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US20070208036A1 - Arylalkanes, arylalkenes and aryl-azaalkanes, pharmaceutical compositions containing these compounds and processes for preparing them - Google Patents

Arylalkanes, arylalkenes and aryl-azaalkanes, pharmaceutical compositions containing these compounds and processes for preparing them Download PDF

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US20070208036A1
US20070208036A1 US11/743,393 US74339307A US2007208036A1 US 20070208036 A1 US20070208036 A1 US 20070208036A1 US 74339307 A US74339307 A US 74339307A US 2007208036 A1 US2007208036 A1 US 2007208036A1
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dihydro
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Klaus Rudolf
Wolfgang Eberlein
Wolfhard Engel
Henri Doods
Gerhard Hallermayer
Eckhart Bauer
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Boehringer Ingelheim Pharma GmbH and Co KG
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Boehringer Ingelheim Pharma GmbH and Co KG
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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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds of general formula R-Z 1 -Z 2 -Z 3 R 1 (I), the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, pharmaceutical compositions containing these compounds, their use and processes for preparing them.
  • R denotes the H 2 N group or the group of formula wherein
  • protecting groups mentioned in the preceding definitions are meant the protecting groups familiar from peptide chemistry, especially
  • the present invention relates to racemates if the compounds of general formula I have only one chiral element.
  • the application also includes the individual diastereomeric pairs of antipodes or mixtures thereof which are obtained if there is more than one chiral element in the compounds of general formula (I).
  • Z 2 denotes the group —CH ⁇ CH—
  • the (E)-configured diastereomers are preferred.
  • the compounds of general formula (I) have valuable pharmacological properties, based on their selective CGRP-antagonistic properties.
  • the invention further relates to pharmaceutical compositions containing these compounds, their use and the preparation thereof.
  • R denotes the H 2 N group, if Z 1 and Z 3 each denote the CO group and R 1 is at least disubstituted by the H 2 N group and an additional substituent or if Z 2 does not contain an imino group,
  • Particularly preferred compounds of the above general formula I are those wherein R denotes the H 2 N group, if Z 1 and Z 3 each denote the CO group and R 1 is at least disubstituted by the H 2 N group and an additional substituent or if Z 2 does not contain an imino group, or the group of formula wherein
  • R denotes the H 2 N group
  • Z 1 and Z 3 each denote the CO group and R 1 is at least disubstituted by the H 2 N group and an additional substituent or if Z 2 does not contain an imino group
  • R denotes the group of formula wherein
  • the compounds of general formula I are prepared by methods known in principle. The following methods have proved particularly suitable for preparing the compounds of general formula I according to the invention:
  • Z 1 denotes the methylene group
  • Z 2 denotes one of the groups —(CH 2 ) 2 , —(CH 2 ) 3 — or —CH ⁇ CH—
  • Z 3 denotes the carbonyl group
  • R has the meanings given hereinbefore with the exception of a 4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-[1.4′]bipiperidinyl-1′-yl group:
  • R′—H (IVa) alkylating a compound of general formula R′—H (IVa), wherein R′ has the meanings given for R hereinbefore with the exception of a 4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-[1.4′]bipiperidinyl-1′-yl group, with a compound of general formula X—CH 2 -Z 2 -Z 3 -R 1 (V), wherein R 1 is as hereinbefore defined, Z 2 denotes one of the groups —(CH 2 ) 2 , —(CH 2 ) 3 — or —CH ⁇ CH—, Z 3 denotes the carbonyl group and X denotes a leaving group, e.g.
  • a halogen atom such as the chlorine, bromine or iodine atom, an alkylsulphonyloxy group with 1 to 10 carbon atoms in the alkyl moiety, a phenylsulphonyloxy or naphthylsulphonyloxy group optionally mono-, di- or trisubstituted by chlorine or bromine atoms, by methyl or nitro groups, whilst the substituents may be identical or different.
  • the reaction is carried out with or without auxiliary bases at temperatures between 0° C. and +140° C., preferably between +20° C. and +100° C., and preferably in the presence of solvents.
  • the auxiliary bases used may be alkali metal and alkaline earth metal hydroxides, e.g. sodium hydroxide, potassium hydroxide or barium hydroxide, but preferably alkali metal carbonates, e.g. sodium carbonate, potassium carbonate or caesium carbonate, and also alkali metal acetates, e.g. sodium or potassium acetate, as well as tertiary amines, e.g.
  • the solvents used may be, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, but preferably dipolar aprotic solvents such as acetonitrile, dimethyl formamide, dimethyl acetamide, N-methyl-pyrrolidone, methyl-isobutylketone or mixtures thereof; if alkali metal or alkaline earth metal hydroxides, alkali metal carbonates or acetates are used as the auxiliary bases, water may also be added to the reaction mixture as cosolvent.
  • water may also be added to the reaction mixture as cosolvent.
  • Z 1 denotes the carbonyl group
  • Z 2 denotes one of the groups —(CH 2 ) 2 — or —(CH 2 ) 3 , wherein a hydrogen atom may be replaced by a C 1-3 -alkyl or a hydroxy group
  • a hydrogen atom bound to a carbon atom and/or the hydrogen atom of the imino group may each be replaced by a C 1-3 -alkyl group, or the group —CH ⁇ CH—
  • Z 3 denotes the methylene or carbonyl group:
  • the coupling is preferably carried out using methods known from peptide chemistry (cf. e.g. Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for example using carbodiimides such as e.g. dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide (DIC) or ethyl-(3-dimethylaminopropyl)-carbodiimide, O-(1H-benzotriazol-1-yl)-N,N—N′,N′-tetramethyluronium hexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP).
  • DCC dicyclohexylcarbodiimide
  • DI diisopropyl carbodiimide
  • any possible racemisation can additionally be suppressed, if desired, or the reaction speed can be increased.
  • the couplings are normally carried out with equimolar amounts of the coupling components as well as the coupling reagent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethyl formamide (DMF), dimethyl acetamide (DMA), N-methylpyrrolidone (NMP) or mixtures thereof and at temperatures between ⁇ 30 and +30° C., preferably ⁇ 20 and +20° C.
  • DIEA N-ethyl-diisopropylamine
  • ünig base is preferably used as an additional auxiliary base.
  • anhydride process is used as a further coupling method for synthesising compounds of general formula I (cf. also: M. Bodanszky, “Peptide Chemistry”, Springer-Verlag 1988, p. 58-59; M. Bodanszky, “Principles of Peptide Synthesis”, Springer-Verlag 1984, p. 21-27).
  • the Vaughan variant of the mixed anhydride process is preferred (J. R. Vaughan Jr., J. Amer. Chem. Soc.
  • Z 1 denotes the carbonyl group
  • Z 2 denotes one of the groups —(CH 2 ) 2 — or —(CH 2 ) 3 , wherein a hydrogen atom may be replaced by a C 1-3 -alkyl or hydroxy group
  • a hydrogen atom bound to a carbon atom and/or the hydrogen atom of the imino group may each be replaced by a C 1-3 -alkyl group, or the group —CH ⁇ CH—
  • Z 3 denotes a methylene or carbonyl group:
  • Z 2 denotes one of the groups —(CH 2 ) 2 — or —(CH 2 ) 3 , wherein a hydrogen atom may be replaced by a C 1-3 -alkyl or a hydroxy group, one of the groups —CH 2 —NH— or —(CH 2 ) 2 —NH, wherein a hydrogen atom bound to a carbon atom and/or the hydrogen atom of the imino group may each be replaced by a C 1-3 -alkyl group, or the group —CH ⁇ CH—, Z 3 denotes a methylene or carbonyl group and Nu denotes a leaving group, e.g.
  • a halogen atom such as the chlorine, bromine or iodine atom, an alkylsulphonyloxy group with 1 to 10 carbon atoms in the alkyl moiety, a phenylsulphonyloxy or naphthylsulphonyloxy group optionally mono-, di- or trisubstituted by chlorine or bromine atoms, by methyl or nitro groups, whilst the substituents may be identical or different, a 1H-imidazol-1-yl, a 1H-pyrazol-1-yl optionally substituted by 1 or 2 methyl groups in the carbon skeleton, a 1H-1,2,4-triazol-1-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3,4-tetrazol-1-yl, a vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophen
  • the reaction is carried out under Schotten-Baumann or Einhorn conditions, i.e. the components are reacted in the presence of at least one equivalent of an auxiliary base at temperatures between ⁇ 50° C. and +120° C., preferably ⁇ 10° C. and +30° C., and optionally in the presence of solvents.
  • the auxiliary bases used are preferably alkali metal and alkaline earth metal hydroxides, e.g. sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates, e.g. sodium carbonate, potassium carbonate or caesium carbonate, alkali metal acetates, e.g. sodium or potassium acetate, as well as tertiary amines, e.g.
  • the solvents used may be, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethyl formamide, dimethyl acetamide, N-methyl-pyrrolidone or mixtures thereof; if alkali metal or alkaline earth metal hydroxides, alkali metal carbonates or acetates are used as the auxiliary bases, water may also be added to the reaction mixture as cosolvent.
  • the catalytic hydrogenation may be carried out both with heterogeneous and with homogeneous catalysts.
  • heterogeneous catalysts those consisting of metals of the sub-group of the Periodic Table are preferred, e.g. Raney nickel (R—Ni), palladium on charcoal, nickel reduced with sodium borohydride, or nickel boride (Paul, Buisson and Joseph, Ind. Eng. Chem. 44, 1006 (1952); Brown, J. C. S. Chem. Commun. 1969, 952, J. Org. Chem. 35, 1900 (1973); Brown and Ahuja, J. Org. Chem. 38, 2226 (1973), J. C. S. Chem. Commun.
  • any nitro groups present in the groups R or R 1 are simultaneously reduced to amino groups, while if excessively high temperatures are used nitrile groups are also reduced to aminomethyl groups.
  • the abovementioned homogeneous catalyst chlorotris(triphenylphosphine) on the other hand leaves intact any nitro or cyano groups present during the hydrogenation of the C ⁇ C-double bonds in compounds of general formula VIII.
  • the hydrogenations are carried out at temperatures between ⁇ 5° C. and +50° C., preferably between +15 and +25° C. and most preferably at room temperature.
  • Both the catalyst and the hydrogen required can be produced in situ, for example by treating hexachloroplatinic(IV)-acid or rhodium(III)-chloride with sodium borohydride (Brown and Sivasankaran, J. Am. Chem. Soc. 84, 2828 (1962); Brown and Brown, J. Am. Chem. Soc. 84, 1494, 1495, 2829 (1962), J. Org. Chem. 31, 3989 (1966); Brown, Sivasankaran and Brown, J. Org. Chem. 28, 214 (1963)).
  • solvents which are particularly suitable for the catalytic hydrogenations in question are ethanol, methanol, ethyl acetate, 1,4-dioxane and acetic acid, if miscible therewith, optionally with the addition of water, and mixtures of these solvents.
  • the coupling is preferably carried out using methods known from peptide chemistry (cf. e.g. Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for example using carbodiimides such as e.g. dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide (DIC) or ethyl-(3-dimethylaminopropyl)-carbodiimide, O-(1H-benzotriazol-1-yl)-N,N—N′,N′-tetramethyluronium hexafluorophosphate (HBTU) or -tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP).
  • DCC dicyclohexylcarbodiimide
  • DI diisopropyl carbodiimide
  • any possible racemisation can additionally be suppressed, if desired, or the reaction speed can be increased.
  • the couplings are normally carried out with equimolar amounts of the coupling components as well as the coupling reagent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethyl formamide (DMF), dimethyl acetamide (DMA), N-methylpyrrolidone (NMP) or mixtures thereof and at temperatures between ⁇ 30 and +30° C., preferably ⁇ 20 and +20° C.
  • DIEA N-ethyl-diisopropylamine
  • ünig base is preferably used as an additional auxiliary base.
  • anhydride process is used as a further coupling method for synthesising compounds of general formula I (cf. also: M. Bodanszky, “Peptide Chemistry”, Springer-Verlag 1988, p. 58-59; M. Bodanszky, “Principles of Peptide Synthesis”, Springer-Verlag 1984, p. 21-27).
  • the Vaughan variant of the mixed anhydride process is preferred (J. R. Vaughan Jr., J. Amer. Chem. Soc.
  • Z 1 denotes a methylene or carbonyl group or, if Z 2 denotes a divalent group of general formula III, Z 1 may also denote a bond,
  • Z 2 denotes one of the groups —CH 2 —NH— or —(CH 2 ) 2 —NH, wherein a hydrogen atom bound to a carbon atom and/or the hydrogen atom of the imino group may each be replaced by a C 1-3 -alkyl group, or Z 1 denotes a divalent group of general formula wherein m and n independently of one another denote one of the numbers 1, 2, 3 or 4 and Z 3 denotes the carbonyl group: coupling a compound of general formula wherein R 1 is as hereinbefore defined and Nu denotes a leaving group, e.g.
  • a halogen atom such as the chlorine, bromine or iodine atom, an alkylsulphonyloxy group with 1 to 10 carbon atoms in the alkyl moiety, a phenylsulphonyloxy or naphthylsulphonyloxy group optionally mono-, di- or trisubstituted by chlorine or bromine atoms, by methyl or nitro groups, whilst the substituents may be identical or different, a 1H-imidazol-1-yl, a 1H-pyrazol-1-yl optionally substituted by 1 or 2 methyl groups in the carbon skeleton, a 1H-1,2,4-triazol-1-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3,4-tetrazol-1-yl, a vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophen
  • the reaction is carried out under Schotten-Baumann or Einhorn conditions, i.e. the components are reacted in the presence of at least one equivalent of an auxiliary base at temperatures between ⁇ 50° C. and +120° C., preferably ⁇ 10° C. and +30° C., and optionally in the presence of solvents.
  • the auxiliary bases used are preferably alkali metal and alkaline earth metal hydroxides, e.g. sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates, e.g. sodium carbonate, potassium carbonate or caesium carbonate, alkali metal acetates, e.g. sodium or potassium acetate, as well as tertiary amines, e.g.
  • the solvents used may be, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethyl formamide, dimethyl acetamide, N-methyl-pyrrolidone or mixtures thereof; if alkali metal or alkaline earth metal hydroxides, alkali metal carbonates or acetates are used as the auxiliary bases, water may also be added to the reaction mixture as cosolvent.
  • Z 1 denotes the carbonyl group
  • Z 2 denotes one of the groups —NH—CH 2 — or —NH—(CH 2 ) 2 , wherein a hydrogen atom bound to a carbon atom and/or the hydrogen atom of the imino group may each be replaced by a C 1-3 -alkyl group and
  • Z 3 denotes the methylene or carbonyl group:
  • the reactions which are theoretically two-step reactions are usually carried out as one-pot processes, preferably by reacting one of the two components XI or XIII with equimolar quantities of the carbonic acid derivative of general formula XII in a suitable solvent at lower temperature in the first stage, then adding at least equimolar amounts of the other component XIII or XI and finishing the reaction at elevated temperature.
  • the reactions with bis-(trichloromethyl)-carbonate are preferably carried out in the presence of at least 2 equivalents (based on bis-(trichloromethyl)-carbonate) of a tertiary base, e.g.
  • solvents which should be anhydrous, include tetrahydrofuran, dioxane, dimethyl formamide, dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone or acetonitrile; if bis-(trichloromethyl)-carbonate is used as the carbonyl component anhydrous chlorohydrocarbons such as dichloromethane, 1,2-dichloroethane or trichloroethylene are preferred.
  • the reaction temperatures for the first reaction step are between ⁇ 30 and +25° C., preferably ⁇ 5 and +10° C., for the second reaction step they are between +15° C. and the boiling temperature of the solvent used, preferably between +20° C.
  • alkaline saponification of the esters of general formula (Ia) lithium hydroxide, sodium hydroxide and potassium hydroxide are preferred; however, other alkali metal hydroxides such as caesium hydroxide, or alkaline earth metal hydroxides, for example barium hydroxide, or tetralkylammonium hydroxides are also suitable.
  • the procedure is carried out in aqueous solution and advantageously with the addition of water-miscible co-solvents, preferably alcohols such as methanol, ethanol or 2-ethoxyethanol, or ethers such as tetrahydrofuran or 1,4-dioxane.
  • Suitable temperatures for alkaline saponification are between ⁇ 10° C.
  • Dilute aqueous organic or inorganic acids e.g. acetic acid, oxalic acid, methanesulphonic acid, hydrochloric acid, sulphuric acid and phosphoric acid are suitable for liberating the basic carboxylic acids from the salts thereof formed initially.
  • the acid hydrolysis is carried out using dilute to semi-concentrated aqueous, organic or inorganic acids such as hydrochloric acid, hydrobromic acid, trichloroacetic acid or sulphuric acid, and in the presence or absence of cosolvents such as methanol, ethanol, acetic acid or dioxane. Suitable temperatures are between ambient temperature and 100° C.; the boiling temperature of the solvent mixture used is preferred.
  • R-Z 1 -Z 2 -Z 3 -R 1d (Id) of a compound of general formula R-Z 1 -Z 2 -Z 3 -R 1d (Id), wherein R is as hereinbefore defined, Z 1 and Z 3 each denote the carbonyl group, Z 2 denotes the group —(CH 2 ) 2 — and the group R 1d denotes a phenyl group which carries a nucleophilically exchangeable function, preferably a fluorine, chlorine, bromine or iodine atom, in the 4 position relative to the point of attachment, but may otherwise be substituted as described hereinbefore, with a corresponding amine, for example with dimethylamine, piperidine, 1-(3-dimethylaminopropyl)piperazine, [4,1′]bi-piperidinyl, 4-(4-methyl-1-piperazin
  • the reactions are carried out in excess secondary dialkylamine as solvent or using dipolar, aprotic solvents such as dimethylsulphoxide, dimethylformamide or sulpholane, and at temperatures of between 50 and 160° C., preferably 70 and 140° C. It may also be advantageous to add potassium carbonate to the reaction mixture.
  • R is uniformly mono-, di- or trisubstituted in the carbon skeleton by an aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group:
  • R e has the meanings given for R hereinbefore with the proviso that it is mono-, di- or trisubstituted in the carbon skeleton by the carboxy group, and R 1 , Z 1 , Z 2 and Z 3 are as hereinbefore defined, with ammonia or a corresponding alkylamine, for example ethanolamine, or a dialkylamine, for example 1-methylpiperazine or morpholine.
  • the coupling is preferably carried out using methods known from peptide chemistry (cf. e.g. Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for example using carbodiimides such as e.g. dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide (DIC) or ethyl-(3-dimethylaminopropyl)-carbodiimide, O-(1H-benzotriazol-1-yl)-N,N—N′,N′-tetramethyluronium hexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP).
  • DCC dicyclohexylcarbodiimide
  • DI diisopropyl carbodiimide
  • any possible racemisation can additionally be suppressed, if desired, or the reaction speed can be increased.
  • the couplings are normally carried out with equimolar amounts of the coupling components as well as the coupling reagent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethyl formamide (DMF), dimethyl acetamide (DMA), N-methylpyrrolidone (NMP) or mixtures thereof and at temperatures between ⁇ 30 and +30° C., preferably ⁇ 20 and +20° C.
  • DIEA N-ethyl-diisopropylamine
  • ünig base is preferably used as an additional auxiliary base.
  • anhydride process is used as a further coupling method for synthesising compounds of general formula I (cf. also: M. Bodanszky, “Peptide Chemistry”, Springer-Verlag 1988, p. 58-59; M. Bodanszky, “Principles of Peptide Synthesis”, Springer-Verlag 1984, p. 21-27).
  • the Vaughan variant of the mixed anhydride process is preferred (J. R. Vaughan Jr., J. Amer. Chem. Soc.
  • the aminolysis reaction is carried out in water or inert, usually polar and water-miscible solvents, such as tetrahydrofuran, 1,4-dioxane, pyridine, acetic acid or dimethylformamide, or in mixtures thereof and at temperatures between 0° C. and 100° C.
  • polar and water-miscible solvents such as tetrahydrofuran, 1,4-dioxane, pyridine, acetic acid or dimethylformamide, or in mixtures thereof
  • alcohols such as methanol or ethanol
  • R G denotes a methyl, ethyl, cycloalkyl or phenyl group and Nu denotes a leaving group such as a halogen atom, e.g. the chlorine, bromine or iodine atom, an alkylsulphonyloxy group with 1 to 10 carbon atoms in the alkyl moiety, a phenylsulphonyloxy or naphthylsulphonyloxy group optionally mono-, di- or trisubstituted by chlorine or bromine atoms or by methyl or nitro groups, wherein the substituents may be identical or different, a 1H-imidazol-1-yl, a 1H-pyrazol-1-yl optionally substituted by 1 or 2 methyl groups in the carbon skeleton, a 1H-1,2,4-triazol-1-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3,4-
  • a leaving group such as
  • the reaction is carried out under Schotten-Baumann or Einhorn conditions, i.e. the components are reacted in the presence of at least one equivalent of an auxiliary base at temperatures between ⁇ 50° C. and +120° C., preferably ⁇ 10° C. and +30° C., and optionally in the presence of solvents.
  • the auxiliary bases used are preferably alkali metal and alkaline earth metal hydroxides, e.g. sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates, e.g. sodium carbonate, potassium carbonate or caesium carbonate, alkali metal acetates, e.g. sodium or potassium acetate, as well as tertiary amines, e.g.
  • the solvents used may be, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethyl formamide, dimethyl acetamide, N-methyl-pyrrolidone or mixtures thereof; if alkali metal or alkaline earth metal hydroxides, alkali metal carbonates or acetates are used as the auxiliary bases, water may also be added to the reaction mixture as cosolvent.
  • R f a compound of general formula R f -Z 1 -Z 2 -Z 3 -R 1 (If), wherein R 1 , Z 1 , Z 2 and Z 3 are as hereinbefore defined and the group R f has the meanings given for R hereinbefore, with the proviso that it is substituted in the carbon skeleton by an amino group, with cyanic acid which is produced in situ from alkali metal cyanates, for example sodium cyanate or potassium cyanate, and dilute inorganic acids such as hydrochloric acid or sulphuric acid.
  • the reaction is carried out in suitable, water-miscible solvents, preferably tetrahydrofuran or 1,4-dioxane, and using water as cosolvent.
  • Suitable reaction temperatures are between ⁇ 5 and +50° C., preferably 0 and +25° C. p)
  • Z 2 has the meanings given hereinbefore with the exception of the group —CH ⁇ CH—: catalytic hydrogenation of a compound of general formula R g -Z 1 -Z 2 -Z 3 -R 1 (Ig), wherein R 1 , Z 1 , Z 2 and Z 3 are as hereinbefore defined and the group R g has the meanings given for R hereinbefore, with the proviso that it is substituted in the carbon skeleton by a nitrile group.
  • Nickel and palladium catalysts have proved suitable for the catalysis, e.g. Raney nickel (R—Ni), palladium on charcoal and nickel reduced with sodium borohydride or nickel boride (Paul, Buisson and Joseph, Ind. Eng. Chem. 44, 1006 (1952); Brown, J. C. S. Chem. Commun. 1969, 952, J. Org. Chem. 35, 1900 (1973); Brown and Ahuja, J. Org. Chem. 38, 2226 (1973), J. C. S. Chem. Commun. 1973, 553; Schreifels, Maybury and Swartz, J. Org. Chem. 46, 1263 (1981); Nakao and Fujishige, Chem. Lett.
  • Palladium catalysts are also suitable for hydrogenating compounds of general formula Ig under acid conditions, i.e. in the presence of hydrochloric acid, sulphuric acid or phosphoric acid. Whereas nickel catalysts generally require slightly elevated temperatures between 40 and 100° C., the hydrogenations in question can be successfully carried out at ambient temperature using the palladium catalyst mentioned above.
  • Suitable hydrogen pressures are between normal pressure and 250 bar, while if palladium on charcoal is used as catalyst pressures of up to 10 bar are preferred.
  • Suitable solvents are alcohols such as methanol or ethanol, ethers such as tetrahydrofuran or 1,4-dioxane, or esters, e.g. methyl acetate or ethyl acetate. Any C ⁇ C double bonds which may have been present in the chain Z 1 -Z 2 -Z 3 -Z 4 -Z 5 of the starting material Ig are also saturated during the hydrogenation.
  • arylalkanes, arylalkenes and aryl-azaalkanes of general formula I according to the invention contain a chiral centre in some cases.
  • some of the compounds may also occur in the form of two geometric isomers; the methods of synthesis described hereinbefore predominantly produce the (E) isomers.
  • the invention includes the individual isomers as well as the mixtures thereof.
  • the diastereomers may be separated on the basis of their different physico-chemical properties, e.g. by fractional crystallisation from suitable solvents, by high pressure liquid or column chromatography, using chiral or preferably non-chiral stationary phases.
  • Racemates covered by general formula (I) may be separated for example by HPLC on suitable chiral stationary phases (e.g. Chiral AGP, Chiralpak AD). Racemates which contain a basic or acidic function can also be separated via the diastereomeric, optically active salts which are produced on reacting with an optically active acid, for example (+) or ( ⁇ )-tartaric acid, (+) or ( ⁇ )-diacetyl tartaric acid, (+) or ( ⁇ )-monomethyl tartrate or (+)-camphorsulphonic acid, or an optically active base, for example with (R)-(+)-1-phenylethylamine, (S)-( ⁇ )-1-phenylethylamine or (S)-brucine.
  • an optically active acid for example (+) or ( ⁇ )-tartaric acid, (+) or ( ⁇ )-diacetyl tartaric acid, (+) or ( ⁇ )-monomethyl tartrate or (+)-camphorsulphonic acid, or an optically active base
  • the racemate of a compound of general formula (I) is reacted with, one of the abovementioned optically active acids or bases in equimolar amounts in a solvent and the resulting crystalline, diastereomeric, optically active salts thereof are separated using their different solubilities.
  • This reaction may be carried out in any type of solvent provided that it is sufficiently different in terms of the solubility of the salts.
  • methanol, ethanol or mixtures thereof for example in a ratio by volume of 50:50, are used.
  • each of the optically active salts is dissolved in water, neutralised with a base such as sodium carbonate or potassium carbonate, sodium hydroxide solution or potassium hydroxide solution and in this way the corresponding free compound is obtained in the (+) or ( ⁇ ) form.
  • a base such as sodium carbonate or potassium carbonate, sodium hydroxide solution or potassium hydroxide solution
  • the (R) or (S) enantiomer alone or a mixture of two optically active diastereomeric compounds covered by general formula I may also be obtained by performing the syntheses described above with a suitable reaction component in the (R) or (S) configuration.
  • 4-Aryl-4-oxobutanoic acids of general formula VI may either easily be prepared analogously to methods known from the literature or may be obtained by catalytic hydrogenation of 4-aryl-4-oxo-2-butenoic acids, which may in turn be synthesised from suitable alkanophenones by a process described in published German patent applications 2 047 806 and 2 103 749, by condensation with glyoxylic acid hydrate under acid conditions.
  • Compounds of general formula VII may be obtained from VI by conventional methods known from the literature.
  • the compounds of general formula I obtained may, if they contain suitable basic functions, be converted, particularly for pharmaceutical use, into their physiologically acceptable salts with inorganic or organic acids.
  • suitable acids include for example hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, mandelic acid, malic acid, citric acid, tartaric acid or maleic acid.
  • the new compounds of formula (I), if they contain an acid function, for example a carboxy group, may if desired be converted into the addition salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable addition salts thereof.
  • Suitable bases for this include, for example, sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
  • the new compounds of general formula I and the physiologically acceptable salts thereof have CGRP-antagonistic properties and exhibit good affinities in CGRP receptor binding studies.
  • the compounds display CGRP-antagonistic properties in the pharmacological test systems described hereinafter.
  • SK-N-MC cells are cultivated in “Dulbecco's modified Eagle medium”. The medium is removed from confluent cultures. The cells are washed twice with PBS buffer (Gibco 041-04190 M), detached by the addition of PBS buffer mixed with 0.02% EDTA, and isolated by centrifuging. After resuspension in 20 ml of “Balanced Salts Solution” [BSS (in mM): NaCl 120, KCl 5.4, NaHCO 3 16.2, MgSO 4 0.8, NaHPO 4 1.0, CaCl 2 1.8, D-glucose 5.5, HEPES 30, pH 7.40] the cells are centrifuged twice at 100 ⁇ g and resuspended in BSS.
  • BSS “Balanced Salts Solution”
  • the cells are homogenised using an Ultra-Turrax and centrifuged for 10 minutes at 3000 ⁇ g. The supernatant is discarded and the pellet is recentrifuged in Tris buffer (10 mM Tris, 50 mM NaCl, 5 mM MgCl 2 , 1 mM EDTA, pH 7.40) enriched with 1% bovine serum albumin and 0.1% bacitracin, and resuspended (1 ml/1000000 cells). The homogenised product is frozen at ⁇ 80° C. The membrane preparations are stable for more than 6 weeks under these conditions.
  • the homogenised product is diluted 1:10 with assay buffer (50 mM Tris, 150 mM NaCl, 5 mM MgCl 2 , 1 mM EDTA, pH 7.40) and homogenised for 30 seconds with an Ultra-Turrax. 230 ⁇ l of the homogenised product are incubated for 180 minutes at ambient temperature with 50 pM 125 I-iodotyrosyl-Calcitonin-Gene-Related Peptide (Amersham) and increasing concentrations of the test substances in a total volume of 250 ⁇ l. The incubation is ended by rapid filtration through GF/B-glass fibre filters treated with polyethyleneimine (0.1%) using a cell harvester. The protein-bound radioactivity is measured using a gamma counter. Non-specific binding is defined as the bound radioactivity in the presence of 1 ⁇ M human CGRP-alpha during incubation.
  • assay buffer 50 mM Tris, 150 mM NaCl, 5 mM
  • concentration binding curves are analysed using computer-aided non-linear curve matching.
  • the compounds of general formula I show IC 50 values ⁇ 10000 nM in the test described.
  • SK-N-MC cells (1 million cells) are washed twice with 250 ⁇ l incubation buffer (Hanks' HEPES, 1 mM 3-isobutyl-1-methylxanthine, 1% BSA, pH 7.4) and pre-incubated at 37° C. for 15 minutes. After the addition of CGRP (10 ⁇ l) as agonist in increasing concentrations (10 ⁇ 11 to 10 ⁇ 6 M), or additionally the substance in 3 to 4 different concentrations, the mixture is incubated for another 15 minutes.
  • Intracellular cAMP is then extracted by the addition of 20 ⁇ l of 1M HCl and centrifugation (2000 ⁇ g, 4° C., for 15 minutes). The supernatants are frozen in liquid nitrogen and stored at ⁇ 20° C.
  • the cAMP contents of the samples are determined by radioimmunoassay (Messrs. Amersham) and the pA 2 values of antagonistically acting substances are determined graphically.
  • the compounds of general formula I exhibit CGRP-antagonistic properties in the in vitro test model described, in a dosage range of between 10 ⁇ 11 to 10 ⁇ 5 M.
  • the compounds of general formula I and the salts thereof with physiologically acceptable acids or bases are thus suitable for the acute and prophylactic treatment of headaches, particularly migraine or cluster headaches.
  • the compounds of general formula I also have a positive effect on the following diseases: non-insulin-dependent diabetes mellitus (“NIDDM”), cardiovascular diseases, morphine tolerance, skin diseases, particularly thermal and radiation-induced skin damage including sunburn, inflammatory diseases, e.g. inflammatory diseases of the joints (arthritis), inflammatory lung diseases, allergic rhinitis, asthma, diseases accompanied by excessive vasodilatation and consequent reduced circulation of blood through the tissues, e.g. shock and sepsis.
  • NIDDM non-insulin-dependent diabetes mellitus
  • the symptoms of menopausal hot flushes in estrogen-deficient women caused by vasodilatation and increased blood flow are favourably affected by the CGRP-antagonists of the present application in a preventive and acute-therapeutic capacity, this therapeutic approach being distinguished from hormone replacement by the absence of side effects.
  • the compounds of general formula I have a general pain-relieving effect.
  • the dosage required to achieve a corresponding effect is conveniently 0.001 to 30 mg/kg of body weight, preferably 0.01 to 5 mg/kg of body weight, when administered intravenously or subcutaneously and 0.01 to 50 mg/kg of body weight, preferably 0.1 to 30 mg/kg of body weight when administered orally, nasally or by inhalation, 1 to 3 ⁇ a day in each case.
  • the compounds of general formula I prepared according to the invention optionally combined with other active substances such as e.g. antiemetics, prokinetics, neuroleptics, antidepressants, neurokinine antagonists, anti-convulsants, histamine-H1 receptor antagonists, antimuscarinics, ⁇ -blockers, ⁇ -agonists and ⁇ -antagonists, ergot alkaloids, mild analgesics, non-steroidal antiinflammatories, corticosteroids, calcium antagonists, 5-HT 1D agonists or other anti-migraine agents, together with one or more inert conventional carriers and/or diluents, e.g.
  • active substances such as e.g. antiemetics, prokinetics, neuroleptics, antidepressants, neurokinine antagonists, anti-convulsants, histamine-H1 receptor antagonists, antimuscarinics, ⁇ -blockers, ⁇ -agonists and ⁇ -antagonists, ergot alkaloids,
  • the active substances which may be used for the abovementioned combinations thus include, for example, meloxicam, ergotamine, dihydroergotamine, metoclopramide, domperidone, diphenhydramine, cyclizine, promethazine, chlorpromazine, dexamethasone, flunarizine, dextropropoxyphene, meperidine, propranolol, nadolol, atenolol, clonidine, indoramine, carbamazepine, phenyloin, valproate, amitryptilin, lidocaine, diltiazem or sumatriptan and other 5-HT 1D -agonists such as, for example, naratriptan, zolmitriptan, avitriptan, rizatriptan and eletriptan.
  • the dosage of these active substances is expediently 1 ⁇ 5 of the lowest recommended dose to 1/1 of the normally recommended dose, i.
  • the invention further relates to the use of, the compounds of general formula I as valuable adjuvants for the production and purification (by affinity chromatography) of antibodies as well as in RIA and ELISA assays, after suitable radioactive labelling, for example by direct labelling with 125 I or 131 I or by tritiation of suitable precursors, for example by replacing halogen atoms with tritium; and as a diagnostic or analytical adjuvant in neurotransmitter research.
  • a solution of 3.5 g (0.01 mol) of 4-(4-amino-3,5-dibromophenyl)-4-oxobutanoic acid in 50 ml of 1N aqueous sulphuric acid was treated dropwise with a solution of 0.76 g (0.011 mol) of sodium nitrite in 10 ml of water while maintaining a reaction temperature of ⁇ 5 to 0° C.
  • the mixture was stirred for a further 30 minutes at a temperature of 0° C., then 50 ml of hypo-phosphorous acid were added dropwise while maintaining the same temperature and stirred for another 1 hour at a temperature of 0° C.
  • the mixture was decolorised and a colourless crystalline substance was precipitated.
  • the dioxane was distilled off in vacuo, and the aqueous residue was extracted exhaustively with a total of 1 l of ethyl acetate.
  • the combined ethyl acetate extracts were washed once with 200 ml of water, twice with 250 ml of a saturated sodium hydrogen carbonate solution and once with 200 ml of water, dried over sodium sulphate and concentrated by evaporation in vacuo.
  • the brownish oil remaining was taken up in 150 ml of diisopropylether and when left to stand colourless crystals were precipitated after about 15 hours, which were then suction filtered and dried. Yield: 31.5 g (29% of theoretical).
  • the mixture was concentrated by evaporation in vacuo and the residue was treated with 200 ml dichloromethane and 200 ml of water. It was filtered, the methylene chloride phase was dried over sodium sulphate and freed from solvent.
  • the residue was purified by chromatography on silica gel (30-60 ⁇ m) using dichloromethane/EE/MeOH/cyclohexane/conc. ammonia (59/25/7.5/7.5/1 v/v/v/v/v/v) as eluant, then on silica gel using dichloromethane/EE (1/1 v/v) as eluant.
  • R f 0.75 (dichloromethane/EE/MeOH/cyclohexane/conc. ammonia 59/25/7.5/7.5/1 v/v/v/v/v/v)
  • reaction mixture was concentrated by evaporation in vacuo, the solid residue was digested with 50 ml of water and tert.butylmethylether, suction filtered and dried in a circulating air dryer at 50° C. 19.9 g (91% of theoretical) of pale yellow crystals were obtained, R f 0.6 (eluant: dichloromethane/EE/cyclohexane/methanol/conc. ammonia 300/80/25/25/3 v/v/v/v/v/v).
  • Capsules for Powder Inhalation Containing 1 mg of Active Ingredient Composition 1 capsule for powder inhalation contains: active ingredient 1.0 mg lactose 20.0 mg hard gelatine capsules 50.0 mg 71.0 mg Method of Preparation:
  • the active ingredient is ground to the particle size required for inhaled substances.
  • the ground active ingredient is homogeneously mixed with the lactose. The mixture is transferred into hard gelatine capsules.
  • the active ingredient and benzalkonium chloride are dissolved in water and transferred into Respimat® cartridges.
  • Inhalable Solution for Nebulisers Containing 1 mg of Active Ingredient Composition 1 vial contains: active ingredient 0.1 g sodium chloride 0.18 g benzalkonium chloride 0.002 g purified water ad 20.0 ml Method of Preparation:
  • the active ingredient, sodium chloride and benzalkonium chloride are dissolved in water.
  • micronised active ingredient is homogeneously suspended in the mixture of lecithin and propellent gas.
  • the suspension is transferred into a pressurised contained with a metering valve.
  • Active Ingredient Composition active ingredient 1.0 mg sodium chloride 0.9 mg benzalkonium chloride 0.025 mg disodium edetate 0.05 mg purified water ad 0.1 ml Method of Preparation:
  • the active ingredient and the excipients are dissolved in water and transferred into a suitable container.
  • Injectable Solution Containing 5 mg of Active Substance Per 5 ml Composition: active substance 5 mg glucose 250 mg human serum albumin 10 mg glycofurol 250 mg water for injections ad 5 ml Preparation:
  • WfI water for injections
  • human serum albumin is added
  • active ingredient is dissolved with heating; made up to specified volume with WfI; transferred into ampoules under nitrogen gas.
  • Polysorbate 80 sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate are dissolved in water for injections (WfI); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with WfI; transferred into ampoules.
  • Mannitol is dissolved in water for injections (WfI); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with WfI; transferred into vials; freeze-dried.
  • Polysorbate 80 and mannitol are dissolved in water for injections (WfI); transferred into ampoules.
  • Active Substance Composition active substance 20 mg lactose 120 mg maize starch 40 mg magnesium stearate 2 mg Povidone K 25 18 mg Preparation:
  • Active substance, lactose and maize starch are homogeneously mixed; granulated with an aqueous solution of Povidone; mixed with magnesium stearate; compressed in a tablet press; weight of tablet 200 mg.
  • Active Substance Composition active substance 20 mg maize starch 80 mg highly dispersed silica 5 mg magnesium stearate 2.5 mg Preparation:
  • Active substance, maize starch and silica are homogeneously mixed; mixed with magnesium stearate; the mixture is packed into size 3 hard gelatine capsules in a capsule filling machine.
  • Hard fat is melted at about 38° C.; ground active substance is homogeneously dispersed in the molten hard fat; after cooling to about 35° C. it is poured into chilled moulds.
  • Mannitol is dissolved in water for injections (WfI); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with WfI; transferred into ampoules under nitrogen gas.

