AU2002350366A1 - Pyrrolidone carboxamides - Google Patents

Pyrrolidone carboxamides Download PDF

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AU2002350366A1
AU2002350366A1 AU2002350366A AU2002350366A AU2002350366A1 AU 2002350366 A1 AU2002350366 A1 AU 2002350366A1 AU 2002350366 A AU2002350366 A AU 2002350366A AU 2002350366 A AU2002350366 A AU 2002350366A AU 2002350366 A1 AU2002350366 A1 AU 2002350366A1
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phenyl
rac
oxo
ethyl
pyrrolidin
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AU2002350366A
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Volker Breu
Thomas Giller
Kurt Hilpert
Markus Isler
Gunter Schwalm
Matthias Steger
Oliver Valdenaire
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Actelion Pharmaceuticals Ltd
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Actelion Pharmaceuticals Ltd
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    • 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
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • 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
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    • 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

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Description

VERIFICATION OF TRANSLATION RWS Group Ltd, of Europa House, Marsham Way, Gerrards Cross, Buckinghamshire, England, hereby solemnly and sincerely declares that, to the best of its knowledge and belief, the following attached documents, prepared by one of its translators competent in the art and conversant with the English and German languages, is a true and correct translation of the PCT Application filed under No. PCT/CHO2/00725. Dated this 24th day of June 2004 E. SITCH Deputy Managing Director - UK Translation Division For and on behalf of RWS Group Ltd WO 03/059905 PCT/CHO2/00725 - 1 Pyrrolidonecarboxamides The present invention relates to pyrrolidonecarboxamide derivatives. 5 In particular, the invention relates to pyrrolidone carboxamides of the formula 0 10 in which R is phenyl which is optionally monosubstituted or disubstituted in the phenyl radical by alkyl, alkoxy, dialkylamino, halogen or trifluoromethyl, benzyl, phenylethyl or a-hydroxyphenylethyl; 15 naphthyl or naphthylmethyl; thienyl-, furyl-, pyridyl-, l-alkylpyrrolidin-2-yl-, pyrrolidino- or morpholino-alkyl; or cycloalkyl which can optionally possess a fused-on benzene ring;
R
2 is a radical of the formula 20 or (a) (b) X is -CH 2 -, -CO-, -0- or -NR 3 -;
R
3 is hydrogen or alkyl; 25 R 4 is hydrogen or alkoxy;
R
S 5 is phenyl, heteroalkyl, aryloxy, alkoxy, alkanoyl WO 03/059905 PCT/CH02/00725 - 2 or -NR R ;
R
6 is hydrogen, alkyl, aralkyl, cycloalkylalkyl or alkoxycarbonylalkyl; and R is aryl, heteroaryl, alkyl, hydroxyalkyl or acyl; 5 to pharmaceutically utilizable acid addition salts of basic compounds of the formula I, to pharmaceutically utilizable salts of acid compounds of the formula I with bases, to pharmaceutically utilizable esters of compounds of the formula I which contain hydroxyl or 10 carboxyl groups, and to hydrates or solvates thereof. Since the pyrrolidonecarboxamides of the formula I contain at least one asymmetric C atom, they can be present as optically pure enantiomers, as mixtures of 15 enantiomers, such as racemates, or, where appropriate, as optically pure diastereomers, as mixtures of diastereomers, as diastereomeric racemates or as mixtures of diastereomeric racemates. 20 WO 01/07409 Al relates to carbazole derivatives whose general formula partially overlaps with the above formula I but does not specifically describe a single compound covered by the above formula I and, further more, does not contain any sufficiently concrete 25 general pointers in the direction of compounds of the above formula I. The compounds defined at the outset are novel and are distinguished by possessing valuable pharmacodynamic 30 properties. They inhibit the interaction of the neuro peptide Y (NPY) with one of the neuropeptide receptor subtypes (NPY-Y5) and are suitable, in particular, for preventing and treating arthritis, diabetes and, especially, eating disturbances and obesity. 35 The present invention relates to the above compounds as such and as therapeutic active compounds; to processes and intermediates for preparing them; to pharma- WO 03/059905 PCT/CHO2/00725 -3 ceuticals which comprise one of the above compounds; and to the use of the above compounds for preventing and treating arthritis, diabetes and, especially, eating disturbances and obesity or for producing 5 corresponding pharmaceuticals. In the present description, the term "alkyl" denotes, on its own or in combination, a branched or unbranched saturated hydrocarbon radical having from 1 to 8 carbon 10 atoms, preferably having from 1 to 6 carbon atoms and, particularly preferably, having from 1 to 4 carbon atoms. Examples of these radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, the isomeric pentyls, the isomeric hexyls 15 and the isomeric octyls; methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like are preferred. The term "cycloalkyl" denotes, on its own or in 20 combination, a saturated cyclic hydrocarbon radical having 3-8 carbon atoms, preferably having from 3 to 6 carbon atoms, which can be substituted, for example by alkyl groups, such as methyl, and which can possess a fused-on benzene ring. Examples of cycloalkyl groups 25 which are optionally substituted by alkyl are cyclopropyl, methylcyclopropyl, dimethylcyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, methylcyclo pentyl, cyclohexyl, methylcyclohexyl, dimethylcyclo hexyl, cycloheptyl and cyclooctyl; examples of 30 cycloalkyl radicals having a fused-on benzene ring are 1-indanyl, 2-indanyl and the like. The term "hydroxyalkyl" denotes, on its own or in combination, an alkyl group, as described above, with 35 one or two H atoms, preferably one H atom, being replaced with a hydroxyl group. Examples are hydroxymethyl, hydroxyethyl, hydroxypropyl and the like.
WO 03/059905 PCT/CHO2/00725 - 4 The term "alkoxy" denotes, on its own or in combination, an alkyl radical, as described above, which is linked by way of an oxygen bridge. Examples 5 are methoxy, ethoxy and the like. The term "alkanoyl" denotes, onl its own or in combination, an alkyl group, as described above, which is linked by way of a CO bridge. Examples are acetyl., 10 3-methylbutyryl, 2,2-dimethylpropionyl and the like. The term "aryl" denotes, on its own or in combination, a phenyl or naphthyl group, preferably a phenyl group, which can carry up to four, preferably from one to 15 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. Particularly preferred substituents are alkyl and 20 alkoxy. Examples of these aryl groups are phenyl, methylphenyl, dimethylphenyl, ethylphenyl, isopropyl phenyl, methoxyphenyl, methoxymethylphenyl, dimethyl aminophenyl, phenylaminophenyl and the like. 25 The term "aralkyl" denotes, on its own or in combination, an alkyl group, as described above, in which at least one H atom is replaced with an aryl group, as described above, in particular with a phenyl or naphthyl group, which can carry one or more 30 substituents, such as alkyl or alkoxy groups. Examples of these aralkyl radicals are benzyl, phenethyl, 2-(3,4-dimethoxyphenyl)ethyl and the like. The term "heteroaryl" denotes, on its own or in 35 combination, an aromatic monocyclic, bicyclic or tricyclic heterocyclic ring system having from 5 to 10, preferably from 5 to 6, ring members which contains from one to four, preferably from one to two, WO 03/059905 PCT/CHO2/00725 - 5 heteroatoms which are selected, independently of one another, from nitrogen, oxygen and sulphur. Examples of these heteroaryl groups are pyridyl, pyrimidinyl, thiazolyl, thiophenyl, furanyl, tetrazolyl, carbazolyl 5 and the like. These heteroaryl groups can be substituted, expediently monosubstituted, disubstituted or trisubstituted, with suitable substituents primarily being alkyl, alkoxy, amino or aryl groups. Examples are 2-pyridyl, 2-thienyl, 4,6-dimethyl-2-pyrimidinyl and 10 the like. The term "acyl" denotes, alone or in combination, an alkanoyl group, as described above, or a cycloalkyl, aryl, aralkyl or heteroaryl group, as described above, 15 which is linked by way of a CO bridge. Examples are, as mentioned above, acetyl, 3-methylbutyryl and 2,2-dimethylpropionyl as well as cyclopropanecarbonyl, benzoyl, phenylacetyl, 2-methoxybenzoyl, 4-methoxy benzoyl, 3-fluorobenzoyl, benzo[l,3]dioxole-5-carbonyl, 20 furan-2-carbonyl and the like. The term "pharmaceutically utilizable salts" relates to those salts which do not impair the biological effect and properties of the free bases or free acids and 25 which are not undesirable biologically or in some other way. The salts are formed from the free bases using inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably hydrochloric acid, or using 30 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 35 like. The free acids can form salts with inorganic bases or with organic bases. Preferred salts with inorganic bases are, but not exclusively, sodium salts, potassium salts, lithium salts, ammonium salts, calcium WO 03/059905 PCT/CH02/00725 6 salts, magnesium salts and the like. Preferred salts with organic bases are, but not exclusively, salts with primary, secondary and tertiary amines, substituted amines, including all naturally occurring substituted 5 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 10 present as zwitterions. The invention also includes pharmaceutically suitable esters of compounds of the formula I which contain hydroxyl or carboxyl groups. "Pharmaceutically suitable 15 esters" means that, in compounds of the formula I, corresponding functional groups are derivatized to form ester groups such that they are once again retrans formed, in vivo, into their active form. On the one hand, COOH groups can be esterified. Examples of 20 suitable esters of this nature are the alkyl esters and aralkyl esters. Preferred esters of this nature are the methyl, ethyl, propyl, butyl and benzyl esters as well as the (R/S)-l-[(isopropoxycarbonyl)oxy]ethyl esters. The ethyl esters and the isomeric butyl esters are 25 particularly preferred. On the other hand, OH groups can be esterified. Examples of these compounds contain physiologically acceptable and metabolically labile ester groups, such as methoxymethyl ester, methylthiomethyl ester and pivaloyloxymethyl ester, and 30 similar ester groups. Preferred possible meanings for R' are phenyl, 4-tolyl, 2,5-dimethylphenyl, 2-isopropylphenyl, 3-methoxyphenyl, 2-methyl-5-methoxyphenyl, benzyl, 2-phenylethyl, 35 2-(2-pyridyl)ethyl, 2-(2-thienyl)ethyl, 2-indanyl and 2-morpholinoethyl. Other preferred possible meanings for R are cycloheptyl, 2-hydroxy-2-phenylethyl, 2-thienylmethyl, 2-furanylmethyl, 4-chlorobenzyl, WO 03/059905 PCT/CH02/00725 -7 3-fluorophenyl, 2-chlorobenzyl and 2,4-dimethoxybenzyl as well as 2-naphthyl, naphthalen-l-ylmethyl, 4-di methylaminophenyl, 2-pyrrolidin-1-ylethyl, 1-methyl pyrrolidin-2-ylethyl, 4-isopropylphenyl and 3,5-bis 5 trifluoromethylphenyl. Particularly preferred possible meanings for R are 2,5-dimethylphenyl, 2-isopropylphenyl and 2-methyl 5-methoxyphenyl. 10 Preferred possible meanings for RK 2 are biphenyl-4-yl, 4-methoxyphenyl, 4-phenoxyphenyl, 4-dimethylamino phenyl, 4-diethylaminophenyl, 4-phenylaminophenyl, 4-[N-ethyl-N-(2-hydroxyethyl)amino]phenyl, 4-(N-ethyl 15 N-isopropylamino)phenyl, 4-N-(4,6-dimethyl-2-pyrimi dinyl)aminophenyl, 4-[N-ethyl-N-(4,6-dimethyl-2-pyrimi dinyl)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. 20 Other preferred possible meanings for R 2 are 4-(N-ethoxycarbonylmethyl-N-phenylamino)phenyl, 4-(N ethyl-N-phenylamino)phenyl, 4-(N-methyl-N-phenylamino phenyl, 4-(N-cyclopropylmethyl-N-phenylamino)phenyl, 4-(N-isobutyl-N-phenylamino)phenyl, 4-(2-methoxy 25 benzoylamino)phenyl, 4-(2,2-dimethylpropionylamino) phenyl, 4-(3-methylbutyrylamino)phenyl, 4-(cyclo propanecarbonylamino)phenyl, 4-(3-fluorobenzoylamino) phenyl and 4-[(furan-2-carbonyl)amino]phenyl as well as biphenyl-3-yl, 9H-fluoren-l-yl, 2-methoxydibenzofuran 30 3-yl, 4-(N-isopropyl-N-phenylamino)phenyl, 4-(N-benzyl N-phenylamino)phenyl, 4-acetylaminophenyl, 4-benzoyl aminophenyl, 4-phenylacetylaminophenyl, 4 [(benzo[l,3]dioxole-5-carbonyl)amino]phenyl and 4-(4 methoxybenzoylamino)phenyl. 35 Particularly preferred possible meanings of 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-di- WO 03/059905 PCT/CH02/00725 - 8 methyl-2-pyrimidinyl)amino]phenyl, 4-(4,6-dimethyl 2-pyrimidinyl)amino]phenyl, 4-phenylaminophenyl, 4-diethylaminophenyl, 4-(N-ethyli-N-isopropylamino) phenyl, 4-(N-ethoxycarbonylmethyl-N-phenylamino)phenyl, 5 4-(N-ethyl-N-phenylamino)phenyl, 4-(N-methyl-N-phenyl amino)phenyl and 2,4-dimethoxybenzyl. Representative examples of preferred compounds of formula I are: 10 rac. N-(9-Ethyl-9H-carbazol-3-yl)-5-oxo-1-(2-pyridin 2-ylethyl)pyrrolidine-3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-(2-hydroxy 2-phenylethyl)-5-oxopyrrolidine-3-carboxamide; 15 rac. N-(4-Diethylaminophenyl)-1-(2,5-dimethylphenyl) 5-oxopyrrolidine-3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-5-oxo-1-(2-thiophen 2-ylethyl)pyrrolidine-3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-(4-chlorobenzyl) 20 5-oxopyrrolidine-3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-5-oxo-1-thiophen 2-ylmethylpyrrolidine-3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-l-furan-2-ylmethyl 5-oxopyrrolidine-3-carboxamide; 25 rac. N-(9-Ethyl-9H-carbazol-3-yl)-l-(2-isopropyl phenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-(5-methoxy 2-methylphenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-[4-(Ethylisopropylamino)phenyl]-l-(2,5-dimethyl 30 phenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-5-oxo-l-phenethylpyr rolidine-3-carboxamide; rac. Ethyl [(4-{[1-(2,5-dimethylphenyl)-5-oxopyr rolidine-3-carbonyl]amino}phenyl)phenylamino]acetate; 35 rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-cycloheptyl-5-oxo pyrrolidine-3-carboxamide; rac. N-{4-[(4,6-Dimethylpyrimidin-2-yl)ethylamino] phenyl}-1-(5-methoxy-2-methylphenyl)-5-oxopyrrolidine- WO 03/059905 PCT/CHO2/00725 -9- 3-carboxamide; rac. N-{4-[Ethyl-(2-hydroxyethyl)amino]phenyl} 1-(2,5-dimethylphenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-[4-(Ethylphenylamino)phenyl]-1-(2,5-dimethyl 5 phenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)--(3-methoxyphenyl) 5-oxopyrrolidine-3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-(2-chlorobenzyl) 5-oxopyrrolidine-3-carboxamide; 10 rac. N-[4-(4,6-Dimethylpyrimidin-2-ylamino)phenyl] 1-(2,5-dimethylphenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-{4-[(4,6-Dimethylpyrimidin-2-yl)methylamino] phenyl}-1-(2,5-dimethylphenyl)-5-oxopyrrolidine 3-carboxamide; 15 rac. N-(9-Ethyl-9H-carbazol-3-yl)-5-oxo-1-phenyl pyrrolidine-3-carboxamide; rac. N-{4-[(4,6-Dimethylpyrimidin-2-yl)methylamino] phenyl}-5-oxo-1-p-tolylpyrrolidine-3-carboxamide; rac. N-[4-(Isopropylphenylamino)phenyl]-1-( 2 ,5-di 20 methylphenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-[4-(Ethylphenylamino)phenyl]-1-(2-isopropyl phenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-{4-[(4,6-Dimethylpyrimidin-2-yl)ethylamino] phenyl}-5-oxo-l-(2-pyridin-2-ylethyl)pyrrolidine 25 3-carboxamide; rac. N-[4-(4,6-Dimethylpyrimidin-2-ylamino)phenyl] 1-(2-isopropylphenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-[4-(4,6-Dimethylpyrimidin-2-ylamino)phenyl] 1-(5-methoxy-2-methylphenyl)-5-oxopyrrolidine 30 3-carboxamide; rac. N-[4-(Methylphenylamino)phenyl]-l-(2,5-dimethyl phenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-[4-(Methylphenylamino)phenyl]-- -(2-isopropyl phenyl)-5-oxopyrrolidine-3-carboxamide; 35 rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-(4-isopropyl phenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-l-(3-fluorophenyl) 5-oxopyrrolidine-3-carboxamide; WO 03/059905 PCT/CHO2/00725 - 10 rae. N-(4-Phenylawinphenyl)-1-(2,5-dimethylphenyl) 5-oxopyrrolidine-3-carboxamide; rae. N-[4-(4,6-Dimethylpyrimidifl2ylamile)pheflyl> 1-indan-2-yl-5-oxopyrrolidine-3-arboxanide; 5 rae. N-[4-(Ethylphenylamnino)phenyl]l-(5-methoxy 2-methyiphenyl) -5-oxopyrrolidine-3-carboxamide; rae. N-{4-[ (4,6-Dimethylpyrimidin-2-yl)methylaminlV phenyl}-1- (2-isopropyiphenyl) -5-oxopyrrolidine 3-ca rboxamide; 10 rae. N- (9-Ethyl-9H-carbazol-3-yi) -1-benzyl-5-oxopyr rolidine-3-carboxamide; rae. N-[4-(4,6-Dimethylpyrimidin-2-ylamino)phelyl] 5-oxo-1-p-tolylpyrrolidine-3-carboxamide; rae. N- (9-Ethyl-9H-carbazol-3-yl) -1-indan-2-yi-5-oxo 15 pyrrolidine-3-carboxamide; rae. N-{4-[ (4,6-Dimethyipyrimidin-2-yl)ethyiamino] phenyl(-1- (2-hydroxy-2-phenylethyl) -5-oxo-pyrrolidine 3-ca rboxamide; rae. N-(Biphenyl-4-yl)-1-(2,5-dimethyipheflyl)-5-oxopyr 20 rolidine-3-earboxamide; rae. N- [4- (Cyclopropylmethylphenylamino) phenyl] 1- (5-methoxy-2-methylphenyl) -5-oxopyrrolidine-3-earbox amide; rae. N-[4-(Isopropyiphenylarnino)phenyl]-1-(2-isopropyl 25 phenyl) -5-oxopyrrolidine-3-carboxamide; rae. N-(4-Phenylaminophenyl)-1-(2-isopropylpheflyl)V 5-oxopyrrolidine-3-earboxamide; rae. N-{4-[ (4,6-Dimethylpyrimidin-2-yl)methylamino] phenyi}-1- (5-methoxy-2-methylphenyl) -5-oxopyrrolidine 30 3-earboxamide; rae. N-{4-[ (4,6-Dimethyipyrimidin-2-yl)ethylaminoV phenyi}-1- (3-methoxyphenyl) -5-oxopyrrolidine-3-earbox amide; rae. N-{4-[ (4,6-Dimethyipyrimidin-2-yl)methylamino> 35 phenyl}-5-oxo--n-tolylpyrrolidine-3-carboxamide; rae. N- [4- (Cyclopropyimethylphenylamino) phenyl -1- (2,5 dimethyiphenyl) -5-oxopyrroiidine-3-earboxamide; rae. N-{4-[ (4,6-Dimethylpyrimidin-2-yl)ethylamino]- WO 03/059905 PCT/CH02/00725 - 11 phenyl}-l-(2-isopropylphenyl)-5-oxopyrrolidine 3-carboxamide; rac. Ethyl [(4-{[l-(5-methoxy-2-methylphenyl)-5-oxopyr rolidine-3-carbonyl]amino}phenyl)phenylamino]acetate; 5 rac. N-[4-(Cyclopropylmethylphenylamino)phenyl] 1-(2-isopropylphenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-[4-(Ethylphenriylamino)phenyl]-l-indan-2-yl-5-oxo pyrrolidine-3-carboxamide; and rac. N-[4-(Isobutylphenylamino)phenyl]-1-(2-isopropyl 10 phenyl)-5-oxopyrrolidine-3-carboxamide. Other representative examples of preferred compounds of formula I are: 15 rac. N-[4-(2-Methoxybenzoylamino)phenyl]-1-(2,5-di methylphenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-[4-(2,2-Dimethylpropionylamino)phenyl]-l (2,5-dimethylphenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-l-(2-morpholin- 4 -yl 20 ethyl)-5-oxopyrrolidine-3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-5-oxo-1-p tolylpyrrolidine-3-carboxamide; and rac. N-(9-Ethyl-9H-carbazol-3-yl)-l-(2,4-dimethoxy benzyl)-5-oxopyrrolidine-3-carboxamide; as well as 25 rac. N-[4-(4,6-Dimethylpyrimidin-2-ylamino)phenyl]-l (4-dimethylaminophenyl)-5-oxopyrrolidine-3-carboxamide; and rac. N-[4-(4,6-Dimethylpyrimidin-2-yl)methylamino phenyl]-1-(4-dimethylaminophenyl)-5-oxopyrrolidine 30 3-carboxamide. Compounds of the formula I can be prepared, according to the invention, by reacting a pyrrolidonecarboxylic acid of the formula III (see scheme below), in which R' 35 has the meaning mentioned at the outset, or a reactive derivative thereof, with an amine of the formula IV, in which R 2 has the meaning mentioned at the outset, or a reactive derivative thereof. Any stereoisomeric WO 03/059905 PCT/CH02/00725 - 12 mixtures, such as racemates, which are obtained can, if desired, be resolved using generally customary methods. In order to prepare the corresponding pyrrolidone 5 carboxylic acid of the formula III, it is possible, for example, to take the following route, with the substituents and indices given in the following scheme having the meanings mentioned at the outset unless otherwise indicated; this route consists in reacting an 10 amine of the formula II, such as aniline or the like, in a solvent, such as water, dioxane, ethanol or the like, at elevated temperature, with itaconic acid (Buzas et al., Chim Ther 7, 398-403, 1972). 15 Scheme O OH 0 0 R2 02H OH BEN2 HX N NNH2 ONN Nil 2 N ----- m. 0 N RI kR (I) (H) (Iv) ( The compounds of the formula I can be prepared by reacting a pyrrolidonecarboxylic acid of the 20 formula III with an amine of the formula IV. For this, the pyrrolidonecarboxylic acid of the formula III is expediently converted, where appropriate in a suitable solvent, such as toluene, into the corresponding acid chloride using a halogenating agent such as SOC1 2 or 25 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. 30 In a process variant, the pyrrolidonecarboxylic acid of the formula III is reacted with an amine of the WO 03/059905 PCT/CHO02/00725 - 13 formula IV in the added presence of a coupling reagent, such as EDC, DCC or BOP, in a solvent, such as DMF, and, where appropriate, in the presence of a base, such as triethylamine. 5 Compounds of the formula I in which R 2 is a radical of the formula (b), R 5 is -NRER 7 and R7 is acyl can also be prepared by acylating a corresponding compound in which R' is hydrogen, such as rac. N-(4-aminophenyl)-l-(2,5 10 dimethylphenyl)-5-oxopyrrolidine-3-carboxamide, for example using acetyl chloride, isovaleryl chloride, cyclopropylcarbonyl chloride, benzoyl chloride, phenylacetyl chloride, 2-methoxybenzoyl chloride, piperonyloyl chloride, pivaloyl chloride, 4 15 methoxybenzoyl chloride, 3-fluorobenzoyl chloride and the like. While only some of the pyrrolidonecarboxylic acids of the formula III are known, they can be prepared by 20 methods which are known per se and with which every skilled person is familiar, for example using the abovementioned method (Buzas et al., Chim Ther 7, 398 403, 1972); furthermore, some of the examples which follow contain information regarding the preparation of 25 particular pyrrolidonecarboxylic acids of the formula III. Some of the amines of the formula IV are also known or can be prepared by methods which are known per se; some 30 of the examples which follow also contain information regarding the preparation of particular amines of the formula IV. Insofar as the starting compounds of the formulae III 35 and IV, and also the nitro precursors of the compounds of the formula IV, are novel, they also form part of the subject matter of the present invention. Thus, the following compounds of the formula IV and their WO 03/059905 PCT/CHO2/00725 - 14 nitroprecursors, in particular: ethyl [(4-nitrophenyl)phenylamino]acetate; ethyl [(4-aminophenyl)phenylamino]acetate; 5 cyclopropylmethyl(4-nitrophenyl)phenylamine; N-cyclopropylmethyl-N-phenylphenylene-l,4-diamine; isobutyl(4-nitrophenyl)phenylamine; N-isobutyl-N-phenylphenylene-1,4-diamine; ethyl [(4-nitrophenyl)phenylamino]pentanoate; 10 ethyl [(4-aminophenyl)phenylamino]pentanoate; benzyl(4-nitrophenyl)phenylamine; and N-benzyl-N-phenylphenylene-1,4-diamine; as well as the following compounds of the formula III: 15 rac. l-indan-2-yl-5-oxopyrrolidine-3-carboxylic acid; rac. l-naphthalen-2-yl-5-oxopyrrolidine-3-carboxylic acid; rac. 1-(5-methoxy-2-methylphenyl)-5-oxopyrrolidine 20 3-carboxylic acid; rac. 5-oxo-l-(2-pyridin-2-ylethyl)pyrrolidine 3-carboxylic acid; rac. l-cycloheptyl-5-oxopyrrolidine-3-carboxylic acid; rac. 1-(2-hydroxy-2-phenylethyl)-5-oxopyrrolidine 25 3-carboxylic acid; rac. 5-oxo-l-(2-pyrrolidin-l-ylethyl)pyrrolidine 3-carboxylic acid; rac. 1-[2-(1-methylpyrrolidin-2-yl)ethyl]-5-oxopyr rolidine-3-carboxylic acid; and 30 rac. 1-(3-fluorophenyl)-5-oxopyrrolidine-3-carboxylic acid; are part of the subject matter of the present invention. 35 As mentioned at the outset, the compounds of the formula I and their pharmaceutically utilizable salts and esters are novel and possess valuable WO 03/059905 PCT/CHO2/00725 - 15 pharmacological properties. In particular, they inhibit the interaction of the neuropeptide Y (NPY) with one of the neuropeptide receptor subtypes (NPY-Y5) . NPY is a regulatory, 36-amino acid peptide belonging to the 5 pancreatic polypeptide family. NPY is the most widespread neuropeptide in the central and peripheral nervous systems and has prominent and complex effects on nutrient uptake, anxiety, depression, circadian rhythm, sexual function, reproduction, memory function, 10 migraine, pain, epileptic seizures, blood pressure, cerebral hemorrhages, shock, sleep disturbance, diarrhea, etc. NPY interacts with a heterogeneous population of at 15 least five NPY receptor subtypes, i.e. Y1-Y5, which activate adenylate cyclase using a G protein. One of the most prominent effects is the induction of nutrient uptake in vertebrates. Recent investigations involving the selective activation and blocking of the individual 20 NPY receptors have shown that it is principally the NPY-Y5 receptor which is responsible for appetite inducing signals. Obesity is an important and increasing problem in the 25 industrialized world. Obesity is associated with a variety of diseases such as non-insulin-dependent diabetes (type II diabetes), high blood pressure, coronary diseases of the heart, dyslipidemia etc., and has an influence on the life expectancy and quality of 30 life of the population affected. For this reason, there is a need for pharmaceutical substances which exert an influence on eating habits. The NPY-Y5 receptor is a possible target for a corresponding pharmacological intervention. Using a low molecular weight compound to 35 inhibit this receptor represents an attractive possibility for preventing or treating the above diseases.
WO 03/059905 PCT/CHO2/00725 - 16 Because of their property of inhibiting the interaction of neuropeptide Y with the neuropeptide Y5 receptor subtype, the compounds of the formula I, and their pharmaceutically utilizable salts and esters, are 5 suitable for preventing and treating arthritis, diabetes and, in particular, eating disturbances and obesity. The valuable pharmacodynamic properties of the novel 10 compounds according to the invention can be demonstrated using the methods which are described below. Cloning the mouse NPY-Y5 receptor cDNAs 15 The full-length cDNA which contains the mouse NPY-Y5 (mNPY-Y5) receptor coding was amplified from mouse brain cDNA using specific primers, which were custom-made on the basis of published sequences, and employing Pfu DNA polymerase (Stratagene). The 20 amplification product was subcloned into a mammalian expression vector pcDNA3 using EcoRI and XhoI restriction sites. Positive clones were sequenced; one clone, which contained the published sequence, was selected for preparing stable cell clones. 25 Stable transfection Human embryonic kidney 293 (HEK293) cells were transfected with 10 gg of mNPY5 DNA using Lipofectamine reagent (Gibco BRL) in accordance with the 30 manufacturer's instructions. Two days after the transfection, the geneticin selection (1 mg/ml) was initiated and several stable clones were isolated. One of the clones was used for further pharmacological characterization. 35 Radioligand competition binding Human embryonic kidney cells (HEK293) which express recombinant mouse NPY-Y5 receptors (mNPY-Y5) were WO 03/059905 PCT/CH02/00725 - 17 disrupted by being frozen/thawed three times in hypotonic Tris buffer (5 mM, pH 7.4, 1 mM MgCl 2 ), after which they were homogenized and centrifuged at 72 000 G for 15 minutes. The precipitate was washed twice with 5 Tris buffer (pH 7.4) containing 25 mM MgCl 2 , 250 mM sucrose, 0.1 mM phenylmethylsulfonyl fluoride and 0.1 mM 1,10-phenanthroline, then resuspended in the same buffer and stored in aliquots at -80 0 C. The protein was determined by the Lowry method using bovine 10 serum albumin (BSA) as the standard. The competition binding analysis was carried out in 250 pl of 25 mM Hepes buffer (pH 7.4, 2.5 mM CaC1 2 , 1 mM MgCl 2 , 1% bovine serum albumin and 0.01% sodium 15 azide) which 5 ig of protein, 100 pM 1 2 I-labeled peptide YY (PYY) and 10 Il of a DMSO solution containing increasing quantities of DMSO solution containing unlabeled test compound. After a one-hour incubation at 22oC, the bound ligand was separated from 20 the unbound ligand by means of filtration through a glass fiber filter. Nonspecific binding was determined in the presence of 1 M unlabeled PYY. Specific binding is defined as the difference between total binding and nonspecific binding. An IC 50 value is defined as the 25 concentration of the antagonist which displaces 50% of the 125I-labeled neuropeptide Y. This concentration is determined by linear regression analysis following logit/log transformation of the binding values. 30 In the above-described test, preferred compounds according to the invention exhibit IC 50 values of less than 1000 nM, while particularly preferred compounds exhibit IC5 0 values of less than 100 nM and very particularly preferred compounds exhibit ICs 5 0 values of 35 less than 50 nM. The results which were obtained in the above-described test using representative compounds of the formula I as WO 03/059905 PCT/CH02/00725 - 18 test compounds are compiled in the following table. Substance NPY5 ICs 0 (riM) rac. N-(9-Ethyl-9H-carbazol-3-yl)-5-oxo-1- 0.003 (2-pyridin-2-ylethyl)pyrrolidine-3-carboxamide rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-(2-hydroxy- 0.008 2-phenylethyl)-5-oxopyrrolidine-3-carboxamide rac. N-(4-Diethylaminophenyl)-1-(2,5-dimethyl- 0.009 phenyl)-5-oxopyrrolidine-3-carboxamide rac. N-(9-Ethyl-9H-carbazol-3-yl)-5-oxo-1-(2-thio- 0.010 phen-2-ylethyl)pyrrolidine-3-carboxamide rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-(4-chloro- 0.010 benzyl)-5-oxopyrrolidine-3-carboxamide rac. N-(9-Ethyl-9H-carbazol-3-yl)-5-oxo-1-thiophen- 0.010 2-ylmethylpyrrolidine-3-carboxamide rac. N-(9-Ethyl-9H-carbazol-3-yl)--furan-2-yl- 0.010 methyl-5-oxopyrrolidine-3-carboxamide rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-(2-isopropyl- 0.010 phenyl)-5-oxopyrrolidine-3-carboxamide rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-(5-methoxy- 0.010 2-methylphenyl)-5-oxopyrrolidine-3-carboxamide rac. N-[4-(Ethylisopropylamino)phenyl]-1-(2,5-di- 0.010 methylphenyl)-5-oxopyrrolidine-3-carboxamide rac. N-(9-Ethyl-9H-carbazol-3-yl)-5-oxo-l-phenethyl- 0.012 pyrrolidine-3-carboxamide rac. Ethyl [(4-{ [1-(2,5-dimethylphenyl)-5-oxopyr- 0.013 rolidine-3-carbonyl]amino}phenyl)phenylamino]acetate rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-cycloheptyl-5- 0.015 oxopyrrolidine-3-carboxamide rac. N-{4-[(4,6-Dimethylpyrimidin-2-yl)ethylamino]- 0.015 phenyl}-1-(5-methoxy-2-methylphenyl)-5-oxopyrrol idine-3-carboxamide WO 03/059905 PCT/CH02/00725 -19 rae. N-{4--Ethyl-(2-hydroxyethyl)amino]phenyl}- 0.016 1- (2, 5-dimethyiphenyl) -5-oxepyrrolidine-3-earbox amide rae. N-[4-(Ethylphenylamino)phenyl]l-(2,5-dimethyl- 0.017 phenyl) -5-oxopyrrolidine-3-earboxamide rac. N-(9-Ethyl-9H--earbazoi--3-yl)-1-(3-methoxy- 0.020 phenyl) -5-oxopyrrolidiie-3--carboxamide rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-(2-ehloro- 0.020 benzyl) -5-oxopyrrolidine-3-carboxamide rae. 1-4-(4,6-Dimethylpyrimidin-2-ylamino)phenyl]- 0.020 1- (2, 5-dimethyiphenyl) -5-oxopyrrolidine-3-carbox amiderae. N-{4-[ (4,6-Dimethylpyrimidin-2-yl)methylamino]- 0.020 phenyi}-1- (2, 5-dimethyiphenyl) -5-oxopyrrolidine 3-carboxamide rae. N-(9-Ethyi-9H-carbazol-3-yl)-5-oxo-l-phelyl- 0.021 pyrrolidine-3-carboxamide rae. N-(4-( (4,6-Dimethylpyrimidin-2-yl)methylamino]- 0.022 phenyl I-5-oxo-i-p-tolylpyrrolidine-3-earboxamide rae. N-[4-(Isopropylphenylamino)phenyil]-l-2,5-di- 0.022 methyiphenyl) -S-oxopyrrolidine-3-carboxamide rae. N-[4-(Ethyiphenyiamino)phenyl]-1-(2-isopropyl- 0.023 phenyl) -5-oxopyrrolidine-3-earboxamide rae. N-{4-[ (4,6-Dimethylpyrimidin-2--yl)ethylaminol- 0.024 phenyi}-5-oxo-1- (2-pyridin-2-ylethyi)pyrrolidine 3-earboxamide