WO2003059905A1 - Pyrrolidone carboxamides - Google Patents

Pyrrolidone carboxamides Download PDF

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Publication number
WO2003059905A1
WO2003059905A1 PCT/CH2002/000725 CH0200725W WO03059905A1 WO 2003059905 A1 WO2003059905 A1 WO 2003059905A1 CH 0200725 W CH0200725 W CH 0200725W WO 03059905 A1 WO03059905 A1 WO 03059905A1
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Prior art keywords
phenyl
rac
carboxylic acid
amide
ethyl
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PCT/CH2002/000725
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German (de)
French (fr)
Inventor
Markus Isler
Thomas Giller
Günter SCHWALM
Matthias Steger
Kurt Hilpert
Oliver Valdenaire
Volker Breu
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Actelion Pharmaceuticals Ltd
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Application filed by Actelion Pharmaceuticals Ltd filed Critical Actelion Pharmaceuticals Ltd
Priority to AU2002350366A priority Critical patent/AU2002350366A1/en
Priority to KR10-2004-7010431A priority patent/KR20040072697A/en
Priority to US10/500,604 priority patent/US7067549B2/en
Priority to JP2003560008A priority patent/JP2005521651A/en
Priority to EP02785006A priority patent/EP1463724A1/en
Priority to MXPA04006458A priority patent/MXPA04006458A/en
Priority to CA002471620A priority patent/CA2471620A1/en
Publication of WO2003059905A1 publication Critical patent/WO2003059905A1/en
Priority to NO20043192A priority patent/NO20043192L/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to pyrrolidone carboxamide derivatives.
  • the invention relates to pyrrolidone carboxamides of the formula
  • R 1 in the phenyl radical optionally mono- or disubstituted phenyl, benzyl, phenylethyl or ⁇ -hydroxyphenylethyl by alkyl, alkoxy, dialkylamino, halogen or trifluoromethyl; Naphthyl or naphthylmethyl; Thienyl, furyl, pyridyl, l-alkylpyrrolidin-2-yl, pyrrolidino or morpholino alkyl; or cycloalkyl, which may optionally have a fused-on benzene ring;
  • R z is a radical of the formula
  • R 3 is hydrogen or alkyl
  • R 4 is hydrogen or alkoxy
  • R 5 phenyl, heteroalkyl, aryloxy, alkoxy, alkanoyl or
  • R 6 is hydrogen, alkyl, aralkyl, cycloalkylalkyl or alkoxycarbonylalkyl
  • R 7 represents aryl, heteroaryl, alkyl, hydroxyalkyl or acyl
  • pharmaceutically usable acid addition salts of basic compounds of formula I pharmaceutically usable salts of acid compounds of formula I with bases, pharmaceutically usable esters of hydroxyl or carboxy group-containing compounds of formula I and hydrates or solvates thereof.
  • the pyrrolidone carboxamides of the formula I contain at least one asymmetric carbon atom, they can be used as optically pure enantiomers, as mixtures of enantiomers, such as racemates, or optionally as optically pure diastereomers, as mixtures of diastereomers, as diastereomeric racemates or as mixtures of diastereomeric racemates are present.
  • WO 01/07409 AI relates to carbazole derivatives, the general formula of which partially overlaps with the above formula I, but does not specifically describe a single compound falling under the above formula I and also does not contain any sufficiently specific general information in the direction of compounds of the above formula I.
  • the substances defined at the beginning are new and are characterized by valuable pharmacodynamic properties. They inhibit the interaction of the neuropeptide Y (NPY) with one of the neuropeptide receptor subtypes (NPY-Y5) and are particularly suitable for the prevention and treatment of Arthritis, diabetes and especially eating disorders and obesity.
  • NPY neuropeptide Y
  • NPY-Y5 neuropeptide receptor subtypes
  • the present invention relates to the above substances as such and as therapeutic active substances; Processes and intermediates for their manufacture; Medicaments containing one of the above substances; and the use of the above substances for the prevention and treatment of arthritis, diabetes and especially eating disorders and obesity or for the production of corresponding medicaments.
  • ⁇ X alkyl ⁇ denotes a branched or unbranched saturated hydrocarbon radical having 1 to 8 carbon atoms, preferably having 1 to 6 carbon atoms and particularly preferably having 1 to 4 carbon atoms.
  • radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl isobutyl, sec-butyl, tert-butyl, the isomeric pentyls, the isomeric hexyls and the isomeric octyls; methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like are preferred. the like
  • cycloalkyl denotes a saturated cyclic hydrocarbon residue with 3-8 carbon atoms, preferably with 3 to 6 carbon atoms, which can be substituted, e.g. by alkyl groups, such as methyl, and which may have a fused-on benzene ring.
  • alkyl groups such as methyl
  • cycloalkyl groups optionally substituted by alkyl are cyclopropyl, methylcyclopropyl, dimethylcyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl,
  • Examples of cycloalkyl radicals with a fused benzene ring are 1-indanyl, 2-indanyl and. like.
  • hydroxyalkyl denotes an alkyl group as described above, wherein one or two H atoms, preferably one H atom, has been replaced by a hydroxy group. Examples are hydroxymethyl, hydroxyethyl, hydroxypropyl and. like.
  • alkoxy denotes an alkyl radical linked via an oxygen bridge, as described above. Examples are methoxy, ethoxy and the like. like.
  • alkanoyl denotes an alkyl group linked via a CO bridge, as described above. Examples are acetyl, 3-methylbutyryl, 2, 2-dimethylpropionyl and. like.
  • aryl denotes a phenyl or naphthyl group, preferably a phenyl group, which can carry up to four, preferably one to three and particularly preferably one or two substituents.
  • substituents are alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, nitro, fluoro, bromo, chloro, hydroxy, dialkylamino and the like.
  • Particularly preferred substituents are alkyl and alkoxy.
  • aryl groups are phenyl, methylphenyl, dimethylphenyl, ethylphenyl, isopropylphenyl, methoxyphenyl, methoxymethylphenyl, dimethylaminophenyl, phenylaminophenyl and the like. like.
  • aralkyl denotes an alkyl group as described above in which at least one H atom is replaced by an aryl group, as described above, in particular by a phenyl or naphthyl group which can carry one or more substituents, such as alkyl or alkoxy groups.
  • aralkyl radicals are benzyl, phenethyl, 2- (3, 4-dimethoxyphenyl) ethyl and. like.
  • heteroaryl denotes an aromatic mono- or tricyclic heterocyclic ring system with 5 to 10, preferably 5 to 6, ring members which contains one to four, preferably one to two, heteroatoms which are independent of one another are selected from nitrogen, oxygen and sulfur.
  • heteroaryl groups are pyridyl, pyrimidinyl, thiazolyl, thiophenyl, furanyl, tetrazolyl, carbazolyl and the like.
  • Such heteroaryl groups can be substituted, expediently mono, di or trisubstituted, the substituents being primarily alkyl, alkoxy, amino or aryl groups. Examples are 2-pyridyl, 2-thienyl, 4, 6-dimethyl-2-pyrimidinyl and the like. like.
  • acyl denotes an alkanoyl group, as described above, or a cycloalkyl, aryl, aralkyl, or heteroaryl group linked via a CO bridge, as described above.
  • alkanoyl group as described above
  • a cycloalkyl, aryl, aralkyl, or heteroaryl group linked via a CO bridge as described above.
  • examples are, as mentioned above, acetyl, 3-methylbutyryl and 2,2-dimethylpropionyl as well as cyclopropane carbonyl, benzoyl, phenylacetyl, 2-methoxybenzoyl, 4-methoxybenzoyl, 3-fluorobenzoyl, benzo [1, 3] dioxol-5-carbonyl, furan -2- carbonyl and like.
  • salts refers to those salts which have the biological effect and Do not diminish the properties of the free bases or free acids and which are not biologically or otherwise undesirable.
  • the salts are made from the free bases using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.
  • hydrochloric acid or by means of organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, tartaric acid, salicylic acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
  • organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, tartaric acid, salicylic acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
  • organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, tartaric acid, salicylic acid
  • Preferred salts with organic bases are, but not exclusively, salts with primary, secondary and tertiary amines, substituted amines, including all naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine , Lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins and the like.
  • Compounds of formula I can also be present as a zwitterion.
  • the invention also encompasses pharmaceutically suitable esters of compounds of the formula I containing hydroxyl or carboxy groups.
  • “Pharmaceutically suitable esters” means that corresponding compounds in formula I are derivatized to ester groups in such a way that they are transformed back into their active form in vivo .
  • COOH groups can be esterified.
  • suitable such esters are the alkyl and aralkyl esters. Preferred such esters are the methyl, ethyl, propyl, butyl and benzyl esters and the (R / S) -1- [(isopropoxycarbonyl) oxy] ethyl esters.
  • the ethyl esters and the isomeric butyl esters are particularly preferred.
  • OH groups can be esterified. Examples of such compounds contain physiologically acceptable and metabolically labile ester groups, such as methoxymethyl ester, methyl thiomethyl ester,
  • R 1 Preferred meanings for R 1 are phenyl, 4-tolyl, 2, 5-dimethylphenyl, 2-isopropylphenyl, 3-methoxyphenyl, 2-methyl-5-methoxyphenyl, benzyl, 2-phenylethyl, 2- (2-pyridyl) ethyl, 2 - (2-thienyl) ethyl, 2-indanyl and 2-morpholinoethyl.
  • R 1 is cycloheptyl, 2-hydroxy-2-phenylethyl, 2-thienylmethyl, 2-furanylmethyl, 4-chlorobenzyl, 3-fluorophenyl, 2-chlorobenzyl and 2,4-dimethoxybenzyl and also 2-naphthyl, naphthalene 1-ylmethyl, 4-dimethylaminophenyl, 2-pyrrolidin-1-ylethyl, 1-methylpyrrolidin-2-ylethyl, 4-isopropylphenyl and 3,5-bis-trifluoromethylphenyl.
  • R 1 Particularly preferred meanings for R 1 are 2, 5-dimethylphenyl, 2-isopropylphenyl and 2-methyl-5-methoxyphenyl.
  • R 2 Preferred meanings for R 2 are biphenyl-4-yl, 4-methoxyphenyl, 4-phenoxyphenyl, 4-dimethylaminophenyl, 4-diethylaminophenyl, 4-phenylaminophenyl, 4- [N-ethyl-N- (2-hydoxyethyl) amino] phenyl, 4- (N-ethyl-N-isopropylamino) phenyl, 4-N- (4,6-dimethyl-2-pyrimidinyl) aminophenyl, 4- [N-ethyl-N- (4,6-dimethyl-2-pyrimidinyl) amino] phenyl, 4- [N-methyl-N- (4,6-dimethyl-2-pyrimidinyl) amino] phenyl, 4-acetylphenyl, 9H- Fluoren-2-yl, 9-oxo-9H-fluoren-2-yl and 9-ethylcarbazol-3-yl
  • R 2 Particularly preferred meanings for R 2 are 9-ethyl-9H-carbazol-3-yl, 4- [N-ethyl-N- (4, 6, dimethyl-2-pyrimidinyl) amino] phenyl, 4- [N-methyl- N- (4, 6, dimethyl-2-pyrimidinyl) amino] phenyl, 4- (4, 6, dimethyl-2-pyrimidinyl) amino] phenyl, 4-phenylaminophenyl, 4-
  • 5-oxo-l-phenyl-pyrrolidin-3-carboxylic acid (9-ethyl-9H-carbazol-3-yl) amide; rac. 5-oxo-l-p-tolyl-pyrrolidin-3-carboxylic acid- ⁇ 4- [(4, 6-dimethyl-pyrimidin-2-yl) methylamino] phenyl ⁇ amide; rac. 1- (2, 5-dimethylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (isopropylphenylamino) phenyl] amide; rac. 1- (2-isopropylphenyl) -5-oxopyrrplidine-3-carboxylic acid
  • the compounds of the formula I can be prepared according to the invention by reacting a pyrrolidone carboxylic acid of the formula III (see scheme below), in which R 1 has the meaning mentioned at the outset, or a reactive derivative thereof, with an amine of the formula IV, in which R 2 is the initially mentioned Has meaning, or a reactive derivative thereof. Any stereoisomer mixtures obtained, such as racemates, can, if desired, be separated by generally customary methods.
  • the compounds of formula I can by reacting a pyrrolidone carboxylic acid of formula III with an amine Formula IV are made.
  • a pyrrolidone carboxylic acid of formula III if appropriate in a suitable solvent, such as, for example, toluene, is converted into the corresponding acid chloride using a halogenating agent, such as, for example, SO 2 or POCl 3 .
  • This reactive derivative of the pyrrolidone carboxylic acid of the formula III is then reacted with an amine of the formula IV in a suitable solvent, such as methylene chloride, in the presence of a base, such as triethylamine.
  • the pyrrolidone carboxylic acid of the formula III is reacted with an amine of the formula IV with the addition of a coupling reagent, such as EDC, DCC or BOP, in a solvent, such as DMF, if appropriate in the presence of a base, such as triethylamine.
  • a coupling reagent such as EDC, DCC or BOP
  • a solvent such as DMF
  • R 5 -NR 6 R 7 and R 7 are acyl
  • R 7 is hydrogen, such as rac. 1- (2,5-dimethyl-phenyl) -5-oxopyrrolidine-3-cabonic acid- (4-aminophenyl) -amide, acylated, for example using acetyl chloride, isovaleryl chloride,
  • the pyrrolidone carboxylic acids of the formula III are only partially known but can be prepared by methods known per se and familiar to any person skilled in the art, for example by the method mentioned above (Buzas et al., Chim Ther 7, 398-403, 1972); In addition, some of the following examples contain information regarding the preparation of certain pyrrolidone carboxylic acids of the formula III.
  • amines of the formula IV are also known or can be prepared by methods known per se; Some of the examples below also contain information regarding the preparation of certain amines of the formula IV.
  • the compounds of the formula I and their pharmaceutically acceptable salts and esters are new and have valuable pharmacological properties. In particular, they inhibit the interaction of the neuropeptide Y
  • NPY neuropeptide receptor subtypes
  • NPY is a 36 amino acid regulatory peptide of the pancreatic polypeptide family. NPY is the most common neuropeptide in the central and peripheral nervous system and has prominent and complex effects on food intake, anxiety, depression, circadian rhythm, sexual function, reproduction, memory function, migraine, pain, epiletpic seizures, blood pressure, cerebral bleeding, shock, sleep disorders, diarrhea etc
  • NPY interacts with a heterogeneous population of at least five NPY receptor subtypes, Y1-Y5, which activate adenylate cyclase using a G protein.
  • Y1-Y5 NPY receptor subtypes
  • One of the most prominent effects is the induction of food intake in vertebrates.
  • Recent studies with selective activation and blocking of the individual NPY receptors have shown that the NPY-Y5 receptor is mainly responsible for appetite-inducing signals.
  • Obesitas is a major and growing problem in the industrialized world. Obesitas is associated with various diseases, such as non-insulin-dependent diabetes (type II diabetes), high blood pressure, coronary artery disease, dislipidemia, etc., and affects the life expectancy and quality of life of the affected population.
  • the NPY-Y5 receptor is a possible target for a corresponding pharmacological intervention. Inhibition of this receptor by a low-molecular compound is an attractive way of preventing or treating the above diseases.
  • the compounds of the formula I and their pharmaceutically acceptable salts and esters are suitable for the prevention and treatment of arthritis, diabetes and especially eating disorders and obesity.
  • the "full-length" cDNA which contains the mouse NPY-Y5 (mNPY-Y5) receptor coding, was generated from mouse brain cDNA with the aid of specific "primers", which were tailored on the basis of published sequences and using Pfu DNA polymerase (Stratagene) were amplified.
  • the amplification product was subcloned in a mammalian expression vector pcDNA3 by Eco RI and Xhol Restriction Sites. Positive clones were sequenced Clone containing the published sequence was selected for the production of stable Zeil clones.
  • HEK293 Human embryonic "kidney 293" (HEK293) cells were transfected with 10 ⁇ g mNPY5 DNA with the aid of lipofectamine reagent (Gibco BRL) according to the manufacturer's instructions. 2 days after the transfection, the Geneticin Selection (lmg / ml) was initialized and several stable clones were isolated. One of the clones was used for further pharmacological characterization.
  • HEK293 Human embryonic kidney cells (HEK293), which express recombinant mouse NPY-Y5 receptors (mNPY-Y5), were broken up by freezing / thawing three times in hypotonic Tris buffer (5mM, pH7.4, ImM MgCl 2 ), then homogenized and during Centrifuged at 72,000 G for 15 minutes.
  • hypotonic Tris buffer 5mM, pH7.4, ImM MgCl 2
  • the precipitate was washed twice with Tris buffer (pH7.4) containing 25 mM MgCl 2 , 250 mM succrose, 0.1 mM phenylmethylsulfonyl fluoride and 0.1 mM 1, 10-phenanthroline, resuspended in the same buffer and stored in aliquots at -80 ° C ,
  • the protein was determined by Lowry's method using Bovine Serum Albumin (BSA) as the standard.
  • BSA Bovine Serum Albumin
  • the competition binding analysis was carried out in 250 ul of 25mM Hepes buffer (pH7.4, 2.5mM CaCl2, ImM MgC12, 1% bovine serum albumin and 0.01% sodium azide) containing 5 ⁇ g protein, 100pM 125 I-labeled peptide YY (PYY ) and 10 ⁇ l of a DMSO solution with increasing amounts of unlabelled test compound containing DMSO solution. After incubation at 22 ° C. for one hour, the bound and unbound ligand were separated by filtration through glass fiber filters. Non-specific binding was determined in the presence of 1 ⁇ M unlabeled PYY. Specific binding is defined as the difference between total and non-specific binding. IC 5 0 values are defined as that concentration of the antagonist which 50% of the 125 I-labeled neuropeptide Y displaced. This concentration is determined by linear regression analysis after logit / log transformation of the binding values.
  • preferred compounds according to the invention show IC50 values below 100 nm, particularly preferred compounds show IC50 values below 100 nM, very particularly preferred values below 50 nM.
  • the compounds according to the invention can be brought into suitable pharmaceutical dosage forms by methods which are generally known and familiar to any person skilled in the art.
  • Such dosage forms are, for example, tablets, coated tablets, dragées, capsules, injection solutions, etc.
  • Excipients and auxiliaries which are suitable for the preparation of such pharmaceutical dosage forms are likewise generally known and familiar to any person skilled in the art .
  • these dosage forms can also contain further pharmcologically active compounds.
  • the dosage of the compounds according to the invention or of the dosage forms containing them is to be adjusted by the attending physician according to the patient's particular needs.
  • a daily dose of 0.1-20 mg, preferably 0.5-5 mg, of a compound according to the invention per kg of body weight of the patient should be appropriate.
  • the following examples are intended to explain the invention in greater detail, but in no way limit its scope.
  • Example 4 (R 1 is 2, 5-dimethylphenyl) a) Analogously to Example 1, rac. 1- (2, 5-Dimethylphenyl) -5-oxo-l-pyrrolidine-3-carboxylic acid using the amines below produced the following products:
  • Example 5a l-Indan-2-yl-5-oxopyrrolidin-3-carboxylic acid was prepared analogously to Example 3b) but using indan-2-amine instead of benzylamine.
  • Example 6 (R 1 is 2-naphthyl)
  • Example 6a The rac required for Example 6a.
  • l-Naphthalin-2-yl-5-oxopyrrolidin-3-carboxylic acid was prepared analogously to Example 3b), but using 2-naphthylamine instead of benzylamine.
  • Example 7a 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid was prepared analogously to Example 3b) but using isopropylamine instead of benzylamine.
  • Example 9a The rac required for Example 9a. 1- (5-methoxy ⁇ 2-methyl-phenyl) -5-oxo-pyrrolidine-3-carboxylic acid was prepared analogously to Example 3b) but using 5 ⁇ methoxy-2-methyl-aniline instead of benzylamine.
  • Example 10a 1- (5-Methoxy-2-methyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid was prepared analogously to Example 3b), but using 4- (2-aminoethyl) morpholine instead of benzylamine:
  • Example 14a The rac required for Example 14a.
  • 1- (3-methoxy-phenyl-5-oxopyrrolidine-3-carboxylic acid was prepared analogously to Example 3b) but using m-anisidine instead of benzylamine.
  • Example 15a l-Cycloheptyl-5-oxopyrrolidine-3-carboxylic acid was prepared analogously to Example 3b), but using cycloheptylamine instead of benzylamine; MS (M + H) 226.1, MS (M-H) 224.1.
  • Example 16a The rac required for Example 16a.
  • 1-Naphthalin-l-ylmethyl-5-oxo-pyrrolidin-3-carboxylic acid was prepared analogously to Example 3b) but using 1-naphthylmethylamine instead of benzylamine; MS (M + H) 270.1, MS (M-H) 268.1.
  • Example 18a The rac required for Example 18a. 1- (2-Hydroxy-2-phenyl-ethyl) -5-oxopyrrolidine-3-carboxylic acid was prepared analogously to Example 3b) but using 2-hydroxy-2-phenyl-ethylamine instead of benzylamine; MS (M + H) 250.1, MS (M-H) 248.1.
  • Example 22a 1- (4-Dimethylaminophenyl) -5-oxopyrrolidine-3-carboxylic acid was prepared analogously to Example 3b) but using N, N-dimethyl-p-phenylenediamine instead of benzylamine; MS (M + H) 249.1, MS (M-H) 247.1.
  • Example 24 (R 1 is 1-methyl-pyrolidin-2-yl-ethyl) a) Analogous to Example 1, rac. 1- [2- (1-Methyl-pyrrolidin-2-yl) -ethyl] -5-oxo-pyrrolidin-3-carboxylic acid produced the following product using the following amine:
  • Example 24a The rac required for Example 24a.
  • 1- [2- (1-Methylpyrrolidin-2-yl) ethyl] -5-oxo-pyrrolidin-3-carboxylic acid was analogous to Example 3b) but using 2- (2-aminoethyl) -1-methylpyrrolidine instead made by benzylamine; MS (M + H) 241.2, MS (M-H) 239.1.
  • Example 25a 1- (4-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid was prepared analogously to Example 3b), but using 4-isopropylaniline instead of benzylamine; MS (M + H) 248.1, MS (M-H) 246.1.
  • Example 26 (R 1 is 3,5-bis-trifluoromethyl-phenyl) a) Analogously to Example 1, the following product was prepared from rac.1- (3,5-bis-trifluoromethyl-phenyl) -5-oxo-pyrrolidine-3-carboxylic acid using the following amine:
  • Example 26a 1- (3,5-Bis-trifluoromethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid was prepared analogously to Example 3b) but using 3,5-bis (trifluoromethyl) aniline instead of benzylamine.
  • Example 27a 1- (3-fluorophenyl) -5-oxopyrrolidine-3-carboxylic acid was prepared analogously to Example 3b), but using 3-fluoroaniline instead of benzylamine; MS (M + H) 224.2, MS (M-H) 222.1.
  • Example 28 (R 1 is 2-chloro-benzyl) a) Analogous to Example 1, rac. 1- (2-chloro-benzyl) -5-oxo-pyrrolidine-3-carboxylic acid using the following amine produced the following product:
  • Example 28a The rac required for Example 28a. 1- (2-chloro-benzyl) -5-oxopyrrolidine-3-carboxylic acid was prepared analogously to Example 3b) but using 2-chloro-benzylamine instead of benzylamine; MS (M + H) 254.1, MS (M-H) 252.1.
  • Example 29 Analogously to Example 29, the following racemic compounds can be separated into the corresponding enantiomers: rac. 5-oxo-1- (2-pyridin-2-yl-ethyl) -pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; rac. 1- (2-hydroxy-2-phenyl-ethyl) -5-oxo-pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; rac.
  • Example 34a The 1- (2, 4-dimethoxy-benzyl) -5-oxopyrrolidine-3-carboxylic acid required for Example 34a was prepared analogously to Example 3b) but using 2, 4-dimethoxybenzylamine; MS (M + H) 280.1, MS (M-H) 278.1.
  • a compound of formula I can be used in a manner known per se as an active ingredient for the production of tablets of the following composition:
  • a compound of formula I can be used in a manner known per se as an active ingredient for the production of capsules of the following composition:

Abstract

Pyrrolidone carboxamides of formula (I) where R2 = a group of formula (a) or (b), R5 = phenyl, heteroalkyl, aryloxy, alkoxy, alkanoyl or -NR?6R7 and R1, X, R3, R4, R6 and R7¿ have the meanings given in the description and the claims, pharmaceutically applicable acid addition salts with basic compounds of formula (I), pharmaceutically applicable salts of acid compounds of formula (I) with bases, pharmaceutically applicable esters of hydroxy- or carboxy-group containing compounds of formula (I) and hydrates and solvates thereof, inhibit the interaction of neuropeptide Y (NPY) with one of the neuropeptide receptor subtypes (NPY-Y5) and are particularly suitable for the prevention and treatment of arthritis, diabetes and especially eating disorders and obesity. The above can be produced by known methods and converted into a galenic dosage form.

Description

Pyrrolidon-carboxamidePyrrolidone-carboxamides
Die vorliegende Erfindung betrifft Pyrrolidoncarboxamid Derivate .The present invention relates to pyrrolidone carboxamide derivatives.
Insbesondere betrifft die Erfindung Pyrrolidoncarboxamide der FormelIn particular, the invention relates to pyrrolidone carboxamides of the formula
Figure imgf000003_0001
Figure imgf000003_0001
worin R1 im Phenylrest gegebenenfalls durch Alkyl, Alkoxy, Dialkylamino, Halogen oder Trifluormethyl mono- oder disubstituiertes Phenyl, Benzyl, Phenylethyl oder α- Hydroxyphenylethyl; Naphthyl oder Naphthylmethyl; Thienyl-, Furyl-, Pyridyl-, l-Alkylpyrrolidin-2-yl-, Pyrrolidino- oder Morpholino-alkyl; oder Cycloalkyl, welches gegebenenfalls einen ankondensierten Benzolring aufweisen kann;wherein R 1 in the phenyl radical optionally mono- or disubstituted phenyl, benzyl, phenylethyl or α-hydroxyphenylethyl by alkyl, alkoxy, dialkylamino, halogen or trifluoromethyl; Naphthyl or naphthylmethyl; Thienyl, furyl, pyridyl, l-alkylpyrrolidin-2-yl, pyrrolidino or morpholino alkyl; or cycloalkyl, which may optionally have a fused-on benzene ring;
Rz einen Rest der FormelR z is a radical of the formula
Figure imgf000003_0002
Figure imgf000003_0002
(a) (b)(a) (b)
X -CH2-, -CO-, -0- oder -NRJ-; R3 Wasserstoff oder Alkyl; R4 Wasserstoff oder Alkoxy; R5 Phenyl, Heteroalkyl, Aryloxy, Alkoxy, Alkanoyl oderX -CH 2 -, -CO-, -0- or -NR J -; R 3 is hydrogen or alkyl; R 4 is hydrogen or alkoxy; R 5 phenyl, heteroalkyl, aryloxy, alkoxy, alkanoyl or
-NR6R7; R6 Wasserstoff, Alkyl, Aralkyl, Cycloalkylalkyl oder Alkoxycarbonylalkyl; und R7 Aryl, Heteroaryl, alkyl, Hydroxyalkyl oder Acyl bedeuten; pharmazeutisch verwendbare Säureadditionssalze von basischen Verbindungen der Formel I, pharmazeutisch verwendbare Salze von sauren Verbindungen der Formel I mit Basen, pharmazeutisch verwendbare Ester von Hydroxy- oder Carboxygruppen enthaltenden Verbindungen der Formel I sowie Hydrate oder Solvate davon.-NR 6 R 7 ; R 6 is hydrogen, alkyl, aralkyl, cycloalkylalkyl or alkoxycarbonylalkyl; and R 7 represents aryl, heteroaryl, alkyl, hydroxyalkyl or acyl; pharmaceutically usable acid addition salts of basic compounds of formula I, pharmaceutically usable salts of acid compounds of formula I with bases, pharmaceutically usable esters of hydroxyl or carboxy group-containing compounds of formula I and hydrates or solvates thereof.
Da die Pyrrolidoncarboxamide der Formel I zumindest ein asymmetrisches C-Atom enthalten, können sie als optisch reine Enantiomere, als Mischungen von Enantiomeren, wie zum Beispiel Racemate, oder gegebenenfalls als optisch reine Diastereomere, als Mischungen von Diastereomeren, als diastereomere Racemate oder als Mischungen von diastereomeren Racematen vorliegen.Since the pyrrolidone carboxamides of the formula I contain at least one asymmetric carbon atom, they can be used as optically pure enantiomers, as mixtures of enantiomers, such as racemates, or optionally as optically pure diastereomers, as mixtures of diastereomers, as diastereomeric racemates or as mixtures of diastereomeric racemates are present.
WO 01/07409 AI betrifft Carbazol-Derivate, deren allgemeine Formel mit der obigen Formel I teilweise überlappt, beschreibt aber keine einzige unter die obige Formel I fallende Verbindung spezifisch und enthält auch keine hinreichend konkreten allgemeinen Hinweise in Richtung auf Verbindungen der obigen Formel I .WO 01/07409 AI relates to carbazole derivatives, the general formula of which partially overlaps with the above formula I, but does not specifically describe a single compound falling under the above formula I and also does not contain any sufficiently specific general information in the direction of compounds of the above formula I.
Die eingangs definierten Stoffe sind neu und zeichnen sich durch wertvolle pharmakodynamische Eigenschaften aus. Sie hemmen die Interaktion des Neuropeptids Y (NPY) mit einem der Neuropeptid-Rezeptor-Subtypen (NPY-Y5) und eignen sich insbesondere für die Vorbeugung und Behandlung von Arthritis, Diabetes und speziell von Essstörungen und Obesitas .The substances defined at the beginning are new and are characterized by valuable pharmacodynamic properties. They inhibit the interaction of the neuropeptide Y (NPY) with one of the neuropeptide receptor subtypes (NPY-Y5) and are particularly suitable for the prevention and treatment of Arthritis, diabetes and especially eating disorders and obesity.
Gegenstand der vorliegenden Erfindung sind die obigen Stoffe als solche und als therapeutische Wirkstoffe; Verfahren und Zwischenprodukte zu deren Herstellung; Arzneimittel, enthaltend einen der obigen Stoffe; und die Verwendung der obigen Stoffe zur Vorbeugung und Behandlung von Arthritis, Diabetes und speziell von Essstörungen und Obesitas bzw. zur Herstellung entsprechender Arzneimittel.The present invention relates to the above substances as such and as therapeutic active substances; Processes and intermediates for their manufacture; Medicaments containing one of the above substances; and the use of the above substances for the prevention and treatment of arthritis, diabetes and especially eating disorders and obesity or for the production of corresponding medicaments.
In der vorliegenden Beschreibung bezeichnet der Begriff ΛXAlkylλ, alleine oder in Kombination, einen verzweigten oder unverzweigten gesättigten Kohlenwasserstoffrest mit 1 bis 8 Kohlenstoffatomen, bevorzugt mit 1 bis 6 Kohlenstoffatomen und speziell bevorzugt mit 1 bis 4 Kohlenstoffatomen. Beispiele für solche Reste sind Methyl, Ethyl, n-Propyl, Isopropyl, n-Butyl Isobutyl, sek.-Butyl, tert-Butyl, die isomeren Pentyle, die isomeren Hexyle und die isomeren Octyle; bevorzugt sind Methyl, Ethyl, n- Propyl, Isopropyl, n-Butyl, Isobutyl u. dgl .In the present description, the term ΛX alkyl λ , alone or in combination, denotes a branched or unbranched saturated hydrocarbon radical having 1 to 8 carbon atoms, preferably having 1 to 6 carbon atoms and particularly preferably having 1 to 4 carbon atoms. Examples of such radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl isobutyl, sec-butyl, tert-butyl, the isomeric pentyls, the isomeric hexyls and the isomeric octyls; methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like are preferred. the like
Der Begriff "Cycloalkyl", alleine oder in Kombination, bezeichnet einen gesättigten cyclischen Kohlenwasserstoffrest mit 3-8 Kohlenstoffatomen, bevorzugt mit 3 bis 6 Kohlenstoffatomen, welcher substituiert sein kann, z.B. durch Alkylgruppen, wie Methyl, und welcher einen ankondensierten Benzolring aufweisen kann. Beispiele für gegebenenfalls durch Alkyl substituierte Cycloalkylgruppen sind Cyclopropyl, Methylcyclopropyl, Dimethylcyclopropyl, Cyclobutyl, Mehtylcyclobutyl, Cyclopentyl, Methylcyclopentyl, Cyclohexyl,The term "cycloalkyl", alone or in combination, denotes a saturated cyclic hydrocarbon residue with 3-8 carbon atoms, preferably with 3 to 6 carbon atoms, which can be substituted, e.g. by alkyl groups, such as methyl, and which may have a fused-on benzene ring. Examples of cycloalkyl groups optionally substituted by alkyl are cyclopropyl, methylcyclopropyl, dimethylcyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl,
Methylcyclohexyl, Dimethylcyclohexyl, Cycloheptyl, und Cyclooctyl; Beispiele für Cycloalkylreste mit einem ankondensierten Benzolring sind 1-Indanyl, 2-Indanyl u. dgl.Methylcyclohexyl, dimethylcyclohexyl, cycloheptyl, and cyclooctyl; Examples of cycloalkyl radicals with a fused benzene ring are 1-indanyl, 2-indanyl and. like.