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Abstract

The present invention relates to compounds of general formula
R-Z1-Z2-Z3-R  (I), wherein
  • R, R1 and Z1 to Z3 are defined as in claim 1, the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, which have valuable pharmacological properties, particularly CGRP-antagonistic properties, pharmaceutical compositions containing these compounds, their use and processes for preparing them.

Description

  • The present invention relates to compounds of general formula
    R-Z1-Z2-Z3R1  (I),
    the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, pharmaceutical compositions containing these compounds, their use and processes for preparing them.
  • In the above general formula I
    R denotes the H2N group or the group of formula
    Figure US20070208036A1-20070906-C00001
    wherein
      • o denotes the number 1 or, if Y does not denote a nitrogen atom, also denotes the number 0.
      • p denotes the number 1 or, if Y does not denote a nitrogen atom, also denotes the number 0.
      • Y denotes the carbon atom or, if Y is not linked to a heteroatom, may also denote the nitrogen atom,
      • R2 denotes a pair of free electrons, if Y denotes the nitrogen atom, or, if Y denotes the carbon atom, denotes the hydrogen atom or an alkyl group with 1 to 3 carbon atoms,
      • R3 and R4 denote hydrogen atoms or together denote an alkylene bridge with 1 to 3 carbon atoms,
      • R5 and R6 denote hydrogen atoms or together denote a one-to three-membered unbranched alkylene bridge wherein a methylene group may be replaced by a methylimino group,
      • RN denotes a saturated, mono- or diunsaturated 5- to 7-membered aza, diaza, triaza, oxaza, thiaza, thiadiaza or S,S-dioxido-thiadiaza heterocycle,
        • wherein the abovementioned heterocycles may be linked via a carbon or nitrogen atom and
        • adjacent to a nitrogen atom may contain a carbonyl, thioxo or iminocarbonyl group or two carbonyl groups or a carbonyl group and a thioxo or iminocarbonyl group, wherein the abovementioned iminocarbonyl groups may be substituted by a cyano group or by an alkoxycarbonyl group with 1 to 4 carbon atoms in the alkyl moiety,
        • may be substituted at one of the nitrogen atoms by an alkanoyl, hydroxycarbonylalkyl or alkoxycarbonylalkyl group,
        • may be substituted at one or two carbon atoms by a branched or unbranched alkyl group, by a phenyl, phenylmethyl, naphthyl, biphenylyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl or 1-methylimidazolyl group, wherein the substituents may be identical or different,
        • wherein additionally an unbranched alkylene group with 3 to 6 carbon atoms may be attached to the above-mentioned 5- to 7-membered heterocycles via two adjacent carbon atoms or the group ═CH—S—CH═ may be attached to the abovementioned 5- to 7-membered saturated heterocycles via two adjacent carbon atoms or
        • an olefinic double bond of one of the abovementioned unsaturated heterocycles may be fused to a benzene, pyridine, diazine, 1,3-oxazole, thiophene, furan, thiazole, pyrrole, N-methyl-pyrrole, quinoline, imidazole or N-methyl-imidazole ring,
      • or, if Y denotes the carbon atom, RN denotes the hydroxy group, a benzoylaminocarbonylamino group, a phenylamino group optionally substituted at the aniline nitrogen by an aminocarbonyl group or a phenylmethylamino group optionally substituted at the benzylamine nitrogen by an alkoxycarbonyl group,
        • wherein the phenyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl or 1-methylimidazolyl groups contained in the groups mentioned under RN as well as benzo-, thieno-, pyrido-, diazino- and quinolino-fused heterocycles in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, by cycloalkyl groups with 3 to 8 carbon atoms, nitro, alkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl, alkylsulphonylamino, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, cycloalkanecarbonylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkylaminocarbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, [4-(1-piperidinyl)-piperidinyl]carbonyl, [4-(1-piperidinyl)-piperidinyl]carbonylamino, methylenedioxy, aminocarbonylamino, aminocarbonylaminoalkyl, alkylaminocarbonylamino, dialkylaminocarbonylamino, aminomethyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, wherein the substituents may be identical or different and the abovementioned benzoyl, benzoylamino, benzoylaminocarbonylamino and benzoylmethylamino groups may in turn additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom, an alkyl, trifluoromethyl, amino or acetylamino group,
        • and the alkyl groups contained in the abovementioned groups, unless otherwise stated, may contain 1 to 5 carbon atoms,
          or, if Z1-Z2-Z3 denotes the divalent group CO—CH2—CH2—CO, R may also denote the 4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-[1.4′]bipiperidinyl-1′-yl group,
          Z1 denotes a methylene or carbonyl group or, if Z2 denotes a divalent group of general formula III, may also denote a bond,
          Z2 denotes one of the groups —(CH2)2— or —(CH2)3—,
      • wherein a hydrogen atom may be replaced by a C1-3-alkyl or a hydroxy group,
        one of the groups —NH—CH2, —CH2—NH, —NH—(CH2)2— or —(CH2)2—NH—,
      • wherein a hydrogen atom bound to a carbon atom and/or the hydrogen atom of the imino group may each be replaced by a C1-3-alkyl group and the nitrogen atoms are each linked to a carbonyl group of the groups Z1 or Z3,
        the group —CH═CH— or a divalent group of general formula
        Figure US20070208036A1-20070906-C00002
        wherein
      • m and n independently of one another denote one of the numbers 1, 2, 3 or 4 and the nitrogen atom is linked to a carbonyl group of the group Z3,
        Z3 denotes the methylene or carbonyl group,
      • wherein at least one of the groups Z1 and Z3 denotes a carbonyl group, and
        R1 denotes a phenyl, 1-naphthyl, 2-naphthyl, benzimidazolyl, 1,3-dihydro-2-oxobenzimidazolyl, octahydro-9-phenanthryl or benzodioxolanyl group,
      • wherein the abovementioned aromatic and heteroaromatic groups in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine, bromine or iodine atoms, by alkyl groups, by cycloalkyl groups with 3 to 8 carbon atoms, phenylalkyl groups, hydroxy, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonyl, carboxy, dialkylaminoalkyl, amino, aminoalkyl, alkylamino, dialkylamino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, 4-(dialkylaminoalkyl)-1-piperazinyl, piperidinyl, 4-(1-piperidinyl)-1-piperidinyl, 4-(4-methyl-1-piperazinyl)-1-piperidinyl, 4-(4-dialkylaminoalkyl-1-piperazinyl)-1-piperidinyl, nitro, methanesulphonyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups and the substituents may be identical or different and the abovementioned benzoyl, benzoylamino and benzoylmethylamino groups may in turn additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino or acetylamino group,
        wherein the hydroxy, amino and imidazolyl groups contained in the abovementioned groups may be substituted with protecting groups well known from peptide chemistry, preferably with the acetyl, benzyloxycarbonyl or tert.butyloxycarbonyl group,
        all the abovementioned alkyl and alkoxy groups and the alkyl or alkylene moieties present inside the other groups specified may contain 1 to 7 carbon atoms, unless otherwise stated, and
        all the abovementioned cycloalkyl groups and the cycloalkyl groups present inside the other groups specified may contain 5 to 10 carbon atoms, unless otherwise stated.
  • By the protecting groups mentioned in the preceding definitions are meant the protecting groups familiar from peptide chemistry, especially
  • a phenylalkoxycarbonyl group with 1 to 3 carbon atoms in the alkoxy moiety optionally substituted in the phenyl nucleus by a halogen atom, by a nitro or phenyl group, by one or two methoxy groups,
      • for example the benzyloxycarbonyl, 2-nitro-benzyloxycarbonyl, 4-nitro-benzyloxycarbonyl, 4-methoxy-benzyloxycarbonyl, 2-chloro-benzyloxycarbonyl, 3-chloro-benzyloxycarbonyl, 4-chloro-benzyloxycarbonyl, 4-biphenylyl-α,α-dimethyl-benzyloxycarbonyl or 3,5-dimethoxy-α,α-dimethyl-benzyloxycarbonyl group,
        an alkoxycarbonyl group having a total of 1 to 5 carbon atoms in the alkyl moiety,
      • for example the methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, 1-methylpropoxycarbonyl, 2-methylpropoxy-carbonyl or tert.butyloxycarbonyl group,
        the allyloxycarbonyl, 2,2,2-trichloro-(1,1-dimethylethoxy)-carbonyl or 9-fluorenylmethoxycarbonyl group or
        the formyl, acetyl or trifluoroacetyl group.
  • The present invention relates to racemates if the compounds of general formula I have only one chiral element. However, the application also includes the individual diastereomeric pairs of antipodes or mixtures thereof which are obtained if there is more than one chiral element in the compounds of general formula (I). Of the compounds that come under general formula I wherein Z2 denotes the group —CH═CH—, the (E)-configured diastereomers are preferred.
  • The compounds of general formula (I) have valuable pharmacological properties, based on their selective CGRP-antagonistic properties. The invention further relates to pharmaceutical compositions containing these compounds, their use and the preparation thereof.
  • Preferred compounds of the above general formula I are those wherein
  • R denotes the H2N group, if Z1 and Z3 each denote the CO group and R1 is at least disubstituted by the H2N group and an additional substituent or if Z2 does not contain an imino group,
  • or the group of formula
    Figure US20070208036A1-20070906-C00003
    wherein
      • o, p, R5, R6 and Y are as hereinbefore defined,
      • R2 denotes a pair of free electrons, if Y denotes the nitrogen atom, or, if Y denotes the carbon atom, R2 denotes the hydrogen atom or a methyl group,
      • R3 and R4 denote hydrogen atoms or together denote an alkylene bridge with 2 to 3 carbon atoms,
      • RN denotes a monocyclic saturated, mono- or diunsaturated 5- to 7-membered aza, diaza, triaza, oxaza, thiaza, thiadiaza or S,S-dioxido-thiadiaza heterocycle containing one to two imino groups,
        • wherein the abovementioned heterocycles are linked via a carbon or nitrogen atom and
        • adjacent to a nitrogen atom contain a carbonyl, thioxo or iminocarbonyl group or two carbonyl groups or a carbonyl group and a thioxo or iminocarbonyl group,
        • wherein the abovementioned iminocarbonyl groups may be substituted by a cyano group or by an alkoxycarbonyl group with 1 to 4 carbon atoms in the alkyl moiety,
        • the abovementioned heterocycles containing two imino groups may be substituted at one of the imino-nitrogen atoms by an alkanoyl, hydroxycarbonylalkyl or alkoxycarbonylalkyl group with 1 to 3 carbon atoms in the alkyl moieties,
        • may be substituted at one or two carbon atoms by an unbranched alkyl group, by a phenyl, phenylmethyl, naphthyl, biphenylyl or thienyl group, wherein the substituents may be identical or different,
        • and wherein additionally an unbranched alkylene group with 3 to 4 carbon atoms may be attached to the abovementioned 5- to 7-membered heterocycles via two adjacent carbon atoms or the group ═CH—S—CH═ may be attached to the abovementioned 5- to 7-membered saturated heterocycles via two adjacent carbon atoms or
        • an olefinic double bond of one of the abovementioned unsaturated heterocycles may be fused to a benzene, pyridine, diazine, thiophene or quinoline ring, with the provisos that
        • (i) RN does not take on the meaning of the 2,6-dioxo-3-phenyl-3,4,5,6-tetrahydro-1H-pyrimidin-3-yl group, the 2-oxo-1,3,4,5-tetrahydro-1-imidazolyl group optionally monosubstituted by an acyl group in the 3 position and the 2(1H)-oxo-3,4,5,6-tetrahydro-1-pyrimidinyl group and
        • (ii) R1 does not denote a 2-alkoxy-4-amino-5-chlorophenyl, 2-alkoxy-4-amino-5-bromophenyl, 2-alkoxy-4-acetylamino-5-chlorophenyl or 2-alkoxy-4-acetylamino-5-bromophenyl group if RN takes on the meaning of the 1,3-dihydro-2(2H)-oxobenzimidazol-1-yl, 1,3-dihydro-2(2H)-thioxobenzimidazol-1-yl, 2(1H)-oxoquinoxalin-1-yl, 3-oxo-2,3-dihydrobenzoxazin-4-yl, 3-oxo-2,3,4,5-tetrahydrobenz[f][1,4]oxazepin-4-yl or 2(1H)-oxoquinolin-3-yl group,
      • or, if Y denotes the carbon atom, with the proviso that
        • (i) R1 does not denote a 2-alkoxy-4-amino-5-bromophenyl, 2-alkoxy-4-amino-5-chlorophenyl or naphthyl group or
        • (ii) Z2 does not denote a group containing N or
        • (iii) Z1 and Z3 each denote the CO group,
      • RN may also represent the hydroxy group
      • or, if Y denotes the carbon atom and Z1 and Z3 each denote the CO group, a benzoylaminocarbonylamino group, a phenylamino group optionally at least monosubstituted at the aniline nitrogen by an aminocarbonyl group and in the phenyl moiety,
      • or, if Y denotes the carbon atom, Z1 and Z3 each denote the CO group and in the group of general formula (II) o and p each assume the value 1, a phenylmethylamino group optionally at least monosubstituted at the benzylamine nitrogen by a C1-4-alkoxy-carbonyl group and in the phenyl moiety,
        • wherein the phenyl and thienyl groups contained in the groups mentioned under RN as well as benzo-, thieno-, pyrido-, diazino- and quinolino-fused heterocycles may additionally be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms, by methyl groups, by cycloalkyl groups with 5 to 6 carbon atoms, nitro, methoxy, methylthio, methylsulphinyl, methylsulphonyl, methanesulphonylamino, phenyl, trifluoromethyl, methoxycarbonyl, carboxy, hydroxy, amino, acetylamino, cyclohexanecarbonylamino, aminocarbonyl, hydroxyethylaminocarbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, [4-(1-piperidinyl)-piperidinyl]carbonyl, [4-(1-piperidinyl)piperidinyl]-carbonylamino, aminocarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, aminomethyl, acetyl, cyano or trifluoromethoxy groups, wherein the substituents may be identical or different,
          or, if Z1-Z2-Z3 denotes the divalent group CO—CH2—CH2—CO, R may also denote the 4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-[1.4′]bipiperidinyl-1′-yl group,
          Z1 denotes the methylene or carbonyl group or, if Z2 denotes a divalent group of general formula III, may also denote a bond,
          Z2 denotes one of the groups —(CH2)2— or —(CH2)3—,
      • wherein a hydrogen atom may be replaced by a C1-3-alkyl or a hydroxy group,
        one of the groups
        —NH—CH2, —CH2—NH, —NH— (CH2)2— or —(CH2)2—NH—,
      • wherein the nitrogen atoms are each linked to a carbonyl group of the groups Z1 or Z3 and
      • the hydrogen atom of the imino group may in each case be replaced by a C1-3-alkyl group,
        the group —CH═CH— or, if R1 does not denote an aromatic or heteroaromatic group substituted by cycloalkyl or phenyl groups or RN is not linked via an imino group bound in the adjacent position to a fused-on benzene ring, it also denotes a divalent group of general formula
        Figure US20070208036A1-20070906-C00004
        wherein
      • m and n independently of one another denote one of the numbers 1, 2 or 3 and
      • the nitrogen atom is linked to the group Z3 with the meaning of a carbonyl group,
        Z3 denotes the carbonyl group or, if RN is not linked via an imino group bound in the adjacent position to a fused-on aromatic or heteroaromatic ring, it also denotes the methylene group,
      • wherein at least one of the groups Z1 and Z3 denotes a carbonyl group and the sequence Z1-Z2-Z3 is at least four-membered, and
        R1 denotes a mono-, di- or trisubstituted phenyl group, a benzimidazolyl, 1,3-dihydro-2-oxobenzimidazolyl, octahydro-9-phenanthryl or benzodioxolanyl group or, if Z1 and Z3 each denote the CO group, R1 may also denote a 1-naphthyl or 2-naphthyl group,
      • wherein the abovementioned aromatic and heteroaromatic groups may be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine, bromine or iodine atoms, by alkyl groups with 1 to 4 carbon atoms, by cycloalkyl groups with 5 to 6 carbon atoms, hydroxy, alkoxy, phenyl, trifluoromethyl, methoxycarbonyl, ethoxycarbonyl, carboxy, amino, aminomethyl, methylamino, dimethylamino, acetylamino, 4-[3-(dimethylaminopropyl)]-1-piperazinyl, piperidinyl, 4-(1-piperidinyl)-1-piperidinyl, 4-(4-methyl-1-piperazinyl)-1-piperidinyl, 4-[4-(3-dimethylaminopropyl)-1-piperazinyl]-1-piperidinyl, nitro, methanesulphonyloxy, aminocarbonyl, acetyl, cyano or trifluoromethoxy groups and the substituents may be identical or different,
        wherein all the abovementioned alkyl and alkoxy groups and the alkyl or alkylene moieties present inside the other groups specified may contain 1 to 5 carbon atoms unless otherwise stated,
        the tautomers, diastereomers, enantiomers and salts thereof.
  • Particularly preferred compounds of the above general formula I are those wherein
    R denotes the H2N group, if Z1 and Z3 each denote the CO group and R1 is at least disubstituted by the H2N group and an additional substituent or if Z2 does not contain an imino group, or the group of formula
    Figure US20070208036A1-20070906-C00005
    wherein
      • o, p and Y are as hereinbefore defined,
      • R2 denotes a pair of free electrons, if Y denotes the nitrogen atom, or, if Y denotes the carbon atom, R2 denotes the hydrogen atom or a methyl group,
      • R3 and R4 denote hydrogen atoms or together denote an alkylene bridge with 2 carbon atoms,
      • R5 and R6 denote hydrogen atoms or together denote an n-propylene bridge wherein the central methylene group may be replaced by a methylimino group,
      • RN denotes a monocyclic saturated, mono- or diunsaturated 5- to 7-membered aza, diaza, triaza, thiadiaza or S,S-dioxido-thiadiaza heterocycle containing one to two imino groups,
        • wherein the abovementioned heterocycles are linked via a carbon or nitrogen atom and
        • adjacent to a nitrogen atom contain a carbonyl, thioxo or iminocarbonyl group or two carbonyl groups or a carbonyl group and a thioxo or iminocarbonyl group, wherein the abovementioned iminocarbonyl groups may be substituted by a cyano group or by a tert.butoxycarbonyl group,
        • the abovementioned heterocycles containing two imino groups may be substituted at one of the imino-nitrogen atoms by an acetyl, carboxymethyl or methoxycarbonyl-methyl group,
        • may be substituted at one or two carbon atoms by a methyl group, by a phenyl, phenylmethyl, naphthyl, biphenylyl or thienyl group, wherein the substituents may be identical or different,
        • and wherein additionally an unbranched alkylene group with 4 carbon atoms may be attached to the abovementioned 5- to 7-membered heterocycles via two adjacent carbon atoms or the group ═CH—S—CH═ may be attached to the abovementioned 5- to 7-membered saturated heterocycles via two adjacent carbon atoms or
        • an olefinic double bond of one of the abovementioned unsaturated heterocycles may be fused to a benzene, pyridine, diazine, thiophene or quinoline ring,
        • with the provisos that
        • (i) RN does not take on the meaning of the 2,6-dioxo-3-phenyl-3,4,5,6-tetrahydro-1H-pyrimidin-3-yl group, the 2-oxo-1,3,4,5-tetrahydro-1-imidazolyl group optionally monosubstituted in the 3 position by an acyl group and the 2(1H)-oxo-3,4,5,6-tetrahydro-1-pyrimidinyl group, and
        • (ii) R1 does not denote a 2-alkoxy-4-amino-5-chlorophenyl, 2-alkoxy-4-amino-5-bromophenyl, 2-alkoxy-4-acetylamino-5-chlorophenyl or 2-alkoxy-4-acetylamino-5-bromophenyl group, if RN takes on the meaning of the 1,3-dihydro-2(2H)-oxobenzimidazol-1-yl, 1,3-dihydro-2(2H)-thioxobenzimidazol-1-yl, 2(1H)oxoquinoxalin-1-yl, 3-oxo-2,3-dihydrobenzoxazin-4-yl, 3-oxo-2,3,4,5-tetrahydrobenz[f][1,4]oxazepin-4-yl or 2(1H)-oxoquinolin-3-yl group,
      • or, if Y denotes the carbon atom, with the proviso that
        • (i) R1 does not denote a 2-alkoxy-4-amino-5-bromophenyl, 2-alkoxy-4-amino-5-chlorophenyl or naphthyl group or
        • (ii) Z2 does not denote a group containing N, or
        • (iii) Z1 and Z3 each denote the CO group,
      • RN may also denote the hydroxy group,
      • or, if Y denotes the carbon atom and Z1 and Z3 each denote the CO group, a benzoylaminocarbonylamino group, a phenylamino group optionally at least monosubstituted by an aminocarbonyl group at the aniline nitrogen and in the phenyl moiety,
      • or, if Y denotes the carbon atom, Z1 and Z3 each denote the CO group and in the group of general formula (II) o and p each assume the value 1, a phenylmethylamino group optionally at least monosubstituted by a tert. butoxycarbonyl group at the benzylamine nitrogen and in the phenyl moiety,
        • wherein the phenyl and thienyl groups contained in the groups mentioned under RN as well as benzo-, thieno-, pyrido-, diazino- and quinolino-fused heterocycles may additionally be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms, by methyl, nitro, methoxy, methanesulphonylamino, phenyl, trifluoromethyl, methoxycarbonyl, carboxy, hydroxy, amino, acetylamino, cyclohexanecarbonylamino, aminocarbonyl, hydroxyethylaminocarbonyl, (4-morpholinyl)carbonyl, (4-methyl-1-piperazinyl)-carbonyl, [4-(1-piperidinyl)-1-piperidinyl]carbonyl, [4-(1-piperidinyl)piperidinyl]carbonylamino, aminomethyl or aminocarbonylamino groups, wherein the substituents may be identical or different,
          or, if Z1-Z2-Z3 denotes the divalent group CO—CH2—CH2—CO, R may also denote the 4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-[1.4′]bipiperidinyl-1′-yl group,
          Z1 denotes a methylene or carbonyl group or, if Z2 denotes a divalent group of general formula III, may also denote a bond,
          Z2 denotes one of the groups —(CH2)2— or —(CH2)3—,
      • wherein a hydrogen atom may be replaced by a C1-3-alkyl or hydroxy group,
        one of the groups
        —NH—CH2, —CH2—NH— or —(CH2)2—NH—,
      • wherein the nitrogen atoms are each linked to a carbonyl group of the groups Z1 or Z3 and the hydrogen atom of the imino group may be replaced by a C1-3-alkyl group in each case,
        the group —CH═CH— or, if R1 does not denote an aromatic or heteroaromatic group substituted by cycloalkyl or phenyl groups or RN is not linked via an imino group bound in the adjacent position to a fused-on benzene ring, it may also denote a divalent group of general formula
        Figure US20070208036A1-20070906-C00006
        wherein
      • m denotes one of the numbers 1 or 2 and n denotes one of the numbers 1, 2 or 3 and the nitrogen atom is linked to the group Z3 with the meaning of a carbonyl group,
        Z3 denotes the carbonyl group or, if RN is not linked via an imino group bound in the adjacent position to a fused-on aromatic or heteroaromatic ring, it may also denote the methylene group,
      • wherein at least one of the groups Z1 and Z3 denotes a carbonyl group and the sequence Z1-Z2-Z3 is at least four-membered, and
        R1 denotes a monosubstituted phenyl group, a 5-benzimidazolyl, 1,3-dihydro-2-oxobenzimidazol-5-yl, octahydro-9-phenanthryl or 5-benzodioxolanyl group or, if Z1 and Z3 each denote the CO group, it may also denote a 1-naphthyl or 2-naphthyl group,
      • wherein the abovementioned aromatic and heteroaromatic groups may additionally be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine, bromine or iodine atoms, by alkyl groups with 1 to 4 carbon atoms, by cyclohexyl, hydroxy, alkoxy groups with up to 3 carbon atoms in the alkyl moiety, phenyl, trifluoromethyl, methoxycarbonyl, ethoxycarbonyl, carboxy, amino, aminomethyl, methylamino, dimethylamino, acetylamino, 4-[3-(dimethylaminopropyl)-1-piperazinyl, piperidinyl, 4-(1-piperidinyl)-1-piperidinyl, 4-(4-methyl-1-piperazinyl)-1-piperidinyl, 4-[4-(3-dimethylaminopropyl)-1-piperazinyl)-1-piperidinyl, nitro, cyano or trifluoromethoxy groups and the substituents may be identical or different,
        the tautomers, diastereomers, enantiomers and salts thereof.
  • Most particularly preferred compounds of the above general formula I are those wherein
    R denotes the H2N group, if Z1 and Z3 each denote the CO group and R1 is at least disubstituted by the H2N group and an additional substituent or if Z2 does not contain an imino group, or R denotes the group of formula
    Figure US20070208036A1-20070906-C00007
    wherein
      • Y denotes the carbon atom and o and p independently of one another denote the numbers 1 or 0 or
      • Y denotes the nitrogen atom and o and p each represent the number 1,
      • R2 denotes a pair of free electrons, if Y denotes the nitrogen atom, or, if Y denotes the carbon atom, R2 denotes the hydrogen atom or the methyl group,
      • R3 and R4 denote hydrogen atoms or together denote an ethylene bridge,
      • R5 and R6 denote hydrogen atoms or together denote a —CH2—N(CH3)—CH2— bridge,
      • RN denotes a 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 3,4-dihydro-2(1H)-oxopyrido-[2,3-d]pyrimidin-3-yl, 4-phenyl-1,3,4,5-tetrahydro-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-methyl-4-phenyl-2H-2-oxoimidazol-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl, 2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-2-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxopyrido[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxopyrido[4,3-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-d]pyrimidin-3-yl, 3,4,4a,5,6,7,8,8a-octahydro-2(1H)-oxoquinazolin-3-yl, 2,5-dioxo-4-(phenylmethyl)-imidazolidin-1-yl, 2,5-dioxo-4-phenyl-imidazolidin-1-yl, 3,4-dihydro-2,2-dioxido-2,1,3-benzothiadiazin-3-yl, 1,3-dihydro-4-(2-naphthyl)-2H-2-oxoimidazol-1-yl, 4-(4-biphenylyl)-1,3-dihydro-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 2-(dimethylethoxycarbonylamino)-3,4-dihydroquinazolin-3-yl, 2-amino-3,4-dihydroquinazolin-3-yl, 3,4-dihydro-2(1H)-thioxoquinazolin-3-yl, 3,4-dihydro-2(1H)-cyanoiminoquinazolin-3-yl, 2,3,4,5-tetrahydro-2(1H)-oxo-1,3-benzodiazepin-3-yl or 2,4(1H, 3H)-dioxoquinazolin-3-yl group or,
      • if R1 does not denote a 2-alkoxy-4-amino-5-chlorophenyl, 2-alkoxy-4-amino-5-bromophenyl, 2-alkoxy-4-acetylamino-5-chlorophenyl or 2-alkoxy-4-acetylamino-5-bromophenyl group, may also denote a 1,3-dihydro-2(2H)-oxobenzimidazol-1-yl or 2(1H)-oxoquinolin-3-yl group,
        • wherein the abovementioned mono- and bicyclic heterocycles containing two imino groups may be substituted at one of the imino-nitrogen atoms by an acetyl, carboxymethyl or methoxycarbonylmethyl group and/or
        • may additionally be mono-, di- or trisubstituted in the carbon skeleton and/or at the phenyl groups contained in these groups by fluorine, chlorine or bromine atoms, by methyl groups, nitro, methoxy, methanesulphonylamino, phenyl, trifluoromethyl, methoxycarbonyl, carboxy, hydroxy, amino, acetylamino, cyclohexanecarbonylamino, aminocarbonyl, hydroxyethylaminocarbonyl, (4-morpholinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, [4-(1-piperidinyl)-1-piperidinyl]carbonyl, [4-(1-piperidinyl)piperidinyl]-carbonylamino or aminocarbonylamino groups, wherein the substituents may be identical or different and multiple substitution with the last six substituents is excluded,
      • or, if Y denotes the carbon atom, with the proviso that
        • (i) R1 does not denote a 2-alkoxy-4-amino-5-bromophenyl, 2-alkoxy-4-amino-5-chlorophenyl or naphthyl group or
        • (ii) Z2 does not denote a group containing N,
      • RN may also denote the hydroxy group,
      • or, if Y denotes the carbon atom and Z1 and Z3 each denote the CO group, a benzoylaminocarbonylamino group, a phenylamino group optionally at least monosubstituted by an aminocarbonyl group at the aniline nitrogen and in the phenyl moiety
      • or, if Y denotes the carbon atom, Z1 and Z3 each denote the CO group and in the group of general formula (II) o and p each assume the value 1, a phenylmethylamino group optionally at least monosubstituted by a tert. butoxycarbonyl group at the benzylamine nitrogen and in the phenyl moiety,
        or, if Z-Z2-Z3 denotes the divalent group CO—CH2—CH2—CO, R may also denote the 4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-[1.4′]bipiperidinyl-1′-yl group,
        Z1 denotes the methylene or carbonyl group or, if Z2 denotes a divalent group of general formula III, may also denote a bond,
        Z2 denotes one of the groups —(CH2)2— or —(CH2)3—,
      • wherein a hydrogen atom may be replaced by a methyl or hydroxy group,
        one of the groups
        —NH—CH2, —CH2—NH— or —(CH2)2—NH—,
      • wherein the nitrogen atoms are each linked to a carbonyl group of the groups Z1 or Z3 and the hydrogen atom of the imino group may be replaced in each case by the methyl group,
        the group —CH═CH— or, if R1 does not represent an aromatic or heteroaromatic group substituted by cycloalkyl or phenyl groups or RN is not linked via an imino group bound in the adjacent position to a fused-on benzene ring, it also denotes a divalent group of general formula.
        Figure US20070208036A1-20070906-C00008
        wherein
      • m denotes one of the numbers 1 or 2 and n denotes one of the numbers 1, 2 or 3 and the nitrogen atom is linked to the group Z3 with the meaning of a carbonyl group,
        Z3 denotes the carbonyl group or, if RN is not linked via an imino group bound in the adjacent position to a fused-on aromatic or heteroaromatic ring, it also denotes the methylene group,
      • wherein at least one of the groups Z1 and Z3 denotes the carbonyl group and the sequence Z1-Z2-Z3 is at least four-membered, and
        R1 is as hereinbefore defined under the particularly preferred compounds, the tautomers, diastereomers, enantiomers and salts thereof.
  • The following are listed as examples of most particularly preferred compounds:
    • (1) 1-{1-[4-(4-amino-3,5-dibromophenyl)-4-oxobutyl]-4-piperidinyl]-1,3-dihydro-2(2H)-benzimidazolone
    • (2) 1-{1-[4-(4-amino-3,5-dibromophenyl)-4-oxobutyl]-4-piperidinyl}-1,3-dihydro-6-methyl-2(2H)-benzimidazolone
    • (3) 1-{1-[4-(4-amino-3,5-dibromophenyl)-4-oxobutyl]-4-piperidinyl}-1,3-dihydro-5-methyl-2(2H)-benzimidazolone
    • (4) 1-{1-[4-(4-amino-3,5-dibromophenyl)-4-oxobutyl]-4-piperidinyl}-1,3-dihydro-5-nitro-2(2H)-benzimidazolone
    • (5) 5-amino-1-{1-[4-(4-amino-3,5-dibromophenyl)-4-oxobutyl]-4-piperidinyl}-1,3-dihydro-2(2H)-benzimidazolone
    • (6) 5-acetylamino-1-{1-[4-(4-amino-3,5-dibromophenyl)-4-oxobutyl]-4-piperidinyl}-1,3-dihydro-2(2H)-benzimidazolone
    • (7) 3-acetyl-5-acetylamino-1-{1-[4-(4-amino-3,5-dibromophenyl)-4-oxobutyl]-4-piperidinyl}-1,3-dihydro-2(2H)-benzimidazolone
    • (8) 1-{1-[4-(4-amino-3,5-dibromophenyl)-4-oxobutyl]-4-piperidinyl}-5-cyclohexanecarbonylamino-1,3-dihydro-2(2H)-benzimidazolone
    • (9) 5-aminocarbonylamino-1-{1-[4-(4-amino-3,5-dibromophenyl)-4-oxobutyl]-4-piperidinyl}-1,3-dihydro-2(2H)-benzimidazolone
    • (10) 3-{1-[4-(4-amino-3,5-dibromophenyl)-4-oxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (11) 1-{1-[4-(4-amino-3,5-dibromophenyl)-4-oxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (12) 1-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-1,3-dihydro-4-phenyl-2(2H)-imidazolone
    • (13) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-pyrido[2,3-d]pyrimidinone
    • (14) 1-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-4-phenyl-1,3,4,5-tetrahydro-2(2H)-imidazolone
    • (15) 1-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-1,3-dihydro-5-methyl-4-phenyl-2(2H)-imidazolone
    • (16) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-8-methyl-2(1H)-quinazolinone
    • (17) 3-{1-[4-(4-acetylamino-3-bromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-8-methyl-2(1H)-quinazolinone
    • (18) 3-{1-[4-(4-acetylamino-3-bromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (19) 1-[(1-[4-(4-acetylamino-3-bromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-1,3-dihydro-2(2H)-benzimidazolone
    • (20) 1-{1-[4-(4-amino-3-bromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-1,3-dihydro-2(2H)-benzimidazolone
    • (21) 1-{1-[4-(4-acetylamino-3-bromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-1,3-dihydro-4-phenyl-2(2H)-imidazolone
    • (22) 3-{1-[4-(4-amino-3-bromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (23) 3-{1-[4-(4-amino-3-bromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-8-methyl-2(1H)-quinazolinone
    • (24) 1-{1-[4-(4-amino-3-bromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-1,3-dihydro-4-phenyl-2(2H)-imidazolone
    • (25) 3,4-dihydro-3-{1-[1,4-dioxo-4-(4-methoxyphenyl)butyl]-4-piperidinyl}-2(1H)-quinazolinone
    • (26) 3,4-dihydro-3-{1-[4-(4-chlorophenyl)-1,4-dioxobutyl]-4-piperidinyl}-2(1H)-quinazolinone
    • (27) 3,4-dihydro-3-{1-[1,4-dioxo-4-(4-methylamino-3-nitrophenyl)butyl]-4-piperidinyl}-2(1H)-quinazolinone
    • (28) 3,4-dihydro-3-{1-[4-(4-chloro-3-nitrophenyl)-1,4-dioxobutyl]-4-piperidinyl}-2(1H)-quinazolinone
    • (29) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-6,7-dimethoxy-2(1H)-quinazolinone
    • (30) 3-{1-[4-(1H-benzimidazol-5-yl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (31) 3-{1-[4-(1,3-dihydro-2(2H)-oxobenzimidazol-5-yl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (32) (R,S)-3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-3-pyrrolidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (33) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-8-methoxy-2(1H)-quinazolinone
    • (34) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-5-chloro-3,4-dihydro-2(1H)-quinazolinone
    • (35) 3-{1-[4-(3-amino-4-chlorophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (36) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-thieno[3,4-d]pyrimidinone
    • (37) 1-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-1,3-dihydro-4-(3-trifluoromethylphenyl)-2(2H)-imidazolone
    • (38) 1-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-1,3-dihydro-4-(3-thienyl)-2(2H)-imidazolone
    • (39) 2-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-2,4-dihydro-5-phenyl-3(3H)-1,2,4-triazolone
    • (40) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-thieno[3,2-d]pyrimidinone (41) 1-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-1,3-dihydro-4-(4-trifluoromethylphenyl)-2(2H)-imidazolone
    • (42) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-pyrido[3,4-d]pyrimidinone
    • (43) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-pyrido[4,3-d]pyrimidinone
    • (44) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-6-hydroxy-2(1H)-quinazolinone
    • (45) (E)-3-{1-[4-(4-bromophenyl)-1,4-dioxo-2-buten-1-yl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (46) (E)-3,4-dihydro-3-{1-[4-(3,4-dimethylphenyl)-1,4-dioxo-2-buten-1-yl]-4-piperidinyl}-2(1H)-quinazolinone
    • (47) (E)-3,4-dihydro-3-{1-[1,4-dioxo-4-(4-hydroxyphenyl)-2-buten-1-yl]-4-piperidinyl}-2(1H)-quinazolinone
    • (48) (E)-3,4-dihydro-3-{1-[1,4-dioxo-4-(1-naphthyl)-2-buten-1-yl]-4-piperidinyl}-2(1H)-quinazolinone
    • (49) (E)-3,4-dihydro-3-{1-[4-[4-(1,1-dimethylethyl)phenyl]-1,4-dioxo-2-buten-1-yl]-4-piperidinyl}-2(1H)-quinazolinone
    • (50) (E)-3-{1-[4-(3,4-dichlorophenyl)-1,4-dioxo-2-buten-1-yl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (51) (E)-3,4-dihydro-3-{1-[1,4-dioxo-4-(3-nitrophenyl)-2-buten-1-yl]-4-piperidinyl}-2(1H)-quinazolinone
    • (52) (E)-3,4-dihydro-3-{1-[1,4-dioxo-4-(3-methylphenyl)-2-buten-1-yl]-4-piperidinyl}-2(1H)-quinazolinone
    • (53) (E)-3,4-dihydro-3-{1-[4-(4-cyclohexylphenyl)-1,4-dioxo-2-buten-1-yl]-4-piperidinyl}-2(1H)-quinazolinone
    • (54) (E)-3-{1-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-1,4-dioxo-2-buten-1-yl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (55) (E)-3-{1-[4-(4-chloro-3-methylphenyl)-1,4-dioxo-2-buten-1-yl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (56) (E)-3-{1-[4-(3-bromo-4-nitrophenyl)-1,4-dioxo-2-buten-1-yl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (57) (E)-3-{1-[4-(3-bromophenyl)-1,4-dioxo-2-buten-1-yl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (58) 4-amino-3,5-dibromo-N-{2-[4-(1,3-dihydro-2(2H)-oxo-1-benzimidazolyl)-1-piperidinyl]ethyl}-benzamide
    • (59) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperazinyl}-2(1H)-quinolinone
    • (60) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1-oxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (61) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperazinyl}-2(1H)-quinoxalinone
    • (62) 3-{1-[4-(4-biphenylyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (63) 1-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-1-(4-fluorophenyl)-urea
    • (64) 1-{1-[4-(4-amino-3,5-dibromophenyl)-1-oxobutyl]-4-piperidinyl}-1,3-dihydro-4-phenyl-2(2H)-imidazolone