rae. N-[4-(4, 6-Dimethylpyrimidin-2-ylamino)pheny]-- 0.025 1- (2-isopropyiphenyl) -5-oxopyrroiidine-3-carboxamide rae. N-[4-(4, 6-Dimethyipyrimidin-2--yiamino)phenyi]- 0.026 1- (5-methoxy-2-methyiphenyi) -5-oxopyrrolidine 3-earboxamide rae. N-[4-(Methylphenylamino)phenyl]-1-(2,5-di- 0.026 methyiphenyl) -5-oxopyrrolidine-3-earboxamide rae. N-[4-(Methylphenylamino)phenyl]-1-(2-isopropyl- 0.020 phenyl) -5-oxopyrroiidine-3--earboxamide rae. N-(9-Ethyi-9H--earbazoi-3-yl) -1-(4-isopropyl- 0.030 phenyl) -5-oxopyrrolidine-3--earboxamide ___ WO 03/059905 PCT/CH02/00725 - 20 rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-(3-fluoro- 0.030 phenyl)-5-oxopyrrolidine-3-carboxamide rac. N-(4-Phenylaminophenyl)-1l-(2,5-dimethylphenyl)- 0.030 5-oxopyrrolidine-3-carboxamide rac. N-[4-(4,6-Dimethylpyrimidin-2-ylamino)phenyl]- 0.030 1-indan-2-yl-5-oxopyrrolidine-3-carboxamide rac. N-[4-(Ethylphenylamino)phenyl]-1-(5-methoxy- 0.030 2-methylphenyl)-5-oxopyrrolidine-3-carboxamide rac. N-{4-[(4,6-Dimethylpyrimidin-2-yl)methylamino]- 0.031 phenyl}-1-(2-isopropylphenyl)-5-oxopyrrolidine 3-carboxamide rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-benzyl-5-oxopyr- 0.032 rolidine-3-carboxamide rac. N-[4-(4,6-Dimethylpyrimidin-2-ylamino)phenyl]- 0.032 5-oxo-l-p-tolylpyrrolidine-3-carboxamide rac. N-(9-Ethyl-9H-carbazol-3-yl)-l-indan-2-yl- 0.032 5-oxopyrrolidine-3-carboxamide rac. N-{4-[(4,6-Dimethylpyrimidin-2-yl)ethylamino]- 0.033 phenyl}-l-(2-hydroxy-2-phenylethyl)-5-oxo-pyrrol idine-3-carboxamide rac. N-(Biphenyl-4-yl)-1-(2,5-dimethylphenyl)-5-oxo- 0.034 pyrrolidine-3-carboxamide rac. N-[4-(Cyclopropylmethylphenylamino)phenyl]- 0.034 1-(5-methoxy-2-methylphenyl)-5-oxopyrrolidine-3-car boxamide rac. N-[4-(Isopropylphenylamino)phenyl]-1-(2- 0.034 isopropylphenyl)-5-oxopyrrolidine-3-carboxamide rac. N-(4-Phenylaminophenyl)-1-(2-isopropylphenyl)- 0.041 5-oxopyrrolidine-3-carboxamide rac. N-(4-[(4,6-Dimethylpyrimidin-2-yl)methylamino]- 0.041 phenyl}-l-(5-methoxy-2-methylphenyl)-5-oxopyrrol idine-3-carboxamide rac. N-{4-[(4,6-Dimethylpyrimidin-2-yl)ethylamino]- 0.044 phenyl}-1-(3-methoxyphenyl)-5-oxopyrrolidine-3-car boxamide rac. N-(4-Isopropylphenyl)-1-(2,5-dimethylphenyl)-5- 0.045 oxopyrrolidine-3-carboxamide WO 03/059905 PCT/CH02/00725 - 21 rac. N-[4-(Cyclopropylmethylphenylamino)phenyl]-1- 0.045 (2,5-dimethylphenyl)-5-oxopyrrolidine-3-carboxamide rac. N-{4-[(4,6-Dimethylpyrimidin-2-yl)ethylamino]- 0.046 phenyl}-l-(2-isopropylphenyl)-5-oxopyrrolidine 3-carboxamide rac. Ethyl [(4-{[1-(5-methoxy-2-methylphenyl)-5-oxo- 0.046 pyrrolidine-3-carbonyl]amino}phenyl)phenylamino] acetate rac. N-[4-(Cyclopropylmethylphenylamino)phenyl]- 0.047 1-(2-isopropylphenyl)-5-oxopyrrolidine-3-carboxamide rac. N-[4-(Ethylphenylamino)phenyl]-l-indan-2-yl- 0.049 5-oxopyrrolidine-3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-l-(2-morpholin-4- 0.01 ylethyl)-5-oxopyrrolidine-3-carboxamide rac. N-(9-Ethyl-9H-carbazol-3-yl)-5-oxo-l-p-tolyl- 0.03 pyrrolidine-3-carboxamide rac. N-(9-Ethyl-9H-carbazol-3-yl)-l-(2,4-dimethoxy- 0.02 benzyl)-5-oxopyrrolidine-3-carboxamide Methods which are well known and familiar to every skilled person can be used to bring the compounds according to the invention into suitable pharmaceutical 5 forms for administration. Examples of these administration forms are tablets, lacquered tablets, sugar-coated tablets, capsules, solutions for injection, etc. Excipients and auxiliary substances which are suitable for producing these pharmaceutical 10 administration forms are likewise well known and familiar to every skilled person. In addition to one or more compounds according to the invention, these administration forms can also comprise additional pharmacological active compounds. 15 The attending physician has to adjust the dosage of the compounds according to the invention, or of the administration forms which comprise them, in dependence on the particular requirements of the patient. In 20 general, a daily dose of 0.1-20 mg, preferably 0.5- WO 03/059905 PCT/CHO2/00725 - 22 5 mg, of a compound according to the invention per kg of the patient's body weight ought to be appropriate. The following examples are intended to clarify the 5 invention without, however, restricting its scope in any way. Example 1 (R1 is phenyl) 10 20.5 mg (0.1 mmol) of rac. 5-oxo-l-phenylpyrrolidine-3 carboxylic acid (Buzas et al., Chim Ther 7, 398-403, 1972), dissolved in 0.5 ml of methylene chloride/DMF (9:1), were added to solid phase coupling reagents (DCC, loading 1.7 mmol/g). The mixture was shaken for 15 5 minutes after which 13.6 mg (0.1 mmol) of N,N dimethyl-p-phenylenediamine, dissolved in 0.5 ml of methylene chloride/DMF (9:1), were added and the mixture was shaken at room temperature overnight. The solid was then filtered off and the filtrate was 20 evaporated; the residue was dissolved in 1 ml of methylene chloride and methylisocyanate polystyrene (1.8 mmol/g) (solid phase scavenger) was then added to the solution, which was shaken at room temperature for 12 hours and then filtered; Tris(2-aminoethyl)amine 25 polystyrene (3.4 mmol/g) was then added to the filtrate, which was shaken at room temperature for 12 hours and then filtered; the filtrate was evaporated. This resulted in 18 mg of colorless rac. N (4-dimethylaminophenyl)-5-oxo-l1-phenylpyrrolidine-3 30 carboxamide, MS (M+H) 324.3, MS (M-H) 322.5. Example 2 (R 1 is phenyl) The following products were prepared in analogy with 35 example 1 and using the amines which are listed below: a) from 4-phenoxyaniline, rac. N-(4-phenoxyphenyl)-5 oxo-1-phenylpyrrolidine-3-carboxamide, MS(M+H) 373.3, WO 03/059905 PCT/CHO2/00725 - 23 MS(M-H) 371.4. b) from 2-(3,4-dimethoxyphenyl)ethylamine, rac. N-[2 (3,4-dimethoxyphenyl)ethyl]-5-oxo-1-phenylpyrrolidine 5 3-carboxamide, MS(M+H) 369.3. c) from N-(4-aminophenyl)-N-ethyl-4,6-dimethyl-2-pyrim idine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)ethyl amino]phenyl}-5-oxo-1-phenylpyrrolidine-3-carboxamide, 10 MS(M+H) 430.3, MS(M-H) 428.5. d) from 2-aminofluorene, rac. N-(9H-fluoren-2-yl)-5 oxo-1-phenylpyrrolidine-3-carboxamide, MS(M+H9) 369.3, MS(M-H) 367.4. 15 e) from 3-aminobiphenyl, rac. N-(biphenyl-3-yl)-5-oxo 1-phenylpyrrolidine-3-carboxamide, MS(M+H) 357.2, MS(M-H) 355.4. 20 f) from N-(4-aminophenyl)-4,6-dimethyl-2-pyrimidine amine, N-[4-(4,6-dimethylpyrimidin-2-ylamino)phenyl] 5-oxo-1-phenylpyrrolidine-3-carboxamide, MS(M+H) 402.3, MS(M-H) 400.5. 25 g) from N-(4-aminophenyl)-N-methyl-4,6-dimethyl-2-pyr imidine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)methyl amino]phenyl}-5-oxo-1-phenylpyrrolidine-3-carboxamide, MS(M+H) 416.3, MS(M-H) 414.5. 30 h) from N-phenyl-1,4-phenylenediamine, rac. N-(4 phenylaminophenyl)-5-oxo-1-phenylpyrrolidine-3-carbox amide, MS(M+H) 372.2, MS(M-H) 370.5. i) from 3-amino-9-ethylcarbazole, rac. N-(9-ethyl 35 9H-carbazol-3-yl)-5-oxo-1-phenylpyrrolidine-3-carbox amide, MS(M+H) 398.2, MS(M-H) 396.3.
WO 03/059905 PCT/CHO2/00725 - 24 Example 3 (R1 is benzyl) a) The following products were prepared from rac. l-benzyl-5-oxo-l-pyrrolidine-3-carboxylic acid, in 5 analogy with example 1, using the amines which are listed below: al) from N-(4-aminophenyl)-N-ethyl-4,6-dimethyl-2-pyr imidine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)ethyl 10 amino]phenyl}-l-benzyl-5-oxopyrrolidine-3-carboxamide, MS(M+H) 444.3, MS(M-H) 442.5. a2) from N-(4-aminophenyl)-N-methyl-4,6-dimethyl-2-pyr imidine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)methyl 15 amino]phenyl}-l-benzyl-5-oxopyrrolidine-3-carboxamide, MS(M+H) 430.4, MS(M-H) 428.5. a3) from 3-amino-9-ethylcarbazole, rac. N-(9-ethyl-9H carbazol-3-yl)-l-benzyl-5-oxopyrrolidine-3-carboxamide, 20 MS(M+H) 412.1, MS(M-H) 410.3. b) The rac. l-benzyl-5-oxo-l-pyrrolidine-3-carboxylic acid which was required for example 3a was prepared from benzylamine and itaconic acid in analogy with a 25 protocol published by Buzas et al. (Chim Ther 7, 398 403 (1972)). Example 4 (R I is 2,5-dimethylphenyl) 30 a) The following products were prepared from rac. 1-(2,5-dimethylphenyl)-5-oxo-l-pyrrolidine-3-carboxylic acid, in analogy with example 1, using the amines which are listed below: 35 al) from 4'-aminoacetophenone, rac. N-(4-acetylphenyl) 1-(2,5-dimethylphenyl)-5-oxopyrrolidine-3-carboxamide, MS(M+H) 351.3, MS(M-H) 349.5.
WO 03/059905 PCT/CHO2/00725 - 25 a2) from 3-aminobiphenyl, rac. N-(biphenyl-3-yl)-1 (2,5-dimethylphenyl)-5-oxopyrrolidine-3-carboxamide, MS(M+H) 385.3, MS(M-H) 383.4. 5 a3) from 3-amino-2-methoxydibenzofuran, rac. N-(2-meth oxydibenzofuran-3-yl)-1-(2,5-dimethylphenyl)-5-oxopyr rolidine-3-carboxamide, MS(M+H) 429.2, MS(M-H) 427.4. a4) from 2-amino-9-fluorenone, rac. N-(9-oxo-9H 10 fluoren-2-yl)-1-(2,5-dimethylphenyl)-5-oxopyrrolidine 3-carboxamide, MS(M+H) 411.2, MS(M-H) 409.4. a5) from 2-aminofluorene, rac. N-(9H-fluoren-2-yl)-1 (2,5-dimethylphenyl)-5-oxopyrrlidine-3-carboxamide, 15 MS(M+H) 397.3, MS(M-H) 395.5. a6) from N-(4-aminophenyl)-N-ethyl-4,6-dimethyl-2-pyr imidine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)ethyl amino]phenyl}-1-(2,5-dimethylphenyl)-5-oxopyrrolidine 20 3-carboxamide, MS(M+H) 458.4, MS(M-H) 456.5. a7) from N-(4-aminophenyl)-4,6-dimethyl-2-pyrimidine amine, rac. N-[4-(4,6-dimethylpyrimidin-2-ylamino) phenyl]-1-(2,5-dimethylphenyl)-5-oxopyrrolidine-3-car 25 boxamide, MS(M+H) 430.4, MS(M-H) 428.5. a8) from N-(4-aminophenyl-N-methyl-4,6-dimethyl-2-pyr imidine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)methyl amino]phenyl}-1-(2,5-dimethylphenyl)-5-oxopyrrolidine 30 3-carboxamide, MS(M+H) 444.4, MS(M-H) 442.5. a9) from N-phenyl-1,4-phenylenediamine, rac. N (4-phenylaminophenyl)-1-(2,5-dimethylphenyl)-5-oxopyr rolidine-3-carboxamide, MS(M+H) 400.3, MS(M-H) 398.5. 35 al0) from N,N-dimethyl-p-phenylenediamine, rac. N-(4 dimethylaminophenyl)-1-(2,5-dimethylphenyl)-5 oxopyrrolidine-3-carboxamide, MS(M+H) 352.3, WO 03/059905 PCT/CH02/00725 - 26 MS(M-H) 350.5. all) from p-methoxyaniline, rac. N-(4-methoxyphenyl)-1 (2,5-dimethylphenyl)-5-oxopyrrolidine-3-carboxamide, 5 MS(M+H) 339.2, MS(M-H) 337.4. a12) from N-ethyl-N-(2-hydroxyethyl)-p-phenylene diamine, rac. N-{4-[ethyl-(2 hydroxyethyl)amino]phenyl}-l-(2,5-dimethylphenyl)-5 10 oxopyrrolidine-3-carboxamide, MS(M+H) 396.4, MS(M H) 394.5. a13) from 4-amino-N-ethyl-N-isopropylaniline, rac. N [4-(ethylisopropylamino)phenyl]-1-(2,5-dimethylphenyl) 15 5-oxopyrrolidine-3-carboxamide, MS(M+H) 394.4, MS(M-H) 392.5. a14) from 4-amino-N,N-diethylaniline, rac. N-(4-di ethylaminophenyl)-1-(2,5-dimethylphenyl)-5-oxopyrrolid 20 ine-3-carboxamide, MS(M+H) 380.4, MS(M-H) 378.5. a15) from l-amino-9-fluorene, rac. N-(9H-fluoren-1-yl) 1-(2,5-dimethylphenyl)-5-oxopyrrolidine-3-carboxamide, MS(M+H) 397.3, MS(M-H) 395.5. 25 a16) from 4-aminobiphenyl, rac. N-(biphenyl-4-yl)-1 (2,5-dimethylphenyl)-5-oxopyrrolidine-3-carboxamide, MS(M+H) 385.3, MS(M-H) 383.4. 30 a17) from ethyl [(4-aminophenyl)phenylamino]acetate (example 4b2), rac. ethyl [(4-{[1-(2,5-dimethylphenyl) 5-oxopyrrolidine-3-carbonyl]amino}phenyl)phenylamino] acetate, MS(M+H) 486.4, MS(M-H) 484.5. 35 a18) from N-cyclopropylmethyl-N-phenylphenylene-1,4 diamine (example 4e2), rac. N-[4-(cyclopropylmethyl phenylamino)phenyl]-1-(2,5-dimethylphenyl)-5-oxopyr rolidine-3-carboxamide, MS(M+H) 454.15, MS(M-H) 454.5.
WO 03/059905 PCT/CHO2/00725 - 27 a19) from N-isobutyl-N-phenylphenylene-l,4-diamine (example 4d2), rac. N-[4-(isobutylphenylamino)phenyl] 1-(2,5-dimethylphenyl)-5-oxopyrrolidine-3-carboxamide, MS(M+H) 456.4, MS(M-H) 454.5. 5 a20) from N-methyl-N-phenylphenylene-l,4-diamine (example 4e2), rac. N-[4-(methylphenylamino)phenyl]-l (2,5-dimethylphenyl)-5-oxopyrrolidine-3-carboxamide, MS(M+H) 414.3, MS(M-H) 412.5. 10 a21) from ethyl [(4-aminophenyl)phenylamino]pentanoate (example 4f2), rac. ethyl 5-[(4-{[1-(2,5-dimethyl phenyl)-5-oxopyrrolidine-3-carbonyl]amino}phenyl) phenylamino]pentanoate, MS(M+H) 528.5. 15 a22) from N-benzyl-N-phenyl-l,4-diamine (example 4g2), rac. N-[4-(benzylphenylamino)phenyl]-l-(2,5-dimethyl phenyl)-5-oxopyrrolidine-3-carboxamide, MS(M+H) 490.3, MS(M-H) 488.5. 20 a23) from N-isopropyl-N-phenyl-l,4-diamine (example 4h2), rac. N-[4-(isopropylphenylamino)phenyl]-l-(2,5 dimethylphenyl)-5-oxopyrrolidine-3-carboxamide, MS(M+H) 442.4, MS(M-H) 440.5. 25 a24) from N-ethyl-N-phenyl-1,4-diamine (example 4i2), rac. N-[4-(ethylphenylamino)phenyl]-1-(2,5-dimethyl phenyl)-5-oxopyrrolidine-3-carboxamide, MS(M+H) 428.4, MS(M-H) 426.5. 30 b) The rac. 2,5-dimethylphenyl-5-oxo-1-pyrrolidine-3 carboxylic acid which was required for example 4a was prepared in analogy with example 3b) but using 2,5 dimethylaniline in place of benzylamine. 35 bl) The ethyl [(4-aminophenyl)phenylamino]acetate required in example 4a17) was prepared as follows: 62 mg of sodium hydride dispersion (60%), and then WO 03/059905 PCT/CH02/00725 - 28 178 il of ethyl bromoacetate, were added to a solution of 300 mg of 4-nitrodiphenylamine in 3 ml of DMF. The reaction mixture was stirred at room temperature for 16 hours and then at 50°C for 4 hours, after which it 5 was cooled down and diluted with 3 ml of toluene; the solution was then filtered. The filtrate was evaporated and the residue was purified by chromatography on silica gel (pentane/toluene). This resulted in 197 mg of pure ethyl [(4-nitrophenyl)phenylamino]acetate. 10 b2) The 197 mg of ethyl [(4-nitrophenyl)phenyl amino]acetate which were obtained as described in example 4b1 were dissolved in 2 ml of methanol after which 20 mg of palladium/charcoal catalyst were added 15 and the mixture was hydrogenated at room temperature for 3 hours. After the reaction mixture had been filtered and the filtrate evaporated, 173 mg of ethyl [(4-aminophenyl)phenylamino]acetate, MS(M+H) 271.1, were obtained. 20 cl) The cyclopropylmethyl(4-nitrophenyl)phenylamine was prepared in analogy with example 4b1 but using (bromomethyl)cyclopropane in place of ethyl bromoacetate. 25 c2) The N-cyclopropylmethyl-N-phenylphenylene-l,4 diamine, MS(M+H) 239.3, was prepared in analogy with example 4b2 but using the product from example 4cl. 30 dl) The isobutyl(4-nitrophenyl)phenylamine was prepared in analogy with example 4b1 but using 3-bromo-2 methylpropane in place of ethyl bromoacetate. d2) The N-isobutyl-N-phenylphenylene-l,4-diamine, 35 MS(M+H) 241.3, was prepared in analogy with example 4b2 but using the product from example 4d1. el) The methyl(4-nitrophenyl)phenylamine was prepared WO 03/059905 PCT/CHO2/00725 - 29 in analogy with example 4b1 but using methyl iodide in place of ethyl bromoacetate. e2) The N-methyl-N-phenylphenylene-l,4-diamine, MS(M+H) 5 199.3, was prepared in analogy with example 4b2 but using the product from example 4e1. fl) The ethyl [(4-nitrophenyl)phenylamino]pentanoate was prepared in analogy with example 4b1 but using 10 ethyl bromopentanoate in place of ethyl bromoacetate. f2) The ethyl [(4-aminophenyl)phenylamino]pentanoate, MS(M+H) 313.2, was prepared in analogy with example 4b2 but using the product from example 4fl. 15 gl) The benzyl (4-nitrophenyl)phenylamine was prepared in analogy with example 4b1 but using benzyl bromide in place of ethyl bromoacetate. 20 g2) The N-benzyl-N-phenylphenylene-l,4-diamine, MS(M+H) 275.3, was prepared in analogy with example 4b2 but using the product from example 4g1. hl) The isopropyl(4-nitrophenyl)phenylamine was 25 prepared in analogy with example 4b1 but using 2-bromo propane in place of ethyl bromoacetate. h2) The N-isopropyl-N-phenylphenylene-l,4-diamine, MS(M+H) 227.3, was prepared in analogy with example 4b2 30 but using the product from example 4hl. il) The ethyl(4-nitrophenyl)phenylamine was prepared in analogy with example 4b1 but using bromoethane in place of ethyl bromoacetate. 35 i2) The N-ethyl-N-phenylphenylene-l,4-diamine, MS(M+H) 213.3, was prepared in analogy with example 4b2 but using the product from example 4il.
