me Me N CH N 01-712 COOH Phenyl Meüiyl - CH = CH- CH 2 - 4-OMe-Phenyl Me Me N CH N 0
1-713 COOH Phenyl CH2-0-CH2- CH3 - CH2-CH2- 4-Cl-Phenyl Me Me CH N N 01-713 COOH phenyl CH 2 -0-CH 2 - CH 3 - CH2-CH 2 - 4-Cl-phenyl Me Me CH NN 0
1-714 COOH Phenyl Methyl - CH2-CH2- 4-Cl-Phenyl Me Me N N N 01-714 COOH Phenyl Methyl - CH2-CH 2 - 4-Cl-Phenyl Me Me NNN 0
1-715 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- CH2- 3-OMe-Phenyl Me Me N N N 01-715 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 3-OMe-Phenyl Me Me NNN 0
1-716 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- CH2- 3-OMe-Phenyl Ethyl Me CH N N 01-716 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 3-OMe-Phenyl Ethyl Me CH NN 0
1-717 COOH Phenyl Meüiyl - CH=CH- CH2- 3-Cl-4-OMe-Phenyl Ethyl Me CH N N 01-717 COOH Phenyl Meüiyl - CH = CH- CH 2 - 3-Cl-4-OMe-Phenyl Ethyl Me CH NN 0
1-718 COOH Phenyl Methyl - CH=CH- CH - 3-Cl-4-OMe-Phenyl OMe O- CH2-CH2-C N N 01-718 COOH phenyl methyl - CH = CH-CH - 3-Cl-4-OMe-phenyl OMe O-CH 2 -CH 2 -CNN 0
1-719 COOH Phenyl Methyl - CH2-CH2- Phenyl OMe Me CH N N 0 " 3 O 1-720 H1-719 COOH phenyl methyl - CH 2 -CH 2 - phenyl OMe Me CH NN 0 "3 O 1-720 H
COOH Phenyl -CH2-CH2-CF3 - CH2-CH2- Phenyl Me Me CH N N 0 M ■0 so so © ks. o COOH phenyl -CH 2 -CH 2 -CF 3 - CH2-CH2-phenyl Me Me CH NN 0 M ■ 0 so so © ks. O
Nr. R1 R5 R4 Q R* R2 R3 Z X Y WNo.R 1 R 5 R 4 QR * R 2 R 3 ZXYW
1-721 COOH 4-F-Phenyl Methyl OMe Me CH N N O so1-721 COOH 4-F-phenyl methyl OMe Me CH N N O so
-CH=CH-CH2- 3,4-Di-OMe-Phenyl-CH = CH-CH 2 - 3,4-di-OMe-phenyl
1-722 COOH 4-Cl-Phenyl Meüiyl -CH2-CH2-CH2- 4-SMe-Phenyl OMe 0- CH2-CH2-C N N 0 *- o1-722 COOH 4-Cl-Phenyl Meüiyl -CH 2 -CH 2 -CH 2 - 4-SMe-Phenyl OMe 0- CH 2 -CH 2 -CNN 0 * - o
1-723 COOH 4-Cl-Phenyl Meüiyl -CH2-CH2-CH2- 4-OEt, 3-OMe-Phenyl OMe Me CH N N 01-723 COOH 4-Cl-Phenyl Meüiyl -CH 2 -CH 2 -CH 2 - 4-OEt, 3-OMe-Phenyl OMe Me CH NN 0
1-724 COOH 4-Cl-Phenyl Methyl -CH2-CH2- 4-OEt-Phenyl OMe Me CH N N 01-724 COOH 4-Cl-Phenyl Methyl -CH 2 -CH 2 - 4-OEt-Phenyl OMe Me CH NN 0
1-725 COOH 4-Cl-Phenyl CF3 - CH2-CH2- 4-OEt-Phenyl Me Me CH N N 01-725 COOH 4-Cl-Phenyl CF 3 - CH 2 -CH 2 - 4-OEt-Phenyl Me Me CH NN 0
1-726 COOMe Phenyl Meüiyl -CH=CH-CH2- 3,4-Di-OMe-Phenyl Me Me CH N N 01-726 COOMe Phenyl Meüiyl -CH = CH-CH 2 - 3,4-Di-OMe-Phenyl Me Me CH NN 0
