WO2009103478A1 - Dérivés de pyridone et de pyridazinone comme antagonistes de la mch - Google Patents

Dérivés de pyridone et de pyridazinone comme antagonistes de la mch Download PDF

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WO2009103478A1
WO2009103478A1 PCT/EP2009/001081 EP2009001081W WO2009103478A1 WO 2009103478 A1 WO2009103478 A1 WO 2009103478A1 EP 2009001081 W EP2009001081 W EP 2009001081W WO 2009103478 A1 WO2009103478 A1 WO 2009103478A1
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Prior art keywords
pyridin
ethyl
tetrahydro
isoquinolin
ylmethoxy
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PCT/EP2009/001081
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English (en)
Inventor
Dirk Stenkamp
Ralph-Michael Budzinski
Armin Heckel
Joerg Kley
Thorsten Lehmann-Lintz
Stephan Georg Mueller
Thorsten Oost
Gerald Juergen Roth
Klaus Rudolf
Marcus Schindler
Ralf Lotz
Leo Thomas
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Boehringer Ingelheim International Gmbh
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Publication of WO2009103478A1 publication Critical patent/WO2009103478A1/fr

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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
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/69—Two or more oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three 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
    • C07D237/14—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three 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
    • C07D237/14—Oxygen atoms
    • C07D237/16—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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 pyridone and pyridazinone derivatives, the physiologically acceptable salts thereof as well as their use as MCH antagonists and their use in preparing a pharmaceutical preparation which is suitable for the prevention and/or treatment of symptoms and/or diseases caused by MCH or causally connected with MCH in some other way.
  • the invention also relates to the use of a compound according to the invention for influencing eating behaviour and for reducing body weight and/or for preventing any increase in body weight in a mammal. It further relates to compositions and medicaments containing a compound according to the invention and processes for preparing them.
  • BMI Body Mass Index
  • MCH antagonists cf. inter alia WO 01/21577, WO 01/82925.
  • MCH Melanin-concentrating hormone
  • WO 2005/018557 (Pharmacia Corp.) substituted pyridinones are described.
  • the WO 2004/087677 (Pharmacia Corp.) is related to pyrimidone derivatives and the WO 03/059891 as well as the WO 2005/007632 (Pharmacia Corp.) refer to pyridazinone derivatives. These compounds are described as modulators of p38 MAP kinase.
  • the aim of the present invention is to identify compounds which are especially effective as MCH antagonists. Another aim of this invention is to provide compounds which are effective as MCH antagonists and which possess advantageous pharmacokinetic properties.
  • the invention also sets out to provide compounds which can be used to influence the eating habits of mammals and achieve a reduction in body weight, particularly in mammals, and/or prevent an increase in body weight.
  • the present invention further sets out to provide new pharmaceutical compositions which are suitable for the prevention and/or treatment of symptoms and/or diseases caused by MCH or otherwise causally connected to MCH.
  • the aim of this invention is to provide pharmaceutical compositions for the treatment of metabolic disorders such as obesity and/or diabetes as well as diseases and/or disorders which are associated with obesity and diabetes.
  • Other objectives of the present invention are concerned with demonstrating advantageous uses of the compounds according to the invention.
  • the invention also sets out to provide a process for preparing the compounds according to the invention. Other aims of the present invention will be immediately apparent to the skilled man from the foregoing remarks and those that follow.
  • the present invention relates to one or more compounds selected from the group consisting of the following pyridone and pyridazinone derivatives
  • one or more C atoms may additionally be mono- or polysubstituted by F, and in each case one or two C atoms independently of one another may additionally have a substituent selected from the group Cl, Br 1 cyano, d-4-alkyl, C- M -alkoxy, difluoromethyl, trifluoromethyl, hydroxy, acetylamino, aminocarbonyl, difluoromethoxy, and trifluoromethoxy, and
  • an H atom bound to an N atom may in each case be replaced by a group which can be cleaved in vivo,
  • the invention also relates to the compounds in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of the tautomers and in the form of the free bases or corresponding acid addition salts with pharmacologically acceptable acids.
  • the subject of the invention also includes the compounds according to the invention, including their salts, wherein one or more hydrogen atoms are replaced by deuterium.
  • This invention also includes the physiologically acceptable salts of the compounds according to the invention as described above and hereinafter.
  • compositions containing at least one compound according to the invention and/ or a salt according to the invention optionally together with one or more physiologically acceptable excipients.
  • compositions containing at least one compound according to the invention and/ or a salt according to the invention optionally together with one or more inert carriers and/or diluents.
  • This invention also relates to the use of at least one compound according to the invention and/or a salt according to the invention, for influencing the eating behaviour of a mammal.
  • the invention further relates to the use of at least one compound according to the invention and/or a salt according to the invention, for reducing the body weight and/ or for preventing an increase in the body weight of a mammal.
  • the invention also relates to the use of at least one compound according to the invention and/or a salt according to the invention, for preparing a pharmaceutical composition with an MCH receptor-antagonistic activity, particularly with an MCH-1 receptor-antagonistic activity.
  • This invention also relates to the use of at least one compound according to the invention and/or a salt according to the invention, for preparing a pharmaceutical composition which is suitable for the prevention and/or treatment of symptoms and/or diseases which are caused by MCH or are otherwise causally connected with MCH.
  • a further object of this invention is the use of at least one compound according to the invention and/or a salt according to the invention, for preparing a pharmaceutical composition which is suitable for the prevention and/or treatment of metabolic disorders and/or eating disorders, particularly obesity, bulimia, bulimia nervosa, cachexia, anorexia, anorexia nervosa and hyperphagia.