    • (65) 3-{1-[4-(3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (66) 3-{1-[1,4-dioxo-4-(2-methoxyphenyl)butyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (67) 3-{1-[1,4-dioxo-4-(4-fluorophenyl)butyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (68) 1-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-methyl-4-piperidinyl}-1,3-dihydro-2(2H)-benzimidazolone
    • (69) 3-{1-[4-(4-acetylamino-3-bromophenyl)-1-oxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (70) 3-{1-[4-(4-amino-3-bromophenyl)-1-oxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (71) (E)-3-{1-[4-(4-cyanophenyl)-1,4-dioxo-2-buten-1-yl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (72) 3-{1-[4-(4-cyanophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (73) (R,S)-3-{1-[4-(4-amino-3-cyano-5-fluorophenyl)-1,4-dioxo-2-hydroxybutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (74) (E)-3-{1-[4-(4-amino-3-cyano-5-fluorophenyl)-1,4-dioxo-2-buten-1-yl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (75) 3-{1-[4-(4-amino-3-cyano-5-fluorophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (76) 3-{1-[4-(4-aminomethyl)phenyl]-1-oxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (77) 1-{1-[4-(4-amino-3-cyano-5-fluorophenyl)-1,4-dioxobutyl]-4-piperidinyl}-1,3-dihydro-4-phenyl-2(2H)-imidazolone
    • (78) 2-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-1,1-dioxido-1,2,4-benzothiadiazin-3(4H)-one
    • (79) 3-{1′-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-[1.4′]bipiperidinyl-4-yl}-3,4-dihydro-2(1H)-quinazolinone
    • (80) 1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-hydroxypiperidine
    • (81) 3-[1′-(4-amino-3,5-dibromobenzoyl)-[1.4′]bipiperidinyl-4-yl]-3,4-dihydro-2(1H)-quinazolinone
    • (82) (E)-3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxo-2-buten-1-yl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (83) (E)-1-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxo-2-buten-1-yl]-4-piperidinyl}-1,3-dihydro-4-phenyl-2(2H)-imidazolone
    • (84) (E)-4-amino-3,5-dibromo-γ-oxobenzenebutenoic acid amide
    • (85) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-2(1H)-quinolinone
    • (86) (R,S)-3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinolinone
    • (87) 1-(4-amino-3,5-dibromobenzoyl)-3-{[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl}-azetidine
    • (88) 1-(3,5-dibromo-4-hydroxybenzoyl)-3-{[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl}-azetidine
    • (89) 3-[1′-(4-amino-3,5-dibromobenzoyl)-[1.41]bipiperidinyl-4-yl]-2,4(1H, 3H)-quinazolinedione
    • (90) 1-[1′-(4-amino-3,5-dibromobenzoyl)-[1.4′]bipiperidinyl-4-yl]-1,3-dihydro-4-phenyl-2(2H)-imidazolone
    • (91) 3-[1′-(3,5-dibromo-4-hydroxybenzoyl)-[1.4′]bipiperidinyl-4-yl]-3,4-dihydro-2(1H)-quinazolinone
    • (92) 3-[1′-(3,5-dibromo-4-hydroxybenzoyl)-[1.4′]bipiperidinyl-4-yl]-2,4(1H, 3H)-quinazolinedione:
    • (93) 1-[1′-(3,5-dibromo-4-hydroxybenzoyl)-[1.4′]bipiperidinyl-4-yl]-1,3-dihydro-4-phenyl-2(2H)-imidazolone
    • (94) 1-[1′-(4-amino-3,5-dibromobenzoyl)-[1.4′]bipiperidinyl-4-yl]-1,3-dihydro-4-(3-trifluoromethylphenyl)-2(2H)-imidazolone
    • (95) 1-[1′-(4-amino-3,5-dibromobenzoyl)-[1.4′]bipiperidinyl-4-yl]-1,3-dihydro-5-hydroxy-4-(3-trifluoromethylphenyl)-2(2H)-imidazolone
    • (96) 1′-(4-amino-3,5-dibromobenzoyl)-4-{[[(3-trifluoromethyl-benzoyl)amino]carbonyl]amino}-[1.4′]bipiperidinyl
    • (97) 1-[1′-(3,5-dibromo-4-hydroxybenzoyl)-[1.4′]bipiperidinyl-4-yl]-1,3-dihydro-4-(3-trifluoromethylphenyl)-2(2H)-imidazolone
    • (98) 1-(4-amino-3,5-dibromobenzoyl)-3-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-azetidine
    • (99) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-3-azetidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (100) 1-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-4-(4-amino-3,5-dibromophenyl)-1,3-dihydro-2(2H)-imidazolone
    • (101) 3,4-dihydro-3-{1-[4-(3-fluoro-4-methoxyphenyl)-1,4-dioxobutyl]-4-piperidinyl}-2(1H)-quinazolinone
    • (102) 3-{1-[4-(3,5-dibromo-4-methylphenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (103) (E)-3-{1-[4-[3-chloro-4-(dimethylamino)phenyl]-1,4-dioxo* 2-buten-1-yl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (104) 3-{1-[4-[3-chloro-4-(dimethylamino)phenyl]-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (105) 3-{1-[4-[3-chloro-4-[4-(3-dimethylaminopropyl)-1-piperazinyl]phenyl]-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (106) 3-{1-[4-[3-bromo-4-[[1.4′]bipiperidinyl-1′-yl]phenyl]-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (107) 3-{1-[4-[3-bromo-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (108) 3-{1-[4-[3-bromo-4-[4-(3-dimethylaminopropyl)-1-piperazinyl]phenyl]-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (19) N-[2-(4-amino-3,5-dibromophenyl)-2-oxoethyl]-N-methyl-4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-piperidine-1-carboxamide
    • (110) 3-{1-[4-[3,5-d]bromo-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl[-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (111) 3-{1-[4-[3,5-d]bromo-4-[4-[4-(3-dimethylaminopropyl)-1-piperazinyl]-1-piperidinyl]phenyl]-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (112) 1-{1-[4-(4-amino-3,5-dibromophenyl)-4-oxobutyl]-4-piperidinyl)-1,3-dihydro-3-methoxycarbonylmethyl-2(2H)-benzimidazolone
    • (113) 1-{1-[4-(4-amino-3,5-dibromophenyl)-4-oxobutyl]-4-piperidinyl}-1,3-dihydro-3-carboxymethyl-2(2H)-benzimidazolone
    • (114) 1-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-1,3-dihydro-2(2H)-benzimidazolone
    • (115) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (116) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-1,3-dihydro-7-hydroxy-2(2H)-imidazo[4,5-d]-pyrimidinone
    • (117) methyl 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-oxoquinazolin-7-carboxylate
    • (118) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-oxoquinazolin-7-carboxylic acid
    • (119) 1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-(2-aminocarbonylaminobenzeneamino)-piperidine
    • (120) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-oxoquinazolin-7-carboxamide
    • (121) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-7-[(4-methyl-1-piperazinyl)carbonyl]-2(1H)-quinazolinone
    • (122) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-7-[(4-morpholinyl)carbonyl]-2(1H)-quinazolinone
    • (123) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-N-(2-hydroxyethyl)-2(1H)-oxoquinazolin-7-carboxamide
    • (124) 1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-(2-methanesulphonylaminobenzeneamino)-piperidine
    • (125) N-[2-(4-amino-3,5-dibromophenyl)-2-oxoethyl]-4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-piperidine-1-carboxamide
    • (126) 4-amino-3,5-dibromo-N-{3-[4-(1,3-dihydro-2(2H)-oxo-1-benzimidazolyl)-1-piperidinyl]-3-oxopropyl}-benzamide
    • (127) 4-amino-3,5-dibromo-N-{3-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-3-oxopropyl}-benzamide
    • (128) 4-amino-3,5-dibromo-N-{2-[4-(1,3-dihydro-2(2H)-oxo-1-benzimidazolyl)-1-piperidinyl]-2-oxoethyl})-benzamide
    • (129) 4-amino-3,5-dibromo-N-{2-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-oxoethyl}-benzamide
    • (130) 4-amino-3,5-dibromo-N-{2-[4-(1,3-dihydro-4-phenyl-2(2H)-oxo-imidazol-1-yl)-1-piperidinyl]-2-oxoethyl}-benzamide
    • (131) 1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-N-(1,1-dimethylethoxycarbonyl)-N-[(2-aminocarbonylaminophenyl)methyl]-4-piperidineamine
    • (132) 3-{1-[4-(4-acetylamino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (133) 1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-N-[(2-aminocarbonylaminophenyl)methyl]-4-piperidineamine
    • (134) 1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-N-[(2-methanesulphonylaminophenyl)methyl]-4-piperidineamine
    • (135) 4-amino-3,5-dibromo-N-{3-[4-(1,3-dihydro-4-phenyl-2(2H)-oxo-imidazol-1-yl)-1-piperidinyl]-3-oxopropyl}-benzamide
    • (136) 4-amino-3,5-dibromo-N-{2-[4-(1,3-dihydro-2(2H)-oxo-1-benzimidazolyl)-1-piperidinyl]-2-oxoethyl}-N-methyl-benzamide
    • (137) 4-amino-3,5-dibromo-N-{2-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-oxoethyl}-N-methyl-benzamide
    • (138) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4,4a,5,6,7,8,8a-octahydro-2(1H)-quinazolinone
    • (139) N-{2-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-oxoethyl}-2-naphthalenecarboxamide
    • (140) N-{2-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-oxoethyl}-1-naphthalenecarboxamide
    • (141) 4-amino-3-chloro-N-{2-[4-(1,3-dihydro-2(2H)-oxo-1-benzimidazolyl)-1-piperidinyl]ethyl}-5-trifluoromethylbenzamide
    • (142) 1,3-dihydro-1-{1-[4-(2-naphthyl)-1,4-dioxobutyl]-4-piperidinyl}-2(2H)-benzimidazolone
    • (143) 3,4-dihydro-3-{1-[4-(2-naphthyl)-1,4-dioxobutyl]-4-piperidinyl}-2(1H)-quinazolinone
    • (144) 1,3-dihydro-1-{1-[4-(1-naphthyl)-1,4-dioxobutyl]-4-piperidinyl}-2(2H)-benzimidazolone
    • (145) 3,4-dihydro-3-{1-[4-(1-naphthyl)-1,4-dioxobutyl]-4-piperidinyl}-2(1H)-quinazolinone
    • (146) (R,S)-3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxo-2-methylbutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (147) 1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-N-{2-{[1.4′]bipiperidinyl-1′-ylcarbonylamino}phenylmethyl}-4-piperidineamine
    • (148) 3-{8-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-8-azabicyclo[3.2.1]oct-3-yl}-3,4-dihydro-2(1H)-quinazolinone
    • (149) 3-{3-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-7-methyl-3,7-diazabicyclo[3.3.1]non-9-yl}-3,4-dihydro-2(1H)-quinazolinone (diastereomer to compound no. 150)
    • (150) 3-{3-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-7-methyl-3,7-diazabicyclo[3.3.1]non-9-yl}-3,4-dihydro-2(1H)-quinazolinone (diastereomer to compound no. 149)
    • (151) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-5-(phenylmethyl)-imidazolidin-2,4-dione
    • (152) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-5-phenyl-imidazolidin-2,4-dione
    • (153) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2,1,3-benzothiadiazin-2,2-dioxide
    • (154) 1-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-1,3-dihydro-4-(4-fluorophenyl)-2(2H)-imidazolone
    • (155) 4-amino-N-{2-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-oxoethyl}-3-fluoro-5-iodobenzamide
    • (156) 1-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-1,3-dihydro-4-(2-naphthyl)-2(2H)-imidazolone
    • (157) 1-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-4-(4-biphenylyl)-1,3-dihydro-2(2H)-imidazolone
    • (158) 1-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-1,3-dihydro-4-(2-methoxyphenyl)-2(2H)-imidazolone
    • (159) 1-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-4-(3,4-dichlorophenyl)-1,3-dihydro-2(2H)-imidazolone
    • (160) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl)-6-chloro-3,4-dihydro-2(1H)-quinazolinone
    • (161) 3-[1′-(4-amino-3,5-dibromobenzoyl)-[1.4′]bipiperidinyl-4-yl]-5-(phenylmethyl)-imidazolidin-2,4-dione
    • (162) 1-[1′-(4-amino-3,5-dibromobenzoyl)-[1.4′]bipiperidinyl-4-yl]-1,3-dihydro-4-(2-naphthyl)-2(2H)-imidazolone
    • (163) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-1,3-dihydro-2(2H)-imidazo[4.5-c]quinolinone
    • (164) 3-{1-[1,4-dioxo-4-(1,2,3,4,5,6,7,8-octahydro-9-phenanthryl)butyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (165) (R,S)-1-(4-amino-3,5-dibromobenzoyl)-3-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-pyrrolidine
    • (166) (R,S)-1-(3,4-dichlorobenzoyl)-3-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-pyrrolidine
    • (167) (E)-3-{1-[4-(4-biphenylyl)-1,4-dioxo-2-buten-1-yl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (168) (E)-3,4-dihydro-3-{1-[1,4-dioxo-4-(4-ethoxycarbonylphenyl)-2-buten-1-yl]-4-piperidinyl)-2(1H)-quinazolinone
    • (169) (E)-3,4-dihydro-3-{1-[1,4-dioxo-4-(3,4,5-trimethoxyphenyl)-2-buten-1-yl]-4-piperidinyl}-2(1H)-quinazolinone
    • (170) (E)-3,4-dihydro-3-{1-[1,4-dioxo-4-(3-trifluoromethoxyphenyl)-2-buten-1-yl]-4-piperidinyl}-2(1H)-quinazolinone
    • (171) (E)-3,4-dihydro-3-{1-[1,4-dioxo-4-(3-ethylphenyl)-2-buten-1-yl]-4-piperidinyl}-2(1H)-quinazolinone
    • (172) (E)-3,4-dihydro-3-{1-[1,4-dioxo-4-(3-methoxyphenyl)-2-buten-1-yl]-4-piperidinyl}-2(1H)-quinazolinone
    • (173) (E)-3,4-dihydro-3-{1-[1,4-dioxo-4-(4-methylethoxyphenyl)-2-buten-1-yl]-4-piperidinyl}-2(1H)-quinazolinone
    • (174) (E)-3,4-dihydro-3-{1-[1,4-dioxo-4-(3-fluoro-4-methoxyphenyl)-2-buten-1-yl]-4-piperidinyl}-2(1H)-quinazolinone
    • (175) (E)-3,4-dihydro-3-{1-[1,4-dioxo-4-[4-(1-piperidinyl)-phenyl]-2-buten-1-yl]-4-piperidinyl}-2(1H)-quinazolinone
    • (176) (E)-3,4-dihydro-3-{1-[1,4-dioxo-4-(3,4-methylenedioxy-phenyl)-2-buten-1-yl]-4-piperidinyl}-2(1H)-quinazolinone
    • (177) (E)-3,4-dihydro-3-{1-[1,4-dioxo-4-(4-trifluoromethyl-phenyl)-2-buten-1-yl]-4-piperidinyl}-2(1H)-quinazolinone
    • (178) (E)-3,4-dihydro-3-{1-[1,4-dioxo-4-(4-carboxyphenyl)-2-buten-1-yl]-4-piperidinyl}-2(1H)-quinazolinone
    • (179) 3-{1-[5-(4-amino-3,5-dibromophenyl)-1,5-dioxopentyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (180) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-2-(1,1-dimethylethoxycarbonylamino)-3,4-dihydroquinazoline
    • (181) 2-amino-3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydroquinazoline
    • (182) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinethione
    • (183) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-2-cyanimino-1,2,3,4-tetrahydroquinazoline
    • (184) (R,S)-3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxo-3-methylbutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
    • (185) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-7-methoxy-2,3,4,5-tetrahydro-1,3-benzodiazepin-2(1H)-one
    • (186) 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-2,3,4,5-tetrahydro-1,3-benzodiazepin-2(1H)-one
    • (187) 1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-N-(1,1-dimethylethoxycarbonyl-N-[(2-methanesulphonylaminophenyl)-methyl]-4-piperidineamine
    • (188) 1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-N-(1,1-dimethylethoxycarbonyl-N-{2-{[1.4′]bipiperidinyl-1′-ylcarbonylamino}phenylmethyl}-4-piperidineamine,
      but particularly the abovementioned compounds (12), (37), (38), (81), (82), (83), (115), (117), (120), (123), (163) and (182),
      and the salts thereof.
  • The compounds of general formula I are prepared by methods known in principle. The following methods have proved particularly suitable for preparing the compounds of general formula I according to the invention:
  • a) In order to prepare compounds of general formula I wherein Z1 denotes the methylene group, Z2 denotes one of the groups —(CH2)2, —(CH2)3— or —CH═CH— and Z3 denotes the carbonyl group and
  • R has the meanings given hereinbefore with the exception of a 4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-[1.4′]bipiperidinyl-1′-yl group:
  • alkylating a compound of general formula
    R′—H  (IVa),
    wherein
    R′ has the meanings given for R hereinbefore with the exception of a 4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-[1.4′]bipiperidinyl-1′-yl group,
    with a compound of general formula
    X—CH2-Z2-Z3-R1  (V),
    wherein
    R1 is as hereinbefore defined,
    Z2 denotes one of the groups —(CH2)2, —(CH2)3— or —CH═CH—,
    Z3 denotes the carbonyl group and
    X denotes a leaving group, e.g. a halogen atom such as the chlorine, bromine or iodine atom, an alkylsulphonyloxy group with 1 to 10 carbon atoms in the alkyl moiety, a phenylsulphonyloxy or naphthylsulphonyloxy group optionally mono-, di- or trisubstituted by chlorine or bromine atoms, by methyl or nitro groups, whilst the substituents may be identical or different.
  • The reaction is carried out with or without auxiliary bases at temperatures between 0° C. and +140° C., preferably between +20° C. and +100° C., and preferably in the presence of solvents. The auxiliary bases used may be alkali metal and alkaline earth metal hydroxides, e.g. sodium hydroxide, potassium hydroxide or barium hydroxide, but preferably alkali metal carbonates, e.g. sodium carbonate, potassium carbonate or caesium carbonate, and also alkali metal acetates, e.g. sodium or potassium acetate, as well as tertiary amines, e.g. pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine, N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine, 1,4-diazabicyclo[2,2,2]octane or 1,8-diazabicyclo[5,4,0]undec-7-ene, the solvents used may be, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, but preferably dipolar aprotic solvents such as acetonitrile, dimethyl formamide, dimethyl acetamide, N-methyl-pyrrolidone, methyl-isobutylketone or mixtures thereof; if alkali metal or alkaline earth metal hydroxides, alkali metal carbonates or acetates are used as the auxiliary bases, water may also be added to the reaction mixture as cosolvent. To increase the reactivity of the group X in the starting materials of general formula V organic or preferably inorganic iodides such as sodium or potassium iodide are also added to the reaction mixture.
  • b) In order to prepare compounds of general formula I wherein Z1 denotes the carbonyl group, Z2 denotes one of the groups —(CH2)2— or —(CH2)3, wherein a hydrogen atom may be replaced by a C1-3-alkyl or a hydroxy group, one of the groups —CH2—NH— or —(CH2)2—NH, wherein a hydrogen atom bound to a carbon atom and/or the hydrogen atom of the imino group may each be replaced by a C1-3-alkyl group, or the group —CH═CH— and Z3 denotes the methylene or carbonyl group:
  • Coupling a carboxylic acid of general formula
    HOOC-Z2-Z3-R1  (VI),
    wherein
    R1 is as hereinbefore defined,
    Z2 denotes one of the groups —(CH2)2— or —(CH2)3, wherein a hydrogen atom may be replaced by a C1-3-alkyl or a hydroxy group, one of the groups —CH2—NH— or —(CH2)2—NH, wherein a hydrogen atom bound to a carbon atom and/or the hydrogen atom of the imino group may each be replaced by a C1-3-alkyl group, or the group —CH═CH—, and Z3 denotes the methylene or carbonyl group,
    with a compound of general formula
    R—H  (IV),
    wherein
    R is as hereinbefore defined.
  • The coupling is preferably carried out using methods known from peptide chemistry (cf. e.g. Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for example using carbodiimides such as e.g. dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide (DIC) or ethyl-(3-dimethylaminopropyl)-carbodiimide, O-(1H-benzotriazol-1-yl)-N,N—N′,N′-tetramethyluronium hexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP). By adding 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt) any possible racemisation can additionally be suppressed, if desired, or the reaction speed can be increased. The couplings are normally carried out with equimolar amounts of the coupling components as well as the coupling reagent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethyl formamide (DMF), dimethyl acetamide (DMA), N-methylpyrrolidone (NMP) or mixtures thereof and at temperatures between −30 and +30° C., preferably −20 and +20° C. If necessary, N-ethyl-diisopropylamine (DIEA) (Hünig base) is preferably used as an additional auxiliary base.
  • The so-called anhydride process is used as a further coupling method for synthesising compounds of general formula I (cf. also: M. Bodanszky, “Peptide Chemistry”, Springer-Verlag 1988, p. 58-59; M. Bodanszky, “Principles of Peptide Synthesis”, Springer-Verlag 1984, p. 21-27). The Vaughan variant of the mixed anhydride process is preferred (J. R. Vaughan Jr., J. Amer. Chem. Soc. 73, 3547 (1951)), in which the mixed anhydride of the optionally N2-protected α-amino acid which is to be coupled and monoisobutyl carbonate is obtained, using isobutyl chlorocarbonate in the presence of bases such as 4-methyl-morpholine or 4-ethylmorpholine. The preparation of this mixed anhydride and the coupling with amines are carried out in a one-pot process, using the abovementioned solvents and at temperatures between −20 and +20° C., preferably 0 and +20° C.
  • c) In order to prepare compounds of general formula I wherein Z1 denotes the carbonyl group, Z2 denotes one of the groups —(CH2)2— or —(CH2)3, wherein a hydrogen atom may be replaced by a C1-3-alkyl or hydroxy group, one of the groups —CH2—NH— or —(CH2)2—NH, wherein a hydrogen atom bound to a carbon atom and/or the hydrogen atom of the imino group may each be replaced by a C1-3-alkyl group, or the group —CH═CH— and Z3 denotes a methylene or carbonyl group:
  • coupling a compound of general formula
    Nu-CO-Z2-Z3-R1  (VII),
    wherein
    R1 is as hereinbefore defined,
    Z2 denotes one of the groups —(CH2)2— or —(CH2)3, wherein a hydrogen atom may be replaced by a C1-3-alkyl or a hydroxy group,
    one of the groups —CH2—NH— or —(CH2)2—NH, wherein a hydrogen atom bound to a carbon atom and/or the hydrogen atom of the imino group may each be replaced by a C1-3-alkyl group, or the group —CH═CH—,
    Z3 denotes a methylene or carbonyl group and Nu denotes a leaving group, e.g. a halogen atom such as the chlorine, bromine or iodine atom, an alkylsulphonyloxy group with 1 to 10 carbon atoms in the alkyl moiety, a phenylsulphonyloxy or naphthylsulphonyloxy group optionally mono-, di- or trisubstituted by chlorine or bromine atoms, by methyl or nitro groups, whilst the substituents may be identical or different, a 1H-imidazol-1-yl, a 1H-pyrazol-1-yl optionally substituted by 1 or 2 methyl groups in the carbon skeleton, a 1H-1,2,4-triazol-1-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3,4-tetrazol-1-yl, a vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl, pentafluorophenyl, pyranyl or pyridinyl, a dimethylaminyloxy, 2(1H)-oxopyridin-1-yloxy, 2,5-dioxopyrrolidin-1-yloxy, phthalimidyloxy, 1H-benzotriazol-1-yloxy or azide group,
    with a compound of general formula
    R—H  (IV),
    wherein
    R is as hereinbefore defined.
  • The reaction is carried out under Schotten-Baumann or Einhorn conditions, i.e. the components are reacted in the presence of at least one equivalent of an auxiliary base at temperatures between −50° C. and +120° C., preferably −10° C. and +30° C., and optionally in the presence of solvents. The auxiliary bases used are preferably alkali metal and alkaline earth metal hydroxides, e.g. sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates, e.g. sodium carbonate, potassium carbonate or caesium carbonate, alkali metal acetates, e.g. sodium or potassium acetate, as well as tertiary amines, e.g. pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine, N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine, 1,4-diazabicyclo[2,2,2]octane or 1,8-diazabicyclo[5,4,0]undec-7-ene, the solvents used may be, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethyl formamide, dimethyl acetamide, N-methyl-pyrrolidone or mixtures thereof; if alkali metal or alkaline earth metal hydroxides, alkali metal carbonates or acetates are used as the auxiliary bases, water may also be added to the reaction mixture as cosolvent.
  • d) In order to prepare compounds of general formula I wherein Z1 and Z3 each denote the carbonyl group and Z2 denotes the group —(CH2)2—:
  • catalytically hydrogenating a compound of general formula
    R—CO—CH═CH—CO—R1  (I′),
    wherein
    R and R1 are as hereinbefore defined.
  • The catalytic hydrogenation may be carried out both with heterogeneous and with homogeneous catalysts. Of the heterogeneous catalysts those consisting of metals of the sub-group of the Periodic Table are preferred, e.g. Raney nickel (R—Ni), palladium on charcoal, nickel reduced with sodium borohydride, or nickel boride (Paul, Buisson and Joseph, Ind. Eng. Chem. 44, 1006 (1952); Brown, J. C. S. Chem. Commun. 1969, 952, J. Org. Chem. 35, 1900 (1973); Brown and Ahuja, J. Org. Chem. 38, 2226 (1973), J. C. S. Chem. Commun. 1973, 553; Schreifels, Maybury and Swartz, J. Org. Chem. 46, 1263 (1981); Nakao and Fujishige, Chem. Lett. 1981, 925; Nakao, Chem. Lett. 1982, 997), platinum metal, platinum on charcoal, platinum(IV)-oxide, rhodium, ruthenium, sodium hydride-sodium methoxide-nickel(II)-acetate (Brunet, Gallois and Caubère, J. Org. Chem. 45, 1937, 1946 (1980)), of the homogeneous catalysts chlorotris(triphenylphosphine) and RhCl(Ph3P)3 (Wilkinson's catalyst; Abstract: Jardine, Prog. Inorg. Chem. 28, 63-202 (1981)) are preferred. When using the abovementioned heterogeneous catalysts, any nitro groups present in the groups R or R1 are simultaneously reduced to amino groups, while if excessively high temperatures are used nitrile groups are also reduced to aminomethyl groups. The abovementioned homogeneous catalyst chlorotris(triphenylphosphine) on the other hand leaves intact any nitro or cyano groups present during the hydrogenation of the C═C-double bonds in compounds of general formula VIII. The hydrogenations are carried out at temperatures between −5° C. and +50° C., preferably between +15 and +25° C. and most preferably at room temperature. Both the catalyst and the hydrogen required can be produced in situ, for example by treating hexachloroplatinic(IV)-acid or rhodium(III)-chloride with sodium borohydride (Brown and Sivasankaran, J. Am. Chem. Soc. 84, 2828 (1962); Brown and Brown, J. Am. Chem. Soc. 84, 1494, 1495, 2829 (1962), J. Org. Chem. 31, 3989 (1966); Brown, Sivasankaran and Brown, J. Org. Chem. 28, 214 (1963)). Examples of solvents which are particularly suitable for the catalytic hydrogenations in question are ethanol, methanol, ethyl acetate, 1,4-dioxane and acetic acid, if miscible therewith, optionally with the addition of water, and mixtures of these solvents.
    e) In order to prepare compounds of general formula I wherein Z1 denotes a methylene or carbonyl group or, if Z2 denotes a divalent group of general formula III, may also denote a bond, Z2 denotes one of the groups —CH2—NH— or —(CH2)2—NH, wherein a hydrogen atom bound to a carbon atom and/or the hydrogen atom of the imino group may each be replaced by a C1-3-alkyl group, or a divalent group of general formula
    Figure US20070208036A1-20070906-C00009
    wherein
    m and n independently of one another denote one of the numbers 1, 2, 3 or 4 and
    Z3 denotes the carbonyl group:
    coupling a carboxylic acid of general formula
    Figure US20070208036A1-20070906-C00010
    wherein
    R1 is as hereinbefore defined,
    with a compound of general formula
    R-Z1-Z2-H  (IX),
    wherein
    R is as hereinbefore defined,
    Z1 denotes a methylene or carbonyl group or, if Z2 denotes a divalent group of general formula III, may also denote a bond, Z2 denotes one of the groups —CH2—NH— or —(CH2)2—NH, wherein a hydrogen atom bound to a carbon atom and/or the hydrogen atom of the imino group may each be replaced by a C1-3-alkyl group, or a divalent group of general formula
    Figure US20070208036A1-20070906-C00011
    wherein
    m and n independently of one another denote one of the numbers 1, 2, 3 or 4 and
    Z3 denotes the carbonyl group.
  • The coupling is preferably carried out using methods known from peptide chemistry (cf. e.g. Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for example using carbodiimides such as e.g. dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide (DIC) or ethyl-(3-dimethylaminopropyl)-carbodiimide, O-(1H-benzotriazol-1-yl)-N,N—N′,N′-tetramethyluronium hexafluorophosphate (HBTU) or -tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP). By adding 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt) any possible racemisation can additionally be suppressed, if desired, or the reaction speed can be increased. The couplings are normally carried out with equimolar amounts of the coupling components as well as the coupling reagent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethyl formamide (DMF), dimethyl acetamide (DMA), N-methylpyrrolidone (NMP) or mixtures thereof and at temperatures between −30 and +30° C., preferably −20 and +20° C. If necessary, N-ethyl-diisopropylamine (DIEA) (Hünig base) is preferably used as an additional auxiliary base.
  • The so-called anhydride process is used as a further coupling method for synthesising compounds of general formula I (cf. also: M. Bodanszky, “Peptide Chemistry”, Springer-Verlag 1988, p. 58-59; M. Bodanszky, “Principles of Peptide Synthesis”, Springer-Verlag 1984, p. 21-27). The Vaughan variant of the mixed anhydride process is preferred (J. R. Vaughan Jr., J. Amer. Chem. Soc. 73, 3547 (1951)), in which the mixed anhydride of the optionally N2-protected α-amino acid which is to be coupled and monoisobutyl carbonate, is obtained using isobutyl chlorocarbonate in the presence of bases such as 4-methyl-morpholine or 4-ethylmorpholine. The preparation of this mixed anhydride and the coupling with amines are carried out in a one-pot process, using the abovementioned solvents and at temperatures between −20 and +20° C., preferably 0 and +20° C.
  • f) In order to prepare compounds of general formula I wherein
  • Z1 denotes a methylene or carbonyl group or, if Z2 denotes a divalent group of general formula III, Z1 may also denote a bond,
  • Z2 denotes one of the groups —CH2—NH— or —(CH2)2—NH, wherein a hydrogen atom bound to a carbon atom and/or the hydrogen atom of the imino group may each be replaced by a C1-3-alkyl group, or Z1 denotes a divalent group of general formula
    Figure US20070208036A1-20070906-C00012
    wherein
    m and n independently of one another denote one of the numbers 1, 2, 3 or 4 and
    Z3 denotes the carbonyl group:
    coupling a compound of general formula
    Figure US20070208036A1-20070906-C00013
    wherein
    R1 is as hereinbefore defined and
    Nu denotes a leaving group, e.g. a halogen atom such as the chlorine, bromine or iodine atom, an alkylsulphonyloxy group with 1 to 10 carbon atoms in the alkyl moiety, a phenylsulphonyloxy or naphthylsulphonyloxy group optionally mono-, di- or trisubstituted by chlorine or bromine atoms, by methyl or nitro groups, whilst the substituents may be identical or different, a 1H-imidazol-1-yl, a 1H-pyrazol-1-yl optionally substituted by 1 or 2 methyl groups in the carbon skeleton, a 1H-1,2,4-triazol-1-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3,4-tetrazol-1-yl, a vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl, pentafluorophenyl, pyranyl or pyridinyl, a dimethylaminyloxy, 2(1H)-oxopyridin-1-yloxy, 2,5-dioxopyrrolidin-1-yloxy, phthalimidyloxy, 1H-benzotriazol-1-yloxy or azide group,
    with a compound of general formula
    R-Z1-Z2H  (IX),
    wherein
    R is as hereinbefore defined,
    Z1 denotes a methylene or carbonyl group or, if Z2 denotes a divalent group of general formula III, may also denote a bond,
    Z2 denotes-one of the groups —CH2—NH— or —(CH2)2—NH wherein a hydrogen atom bound to a carbon atom and/or the hydrogen atom of the imino group may each be replaced by a C1-3-alkyl group, or a divalent group of general formula
    Figure US20070208036A1-20070906-C00014
    wherein
    m and n independently of one another denote one of the numbers 1, 2, 3 or 4 and
    Z3 denotes the carbonyl group.
  • The reaction is carried out under Schotten-Baumann or Einhorn conditions, i.e. the components are reacted in the presence of at least one equivalent of an auxiliary base at temperatures between −50° C. and +120° C., preferably −10° C. and +30° C., and optionally in the presence of solvents. The auxiliary bases used are preferably alkali metal and alkaline earth metal hydroxides, e.g. sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates, e.g. sodium carbonate, potassium carbonate or caesium carbonate, alkali metal acetates, e.g. sodium or potassium acetate, as well as tertiary amines, e.g. pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine, N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine, 1,4-diazabicyclo[2,2,2]octane or 1,8-diazabicyclo[5,4,0]undec-7-ene, the solvents used may be, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethyl formamide, dimethyl acetamide, N-methyl-pyrrolidone or mixtures thereof; if alkali metal or alkaline earth metal hydroxides, alkali metal carbonates or acetates are used as the auxiliary bases, water may also be added to the reaction mixture as cosolvent.
  • g) In order to prepare compounds of general formula I wherein R and R1 are as hereinbefore defined, with the proviso that they must not carry any free amino groups,
  • Z1 denotes the carbonyl group,
  • Z2 denotes one of the groups —NH—CH2— or —NH—(CH2)2, wherein a hydrogen atom bound to a carbon atom and/or the hydrogen atom of the imino group may each be replaced by a C1-3-alkyl group and
  • Z3 denotes the methylene or carbonyl group:
  • reacting an amine of general formula,
    R″—H  (XI),
    wherein
    R″ has the meanings given for R hereinbefore, with the proviso that the group does not contain a free amino group,
    with a carbonic acid derivative of general formula
    Figure US20070208036A1-20070906-C00015
    wherein
    X1 denotes a nucleofugic group, preferably the 1H-imidazol-1-yl, 1H-1,2,4-triazol-1-yl, trichloromethoxy or 2,5-dioxo-pyrrolidin-1-yloxy group,
    and with a compound of general formula
    H-Z2-Z3-R1′  (XIII),
    wherein
    the group R1′ has the meanings given for R1 hereinbefore, with the proviso that the group does not contain a free amino group,
    Z2 denotes one of the groups —NH—CH2— or —NH— (CH2)2, wherein a hydrogen atom bound to a carbon atom and/or the hydrogen atom of the imino group may each be replaced by a C1-3-alkyl group and
    Z3 denotes the methylene or carbonyl group.
  • The reactions which are theoretically two-step reactions are usually carried out as one-pot processes, preferably by reacting one of the two components XI or XIII with equimolar quantities of the carbonic acid derivative of general formula XII in a suitable solvent at lower temperature in the first stage, then adding at least equimolar amounts of the other component XIII or XI and finishing the reaction at elevated temperature. The reactions with bis-(trichloromethyl)-carbonate are preferably carried out in the presence of at least 2 equivalents (based on bis-(trichloromethyl)-carbonate) of a tertiary base, e.g. triethylamine, N-ethyl-diisopropylamine, pyridine, 1,5-diazabicyclo[4,3,0]non-5-ene, 1,4-diazabicyclo[2,2,2]octane or 1,8-diazabicyclo[5,4,0]undec-7-ene. Examples of solvents, which should be anhydrous, include tetrahydrofuran, dioxane, dimethyl formamide, dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone or acetonitrile; if bis-(trichloromethyl)-carbonate is used as the carbonyl component anhydrous chlorohydrocarbons such as dichloromethane, 1,2-dichloroethane or trichloroethylene are preferred. The reaction temperatures for the first reaction step are between −30 and +25° C., preferably −5 and +10° C., for the second reaction step they are between +15° C. and the boiling temperature of the solvent used, preferably between +20° C. and +70° C. (cf. also: H. A. Staab and W. Rohr, “Synthesen mit heterocyclischen Amiden (Azoliden)”, Neuere Methoden der Präparativen Organischen Chemie, Vol. V, p. 53-93, Verlag Chemie, Weinheim/Bergstr., 1967; P. Majer and R. S. Randad, J. Org. Chem. 59, 1937-1938 (1994); K. Takeda, Y. Akagi, A. Saiki, T. Sukahara and H. Ogura, Tetrahedron Letters 24 (42), 4569-4572 (1983)).
  • h) In order to prepare compounds of general formula I wherein at least one of the groups R and R1 contains one or more carboxy groups:
  • alkaline saponification of a carboxylic acid ester of general formula
    Ra-Z1-Z2-Z3R1a  (Ia),
    wherein
    Z1, Z2 and Z3 are as hereinbefore defined and
    Ra and R1a have the meanings given for R and R1, respectively, hereinbefore, with the proviso that at least one of these groups contains one or more alkoxycarbonyl groups,
    optionally followed by treatment with dilute organic or inorganic acids in order to liberate the basic carboxylic acids from the salts initially formed.
  • For the alkaline saponification of the esters of general formula (Ia), lithium hydroxide, sodium hydroxide and potassium hydroxide are preferred; however, other alkali metal hydroxides such as caesium hydroxide, or alkaline earth metal hydroxides, for example barium hydroxide, or tetralkylammonium hydroxides are also suitable. The procedure is carried out in aqueous solution and advantageously with the addition of water-miscible co-solvents, preferably alcohols such as methanol, ethanol or 2-ethoxyethanol, or ethers such as tetrahydrofuran or 1,4-dioxane. Suitable temperatures for alkaline saponification are between −10° C. and the boiling temperature of the water/solvent mixture used, but ambient temperature is preferred. Dilute aqueous organic or inorganic acids, e.g. acetic acid, oxalic acid, methanesulphonic acid, hydrochloric acid, sulphuric acid and phosphoric acid are suitable for liberating the basic carboxylic acids from the salts thereof formed initially.
  • i) In order to prepare compounds of general formula I wherein at least one of the groups R and R1 contains one or more amino groups: acid hydrolysis of an acylamine of general formula
    Rb-Z1-Z2-Z3R1b  (Ib),
    wherein
    Z1, Z2 and Z3 are as hereinbefore defined,