WO 03/059905 PCT/CHO2/00725 - 30 Example 5 (R1 is indan-2-yl) a) The following products were prepared from rac. l-indan-2-yl-5-oxopyrrolidine-3-carboxylic cid, in 5 analogy with example 1, using the amines which are listed below: al) from 3-aminobiphenyl, rac. N-(biphenyl-3-yl)-1 indan-2-yl-5-oxopyrrolidine-3-carboxamide, 10 MS(M+H) 397.3, MS(M-H) 395.5. a2) from 3-amino-2-methoxydibenzofuran, rac. N-(2 methoxydibenzofuran-3-yl)-l-indan-2-yl-5-oxopyrrolid ine-3-carboxamide, MS(M+H) 441.2, MS(M-H) 439.5. 15 a3) from 2-amino-9-fluorenone, rac. N-(9-oxo-9H fluoren-2-yl)-l-indan-2-yl-5-oxopyrrolidine-3-carbox amide, MS(M+H) 423.2, MS(M-H) 421.4. 20 a4) from 2-aminofluorene, rac. N-(9H-fluoren-2-yl)-l indan-2-yl-5-oxopyrrolidine-3-carboxamide, MS(M+H) 409.3, MS(M-H) 407.5. a5) from N-(4-aminophenyl)-N-ethyl-4,6-dimethyl-2-pyr 25 imidine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)ethyl amino]phenyl}-l-indan-2-yl-5-oxopyrrolidine-3-carbox amide, MS(M+H) 470.4, MS(M-H) 468.5. a6) from N-(4-aminophenyl)-4,6-dimethyl-2-pyrimidine 30 amine, rac. N-[4-(4,6-dimethylpyrimidin-2-ylamino) phenyl]-l-indan-2-yl-5-oxopyrrolidine-3-carboxamide, MS(M+H) 442.4, MS(M-H) 440.5. a7) from N-(4-aminophenyl)-N-methyl-4,6-dimethyl-2-pyr 35 imidine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)methyl amino]phenyl}-l-indan-2-yl-5-oxopyrrolidine-3-carbox amide, MS(M+H) 456.3, MS(M-H) 454.5.
WO 03/059905 PCT/CHO2/00725 - 31 a8) from N-phenyl-l,4-phenylenediamine, rac. N-(4 phenylaminophenyl)-l-indan-2-yl-5-oxopyrrolidine-3 carboxamide, MS(M+H) 412.3, MS(M-H) 410.5. 5 a9) from l-amino-9-fluorene, rac. N-(9H-fluoren-l-yl) 1-indan-2-yl-5-oxopyrrolidine-3-carboxamide, MS(M+H) 409.3, MS(M-H) 407.5. alO0) from 4-aminobiphenyl, rac. N-(biphenyl-4-yl)-1 10 indan-2-yl-5-oxopyrrolidine-3-carboxamide, MS(M+H) 397.3, MS(M-H) 395.5. all) from 3-amino-9-ethylcarbazole, rac. N-(9-ethyl-9H carbazol-3-yl)-l-indan-2-yl-5-oxopyrrolidine-3-carbox 15 amide, MS(M+H) 438.4, MS(M-H) 436.3. a12) from N,N-dimethyl-p-phenylenediamine, rac. N-(4 dimethylaminophenyl)-l-indan-2-yl-5-oxopyrrolidine-3 carboxamide, MS(M+H) 364.3, MS(M-H) 362.1. 20 a13) from ethyl [(4-aminophenyl)phenylamino]acetate (see example 3a22), rac. ethyl ({4-[(l-indan-2-yl-5 oxopyrrolidine-3-carbonyl)amino]phenyl}phenylamino) acetate, MS(M+H) 498.3, MS(M-H) 496.5. 25 a14) from N-cyclopropylmethyl-N-phenylphenylene-1,4-di amine (see example 3a23), rac. N-[4-(cyclopropylmethyl phenylamino)phenyl]-l-indan-2-yl-5-oxopyrrolidine 3-carboxamide, MS(M+H) 466.4, MS(M-H) 464.5. 30 al5) from N-isobutyl-N-phenylphenylene-l,4-diamine (example 4d2), rac. N-[4-(isobutylphenylamino)phenyl] 1-indan-2-yl-5-oxopyrrolidine-3-carboxamide, MS(M+H) 468.3, MS(M-H) 466.5. 35 a16) from N-methyl-N-phenylphenylene-l,4-diamine (example 4e2), rac. N-[4-(methylphenylamino)phenyl] l-indan-2-yl-5-oxopyrrolidine-3-carboxamide, WO 03/059905 PCT/CHO2/00725 - 32 MS(M+H) 426.3, MS(M-H) 424.5. al7) from ethyl [(4-aminophenyl)phenylamino]pentanoate (example 4f2), rac. ethyl 5-({4-[(l-indan-2-yl-5 5 oxopyrrolidine-3-carbonyl)amino]phenyl}phenylamino) pentanoate, MS(M+H) 540.4, MS(M-H) 538.5. al8) from N-benzyl-N-phenylphenylene-l,4-diamine (example 4g2), rac. N-[4-(benzylphenylamino)phenyl]-l 10 indan-2-yl-5-oxopyrrolidine-3-carboxamide, MS(M+H) 502.3, MS(M-H) 500.5. a19) from N-isopropyl-N-phenylphenylene-1,4-diamine (example 4h2), rac. N-[4-(isopropylphenylamino)phenyl] 15 l-indan-2-yl-5-oxopyrrolidine-3-carboxamide, MS(M+H) 454.4, MS(M-H) 452.5. a20) from N-ethyl-N-phenylphenylene-l,4-diamine (example 4i2), rac. N-[4-(ethylphenylamino)phenyl] 20 l-indan-2-yl-5-oxopyrrolidine-3-carboxamide, MS(M+H) 440.3, MS(M-H) 438.5. b) The rac. l-indan-2-yl-5-oxopyrrolidine-3-carboxylic acid required for example Sa was prepared in analogy 25 with example 3b) but using indan-2-amine in place of benzylamine. Example 6 (R1 is 2-naphthyl) 30 a) The following products were prepared from rac. 1 naphthalen-2-yl-5-oxopyrrolidine-3-carboxylic acid, in analogy with example 1, using the amines which are listed below: 35 al) from 4-phenoxyaniline, rac. N-(4-phenoxyphenyl)-l naphthalen-2-yl-5-oxopyrrolidine-3-carboxamide, MS(M+H) 423.4, MS(M-H) 421.3.
WO 03/059905 PCT/CHO2/00725 - 33 a2) from N,N-dimethyl-p-phenylenediamine, rac. N-(4-di methylaminophenyl)-l-naphthalen-2-yl-5-oxopyrrolidine 3-carboxamide, MS(M+H) 374.3, MS(M-H) 372.5. 5 b) The rac. l-naphthalen-2-yl-5-oxopyrrolidine 3-carboxylic acid required for example 6a was prepared in analogy with example 3b) but using 2-naphthylamine in place of benzylamine. 10 Example 7 (R 1 is 2-isopropylphenyl) a) The following products were prepared from rac. 1-(2 isopropylphenyl)-5-oxopyrrolidine-3-carboxylic acid, in analogy with example 1, using the amines which are 15 listed below: al) from N-(4-aminophenyl)-4,6-dimethyl-2-pyrimidine amine, rac. N-[4-(4,6-dimethylpyrimidin-2-ylamino) phenyl]-1-(2-isopropylphenyl)-5-oxopyrrolidine-3-car 20 boxamide, MS(M+H) 444.4, MS(M-H) 442.5. a2) from N-(4-aminophenyl)-N-methyl-4,6-dimethyl-2-pyr imidine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)methyl amino]phenyl}-l-(2-isopropylphenyl)-5-oxopyrrolidine-3 25 carboxamide, MS(M+H) 458.4, MS(M-H) 456.5. a3) from N-(4-aminophenyl)-N-ethyl-4,6-dimethyl-2-pyr imidine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)ethyl amino]phenyl}-1-(2-isopropylphenyl)-5-oxopyrrolidine-3 30 carboxamide, MS(M+H) 472.2, MS(M-H) 470.5. a4) from N-phenyl-l,4-phenylenediamine, rac. N-(4 phenylaminophenyl)-1-(2-isopropylphenyl)-5-oxopyr rolidine-3-carboxamide, MS(M+H) 414.3, MS(M-H) 412.5. 35 aS) from 3-amino-9-ethylcarbazole, rac. N-(9-ethyl-9H carbazol-3-yl)-1-(2-isopropylphenyl)-5-oxopyrrolidine 3-carboxamide, MS(M+H) 440'.4, MS(M-H) 438.3.
WO 03/059905 PCT/CH02/00725 - 34 a6) from ethyl [(4-aminophenyl)phenylamino]acetate (see example 3a22), rac. ethyl [(4-f {[l-(2-isopropylphenyl) 5-oxopyrrolidine-3-carbonyl]amino}phenyl)phenylamino] 5 acetate, MS(M+H) 500.3, MS(M-H) 498.5. a7) from N-cyclopropylmethyl-N-phenylphenylene-l,4-di amine (see example 3a23), rac. N-[4-(cyclopropylmethyl phenylamino)phenyl]-1-(2-isopropylphenyl)-5-oxopyr 10 rolidine-3-carboxamide, MS(M+H) 468.4, MS(M-H) 466.5. aB) from N-isobutyl-N-phenylphenylene-l,4-diamine (example 4d2), rac. N-[4-(isobutylphenylamino)phenyl] 1-(2-isopropylphenyl)-5-oxopyrrolidine-3-carboxamide, 15 MS(M+H) 470.4, MS(M-H) 468.5. a9) from N-methyl-N-phenylphenylene-l,4-diamine (example 4e2), rac. N-[4-(methylphenylamino)phenyl] 1-(2-isopropylphenyl)-5-oxopyrrolidine-3-carboxamide, 20 MS(M+H) 428.4, MS(M-H) 426.5. al0) from ethyl [(4-aminophenyl)phenylamino]pentanoate (example 4f2), rac. ethyl 5-[(4-{[l-(2-isopropyl phenyl)-5-oxopyrrolidine-3-carbonyl]amino}phenyl) 25 phenylamino]pentanoate, MS(M+H) 542.4, MS(M-H) 540.6. all) from N-benzyl-N-phenylphenylene-l,4-diamine (example 4g2), rac. N-[4-(benzylphenylamino)phenyl]-l (2-isopropylphenyl)-5-oxopyrrolidine-3-carboxamide, 30 MS(M+H) 504.3, MS(M-H) 502.5. al2) from N-isopropyl-N-phenylphenylene-l,4-diamine (example 4h2), rac. N-[4-(isopropylphenylamino)phenyl] 1-(2-isopropylphenyl)-5-oxopyrrolidine-3-carboxamide, 35 MS(M+H) 456.4, MS(M-H) 454.5. a13) from N-ethyl-N-phenylphenylene-1,4-diamine (example 4i2), rac. N-[4-(ethylphenylamino)phenyl]- WO 03/059905 PCT/CHO2/00725 - 35 1-( 2 -isopropylphenyl)-5-oxopyrrolidine-3-carboxamide, MS(M+H) 442.4, MS(M-H) 440.5. b) The rac. 1-( 2 -isopropylphenyl)-5-oxopyrrolidine-3 5 carboxylic acid required for example 7a was prepared in analogy with example 3b) but using isopropylamine in place of benzylamine. Example 8 (R 1 is 2-phenylethyl) 10 a) The following products were prepared from rac. 5 oxo-l-phenethylpyrrolidine-3-carboxylic acid, in analogy with example 1, using the amines which are listed below: 15 al) from 4-phenoxyaniline, rac. N-(4-phenoxyphenyl)-5 oxo-l-phenethylpyrrolidine-3-carboxamide, MS(M+H) 401.3, MS(M-H) 399.5. 20 a2) from N,N-dimethyl-p-phenylenediamine, rac. N-(4 dimethylaminophenyl)-5-oxo-1-phenethylpyrrolidine-3 carboxamide, MS(M+H) 352.3, MS(M-H) 350.5. a3) from N-(4-aminophenyl)-N-ethyl-4,6-dimethyl-2-pyr 25 imidine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)ethyl amino]phenyl}-5-oxo-1-phenethylpyrrolidine-3-carbox amide, MS(M+H) 458.4, MS(M-H) 456.5. a4) from 3-aminobiphenyl, rac. N-(biphenyl-3-yl)-5-oxo 30 l-phenethylpyrrolidine-3-carboxamide, MS(M+H) 385.2, MS(M-H) 383.4. a5) from 2-amino-9-fluorenone, rac. N-(9-oxo-9H fluoren-2-yl)-5-oxo-l-phenethylpyrrolidine-3-carbox 35 amide, MS(M+H) 411.3, MS(M-H) 409.4. a6) from 2-aminofluorene, rac. N-(9H-fluoren-2-yl)-5 oxo-l-phenethylpyrrolidine-3-carboxamide, WO 03/059905 PCT/CH02/00725 - 36 MS(M+H) 397.3, MS(M-H) 395.5. a7) from N-( 4 -aminophenyl)-4,6-dimethyl-2-pyrimidine amine, rac. N-[ 4
-(
4 ,6-dimethylpyrimidin-2-ylamino) 5 phenyl]-5-oxo-l-phenethylpyrrolidine-3-carboxamide, MS(M+H) 430.3, MS(M-H) 428.5. a8) from N-(4-aminophenyl)-N-methyl-4,6-dimethyl-2-pyr imidine, rac. N-{4-[( 4 ,6-dimethylpyrimidin-2-yl)methyl 10 amino]phenyl}-5-oxo-l-phenethylpyrrolidine-3-carbox amide, MS(M+H) 444.3, MS(M-H) 442.5. a9) from N-phenyl-l,4-phenylenediamine, rac. N-(4-phen ylaminophenyl)-5-oxo-1-phenethylpyrrolidine-3-carbox 15 amide, MS(M+H) 400.3, MS(M-H) 398.5. al0) from 4-aminobiphenyl, rac. N-(biphenyl-4-yl) 5-oxo-l-phenethylpyrrolidine-3-carboxamide, MS(M+) 385.4, MS(M-H) 383.4. 20 all) from 3 -amino-9-ethylcarbazole, rac. N-(9-ethyl-9H carbazol-3-yl)-5-oxo-1-phenethylpyrrolidine-3 carboxamide, MS(M+H) 426.3, MS(M-H) 424.4. 25 b) The rac. 5-oxo-l-phenethylpyrrolidine-3-carboxylic acid required for example 8a was prepared in analogy with example 3b) but using phenethylamine in place of benzylamine. 30 Example 9 (R 1 is 5-methoxy-2-methylphenyl) a) The following compounds were prepared from rac. 1-(5-methoxy-2-methylphenyl)-5-oxopyrrolidine-3-carbox ylic acid, in analogy with example 1, using the amines 35 which are listed below: al) from N-(4-aminophenyl)-4,6-dimethyl-2-pyrimidine amine, rac. N-[4-(4,6-dimethylpyrimidin-2-ylamino)- WO 03/059905 PCT/CHO2/00725 - 37 phenyl]-1-(5-methoxy-2-methylphenyl)-5-oxopyrrolidine 3-carboxamide, MS(M+H) 446.4, MS(M-H) 444.5. a2) from N-(4-aminophenyl)-N-methyl-4,6-dimethyl-2-pyr 5 imidine, rac. N-{4-[( 4 ,6-dimethylpyrimidin-2-yl)methyl amino]phenyl}-1-(5-methoxy-2-methylphenyl)-5-oxopyrrol idine-3-carboxamide, MS(M+H) 460.4, MS(M-H) 458.5. a3) from N-(4-aminophenyl)-N-ethyl-4,6-dimethyl-2-pyr-, 10 imidine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)ethyl amino]phenyl}-1-(5-methoxy-2-methylphenyl)-5-oxopyrrol idine-3-carboxamide, MS(M+H) 474.0, MS(M-H) 472.5. a4) from N-phenyl-1,4-phenylenediamine, rac. N-(4-phen 15 ylaminophenyl)-1-(5-methoxy-2-methylphenyl)-5-oxopyr rolidine-3-carboxamide, MS(M+H) 416.3, MS(M-H) 414.5. a5) from 3-amino-9-ethylcarbazole, rac. N-(9-ethyl-9H carbazol-3-yl)-1-(5-methoxy-2-methylphenyl)-5-oxopyr 20 rolidine-3-carboxamide, MS(M+H) 442.6, MS(M-H) 440.3. a6) from ethyl [(4-aminophenyl)phenylamino]acetate (see example 3a22), rac. ethyl [(4-{[1-(5-methoxy-2-meth ylphenyl)-5-oxopyrrolidine-3-carbonyl]amino}phenyl) 25 phenylamino]acetate, MS(M+H) 502.3, MS(M-H) 500.5. a7) from N-cyclopropylmethyl-N-phenylphenylene-l,4-di amine (see example 3a23), rac. N-[4-(cyclopropylmethyl phenylamino)phenyl]-1-(5-methoxy-2-methylphenyl)-5-oxo 30 pyrrolidine-3-carboxamide, MS(M+H) 470.4, MS(M-H) 468.5. a8) from N-isobutyl-N-phenylphenylene-1,4-diamine (example 4d2), rac. N-[4-(isobutylphenylamino)phenyl] 1-(5-methoxy-2-methylphenyl-5-oxopyrrolidine-3-carbox 35 amide, MS(M+H) 472.3, MS(M-H) 470.5. a9) from N-methyl-N-phenylphenylene-1,4-diamine (example 4e2), rac. N-[4-(methylphenylamino)phenyl]-l- WO 03/059905 PCT/CHO2/00725 - 38 (5-methoxy-2-methylphenyl)-5-oxopyrrolidine-3-carbox amide, MS(M+H) 430.3, MS(M-H) 428.5. al0) from ethyl [( 4 -aminophenyl)phenylamino]pentanoate 5 (example 4f2), rac. ethyl 5-[(4-{[I-(5-methoxy-2-meth ylphenyl)-5-oxopyrrolidine-3-carbonyl]amino}phenyl) phenylamino]pentanoate, MS(M+H) 544.5, MS(M-H) 542.6. all) from N-benzyl-N-phenylphenylene-l,4-diamine 10 (example 4g2), rac. N-[4-(benzylphenylamino)phenyl]-l (5-methoxy-2-methylphenyl)-5-oxopyrrolidine-3 carboxamide, MS(M+H) 506.3, MS(M-H) 504.5. a12) from N-isopropyl-N-phenylphenylene-1,4-diamine 15 (example 4h2), rac. N-[4-(isopropylphenylamino)phenyl] 1-(5-methoxy-2-methylphenyl)-5-oxopyrrolidine-3 carboxamide, MS(M+H) 458.4, MS(M-H) 456.5. a13) from N-ethyl-N-phenylphenylene-l,4-diamine 20 (example 4i2); rac. N-[4-(ethylphenylamino)phenyl]-l (5-methoxy-2-methylphenyl)-5-oxopyrrolidine-3 carboxamide, MS(M+H) 444.4, MS(M-H) 442.5. b) The rac. 1-(5-methoxy-2-methylphenyl)-5-oxopyrrol 25 idine-3-carboxylic acid required for example 9a was prepared in analogy with example 3b) but using 5-methoxy-2-methylaniline in place of benzylamine. Example 10 (R i is morpholinoethyl) 30 a) The following products were prepared from rac. 1 (2-morpholin-4-ylethyl)-5-oxopyrrolidine-3-carboxylic acid, in analogy with example 1, using the amines which are listed below: 35 al) from 2-aminofluorene, rac. N-(9H-fluoren-2-yl)-l (2-morpholin-4-ylethyl)-5-oxopyrrolidine-3-carboxamide, MS(M+H) 406.4, MS(M-H) 404.5.