  • the invention also relates to the use of at least one compound according to the invention and/or a salt according to the invention, for preparing a pharmaceutical composition which is suitable for the prevention and/or treatment of diseases and/or disorders associated with obesity, particularly diabetes, especially type Il diabetes, complications of diabetes including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, pathological glucose tolerance, encephalorrhagia, cardiac insufficiency, cardiovascular diseases, particularly arteriosclerosis and high blood pressure, arthritis and gonitis.
  • diseases and/or disorders associated with obesity particularly diabetes, especially type Il diabetes, complications of diabetes including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, pathological glucose tolerance, encephalorrhagia, cardiac insufficiency, cardiovascular diseases, particularly arteriosclerosis and high blood pressure, arthritis and gonitis.
  • the present invention relates to the use of at least one compound according to the invention and/or a salt according to the invention, for preparing a pharmaceutical composition which is suitable for the prevention and/or treatment of hyperlipidaemia, cellulitis, fat accumulation, malignant mastocytosis, systemic mastocytosis, emotional disorders, affective disorders, depression, anxiety, sleep disorders, reproductive disorders, sexual disorders, memory disorders, epilepsy, forms of dementia and hormonal disorders.
  • the invention also relates to the use of at least one compound according to the invention and/or a salt according to the invention, for preparing a pharmaceutical composition which is suitable for the prevention and/or treatment of urinary problems, such as for example urinary incontinence, overactive bladder, urgency, nycturia and enuresis.
  • urinary problems such as for example urinary incontinence, overactive bladder, urgency, nycturia and enuresis.
  • the invention further relates to the use of at least one compound according to the invention and/ or a salt according to the invention, for preparing a pharmaceutical composition which is suitable for the prevention and/or treatment of dependencies and/or withdrawal symptoms.
  • the invention also relates to a pharmaceutical composition containing a first active substance which is selected from the compounds according to the invention and/or the corresponding salts, as well as a second active substance which is selected from the group consisting of active substances for the treatment of diabetes, active substances for the treatment of diabetic complications, active substances for the treatment of obesity, preferably other than MCH antagonists, active substances for the treatment of high blood pressure, active substances for the treatment of dyslipidaemia or hyperlipidaemia, including arteriosclerosis, active substances for the treatment of arthritis, active substances for the treatment of anxiety states and active substances for the treatment of depression, optionally together with one or more inert carriers and/or diluents.
  • a pharmaceutical composition containing a first active substance which is selected from the compounds according to the invention and/or the corresponding salts, as well as a second active substance which is selected from the group consisting of active substances for the treatment of diabetes, active substances for the treatment of diabetic complications, active substances for the treatment of obesity, preferably other than MCH antagonists, active substances for the
  • the starting materials and intermediate products used in the synthesis of one or more of the compounds according to the invention are also a subject of this invention.
  • the invention relates to one or more of the compounds comprising an 2-oxoethyl-spacer linked to the pyridinone or pyridazinone group wherein said compounds are selected from the group consisting of 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11 , 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.20, 1.21, 1.22, 2.1 , 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 3.1 , 3.2, 3.3, 4.1 , 4.2, 5.1 , 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 6.1 , 6.2, 6.3, 7.1 , 7.2, 7.3, 7.4, 7.5, 8.1 , 8.2, 8.3, 8.4, 8.5, 8.6, 9.1 , 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 10.1 , 10.2,
  • a preferred subset relates to one or more of the compounds comprising an amino-group which is not part of an azabicyclic moiety wherein said compounds are selected from the group consisting of 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11 , 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.20, 1.21 , 1.22, 2.1 , 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 3.1 , 3.2, 3.3, 4.1 , 4.2, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 6.1, 6.2, 6.3, 7.1, 7.2, 7.3, 7.4, 7.5, 8.1 , 8.2, 8.3, 8.4, 8.5, 8.6, 9.1 , 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 10.1 , 10.2, 11.1 ,
  • another preferred subset relates to one or more of the compounds comprising an azabicyclic moiety wherein the compounds are selected from the group consisting of 13.1 , 13.2, 14.1 , 14.2, 15.1 , 15.2, 16.1 , 16.2, 16.3, 16.4, 16.5, 17.1, 17.2, 17.3, 24.1, 24.2, 25.1 , 25.2, 26.1, 26.2, 27.1, 27.2, 31.1, 31.2, 32.1, 32.2, 34, 40.1 , 40.2, 40.3, 41.1 , 41.2, 42.1 , 42.2, 43.1 , 44.1 , 44.2, 45.1 , and 45.2, including the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof.
  • the invention relates to one or more of the compounds comprising an azabicyclic moiety which is linked to the pyridinone or pyridazinone group via an an optionally substituted ethylene spacer wherein said compounds are selected from the group consisting of 18.1 , 18.2, 19.1 , 19.2, 20.1 , 20.2, 21.1 , 21.2, 21.3, 21.4, 21.5, 22.1, 22.2, 28.1, 28.2, 29.1, 29.2, 33.1 , 33.2, 35.1, 35.2, 35.3, 35.4, 35.5, 35.6, 35.7, 36.1 , 36.2, 36.3, 36.4, 36.5, 37.1 , 37.2, 37.3, 38.1 , 38.2, 38.3, 38.4, 38.5, 39.1 , 39.2, 46.1 , 46.2, 47.1 , 47.2, 48, 49.1 , 49.2, 49.3, 49.4, 50.1 , 50.2, 51.1 , 51.2, 57, 58, 59
  • a preferred subset relates to one or more of the compounds comprising an azabicyclic moiety which is linked to the pyridinone or pyridazinone group via a not further substituted ethylene spacer wherein said compounds are selected from the group consisting of 18.1 , 18.2, 19.1 , 19.2, 20.1 , 20.2, 21.1 , 21.2, 21.3, 21.4, 21.5, 22.1, 22.2, 28.1 , 28.2, 29.1 , 29.2, 33.1 , 33.2, 35.1 , 35.2, 35.3, 35.4, 35.5, 35.6, 35.7,
  • another preferred subset relates to one or more of the compounds comprising an azabicyclic moiety which is linked to the pyridinone or pyridazinone group via an 1 ,1-difluoroethylene spacer wherein said compounds are selected from the group consisting of 57, 58, 59, 60, 61 , including the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof.