    Rb and R1b have the meanings given hereinbefore for R and R1, respectively, with the proviso that Rb is substituted by an acetylamino, propionylamino, cycloalkanecarbonylamino or benzoylamino group and/or R1b is substituted by an acetylamino, propionylamino or benzoylamino group.
  • The acid hydrolysis is carried out using dilute to semi-concentrated aqueous, organic or inorganic acids such as hydrochloric acid, hydrobromic acid, trichloroacetic acid or sulphuric acid, and in the presence or absence of cosolvents such as methanol, ethanol, acetic acid or dioxane. Suitable temperatures are between ambient temperature and 100° C.; the boiling temperature of the solvent mixture used is preferred.
  • j) In order to prepare compounds of general formula I wherein the group R contains one or two primary or secondary amino groups:
  • acidolysis of a compound of general formula
    Rc-Z1-Z2-Z3R1  (Ic),
    wherein
    R1, Z1, Z2 and Z3 are as hereinbefore defined and
    Rc has the meanings given for R hereinbefore, with the proviso that this group contains one or two primary or secondary amino groups which are substituted by a tert.alkoxycarbonyl group. Acidolysis with trifluoroacetic acid is preferred, working with or without inert solvents, e.g. dichloromethane, and preferably in the absence of water. Suitable temperatures are between −50 and +90° C., preferably between 0° C. and room temperature. It has also proved satisfactory to carry out the acidolysis of compounds of general formula (1c) with methanolic hydrochloric acid solution under reflux conditions, although experience has shown that an attack on carboxamide and ester functions cannot be entirely ruled out, which is why the trifluoroacetic acid variant is generally the method of choice.
    k) In order to prepare compounds of general formula I wherein
    Z1 and Z3 each denote the carbonyl group,
    Z2 denotes the group —(CH2)2— and
    the group R1 denotes a phenyl group which carries a tertiary amino group in the 4 position relative to the point of attachment but may otherwise be substituted as described hereinbefore:
    nucleophilic aromatic substitution (cf. also: Jerry March, Advanced Organic Chemistry, Third Edition, page 576-578, published by John Wiley & Sons, New York-Chichester-Brisbane-Toronto-Singapore, 1985) of a compound of general formula
    R-Z1-Z2-Z3-R1d  (Id),
    wherein
    R is as hereinbefore defined,
    Z1 and Z3 each denote the carbonyl group,
    Z2 denotes the group —(CH2)2— and
    the group R1d denotes a phenyl group which carries a nucleophilically exchangeable function, preferably a fluorine, chlorine, bromine or iodine atom, in the 4 position relative to the point of attachment, but may otherwise be substituted as described hereinbefore,
    with a corresponding amine, for example with dimethylamine, piperidine, 1-(3-dimethylaminopropyl)piperazine, [4,1′]bi-piperidinyl, 4-(4-methyl-1-piperazinyl)piperidine or 4-[4-(3-dimethylaminopropyl)-1-piperazinyl]piperidine.
  • The reactions are carried out in excess secondary dialkylamine as solvent or using dipolar, aprotic solvents such as dimethylsulphoxide, dimethylformamide or sulpholane, and at temperatures of between 50 and 160° C., preferably 70 and 140° C. It may also be advantageous to add potassium carbonate to the reaction mixture.
  • l) In order to prepare compounds of general formula I wherein the group. R is uniformly mono-, di- or trisubstituted in the carbon skeleton by an aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group:
  • coupling a compound of general formula
    Re-Z1-Z2-Z3-R1  (Ie),
    wherein
    the group Re has the meanings given for R hereinbefore with the proviso that it is mono-, di- or trisubstituted in the carbon skeleton by the carboxy group, and R1, Z1, Z2 and Z3 are as hereinbefore defined,
    with ammonia or a corresponding alkylamine, for example ethanolamine, or a dialkylamine, for example 1-methylpiperazine or morpholine.
  • The coupling is preferably carried out using methods known from peptide chemistry (cf. e.g. Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for example using carbodiimides such as e.g. dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide (DIC) or ethyl-(3-dimethylaminopropyl)-carbodiimide, O-(1H-benzotriazol-1-yl)-N,N—N′,N′-tetramethyluronium hexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP). By adding 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt) any possible racemisation can additionally be suppressed, if desired, or the reaction speed can be increased. The couplings are normally carried out with equimolar amounts of the coupling components as well as the coupling reagent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethyl formamide (DMF), dimethyl acetamide (DMA), N-methylpyrrolidone (NMP) or mixtures thereof and at temperatures between −30 and +30° C., preferably −20 and +20° C. If necessary, N-ethyl-diisopropylamine (DIEA) (Hünig base) is preferably used as an additional auxiliary base.
  • The so-called anhydride process is used as a further coupling method for synthesising compounds of general formula I (cf. also: M. Bodanszky, “Peptide Chemistry”, Springer-Verlag 1988, p. 58-59; M. Bodanszky, “Principles of Peptide Synthesis”, Springer-Verlag 1984, p. 21-27). The Vaughan variant of the mixed anhydride process is preferred (J. R. Vaughan Jr., J. Amer. Chem. Soc. 73, 3547 (1951)), in which the mixed anhydride of the optionally N2-protected α-amino acid which is to be coupled and monoisobutyl carbonate is obtained, using isobutyl chlorocarbonate in the presence of bases such as 4-methyl-morpholine or 4-ethylmorpholine. The preparation of this mixed anhydride and the coupling with amines are carried out in a one-pot process, using the abovementioned solvents and at temperatures between −20 and +20° C., preferably 0 and +20° C.
  • m) In order to prepare compounds of general formula I wherein the group R is substituted in the carbon skeleton by an acetylamino group or in the carbon skeleton by an acetylamino group and at the same time is substituted at one of the aza-nitrogen atoms by an acetyl group:
  • aminolysis of acetic anhydride by a compound of general formula
    Rf-Z1-Z2-Z3-R1  (If),
    wherein
    R1, Z1, Z2 and Z3 are as hereinbefore defined and the group Rf has the meanings given for R hereinbefore with the proviso that it is substituted in the carbon skeleton by an amino group.
  • The aminolysis reaction is carried out in water or inert, usually polar and water-miscible solvents, such as tetrahydrofuran, 1,4-dioxane, pyridine, acetic acid or dimethylformamide, or in mixtures thereof and at temperatures between 0° C. and 100° C. In order to obtain selective acetylation of the amino group in the carbon skeleton, it is preferable to use alcohols such as methanol or ethanol as the solvents and to carry out the procedure at ambient temperature.
  • n) In order to prepare compounds of general formula I wherein the group R is as hereinbefore defined, with the proviso that it is substituted in the carbon skeleton by an acetylamino, propionylamino, cycloalkanecarbonylamino or benzoylamino group:
  • coupling a compound of general formula
    Figure US20070208036A1-20070906-C00016
    wherein
    RG denotes a methyl, ethyl, cycloalkyl or phenyl group and Nu denotes a leaving group such as a halogen atom, e.g. the chlorine, bromine or iodine atom, an alkylsulphonyloxy group with 1 to 10 carbon atoms in the alkyl moiety, a phenylsulphonyloxy or naphthylsulphonyloxy group optionally mono-, di- or trisubstituted by chlorine or bromine atoms or by methyl or nitro groups, wherein the substituents may be identical or different, a 1H-imidazol-1-yl, a 1H-pyrazol-1-yl optionally substituted by 1 or 2 methyl groups in the carbon skeleton, a 1H-1,2,4-triazol-1-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3,4-tetrazol-1-yl, a vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl, pentafluorophenyl, pyranyl or pyridinyl, a dimethylaminyloxy, 2(1H)-oxopyridin-1-yloxy, 2,5-dioxopyrrolidin-1-yloxy, phthalimidyloxy, 1H-benzotriazol-1-yloxy or azide group,
    with a compound of general formula
    Rf-Z1-Z2-Z3-R1  (If),
    wherein
    R1, Z1, Z2 and Z3 are as hereinbefore defined and
    the group Rf has the meanings given for R hereinbefore with the proviso that it is substituted in the carbon skeleton by an amino group.
  • The reaction is carried out under Schotten-Baumann or Einhorn conditions, i.e. the components are reacted in the presence of at least one equivalent of an auxiliary base at temperatures between −50° C. and +120° C., preferably −10° C. and +30° C., and optionally in the presence of solvents. The auxiliary bases used are preferably alkali metal and alkaline earth metal hydroxides, e.g. sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates, e.g. sodium carbonate, potassium carbonate or caesium carbonate, alkali metal acetates, e.g. sodium or potassium acetate, as well as tertiary amines, e.g. pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine, N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine, 1,4-diazabicyclo[2,2,2]octane or 1,8-diazabicyclo[5,4,0]undec-7-ene, the solvents used may be, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethyl formamide, dimethyl acetamide, N-methyl-pyrrolidone or mixtures thereof; if alkali metal or alkaline earth metal hydroxides, alkali metal carbonates or acetates are used as the auxiliary bases, water may also be added to the reaction mixture as cosolvent.
  • o) In order to prepare compounds of general formula I wherein the group R is as hereinbefore defined with the proviso that it is substituted in the carbon skeleton by an aminocarbonylamino group:
  • reacting a compound of general formula
    Rf-Z1-Z2-Z3-R1  (If),
    wherein
    R1, Z1, Z2 and Z3 are as hereinbefore defined and the group Rf has the meanings given for R hereinbefore, with the proviso that it is substituted in the carbon skeleton by an amino group,
    with cyanic acid which is produced in situ from alkali metal cyanates, for example sodium cyanate or potassium cyanate, and dilute inorganic acids such as hydrochloric acid or sulphuric acid. The reaction is carried out in suitable, water-miscible solvents, preferably tetrahydrofuran or 1,4-dioxane, and using water as cosolvent. Suitable reaction temperatures are between −5 and +50° C., preferably 0 and +25° C.
    p) In order to prepare compounds of general formula I wherein the group R is as hereinbefore defined, with the proviso that it is substituted by an aminomethyl group in the carbon skeleton, and
    Z2 has the meanings given hereinbefore with the exception of the group —CH═CH—:
    catalytic hydrogenation of a compound of general formula
    Rg-Z1-Z2-Z3-R1  (Ig),
    wherein
    R1, Z1, Z2 and Z3 are as hereinbefore defined and the group Rg has the meanings given for R hereinbefore, with the proviso that it is substituted in the carbon skeleton by a nitrile group.
  • Nickel and palladium catalysts have proved suitable for the catalysis, e.g. Raney nickel (R—Ni), palladium on charcoal and nickel reduced with sodium borohydride or nickel boride (Paul, Buisson and Joseph, Ind. Eng. Chem. 44, 1006 (1952); Brown, J. C. S. Chem. Commun. 1969, 952, J. Org. Chem. 35, 1900 (1973); Brown and Ahuja, J. Org. Chem. 38, 2226 (1973), J. C. S. Chem. Commun. 1973, 553; Schreifels, Maybury and Swartz, J. Org. Chem. 46, 1263 (1981); Nakao and Fujishige, Chem. Lett. 1981, 925; Nakao, Chem. Lett. 1982, 997). Generally, it has proved suitable to work in a neutral or slightly alkaline medium, particularly when using Raney nickel as catalyst, while it is usually beneficial to add ammonia to the reaction mixture. Palladium catalysts are also suitable for hydrogenating compounds of general formula Ig under acid conditions, i.e. in the presence of hydrochloric acid, sulphuric acid or phosphoric acid. Whereas nickel catalysts generally require slightly elevated temperatures between 40 and 100° C., the hydrogenations in question can be successfully carried out at ambient temperature using the palladium catalyst mentioned above.
  • Suitable hydrogen pressures are between normal pressure and 250 bar, while if palladium on charcoal is used as catalyst pressures of up to 10 bar are preferred. Suitable solvents are alcohols such as methanol or ethanol, ethers such as tetrahydrofuran or 1,4-dioxane, or esters, e.g. methyl acetate or ethyl acetate. Any C═C double bonds which may have been present in the chain Z1-Z2-Z3-Z4-Z5 of the starting material Ig are also saturated during the hydrogenation.
  • q) In order to prepare compounds of general formula I wherein R is the 4-[3,4-dihydro-2(1H)-thioxoquinazolin-3-yl]-1-piperidinyl or 4-[3,4-dihydro-2(1H)-cyanoiminoquinazolin-3-yl]-1-piperidinyl group:
  • reacting a diamine of general formula
    Figure US20070208036A1-20070906-C00017
    wherein
    R1, Z1, Z2 and Z3 are as hereinbefore defined,
    with one of the carbonic acid derivatives N,N′-thiocarbonyldiimidazole or cyanoimino-diphenylcarbonate. The reactions are carried out at temperatures between 20° C. and +100° C., preferably between +40° C. and +120° C., and using inert solvents, for example dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethylformamide, dimethylacetamide, N-methyl-pyrrolidone or mixtures thereof.
  • The arylalkanes, arylalkenes and aryl-azaalkanes of general formula I according to the invention contain a chiral centre in some cases. As a result of a C═C double bond which may in certain circumstances be present in the chain -Z2-Z3-, some of the compounds may also occur in the form of two geometric isomers; the methods of synthesis described hereinbefore predominantly produce the (E) isomers. The invention includes the individual isomers as well as the mixtures thereof.
  • The diastereomers may be separated on the basis of their different physico-chemical properties, e.g. by fractional crystallisation from suitable solvents, by high pressure liquid or column chromatography, using chiral or preferably non-chiral stationary phases.
  • Racemates covered by general formula (I) may be separated for example by HPLC on suitable chiral stationary phases (e.g. Chiral AGP, Chiralpak AD). Racemates which contain a basic or acidic function can also be separated via the diastereomeric, optically active salts which are produced on reacting with an optically active acid, for example (+) or (−)-tartaric acid, (+) or (−)-diacetyl tartaric acid, (+) or (−)-monomethyl tartrate or (+)-camphorsulphonic acid, or an optically active base, for example with (R)-(+)-1-phenylethylamine, (S)-(−)-1-phenylethylamine or (S)-brucine.
  • According to a conventional method of separating isomers, the racemate of a compound of general formula (I) is reacted with, one of the abovementioned optically active acids or bases in equimolar amounts in a solvent and the resulting crystalline, diastereomeric, optically active salts thereof are separated using their different solubilities. This reaction may be carried out in any type of solvent provided that it is sufficiently different in terms of the solubility of the salts. Preferably, methanol, ethanol or mixtures thereof, for example in a ratio by volume of 50:50, are used. Then each of the optically active salts is dissolved in water, neutralised with a base such as sodium carbonate or potassium carbonate, sodium hydroxide solution or potassium hydroxide solution and in this way the corresponding free compound is obtained in the (+) or (−) form.
  • The (R) or (S) enantiomer alone or a mixture of two optically active diastereomeric compounds covered by general formula I may also be obtained by performing the syntheses described above with a suitable reaction component in the (R) or (S) configuration.
  • The starting materials of general formulae V, VIII, X, XII, XIII and XIV required for the synthesis of the compounds of general formula I are commercially obtainable or may be prepared by methods known from the literature. Compounds of general formulae IV, IVa and XI are described in WO 98/11128 or are prepared analogously to the processes described therein. Compounds of general formula IX may easily be obtained from compounds of general formula IV analogously to methods known from the literature. Compounds of general formulae Ia, Ib, Ic, Id, Ie, If, Ig, I′ and XV may easily be obtained using the methods described in the present application. 4-Aryl-4-oxobutanoic acids of general formula VI may either easily be prepared analogously to methods known from the literature or may be obtained by catalytic hydrogenation of 4-aryl-4-oxo-2-butenoic acids, which may in turn be synthesised from suitable alkanophenones by a process described in published German patent applications 2 047 806 and 2 103 749, by condensation with glyoxylic acid hydrate under acid conditions. Compounds of general formula VII may be obtained from VI by conventional methods known from the literature.
  • The compounds of general formula I obtained may, if they contain suitable basic functions, be converted, particularly for pharmaceutical use, into their physiologically acceptable salts with inorganic or organic acids. Suitable acids include for example hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, mandelic acid, malic acid, citric acid, tartaric acid or maleic acid.
  • Moreover, the new compounds of formula (I), if they contain an acid function, for example a carboxy group, may if desired be converted into the addition salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable addition salts thereof. Suitable bases for this include, for example, sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
  • The new compounds of general formula I and the physiologically acceptable salts thereof have CGRP-antagonistic properties and exhibit good affinities in CGRP receptor binding studies. The compounds display CGRP-antagonistic properties in the pharmacological test systems described hereinafter.
  • The following experiments were carried out to demonstrate the affinity of compounds of general formula I for human CGRP-receptors and their antagonistic properties:
  • A. Binding Studies with SK-N-MC Cells (Expressing the Human CGRP Receptor)
  • SK-N-MC cells are cultivated in “Dulbecco's modified Eagle medium”. The medium is removed from confluent cultures. The cells are washed twice with PBS buffer (Gibco 041-04190 M), detached by the addition of PBS buffer mixed with 0.02% EDTA, and isolated by centrifuging. After resuspension in 20 ml of “Balanced Salts Solution” [BSS (in mM): NaCl 120, KCl 5.4, NaHCO3 16.2, MgSO4 0.8, NaHPO4 1.0, CaCl2 1.8, D-glucose 5.5, HEPES 30, pH 7.40] the cells are centrifuged twice at 100×g and resuspended in BSS. After the number of cells has been determined, the cells are homogenised using an Ultra-Turrax and centrifuged for 10 minutes at 3000×g. The supernatant is discarded and the pellet is recentrifuged in Tris buffer (10 mM Tris, 50 mM NaCl, 5 mM MgCl2, 1 mM EDTA, pH 7.40) enriched with 1% bovine serum albumin and 0.1% bacitracin, and resuspended (1 ml/1000000 cells). The homogenised product is frozen at −80° C. The membrane preparations are stable for more than 6 weeks under these conditions.
  • After thawing, the homogenised product is diluted 1:10 with assay buffer (50 mM Tris, 150 mM NaCl, 5 mM MgCl2, 1 mM EDTA, pH 7.40) and homogenised for 30 seconds with an Ultra-Turrax. 230 μl of the homogenised product are incubated for 180 minutes at ambient temperature with 50 pM 125I-iodotyrosyl-Calcitonin-Gene-Related Peptide (Amersham) and increasing concentrations of the test substances in a total volume of 250 μl. The incubation is ended by rapid filtration through GF/B-glass fibre filters treated with polyethyleneimine (0.1%) using a cell harvester. The protein-bound radioactivity is measured using a gamma counter. Non-specific binding is defined as the bound radioactivity in the presence of 1 μM human CGRP-alpha during incubation.
  • The concentration binding curves are analysed using computer-aided non-linear curve matching.
  • The compounds of general formula I show IC50 values≦10000 nM in the test described.
  • B. CGRP Antagonism in SK-N-MC cells
  • SK-N-MC cells (1 million cells) are washed twice with 250 μl incubation buffer (Hanks' HEPES, 1 mM 3-isobutyl-1-methylxanthine, 1% BSA, pH 7.4) and pre-incubated at 37° C. for 15 minutes. After the addition of CGRP (10 μl) as agonist in increasing concentrations (10−11 to 10−6 M), or additionally the substance in 3 to 4 different concentrations, the mixture is incubated for another 15 minutes.
  • Intracellular cAMP is then extracted by the addition of 20 μl of 1M HCl and centrifugation (2000×g, 4° C., for 15 minutes). The supernatants are frozen in liquid nitrogen and stored at −20° C.
  • The cAMP contents of the samples are determined by radioimmunoassay (Messrs. Amersham) and the pA2 values of antagonistically acting substances are determined graphically.
  • The compounds of general formula I exhibit CGRP-antagonistic properties in the in vitro test model described, in a dosage range of between 10−11 to 10−5 M.
  • In view of their pharmacological properties the compounds of general formula I and the salts thereof with physiologically acceptable acids or bases are thus suitable for the acute and prophylactic treatment of headaches, particularly migraine or cluster headaches. Moreover, the compounds of general formula I also have a positive effect on the following diseases: non-insulin-dependent diabetes mellitus (“NIDDM”), cardiovascular diseases, morphine tolerance, skin diseases, particularly thermal and radiation-induced skin damage including sunburn, inflammatory diseases, e.g. inflammatory diseases of the joints (arthritis), inflammatory lung diseases, allergic rhinitis, asthma, diseases accompanied by excessive vasodilatation and consequent reduced circulation of blood through the tissues, e.g. shock and sepsis. The symptoms of menopausal hot flushes in estrogen-deficient women caused by vasodilatation and increased blood flow are favourably affected by the CGRP-antagonists of the present application in a preventive and acute-therapeutic capacity, this therapeutic approach being distinguished from hormone replacement by the absence of side effects. Furthermore, the compounds of general formula I have a general pain-relieving effect.
  • The dosage required to achieve a corresponding effect is conveniently 0.001 to 30 mg/kg of body weight, preferably 0.01 to 5 mg/kg of body weight, when administered intravenously or subcutaneously and 0.01 to 50 mg/kg of body weight, preferably 0.1 to 30 mg/kg of body weight when administered orally, nasally or by inhalation, 1 to 3× a day in each case.
  • For this, the compounds of general formula I prepared according to the invention, optionally combined with other active substances such as e.g. antiemetics, prokinetics, neuroleptics, antidepressants, neurokinine antagonists, anti-convulsants, histamine-H1 receptor antagonists, antimuscarinics, β-blockers, α-agonists and α-antagonists, ergot alkaloids, mild analgesics, non-steroidal antiinflammatories, corticosteroids, calcium antagonists, 5-HT1D agonists or other anti-migraine agents, together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, may be formulated into conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, solutions, metered dose aerosols or suppositories.
  • The active substances which may be used for the abovementioned combinations thus include, for example, meloxicam, ergotamine, dihydroergotamine, metoclopramide, domperidone, diphenhydramine, cyclizine, promethazine, chlorpromazine, dexamethasone, flunarizine, dextropropoxyphene, meperidine, propranolol, nadolol, atenolol, clonidine, indoramine, carbamazepine, phenyloin, valproate, amitryptilin, lidocaine, diltiazem or sumatriptan and other 5-HT1D-agonists such as, for example, naratriptan, zolmitriptan, avitriptan, rizatriptan and eletriptan. The dosage of these active substances is expediently ⅕ of the lowest recommended dose to 1/1 of the normally recommended dose, i.e. for example 20 to 100 mg of sumatriptan.
  • The invention further relates to the use of, the compounds of general formula I as valuable adjuvants for the production and purification (by affinity chromatography) of antibodies as well as in RIA and ELISA assays, after suitable radioactive labelling, for example by direct labelling with 125I or 131I or by tritiation of suitable precursors, for example by replacing halogen atoms with tritium; and as a diagnostic or analytical adjuvant in neurotransmitter research.
  • The Examples which follow are intended to illustrate the invention:
  • Preliminary Remarks:
  • Satisfactory elementary analyses, IR, UV, 1H-NMR and generally also mass spectra have been obtained for all the compounds. Unless otherwise stated, Rf values were obtained using ready-made silica gel TLC plates 60 F254 (E. Merck, Darmstadt, Item no. 5729) without chamber saturation. If no detailed information is given as to the configuration, it is not clear whether it is a pure enantiomer or whether partial or even complete racemisation has occurred. The following eluants or mixtures of eluants were used for the chromatography:
    • El A=ethyl acetate/methanol 100/5 v/v
    • El B=ethyl acetate/methanol 80/20 v/v
    • El C=ethyl acetate/methanol/conc. ammonia 80/20/1 v/v/v
    • El D=dichloromethane/cyclohexane/methanol/conc. ammonia 350/75/75/10 v/v/v/v
    • El E=ethyl acetate/glacial acetic acid 99/1 v/v
    • El F=ethyl acetate/methanol/glacial acetic acid 90/10/1 v/v/v
    • El G=dichloromethane/methanol/conc. ammonia 90/10/1 v/v/v
    • El H=petroleum ether/ethyl acetate 1/1 v/v
    • El I=dichloromethane/methanol/glacial acetic acid 90/10/1.5 v/v/v
    • El K=dichloromethane/isopropanol 9/1 v/v.
    • El L=ethyl acetate/methanol 9/1 v/v
    • El M=dichloromethane/methanol/conc. ammonia 75/25/5 v/v/v
    • El N=dichloromethane/ethyl acetate, 1/1 v/v
    • El O=dichloromethane/methanol 95/5 v/v
  • The following abbreviations are used in the description of the experiments:
    • Mp.: melting point
    • (D): (decomposition)
    • DIEA: N,N-diisopropyl-ethylamine
    • Boc: (1,1-dimethylethoxy)carbonyl
    • TBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate
    • HOBt: 1-hydroxybenzotriazole-hydrate
    • CDT: 1,1′-carbonyldi-(1,2,4-triazole)
    • THF: tetrahydrofuran
    • DMF: dimethyl formamide
    • EE: ethyl acetate
    • PE: petroleum ether
    • LM: solvents
    • I. No.: Item number
  • The meanings of the symbols consisting of letters and numbers used in the Examples are shown in the following summary:
    Figure US20070208036A1-20070906-C00018
    Figure US20070208036A1-20070906-C00019
    Figure US20070208036A1-20070906-C00020
    Figure US20070208036A1-20070906-C00021
    Figure US20070208036A1-20070906-C00022
    Figure US20070208036A1-20070906-C00023
    Figure US20070208036A1-20070906-C00024
    Figure US20070208036A1-20070906-C00025
    Figure US20070208036A1-20070906-C00026
    Figure US20070208036A1-20070906-C00027
    Figure US20070208036A1-20070906-C00028
    Figure US20070208036A1-20070906-C00029
    Figure US20070208036A1-20070906-C00030
    Figure US20070208036A1-20070906-C00031
    Figure US20070208036A1-20070906-C00032
    Figure US20070208036A1-20070906-C00033
    Figure US20070208036A1-20070906-C00034
    Figure US20070208036A1-20070906-C00035
    Figure US20070208036A1-20070906-C00036
    Figure US20070208036A1-20070906-C00037
    Figure US20070208036A1-20070906-C00038
    Figure US20070208036A1-20070906-C00039
    Figure US20070208036A1-20070906-C00040
    Figure US20070208036A1-20070906-C00041
    A. Preparation of Intermediate Compounds
    • EXAMPLE A1 1-(4-amino-3,5-dibromophenyl)-4-chloro-1-butanone
  • 115 ml (2.107 mol) of bromine were added dropwise to a solution of 262 g (1.119 mol) of 1-(4-aminophenyl)-4-chloro-1-butanone-hydrochloride (base: m.p. 88-89° C. (decomp.), hydrochloride: m.p. 164-167° C. (decomp.), prepared by reacting 1-(4-acetylaminophenyl)-4-chloro-1-butanone with semi-concentrated hydrochloric acid) in a mixture of 1700 ml of glacial acetic acid and 850 ml of water, with stirring and external cooling with ice water. The precipitate formed was suction filtered, washed thoroughly twice with an ice-cold mixture of 170 ml of glacial acetic acid and 85 ml of water, then with pure water, and dried in vacuo at a temperature of 40° C. Yield: 293 g (74% of theoretical). M.p.: 83-84 C.
    • EXAMPLE A2
  • Preparation of Compounds of the General Structure:
    Figure US20070208036A1-20070906-C00042
    • (E)-4-(3,5-dibromo-4-fluorophenyl)-4-oxo-2-butenoic acid
  • A mixture of 14.8 g (50.12 mmol) of 3,5-dibromo-4-fluoro-acetophenone, 6.9 g (74.92 mmol) of glyoxylic acid hydrate and 150 ml glacial acetic acid was refluxed for 20 hours. The glacial acetic acid was half distilled off, then water was added to the cooled mixture until a yellow precipitate was formed. The product precipitated was suction filtered, washed thoroughly with water and dried in a circulating air dryer until a constant weight was achieved. After recrystallisation from ethanol, 4.9 g (28% of theoretical) of slightly yellowish crystals were obtained, Rf 0.82 (El F).
    IR (KBr): 1705, 1672 (C═O)
    MS: ESI: (M − H)− = 348/350/352 (Br2)
  • The following were obtained accordingly:
    %
    N B C Remarks yield El Rf MS IR [cm-1] m.p. [° C.]
    OH B3 C11 condensation 67 1691, slightly yellowish
    with the addition 1666 (C═O) crystals
    of TsOH
    OH B3 C12 condensation 72 1695, slightly yellowish
    with the addition 1660 (C═O) crystals
    of TsOH
    OH B3 C13 condensation 55 M+ = 192 1695, slightly yellowish
    with the addition 1653 (C═O) crystals
    of TsOH
    OH B3 C14 condensation 51 1701, slightly yellowish
    with the addition 1668 (C═O) crystals
    of TsOH
    OH B3 C15 condensation 79 1697, slightly yellowish
    with the addition 1662 (C═O) crystals
    of TsOH
    OH B3 C16 52 M+ = 243/ 1709, 1689, 139-141 (EtOH);
    245/ 1666 (C═O) yellow
    247 (Cl2)
    OH B3 C17 condensation 59 1697, orange crystals
    with the addition 1678 (C═O)
    of TsOH
    OH B3 C18 condensation 66 1705, 1687, slightly yellowish
    with the addition 1666 (C═O) crystals
    of TsOH
    OH B3 C19 condensation 86 1699, slightly yellowish
    with the addition 1664 (C═O) crystals
    of TsOH
    OH B3 C20 condensation 82 1703, slightly yellowish
    with the addition 1660 (C═O) crystals
    of TsOH
    OH B3 C21 condensation 73 1712, 1691, slightly yellowish
    with the addition 1664 (C═O) crystals
    of TsOH
    OH B3 C22 condensation 65 M+ = 299/ 1707, orange-yellow
    with the addition 301 (Br) 1678 (C═O); 1520, crystals
    of TsOH 1358 (NO2)
    OH B3 C23 condensation 74 1714, 1697, slightly yellowish
    with the addition 1669 (C═O) crystals
    of TsOH
    OH B3 C26 59 1703.0, slightly yellowish
    1664.5 (C═O) crystals
    OH B3 C27 43 1708.8, slightly yellowish
    1666.4 (C═O) crystals
    OH B3 C28 15 2233.4 (CN); slightly yellowish
    1712.7, crystals
    1666.4 (C═O)
    OH B3 C29 4 M+ = 234 3429.2, slightly yellowish
    3350.2 (NH2); crystals
    2229.6 (CN); 1697.3,
    1647.1 (C═O)
    OH B3 C1 21 slightly yellowish
    crystals
    OH B3 C33 condensation 78 1701, 210-215; yellow
    with the addition 1674 (C═O) crystals
    of TsOH
    OH B3 C34 condensation 33 (M + H)+ = 252.1, 1711, slightly yellowish
    with the addition 254.1 (Cl) 1662 (C═O) crystals
    of TsOH
    OH B3 C46 condensation 31 yellow crystals
    with the addition
    of TsOH
    OH B3 C47 condensation 36 yellow crystals
    with the addition
    of TsOH
    OH B3 C48 condensation 64 slightly yellowish
    with the addition crystals
    of TsOH
    OH B3 C49 condensation 72 slightly yellowish
    with the addition crystals
    of TsOH
    OH B3 C50 condensation 33 1700, slightly yellowish
    with the addition 1670 (C═O) crystals
    of TsOH
    OH B3 C51 condensation 54 1701, yellow crystals
    with the addition 1664 (C═O)
    of TsOH
    OH B3 C52 condensation 32 1707, yellow crystals
    with the addition 1662 (C═O)
    of TsOH
    OH B3 C53 condensation 50 M+ = 259 1718 (C═O) orange-yellow
    with the addition crystals
    of TsOH
    OH B3 C54 condensation 34 yellow crystals
    with the addition
    of TsOH
    OH B3 C55 condensation 42 E 0.75 1709, 1693, slightly yellowish
    with the addition 1668 (C═O) crystals
    of TsOH
    OH B3 C57 23 F 0.69 M+ = 271/ 1709, 1689, 138-140; slightly
    274 (Br) 1664 (C═O) yellowish
    • EXAMPLE A3
  • Preparation of Compounds of the General Structure:
    Figure US20070208036A1-20070906-C00043
    • 4-(3-bromo-4-fluorophenyl)-4-oxobutanoic acid
  • A solution of 6.2 g (0.023 mol) of (E)-4-(3-bromo-4-fluorophenyl)-4-oxo-2-butenoic acid in a mixture of 200 ml ethanol and 25 ml tetrahydrofuran was hydrogenated in the presence of 1.0 g of 10% platinum/charcoal at ambient temperature under a pressure of 50 psi until the uptake of hydrogen was complete. The residue remaining after the catalyst and solvent had been eliminated crystallised spontaneously and after being washed thoroughly with diisopropylether yielded 1.7 g (27% of theoretical) of colourless crystals, m.p. 108-110° C. and Rf 0.73 (El F).
    IR (KBr): 1711, 1687 (C═O) cm−1
    MS: ESI: (M − H)− = 273/275 (Br)
  • The following were obtained accordingly:
    %
    N B C Remarks yield El Rf MS IR [cm−1] m.p. [° C.]
    OH B2 C26 H2/R—Ni/ 51 1708.8, colourless
    EE 1664.5 (C═O) crystals
    OH B2 C27 H2/R—Ni/ 61 1695.3, 88-90
    EE 1678.0 (C═O) (EtOH/H2O
    1/2 v/v)
    OH B2 C29 H2/R—Ni, 90 3494.8, colourless
    EE/MeOH 3375.2 (NH2); crystals
    (2/3 v/v) 2223.8 (CN); 1714.6,
    1674.1 (C═O)
    OH B2 C16 H2/Pd—C, 37 F 0.78 ESI: (M − H)− = 245/ 1707, 157-159
    EtOH/THF 247/ 1689 (C═O)
    (10/1 v/v) 249 (Cl2)
    OH B2 C58 H2/Pt—C, 55 F 0.88 M+ = 351/ 1705, colourless
    EtOH/THF 353/ 1689 (C═O) crystals
    (5/1 v/v) 355 (Br2)
    OH B2 C33 H2/Pt—C, 99 1701, colourless
    EtOH/THF 1684 (C═O) crystals
    (10/1 v/v)
    • EXAMPLE A4 4-(4-amino-3,5-dibromophenyl)-4-oxobutanoic acid
  • A solution of 73.7 g (0.461-mol) of bromine in 150 ml glacial acetic acid was added dropwise at ambient temperature to a solution of 50.0 g (0.213 mol) of 4-(4-acetylaminophenyl)-4-oxobutanoic acid in 500 ml of 80% acetic acid. The mixture was finally heated to 50° C. for a further 30 minutes. The precipitate formed after cooling was suction filtered, washed with diethylether and dried in a circulating air dryer at 40° C. The desired compound of m.p. 200-202° C. was obtained in a yield of 33.1 g (44% of theoretical).
    MS: M+ = 349/351/353 (Br2)
    IR (KBr): 3487.1, 3382.9 (NH2); 1701.1, 1672.2 (C═O) cm−1
  • The following were obtained accordingly:
    %
    N B C remarks yield El Rf MS IR [cm−1] m.p. [° C.]
    OH B2 C1 2 mol Br2/80% 44 M+ = 349/ 3487.1, 200-202
    AcOH 351/ 3382.9 (NH2); 1701.1,
    353 (Br2) 1672.2 (C═O)
    H3CO B2 C1 2 mol Br2/80% 98 colourless
    AcOH/NaOAc crystals (from
    MeOH)
    OH B2 C2 1 mol Br2/80% 26 M+ = 313/ 3315.4 (NH), 186-187
    AcOH/NaOAc 315 (Br) 1708.8, (diisopropyl-
    1670.3 (C═O) ether)
    OH B5 C1 2 mol Br2/80% 95 1699.2 (C═O) colourless
    AcOH/NaOAc crystals
    OH B5 C2 1 mol Br2/80% 79 3265.1 (NH), colourless
    AcOH 1693.4, crystals (from
    1662.5 (C═O) isopropanol/
    water 1/2 v/v)
    OH B17 C1 2 mol Br2/80% 89 3487, 3388 (NH2); colourless
    AcOH 1691, 1662 (C═O) crystals
    OH B18 C1 2 mol Br2/80% 49 F 0.60 3458.2, colourless
    AcOH 3361.7 (NH2); crystals
    1739.7 (C═O)
    OH B15 C1 2 mol Br2/80% 75 ESI: (M + H)+ = 363/ 1743 (C═O) colourless
    AcOH/NaOAc 365/ crystals
    367 (Br2)
    • EXAMPLE A5 (3,5-dibromo-4-fluorophenyl)-ethanone and (3-bromo-4-fluorophenyl)-ethanone
  • 69 g (0.5 mol) of p-fluoroacetophenone were added dropwise to 200.0 g (1.5 mol) of finely powdered aluminium chloride with stirring, during which time the mixture heated up to 70° C. It was kept at 75-80° C. for another 20 minutes and then 184 g (1.15 mol) of bromine were added at this temperature within 2.5 hours. Finally, the resulting mixture was heated to 90° C. for another 3 hours. After being cooled and decolorised the mixture was divided between water and tert.butylmethyl ether. Working up the organic phase yielded 130 g of a brownish-black oil which was separated into 2 fractions on silica gel using toluene as eluant:
  • a) 41.2 g (28% of theoretical) of colourless crystals, m.p. 59-62° C. and Rf=0.53 (toluene), which were identified as 1-(3,5-dibromo-4-fluorophenyl)-1-ethanone by spectroscopy.
    IR (KBr): 1685 (C═O) cm−1
    MS: M+ = 294/296/298 (Br2)
  • b) 46.0 g (42% of theoretical) of colourless crystals, m.p. 52-55° C. and Rf=0.41 (toluene), which were identified as 1-(3-bromo-4-fluorophenyl)-1-ethanone by spectroscopy.
    IR (KBr): 1682 (C═O) cm−1
