EP1463724A1 - Pyrrolidon-carboxamide - Google Patents

Pyrrolidon-carboxamide

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Publication number
EP1463724A1
EP1463724A1 EP02785006A EP02785006A EP1463724A1 EP 1463724 A1 EP1463724 A1 EP 1463724A1 EP 02785006 A EP02785006 A EP 02785006A EP 02785006 A EP02785006 A EP 02785006A EP 1463724 A1 EP1463724 A1 EP 1463724A1
Authority
EP
European Patent Office
Prior art keywords
phenyl
rac
carboxylic acid
amide
ethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02785006A
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German (de)
English (en)
French (fr)
Inventor
Markus Isler
Thomas Giller
Günter SCHWALM
Matthias Steger
Kurt Hilpert
Oliver Valdenaire
Volker Breu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Actelion Pharmaceuticals Ltd
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Actelion Pharmaceuticals Ltd
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Publication date
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Publication of EP1463724A1 publication Critical patent/EP1463724A1/de
Withdrawn legal-status Critical Current

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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:

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US20080125403A1 (en) 2004-04-02 2008-05-29 Merck & Co., Inc. Method of Treating Men with Metabolic and Anthropometric Disorders
US7880001B2 (en) 2004-04-29 2011-02-01 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme
US20100222316A1 (en) 2004-04-29 2010-09-02 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US8415354B2 (en) 2004-04-29 2013-04-09 Abbott Laboratories Methods of use of inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US8198331B2 (en) 2005-01-05 2012-06-12 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
WO2006074244A2 (en) 2005-01-05 2006-07-13 Abbott Laboratories Adamantyl derivatives as inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US20090192198A1 (en) 2005-01-05 2009-07-30 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US20090264650A1 (en) * 2005-03-31 2009-10-22 Nobuo Cho Prophylactic/Therapeutic Agent for Diabetes
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US7435833B2 (en) 2006-04-07 2008-10-14 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme
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EP2480531B1 (en) * 2009-09-21 2014-11-05 ChemoCentryx, Inc. Pyrrolidinone carboxamide derivatives as chemerin-r (chemr23) modulators
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US10968176B2 (en) 2014-09-14 2021-04-06 Nanosynthons Llc Pyrrolidone derivatives, oligomers and polymers
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