  • the compounds according to the invention as described hereinbefore and hereinafter may optionally be substituted.
  • one or more C atoms are additionally mono- or polysubstituted by F, and/or one or two C atoms independently of one another additionally have a substituent selected from the group Cl, Br, cyano, d-4-alkyl, CWalkoxy, difluoromethyl, trifluoromethyl, hydroxy, acetylamino, aminocarbonyl, difluoromethoxy, and trifluoromethoxy.
  • Preferred substituents are F, Cl, cyano, methyl, ethyl, methoxy, ethoxy, difluoromethyl, trifluoromethyl, hydroxy, acetylamino, aminocarbonyl, difluoromethoxy, and trifluoromethoxy, most preferably F, Cl, cyano, methyl, methoxy, difluoromethyl, trifluoromethyl, and hydroxy,
  • the H atom bound to an N atom may in each case be replaced by a group which can be cleaved in vivo.
  • a group which can be cleaved in vivo from an N atom is meant, for example, a hydroxy group, an acyl group such as the benzoyl or pyridinoyl group or a Ci.i6-alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a Cvi ⁇ -alkoxycarbonyl group such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl
  • Re denotes a Ci. 8 -alkyl, C 5 -7-cycloalkyl, phenyl or phenyl- Ci_ 3 -alkyl group,
  • R f denotes a hydrogen atom, a Ci. 3 -alkyl, C 5 . 7 -cycloalkyl or phenyl group and
  • Rg denotes a hydrogen atom, a Ci -3 -alkyl or R 8 CO-O-(R f CR h )-O group wherein R e and R f are as hereinbefore defined and R h is a hydrogen atom or a Ci -3 -alkyl group,
  • the residues and substituents described above may be mono- or polysubstituted by fluorine as described.
  • Preferred fluorinated alkyl groups are fluoromethyl, difluoromethyl and trifluoromethyl.
  • Preferred fluorinated alkoxy groups are fluoromethoxy, difluoromethoxy and trifluoromethoxy.
  • Preferred fluorinated alkylsulphinyl and alkylsulphonyl groups are trifluoromethylsulphinyl and trifluoromethylsulphonyl.
  • the compounds according to the invention may have basic groups such as e.g. amino functions.
  • the compounds according to the invention may therefore be present as internal salts, as salts with pharmaceutically useable inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, sulphonic acid or organic acids (such as for example maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) inter alia.
  • the compounds according to the invention may be obtained using methods of synthesis which are known to the one skilled in the art and described in the literature of organic synthesis. Preferably the compounds are obtained as described in the experimental section.
  • Stereoisomeric compounds according to the invention may chiefly be separated by conventional methods.
  • the diastereomers are 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 of compounds according to the invention 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 (+)-cam- phorsulphonic 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 (+)-cam- phorsulphonic acid, or
  • the racemate of a compound according to the invention is reacted with one of the above-mentioned 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, carefully neutralised with a base such as sodium carbonate or potassium carbonate, or with a suitable acid, e.g. with dilute hydrochloric acid or aqueous methanesulphonic acid 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 according to the invention may also be obtained by performing the syntheses described above with a suitable reaction component in the (R) or (S) configuration.
  • the compounds according to the invention may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically and pharmacologically acceptable salts thereof.
  • These salts may be present on the one hand as physiologically and pharmacologically acceptable acid addition salts of the compounds according to the invention with inorganic or organic acids.
  • the acid addition salts may be prepared, for example, using hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
  • mixtures of the above mentioned acids may be used.
  • the compounds according to the present invention including the physiologically acceptable salts, are effective as antagonists of the MCH receptor, particularly the MCH-1 receptor, and exhibit good affinity in MCH receptor binding studies. Pharmacological test systems for MCH- antagonistic properties are described in the following experimental section.
  • the compounds according to the invention are advantageously suitable as pharmaceutical active substances for the prevention and/or treatment of symptoms and/or diseases caused by MCH or causally connected with MCH in some other way.
  • the compounds according to the invention have low toxicity, they are well absorbed by oral route and have good intracerebral transitivity, particularly brain accessibility.
  • AUC area under the curve
  • AUC brain to plasma ratio which can be expressed as AUC (brain)/AUC (plasma)
  • cerebrospinal fluid (CSF) levels cerebrospinal fluid (ti /2 ), in each case in particular in preclinical species such as for example rat, monkey, dog, pig, etc.
  • the procedures to determine said pharmacokinetic properties are well known to the one skilled in the art and are described in textbooks and literature.
  • Compounds and pharmaceutical compositions according to this invention can be tested for their efficacy on body weight reduction in rats with diet-induced obesity.
  • obesity is induced in female HanWistar rats by feeding them a cafeteria diet in addition to their standard diet for 4 to 8 weeks.