1-727 COOH Phenyl Meüiyl -CH=CH-CH2- 3,4-Di-OMe-Phenyl Me Me N CH N 01-727 COOH Phenyl Meüiyl -CH = CH-CH 2 - 3,4-Di-OMe-Phenyl Me Me N CH N 0
1-728 COOH Phenyl Meüiyl -CH=CH-CH2- 3,4-Di-OMe-Phenyl OMe 0-CH2-CH2-C N N s1-728 COOH Phenyl Meüiyl -CH = CH-CH 2 - 3,4-Di-OMe-Phenyl OMe 0-CH 2 -CH 2 -CNN s
1-729 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- CH2- 3-OMe-Phenyl OMe Me CH N N 01-729 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 3-OMe-Phenyl OMe Me CH NN 0
1-730 COOH 4-Cl-Phenyl Meüiyl -CH2-CH-CH2- 3-OMe-Phenyl Me Me CH N N 01-730 COOH 4-Cl-Phenyl Meüiyl -CH 2 -CH-CH 2 - 3-OMe-Phenyl Me Me CH NN 0
1-731 COOH 4-Cl-Phenyl Meüiyl -CH2-CH2- 4-OMe-Phenyl Ethyl Me CH N N 01-731 COOH 4-Cl-Phenyl Meüiyl -CH 2 -CH2- 4-OMe-Phenyl Ethyl Me CH NN 0
1-732 COOH in1-732 COOH in
4-Cl-Phenyl Meüiyl -CH2-CH2- 4-OMe-Phenyl OMe O-CH2-CH2-C N N 0 α>4-Cl-Phenyl Meüiyl -CH 2 -CH 2 - 4-OMe-Phenyl OMe O-CH 2 -CH 2 -CNN 0 α>
1-733 COOH Phenyl Methyl -CH=CH-CH2- Cyclohexyl OMe Me CH N N 01-733 COOH phenyl methyl -CH = CH-CH 2 - cyclohexyl OMe Me CH NN 0
1-734 COOH Phenyl CH2-0-CH2- -CH2-CH2- 4-OEt-3-OMe-Phenyl OMe CH3 CH2-CH2-CH2-C N N 01-734 COOH Phenyl CH 2 -0-CH 2 - -CH 2 -CH 2 - 4-OEt-3-OMe-Phenyl OMe CH 3 CH 2 -CH 2 -CH2-C NN 0
1-735 COOH Phenyl Meüiyl -CH2-CH2- 4-OEt-3~OMe-Phenyl OMe 0-CH2-CH2-C N N 01-735 COOH Phenyl Meüiyl -CH2-CH2- 4-OEt-3 ~ OMe-Phenyl OMe 0-CH 2 -CH 2 -CNN 0
1-736 COOH 4-Cl-Phenyl Meüiyl -CH2-CH2-CH2- 4-SMe-Phenyl Me Me N N N 01-736 COOH 4-Cl-Phenyl Meüiyl -CH 2 -CH 2 -CH 2 - 4-SMe-Phenyl Me Me NNN 0
1-737 COOH 4-Cl-Phenyl Meüiyl -CH2-CH2-CH2- 4-SMe-Phenyl Ethyl Me CH N N 01-737 COOH 4-Cl-Phenyl Meüiyl -CH 2 -CH 2 -CH 2 - 4-SMe-Phenyl Ethyl Me CH NN 0
1-738 COOH Phenyl Methyl -CH=CH-CH- Cyclohexyl Me Me CH N N 01-738 COOH phenyl methyl -CH = CH-CH- cyclohexyl Me Me CH N N 0
1-739 COOH Phenyl Methyl -CH=CH-CH2- 4-Me-Phenyl Me Me N N N s1-739 COOH phenyl methyl -CH = CH-CH 2 - 4-Me-Phenyl Me Me NNN s
1-740 COOH 4-Cl-Phenyl Meüiyl -CH2-CH2- 3 , 4-M et hy 1 endi oxypheny 1 Ethyl Me CH N N 01-740 COOH 4-Cl-Phenyl Meüiyl -CH 2 -CH 2 - 3, 4-M et hy 1 endi oxypheny 1 Ethyl Me CH NN 0
1-741 COOH 4-Cl-Phenyl CH2-O-CH2- -CH2-CH2- 3 ,4-Methylendioxyphenyl OMe CH3 O-CH2-CH2-C N N 0 H W so so κ> 1-741 COOH 4-Cl-phenyl CH 2 -O-CH 2 - -CH 2 -CH 2 - 3, 4-methylenedioxyphenyl OMe CH 3 O-CH 2 -CH 2 -CNN 0 HW so so κ>