Der Begriff "Hydroxyalkyl", alleine oder in Kombination, bezeichnet eine Alkylgruppe, wie oben beschrieben, wobei eines oder zwei H Atome, bevorzugt ein H-Atom, durch eine Hydroxygruppe ersetzt ist. Beispiel sind Hydroxymethyl, Hydroxyethyl, Hydroxypropyl u. dgl.The term "hydroxyalkyl", alone or in combination, denotes an alkyl group as described above, wherein one or two H atoms, preferably one H atom, has been replaced by a hydroxy group. Examples are hydroxymethyl, hydroxyethyl, hydroxypropyl and. like.
Der Begriff "Alkoxy", alleine oder in Kombination, bezeichnet einen über eine Sauerstoffbrücke verknüpften Alkylrest, wie oben beschrieben. Beispiele sind Methoxy, Ethoxy u. dgl.The term "alkoxy", alone or in combination, denotes an alkyl radical linked via an oxygen bridge, as described above. Examples are methoxy, ethoxy and the like. like.
Der Begriff "Alkanoyl", allein oder in Kombination, bezeichnet eine über eine CO-Brücke verknüpfte Alkylgruppe, wie oben beschrieben. Beispiele sind Acetyl, 3- Methylbutyryl, 2, 2-Dimethylpropionyl u. dgl.The term "alkanoyl", alone or in combination, denotes an alkyl group linked via a CO bridge, as described above. Examples are acetyl, 3-methylbutyryl, 2, 2-dimethylpropionyl and. like.
Der Begriff "Aryl", alleine oder in Kombination, bezeichnet eine Phenyl- oder Naphthylgruppe, bevorzugt eine Phenylgruppe, welche bis zu vier, bevorzugt einen bis drei und speziell bevorzugt einen oder zwei Substituenten tragen kann. Beispiele solcher Substituenten sind Alkyl, Hydroxyalkyl, Alkoxy, Alkoxyalkyl, Nitro, Fluoro, Bromo, Chloro, Hydroxy, Dialkylamino u. dgl. Speziell bevorzugte Substituenten sind Alkyl und Alkoxy. Beispiele von solchen Arylgruppen sind Phenyl, Methylphenyl, Dimethylphenyl, Ethylphenyl, Isopropylphenyl, Methoxyphenyl, Methoxymethylphenyl, Dimethylaminophenyl, Phenylaminophenyl u. dgl.The term "aryl", alone or in combination, denotes a phenyl or naphthyl group, preferably a phenyl group, which can carry up to four, preferably one to three and particularly preferably one or two substituents. Examples of such substituents are alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, nitro, fluoro, bromo, chloro, hydroxy, dialkylamino and the like. Like. Particularly preferred substituents are alkyl and alkoxy. Examples of such aryl groups are phenyl, methylphenyl, dimethylphenyl, ethylphenyl, isopropylphenyl, methoxyphenyl, methoxymethylphenyl, dimethylaminophenyl, phenylaminophenyl and the like. like.
Der Begriff" "Aralkyl", alleine oder in Kombination, bezeichnet eine Alkylgruppe, wie oben beschrieben, in welcher mindestens ein H-Atom durch eine Arylgruppe, wie oben beschrieben, ersetzt ist, insbesondere durch eine Phenyl- oder Naphthylgruppe, welche einen oder mehrere Substituenten tragen kann, wie Alkyl- oder Alkoxygruppen. Beispiele solcher Aralkylreste sind Benzyl, Phenethyl, 2- (3, 4-Dimethoxyphenyl) ethyl u. dgl.The term " " aralkyl ", alone or in combination, denotes an alkyl group as described above in which at least one H atom is replaced by an aryl group, as described above, in particular by a phenyl or naphthyl group which can carry one or more substituents, such as alkyl or alkoxy groups. Examples of such aralkyl radicals are benzyl, phenethyl, 2- (3, 4-dimethoxyphenyl) ethyl and. like.
Der Begriff "Heteroaryl", alleine oder in Kombination, bezeichnet ein aromatisches mono- bi- oder tricyclisches heterocyclisches Ringsystem mit 5 bis 10, bevorzugt 5 bis 6, Ringgliedern, welches ein bis vier, bevorzugt ein bis zwei, Heteroatome enthält, welche voneinander unabhängig aus Stickstoff, Sauerstoff und Schwefel ausgewählt sind. Beispiele solcher Heteroarylgruppen sind Pyridyl, Pyrimidinyl, Thiazolyl, Thiophenyl, Furanyl, Tetrazolyl, Carbazolyl u. dgl. Solche Heteroarylgruppen können substituiert sein, zweckmässigerweise mono, di oder trisubstituiert, wobei als Substituenten in erster Linie Alkyl-, Alkoxy-, Amino- oder Arylgruppen in Frage kommen. Beispiele sind 2-Pyridyl, 2-Thienyl, 4 , 6-Dimethyl-2- pyrimidinyl u. dgl.The term "heteroaryl", alone or in combination, denotes an aromatic mono- or tricyclic heterocyclic ring system with 5 to 10, preferably 5 to 6, ring members which contains one to four, preferably one to two, heteroatoms which are independent of one another are selected from nitrogen, oxygen and sulfur. Examples of such heteroaryl groups are pyridyl, pyrimidinyl, thiazolyl, thiophenyl, furanyl, tetrazolyl, carbazolyl and the like. Such heteroaryl groups can be substituted, expediently mono, di or trisubstituted, the substituents being primarily alkyl, alkoxy, amino or aryl groups. Examples are 2-pyridyl, 2-thienyl, 4, 6-dimethyl-2-pyrimidinyl and the like. like.
Der Begriff "Acyl", allein oder in Kombination, bezeichnet eine Alkanoylgruppe, wie oben beschrieben, oder eine über eine CO-Brücke verknüpfte Cycloalkyl-, Aryl-, Aralkyl- oder Heteroarylgruppe, wie oben beschrieben. Beispiele sind, wie oben erwähnt, Acetyl, 3-Methylbutyryl und 2,2- Dimethylpropionyl sowie Cyclopropancarbonyl, Benzoyl, Phenylacetyl, 2-Methoxybenzoyl, 4-Methoxybenzoyl, 3- Fluorobenzoyl, Benzo [1, 3] dioxol-5-carbonyl, Furan-2- carbonyl u. dgl.The term "acyl", alone or in combination, denotes an alkanoyl group, as described above, or a cycloalkyl, aryl, aralkyl, or heteroaryl group linked via a CO bridge, as described above. Examples are, as mentioned above, acetyl, 3-methylbutyryl and 2,2-dimethylpropionyl as well as cyclopropane carbonyl, benzoyl, phenylacetyl, 2-methoxybenzoyl, 4-methoxybenzoyl, 3-fluorobenzoyl, benzo [1, 3] dioxol-5-carbonyl, furan -2- carbonyl and like.
Der Begriff "pharmazeutisch verwendbare Salze" bezieht sich auf solche Salze, welche die biologische Wirkung und Eigenschaften der freien Basen oder freien Säuren nicht mindern und welche nicht biologisch oder anderweitig unerwünscht sind. Die Salze werden aus den freien Basen mittels anorganischer Säuren, wie Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Salpetersäure, Phosphorsäure u. dgl., bevorzugt Salzsäure, oder mittels organischer Säuren, wie Essigsäure, Propionsäure, Glycolsäure, Brenztraubensäure, Oxalsäure, Maleinsäure, Malonsäure, Bernsteinsäure, Weinsäure, Salicylsäure, Citronensäure, Benzoesäure, Mandelsäure, Methansulfonsäure, p-Toluolsulfonsäure u. dgl. gebildet. Die freien Säuren können mit anorganischen Basen oder mit organischen Basen Salze bilden. Bevorzugte Salze mit anorganischen Basen sind, aber nicht ausschliesslich, Natrium-, Kalium-, Lithium-, Ammonium-, Calcium-, Magnesiumsalze u. dgl. Bevorzugte Salze mit organischen Basen sind, aber nicht ausschliesslich, Salze mit primären, sekundären und tertiären Aminen, substituierten Aminen, einschliesslich alle natürlich vorkommenden substituierten Amine, Cyclische Amine und basische lonenaustauschharze, wie Isopropylamin, Trimethylamin, Diethylamin, Triethylamin, Tripropylamin, Ethanolamin, Lysin, Arginin, N-Ethylpiperidin, Piperidin, Polyamin-Harze u. dgl. Verbindungen der Formel I können auch als Zwitterion vorliegen.The term "pharmaceutically acceptable salts" refers to those salts which have the biological effect and Do not diminish the properties of the free bases or free acids and which are not biologically or otherwise undesirable. The salts are made from the free bases using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Like., Preferably hydrochloric acid, or by means of organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, tartaric acid, salicylic acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, p-toluenesulfonic acid and the like. Like. Formed. The free acids can form salts with inorganic bases or with organic bases. Preferred salts with inorganic bases are, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like. Like. Preferred salts with organic bases are, but not exclusively, salts with primary, secondary and tertiary amines, substituted amines, including all naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine , Lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins and the like. Like. Compounds of formula I can also be present as a zwitterion.
Die Erfindung umfasst auch pharmazeutisch geeignete Ester von Hydroxy- oder Carboxygruppen enthaltenden Verbindungen der Formel I. "Pharmazeutisch geeignete Ester" bedeutet dass in Verbindungen der Formel I entsprechende funktionelle Gruppen so zu Estergruppen derivatisiert sind, dass sie in vivo wieder in ihre aktive Form zurücktransformiert werden. Einerseits können COOH-Gruppen verestert sein. Beispiele geeigneter derartiger Ester sind die Alkyl- und Aralkylester . Bevorzugte derartige Ester sind die Methyl-, Ethyl-, Propyl-, Butyl- und Benzylester sowie die (R/S) -1- [ (Isopropoxycarbonyl) oxy] ethylester . Besonders bevorzugt sind die Ethylester und die isomeren Butylester. Anderseits können OH-Gruppen verestert sein. Beispiele solcher Verbindungen enthalten physiologisch akzeptable und metabolisch labile Estergruppen, wie Methoxymethylester-, Methylthiomethylester-,The invention also encompasses pharmaceutically suitable esters of compounds of the formula I containing hydroxyl or carboxy groups. "Pharmaceutically suitable esters" means that corresponding compounds in formula I are derivatized to ester groups in such a way that they are transformed back into their active form in vivo , On the one hand, COOH groups can be esterified. Examples of suitable such esters are the alkyl and aralkyl esters. Preferred such esters are the methyl, ethyl, propyl, butyl and benzyl esters and the (R / S) -1- [(isopropoxycarbonyl) oxy] ethyl esters. The ethyl esters and the isomeric butyl esters are particularly preferred. On the other hand, OH groups can be esterified. Examples of such compounds contain physiologically acceptable and metabolically labile ester groups, such as methoxymethyl ester, methyl thiomethyl ester,
Pivaloyloxymethylester- und ähnliche Estergruppen.Pivaloyloxymethyl ester and similar ester groups.
Bevorzugte Bedeutungsmöglichkeiten für R1 sind Phenyl, 4- Tolyl, 2, 5-Dimethylphenyl, 2-Isopropylphenyl, 3- Methoxyphenyl, 2-Methyl-5-methoxyphenyl, Benzyl, 2- Phenylethyl, 2- (2-Pyridyl) ethyl, 2- (2-Thienyl) ethyl, 2- Indanyl und 2-Morpholinoethyl . Weitere bevorzugte Bedeutungsmöglichkeiten für R1 sind Cycloheptyl, 2-Hydroxy- 2-phenylethyl, 2-Thienylmethyl, 2-Furanylmethyl, 4- Chlorbenzyl, 3-Fluorphenyl, 2-Chlorbenzyl und 2,4- Dimethoxybenzyl sowie auch 2-Naphthyl, Naphthalin-1- ylmethyl, 4-Dimethylaminophenyl, 2-Pyrrolidin-l-ylethyl, 1- Methylpyrrolidin-2-ylethyl, 4-Isopropylphenyl und 3,5-Bis- trifluormethylphenyl .Preferred meanings for R 1 are phenyl, 4-tolyl, 2, 5-dimethylphenyl, 2-isopropylphenyl, 3-methoxyphenyl, 2-methyl-5-methoxyphenyl, benzyl, 2-phenylethyl, 2- (2-pyridyl) ethyl, 2 - (2-thienyl) ethyl, 2-indanyl and 2-morpholinoethyl. Further preferred meanings for R 1 are cycloheptyl, 2-hydroxy-2-phenylethyl, 2-thienylmethyl, 2-furanylmethyl, 4-chlorobenzyl, 3-fluorophenyl, 2-chlorobenzyl and 2,4-dimethoxybenzyl and also 2-naphthyl, naphthalene 1-ylmethyl, 4-dimethylaminophenyl, 2-pyrrolidin-1-ylethyl, 1-methylpyrrolidin-2-ylethyl, 4-isopropylphenyl and 3,5-bis-trifluoromethylphenyl.
Besonders bevorzugte Bedeutungsmöglichkeiten für R1 sind 2, 5-Dimethylphenyl, 2-Isopropylphenyl und 2-Methyl-5- Methoxyphenyl .Particularly preferred meanings for R 1 are 2, 5-dimethylphenyl, 2-isopropylphenyl and 2-methyl-5-methoxyphenyl.
Bevorzugte Bedeutungsmöglichkeiten für R2 sind Biphenyl-4- yl, 4-Methoxyphenyl, 4-Phenoxyphenyl, 4- Dimethylaminophenyl, 4-Diethylaminophenyl, 4- Phenylaminophenyl, 4- [N-Ethyl-N- (2-hydoxyethyl) amino] phenyl, 4- (N-Ethyl-N-isopropylamino) phenyl, 4-N-(4,6- Dimethyl-2-pyrimidinyl) aminophenyl, 4- [N-Ethyl-N- (4,6- dimethyl-2-pyrimidinyl) amino] phenyl, 4- [N-Methyl-N- (4,6- dimethyl-2-pyrimidinyl) amino] phenyl, 4-Acetylphenyl, 9H- Fluoren-2-yl, 9-Oxo-9H-fluoren-2-yl und 9-Ethylcarbazol-3- yl . Weitere bevorzugte Bedeutungsmöglichkeiten für R2 sindPreferred meanings for R 2 are biphenyl-4-yl, 4-methoxyphenyl, 4-phenoxyphenyl, 4-dimethylaminophenyl, 4-diethylaminophenyl, 4-phenylaminophenyl, 4- [N-ethyl-N- (2-hydoxyethyl) amino] phenyl, 4- (N-ethyl-N-isopropylamino) phenyl, 4-N- (4,6-dimethyl-2-pyrimidinyl) aminophenyl, 4- [N-ethyl-N- (4,6-dimethyl-2-pyrimidinyl) amino] phenyl, 4- [N-methyl-N- (4,6-dimethyl-2-pyrimidinyl) amino] phenyl, 4-acetylphenyl, 9H- Fluoren-2-yl, 9-oxo-9H-fluoren-2-yl and 9-ethylcarbazol-3-yl. Further preferred meanings for R 2 are
4- (N-Ethoxycarbonylmethyl-N-phenyl-amino) -phenyl, 4- (N-4- (N-ethoxycarbonylmethyl-N-phenylamino) phenyl, 4- (N-
Ethyl-N-phenyl-amino) -phenyl, 4- (N-Methyl-N-phenyl-amino- phenyl, 4- (N-Cyclopropylmethyl-N-phenyl-amino) -phenyl, 4-Ethyl-N-phenylamino) phenyl, 4- (N-methyl-N-phenylamino phenyl, 4- (N-cyclopropylmethyl-N-phenylamino) phenyl, 4-
(N-Isobutyl-N-phenyl-amino) -phenyl, 4- (2-Methoxy- benzoylamino) -phenyl, 4- (2, 2-Dimethyl-propionylamino) - phenyl, 4- (3-Methyl-butyrylamino) -phenyl, 4-(N-isobutyl-N-phenylamino) phenyl, 4- (2-methoxybenzoylamino) phenyl, 4- (2, 2-dimethylpropionylamino) phenyl, 4- (3-methylbutyrylamino) - phenyl, 4-
(Cyclopropancarbonyl-amino) -phenyl, 4- (3-Fluoro- benzoylamino) -phenyl und 4- [ (Furan-2-carbonyl) -amino] - phenyl sowie auch Biphenyl-3-yl, 9H-Fluoren-l-yl, 2- Methoxydibenzofuran-3-yl, 4- (N-Isopropyl-N- phenylamino) phenyl, 4- (N-Benzyl-N-phenylamino) phenyl, 4- Acetylaminophenyl, 4-Benzoylaminophenyl, 4- Phenylacetylaminophenyl, 4- [ (Benzo [1, 3] dioxol-5- carbonyl) amino] phenyl und 4- (4-Methoxybenzoylamino) phenyl .(Cyclopropanecarbonylamino) phenyl, 4- (3-fluorobenzoylamino) phenyl and 4- [(furan-2-carbonyl) amino] phenyl as well as biphenyl-3-yl, 9H-fluoren-l-yl , 2-methoxydibenzofuran-3-yl, 4- (N-isopropyl-N-phenylamino) phenyl, 4- (N-benzyl-N-phenylamino) phenyl, 4-acetylaminophenyl, 4-benzoylaminophenyl, 4-phenylacetylaminophenyl, 4- [ (Benzo [1,3] dioxol-5-carbonyl) amino] phenyl and 4- (4-methoxybenzoylamino) phenyl.
Besonders bevorzugte Bedeutungsmöglichkeiten für R2 sind 9- Ethyl-9H-carbazol-3-yl, 4- [N-Ethyl-N- (4 , 6, dimethyl-2- pyrimidinyl) amino] phenyl, 4- [N-Methyl-N- (4, 6, dimethyl-2- pyrimidinyl) amino] phenyl, 4- (4, 6, dimethyl-2- pyrimidinyl) amino] phenyl, 4-Phenylaminophenyl, 4-Particularly preferred meanings for R 2 are 9-ethyl-9H-carbazol-3-yl, 4- [N-ethyl-N- (4, 6, dimethyl-2-pyrimidinyl) amino] phenyl, 4- [N-methyl- N- (4, 6, dimethyl-2-pyrimidinyl) amino] phenyl, 4- (4, 6, dimethyl-2-pyrimidinyl) amino] phenyl, 4-phenylaminophenyl, 4-
Diethylaminophenyl, 4- (N-Ethyl-N-isopropylamino) phenyl, 4-Diethylaminophenyl, 4- (N-ethyl-N-isopropylamino) phenyl, 4-
(N-Ethoxycarbonylmethyl-N-phenylamino) phenyl, 4- (N-Ethyl-N- phenylamino) phenyl, 4- (N-Methyl-N-phenylamino) phenyl und 2 , 4-Dimethoxybenzyl .(N-ethoxycarbonylmethyl-N-phenylamino) phenyl, 4- (N-ethyl-N-phenylamino) phenyl, 4- (N-methyl-N-phenylamino) phenyl and 2,4-dimethoxybenzyl.
Repräsentative Beispiele bevorzugter Verbindungen der Formel I sind:Representative examples of preferred compounds of formula I are:
rac. 5-Oxo-l- (2-pyridin-2-yl-ethyl) -pyrrolidin-3- carbonsäure- (9-ethyl-9H-carbazol-3-yl) -amid; rac. 1- (2-Hydroxy-2-phenyl-ethyl) -5-oxo-pyrrolidin-3- carbonsäure- (9-ethyl-9H-carbazol-3-yl) -amid; rac . 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- (4-diethylamino-phenyl) -amid; rac. 5-Oxo-l- (2-thiophen-2-yl-ethyl) -pyrrolidin-3- carbonsäure- (9-ethyl-9H-carbazol-3-yl) -amid; rac. 1- (4-Chlor-benzyl) -5-oxo-pyrrolidin-3-carbonsäure- (9- ethyl-9H-carbazol-3-yl) -amid; rac . 5-Oxo-l-thiophen-2-ylmethyl-pyrrolidin-3-carbonsäure-rac. 5-oxo-1- (2-pyridin-2-yl-ethyl) -pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; rac. 1- (2-hydroxy-2-phenyl-ethyl) -5-oxo-pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; rac. 1- (2,5-dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid- (4-diethylamino-phenyl) -amide; rac. 5-oxo-1- (2-thiophene-2-yl-ethyl) -pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; rac. 1- (4-chloro-benzyl) -5-oxopyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; rac. 5-Oxo-l-thiophen-2-ylmethyl-pyrrolidine-3-carboxylic acid
( 9-ethyl-9H-carbazol-3-yl) -amid; rac. l-Furan-2-ylmethyl-5-oxo-pyrrolidin-3-carbonsäure- (9- ethyl-9H-carbazol-3-yl) -amid; rac . 1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure-(9-ethyl-9H-carbazol-3-yl) amide; rac. l-furan-2-ylmethyl-5-oxopyrrolidin-3-carboxylic acid (9-ethyl-9H-carbazol-3-yl) amide; rac. 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid
( 9-ethyl-9H-carbazol-3-yl) -amid, rac. 1- (5-Methoxy-2-methyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- (9-ethyl-9H-carbazol-3-yl) -amid; rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (ethyl-isopropyl-amino) -phenyl] -amid; rac. 5-Oxo-l-phenethyl-pyrrolidin-3-carbonsäure- (9-ethyl-(9-ethyl-9H-carbazol-3-yl) amide, rac. 1- (5-methoxy-2-methylphenyl) -5-oxopyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; rac. 1- (2, 5-Dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (ethyl-isopropylamino) phenyl] amide; rac. 5-oxo-l-phenethyl-pyrrolidine-3-carboxylic acid- (9-ethyl-
9H-carbazol-3-yl) -amid; rac. [ (4-{ [1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonyl] -amino} -phenyl) -phenyl-amino] -essigsäure- ethylester; rac. l-Cycloheptyl-5-oxo-pyrrolidin-3-carbonsäure- (9-ethyl-9H-carbazol-3-yl) amide; rac. [(4- {[1- (2,5-dimethylphenyl) -5-oxopyrrolidine-3-carbonyl] amino} phenyl) phenylamino] acetic acid, ethyl ester; rac. l-cycloheptyl-5-oxopyrrolidine-3-carboxylic acid- (9-ethyl-
9H-carbazol-3-yl) -amid; rac. 1- (5-Methoxy-2-methyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- { 4- [ (4 , 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] - phenyl } -amid; rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure-{4- [ethyl- (2-hydroxy-ethyl) -amino] -phenyl } - amid; rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-ρyrrolidin-3- carbonsäure- [4- (ethyl-phenyl-amino) -phenyl] -amid; rac. 1- (3-Methoxy-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- (9-ethyl-9H-carbazol-3-yl) -amid; O 03/0599059H-carbazol-3-yl) amide; rac. 1- (5-methoxy-2-methylphenyl) -5-oxopyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethylpyrimidin-2-yl) ethylamino] phenyl} - amide; rac. 1- (2, 5-Dimethylphenyl) -5-oxopyrrolidine-3-carboxylic acid {4- [ethyl- (2-hydroxyethyl) amino] phenyl} amide; rac. 1- (2, 5-Dimethylphenyl) -5-oxo-pyrrolidine-3-carboxylic acid- [4- (ethylphenylamino) phenyl] amide; rac. 1- (3-methoxy-phenyl) -5-oxo-pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; O 03/059905
- 10 - rac . 1- (2-Chlor-benzyl) -5-oxo-pyrrolidin-3-carbonsäure- ( 9- ethyl-9H-carbazol-3-yl ) -amid; rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) -phenyl] - amid; rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure-{4- [ (4, 6-dimethyl-pyrimidin-2-yl) -methyl- amino] -phenyl } -amid; rac. 5-Oxo-l-phenyl-pyrrolidin-3-carbonsäure- (9-ethyl-9H- carbazol-3-yl) -amid; rac. 5-Oxo-l-p-tolyl-pyrrolidin-3-carbonsäure-{4- [ ( 4 , 6- dimethyl-pyrimidin-2-yl) -methyl-amino] -phenyl} -amid; rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (isopropyl-phenyl-amino) -phenyl] -amid; rac . 1- (2-Isopropyl -phenyl) -5-oxo-pyrrplidin-3-carbonsäure-- 10 - rac. 1- (2-chloro-benzyl) -5-oxopyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; rac. 1- (2, 5-Dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) phenyl] amide; rac. 1- (2, 5-Dimethylphenyl) -5-oxo-pyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) methylamino] phenyl} amide; rac. 5-oxo-l-phenyl-pyrrolidin-3-carboxylic acid (9-ethyl-9H-carbazol-3-yl) amide; rac. 5-oxo-l-p-tolyl-pyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) methylamino] phenyl} amide; rac. 1- (2, 5-dimethylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (isopropylphenylamino) phenyl] amide; rac. 1- (2-isopropylphenyl) -5-oxopyrrplidine-3-carboxylic acid
[ 4- (ethyl-phenyl-amino) -phenyl] -amid; rac . 5-Oxo-l- (2-pyridin-2-yl-ethyl) -pyrrolidin-3- carbonsäure- { 4- [ ( 4 , 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] - phenyl } -amid; rac . 1- (2-Isopropyl -phenyl) -5-oxo-pyrrolidin-3-carbonsäure-[4- (ethylphenylamino) phenyl] amide; rac. 5-oxo-1- (2-pyridin-2-yl-ethyl) -pyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] - phenyl} - amide; rac. 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid
[4- ( 4 , 6-dimethyl-pyrimidin-2-ylamino) -phenyl] -amid; rac . 1- ( 5-Methoxy-2-methyl-phenyl ) -5-oxo-pyrrolidin-3- carbonsäure- [ 4- ( 4 , 6-dimethyl-pyrimidin-2-ylamino) -phenyl] - amid; rac . 1- (2 , 5-Dimethyl-phenyl ) -5-oxo-pyrrolidin-3- carbonsäure- [ 4- (methyl-phenyl-amino) -phenyl] -amid; rac . 1- (2-Isopropyl-phenyl) -5-oxo-ρyrrolidin-3-carbonsäure-[4- (4, 6-dimethyl-pyrimidin-2-ylamino) phenyl] amide; rac. 1- (5-methoxy-2-methylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (4,6-dimethylpyrimidin-2-ylamino) phenyl] amide; rac. 1- (2, 5-dimethylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (methylphenylamino) phenyl] amide; rac. 1- (2-isopropylphenyl) -5-oxo-pyrrolidine-3-carboxylic acid
[4- (methyl-phenyl-amino) -phenyl] -amid; rac . 1- ( 4-Isopropyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- ( 9-ethyl-9H-carbazol-3-yl) -amid; rac . 1- (3-Fluor-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- ( 9- ethyl-9H-carbazol-3-yl ) -amid; rac . 1- (2 , 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- (4-phenylamino-phenyl) -amid; rac . l-Indan-2-yl-5-oxo-pyrrolidin-3-carbonsäure- [ 4- ( 4 , 6- dimethyl-pyrimidin-2-ylamino) -phenyl] -amid; rac. 1- (5-Methoxy-2-methyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (ethyl-phenyl-amino) -phenyl] -amid; rac. 1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure-[4- (methylphenylamino) phenyl] amide; rac. 1- (4-isopropylphenyl) -5-oxo-pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; rac. 1- (3-fluorophenyl) -5-oxopyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; rac. 1- (2,5-dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid (4-phenylamino-phenyl) -amide; rac. l-indan-2-yl-5-oxopyrrolidin-3-carboxylic acid- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) phenyl] amide; rac. 1- (5-methoxy-2-methylphenyl) -5-oxopyrrolidine-3-carboxylic acid [4- (ethylphenylamino) phenyl] amide; rac. 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid
{4- [ (4, 6-dimethyl-pyrimidin-2-yl) -methyl-amino] -phenyl }- amid; rac. l-Benzyl-5-oxo-pyrrolidin-3-carbonsäure- (9-ethyl-9H- carbazol-3-yl) -amid; rac. 5-Oxo-l-p-tolyl-pyrrolidin-3-carbonsäure- [4- (4, 6- dimethyl-pyrimidin-2-ylamino) -phenyl] -amid; rac. l-Indan-2-yl-5-oxo-pyrrolidin-3-carbonsäure- (9-ethyl-{4- [(4, 6-dimethyl-pyrimidin-2-yl) methylamino] phenyl} amide; rac. l-benzyl-5-oxopyrrolidin-3-carboxylic acid (9-ethyl-9H-carbazol-3-yl) amide; rac. 5-oxo-l-p-tolyl-pyrrolidine-3-carboxylic acid- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) phenyl] amide; rac. l-indan-2-yl-5-oxo-pyrrolidin-3-carboxylic acid- (9-ethyl-
9H-carbazol-3-yl) -amid; rac. 1- (2-Hydroxy-2-phenyl-ethyl) -5-oxo-pyrrolidin-3- carbonsäure- { 4- [ (4, 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] - phenyl } -amid; rac . 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure-biphenyl-4-ylamid; rac . 1- (5-Methoxy-2-methyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (cyclopropylmethyl-phenyl-amino) -phenyl] - amid; rac . 1- (2-Isopropyl -phenyl) -5-oxo-pyrrolidin-3-carbonsäure-9H-carbazol-3-yl) amide; rac. 1- (2-Hydroxy-2-phenyl-ethyl) -5-oxo-pyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) ethylamino] - phenyl} - amide; rac. 1- (2, 5-Dimethylphenyl) -5-oxopyrrolidine-3-carboxylic acid biphenyl-4-ylamide; rac. 1- (5-methoxy-2-methylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (cyclopropylmethylphenylamino) phenyl] amide; rac. 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid
[4- (isopropyl-phenyl-amino) -phenyl] -amid; rac . 1- (2-Isopropyl-phenyl ) -5-oxo-pyrrolidin-3-carbonsäure- ( 4 -phenyla ino-phenyl ) -amid ; rac . 1- (5-Methoxy-2-methyl -phenyl) -5-oxo-pyrrolidin-3- carbonsäure-{4- [ (4, 6-dimethyl-pyrimidin-2-yl) -methyl- amino] -phenyl} -amid; rac . 1- (3-Methoxy-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- {4- [ (4, 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] -phenyl}- amid; rac . 5-Oxo-l-m-tolyl-pyrrolidin-3-carbonsäure- { 4- [ (4,6- dimethyl-pyrimidin-2-yl) -methyl-amino] -phenyl} -amid; rac . 1- (2 , 5 -Dirne thyl -phenyl ) -5-oxo-pyrrolidin-3- carbonsäure- [ 4- (cyclopropylmethyl-phenyl-amino) -phenyl] - amid; rac. 1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- {4-[ (4, 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] -phenyl }- amid; rac. [ (4-{ [1- (5-Methoxy-2-methyl-phenyl) -5-oxo-pyrrolidin-[4- (isopropylphenylamino) phenyl] amide; rac. 1- (2-isopropyl-phenyl) -5-oxo-pyrrolidine-3-carboxylic acid- (4-phenyla-ino-phenyl) -amide; rac. 1- (5-Methoxy-2-methylphenyl) -5-oxo-pyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) methylamino] phenyl} - amide; rac. 1- (3-methoxyphenyl) -5-oxopyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethylpyrimidin-2-yl) ethylamino] phenyl} amide; rac. 5-oxo-im-tolyl-pyrrolidin-3-carboxylic acid- {4- [(4,6-dimethyl-pyrimidin-2-yl) methylamino] phenyl} amide; rac. 1- (2, 5 -Dirne thyl-phenyl) -5-oxo-pyrrolidin-3-carboxylic acid- [4- (cyclopropylmethyl-phenyl-amino) -phenyl] amide; rac. 1- (2-isopropylphenyl) -5-oxopyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethylpyrimidin-2-yl) ethylamino] phenyl} amide; rac. [(4- {[1- (5-methoxy-2-methylphenyl) -5-oxopyrrolidine
3-carbonyl] -amino} -phenyl) -phenyl-amino] -essigsäure-ethyl ester; rac. 1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure-3-carbonyl] amino} phenyl) phenylamino] acetic acid ethyl ester; rac. 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid
[4- (cyclopropylmethyl-phenyl-amino) -phenyl] -amid; rac. l-Indan-2-yl-5-oxo-pyrrolidin-3-carbonsäure- [4- (ethyl- phenyl-amino) -phenyl] -amid; und rac. 1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- [4- (isobutyl-phenyl-amino) phenyl] amid.[4- (cyclopropylmethylphenylamino) phenyl] amide; rac. l-indan-2-yl-5-oxopyrrolidin-3-carboxylic acid [4- (ethylphenylamino) phenyl] amide; and rac. 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (isobutylphenylamino) phenyl] amide.
Weitere repräsentative Beispiele bevorzugter Verbindungen der Formel I sind:Further representative examples of preferred compounds of the formula I are:
rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (2-methoxy-benzoylamino) -phenyl] -amid; rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (2, 2-Dimethyl-propionylamino) phenyl] -amid; rac. 1- (2-Morpholin-4-yl-ethyl) -5-oxo-pyrrolidin-3- carbonsäure- (9-ethyl-9H-carbazol-3-yl) -amid; rac. 5-Oxo-l-p-tolyl-pyrrolidin-3-carbonsäure- (9-ethyl-9H- carbazol-3-yl) -amid; und rac. 1- (2, 4-Dimethoxy-benzyl) -5-oxo-pyrrolidin-3- carbonsäure- (9-ethyl-9H-carbazol-3-yl) -amid; sowie auch rac. 1- (4-Dimethylamino-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (4, 6-dimethyl-pyrimidin-2- ylamino) phenyl] amid; und rac. 1- (4-Dimethylamino-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (4, 6-dimethyl-pyrimidin~2-yl) methyl- aminophenyl] amid.rac. 1- (2,5-dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (2-methoxy-benzoylamino) phenyl] amide; rac. 1- (2, 5-Dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (2, 2-dimethyl-propionylamino) phenyl] -amide; rac. 1- (2-morpholin-4-yl-ethyl) -5-oxopyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; rac. 5-oxo-l-tolyl-pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; and rac. 1- (2,4-dimethoxy-benzyl) -5-oxo-pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; as well as rac. 1- (4-Dimethylamino-phenyl) -5-oxo-pyrrolidine-3-carboxylic acid- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) phenyl] amide; and rac. 1- (4-Dimethylamino-phenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (4, 6-dimethylpyrimidine ~ 2-yl) methylaminophenyl] amide.