  • the cafeteria diet consists of a mixture of palatable commercially available supermarket foods to stimulate energy intake.
  • the rats with diet-induced obesity are treated once or twice daily for for example 2 to 4 weeks by oral administration of either one or more compound according to this invention or vehicle which is usually 0.5% aqueous hydroxyethylcellulose.
  • the animals Prior to start of treatment, the animals are randomized for body weight and the cafeteria diet feeding is continued throughout the study. At the end of the study, the body weight of animals treated with compounds according to this invention is compared to vehicle treatment.
  • MCH antagonists which contain at least one compound according to the invention are particularly suitable in mammals, such as for example rats, mice, guinea pigs, hares, dogs, cats, sheep, horses, pigs, cattle, monkeys and humans, for the treatment and/or prevention of symptoms and/or diseases which are caused by MCH or are otherwise causally connected with MCH.
  • Diseases caused by MCH or otherwise causally connected with MCH are particularly metabolic disorders, such as for example obesity, and eating disorders, such as for example bulimia, including bulimia nervosa.
  • the indication obesity includes in particular exogenic obesity, hyperinsulinaemic obesity, hyperplasmic obesity, hyperphyseal adiposity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, alimentary obesity, hypogonadal obesity, central obesity.
  • This range of indications also includes cachexia, anorexia and hyperphagia.
  • Compounds according to the invention may be particularly suitable for reducing hunger, curbing appetite, controlling eating behaviour and/or inducing a feeling of satiation.
  • the diseases caused by MCH or otherwise causally connected with MCH also include hyperlipidaemia, cellulitis, fatty accumulation, malignant mastocytosis, systemic mastocytosis, emotional disorders, affectivity disorders, depression, anxiety states, reproductive disorders, sexual disorders, memory disorders, epilepsy, forms of dementia and hormonal disorders.
  • Compounds according to the invention are also suitable as active substances for the prevention and/or treatment of other illnesses and/or disorders, particularly those which accompany obesity, such as for example diabetes, diabetes mellitus, particularly type Il diabetes, hyperglycaemia, particularly chronic hyperglycaemia, complications of diabetes including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, etc., insulin resistance, pathological glucose tolerance, encephalorrhagia, cardiac insufficiency, cardiovascular diseases, particularly arteriosclerosis and high blood pressure, arthritis and gonitis.
  • other illnesses and/or disorders particularly those which accompany obesity
  • obesity such as for example diabetes, diabetes mellitus, particularly type Il diabetes, hyperglycaemia, particularly chronic hyperglycaemia, complications of diabetes including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, etc., insulin resistance, pathological glucose tolerance, encephalorrhagia, cardiac insufficiency, cardiovascular diseases, particularly arteriosclerosis and high blood pressure, arthritis and gonitis.
  • MCH antagonists and formulations according to the invention may advantageously be used in combination with a dietary therapy, such as for example a dietary diabetes treatment, and exercise.
  • Another range of indications for which the compounds according to the invention are advantageously suitable is the prevention and/or treatment of micturition disorders, such as for example urinary incontinence, hyperactive bladder, urgency, nycturia, enuresis, while the hyperactive bladder and urgency may or may not be connected with benign prostatic hyperplasia.
  • the compounds according to the invention are potentially suitable for preventing and/or treating dependencies, such as for example alcohol and/or nicotine dependency, and/or withdrawal symptoms, such as for example weight gain in smokers coming off nicotine.
  • dependencies is generally meant here an irresistible urge to take an addictive substance and/or to perform certain actions, particularly in order to either achieve a feeling of wellbeing or to eliminate negative emotions.
  • the term "dependency” is used here to denote a dependency on an addictive substance.
  • withdrawal symptoms are meant here, in general, symptoms which occur or may occur when addictive substances are withdrawn from patients dependent on one or more such substances.
  • the compounds according to the invention are potentially suitable particularly as active substances for reducing or ending tobacco consumption, for the treatment or prevention of a nicotine dependency and/or for the treatment or prevention of nicotine withdrawal symptoms, for reducing the craving for tobacco and/or nicotine and generally as an anti-smoking agent.
  • the compounds according to the invention may also be useful for preventing or at least reducing the weight gain typically seen when smokers are coming off nicotine.
  • the substances may also be suitable as active substances which prevent or at least reduce the craving for and/or relapse into a dependency on addictive substances.
  • addictive substances refers particularly but not exclusively to substances with a psycho-motor activity, such as narcotics or drugs, particularly alcohol, nicotine, ***e, amphetamine, opiates, benzodiazepines and barbiturates.
  • the dosage required to achieve such an effect is conveniently, by intravenous or subcutaneous route, 0.001 to 30 mg/kg of body weight, preferably 0.01 to 5 mg/kg of body weight, and by oral or nasal route or by inhalation, 0.01 to 50 mg/kg of body weight, preferably 0.1 to 30 mg/kg of body weight, in each case 1 to 3 x daily.
  • the compounds prepared according to the invention may be formulated, optionally in conjunction with other active substances as described hereinafter, together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, 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, to produce conventional galenic preparations such as plain or coated tablets, capsules, lozenges, powders, granules, solutions, emulsions, syrups, aerosols for inhalation, ointments or suppositories.
  • inert conventional carriers and/or diluents e.g. with corn starch, lactose, glucose, microcrystalline cellulose,
  • compositions containing at least one compound according to the invention and/ or a salt according to the invention optionally together with one or more physiologically acceptable excipients may also be for example foodstuffs which may be solid or liquid, in which the compound according to the invention is incorporated.