Nr. R1 R5 R4 Q R6 R2 R3 Z X Y W s© SONo.R 1 R5 R 4 Q R6 R 2 R 3 ZXYW s © SO
1-742 COOH Phenyl - C(Phenyl)=CH-1-742 COOH phenyl - C (phenyl) = CH-
Meüiyl Phenyl OMe Me CH N N 0 CH2- SO s©Meüiyl Phenyl OMe Me CH NN 0 CH 2 - SO s ©
1-743 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- CH2- 3,5-Di-OMe-Phenyl OMe Me CH N N 0 OO1-743 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 3,5-Di-OMe-Phenyl OMe Me CH NN 0 OO
1-744 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- CH2- 3,5-Di-OMe-Phenyl Me Me CH N N 01-744 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 3,5-Di-OMe-Phenyl Me Me CH NN 0
1-745 COOH Phenyl Meüiyl - CH2-CH2- 4-Cl-Phenyl CF3 Me CH N N 01-745 COOH Phenyl Meüiyl - CH 2 -CH 2 - 4-Cl-Phenyl CF 3 Me CH NN 0
1-746 COOH Phenyl Meüiyl - CH2-CH2- 4-Cl-Phenyl OMe Me CH N N 01-746 COOH Phenyl Meüiyl - CH 2 -CH2- 4-Cl-Phenyl OMe Me CH NN 0
1-747 COOH 4-F-Phenyl Methyl - CH=CH- CH2- Phenyl Me Me CH N N 01-747 COOH 4-F-Phenyl Methyl - CH = CH- CH 2 - Phenyl Me Me CH NN 0
1-748 COOH 4-F-Phenyl CH2-0-CH2- CH3 - CH=CH- CH2- Phenyl Me Me N N N 01-748 COOH 4-F-Phenyl CH 2 -0-CH 2 - CH 3 - CH = CH-CH 2 - Phenyl Me Me NNN 0
1-749 COOH Phenyl Methyl - CH2-CH2- 4-OEt-3-OMe-Phenyl Me Me N N N 01-749 COOH Phenyl Methyl - CH 2 -CH 2 - 4-OEt-3-OMe-Phenyl Me Me NNN 0
1-750 COOH 4-Cl-Phenyl Methyl - CH2-CH2- CH2- 4-SMe-Phenyl OMe Me CH N N 01-750 COOH 4-Cl-Phenyl Methyl - CH 2 -CH 2 - CH 2 - 4-SMe-Phenyl OMe Me CH NN 0
1-751 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- CH2- 4-SMe-Phenyl Me Me CH N N 0 in1-751 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-SMe-Phenyl Me Me CH NN 0 in
1-752 COOH Phenyl Methyl - CH2-CH2- 4-OEt-3-OMe-Phenyl Ethyl Me CH N N 0 so1-752 COOH phenyl methyl - CH 2 -CH 2 - 4-OEt-3-OMe-phenyl ethyl Me CH NN 0 see above
1-753 COOH Phenyl Methyl - C(Phenyl)=CH- Phenyl Ethyl Me CH N N 0 CH2-1-753 COOH phenyl methyl - C (phenyl) = CH- phenyl ethyl Me CH NN 0 CH 2 -
1-754 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- Naphth-2-yl Ethyl Me CH N N 01-754 COOH 4-Cl-phenylmeiyl - CH 2 -CH 2 - naphth-2-yl ethyl Me CH NN 0
1-755 COOH 4-Cl-Phenyl Methyl - CH2-CH2- NaphÜι-2-yl OMe O- CH2-CH2-C N N 01-755 COOH 4-Cl-Phenyl Methyl - CH 2 -CH 2 - NaphÜι-2-yl OMe O- CH 2 -CH 2 -CNN 0