WO 03/059905 PCT/CHO2/00725 - 39 a2) from N-(4-aminophenyl)-N-ethyl-4,6-dimethyl-2-pyr imidine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)ethyl amino]phenyl}-l-(2-morpholin-4-ylethyl)-5 5 oxopyrrolidine-3-carboxamide, MS(M+H) 467.3, MS(M H) 4465.5. a3) from 3 -amino-9-ethylcarbazole, rac. N-(9-ethyl-9H carbazol-3-yl)-1-(2-morpholin-4-ylethyl)-5-oxopyrrol 10 idine-3-carboxamide, MS(M+H) 435.5, MS(M-H) 433.3. b) The rac. l-(5-methoxy-2-methylphenyl)-5 oxopyrrolidine-3-carboxylic acid required for example 10a was prepared in analogy with example 3b) but using 15 4-(2-aminoethyl)morpholine in place of benzylamine. Example 11 (R I is thien-2-ylethyl) a) The following products were prepared from rac. 20 5-oxo-l-(2-thiophen-2-ylethyl)pyrrolidine-3-carboxylic acid, in analogy with example 1, using the amines which are listed below: al) from N-(4-aminophenyl)-4,6-dimethyl-2-pyrimidine 25 amine, rac. N-[4-(4,6-dimethylpyrimidin-2-ylamino) phenyl]-5-oxo-l-(2-thiophen-2-ylethyl)pyrrolidine-3 carboxamide, MS(M+H) 436.3, MS(M-H) 434.5. a2) from N-(4-aminophenyl)-N-methyl-4,6-dimethyl-2-pyr 30 imidine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)methyl amino]phenyl}-5-oxo-l-(2-thiophen-2-ylethyl)pyrrolid ine-3-carboxamide, MS(M+H) 450.3, MS(M-H) 448.4. a3) from N-(4-aminophenyl)-N-ethyl-4,6-dimethyl-2-pyr 35 imidine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)ethyl amino]phenyl}-5-oxo-l-(2-thiophen-2-ylethyl)pyrrolid ine-3-carboxamide, MS(M+H) 464.5, MS(M-H) 462.5.
WO 03/059905 PCT/CHO2/00725 - 40 a4) from N-phenyl-1,4-phenylenediamine, rac. N (4-phenylaminophenyl)-5-oxo-l-(2-thiophen-2-ylethyl) pyrrolidine-3-carboxamide, MS(M+H) 406.2, MS(M-H) 404.4. 5 aS) from 3-amino-9-ethylcarbazole, rac. N-(9-ethyl-9H carbazol-3-yl)-5-oxo-l-(2-thiophen-2-ylethyl)pyrrolid ine-3-carboxamide, MS(M+H) 432.2, MS(M-H) 430.2. b) The rac. 5-oxo-l-(2-thiophen-2-ylethyl)pyrrolidine 10 3-carboxylic acid required for example lla was prepared in analogy with example 3b) but using 2-thiophene ethylamine in place of benzylamine. Example 12 (R 1 is 2-pyridin-2-ylethyl) 15 a) The following products were prepared from rac. 5 oxo-l-(2-pyridin-2-ylethyl)pyrrolidine-3-carboxylic acid, in analogy with example 1, using the amines which are listed below: 20 al) from N-(4-aminophenyl)-4,6-dimethyl-2-pyrimidine amine, rac. N-[4-(4,6-dimethylpyrimidin-2-ylamino) phenyl]-5-oxo-l-(2-pyridin-2-ylethyl)pyrrolidine 3-carboxamide, MS(M+H) 431.3, MS(M-H) 429.5. 25 a2) from N-(4-aminophenyl)-N-methyl-4,6-dimethyl-2-pyr imidine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)methyl amino]phenyl}-5-oxo-l-( 2 -pyridin-2-ylethyl)pyrrolidine 3-carboxamide, MS(M+H) 445.3, MS(M-H) 443.5. 30 a3) from N-(4-aminophenyl)-N-ethyl-4,6-dimethyl-2-pyr imidine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)ethyl amino]phenyl}-5-oxo-l-( 2 -pyridin-2-ylethyl)pyrrolidine 3-carboxamide, MS(M+H) 459.3, MS(M-H) 457.5. 35 a4) from N-phenyl-l,4-phenylenediamine, rac. N-(4-phen ylaminophenyl)-5-oxo-1-(2-pyridin-2-ylethyl)pyrrolid ine-3-carboxamide, MS(M+H) 401.3, MS(M-H) 399.5.
WO 03/059905 PCT/CH02/00725 - 41 a5) from 3 -amino-9-ethylcarbazole, rac. N-(9-ethyl-9H carbazol-3-yl)-5-oxo-l-( 2 -pyridin-2-ylethyl)pyrrolid ine-3-carboxamide, MS(M+H) 427.5, MS(M-H) 425.4. 5 b) The rac. 5-oxo-l-(2-pyridin-2-ylethyl)pyrrolidine-3 carboxylic acid required for example 12a was prepared in analogy with example 3b) but using 2-(2 aminoethyl)pyridine in place of benzylamine. 10 Example 13 (R1 is p-tolyl) a) The following products were prepared from rac. 5-oxo-l-p-tolylpyrrolidine-3-carboxylic acid, in analogy with example 1, using the amines which are 15 listed below: al) from N-(4-aminophenyl)-4,6-dimethyl-2-pyrimidine amine, rac. N-[4-(4,6-dimethylpyrimidin-2-ylamino) phenyl]-5-oxo-l-p-tolylpyrrolidine-3-carboxamide, 20 MS(M+H) 416.4, MS(M-H) 414.5. a2) from N-(4-aminophenyl)-N-methyl-4,6-dimethyl-2-pyr imidine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)methyl amino]phenyl}-5-oxo-1-p-tolylpyrrolidine-3-carboxamide, 25 MS(M+H) 430.4, MS(M-H) 428.4. a3) from N-(4-aminophenyl)-N-ethyl-4,6-dimethyl-2-pyr imidine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)ethyl amino]phenyl}-5-oxo-l-p-tolylpyrrolidine-3-carboxamide, 30 MS(M+H) 444.3, MS(M-H) 442.5. a4) from N-phenyl-l,4-phenylenediamine, rac. N-(4 phenylaminophenyl)-5-oxo-l-p-tolylpyrrolidine-3 carboxamide, MS(M+H) 386.3, MS(M-H) 384.4. 35 aS) from 3-amino-9-ethylcarbazole, rac. N-(9-ethyl-9H carbazol-3-yl)-5-oxo-l-p-tolylpyrrolidine-3-carbox amide, MS(M+H) 412.1, MS(M-H) 410.3.
WO 03/059905 PCT/CH02/00725 - 42 b) The rac. 5-oxo-l-p-tolylpyrrolidine-3-carboxylic acid required for example 13a was prepared in analogy with example 3b) but using p-toluidine in place of benzylamine. 5 Example 14 (R3 is m-methoxyphenyl) a) The following products were prepared from rac. 1-(3 methoxyphenyl)-5-oxopyrrolidine-3-carboxylic acid, in 10 analogy with example 1, using the amines which are listed below: al) from N-(4-aminophenyl)-4,6-dimethyl-2-pyrimidine amine, rac. N-[4-(4,6-dimethylpyrimidin-2-ylamino) 15 phenyl]-1-(3-methoxyphenyl)-5-oxopyrrolidine-3-carbox amide, MS(M+H) 432.2, MS(M-H) 430.5. a2) from N-(4-aminophenyl)-N-methyl-4,6-dimethyl-2-pyr imidine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)methyl 20 amino]phenyl}-l-(3-methoxyphenyl)-5-oxopyrrolidine 3-carboxamide, MS(M+H) 446.4, MS(M-H) 444.5. a3) from N-(4-aminophenyl)-N-ethyl-4,6-dimethyl-2-pyr imidine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)ethyl 25 amino]phenyl}-l-(3-methoxyphenyl)-5-oxopyrrolidine 3-carboxamide, MS(M+H) 460.3, MS(M-H) 458.5. a4) from N-phenyl-l,4-phenylenediamine, rac. N-(4-phen ylaminophenyl)-1-(3-methoxyphenyl)-5-oxopyrrolidine 30 3-carboxamide, MS(M+H) 402.2, MS(M-H) 400.4. a5) from 3-amino-9-ethylcarbazole, rac. N-(9-ethyl-9H carbazol-3-yl)-1-(3-methoxyphenyl)-5-oxopyrrolidine 3-carboxamide, MS(M+H) 428.2, MS(M-H) 426.3. 35 b) The rac. 1-(3-methoxyphenyl)-5-oxopyrrolidine-3-car boxylic acid required for example 14a was prepared in analogy with example 3b) but using m-anisidine in place WO 03/059905 PCT/CH02/00725 - 43 of benzylamine. Example 15 (R 1 is cycloheptyl) 5 a) The following products were prepared from rac. l-cycloheptyl-5-oxopyrrolidine-3-carboxylic acid, in analogy with example 1, using the amines which are listed below: 10 al) from N-(4-aminophenyl)-4,6-dimethyl-2-pyrimidine amine, rac. N-[4-(4,6-dimethylpyrimidin-2 ylamino)phenyl]-l-cycloheptyl-5-oxopyrrolidine-3 carboxamide, MS(M+H) 422.5, MS(M-H) 420.5. 15 a2) from N-(4-aminophenyl)-N-methyl-4,6-dimethyl-2-pyr imidine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)methyl amino]phenyl}-l-cycloheptyl-5-oxopyrrolidine-3-carbox amide, MS(M+H) 436.6, MS(M-H) 434.0. 20 a3) from N-(4-aminophenyl)-N-ethyl-4,6-dimethyl-2-pyr imidine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)ethyl amino]phenyl}-l-cycloheptyl-5-oxopyrrolidine-3-carbox amide, MS(M+H) 450.6, MS(M-H) 448.6. 25 a4) from N-phenyl-l,4-phenylenediamine, rac. N-(4 phenylaminophenyl)-l-cycloheptyl-5-oxopyrrolidine-3 carboxamide, MS(M+H) 392.4, MS(M-H) 390.5. a5) from 3-amino-9-ethylcarbazole, rac. N-(9-ethyl-9H 30 carbazol-3-yl)-l-cycloheptyl-5-oxopyrrolidine-3 carboxamide, MS(M+H) 418.5, MS(M-H) 426.3. b) The rac. l-cycloheptyl-5-oxopyrrolidine-3-carboxylic acid required for example 15a was prepared in analogy 35 with example 3b) but using cycloheptylamine in place of benzylamine; MS(M+H) 226.1, MS(M-H) 224.1.
WO 03/059905 PCT/CHO2/00725 - 44 Example 16 (R is naphthalen-1-ylmethyl) a) The following products were prepared from rac. 1-naphthalen-l-ylmethyl-5-oxopyrrolidine-3-carboxylic 5 acid, in analogy with example 1, using the amines which are listed below: al) from N-(4-aminophenyl)-4,6-dimethyl-2-pyrimidine amine, rac. N-[4-(4,6-dimethylpyrimidin-2-ylamino) 10 phenyl]-1-naphthalen-l-ylmethyl-5-oxopyrrolidine-3-car boxamide, MS(M+H) 466.3, MS(M-H) 464.3. a2) from N-(4-aminophenyl)-N-methyl-4,6-dimethyl-2-pyr imidine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)methyl 15 amino]phenyl}-1-naphthalen-l-ylmethyl-5-oxopyrrolidine 3-carboxamide, MS(M+H) 480.4, MS(M-H) 478.5 a3) from N-(4-aminophenyl)-N-ethyl-4,6-dimethyl-2-pyr imidine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)ethyl 20 amino]phenyl}-1-naphthalen-l-ylmethyl-5-oxopyrrolidine 3-carboxamide, MS(M+H) 494.4, MS(M-H) 492.5. b) The rac. 1-naphthalen-1-ylmethyl-5-oxopyrrolidine 3-carboxylic acid required for example 16a was prepared 25 in analogy with example 3b) but using 1-naphthyl methylamine in place of benzylamine; MS(M+H) 270.1, MS(M-H) 268.1. Example 18 (R 1 is 2-hydroxy-2-phenylethyl) 30 a) The following products were prepared from rac. 1 (2-hydroxy-2-phenylethyl)-5-oxopyrrolidine-3-carboxylic acid, in analogy with example 1, using the amines which are listed below: 35 al) from N-(4-aminophenyl)-4,6-dimethyl-2-pyrimidine amine, rac. N-[4-(4,6-dimethylpyrimidin-2-ylamino)phen yl]-1-(2-hydroxy-2-phenylethyl)-5-oxopyrrolidine- WO 03/059905 PCT/CHO2/00725 - 45 3-carboxamide, MS(M+H) 446.4, MS(M-H) 444.5. a2) from N-(4-aminophenyl)-N-methyl-4,6-dimethyl-2-pyr imidine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)methyl 5 amino]phenyl}-1-(2-hydroxy-2-phenylethyl)-5-oxopyrrol idine-3-carboxamide, MS(M+H) 460.6, MS(M-H) 458.5. a3) from N-(4-aminophenyl)-N-ethyl-4,6-dimethyl-2-pyr imidine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)ethyl 10 amino]phenyl}-1-(2-hydroxy-2-phenylethyl)-5-oxopyrrol idine-3-carboxamide, MS(M+H) 475.6, MS(M-H) 472.5. a4) from N-phenyl-1,4-phenylenediamine, rac. N-(4-phen ylaminophenyl)-1-(2-hydroxy-2-phenylethyl)-5-oxopyr 15 rolidine-3-carboxamide, MS(M+H) 416.3, MS(M-H) 414.5. a5) from 3-amino-9-ethylcarbazole, rac. N-(9-ethyl-9H carbazol-3-yl)-1-(2-hydroxy-2-phenylethyl)-5-oxopyr rolidine-3-carboxamide, MS(M+H) 442.6, MS(M-H) 440.3. 20 b) The rac. 1-(2-hydroxy-2-phenylethyl)-5-oxopyrrolid ine-3-carboxylic acid required for example 18a was prepared in analogy with example 3b) but using 2 hydroxy-2-phenylethylamine in place of benzylamine; 25 MS(M+H) 250.1, MS(M-H) 248.1. Example 18 (R I is m-tolyl) a) The following products were prepared from rac. 30 5-oxo-1-m-tolylpyrrolidine-3-carboxylic acid, in analogy with example 1, using the amines which are listed below: al) from N-(4-aminophenyl)-4,6-dimethyl-2-pyrimidine 35 amine, rac. N-[4-(4,6-dimethylpyrimidin-2-ylamino) phenyl]-5-oxo-1-m-tolylpyrrolidine-3-carboxamide, MS(M+H) 416.3, MS(M-H) 414.5.
WO 03/059905 PCT/CHO2/00725 - 46 a2) from N-(4-aminophenyl)-N-methyl-4,6-dimethyl-2-pyr imidine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)methyl amino]phenyl}-5-oxo-l-m-tolylpyrrolidine-3-carboxamide, MS(M+H) 430, MS(M-H) 428.5. 5 a3) from N-(4-aminophenyl)-N-ethyl-4,6-dimethyl-2-pyr imidine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)ethyl amino]phenyl}-5-oxo-l-m-tolylpyrrolidine-3-carboxamide, MS(M+H) 444.6, MS(M-H) 442.5. 10 a4) from N-phenyl-l,4-phenylenediamine, rac. N-(4-phen ylaminophenyl)-5-oxo-1-N-tolylpyrrolidine-3-carbox amide, MS(M+H) 386.3, MS(M-H) 384.5. 15 b) The rac. 5-oxo-l-m-tolylpyrrolidine-3-carboxylic acid required for example 18a was prepared in analogy with example 3b) but using m-toluidine in place of benzylamine; MS(M+H) 220.1, MS(M-H) 218.1. 20 Example 19 (R' is 2-thienylmethyl) a) The following product was prepared from rac. 5-oxo 1-(2-thienylmethyl)pyrrolidine-3-carboxylic acid (Maybridge), in analogy with example 1, using the amine 25 which is listed below: al) from 3-amino-9-ethylcarbazole, rac. N-(9-ethyl-9H carbazol-3-yl)-5-oxo-1-thiophen-2-ylmethylpyrrolidine 3-carboxamide, MS(M+H) 418.1, MS(M-H) 416.2. 30 Example 20 (R1 is 2-furylmethyl) a) The following products were prepared from rac. 1-(2 furylmethyl)-5-oxopyrrolidine-3-carboxylic acid 35 (Maybridge), in analogy with example 1 using the amines which are listed below: al) from N-(4-aminophenyl)-4,6-dimethyl-2-pyrimidine- WO 03/059905 PCT/CHO2/00725 - 47 amine, rac. N-[4-(4i6-dimethylpyrimidin-2-ylamino)phen yl]-l-furan-2-ylmethyl-5-oxopyrrolidine-3-carboxamide, MS(M+H) 406.3, MS(M-H) 404.5. 5 a2) from N-(4-aminophenyl)-N-methyl-4,6-dimethyl- 2 -pyr imidine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)methyl amino]phenyl}-l1-furan-2-ylmethyl-5-oxopyrrolidine 3-carboxamide, MS(M+H) 420.5, MS(M-H) 418.5. 10 a3) from N-(4-aminophenyl)-N-ethyl-4,6-dimethyl-2-pyr imidine, rac. N-{4-[4,6-dimethylpyrimidin-2-yl)ethyl amino]phenyl}-l-furan-2-ylmethyl-5-oxopyrrolidine 3-carboxamide, MS(M+H) 434.6, MS(M-H) 432.5. 15 a4) from N-phenyl-l,4-phenylenediamine, rac. N-(4 phenylaminophenyl)-l-furan-2-ylmethyl-5-oxopyrrolidine 3-carboxamide, MS(M+H) 376.3, MS(M-H) 474.5. a5) from 3-amino-9-ethylcarbazole, rac. N-(9-ethyl-9H 20 carbazol-3-yl)-l-furan-2-ylmethyl-5-oxopyrrolidine 3-carboxamide, MS(M+H) 401.9, MS(M-H) 400.1. Example 21 (R1 is p-chlorobenzyl) 25 a) The following product was prepared from rac. 1-(4 chlorobenzyl)-5-oxopyrrolidine-3-carboxylic acid (Maybridge), in analogy with example 1, using the amine which is listed below: 30 al) from 3-amino-9-ethylcarbazole, rac. N-(9-ethyl-9H carbazol-3-yl)-1-(4-chlorobenzyl)-5-oxopyrrolidine-3 carboxamide, MS(M+H) 446.1, MS(M-H) 444.1. Example 22 (R 1 is p-dimethylaminophenyl) 35 a) In analogy with example 1, and using suitable amines, rac. 1-(4-dimethylaminophenyl)-5-oxopyrrolid ine-3-carboxylic acid can be converted into products of WO 03/059905 PCT/CHO2/00725 - 48 the formula I. al) from N-(4-aminophenyl)-4,6-dimethyl-2-pyrimidine amine, rac. N-[4-(4,6-dimethylpyrimidin-2-ylamino) 5 phenyl]-1-(4-dimethylaminophenyl)-5-oxopyrrolidine 3-carboxamide, MS(M+H) 445.2, MS(M-H) 443.5. a2) from N-(4-aminophenyl)-N-methyl-4,6-dimethyl-2-pyr imidine-amine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)-. 10 methylamino]phenyl}-l-(4-dimethylaminophenyl)-5-oxopyr rolidine-3-carboxamide, MS(M+H) 459.4, MS(M-H) 457.5. b) The rac. 1-(4-dimethylaminophenyl)-5-oxopyrrolidine 3-carboxylic acid required for example 22a was prepared 15 in analogy with example 3b but using N,N-dimethyl p-phenylenediamine in place of benzylamine; MS(M+H) 249.1, MS(M-H) 247.1. Example 23 (R 1 is 2-pyrrolidin-1-ylethyl) 20 a) The following product was prepared from rac. 5-oxo 1-(2-pyrrolidin-l-ylethyl)pyrrolidine-3-carboxylic acid, in analogy with example 1, using the amine which is listed below: 25 al) from N-(4-aminophenyl)-N-ethyl-4,6-dimethyl-2-pyr imidine, rac. N-{4-[(4,6-dimethylpyrimidin-2-yl)ethyl amino]phenyl}-5-oxo-l-(2-pyrrolidin-l-ylethyl)pyrrolid ine-3-carboxamide, MS(M+H) 451.2, MS(M-H) 449.3. 30 b) The rac. 5-oxo-l-(2-pyrrolidin-l-ylethyl)pyrrolid ine-3-carboxylic acid required for example 23a was prepared in analogy with example 3b) but using 1 (2-aminoethyl)pyrrolidine in place of benzylamine; 35 MS(M+H) 227.1, MS(M-H) 225.1.