    MS: M+ = 216/218 (Br)
  • The following was obtained accordingly:
    N B C remarks % yield MS IR [cm−1] m.p. [° C.]
    — H3CCO C33 Br2/ 76 1685 94-98
    AlCl3 (C═O) (isopropanol)
    • EXAMPLE A6 γ-oxo-1H-benzimidazol-5-butanoic acid
  • Prepared analogously to Example 5 from methyl γ-oxo-1H-benzimidazol-5-butanoate, lithium hydroxide and water in the presence of tetrahydrofuran in a yield of 78% of theoretical. Colourless crystals, m.p. 251-255° C. (decomp.).
  • IR (KBr): 1672.2 (C═O) cm−1
  • The following were obtained accordingly:
    N B C remarks % yield IR [cm−1] m.p. [° C.]
    OH B2 C1 NaOH/dioxane/ 90 3485.2, 3382.9 (NH2); 1701.1, colourless
    H2O 1672.2 (C═O) crystals
    OH B2 C41 NaOH/dioxane/ 89 3247.9 (NH); 1710.8,
    H2O 1689.5 (C═O)
    H3CO B14 C1 NaOH/dioxane/ 55
    H2O
    OH B2 C45 NaOH/MeOH/ 96 1697, 1674 (C═O) colourless
    H2O crystals
    OH B2 C9 LiOH/THF/H2O 99 3356.6, 3223.2 (NH); 1718.5, colourless
    1689.5, 1660.6 (C═O) crystals
    • EXAMPLE A7 4-(3,5-dibromophenyl)-4-oxobutanoic acid
  • A solution of 3.5 g (0.01 mol) of 4-(4-amino-3,5-dibromophenyl)-4-oxobutanoic acid in 50 ml of 1N aqueous sulphuric acid was treated dropwise with a solution of 0.76 g (0.011 mol) of sodium nitrite in 10 ml of water while maintaining a reaction temperature of −5 to 0° C. The mixture was stirred for a further 30 minutes at a temperature of 0° C., then 50 ml of hypo-phosphorous acid were added dropwise while maintaining the same temperature and stirred for another 1 hour at a temperature of 0° C. The mixture was decolorised and a colourless crystalline substance was precipitated. The mixture was diluted with 100 ml of water, the precipitate formed was suction filtered, washed thoroughly with water and then dried in a circulating air dryer. 3.1 g (92% of theoretical) of colourless crystals were obtained, m.p. 137-138° C.
    IR (KBr): 1705.0 (C═O) cm−1
    MS: M+ = 334/336/338 (Br2)
    • EXAMPLE A8 1-[[1.4′]bipiperidinyl-4-yl]-1,3-dihydro-4-(3-trifluoromethyl-phenyl)-2(2H)-imidazolone-bis-(trifluoroacetate)
  • Prepared analogously to Example 7 from 1-[1′-(dimethylethoxy-carbonyl)-[1.4′]bipiperidinyl-4-yl]-1,3-dihydro-4-(3-trifluoromethylphenyl)-2(2H)-imidazolone and trifluoroacetic acid in the presence of dichloromethane as solvent in a yield of 71% of theoretical. Colourless crystals.
    IR (KBr): 1679.7 (C═O) cm−1
    MS: M+ = 394
  • The following were obtained accordingly:
    %
    N B C remarks yield EI Rf MS IR [cm−1] m.p. [° C.]
    N87 H — CF3CO2H/ 97 1701.1, amorphous bis-
    CH2Cl2 1674.1 (C═O) (trifluoroacetate)
    N81 H — CF3CO2H/ 47 M+ = 326 1678 (C═O) amorphous bis-
    CH2Cl2 (trifluoroacetate)
    N93 B2 C1 from N94—B2—C1 59 M+ = 536/ Colourless
    with CF3CO2H/ 538/ crystalline
    CH2Cl2 540 (Br2) trifluoroacetate
    N89 H — CF3CO2H 77 M+ = 288 1662.5 (C═O); Colourless
    1207.4, 1176.5, crystalline
    1132.1 (trifluoroacetate) trifluoroacetate
    N4 H — CF3CO2H/ 37 3292.3 (NH);
    CH2Cl2 1714.6 (C═O);
    1516.0, 1494.7,
    1334.7 (NO2)
    N85 H — CF3CO2H/ 99 1712, Colourless
    CH2Cl2 1676 (C═O) crystalline
    trifluoroacetate
    N86 H — CF3CO2H/ 96 Colourless
    CH2Cl2 crystalline bis-
    (trifluoroacetate)
    N98 CH2Ph — from 92 D 0.68 3485, Colourless
    Boc-N98—CH2Ph 3379 (NH, NH2); crystalline bis-
    and CF3CO2H/ 1670.3 (C═O) (trifluoroacetate),
    CH2Cl2 from
    diisopropylether/
    ethanol 9/1 v/v
    N93 CH2Ph — from N95—CH2Ph 99 D 0.74
    and CF3CO2H/
    CH2Cl2
    • EXAMPLE A9 4-amino-3-bromobenzenebutanoic acid
  • A mixture of 0.13 g (0.008662 mol) of 4-acetylamino-3-bromobenzenebutanoic acid and 10 ml of. conc. hydrochloric acid was refluxed for 24 hours. The colourless, needle-shaped crystals of Rf 0.53 (eluant: dichloromethane/methanol 9/1 v/v) precipitated after cooling were identified by spectroscopy as the hydrochloride of the desired 4-amino-3-bromobenzenebutanoic acid. The crystals were dissolved in a little water, and the solution formed was adjusted to pH 6 using concentrated potassium carbonate solution. The precipitate was suction filtered, washed with water and dried in a circulating air dryer at 60° C. Yield: 1.35 g (60% of theoretical).
  • IR (KBr): 3440.8, 3357.9 (NH); 1693.4 (C═O) cm−1
  • The following was obtained accordingly:
    %
    N B C remarks yield EI Rf MS IR [cm−1] m.p. [° C.]
    OH B17 C59 conc. HCl 92 3464, 3352 (NH); colourless
    1705, crystals
    1653 (C═O)
    OH B18 C59 conc. HCl 92 I 0.66 3483.2, 3398.4, 170-172
    3375.2 (NH2); (water)
    1705.0,
    1656.8 (C═O)
    OH B15 C59 from ethyl 4-(4- 60 F 0.8 ESI: 1712,
    aminophenyl)-2- (M + H)+=208 1689 (C═O)
    ethoxycarbonyl-3-methyl-
    4-oxobutanoate; ethanolic
    HCl/semiconc. HCl 5/2
    v/v
    • EXAMPLE A10 3-{1-[4-(3,4-dichlorophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone
  • Prepared analogously to Example 2 from 3,4-dichloro-γ-oxobenzenebutanoic acid and 3-(4-piperidinyl)-3,4-dihydro-2(1H)-quinazolinone in the presence of TBTU in a yield of 73% of theoretical. Colourless crystals, m.p. 224-226° C. and Rf 0.15 (El EE).
    IR (KBr): 1666 (C═O) cm−1
    MS: ESI: (M + H)+ = 482/484/486 (Cl2)
  • The following were prepared accordingly:
    %
    N B C remarks yield EI Rf MS IR [cm−1] m.p. [° C.]
    N10 B2 C57 THF as solvent; 73 G 0.75 M+ = 487/ 3205 (NH); 1666, colourless
    DIEA as base 489 (Br); ESI: 1645 (C═O) crystals
    (M + Na)+ = 510/
    512 (Br);
    (2M + Na)+ = 997/
    999/
    1001 (Br)
    N10 B2 C58 THF as solvent; 78 F 0.82 ESI: (M + Na)+ = 588/ 1660 (C═O) 212-215
    DIEA as base 590/
    592 (Br2)
    N94 B2 C1 THF/DMF 5/1 as 66 H 0.65 M+ = 736/ 3469, 3357 (NH,
    solvent; NEt3 as 738/ NH2); 1751,
    base 740 (Br2) 1691,
    1649 (C═O)
    N89 Boc — from N10—H and 76 M+ = 388 3427.3, 272-275
    N-Boc-glycine, 3321.2 (NH, NH2);
    THF/DMF 1/1 as 1722.3, 1666.4,
    solvent; DIEA as 1645.2 (C═O)
    base
    N88 Ph2CH — from N10—H and 64 M+ = 480 1664.5 (C═O) hydrochloride:
    1-benzhydryl- 164-165
    azetidine-3-
    carboxylic acid;
    THF as solvent;
    DIEA as base
    • EXAMPLE A11 4-acetylaminobenzenebutanoic acid
  • Prepared analogously to Example 10, but using ethanol as solvent, from 4-aminobenzenebutanoic acid and acetic anhydride in a yield of 62. % of theoretical. Colourless crystals. IR (KBr): 3342.4 (NH); 1714.6, 1643.4 (C═O) cm−1
  • The following was obtained accordingly, but in the absence of a solvent and using p-toluenesulphonic acid as catalyst:
    % m.p.
    N B C remarks yield MS IR [cm−1] [° C.]
    H3CO B2 C41 Ac2O/ 38 M+ = 405/ colourless
    TsOH/ 407/409 crystals
    130° C. (Br2)
    • EXAMPLE A12 3-[1′-(1,1-dimethylethoxycarbonyl)-[1.4 ′]bipiperidinyl-4-yl]-5-(phenylmethyl)-imidazolidin-2,4-dione
  • A mixture of 5.5 g (20.2 mmol) of 3-(4-piperidinyl)-5-(phenylmethyl)-imidazolidin-2,4-dione, 4.0 g (20.1 mmol) of 1-(1,1-dimethylethoxycarbonyl)-4-piperidinone, 8 ml (20 mmol) of titanium(IV)-isopropoxide and 100 ml of anhydrous ethanol was stirred for 1 hour at ambient temperature. Then 0.89 g (13.45 mmol) of 95% sodium cyanoborohydride was added, the mixture was adjusted to pH 5 by the dropwise addition of glacial acetic acid and stirred overnight at ambient temperature. The mixture was stirred into 200 ml of water and freed from the precipitate formed. The filtrate was evaporated down in vacuo until no more ethanol passed over, the aqueous phase remaining was made alkaline with sodium hydroxide and extracted exhaustively with dichloromethane. Conventional working up of the extracts yielded 5.0 g (54% of theoretical) of colourless crystals.
  • IR (KBr): 1772, 1712 (C═O) cm−1
  • The following were obtained accordingly:
    %
    N B C remarks yield MS IR [cm−1] m.p. [° C.]
    N86 Boc — from N65—H and N-Boc-4- 6 1682, 1632 (C═O) colourless
    piperidinone crystals
    N78 CH2Ph — from N10—H and N-benzyl- 33 M+ = 390 3305 (NH); colourless
    3-pyrrolidinone 1666 (C═O) crystals
    N77 Boc — from N12—H and N-Boc-4- 38 M+ = 426 3435 (NH); colourless
    piperidinone 1684 (C═O) crystals
    N82 Boc — from N22—H and N-Boc-4- 86 M+ = 494 1676, 1645 (C═O) colourless
    piperidinone crystals
    N103 CH2Ph — from o-nitrobenzylamine 35 M+ = 380 3417.7 (NH); pale yellow
    and 7-methyl-3- 1668.3 (C═O); 1355.9 (NO2) oil
    (phenylmethyl)-3,7-
    diazabicyclo[3.3.1]-nonan-
    9-one
    • EXAMPLE A13 N-(2-aminophenylmethyl)-N-(1,1-dimethylethoxycarbonyl)-1-(phenylmethyl)-4-piperidineamine
  • A solution of 60.6 g (278 mmol) of di-tert.butyldicarbonate in 400 ml of dioxane was added dropwise, within two hours, to a mixture of 80.0 g (270.8 mmol) of N-(2-aminophenylmethyl)-1-(phenylmethyl)-4-piperidineamine, 39.2 ml (280 mmol) of triethylamine, 500 ml of dioxane and 450 ml of water, while maintaining a reaction temperature of 5-10° C. The mixture was stirred for a further 3 hours while cooling externally with ice water, then for 60 hours at ambient temperature. The dioxane was distilled off in vacuo, and the aqueous residue was extracted exhaustively with a total of 1 l of ethyl acetate. The combined ethyl acetate extracts were washed once with 200 ml of water, twice with 250 ml of a saturated sodium hydrogen carbonate solution and once with 200 ml of water, dried over sodium sulphate and concentrated by evaporation in vacuo. The brownish oil remaining was taken up in 150 ml of diisopropylether and when left to stand colourless crystals were precipitated after about 15 hours, which were then suction filtered and dried. Yield: 31.5 g (29% of theoretical).
  • IR (KBr): 3438.8, 3363.7 (NH, NH2); 1666.4, 1639.4 (C═O) cm−1
  • The following were obtained accordingly:
    %
    N B C remarks yield El Rf
    N96 CH2Ph — from N97—CH2Ph and Boc2O 98 K 0.81
    N94 CH2Ph — from N95—CH2Ph and Boc2O 98
    N71 CH2Ph — from N72—CH2Ph and Boc2O 11
    • EXAMPLE A14 4-dimethylamino-3-chloroacetophenone
  • A mixture of 9.45 g (0.05 mol) of 3,4-dichloroacetophenone, 6.2 ml (0.1 mol) of dimethylamine and 2 ml of DIEA was stirred for 20 hours in an autoclave and at a reaction temperature of 120° C. After cooling the reaction mixture was divided between dichloromethane and water, the organic phase washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated by evaporation. The residue remaining was purified by column chromatography on silica gel, eluting first with toluene, then with tert.butyl-methyl ether. The appropriate eluates were combined and after working up in the usual way yielded 5.6 g (57% of theoretical) of the desired substance as a colourless oil.
    IR (KBr): 1678 (C═O) cm−1
    MS: (M + H)+ = 198/200 (Cl); (M + Na)+ = 220/222 (Cl);
    (2M + Na)+ = 417/419 (Cl)
  • The following was obtained accordingly:
    N B C remarks % yield MS IR [cm−1] m.p. [° C.]
    N116 Boc — from 1-(dimethylethoxy- 100 reddish-brown
    carbonyl)-4-piperidineamine, 2- oil
    fluoro-5-nitroaniline and K2CO3
    in DMSO/H2O 4/1 v/v
    N4 CH2Ph — from 1-(phenylmethyl)-4- 82 M+ = 352 yellow crystals
    piperidineamine, N-
    (dimethylethoxy-carbonyl)-2-
    fluoro-5-nitroaniline in DMSO/
    100° C.
    • EXAMPLE A15 1-(Diphenylmethyl)-3-[(2-nitrophenylmethyl)amino]-azetidine
  • A mixture of 45.0 g (0.189 mol) of 3-amino-1-(diphenylmethyl)-azetidine, 28.7 g (0.190 mol) of 2-nitrobenzaldehyde and 280 ml of methanol was stirred for 3 hours at ambient temperature. Then 7.4 g (0.196 mol) of sodium borohydride were added followed, after a further 2 hours, by another 6.0 g of sodium borohydride and 300 ml of methanol and after a further 16 hours by 4.0 g of sodium borohydride, and the mixture was stirred for a further 4 hours at ambient temperature. The mixture was concentrated by evaporation in vacuo and the residue was treated with 200 ml dichloromethane and 200 ml of water. It was filtered, the methylene chloride phase was dried over sodium sulphate and freed from solvent. The residue was purified by chromatography on silica gel (30-60 μm) using dichloromethane/EE/MeOH/cyclohexane/conc. ammonia (59/25/7.5/7.5/1 v/v/v/v/v) as eluant, then on silica gel using dichloromethane/EE (1/1 v/v) as eluant. After the appropriate fractions had been worked up, 20.0 g (28% of theoretical) of the desired compound were obtained in the form of a pale yellow oil.
    IR (KBr): 1342 (NO2) cm−1
    MS: ESI: (M + H)+ = 374; (M + Na)+ = 396
  • The following were obtained accordingly:
    %
    N B C remarks yield MS m.p. [° C.]
    N97 CH2Ph — from 2-nitrobenzaldehyde, 4- 91 pale yellow oil
    amino-1-benzylpiperidine and
    NaBH4/MeOH
    N99 CH2Ph — from 5-chloro-2- 92 pale yellow oil
    nitrobenzaldehyde, 4-amino-
    1-benzylpiperidine and NaBH4/
    MeOH
    N101 CH2Ph — from 5-hydroxy-2- 81 M+ = 341 182;
    nitrobenzaldehyde, 4-amino- pale yellow
    1-benzylpiperidine and NaBH4/ crystals
    MeOH
    N102 CH2Ph — from 2-nitrobenzaldehyde, 8- 76 M+ = 351; pale yellow oil
    (phenylmethyl)-8- ESI: (M + H)+ = 352
    azabicyclo[3.2.1]oct-3-ylamine
    and NaBH4/MeOH
    N110 CH2Ph — from 3-methyl-2- 100
    nitrobenzaldehyde, 4-amino-
    1-benzylpiperidine and NaBH4/
    MeOH
    • EXAMPLE A16 3-[(2-aminophenylmethyl)amino]-1-(diphenylmethyl)-azetidine
  • A solution of 20.0 g (0.5355 mol) of 1-(diphenylmethyl)-3-[(2-nitrophenylmethyl)amino]-azetidine in 200 ml of methanol was hydrogenated in the presence of 4 g of 5% rhodium/charcoal for 5 hours at ambient temperature. The catalyst was filtered off, the filtrate was concentrated by evaporation in vacuo. 17.7 g (96% of theoretical) of a colourless, highly viscous oil were obtained, which was further processed without any additional purification.
  • Rf=0.75 (dichloromethane/EE/MeOH/cyclohexane/conc. ammonia 59/25/7.5/7.5/1 v/v/v/v/v)
  • MS: M+=343; ESI: (M+H)+=344; (M+Na)+=366
  • The following were obtained accordingly:
    %
    N B C remarks yield El Rf IR [cm−1] m.p. [° C.]
    N93 CH2Ph — from N97—CH2Ph, H2, 97 D 0.64 colourless oil
    5% Rh—C, MeOH
    N104 CH2Ph — from N102—CH2Ph, 68 colourless oil
    H2, 5% Rh—C, MeOH
    N105 CH2Ph — from N103—CH2Ph, 94 colourless oil
    H2, 5% Rh—C, MeOH
    N107 CH2Ph — from N99—CH2Ph, H2, 95 D 0.74 colourless oil
    5% Rh—C, MeOH
    N95 CH2Ph — from N96—CH2Ph, H2, 38 D 0.87 colourless
    5% Rh—C, MeOH crystals
    N108 CH2Ph — from N101—CH2Ph, 99 D 0.47 3338 (NH) colourless
    H2, 5% Rh—C, MeOH crystals
    H3CO B2 C61 from H3CO—B2—C62, 95 3458.2, 3408.0, 117
    H2, R—Ni, EE 3357.9 (NH2); 1732.0,
    1706.9, 1658.7 (C═O)
    N109 CH2Ph — from N110—CH2Ph, 98 D 0.42 colourless oil
    H2, 5% Rh—C, MeOH
    HO B2 C10 from HO—B2—C7, H2, 20 3475.5, 3377.2 (NH2); colourless
    Pt—C, MeOH 1716.5, 1679.9 (C═O) crystals
    N111 CH2Ph — from N112—CH2Ph, 99 D 0.31
    H2, 5% Rh—C, MeOH
    • EXAMPLE A17 3-{[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl}-azetidine-hydrochloride
  • A solution of 2.07 g (4.0033 mmol) of 1-(diphenylmethyl)-3-{[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl}-azetidine-hydrochloride in a mixture of 100 ml of methanol and 2 ml of water was hydrogenated at a temperature of 50° C. and in the presence of 0.5 g of 10% palladium/charcoal until the uptake of hydrogen had ended. After removal of the catalyst and solvent 1.36 g (97% of theoretical) of the desired compound were obtained in the form of a colourless, porous substance.
    IR (KBr): 1652.9 (C═O) cm−1
    MS: M+ = 314
  • The following were obtained accordingly:
    %
    N B C remarks yield El Rf MS IR [cm−1] m.p. [° C.]
    N53 H — from N53—CH2Ph, H2, 83 D 0.07 3433.1, colourless
    10% Pd—C, MeOH 3323.2 (NH, NH2); crystals
    1681.8 (C═O)
    N58 H — from N58—CH2Ph, H2, 88 D 0.32 colourless,
    10% Pd—C, MeOH amorphous
    N59 H — from N59—CH2Ph, H2, 83 D 0.18 colourless oil
    10% Pd—C, MeOH
    N60 H — from N60—CH2Ph, H2, 91 colourless oil
    10% Pd—C, MeOH,
    presumably a mixture
    of geometric isomers
    N61 H — from N61—CH2Ph, H2, 66 D 0.24 crystals
    10% Pd—C, MeOH
    N71 H — from N71—CH2Ph, H2, 91 D 0.15 colourless
    10% Pd—C, MeOH crystals
    N92 H — from N92—CH2Ph, H2, 52 D 0.42 M+ = 499 1687.6, colourless oil
    10% Pd—C, MeOH 1660.6 (C═O)
    N94 H — from N94—CH2Ph, H2, 84 colourless,
    10% Pd—C, MeOH amorphous
    N79 H — from N79—CHPh2, H2, 65 D 0.17 ESI: (M + H)+ = 287 1662 (C═O)
    10% Pd—C, MeOH/
    1N aq. HCl (10/1 v/v)
    N76 H — from N76—CHPh2, H2, 20 D 0.22 ESI: (M + H)+ = 204
    10% Pd—C, MeOH/
    1N aq. HCl (2/1 v/v)
    N5 H — from N4—CH2Ph, H2, 92 3375.2, colourless
    10% Pd—C, AcOH 3236.4 (NH, NH2); crystals
    1678.0 (C═O)
    N16 H — from N16—CH2Ph, H2, 99
    20% Pd—C, MeOH
    N29 H — from N29—CH2Ph, H2, 54 3246 (NH); >260
    10% Pd—C, MeOH 1658 (C═O) (MeOH)
    N78 H — from N78—CH2Ph, H2, 71 M 0.35 3205 (NH); colourless
    10% Pd—C, MeOH 1666 (C═O) crystals
    N74 H — from N74—CH2Ph, H2, 70 M 0.44 ESI: (M + H)+ = 276; 3323, 3222 (NH); colourless
    10% Pd—C, MeOH (M − H)− = 276; 2852, crystals
    (2M + H)+ = 551; 2833(OCH3);
    (2M − H)− = 549 1658 (C═O)
    N91 H — from N91—CH2Ph, H2, 96 D 0.18 1689.5 (C═O); colourless,
    10% Pd—C, MeOH 1367.4, amorphous
    1155.3 (SO2—N)
    — H C63 from PhCH2—C63, H2, 93 ESI: (M + H)+ = 255 colourless oil
    10% Pd—C, MeOH
    • EXAMPLE A18 6-chloro-3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone
  • 2.17 g (15.178 mmol) of 1-chloroethyl chlorocarbonate were added to a solution of 4.5 g (12.645 mmol) of 6-chloro-3,4-dihydro-3-[(1-(phenylmethyl)-4-piperidinyl]-2(1H)-quinazolinone in 100 ml of anhydrous ethylene chloride and the mixture was refluxed for 1 hour. After the addition of 20 ml of methanol the mixture was refluxed for a further 3 hours. It was left to cool, 1.05 ml of 12M hydrochloric acid were added and the resulting mixture was evaporated down in vacuo. The residue was carefully triturated with petroleum ether and with diethylether one after the other. The crystals were taken up in a little water, the solution obtained was made clearly alkaline with sodium hydroxide solution and extracted exhaustively with EE. The combined ethyl acetate extracts were dried over potassium carbonate and brought to dryness in vacuo. The crystals remaining were triturated with diisopropylether and suction filtered. After drying in a circulating air dryer, 3.21 g (96% of theoretical) of colourless crystals were obtained.
    • EXAMPLE A19 Methyl 4-(1,3-dihydro-2(2H)-oxobenzimidazol-5-yl)-4-oxobutanoate
  • A mixture of 20.0 g (0.09 mol) of methyl 4-(3,4-diaminophenyl)-4-oxobutanoate, 16.2 g (0.1 mol) of N,N′-carbonyldiimidazole and 250 ml of tetrahydrofuran was heated to 60° C. with stirring for 90 minutes. After cooling the mixture was stirred into 500 ml of ice water, the precipitate formed was suction filtered and washed with diethylether. After drying in vacuo 14.85 g (67% of theoretical) of colourless crystals were obtained.
  • IR (KBr): 1728.1, 1699.2, 1674.1 (C═O) cm−1
  • The following were obtained accordingly:
    %
    N B C remarks yield El Rf MS IR [cm−1] m.p. [° C.]
    N58 CH2Ph — from N104—CH2Ph 18 M+ = 347 1664.5 (C═O)
    and CDI in DMF
    N59 CH2Ph — mixture of 22 ESI: (M + H)+ = 377 colourless,
    diastereomers, amorphous
    partly separable;
    from N105—CH2Ph
    and CDI in DMF
    N69 CH2Ph — from N69—CH2Ph 46 D 0.84 colourless crystals
    and CDI in DMF (acetone)
    N61 CH2Ph — from N-[1- 93 D 0.6 M+ = 363 3249.9 (NH); colourless crystals
    (phenylmethyl)-4- 1764.8, (diisopropylether)
    piperidinyl]-D,L- 1708.8 (C═O)
    phenylglycinamide
    and CDI in DMF
    N16 CH2Ph — from N109—CH2Ph 45 1662.5 (C═O)
    and CDI in DMF
    N29 CH2Ph — from N108—CH2Ph 50 1664 (C═O) colourless crystals
    and CDI in DMF
    N76 CHPh2 — from N106—CH2Ph 6 1669 (C═O) colourless crystals
    and CDI in DMF (diisopropylether)
    N76 CHPh2 — from N106—CH2Ph 32 3207 (NH); colourless crystals
    and CDI in DMF 1660 (C═O) (diisopropylether)
    N74 CH2Ph — from N111—CH2Ph 84 D 0.71 colourless crystals
    and CDI in DMF
    N4 Boc — from N116—Boc 6 D 0.57 M+ = 362 pale yellow
    and CDI in THF crystals
    • EXAMPLE A20 N-[(2-aminocarbonylaminophenyl)methyl]-N-(1,1-dimethylethoxy-carbonyl)-1-(phenylmethyl)-4-piperidineamine
  • 2.0 g (0.03 mol) of sodium cyanate were added to a solution of 7.91 g (0.02 mol) of N-[(2-aminophenyl)methyl]-N-(1,1-dimethylethoxycarbonyl)-1-(phenylmethyl)-4-piperidineamine in a mixture of 5.5 ml glacial acetic acid and 80 ml of water and the mixture was stirred overnight at ambient temperature. The mixture was made slightly alkaline by the addition of saturated sodium hydrogen carbonate solution, then extracted exhaustively with EE. The combined ethyl acetate extracts were washed with water, dried over sodium sulphate and concentrated by evaporation in vacuo. 8.7 g (99% of theoretical) of colourless crystals were obtained, Rf 0.71 (El D), which were further processed without any additional purification.
    • EXAMPLE A21 N-{2-{[1,4′]bipiperidinyl-1′-ylcarbonylamino}phenylmethyl}-N-(1,1-dimethylethoxycarbonyl)-1-(phenylmethyl)-4-piperidine-amine
  • A mixture of 2.56 g (15.6 mmol) of CDT, 5.14 g (13 mmol) of N-[(2-aminophenyl)methyl]-N-(1,1-dimethylethoxycarbonyl)-1-(phenylmethyl)-4-piperidineamine and 200 ml of tetrahydrofuran was stirred for 0.5 hours while cooling with ice and then for 30 minutes at ambient temperature. 2.4 g (14.3 mmol) of [1,4′]piperidinyl were added with stirring and the mixture was refluxed for 4 hours. The reaction mixture was diluted with 200 ml of ethyl acetate and the organic phase washed twice with 150 ml of aqueous saturated sodium hydrogen carbonate solution and once with 100 ml of saturated aqueous sodium chloride solution. After the organic phase had been dried and the solvent eliminated in vacuo the residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: dichloromethane/isopropanol=9/1 (v/v)). 5.0 g (65% of theoretical) of a colourless amorphous product were obtained, Rf 0.5 (El D).
  • IR (KBr): 1687.6, 1660.6 cm−1 (C═O)
    • EXAMPLE A22 2-amino-3-[1-(phenylmethyl)-4-piperidinyl]-3,4-dihydro-quinazoline
  • A solution of 10.0 g (33.85 mmol) of N-[(2-aminophenyl)methyl]-1-(phenylmethyl)-4-piperidineamine in 150 ml of anhydrous ethanol was combined with 4.0 g (37.76 mmol) of bromocyanogen added batchwise. The mixture was left to stand overnight at ambient temperature, the ethanol was eliminated in vacuo and the residue was distributed between dichloromethane and 1N sodium hydroxide solution. After working up in the conventional way, 9.3 g (86% of theoretical) of colourless crystals were obtained, Rf 0.4 (El D), which were further processed without any additional purification.
    • EXAMPLE A23 N-[2-(5-methoxy-2-nitrophenyl)ethyl]-1-(phenylmethyl)-4-piperidineamine
  • 34.0 ml (268.2 mmol) of trimethylsilyl chloride were slowly added dropwise to a solution of 27.0 g (70.4 mmol) of 5-methoxy-2-nitro-N-[1-(phenylmethyl)-4-piperidinyl]-benzeneacetamide in 400 ml of anhydrous tetrahydrofuran and then stirred for another 1 hour at ambient temperature. 4.9 g (213.7 mmol) of lithium borohydride were added batchwise, stirring was continued for another 30 minutes at ambient temperature and then for 4 hours at reflux temperature. After cooling, 25 ml of water and 25 ml of semiconcentrated hydrochloric acid were added dropwise one after the other and the mixture was refluxed for 90 minutes. It was left to stand overnight at ambient temperature, then cooled in an ice bath and the precipitate formed was suction filtered. The aqueous phase of the filtrate was made ammoniacal and extracted exhaustively with EE. The combined ethyl acetate extracts were dried with sodium sulphate, then combined with ethereal hydrogen chloride solution until the precipitation ended. The product precipitated was combined with the earlier precipitate, presumed to be the dihydrochloride of the desired compound, suspended in ethanol and suction filtered. The filter cake was dissolved in 100 ml of water, the solution was made ammoniacal and extracted exhaustively with EE. Conventional working up of the ethyl acetate extracts yielded a pale yellow oil, Rf 0.69 (El D). Yield: 11.3 g (43% of theoretical).
    IR (KBr): 1514, 1338 (NO2) cm−1
    MS: ESI: (M + H)+ = 370
    • EXAMPLE A24 5-methoxy-2-nitro-N-[1-(phenylmethyl)-4-piperidinyl]-benzene-acetamide
  • 9.24 g (56.98 mmol) of N,N′-carbonyldiimidazole were added to a solution of 12.0 g (56.8 mmol) of 5-methoxy-2-nitrobenzene-acetic acid in 100 ml of tetrahydrofuran and the mixture was stirred for 40 minutes at a reaction temperature of 40° C. After the addition of 11.6 g (56.88 mmol) of 1-(phenylmethyl)-4-piperidineamine the mixture was heated to 40° C. for another hour. The reaction mixture was concentrated by evaporation in vacuo, the solid residue was digested with 50 ml of water and tert.butylmethylether, suction filtered and dried in a circulating air dryer at 50° C. 19.9 g (91% of theoretical) of pale yellow crystals were obtained, Rf 0.6 (eluant: dichloromethane/EE/cyclohexane/methanol/conc. ammonia 300/80/25/25/3 v/v/v/v/v).
    IR (KBr): 1638 (C═O) cm−1
    MS: ESI: (M + H)+ = 384; (M + Na)+ = 406; (M − H)− = 382;
    (M − H + HCl)− = 418/420 (Cl)
    • EXAMPLE A25 4-(1,3-dihydro-2(2H)-oxo-1-benzimidazolyl)-1-{[2-[(1,1-di-methylethoxycarbonyl)amino]ethyl}piperidine
  • A solution of 12.4 g (55.3 mmol) of 2-bromo-N-(1,1-dimethylethoxycarbonyl)-ethylamine in 50 ml, tetrahydrofuran was added dropwise to a solution of 12 g (55.2 mmol) of 4-(1,3-dihydro-2(2H)-oxo-1-benzimidazolyl)piperidine and 15.3 ml (110.4 mmol) of triethylamine in 300 ml tetrahydrofuran. The mixture was refluxed for 20 hours and, after cooling, the triethylamine hydrobromide precipitated was eliminated. The remaining solution was concentrated by evaporation in vacuo, the residue was dissolved in 1 l of EE, the solution washed twice with 200 ml of water, dried over sodium sulphate and evaporated down again. 11.7 g (59% of theoretical) of a colourless, waxy substance were obtained, which was used without any further purification.
  • IR (KBr): 3382.9 (NH); 1689.5 (C═O) cm−1
    • EXAMPLE A26 3-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1-(diphenylmethyl)-azetidine
  • A mixture of 19.7 g (0.0621 mol) of 1-(diphenylmethyl)-3-mesyloxyazetidine, 14.4 g (0.0623 mol) of 3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone, 100 ml of dimethylformamide and 12 ml of triethylamine was heated to a reaction temperature of 90° C. for 4 hours. The initially clear solution increasingly became a crystal slurry. After cooling the precipitate was suction filtered, crystallised once from 20 ml of hot dimethylformamide and the product washed thoroughly with water and ethanol. After drying in a circulating air dryer 13.8 g (49% of theoretical) of colourless crystals were obtained, Rf 0.76 (El D).
  • IR (KBr): 1662 (C═O) cm−1
    • EXAMPLE A27 N-(1,1-dimethylethoxycarbonyl)-N-[(2-methanesulphonylamino-phenyl)-methyl]-1-(phenylmethyl)-4-piperidineamine
  • 1.64 ml (21 mmol) of methanesulphonyl chloride was added dropwise to a solution of 7.91 g (20 mmol) of N-(1,1-dimethylethoxycarbonyl)-N-[(2-aminophenyl)methyl]-1-(phenylmethyl)-4-piperidineamine and 3.0 ml (21 mmol) of triethylamine in 100 ml of tetrahydrofuran and the mixture was then kept for 12 hours at ambient temperature. It was then diluted with 100 ml of EE and extracted twice with 70 ml of saturated sodium hydrogen carbonate solution. The ethyl acetate phase was dried over sodium sulphate and concentrated by evaporation in vacuo. 8.7 g (92% of theoretical) of a colourless substance were obtained, Rf 0.85 (El D), which were used in the next step without any further purification.
    • EXAMPLE A28 4-(4-acetylaminophenyl)-2-methyl-4-oxobutanoic acid
  • 22 ml (0.28 mol) of dimethylformamide were added dropwise to 133.34 g (1.0 mol) of finely powdered aluminium chloride within 20 minutes, while cooling externally with ice. After the strongly exothermic reaction died down, 13.517 g (0.1 mol) of acetanilide and 11.413 g (0.1 mol) of methylsuccinic acid anhydride were added all at once and at an initial temperature of 60° C., during which time the mixture heated up to about 80° C. It was kept for another 3 hours at a temperature of 60-70° C., the still hot mixture was stirred into 1 kg of crushed ice, 60 ml, of conc. hydrochloric acid were added and the mixture was left to stand overnight at ambient temperature. The precipitate formed was suction filtered and thoroughly washed with water. It was taken up in 150 ml of methanol, stirred for 30 minutes at 50° C., then for another 30 minutes while cooling externally with ice and the precipitate was suction filtered. After drying in a circulating air dryer at 60° C., 10.4 g (42% of theoretical) of colourless crystals were obtained, m.p. 229-231° C. and Rf 0.48 (El I).
  • IR (KBr): 1714.6, 1662.5 cm−1 (C═O)
  • The following were obtained accordingly:
    %
    N B C remarks yield El Rf MS IR [cm−1] m.p. [° C.]
    H3CO B2 C45 from octahydro- 50 1730, 75-77
    phenanthrene, 3- 1675 (C═O) (petrol)
    methoxycarbonyl-
    propionylchloride and
    AlCl3/ethylene
    chloride
    HO B17 C60 from acetanilide, 12 3336.7 (NH); colourless
    glutaric acid anhydride 1708.8, crystals
    and AlCl3/DMF 1674.1 (C═O) (MeOH)
    H3CCHCl B7 C60 from acetanilide, 2- 66 H 0.3 ESI: (M − H)− = 224/ 1670 (C═O)
    chloropropionylchloride 226 (Cl)
    and AlCl3/CH2Cl2
    • EXAMPLE A29 Ethyl 4-(4-acetylaminophenyl)-2-(ethoxycarbonyl)-3-methyl-4-oxobutanoate
  • 24.407 ml (0.16 mol) of diethyl malonate were added dropwise to a suspension of 7.631 g (0.159 mol) of sodium hydride in 90 ml of anhydrous dimethylformamide under a nitrogen atmosphere, the mixture was heated for 90 minutes to 50° C., then 37.462 g (0.166 mol) of 1-(4-acetylaminophenyl)-2-chloro-1-propanone were added and heating was continued for a further 3 hours to 80° C. After cooling the mixture was stirred into 1 l of ice water, saturated with sodium chloride and extracted exhaustively with ethyl acetate. The combined ethyl acetate extracts were dried over sodium sulphate, filtered over activated charcoal and concentrated by evaporation in vacuo, and the residue was purified by column chromatography on silica gel. After working up in the usual way 45.0 g (80% of theoretical) of a colourless oil were obtained, Rf 0.7 (El: EE).
    IR (KBr): 1747, 1732, 1676 cm−1 (C═O)
    MS: M+ = 349
    • EXAMPLE A30 1-(4-amino-3,5-dibromophenyl)-2-methylamino-1-ethanone-hydrochloride
  • A solution of 10.2 g (0.027 mol) of 4-amino-3,5-dibromophenacyl bromide in 100 ml of dichloromethane was heated to 50° C. for 4 hours in a vibrating autoclave and in the presence of 3.64 ml (0.062 mol) of methylamine. After cooling the mixture was extracted three times with 50 ml of water, the dichloromethane phase was dried over sodium sulphate, then diluted with 300 ml of diethylether, and ethereal hydrochloric acid was added dropwise until the precipitation reaction had ended. The mixture was cooled overnight to −15° C., the precipitate was suction filtered and dried in a vacuum drying chamber at 40° C. Yield: 6.0 g (61% of theoretical).
  • MS: M+=320/322/324 (Br2); ESI: (M+H)+=321/323/325 (Br2) The product was used without purification, as the by-product detectable by mass spectroscopy (ESI: (M2+H)+=609/611/613/615/617/619 (Br4)), presumably N,N′-bis-(4-amino-3,5-dibromophenacyl)-methylamine, was not expected to cause any complications in the subsequent reaction.
    • EXAMPLE A31 2-amino-1-(4-amino-3,5-dibromophenyl)-1-ethanone-hydrochloride
  • 7.5 g (53.8 mmol) of urotropine were added to a solution of 20.0 g (53.8 mmol) of 4-amino-α,3,5-tribromoacetophenone in 600 ml of dichloromethane and stirred overnight at ambient temperature. The precipitate formed was suction filtered, washed with dichloromethane and dried in vacuo, then suspended in 600 ml ethanol. The mixture obtained was combined with 100 ml of conc. hydrochloric acid and refluxed for 2½ hours. After cooling the precipitate formed was suction filtered, carefully washed with cold ethanol and dried in vacuo. Yield of colourless crystals: 18.5 g (100% of theoretical).
  • IR (KBr): 3477.5, 3431.2, 3323.2 (NH2); 1679.9 (C═O) cm−1
    • EXAMPLE A32 1-(Diphenylmethyl)-3-(phthalimido)-azetidine
  • A mixture of 75 g (0.235 mol) of 1-(diphenylmethyl)-3-(methanesulphonyloxy)-azetidine, 47.1 g (0.254 mol) of potassium phthalimide and 800 ml of dimethylformamide was refluxed for 1% hours, during which time a fine precipitate gradually settled out. After cooling the precipitate was filtered off and the solvent was evaporated off in vacuo, finally under a high vacuum. The colourless residue crystallised when left to stand. Yield: 78.0 g (90% of theoretical). Rf=0.95 (El N).
    • EXAMPLE A33 3-amino-1-(diphenylmethyl)-azetidine
  • 572 ml of 40% aqueous methylamine solution and 300 ml of water were added successively to a suspension of 78.0 g (0.212 mol) of 1-(diphenylmethyl)-3-(phthalimido)-azetidine in 480 ml of ethanol. After 7 days' stirring at ambient temperature a clear solution had formed, which was freed from excess methylamine and ethanol in vacuo. The aqueous solution remaining was extracted exhaustively with ethyl acetate. The ethyl acetate extracts were dried over sodium sulphate and dried in vacuo. 45.0 g (89% of theoretical) of a colourless oil were obtained, which was further processed without any additional purification.
    • EXAMPLE A34 4-[4-(methylamino)-3-nitrophenyl]-4-oxobutanoic acid
  • A solution of 20.0 g (0.0776 mol) of 4-(4-chloro-3-nitrophenyl)-4-oxobutanoic acid in 200 ml of 40% aqueous methylamine solution was stirred for 3 hours in a sealed vessel. Then the mixture was diluted with the same volume of water and acidified with acetic acid. The product precipitated was suction filtered, thoroughly washed with water and dried at 50° C. in a circulating air dryer. 18.5 g (95% of theoretical) of the desired compound were obtained in the form of yellow crystals.
    • EXAMPLE A35 4-(4-chloro-3-nitrophenyl)-4-oxobutanoic acid
  • While cooling externally with a mixture of ice and common salt, 21.3 g (0.1 mol) of 4-(4-chlorophenyl)-4-oxobutanoic acid were added batchwise to 100 ml of fuming nitric acid in such a way that the temperature of the mixture did not exceed 0° C. The mixture was stirred for another 1 hour at an internal temperature of between −5 and 0° C., then stirred into 1 l of ice water, after ½ hour the precipitate was collected on a filter, thoroughly washed with water until free from acid, and the crystalline product was dried in a circulating air dryer. 23.4 g (91% of theoretical) of pale yellow crystals were obtained.
    • EXAMPLE A36 Methyl 4-(1H-benzimidazol-5-yl)-4-oxobutanoate
  • 75 ml of phosphorus(III)oxychloride were slowly added dropwise, while cooling externally with water, to a solution of 20.0 g (0.09 mol) of methyl 4-(3,4-diaminophenyl)-4-oxobutanoate in 50 ml of formic acid and the mixture was then stirred for another 40 minutes at a reaction temperature of 60° C. It was left to cool, then the mixture was stirred into 500 g of crushed ice while cooling externally with ice and made weakly ammoniacal. It was then extracted exhaustively with ethyl acetate, the combined extracts were dried over magnesium sulphate and concentrated by evaporation in vacuo. 8.29 g (40% of theoretical) of a colourless, crystalline substance were obtained.
  • IR (KBr): 1732.0, 1679.9 cm−1 (C═O)
    • EXAMPLE A37 1-(3-dimethylaminopropyl)-4-[1-(phenylmethyl)-4-piperidinyl]-piperazine
  • To a solution of 27.8 g (0.15 mol) of 1-(phenylmethyl)-4-piperidinone and 26.5 g (0.15 mol) of 1-(3-dimethylaminopropyl)-piperazine in 500 ml of tetrahydrofuran were added 200 mg of p-toluenesulphonic acid and 13.5 g (0.225 mol) of glacial acetic acid, followed by 47.7 g (0.225 mol) of sodium triacetoxyborohydride, in small batches, and the mixture was stirred overnight at ambient temperature. 100 ml of water were added dropwise while stirring was continued and after 30 minutes sufficient potassium carbonate was added to produce a precipitate that could be filtered off. It was filtered and the filter cake washed thoroughly with THF and diethylether in succession. The combined filtrates were concentrated by evaporation in vacuo, the residue was purified by column chromatography on 400 g of aluminium oxide (A2O3—ICN, activity stage 3) using EE/MeOH (95/5 v/v) as eluant. A colourless oil, Rf 0.33 (El O), was obtained in a yield of 35.0 g (68% of theoretical).
  • MS: ESI: (M+H)+=345
  • B. Preparation of the Final Compounds
    • EXAMPLE 1
  • Preparation of Compounds of General Formula:
    Figure US20070208036A1-20070906-C00044
    • 1-{1-[4-(4-amino-3,5-dibromophenyl)-4-oxobutyl]-4-piperidinyl}-1,3-dihydro-2(2H)-benzimidazolone-hydrochloride (Item no. 1)