1-756 COOH Phenyl CH2-0-CH2- CH3 - CH=CH- CH2- Phenyl OMe 0- CH2-CH2-C N N s1-756 COOH phenyl CH 2 -0-CH 2 - CH 3 - CH = CH- CH 2 - phenyl OMe 0- CH 2 -CH 2 -CNN s
1-757 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- CH2- 4-OEt-Phenyl Me Me CH N N 01-757 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-OEt-Phenyl Me Me CH NN 0
1-758 COOH 4-Cl-Phenyl Meüiyl — CH2-CH2— CH2- 4-OEt-Phenyl Ethyl Me CH N N 01-758 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-OEt-Phenyl Ethyl Me CH NN 0
1-759 COOH Phenyl Methyl - CH2-CH2- CH2- 4-OEt-Phenyl CF3 Me CH N N 01-759 COOH phenyl methyl - CH 2 -CH 2 - CH 2 - 4-OEt-phenyl CF 3 Me CH NN 0
1-760 COOH Phenyl Meüiyl - CH2-CH2- CH2- 4-OEt-Phenyl OMe Me CH N N 0 n "0 1-761 COOH 4-Cl-Phenyl Methyl - CH2-CH2- 4-OMe-Phenyl Me Me CH N N 0 H1-760 COOH Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 4-OEt-Phenyl OMe Me CH NN 0 n "0 1-761 COOH 4-Cl-Phenyl Methyl - CH 2 -CH 2 - 4-OMe-Phenyl Me Me CH NN 0 H
W "0 so soW "0 so so
© J© J
© 00 © 00
Nr. R1 R5 R4 Q R6 R2 R3 Z X Y W s©No.R 1 R 5 R 4 QR 6 R 2 R 3 ZXYW s ©
1-762 COOH 4-Cl-Phenyl Methyl N 0 so1-762 COOH 4-Cl-phenyl methyl N 0 so
- CH2-CH2- 4-OMe-Phenyl Me Me N N- CH 2 -CH 2 - 4-OMe-Phenyl Me Me NN
**
1-763 COOH 4-Cl-Phenyl Methyl - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl Ethyl Me CH N N 0 SO- SO 001-763 COOH 4-Cl-phenyl methyl - CH 2 -CH 2 - CH 2 - 3,4-di-OMe-phenyl ethyl Me CH NN 0 SO-SO 00
1-764 COOH 4-Cl-Phenyl Meüiyl - CH2-CH2- CH2- 3,4-Di-OMe-Phenyl OMe 0- CH -CH2-C N N 0 1-765 COOH Phenyl Methyl - CH2-CH2- CH2- 4-OEt-Phenyl Me Me CH N N 01-764 COOH 4-Cl-Phenyl Meüiyl - CH 2 -CH 2 - CH 2 - 3,4-Di-OMe-Phenyl OMe 0- CH -CH 2 -CNN 0 1-765 COOH phenyl methyl - CH 2 -CH 2 - CH 2 - 4-OEt-phenyl Me Me CH NN 0
σ. oσ. O
nn
H w soH w so
SOSO
K»K »
©©
00 00
6161
Beispiel 17Example 17
Gemäß dem oben beschriebenen Bindungstest wurden für die nach- folgend 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 (R—Werte)Receptor binding data (R values)
Beispiel ETA [nM] ETB [nM]Example ET A [nM] ET B [nM]
3 20 703 20 70
6 95 7806 95 780
7 35 707 35 70
8 72 5808 72 580
9 36 759 36 75
10 700 100010 700 1000
11 95 10011 95 100
12 90 85012 90 850
13 350 93013 350 930
14 100 14514 100 145
15 45 140 16 40 230 15 45 140 16 40 230

Claims