  • one or more additional active substances are selected from among active substances for the treatment of diabetes, active substances for the treatment of diabetic complications, - active substances for the treatment of obesity, preferably other than MCH antagonists, active substances for the treatment of high blood pressure, active substances for the treatment of hyperlipidaemia, including arteriosclerosis, active substances for the treatment of dyslipidaemia, including arteriosclerosis, active substances for the treatment of arthritis, - active substances for the treatment of anxiety states, active substances for the treatment of depression.
  • active substances for the treatment of diabetes are insulin sensitisers, insulin secretion accelerators, biguanides, insulins, ⁇ -glucosidase inhibitors, ⁇ 3 adreno-receptor agonists.
  • Insulin sensitisers include glitazones, particularly pioglitazone and its salts (preferably hydrochloride), troglitazone, rosiglitazone and its salts (preferably maleate), JTT-501 , GI-262570, MCC-555, YM-440, DRF-2593, BM-13-1258, KRP-297, R-119702 and GW- 1929.
  • Insulin secretion accelerators include sulphonylureas, such as for example tolbutamide, chloropropamide, tolazamide, acetohexamide, glyclopyramide and its ammonium salts, glibenclamide, gliclazide, glimepiride. Further examples of insulin secretion accelerators are repaglinide, nateglinide, mitiglinide (KAD-1229) and JTT-608.
  • Biguanides include metformin, buformin and phenformin.
  • Insulins include those obtained from animals, particularly cattle or pigs, semisynthetic human insulins which are synthesised enzymatically from insulin obtained from animals, human insulin obtained by genetic engineering, e.g. from E ⁇ scherichi coli or yeasts. Moreover, the term insulin also includes insulin-zinc (containing 0.45 to 0.9 percent by weight of zinc) and protamine-insulin-zinc obtainable from zinc chloride, protamine sulphate and insulin. Insulin may also be obtained from insulin fragments or derivatives (for example INS-1 , etc.).
  • Insulin may also include different kinds, e.g. with regard to the onset time and duration of effect ("ultra immediate action type”, “immediate action type”, “two phase type”,
  • ⁇ -Glucosidase inhibitors include acarbose, voglibose, miglitol, emiglitate.
  • Adreno receptor agonists include AJ-9677, BMS-196085, SB-226552, AZ40140.
  • Active substances for the treatment of diabetes other than those mentioned above include ergoset, pramlintide, leptin, BAY-27-9955 as well as glycogen phosphorylase inhibitors, sorbitol dehydrogenase inhibitors, protein tyrosine phosphatase 1B inhibitors, dipeptidyl protease inhibitors, glipazide, glyburide.
  • Active substances for the treatment of diabetes or diabetic complications furthermore include for example aldose reductase inhibitors, glycation inhibitors and protein kinase C inhibitors, DPPIV blockers, GLP-1 or GLP-2 analogues and SGLT-2 inhibitors.
  • Aldose reductase inhibitors are for example tolrestat, epalrestat, imirestat, zenarestat, SNK-860, zopolrestat, ARI-50i, AS-3201.
  • Protein Kinase C inhibitors are for example NGF, LY-333531.
  • DPPIV blockers are for example LAF237 (Novartis), MK431 (Merck) as well as 815541 , 823093 and 825964 (all GlaxoSmithkline).
  • GLP-1 analogues are for example Liraglutide (NN2211 ) (NovoNordisk), CJC1131 (Conjuchem), Exenatide (Amylin).
  • SGLT-2 inhibitors are for example AVE-2268 (Aventis) and T-1095 (Tanabe, Johnson&Johnson).
  • Active substances other than those mentioned above for the treatment of diabetic complications include alprostadil, thiapride hydrochloride, cilostazol, mexiletine hydrochloride, ethyl eicosapentate, memantine, pimagedine (ALT-711).
  • Active substances for the treatment of obesity include lipase inhibitors and anorectics.
  • a preferred example of a lipase inhibitor is orlistat.
  • Examples of preferred anorectics are phentermine, mazindol, dexfenfluramine, fluoxetine, sibutramine, baiamine, (S)-sibutramine, SR-141716, NGD-95-1.
  • Active substances other than those mentioned above for the treatment of obesity include lipstatin.
  • the active substance group of anti- obesity active substances also includes the anorectics, of which the ⁇ 3 agonists, thyromimetic active substances and NPY antagonists should be emphasised.
  • the range of substances which may be considered as preferred anti-obesity or anorectic active substances is indicated by the following additional list, by way of example: phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a cholecystokinin-A (hereinafter referred to as CCK-A) agonist, a monoamine reuptake inhibitor (such as for example sibutramine), a sympathomimetic active substance, a serotonergic active substance (such as for example dexfenfluramine, fenfluramine, a 5-HT2C agonist such as BVT.933 or APD356, or duloxetine), a dopamine antagonist (such as for example bromocriptine or prami
  • anorectics include bombesin agonists, dehydroepiandrosterone or its analogues, glucocorticoid receptor agonists and antagonists, orexin receptor antagonists, urocortin binding protein antagonists, agonists of the Glucagon-like Peptide-1 receptor, such as for example exendin, AC 2993, CJC- 1131 , ZP10 or GRT0203Y, DPPIV inhibitors and ciliary neurotrophic factors, such as for example axokines.
  • forms of therapy which produce weight loss by increasing the fatty acid oxidation in the peripheral tissue, such as for example inhibitors of acetyl-CoA carboxylase.
  • Active substances for the treatment of high blood pressure include inhibitors of angiotensin converting enzyme, calcium antagonists, potassium channel openers and angiotensin Il antagonists.