Die Verbindungen der Formel I können erfindungsgemäss hergestellt werden durch Umsetzung einer Pyrrolidoncarbonsäure der Formel III (siehe nachstehendes Schema) , worin R1 die eingangs erwähnte Bedeutung besitzt, oder einem reaktionsfähigen Derivat davon, mit einem Amin der Formel IV, worin R2 die eingangs erwähnte Bedeutung besitzt, oder einem reaktionsfähigen Derivat davon. Allfällig erhaltene Stereoisomerengemische, wie Racemate, können erwünschtenfalls nach allgemein üblichen Methoden aufgetrennt werden.The compounds of the formula I can be prepared according to the invention by reacting a pyrrolidone carboxylic acid of the formula III (see scheme below), in which R 1 has the meaning mentioned at the outset, or a reactive derivative thereof, with an amine of the formula IV, in which R 2 is the initially mentioned Has meaning, or a reactive derivative thereof. Any stereoisomer mixtures obtained, such as racemates, can, if desired, be separated by generally customary methods.
Zur Herstellung der entsprechenden Pyrrolidoncarbonsäure der Formel III kann zum Beispiel folgender Weg beschritten werden, wobei die im nachfolgenden Schema angegebenen Substituenten und Indices, soweit nicht anders vermerkt, die eingangs angegebenen Bedeutungen haben; dieser Weg besteht darin, dass man ein Amin der Formel II, wie Anilin o. dgl., in einem Lösungsmittel, wie Wasser, Dioxan, Ethanol o. dgl. bei erhöhter Temperatur mit Itaconsäure umsetzt (Buzas et al . , Chim Ther 7, 398-403, 1972).To prepare the corresponding pyrrolidone carboxylic acid of the formula III, the following route can be followed, for example, where the substituents and indices given in the following scheme, unless otherwise stated, have the meanings given at the beginning; this approach consists in reacting an amine of the formula II, such as aniline or the like, in a solvent, such as water, dioxane, ethanol or the like, with itaconic acid at elevated temperature (Buzas et al., Chim Ther 7, 398-403, 1972).
Schemascheme
Figure imgf000015_0001
Figure imgf000015_0001
(II) (III) (IV) (I)(II) (III) (IV) (I)
Die Verbindungen der Formel I können durch Umsetzen einer Pyrrolidoncarbonsäure der Formel III mit einem Amin der Formel IV hergestellt werden. Dazu wird zweckmässigerweise die Pyrrolidoncarbonsäure der Formel III, gegebenenfalls in einem geeigneten Lösungsmittel, wie beispielsweise Toluol, mit einem Halogenierungsmittel, wie beispielsweise S0C12 oder POCl3, in das entsprechende Säurechlorid verwandelt. Dieses reaktive Derivat der Pyrrolidoncarbonsäure der Formel III wird anschliessend mit einem Amin der Formel IV in einem geeigneten Lösungsmittel, wie Methylenchlorid, in Gegenwart einer Base, wie beispielsweise Triethylamin, umgesetzt.The compounds of formula I can by reacting a pyrrolidone carboxylic acid of formula III with an amine Formula IV are made. For this purpose, the pyrrolidone carboxylic acid of the formula III, if appropriate in a suitable solvent, such as, for example, toluene, is converted into the corresponding acid chloride using a halogenating agent, such as, for example, SO 2 or POCl 3 . This reactive derivative of the pyrrolidone carboxylic acid of the formula III is then reacted with an amine of the formula IV in a suitable solvent, such as methylene chloride, in the presence of a base, such as triethylamine.
In einer Verfahrensvariante wird die Pyrrolidoncarbonsäure der Formel III mit einem Amin der Formel IV unter Zusatz eines Kupplungsreagens, wie beispielsweise EDC, DCC oder BOP, in einem Lösungsmittel, wie beispielsweise DMF, gegebenenfalls in Gegenwart einer Base, wie beispielsweise Triethylamin, umgesetzt.In one process variant, the pyrrolidone carboxylic acid of the formula III is reacted with an amine of the formula IV with the addition of a coupling reagent, such as EDC, DCC or BOP, in a solvent, such as DMF, if appropriate in the presence of a base, such as triethylamine.
Verbindungen der Formel I, worin R2 einen Rest der Formel (b) , R5 -NR6R7 und R7 Acyl bedeuten, können auch dadurch hergestellt werden, dass man eine entsprechende Verbindung, worin aber R7 Wasserstoff bedeutet, wie z.B. rac. l-(2,5- Dimethyl-phenyl) -5-oxo-pyrrolidin-3-cabonsäure- (4-amino- phenyl) -amid, acyliert, beispielsweise mittels Acetylchlorid, Isovalerylchlorid,Compounds of the formula I in which R 2 is a radical of the formula (b), R 5 -NR 6 R 7 and R 7 are acyl can also be prepared by a corresponding compound, but in which R 7 is hydrogen, such as rac. 1- (2,5-dimethyl-phenyl) -5-oxopyrrolidine-3-cabonic acid- (4-aminophenyl) -amide, acylated, for example using acetyl chloride, isovaleryl chloride,
Cyclopropylcarbonylchlorid, Benzoylchlorid,Cyclopropylcarbonyl chloride, benzoyl chloride,
Phenylessigsäurechlorid, 2-Methoxybenzoylchlorid,Phenylacetic acid chloride, 2-methoxybenzoyl chloride,
Piperonyloylchlorid, Pivaloylchlorid, 4-Piperonyloyl chloride, pivaloyl chloride, 4-
Methoxybenzoylchlorid, 3-Fluorbenzoylchlorid u. dgl.Methoxybenzoyl chloride, 3-fluorobenzoyl chloride and the like. like.
Die Pyrrolidoncarbonsäuren der Formel III sind nur teilweise bekannt aber nach an sich bekannten und jedem Fachmann geläufigen Methoden herstellbar, beispielsweise nach der oben erwähnten Methode (Buzas et al . , Chim Ther 7, 398-403, 1972); zudem enthalten einige der nachfolgenden Beispiele Angaben betreffend die Herstellung bestimmter Pyrrolidoncarbonsäuren der Formel III.The pyrrolidone carboxylic acids of the formula III are only partially known but can be prepared by methods known per se and familiar to any person skilled in the art, for example by the method mentioned above (Buzas et al., Chim Ther 7, 398-403, 1972); In addition, some of the following examples contain information regarding the preparation of certain pyrrolidone carboxylic acids of the formula III.
Die Amine der Formel IV sind ebenfalls teilweise bekannt oder nach an sich bekannten Methoden herstellbar; einige der nachfolgenden Beispiele enthalten auch Angaben betreffend die Herstellung bestimmter Amine der Formel IV.Some of the amines of the formula IV are also known or can be prepared by methods known per se; Some of the examples below also contain information regarding the preparation of certain amines of the formula IV.
Soweit die Ausgangsprodukte der Formeln III und IV sowie die Nitro-Vorläufer der Verbindungen der Formel IV neu sind, bilden sie ebenfalls Gegenstand der vorliegenden Erfindung. So sind insbesondere die folgenden Verbindungen der Formel IV sowie deren Nitro-Vorläufer:Insofar as the starting products of the formulas III and IV and the nitro precursors of the compounds of the formula IV are new, they likewise form the subject of the present invention. The following are particularly the compounds of formula IV and their nitro precursors:
[ (4-Nitro-phenyl) -phenyl-amino] -essigsäure-ethylester;[(4-nitro-phenyl) phenylamino] acetic acid ethyl ester;
[ (4-Amino-phenyl) -phenyl-amino] -essigsäure-ethylester; Cyclopropylmethyl- (4-nitro-phenyl) -phenyl-amin; N-Cyclopropylmethyl-N-phenyl-phenylen-1, 4-diamin; Isobutyl- (4-nitro-phenyl) -phenyl-amin; N-Isobutyl-N-phenyl-phenylen-1, 4-diamin; [ (4-Nitro-phenyl) -phenyl-amino] -pentansäure-ethylester; [ (4-Amino-phenyl) -phenyl-amino] -pentansäure-ethylester; Benzyl- (4-nitro-phenyl) -phenyl-amin; und N-Benzyl-N-phenyl-phenylen-1, 4-diamin;[[4-aminophenyl) phenylamino] acetic acid ethyl ester; Cyclopropylmethyl- (4-nitro-phenyl) phenylamine; N-cyclopropylmethyl-N-phenylphenylene-1,4-diamine; Isobutyl- (4-nitro-phenyl) phenylamine; N-isobutyl-N-phenylphenylene-1,4-diamine; [(4-nitro-phenyl) phenylamino] pentanoic acid ethyl ester; [(4-aminophenyl) phenylamino] pentanoic acid ethyl ester; Benzyl- (4-nitro-phenyl) phenylamine; and N-benzyl-N-phenyl-phenylene-1,4-diamine;
sowie die folgenden Verbindungen der Formel III:as well as the following compounds of formula III:
rac 1-Indan-2-y1-5-oxo-pyrrolidin-3-carbonsäure; rac. l-Naphthalin-2-yl-5-oxo-pyrrolidin-3-carbonsäure; rac. 1- (5-Methoxy-2-methyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure; rac. 5-Oxo-l- (2-pyridin-2-yl-ethyl) -pyrrolidin-3- carbonsäure; rac . l-Cycloheptyl-5-oxo-pyrrolidin-3-carbonsäure; rac. 1- (2-Hydroxy-2-phenyl-ethyl) -5-oxo-pyrrolidin-3- carbonsäure; rac . 5-Oxo-l- (2-pyrrolidin-l-yl-ethyl) -pyrrolidin-3- carbonsäure; rac. l-[2- (l-Methyl-pyrrolidin-2-yl) -ethyl] -5-oxo- pyrrolidin-3-carbonsäure; und rac. 1- (3-Fluor-phenyl) -5-oxo-pyrrolidin-3-carbonsäure;rac 1-indan-2-y1-5-oxo-pyrrolidine-3-carboxylic acid; rac. l-naphthalene-2-yl-5-oxo-pyrrolidine-3-carboxylic acid; rac. 1- (5-methoxy-2-methylphenyl) -5-oxopyrrolidine-3-carboxylic acid; rac. 5-oxo-1- (2-pyridin-2-yl-ethyl) pyrrolidin-3-carboxylic acid; rac. l-cycloheptyl-5-oxo-pyrrolidine-3-carboxylic acid; rac. 1- (2-hydroxy-2-phenyl-ethyl) -5-oxo-pyrrolidine-3-carboxylic acid; rac. 5-oxo-1- (2-pyrrolidin-1-yl-ethyl) -pyrrolidine-3-carboxylic acid; rac. 1- [2- (1-methyl-pyrrolidin-2-yl) ethyl] -5-oxopyrrolidin-3-carboxylic acid; and rac. 1- (3-fluoro-phenyl) -5-oxo-pyrrolidine-3-carboxylic acid;
Gegenstand der vorliegenden Erfindung.Subject of the present invention.
Wie eingangs erwähnt, sind die Verbindungen der Formel I und ihre pharmazeutisch verwendbaren Salze und Ester neu und besitzen wertvolle pharmakologische Eigenschaften. Insbesondere hemmen sie die Interaktion des Neuropeptid YAs mentioned at the outset, the compounds of the formula I and their pharmaceutically acceptable salts and esters are new and have valuable pharmacological properties. In particular, they inhibit the interaction of the neuropeptide Y
(NPY) mit einem der Neuropeptid-Rezeptor-Subtypen (NPY-Y5) .(NPY) with one of the neuropeptide receptor subtypes (NPY-Y5).
NPY ist ein regulatorisches 36 Aminosäure-Peptid der pankreatischen Polypeptid-Familie. NPY ist das meist verbreitete Neuropeptid im zentralen und peripheren Nervensystem und hat prominente und komplexe Effekte auf Nahrungsaufnahme, Angst, Depression, zirkadianen Rhythmus, Sexualfunktion, Reproduktion, Erinnerungsfunktion, Migräne, Schmerz, epiletpische Anfälle, Blutdruck, zerebrale Blutungen, Schock, Schlafstörung, Durchfall u.s.w.NPY is a 36 amino acid regulatory peptide of the pancreatic polypeptide family. NPY is the most common neuropeptide in the central and peripheral nervous system and has prominent and complex effects on food intake, anxiety, depression, circadian rhythm, sexual function, reproduction, memory function, migraine, pain, epiletpic seizures, blood pressure, cerebral bleeding, shock, sleep disorders, diarrhea etc
NPY interagiert mit einer heterogenen Population von mindestens fünf NPY-Rezeptorsubtypen, Y1-Y5, welche mittels eines G-Proteins Adenylat-Cyclase aktivieren. Einer der prominentesten Effekte ist die Induktion von Nahrungsaufnahme in Vertebraten. Neuere Untersuchungen mit selektivem Aktivieren und Blockieren der einzelnen NPY- Rezeptoren haben ergeben, dass hauptsächlich der NPY-Y5- Rezeptor für Appetit auslösende Signale verantwortlich ist. Obesitas ist in der industrialisierten Welt ein bedeutendes und zunehmendes Problem. Obesitas ist assoziiert mit verschiedenen Krankheiten, wie zum Beispiel mit nichtInsulin-abhängigem Diabetes (Typ II-Diabetes) , Bluthochdruck, koronaren Herzkrankheiten, Dislipidämie etc., und beeinflusst die Lebenserwartung und Lebensqualität der betroffenen Population. Aus diesem Grund besteht ein Bedarf an pharmazeutischen Stoffen, die die Essgewohnheiten beeinflussen. Der NPY-Y5-Rezeptor ist ein möglicher Zielort einer entsprechenden pharmakologischen Intervention. Hemmung dieses Rezeptors durch eine niedermolekulare Verbindung ist eine attraktive Möglichkeit einer Vorbeugung bzw. Behandlung obiger Krankheiten.NPY interacts with a heterogeneous population of at least five NPY receptor subtypes, Y1-Y5, which activate adenylate cyclase using a G protein. One of the most prominent effects is the induction of food intake in vertebrates. Recent studies with selective activation and blocking of the individual NPY receptors have shown that the NPY-Y5 receptor is mainly responsible for appetite-inducing signals. Obesitas is a major and growing problem in the industrialized world. Obesitas is associated with various diseases, such as non-insulin-dependent diabetes (type II diabetes), high blood pressure, coronary artery disease, dislipidemia, etc., and affects the life expectancy and quality of life of the affected population. For this reason, there is a need for pharmaceutical substances that influence eating habits. The NPY-Y5 receptor is a possible target for a corresponding pharmacological intervention. Inhibition of this receptor by a low-molecular compound is an attractive way of preventing or treating the above diseases.
Aufgrund ihrer Eigenschaft, die Interaktion des Neuropeptid Y mit dem Neuropeptid Y5-Rezeptor-Subtyp zu hemmen, eignen sich die Verbindungen der Formel I und deren pharmazeutisch verwendbaren Salze und Ester für die Vorbeugung und Behandlung von Arthritis, Diabetes und speziell von Essstörungen und Obesitas.Because of their property of inhibiting the interaction of the neuropeptide Y with the neuropeptide Y5 receptor subtype, the compounds of the formula I and their pharmaceutically acceptable salts and esters are suitable for the prevention and treatment of arthritis, diabetes and especially eating disorders and obesity.
Die wertvollen pharmakodynamischen Eigenschaften der erfindungsgemässen neuen Verbindungen lassen sich durch die nachfolgend beschriebenen Methoden nachweisen.The valuable pharmacodynamic properties of the novel compounds according to the invention can be demonstrated by the methods described below.
Klonen der mouse NPY-Y5 receptor cDNA' sCloning the mouse NPY-Y5 receptor cDNA 's
Die "full-length" cDNA, welche die Maus-NPY-Y5 (mNPY-Y5)- Receptor-Codierung enthält, wurde aus Maushirn cDNA mit Hilfe von spezifischen "Primern", welche aufgrund von publizierten Sequenzen massgeschneidert und unter Verwendung von Pfu-DNA-Polymerase (Stratagene) amplifiziert wurden. Das Amplifizierungsprodukt wurde in einem Mammalian Expressions Vektor pcDNA3 durch Eco RI und Xhol Restriction Sites subkloniert. Positive Klone wurden sequenziert, ein Klon, welcher die publizierte Sequenz enthält, wurde für die Herstellung von stabilen Zeil Klonen ausgewählt.The "full-length" cDNA, which contains the mouse NPY-Y5 (mNPY-Y5) receptor coding, was generated from mouse brain cDNA with the aid of specific "primers", which were tailored on the basis of published sequences and using Pfu DNA polymerase (Stratagene) were amplified. The amplification product was subcloned in a mammalian expression vector pcDNA3 by Eco RI and Xhol Restriction Sites. Positive clones were sequenced Clone containing the published sequence was selected for the production of stable Zeil clones.
Stabile Transfektion Humane embryonische "kidney 293" (HEK293) Zellen wurden mit 10 μg mNPY5 DNA mit Hilfe von Lipofektamine-Reagens (Gibco BRL) nach Angabe des Herstellers transfektiert . 2 Tage nach der Transfektion wurde die Geneticin Selection (lmg/ml) initialisiert, und mehrere stabile Klone wurden isoliert. Einer der Klone wurde für weitere pharmakologische Charakterisierung verwendet.Stable transfection Human embryonic "kidney 293" (HEK293) cells were transfected with 10 μg mNPY5 DNA with the aid of lipofectamine reagent (Gibco BRL) according to the manufacturer's instructions. 2 days after the transfection, the Geneticin Selection (lmg / ml) was initialized and several stable clones were isolated. One of the clones was used for further pharmacological characterization.
Radioligand Competition BindingRadioligand Competition Binding
Humane embryonische Nierenzellen (HEK293) , welche rekombinante Maus-NPY-Y5-Rezeptoren (mNPY-Y5) exprimieren, wurden durch dreimaliges Einfrieren/Auftauen in hypotonischem Tris Puffer (5mM, pH7.4, ImM MgCl2) aufgebrochen, anschliessend homogenisiert und während 15 Minuten bei 72 '000 G zentrifugiert . Der Niederschlag wurde zweimal mit Tris Puffer (pH7.4), der 25mM MgCl2, 250 mM Succrose, 0.1 mM Phenylmethylsulfonylfluorid und 0.1 mM 1, 10-Phenanthrolin enthielt, gewaschen, im gleichen Puffer resuspendiert und in Aliquots bei -80°C aufbewahrt. Das Protein wurde gemäss der Methode von Lowry unter Verwendung von Bovine Serum Albumin (BSA) als Standard bestimmt.Human embryonic kidney cells (HEK293), which express recombinant mouse NPY-Y5 receptors (mNPY-Y5), were broken up by freezing / thawing three times in hypotonic Tris buffer (5mM, pH7.4, ImM MgCl 2 ), then homogenized and during Centrifuged at 72,000 G for 15 minutes. The precipitate was washed twice with Tris buffer (pH7.4) containing 25 mM MgCl 2 , 250 mM succrose, 0.1 mM phenylmethylsulfonyl fluoride and 0.1 mM 1, 10-phenanthroline, resuspended in the same buffer and stored in aliquots at -80 ° C , The protein was determined by Lowry's method using Bovine Serum Albumin (BSA) as the standard.
Die Kompetitions-Bindungs-Analyse wurde in 250 ul 25mM Hepes Puffer (pH7.4, 2.5mM CaCl2, ImM MgC12, 1% bovine serum albumin und 0.01% Natriumazid) , welcher 5 μg Protein, lOOpM 125I-markiertes Peptid YY (PYY) und 10 μl einer DMSO- Lösung mit ansteigenden Mengen unmarkierter Test-Verbindung enthaltenden DMSO Lösung, durchgeführt. Nach einstündiger Inkubation bei 22 °C wurde der gebundene vom ungebundenen Ligand durch Filtration über Glasfiberfilter getrennt. Nicht-spezifisches Binding wurde in Gegenwart von lμM unmarkiertem PYY ermittelt. Spezifisches Binding ist definiert als die Differenz zwischen totalem und nichtspezifischem Binding. IC50 Werte werden definiert als diejenige Konzentration des Antagonisten, welche 50% des 125I-markierten Neuropeptid Y verdrängt. Diese Konzentration wird durch lineare Regressions Analyse nach logit/log- Transformation der Bindungs-Werte ermittelt.The competition binding analysis was carried out in 250 ul of 25mM Hepes buffer (pH7.4, 2.5mM CaCl2, ImM MgC12, 1% bovine serum albumin and 0.01% sodium azide) containing 5 μg protein, 100pM 125 I-labeled peptide YY (PYY ) and 10 μl of a DMSO solution with increasing amounts of unlabelled test compound containing DMSO solution. After incubation at 22 ° C. for one hour, the bound and unbound ligand were separated by filtration through glass fiber filters. Non-specific binding was determined in the presence of 1μM unlabeled PYY. Specific binding is defined as the difference between total and non-specific binding. IC 5 0 values are defined as that concentration of the antagonist which 50% of the 125 I-labeled neuropeptide Y displaced. This concentration is determined by linear regression analysis after logit / log transformation of the binding values.
Bevorzugte erfindungsgemässe Verbindungen zeigen in dem oben beschrieben Test IC50 Werte unter lOOOnM, besonders bevorzugte Verbindungen zeigen IC50 Werte unter 100 nM, ganz besonders bevorzugte unter 50 nM.In the test described above, preferred compounds according to the invention show IC50 values below 100 nm, particularly preferred compounds show IC50 values below 100 nM, very particularly preferred values below 50 nM.
Die im vorstehend beschriebenen Test unter Verwendung von repräsentativen Verbindungen der Formel I alsThe test described above using representative compounds of formula I as
Testverbindungen erhaltenen Ergebnisse sind in der folgenden Tabelle zusammengestellt.Results obtained from test compounds are summarized in the following table.
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Die erfindungsgemässen Verbindungen können nach allgemein bekannten und jedem Fachmann geläufigen Methoden in geeignete galenische Darreichungsformen gebracht werden Solche Darreichungsformen sind beispielsweise Tabletten, Lacktabletten, Dragees, Kapseln, Injektionslösungen usw. Zur Herstellung solcher galenischer Darreichungsformen geeignete Exzipientien und Hilfsstoffe sind ebenfalls allgemein bekannt und jedem Fachmann geläufig. Ausser einer „oder mehreren erfindungsgemässen Verbindungen können diese Darreichungsformen auch noch weitere pharmkologisch aktive Verbindungen enthalten.The compounds according to the invention can be brought into suitable pharmaceutical dosage forms by methods which are generally known and familiar to any person skilled in the art. Such dosage forms are, for example, tablets, coated tablets, dragées, capsules, injection solutions, etc. Excipients and auxiliaries which are suitable for the preparation of such pharmaceutical dosage forms are likewise generally known and familiar to any person skilled in the art , In addition to one or more compounds according to the invention, these dosage forms can also contain further pharmcologically active compounds.
Die Dosierung der erfindungsgemässen Verbindungen bzw. der sie enthaltenden Darreichungsformen ist vom behandelnden Arzt nach den jeweiligen Bedürfnissen des Patienten anzupassen. Im Allgemeinen dürfte eine Tagesdosis von 0.1- 20 mg, bevorzugt 0.5-5 mg einer erfindungsgemässen Verbindung pro kg Körpergewicht des Patienten angebracht sein. Die nachfolgenden Beispiele sollen die Erfindung näher erläutern, ihren Umfang jedoch in keiner Weise einschränken .The dosage of the compounds according to the invention or of the dosage forms containing them is to be adjusted by the attending physician according to the patient's particular needs. In general, a daily dose of 0.1-20 mg, preferably 0.5-5 mg, of a compound according to the invention per kg of body weight of the patient should be appropriate. The following examples are intended to explain the invention in greater detail, but in no way limit its scope.
Beispiel 1 (R1 ist Phenyl)Example 1 (R 1 is phenyl)
20.5 mg (0.1 mmol) rac. 5-Oxo-l-phenyl-pyrrolidin-3- carbonsäure (Buzas et al., Chim Ther 7, 398-403, 1972), gelöst in 0.5 ml Methylenchlorid/DMF (9:1), wurden zu Festphasen-Kupplungsreagenzien (DCC, loading 1.7 mmol/g) gegeben. Die Mischung wurde während 5 Minuten geschüttelt, dann wurden 13.6 mg (0.1 mmol) N,N-Dimethyl-p- phenylendiamin, gelöst in 0.5 ml Methylenchlorid/DMF (9:1), zugegeben, und die Mischung wurde über Nacht bei Raumtemperatur geschüttelt. Dann wurde der Feststoff abfiltriert, das Filtrat eingedampft, der Rückstand in 1 ml Methylenchlorid gelöst, die Lösung mit Methylisocyanat- Polystyrol (1.8 mmol/g) (Festphasen 'scavenger') versetzt, 12 Stunden bei Raumtemperatur geschüttelt, filtriert, dann das Filtrat mit Tris- (2-aminoethyl) -amin-Polystyrol (3.4 mmol/g) versetzt, 12 Stunden bei Raumtemperatur geschüttelt, filtriert und das Filtrat eingedampft. Man erhielt so 18 mg farbloses rac. 5-Oxo-l-phenyl-pyrrolidin- 3-carbonsäure- (4-dimethylamino-phenyl) -amid, MS (M+H) 324,3, MS (M-H) 322.5.20.5 mg (0.1 mmol) rac. 5-Oxo-1-phenyl-pyrrolidine-3-carboxylic acid (Buzas et al., Chim Ther 7, 398-403, 1972), dissolved in 0.5 ml methylene chloride / DMF (9: 1), were converted into solid-phase coupling reagents (DCC , loading 1.7 mmol / g). The mixture was shaken for 5 minutes, then 13.6 mg (0.1 mmol) of N, N-dimethyl-p-phenylenediamine dissolved in 0.5 ml of methylene chloride / DMF (9: 1) was added and the mixture was shaken at room temperature overnight , The solid was then filtered off, the filtrate was evaporated, the residue was dissolved in 1 ml of methylene chloride, the solution was treated with methyl isocyanate-polystyrene (1.8 mmol / g) (solid phase 'scavenger'), shaken for 12 hours at room temperature, filtered, then the filtrate was added Tris- (2-aminoethyl) amine polystyrene (3.4 mmol / g) was added, shaken at room temperature for 12 hours, filtered and the filtrate evaporated. This gave 18 mg of colorless rac. 5-oxo-l-phenyl-pyrrolidine-3-carboxylic acid- (4-dimethylaminophenyl) amide, MS (M + H) 324.3, MS (M-H) 322.5.
Beispiel 2 (R1 ist Phenyl)Example 2 (R 1 is phenyl)
Analog Beispiel 1 wurden unter Verwendung der nachstehenden Amine folgende Produkte hergestellt: a) aus 4-Phenoxyanilin das rac. 5-Oxo-l-phenyl-pyrrolidin- 3-carbonsäure- (4-phenoxy-phenyl) -amid, MS (M+H) 373.3, MS (M- H) 371.4.The following products were prepared analogously to Example 1 using the following amines: a) from 4-phenoxyaniline the rac. 5-oxo-l-phenyl-pyrrolidine-3-carboxylic acid- (4-phenoxy-phenyl) -amide, MS (M + H) 373.3, MS (M-H) 371.4.
b) aus 2- (3, 4-Dimethoxyphenyl) ethylamin das rac. 5-Oxo-l- phenyl-pyrrolidin-3-carbonsäure- [2- (3, 4-dimethoxy-phenyl) - ethyl] -amid, MS (M+H) 369.3.b) from 2- (3, 4-dimethoxyphenyl) ethylamine the rac. 5-oxo-1-phenyl-pyrrolidine-3-carboxylic acid- [2- (3,4-dimethoxyphenyl) ethyl] amide, MS (M + H) 369.3.
c) aus N- (4-Aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidin das rac. 5-Oxo-l-phenyl-pyrrolidin-3-carbonsäure-{ 4- [ (4, 6- dimethyl-pyrimidin-2-yl) -ethyl-amino] -phenyl} -amid, MS (M+H) 430.3, MS(M-H) 428.5.c) from N- (4-aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidine the rac. 5-oxo-1-phenyl-pyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) ethylamino] phenyl} amide, MS (M + H) 430.3, MS (MH) 428.5.
d) aus 2-Aminofluoren das rac. 5-Oxo-l-phenyl-pyrrolidin-3- carbonsäure- ( 9H-fluoren-2-yl) -amid, MS(M+H9) 369.3, MS (M-H)d) from 2-aminofluorene the rac. 5-oxo-l-phenyl-pyrrolidin-3-carboxylic acid- (9H-fluoren-2-yl) -amide, MS (M + H9) 369.3, MS (M-H)
367.4.367.4.
e) aus 3-Aminobiphenyl das rac. 5-Oxo-l-phenyl-pyrrolidin- 3-carbonsäure-biphenyl-3-ylamid, MS (M+H) 357.2, MS (M-H) 355.4.e) from 3-aminobiphenyl the rac. 5-oxo-l-phenyl-pyrrolidine-3-carboxylic acid biphenyl-3-ylamide, MS (M + H) 357.2, MS (M-H) 355.4.
f) aus N- ( 4-Aminophenyl) -4 , 6-dimethyl-2-pyrimidinamin das rac . 5-Oxo-l-phenyl-pyrrolidin-3-carbonsäure- [ 4- ( 4 , 6- dimethyl-pyrimidin-2-ylamino) -phenyl] -amid, MS (M+H) 402 . 3 , MS (M-H) 400 . 5 .f) from N- (4-aminophenyl) -4, 6-dimethyl-2-pyrimidinamine the rac. 5-Oxo-1-phenyl-pyrrolidine-3-carboxylic acid- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) phenyl] amide, MS (M + H) 402. 3, MS (M-H) 400. 5.
g) aus N- (4-Aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidin das rac. 5-Oxo-l-phenyl-pyrrolidin-3-carbonsäre-{ 4- [ (4, 6- dimethyl-pyrimidin-2-yl) -methyl-amino] -phenyl} amid, MS (M+H) 416.3, MS(M-H) 414.5.g) from N- (4-aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidine the rac. 5-Oxo-1-phenyl-pyrrolidine-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) methylamino] phenyl} amide, MS (M + H) 416.3, MS (MH) 414.5.
h) aus N-Phenyl-1, 4-phenylenediamin das rac. 5-Oxo-l- phenyl-pyrrol'idin-3-carbonsäure- (4-phenylamino-phenyl) - amid, MS (M+H) 372.2, MS (M-H) 370.5. i) aus 3-Amino-9-ethylcarbazol das rac. 5-Oxo-l-phenyl- pyrrolidin-3-carbonsäure- (9-ethyl-9H-carbazol-3-yl) -amid, MS(M+H) 398.2, MS (M-H) 396.3.h) from N-phenyl-1, 4-phenylenediamine the rac. 5-oxo-l- phenyl-pyrrol 'idin-3-carboxylic acid (4-phenylamino-phenyl) - amide, MS (M + H) 372.2, MS (MH) 370.5. i) from 3-amino-9-ethylcarbazol the rac. 5-oxo-l-phenyl-pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide, MS (M + H) 398.2, MS (MH) 396.3.
Beispiel 3 (R1 ist Benzyl)Example 3 (R 1 is benzyl)
a) Analog Beispiel 1 wurden aus rac. l-Benzyl-5-oxo-l- pyrrolidin-3-carbonsäure unter Verwendung der nachstehenden Amine folgende Produkte hergestellt:a) Analogously to Example 1, rac. l-Benzyl-5-oxo-l-pyrrolidine-3-carboxylic acid produced the following products using the following amines:
al) aus N- (4-Aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidin das rac. l-Benzyl-5-oxo-pyrrolidin-3-carbonsäure-{4- [ (4, 6- dimethyl-pyrimidin-2-yl) -ethyl-amino] -phenyl} -amid, MS (M+H) 444.3, MS(M-H) 442.5.al) from N- (4-aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidine the rac. l-benzyl-5-oxopyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethylpyrimidin-2-yl) ethylamino] phenyl} amide, MS (M + H) 444.3, MS (MH) 442.5.
a2) aus N- (4-Aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidin das rac. l-Benzyl-5-oxo-pyrrolidin-3-carbonsäure-{ 4- [ (4, 6- dimethyl-pyrimidin-2-yl) -methyl-amino] -phenyl} -amid, MS(M+H) 430.4, MS (M-H) 428.5.a2) from N- (4-aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidine the rac. l-benzyl-5-oxopyrrolidine-3-carboxylic acid- {4- [(4, 6-dimethylpyrimidin-2-yl) methylamino] phenyl} amide, MS (M + H) 430.4, MS (MH) 428.5.
a3) aus 3-Amino-9-ethylcarbazol das rac. l-Benzyl-5-oxo- pyrrolidin-3-carbonsäure- (9-ethyl-9H-carbazol-3-yl) -amid, MS (M+H) 412.1, MS (M-H) 410.3.a3) from 3-amino-9-ethylcarbazole the rac. 1-Benzyl-5-oxopyrrolidin-3-carboxylic acid (9-ethyl-9H-carbazol-3-yl) amide, MS (M + H) 412.1, MS (M-H) 410.3.
b) Die für Beispiel 3a benötigte rac. l-Benzyl-5-oxo-l- pyrrolidin-3-carbonsäure wurde analog zu einer Vorschrift von Buzas et al . (Chim Ther 7, 398-403 (1972)) aus Benzylamin und Itaconsäure hergestellt.b) The rac required for Example 3a. l-Benzyl-5-oxo-l-pyrrolidine-3-carboxylic acid was analogous to a protocol by Buzas et al. (Chim Ther 7, 398-403 (1972)) from benzylamine and itaconic acid.