62Patentansprüche 62 Patent claims
1. Carbonsäurederivate der Formel I1. Carboxylic acid derivatives of the formula I.
R2 R 2
R4 R 4
Hi //?~" WiHi //? ~ " Wi
R—Q—W- -c—O— <(R — Q — W- -c — O— <(
R5 R1 X= .3 R wobei die Substituenten folgende Bedeutung besitzen:R 5 R 1 X = . 3 R where the substituents have the following meanings:
R1 Tetrazol oder eine GruppeR 1 tetrazole or a group
O syO sy
RR
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, Cι-C8-Alkyl,C 3 -C 8 cycloalkyl, -CC 8 alkyl,
CH2-Phenyl gegebenenfalls substituiert,CH 2 phenyl optionally substituted,
C3-C6-Alkenyl- oder eine C3-C6-Alkinylgruppe gegebenenfalls substituiert oderC 3 -C 6 alkenyl or a C 3 -C 6 alkynyl group optionally substituted or
Phenyl gegebenenfalls substituiert.Phenyl optionally substituted.
b) ein über ein Stickstoffatom verknüpfter 5-gliedriger Heteroaromat . 63 c) eine Gruppeb) a 5-membered heteroaromatic linked via a nitrogen atom. 63 c) a group
—0~(CH2)— S—R—0 ~ (CH 2 ) - S — R
in der k die Werte 0, 1 und 2, p die Werte 1, 2, 3 und 4 annehmen kann und R8 fürin which k can assume the values 0, 1 and 2, p the values 1, 2, 3 and 4 and R 8 for
Cι-C4-Alkyl, C3-C8-Cycloalkyl, C3-C6-Alkenyl, C3-C3-Alkinyl oder gegebenenfalls substituiertes Phenyl steht.-C-C 4 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 6 alkenyl, C 3 -C 3 alkynyl or optionally substituted phenyl.
d) ein Restd) a rest
00
I II I
99
N— S - -R H " worin R9 bedeutet :N - S - -R H "where R 9 means:
Cι-C4-Alkyl, C3-C6-Alkenyl, C3-C6-Alkinyl , C3-C8-Cyclo- alkyl, wobei diese Reste einen Cι-C4-Alkoxy-, Cι-C-Alkyl- thio- und/oder einen Phenylrest tragen können;C 1 -C 4 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C 8 cycloalkyl, these radicals being a C 1 -C 4 alkoxy, C 1 -C 4 alkyl - Can carry thio and / or a phenyl radical;
Phenyl, gegebenenfalls substituiert.Phenyl, optionally substituted.