  • Inhibitors of angiotensin converting enzyme include captopril, enalapril, alacepril, delapril (hydrochloride), lisinopril, imidapril, benazepril, cilazapril, temocapril, trandolapril, manidipine (hydrochloride).
  • calcium antagonists examples include nifedipine, amlodipine, efonidipine, nicardipine.
  • Potassium channel openers include levcromakalim, L-27152, AL0671, NIP-121.
  • Angiotensin Il antagonists include telmisartan, losartan, candesartan cilexetil, valsartan, irbesartan, CS-866, E4177.
  • Active substances for the treatment of hyperlipidaemia include HMG-CoA reductase inhibitors, fibrate compounds.
  • HMG-CoA reductase inhibitors include pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, lipantil, itavastatin, ZD-4522 and their salts.
  • Fibrate compounds include fenofibrate, bezafibrate, clinofibrate, clofibrate and simfibrate.
  • Active substances for the treatment of dyslipidaemia include e.g. medicaments which raise the HDL level, such as e.g. nicotinic acid and derivatives and preparations thereof, such as e.g. niaspan, as well as agonists of the nicotinic acid receptor.
  • medicaments which raise the HDL level such as e.g. nicotinic acid and derivatives and preparations thereof, such as e.g. niaspan, as well as agonists of the nicotinic acid receptor.
  • NSAIDs non-steroidal antiinflammatory drugs
  • COX2 inhibitors such as for example meloxicam or ibuprofen.
  • Active substances for the treatment of anxiety states include chlordiazepoxide, diazepam, oxozolam, medazepam, cloxazolam, bromazepam, lorazepam, alprazolam, fludiazepam.
  • Active substances for the treatment of depression include fluoxetine, fluvoxamine, imipramine, paroxetine, sertraline.
  • the dosage for these active substances is conveniently 1/5 of the lowest normal recommended dose up to 1/1 of the normal recommended dose. 4
  • the invention also relates to the use of at least one compound according to the invention and/ or a salt according to the invention for influencing the eating behaviour of a mammal.
  • This use is particularly based on the fact that compounds according to the invention may be suitable for reducing hunger, curbing appetite, controlling eating behaviour and/or inducing a feeling of satiety.
  • the eating behaviour is advantageously influenced so as to reduce food intake. Therefore, the compounds according to the invention are advantageously used for reducing body weight.
  • Another use according to the invention is the prevention of increases in body weight, for example in people who had previously taken steps to lose weight and are interested in maintaining their lower body weight.
  • a further use may be the prevention of weight gain in a co-medication with a substance generally causing weight gain (such a glitazones).
  • a substance generally causing weight gain such a glitazones
  • it is preferably a non- therapeutic use.
  • a non-therapeutic use might be a cosmetic use, for example to alter the external appearance, or an application to improve general health.
  • the compounds according to the invention are preferably used non-therapeutically for mammals, particularly humans, not suffering from any diagnosed eating disorders, no diagnosed obesity, bulimia, diabetes and/or no diagnosed micturition disorders, particularly urinary incontinence.
  • the compounds according to the invention are suitable for non-therapeutic use in people whose BMI (body mass index), defined as their body weight in kilograms divided by their height (in metres) squared, is below a level of 30, particularly below 25.
  • the ratios given for the eluents relate to units by volume of the solvent in question.
  • the units by volume for NH 3 relate to a concentrated solution of NH 3 in water.
  • Silica gel made by Millipore (MATREXTM, 35-70 my) is used for chromatographic purification.
  • Alox (E. Merck, Darmstadt, aluminium oxide 90 standardised, 63-200 ⁇ m, Item no. 1.01097.9050) is used for chromatographic purification. Purity data given for compounds are based on 1 H-NMR.
  • HPLC data are measured under the following parameters:
  • mobile phase A waterformic acid 99.9:0.1 mobile phase
  • B acetonitrile:formic acid 99.9:0.1 mobile phase
  • C water:NH 4 OH 99.9:0.1
  • D acetonitrile: NH 4 OH 99.9:0.1
  • method A analytical column: Zorbax column (Agilent Technologies), SB (Zorbax stable bond) - C18; 3.5 ⁇ m; 4.6 mm x 75 mm; column temperature: RT gradient: time in min %A %B flow rate in ml/min 0.00 95.0 5.0 1.60
  • method E analytical column: Zorbax column (Agilent Technologies), SB (Zorbax stable bond) - C18; 3.5 ⁇ m; 4.6 mm x 75 mm; column temperature: RT gradient: time in min %A %B flow rate in ml/min 0.00 95.0 5.0 1.60
  • method F analytical column: Zorbax column (Agilent Technologies), SB (Zorbax stable bond) - C18; 3.5 ⁇ m; 4.6 mm x 75 mm; column temperature: RT gradient: time in min %A %B flow rate in ml/min
  • method J analytical column: Zorbax column (Agilent Technologies), SB (Zorbax stable bond) - C18; 1.8 ⁇ m; 3.0 mm x 30 mm; column temperature: RT gradient: time in min %A %B flow rate in ml/min
  • method K analytical column: Waters XBridge - C18; 2.5 ⁇ m; 3.0 mm x 30 mm; column temperature: RT gradient: time in min %C %D flow rate in ml/min
  • method L analytical column: Zorbax column (Agilent Technologies), SB (Zorbax stable bond) - C18; 1.8 ⁇ m; 3.0 mm x 30 mm; column temperature: RT gradient: time in min %A %B flow rate in ml/min
  • method M analytical column: Waters XBridge - C18; 2.5 ⁇ m; 3.0 mm x 30 mm; column temperature: RT gradient: time in min %C %D flow rate in ml/min 0.00 95.0 5.0 1.40 0.80 10.0 90.0 1.40 2.00 10.0 90.0 1.40 2.20 95.0 5.00 1.40
  • methylmagnesium bromide (12 mL of a 3M solution in diethyl ether, 36 mmol) is added to a solution of Weinreb amide 5b (4-Hydroxymethyl-3,N-dimethoxy-N-methyl- benzamide, 2.70 g, 12.0 mmol) in anhydrous THF (50 mL). After stirring for 1.5 h at 0 0 C, another 2 equivalents of methylmagnesium bromide (8 mL) are added to the reaction mixture. After 30 min, the reaction mixture is carefully poured into saturated aqueous ammonium chloride solution and extracted several times with tert-butylmethylether.