Beispiel 4 (R1 ist 2 ,5-Dimethylphenyl) a) Analog Beispiel 1 wurden aus rac. 1- (2, 5-Dimethyl- phenyl) -5-oxo-l-pyrrolidin-3-carbonsäure unter Verwendung der nachstehenden Amine folgende Produkte hergestellt:Example 4 (R 1 is 2, 5-dimethylphenyl) a) Analogously to Example 1, rac. 1- (2, 5-Dimethylphenyl) -5-oxo-l-pyrrolidine-3-carboxylic acid using the amines below produced the following products:
al) aus 4' -Amino-acetophenon das rac. 1- (2, 5-Dimethyl- phenyl) -5-oxo-pyrrolidin-3-carbonsäure- (4-acetyl-phenyl) - amid, MS (M+H) 351.3, MS (M-H) 349.5.al) from 4 '-amino-acetophenone the rac. 1- (2, 5-Dimethylphenyl) -5-oxopyrrolidine-3-carboxylic acid- (4-acetylphenyl) amide, MS (M + H) 351.3, MS (M-H) 349.5.
a2) aus 3-Aminobiphenyl das rac. 1- (2, 5-Dimethyl-phenyl) -5- oxo-pyrrolidin-3-carbonsäure-biphenyl-3-ylamid, MS (M+H) 385.3, MS(M-H) 383.4.a2) from 3-aminobiphenyl the rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidine-3-carboxylic acid-biphenyl-3-ylamide, MS (M + H) 385.3, MS (M-H) 383.4.
a3) aus 3-Amino-2-methoxydibenzofuran das rac. l-(2,5- Dimethyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- (2-methoxy- dibenzofuran-3-yl)-amid, MS (M+H) 429.2, MS (M-H) 427.4.a3) from 3-amino-2-methoxydibenzofuran the rac. 1- (2,5-Dimethyl-phenyl) -5-oxopyrrolidin-3-carboxylic acid- (2-methoxydibenzofuran-3-yl) -amide, MS (M + H) 429.2, MS (M-H) 427.4.
a4) aus 2-Amino-9-fluorenon das rac. 1- (2, 5-Dimethyl- phenyl) -5-oxo-pyrrolidin-3-carbonsäure- (9-oxo-9H-fluoren-2- yl)-amid, MS (M+H) 411.2, MS (M-H) 409.4.a4) from 2-amino-9-fluorenone the rac. 1- (2, 5-Dimethylphenyl) -5-oxo-pyrrolidin-3-carboxylic acid- (9-oxo-9H-fluoren-2-yl) -amide, MS (M + H) 411.2, MS (MH) 409.4.
a5) aus 2-Aminofluoren das rac. 1- (2, 5-Dimethyl-phenyl) -5- oxo-pyrrolidin-3-carbonsäure- (9H-fluoren-2-yl) -amid, MS(M+H) 397.3, MS (M-H) 395.5.a5) from 2-aminofluorene the rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3-carboxylic acid- (9H-fluoren-2-yl) -amide, MS (M + H) 397.3, MS (M-H) 395.5.
a6) aus N- (4-Aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidin das rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure-{4- [ (4, 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] - phenyl}-amid, MS (M+H) 458.4, MS (M-H) 456.5.a6) from N- (4-aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidine the rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) ethylamino] phenyl} amide, MS (M + H) 458.4, MS (MH) 456.5.
a7) aus N- (4-Aminophenyl) -4, 6-dimethyl-2-pyrimidinamin das rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) -phenyl] - amid, MS (M+H)' 430.4, MS (M-H) 428.5. a8) aus N- (4-Aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidin das rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure-{4- [ (4, 6-dimethyl-pyrimidin-2-yl) -methyl- amino] -phenyl} -amid, MS (M+H) 444.4, MS (M-H) 442.5.a7) from N- (4-aminophenyl) -4, 6-dimethyl-2-pyrimidinamine the rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3-carboxylic acid- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) phenyl] amide, MS (M + H) ' 430.4, MS (MH) 428.5. a8) from N- (4-aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidine the rac. 1- (2, 5-Dimethyl-phenyl) -5-oxopyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) methylamino] phenyl} amide, MS (M + H) 444.4, MS (MH) 442.5.
a9) aus N-Phenyl-1, 4-phenylendiamin das rac. l-(2,5- Dimethyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- (4- phenylamino-phenyl) -amid, MS (M+H) 400.3, MS (M-H) 398.5.a9) from N-phenyl-1,4-phenylenediamine the rac. 1- (2,5-Dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid- (4-phenylamino-phenyl) -amide, MS (M + H) 400.3, MS (M-H) 398.5.
alO) aus N,N-Dimethyl-p-phenylendiamin das rac. l-(2,5- Dimethyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- (4- dimethylamino-phenyl)-amid, MS (M+H) 352.3, MS (M-H) 350.5.alO) from N, N-dimethyl-p-phenylenediamine the rac. 1- (2,5-Dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid- (4-dimethylamino-phenyl) -amide, MS (M + H) 352.3, MS (M-H) 350.5.
all) aus p-Methoxyanilin das rac. 1- (2, 5-Dimethyl-phenyl) - 5-oxo-pyrrolidin-3-carbonsäure- (4-methoxy-phenyl) -amid, MS(M+H) 339.2, MS (M-H) 337.4.all) from p-methoxyaniline the rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidine-3-carboxylic acid- (4-methoxy-phenyl) -amide, MS (M + H) 339.2, MS (M-H) 337.4.
al2) aus N-Ethyl-N- (2-hydroxyethyl) -p-phenylendiamin das rac . 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- { 4- [ethyl- (2-hydroxy-ethyl) -amino] -phenyl }- amid, MS (M+H) 396.4, MS (M-H) 394.5.al2) from N-ethyl-N- (2-hydroxyethyl) -p-phenylenediamine the rac. 1- (2, 5-Dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid {4- [ethyl- (2-hydroxyethyl) amino] phenyl} amide, MS (M + H) 396.4, MS (MH) 394.5.
al3) aus 4-Amino-N-ethyl-N-isopropylanilin das rac. l-(2,5- Dimethyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- [4- (ethyl- isopropyl-amino) -phenyl] -amid, MS (M+H) 394.4, MS (M-H) 392.5.al3) from 4-amino-N-ethyl-N-isopropylaniline the rac. 1- (2,5-dimethylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (ethylisopropylamino) phenyl] amide, MS (M + H) 394.4, MS (MH) 392.5.
al4) aus 4-Amino-N,N-diethylanilin das rac. l-(2,5- Dimethyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- (4- diethylamino-phenyl)-amid, MS (M+H) 380.4, MS (M-H) 378.5.al4) from 4-amino-N, N-diethylaniline the rac. 1- (2,5-Dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid- (4-diethylamino-phenyl) -amide, MS (M + H) 380.4, MS (M-H) 378.5.
al5) aus l-Amino-9-fluoren das rac. 1- (2, 5-Dimethyl- phenyl) -5-oxö-pyrrolidin-3-carbonsäure- (9H-fluoren-l-yl) - amid, MS (M+H) 397.3, MS (M-H) 395.5. al6) aus 4-Aminobiphenyl das rac. 1- (2, 5-Dimethyl-phenyl) - 5-oxo-pyrrolidin-3-carbonsäure-biphenyl-4-ylamid, MS (M+H) 385.3, MS(M-H) 383.4.al5) from l-amino-9-fluorene the rac. 1- (2, 5-Dimethylphenyl) -5-oxo-pyrrolidin-3-carboxylic acid- (9H-fluoren-l-yl) amide, MS (M + H) 397.3, MS (MH) 395.5. al6) from 4-aminobiphenyl the rac. 1- (2, 5-Dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid biphenyl-4-ylamide, MS (M + H) 385.3, MS (MH) 383.4.
al7) aus [ (4-Amino-phenyl) -phenyl-amino] -essigsäure- ethylester (Beispiel 4b2) der rac. [ (4-{ [1- (2, 5-Dimethyl- phenyl) -5-oxo-pyrrolidin-3-carbonyl] -amino} -phenyl) -phenyl- amino] -essigsäure-ethylester, MS(M+H) 486.4, MS (M-H) 484.5.al7) from [(4-aminophenyl) phenylamino] acetic acid ethyl ester (Example 4b2) of rac. [(4- {[1- (2, 5-dimethylphenyl) -5-oxopyrrolidin-3-carbonyl] amino} phenyl) phenylamino] ethyl acetate, MS (M + H) 486.4, MS (MH) 484.5.
al8) aus N-Cyclopropylmethyl-N-phenyl-phenylen-1, 4-diamin (Beispiel 4c2) das rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo- pyrrolidin-3-carbonsäure- [4- (cyclopropylmethyl-phenyl- amino) -phenyl] -amid, MS (M+H) 454.15, MS (M-H) 454.5.al8) from N-cyclopropylmethyl-N-phenyl-phenylene-1,4-diamine (Example 4c2) the rac. 1- (2, 5-Dimethylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (cyclopropylmethylphenylamino) phenyl] amide, MS (M + H) 454.15, MS (MH) 454.5.
al9) aus N-Isobutyl-N-phenyl-phenylen-1, 4-diamin (Beispiel 4d2) das rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (isobutyl-phenyl-amino) -phenyl] -amid, MS(M+H) 456.4, MS (M-H) 454.5.al9) from N-isobutyl-N-phenyl-phenylene-1,4-diamine (Example 4d2) the rac. 1- (2,5-dimethylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (isobutylphenylamino) phenyl] amide, MS (M + H) 456.4, MS (MH) 454.5.
a20) aus N-Methyl-N-phenyl-phenylen-l, 4-diamin (Beispiel 4e2) das rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (methyl-phenyl-amino) -phenyl] -amid, MS (M+H) 414.3, MS(M-H) 412.5.a20) from N-methyl-N-phenyl-phenylene-1,4-diamine (Example 4e2) the rac. 1- (2, 5-Dimethylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (methylphenylamino) phenyl] amide, MS (M + H) 414.3, MS (MH) 412.5.
a21) aus [ (4-Amino-phenyl) -phenyl-amino] -pentansäure- ethylester (Beispiel 4f2) der rac. 5- [ (4-{ [1- (2 , 5-Dimethyl- phenyl) -5-oxo-pyrrolidin-3-carbonyl] -amino} -phenyl) -phenyl- amino] -pentasäure-ethyl ester, MS (M+H) 528.5.a21) from [(4-aminophenyl) phenylamino] pentanoic acid ethyl ester (Example 4f2) of rac. 5- [(4- {[1- (2,5-dimethylphenyl) -5-oxopyrrolidine-3-carbonyl] amino} phenyl) phenylamino] penta acid ethyl ester, MS (M + H) 528.5.
a22) aus N-Benzyl-N-phenyl-1, 4-diamine (Beispiel 4g2) das rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [.4- (benzyl-phenyl-amino) -phenyl] -amid, MS (M+H) 490.3, MS(M-H) 488.5. a23) aus N-Isopropyl-N-phenyl-1, 4-diamine (Beispiel 4h2) das rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (isopropyl-phenyl-amino) -phenyl] -amid, MS (M+H) 442.4, MS (M-H) 440.5.a22) from N-benzyl-N-phenyl-1, 4-diamine (Example 4g2) the rac. 1- (2, 5-Dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid- [.4- (benzylphenylamino) phenyl] amide, MS (M + H) 490.3, MS (MH ) 488.5. a23) from N-isopropyl-N-phenyl-1,4-diamine (Example 4h2) the rac. 1- (2, 5-Dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (isopropylphenylamino) phenyl] amide, MS (M + H) 442.4, MS (MH) 440.5.
a24) aus N-Ethyl-N-phenyl-1, 4-diamine (Beispiel 4i2) das rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (ethyl-phenyl-amino) -phenyl] -amid, MS (M+H) 428.4, MS(M-H) 426.5.a24) from N-ethyl-N-phenyl-1, 4-diamine (Example 4i2) the rac. 1- (2,5-dimethylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (ethylphenylamino) phenyl] amide, MS (M + H) 428.4, MS (MH) 426.5.
b) Die für Beispiel 4a benötigte rac. 2, 5-Dimethyl-phenyl- 5-oxo-l-pyrrolidin-3-carbonsäure wurde analog Beispiel 3b) jedoch unter Verwendung von 2, 5-Dimethylanilin anstelle von Benzylamin hergestellt.b) The rac required for Example 4a. 2, 5-Dimethyl-phenyl-5-oxo-l-pyrrolidine-3-carboxylic acid was prepared analogously to Example 3b), but using 2, 5-dimethylaniline instead of benzylamine.
bl) Der in Beispiel 4al7) benötigte [ (4-Amino-phenyl) - phenyl-amino] -essigsäure-ethylester wurde wie folgt hergestellt : Zu einer Lösung von 300mg 4-Nitrodiphenylamin in 3ml DMF gab man 62mg Natriumhydrid-Dispersion (60%) und anschliessend 178μl Bromessigsäureethylester . Man rührte das Reaktionsgemisch 16 Stunden bei Raumtemperatur, dann 4 Stunden bei 50 °C, kühlte ab, verdünnte mit 3ml Toluol und filtrierte die Lösung. Das Filtrat wurde eingedampft und der Rückstand durch Chromatographie an Kieselgel (Pentan/Toluol) gereinigt. Man erhielt so 197 mg reinen [ (4-Nitro-phenyl) -phenyl-amino] -essigsäure-ethylester.bl) The ethyl [(4-aminophenyl) phenylamino] acetic acid required in Example 4al7) was prepared as follows: 62 mg of sodium hydride dispersion (60%) were added to a solution of 300 mg of 4-nitrodiphenylamine in 3 ml of DMF ) and then 178μl ethyl bromoacetate. The reaction mixture was stirred for 16 hours at room temperature, then for 4 hours at 50 ° C., cooled, diluted with 3 ml of toluene and the solution was filtered. The filtrate was evaporated and the residue was purified by chromatography on silica gel (pentane / toluene). This gave 197 mg of pure [(4-nitro-phenyl) phenylamino] acetic acid ethyl ester.
b2) Die nach Beispiel 4bl erhaltenen 197 mg [ (4-Nitro- phenyl) -phenyl-amino] -essigsäure-ethylester wurden in 2 ml Methanol gelöst, mit 20 mg Palladium/Kohle Katalysator versetzt und' 3 Stunden bei Raumtemperatur hydriert. Nach Filtration des Reaktionsgemisches und Eindampfen des Filtrates erhielt man 173mg [ (4-Amino-phenyl) -phenyl- amino] -essigsäure-ethylester, MS (M+H) 271.1.b2) The palladium / carbon obtained according to Example 4bl 197 mg [(4-nitro-phenyl) -phenyl-amino] -acetic acid ethyl ester were dissolved in 2 ml of methanol, 20 mg of catalyst was added and 'hydrogenated for 3 hours at room temperature. After filtering the reaction mixture and evaporating the Filtrates were obtained 173 mg [(4-aminophenyl) phenylamino] acetic acid ethyl ester, MS (M + H) 271.1.
cl) Analog zu Beispiel 4bl, jedoch unter Verwendung von (Bromomethyl) cyclopropan anstelle von Bromessigsäure- ethylester wurde das Cyclopropylmethyl- (4-nitro-phenyl) - phenyl-amin hergestellt.cl) Analogously to Example 4bl, but using (bromomethyl) cyclopropane instead of ethyl bromoacetate, the cyclopropylmethyl- (4-nitro-phenyl) phenylamine was prepared.
c2) Analog zu Beispiel 4b2, jedoch unter Verwendung des Produktes aus Beispiel 4cl wurde das N-Cyclopropylmethyl-N- phenyl-phenylen-1, 4-diamin hergestellt MS (M+H) 239.3.c2) Analog to Example 4b2, but using the product from Example 4cl, the N-cyclopropylmethyl-N-phenyl-phenylene-1,4-diamine was prepared MS (M + H) 239.3.
dl) Analog zu Beispiel 4bl, jedoch unter Verwendung von 3- Brom-2-methylpropan anstelle von Bromessigsäure-ethylester wurde das Isobutyl- (4-nitro-phenyl) -phenyl-amin hergestellt.dl) Analogously to Example 4bl, but using 3-bromo-2-methylpropane instead of ethyl bromoacetate, the isobutyl- (4-nitro-phenyl) -phenylamine was prepared.
d2) Analog zu Beispiel 4b2, jedoch unter Verwendung des Produktes aus Beispiel 4dl wurde das N-Isobutyl-N-phenyl- phenylen-l,4-diamin hergestellt, MS (M+H) 241.3.d2) Analog to Example 4b2, but using the product from Example 4dl, the N-isobutyl-N-phenylphenylene-1,4-diamine was prepared, MS (M + H) 241.3.
el) Analog zu Beispiel 4bl, jedoch unter Verwendung von Methyljodid anstelle von Bromessigsäure-ethylester wurde das Methyl- (4-nitro-phenyl) -phenyl-amin hergestellt.el) The methyl (4-nitro-phenyl) phenylamine was prepared analogously to Example 4bl, but using methyl iodide instead of ethyl bromoacetate.
e2) Analog zu Beispiel 4b2, jedoch unter Verwendung des Produktes aus Beispiel 4el wurde das N-Methyl-N-phenyl- phenylen-l, 4-diamin hergestellt, MS (M+H) 199.3.e2) Analogously to Example 4b2, but using the product from Example 4el, the N-methyl-N-phenylphenylene-1,4-diamine was prepared, MS (M + H) 199.3.
fl) Analog zu Beispiel 4bl, jedoch unter Verwendung von Bro pentansäure-ethylester anstelle von Bromessigsäure- ethylester wurde der [ (4-Nitro-phenyl) -phenyl-amino] - pentansäure-ethylester hergestellt . f2) Analog zu Beispiel 4b2, jedoch unter Verwendung des Produktes aus Beispiel 4fl wurde der [ (4-Amino-phenyl) - phenyl-amino] -pentansäure-ethylester hergestellt, MS (M+H) 313.2.fl) Analogously to Example 4bl, but using ethyl pentanoate instead of ethyl bromoacetate, the ethyl [(4-nitrophenyl) phenylamino] pentanoate was prepared. f2) Analogously to Example 4b2, but using the product from Example 4fl, the [(4-aminophenyl) phenylamino] pentanoic acid ethyl ester was prepared, MS (M + H) 313.2.
gl) Analog zu Beispiel 4bl, jedoch unter Verwendung von Benzylbromid anstelle von Bromessigsäure-ethylester wurde das Benzyl- (4-nitro-phenyl) -phenyl-amin hergestellt.gl) Analog to Example 4bl, but using benzyl bromide instead of ethyl bromoacetate, the benzyl- (4-nitro-phenyl) -phenyl-amine was prepared.
g2) Analog zu Beispiel 4b2, jedoch unter Verwendung des Produktes aus Beispiel 4gl wurde das N-Benzyl-N-phenyl- phenylen-1, 4-diamin hergestellt, MS (M+H) 275.3.g2) Analogously to Example 4b2, but using the product from Example 4gl, the N-benzyl-N-phenylphenylene-1,4-diamine was prepared, MS (M + H) 275.3.
hl) Analog zu Beispiel 4bl, jedoch unter Verwendung von 2- Brompropan anstelle von Bromessigsäure-ethylester wurde das Isopropyl- (4-nitro-phenyl) -phenyl-amin hergestellt.hl) Analogously to Example 4bl, but using 2-bromopropane instead of ethyl bromoacetate, the isopropyl- (4-nitro-phenyl) -phenyl-amine was prepared.
h2) Analog Beispiel 4b2, jedoch unter Verwendung des Produktes aus Beispiel 4hl wurde das N-Isopropyl-N-phenyl- phenylen-l,4-diamin hergestellt, MS (M+H) 227.3.h2) Analogously to Example 4b2, but using the product from Example 4hl, the N-isopropyl-N-phenylphenylene-1,4-diamine was prepared, MS (M + H) 227.3.
il) Analog zu Beispiel 4bl, jedoch unter Verwendung von Bromethan anstelle von Bromessigsäure-ethylester wurde das Ethyl- (4-nitro-phenyl) -phenyl-amin hergestellt .il) Analogously to Example 4bl, but using bromoethane instead of ethyl bromoacetate, the ethyl (4-nitro-phenyl) phenylamine was prepared.
i2) Analog zu Beispiel 4b2, jedoch unter Verwendung des Produktes aus Beispiel 4il wurde das N-Ethyl-N-phenyl- phenylen-1, 4-diamine hergestellt, MS (M+H) 213.3.i2) Analogously to Example 4b2, but using the product from Example 4il, the N-ethyl-N-phenylphenylene-1,4-diamine was prepared, MS (M + H) 213.3.
Beispiel 5 (R ist Indan-2-yl)Example 5 (R is indan-2-yl)
a) Analog zu Beispiel 1 wurden aus rac. l-Indan-2-yl-5-oxo- pyrrolidin-3-carbonsäure unter Verwendung der nachstehenden Amine folgende Produkte hergestellt: al) aus 3-Aminobiphenyl das rac. l-Indan-2-yl-5-oxo- pyrrolidin-3-carbonsäure-biphenyl-3-ylamid, MS (M+H) 397.3, MS(M-H) 395.5.a) Analogously to Example 1, rac. l-Indan-2-yl-5-oxopyrrolidin-3-carboxylic acid using the amines below produced the following products: al) from 3-aminobiphenyl the rac. l-Indan-2-yl-5-oxopyrrolidin-3-carboxylic acid biphenyl-3-ylamide, MS (M + H) 397.3, MS (MH) 395.5.
a2) aus 3-Amino-2-methoxydibenzofuran das rac. l-Indan-2- yl-5-oxo-pyrrolidin-3-carbonsäure- (2-methoxy-dibenzofuran- 3-yl)-amid, MS (M+H) 441.2, MS (M-H) 439.5.a2) from 3-amino-2-methoxydibenzofuran the rac. l-Indan-2-yl-5-oxopyrrolidin-3-carboxylic acid- (2-methoxy-dibenzofuran-3-yl) -amide, MS (M + H) 441.2, MS (M-H) 439.5.
a3) aus 2-Amino-9-fluorenon das rac. l-Indan-2-yl-5-oxo- pyrrolidin-3-carbonsäure- (9-oxo-9H-fluoren-2-yl) -amid, MS(M+H) 423.2, MS (M-H) 421.4.a3) from 2-amino-9-fluorenone the rac. l-Indan-2-yl-5-oxopyrrolidin-3-carboxylic acid- (9-oxo-9H-fluoren-2-yl) -amide, MS (M + H) 423.2, MS (M-H) 421.4.
a4) aus 2-Aminofluoren das rac. l-Indan-2-yl-5-oxo- pyrrolidin-3-carbonsäure- (9H-fluoren-2-yl) -amid, MS (M+H) 409.3, MS(M-H) 407.5.a4) from 2-aminofluorene the rac. l-Indan-2-yl-5-oxopyrrolidin-3-carboxylic acid (9H-fluoren-2-yl) amide, MS (M + H) 409.3, MS (M-H) 407.5.
a5) aus N- (4-Aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidin das rac. l-Indan-2-yl-5-oxo-pyrrolidin-3-carbonsäure- { 4- [ (4 , 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] -phenyl} -amid, MS(M+H) 470.4, MS (M-H) 468.5.a5) from N- (4-aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidine the rac. l-Indan-2-yl-5-oxopyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethylpyrimidin-2-yl) ethylamino] phenyl} amide, MS (M + H) 470.4, MS (MH) 468.5.
a6) aus N- (4-Aminophenyl) -4, 6-dimethyl-2-pyrimidinamin das rac. l-Indan-2-yl-5-oxo-pyrrolidin-3-carbonsäure- [4- (4 , 6- dimethyl-pyrimidin-2-ylamino) -phenyl] -amid, MS (M+H) 442.4, MS(M-H) 440.5.a6) from N- (4-aminophenyl) -4, 6-dimethyl-2-pyrimidinamine the rac. l-Indan-2-yl-5-oxopyrrolidin-3-carboxylic acid- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) phenyl] amide, MS (M + H) 442.4, MS ( MH) 440.5.
a7) aus N- (4-Aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidin das rac. l-Indan-2-yl-5-oxo-pyrrolidin-3-carbonsäure- { 4- [ (4, 6-dimethyl-pyrimidin-2-yl) -methyl-amino] -phenyl} -amid, MS(M+H) 456.3, MS (M-H) 454.5. a8) aus N-Phenyl-1, 4-phenylenediamin das rac. l-Indan-2-yl- 5-oxo-pyrrolidin-3-carbonsäure- (4-phenylamino-phenyl) -amid, MS (M+H) 412.3, MS (M-H) 410.5.a7) from N- (4-aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidine the rac. l-Indan-2-yl-5-oxopyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethylpyrimidin-2-yl) methylamino] phenyl} amide, MS (M + H) 456.3, MS (MH) 454.5. a8) from N-phenyl-1,4-phenylenediamine the rac. l-Indan-2-yl-5-oxopyrrolidin-3-carboxylic acid- (4-phenylamino-phenyl) -amide, MS (M + H) 412.3, MS (MH) 410.5.
a9) aus l-Amino-9-fluoren das rac. l-Indan-2-yl-5-oxo- pyrrolidin-3-carbonsäure- (9H-fluoren-1-yl) -amid, MS (M+H) 409.3, MS(M-H) 407.5.a9) from l-amino-9-fluorene the rac. l-indan-2-yl-5-oxopyrrolidin-3-carboxylic acid (9H-fluoren-1-yl) amide, MS (M + H) 409.3, MS (M-H) 407.5.
alO) aus 4-Aminobiphenyl das rac. l-Indan-2-yl-5-oxo- pyrrolidin-3-carbonsäure-biphenyl-4-ylamid, MS (M+H) 397.3, MS(M-H) 395.5.alO) from 4-aminobiphenyl the rac. 1-Indan-2-yl-5-oxopyrrolidin-3-carboxylic acid biphenyl-4-ylamide, MS (M + H) 397.3, MS (M-H) 395.5.
all) aus 3-Amino-9-ethylcarbazol das rac. l-Indan-2-yl-5- oxo-pyrrolidin-3-carbonsäure- ( 9-ethyl-9H-carbazol-3-yl) - amid, MS (M+H) 438.4, MS (M-H) 436.3.all) from 3-amino-9-ethylcarbazole the rac. l-Indan-2-yl-5-oxopyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) amide, MS (M + H) 438.4, MS (M-H) 436.3.
al2) aus N,N-Dimethyl-p-phenylenediamin das rac. l-Indan-2- yl-5-oxo-pyrrolidin-3-carbonsäure- (4-dimethylamino-phenyl) - amid, MS (M+H) 364.3, MS (M-H) 362.1.al2) from N, N-dimethyl-p-phenylenediamine the rac. l-indan-2-yl-5-oxopyrrolidine-3-carboxylic acid- (4-dimethylamino-phenyl) amide, MS (M + H) 364.3, MS (M-H) 362.1.
al3 ) aus [ ( 4-Amino-phenyl ) -phenyl-amino] -essigsäure- ethylester ( sieheBeispiel 3a22 ) der rac . ( { 4- [ ( l-Indan-2- yl-5-oxo-pyrrolidin-3-carbonyl ) -amino] -phenyl } -phenyl- amino) -essigsäuzre-ethyl ester, MS (M+H) 498 . 3 , MS (M-H) 496 .5 .al3) from [(4-aminophenyl) phenylamino] acetic acid ethyl ester (see Example 3a22) of rac. ({4- [(l-Indan-2-yl-5-oxopyrrolidin-3-carbonyl) amino] phenyl} phenylamino) acetic acid ethyl ester, MS (M + H) 498. 3, MS (M-H) 496.5.
al4) aus N-Cyclopropylmethyl-N-phenyl-phenylen-1, 4-diamin (siehe Beispiel 3a23) das rac. l-Indan-2-yl-5-oxo- pyrrolidin-3-carbonsäure- [4- (cyclopropylmethyl-phenyl- amino) -phenyl] -amid, MS (M+H) 466.4, MS (M-H) 464.5.al4) from N-cyclopropylmethyl-N-phenyl-phenylene-1,4-diamine (see Example 3a23) the rac. l-Indan-2-yl-5-oxopyrrolidin-3-carboxylic acid- [4- (cyclopropylmethylphenylamino) phenyl] amide, MS (M + H) 466.4, MS (M-H) 464.5.
al5) aus N-Isobutyl-N-phenyl-phenylen-1, 4-diamin (Beispiel 4d2) das rac. l-Indan-2-yl-5-oxo-pyrrolidin-3-carbonsäure- [4- (isobutyl-phenyl-amino) -phenyl] -amid, MS (M+H) 468.3, MS(M-H) 466.5.al5) from N-isobutyl-N-phenyl-phenylene-1,4-diamine (Example 4d2) the rac. l-indan-2-yl-5-oxo-pyrrolidine-3-carboxylic acid [4- (isobutylphenylamino) phenyl] amide, MS (M + H) 468.3, MS (MH) 466.5.
al6) aus N-Methyl-N-phenyl-phenylen-l, 4-diamin (Beispiel 4e2) das rac. l-Indan-2-yl-5-oxo-pyrrolidin-3-carbonsäure- [4- (methyl-phenyl-amino) -phenyl] -amid, MS (M+H) 426.3, MS (M- H) 424.5.al6) from N-methyl-N-phenyl-phenylene-1,4-diamine (Example 4e2) the rac. l-Indan-2-yl-5-oxopyrrolidin-3-carboxylic acid- [4- (methylphenylamino) phenyl] amide, MS (M + H) 426.3, MS (M- H) 424.5.
al7) aus [ (4-Amino-phenyl) -phenyl-amino] -pentansäure- ethylester (Beispiel 4f2) der rac. 5- ( { 4- [ (l-Indan-2-yl-5- oxo-pyrrolidin-3-carbonyl) -amino] -phenyl} -phenyl-amino) - pentansäure-ethyl ester, MS (M+H) 540.4, MS (M-H) 538.5.al7) from [(4-aminophenyl) phenylamino] pentanoic acid ethyl ester (Example 4f2) of rac. 5- ({4- [(l-Indan-2-yl-5-oxopyrrolidin-3-carbonyl) amino] phenyl} phenylamino) pentanoic acid ethyl ester, MS (M + H) 540.4 , MS (MH) 538.5.
al8) aus N-Benzyl-N-phenyl-phenylen-1, 4-diamin (Beispiel 4g2) das rac. l-Indan-2-yl-5-oxo-pyrrolidin-3-carbonsäure- [4- (benzyl-phenyl-amino) -phenyl] -amid, MS (M+H) 502.3, MS (M- H) 500.5.al8) from N-benzyl-N-phenyl-phenylene-1,4-diamine (Example 4g2) the rac. l-Indan-2-yl-5-oxopyrrolidin-3-carboxylic acid- [4- (benzylphenylamino) phenyl] amide, MS (M + H) 502.3, MS (M- H) 500.5.
al9) aus N-Isopropyl-N-phenyl-phenylen-1, 4-diamin (Beispiel 4h2) das rac. l-Indan-2-yl-5-oxo-pyrrolidin-3-carbonsäure- [4- (isopropyl-phenyl-amino) -phenyl] -amidMS (M+H) 454.4 , MS (M-H) 452.5.al9) from N-isopropyl-N-phenyl-phenylene-1,4-diamine (Example 4h2) the rac. l-Indan-2-yl-5-oxopyrrolidin-3-carboxylic acid- [4- (isopropylphenylamino) phenyl] amide MS (M + H) 454.4, MS (M-H) 452.5.
a20) aus N-Ethyl-N-phenyl-phenylen-1, 4-diamin (Beispiel 4i2) das rac. l-Indan-2-yl-5-oxo-pyrrolidin-3-carbonsäure- [4- (ethyl-phenyl-amino) -phenyl] -amid, MS (M+H) 440.3, MS (M- H) 438.5.a20) from N-ethyl-N-phenyl-phenylene-1,4-diamine (Example 4i2) the rac. l-Indan-2-yl-5-oxopyrrolidin-3-carboxylic acid- [4- (ethylphenylamino) phenyl] amide, MS (M + H) 440.3, MS (M- H) 438.5.
b) Die für Beispiel 5a benötigte rac. l-Indan-2-yl-5-oxo- pyrrolidin-3-carbonsäure wurde analog Beispiel 3b) jedoch unter Verwendung von Indan-2-amin anstelle von Benzylamin hergestellt . Beispiel 6 (R1 ist 2-Naphthyl)b) The rac required for Example 5a. l-Indan-2-yl-5-oxopyrrolidin-3-carboxylic acid was prepared analogously to Example 3b) but using indan-2-amine instead of benzylamine. Example 6 (R 1 is 2-naphthyl)
a) Analog Beispiel 1 wurden aus rac. l-Naphthalin-2-yl-5- oxo-pyrrolidin-3-carbonsäure unter Verwendung der nachstehenden Amine folgende Produkte hergestellt:a) Analogously to Example 1, rac. l-Naphthalin-2-yl-5-oxo-pyrrolidin-3-carboxylic acid produced the following products using the following amines:
al) aus 4-Phenoxyanilin das rac. l-Naphthalin-2-yl-5-oxo- pyrrolidin-3-carbonsäure- (4-phenoxy-phenyl) amid, MS (M+H) 423.4, MS(M-H) 421.3.al) from 4-phenoxyaniline the rac. l-Naphthalin-2-yl-5-oxopyrrolidin-3-carboxylic acid- (4-phenoxy-phenyl) amide, MS (M + H) 423.4, MS (M-H) 421.3.
a2) aus N,N-Dimethyl-p-phenylenediamin das rac. 1- Naphthalin-2-yl-5-oxo-pyrrolidin-3-carbonsäure- (4- dimethylamino-phenyl)-amid, MS (M+H) 374.3, MS (M-H) 372.5.a2) from N, N-dimethyl-p-phenylenediamine the rac. 1-Naphthalin-2-yl-5-oxo-pyrrolidin-3-carboxylic acid- (4-dimethylamino-phenyl) -amide, MS (M + H) 374.3, MS (M-H) 372.5.
b) Die für Beispiel 6a benötigte rac. l-Naphthalin-2-yl-5- oxo-pyrrolidin-3-carbonsäure wurde analog zu Beispiel 3b) jedoch unter Verwendung von 2-Naphthylamin anstelle von Benzylamin hergestellt.b) The rac required for Example 6a. l-Naphthalin-2-yl-5-oxopyrrolidin-3-carboxylic acid was prepared analogously to Example 3b), but using 2-naphthylamine instead of benzylamine.