e) ein Reste) a rest
1313
RR
//
—N 14—N 14
RR
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-C8-Cycloalkyl, C3-C8-Alkenyl ,Hydrogen, -CC 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 alkenyl,
C3-C8-Alkinyl, Benzyl, Phenyl, gegebenenfalls substituiert,C 3 -C 8 alkynyl, benzyl, phenyl, optionally substituted,
oder R13 und R14 bilden gemeinsam eine zu einem Ring geschlossene, gegebenenfalls substituierteor R 13 and R 14 together form an optionally substituted closed ring
C4-C7-Alkylenkette, die ein Heteroatom enthalten kann. 64C 4 -C 7 alkylene chain, which may contain a hetero atom. 64
R2 Wasserstoff, Hydroxy, NH2, NH(Cι-C-Alkyl) ,R 2 is hydrogen, hydroxy, NH 2 , NH (-CC alkyl),
N(C1-C4-Alkyl)2, Halogen, Cι-C4-Alkyl, C2-C-Alkenyl, C2-C4-Alkinyl, Cι-C4-Halogenalkyl, Cι-C4-Alkoxy, Cι-C4-Halogenalkoxy oder C1-C4-Alkylthio, oder CR2 ist mit CR10 wie unten angegeben zu einem 5- oder 6-gliedrigen Ring verknüpft;N (C 1 -C 4 alkyl) 2, halogen, Cι-C 4 alkyl, C 2 -C alkenyl, C 2 -C 4 alkynyl, Cι-C4 haloalkyl, Cι-C 4 alkoxy, Cι-C 4 -haloalkoxy or C 1 -C 4 -alkylthio, or CR 2 as indicated to form a 5- or 6-membered ring linked to CR 10 below;
X Stickstoff oder Methin;X nitrogen or methine;
Y Stickstoff oder Methin;Y nitrogen or methine;
Z Stickstoff oder CR10, worin Rio Wasserstoff, Halogen,Z nitrogen or CR 10 , where R i o is hydrogen, halogen,
Hydroxy, Cι-C4-Halogenalkyl oder Cι-C4-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(Cι-C4-Alkyl) , ersetzt sein können;Hydroxy, -CC 4 -haloalkyl or -CC 4 -alkyl means or CR 10 together with CR 2 or CR 3 forms a 5- or 6-membered alkylene or alkenylene ring, which can optionally be substituted, and in each case one or several methylene groups can be replaced by oxygen, sulfur, -NH or -N (-CC 4 alkyl);
R3 Wasserstoff, Hydroxy, NH2 , NH (Cι-C4-Alkyl) ,R 3 is hydrogen, hydroxy, NH 2 , NH (-CC 4 alkyl),
N(Cι-C4-Alkyl)2, Halogen, Cι-C4-Alkyl, C2-C4-Alkenyl, C2-C4-Alkinyl, Cι-C4-Hydroxyalkyl, Cι-C4-Halogenalkyl, Cχ-C4-Alkoxy, Cι-C-Halogenalkoxy, Cι-C4-Alkylthio; oder CR3 ist mit CR10 wie oben angegeben zu einem 5- oder 6-gliedrigen Ring verknüpft;N (Cι-C4 alkyl) 2, halogen, Cι-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, Cι-C 4 hydroxyalkyl, Cι-C 4 haloalkyl, Cχ-C 4 alkoxy, Cι-C haloalkoxy, Cι-C 4 alkylthio; or CR 3 is linked to CR 10 to a 5- or 6-membered ring as stated above;
R4 Cι-C4-Alkyl,C2-C4-Alkenyl, C2-C-Alkinyl, gegebenenfalls substituiert;R 4 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C alkynyl, optionally substituted;
R5 Phenyl oder Naphthyl, gegebenenfalls substituiert, oderR 5 phenyl or naphthyl, optionally substituted, or
Phenyl oder Naphthyl, das orthoständig über eine direkte Bindung, eine Methylen-, Ethylen- oder Ethenylengruppe, ein Sauerstoff- oder Schwefelatom oder eine S0-, NH- oder N-Alkyl-Gruppe mit R4 verbunden istPhenyl or naphthyl, which is ortho-linked to R 4 via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO, NH or N-alkyl group