  • 2-Bromo-1-(3-fluoro-4-hydroxymethyl-phenyl)-ethanone is prepared following preparation 1a from 280 mg (0.99 mmol) 1-[4-(tert-butyl-dimethyl-silanyloxyrnethyl)-3-fluoro-phenyl]- ethanone (preparation 6e) and 478 mg (0.99 mmol) tetrabutylammonium-tribromide. Yield: 230 mg (94% of theory); R r value: 0.3 (silica gel, mixture J).
  • the Grignard solution is added to a suspension of the Weinreb amide 2-(4-benzyloxy-2- oxo-2H-pyridin-1-yl)-N-methoxy-N-methyl-acetamide (preparation 8, 1.06 g, 3.50 mmol) in THF (20 mL), while keeping the temperature below 0 0 C.
  • the reaction mixture is poured into 1 N aqueous HCI, tert-butylmethylether is added and the mixture is stirred for 2 h at room temperature. The formed precipitate is filtered off, washed with terf-butylmethylether and dried in vacuo.
  • 5-(5-Bromo-pyridin-2-ylmethoxy)-2H-pyridazin-3-one is prepared following preparation 10.4b from 5.30 g (14.5 mmol) 5-(5-bromo-pyridin-2-ylmethoxy)-2-(tetrahydro-pyran-2-yl)-2H- pyridazin-3-one (preparation 10.5a).
  • 4-(4-Methoxy-benzyloxy)-1H-pyridin-2-one is prepared as described for preparation 10.1 , employing 4-methoxybenzyl chloride as the alkylating agent and DMSO as solvent.
  • the reaction mixture is poured into water under vigorous stirring, the formed precipitate is filtered off, washed with tert-butylmethylether and dried. The solid is triturated with acetonitrile, collected and dried.
  • 5-(5-Fluoro-pyridin-2-ylmethoxy)-2H-pyridazin-3-one is prepared following preparation 10.4b from 800 mg (2.62 mmol) 5-(5-fluoro-pyridin-2-ylmethoxy)-2-(tetrahydro-pyran-2-yl)-2/-/- pyridazin-3-one.
  • 2-Bromo-1-[4-(1-hydroxy-ethyl)-phenyl]-ethanone is prepared following preparation 1a from 600 mg (3.65 mmol) 1-[4-(1-hydroxy-ethyl)-phenyl]-ethanone.
  • reaction mixture is stirred for 3 h at RT. An additional 0.12 g 4- methylbenzenesulfonyl chloride plus 0.07 mL pyridine is added and the reaction mixture is stirred overnight. The reaction mixture is poured into ice water and extracted with dichloromethane. The organic layer is dried over MgSO 4 and evaporated in vacuo. The remaining residue is purified chromatographically (silica gel, gradient from 20% to 50% ethyl acetate in cyclohexane).
  • S-dihydro-isoindole ⁇ - carboxylic acid fe/t-butyl ester is prepared following preparation 1b (DMSO as solvent) from 205 mg (0.86 mmol) 5-(5-chloro-pyridin-2-ylmethoxy)-2/-/-pyridazin-3-one (preparation 10.4) and 360 mg (0.86 mmol) ⁇ -p ⁇ toluene ⁇ -sulfonyloxyJ-ethylJ-I .S-dihydro-isoindole ⁇ -carboxylic acid tert-butyl ester (preparation 13).
  • reaction mixture After cooling, the reaction mixture is quenched with aqueous sodium bicarbonate solution.
  • reaction mixture is quenched with aqueous sodium bicarbonate solution.
  • organic layer is washed with water, dried over MgSO 4 and concentrated in vacuo.
  • the resulting solid is triturated with acetonitrile, the precipitate is filtered off and dried.
  • reaction mixture is poured into 50 mL aqueous ammonium chloride solution and the aqueous phase is extracted with EtOAc. The combined organic phase is washed with water, dried over MgSO 4 . After filtration and evaporation of the solvent, the residue is purified via reverse HPLC chromatography (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 5:95). Yield: 47% of theory; R r value: 0.4 (silica gel, mixture D).
  • reaction mixture is cooled to -60 0 C and 0.88 g (20.0 mmol) oxirane in 2.0 mL THF is added. The cooling bath is removed and the reaction is warmed to RT.
  • the reaction mixture is poured into 50 mL aqueous ammonium chloride solution and the aqueous phase is extracted with EtOAc. The combined organic phase is washed with water, dried over MgSO 4 . After filtration and evaporation of the solvent, the residue is purified via reverse HPLC chromatography (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 5:95).
  • Example 1.1 The following examples are prepared as described for Example 1.1.