  • A mixture of 30.6 g (0.0861 mol) of 1-(4-amino-3,5-dibromophenyl)-4-chloro-1-butanone, 18.6 g (0.0856 mol) of 1-(4-piperidinyl)-1,3-dihydro-2(2H)-benzimidazolone, 18.2 g (0.172 mol) of anhydrous sodium carbonate, 2.0 g of potassium iodide and 800 ml of methylisobutylketone was refluxed for 130 hours. After cooling the mixture was extracted once with 500 ml of water, the organic phase was dried over sodium sulphate and concentrated by evaporation in vacuo. The residue was dissolved in 50 ml of anhydrous ethanol and the equivalent amount of ethanolic hydrogen chloride solution was added dropwise. After standing for 24 hours at ambient temperature the colourless crystals precipitated were suction filtered and dried in vacuo. Yield: 27.0 g (55% of theoretical). M.p.: 297-299 C (decomp.) (ethanol/water 95/5 v/v). Rf 0.21 (El A). C22H24Br2N4O2*HCl (572.73)
    Calc.: C 46.14 H 4.40 Br 27.90 Cl 6.19 N 9.78
    Found: 45.10 4.92 27.65 6.09 9.95
  • The following were prepared analogously:
    Item Ex. %
    no. N B C no. remarks yield El Rf MS IR [cm−1]
    2 N2 B1 C1 1 DMF/DMSO 2/1 29 A 0.21 m/e = 244; 1687.6 (C═O)
    as solvent; NEt3 257; 276
    as base
    3 N3 B1 C1 1 DMSO as solvent; 21 A 0.28 ESI: (M + H)+ = 549/ 1695.3 (C═O)
    NEt3 as base 551/
    553 (Br2)
    4 N4 B1 C1 1 DMSO as solvent; 48 A 0.53 m/e = 288/ 1685.7,
    NEt3 as base 289 1712.7 (C═O); 1492.8,
    1332.7 (NO2)
    5 N5 B1 C1 1 DMF as solvent; 22 B 0.23 3442.7,
    Na2CO3 as base 3364.5 (NH, NH2);
    1683.8 (C═O)
    10 N10 B1 C1 1 DMF as solvent; 3 B 0.5 ESI: (M + H)+ = 549/ 1666.4 (C═O)
    NEt3 as base 551/
    553 (Br2)
    11 N11 B1 C1 1 acetone/MeCO$$Bu 30 B 0.24 1668.3 (C═O)
    as solvent;
    Na2CO3 as base
    113 N42 B1 C1 1 DMF as solvent; 18 A 0.25 ESI: (M + H)+ = 607/ 1703.0 (C═O)
    NEt3 as base 609/
    611 (Br2)
    • EXAMPLE 2
  • Preparation of compounds of general formula:
    Figure US20070208036A1-20070906-C00045
    • 1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-1,3-dihydro-4-phenyl-2(2H)-imidazolone (Item no. 12)
  • A mixture of 1.0 g (2.849 mmol) of 4-amino-3,5-dibromo-γ-oxo-benzenebutanoic acid, 1.04 g (2.91 mmol) of 1,3-dihydro-1-(4-piperidinyl)-4-phenyl-2(2H)-imidazolone, 0.935 g (2.912 mmol) of TBTU, 1.02 ml (5.77 mmol) of DIEA and 50 ml of tetrahydrofuran was stirred for 1 hour at ambient temperature. The reaction mixture was diluted with 300 ml of water and acidified slightly with citric acid. The precipitate formed was suction filtered and washed carefully with water, then with 3 ml of tetrahydrofuran, and finally dried in a circulating air dryer at a temperature of 60° C. 1.3 g (79% of theoretical) of a colourless, crystalline product were obtained, Rf 0.47 (El A).
    IR (KBr): 1679.9 cm−1 (C═O)
    MS: M+ = 574/576/578 (Br2)
  • The following were prepared analogously:
    Item %
    no. N B C Remarks yield El Rf MS IR [cm−1] m.p. [° C.]
    13 N13 B2 C1 THF/DMF 1/1 25 A 0.47 ESI: (M + H)+ = 564/ 1670.3 (C═O) >225
    as solvent 566/
    568 (Br2); (M + Na)+ = 586/
    588/590 (Br2)
    14 N14 B2 C1 DMF as 73 A 0.48 M+ = 576/578/ 1697.3 (C═O)
    solvent; NEt3 580 (Br2)
    as base
    15 N15 B2 C1 DMF as 67 A 0.48 M+ = 588/590/ 1678.0,
    solvent; DIEA 592 (Br2) 1647.1 (C═O)
    as base
    16 N16 B2 C1 DMF as 47 A 0.58 1656.8 (C═O)
    solvent; DIEA
    as base
    17 N16 B2 C2 DMF as 19 A 0.63 M+ = 540/542 (Br) 1670.3 (C═O)
    solvent; DIEA
    as base
    18 N10 B2 C2 DMF as 69 A 0.43 M+ = 526/528 (Br) 1701.1, 243
    solvent; DIEA 1687.6, (MeOH)
    as base 1664.5 (C═O)
    19 N1 B2 C2 DMF as 61 A 0.39 M+ = 512/514 (Br) 1685.7 (C═O) 128
    solvent, DIEA
    as base
    21 N12 B2 C2 DMF as 78 B 0.70 243
    solvent; DIEA (MeOH)
    as base
    25 N10 B2 C4 DMF as 47 B 0.79 M+ = 421 1674, 171-172
    solvent; NEt3 1657 (C═O) (MeOH)
    as base
    26 N10 B2 C5 DMF as 68 A 0.40 M+ = 425/427 (Cl) 1689.5, 237-238
    solvent; NEt3 1662.5, (MeOH)
    as base 1654.8 (C═O)
    27 N10 B2 C6 DMF as 85 A 0.25 M+ = 465 1666.4 (C═O) 258-259
    solvent; NEt3 (decomp.)
    as base
    28 N10 B2 C7 DMF as 54 A 0.33 M+ = 470/472 (Cl) 1689.5, 207-209
    solvent; NEt3 1668.3,
    as base 1631.7 (C═O)
    29 N17 B2 C1 THF as 81 A 0.30 M+ = 622/624/ 1654.8 (C═O) 256-258
    solvent; NEt3 626 (Br2) (acetonitrile)
    as base
    30 N10 B2 C8 THF as 59 B 0.53 1652.9, colourless
    solvent; NEt3 1633.6 (C═O) crystals
    as base
    31 N10 B2 C9 THF as 88 B 0.71 M+ = 447 1703.0, colourless
    solvent; NEt3 1670.3 (C═O) crystals
    as base
    32 N18 B2 C1 THF as 61 A 0.38 M+ = 548/550/ 1656.8 (C═O) colourless
    solvent; NEt3 552 (Br2) crystals
    as base
    33 N19 B2 C1 THF as 85 A 0.48 M+ = 592/594/ 1664.5 (C═O) colourless
    solvent; NEt3 596 (Br2) crystals
    as base
    34 N20 B2 C1 THF as 83 A 0.50 ESI: (M + H)+ = 597/ 1664.5 (C═O) colourless
    solvent; NEt3 599/ crystals
    as base 601 (Br2Cl); (M + Na)+ = 619/
    621/623/
    625 (Br2Cl)
    35 N10 B2 C10 THF as 10 A 0.34 M+ = 440/442 (Cl) 1668.3,
    solvent; NEt3 1647.1 (C═O)
    as base
    36 N21 B2 C1 THF as 85 A 0.45 M+ = 568/570/ 1652.9 (C═O) colourless
    solvent; NEt3 572 (Br2) crystals
    as base
    37 N22 B2 C1 THF/DMF 5/1 37 A 0.25 M+ = 642/644/ 1685.7 (C═O) colourless
    as solvent; 646 (Br2) crystals
    DIEA as base
    38 N23 B2 C1 DMF as 6 A 0.18 M+ = 580/582/ 1683.8 (C═O)
    solvent; DIEA 584 (Br2)
    as base
    39 N24 B2 C1 DMF as 43 A 0.48 M+ = 575/577/ 1685.7 (C═O)
    solvent; DIEA 579 (Br2)
    as base
    40 N25 B2 C1 DMF as 26 A 0.52 1658.7 (C═O)
    solvent; DIEA
    as base
    41 N26 B2 C1 THF as 15 A 0.47 M+ = 642/644/
    solvent; NEt3 646 (Br2)
    as base
    42 N27 B2 C1 DMF as 72 A 0.57 M+ = 563/565/ 1668 (C═O) >250  
    solvent, DIEA 567 (Br2)
    as base
    43 N28 B2 C1 DMF as 53 A 0.48 M+ = 563/565/ 1662 (C═O) >250  
    solvent; DIEA (Br2)
    as base
    44 N29 B2 C1 DMF as 72 A 0.46 M+ = 578/580/ 1651 (C═O) colourless
    solvent; DIEA 582 (Br2) crystals
    as base
    45 N10 B3 C11 THF as 57 A 0.70 M+ = 467/469 (Br) 1664 (C═O) colourless
    solvent; NEt3 crystals
    as base
    46 N10 B3 C12 THF as 77 A 0.68 M+ = 417 1662 (C═O) colourless
    solvent; NEt3 crystals
    as base
    47 N10 B3 C13 THF as 80 A 0.60 M+ = 405 1655 (C═O) colourless
    solvent; NEt3 crystals
    as base
    48 N10 B3 C14 THF as 52 A 0.63 M+ = 439 colourless
    solvent; NEt3 crystals
    as base
    49 N10 B3 C15 THF as 50 A 0.72 M+ = 445 colourless
    solvent; NEt3 crystals
    as base
    50 N10 B3 C16 THF as 53 A 0.65 M+ = 457/459/ 1666 (C═O) colourless
    solvent; NEt3 461 (Cl2) crystals
    as base
    51 N10 B3 C17 THF as 65 A 0.57 M+ = 434 1668 (C═O) colourless
    solvent; NEt3 crystals
    as base
    52 N10 B3 C18 THF as 34 A 0.66 M+ = 403 1660 (C═O) colourless
    solvent; NEt3 crystals
    as base
    53 N10 B3 C19 THF as 59 A 0.73 M+ = 471 1668, 1630 colourless
    solvent; NEt3 (C═O) crystals
    as base
    54 N10 B3 C20 THF as 46 A 0.77 M+ = 517 1657 (C═O) colourless
    solvent; NEt3 crystals
    as base
    55 N10 B3 C21 THF as 59 A 0.70 ESI: (M + Na)+ = 460/ 1664, colourless
    solvent; NEt3 462 (Cl); 1639 (C═O) crystals
    as base (2M + Na)+ = 897/
    899/901 (2Cl)
    56 N10 B3 C22 THF as 8 A 0.72 M+ = 512/514 (Br) 1664 (C═O)
    solvent; NEt3
    as base
    57 N10 B3 C23 THF as 4 A 0.68
    solvent; NEt3
    as base
    59 N30 B2 C1 THF/DMF 3/1 93 A 0.59 ESI: (M + H)+ = 561/ 272-274
    as solvent; 563/ (decomp.)
    NEt3 as base 565 (Br2); (M + Na)+ = 583/
    585/
    587 (Br2)
    60 N10 B5 C1 THF as 46 A 0.53 ESI: (M + H)+ = 549/ 1668.3 (C═O)
    solvent; DIEA 551/
    as base 553 (Br2); (M + Na)+ = 571/
    573/
    575 (Br2)
    61 N31 B2 C1 THF as 94 A 0.88 M+ = 561/563/ 1668.3, 1652.9 246-252
    solvent; NEt3 565 (Br2) (C═O)
    as base
    62 N10 B2 C24 THF/DMF 1/1 58 A 0.46 M+ = 467 1678.0, decomp.
    as solvent; (C═O) from about
    NEt3 as base 200
    63 N32 B2 C1 THF as 42 A 0.20 1670.3, 207
    solvent; DIEA 1645.2 (C═O) (decomp.)
    as base
    64 N12 B5 C1 THF as 31 A 0.24 M+ = 560/562/ 1679.9 (C═O) 162.5-163.5
    solvent; DIEA 564 (Br2) (diisopropyl-
    as base ether)
    65 N10 B2 C25 THF/DMF 1/1 65 A 0.54 M+ = 547/549/ 1666.4 (C═O) 212-214
    as solvent; 551 (Br2) (EtOH/
    DIEA as base active
    charcoal)
    66 N10 B2 C26 THF as 52 A 0.39 M+ = 421 1668.3 (C═O) 174-175
    solvent; DIEA (AcOEt)
    as base
    67 N10 B2 C27 THF as 18 A 0.38 M+ = 409 1668.3 (C═O) 164-166
    solvent; DIEA (diisopropyl-
    as base ether)
    68 N1 B5 C1 THF as 46 A 0.60 M+ = 534/536/ 1703.0 (C═O) 172-173
    solvent; DIEA 538 (Br2) (diisopropyl-
    as base ether)
    69 N33 B2 C1 THF as 65 A 0.76 M+ = 562/564/ 1691.5 (C═O) 225-226
    solvent; DIEA 566 (Br2) (94%
    as base EtOH)
    70 N10 B5 C2 THF as 39 A 0.23 M+ = 512/514 (Br) 1666.4 (C═O) 94-98
    solvent; DIEA (diisopropyl-
    as base ether)
    71 N10 B5 C3 THF as 76 A 0.48 M+ = 470/472 (Br) 1668.3 (C═O) 181-183
    solvent; DIEA (diisopropyl-
    as base ether)
    72 N10 B3 C28 THF as 26 A 0.55 2229.6 (CN); 191-193
    solvent; DIEA 1668.3 (C═O) (EtOH)
    as base
    74 N10 B6 C29 THF as 40 A 0.48 ESI: (M + H)+ = 466; 2221.9 (CN); 148-151
    solvent; DIEA (M + Na)+ = 488 1635.5 (CON)
    as base
    75 N10 B3 C29 by-product of 4 A 0.60 ESI: (M + H)+ = 448; 1666.4 (C═O) colourless
    synthesis of (M + Na)+ = 470 crystals
    Item no. (74)
    76 N10 B2 C29 THF as 49 A 0.44 M+ = 449 2221.9 (CN);
    solvent; DIEA 1664.5 (C═O);
    as base 1637.5 (CON)
    78 N1 B2 C29 THF as 47 A 0.14 M+ = 461 1658.7 (C═O)
    solvent; DIEA
    as base
    79 N34 B2 C1 THF as 87 A 0.87 ESI: (M + H)+ = 613/ 1706.9 (C═O) colourless
    solvent; NEt3 615/ crystals
    as base 617 (Br2); (M + Na)+ = 635/
    637/
    639 (Br2)
    81 N35 B2 C1 by-product of 15 A 0.37 ESI: (M + H)+ = 433/ 1651(amide-
    synthesis of 435/ C═O)
    Item no. (80) 437 (Br2); (M + Na)+ = 455/
    457/
    459 (Br2); (M − H)− = 431/
    433/
    435 (Br2)
    83 N10 B3 C1 THF as 9 A 0.50 ESI: (M + H)+ = 561/ 1662.5 (C═O)
    solvent; DIEA 563/
    as base 565 (Br2); (M + Na)+ = 583/
    585/
    587 (Br2); (2M + Na)+ = 1144/
    1146/
    1148/1150 (Br4);
    (M + NH4)+ = 578/
    580/
    582 (Br2)
    84 N12 B3 C1 THF as 9 A 0.22 M+ = 572/574/ 1683.8 (C═O)
    solvent; DIEA 576 (Br2)
    as base
    85 N36 B3 C1 THF as 17 A 0.72 M+ = 346/348/ 1674.1 (C═O)
    solvent; DIEA 350 (Br2)
    as base
    86 N30 B2 C1 THF as 12 A 0.42 (M + Na)+ = 582/ 1651.0 (C═O) colourless
    solvent; NEt3 584/ crystals
    as base 586 (Br2)
    87 N37 B2 C1 THF as 18 A 0.64 M+ = 561/563/ 1676.0 (C═O) colourless
    solvent; NEt3 565 (Br2) crystals
    as base
    100 N76 B2 C1 THF/DMF 5/1 40 A 0.33 M+ = 534/536/ 1669 (C═O) colourless
    as solvent; 538 (Br2) crystals
    NEt3 as base
    101 N41 B2 C1 THF as 38 A 0.22 M+ = 745/ 1680 (C═O) colourless
    solvent; NEt3 747/749/ crystals
    as base 751/753 (Br4)
    102 N10 B2 C32 THF/DMF 5/1 77 A 0.25 M+ = 439 1666 (C═O) 169-170
    as solvent; (MeOH)
    NEt3 as base
    103 N10 B2 C33 THF/DMF 4/1 42 A 0.50 M+ = 561/563/ 1662 (C═O) colourless
    as solvent; 565 (Br2) crystals
    NEt3 as base
    104 N10 B3 C34 THF/DMF 5/1 38 A 0.48 M+ = 466/468 (Cl) 1666,
    as solvent; 1657 (C═O)
    DIEA as base
    115 N1 B2 C1 THF/DMF 5/1 87 A 0.48 ESI: (M + H)+ = 549/ 3450.4,
    as solvent; 551/ 3325.1 (NH, NH2);
    NEt3 as base 553 (Br2); (M + Na)+ = 571/ 1662.5 (C═O)
    573/
    575 (Br2)
    116 N10 B2 C1 THF/DMF 5/1 77 A 0.52 ESI: (M + H)+ = 563/ 3448.5,
    as solvent; 565/ 3325.1,
    NEt3 as base 567 (Br2); (M + Na)+ = 585/ 3207.4 (NH, NH2);
    587/ 1662.5 (C═O)
    589 (Br2)
    117 N44 B2 C1 THF/DMF 1/1 27 A 0.10 ESI: (M + H)+ = 567/ 1679.9 (C═O)
    as solvent; 569/
    NEt3 as base 571 (Br2); (M + Na)+ = 589/
    591/
    593 (Br2); (M − H)− = 567/
    569/571 (Br2)
    118 N45 B2 C1 THF/DMF 5/1 73 A 0.58 M+ = 620/622/ 1722.3,
    as solvent; 624 (Br2) 1670.3 (C═O)
    NEt3 as base
    120 N47 B2 C1 DMF as 75 A 0.32 ESI: (M + H)+ = 566/ 3471.7,
    solvent; DIEA 568/ 3367.5 (NH, NH2);
    as base 570 (Br2); (M + Na)+ = 588/ 1664.5,
    590/592 (Br2) 1631.7 (C═O)
    125 N52 B2 C1 THF as 36 A 0.87 M+ = 600/602/ 1652.9 (C═O)
    solvent; DIEA 604 (Br2)
    as base
    127 N1 B12 C1 THF as 71 A 0.32 M+ = 563/565/ 1701, 1674,
    solvent; DIEA 567 (Br2) 1624 (C═O)
    as base
    128 N10 B12 C1 THF as 81 A 0.25 M+ = 577/579/ 1653,
    solvent; DIEA 581 (Br2) 1635 (C═O)
    as base
    129 N1 B13 C1 THF as 29 A 0.48 M+ = 549/551/ 1697,
    solvent; DIEA 553 (Br2) 1632 (C═O)
    as base
    130 N10 B13 C1 THF as 27 A 0.48 1655 (C═O)
    solvent; DIEA
    as base
    131 N12 B13 C1 THF as 26 A 0.20 M+ = 575/577/ 1674 (C═O)
    solvent; DIEA 579 (Br2)
    as base
    132 N53 B2 C1 THF as 20 A 0.66 ESI: (M + H)+ = 680/ 1689.5 (C═O)
    solvent; DIEA 682/
    as base 684 (Br2); (M + Na)+ = 702/
    704/706 (Br2)
    133 N10 B2 C41 THF/DMF 5/1 65 A 0.25 M+ = 604/606/ 1697.3,
    as solvent; 608 (Br2) 1639.4 (C═O)
    NEt3 as base
    136 N12 B12 C1 THF as 10 A 0.10 M+ = 589/591/ 1678 (C═O)
    solvent; DIEA 593 (Br2)
    as base
    137 N1 B14 C1 THF as 88 A 0.25 M+ = 563/565/ 1703 (C═O)
    solvent; DIEA 567 (Br2)
    as base
    138 N10 B14 C1 THF as 69 A 0.20 M+ = 577/579/ 1662 (C═O)
    solvent; DIEA 581 (Br2)
    as base
    139 N56 B2 C1 THF as 33 A 0.08 M+ = 568/570/ 3456.2 (NH,
    solvent; DIEA 572 (Br2) NH2); 1671.1,
    as base 1651.0 (C═O)
    143 N1 B2 C42 THF as 86 A 0.44 M+ = 427 1689.5 (C═O)
    solvent; DIEA
    as base
    144 N10 B2 C42 THF as 84 A 0.47 M+ = 441 1668.3 (C═O)
    solvent; DIEA
    as base
    145 N1 B2 C14 THF as 81 A 0.45 M+ = 427 1695.3,
    solvent; DIEA 1641.3 (C═O)
    as base
    146 N10 B2 C14 THF as 52 A 0.52 M+ = 441 1666.4 (C═O)
    solvent; DIEA
    as base
    147 N10 B15 C1 THF as 73 A 0.63 M+ = 576/578/ 3485.2 (NH,
    solvent; DIEA 580 (Br2) NH2);
    as base 1670.3 (C═O)
    149 N58 B2 C1 THF/DMF 5/1 57 A 0.72 M+ = 588/590/ 1670.3 (C═O)
    as solvent; 592 (Br2)
    NEt3 as base
    150 N59 B2 C1 THF/DMF 5/1 53 B 0.20 (M + H)+ = 618/ 1674.1 (C═O)
    as solvent; 620/622 (Br2)
    NEt3 as base
    151 N60 B2 C1 by-product of 12 A 0.11 M+ = 617/619/ 1672.2 (C═O)
    synthesis of 621 (Br2)
    Item no. (150)
    152 N61 B2 C1 THF as 62 A 0.70 M+ = 604/606/ 1705 (C═O)
    solvent; DIEA 606 (Br2)
    as base
    153 N62 B2 C1 THF/DMF 5/1 63 A 0.76 M+ = 590/592/ 1712.7,
    as solvent; 594 (Br2) 1674.1 (C═O)
    NEt3 as base
    154 N63 B2 C1 THF/DMF 5/1 70 A 0.89 M+ = 598/600/ 1672.2 (C═O)
    as solvent; 602 (Br2)
    NEt3 as base
    155 N64 B2 C1 THF as 71 A 0.21 M+ = 592/594/ 1680,
    solvent; NEt3 592 (Br2) 1647 (C═O)
    as base
    157 N65 B2 C1 THF as 90 A 0.30 M+ = 624/626/ 1683.8 (C═O)
    solvent; DIEA 628 (Br2)
    as base
    158 N66 B2 C1 THF/DMF 5/1 64 M+ = 650/652/ 1674.1 (C═O)
    as solvent; 654 (Br2)
    NEt3 as base
    159 N67 B2 C1 THF as 77 A 0.20 ESI: (M + H)+ = 605/ 1682 (C═O)
    solvent; DIEA 607/
    as base 609 (Br2); (M + Na)+ = 627/
    629/631 (Br2)
    160 N68 B2 C1 THF/DMF 5/1 80 A 0.30 1684 (C═O)
    as solvent;
    NEt3 as base
    161 N69 B2 C1 THF as 98 A 0.55 M+ = 596/598/ 1670 (C═O)
    solvent; DIEA 600 (Br2Cl)
    as base
    164 N70 B2 C1 THF/DMF 5/1 20 A 0.35 M+ = 599/601/ 1695,
    as solvent; 603 (Br2) 1678 (C═O)
    NEt3 as base
    165 N10 B2 C45 THF as 71 A 0.64 M+ = 499 1658 (C═O)
    solvent; DIEA
    as base
    168 N10 B3 C24 THF as 37 A 0.68 M+ = 465 1658 (C═O)
    solvent; NEt3
    as base
    169 N10 B3 C46 THF as 61 A 0.65 M+ = 461 3473 (NH, NH2);
    solvent; DIEA 1705,
    as base 1658 (C═O)
    170 N10 B3 C47 THF as 52 A 0.43 M+ = 479 1668 (C═O)
    solvent; DIEA
    as base
    171 N10 B3 C48 THF as 60 A 0.62 M+ = 473 1658 (C═O)
    solvent; DIEA
    as base
    172 N10 B3 C49 THF/DMF 5/1 32 A 0.65 M+ = 417 1660 (C═O)
    as solvent;
    DIEA as base
    173 N10 B3 C50 THF as 33 A 0.58 M+ = 419 1658 (C═O)
    solvent; NEt3
    as base
    174 N10 B3 C51 THF as 38 A 0.59 M+ = 447 1671,
    solvent; NEt3 1658 (C═O)
    as base
    175 N10 B3 C52 THF/DMF 5/1 64 A 0.43 M+ = 437 1664 (C═O)
    as solvent;
    NEt3 as base
    176 N10 B3 C53 THF as 23 A 0.54 M+ = 472 1666 (C═O)
    solvent; DIEA
    as base
    177 N10 B3 C54 THF as 14 A 0.61 M+ = 433 1658 (C═O)
    solvent; NEt3
    as base
    178 N10 B3 C55 THF/DMF 5/1 10 A 0.71 M+ = 457
    as solvent;
    NEt3 as base
    180 N10 B17 C1 THF as 55 A 0.50 M+ = 576/578/ 3471,
    solvent; DIEA 580 (Br2) 3352 (NH, NH2);
    as base 1664 (C═O)
    181 N71 B2 C1 THF/DMF 5/1 60 A 0.94 ESI: (M + H)+ = 662/ 1674,
    as solvent; 664/666 (Br2) 1637 (C═O)
    NEt3 as base
    185 N10 B18 C1 THF/DMF 5/1 48 A 0.66 M+ = 576/578/ 1662 (C═O)
    as solvent; 580 (Br2)
    NEt3 as base
    186 N74 B2 C1 THF as 90 A 0.51 ESI: (M − H)− = 606/ 1660 (C═O)
    solvent; DIEA 608/610 (Br2)
    as base
    187 N75 B2 C1 THF as 95 A 0.60 ESI: (M − H)− = 575/ 1658 (C═O)
    solvent; DIEA 577/
    as base 579 (Br2); (M + Na)+ = 599/
    601/
    603 (Br2); M+ = 576/
    578/580 (Br2)
    188 N91 B2 C1 THF as 19 ESI: (M + Na)+ = 737/ 1681.8,
    solvent; DIEA 739/741 (Br2) 1645.2 (C═O)
    as base
    189 N92 B2 C1 THF as 45 ESI: (M + H)+ = 831/ 3458.2,
    solvent; DIEA 833/835 (Br2) 3381.0,
    as base 3338.6 (NH, NH2);
    1652.9 (C═O)
    • EXAMPLE 3 4-amino-3,5-dibromo-N-{2-[4-(1,3-dihydro-2(2H)-oxo-1-benzimidazolyl)-1-piperidinyl]ethyl}-benzamide (Item no. 58)
  • A mixture of 0.279 g (1.0 mmol) of 4-amino-3,5-dibromobenzoic acid, 0.489 g (1.0 mmol) of 1-[1-(2-aminoethyl)-4-piperidinyl)]-1,3-dihydro-2(2H)-benzimidazolone, 0.321 g (1.0 mmol) of TBTU, 2 ml of triethylamine and 50 ml DMF was stirred overnight at ambient temperature. The reaction mixture was diluted with 300 ml of water. The precipitate formed was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: ethyl acetate/methanol=95/5/(v/v/)). After the appropriate eluates had been worked up, 200 mg (37% of theoretical) of a colourless crystalline product were obtained, m.p. 228-229° C. and Rf 0.12 (El A).
  • IR (KBr): 3468, 3364, 3318 (NH, NH2); 1697 cm−1 (C═O)
  • The following were prepared analogously:
    Item %
    no. N B C remarks yield El Rf MS IR [cm−1] m.p. [° C.]
    80 N77 B2 C1 THF as 23 B 0.23 ESI: (M + H)+ = 646/ 1668.3 (C═O)
    solvent; DIEA 648/
    as base 650 (Br2); (M + Na)+ = 668/
    670/
    672 (Br2)
    82 N77 B7 C1 THF as 25 B 0.37 M+ = 589/ 1670.3 (C═O)
    solvent; DIEA 591/
    as base 593 (Br2)
    88 N88 B7 C1 THF/DMF 5/1 47 A 0.17 M+ = 589/ 1664.5,
    as solvent; 591/ 1645.2 (C═O)
    DIEA as base 593 (Br2)
    89 N88 B7 C31 THF/DMF 5/1 23 A 0.13 ESI: (M − H)− = 589/ 1652.9 (C═O) colourless
    as solvent; 591/ crystals
    DIEA as base 593 (Br2)
    90 N80 B7 C1 by-product of 10 B 0.46 M+ = 603/ 1710.6,
    synthesis of 605/ 1660.4 (C═O)
    Item no. 82 607 (Br2)
    91 N81 B7 C1 THF as 8 B 0.37 ESI: (M + H)+ = 602/ 1678 (C═O)
    solvent; DIEA 604/
    as base 606 (Br2); (M + Na)+ = 624/
    626/
    628 (Br2)
    92 N77 B7 C31 by-product of 5 B 0.28 ESI: (M + H)+ = 591/ 1672 (C═O)
    synthesis of 593/
    Item no. 93 595 (Br2); (M + Na)+ = 613/
    615/
    617 (Br2)
    93 N80 B7 C31 THF/DMF 5/1 2 B 0.37 ESI: (M + H)+ = 605/
    as solvent; 607/
    DIEA as base 609 (Br2); (M − H)− = 603/
    605/
    607 (Br2)
    94 N81 B7 C31 THF as 12 B 0.29 M+ = 602/ 1682 (C═O)
    solvent; DIEA 604/
    as base 606 (Br2); ESI:
    (M + H)+ = 603/
    605/
    607 (Br2); (M − H)− = 601/
    603/
    605 (Br2)
    95 N82 B7 C1 DMF as 15 B 0.44 M+ = 669/ 3483,
    solvent; DIEA 671/ 3386 (NH, NH2);
    as base 673 (Br2) 1689 (C═O)
    96 N83 B7 C1 by-product of 8 A 0.19 M+ = 685/ 1714 (C═O)
    synthesis of 687/
    Item no. 95 689 (Br2)
    97 N84 B7 C1 by-product of 3 A 0.14 ESI: (M + H)+ = 674/ 3481,
    synthesis of 676/ 3375 (NH, NH2);
    Item no. 95 678 (Br2); (M + Na)+ = 696/ 1693 (C═O)
    698/
    700 (Br2)
    98 N82 B7 C31 DMF as 15 B 0.34 ESI: (M + H)+ = 671/ 1684 (C═O)
    solvent; DIEA 673/
    as base 675 (Br2); (M − H)− = 669/
    671/
    673 (Br2)
    99 N79 B7 C1 THF as 44 A 0.28 M+ = 561/ 1639 (C═O) 149-151
    solvent; DIEA 563/ (decomp.)
    as base 565 (Br2) (AcOEt)
    142 N87 B7 C43 THF as 37 A 0.12 M+ = 482/ 1689,
    solvent; DIEA 484 (Cl) 1634 (C═O)
    as base
    156 N89 B7 C44 THF/DMF 1/1 58 A 0.43 ESI: (M + H)+ = 552; 3332.8 (NH,
    as solvent; (M + Na)+ = 574 NH2);
    NEt3 as base 1660.8 (C═O)
    162 N85 B7 C1 THF as 32 A 0.12 M+ = 631/ 3440 (NH, colourless
    solvent; DIEA 633/ NH2); crystals
    as base 635 (Br2) 1707 (C═O)
    163 N86 B7 C1 THF/DMF 3/1 25 B 0.44 M+ = 651/ 3464,
    as solvent; 653/ 3373 (NH, NH2);
    DIEA as base 655 (Br2) 1685 (C═O)
    166 N78 B7 C1 THF as 32 A 0.19 M+ = 575/ 3411,
    solvent; DIEA 577/ 3319 (NH, NH2);
    as base 579 (Br2) 1657 (C═O)
    167 N78 B7 C16 THF as 58 A 0.13 M+ = 472/ 1664 (C═O)
    solvent; DIEA 474/
    as base 476 (Cl2)
    • EXAMPLE 4
  • Preparation of Compounds of General Formula:
    Figure US20070208036A1-20070906-C00046
    • N-{2-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-oxoethyl}-2-naphthalenecarboxamide (Item no. 140)
  • A mixture of 0.5 g (1.243 mmol) of 3-[1-(2-amino-1-oxoethyl)-4-piperidinyl)]-3,4-dihydro-2(1H)-quinazolinone-trifluoroacetate, 0.33 g (1.731 mmol) of 2-naphthoyl chloride, 0.5 ml of triethylamine and 100 ml acetonitrile was stirred night at ambient temperature. The colourless crystals precipitated were suction filtered, thoroughly washed with water and dried in vacuo. Yield: 0.47 g (85% of theoretical). Rf 0.34 (El A).
    IR (KBr): 3386.8 (NH, NH2); 1670.3, 1633.6 (C═O)
    MS: M+ = 442
  • The following was prepared analogously:
    Item no. N B C remarks % yield El Rf MS IR [cm−1]
    141 N89 B7 C14 acetonitrile as solvent; 46 A 0.34 M+ = 442 1654.8 (C═O)
    NEt3 as base
    • EXAMPLE 51 (E)-3,4-dihydro-3-{1-[1,4-dioxo-4-(4-carboxyphenyl)-2-buten-1-yl]-4-piperidinyl}-2(1H)-quinazolinone (Item no. 179)
  • A solution of 0.24 g (10.0 mmol) of lithium hydroxide in 20 ml of water was added to a solution of 1.2 g (2.6 mmol) of (E)-3,4-dihydro-3-{1-[1,4-dioxo-4-(4-ethoxycarbonylphenyl)-2-buten-1-yl]-4-piperidinyl}-2(1H)-quinazolinone (Item no. 169) in 20 ml of THF. After stirring for 4 hours at ambient temperature the mixture was diluted with 200 ml of water and extracted once with 100 ml of tert.butylmethylether. The aqueous phase was acidified with 1N hydrochloric acid and extracted five times with a mixture of dichloromethane and methanol (9/1 v/v). The combined organic extracts were dried over sodium sulphate and concentrated by evaporation in vacuo. The residue remaining was triturated with diethylether and suction filtered. After drying in a circulating air dryer 0.5 g (44% of theoretical) of colourless crystals were obtained. Rf 0.72 (EE/MeOH/AcOH 80/20/5 v/v/v) or 0.43 (El D).
    IR (KBr): 1689 (C═O)
    MS: no M+
  • The following were prepared analogously:
    Item %
    no. N B C remarks yield El Rf MS IR [cm−1]
    114 N43 B1 C1 saponification of 58 D 0.13 ESI: (M + H)+ = 593/ 1693.4 (C═O)
    the methyl ester 595/597 (Br2);
    Item no. 113 with (M + Na)+ = 615/
    LiOH/NaOH 1/20 617/619 (Br2)
    in water/MeOH 1/1
    (v/v)
    119 N46 B2 C1 saponification of 76 A 0.08 M+ = 606/608/ 3417.7,
    the methyl ester 610 (Br2) 3328.9 (NH, NH2); 1664.5,
    Item no. 118 with 1649.0 (C═O)
    NaOH in
    water/MeOH 3/1
    (v/v)
    • EXAMPLE 6
  • Preparation of Compounds of General Formula:
    Figure US20070208036A1-20070906-C00047
    • 3-{1-[4-(4-amino-3-bromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone (Item no. 22)
  • A mixture of 1.5 g (2.84 mmol) of 3-{1-[4-(4-acetylamino-3-bromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone and 150 ml of conc. hydrochloric acid was refluxed for 1 hour. The residue was digested with water, the solid precipitated was suction filtered, recrystallised from acetonitrile and dried in vacuo. Yield: 0.88 g (64% of theoretical). Rf 0.34 (El A).
    IR (KBr): 3471.7, 3342.4 (NH, NH2); 1666.4 (C═O)
    MS: M+ = 484/486 (Br)
  • The following were prepared analogously:
    Item Ex. %
    no. N B C no. Remarks yield El Rf MS IR [cm−1] m.p. [° C.]
    20 N1 B2 C3 6 prepared 62 A 0.34 ESI: (M + H)+ = 471/
    from Item 473 (Br);
    no. (19) (M + Na)+ = 493/
    495 (Br)
    23 N16 B2 C3 6 prepared 81 A 0.35 M+ = 498/   1663 (C═O)
    from Item 500 (Br)
    no. (17)
    24 N12 B2 C3 6 prepared 60 B 0.77 M+ = 496/ 1679.9 (C═O) 267 (MeOH)
    from Item 498 (Br)
    no. (21)
    • EXAMPLE 7 1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-N-[(2-amino-carbonylaminophenyl)methyl]-4-piperidineamine (Item no. 134)
  • 2 ml of trifluoroacetic acid were added to a mixture of 0.20 g (0.2935 mmol) of 1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-N-dimethylethoxycarbonyl-N-[(2-aminocarbonylaminophenyl)methyl]-4-piperidineamine (Item no. 132) in 20 ml of methylene chloride. The reaction mixture was stirred for 2 hours at ambient temperature and then evaporated down in vacuo. The residue remaining was triturated with ether and the beige-coloured amorphous solid obtained (0.15 g; 74% of theoretical) was suction filtered.
    IR (KBr): 1678.0 (C═O) cm−1
    Rf: 0.20 (El B)
    ESI-MS: (M + H)+ = 580/582/584 (Br2)
  • The following were prepared analogously:
    Item %
    no. N B C remarks yield El Rf MS IR [cm−1]
    135 N55 B2 C1 prepared from 55 A 0.32 ESI: (M + H)+ = 615/ 1674.1 (C═O)
    Item no. (188) 617/619 (Br2)
    148 N57 B2 C1 prepared from 66 D 0.76 ESI: (M + H)+ = 731/ 1676.0 (C═O)
    Item no. (189) 733/735 (Br2);
    (M + 2H)++ = 366/
    367/368 (Br2)
    182 N72 B2 C1 prepared from 100 D 0.33 M+ = 561/563/ 3448 (NH, NH2);
    Item no. (181) 565 (Br2) 1674, 1646 (C═O)
    • EXAMPLE 8
  • Preparation of Compounds of General Formula:
    Figure US20070208036A1-20070906-C00048
    • 3-{1-[4-[3-chloro-4-[4-(3-dimethylaminopropyl)-1-piperazinyl]-phenyl]-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone (Item no. 106)
  • A mixture of 921 mg (2.00 mmol) of 3-{1-[4-(3,4-dichloro-phenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone, 377 mg (2.2 mmol) of 1-(3-dimethylaminopropyl)-piperazine, 10 ml of DMSO and 0.276 g (2.00 mmol) of potassium carbonate was stirred for 24 hours at a reaction temperature of 85° C. The mixture was diluted with 200 ml of water, then extracted exhaustively with EE. The combined extracts were dried over sodium sulphate and concentrated by evaporation in vacuo. The residue remaining was purified twice by column chromatography on silica gel (Amicon, 35-70 μm) (dichloromethane/methanol/conc. ammonia 70/30/1 v/v/v as eluant). The appropriate eluates were combined and after working up in the usual way yielded 30.0 mg (2.5% of theoretical) of the desired substance as a colourless, amorphous substance. Rf 0.68 (El D) or 0.35 (eluant: dichloromethane/methanol/conc. ammonia 50/50/1 v/v/v).
    MS: M+ = 594/596 (Cl); ESI: (M + H)+ = 595/597 (Cl)
  • The following were prepared analogously:
    Item
    no. N B C remarks % yield El Rf MS IR [cm−1]
    107 N10 B2 C36 exchange of F in 13 C 0.26 ESI: (M + H)+ = 636/ 1668 (C═O)
    the p position for 638 (Br)
    acyl
    108 N10 B2 C37 exchange of F in 15 D 0.72 ESI: (M + H)+ = 651/ 1668 (C═O)
    the p position for 653 (Br)
    acyl
    109 N10 B2 C38 exchange of F in 27 D 0.65 ESI: (M + H)+ = 639/ 1668 (C═O)
    the p position for 641 (Br)
    acyl
    111 N10 B2 C39 exchange of F in 1.4 C 0.18 M+ = 728/730/
    the p position for 732 (Br2); ESI: (M + H)+ = 729/
    acyl 731/733 (Br2)
    112 N10 B2 C40 exchange of F in 3.0 D 0.78 ESI: (M + H)+ = 800/
    the p position for 802/804 (Br2)
    acyl
    • EXAMPLE 9
  • Preparation of compounds of general formula:
    Figure US20070208036A1-20070906-C00049
    • 3-(1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-oxoquinazolin-7-carboxamide (Item no. 121)
  • Prepared analogously to Example 2 from 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-oxoquinazoline-7-carboxylic acid (Item no. 119), ammonium carbonate and TBTU in the presence of THF/DMF (5/1 v/v) and triethylamine in a quantitative yield.
    IR (KBr): 3415.7 (NH, NH2); 1652.9 (C═O)
    MS: M+ = 605/607/609 (Br2)
  • The following were prepared analogously:
    Item
    no. N B C remarks % yield El Rf MS IR [cm−1]
    122 N49 B2 C1 THF/DMF 5/1 as 88 D 53 M+ = 688/690/ 1633.6 (C═O)
    solvent; NEt3 as 692 (Br2)
    base
    123 N50 B2 C1 THF/DMF 5/1 as 85 A 0.15 M+ = 675/677/ 1672.2,
    solvent; NEt3 as 679 (Br2) 1635.5 (C═O)
    base
    124 N51 B2 C1 THF/DMF 5/1 as 82 B 0.50 M+ = 649/651/ 1662.5 (C═O)
    solvent; NEt3 as 653 (Br2)
    base
    • EXAMPLE 10 5-acetylamino-1-{1-[4-(4-amino-3,5-dibromophenyl)-4-oxobutyl]-4-piperidinyl}-1,3-dihydro-2(2H)-benzimidazolone (Item no. 6) and 3-acetyl-5-acetylamino-1-{1-[4-(4-amino-3,5-dibromophenyl)-4-oxobutyl]-4-piperidinyl}-1,3-dihydro-2(2H)-benzimidazolone (Item no. 7)
  • 73.5 mg (0.72 mmol) of acetic anhydride were added to a solution of 200 mg (0.363 mmol) of 5-amino-1-{1-[4-(4-amino-3,5-dibromophenyl)-4-oxobutyl]-4-piperidinyl}-1,3-dihydro-2(2H)-benzimidazolone in 20 ml of THF at a reaction temperature of 0° C. and then stirred for 2 hours at ambient temperature, followed by 1 hour at an internal temperature of 50° C. The mixture was evaporated down in vacuo, the residue was resolved by column chromatography on silica gel (30-60 μm) using dichloromethane/methanol/cyclohexane/conc. ammonia 400/40/40/2.5 v/v/v/v as eluant. By working up the appropriate fractions, 39 mg (17% of theoretical) of 3-acetyl-5-acetylamino-1-{1-[4-(4-amino-3,5-dibromophenyl)-4-oxobutyl]-4-piperidinyl}-1,3-dihydro-2(2H)-benzimidazolone (Item no. 7), colourless crystals (diisopropylether), Rf 0.26 (El A); IR (KBr): 1732.0, 1675.0 (C═O); MS: M+=633/635/637 (Br2), and 22 mg (10% of theoretical) of 5-acetylamino-1-{1-[4-(4-amino-3,5-dibromophenyl)-4-oxobutyl]-4-piperidinyl}-1,3-dihydro-2(2H)-benzimidazolone (Item no. 6), colourless crystals (diisopropylether), Rf 0.29 (El B); IR (KBr): 1695.3 (C═O—); MS: M+=591/593/595 (Br2), were obtained.
    • EXAMPLE 11 1-{1-[4-(4-amino-3,5-dibromophenyl)-4-oxobutyl]-4-piperidinyl}-5-cyclohexanecarbonylamino-1,3-dihydro-2(2H)-benzimidazolone (Item no. 8)
  • 58.64 mg (0.40 mmol) of cyclohexanecarboxylic acid chloride were added to a solution of 200 mg (0.363 mmol) of 5-amino-1-{1-[4-(4-amino-3,5-dibromophenyl)-4-oxobutyl]-4-piperidinyl}-1,3-dihydro-2(2H)-benzimidazolone and 0.056 ml (0.40 mmol) of triethylamine in 10 ml of THF at a reaction temperature of 0° C. and the suspension formed was then stirred for 2 hours at ambient temperature. The mixture was evaporated down in vacuo, the residue was purified by column chromatography on silica gel (30-60 μm) using dichloromethane/methanol/cyclohexane/conc. ammonia 400/40/40/2.5 v/v/v/v as eluant. By working up the appropriate fractions 106 mg (44% of theoretical) of the desired compound were obtained in the form of colourless crystals (diisopropyl-ether), Rf 0.67 (El B).
  • IR (KBr): 1695.3 (C═O)
  • MS: (M−H2O)+=641/643/645 (Br2)
    • EXAMPLE 12 5-aminocarbonylamino-1-{1-[4-(4-amino-3,5-dibromophenyl)-4-oxobutyl]-4-piperidinyl}-1,3-dihydro-2(2H)-benzimidazolone (Item no. 9)
  • 1.5 ml of 1N hydrochloric acid, followed by 47 mg (0.723 mmol) of sodium cyanate were added to a solution of 200 mg (0.363 mmol) of 5-amino-1-{1-[4-(4-amino-3,5-dibromophenyl)-4-oxobutyl]-4-piperidinyl}-1,3-dihydro-2(2H)-benzimidazolone in 5 ml of THF at a reaction temperature of 0° C. The ice bath was removed and the mixture was stirred overnight at ambient temperature. The orange-coloured solution was carefully combined with 100 ml of conc. aqueous sodium hydrogen carbonate solution and overlaid with 50 ml of tert.butylmethyl ether. The precipitate formed was suction filtered and purified by column chromatography on silica gel (30-60 μm) using dichloromethane/methanol/cyclohexane/conc. ammonia 400/40/40/2.5 v/v/v/v as eluant. By working up the appropriate fractions 106 mg (44% of theoretical) of the desired compound were obtained in the form of colourless crystals (THF/diethylether 1/1 v/v)), Rf 0.12 (El B).
  • IR (KBr): 3435.0, 3354.0 (NH, NH2); 1701.1, 1662.5 (C═O)
  • MS: ESI: (M+H)+=593/595/597 (Br2); (M+Na)+=615/617/619 (Br2)
    • EXAMPLE 13
  • Preparation of Compounds of General Formula:
    Figure US20070208036A1-20070906-C00050
    • 3-{1-[4-(3-chloro-4-dimethylaminophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone (Item no. 105)
  • A solution of 1.05 g (2.248 mmol) of (E)-3-{1-[4-(3-chloro-4-dimethylaminophenyl)-1,4-dioxo-2-buten-1-yl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone (Item no. 104) in 110 ml of an ethanol-THF mixture (10/1 v/v) was hydrogenated at ambient temperature in the presence of 0.5 g of platinum on active charcoal until the uptake of hydrogen had ended. The mixture was freed from catalyst and solvent and purified by chromatography on silica gel using dichloromethane/methanol/conc. ammonia (95/5/0.3 v/v/v) as eluant. 0.36 g (34% of theoretical) of a colourless substance were obtained, Rf 0.31 (El A).
    IR (KBr): 1672, 1660 (C═O)
    MS: M+ = 468/470 (Cl)
  • The following was prepared analogously:
    Item
    no. N B C remarks % yield El Rf MS IR [cm−1]
    73 N10 B2 C28 Raney Ni as catalyst; 45 A 0.30 M+ = 416 2229.6 (CN);
    MeOH as solvent 1664.5 (C═O)
    • EXAMPLE 14 3-{1-[4-(4-aminomethylphenyl)-1-oxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone (Item no. 77)
  • A solution of 0.48 g (1.153 mmol) of 3-{1-[4-(4-cyanophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone (Item no. 73) and 1.15 ml of 1N hydrochloric acid in 100 ml of methanol was hydrogenated at ambient temperature under 3 bar of pressure in the presence of 0.25 g of 10% palladium on active charcoal until the uptake of hydrogen had ended. The mixture was freed from catalyst and solvent and yielded 0.27 g (58% of theoretical) of a colourless substance, Rf 0.30 (El A).
    IR (KBr): 1662.5 (C═O)
    MS: M+ = 406; ESI: (M + H)+ = 407
    • EXAMPLE 15
  • Preparation of Compounds of General Formula:
    Figure US20070208036A1-20070906-C00051
    • N-[2-(4-amino-3,5-dibromophenyl)-2-oxoethyl]-N-methyl-4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-piperidine-1-carboxamide (Item no. 110)
  • A mixture of 693.9 mg (3.0 mmol) of 3-(4-piperidinyl)-3,4-dihydro-2(1H)-quinazolinone, 1.2 ml of DIEA and 50 ml of dichloromethane was added dropwise to a solution of 326.4 mg (1.1 mmol) of triphosgene in 50 ml of dichloromethane within 30 minutes. Then a mixture of 1075.4 mg (3.0 mmol) of 1-(4-amino-3,5-dibromophenyl)-2-methylaminoethanone-hydrochloride, 2.4 ml DIEA and 50 ml dichloromethane was added all at once and stirred for 2 hours at ambient temperature. The mixture washed with 50 ml of dilute aqueous citric acid solution, dried over sodium sulphate, then freed from solvent. The residue remaining was purified by column chromatography on silica gel (Amicon, 35-70 μm) using EE/MeOH/conc. ammonia 95/5/0.5 v/v/v as eluant. The crystalline product was stirred with EtOH, suction filtered and, after washing with diethyl-ether, dried in a circulating air dryer. Yield: 0.1 g (6% of theoretical). M.p. 268-270° C. Rf 0.48 (El A).
    IR (KBr): 3442 (NH, NH2), 1664 (C═O)
    MS: M+ =577/579/581 (Br2);
    ESI: (M−H)− = 576/578/580 (Br2); (M + Na)+ = 600/602/604 (Br2)
  • The following was prepared analogously:
    Item %
    no. N B C remarks yield El Rf MS IR [cm−1]
    126 N10 B11 C1 CDT (instead of 43 A 0.50 ESI: (M − H)− = 562/ 3450.4, 3323.2 (NH,
    triphosgene)/ 564/566 (Br2) NH2); 1662.5 (C═O)
    DIEA/THF
    • EXAMPLE 16
  • Preparation of Compounds of General Formula:
    Figure US20070208036A1-20070906-C00052
    • 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinethione (Item no. 183)
  • A mixture of 0.5 g (0.929 mmol) of 1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-N-[(2-aminophenyl)methyl]-4-piperidineamine, 0.2 g (1.122 mmol) of N,N′-thiocarbonyldi-imidazole and 50 ml of DMF was stirred for 1.5 hours at a temperature of 100° C. After cooling the mixture was stirred into 300 ml of water, the precipitate formed was suction filtered, washed thoroughly with 5 ml of methanol and diethyl ether and dried in vacuo. 480 mg (89% of theoretical) of the desired substance were obtained in the form of colourless crystals, Rf 0.97 (El A).
    IR (KBr): 1669 (C═O)
    MS: M+ = 578/580/582 (Br2)
  • The following was prepared analogously:
    Item %
    no. N B C remarks yield El Rf MS IR [cm−1] m.p. [° C.]
    184 N73 B2 C1 cyanoimino- 91 A 0.91 M+ = 586/ 2187 (CN) colourless
    diphenylcarbonate 588/ crystals
    instead of N,N′- 590 (Br2)
    thiocarbonyl-
    diimidazole/DMF/
    100° C.
  • The Examples which follow illustrate the preparation of some pharmaceutical formulations which contain any desired compound of general formula I as active ingredient:
    • EXAMPLE I
  • Capsules for Powder Inhalation Containing 1 mg of Active Ingredient
    Composition:
    1 capsule for powder inhalation contains:
    active ingredient  1.0 mg
    lactose 20.0 mg
    hard gelatine capsules 50.0 mg
    71.0 mg