WO 03/059905 PCT/CHO2/00725 - 49 Example 24 (R' is 1-methylpyrrolidin-2-ylethyl) a) The following product was prepared from rac. 1-[2 (1-methylpyrrolidin-2-yl)ethyl]-5-oxopyrrolidine-3-car 5 boxylic acid, in analogy with example 1, using the amine which is listed below: al) from 3-amino-9-ethylcarbazole, rac. N-(9-ethyl-9H carbazol-3-yl)-1-[2-(l-methylpyrrolidin-2-yl)ethyl]-5 10 oxopyrrolidine-3-carboxamide, MS(M+H) 433.4, MS(M-H) 431.3. b) The rac. 1-[2-(l1-methylpyrrolidin-2-yl)ethyl]-5-oxo pyrrolidine-3-carboxylic acid required for example 24a 15 was prepared in analogy with example 3b) but using 2 (2-aminoethyl)-1-methylpyrrolidine in place of benzylamine; MS(M+H) 241.2, MS(M-H) 239.1. Example 25 (R1 is 4-isopropylphenyl) 20 a) The following product was prepared from rac. 1 (4-isopropylphenyl)-5-oxopyrrolidine-3-carboxylic acid, in analogy with example 1, using the amine which is listed below: 25 al) from 3-amino-9-ethylcarbazole, rac. N-(9-ethyl-9H carbazol-3-yl)-1-(4-isopropylphenyl)-5-oxopyrrolidine 3-carboxamide, MS(M+H) 440.4, MS(M-H) 438.3. 30 b) The rac. l-(4-isopropylphenyl)-5-oxopyrrolidine 3-carboxylic acid required for example 25a was prepared in analogy with example 3b) but using 4-isopropyl aniline in place of benzylamine; MS(M+H) 248.1, MS(M-H) 246.1. 35 Example 26 (R 1 is 3,5-bis-(trifluoromethyl)-phenyl) a) The following product was prepared from rac. 1- WO 03/059905 PCT/CH02/00725 - 50 (3,5-bis-(trifluoromethyl)-phenyl)-5-oxopyrrolidine-3 carboxylic acid, in analogy with example 1, using the amine which is listed below: 5 al) from 3-amino-9-ethylcarbazole, rac. N-(9-ethyl-9H carbazol-3-yl)-1-(3,5-bistrifluoromethylphenyl)-5 oxopyrrolidine-3-carboxamide, MS(M+H) 534.4. b) The rac. 1-(3,5-bistrifluoromethylphenyl)-5-oxopyr 10 rolidine-3-carboxylic acid required for example 26a was prepared in analogy with example 3b) but using 3,5 bis(trifluoromethyl)aniline in place of benzylamine. Example 27 (R 1 is 3-fluorophenyl) 15 a) The following product was prepared from rac. 1-(3 fluorophenyl)-5-oxopyrrolidine-3-carboxylic acid, in analogy with example 1, using the amine which is listed below: 20 al) from 3-amino-9-ethylcarbazole, rac. N-(9-ethyl-9H carbazol-3-yl)-1-(3-fluorophenyl)-5-oxopyrrolidine-3 carboxamide, MS(M+H) 416.1, MS(M-H) 414.2. 25 b) The rac. l-(3-fluorophenyl)-5-oxopyrrolidine-3 carboxylic acid required for example 27a was prepared in analogy with example 3b) but using 3-fluoroaniline in place of benzylamine; MS(M+H) 224.2, MS(M-H) 222.1. 30 Example 28 (R 1 is 2-chlorobenzyl) a) The following product was prepared from rac. 1 (2-chlorobenzyl)-5-oxopyrrolidine-3-carboxylic acid, in analogy with example 1, using the amine which is listed 35 below: al) from 3-amino-9-ethylcarbazole, rac. N-(9-ethyl-9H carbazol-3-yl)-1-(2-chlorobenzyl)-5-oxopyrrolidine- WO 03/059905 PCT/CHO2/00725 - 51 3-carboxamide, MS(M+H) 446.2, MS(M-H) 444.2. b) The rac. l-(2-chlorobenzyl)-5-oxopyrrolidine-3-car boxylic acid required for example 28a was prepared in 5 analogy with example 3b) but using 2-chlorobenzylamine in place of benzylamine; MS(M+H) 254.1, MS(M-H) 252.1. Example 29 (Enantiomerically pure compounds) 10 The rac. N-(9-ethyl-9H-carbazol-3-yl)-l-(2-isopropyl phenyl)-5-oxopyrrolidine-3-carboxamide prepared as described in example 7a5) can be resolved into the two enantiomers (a) (R)-N-(9-ethyl-9H-carbazol-3-yl)-l-(2-iso 15 propylphenyl)-5-oxopyrrolidine-3-carboxamide; and (b) (S)-N-(9-ethyl-9H-carbazol-3-yl)-l-(2 isopropylphenyl)-5-oxopyrrolidine-3 carboxamide 20 by means of HPLC on a LichroCART (R,R) Whelk-01 column using a solvent gradient (n-hexane + 0.5% acetic acid/isopropanol + 0.5% acetic acid). Example 30 (Enantiomerically pure compounds) 25 The following racemic compounds can be resolved into the corresponding enantiomers in analogy with example 29: 30 rac. N-(9-Ethyl-9H-carbazol-3-yl)-5-oxo-l-(2-pyridin 2-ylethyl)pyrrolidine-3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-(2-hydroxy 2-phenylethyl)-5-oxopyrrolidine-3-carboxamide; rac. N-(4-Diethylaminophenyl)-1-(2,5-dimethylphenyl) 35 5-oxopyrrolidine-3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-5-oxo-l-(2-thiophen 2-ylethyl)pyrrolidine-3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-l-(4-chlorobenzyl)- WO 03/059905 PCT/CHO2/00725 - 52 5-oxopyrrolidine-3-carboxamide; rac. N- (9-Ethyl-9H-carbazol-3Y1) -5-oxo-1-thiophen 2-ylmethylpyrrolidine-3-carboxamide;~ rac. N- (9-Ethyl-9H-carbazol-3-y1) -- furan-2-ylmethyl 5 5-oxopyrrolidine-3-earboxamide; rac. N- (9-Ethyl-9H-earbazol-3-y1) -1-(5-methoxy 2-methylplienyl) -5-oxopyrrolidine3-carboxamide; rae. N-[4-(Ethylisopropylamiflo)phefylY111(2,5-dimethyl phenyl) -5-oxopyrrolidine-3-carboxamide; 10 rae. N- (9-Ethyl-9H-carbazol-3-Yl) -5-oxo-1-pheflethYlpyr rolidine-3-carboxamide; rae. Ethyl [(4-{ [1- (2, 5-dimethylphefyl)5-oxopyr rolidine-3-carbolyl] aminolphenyl)phenylail]acetate; rac. N- (9-Ethyl-9H-carbazol3yl) -1-cycloheptyl-5-oxo 15 pyrrolidine-3-carboxamide; rae. N-(4-[ (4,6-Dimethylpyrimidifl2-y1)ethylamiflV phenyl}-1- (5-methoxy-2-methylphelYl) -5-oxopyrrolidile 3-carboxamiie; rae. N-{4-[Ethy1-(2-hydroxyethy)amiflo]phell 20 1- (2,5-dimethyiphelyl) -5-oxopyrrolidine-3-carboxamide; rae. N-[4-(Ethylphenylamino)phenfly11I-2,5-dimethyl phenyl) -5-oxopyrrolidifle-3-carboxamide; rae. N- (9-Ethyl-9H-earbazoli3-yl) -1-(3-methoxyphenyl) 5-oxopyrrolidine-3-earboxamide; 25 rae. N-9Ehl9-abzl3-l--2clrbny) 5-oxopyrrolidine-3-arboxamide; rae. N- [4- (4, 6-Dimethylpyrimidi-2-yaio)phell 1- (2, 5-dimethyiphenyl) -5-oxopyrrolidife3-arboxamide; rae. N-(4- [(4, 6-Dimethylpyrimidil-2-y)ethylaminl] 30 phenyl}-l- (2, 5-dimethyiphenyl) -5-oxopyrrolidine 3-earboxamide; rae. N- (9-Ethyl-9H-earbazoli3-yl) -5-oxo-1-phenyl pyrrolidine-3-arboxamide; rae. N-14-[ (4.6-Dimethylpyrimidin-2-yl)methylaminl 35 phnl--x---oyproiie3croaie rae. N-[4-(Isopropylpheflamiflo)phefyli- 2 ,S-di methyiphenyl) -5-oxopyrrolidife3earboxamide; rae. N-[4-(Ethylpheflamiflo)pheyl]i1(2-isopropyli WO 03/059905 PCT/CH02/00725 - 53 phenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-{4-[( 4
,
6 -Dimethylpyrimidin-2-yl)ethylamino] phenyl}-5-oxo-1-(2-pyridin-2-ylethyl)pyrrolidine 3-carboxamide; 5 rac. N-[4-(4, 6 -Dimethylpyrimidin-2-ylamino)phenyl] 1-(2-isopropylphenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-[4-(4,6-Dimethylpyrimidin-2-ylamino)phenyl] 1-(5-methoxy-2-methylphenyl)-5-oxopyrrolidine 3-carboxamide; 10 rac. N-[4-(Methylphenylamino)phenyl]-1-(2,5-dimethyl phenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-[4-(Methylphenylamino)phenyl]-1-(2-isopropyl phenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-(4-isopropyl 15 phenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-(3-fluorophenyl) 5-oxopyrrolidine-3-carboxamide; rac. N-(4-Phenylaminophenyl)-1-(2,5-dimethylphenyl) 5-oxopyrrolidine-3-carboxamide; 20 rac. N-[4-(4,6-Dimethylpyrimidin-2-ylamino)phenyl] l-indan-2-yl-5-oxopyrrolidine-3-carboxamide; rac. N-[4-(Ethylphenylamino)phenyl]-1-(5-methoxy 2-methylphenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-{4-[( 4 ,6-Dimethylpyrimidin-2-yl)methylamino] 25 phenyl}-l-(2-isopropylphenyl)-5-oxopyrrolidine 3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-benzyl-5-oxopyr rolidine-3-carboxamide; rac. N-[ 4
-(
4 ,6-Dimethylpyrimidin-2-ylamino)phenyl] 30 5-oxo-l-p-tolylpyrrolidine-3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-indan-2-yl-5-oxo pyrrolidine-3-carboxamide; rac. N-{4-[( 4
,
6 -Dimethylpyrimidin-2-yl)ethylamino] phenyl}-1-(2-hydroxy-2-phenylethyl)-5-oxo-pyrrolidine 35 3-carboxamide; rac. N-(Biphenyl-4-yl)-1-(2,5-dimethylphenyl)-5-oxopyr rolidine-3-carboxamide; rac. N-[4-(Cyclopropylmethylphenylamino)phenyl]- WO 03/059905 PCT/CH02/00725 - 54 1-(5-methoxy-2-methylphenyl)-5-oxopyrrolidine-3-carbox amide; rac. N-[ 4 -(Isopropylphenylamino)phenyl]-1-(2-isopropyl phenyl)-5-oxopyrrolidine-3-carboxamide; 5 rac. N-(4-Phenylaminophenyl)-1-(2-isopropylphenyl) 5-oxopyrrolidine-3-carboxamide; rac. N-{4-[( 4 ,6-Dimethylpyrimidin-2-yl)methylamino] phenyl}-1-(5-methoxy-2-methylphenyl)-5-oxopyrrolidine 3-carboxamide; 10 rac. N-{4-[(4,6-Dimethylpyrimidin-2-yl)ethylamino] phenyl}-l-(3-methoxyphenyl)-5-oxopyrrolidine-3-carbox amide; rac. N-{4-[(4,6-Dimethylpyrimidin-2-yl)methylamino] phenyl}-5-oxo-1-m-tolylpyrrolidine-3-carboxamide; 15 rac. N-[4-(Cyclopropylmethylphenylamino)phenyl]-1-(2,5 dimethylphenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-{4-[(4,6-Dimethylpyrimidin-2-yl)ethylamino] phenyl}-1-(2-isopropylphenyl)-5-oxopyrrolidine 3-carboxamide; 20 rac. Ethyl [(4-{[l-(5-methoxy-2-methylphenyl)-5-oxopyr rolidine-3-carbonyl]amino}phenyl)phenylamino]acetate; rac. N-[4-(Cyclopropylmethylphenylamino)phenyl] 1-(2-isopropylphenyl)-5-oxopyrrolidine-3-carboxamide; and 25 rac. N-[4-(Ethylphenylamino)phenyl]-l-indan-2-yl-5-oxo pyrrolidine-3-carboxamide. Example 31 (R i is 2,5-dimethylphenyl) 30 a) 29 il of Hunig's base and 1 equivalent of the acid chloride listed below were added to a solution of 50 mg of rac. N-(4-aminophenyl)-l-(2,5-dimethylphenyl)-5 oxopyrrolidine-3-carboxamide in 0.5 ml of methylene chloride. The reaction mixture was stirred overnight at 35 room temperature and then evaporated and the residue was chromatographed on silica gel using ethyl acetate/ ethanol (8:2). The evaporated product fractions in each case yielded approx. 30 mg of product. This method was WO 03/059905 PCT/CHO2/00725 - 55 used to prepare the following compounds: al) with acetyl chloride, rac. N-(4-acetylaminophenyl) 1-(2,5-dimethylphenyl)-5-oxopyrrolidine-3-carboxamide, 5 MS(M+H) 366.3, MS(M-H) 364.4. a2) with isovaleryl chloride, rac. N-[4-(3-methyl butyrylamino)phenyl]-1-(2,5-dimethylphenyl)-5 oxopyrrolidine-3-carboxamide, MS(M+H) 408.3, MS(M 10 H) 406.4. a3) with cyclopropylcarbonyl chloride, rac. N [4-(cyclopropanecarbonylamino)phenyl]-1-(2,5-dimethyl phenyl)-5-oxopyrrolidine-3-carboxamide, MS(M+H) 392.3, 15 MS(M-H) 390.4. a4) with benzoyl chloride, rac. N-(4-benzoylamino phenyl)-1-(2,5-dimethylphenyl)-5-oxopyrrolidine-3-car boxamide, MS(M+H) 428.3, MS(M-H) 426.4. 20 a5) with phenylacetyl chloride, rac. N-(4-phenyl acetylaminophenyl)-1-(2,5-dimethylphenyl)-5-oxopyr rolidine-3-carboxamide, MS(M+H) 442.4, MS(M-H) 440.5. 25 a6) with 2-methoxybenzoyl chloride, rac. N-[4-(2-meth oxybenzoylamino)phenyl]-1-(2,5-dimethylphenyl)-5-oxo pyrrolidine-3-carboxamide, MS(M+H) 458.2, MS(M-H) 456.5. 30 a7) with piperonyloyl chloride, rac. N-{4-[(benzo [1, 3 ]dioxole-5-carbonyl)amino]phenyl}-1-(2,5-dimethyl phenyl)-5-oxopyrrolidine-3-carboxamide, MS(M+H) 472.3, MS(M-H) 470.5. 35 a8) with pivaloyl chloride, rac. N-[4-(2,2-dimethyl propionylamino)phenyl]-1-(2,5-dimethylphenyl)-5-oxopyr rolidine-3-carboxamide, MS(M+H) 408.3, MS(M-H) 406.4.