Beispiel 7 (R1 ist 2-Isopropyl-phenyl)Example 7 (R 1 is 2-isopropylphenyl)
a) Analog zu Beispiel 1 wurden aus rac. 1- (2-Isopropyl- phenyl) -5-oxo-pyrrolidin-3-carbonsäure unter Verwendung der nachstehenden Amine folgende Produkte hergestellt:a) Analogously to Example 1, rac. 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid using the amines below produced the following products:
al) aus N- (4-Aminophenyl) -4, 6-dimethyl-2-pyrimidinamin das rac . 1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) -phenyl] -amid, MS (M+H) 444.4, MS(M-H) 442.5.al) from N- (4-aminophenyl) -4, 6-dimethyl-2-pyrimidinamine the rac. 1- (2-isopropyl-phenyl) -5-oxo-pyrrolidin-3-carboxylic acid- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) phenyl] amide, MS (M + H) 444.4, MS (MH) 442.5.
a2) aus N- (4-Aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidin das rac. 1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure-{4- [ (4, 6-dimethyl-pyrimidin-2-yl) -methyl- amino] -phenyl} -amid, MS (M+H) 458.4, MS (M-H) 456.5. a3) aus N- (4-Aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidin das rac. 1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure-{4- [ (4, 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] - phenyl}-amid, MS (M+H) 472.2, MS (M-H) 470.5.a2) from N- (4-aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidine d as rac. 1- (2-isopropylphenyl) -5-oxopyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethylpyrimidin-2-yl) methylamino] phenyl} amide, MS ( M + H) 458.4, MS (MH) 456.5. a3) from N- (4-aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidine the rac. 1- (2-isopropyl-phenyl) -5-oxo-pyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) ethyl amino] phenyl} amide, MS ( M + H) 472.2, MS (MH) 470.5.
a4) aus N-Phenyl-1, 4-phenylenediamin das rac. 1- (2- Isopropyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- (4- phenylamino-phenyl)-amid, MS (M+H) 414.3, MS (M-H) 412.5.a4) from N-phenyl-1,4-phenylenediamine the rac. 1- (2-isopropyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid- (4-phenylamino-phenyl) -amide, MS (M + H) 414.3, MS (M-H) 412.5.
a5) aus 3-Amino-9-ethylcarbazol das rac. 1- (2-Isopropyl- phenyl) -5-oxo-pyrrolidin-3-carbonsäure- (9-ethyl-9H- carbazol-3-yl)-amid, MS (M+H) 440'.4, MS (M-H) 438.3.a5) from 3-amino-9-ethylcarbazole the rac. 1- (2-isopropylphenyl) -5-oxopyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide, MS (M + H) 440'.4, MS (MH ) 438.3.
a6) aus [ (4-Amino-phenyl) -phenyl-amino] -essigsäure- ethylester (siehe Beispiel 3a22) der rac. [(4-{[l-(2- Isopropyl-phenyl) -5-oxo-pyrrolidin-3-carbonyl] -amino }- phenyl) -phenyl-amino] -essigsäure-ethyl ester, MS (M+H) 500.3, MS(M-H) 498.5.a6) from [(4-aminophenyl) phenylamino] acetic acid ethyl ester (see Example 3a22) of rac. [(4 - {[1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carbonyl] amino} - phenyl) phenylamino] ethyl acetate, MS (M + H) 500.3 , MS (MH) 498.5.
a7) aus N-Cyclopropylmethyl-N-phenyl-phenylen-1, 4-diamin (siehe Beispiel 3a23) das rac. 1- (2-Isopropyl-phenyl) -5- oxo-pyrrolidin-3-carbonsäure- [4- (cyclopropylmethyl-phenyl- amino) -phenyl] -amid, MS (M+H) 468.4, MS (M-H) 466.5a7) from N-cyclopropylmethyl-N-phenyl-phenylene-1,4-diamine (see Example 3a23) the rac. 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (cyclopropylmethylphenylamino) phenyl] amide, MS (M + H) 468.4, MS (M-H) 466.5
a8) aus N-Isobutyl-N-phenyl-phenylen-1, 4-diamin (Beispiel 4d2) das rac. 1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (isobutyl-phenyl-amino) -phenyl] -amid, MS(M+H) 470.4, MS (M-H) 468.5.a8) from N-isobutyl-N-phenyl-phenylene-1,4-diamine (Example 4d2) the rac. 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (isobutylphenylamino) phenyl] amide, MS (M + H) 470.4, MS (M-H) 468.5.
a9) aus N-Methyl-N-phenyl-phenylen-l, 4-diamin (Beispiel 4e2) das rac. 1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (methyl-phenyl-amino) -phenyl] -amid, MS (M+H) 428.4, MS(M-H) 426.5. alO) aus [ (4-Amino-phenyl) -phenyl-amino] -pentansäure ethylester (Beispiel 4f2) der rac. 5- [ (4-{ [1- (2-Isopropyl- phenyl) -5-oxo-pyrrolidin-3-carbonyl] -amino} -phenyl) -phenyl- amino] -pentasäure-ethyl ester, MS (M+H) 542.4, MS (M-H) 540.6.a9) from N-methyl-N-phenyl-phenylene-1,4-diamine (Example 4e2) the rac. 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (methylphenylamino) phenyl] amide, MS (M + H) 428.4, MS (MH) 426.5. alO) from [(4-aminophenyl) phenylamino] pentanoic acid ethyl ester (Example 4f2) of rac. 5- [(4- {[1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carbonyl] amino} phenyl) phenylamino] penta acid ethyl ester, MS (M + H ) 542.4, MS (MH) 540.6.
all) aus N-Benzyl-N-phenyl-phenylen-1, 4-diamin (Beispielall) from N-benzyl-N-phenyl-phenylene-1,4-diamine (example
4g2) das rac. 1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (benzyl-phenyl-amino) -phenyl] -amid, MS (M+H)4g2) the rac. 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (benzylphenylamino) phenyl] amide, MS (M + H)
504.3, MS(M-H) 502.5.504.3, MS (M-H) 502.5.
al2) aus N-Isopropyl-N-phenyl-phenylen-1, 4-diamin (Beispiel 4h2) das rac. 1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (isopropyl-phenyl-amino) -phenyl] -amid, MS(M+H) 456.4, MS (M-H) 454.5.al2) from N-isopropyl-N-phenyl-phenylene-1,4-diamine (Example 4h2) the rac. 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (isopropylphenylamino) phenyl] amide, MS (M + H) 456.4, MS (M-H) 454.5.
al3) aus N-Ethyl-N-phenyl-phenylen-1, -diamin (Beispielal3) from N-ethyl-N-phenyl-phenylene-1, -diamine (example
4i2) das rac. 1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (ethyl-phenyl-amino) -phenyl] -amid, MS (M+H)4i2) the rac. 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (ethylphenylamino) phenyl] amide, MS (M + H)
442.4, MS(M-H) 440.5.442.4, MS (M-H) 440.5.
b) Die für Beispiel 7a benötigte rac. 1- (2-Isopropyl- phenyl) -5-oxo-pyrrolidin-3-carbonsäure wurde analog Beispiel 3b) jedoch unter Verwendung von Isopropylamin anstelle von Benzylamin hergestellt.b) The rac required for Example 7a. 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid was prepared analogously to Example 3b) but using isopropylamine instead of benzylamine.
Beispiel 8 (R1 ist 2-Phenylethyl)Example 8 (R 1 is 2-phenylethyl)
a) Analog Beispiel 1 wurden aus rac. 5-Oxo-l-phenetyl- pyrrolidin-3-carbonsäure unter Verwendung der nachstehenden Amine folgende Produkte hergestellt: al) aus 4-Phenoxyanilin das rac. 5-Oxo-l-phenethyl- pyrrolidin-3-carbonsäure- ( 4-phenoxy-phenyl ) -amid, MS (M+H) 401.3, MS(M-H) 399.5.a) Analogously to Example 1, rac. 5-Oxo-l-phenetyl-pyrrolidine-3-carboxylic acid using the amines below produced the following products: al) from 4-phenoxyaniline the rac. 5-oxo-l-phenethyl-pyrrolidine-3-carboxylic acid- (4-phenoxy-phenyl) -amide, MS (M + H) 401.3, MS (MH) 399.5.
a2) aus N,N-Dimethyl-p-phenylendiamin das rac. 5-Oxo-l- phenethyl-pyrrolidin-3-carbonsäure- ( 4-dimethylamino- phenyl)-amid, MS (M+H) 352.3, MS (M-H) 350.5.a2) from N, N-dimethyl-p-phenylenediamine the rac. 5-oxo-1-phenethyl-pyrrolidine-3-carboxylic acid- (4-dimethylaminophenyl) amide, MS (M + H) 352.3, MS (M-H) 350.5.
a3) aus N- (4-Aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidin das rac. 5-Oxo-l-phenethyl-pyrrolidin-3-carbonsäure-{ 4- [ (4, 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] -phenyl} -amid, MS(M+H) 458.4, MS (M-H) 456.5.a3) from N- (4-aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidine the rac. 5-oxo-1-phenethyl-pyrrolidine-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] -phenyl} -amide, MS (M + H) 458.4, MS (MH) 456.5.
a4) aus 3-Aminobiphenyl das rac. 5-Oxo-l-phenethyl- pyrrolidin-3-carbonsäure-biphenyl-3-ylamid, MS (M+H) 385.2, MS(M-H) 383.4.a4) from 3-aminobiphenyl the rac. 5-oxo-1-phenethyl-pyrrolidine-3-carboxylic acid-biphenyl-3-ylamide, MS (M + H) 385.2, MS (M-H) 383.4.
a5) aus 2-Amino-9-fluorenon das rac. 5-Oxo-l-phenethyl- pyrrolidin-3-carbonsäure- ( 9-oxo-9H-fluoren-2-yl) -amid, MS (M+H) 411.3, MS (M-H) 409.4.a5) from 2-amino-9-fluorenone the rac. 5-oxo-l-phenethyl-pyrrolidin-3-carboxylic acid- (9-oxo-9H-fluoren-2-yl) -amide, MS (M + H) 411.3, MS (M-H) 409.4.
a6) aus 2-Aminofluoren das rac. 5-Oxo-l-phenethyl- pyrrolidin-3-carbonsäure- (9H-fluoren-2-yl) -amid, MS (M+H) 397.3, MS(M-H) 395.5.a6) from 2-aminofluorene the rac. 5-oxo-l-phenethyl-pyrrolidin-3-carboxylic acid (9H-fluoren-2-yl) amide, MS (M + H) 397.3, MS (M-H) 395.5.
a7) aus N- (4-Aminophenyl) -4, 6-dimethyl-2-pyrimidinamin das rac. 5-Oxo-1-phenethyl-pyrrolidin-3-carbonsäure- [4- (4 , 6- dimethyl-pyrimidin-2-ylamino) -phenyl] -amid, MS (M+H) 430.3, MS(M-H) 428.5.a7) from N- (4-aminophenyl) -4, 6-dimethyl-2-pyrimidinamine the rac. 5-oxo-1-phenethyl-pyrrolidine-3-carboxylic acid- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) phenyl] amide, MS (M + H) 430.3, MS (M-H) 428.5.
a8) aus N- (4-Aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidin das rac. 5-Oxo-l-phenethyl-pyrrolidin-3-carbonsäure- { 4- [ (4, 6-dimethyl-pyrimidin-2-yl) -methyl-amino] -phenyl} -amid, MS(M+H) 444.3, MS (M-H) 442.5. a9) aus N-Phenyl-1, 4-phenylenediamin das rac. 5-Oxo-l- phenethyl-pyrrolidin-3-carbonsäure- (4-phenylamino-phenyl) - amid, MS (M+H) 400.3, MS (M-H) 398.5.a8) from N- (4-aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidine the rac. 5-oxo-l-phenethyl-pyrrolidine-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) methylamino] phenyl} amide, MS (M + H) 444.3, MS (MH) 442.5. a9) from N-phenyl-1,4-phenylenediamine the rac. 5-oxo-1-phenethyl-pyrrolidine-3-carboxylic acid- (4-phenylaminophenyl) amide, MS (M + H) 400.3, MS (MH) 398.5.
alO) aus 4-Aminobiphenyl das rac. 5-Oxo-l-phenethyl- pyrrolidin-3-carbonsäure-biphenyl-4-ylamid, MS (M+) 385.4, MS (M-H) 383.4.alO) from 4-aminobiphenyl the rac. 5-oxo-l-phenethyl-pyrrolidine-3-carboxylic acid-biphenyl-4-ylamide, MS (M +) 385.4, MS (M-H) 383.4.
all) aus 3-Amino-9-ethylcarbazol das rac. 5-Oxo-l- phenethyl-pyrrolidin-3-carbonsäure- ( 9-ethyl-9H-carbazol-3- yl)-amid, MS (M+H) 426.3, MS (M-H) 424.4.all) from 3-amino-9-ethylcarbazole the rac. 5-oxo-1-phenethyl-pyrrolidine-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide, MS (M + H) 426.3, MS (M-H) 424.4.
b) Die für Beispiel 8a benötigte rac. 5-Oxo-l-phenethyl- pyrrolidin-3-carbonsäure wurde analog Beispiel 3b) jedoch unter Verwendung von Phenethylamin anstelle von Benzylamin hergestellt :b) The rac required for Example 8a. 5-Oxo-l-phenethyl-pyrrolidine-3-carboxylic acid was prepared analogously to Example 3b), but using phenethylamine instead of benzylamine:
Beispiel 9 (R1 ist 5- ethoxy-2-methylphenyl)Example 9 (R 1 is 5-ethoxy-2-methylphenyl)
a) Analog Beispiel 1 wurden aus rac. 1- (5-Methoxy-2-methyl- phenyl) -5-oxo-pyrrolidin-3-carbonsä.ure unter Verwendung des nachstehenden Amins folgende Verbindungen hergestellt:a) Analogously to Example 1, rac. 1- (5-methoxy-2-methylphenyl) -5-oxopyrrolidine-3-carboxylic acid . The following compounds are produced using the amine below:
al) aus N- (4-Aminophenyl) -4, 6-dimethyl-2-pyrimidinamin das rac. 1- (5-Methoxy-2-methyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) -phenyl] - amid, MS (M+H) 446.4, MS (M-H) 444.5.al) from N- (4-aminophenyl) -4, 6-dimethyl-2-pyrimidinamine the rac. 1- (5-methoxy-2-methylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (4, 6-dimethylpyrimidin-2-ylamino) phenyl] amide, MS (M + H) 446.4, MS (MH) 444.5.
a2) aus N- (4-Aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidin das rac. 1- (5-Methoxy-2-methyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure-{4- [ (4, 6-dimethyl-pyrimidin-2-yl) -methyl- amino] -phenyl} -amid, MS (M+H) 460.4, MS (M-H) 458.5. a3) aus N- (4-Aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidin das rac. 1- (5-Methoxy-2-methyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- { 4- [ ( 4 , 6-dimethyl-pyrimidin-2-yl ) -ethyl-amino] - phenyl} -amid, MS (M+H) 474.0, MS (M-H) 472.5.a2) from N- (4-aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidine the rac. 1- (5-methoxy-2-methylphenyl) -5-oxo-pyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) methylamino] phenyl} - amide, MS (M + H) 460.4, MS (MH) 458.5. a3) from N- (4-aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidine the rac. 1- (5-methoxy-2-methylphenyl) -5-oxopyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethylpyrimidin-2-yl) ethylamino] phenyl} - amide, MS (M + H) 474.0, MS (MH) 472.5.
a4) aus N-Phenyl-1, 4-phenylendiamin das rac. 1- (5-Methoxy- 2-methyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- (4- phenylamino-phenyl)-amid, MS (M+H) 416.3, MS (M-H) 414.5.a4) from N-phenyl-1,4-phenylenediamine the rac. 1- (5-methoxy-2-methylphenyl) -5-oxopyrrolidine-3-carboxylic acid (4-phenylamino-phenyl) -amide, MS (M + H) 416.3, MS (M-H) 414.5.
a5) aus 3-Amino-9-ethylcarbazol das rac. 1- (5-Methoxy-2- methyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- (9-ethyl-9H- carbazol-3-yl)-amid, MS (M+H) 442.6, MS (M-H) 440.3.a5) from 3-amino-9-ethylcarbazole the rac. 1- (5-methoxy-2-methylphenyl) -5-oxo-pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide, MS (M + H) 442.6, MS ( MH) 440.3.
a6) aus [ (4-Amino-phenyl) -phenyl-amino] -essigsäure- ethylester (siehe Beispiel 3a22) der rac. [(4-{[l-(5- Methoxy-2-methyl-phenyl) -5-oxo-pyrrolidin-3-carbonyl] - amino} -phenyl) -phenyl-amino] -essigsäure-ethyl ester, MS (M+H) 502.3, MS (M-H) 500.5.a6) from [(4-aminophenyl) phenylamino] acetic acid ethyl ester (see Example 3a22) of rac. [(4 - {[1- (5-Methoxy-2-methylphenyl) -5-oxopyrrolidine-3-carbonyl] amino} phenyl) phenylamino] ethyl acetate, MS (M + H) 502.3, MS (MH) 500.5.
a7) aus N-Cyclopropylmethyl-N-phenyl-phenylen-1, 4-diamin (siehe Beispiel 3a23) das rac. 1- (5-Methoxy-2-methyl- phenyl) -5-oxo-pyrrolidin-3~carbonsäure- [4-a7) from N-cyclopropylmethyl-N-phenyl-phenylene-1,4-diamine (see Example 3a23) the rac. 1- (5-methoxy-2-methylphenyl) -5-oxo-pyrrolidine-3 ~ carboxylic acid- [4-
(cyclopropylmethyl-phenyl-amino) -phenyl] -amid, MS (M+H) 470.4, MS(M-H) 468.5.(cyclopropylmethylphenylamino) phenyl] amide, MS (M + H) 470.4, MS (M-H) 468.5.
a8) aus N-Isobutyl-N-phenyl-phenylen-1, 4-diamin (Beispiel 4d2) das rac. 1- (5-Methoxy-2-methyl-phenyl) -5-oxo- pyrrolidin-3-carbonsäure- [4- (isobutyl-phenyl-amino) - phenyl] -amid, MS (M+H) 472.3, MS (M-H) 470.5.a8) from N-isobutyl-N-phenyl-phenylene-1,4-diamine (Example 4d2) the rac. 1- (5-methoxy-2-methylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (isobutylphenylamino) phenyl] amide, MS (M + H) 472.3, MS ( MH) 470.5.
a9) aus N-Methyl-N-phenyl-phenylen-l, 4-diamin (Beispiel 4e2) das rac. 1- (5-Methoxy-2-methyl-phenyl) -5-oxo- pyrrolidin-3-carbonsäure- [4- (methyl-phenyl-amino) -phenyl] - amid, MS (M+H) 430.3, MS (M-H) 428.5. alO) aus [ (4-Amino-phenyl) -phenyl-amino] -pentansäure- ethylester (Beispiel 4f2) der rac. 5- [ (4- { [1- (5-Methoxy-2- methyl-phenyl) -5-oxo-pyrrolidin-3-carbonyl] -amino} -phenyl) - phenyl-amino] -pentansäure-ethylester, MS (M+H) 544.5, MS (M- H) 542.6.a9) from N-methyl-N-phenyl-phenylene-1,4-diamine (Example 4e2) the rac. 1- (5-methoxy-2-methylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (methylphenylamino) phenyl] amide, MS (M + H) 430.3, MS ( MH) 428.5. alO) from [(4-aminophenyl) phenylamino] pentanoic acid ethyl ester (Example 4f2) of rac. 5- [(4- {[1- (5-Methoxy-2-methylphenyl) -5-oxopyrrolidin-3-carbonyl] amino} phenyl) phenylamino] pentanoic acid ethyl ester, MS ( M + H) 544.5, MS (M- H) 542.6.
all) aus N-Benzyl-N-phenyl-phenylen-1, 4-diamin (Beispiel 4g2) das rac. 1- (5-Methoxy-2-methyl-phenyl) -5-oxo- pyrrolidin-3-carbonsäure- [4- (benzyl-phenyl-amino) -phenyl] - amid, MS (M+H) 506.3, MS (M-H) 504.5.all) from N-benzyl-N-phenyl-phenylene-1,4-diamine (Example 4g2) the rac. 1- (5-methoxy-2-methylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (benzylphenylamino) phenyl] amide, MS (M + H) 506.3, MS ( MH) 504.5.
al2) aus N-Isopropyl-N-phenyl-phenylen-1, 4-diamin (Beispiel 4h2) das rac. 1- (5-Methoxy-2-methyl-phenyl ) -5-oxo- pyrrolidin-3-carbonsäure- [4- (isopropyl-phenyl-amino) - phenyl] -amid, MS (M+H) 458.4, MS (M-H) 456.5.al2) from N-isopropyl-N-phenyl-phenylene-1,4-diamine (Example 4h2) the rac. 1- (5-Methoxy-2-methylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (isopropylphenylamino) phenyl] amide, MS (M + H) 458.4, MS ( MH) 456.5.
al3) aus N-Ethyl-N-phenyl-phenylen-1, 4-diamin (Beispiel 4i2) das rac. 1- (5-Methoxy-2-methyl-phenyl) -5-oxo- pyrrolidin-3-carbonsäure- [4- (ethyl-phenyl-amino) -phenyl] - amid, MS (M+H) 444.4, MS (M-H) 442.5.al3) from N-ethyl-N-phenyl-phenylene-1,4-diamine (Example 4i2) the rac. 1- (5-methoxy-2-methylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (ethylphenylamino) phenyl] amide, MS (M + H) 444.4, MS ( MH) 442.5.
b) Die für Beispiel 9a benötigte rac. 1- (5-Methoxy~2- methyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure wurde analog Beispiel 3b) jedoch unter Verwendung von 5~Methoxy-2- methyl-anilin anstelle von Benzylamin hergestellt.b) The rac required for Example 9a. 1- (5-methoxy ~ 2-methyl-phenyl) -5-oxo-pyrrolidine-3-carboxylic acid was prepared analogously to Example 3b) but using 5 ~ methoxy-2-methyl-aniline instead of benzylamine.
Beispiel 10 (R1 ist orpholino-ethyl)Example 10 (R 1 is orpholino-ethyl)
a) Analog Beispiel 1 wurden aus rac. 1- (2-Morpholin-4-yl- ethyl) -5-oxo-pyrrolidin-3-carbonsäure unter Verwendung der nachstehenden Amine folgende Produkte hergestellt: al) aus 2-Aminofluoren das rac. 1- (2-Morpholin-4-yl-ethyl) - 5-oxo-pyrrolidin-3-carbonsäure- (9H-fluoren-2-yl) -amid, MS(M+H) 406.4, MS (M-H) 404.5.a) Analogously to Example 1, rac. 1- (2-Morpholin-4-yl-ethyl) -5-oxo-pyrrolidin-3-carboxylic acid using the following amines: al) from 2-aminofluorene the rac. 1- (2-Morpholin-4-yl-ethyl) - 5-oxopyrrolidin-3-carboxylic acid (9H-fluoren-2-yl) amide, MS (M + H) 406.4, MS (MH) 404.5.
a2) aus N- (4-Aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidin das rac. 1- (2-Morpholin-4-yl-ethyl) -5-oxo-pyrrolidin-3- carbonsäure- { 4- [ ( 4 , 6-dimethyl-pyrimidin-2-yl ) -ethyl-amino] - phenyl} -amid, MS (M+H) 467.3, MS (M-H) 4465.5.a2) from N- (4-aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidine the rac. 1- (2-Morpholin-4-yl-ethyl) -5-oxo-pyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] - phenyl} - amide, MS (M + H) 467.3, MS (MH) 4465.5.
a3) aus 3-Amino-9-ethylcarbazol das rac. 1- (2-Morpholin-4- yl-ethyl) -5-oxo-pyrrolidin-3-carbonsäure- (9-ethyl-9H- carbazol-3-yl)-amid, MS (M+H) 435.5, MS (M-H) 433.3.a3) from 3-amino-9-ethylcarbazole the rac. 1- (2-Morpholin-4-yl-ethyl) -5-oxo-pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide, MS (M + H) 435.5, MS ( MH) 433.3.
b) Die für Beispiel 10a benötigte rac. 1- (5-Methoxy-2- methyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure wurde analog Beispiel 3b) jedoch unter Verwendung von 4- (2-Aminoethyl) - morpholin anstelle von Benzylamin hergestellt:b) The rac required for Example 10a. 1- (5-Methoxy-2-methyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid was prepared analogously to Example 3b), but using 4- (2-aminoethyl) morpholine instead of benzylamine:
Beispiel 11 (R1 ist Thien-2-yl-ethyl)Example 11 (R 1 is thien-2-yl-ethyl)
a) Analog Beispiel 1 wurden aus rac. 5-Oxo-l- (2-thiophen-2- yl-ethyl) -pyrrolidin-3-carbonsäure unter Verwendung der nachstehenden Amine folgende Produkte hergestellt:a) Analogously to Example 1, rac. 5-Oxo-l- (2-thiophene-2-yl-ethyl) -pyrrolidine-3-carboxylic acid using the amines below produced the following products:
al) aus N- (4-Aminophenyl) -4, 6-dimethyl-2-pyrimidinamin das rac. 5-Oxo-l- (2-thiophen-2-yl-ethyl) -pyrrolidin-3- carbonsäure- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) -phenyl] - amid, MS (M+H) 436.3, MS (M-H) 434.5.al) from N- (4-aminophenyl) -4, 6-dimethyl-2-pyrimidinamine the rac. 5-oxo-1- (2-thiophene-2-yl-ethyl) -pyrrolidin-3-carboxylic acid- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) -phenyl] amide, MS (M + H) 436.3, MS (MH) 434.5.
a2) aus N- (4-Aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidin das rac. 5-Oxo-l- (2-thiophen-2-yl-ethyl) -pyrrolidin-3- carbonsäure-{4- [ (4, 6-dimethyl-pyrimidin-2-yl) -methyl- amino] -phenyl} -amid, MS (M+H) 450.3, MS (M-H) 448.4. a3) aus N- (4-Aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidin das rac. 5-Oxo-l- (2-thiophen-2-yl-ethyl) -pyrrolidin-3- carbonsäure-{4- [ (4, 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] - phenyl}-amid, MS (M+H) 464.5, MS (M-H) 462.5.a2) from N- (4-aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidine the rac. 5-oxo-1- (2-thiophene-2-yl-ethyl) -pyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) -methylamino] -phenyl} - amide, MS (M + H) 450.3, MS (MH) 448.4. a3) from N- (4-aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidine the rac. 5-oxo-1- (2-thiophene-2-yl-ethyl) -pyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] - phenyl} - amide, MS (M + H) 464.5, MS (MH) 462.5.
a4) aus N-Phenyl-1, 4-phenylendiamin das rac. 5-Oxo-l- (2- thiophen-2-yl-ethyl) -pyrrolidin-3-carbonsäure- (4- phenylamino-phenyl)-amid, MS (M+H) 406.2, MS (M-H) 404.4.a4) from N-phenyl-1,4-phenylenediamine the rac. 5-oxo-1- (2-thiophene-2-yl-ethyl) -pyrrolidin-3-carboxylic acid- (4-phenylamino-phenyl) -amide, MS (M + H) 406.2, MS (M-H) 404.4.
a5) aus 3-Amino-9-ethylcarbazol das rac. 5-Oxo-l- (2- thiophen-2-yl-ethyl) -pyrrolidin-3-carbonsäure- (9-ethyl-9H- carbazol-3-yl)-amid, MS (M+H) 432.2, MS (M-H) 430.2.a5) from 3-amino-9-ethylcarbazole the rac. 5-oxo-1- (2-thiophene-2-yl-ethyl) -pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide, MS (M + H) 432.2, MS ( MH) 430.2.
b) Die für Beispiel 11a benötigte rac. 5-Oxo-l- (2-thiophen- 2-yl-ethyl) -pyrrolidin-3-carbonsäure wurde analog Beispiel 3b) jedoch unter Verwendung von 2-Thiophen-ethylamine anstelle von Benzylamin hergestellt.b) The rac required for Example 11a. 5-Oxo-1- (2-thiophene-2-yl-ethyl) -pyrrolidine-3-carboxylic acid was prepared analogously to Example 3b) but using 2-thiophene-ethylamine instead of benzylamine.
Beispiel 12 (R1 ist 2-Pyridin-2-yl-ethyl)Example 12 (R 1 is 2-pyridin-2-yl-ethyl)
a) Analog Beispiel 1 wurden aus rac. 5-Oxo-l- (2-pyridin-2- yl-ethyl) -pyrrolidin-3-carbonsäure unter Verwendung der nachstehenden Amine folgende Produkte hergestellt:a) Analogously to Example 1, rac. 5-Oxo-1- (2-pyridin-2-yl-ethyl) -pyrrolidin-3-carboxylic acid using the amines below produced the following products:
al) aus N- (4-Aminophenyl) -4 , 6-dimethyl-2-pyrimidinamin das rac. 5-Oxo-l- (2-pyridin-2-yl-ethyl) -pyrrolidin-3- carbonsäure- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) -phenyl] - amid, MS (M+H) 431.3, MS (M-H) 429.5.al) from N- (4-aminophenyl) -4, 6-dimethyl-2-pyrimidinamine the rac. 5-oxo-1- (2-pyridin-2-yl-ethyl) -pyrrolidin-3-carboxylic acid- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) phenyl] amide, MS (M + H) 431.3, MS (MH) 429.5.
a2) aus N- (4-Aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidin das rac. 5-Oxo-l- (2-pyridin-2-yl-ethyl) -pyrrolidin-3- carbonsäure-{4- [ (4, 6-dimethyl-pyrimidin-2-yl) -methyl- amino] -phenyl} -amid, MS (M+H) 445.3, MS (M-H) 443.5. a3) aus N- (4-Aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidin das rac. 5-Oxo-l- (2-pyridin-2-yl-ethyl) -pyrrolidin-3- carbonsäure- { 4- [ ( 4 , 6-dimethyl-pyrimidin-2-yl ) -ethyl-amino] - phenyl}-amid, MS (M+H) 459.3, MS (M-H) 457.5.a2) from N- (4-aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidine the rac. 5-oxo-1- (2-pyridin-2-yl-ethyl) -pyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) -methylamino] -phenyl} - amide, MS (M + H) 445.3, MS (MH) 443.5. a3) from N- (4-aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidine the rac. 5-oxo-1- (2-pyridin-2-yl-ethyl) -pyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] - phenyl} - amide, MS (M + H) 459.3, MS (MH) 457.5.
a4) aus N-Phenyl-1, 4-phenylendiamin das rac. 5-Oxo-l-(2- pyridin-2-yl-ethyl) -pyrrolidin-3-carbonsäure- (4- phenylamino-phenyl)-amid, MS (M+H) 401.3, MS (M-H) 399.5.a4) from N-phenyl-1,4-phenylenediamine the rac. 5-oxo-1- (2-pyridin-2-yl-ethyl) -pyrrolidin-3-carboxylic acid- (4-phenylamino-phenyl) -amide, MS (M + H) 401.3, MS (M-H) 399.5.
a5) aus 3-Amino-9-ethylcarbazole das rac. 5-Oxo-l-(2- pyridin-2-yl-ethyl) -pyrrolidin-3-carbonsäure- (9-ethyl-9H- carbazol-3-yl)-amid, MS (M+H) 427.5, MS (M-H) 425.4.a5) from 3-amino-9-ethylcarbazole the rac. 5-oxo-1- (2-pyridin-2-yl-ethyl) -pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide, MS (M + H) 427.5, MS ( MH) 425.4.
b) Die für Beispiel 12a benötigte rac. 5-Oxo-l- (2-pyridin- 2-yl-ethyl) -pyrrolidin-3-carbonsäure wurde analog Beispiel 3b) jedoch unter Verwendung von 2- (2-Aminoethyl) -pyridin anstelle von Benzylamin hergestellt.b) The rac required for Example 12a. 5-Oxo-1- (2-pyridin-2-yl-ethyl) -pyrrolidin-3-carboxylic acid was prepared analogously to Example 3b) but using 2- (2-aminoethyl) -pyridine instead of benzylamine.