    Method of Preparation:
  • The active ingredient is ground to the particle size required for inhaled substances. The ground active ingredient is homogeneously mixed with the lactose. The mixture is transferred into hard gelatine capsules.
    • EXAMPLE II
  • Inhalable solution for Respimat® Containing 1 mg of Active Ingredient
    Composition:
    1 puff contains:
    active ingredient 1.0 mg
    benzalkonium chloride 0.002 mg
    disodium edetate 0.0075 mg
    purified water ad 15.0 μl

    Method of Preparation:
  • The active ingredient and benzalkonium chloride are dissolved in water and transferred into Respimat® cartridges.
    • EXAMPLE III
  • Inhalable Solution for Nebulisers Containing 1 mg of Active Ingredient
    Composition:
    1 vial contains:
    active ingredient 0.1 g
    sodium chloride 0.18 g
    benzalkonium chloride 0.002 g
    purified water ad 20.0 ml

    Method of Preparation:
  • The active ingredient, sodium chloride and benzalkonium chloride are dissolved in water.
    • EXAMPLE IV
  • Propellent Gas-Operated Metering Aerosol Containing 1 mg of Active Ingredient
    Composition:
    1 puff contains:
    active ingredient 1.0 mg
    lecithin 0.1%
    propellent gas ad 50.0 μl

    Method of Preparation:
  • The micronised active ingredient is homogeneously suspended in the mixture of lecithin and propellent gas. The suspension is transferred into a pressurised contained with a metering valve.
    • EXAMPLE V
  • Nasal Spray Containing 1 mg of Active Ingredient
    Composition:
    active ingredient 1.0 mg
    sodium chloride 0.9 mg
    benzalkonium chloride 0.025 mg
    disodium edetate 0.05 mg
    purified water ad 0.1 ml

    Method of Preparation:
  • The active ingredient and the excipients are dissolved in water and transferred into a suitable container.
    • EXAMPLE VI
  • Injectable Solution Containing 5 mg of Active Substance Per 5 ml
    Composition:
    active substance 5 mg
    glucose 250 mg
    human serum albumin 10 mg
    glycofurol 250 mg
    water for injections ad 5 ml

    Preparation:
  • Glycofurol and glucose are dissolved in water for injections (WfI); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with WfI; transferred into ampoules under nitrogen gas.
    • EXAMPLE VII
  • Injectable Solution Containing 100 mg of Active Substance Per 20 ml
    Composition:
    active substance 100 mg
    monopotassium dihydrogen phosphate = KH2PO4 12 mg
    disodium hydrogen phosphate = Na2HPO4•2H2O 2 mg
    sodium chloride 180 mg
    human serum albumin 50 mg
    Polysorbate 80 20 mg
    water for injections ad 20 ml

    Preparation:
  • Polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate are dissolved in water for injections (WfI); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with WfI; transferred into ampoules.
    • EXAMPLE VIII
  • Lyophilisate Containing 10 mg of Active Substance
    Composition:
    Active substance 10 mg
    Mannitol 300 mg 
    human serum albumin 20 mg

    Preparation:
  • Mannitol is dissolved in water for injections (WfI); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with WfI; transferred into vials; freeze-dried.
    Solvent for lyophilisate:
    Polysorbate 80 = Tween 80 20 mg
    mannitol 200 mg
    water for injections ad 10 ml

    Preparation:
  • Polysorbate 80 and mannitol are dissolved in water for injections (WfI); transferred into ampoules.
    • EXAMPLE IX
  • Tablets Containing 20 mg of Active Substance
    Composition:
    active substance 20 mg
    lactose 120 mg 
    maize starch 40 mg
    magnesium stearate  2 mg
    Povidone K 25 18 mg

    Preparation:
  • Active substance, lactose and maize starch are homogeneously mixed; granulated with an aqueous solution of Povidone; mixed with magnesium stearate; compressed in a tablet press; weight of tablet 200 mg.
    • EXAMPLE X
  • Capsules Containing 20 mg Active Substance
    Composition:
    active substance 20 mg
    maize starch 80 mg
    highly dispersed silica  5 mg
    magnesium stearate 2.5 mg 

    Preparation:
  • Active substance, maize starch and silica are homogeneously mixed; mixed with magnesium stearate; the mixture is packed into size 3 hard gelatine capsules in a capsule filling machine.
    • EXAMPLE XI
  • Suppositories Containing 50 mg of Active Substance
    Composition:
    active substance  50 mg
    hard fat (Adeps solidus) q.s. ad 1700 mg

    Preparation:
  • Hard fat is melted at about 38° C.; ground active substance is homogeneously dispersed in the molten hard fat; after cooling to about 35° C. it is poured into chilled moulds.
    • EXAMPLE XII
  • Injectable Solution Containing 10 mg of Active Substance Per 1 ml
    Composition:
    active substance 10 mg
    mannitol 50 mg
    human serum albumin 10 mg
    water for injections ad 1 ml

    Preparation:
  • Mannitol is dissolved in water for injections (WfI); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with WfI; transferred into ampoules under nitrogen gas.

Claims (12)

1. Arylalkanes, arylalkenes and aryl-azaalkanes of general formula

R-Z1-Z2-Z3-R1  (I),
wherein
R denotes the H2N group or the group of formula
Figure US20070208036A1-20070906-C00053
wherein
denotes the number 1 or, if Y does not denote a nitrogen atom, also denotes the number 0,
p denotes the number 1 or, if Y does not denote a nitrogen atom, also denotes the number 0,
Y denotes the carbon atom or, if Y is not linked to a heteroatom, may also denote the nitrogen atom,
R2 denotes a pair of tree electrons, if Y denotes the nitrogen atom, or, if Y denotes the carbon atom, it denotes the hydrogen atom or an alkyl group with 1 to 3 carbon atoms,
R3 and R4 denote hydrogen atoms or together denote an alkylene bridge with 1 to 3 carbon atoms,
R5 and R6 denote hydrogen atoms or together denote a one-to three-membered unbranched alkylene bridge wherein a methylene group may be replaced by a methylimino group,
RN denotes a saturated, mono- or diunsaturated 5- to 7-membered aza, diaza, triaza, oxaza, thiaza, thiadiaza or S,S-dioxido-thiadiaza heterocycle,
wherein the abovementioned heterocycles may be linked via a carbon or nitrogen atom and
may contain, adjacent to a nitrogen atom, a carbonyl, thioxo or iminocarbonyl group or two carbonyl groups or a carbonyl group and a thioxo or iminocarbonyl group, wherein the abovementioned iminocarbonyl groups may be substituted by a cyano group or by an alkoxycarbonyl group with 1 to 4 carbon atoms in the alkyl moiety,
may be substituted at one of the nitrogen atoms by an alkanoyl, hydroxycarbonylalkyl or alkoxycarbonylalkyl group,
may be substituted at one or two carbon atoms by a branched or unbranched alkyl group, by a phenyl, phenylmethyl, naphthyl, biphenylyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl or 1-methylimidazolyl group, wherein the substituents may be identical or different,
wherein additionally an unbranched alkylene group with 3 to 6 carbon atoms may be attached to the abovementioned 5- to 7-membered heterocycles via two adjacent carbon atoms or the group ═CH—S—CH═ may be attached to the abovementioned 5- to 7-membered saturated heterocycles via two adjacent carbon atoms or
an olefinic double bond of one of the abovementioned unsaturated heterocycles may be fused to a benzene, pyridine, diazine, 1,3-oxazole, thiophene, furan, thiazole, pyrrole, N-methyl-pyrrole, quinoline, imidazole or N-methyl-imidazole ring,
or, if Y denotes the carbon atom, RN denotes the hydroxy group, a benzoylaminocarbonylamino group, a phenylamino group optionally substituted at the aniline nitrogen by an aminocarbonyl group or a phenylmethylamino group optionally-substituted at the benzylamine nitrogen by an alkoxycarbonyl group,
wherein the phenyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl or 1-methylimidazolyl groups contained in the groups mentioned under RN as well as benzo-, thieno-, pyrido-, diazino- and quinolino-fused heterocycles in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, by cycloalkyl groups with 3 to 8 carbon atoms, nitro, alkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl, alkylsulphonylamino, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, cycloalkanecarbonylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkylaminocarbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, [4-(1-piperidinyl)piperidinyl]carbonyl, [4-(1-piperidinyl)piperidinyl]carbonylamino, methylenedioxy, aminocarbonylamino, aminocarbonylaminoalkyl, alkylaminocarbonylamino, dialkylaminocarbonylamino, aminomethyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, wherein the substituents may be identical or different and the abovementioned benzoyl, benzoylamino, benzoylaminocarbonylamino and benzoylmethylamino groups may in turn additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom, an alkyl, trifluoromethyl, amino or acetylamino group,
and the alkyl groups contained in the abovementioned groups, unless otherwise stated, may contain 1 to 5 carbon atoms,
or, if Z1-Z2-Z3 denotes the divalent group CO—CH2—CH2—CO, R may also denote the 4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-[1.4]bipiperidinyl-1′-yl group,
Z1 denotes a methylene or carbonyl group or, if Z2 denotes a divalent group of general formula III, may also denote a bond,
Z2 denotes one of the groups —(CH2)2— or —(CH2)3—,
wherein a hydrogen atom may be replaced by a C1-3-alkyl or a hydroxy group,
one of the groups —NH—CH2, —CH2—NH, —NH—(CH2)2— or —(CH2)2—NH—,
wherein a hydrogen atom bound to a carbon atom and/or the hydrogen atom of the imino group may each be replaced by a C1-3-alkyl group and the nitrogen atoms are each linked to a carbonyl group of the groups Z1 or Z3,
the group —CH═CH— or a divalent group of general formula
Figure US20070208036A1-20070906-C00054
wherein
m and n independently of one another denote one of the numbers 1, 2, 3 or 4 and the nitrogen atom is linked to a carbonyl group of the group Z3,
Z3 denotes the methylene or carbonyl group,
wherein at least one of the groups Z1 and Z3 denotes a carbonyl group, and
R1 denotes a phenyl, 1-naphthyl, 2-naphthyl, benzimidazolyl, 1,3-dihydro-2-oxobenzimidazolyl, octahydro-9-phenanthryl or benzodioxolanyl group,
wherein the abovementioned aromatic and heteroaromatic groups in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine, bromine or iodine atoms, by alkyl groups, by cycloalkyl groups with 3 to 8 carbon atoms, phenylalkyl groups, hydroxy, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonyl, carboxy, dialkylaminoalkyl, amino, aminoalkyl, alkylamino, dialkylamino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, 4-(dialkylaminoalkyl)-1-piperazinyl, piperidinyl, 4-(1-piperidinyl)-1-piperidinyl, 4-(4-methyl-1-piperazinyl)-1-piperidinyl, 4-(4-dialkylaminoalkyl-1-piperazinyl)-1-piperidinyl, nitro, methanesulphonyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups and the substituents may be identical or different and the abovementioned benzoyl, benzoylamino and benzoylmethylamino groups may in turn additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino or acetylamino group,
wherein the hydroxy, amino and imidazolyl groups contained in the abovementioned groups may be substituted with protecting groups well known from peptide chemistry, preferably with the acetyl, benzyloxycarbonyl or tert.butyloxycarbonyl group,
all the abovementioned alkyl and alkoxy groups and the alkyl or alkylene moieties present inside the other groups specified may contain 1 to 7 carbon atoms, unless otherwise stated, and
all the abovementioned cycloalkyl groups and the cycloalkyl groups present inside the other groups specified may contain 5 to 10 carbon atoms, unless otherwise stated,
the tautomers, the diastereomers, the enantiomers and the salts thereof.
2. Compounds of the above general formula I according to claim 1, wherein
R denotes the H2N group, if Z1 and Z3 each denote the CO group and R1 is at least disubstituted by the H2N group and an additional substituent or if Z2 does not contain an imino group,
or the group of formula
Figure US20070208036A1-20070906-C00055
wherein
o, p, R5, R6 and Y are as hereinbefore defined,
R2 denotes a pair of free electrons, if Y denotes the nitrogen atom, or, if Y denotes the carbon atom, R2 denotes the hydrogen atom or a methyl group,
R3 and R4 denote hydrogen atoms or together denote an alkylene bridge with 2 to 3 carbon atoms,
RN denotes a monocyclic saturated, mono- or diunsaturated 5- to 7-membered aza, diaza, triaza, oxaza, thiaza, thiadiaza- or S,S-dioxido-thiadiaza heterocycle containing one to two imino groups,
wherein the abovementioned heterocycles are linked via a carbon or nitrogen atom and
adjacent to a nitrogen atom contain a carbonyl, thioxo or iminocarbonyl group or two carbonyl groups or a carbonyl group and a thioxo or iminocarbonyl group, wherein the abovementioned iminocarbonyl groups may be substituted by a cyano group or by an alkoxycarbonyl group with 1 to 4 carbon atoms in the alkyl moiety,
the abovementioned heterocycles containing two imino groups may be substituted at one of the imino-nitrogen atoms by an alkanoyl, hydroxycarbonylalkyl or alkoxycarbonylalkyl group with 1 to 3 carbon atoms in the alkyl moieties,
may be substituted at one or two carbon atoms by an unbranched alkyl group, by a phenyl, phenylmethyl, naphthyl, biphenylyl or thienyl group, wherein the substituents may be identical or different,
and wherein additionally an unbranched alkylene group with 3 to 4 carbon atoms may be attached to the abovementioned 5- to 7-membered heterocycles via two adjacent carbon atoms or the group ═CH—S—CH═ may be attached to the abovementioned 5- to 7-membered saturated heterocycles via two adjacent carbon atoms or an olefinic double bond of one of the abovementioned unsaturated heterocycles may be fused to a benzene, pyridine, diazine, thiophene or quinoline ring,
with the provisos that
(i) RN does not take on the meaning of the 2,6-dioxo-3-phenyl-3,4,5,6-tetrahydro-1H-pyrimidin-3-yl group, the 2-oxo-1,3,4,5-tetrahydro-1-imidazolyl group optionally monosubstituted by an acyl group in the 3 position and the 2(1H)-oxo-3,4,5,6-tetrahydro-1-pyrimidinyl group and
(ii) R1 does not denote a 2-alkoxy-4-amino-5-chlorophenyl, 2-alkoxy-4-amino-5-bromophenyl, 2-alkoxy-4-acetylamino-5-chlorophenyl or 2-alkoxy-4-acetylamino-5-bromophenyl group if RN takes on the meaning of the 1,3-dihydro-2(2H)-oxobenzimidazol-1-yl, 1,3-dihydro-2(2H)-thioxobenzimidazol-1-yl, 2(1H)-oxoquinoxalin-1-yl, 3-oxo-2,3-dihydrobenzoxazin-4-yl, 3-oxo-2,3,4,5-tetrahydrobenz[f][1,4]oxazepin-4-yl or 22(1H)-oxoquinolin-3-yl group,
or, if Y denotes the carbon atom, with the proviso that
(i) R1 does not denote a 2-alkoxy-4-amino-5-bromophenyl, 2-alkoxy-4-amino-5-chlorophenyl or naphthyl group or
(ii) Z2 does not denote a group containing N or
(iii) Z1 and Z3 each denote the CO group,
RN may also represent the hydroxy group
or, if Y denotes the carbon atom and Z1 and Z3 each denote the CO group, a benzoylaminocarbonylamino group, a phenylamino group optionally at least monosubstituted at the aniline nitrogen by an aminocarbonyl group and in the phenyl moiety,
or, if Y denotes the carbon atom, Z1 and Z3 each denote the CO group and in the group of general formula (II) o and p each assume the value 1, a phenylmethylamino group optionally at least monosubstituted at the benzylamine nitrogen by a C1-4-alkoxy-carbonyl group and in the phenyl moiety,
wherein the phenyl and thienyl groups contained in the groups mentioned under RN as well as benzo-, thieno-, pyrido-, diazino- and quinolino-fused heterocycles may additionally be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms, by methyl groups, by cycloalkyl groups with 5 to 6 carbon atoms, nitro, methoxy, methylthio, methylsulphinyl, methylsulphonyl, methanesulphonylamino, phenyl, trifluoromethyl, methoxycarbonyl, carboxy, hydroxy, amino, acetylamino, cyclohexanecarbonylamino, aminocarbonyl, hydroxyethylaminocarbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, [4-(1-piperidinyl)-piperidinyl]carbonyl, [4-(1-piperidinyl)piperidinyl]-carbonylamino, aminocarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, aminomethyl, acetyl, cyano or trifluoromethoxy groups, wherein the substituents may be identical or different,
or, if Z1-Z2-Z3 denotes the divalent group CO—CH2—CH2—CO, R may also denote the 4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-[1.4′]bipiperidinyl-1′-yl group,
Z1 denotes the methylene or carbonyl group or, if Z2 denotes a divalent group of general formula III, may also denote a bond,
Z2 denotes one of the groups —(CH2)2— or —(CH2)3—,
wherein a hydrogen atom may be replaced by a C1-3-alkyl or a hydroxy group,
one of the groups
—NH—CH2, —CH2—NH, —NH—(CH2)2— or —(CH2)2—NH—,
wherein the nitrogen atoms are each linked to a carbonyl group of the groups Z1 or Z3 and the hydrogen atom of the imino group may in each case be replaced by a C1-3-alkyl group,
the group —CH═CH— or, if R1 does not denote an aromatic or heteroaromatic group substituted by cycloalkyl or phenyl groups or RN is not linked via an imino group bound in the adjacent position to a fused-on benzene ring, it also denotes a divalent group of general formula
Figure US20070208036A1-20070906-C00056
wherein
m and n independently of one another denote one of the numbers 1, 2 or 3 and
the nitrogen atom is linked to the group Z3 with the meaning of a carbonyl group,
Z3 denotes the carbonyl group or, if RN is not linked via an imino group bound in the adjacent position to a fused-on aromatic or heteroaromatic ring, it also denotes the methylene group,
wherein at least one of the groups Z1 and Z3 denotes a carbonyl group and the sequence Z1-Z2-Z3 is at least four-membered, and
R1 denotes a mono-, di- or trisubstituted phenyl group, a benzimidazolyl, 1,3-dihydro-2-oxobenzimidazolyl, octahydro-9-phenanthryl or benzodioxolanyl group or, if Z1 and Z3 each denote the CO group, R1 may also denote a 1-naphthyl or 2-naphthyl group,
wherein the abovementioned aromatic and heteroaromatic groups may be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine, bromine or iodine atoms, by alkyl groups with 1 to 4 carbon atoms, by cycloalkyl groups with 5 to 6 carbon atoms, hydroxy, alkoxy, phenyl, trifluoromethyl, methoxycarbonyl, ethoxycarbonyl, carboxy, amino, aminomethyl, methylamino, dimethylamino, acetylamino, 4-[3-(dimethylaminopropyl)]-1-piperazinyl, piperidinyl, 4-(1-piperidinyl)-1-piperidinyl, 4-(4-methyl-1-piperazinyl)-1-piperidinyl, 4-[4-(3-dimethylaminopropyl)-1-piperazinyl]-1-piperidinyl, nitro, methanesulphonyloxy, aminocarbonyl, acetyl, cyano or trifluoromethoxy groups and the substituents may be identical or different,
wherein all the abovementioned alkyl and alkoxy groups and the alkyl or alkylene moieties present inside the other groups specified may contain 1 to 5 carbon atoms unless otherwise stated,
the tautomers, diastereomers, enantiomers and salts thereof.
3. Compounds of the above general formula I according to claim 1, wherein
R denotes the H2N group, if Z1 and Z3 each denote the CO group and R1 is at least disubstituted by the H2N group and an additional substituent or if Z2 does not contain an imino group, or the group of formula
Figure US20070208036A1-20070906-C00057
wherein
o, p and Y are as hereinbefore defined,
R2 denotes a pair of free electrons, if Y denotes the nitrogen atom, or, if Y denotes the carbon atom, R2 denotes the hydrogen atom or a methyl group,
R3 and R4 denote hydrogen atoms or together denote an alkylene bridge with 2 carbon atoms,
R5 and R6 denote hydrogen atoms or together denote an n-propylene bridge wherein the central methylene group may be replaced by a methylimino group,
RN denotes a monocyclic saturated, mono- or diunsaturated 5- to 7-membered aza, diaza, triaza, thiadiaza or S,S-dioxido-thiadiaza heterocycle containing one to two imino groups,
wherein the abovementioned heterocycles are linked via a carbon or nitrogen atom and adjacent to a nitrogen atom contain a carbonyl, thioxo or iminocarbonyl group or two carbonyl groups or a carbonyl group and a thioxo or iminocarbonyl group,
wherein the abovementioned iminocarbonyl groups may be substituted by a cyano group or by a tert.butoxycarbonyl group,
the abovementioned heterocycles containing two imino groups may be substituted at one of the imino-nitrogen atoms by an acetyl, carboxymethyl or methoxycarbonyl-methyl group,
may be substituted at one or two carbon atoms by a methyl group, by a phenyl, phenylmethyl, naphthyl, biphenylyl or thienyl group, wherein the substituents may be identical or different,
and wherein additionally an unbranched alkylene group with 4 carbon atoms may be attached to the abovementioned 5- to 7-membered heterocycles via two adjacent carbon atoms or the group ═CH—S—CH═ may be attached to the abovementioned 5- to 7-membered saturated heterocycles via two adjacent carbon atoms or an olefinic double bond of one of the abovementioned unsaturated heterocycles may be fused to a benzene, pyridine, diazine, thiophene or quinoline ring,
with the provisos that
(i) RN does not take on the meaning of the 2,6-dioxo-3-phenyl-3,4,5,6-tetrahydro-1H-pyrimidin-3-yl group, the 2-oxo-1,3,4,5-tetrahydro-1-imidazolyl group optionally monosubstituted in the 3 position by an acyl group and the 2(1H)-oxo-3,4,5,6-tetrahydro-1-pyrimidinyl group, and
(ii) R1 does not denote a 2-alkoxy-4-amino-5-chlorophenyl, 2-alkoxy-4-amino-5-bromophenyl, 2-alkoxy-4-acetylamino-5-chlorophenyl or 2-alkoxy-4-acetylamino-5-bromophenyl group, if RN takes on the meaning of the 1,3-dihydro-2(2H)-oxobenzimidazol-1-yl, 1,3-dihydro-2(2H)-thioxobenzimidazol-1-yl, 2(1H)oxoquinoxalin-1-yl, 3-oxo-2,3-dihydrobenzoxazin-4-yl, 3-oxo-2,3,4,5-tetrahydrobenz[f][1,4]oxazepin-4-yl or 2(1H)-oxoquinolin-3-yl group,
or, if Y denotes the carbon atom, with the proviso that
(i) R1 does not denote a 2-alkoxy-4-amino-5-bromophenyl, 2-alkoxy-4-amino-5-chlorophenyl or naphthyl group or
(ii) Z2 does not denote a group containing N, or
(iii) Z1 and Z3 each denote the CO group,
RN may also denote the hydroxy group,
or, if Y denotes the carbon atom and Z1 and Z3 each denote the CO group, a benzoylaminocarbonylamino group, a phenylamino group optionally at least monosubstituted by an aminocarbonyl group at the aniline nitrogen and in the phenyl moiety,
or, if Y denotes the carbon atom, Z1 and Z3 each denote the CO group and in the group of general formula (II) o and p each assume the value 1, a phenylmethylamino group optionally at least monosubstituted by a tert. butoxycarbonyl group at the benzylamine nitrogen and in the phenyl moiety,
wherein the phenyl and thienyl groups contained in the groups mentioned under RN as well as benzo-, thieno-, pyrido-, diazino- and quinolino-fused heterocycles may additionally be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms, by methyl, nitro, methoxy, methanesulphonylamino, phenyl, trifluoromethyl, methoxycarbonyl, carboxy, hydroxy, amino, acetylamino, cyclohexanecarbonylamino, aminocarbonyl, hydroxyethylaminocarbonyl, (4-morpholinyl)carbonyl, (4-methyl-1-piperazinyl)-carbonyl, [4-(1-piperidinyl)-1-piperidinyl]carbonyl, [4-(1-piperidinyl)piperidinyl]carbonylamino, aminomethyl or aminocarbonylamino groups, wherein the substituents may be identical or different,
or, if Z1-Z2-Z3 denotes the divalent group CO—CH2—CH2—CO, R may also denote the 4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-[1.4′]bipiperidinyl-1′-yl group,
Z1 denotes methylene or carbonyl group or, if Z2 denotes a divalent group of general formula III, may also denote a bond,
Z2 denotes one of the groups —(CH2)2— or —(CH2)3—,
wherein a hydrogen atom may be replaced by a C1-3-alkyl or hydroxy group,
one of the groups
—NH—CH2, —CH2—NH— or —(CH2)2—NH—,
wherein the nitrogen atoms are each linked to a carbonyl group of the groups Z1 or Z3 and the hydrogen atom of the imino group may be replaced by a C1-3-alkyl group in each case,
the group —CH═CH— or, if R1 does not denote an aromatic or heteroaromatic group substituted by cycloalkyl or phenyl groups or RN is not linked via an imino group bound in the adjacent position to a fused-on benzene ring, it may also denote a divalent group of general formula
Figure US20070208036A1-20070906-C00058
wherein
m denotes one of the numbers 1 or 2 and n denotes one of the numbers 1, 2 or 3 and the nitrogen atom is linked to the group Z3 with the meaning of a carbonyl group,
Z3 denotes the carbonyl group or, if RN is not linked via an imino group bound in the adjacent position to a fused-on aromatic or heteroaromatic ring, it may also denote the methylene group,
wherein at least one of the groups Z1 and Z3 denotes a carbonyl group and the sequence Z1-Z2-Z3 is at least four-membered, and
R1 denotes a monosubstituted phenyl group, a 5-benzimidazolyl, 1,3-dihydro-2-oxobenzimidazol-5-yl, octahydro-9-phenanthryl or 5-benzodioxolanyl group or, if Z1 and Z3 each denote the CO group, it may also denote a 1-naphthyl or 2-naphthyl group,
wherein the abovementioned aromatic and heteroaromatic groups may additionally be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine, bromine or iodine atoms, by alkyl groups with 1 to 4 carbon atoms, by cyclohexyl, hydroxy, alkoxy groups with up to 3 carbon atoms in the alkyl moiety, phenyl, trifluoromethyl, methoxycarbonyl, ethoxycarbonyl, carboxy, amino, aminomethyl, methylamino, dimethylamino, acetylamino, 4-[3-(dimethylaminopropyl)-1-piperazinyl, piperidinyl, 4-(1-piperidinyl)-1-piperidinyl, 4-(4-methyl-1-piperazinyl)-1-piperidinyl, 4-[4-(3-dimethylaminopropyl)-1-piperazinyl)-1-piperidinyl, nitro, cyano or trifluoromethoxy groups and the substituents may be identical or different,
the tautomers, diastereomers, enantiomers and salts thereof.
4. Compounds of the above general formula I according to claim 1, wherein
R denotes the H2N group, if Z1 and Z3 each denote the CO group and R1 is at least disubstituted by the H2N group and an additional substituent or if Z2 does not contain an imino group, or R denotes the group of formula
Figure US20070208036A1-20070906-C00059
wherein
Y denotes the carbon atom and o and p independently of one another denotes the numbers 1 or 0 or
Y denotes the nitrogen atom and o and p each represent the number 1,
R2 denotes a pair of free electrons, if Y denotes the nitrogen atom, or, if Y denotes the carbon atom, R2 denotes the hydrogen atom or the methyl group,
R3 and R4 denote hydrogen atoms or together denote a ethylene bridge,
R5 and R6 denote hydrogen atoms or together denote a —CH2—N(CH3)—CH2— bridge,
RN denotes a 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 3,4-dihydro-2(1H)-oxopyrido[2,3-d]pyrimidin-3-yl, 4-phenyl-1,3,4,5-tetrahydro-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-methyl-4-phenyl-2H-2-oxoimidazol-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl, 2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-2-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxopyrido[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxopyrido[4,3-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-d]pyrimidin-3-yl, 3,4,4a,5,6,7,8,8a-octahydro-2(1H)-oxoquinazolin-3-yl, 2,5-dioxo-4-(phenylmethyl)-imidazolidin-1-yl, 2,5-dioxo-4-phenyl-imidazolidin-1-yl, 3,4-dihydro-2,2-dioxido-2,1,3-benzothiadiazin-3-yl, 1,3-dihydro-4-(2-naphthyl)-2H-2-oxoimidazol-1-yl, 4-(4-biphenylyl)-1,3-dihydro-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 2-(dimethylethoxycarbonylamino)-3,4-dihydroquinazolin-3-yl, 2-amino-3,4-dihydroquinazolin-3-yl, 3,4-dihydro-2(1H)-thioxoquinazolin-3-yl, 3,4-dihydro-2(1H)-cyanoiminoquinazolin-3-yl, 2,3,4,5-tetrahydro-2(1H)-oxo-1,3-benzodiazepin-3-yl or 2,4(1H, 3H)-dioxoquinazolin-3-yl group or,
if R1 does not denote a 2-alkoxy-4-amino-5-chlorophenyl, 2-alkoxy-4-amino-5-bromophenyl, 2-alkoxy-4-acetylamino-5-chlorophenyl or 2-alkoxy-4-acetylamino-5-bromophenyl group, may also denote a 1,3-dihydro-2(2H)-oxobenzimidazol-1-yl or 2(1H)-oxoquinolin-3-yl group,
wherein the abovementioned mono- and bicyclic heterocycles containing two imino groups may be substituted at one of the imino-nitrogen atoms by an acetyl, carboxymethyl or methoxycarbonylmethyl group and/or
may additionally be mono-, di- or trisubstituted in the carbon skeleton and/or at the phenyl groups contained in these groups by fluorine, chlorine or bromine atoms, by methyl groups, nitro, methoxy, methanesulphonylamino, phenyl, trifluoromethyl, methoxycarbonyl, carboxy, hydroxy, amino, acetylamino, cyclohexanecarbonylamino, aminocarbonyl, hydroxyethylaminocarbonyl, (4-morpholinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, [4-(1-piperidinyl)-1-piperidinyl]carbonyl, [4-(1-piperidinyl)piperidinyl]-carbonylamino or aminocarbonylamino groups, wherein the substituents may be identical or different and multiple substitution with the last six substituents is ruled out,
or, if Y denotes the carbon atom, with the proviso that
(i) R1 does not denote a 2-alkoxy-4-amino-5-bromophenyl, 2-alkoxy-4-amino-5-chlorophenyl or naphthyl group or
(ii) Z2 does not denote an N-containing group,
RN may also denote the hydroxy group,
or, if Y denotes the carbon atom and Z1 and Z3 each denote the CO group, a benzoylaminocarbonylamino group, a phenylamino group optionally at least monosubstituted by an aminocarbonyl group at the aniline nitrogen and in the phenyl moiety
or, if Y denotes the carbon atom, Z1 and Z3 each denote the CO group and in the group of general formula (II) o and p each assume the value 1, a phenylmethylamino group optionally at least monosubstituted by a tert. butoxycarbonyl group at the benzylamine nitrogen and in the phenyl moiety,
or, if Z1-Z2-Z3 denotes the divalent group CO—CH2—CH2—CO, R may also denote the 4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-(1.4′]bipiperidinyl-1′-yl group,
Z1 denotes the methylene or carbonyl group or, if Z2 denotes a divalent group of general formula III, may also denote a bond,
Z2 denotes one of the groups —(CH2)2— or —(CH2)3—,
wherein a hydrogen atom may be replaced by a methyl or hydroxy group,
one of the groups
—NH—CH2, —CH2—NH— or —(CH2)2—NH—,
wherein the nitrogen atoms are each linked to a carbonyl group of the groups Z1 or Z3 and the hydrogen atom of the imino group may be replaced in each case by the methyl group,
the group —CH═CH— or, if R1 does not represent an aromatic or heteroaromatic group substituted by cycloalkyl or phenyl groups or RN is not linked via an imino group bound in the adjacent position to a fused-on benzene ring, it also denotes a divalent group of general formula
Figure US20070208036A1-20070906-C00060
wherein
m denotes one of the numbers 1 or 2 and n denotes one of the numbers 1, 2 or 3 and the nitrogen atom is linked to the group Z3 with the meaning of a carbonyl group,
Z3 denotes the carbonyl group or, if RN is not linked via an imino group bound in the adjacent position to a fused-on aromatic or heteroaromatic ring, it also denotes the methylene group,
wherein at least one of the groups Z1 and Z3 denotes the carbonyl group and the sequence Z1-Z2-Z3 is at least four-membered, and
R1 is defined as in claim 3,
the tautomers, diastereomers, enantiomers and salts thereof.
5. Compounds of the above general formula I according to claims 1 to 4, characterised in that they are described in Examples 1 to 16.
6. The following compounds of general formula I:
1-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-1,3-dihydro-4-phenyl-2(2H)-imidazolone,
1-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-1,3-dihydro-4-(3-trifluoromethylphenyl)-2(2H)-imidazolone,
1-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-1,3-dihydro-4-(3-thienyl)-2(2H)-imidazolone,
3-[1′-(4-amino-3,5-dibromobenzoyl)-[1.4′]bipiperidinyl-4-yl]-3,4-dihydro-2(1H)-quinazolinone,
(E)-3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxo-2-buten-1-yl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone,
(E)-1-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxo-2-buten-1-yl]-4-piperidinyl}-1,3-dihydro-4-phenyl-2(2H)-imidazolone,
3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone,
methyl 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-oxoquinazoline-7-carboxylate,
3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-oxoquinazoline-7-carboxamide,
3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-N-(2-hydroxyethyl)-2(1H)-oxoquinazolin-7-carboxamide,
3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-1,3-dihydro-2(2H)-imidazo[4,5-c]quinolinone and 3-{1-[4-(4-amino-3,5-dibromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinethione
and the salts thereof.
7. Physiologically acceptable salts of the compounds according to at least one of claims 1 to 6 with inorganic or organic acids or bases.
8. Pharmaceutical compositions containing a compound according to at least one of claims 1 to 6 or a physiologically acceptable salt according to claim 7 optionally together with one or more inert carriers and/or diluents.
9. Use of a compound according to at least one of claims-1 to 7 for preparing a pharmaceutical composition which has CGRP-antagonistic properties.
10. Use of a compound according to at least one of claims 1 to 7 for preparing a pharmaceutical composition which is suitable for the acute and prophylactic treatment of headaches, for treating non-insulin-dependent diabetes mellitus, cardiovascular diseases, skin diseases, inflammatory diseases, allergic rhinitis, asthma, diseases which are accompanied by excessive vasodilatation and consequent reductions in blood flow through the tissues, morphine tolerance or for controlling menopausal hot flushes.
11. Process for preparing a pharmaceutical composition according to claim 8, characterised in that a compound according to at least one of claims 1 to 7 is incorporated in one or more inert carriers and/or diluents by a non-chemical method.
12. Process for preparing the compounds of general formula I according to claims 1 to 7, characterised in that
a) in order to prepare a compound of general formula I wherein Z1 denotes the methylene group, Z2 denotes one of the groups —(CH2)2, —(CH2)3— or —CH═CH— and Z3 denotes the carbonyl group and
R has the meanings given in claims 1 to 6 with the exception of a 4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-[1.4′]bipiperidinyl-1′-yl group,
a compound of general formula