WO 03/059905 PCT/CH02/00725 - 56 a9) with 4-methoxybenzoyl chloride, rac. N-[4-(4-meth oxybenzoylamino)phenyl]-1-(2,5-dimethylphenyl)-5-oxo pyrrolidine-3-carboxamide, MS(M+H) 458.2, MS(M-H) 456.4. 5 alO0) with 3-fluorobenzoyl chloride, rac. N-[4 (3-fluorobenzoylamino)phenyl]-1-(2,5-dimethylphenyl) 5-oxopyrrolidine-3-carboxamide, MS(M+H) 446.3, MS(M-H) 444.4. 10 all) with 2-furoyl chloride, rac. N-{4-[(furan-2-car bonyl)amino]phenyl}-l-(2,5-dimethylphenyl)-5-oxopyr rolidine-3-carboxamide, MS(M+H) 418.4, MS(M-H) 416.4. 15 b) The rac. N-(4-aminophenyl)-l-(2,5-dimethylphenyl)-5 oxopyrrolidine-3-carboxamide required in example 31a) was prepared as follows: bl) 1.18 g of p-nitroaniline, 1.95 g of N-(3-di 20 methylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC HCl), 2.22 ml of Hdnig's base and 1.04 g of 4 (N,N-dimethylamino)pyridine were added consecutively to a solution of 2 g of 1-(2,5-dimethylphenyl)-5-oxo-l pyrrolidine-3-carboxylic acid (example 4b) in 28 ml of 25 methylene chloride. The reaction mixture was stirred at 40'C for 3 hours and then taken up in ethyl acetate and washed with water until neutral. The organic phase was evaporated and this resulted in 2.5 g of rac. N (4-nitrophenyl)-1-(2,5-dimethylphenyl)-5-oxopyrrolid 30 ine-3-carboxamide, MS(M+H) 354.1, MS(M-H) 352.3. b2) The 2.5 g of rac. N-(4-nitrophenyl)-l-(2,5-di methylphenyl)-5-oxopyrrolidine-3-carboxamide which were obtained as described in example 31bl) were dissolved 35 in 70 ml of methanol and 70 ml of methylene chloride after which 0.5 g of palladium/charcoal catalyst was added and the mixture was hydrogenated overnight at room temperature. After the reaction mixture had been WO 03/059905 PCT/CHO2/00725 - 57 filtered and the filtrate evaporated, 2.3 g of rac. N (4-aminophenyl)-1-(2,5-dimethylphenyl)-5-oxopyrrolid ine-3-carboxamide, MS(M+H) 324.3, MS(M-H) 322.4, were obtained. 5 Example 32 (Enantiomerically pure compounds) The following racemic compounds can be resolved into the corresponding enantiomers in analogy with example 10 29: rac. N-(4-Acetylaminophenyl)-1-(2,5-dimethylphenyl) 5-oxopyrrolidine-3-carboxamide; 15 rac. N-[4-(3-Methylbutyrylamino)phenyl]--(2,5-dimeth ylphenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-[4-(Cyclopropanecarbonylamino)phenyl]-1-(2,5-di methylphenyl)-5-oxopyrrolidine-3-carboxamide; 20 rac. N-(4-Benzoylaminophenyl)-1l-(2,5-dimethylphenyl) 5-oxopyrrolidine-3-carboxamide; rac. N-(4-Phenylacetylaminophenyl)-1-(2,5-di 25 methylphenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-[4-(2-Methoxybenzoylamino)phenyl]-1-(2,5-di methylphenyl)-5-oxopyrrolidine-3-carboxamide; 30 rac. N-{4-[(Benzo[1,3]dioxole-5-carbonyl)amino]-1-(2,5 dimethylphenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-[4-(2,2-Dimethylpropionylamino)phenyl]-1-(2,5 dimethylphenyl)-5-oxopyrrolidine-3-carboxamide; 35 rac. N-[4-(4-Methoxybenzoylamino)phenyl]-1-(2,5-di methylphenyl)-5-oxopyrrolidine-3-carboxamide; WO 03/059905 PCT/CHO2/00725 - 58 rac. N-[4-(3-Fluorobenzoylamino)phenyl]-l-(2,5-di methylphenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-{4-[(Furan-2-carbonyl)amino]phenyl}-l-(2,5-di 5 methylphenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-l-(2-morpholin-4-yl ethyl)-5-oxopyrrolidine-3-carboxamide; 10 rac. N-(9-Ethyl-9H-carbazol-3-yl)-5-oxo-l-p-tolylpyr rolidine-3-carboxamide; and rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-(2,4 dimethoxybenzyl)-5-oxopyrrolidine-3-carboxamide. 15 Example 33 (Enantiomerically pure compounds) The following racemic compounds can be resolved into the corresponding enantiomers in analogy with example 20 29: rac. N-[4-(Isobutylphenylamino)phenyl]-l-(2-isopropyl phenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-[4-(4,6-Dimethylpyrimidin-2-ylamino)phenyl]-l 25 (4-dimethylaminophenyl)-5-oxopyrrolidine-3-carboxamide; and rac. N-[4-(4,6-Dimethylpyrimidin-2-yl)methylamino phenyl]-1-(4-dimethylaminophenyl)-5-oxopyrrolidine 30 3-carboxamide. Example 34 (RR is 2,4-dimethoxybenzyl) a) rac. N-(9-Ethyl-9H-carbazole-3-yl)-l-(2,4-dimethoxy 35 benzyl)-5-oxopyrrolidine-3-carboxamide was prepared from rac. l-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3 carboxylic acid, in analogy with example 1, using 3 amino-9-ethylcarbazole; MS(M+H) 472.4, MS(M-H) 470.2.
WO 03/059905 PCT/CHO2/00725 - 59 b) The 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-car boxylic acid required for example 34a was prepared in analogy with example 3b) but using 2,4 5 dimethoxybenzylamine; MS(M+H) 280.1, MS(M-H) 278.1. Example A A compound of the formula I can be used, in a manner 10 known per se, as the active compound for producing tablets of the following composition: Per tablet Active compound 200 mg 15 Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethyl cellulose 20 mg 425 mg 20 Example B A compound of the formula I can be used, in a manner known per se, as the active compound for producing 25 capsules of the following composition: Per capsule Active compound 100 mg Corn starch 20 mg 30 Lactose 95 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg WO 03/059905 PCT/CH02/00725 - 60 Patent claims 1. A pyrrolidonecarboxamide of the formula O 0f2
R
1 5 in which
R
1 is phenyl which is optionally monosubstituted or disubstituted in the phenyl radical by alkyl, 10 alkoxy, dialkylamino, halogen or trifluoromethyl, benzyl, phenylethyl or a-hydroxyphenylethyl; naphthyl or naphthylmethyl; thienyl-, furyl-, pyridyl-, l-alkylpyrrolidin-2-yl-, pyrrolidino- or morpholino-alkyl; or cycloalkyl which can 15 optionally possess a fused-on benzene ring;
R
2 is a radical of the formula R4 R or (a) (b) 20 X is -CH 2 -, -CO-, -0- or -NR 3 -;
R
* is hydrogen or alkyl;
R
4 is hydrogen or alkoxy;
R
5 is phenyl, heteroalkyl, aryloxy, alkoxy, alkanoyl or -NR6R 7 ; 25 R 6 is hydrogen, alkyl, aralkyl, cycloalkylalkyl or alkoxycarbonylalkyl; and
R
7 is aryl, heteroaryl, alkyl, hydroxyalkyl or acyl; pharmaceutically utilizable acid addition salts of WO 03/059905 PCT/CHO2/00725 - 61 basic compounds of- the formula I, pharmaceutically utilizable salts of acid compounds of the formula I with bases, pharmaceutically utilizable esters of compounds of the formula I which contain hydroxyl or 5 carboxyl groups, and hydrates or solvates thereof. 2. A compound as claimed in claim 1, in which R 1 is phenyl, 4-tolyl, 2,5-dimethylphenyl, 2-isopropylphenyl, 3-methoxyphenyl, 2-methyl-5-methoxyphenyl, benzyl, 2 10 phenylethyl, 2-(2-pyridyl)ethyl, 2-(2-thienyl)ethyl, 2 indanyl or 2-morpholinoethyl. 3. A compound as claimed in claim 1, in which R i is cycloheptyl, 2-hydroxy-2-phenylethyl, 2-thienylmethyl, 15 2-furanylmethyl, 4-chlorobenzyl, 3-fluorophenyl, 2,4 dimethoxybenzyl or 2-chlorobenzyl. 4. A compound as claimed in claim 1, in which R 1 is 2-naphthyl, naphthalen-l-ylmethyl, 4-dimethylamino 20 phenyl, 2-pyrrolidin-1-ylethyl, l-methylpyrrolidin-2 ylethyl, 4-isopropylphenyl or 3,5-bistrifluoro methylphenyl. 5. A compound as claimed in claim 1, in which R is 25 2,5-dimethylphenyl, 2-isopropylphenyl or 2-methyl-5 methoxyphenyl. 6. A compound as claimed in one of claims 1 to 5, in which R 2 is biphenyl-4-yl, 4-methoxyphenyl, 4-phenoxy 30 phenyl, 4-dimethylaminophenyl, 4-diethylaminophenyl, 4-phenylaminophenyl, 4-[N-ethyl-N-(2-hydroxyethyl) 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 35 N-(4,6-dimethyl-2-pyrimidinyl)amino]phenyl, 4 acetylphenyl, 9H-fluoren-2-yl, 9-oxo-9H-fluoren-2-yl or 9-ethylcarbazol-3-yl.
WO 03/059905 PCT/CH02/00725 - 62 7. A compound as claimed in one of claims 1 to 5, in which R 2 is 4-(N-ethoxycarbonylmethyl-N-phenylamino) phenyl, 4-(N-ethyl-N-phenylamino)phenyl, 4-(N-methyl-N phenylaminophenyl, 4-(N-cyclopropylmethyl-N-phenyl 5 amino)phenyl, 4-(N-isobutyl-N-phenylamino)phenyl, 4 (2-methoxybenzoylamino)phenyl, 4-(2,2-dimethylpropion ylamino)phenyl, 4-(3-methylbutyrylamino)phenyl, 4 (cyclopropanecarbonylamino)phenyl, 4-(3-fluorobenzo ylamino)phenyl or 4-[(furan-2-carbonyl)amino]phenyl. 10 8. A compound as claimed in one of claims 1 to 5, in which R 2 is biphenyl-3-yl, 9H-fluoren-1l-yl, 2 methoxydibenzofuran-3-yl, 4-(N-isopropyl-N-phenyl amino)phenyl, 4-(N-benzyl-N-phenylamino)phenyl, 15 4-acetylaminophenyl, 4-benzoylaminophenyl, 4-phenyl acetylaminophenyl, 4-[(benzo[l,3]dioxole-5-carbonyl) amino]phenyl or 4-(4-methoxybenzoylamino)phenyl. 9. A compound as claimed in one of claims 1 to 5, in 20 which R 2 is 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-phenylamino phenyl, 4-diethylaminophenyl, 4-(N-ethyl-N 25 isopropylamino)phenyl, 4-(N-ethoxycarbonylmethyl-N phenylamino)phenyl, 4-(N-ethyl-N-phenylamino)phenyl, 4 (N-methyl-N-phenylamino)phenyl or 2,4-dimethoxybenzyl. 10. rac. N-(9-Ethyl-9H-carbazol-3-yl)-5-oxo-1-(2 30 pyridin-2-ylethyl)pyrrolidine-3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-(2-hydroxy 2-phenylethyl)-5-oxopyrrolidine-3-carboxamide; rac. N-(4-Diethylaminophenyl)-l-(2,5-dimethylphenyl) 5-oxopyrrolidine-3-carboxamide; 35 rac. N-(9-Ethyl-9H-carbazol-3-yl)-5-oxo-l-(2-thiophen 2-ylethyl)pyrrolidine-3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-l-(4-chlorobenzyl) 5-oxopyrrolidine-3-carboxamide; WO 03/059905 PCT/CHO2/00725 - 63 rac. N-(9-Ethyl-9H-carbazol-3-yl)-5-oxo-1-thiophen 2-ylmethylpyrrolidine-3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-furan-2-ylmethyl 5-oxopyrrolidine-3-carboxamide; 5 rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-(2-isopropyl phenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-(5-methoxy 2-methylphenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-[4-(Ethylisopropylamino)phenyl]-1-(2,5-dimethyl 10 phenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-5-oxo-1-phenethylpyr rolidine-3-carboxamide; rac. Ethyl [(4-{[1-(2,5-dimethylphenyl)-5-oxopyr rolidine-3-carbonyl]amino}phenyl)phenylamino]acetate; 15 rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-cycloheptyl-5-oxo pyrrolidine-3-carboxamide; rac. N-{4-[(4,6-Dimethylpyrimidin-2-yl)ethylamino] phenyl}-1-(5-methoxy-2-methylphenyl)-5-oxopyrrolidine 3-carboxamide; 20 rac. N-{4-[Ethyl-(2-hydroxyethyl)amino]phenyl} 1-(2,5-dimethylphenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-[4-(Ethylphenylamino)phenyl]-1-(2,5-dimethyl phenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-(3-methoxyphenyl) 25 5-oxopyrrolidine-3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-(2-chlorobenzyl) 5-oxopyrrolidine-3-carboxamide; rac. N-[4-(4,6-Dimethylpyrimidin-2-ylamino)phenyl] 1-(2,5-dimethylphenyl)-5-oxopyrrolidine-3-carboxamide; 30 rac. N-{4-[(4,6-Dimethylpyrimidin-2-yl)methylamino] phenyl}-1-(2,5-dimethylphenyl)-5-oxopyrrolidine 3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-5-oxo-1-phenyl pyrrolidine-3-carboxamide; 35 rac. N-{4-[(4,6-Dimethylpyrimidin-2-yl)methylamino] phenyl}-5-oxo-1-p-tolylpyrrolidine-3-carboxamide; rac. N-[4-(Isopropylphenylamino)phenyl]-1-(2,5-di methylphenyl)-5-oxopyrrolidine-3-carboxamide; WO 03/059905 PCT/CHO2/00725 - 64 rac. N-[4-(Ethylphenylamino)phenyl]-1-(2-isopropyl phenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-{4-[(4,6-Dimethylpyrimidin-2-yl)ethylamino] phenyl}-5-oxo-1-(2-pyridin-2-ylethyl)pyrrolidine 5 3-carboxamide; rac. N-[4-(4,6-Dimethylpyrimidin-2-ylamino)phenyl] 1-(2-isopropylphenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-[4-(4,6-Dimethylpyrimidin-2-ylamino)phenyl] 1-(5-methoxy-2-methylphenyl)-5-oxopyrrolidine 10 3-carboxamide; rac. N-[4-(Methylphenylamino)phenyl]--(2,5-dimethyl phenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-[4-(Methylphenylamino)phenyl]-1-(2-isopropyl phenyl)-5-oxopyrrolidine-3-carboxamide; 15 rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-(4-isopropyl phenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-(3-fluorophenyl) 5-oxopyrrolidine-3-carboxamide; rac. N-(4-Phenylaminophenyl)-1-(2,5-dimethylphenyl) 20 5-oxopyrrolidine-3-carboxamide; rac. N-[4-(4,6-Dimethylpyrimidin-2-ylamino)phenyl] 1-indan-2-yl-5-oxopyrrolidine-3-carboxamide; rac. N-[4-(Ethylphenylamino)phenyl]-1-(5-methoxy 2-methylphenyl)-5-oxopyrrolidine-3-carboxamide; 25 rac. N-{4-[(4,6-Dimethylpyrimidin-2-yl)methylamino] phenyl}-1-(2-isopropylphenyl)-5-oxopyrrolidine 3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-benzyl-5-oxopyr rolidine-3-carboxamide; 30 rac. N-[4-(4,6-Dimethylpyrimidin-2-ylamino)phenyl] 5-oxo-1-p-tolylpyrrolidine-3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-indan-2-yl-5-oxo pyrrolidine-3-carboxamide; rac. N-{4-[(4,6-Dimethylpyrimidin-2-yl)ethylamino] 35 phenyl}-1-(2-hydroxy-2-phenylethyl)-5-oxo-pyrrolidine 3-carboxamide; rac. N-(Biphenyl-4-yl)-1-(2,5-dimethylphenyl)-5-oxopyr rolidine-3-carboxamide; WO 03/059905 PCT/CH02/0072 5 - 65 rac. N-[4-(Cyclopropylmethylphenylamino)phenyl] 1-(5-methoxy-2-methylphenyl)-5-oxopyrrolidine-3-carbox amide; rac. N-[4-(Isopropylphenylamino)phenyl]-l-(2-isopropyl 5 phenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-(4-Phenylaminophenyl)-1-(2-isopropylphenyl) 5-oxopyrrolidine-3-carboxamide; rac. N-{4-[(4,6-Dimethylpyrimidin-2-yl)methylamino] phenyl}-1-(5-methoxy-2-methylphenyl)-5-oxopyrrolidine 10 3-carboxamide; rac. N-{4-[(4,6-Dimethylpyrimidin-2-yl)ethylamino] phenyl}-1-(3-methoxyphenyl)-5-oxopyrrolidine-3-carbox amide; rac. N-{4-[(4,6-Dimethylpyrimidin-2-yl)methylamino] 15 phenyl}-5-oxo-l-m-tolylpyrrolidine-3-carboxamide; rac. N-[4-(Cyclopropylmethylphenylamino)phenyl]-1-(2,5 dimethylphenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-{4-[(4,6-Dimethylpyrimidin-2-yl)ethylamino] phenyl}-1-(2-isopropylphenyl)-5-oxopyrrolidine 20 3-carboxamide; rac. Ethyl [(4-{[1-(5-methoxy-2-methylphenyl)-5-oxopyr rolidine-3-carbonyl]amino}phenyl)phenylamino]acetate; rac. N-[4-(Cyclopropylmethylphenylamino)phenyl] 1-(2-isopropylphenyl)-5-oxopyrrolidine-3-carboxamide; 25 rac. N-[4-(Ethylphenylamino)phenyl]-l1-indan- 2 -yl-5-oxo pyrrolidine-3-carboxamide; and rac. N-[4-(Isobutylphenylamino)phenyl]--(2-isopropyl phenyl)-5-oxopyrrolidine-3-carboxamide. 30 11. rac. N-[4-(2-Methoxybenzoylamino)phenyl]-l-( 2
,
5 dimethylphenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-[4-(2,2-Dimethylpropionylamino)phenyl]-l (2,5-dimethylphenyl)-5-oxopyrrolidine-3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-l-(2-morpholin-4-yl 35 ethyl)-5-oxopyrrolidine-3-carboxamide; rac. N-(9-Ethyl-9H-carbazol-3-yl)-5-oxo-1-p-tolyl pyrrolidine-3-carboxamide; and rac. N-(9-Ethyl-9H-carbazol-3-yl)-1-(2,4-dimethoxy- WO 03/059905 PCT/CHO2/00725 - 66 benzyl)-5-oxopyrrolidine-3-carboxamide. 12. rac. N-[4-(4,6-Dimethylpyrimidin-2-ylamino) phenyl]-1-(4-dimethylaminophenyl)-5-oxopyrrolidine-3 5 carboxamide; and rac. N-[4-(4,6-Dimethylpyrimidin-2-yl)methylamino phenyl]-1-(4-dimethylaminophenyl)-5-oxopyrrolidine 3-carboxamide. 10 13. A compound as claimed in one of claims 1 to 12 for use as a therapeutic active compound. 14. A pharmaceutical, comprising a galenic administration form which comprises a compound as 15 claimed in one of claims 1 to 12. 15. The use of compounds as claimed in one of claims 1 to 12 for preventing or treating arthritis, diabetes and, especially, eating disturbances and obesity, or 20 for producing corresponding pharmaceuticals. 16. A process for preparing compounds as claimed in one of claims 1 to 12, characterized in that a pyrrolidinecarboxylic acid of the formula 25 0 DH III in which R 1 has the meaning given in claim 1, or a reactive derivative thereof, is reacted with an amine of the formula lIZNRZ IV 30 in which R 2 has the meaning given in claim 1, or a WO 03/059905 PCT/CHO2/0 0725 - 67 reactive derivative thereof, and, if desired, a stereoisomeric mixture which may possibly be obtained is resolved. 5 17. A process for preparing compounds of the formula I defined in claim 1, in which R 2 is a radical of the formula (b), R 5 is -NR 6
R
7 and R 7 is acyl, characterized in that a corresponding compound, in which, however, R is hydrogen, is acylated and, if desired, a 10 stereoisomeric mixture which may possibly be obtained is resolved. 18. A compound of the formula IV defined in claim 16, or a corresponding nitro precursor, selected from: 15 Ethyl [(4-nitrophenyl)phenylamino]acetate; Ethyl [(4-aminophenyl)phenylamino]acetate; Cyclopropylmethyl(4-nitrophenyl)phenylamine; N-Cyclopropylmethyl-N-phenylphenylene-1,4-diamine; 20 isobutyl(4-nitrophenyl)phenylamine; N-Isobutyl-N-phenylphenylene-1,4-diamine; Ethyl [( 4 -nitrophenyl)phenylamino]pentanoate; Ethyl [( 4 -aminophenyl)phenylamino]pentanoate; Benzyl(4-nitrophenyl)phenylamine; and 25 N-Benzyl-N-phenylphenylene-1,4-diamine. 19. A compound of the formula III defined in claim 16, selected from: 30 rac. 1-Indan-2-yl-5-oxopyrrolidine-3-carboxylic acid; rac. 1-Naphthalen-2-yl-5-oxopyrrolidine-3-carboxylic acid; rac. 1-(5-Methoxy-2-methylphenyl)-5-oxopyrrolidine 3-carboxylic acid; 35 rac. 5-Oxo-1-( 2 -pyridin-2-ylethyl)pyrrolidine-3-car boxylic acid; rac. 1-Cycloheptyl-5-oxopyrrolidine-3-carboxylic acid; rac. 1-(2-Hydroxy-2-phenylethyl)-5-oxopyrrolidine- WO 03/059905 PCT/CHO2/00 725 - 68 3-carboxylic acid; rac. 5-Oxo-1- (2-pyrrolidin-1-ylethyl)pyrrolidine-3-car boxylic acid; rac. 1-[2-(l-Methylpyrrolidin-2-yl)ethyl]-5-oxopyr 5 rolidine-3-carboxylic acid; and rac. 1- (3-Fluorophenyl)-5-oxopyrrolidine-3-carboxylic acid.