Beispiel 13 (R1 ist p-Tolyl)Example 13 (R 1 is p-tolyl)
a) Analog Beispiel 1 wurden aus rac. 5-Oxo-l-p-tolyl- pyrrolidin-3-carbonsäure unter Verwendung der nachstehenden Amine folgende Produkte hergestellt:a) Analogously to Example 1, rac. 5-Oxo-l-p-tolyl-pyrrolidine-3-carboxylic acid using the amines below produced the following products:
al) aus N- (4-Aminophenyl) -4, 6-dimethyl-2-pyrimidinamin das rac . 5-Oxo-l-p-tolyl-pyrrolidin-3-carbonsäure- [4- ( 4 , 6- dimethyl-pyrimidin-2-ylamino) -phenyl] -amid, MS (M+H) 416.4, MS (M-H) 414.5.al) from N- (4-aminophenyl) -4, 6-dimethyl-2-pyrimidinamine the rac. 5-oxo-l-p-tolyl-pyrrolidine-3-carboxylic acid- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) phenyl] amide, MS (M + H) 416.4, MS (M-H) 414.5.
a2) aus N- (4-Aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidin das rac. 5-Oxo-l-p-tolyl-pyrrolidin-3-carbonsäure-{4- [ (4 , 6- dimethyl-pyrimidin-2-yl) -methyl-amino] -phenyl} -amid, MS(M+H) 430.4, MS (M-H) 428.4. a3) aus N- (4-Aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidin das rac. 5-Oxo-l-p-tolyl-pyrrolidin-3-carbonsäure- {4- [ (4 , 6- dimethyl-pyrimidin-2-yl) -ethyl-amino] -phenyl } -amid, MS (M+H) 444.3, MS(M-H) 442.5.a2) from N- (4-aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidine the rac. 5-oxo-l-tolyl-pyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) methylamino] phenyl} amide, MS (M + H) 430.4, MS (MH) 428.4. a3) from N- (4-aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidine the rac. 5-oxo-l-tolyl-pyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] -phenyl} -amide, MS (M + H) 444.3, MS (MH) 442.5.
a4) aus N-Phenyl-1, 4-phenylendiamin das rac. 5-Oxo-l-p- tolyl-pyrrolidin-3-carbonsäure- (4-phenylamino-phenyl) -amid, MS(M+H) 386.3, MS (M-H) 384.4.a4) from N-phenyl-1,4-phenylenediamine the rac. 5-oxo-l-p-tolyl-pyrrolidine-3-carboxylic acid- (4-phenylamino-phenyl) -amide, MS (M + H) 386.3, MS (M-H) 384.4.
a5) aus 3-Amino-9-ethylcarbazol das rac. 5-Oxo-l-p-tolyl- pyrrolidin-3-carbonsäure- (9-ethyl-9H-carbazol-3-yl) -amid, MS (M+H) 412.1, MS (M-H) 410.3.a5) from 3-amino-9-ethylcarbazole the rac. 5-oxo-l-p-tolyl-pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide, MS (M + H) 412.1, MS (M-H) 410.3.
b) Die für Beispiel 13a benötigte rac. 5-Oxo-l-p-tolyl- pyrrolidin-3-carbonsäure wurde analog Beispiel 3b) jedoch unter Verwendung von p-Toluidine anstelle von Benzylamin hergestellt .b) The rac required for Example 13a. 5-Oxo-l-p-tolyl-pyrrolidine-3-carboxylic acid was prepared analogously to Example 3b) but using p-toluidine instead of benzylamine.
Beispiel 14 (R1 ist m-Methoxy-phenyl)Example 14 (R 1 is m-methoxy-phenyl)
a) Analog Beispiel 1 wurden aus rac. 1- (3-Methoxy-phenyl-5- oxo-pyrrolidin-3-carbonsäure unter Verwendung der nachstehenden Amine folgende Produkte hergestellt:a) Analogously to Example 1, rac. 1- (3-Methoxy-phenyl-5-oxopyrrolidine-3-carboxylic acid using the following amines produced the following products:
al) aus N- (4-Aminophenyl) -4, 6-dimethyl-2-pyrimidinamin das rac. 1- (3-Methoxy-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) -phenyl] -amid, MS (M+H) 432.2, MS(M-H) 430.5.al) from N- (4-aminophenyl) -4, 6-dimethyl-2-pyrimidinamine the rac. 1- (3-methoxy-phenyl) -5-oxo-pyrrolidin-3-carboxylic acid- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) phenyl] amide, MS (M + H) 432.2, MS (MH) 430.5.
a2) aus N- (4-Aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidin das rac. 1- (3-Methoxy-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- { 4- [ ( 4 , 6-dimethyl-pyrimidin-2-yl ) -methyl- amino] -phenyl}-amid, MS (M+H) 446.4, MS (M-H) 444.5. a3) aus N- (4-Aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidin das rac. 1- (3-Methoxy-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- { 4- [ (4 , 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] - phenyl} -amid, MS (M+H) 460.3, MS (M-H) 458.5.a2) from N- (4-aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidine the rac. 1- (3-methoxyphenyl) -5-oxopyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethylpyrimidin-2-yl) methylamino] phenyl} amide, MS ( M + H) 446.4, MS (MH) 444.5. a3) from N- (4-aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidine the rac. 1- (3-methoxyphenyl) -5-oxopyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethylpyrimidin-2-yl) ethylamino] phenyl} amide, MS ( M + H) 460.3, MS (MH) 458.5.
a4) aus N-Phenyl-1, 4-phenylendiamin das rac. 1- (3-Methoxy- phenyl) -5-oxo-pyrrolidin-3-carbonsäure- (4-phenylaminophenyl) -amid, MS (M+H) 402.2, MS (M-H) 400.4.a4) from N-phenyl-1,4-phenylenediamine the rac. 1- (3-methoxyphenyl) -5-oxopyrrolidine-3-carboxylic acid- (4-phenylaminophenyl) amide, MS (M + H) 402.2, MS (M-H) 400.4.
a5) aus 3-Amino-9-ethylcarbazol das rac. 1- (3-Methoxy- phenyl) -5-oxo-pyrrolidin-3-carbonsäure- (9-ethyl-9H- carbazol-3-yl)-amid, MS (M+H) 428.2, MS (M-H) 426.3.a5) from 3-amino-9-ethylcarbazole the rac. 1- (3-methoxyphenyl) -5-oxopyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide, MS (M + H) 428.2, MS (M-H) 426.3.
b) Die für Beispiel 14a benötigte rac. 1- (3-Methoxy-phenyl- 5-oxo-pyrrolidin-3-carbonsäure wurde analog Beispiel 3b) jedoch unter Verwendung von m-Anisidin anstelle von Benzylamin hergestellt.b) The rac required for Example 14a. 1- (3-methoxy-phenyl-5-oxopyrrolidine-3-carboxylic acid was prepared analogously to Example 3b) but using m-anisidine instead of benzylamine.
Beispiel 15 (R1 ist Cycloheptyl)Example 15 (R 1 is cycloheptyl)
a) Analog Beispiel 1 wurden aus rac. l-Cycloheptyl-5-oxo- pyrrolidin-3-carbonsäure unter Verwendung der nachstehenden Amine folgende Produkte hergestellt :a) Analogously to Example 1, rac. l-Cycloheptyl-5-oxo-pyrrolidine-3-carboxylic acid produced the following products using the following amines:
al) aus N- (4-Aminophenyl) -4, 6-dimethyl-2-pyrimidinamin das rac. l-Cycloheptyl-5-oxo-pyrrolidin-3-carbonsäure- [4- (4, 6- dimethyl-pyrimidin-2-ylamino) -phenyl] -amid, MS (M+H) 422.5, MS (M-H) 420.5.al) from N- (4-aminophenyl) -4, 6-dimethyl-2-pyrimidinamine the rac. 1-Cycloheptyl-5-oxopyrrolidine-3-carboxylic acid- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) phenyl] amide, MS (M + H) 422.5, MS (M-H) 420.5.
a2) aus N- (4-Aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidin das rac. l-Cycloheptyl-5-oxo-pyrrolidin-3-carbonsäure- { 4- [ (4, 6-dimethyl-pyrimidin-2-yl) -methyl-amino] -phenyl} -amid, MS (M+H) 436.6, MS (M-H) 434.0. a3) aus N- (4-Aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidin das rac. l-Cycloheptyl-5-oxo-pyrrolidin-3-carbonsäure-{4- [ (4, 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] -phenyl} -amid, MS(M+H) 450.6, MS (M-H) 448.6.a2) from N- (4-aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidine the rac. l-Cycloheptyl-5-oxopyrrolidine-3-carboxylic acid- {4- [(4, 6-dimethylpyrimidin-2-yl) methylamino] phenyl} amide, MS (M + H) 436.6, MS (MH) 434.0. a3) from N- (4-aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidine the rac. l-Cycloheptyl-5-oxopyrrolidine-3-carboxylic acid- {4- [(4, 6-dimethylpyrimidin-2-yl) ethylamino] phenyl} amide, MS (M + H) 450.6, MS (MH) 448.6.
a4) aus N-Phenyl-1, 4-phenylendiamin das rac. 1-Cycloheptyl- 5-oxo-pyrrolidin-3-carbonsäure- (4-phenylamino-phenyl) -amid, MS(M+H) 392.4, MS (M-H) 390.5.a4) from N-phenyl-1,4-phenylenediamine the rac. 1-Cycloheptyl-5-oxopyrrolidine-3-carboxylic acid- (4-phenylamino-phenyl) -amide, MS (M + H) 392.4, MS (M-H) 390.5.
a5) aus 3-Amino-9-ethylcarbazol das rac. l-Cycloheptyl-5- oxo-pyrrolidin-3-carbonsäure- (9-ethyl-9H-carbazol-3-yl) - amid, MS (M+H) 418.5, MS (M-H) 426.3.a5) from 3-amino-9-ethylcarbazole the rac. l-Cycloheptyl-5-oxopyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) amide, MS (M + H) 418.5, MS (M-H) 426.3.
b) Die für Beispiel 15a benötigte rac. l-Cycloheptyl-5-oxo- pyrrolidin-3-carbonsäure wurde analog Beispiel 3b) jedoch unter Verwendung von Cycloheptylamin anstelle von Benzylamin hergestellt; MS (M+H) 226.1, MS (M-H) 224.1.b) The rac required for Example 15a. l-Cycloheptyl-5-oxopyrrolidine-3-carboxylic acid was prepared analogously to Example 3b), but using cycloheptylamine instead of benzylamine; MS (M + H) 226.1, MS (M-H) 224.1.
Beispiel 16 (R1 ist Naphthalin-1-ylmethyl)Example 16 (R 1 is naphthalin-1-ylmethyl)
a) Analog Beispiel 1 wurden aus rac. 1-Naphthalin-l- ylmethyl-5-oxo-pyrrolidin-3-carbonsäure unter Verwendung der nachstehenden Amine folgende Produkte hergestellt:a) Analogously to Example 1, rac. 1-Naphthalin-l-ylmethyl-5-oxo-pyrrolidin-3-carboxylic acid using the amines below produced the following products:
al) aus N- (4-Aminophenyl) -4, 6-dimethyl-2-pyrimidinamin das rac . l-Naphthalin-l-ylmethyl-5-oxo-pyrrolidin-3- carbonsäure- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) -phenyl] - amid, MS (M+H) 466.3, MS (M-H) 464.3.al) from N- (4-aminophenyl) -4, 6-dimethyl-2-pyrimidinamine the rac. l-Naphthalin-l-ylmethyl-5-oxo-pyrrolidin-3-carboxylic acid- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) phenyl] amide, MS (M + H) 466.3, MS ( MH) 464.3.
a2) aus N- (4-Aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidin das rac. l-Naphthalin-l-ylmethyl-5-oxo-pyrrolidin-3- carbonsäure-{4- [ (4, 6-dimethyl-pyrimidin-2-yl) -methyl- amino] -phenyl} -amid, MS(M+H) 480.4, MS (M-H) 478.5. a3) aus N- (4-Aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidin das rac. l-Naphthalin-l-ylmethyl-5-oxo-pyrrolidin-3- carbonsäure-{4- [ (4, 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] - phenyl} -amid, MS (M+H) 494.4, MS (M-H) 492.5.a2) from N- (4-aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidine the rac. l-Naphthalin-l-ylmethyl-5-oxopyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) methylamino] phenyl} amide, MS (M + H) 480.4, MS (MH) 478.5. a3) from N- (4-aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidine the rac. l-Naphthalin-l-ylmethyl-5-oxopyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) ethylamino] phenyl} amide, MS (M + H) 494.4, MS (MH) 492.5.
b) Die für Beispiel 16a benötigte rac. 1-Naphthalin-l- ylmethyl-5-oxo-pyrrolidin-3-carbonsäure wurde analog Beispiel 3b) jedoch unter Verwendung von 1- Naphthylmethylamin anstelle von Benzylamin hergestellt; MS (M+H) 270.1, MS (M-H) 268.1.b) The rac required for Example 16a. 1-Naphthalin-l-ylmethyl-5-oxo-pyrrolidin-3-carboxylic acid was prepared analogously to Example 3b) but using 1-naphthylmethylamine instead of benzylamine; MS (M + H) 270.1, MS (M-H) 268.1.
Beispiel 18 (R1 ist 2-Hydroxy-2-phenyl-ethyl)Example 18 (R 1 is 2-hydroxy-2-phenyl-ethyl)
a) Analog Beispiel 1 wurden aus rac. 1- (2-Hydroxy-2-phenyl- ethyl) -5-oxo-pyrrolidin-3-carbonsäure unter Verwendung der nachstehenden Amine folgende Produkte hergestellt:a) Analogously to Example 1, rac. 1- (2-Hydroxy-2-phenyl-ethyl) -5-oxo-pyrrolidine-3-carboxylic acid using the amines below produced the following products:
al) aus N- (4-Aminophenyl) -4, 6-dimethyl-2-pyrimidinamin das rac. 1- (2-Hydroxy-2-phenyl-ethyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) -phenyl] - amid, MS (M+H) 446.4, MS (M-H) 444.5.al) from N- (4-aminophenyl) -4, 6-dimethyl-2-pyrimidinamine the rac. 1- (2-Hydroxy-2-phenyl-ethyl) -5-oxo-pyrrolidin-3-carboxylic acid- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) phenyl] amide, MS (M + H) 446.4, MS (MH) 444.5.
a2) aus N- (4-Aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidin das rac. 1- (2-Hydroxy-2-phenyl-ethyl) -5-oxo-pyrrolidin~3- carbonsäure-{4- [ (4, 6-dimethyl-pyrimidin-2-yl) -methyl- amino] -phenyl} -amid, MS (M+H) 460.6, MS (M-H) 458.5.a2) from N- (4-aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidine the rac. 1- (2-Hydroxy-2-phenyl-ethyl) -5-oxo-pyrrolidine ~ 3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) methylamino] phenyl} - amide, MS (M + H) 460.6, MS (MH) 458.5.
a3) aus N- (4-Aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidin das rac. 1- (2-Hydroxy-2-phenyl-ethyl) -5-oxo-pyrrolidin-3- carbonsäure-{4- [ (4, 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] - phenyl}-amid, MS (M+H) 475.6, MS (M-H) 472.5. a4) aus N-Phenyl-1, 4-phenylendiamin das rac. 1- (2-Hydroxy- 2-phenyl-ethyl) -5-oxo-pyrrolidin-3-carbonsäure- (4- phenylamino-phenyl)-amid, MS (M+H) 416.3, MS (M-H) 414.5.a3) from N- (4-aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidine the rac. 1- (2-Hydroxy-2-phenyl-ethyl) -5-oxo-pyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) ethylamino] - phenyl} - amide, MS (M + H) 475.6, MS (MH) 472.5. a4) from N-phenyl-1,4-phenylenediamine the rac. 1- (2-Hydroxy-2-phenyl-ethyl) -5-oxo-pyrrolidine-3-carboxylic acid- (4-phenylamino-phenyl) -amide, MS (M + H) 416.3, MS (MH) 414.5.
a5) aus 3-Amino-9-ethylcarbazol das rac. 1- (2-Hydroxy-2- phenyl-ethyl) -5-oxo-pyrrolidin-3-carbonsäure- (9-ethyl-9H- carbazol-3-yl)-amid, MS (M+H) 442.6, MS (M-H) 440.3.a5) from 3-amino-9-ethylcarbazole the rac. 1- (2-Hydroxy-2-phenyl-ethyl) -5-oxo-pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide, MS (M + H) 442.6, MS ( MH) 440.3.
b) Die für Beispiel 18a benötigte rac. 1- (2-Hydroxy-2- phenyl-ethyl) -5-oxo-pyrrolidin-3-carbonsäure wurde analog Beispiel 3b) jedoch unter Verwendung von 2-Hydroxy-2- phenyl-ethylamin anstelle von Benzylamin hergestellt; MS(M+H) 250.1, MS(M-H) 248.1.b) The rac required for Example 18a. 1- (2-Hydroxy-2-phenyl-ethyl) -5-oxopyrrolidine-3-carboxylic acid was prepared analogously to Example 3b) but using 2-hydroxy-2-phenyl-ethylamine instead of benzylamine; MS (M + H) 250.1, MS (M-H) 248.1.
Beispiel 18 (R1 ist m-Tolyl)Example 18 (R 1 is m-tolyl)
a) Analog Beispiel 1 wurden aus rac. 5-Oxo-l-m-tolyl- pyrrolidine-3-carbonsäure unter Verwendung der nachstehenden Amine folgende Produkte hergestellt:a) Analogously to Example 1, rac. 5-Oxo-l-m-tolyl-pyrrolidine-3-carboxylic acid using the amines below produced the following products:
al) aus N- (4-Aminophenyl) -4, 6-dimethyl-2-pyrimidinamin das rac. 5-Oxo-l-m-tolyl-pyrrolidin-3-carbonsäure- [4- (4, 6- dimethyl-pyrimidin-2-ylamino) -phenyl] -amid, MS (M+H) 416.3, MS (M-H) 414.5.al) from N- (4-aminophenyl) -4, 6-dimethyl-2-pyrimidinamine the rac. 5-oxo-l-m-tolyl-pyrrolidine-3-carboxylic acid- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) phenyl] amide, MS (M + H) 416.3, MS (M-H) 414.5.
a2) aus N- (4-Aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidin das rac. 5-Oxo-l-m-tolyl-pyrrolidin-3-carbonsäure- { 4- [ (4 , 6- dimethyl-pyrimidin-2-yl) -methyl-amino] -phenyl} -amid, MS (M+H) 430, MS (M-H) 428.5.a2) from N- (4-aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidine the rac. 5-oxo-im-tolyl-pyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) methylamino] phenyl} amide, MS (M + H) 430, MS (MH) 428.5.
a3) aus N- (4-Aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidin das rac. 5-Oxo-l-m-tolyl-pyrrolidin-3-carbonsäure- { 4- [ (4, 6- dimethyl-pyrimidin-2-yl) -ethyl-amino] -phenyl} -amid, MS (M+H) 444.6, MS(M-H) 442.5. a4) aus N-Phenyl-1, 4-phenylendiamin das rac. 5-Oxo-l-m- tolyl-pyrrolidin-3-carbonsäure- (4-phenylamino-phenyl) -amid, MS(M+H) 386.3, MS (M-H) 384.5.a3) from N- (4-aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidine the rac. 5-oxo-im-tolyl-pyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] -phenyl} -amide, MS (M + H) 444.6, MS (MH) 442.5. a4) from N-phenyl-1,4-phenylenediamine the rac. 5-oxo-im-tolyl-pyrrolidine-3-carboxylic acid- (4-phenylaminophenyl) amide, MS (M + H) 386.3, MS (MH) 384.5.
b) Die für Beispiel 18a benötigte rac. 5-Oxo-l-aι-tolyl- pyrrolidin-3-carbonsäure wurde analog Beispiel 3b) jedoch unter Verwendung von m-Toluidin anstelle von Benzylamin hergestellt; MS (M+H) 220.1, MS (M-H) 218.1.b) The rac required for Example 18a. 5-oxo-1-a-tolyl-pyrrolidine-3-carboxylic acid was prepared analogously to Example 3b) but using m-toluidine instead of benzylamine; MS (M + H) 220.1, MS (M-H) 218.1.
Beispiel 19 (R1 ist 2-Thienyl-methyl)Example 19 (R 1 is 2-thienyl-methyl)
a) Analog Beispiel 1 wurde aus rac. 5-Oxo-l-(2- thienylmethyl)pyrrolidine-3-carbonsäure (Maybridge) unter Verwendung des nachstehenden Amins folgendes Produkt hergestellt:a) Analogous to Example 1, rac. 5-Oxo-l- (2-thienylmethyl) pyrrolidine-3-carboxylic acid (Maybridge) using the amine below produced the following product:
al) aus 3-Amino-9-ethylcarbazol das rac. 5-Oxo-l-thiophen- 2-ylmethyl-pyrrolidin-3-carbonsäure- (9-ethyl-9H-carbazol-3- yl)-amid, MS (M+H) 418.1, MS (M-H) 416.2.al) from 3-amino-9-ethylcarbazol the rac. 5-oxo-l-thiophene-2-ylmethyl-pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide, MS (M + H) 418.1, MS (M-H) 416.2.
Beispiel 20 (R1 ist 2-Furyl-methyl)Example 20 (R 1 is 2-furyl-methyl)
a) Analog Beispiel 1 wurden aus rac. 1- (2-Furylmethyl) -5- oxopyrrolidin-3-carbonsäure (Maybridge) unter Verwendung der nachstehenden Amine folgende Produkte hergestellt:a) Analogously to Example 1, rac. 1- (2-Furylmethyl) -5-oxopyrrolidine-3-carboxylic acid (Maybridge) using the amines below produced the following products:
al) aus N- (4-Aminophenyl) -4, 6-dimethyl-2-pyrimidinamin das rac . l-Furan-2-ylmethyl-5-oxo-pyrrolidin-3-carbonsäure- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) -phenyl] -amid, MS (M+H) 406.3, MS(M-H) 404.5.al) from N- (4-aminophenyl) -4, 6-dimethyl-2-pyrimidinamine the rac. l-furan-2-ylmethyl-5-oxo-pyrrolidin-3-carboxylic acid- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) phenyl] amide, MS (M + H) 406.3, MS ( MH) 404.5.
a2) aus N- (4-Aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidin das rac. l-Furan-2-ylmethyl-5-oxo-pyrrolidin-3-carbonsäure- { 4- [ ( 4 , 6-dimethyl-pyrimidin-2-yl) -methyl-amino] -phenyl} - amid, MS (M+H) 420.5, MS (M-H) -418.5.a2) from N- (4-aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidine the rac. l-furan-2-ylmethyl-5-oxo-pyrrolidine-3-carboxylic acid {4- [(4, 6-dimethyl-pyrimidin-2-yl) methylamino] phenyl} amide, MS (M + H) 420.5, MS (MH) -418.5.
a3) aus N- (4-Aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidin das rac. l-Furan-2-ylmethyl-5-oxo-pyrrolidin-3-carbonsäure- {4- [ (4, 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] -phenyl}- a id, MS (M+H) 434.6, MS (M-H) 432.5.a3) from N- (4-aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidine the rac. l-furan-2-ylmethyl-5-oxopyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethylpyrimidin-2-yl) ethylamino] phenyl} - a id, MS (M + H) 434.6, MS (MH) 432.5.
a4) aus N-Phenyl-1, 4-phenylendiamin das rac. l-Furan-2- ylmethyl-5-oxo-pyrrolidin-3-carbonbsäure- (4-phenylaminophenyl) -amid, MS (M+H) 376.3, MS (M-H) 474.5.a4) from N-phenyl-1,4-phenylenediamine the rac. l-furan-2-ylmethyl-5-oxopyrrolidin-3-carboxylic acid- (4-phenylaminophenyl) -amide, MS (M + H) 376.3, MS (M-H) 474.5.
a5) aus 3-Amino-9-ethylcarbazol das rac. l-Furan-2- ylmethyl-5-oxo-pyrrolidin-3-carbonsäure- ( 9-ethyl-9H- carbazol-3-yl)-amid, MS (M+H) 401.9, MS (M-H) 400.1.a5) from 3-amino-9-ethylcarbazole the rac. l-furan-2-ylmethyl-5-oxopyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide, MS (M + H) 401.9, MS (M-H) 400.1.
Beispiel 21 (R1 ist p-Chlorbenzyl)Example 21 (R 1 is p-chlorobenzyl)
a) Analog Beispiel 1 wurde aus rac. 1- (4-Chlorobenzyl) -5- oxopyrrolidine-3-carbonsäure (Maybridge) unter Verwendung des nachstehenden Amins folgendes Produkt hergestellt:a) Analogous to Example 1, rac. 1- (4-Chlorobenzyl) -5-oxopyrrolidine-3-carboxylic acid (Maybridge) using the amine below produced the following product:
al) aus 3-Amino-9-ethylcarbazol das rac. l-(4-Chlor- benzyl) -5-oxo-pyrrolidin-3-carbonsäure- (9-ethyl-9H- carbazol-3-yl)-amid, MS (M+H) 446.1, MS (M-H) 444.1.al) from 3-amino-9-ethylcarbazol the rac. 1- (4-chloro-benzyl) -5-oxopyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide, MS (M + H) 446.1, MS (M-H) 444.1.
Beispiel 22 (R1 ist p-Dimethylamino-phenyl)Example 22 (R 1 is p-dimethylamino-phenyl)
a) Analog Beispiel 1 kann rac. 1- (4-Dimethylamino-phenyl) 5- oxo-pyrrolidin-3-carbonsäure unter Verwendung geeigneter Amine in Produkte der Formel I übergeführt werden.a) Analog to Example 1, rac. 1- (4-Dimethylamino-phenyl) 5-oxopyrrolidine-3-carboxylic acid can be converted into products of the formula I using suitable amines.
al) aus N- (4-Aminophenyl) -4, 6-dimethyl-2-pyrimidinamin das rac. 1- (4-Dimethylamino-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) - phenyl] amid, MS (M+H) 445.2, MS (M-H) 443.5al) from N- (4-aminophenyl) -4, 6-dimethyl-2-pyrimidinamine the rac. 1- (4-dimethylamino-phenyl) -5-oxo-pyrrolidin-3- carboxylic acid- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) phenyl] amide, MS (M + H) 445.2, MS (MH) 443.5
a2) aus N- (4-Aminophenyl) -N-methyl-4 , 6-dimethyl-2- pyrimidinamin das rac. 1- (4-Dimethylamino-phenyl) -5-oxo- pyrrolidin-3-carbonsäure-{4- [ (4 , 6-dimethyl-pyrimidin-2-yl) - methyl-amino] -phenyl} -amid, MS (M+H) 459.4, MS (M-H) 457.5a2) from N- (4-aminophenyl) -N-methyl-4, 6-dimethyl-2-pyrimidinamine the rac. 1- (4-Dimethylamino-phenyl) -5-oxopyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) methylamino] phenyl} amide, MS ( M + H) 459.4, MS (MH) 457.5
b) Die für Beispiel 22a benötigte rac. 1- (4-Dimethylamino- phenyl) -5-oxo-pyrrolidin-3-carbonsäure wurde analog Beispiel 3b) jedoch unter Verwendung von N,N-Dimethyl-p- phenylendiamin anstelle von Benzylamin hergestellt; MS (M+H) 249.1, MS(M-H) 247.1.b) The rac required for Example 22a. 1- (4-Dimethylaminophenyl) -5-oxopyrrolidine-3-carboxylic acid was prepared analogously to Example 3b) but using N, N-dimethyl-p-phenylenediamine instead of benzylamine; MS (M + H) 249.1, MS (M-H) 247.1.
Beispiel 23 (R1 ist 2- Pyrrolidin-1-yl-ethyl)Example 23 (R 1 is 2-pyrrolidin-1-yl-ethyl)
a) Analog Beispiel 1 wurde aus rac. 5-Oxo-l- (2-pyrrolidin- 1-yl-ethyl) -pyrrolidin-3-carbonsäure unter Verwendung des nachstehenden Amins folgendes Produkt hergestellt:a) Analogous to Example 1, rac. 5-Oxo-1- (2-pyrrolidin-1-yl-ethyl) -pyrrolidine-3-carboxylic acid using the amine below produced the following product:
al) aus N- (4-Aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidin das rac. 5-Oxo-l- (2-pyrrolidin-l-yl-ethyl) -pyrrolidin-3- carbonsäure-{4- [ (4, 6~dimethyl-pyrimidin-2-yl) -ethyl-amino] - phenyl} -amid, MS (M+H) 451.2, MS (M-H) 449.3.al) from N- (4-aminophenyl) -N-ethyl-4, 6-dimethyl-2-pyrimidine the rac. 5-oxo-1- (2-pyrrolidin-1-yl-ethyl) -pyrrolidin-3-carboxylic acid- {4- [(4, 6 ~ dimethyl-pyrimidin-2-yl) -ethyl-amino] -phenyl} - amide, MS (M + H) 451.2, MS (MH) 449.3.
b) Die für Beispiel 23a benötigte rac. 5-Oxo-l-(2- pyrrolidin-1-yl-ethyl) -pyrrolidin-3-carbonsäure wurde analog Beispiel 3b) jedoch unter Verwendung von l-(2- Aminoethyl) -pyrrolidin anstelle von Benzylamin hergestellt; MS (M+H) 227.1, MS (M-H) 225.1.b) The rac required for Example 23a. 5-Oxo-l- (2-pyrrolidin-1-yl-ethyl) -pyrrolidin-3-carboxylic acid was prepared analogously to Example 3b) but using l- (2-aminoethyl) -pyrrolidine instead of benzylamine; MS (M + H) 227.1, MS (M-H) 225.1.
Beispiel 24 (R1 ist 1-Methyl- pyrolidin-2-yl-ethyl) a) Analog Beispiel 1 wurde aus rac. 1- [2- (1-Methyl- pyrrolidin-2-yl) -ethyl] -5-oxo-pyrrolidin-3-carbonsäure unter Verwendung des nachstehenden Amins folgendes Produkt hergestellt:Example 24 (R 1 is 1-methyl-pyrolidin-2-yl-ethyl) a) Analogous to Example 1, rac. 1- [2- (1-Methyl-pyrrolidin-2-yl) -ethyl] -5-oxo-pyrrolidin-3-carboxylic acid produced the following product using the following amine:
al) aus 3-Amino-9-ethylcarbazol das rac. 1- [2- (1-Methyl- pyrrolidin-2-yl) -ethyl] -5-oxo-pyrrolidin-3-carbonsäure- (9- ethyl-9H-carbazol-3-yl)-amid, MS (M+H) 433.4, MS (M-H) 431.3.al) from 3-amino-9-ethylcarbazol the rac. 1- [2- (1-Methylpyrrolidin-2-yl) ethyl] -5-oxopyrrolidin-3-carboxylic acid (9-ethyl-9H-carbazol-3-yl) amide, MS (M + H) 433.4, MS (MH) 431.3.
b) Die für Beispiel 24a benötigte rac. 1- [2- (1-Methyl- pyrrolidin-2-yl) -ethyl] -5-oxo-pyrrolidin-3-carbonsäure wurde analog Beispiel 3b) jedoch unter Verwendung von 2- (2- Aminoethyl) -1-methylpyrrolidin anstelle von Benzylamin hergestellt; MS (M+H) 241.2, MS (M-H) 239.1.b) The rac required for Example 24a. 1- [2- (1-Methylpyrrolidin-2-yl) ethyl] -5-oxo-pyrrolidin-3-carboxylic acid was analogous to Example 3b) but using 2- (2-aminoethyl) -1-methylpyrrolidine instead made by benzylamine; MS (M + H) 241.2, MS (M-H) 239.1.
Beispiel 25 (R1 ist 4-Isopropyl-phenyl)Example 25 (R 1 is 4-isopropylphenyl)
a) Analog Beispiel 1 wurde aus rac.1- (4-Isopropyl-phenyl) - 5-oxo-pyrrolidin-3-carbonsäure unter Verwendung des nachstehenden Amins folgendes Produkt hergestellt:a) Analogously to Example 1, the following product was prepared from rac.1- (4-isopropyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid using the following amine:
al) aus 3-Amino-9-ethylcarbazol das rac. 1- (4-Isopropyl- phenyl) -5-oxo-pyrrolidin-3-carbonsäure- (9-ethyl-9H- carbazol-3-yl)-amid, MS (M+H) 440.4, MS (M-H) 438.3.al) from 3-amino-9-ethylcarbazol the rac. 1- (4-isopropylphenyl) -5-oxopyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide, MS (M + H) 440.4, MS (M-H) 438.3.
b) Die für Beispiel 25a benötigte rac. 1- (4-Isopropyl- phenyl) -5-oxo-pyrrolidin-3-carbonsäure wurde analog Beispiel 3b) jedoch unter Verwendung von 4-Isopropylanilin anstelle von Benzylamin hergestellt; MS (M+H) 248.1, MS (M-H) 246.1.b) The rac required for Example 25a. 1- (4-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid was prepared analogously to Example 3b), but using 4-isopropylaniline instead of benzylamine; MS (M + H) 248.1, MS (M-H) 246.1.
Beispiel 26 (R1 ist 3,5-Bis-trifluormethyl-phenyl) a) Analog Beispiel 1 wurde aus rac.1- (3, 5-Bis- trifluoromethyl-phenyl ) -5-oxo-pyrrolidin-3-carbonsäure unter Verwendung des nachstehenden Amins folgendes Produkt hergestellt :Example 26 (R 1 is 3,5-bis-trifluoromethyl-phenyl) a) Analogously to Example 1, the following product was prepared from rac.1- (3,5-bis-trifluoromethyl-phenyl) -5-oxo-pyrrolidine-3-carboxylic acid using the following amine:
al) aus 3-Amino-9-ethylcarbazol das rac. l-(3,5-Bis- trifluoromethyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- (9- ethyl-9H-carbazol-3-yl)-amid, MS (M+H) 534.4.al) from 3-amino-9-ethylcarbazol the rac. 1- (3,5-bis-trifluoromethyl-phenyl) -5-oxopyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide, MS (M + H) 534.4.
b) Die für Beispiel 26a benötigte rac. l-(3,5-Bis- trifluoromethyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure wurde analog Beispiel 3b) jedoch unter Verwendung von 3,5- Bis- (trifluoromethyl) -anilin anstelle von Benzylamin hergestellt .b) The rac required for Example 26a. 1- (3,5-Bis-trifluoromethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid was prepared analogously to Example 3b) but using 3,5-bis (trifluoromethyl) aniline instead of benzylamine.