R′—H  (IVa),
wherein
R′ has the meanings given for R in claims 1 to 6 with the exception of a 4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-[1.4′]bipiperidinyl-1′-yl group,
is reacted with a compound of general formula

X—CH2-Z2-Z3-R1  (V),
wherein
R1 is defined as in claims 1 to 6,
Z2 denotes one of the groups —(CH2)2, —(CH2)3— or —CH═CH—,
Z3 denotes the carbonyl group and
X denotes a leaving group, or
b) in order to prepare a compound of general formula I wherein
Z1 denotes the carbonyl group,
Z2 denotes one of the groups —(CH2)2— or —(CH2)3, wherein a hydrogen atom may be replaced by a C1-3-alkyl or a hydroxy group,
one of the groups —CH2—NH— or —(CH2)2—NH, wherein a hydrogen atom bound to a carbon atom and/or the hydrogen atom of the imino group may each be replaced by a C1-3-alkyl group, or the group —CH═CH— and
Z3 denotes the methylene or carbonyl group,
a carboxylic acid of general formula

HOOC-Z2-Z3-R1  (VI),
wherein
R1 is defined as in claims 1 to 6,
Z2 denotes one of the groups —(CH2)2— or —(CH2)3, wherein a hydrogen atom may be replaced by a C1-3-alkyl or a hydroxy group,
one of the groups —CH2—NH— or —(CH2)2—NH, wherein a hydrogen atom bound to a carbon atom and/or the hydrogen atom of the imino group may each be replaced by a C1-3-alkyl group, or the group —CH═CH—, and
Z3 denotes the methylene or carbonyl group,
is coupled with a compound of general formula

R—H  (IV),
wherein
R has the meanings given in claims 1 to 6, or
c) in order to prepare compounds of general formula I wherein
Z1 denotes the carbonyl group,
Z2 denotes one of the groups —(CH2)2— or —(CH2)3, wherein a hydrogen atom may be replaced by a C1-3-alkyl or hydroxy group, one of the groups —CH2—NH— or —(CH2)2—NH, wherein a hydrogen atom bound to a carbon atom and/or the hydrogen atom of the imino group may each be replaced by a C1-3-alkyl group, or the group —CH═CH— and
Z3 denotes a methylene or carbonyl group,
a compound of general formula

Nu-CO-Z2-Z3-R1  (VII),
wherein
R1 is defined as in claims 1 to 6,
Z2 denotes one of the groups —(CH2)2— or —(CH2)3, wherein a hydrogen atom may be replaced by a C1-3-alkyl or a hydroxy group,
one of the groups —CH2—NH— or —(CH2)2—NH, wherein a hydrogen atom bound to a carbon atom and/or the hydrogen atom of the imino group may each be replaced by a C1-3-alkyl group, or the group —CH═CH—,
Z3 denotes a methylene or carbonyl group and
Nu denotes a leaving group,
is coupled with a compound of general formula

R—H  (IV),
wherein
R is defined as in claims 1 to 6, or
d) in order to prepare a compound of general formula I wherein
Z1 and Z3 each denote the carbonyl group and
Z2 denotes the group —(CH2)2—:
a compound of general formula
R—CO—CH═CH—CO—R1 (I′),
wherein
R and R1 are defined as in claims 1 to 6, is catalytically hydrogenated, or
e) in order to prepare a compound of general formula I wherein
Z1 denotes a methylene or carbonyl group or, if Z2 denotes a divalent group of general formula III, may also denote a bond,
Z2 denotes one of the groups —CH2—NH— or —(CH2)2—NH, wherein a hydrogen atom bound to a carbon atom and/or the hydrogen atom of the imino group may each be replaced by a C1-3-alkyl group, or a divalent group of general formula
Figure US20070208036A1-20070906-C00061
wherein
m and n independently of one another denote one of the numbers 1, 2, 3 or 4 and
Z3 denotes the carbonyl group:
a carboxylic acid of general formula
Figure US20070208036A1-20070906-C00062
wherein
R1 is defined as in claims 1 to 6,
is coupled with a compound of general formula

R-Z1-Z2-H  (IX),
wherein
R is defined as in claims 1 to 6,
Z1 denotes a methylene or carbonyl group or, if Z2 denotes a divalent group of general formula III, may also denote a bond,
Z2 denotes one of the groups —CH2—NH— or —(CH2)2—NH, wherein a hydrogen atom bound to a carbon atom and/or the hydrogen atom of the imino group may each be replaced by a C1-3-alkyl group, or a divalent group of general formula
Figure US20070208036A1-20070906-C00063
wherein
m and n independently of one another denote one of the numbers 1, 2, 3 or 4 and
Z3 denotes the carbonyl group, or
f) in order to prepare a compound of general formula I wherein
Z1 denotes a methylene or carbonyl group or, if Z2 denotes a divalent group of general formula III, Z1 may also denote a bond,
Z2 denotes one of the groups —CH2—NH— or —(CH2)2—NH, wherein a hydrogen atom bound to a carbon atom and/or the hydrogen atom of the imino group may each be replaced by a C1-3-alkyl group, or Z1 denotes a divalent group of general formula
Figure US20070208036A1-20070906-C00064
wherein
m and n independently of one another denote one of the numbers 1, 2, 3 or 4 and
Z3 denotes the carbonyl group,
a compound of general formula
Figure US20070208036A1-20070906-C00065
wherein
R1 is defined as in claims 1 to 6 and
Nu denotes a leaving group,
is coupled with a compound of general formula

R-Z1-Z2-H  (IX),
wherein
R1 is defined as in claims 1 to 6,
Z1 denotes a methylene or carbonyl group or, if Z2 denotes a divalent group of general formula III, may also denote a bond,
Z2 denotes one of the groups —CH2—NH— or —(CH2)2—NH wherein a hydrogen atom bound to a carbon atom and/or the hydrogen atom of the imino group may each be replaced by a C1-3-alkyl group, or a divalent group of general formula
Figure US20070208036A1-20070906-C00066
wherein
m and n independently of one another denote one of the numbers 1, 2, 3 or 4 and
Z3 denotes the carbonyl group, or
g) in order to prepare a compound of general formula I wherein R and R1 are defined as in claims 1 to 6, with the proviso that they must not carry any free amino groups,
Z1 denotes the carbonyl group,
Z2 denotes one of the groups —NH—CH2— or —NH—(CH2)2, wherein a hydrogen atom bound to a carbon atom and/or the hydrogen atom of the imino group may each be replaced by a C1-3-alkyl group and
Z3 denotes the methylene or carbonyl group,
an amine of general formula

R″—H  (XI),
wherein
R″ has the meanings given for R in claims 1 to 6, with the proviso that the group does not contain a free amino group,
is reacted with a carbonic acid derivative of general formula
Figure US20070208036A1-20070906-C00067
wherein
X1 denotes a nucleofugic group and with a compound of general formula

H-Z2-Z3R1′  (XIII),
wherein
the group R1′ has the meanings given for R1 in claims 1 to 6, with the proviso that the group does not contain a free amino group,
Z2 denotes one of the groups —NH—CH2— or —NH—(CH2)2, wherein a hydrogen atom bound to a carbon atom and/or the hydrogen atom of the imino group may each be replaced by a C1-3-alkyl group and
Z3 denotes the methylene or carbonyl group, or
h) in order to prepare a compound of general formula I wherein at least one of the groups R and R1 contains one or more carboxy groups:
a carboxylic acid ester of general formula

Ra-Z1-Z2-Z3-R1a  (Ia),
wherein
Z1, Z2 and Z3 are defined as in claims 1 to 6 and
Ra and R1a have the meanings given for R and R1, respectively, in claims 1 to 6, with the proviso that at least one of these groups contains one or more alkoxycarbonyl groups,
is subjected to alkaline saponification and subsequently, if desired, the basic carboxylic acid is liberated by treatment with a dilute organic or inorganic acid, or
i) in order to prepare a compound of general formula I wherein at least one of the groups R and R1 contains one or more amino groups,
an acylamine of general formula

Rb-Z1-Z2-Z3-R1b  (Ib),
wherein
Z1, z and Z3 are defined as in claims 1 to 6,
Rb and R1b have the meanings given in claims 1 to 6 for R and
R1, respectively, with the proviso that Rb is substituted by an acetylamino, propionylamino, cycloalkanecarbonylamino or benzoylamino group and/or R1b is substituted by an acetylamino, propionylamino or benzoylamino group, is subjected to acid hydrolysis, or
j) in order to prepare a compound of general formula I wherein the group R contains one or two primary or secondary amino groups,
a compound of general formula

Rc-Z1-Z2-Z3-R1  (Ic),
wherein
R, Z1, Z2 and Z3 are defined as in claims 1 to 6 and
Rc has the meanings given for R in claims 1 to 6, with the proviso that this group contains one or two primary or secondary amino groups which are substituted by a tert.alkoxy-carbonyl group, is subjected to acid hydrolysis, or
k) in order to prepare a compound of general formula I wherein
Z1 and Z3 each denote the carbonyl group,
Z2 denotes the group —(CH2)2— and
the group R1 denotes a phenyl group which carries a tertiary amino group in the 4 position relative to the point of attachment but may otherwise be substituted as described in claims 1 to 6,
a compound of general formula

R-Z1-Z2-Z3-R1d  (Id),
wherein
R is defined as in claims 1 to 6,
Z1 and Z3 each denote the carbonyl group,
Z2 denotes the group —(CH2)2— and
the group R1d denotes a phenyl group which carries a nucleophilically exchangeable function in the 4 position relative to the point of attachment, but may otherwise be substituted as described in claims 1 to 6,
is nucleophilically substituted with a corresponding amine or
l) in order to prepare a compound of general formula I wherein the group R is uniformly mono-, di- or trisubstituted in the carbon skeleton by an aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group,
a compound of general formula

Re-Z1-Z2-Z3-R1  (Ie),
wherein
the group Re has the meanings given for R in claims 1 to 6 with the proviso that it is mono-, di- or trisubstituted in the carbon skeleton by the carboxy group, and R1, Z1, Z2 and Z3 are defined as in claims 1 to 6,
is coupled with ammonia or a corresponding alkylamine or dialkylamine, or
m) in order to prepare a compound of general formula I wherein the group R is substituted in the carbon skeleton by an acetylamino group or in the carbon skeleton by an acetylamino group and at the same time is substituted at one of the aza-nitrogen atoms by an acetyl group,
a compound of general formula

Rf-Z1-Z2-Z3-R1  (If),
wherein
R1, Z1, Z2 and Z3 are defined as in claims 1 to 6 and
the group Rf has the meanings given for R in claims 1 to 6, with the proviso that it is substituted in the carbon skeleton by an amino group, is acylated or
n) in order to prepare a compound of general formula I wherein the group R is defined as in claims 1 to 6, with the proviso that it is substituted in the carbon skeleton by an acetylamino, propionylamino, cycloalkanecarbonylamino or benzoylamino group,
a compound of general formula
Figure US20070208036A1-20070906-C00068
wherein
RG denotes a methyl, ethyl, cycloalkyl or phenyl group and
Nu denotes a leaving group
is coupled with a compound of general formula

Rf-Z1-Z2-Z3-R1  (If),
wherein
R1, Z1, Z2 and Z3 are defined as in claims 1 to 6 and the group Rf has the meanings given for R in claims 1 to 6, with the proviso that it is substituted in the carbon skeleton by an amino group, or
o) in order to prepare a compound of general formula I wherein the group R is defined as in claims 1 to 6, with the proviso that it is substituted in the carbon skeleton by an aminocarbonylamino group,
a compound of general formula

R1-Z1-Z2-Z3-R1  (If),
wherein
R1, Z1, Z2 and Z3 are defined as in claims 1 to 6 and the group Rf has the meanings given for R in claims 1 to 6, with the proviso that it is substituted in the carbon skeleton by an amino group,
is reacted with cyanic acid, or
p) in order to prepare a compound of general formula I wherein the group R is defined as in claims 1 to 6, with the proviso that it is substituted by an aminomethyl group in the carbon skeleton, and
Z2 has the meanings given in claims 1 to 6 with the exception of the group —CH═CH—,
a compound of general formula

Rg-Z1-Z2-Z3-R1  (Ig),
wherein
R1, Z1, Z2 and Z3 are defined as in claims 1 to 6 and the group Rg has the meanings given for R in claims 1 to 6, with the proviso that it is substituted in the carbon skeleton by a nitrile group,
is catalytically hydrogenated, or
q) in order to prepare a compound of general formula I wherein R is the 4-[3,4-dihydro-2(1H)-thioxoquinazolin-3-yl]-1-piperidinyl or 4-[3,4-dihydro-2(1H)-cyanoiminoquinazolin-3-yl]-1-piperidinyl group,
a diamine of general formula
Figure US20070208036A1-20070906-C00069
wherein
R1, Z1, Z2 and Z3 are defined as in claims 1 to 6,
is reacted with N,N′-thiocarbonyldiimidazole or cyanoimino-diphenylcarbonate and
subsequently, if desired, a compound of general formula I thus obtained which contains a C═C double bond is resolved into the geometric isomers thereof, and/or
a racemate of general formula I thus obtained is resolved into its isomers and/or
a compound of general formula I thus obtained which contains an acid or basic function is converted into the salts thereof.
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106905175A (en) * 2017-03-16 2017-06-30 厦门市瑞思医药科技有限公司 A kind of preparation method of p-aminophenyl butyric acid
CN107652265A (en) * 2017-09-28 2018-02-02 沈阳药科大学 1 (base of piperidines 4) 2 benzimidazole ketone compounds and its application
US10045979B2 (en) * 2014-05-19 2018-08-14 Merial Inc. Anthelmintic compounds
US20210380573A1 (en) * 2018-12-11 2021-12-09 UCB Biopharma SRL Benzimidazolone Derivatives, and Analogues Thereof, as IL-17 Modulators

Families Citing this family (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1317049B1 (en) 2000-06-23 2003-05-26 Sigma Tau Ind Farmaceuti USEFUL COMPOUNDS FOR THE PREPARATION OF MEDICATIONS FOR PHOSPHODIESTERASE INHIBITING ACTIVITIES IV.
US6667327B2 (en) 2002-02-04 2003-12-23 Hoffmann-La Roche Inc. Pyridine amido derivatives
DE10211770A1 (en) * 2002-03-14 2003-10-02 Boehringer Ingelheim Pharma Novel substituted piperidines, pharmaceutical compositions containing them and processes for their preparation
WO2003103669A1 (en) * 2002-04-18 2003-12-18 Schering Corporation 1-(4-piperidinyl) benzimidazolones as histamine h3 antagonists
US7105505B2 (en) 2002-04-18 2006-09-12 Schering Corporation Benzimidazole derivatives useful as histamine H3 antagonists
US7119111B2 (en) * 2002-05-29 2006-10-10 Amgen, Inc. 2-oxo-1,3,4-trihydroquinazolinyl derivatives and methods of use
US7842808B2 (en) 2002-06-05 2010-11-30 Bristol-Myers Squibb Company Anti-migraine spirocycles
CN100558728C (en) 2002-06-05 2009-11-11 布里斯托尔-迈尔斯斯奎布公司 Calcitonin gene related peptide receptor antagonists
US7220862B2 (en) 2002-06-05 2007-05-22 Bristol-Myers Squibb Company Calcitonin gene related peptide receptor antagonists
US7595312B2 (en) * 2002-10-25 2009-09-29 Boehringer Ingelheim Pharma Gmbh & Co. Kg Selected CGRP antagonists, processes for preparing them and their use as pharmaceutical compositions
DE602004017206D1 (en) 2003-10-23 2008-11-27 Hoffmann La Roche BENZAZEPINE DERIVATIVES AS MAO B HEMMER
JP2007524568A (en) 2003-12-05 2007-08-30 ブリストル−マイヤーズ　スクイブ　カンパニー Calcitonin gene-related peptide receptor antagonist
US7569578B2 (en) 2003-12-05 2009-08-04 Bristol-Meyers Squibb Company Heterocyclic anti-migraine agents
TW200533398A (en) 2004-03-29 2005-10-16 Bristol Myers Squibb Co Novel therapeutic agents for the treatment of migraine
DE102004015723A1 (en) 2004-03-29 2005-10-20 Boehringer Ingelheim Pharma Selected CGRP antagonists, process for their preparation and their use as pharmaceuticals
DE102004018795A1 (en) * 2004-04-15 2005-10-27 Boehringer Ingelheim Pharma Gmbh & Co. Kg Selected CGRP antagonists, process for their preparation and their use as pharmaceuticals
US7384930B2 (en) 2004-11-03 2008-06-10 Bristol-Myers Squibb Company Constrained compounds as CGRP-receptor antagonists
US7384931B2 (en) 2004-11-03 2008-06-10 Bristol-Myers Squibb Company Constrained compounds as CGRP-receptor antagonists
US7449586B2 (en) 2004-12-03 2008-11-11 Bristol-Myers Squibb Company Processes for the preparation of CGRP-receptor antagonists and intermediates thereof
US7439237B2 (en) 2005-04-15 2008-10-21 Boehringer Ingelheim International Gmbh Selected CGRP-antagonists, process for preparing them and their use as pharmaceutical compositions
GB0514017D0 (en) * 2005-07-07 2005-08-17 Ionix Pharmaceuticals Ltd Chemical compounds
WO2007015877A2 (en) * 2005-07-20 2007-02-08 Kalypsys, Inc. Inhibitors of p38 kinase and methods of treating inflammatory disorders
EP1909797A4 (en) 2005-08-02 2013-02-27 Neurogen Corp Dipiperazinyl ketones and related analogues
US7834007B2 (en) 2005-08-25 2010-11-16 Bristol-Myers Squibb Company CGRP antagonists
DE102005050892A1 (en) * 2005-10-21 2007-04-26 Boehringer Ingelheim Pharma Gmbh & Co. Kg Selected CGRP antagonists, process for their preparation and their use as pharmaceuticals
EP1779851A1 (en) * 2005-10-31 2007-05-02 Boehringer Ingelheim Pharma GmbH & Co.KG Treatment of diabetes
GB0526042D0 (en) * 2005-12-21 2006-02-01 Syngenta Participations Ag Chemical compounds
WO2009034029A2 (en) * 2007-09-07 2009-03-19 Boehringer Ingelheim International Gmbh 1-substituted 4-heterocyclylpiperidines for use as cgrp antagonists
UA105182C2 (en) 2008-07-03 2014-04-25 Ньюрексон, Інк. Benzoxazines, benzothiazines, and related compounds having nos inhibitory activity
JP6484553B2 (en) * 2012-07-03 2019-03-13 ヘプタレス セラピューティクス リミテッドＨｅｐｔａｒｅｓ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｌｉｍｉｔｅｄ Orexin receptor antagonist
WO2014122474A1 (en) 2013-02-07 2014-08-14 Takeda Pharmaceutical Company Limited Piperidin-1 -yl and azepin-1 -yl carboxylates as muscarinic m4 receptor agonists
GB201519194D0 (en) * 2015-10-30 2015-12-16 Heptares Therapeutics Ltd CGRP receptor antagonists
JP7624690B2 (en) 2016-03-01 2025-01-31 プロペロン セラピューティクス インコーポレイテッド Inhibitors of WDR5 protein-protein binding
CA3015417A1 (en) 2016-03-01 2017-09-08 Propellon Therapeutics Inc. Inhibitors of wdr5 protein-protein binding
MX2020008195A (en) 2018-02-05 2020-11-24 Alkermes Inc Compounds for the treatment of pain.

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4018823A (en) * 1976-04-20 1977-04-19 Morton-Norwich Products, Inc. 4',5'-Dimethoxy-2',3-diaminopropiophenone dihydrochloride
US4073790A (en) * 1974-02-18 1978-02-14 John Wyeth & Brother Limited Piperidino ureas and thioureas
US4199590A (en) * 1977-09-08 1980-04-22 John Wyeth & Brother Limited Piperidino ureas and thioureas
US5190741A (en) * 1989-02-14 1993-03-02 Institut National De La Sante Et De La Recherche Medicale (Inserm) Agents for diagnosing and treating melanomas, aromatic halogenated derivatives usable as such agents and their preparation
US5432172A (en) * 1992-08-03 1995-07-11 The Research Foundation Of State University Of New York Biological applications of alkaloids derived from the tunicate Eudistoma sp.
US5508306A (en) * 1992-11-13 1996-04-16 Synaptic Pharmaceutical Corporation Aromatic amine derivatives
US5747485A (en) * 1995-04-13 1998-05-05 Merck & Co., Inc. Substituted azetidiones as anti-inflammatory and antidegenerative agents

Family Cites Families (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3161645A (en) * 1962-12-18 1964-12-15 Res Lab Dr C Janssen N V 1-(1-aroylpropyl-4-piperidyl)-2-benzimidazolinones and related compounds
JPS4934984B1 (en) * 1969-07-12 1974-09-19
GB1393979A (en) * 1972-12-21 1975-05-14 Wyeth John & Brother Ltd Piperidine derivatives
JPS5755714B2 (en) * 1972-03-18 1982-11-25
US4087531A (en) * 1974-05-16 1978-05-02 Boehringer Ingelheim Gmbh N-(3-(p-Fluoro-benzoyl)-n-propyl)-4-(imidazolidin-2-one-1-yl)-piperidines and salts thereof
DE2423897C3 (en) * 1974-05-16 1979-09-06 C.H. Boehringer Sohn, 6507 Ingelheim N- (p-FluorobenzoyIpropyl) -4piperidylamides, process for their preparation and pharmaceutical preparations
DE2423896A1 (en) * 1974-05-16 1975-11-27 Boehringer Sohn Ingelheim NEW SINGLE SQUARE BRACKETS ON N- (P-FLUOROBENZOYLPROPYL) -4-PIPERIDYL SQUARE BRACKETS FOR -UURA AND METHOD FOR MANUFACTURING IT
US4048058A (en) * 1975-08-13 1977-09-13 Standard Oil Company (Indiana) Methods to be used in reforming processes employing multi-metallic catalysts
JPS5823398B2 (en) * 1975-06-19 1983-05-14 第一製薬株式会社 Piperidylbenzimidazole
FR2322599A1 (en) * 1975-09-05 1977-04-01 Roussel Uclaf NEW BENZAMIDES AND THEIR SALTS, PROCESS FOR PREPARATION AND APPLICATION AS MEDICINAL PRODUCTS OF THESE NEW PRODUCTS
JPS5287176A (en) * 1976-01-13 1977-07-20 Dai Ichi Seiyaku Co Ltd Preparation of benzimidazolylpiperidine derivatives
JPS5297927A (en) * 1976-02-12 1977-08-17 Sumitomo Chem Co Ltd Novel butyrophenone derivatives
JPS5318581A (en) * 1976-08-04 1978-02-20 Sumitomo Chem Co Ltd Novel o-nitrobutyrophenone derivatives
GB1530931A (en) * 1977-05-10 1978-11-01 Wyeth John & Brother Ltd N-(1-(4-phenyl-4-oxobutyl)-4-piperidyl)-2-thiophene carboxamide
FR2424253A1 (en) * 1978-04-27 1979-11-23 Brun Lab Sa Le NEW DERIVATIVES OF PEPTIDES ANALOGUES OF ENKEPHALINS, THEIR METHOD OF PREPARATION AND THEIR THERAPEUTIC APPLICATION
JPS5585562A (en) * 1979-11-08 1980-06-27 Sumitomo Chem Co Ltd O-halogen substituted butyrophenone derivative and preparation of its salt
JPS56142280A (en) * 1980-04-08 1981-11-06 Yoshitomi Pharmaceut Ind Ltd Piperidine compound
JPH0832681B2 (en) * 1985-08-22 1996-03-29 住友化学工業株式会社 2-Yododobutyrophenone derivative and process for producing the same
JP2720897B2 (en) * 1987-08-27 1998-03-04 第一製薬株式会社 Persistent antipsychotics
JPH03232817A (en) * 1990-02-07 1991-10-16 Showa Yakuhin Kako Kk Application agent
JP2871811B2 (en) * 1990-02-28 1999-03-17 サントリー株式会社 7-membered condensed ring compound
US5665756A (en) * 1994-08-03 1997-09-09 Hoechst Marion Roussel, Inc. Aminoalkyloximes useful in the treatment of depression and obsessive compulsive disorders
EP0786997A4 (en) * 1994-10-27 1998-03-11 Merck & Co Inc Muscarine antagonists
US20020019416A1 (en) * 1995-07-24 2002-02-14 Naoki Fukami Esters and amides as pla2 inhibitors
DK0927192T3 (en) 1996-09-10 2004-09-13 Boehringer Ingelheim Pharma Modified amino acids, drugs containing these compounds and methods for their preparation
TWI242011B (en) * 1997-03-31 2005-10-21 Eisai Co Ltd 1,4-substituted cyclic amine derivatives
JPH1171350A (en) * 1997-06-17 1999-03-16 Takeda Chem Ind Ltd Hydroxypiperidine compound and agent thereof
KR100340273B1 (en) 1997-10-14 2002-06-14 야마모토 카즈모토 Biphenyl-5-Alkanoic Acid Derivatives and Use thereof

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4073790A (en) * 1974-02-18 1978-02-14 John Wyeth & Brother Limited Piperidino ureas and thioureas
US4018823A (en) * 1976-04-20 1977-04-19 Morton-Norwich Products, Inc. 4',5'-Dimethoxy-2',3-diaminopropiophenone dihydrochloride
US4199590A (en) * 1977-09-08 1980-04-22 John Wyeth & Brother Limited Piperidino ureas and thioureas
US5190741A (en) * 1989-02-14 1993-03-02 Institut National De La Sante Et De La Recherche Medicale (Inserm) Agents for diagnosing and treating melanomas, aromatic halogenated derivatives usable as such agents and their preparation
US5432172A (en) * 1992-08-03 1995-07-11 The Research Foundation Of State University Of New York Biological applications of alkaloids derived from the tunicate Eudistoma sp.
US5508306A (en) * 1992-11-13 1996-04-16 Synaptic Pharmaceutical Corporation Aromatic amine derivatives
US5747485A (en) * 1995-04-13 1998-05-05 Merck & Co., Inc. Substituted azetidiones as anti-inflammatory and antidegenerative agents

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10045979B2 (en) * 2014-05-19 2018-08-14 Merial Inc. Anthelmintic compounds
CN106905175A (en) * 2017-03-16 2017-06-30 厦门市瑞思医药科技有限公司 A kind of preparation method of p-aminophenyl butyric acid
CN107652265A (en) * 2017-09-28 2018-02-02 沈阳药科大学 1 (base of piperidines 4) 2 benzimidazole ketone compounds and its application
US20210380573A1 (en) * 2018-12-11 2021-12-09 UCB Biopharma SRL Benzimidazolone Derivatives, and Analogues Thereof, as IL-17 Modulators

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