C3-Cg-Cycloalkyl gegebenenfalls substituiert;C 3 -Cg cycloalkyl optionally substituted;
R6 gegebenenfalls substituiertes C3-C8-Cycloalkyl;R 6 optionally substituted C 3 -C 8 cycloalkyl;
Phenyl oder Naphthyl, die jeweils einen oder mehrere der folgenden Reste tragen können: Halogen, R15, Nitro, Mercapto, Carboxy, Cyano, Hydroxy, Amino, Cι-C4-Alkyl, C2-C4-Alkenyl, C2-C-Alkinyl, C3-Ce-Alkenyloxy, Cι-C-Halogenalkyl, C3-C6-Alkinyloxy, Cι-C-Alkylcarbonyl, Cι-C4-Alkoxycarbonyl, Cι-C4~Alkoxy, Cι-C4-Halogenalkoxy, Phenoxy, d-C4-Alkylthio, NH (C1-C4-Alkyl) , N(Cι-C4-Alkyl)2, 65Phenyl or naphthyl, which can carry one each or several of the following radicals: halogen, R15, nitro, mercapto, carboxyl, cyano, hydroxy, amino, Cι-C 4 alkyl, C 2 -C 4 alkenyl, C 2 - C-alkynyl, C 3 -C e -alkenyloxy, -C-C-haloalkyl, C 3 -C 6 -alkynyloxy, Cι-C-alkylcarbonyl, Cι-C 4 -alkoxycarbonyl, Cι-C 4 ~ alkoxy, Cι-C 4 -Haloalkoxy, phenoxy, dC 4 -alkylthio, NH (C 1 -C 4 -alkyl), N (-C-C 4 -alkyl) 2 , 65
Dioxomethylen, Dioxoethylen oder Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach durch Halogen, Nitro, Cyano, Cι-C-Alkyl, Ci-Cj-Halogen- alkyl, Cι-C4-Alkoxy, Cι-C-Halogenalkoxy oder Cι-C4-Alkyl- thio mit der Maßgabe, daß, falls R6 ein unsubstituierterDioxomethylene, 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 6 -haloalkyl, C 1 -C 4 alkoxy, Cι- C-haloalkoxy or -CC 4 alkyl thio with the proviso that if R 6 is an unsubstituted
Phenylrest ist, R2 und R3 nicht gleichzeitig OCH3 bedeuten dürfen;Is phenyl, R 2 and R 3 must not simultaneously mean OCH 3 ;
ein fünf- oder sechsgliedriger Heteroaromat, enthaltend ein bis drei Stickstoffatome und/oder ein Schwefeloder Sauerstoffatom, welcher ein bis vier Halogenatome und/oder einen bis zwei der folgenden Reste tragen kann: Cι-C4-Alkyl, C2-C-Alkenyl, Cι-C4-Halogenalkyl, Cι-C4-Alkoxy, Cι-C-Halogenalkoxy, Cι-C4-Alkyl hio, 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-Halogenalkyl, Cι-C4-Alkoxy, Cι-C4-Halogenalkoxy und/oder Cι-C4-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: -CC 4 alkyl, C 2 -C alkenyl, hio 4 alkyl, phenyl or phenoxy where the phenyl radicals in turn an / or may carry one to three of the following radicals Cι-C4-haloalkyl, Cι-C 4 -alkoxy, C haloalkoxy, Cι-C to five halogen atoms and a : Cι-C 4 -alkyl, C 4 haloalkyl, Cι-C 4 -alkoxy, C 4 -haloalkoxy and / or Cι-C 4 alkylthio;
R15 Cι-C4-Alkyl, Cι-C-Alkylthio, Cι-C-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;R 15 -CC 4 alkyl, -C-alkylthio, -CC alkoxy, which carry one of the following radicals: hydroxy, carboxy, amino, NH (-C 4 -alkyl), N (-C 4 -Alkyl) 2 , carboxamide or CON (C 1 -C 4 -alkyl) 2 ;
W Schwefel oder Sauerstoff;W sulfur or oxygen;
Q ein Spacer, der in seiner Länge einer C-C-Kette entspricht,Q is a spacer that corresponds in length to a C-C chain,
sowie die physiologisch verträglichen Salze, und die enantiomerenreinen sowie diastereoisomerenreinen Formen.as well as the physiologically acceptable salts, and the enantiomerically pure and diastereoisomerically pure forms.