Beispiel 27 (R1 ist 3-Fluor-phenyl)Example 27 (R 1 is 3-fluoro-phenyl)
a) Analog Beispiel 1 wurde aus rac. 1- (3-Fluoro-phenyl) -5- oxo-pyrrolidin-3-carbonsäure unter Verwendung des nachstehenden Amins folgendes Produkt hergestellt:a) Analogous to Example 1, rac. 1- (3-Fluoro-phenyl) -5-oxo-pyrrolidine-3-carboxylic acid using the amine below produced the following product:
al) aus 3-Amino-9-ethylcarbazol das rac. l-(3-Fluor- phenyl) -5-oxo-pyrrolidin-3-carbonsäure- (9-ethyl-9H- carbazol-3-yl)-amid, MS (M+H) 416.1, MS (M-H) 414.2.al) from 3-amino-9-ethylcarbazol the rac. 1- (3-fluorophenyl) -5-oxopyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide, MS (M + H) 416.1, MS (M-H) 414.2.
b) Die für Beispiel 27a benötigte rac. 1- (3-Fluor-phenyl) - 5-oxo-pyrrolidin-3-carbonsäure wurde analog Beispiel 3b) jedoch unter Verwendung von 3-Fluoranilin anstelle von Benzylamin hergestellt; MS (M+H) 224.2, MS (M-H) 222.1.b) The rac required for Example 27a. 1- (3-fluorophenyl) -5-oxopyrrolidine-3-carboxylic acid was prepared analogously to Example 3b), but using 3-fluoroaniline instead of benzylamine; MS (M + H) 224.2, MS (M-H) 222.1.
Beispiel 28 (R1 ist 2-Chlor-benzyl) a) Analog Beispiel 1 wurde aus rac. 1- (2-Chlor-benzyl) -5- oxo-pyrrolidin-3-carbonsäure unter Verwendung des nachstehenden Amins folgendes Produkt hergestellt:Example 28 (R 1 is 2-chloro-benzyl) a) Analogous to Example 1, rac. 1- (2-chloro-benzyl) -5-oxo-pyrrolidine-3-carboxylic acid using the following amine produced the following product:
al) aus 3-Amino-9-ethylcarbazol das rac. l-(2-Chlor- benzyl) -5-oxo-pyrrolidin-3-carbonsäure- (9-ethyl-9H- carbazol-3-yl)-amid, MS (M+H) 446.2, MS (M-H) 444.2.al) from 3-amino-9-ethylcarbazol the rac. 1- (2-chloro-benzyl) -5-oxopyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide, MS (M + H) 446.2, MS (M-H) 444.2.
b) Die für Beispiel 28a benötigte rac. 1- (2-Chlor-benzyl) - 5-oxo-pyrrolidin-3-carbonsäure wurde analog Beispiel 3b) jedoch unter Verwendung von 2-Chlor-benzylamin anstelle von Benzylamin hergestellt; MS (M+H) 254.1, MS (M-H) 252.1.b) The rac required for Example 28a. 1- (2-chloro-benzyl) -5-oxopyrrolidine-3-carboxylic acid was prepared analogously to Example 3b) but using 2-chloro-benzylamine instead of benzylamine; MS (M + H) 254.1, MS (M-H) 252.1.
Beispiel 29 (Ξnantiomerenreine Verbindungen)Example 29 (anti-pure compounds)
Das gemäss Beispiel 7a5) hergestellte rac. 1- (2-Isopropyl- phenyl) -5-oxo-pyrrolidin-3-carbonsäure- (9-ethyl-9H- carbazol-3-yl) -amid kann mittels HPLC auf einer LichroCART (R,R) Whelk-01 Säule mit einem Lösungsmittel-Gradienten (n- Hexan+0.5% Essigsäure/Isopropanol+0.5% Essigsäure) in die beiden EnantiomerenThe rac produced according to Example 7a5). 1- (2-isopropylphenyl) -5-oxo-pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide can be obtained by HPLC on a LichroCART (R, R) Whelk-01 column with a solvent gradient (n-hexane + 0.5% acetic acid / isopropanol + 0.5% acetic acid) into the two enantiomers
(a) (R) -1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- (9-ethyl-9H-carbazol-3-yl) -amid; und(a) (R) -1- (2-isopropylphenyl) -5-oxo-pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; and
(b) (S) -1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- (9-ethyl-9H-carbazol-3-yl) -amid aufgetrennt werden.(b) (S) -1- (2-isopropylphenyl) -5-oxopyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide are separated.
Beispiel 30 (Ξnantiomerenreine Verbindungen)Example 30 (antinantiomerically pure compounds)
Analog zu Beispiel 29 können die nachstehenden racemischen Verbindungen in die entsprechenden Enantiomeren aufgetrennt werden: rac. 5-Oxo-l- (2-pyridin-2-yl-ethyl) -pyrrolidin-3- carbonsäure- (9-ethyl-9H-carbazol-3-yl) -amid; rac. 1- (2-Hydroxy-2-phenyl-ethyl) -5-oxo-pyrrolidin-3- carbonsäure- ( 9-ethyl-9H-carbazol-3-yl) -amid; rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- (4-diethylamino-phenyl) -amid; rac. 5-Oxo-l- (2-thiophen-2-yl-ethyl) -pyrrolidin-3- carbonsäure- (9-ethyl-9H-carbazol-3-yl) -amid; rac. 1- (4-Chlor-benzyl) -5-oxo-pyrrolidin-3-carbonsäure- (9- ethyl-9H-carbazol-3-yl) -amid; rac . 5-Oxo-l-thiophen-2-ylmethyl-pyrrolidin-3-carbonsäure- (9-ethyl-9H-carbazol-3-yl) -amid; rac. l-Furan-2-ylmethyl-5-oxo-pyrrolidin-3-carbonsäure- (9- ethyl-9H-carbazol-3-yl) -amid; rac. 1- (5-Methoxy-2-methyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- ( 9-ethyl-9H-carbazol-3-yl) -amid; rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (ethyl-isopropyl-a ino) -phenyl] -amid; rac. 5-Oxo-l-phenethyl-pyrrolidin-3-carbonsäure- (9-ethyl- 9H-carbazol-3-yl) -amid; rac. [ (4-{ [1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonyl] -amino} -phenyl) -phenyl-amino] -essigsäure- ethylester; rac. l-Cycloheptyl-5-oxo-pyrrolidin-3-carbonsäure- (9-ethyl- 9H-carbazol-3-yl) -amid; rac. 1- (5-Methoxy-2-methyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure-{4- [ (4, 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] - phenyl} -amid; rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- {4- [ethyl- (2-hydroxy-ethyl) -amino] -phenyl }- amid; rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (ethyl-phenyl-amino) -phenyl] -amid; rac. 1- (3-Methoxy-phenyl) -5-oxo-pyrrolidin-3-carbonsäure-Analogously to Example 29, the following racemic compounds can be separated into the corresponding enantiomers: rac. 5-oxo-1- (2-pyridin-2-yl-ethyl) -pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; rac. 1- (2-hydroxy-2-phenyl-ethyl) -5-oxo-pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; rac. 1- (2,5-dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid- (4-diethylamino-phenyl) -amide; rac. 5-oxo-1- (2-thiophene-2-yl-ethyl) -pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; rac. 1- (4-chloro-benzyl) -5-oxopyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; rac. 5-oxo-l-thiophene-2-ylmethyl-pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; rac. l-furan-2-ylmethyl-5-oxopyrrolidin-3-carboxylic acid (9-ethyl-9H-carbazol-3-yl) amide; rac. 1- (5-methoxy-2-methylphenyl) -5-oxopyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; rac. 1- (2, 5-dimethylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (ethyl-isopropyl-a ino) phenyl] amide; rac. 5-oxo-l-phenethyl-pyrrolidin-3-carboxylic acid (9-ethyl-9H-carbazol-3-yl) amide; rac. [(4- {[1- (2,5-dimethylphenyl) -5-oxopyrrolidine-3-carbonyl] amino} phenyl) phenylamino] acetic acid, ethyl ester; rac. l-cycloheptyl-5-oxopyrrolidin-3-carboxylic acid (9-ethyl-9H-carbazol-3-yl) amide; rac. 1- (5-methoxy-2-methylphenyl) -5-oxopyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethylpyrimidin-2-yl) ethylamino] phenyl} - amide; rac. 1- (2, 5-Dimethylphenyl) -5-oxopyrrolidine-3-carboxylic acid {4- [ethyl- (2-hydroxyethyl) amino] phenyl} amide; rac. 1- (2, 5-dimethylphenyl) -5-oxopyrrolidine-3-carboxylic acid [4- (ethylphenylamino) phenyl] amide; rac. 1- (3-methoxy-phenyl) -5-oxo-pyrrolidine-3-carboxylic acid -
(9-ethyl-9H-carbazol-3-yl) -amid; rac. 1- (2-Chlor-benzyl) -5-oxo-pyrrolidin-3-carbonsäure- (9- ethyl-9H-carbazol-3-yl) -amid; rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) -phenyl] - amid; rac . 1- (2 , 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure-{4- [ (4, 6-dimethyl-pyrimidin-2-yl) -methyl- amino] -phenyl } -amid; rac. 5-Oxo-l-phenyl-pyrrolidin-3-carbonsäure- (9-ethyl-9H- carbazol-3-yl) -amid; rac . 5-Oxo-l-p-tolyl-pyrrolidin-3-carbonsäure- { 4- [ (4 , 6- dimethyl-pyrimidin-2-yl) -methyl-amino] -phenyl } -amid; rac . 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [ 4- (isopropyl-phenyl-amino) -phenyl] -amid; rac . 1- ( 2-Isopropyl -phenyl ) -5-oxo-pyrrolidin-3-carbonsäure-(9-ethyl-9H-carbazol-3-yl) amide; rac. 1- (2-chloro-benzyl) -5-oxo-pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; rac. 1- (2, 5-Dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) phenyl] amide; rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) methylamino] phenyl} amide; rac. 5-oxo-l-phenyl-pyrrolidin-3-carboxylic acid (9-ethyl-9H-carbazol-3-yl) amide; rac. 5-oxo-l-p-tolyl-pyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) methylamino] phenyl} amide; rac. 1- (2,5-dimethylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (isopropylphenylamino) phenyl] amide; rac. 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid
[ 4- (ethyl-phenyl-amino) -phenyl] -amid; rac . 5-Oxo-l- (2-pyridin-2-yl-ethyl) -pyrrolidin-3- carbonsäure- { 4- [ ( 4 , 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] - phenyl } -amid; rac. 1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure-[4- (ethylphenylamino) phenyl] amide; rac. 5-oxo-1- (2-pyridin-2-yl-ethyl) -pyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] - phenyl} - amide; rac. 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid
[4- (4, 6-dimethyl-pyrimidin-2-ylamino) -phenyl] -amid; rac. 1- (5-Methoxy-2-methyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) -phenyl] - amid; rac . 1- (2 , 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (methyl-phenyl-amino) -phenyl] -amid; rac . 1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- [4- (methyl-phenyl-amino) -phenyl] -amid; rac. 1- (4-Isopropyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure-[4- (4, 6-dimethyl-pyrimidin-2-ylamino) phenyl] amide; rac. 1- (5-methoxy-2-methylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (4,6-dimethylpyrimidin-2-ylamino) phenyl] amide; rac. 1- (2, 5-dimethylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (methylphenylamino) phenyl] amide; rac. 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (methylphenylamino) phenyl] amide; rac. 1- (4-isopropyl-phenyl) -5-oxo-pyrrolidine-3-carboxylic acid -
(9-ethyl-9H-carbazol-3-yl) -amid; rac . 1- (3-Fluor-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- ( 9- ethyl-9H-carbazol-3-yl) -amid; rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- (4-phenylamino-phenyl) -amid; rac. l-Indan-2-yl-5-oxo-pyrrolidin-3-carbonsäure- [4- (4, 6- dimethyl-pyrimidin-2-ylamino) -phenyl] -amid; rac. 1- (5-Methoxy-2-methyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (ethyl-phenyl-amino) -phenyl] -amid; rac. 1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure-(9-ethyl-9H-carbazol-3-yl) amide; rac. 1- (3-fluorophenyl) -5-oxopyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; rac. 1- (2,5-dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid (4-phenylamino-phenyl) -amide; rac. l-indan-2-yl-5-oxopyrrolidin-3-carboxylic acid- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) phenyl] amide; rac. 1- (5-methoxy-2-methylphenyl) -5-oxopyrrolidine-3-carboxylic acid [4- (ethylphenylamino) phenyl] amide; rac. 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid
{4- [ (4, 6-dimethyl-pyrimidin-2-yl) -methyl-amino] -phenyl }- amid; rac. l-Benzyl-5-oxo-pyrrolidin-3-carbonsäure- (9-ethyl-9H- carbazol-3-yl) -amid; rac. 5-Oxo-1-p-tolyl-pyrrolidin-3-carbonsäure- [4- ( , 6- dimethyl-pyrimidin-2-ylamino) -phenyl] -amid; rac. l-Indan-2-yl-5-oxo-pyrrolidin-3-carbonsäure- (9-ethyl- 9H-carbazol-3-yl) -amid; rac. 1- (2-Hydroxy-2-phenyl-ethyl) -5-oxo-pyrrolidin-3- carbonsäure-{ 4- [ (4, 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] - phenyl } -amid; rac. 1- (2, 5-Dimethyl-phenyl) -5~oxo-pyrrolidin-3- carbonsäure-biphenyl-4-ylamid; rac. 1- (5-Methoxy-2-methyl-phenyl) -5~oxo-pyrrolidin-3- carbonsäure- [4- (cyclopropylmethyl-phenyl-amino) -phenyl] - amid; rac. 1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- [4- (isopropyl-phenyl-amino) -phenyl] -amid; rac. 1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure-{4- [(4, 6-dimethyl-pyrimidin-2-yl) methylamino] phenyl} amide; rac. l-benzyl-5-oxopyrrolidin-3-carboxylic acid (9-ethyl-9H-carbazol-3-yl) amide; rac. 5-oxo-1-p-tolyl-pyrrolidine-3-carboxylic acid- [4- (, 6-dimethyl-pyrimidin-2-ylamino) phenyl] amide; rac. l-indan-2-yl-5-oxopyrrolidin-3-carboxylic acid (9-ethyl-9H-carbazol-3-yl) amide; rac. 1- (2-Hydroxy-2-phenyl-ethyl) -5-oxo-pyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) ethylamino] - phenyl} - amide; rac. 1- (2, 5-Dimethylphenyl) -5 ~ oxo-pyrrolidin-3-carboxylic acid biphenyl-4-ylamide; rac. 1- (5-methoxy-2-methylphenyl) -5 ~ oxopyrrolidine-3-carboxylic acid- [4- (cyclopropylmethylphenylamino) phenyl] amide; rac. 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (isopropylphenylamino) phenyl] amide; rac. 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid
(4-phenylamino-phenyl) -amid; rac. 1- (5-Methoxy-2-methyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- { 4- [ ( 4 , 6-dimethyl-pyrimidin-2-yl) -methyl- amino] -phenyl } -amid; rac . 1- (3-Methoxy-phenyl) -5-oxo-pyrrolidin-3-carbonsäure-(4-phenylaminophenyl) amide; rac. 1- (5-methoxy-2-methylphenyl) -5-oxo-pyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) methylamino] phenyl} - amide; rac. 1- (3-methoxy-phenyl) -5-oxo-pyrrolidine-3-carboxylic acid -
{ 4- [ ( 4 , 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] -phenyl } - amid; rac . 5-Oxo-l-m-tolyl-pyrrolidin-3-carbonsäure- { 4- [ ( 4 , 6- dimethyl-pyrimidin-2-yl) -methyl-amino] -phenyl } -amid; rac . 1- (2 , 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (cyclopropylmethyl-phenyl-amino) -phenyl] - amid; rac . 1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure-{4- [(4, 6-dimethyl-pyrimidin-2-yl) ethylamino] phenyl} amide; rac. 5-oxo-im-tolyl-pyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) methylamino] phenyl} amide; rac. 1- (2, 5-Dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (cyclopropylmethylphenylamino) phenyl] amide; rac. 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid
{ 4- [ ( 4 , 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] -phenyl } - amid; rac. [ (4- { [1- (5-Methoxy-2-methyl-phenyl) -5-oxo-pyrrolidin- 3-carbonyl] -amino} -phenyl) -phenyl-amino] -essigsäure-ethyl ester; rac . 1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- [4- (cyclopropylmethyl-phenyl-amino) -phenyl] -amid; und rac . l-Indan-2-yl-5-oxo-pyrrolidin-3-carbonsäure- [4- (ethyl- phenyl-amino) -phenyl] -amid.{4- [(4, 6-dimethyl-pyrimidin-2-yl) ethylamino] phenyl} amide; rac. [(4- {[1- (5-Methoxy-2-methylphenyl) -5-oxopyrrolidine-3-carbonyl] amino} phenyl) phenylamino] acetic acid ethyl ester; rac. 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (cyclopropylmethylphenylamino) phenyl] amide; and rac. l-Indan-2-yl-5-oxopyrrolidin-3-carboxylic acid [4- (ethylphenylamino) phenyl] amide.
Beispiel 31 (R1 ist 2 ,5-Dimethylphenyl)Example 31 (R 1 is 2, 5-dimethylphenyl)
a) Zu einer Lösung von 50 mg rac. 1- (2, 5-Dimethyl-phenyl) - 5-oxo-pyrrolidin-3-carbonsäure- (4-amino-phenyl) -amid in 0.5 ml Methylenchloride wurden 29 μl Hünigsbase und 1 Equivalent des nachstehenden Säurechlorids zugegeben. Das Reaktionsgemisch wurde über Nacht bei Raumtemperatur gerührt, eingedampft und der Rückstand mit Essigester- Ethanol (8:2) an Kieselgel chromatographiert . Die eingedampften Produktfraktionen ergaben so jeweils ca 30 mg Produkt. Mit diesem Verfahren wurden folgende Verbindungen hergestellt:a) To a solution of 50 mg rac. 1- (2, 5-Dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid- (4-aminophenyl) -amide in 0.5 ml of methylene chloride, 29 μl of Hunigs base and 1 equivalent of the following acid chloride were added. The reaction mixture was stirred at room temperature overnight, evaporated and the residue was chromatographed on silica gel using ethyl acetate-ethanol (8: 2). The evaporated product fractions each gave about 30 mg of product. The following connections were made with this method:
al) mit Acetylchlorid das rac. 1- (2, 5-Dimethyl-phenyl) -5- oxo-pyrrolidin-3-carbonsäure- (4-acetylamino-phenyl) -amid, MS (M+H) 366.3, MS (M-H) 364.4. a2) mit Isovalerylchlorid das rac. 1- (2, 5-Dimethyl-phenyl) - 5-oxo-pyrrolidin-3-carbonsäure- [4- (3-methyl-butyrylamino) - phenyl] -amid, MS (M+H) 408.3, MS (M-H) 406.4.al) with acetyl chloride, the rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidine-3-carboxylic acid- (4-acetylamino-phenyl) -amide, MS (M + H) 366.3, MS (MH) 364.4. a2) with isovaleryl chloride, the rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidine-3-carboxylic acid- [4- (3-methyl-butyrylamino) - phenyl] -amide, MS (M + H) 408.3, MS (MH) 406.4.
a3) mit Cyclopropylcarbonylchlorid das rac. l-(2,5- Dimethyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- [4- (cyclopropancarbonyl-amino) -phenyl] -amid, MS (M+H) 392.3, MS (M-H) 390.4.a3) with cyclopropylcarbonyl chloride the rac. 1- (2,5-dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (cyclopropanecarbonylamino) phenyl] amide, MS (M + H) 392.3, MS (M-H) 390.4.
a4) mit Benzoylchlorid das rac. 1- (2, 5-Dimethyl-phenyl) -5- oxo-pyrrolidin-3-carbonsäure- (4-benzoylamino-phenyl) -amid, MS (M+H) 428.3, MS (M-H) 426.4.a4) with benzoyl chloride the rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidine-3-carboxylic acid- (4-benzoylamino-phenyl) -amide, MS (M + H) 428.3, MS (M-H) 426.4.
a5) mit Phenylessigsäurechlorid das rac. 1- (2, 5-Dimethyl- phenyl) -5-oxo-pyrrolidin-3-carbonsäure- (4- phenylacetylamino-phenyl) -amid, MS (M+H) 442.4, MS (M-H) 440.5.a5) with phenylacetic acid chloride the rac. 1- (2, 5-Dimethylphenyl) -5-oxopyrrolidine-3-carboxylic acid (4-phenylacetylamino-phenyl) -amide, MS (M + H) 442.4, MS (M-H) 440.5.
a6) mit 2-Methoxybenzoylchlorid das rac. 1- (2, 5-Dimethyl- phenyl) -5-oxo-pyrrolidin-3-carbonsäure- [4- (2-methoxy- benzoylamino) -phenyl] -amid, MS (M+H) 458.2, MS (M-H) 456.5.a6) with 2-methoxybenzoyl chloride the rac. 1- (2, 5-Dimethylphenyl) -5-oxo-pyrrolidine-3-carboxylic acid- [4- (2-methoxybenzoylamino) phenyl] amide, MS (M + H) 458.2, MS (MH) 456.5.
a7) mit Piperonyloylchlorid das rac. 1- (2, 5-Dimethyl- phenyl) -5-oxo-pyrrolidin-3-carbonsäure- { 4- [ (benzo [1, 3] dioxole-5-carbonyl) -amino] -phenyl} -amid, MS (M+H) 472.3, MS (M-H) 470.5.a7) with piperonyloyl chloride, the rac. 1- (2, 5-Dimethylphenyl) -5-oxo-pyrrolidine-3-carboxylic acid- {4- [(benzo [1, 3] dioxole-5-carbonyl) amino] phenyl} amide, MS ( M + H) 472.3, MS (MH) 470.5.
a8) mit Pivaloylchlorid das rac. 1- (2, 5-Dimethyl-phenyl) -5- oxo-pyrrolidin-3-carbonsäure- [4- (2, 2-dimethyl- propionylamino) -phenyl] -amid, MS (M+H) 408.3, MS (M-H) 406.4. a9) mit 4-Methoxybenzoylchlorid das rac. 1- (2, 5-Dimethyl- phenyl) -5-oxo-pyrrolidin-3-carbonsäure- [4- (4-methoxy- benzoylamino) -phenyl] -amid, MS (M+H) 458.2, MS (M-H) 456.4.a8) with pivaloyl chloride, the rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidine-3-carboxylic acid- [4- (2, 2-dimethyl-propionylamino) -phenyl] -amide, MS (M + H) 408.3, MS ( MH) 406.4. a9) with 4-methoxybenzoyl chloride the rac. 1- (2, 5-Dimethylphenyl) -5-oxo-pyrrolidine-3-carboxylic acid- [4- (4-methoxybenzoylamino) phenyl] amide, MS (M + H) 458.2, MS (MH) 456.4.
alO) mit 3-Fluorobenzoylchlorid das rac. 1- (2, 5-Dimethyl- phenyl) -5-oxo-pyrrolidin-3-carbonsäure- [4- (3- fluorobenzoylamino) -phenyl] -amid, MS (M+H) 446.3, MS (M-H) 444.4.alO) with 3-fluorobenzoyl chloride the rac. 1- (2, 5-Dimethylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (3-fluorobenzoylamino) phenyl] amide, MS (M + H) 446.3, MS (M-H) 444.4.
all) mit 2-Furoylchlorid das rac. 1- (2, 5-Dimethyl-phenyl) - 5-oxo-pyrrolidin-3-carbonsäure-{4- [ (furan-2-carbonyl) - amino] -phenyl} -amid, MS (M+H) 418.4, MS (M-H) 416.4.all) with 2-furoyl chloride the rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidine-3-carboxylic acid- {4- [(furan-2-carbonyl) - amino] -phenyl} -amide, MS (M + H) 418.4, MS (MH) 416.4.
b) Das in Beispiel 31a) benötigte rac. 1- (2, 5-Dimethyl- phenyl) -5-oxo-pyrrolidin-3-carbonsäure- (4-amino-phenyl) - amid wurde wie folgt hergestellt:b) The rac required in Example 31a). 1- (2, 5-Dimethylphenyl) -5-oxopyrrolidine-3-carboxylic acid (4-aminophenyl) amide was prepared as follows:
bl) Zu einer Lösung von 2 g 1- (2, 5-Dimethyl-phenyl) -5-oxo- l-pyrrolidin-3-carbonsäure (Beispiel 4b) in 28mlbl) To a solution of 2 g of 1- (2, 5-dimethyl-phenyl) -5-oxo-l-pyrrolidine-3-carboxylic acid (Example 4b) in 28 ml
Methylenchlorid gab man nacheinander 1.18 g p-Nitroanilin,Methylene chloride was added in succession 1.18 g of p-nitroaniline,
1.95 g N- (3-Dimethylaminopropyl) -N' -ethylcarbodiimid- hydrochlorid (EDC HC1) , 2.22 ml Hünigsbase und 1.04 g 4-1.95 g of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDC HC1), 2.22 ml of Hunigs base and 1.04 g of 4-
(N,N-Dimethylamino) -pyridin. Das Reaktionsgemisch wurde 3 Stunden bei 40 °C gerührt, dann in Essigester aufgenommen und mit Wasser neutral gewaschen. Die organische Phase wurde eingedampft und man erhiellt so 2.5 g rac l-(2,5-(N, N-dimethylamino) pyridine. The reaction mixture was stirred at 40 ° C. for 3 hours, then taken up in ethyl acetate and washed neutral with water. The organic phase was evaporated and 2.5 g of rac l- (2.5-
Dimethyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- (4-nitro- phenyl)-amid, MS (M+H) 354.1, MS (M-H) 352.3.Dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid- (4-nitro-phenyl) -amide, MS (M + H) 354.1, MS (M-H) 352.3.
b2) Die nach Beispiel 31bl) erhaltenen 2.5 g rac. l-(2,5- Dimethyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- (4-nitro- phenyl)-amid wurden in 70 ml Methanol und 70 ml Methylenchlorid gelöst, mit 0.5 g Palladium/Kohle Katalysator versetzt und über Nacht bei Raumtemperatur hydriert. Nach Filtration des Reaktionsgemisches und Eindampfen des Filtrates erhielt man 2.3 g rac. l-(2,5~ Dimethyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- (4-amino- phenyl) -amid, MS (M+H) 324.3, MS (M-H) 322.4.b2) The 2.5 g of rac obtained in Example 31bl). 1- (2,5-Dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid (4-nitrophenyl) amide was dissolved in 70 ml of methanol and 70 ml of methylene chloride, with 0.5 g of palladium / carbon Catalyst added and hydrogenated overnight at room temperature. After filtering the reaction mixture and evaporating the filtrate, 2.3 g of rac were obtained. 1- (2,5 ~ dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid- (4-aminophenyl) -amide, MS (M + H) 324.3, MS (MH) 322.4.
Beispiel 32 (Enantiomerenreine Verbindungen)Example 32 (Enantiomerically Pure Compounds)
Analog zu Beispiel 29 können die nachstehenden racemischen Verbindungen in die entsprechenden Enantiomeren aufgetrennt werden:Analogously to Example 29, the following racemic compounds can be separated into the corresponding enantiomers:
rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- (4-acetylamino-phenyl) -amid;rac. 1- (2,5-dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid- (4-acetylamino-phenyl) -amide;
rac . 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (3-methyl-butyrylamino) -phenyl] -amid;rac. 1- (2, 5-Dimethylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (3-methylbutyrylamino) phenyl] amide;
rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (cyclopropanecarbonyl-amino) -phenyl] -amid;rac. 1- (2, 5-Dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (cyclopropanecarbonylamino) phenyl] amide;
rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- (4-benzoylamino-phenyl) -amid;rac. 1- (2,5-dimethylphenyl) -5-oxopyrrolidine-3-carboxylic acid (4-benzoylamino-phenyl) amide;
rac . 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- (4-phenylacetylamino-phenyl) -amid;rac. 1- (2,5-dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid (4-phenylacetylamino-phenyl) -amide;
rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (2-methoxy-benzoylamino) -phenyl] -amid;rac. 1- (2,5-dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (2-methoxy-benzoylamino) phenyl] amide;
rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure-{4- [ (benzo [1,3] dioxole-5-carbonyl) -amino] - phenyl } -amid; rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (2, 2-dimethyl-propionylamino) -phenyl] -amid;rac. 1- (2,5-dimethylphenyl) -5-oxopyrrolidine-3-carboxylic acid {4- [(benzo [1,3] dioxole-5-carbonyl) amino] phenyl} amide; rac. 1- (2,5-dimethylphenyl) -5-oxopyrrolidine-3-carboxylic acid [4- (2,2-dimethylpropionylamino) phenyl] amide;
rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (4-methoxy-benzoylamino) -phenyl] -amid;rac. 1- (2,5-dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (4-methoxy-benzoylamino) phenyl] amide;
rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (3-fluoro-benzoylamino) -phenyl] -amid;rac. 1- (2, 5-Dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (3-fluoro-benzoylamino) phenyl] amide;
rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- { 4- [ (furan-2-carbonyl) -amino] -phenyl } -amid;rac. 1- (2,5-dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid- {4- [(furan-2-carbonyl) amino] phenyl} amide;
rac. 1- (2-Morpholin-4-yl-ethyl) -5-oxo-pyrrolidin-3- carbonsäure- (9-ethyl-9H-carbazol-3-yl) -amid;rac. 1- (2-morpholin-4-yl-ethyl) -5-oxopyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide;
rac. 5-Oxo-l-p-tolyl-pyrrolidin-3-carbonsäure- (9~ethyl-9H- carbazol-3-yl) -amid; undrac. 5-oxo-l-p-tolyl-pyrrolidin-3-carboxylic acid- (9 ~ ethyl-9H-carbazol-3-yl) -amide; and
rac. 1- (2, 4-Dimethoxy-benzyl) -5-oxo-pyrrolidin-3- carbonsäure- (9-ethyl-9H-carbazol-3-yl) -amid.rac. 1- (2,4-Dimethoxy-benzyl) -5-oxo-pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide.
Beispiel 33 (Ξnantiomerenreine Verbindungen)Example 33 (antinantiomerically pure compounds)
Analog zu Beispiel 29 können die nachstehenden racemischen Verbindungen in die entsprechenden Enantiomeren aufgetrennt werden:Analogously to Example 29, the following racemic compounds can be separated into the corresponding enantiomers:
rac . 1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- [4- (isobutyl-phenyl-amino) phenyl] amid; rac. 1- (4-Dimethylamino-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (4, 6-dimethyl-pyrimidin-2- ylamino) phenyl] amid; und rac. 1- (4-Dimethylamino-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (4, 6-dimethyl-pyrimidin-2-yl)methyl- aminophenyl] amid.rac. 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (isobutylphenylamino) phenyl] amide; rac. 1- (4-Dimethylamino-phenyl) -5-oxo-pyrrolidine-3-carboxylic acid- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) phenyl] amide; and rac. 1- (4-Dimethylamino-phenyl) -5-oxo-pyrrolidin-3-carboxylic acid- [4- (4, 6-dimethyl-pyrimidin-2-yl) methylaminophenyl] amide.
Beispiel 34 (R1 ist 2 ,4-Dimethoxybenzyl)Example 34 (R 1 is 2, 4-dimethoxybenzyl)
a) Analog Beispiel 1 wurde aus rac. 1- (2, 4-Dimethoxy- benzyl) -5-oxo-pyrrolidin-3-carbonsäure unter Verwendung von 3-Amino-9-ethylcarbazol das rac. 1- (2, 4-Dimethoxy-benzyl) - 5-oxo-pyrrolidin-3-carbonsäure- (9-ethyl-9H-carbazol-3-yl) - amid hergestellt; MS (M+H) 472.4, MS (M-H) 470.2.a) Analogous to Example 1, rac. 1- (2, 4-Dimethoxy-benzyl) -5-oxo-pyrrolidine-3-carboxylic acid using 3-amino-9-ethylcarbazole the rac. 1- (2, 4-Dimethoxy-benzyl) - 5-oxo-pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) - amide; MS (M + H) 472.4, MS (M-H) 470.2.
b) Die für Beispiel 34a benötigte 1- (2, 4-Dimethoxy-benzyl) - 5-oxo-pyrrolidin-3-carbonsäure wurde analog Beispiel 3b) jedoch unter Verwendung von 2, 4-Dimethoxybenzylamin hergestellt; MS (M+H) 280.1, MS (M-H) 278.1.b) The 1- (2, 4-dimethoxy-benzyl) -5-oxopyrrolidine-3-carboxylic acid required for Example 34a was prepared analogously to Example 3b) but using 2, 4-dimethoxybenzylamine; MS (M + H) 280.1, MS (M-H) 278.1.