Claims (19)

1. Pyrrolidoncarboxamide der Formel 5 O worin R im Phenylrest gegebenenfalls durch Alkyl, Alkoxy, 10 Dialkylamino, Halogen oder Trifluormethyl mono- oder disubstituiertes Phenyl, Benzyl, Phenylethyl oder a Hydroxyphenylethyl; Naphthyl oder Naphthylmethyl; Thienyl-, Furyl-, Pyridyl-, 1-Alkylpyrrolidin-2-yl-, Pyrrolidino- oder Morpholino-alkyl; oder Cycloalkyl, 15 welches gegebenenfalls einen ankondensierten Benzolring aufweisen kann; R 2 einen Rest der Formel 20 R4 oderR (a) (b) 25 X -CH 2 -, -CO-, -0- oder -NR -; R 3 Wasserstoff oder Alkyl; R 4 Wasserstoff oder Alkoxy; R 5 Phenyl, Heteroalkyl, Aryloxy, Alkoxy, Alkanoyl oder -NR 6 R 7 ; 30 R 6 Wasserstoff, Alkyl, Aralkyl, Cycloalkylalkyl oder Alkoxycarbonylalkyl; und WO 03/059905 PCT/CH02/00725 - 69 R 7 Aryl, Heteroaryl, alkyl, Hydroxyalkyl oder Acyl bedeuten; pharmazeutisch verwendbare Saureadditionssalze von basischen Verbindungen der Formel I, pharmazeutisch 5 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. 10 2. Verbindungen gemass Anspruch 1, worin R 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 oder 2-Morpholinoethyl bedeutet. 15
3. Verbindungen gemdss Anspruch 1, worin R1 Cycloheptyl, 2-Hydroxy-2-phenylethyl, 2-Thienylmethyl, 2-Furanylmethyl,
4-Chlorbenzyl, 3-Fluorphenyl, 2,4-Dimethoxybenzyl oder 2 Chlorbenzyl bedeutet. 20 4. Verbindungen gemass Anspruch 1, worin R 1 2-Naphthyl, Naphthalin-1-ylmethyl, 4-Dimethylaminophenyl, 2-Pyrrolidin 1-ylethyl, l-Methylpyrrolidin-2-ylethyl, 4-Isopropylphenyl oder 3,5-Bis-trifluormethylphenyl bedeutet. 25
5. Verbindungen gemass Anspruch 1, worin R 2,5 Dimethylphenyl, 2-Isopropylphenyl oder 2-Methyl-5 Methoxyphenyl bedeutet. 30
6. Verbindungen gemass einem der Ansprtiche 1 bis 5, worin 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- WO 03/059905 PCT/CH02/00725 - 70 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, 5 9-Oxo-9H-fluoren-2-yl oder 9-Ethylcarbazol-3-yl bedeutet.
7. Verbindungen gemass einem der Ansprtiche 1 bis 5, worin R 2 4-(N-Ethoxycarbonylmethyl-N-phenyl-amino)-phenyl, 4-(N Ethyl-N-phenyl-amino)-phenyl, 4-(N-Methyl-N-phenyl-amino 10 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 (Cyclopropancarbonyl-amino)-phenyl, 4-(3-Fluoro 15 benzoylamino)-phenyl oder 4-[(Furan-2-carbonyl)-amino] phenyl bedeutet
8. Verbindungen gemass einem der Ansprtiche 1 bis 5, worin R 2 Biphenyl-3-yl, 9H-Fluoren-l-yl, 2-Methoxydibenzofuran-3 20 yl, 4-(N-Isopropyl-N-phenylamino)phenyl, 4-(N-Benzyl-N phenylamino)phenyl, 4-Acetylaminophenyl, 4 Benzoylaminophenyl, 4-Phenylacetylaminophenyl, 4 [(Benzo[l,3]dioxol-5-carbonyl)amino]phenyl oder 4-(4 Methoxybenzoylamino)phenyl bedeutet. 25
9. Verbindungen gemass einem der Ansprche 1 bis 5, worin 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 pyrimidinyl)amino]phenyl, 4- (4,6,dimethyl-2 30 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.
WO 03/059905 PCT/CH02/00725 - 71 10. rac. 5-Oxo-l-(2-pyridin-2-yl-ethyl)-pyrrolidin-3 carbonshure-(9-ethyl-9H-carbazol-3-yl)-amid; rac. 1-(2-Hydroxy-2-phenyl-ethyl)-5-oxo-pyrrolidin-3 5 carbonsaure-(9-ethyl-9H-carbazol-3-yl)-amid; rac. 1-(2,5-Dimethyl-phenyl)-5-oxo-pyrrolidin-3 carbonsaure-(4-diethylamino-phenyl)-amid; rac. 5-Oxo-1-(2-thiophen-2-yl-ethyl)-pyrrolidin-3 carbonsaure-(9-ethyl-9H-carbazol-3-yl)-amid; 10 rac. 1-(4-Chlor-benzyl)-5-oxo-pyrrolidin-3-carbonshure-(9 ethyl-9H-carbazol-3-yl)-amid; rac. 5-Oxo-l-thiophen-2-ylmethyl-pyrrolidin-3-carbonsaure (9-ethyl-9H-carbazol-3-yl)-amid; rac. 1-Furan-2-ylmethyl-5-oxo-pyrrolidin-3-carbonsaure-(9 15 ethyl-9H-carbazol-3-yl)-amid; rac. 1-(2-Isopropyl-phenyl)-5-oxo-pyrrolidin-3-carbonsaure (9-ethyl-9H-carbazol-3-yl)-amid, rac. 1-(5-Methoxy-2-methyl-phenyl)-5-oxo-pyrrolidin- 3 carbonsaure-(9-ethyl-9H-carbazol-3-yl)-amid; 20 rac. 1-(2,5-Dimethyl-phenyl)-5-oxo-pyrrolidin-3 carbonsaure-[4-(ethyl-isopropyl-amino)-phenyl]-amid; rac. 5-Oxo-l-phenethyl-pyrrolidin-3-carbonsaure-(9-ethyl 9H-carbazol-3-yl)-amid; rac. [(4-{[1-(2,5-Dimethyl-phenyl)-5-oxo-pyrrolidin-3 25 carbonyl]-amino}-phenyl)-phenyl-amino]-essigsaure ethylester; rac. 1-Cycloheptyl-5-oxo-pyrrolidin-3-carbonsaure-(9-ethyl 9H-carbazol-3-yl)-amid; rac. 1-(5-Methoxy-2-methyl-phenyl)-5-oxo-pyrrolidin-3 30 carbonsaure-{4-[(4,6-dimethyl-pyrimidin-2-yl)-ethyl-amino] phenyl}-amid; rac. 1-(2,5-Dimethyl-phenyl)-5-oxo-pyrrolidin-3 carbonsbure-{4-[ethyl-(2-hydroxy-ethyl)-amino]-phenyl} amid; WO 03/059905 PCT/CH02/00725 - 72 rac. 1-(2,5-Dimethyl-phenyl)-5-oxo-pyrrolidin-3 carbonsaure-[4-(ethyl-phenyl-amino)-phenyl]-amid; rac. 1-(3-Methoxy-phenyl)-5-oxo-pyrrolidin-3-carbonsaure (9-ethyl-9H-carbazol-3-yl)-amid; 5 rac. 1-(2-Chlor-benzyl)-5-oxo-pyrrolidin-3-carbonshure-(9 ethyl-9H-carbazol-3-yl)-amid; rac. 1-(2,5-Dimethyl-phenyl)-5-oxo-pyrrolidin-3 carbonshure-[4-(4,6-dimethyl-pyrimidin-2-ylamino)-phenyl] amid; 10 rac. 1-(2,5-Dimethyl-phenyl)-5-oxo-pyrrolidin-3 carbonsaure-{4-[(4,6-dimethyl-pyrimidin-2-yl)-methyl amino]-phenyl}-amid; rac. 5-Oxo-1-phenyl-pyrrolidin-3-carbonshure-(9-ethyl-9H carbazol-3-yl)-amid; 15 rac. 5-Oxo-l-p-tolyl-pyrrolidin-3-carbonsaure-{4-[(4,6 dimethyl-pyrimidin-2-yl)-methyl-amino]-phenyl}-amid; rac. 1-(2,5-Dimethyl-phenyl)-5-oxo-pyrrolidin-3 carbonsaure-[4-(isopropyl-phenyl-amino)-phenyl]-amid; rac. 1-(2-Isopropyl-phenyl)-5-oxo-pyrrolidin-3-carbonsaure 20 [4-(ethyl-phenyl-amino)-phenyl]-amid; rac. 5-Oxo-l-(2-pyridin-2-yl-ethyl)-pyrrolidin-3 carbonsaure-{4-[(4,6-dimethyl-pyrimidin-2-yl)-ethyl-amino] phenyl}-amid; rac. 1-(2-Isopropyl-phenyl)-5-oxo-pyrrolidin-3-carbonshure 25 [4-(4,6-dimethyl-pyrimidin-2-ylamino)-phenyl]-amid; rac. 1-(5-Methoxy-2-methyl-phenyl)-5-oxo-pyrrolidin-3 carbonsaure-[4-(4,6-dimethyl-pyrimidin-2-ylamino)-phenyl] amid; rac. 1-(2,5-Dimethyl-phenyl)-5-oxo-pyrrolidin-3 30 carbonshure-[4-(methyl-phenyl-amino)-phenyl]-amid; rac. 1-(2-Isopropyl-phenyl)-5-oxo-pyrrolidin-3-carbonsaure [4-(methyl-phenyl-amino)-phenyl]-amid; rac. 1-(4-Is6propyl-phenyl)-5-oxo-pyrrolidin-3-carbonsaure (9-ethyl-9H-carbazol-3-yl)-amid; WO 03/059905 PCT/CH02/00725 - 73 rac. 1-(3-Fluor-phenyl)-5-oxo-pyrrolidin-3-carbonsaure-(9 ethyl-9H-carbazol-3-yl)-amid; rac. 1-(2,5-Dimethyl-phenyl)-5-oxo-pyrrolidin-3 carbonsaure-(4-phenylamino-phenyl)-amid; 5 rac. 1-Indan-2-yl-5-oxo-pyrrolidin-3-carbonshure-[4-(4,6 dimethyl-pyrimidin-2-ylamino)-phenyl]-amid; rac. 1-(5-Methoxy-2-methyl-phenyl)-5-oxo-pyrrolidin-3 carbonshure-[4-(ethyl-phenyl-amino)-phenyl]-amid; rac. 1-(2-Isopropyl-phenyl)-5-oxo-pyrrolidin-3-carbonsaure 10 {4-[(4,6-dimethyl-pyrimidin-2-yl)-methyl-amino]-phenyl} amid; rac. l-Benzyl-5-oxo-pyrrolidin-3-carbonsaure-(9-ethyl-9H carbazol-3-yl)-amid; rac. 5-Oxo-l-p-tolyl-pyrrolidin-3-carbonsaure-[4-(4,6 15 dimethyl-pyrimidin-2-ylamino)-phenyl]-amid; rac. 1-Indan-2-yl-5-oxo-pyrrolidin-3-carbonsAure-(9-ethyl 9H-carbazol-3-yl)-amid; rac. 1-(2-Hydroxy-2-phenyl-ethyl)-5-oxo-pyrrolidin-3 carbonshure-{4-[(4,6-dimethyl-pyrimidin-2-yl)-ethyl-amino] 20 phenyl}-amid; rac. 1-(2,5-Dimethyl-phenyl)-5-oxo-pyrrolidin-3 carbonshure-biphenyl-4-ylamid; rac. 1-(5-Methoxy-2-methyl-phenyl)-5-oxo-pyrrolidin-3 carbonsaure-[4-(cyclopropylmethyl-phenyl-amino)-phenyl] 25 amid; rac. 1-(2-Isopropyl-phenyl)-5-oxo-pyrrolidin-3-carbonsaure [4-(isopropyl-phenyl-amino)-phenyl]-amid; rac. 1-(2-Isopropyl-phenyl)-5-oxo-pyrrolidin-3-carbonsaure (4-phenylamino-phenyl)-amid; 30 rac. 1-(5-Methoxy-2-methyl-phenyl)-5-oxo-pyrrolidin-3 carbonsaure-{4-[(4,6-dimethyl-pyrimidin-2-yl)-methyl amino]-phenyl}-amid; WO 03/059905 PCT/CH02/00725 - 74 rac. 1-(3-Methoxy-phenyl)-5-oxo-pyrrolidin-3-carbonsaure {4-[(4,6-dimethyl-pyrimidin-2-yl)-ethyl-amino]-phenyl} amid; rac. 5-Oxo-l-m-tolyl-pyrrolidin-3-carbonshure-{4-[(4,6 5 dimethyl-pyrimidin-2-yl)-methyl-amino]-phenyl}-amid; rac. 1-(2,5-Dimethyl-phenyl)-5-oxo-pyrrolidin-3 carbonsaure-[4-(cyclopropylmethyl-phenyl-amino)-phenyl] amid; rac. 1-(2-Isopropyl-phenyl)-5-oxo-pyrrolidin-3-carbonsaure 10 {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]-essigsaure-ethyl ester; 15 rac. 1-(2-Isopropyl-phenyl)-5-oxo-pyrrolidin-3-carbonsaure [4-(cyclopropylmethyl-phenyl-amino)-phenyl]-amid; rac. l-Indan-2-yl-5-oxo-pyrrolidin-3-carbonsaure-[4-(ethyl phenyl-amino)-phenyl]-amid; und rac. 1-(2-Isopropyl-phenyl)-5-oxo-pyrrolidin-3-carbonsAure 20 [4-(isobutyl-phenyl-amino)phenyl]amid.
11. rac. l-(2,5-Dimethyl-phenyl)-5-oxo-pyrrolidin-3 carbonsaure-[4-(2-methoxy-benzoylamino)-phenyl]-amid; rac. 1-(2,5-Dimethyl-phenyl)-5-oxo-pyrrolidin-3 25 carbonsaure-[4-(2,2-Dimethyl-propionylamino)phenyl]-amid; rac. 1-(2-Morpholin-4-yl-ethyl)-5-oxo-pyrrolidin- 3 carbonshure-(9-ethyl-9H-carbazol-3-yl)-amid; rac. 5-Oxo-l-p-tolyl-pyrrolidin-3-carbonshure-(9-ethyl-9H carbazol-3-yl)-amid; und 30 rac. 1-(2,4-Dimethoxy-benzyl)-5-oxo-pyrrolidin-3 carbonshure-(9-ethyl-9H-carbazol-3-yl)-amid.
WO 03/059905 PCT/CH02/00725 - 75 12. rac. 1-(4-Dimethylamino-phenyl)-5-oxo-pyrrolidin-3 carbonshure-[4-(4,6-dimethyl-pyrimidin-2 ylamino)phenyl]amid; und rac. 1-(4-Dimethylamino-phenyl)-5-oxo-pyrrolidin-3 5 carbonshure-[4-(4,6-dimethyl-pyrimidin-2-yl)methyl aminophenyl]amid.
13. Verbindungen gemass einem der Ansprtche 1 bis 12 zur Anwendung als therapeutische Wirkstoffe. 10
14. Arzneimittel, bestehend aus einer galenischen Darreichungsform, enthaltend eine Verbindung gemass einem der Ansprtche 1 bis 12.
15 15. Verwendung von Verbindungen gemAss einem der Ansprtche 1 bis 12 zur Vorbeugung oder Behandlung von Arthritis, Diabetes und speziell von Essstbrungen und Obesitas bzw. zur Herstellung entsprechender Arzneimittel. 20
16. Verfahren zur Herstellung von Verbindungen gemass einem der Anspriche 1 bis 12, dadurch gekennzeichnet, dass man eine Pyrrolidoncarbonsaure der Formel 0 25 OH III 30 worin R 1 die in Anspruch 1 angegebene Bedeutung besitzt, oder ein reaktionsfahiges Derivat davon, mit einem Amin der Formel WO 03/059905 PCT/CH02/00725 - 76 R,2 IV 5 worin R 2 die in Anspruch 1 angegebene Bedeutung besitzt, oder einem reaktionsfahigen Derivat davon, umsetzt und 10 erwinschtenfalls ein allfallig erhaltenes Stereoisomerengemisch auftrennt.
17. Verfahren zur Herstellung von Verbindungen der in Anspruch 1 definierten Formel I, worin R einen Rest der 15 Formel (b), R s -NR 6 R' und R 7 Acyl bedeuten, dadurch gekennzeichnet, dass man eine entsprechende Verbindung, worin aber R 7 Wasserstoff bedeutet, acyliert und erwtnschtenfalls ein allfallig erhaltenes Stereoisomerengemisch auftrennt. 20
18. Eine Verbindung der in Anspruch 16 definierten Formel IV bzw. ein entsprechender Nitro-Vorlaufer, ausgewdhlt aus: [(4-Nitro-phenyl)-phenyl-amino]-essigsaure-ethylester; 25 [(4-Amino-phenyl)-phenyl-amino]-essigsaure-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; 30 [(4-Nitro-phenyl)-phenyl-amino]-pentanshure-ethylester; [(4-Amino-phenyl)-phenyl-amino]-pentanshure-ethylester; Benzyl-(4-nitro-phenyl)-phenyl-amin; und N-Benzyl-N-phenyl-phenylen-1,4-diamin. WO 03/059905 PCT/C1102/00725 - 77
19. Elne Verbindung der in Anspruch 16 definierten Formel III, ausgewahlt aus: rac 1-Indan-2-y1-5-oxo-pyrrolidin-3-carbons, ure; 5 rac. 1-Naphthalin-2-yl-5-oxo-pyrrolidin-3-carbonsaure; rac. 1- (5-Methoxy-2-methyl-phenyl) -5-oxo--pyrrolidin-3 carbon sure; rac. 5-Oxo-l- (2-pyridin-2-yl-ethyl) -pyrrolidin-3 carbonsaure; 10 rac. 1-Cyclohepty1-5-oxo-pyrrolidin-3-carbonsaure; rac. 1- (2-Hydroxy--2-phenyl-ethyl) -5-oxo-pyrrolidin-3 carbonsaure; rac. 5-Oxo-1-(2-pyrrolidin-1-yl-ethyl) -pyrrolidin-3 carbonsdure; 15 rac. 1- [2- (1-Methyl-pyrrolidini-2-yl) -ethyl] -5-oxo pyrrolidin-3-carbonsaure; und rac. 1- (3-Fluor-phenyl) -5-oxo-pyrrolidin-3-carbons~iure.
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