2. Arzneimittelzubereitungen zur peroralen, parenteralen und intraperitonealen Anwendung, enthaltend neben den üblichen Arzneimittelhilfsstoffen, mindestens ein Carbonsäurederivat I gemäß Anspruch 1.2. Pharmaceutical preparations for oral, parenteral and intraperitoneal 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 1 als Endo- thelin-Rezeptorantagonisten.4. Use of the compounds I according to claim 1 as endothelin receptor antagonists.
5. Verwendung der Carbonsäurederivate I gemäß Anspruch 1 zur Herstellung von Arzneimitteln zur Behandlung von Krankheiten, bei denen erhöhte Endothelinspiegel auftreten. 665. Use of the carboxylic acid derivatives I according to claim 1 for the manufacture of medicaments for the treatment of diseases in which increased endothelin levels occur. 66
6. Verwendung der Carbonsäurederivate I gemäß Anspruch 1 zur Behandlung von chronischer Herzinsuffizienz, Myokardinfarkt , Atherosklerose, Arrhythmie, Angina Pectoris, Restenose, Bluthochdruck, pulmonalem Hochdruck, akutem/chronischen Nieren-6. Use of the carboxylic acid derivatives I according to claim 1 for the treatment of chronic heart failure, myocardial infarction, atherosclerosis, arrhythmia, angina pectoris, restenosis, high blood pressure, pulmonary high pressure, acute / chronic kidney
5 versagen, Niereninsuffizienz, zerebraler Ischämie, Asthma, benigne Prostatahyperplasie und Prostatakrebs.5 fail, renal 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,7. Use of the carboxylic acid derivatives I according to / claim 1 in combination with inhibitors of the renin-angiotensin system,
10 gemischten ACE/Neutrale Endopeptidase (NEP) -Hemmern, ß-Blockern.10 mixed ACE / neutral endopeptidase (NEP) inhibitors, β-blockers.
8. Verwendung von Verbindungen der Formel IV8. Use of compounds of formula IV
1515
*.- * .-
R— Q" w» HR - Q "w» H
-OH IV I worin die Reste R1, R4, R5, R6, Q und W die in Anspruch 1 2" angegebene Bedeutung haben, als Ausgangsmaterial zur Synthese von gemischten ETA/ETB-Rezeptorantagonisten.-OH IV I wherein the radicals R 1 , R 4 , R 5 , R 6 , Q and W have the meaning given in claim 1 2 ", as starting material for the synthesis of mixed ET A / ET B receptor antagonists.
9. Ein strukturelles Fragment der Formel9. A structural fragment of the formula
2525
HH
-Q—W- -c- .o- --Q — W- -c- . o- -
worin die Reste R1, R4, R5, R6, Q und W die in Anspruch 1 JU angegebene Bedeutung haben, als strukturelles Element m einem gemischten ETA/ETB-Rezeptorantagonisten.wherein the radicals R 1 , R 4 , R 5 , R 6 , Q and W have the meaning given in claim 1 JU , as a structural element in a mixed ET A / ET B receptor antagonist.
3535
4040
45 45
EP99906251A 1998-03-04 1999-02-25 Novel unsymmetrically substituted carboxylic acid derivatives, method for producing them, and their use as mixed et a?/et b?-receptor antagonists Withdrawn EP1060167A1 (en)

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PCT/EP1999/001208 WO1999044998A1 (en) 1998-03-04 1999-02-25 Novel unsymmetrically substituted carboxylic acid derivatives, method for producing them, and their use as mixed eta/etb-receptor antagonists

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