Beispiel AExample A
Eine Verbindung der Formel I kann man in an sich bekannter Weise als Wirkstoff zur Herstellung von Tabletten der folgenden Zusammensetzung verwenden:A compound of formula I can be used in a manner known per se as an active ingredient for the production of tablets of the following composition:
Pro TablettePer tablet
Wirkstoff 200 mgActive ingredient 200 mg
Mikrokristalline Cellulose 155 mgMicrocrystalline cellulose 155 mg
Maisstärke 25 mgCorn starch 25 mg
Talk 25 mgTalc 25 mg
Hydroxypropylmethylcellulose 20 mgHydroxypropyl methyl cellulose 20 mg
425 mg Beispiel B425 mg Example B
Eine Verbindung der Formel I kann man in an sich bekannter Weise als Wirkstoff zur Herstellung von Kapseln folgender Zusammensetzung verwenden:A compound of formula I can be used in a manner known per se as an active ingredient for the production of capsules of the following composition:
Pro TablettePer tablet
Wirkstoff 100 mgActive ingredient 100 mg
Maisstärke 20 mg Milchzucker 95 mgCorn starch 20 mg milk sugar 95 mg
Talk 4.5 mgTalc 4.5 mg
Magnesiumstearat 0.5 mgMagnesium stearate 0.5 mg
220.0 mg 220.0 mg

Claims

Patentansprüche claims
1. Pyrrolidoncarboxamide der Formel1. Pyrrolidone carboxamides of the formula
Figure imgf000070_0001
Figure imgf000070_0001
worinwherein
R1 im Phenylrest gegebenenfalls durch Alkyl, Alkoxy, Dialkylamino, Halogen oder Trifluormethyl mono- oder disubstituiertes Phenyl, Benzyl, Phenylethyl oder α- Hydroxyphenylethyl; Naphthyl oder Naphthylmethyl; Thienyl-, Furyl-, Pyridyl-, l-Alkylpyrrolidin-2-yl-, Pyrrolidino- oder Morpholino-alkyl; oder Cycloalkyl, welches gegebenenfalls einen ankondensierten Benzolring aufweisen kann;R 1 in the phenyl radical optionally mono- or disubstituted phenyl, benzyl, phenylethyl or α-hydroxyphenylethyl by alkyl, alkoxy, dialkylamino, halogen or trifluoromethyl; Naphthyl or naphthylmethyl; Thienyl, furyl, pyridyl, l-alkylpyrrolidin-2-yl, pyrrolidino or morpholino alkyl; or cycloalkyl, which may optionally have a fused-on benzene ring;
R2 einen Rest der FormelR 2 is a radical of the formula
Figure imgf000070_0002
Figure imgf000070_0002
(a) (b)(a) (b)
X -CH2-, -CO-, -0- oder -NR3-;X -CH 2 -, -CO-, -0- or -NR 3 -;
R3 Wasserstoff oder Alkyl;R 3 is hydrogen or alkyl;
R4 Wasserstoff oder Alkoxy;R 4 is hydrogen or alkoxy;
R5 Phenyl, Heteroalkyl, Aryloxy, Alkoxy, Alkanoyl oder -NR6R7; R6 Wasserstoff, Alkyl, Aralkyl, Cycloalkylalkyl oderR 5 is phenyl, heteroalkyl, aryloxy, alkoxy, alkanoyl or -NR 6 R 7 ; R 6 is hydrogen, alkyl, aralkyl, cycloalkylalkyl or
Alkoxycarbonylalkyl; und R7 Aryl, Heteroaryl, alkyl, Hydroxyalkyl oder Acyl bedeuten; pharmazeutisch verwendbare Säureadditionssalze von basischen Verbindungen der Formel I, pharmazeutisch verwendbare Salze von sauren Verbindungen der Formel I mit Basen, pharmazeutisch verwendbare Ester von Hydroxy- oder Carboxygruppen enthaltenden Verbindungen der Formel I sowie Hydrate oder Solvate davon.alkoxycarbonylalkyl; and R 7 represents aryl, heteroaryl, alkyl, hydroxyalkyl or acyl; pharmaceutically usable acid addition salts of basic compounds of formula I, pharmaceutically usable salts of acid compounds of formula I with bases, pharmaceutically usable esters of hydroxyl or carboxy group-containing compounds of formula I and hydrates or solvates thereof.
2. Verbindungen gemäss Anspruch 1, worin R1 Phenyl, 4-2. Compounds according to claim 1, wherein R 1 is phenyl, 4-
Tolyl, 2, 5-Dimethylphenyl, 2-Isopropylphenyl, 3-Tolyl, 2, 5-dimethylphenyl, 2-isopropylphenyl, 3-
Methoxyphenyl, 2-Methyl-5-methoxyphenyl, Benzyl, 2-Methoxyphenyl, 2-methyl-5-methoxyphenyl, benzyl, 2-
Phenylethyl, 2- (2-Pyridyl) ethyl, 2- (2-Thienyl) ethyl, 2- Indanyl oder 2-Morpholinoethyl bedeutet.Phenylethyl, 2- (2-pyridyl) ethyl, 2- (2-thienyl) ethyl, 2-indanyl or 2-morpholinoethyl means.
3. Verbindungen gemäss Anspruch 1, worin R1 Cycloheptyl, 2-Hydroxy-2-phenylethyl, 2-Thienylmethyl, 2-Furanylmethyl, 4-Chlorbenzyl, 3-Fluorphenyl, 2, 4-Dimethoxybenzyl oder 2- Chlorbenzyl bedeutet.3. Compounds according to claim 1, wherein R 1 is cycloheptyl, 2-hydroxy-2-phenylethyl, 2-thienylmethyl, 2-furanylmethyl, 4-chlorobenzyl, 3-fluorophenyl, 2, 4-dimethoxybenzyl or 2-chlorobenzyl.
4. Verbindungen gemäss Anspruch 1, worin R1 2-Naphthyl, Naphthalin-1-ylmethyl, 4-Dimethylaminophenyl, 2-Pyrrolidin- 1-ylethyl, l-Methylpyrrolidin-2-ylethyl, 4-Isopropylphenyl oder 3, 5-Bis-trifluormethylphenyl bedeutet.4. Compounds according to claim 1, wherein R 1 is 2-naphthyl, naphthalen-1-ylmethyl, 4-dimethylaminophenyl, 2-pyrrolidin-1-ylethyl, l-methylpyrrolidin-2-ylethyl, 4-isopropylphenyl or 3,5-bis trifluoromethylphenyl means.
5. Verbindungen gemäss Anspruch 1, worin R1 2,5- Dimethylphenyl, 2-Isopropylphenyl oder 2-Methyl-5- Methoxyphenyl bedeutet.5. Compounds according to claim 1, wherein R 1 is 2,5-dimethylphenyl, 2-isopropylphenyl or 2-methyl-5-methoxyphenyl.
6. Verbindungen gemäss einem der Ansprüche 1 bis 5, worin R2 Biphenyl-4-yl, 4-Methoxyphenyl, 4-Phenoxyphenyl, 4- Dimethylaminophenyl, 4-Diethylaminophenyl, 4- Phenylaminophenyl, 4- [N-Ethyl-N- (2- hydoxyethyl) amino] phenyl, 4- (N-Ethyl-N- isopropylamino) phenyl, 4-N- (4, 6-Dimethyl~2- pyrimidinyl) aminophenyl, 4- [N-Ethyl-N- (4 , 6-dimethyl-2- pyrimidinyl) amino] phenyl, 4- [N-Methyl-N- (4 , 6-dimethyl-2- pyrimidinyl) amino] phenyl, 4-Acetylphenyl, 9H-Flüoren-2-yl, 9-Oxo-9H-fluoren-2-yl oder 9-Ethylcarbazol-3-yl bedeutet.6. Compounds according to any one of claims 1 to 5, wherein R 2 biphenyl-4-yl, 4-methoxyphenyl, 4-phenoxyphenyl, 4-dimethylaminophenyl, 4-diethylaminophenyl, 4-phenylaminophenyl, 4- [N-ethyl-N- ( 2-hydoxyethyl) amino] phenyl, 4- (N-ethyl-N- isopropylamino) phenyl, 4-N- (4,6-dimethyl ~ 2-pyrimidinyl) aminophenyl, 4- [N-ethyl-N- (4,6-dimethyl-2-pyrimidinyl) amino] phenyl, 4- [N- Methyl-N- (4, 6-dimethyl-2-pyrimidinyl) amino] phenyl, 4-acetylphenyl, 9H-fluorene-2-yl, 9-oxo-9H-fluoren-2-yl or 9-ethylcarbazol-3-yl means.
7. Verbindungen gemäss einem der Ansprüche 1 bis 5, worin R2 4- (N-Ethoxycarbonylmethyl-N-phenyl-amino) -phenyl, 4- (N- Ethyl-N-phenyl-amino) -phenyl, 4- (N-Methyl-N-phenyl-amino- phenyl, 4- (N-Cyclopropylmethyl-N-phenyl-amino) -phenyl, 4-7. Compounds according to any one of claims 1 to 5, wherein R 2 4- (N-ethoxycarbonylmethyl-N-phenylamino) phenyl, 4- (N-ethyl-N-phenylamino) phenyl, 4- (N -Methyl-N-phenyl-amino-phenyl, 4- (N-cyclopropylmethyl-N-phenyl-amino) -phenyl, 4-
(N-Isobutyl-N-phenyl-amino) -phenyl, 4- (2-Methoxy- benzoylamino) -phenyl, 4- (2, 2-Dimethyl-propionylamino) - phenyl, 4- (3-Methyl-butyrylamino) -phenyl, 4-(N-isobutyl-N-phenylamino) phenyl, 4- (2-methoxybenzoylamino) phenyl, 4- (2, 2-dimethylpropionylamino) phenyl, 4- (3-methylbutyrylamino) - phenyl, 4-
(Cyclopropancarbonyl-amino) -phenyl, 4- (3-Fluoro- benzoylamino) -phenyl oder 4- [ (Furan-2-carbonyl) -amino] - phenyl bedeutet(Cyclopropanecarbonylamino) phenyl, 4- (3-fluorobenzoylamino) phenyl or 4- [(furan-2-carbonyl) amino] phenyl
8. Verbindungen gemäss einem der Ansprüche 1 bis 5, worin R2 Biphenyl-3-yl, 9H-Fluoren-l-yl, 2-Methoxydibenzofuran-3- yl, 4- (N-Isopropyl-N-phenylamino) phenyl, 4- (N-Benzyl-N- phenylamino) phenyl, 4-Acetylaminophenyl, 4-8. Compounds according to any one of claims 1 to 5, wherein R 2 biphenyl-3-yl, 9H-fluoren-l-yl, 2-methoxydibenzofuran-3-yl, 4- (N-isopropyl-N-phenylamino) phenyl, 4 - (N-Benzyl-N-phenylamino) phenyl, 4-acetylaminophenyl, 4-
Benzoylaminophenyl, 4-Phenylacetylaminophenyl, 4-Benzoylaminophenyl, 4-phenylacetylaminophenyl, 4-
[ (Benzo [1, 3] dioxol-5-carbonyl) amino] phenyl oder 4- (4-[(Benzo [1, 3] dioxol-5-carbonyl) amino] phenyl or 4- (4-
Methoxybenzoylamino) phenyl bedeutet .Methoxybenzoylamino) phenyl means.
9. Verbindungen gemäss einem der Ansprüche 1 bis 5, worin R2 9-Ethyl-9H-carbazol-3-yl, 4- [N-Ethyl-N- (4, 6, dimethyl-2- pyrimidinyl) amino] phenyl, 4- [N-Methyl-N- (4,6, dimethyl-2- pyri idinyl) amino] phenyl, 4- (4, 6, dimethyl-2- pyrimidinyl) amino] phenyl, 4-Phenylaminophenyl, 4- Diethylaminophenyl, 4- (N-Ethyl-N-isopropylamino) phenyl, 4- (N-Ethoxycarbonylmethyl-N-phenylamino) phenyl, 4- (N-Ethyl-N- phenylamino) phenyl, 4- (N-Methyl-N-phenylamino) phenyl oder 2, 4-Dimethoxybenzyl bedeutet. 9. Compounds according to any one of claims 1 to 5, wherein R 2 9-ethyl-9H-carbazol-3-yl, 4- [N-ethyl-N- (4, 6, dimethyl-2-pyrimidinyl) amino] phenyl, 4- [N-methyl-N- (4,6, dimethyl-2-pyridinyl) amino] phenyl, 4- (4, 6, dimethyl-2-pyrimidinyl) amino] phenyl, 4-phenylaminophenyl, 4-diethylaminophenyl, 4- (N-ethyl-N-isopropylamino) phenyl, 4- (N-ethoxycarbonylmethyl-N-phenylamino) phenyl, 4- (N-ethyl-N-phenylamino) phenyl, 4- (N-methyl-N-phenylamino) phenyl or 2, 4-dimethoxybenzyl means.
10. rac . 5-Oxo-l- ( 2-pyridin-2-yl-ethyl) -pyrrolidin-3- carbonsäure- (9-ethyl-9H-carbazol-3-yl) -amid; rac. 1- (2-Hydroxy-2-phenyl-ethyl) -5-oxo-pyrrolidin-3- carbonsäure- (9-ethyl-9H-carbazol-3-yl) -amid; rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin~3- carbonsäure- (4-diethylamino-phenyl) -amid; rac . 5-Oxo-l- (2-thiophen-2-yl-ethyl) -pyrrolidin-3- carbonsäure- (9-ethyl-9H-carbazol-3-yl) -amid; rac. 1- (4-Chlor-benzyl) -5-oxo-pyrrolidin-3-carbonsäure- (9- ethyl-9H-carbazol-3-yl) -amid; rac . 5-Oxo-l-thiophen-2-ylmethyl-pyrrolidin-3-carbonsäure-10. rac. 5-oxo-1- (2-pyridin-2-yl-ethyl) -pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; rac. 1- (2-hydroxy-2-phenyl-ethyl) -5-oxo-pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; rac. 1- (2,5-dimethylphenyl) -5-oxopyrrolidine ~ 3-carboxylic acid (4-diethylamino-phenyl) amide; rac. 5-oxo-1- (2-thiophene-2-yl-ethyl) -pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; rac. 1- (4-chloro-benzyl) -5-oxopyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; rac. 5-Oxo-l-thiophen-2-ylmethyl-pyrrolidine-3-carboxylic acid
(9-ethyl-9H-carbazol-3-yl) -amid; rac. l-Furan-2-ylmethyl-5-oxo-pyrrolidin-3-carbonsäure- (9- ethyl-9H-carbazol-3-yl) -amid; rac . 1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure-(9-ethyl-9H-carbazol-3-yl) amide; rac. l-furan-2-ylmethyl-5-oxopyrrolidin-3-carboxylic acid (9-ethyl-9H-carbazol-3-yl) amide; rac. 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid
(9-ethyl-9H-carbazol-3-yl) -amid, rac. 1- (5-Methoxy-2-methyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- ( 9-ethyl-9H-carbazol-3-yl) -amid; rac . 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [ 4- (ethyl-isopropyl-amino) -phenyl] -amid; rac . 5-Oxo-l-phenethyl-pyrrolidin-3-carbonsäure- ( 9-ethyl-(9-ethyl-9H-carbazol-3-yl) amide, rac. 1- (5-methoxy-2-methylphenyl) -5-oxopyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; rac. 1- (2, 5-Dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (ethyl-isopropylamino) phenyl] amide; rac. 5-oxo-l-phenethyl-pyrrolidine-3-carboxylic acid- (9-ethyl-
9H-carbazol-3-yl) -amid; rac. [ (4-{ [1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonyl] -amino} -phenyl) -phenyl-amino] -essigsäure- ethylester; rac. l-Cycloheptyl-5-oxo-pyrrolidin-3-carbonsäure- (9-ethyl-9H-carbazol-3-yl) amide; rac. [(4- {[1- (2,5-dimethylphenyl) -5-oxopyrrolidine-3-carbonyl] amino} phenyl) phenylamino] acetic acid, ethyl ester; rac. l-cycloheptyl-5-oxopyrrolidine-3-carboxylic acid- (9-ethyl-
9H-carbazol-3-yl) -amid; rac. 1- (5-Methoxy-2-methyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- {4- [ (4, 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] - phenyl} -amid; rac . 1- (2, 5-Dimethyl-phenyl ) -5-oxo-pyrrolidin-3- carbonsäure-{"4- [ethyl- (2-hydroxy-ethyl) -amino] -phenyl } - amid; rac . 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (ethyl-phenyl-amino) -phenyl] -amid; rac. 1- (3-Methoxy-phenyl) -5-oxo-pyrrolidin-3-carbonsäure-9H-carbazol-3-yl) amide; rac. 1- (5-methoxy-2-methylphenyl) -5-oxopyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethylpyrimidin-2-yl) ethylamino] phenyl} - amide; rac. 1- (2, 5-Dimethylphenyl) -5-oxopyrrolidine-3-carboxylic acid { " 4- [ethyl- (2-hydroxyethyl) amino] phenyl} amide; rac. 1- (2, 5-dimethylphenyl) -5-oxopyrrolidine-3-carboxylic acid [4- (ethylphenylamino) phenyl] amide; rac. 1- (3-methoxy-phenyl) -5-oxo-pyrrolidine-3-carboxylic acid -
( 9-ethyl-9H-carbazol-3-yl) -amid; rac. 1- (2-Chlor-benzyl) -5-oxo-pyrrolidin-3-carbonsäure- (9- ethyl-9H-carbazol-3-yl) -amid; rac . 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) -phenyl] - amid; rac. 1- (2, 5-Dimethyl-phenyl ) -5-oxo-pyrrolidin-3- carbonsäure-{ 4- [ (4, 6-dimethyl-pyrimidin-2-yl) -methyl- amino] -phenyl } -amid; rac. 5-Oxo-l-phenyl-pyrrolidin-3-carbonsäure- (9-ethyl-9H- carbazol-3-yl) -amid; rac. 5-Oxo-l-p-tolyl-pyrrolidin-3-carbonsäure- { 4- [ (4 , 6- dimethyl-pyrimidin-2-yl) -methyl-amino] -phenyl} -amid; rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (isopropyl-phenyl-amino) -phenyl] -amid; rac. 1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- [4- (ethyl-phenyl-amino) -phenyl] -amid; rac. 5-Oxo-l- (2-pyridin-2-yl-ethyl) -pyrrolidin-3- carbonsäure- { 4- [ ( 4 , 6-dimethyl-pyrimidin-2-yl ) -ethyl-amino] - phenyl } -amid; rac. 1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) -phenyl] -amid; rac. 1- (5-Methoxy-2-methyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) -phenyl] - amid; rac. 1- (2,5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (methyl-phenyl-amino) -phenyl] -amid; rac . 1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure-(9-ethyl-9H-carbazol-3-yl) amide; rac. 1- (2-chloro-benzyl) -5-oxo-pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; rac. 1- (2, 5-Dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) phenyl] amide; rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) methylamino] phenyl} amide; rac. 5-oxo-l-phenyl-pyrrolidin-3-carboxylic acid (9-ethyl-9H-carbazol-3-yl) amide; rac. 5-oxo-l-p-tolyl-pyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) methylamino] phenyl} amide; rac. 1- (2, 5-dimethylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (isopropylphenylamino) phenyl] amide; rac. 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid [4- (ethylphenylamino) phenyl] amide; rac. 5-oxo-1- (2-pyridin-2-yl-ethyl) -pyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] - phenyl} - amide; rac. 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid [4- (4,6-dimethylpyrimidin-2-ylamino) phenyl] amide; rac. 1- (5-methoxy-2-methylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (4,6-dimethylpyrimidin-2-ylamino) phenyl] amide; rac. 1- (2,5-dimethylphenyl) -5-oxopyrrolidine-3-carboxylic acid [4- (methylphenylamino) phenyl] amide; rac. 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid
[4- (methyl-phenyl-amino) -phenyl] -amid; rac. 1- (4-Isόpropyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- (9-ethyl-9H-carbazol-3-yl) -amid; rac. 1- (3-Fluor-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- (9- ethyl-9H-carbazol-3-yl) -amid; rac . 1- (2 , 5-Dimethyl-phenyl ) -5-oxo-pyrrolidin-3- carbonsäure- (4-phenylamino-phenyl) -amid; rac . l-Indan-2-yl-5-oxo-pyrrolidin-3-carbonsäure- [4- ( 4 , 6- dimethyl-pyrimidin-2-ylamino) -phenyl] -amid; rac . 1- (5-Methoxy-2-methyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (ethyl-phenyl-amino) -phenyl] -amid; rac . 1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- { 4- [ (4 , 6-dimethyl-pyrimidin-2-yl) -methyl-amino] -phenyl } - amid; rac . l-Benzyl-5-oxo-pyrrolidin-3-carbonsäure- ( 9-ethyl-9H- carbazol-3-yl) -amid; rac . 5-Oxo-l-p-tolyl-pyrrolidin-3-carbonsäure- [ 4- ( 4 , 6- dimethyl-pyrimidin-2-ylamino) -phenyl] -amid; rac . l-Indan-2-yl-5-oxo-pyrrolidin-3-carbonsäure- ( 9-ethyl-[4- (methylphenylamino) phenyl] amide; rac. 1- (4-Isόpropyl-phenyl) -5-oxo-pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; rac. 1- (3-fluorophenyl) -5-oxopyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; rac. 1- (2,5-dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid (4-phenylamino-phenyl) -amide; rac. l-indan-2-yl-5-oxopyrrolidin-3-carboxylic acid- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) phenyl] amide; rac. 1- (5-methoxy-2-methylphenyl) -5-oxopyrrolidine-3-carboxylic acid [4- (ethylphenylamino) phenyl] amide; rac. 1- (2-isopropylphenyl) -5-oxopyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethylpyrimidin-2-yl) methylamino] phenyl} amide; rac. l-benzyl-5-oxopyrrolidin-3-carboxylic acid (9-ethyl-9H-carbazol-3-yl) amide; rac. 5-oxo-l-tolyl-pyrrolidine-3-carboxylic acid- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) phenyl] amide; rac. l-indan-2-yl-5-oxo-pyrrolidin-3-carboxylic acid- (9-ethyl-
9H-carbazol-3-yl) -amid; rac . 1- (2-Hydroxy-2-phenyl-ethyl) -5-oxo-pyrrolidin-3- carbonsäure- { 4- [ (4 , 6-dimethyl-pyrimidin-2-yl ) -ethyl-amino] - phenyl } -amid; rac . 1- (2 , 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure-biphenyl-4-ylamid; rac . 1- (5-Methoxy-2-methyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (cyclopropylmethyl-phenyl-amino) -phenyl] - amid; rac . 1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure-9H-carbazol-3-yl) amide; rac. 1- (2-Hydroxy-2-phenyl-ethyl) -5-oxo-pyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) ethylamino] - phenyl} - amide; rac. 1- (2, 5-Dimethylphenyl) -5-oxopyrrolidine-3-carboxylic acid biphenyl-4-ylamide; rac. 1- (5-methoxy-2-methylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (cyclopropylmethylphenylamino) phenyl] amide; rac. 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid
[4- (isopropyl-phenyl-amino) -phenyl] -amid; rac . 1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure-[4- (isopropylphenylamino) phenyl] amide; rac. 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid
(4-phenylamino-phenyl) -amid; rac. 1- (5-Methoxy-2-methyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure-{4- [ (4, 6-dimethyl-pyrimidin-2-yl) -methyl- amino] -phenyl} -amid; rac . 1- (3-Methoxy-phenyl) -5-oxo-pyrrolidin-3-carbonsäure-(4-phenylaminophenyl) amide; rac. 1- (5-methoxy-2-methylphenyl) -5-oxo-pyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) methylamino] phenyl} - amide; rac. 1- (3-methoxy-phenyl) -5-oxo-pyrrolidine-3-carboxylic acid -
{4- [ (4, 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] -phenyl}- amid; rac . 5-Oxo-l-m-tolyl-pyrrolidin-3-carbonsäure- { 4- [ ( 4 , 6- dimethyl-pyrimidin-2-yl) -methyl-amino] -phenyl } -amid; rac . 1- (2 , 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (cyclopropylmethyl-phenyl-amino) -phenyl] - amid; rac. 1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- {4- [ (4, 6-dimethyl-pyrimidin-2-yl) -ethyl-amino] -phenyl}- amid; rac. [ (4-{ [1- (5-Methoxy-2-methyl-phenyl) -5-oxo-pyrrolidin-{4- [(4, 6-dimethyl-pyrimidin-2-yl) ethylamino] phenyl} amide; rac. 5-oxo-l-m-tolyl-pyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethyl-pyrimidin-2-yl) methylamino] phenyl} amide; rac. 1- (2, 5-Dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (cyclopropylmethylphenylamino) phenyl] amide; rac. 1- (2-isopropylphenyl) -5-oxopyrrolidin-3-carboxylic acid- {4- [(4, 6-dimethylpyrimidin-2-yl) ethylamino] phenyl} amide; rac. [(4- {[1- (5-methoxy-2-methylphenyl) -5-oxopyrrolidine
3-carbonyl] -amino} -phenyl) -phenyl-amino] -essigsäure-ethyl ester; rac. 1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure-3-carbonyl] amino} phenyl) phenylamino] acetic acid ethyl ester; rac. 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid
[4- (cyclopropylmethyl-phenyl-amino) -phenyl] -amid; rac . l-Indan-2-yl-5-oxo-pyrrolidin-3-carbonsäure- [4- (ethyl- phenyl-amino) -phenyl] -amid; und rac . 1- (2-Isopropyl-phenyl) -5-oxo-pyrrolidin-3-carbonsäure- [4- (isobutyl-phenyl-amino) phenyl] amid.[4- (cyclopropylmethylphenylamino) phenyl] amide; rac. l-indan-2-yl-5-oxopyrrolidin-3-carboxylic acid [4- (ethylphenylamino) phenyl] amide; and rac. 1- (2-isopropylphenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (isobutylphenylamino) phenyl] amide.
11. rac. 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (2-methoxy-benzoylamino) -phenyl] -amid; rac . 1- (2, 5-Dimethyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (2, 2-Dimethyl-propionylamino) phenyl] -amid; rac. 1- (2-Morpholin-4-yl-ethyl) -5-oxo-pyrrolidin-3- carbonsäure- (9-ethyl-9H-carbazol-3-yl) -amid; rac. 5-Oxo-l-p-tolyl-pyrrolidin-3-carbonsäure- (9-ethyl-9H- carbazol-3-yl) -amid; und rac. 1- (2, 4-Dimethoxy-benzyl) -5-oxo-pyrrolidin-3- carbonsäure- (9-ethyl-9H-carbazol-3-yl) -amid. 11. rac. 1- (2,5-dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (2-methoxy-benzoylamino) phenyl] amide; rac. 1- (2, 5-Dimethyl-phenyl) -5-oxopyrrolidine-3-carboxylic acid- [4- (2, 2-dimethyl-propionylamino) phenyl] -amide; rac. 1- (2-morpholin-4-yl-ethyl) -5-oxopyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; rac. 5-oxo-l-tolyl-pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide; and rac. 1- (2,4-Dimethoxy-benzyl) -5-oxo-pyrrolidin-3-carboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide.
12. rac. 1- (4-Dimethylamino-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (4 , 6-dimethyl-pyrimidin-2- ylamino) phenyl] amid; und rac. 1- (4-Dimethylamino-phenyl) -5-oxo-pyrrolidin-3- carbonsäure- [4- (4, 6-dimethyl-pyrimidin-2-yl)methyl- aminophenyl] amid.12. rac. 1- (4-Dimethylamino-phenyl) -5-oxo-pyrrolidine-3-carboxylic acid- [4- (4, 6-dimethyl-pyrimidin-2-ylamino) phenyl] amide; and rac. 1- (4-Dimethylamino-phenyl) -5-oxo-pyrrolidin-3-carboxylic acid- [4- (4, 6-dimethyl-pyrimidin-2-yl) methylaminophenyl] amide.
13. Verbindungen gemäss einem der Ansprüche 1 bis 12 zur Anwendung als therapeutische Wirkstoffe.13. Compounds according to any one of claims 1 to 12 for use as therapeutic agents.
14. Arzneimittel, bestehend aus einer galenischen Darreichungsform, enthaltend eine Verbindung gemäss einem der Ansprüche 1 bis 12.14. Medicament consisting of a pharmaceutical dosage form, containing a compound according to one of claims 1 to 12.
15. Verwendung von Verbindungen gemäss einem der Ansprüche 1 bis 12 zur Vorbeugung oder Behandlung von Arthritis, Diabetes und speziell von Essstörungen und Obesitas bzw. zur Herstellung entsprechender Arzneimittel.15. Use of compounds according to any one of claims 1 to 12 for the prevention or treatment of arthritis, diabetes and especially eating disorders and obesity or for the preparation of corresponding medicaments.
16. Verfahren zur Herstellung von Verbindungen gemäss einem der Ansprüche 1 bis 12, dadurch gekennzeichnet, dass man eine Pyrrolidoncarbonsäure der Formel16. A process for the preparation of compounds according to any one of claims 1 to 12, characterized in that a pyrrolidone carboxylic acid of the formula
Figure imgf000077_0001
Figure imgf000077_0001
worin R1 die in Anspruch 1 angegebene Bedeutung besitzt, oder ein reaktionsfähiges Derivat davon, mit einem Amin der Formel IVwherein R 1 has the meaning given in claim 1, or a reactive derivative thereof, with an amine of the formula IV
H, 2 H, 2nd
worin R2 die in Anspruch 1 angegebene Bedeutung besitzt, oder einem reaktionsfähigen Derivat davon, umsetzt und erwünschtenfalls ein allfällig erhaltenes Stereoisomerengemisch auftrennt.wherein R 2 has the meaning given in claim 1, or a reactive derivative thereof, and, if desired, resolves any stereoisomer mixture obtained.
17. Verfahren zur Herstellung von Verbindungen der in Anspruch 1 definierten Formel I, worin R2 einen Rest der Formel (b) , R5 -NR6R7 und R7 Acyl bedeuten, dadurch gekennzeichnet, dass man eine entsprechende Verbindung, worin aber R7 Wasserstoff bedeutet, acyliert und erwünschtenfalls ein allfällig erhaltenes Stereoisomerengemisch auftrennt.17. A process for the preparation of compounds of the formula I defined in claim 1, wherein R 2 is a radical of the formula (b), R 5 -NR 6 R 7 and R 7 are acyl, characterized in that a corresponding compound, but in which R 7 is hydrogen, acylated and, if desired, any stereoisomer mixture obtained is separated.
18 . Eine Verbindung der in Anspruch 16 definierten Formel IV bzw . ein entsprechender Nitro-Vorläufer, ausgewählt aus :18th A compound of the formula IV or. a corresponding nitro precursor, selected from:
[ ( 4-Nitro-phenyl ) -phenyl-amino] -essigsäure-ethylester ; [ ( 4-Amino-phenyl ) -phenyl-amino] -essigsäure-ethylester;[(4-nitro-phenyl) phenylamino] acetic acid ethyl ester; [[4-aminophenyl) phenylamino] acetic acid ethyl ester;
Cyclopropylmethyl- ( 4-nitro-phenyl ) -phenyl-amin;Cyclopropylmethyl- (4-nitro-phenyl) phenylamine;
N-Cyclopropylmethyl-N-phenyl-phenylen-1 , 4-diamin;N-cyclopropylmethyl-N-phenylphenylene-1,4-diamine;
Isobutyl- ( 4-nitro-phenyl) -phenyl-amin;Isobutyl- (4-nitro-phenyl) phenylamine;
N-Isobutyl-N-phenyl-phenylen-1, 4-diamin; [ (4-Nitro-phenyl) -phenyl-amino] -pentansäure-ethylester;N-isobutyl-N-phenylphenylene-1,4-diamine; [(4-nitro-phenyl) phenylamino] pentanoic acid ethyl ester;
[ (4-Amino-phenyl) -phenyl-amino] -pentansäure-ethylester;[(4-aminophenyl) phenylamino] pentanoic acid ethyl ester;
Benzyl- (4-nitro-phenyl) -phenyl-amin; undBenzyl- (4-nitro-phenyl) phenylamine; and
N-Benzyl-N-phenyl-phenylen-1 , 4-diamin . N-benzyl-N-phenyl-phenylene-1,4-diamine.
19. Eine Verbindung der in Anspruch 16 definierten Formel III, ausgewählt aus:19. A compound of formula III defined in claim 16 selected from:
rac l-Indan-2-yl-5-oxo-pyrrolidin-3-carbonsäure; rac. l-Naphthalin-2-yl-5-oxo-pyrrolidin-3-carbonsäure; rac. 1- (5-Methoxy-2-methyl-phenyl) -5-oxo-pyrrolidin-3- carbonsäure; rac. 5-Oxo-l- (2-pyridin-2-yl-ethyl) -pyrrolidin-3- carbonsäure; rac. l-Cycloheptyl-5-oxo-pyrrolidin-3-carbonsäure; rac. 1- (2-Hydroxy-2-phenyl-ethyl) -5-oxo-pyrrolidin-3- carbonsäure; rac. 5-Oxo-l- (2-pyrrolidin-l-yl-ethyl) -pyrrolidin-3- carbonsäure; rac. 1- [2- (l-Methyl-pyrrolidin-2-yl) -ethyl] -5-oxo- pyrrolidin-3-carbonsäure; und rac . 1- (3-Fluor-phenyl) -5-oxo-pyrrolidin-3-carbonsäure . rac l-indan-2-yl-5-oxo-pyrrolidin-3-carboxylic acid; rac. l-naphthalene-2-yl-5-oxo-pyrrolidine-3-carboxylic acid; rac. 1- (5-methoxy-2-methylphenyl) -5-oxopyrrolidine-3-carboxylic acid; rac. 5-oxo-1- (2-pyridin-2-yl-ethyl) pyrrolidin-3-carboxylic acid; rac. l-cycloheptyl-5-oxo-pyrrolidine-3-carboxylic acid; rac. 1- (2-hydroxy-2-phenyl-ethyl) -5-oxo-pyrrolidine-3-carboxylic acid; rac. 5-oxo-1- (2-pyrrolidin-1-yl-ethyl) -pyrrolidine-3-carboxylic acid; rac. 1- [2- (l-methyl-pyrrolidin-2-yl) ethyl] -5-oxopyrrolidin-3-carboxylic acid; and rac. 1- (3-fluoro-phenyl) -5-oxo-pyrrolidine-3-carboxylic acid.
PCT/CH2002/000725 2001-12-31 2002-12-27 Pyrrolidone carboxamides WO2003059905A1 (en)

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EP1914229A4 (en) * 2005-08-09 2009-03-18 Daiichi Sankyo Co Ltd Novel cercosporamide derivative
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US8940902B2 (en) 2006-04-07 2015-01-27 Abbvie Inc. Treatment of central nervous system disorders
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