  • example 1.7 4 equivalents of triethylamine are added to the reaction mixture.
  • example 1.12 and 1.13 the hydrochloride salt of the amine reagent plus 5 equivalents of H ⁇ nig's base (N-ethyl-diisopropylamine) are employed.
  • Examples 1.21 and 1.22 are prepared as described for Example 1.20, starting from examples 1.9 and 1.7, respectively.
  • Example 1.1 The following examples are prepared as described for Example 1.1 starting from 4-benzyloxy- 1-[2-(4-bromomethyl-3-methoxy-phenyl)-2-oxo-ethyl]-1 /-/-pyridin-2-one (preparation 5).
  • Example 1.1 The following examples are prepared as described for Example 1.1 starting from 4-benzyloxy- 1-[2-(4-bromomethyl-2-fluoro-phenyl)-2-ox ⁇ -ethyl]-1H-pyridin-2-one (preparation 4).
  • Example 1.1 The following examples are prepared as described for Example 1.1 starting from 4-benzyloxy- 1 -[2-(4-bromomethyl-3-fluoro-phenyl)-2-oxo-ethyl]-1 /-/-pyridin-2-one (preparation 6).
  • Example 2.1 The following examples are prepared as described for Example 2.1 starting from 5-benzyloxy- 2-[2-(4-bromomethyl-3-fluoro-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one (preparation 7).
  • Example 1.1 The following examples are prepared as described for Example 1.1 starting from 4-benzyloxy- 1 -[2-(5-bromomethyl-pyridin-2-yl)-2-oxo-ethyl]-1 H-pyridin-2-one (preparation 9).
  • Example 1.1 The following examples are prepared as described for Example 1.1 starting from 1-[2-(4- bromomethyl-phenyl)-2-oxo-ethyl]-4-(5-chloro-pyridin-2-ylmethoxy)-1 /-/-pyridin-2-one (preparation 20).
  • Example 1.1 The following examples are prepared as described for Example 1.1 starting from 2-[2-(4- bromomethyl-phenyl)-2-oxo-ethyl]-5-(5-chloro-pyridin-2-ylmethoxy)-2/-/-pyridazin-3-one (preparation 23).
  • Example 1.1 The following examples are prepared as described for Example 1.1 starting from 1-[2-(4- bromomethyl-phenyl)-2-oxo-ethyl]-4-(5-bromo-pyridin-2-ylmethoxy)-1 H-pyridin-2-one (preparation 21 ).
  • Example 1.1 The following examples are prepared as described for Example 1.1 starting from 2-[2-(4- bromomethyl-phenyl)-2-oxo-ethyl]-5-(5-bromo-pyridin-2-ylmethoxy)-2/-/-pyridazin-3-one (preparation 24).
  • Example 13.1 4-Benzyloxy-1- ⁇ 2-oxo-2-[2-(2,2,2-trifluoro-acetyl)-1 ,2 l 3,4-tetrahydro-isoquinolin-7-yl]-ethyl ⁇ - 1 H-pyridin-2-one
  • 4-(5-Chloro-pyridin-2-ylmethoxy)-1-[2-(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo- ethyl]-1 /-/-pyridin-2-one is prepared following example 14.2 from 4-(5-chloro-pyridin-2- ylmethoxy)-1-[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1 H-pyridin-2-one (example
  • Example 16.2 The following examples are prepared as described for Example 16.2 starting from 4-(5- chloro-pyridin-2-ylmethoxy)-1-[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1H-pyridin- 2-one (example 16.1a), employing the corresponding aldehyde in the reductive amination step.
  • 4-(5-Bromo-pyridin-2-ylmethoxy)-1 -[2-(2-methyl-2,3-dihydro-1 H-isoindol-5-yl)-ethyl]-1 H- pyridin-2-one is prepared following example 18.2 from 4-(5-bromo-pyridin-2-ylmethoxy)-1-[2- (2,3-dihydro-1 /-/-isoindol-5-yl)-ethyl]-1 /-/-pyridin-2-one (example 19.1, 60 mg, 0.14 mmol). Yield: 23 mg (37% of theory)
  • 5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(2-methyl-2,3-dihydro-1H-isoindol-5-yl)-ethyl]-2H- pyridazin-3-one is prepared following example 18.2 from 5-(5-Bromo-pyridin-2-ylmethoxy)-2- [2-(2,3-dihydro-1H-isoindol-5-yl)-ethyl]-2H-pyridazin-3-one (example 21.1 , 100 mg, 0.23 mmol).
  • 5-(5-Chloro-pyridin-2-ylmethoxy)-2-[2-(2-methyl-2,3-dihydro-1H-isoindol-5-yl)-ethyl]-2H- pyridazin-3-one is prepared following example 18.2 from 5-(5-chloro-pyridin-2-ylmethoxy)-2- [2-(2,3-dihydro-1H-isoindol-5-yl)-ethyl]-2H-pyridazin-3-one (example 22.1 , 140 mg, 0.37 mmol).
  • example 23a in 15 mL THF is added 1.2 mL of a solution of dimethylamine in THF (2M, 2.40 mmol), 137 ⁇ L glacial acetic acid (137 ⁇ L, 2.40 mmol) and sodium triacetoxyborohydride (508 mg, 2.40 mmol).
  • the mixture is stirred for 48 h at RT, quenched with aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The organic layer is dried over MgSO 4 and concentrated in vacuo.
  • Example 24.1 4-Benzyloxy-1 -[2-(3-methyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo-ethyl]-1 /-/-pyridin-2-one
  • 4-Benzyloxy-1-[2-(3-methyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo-ethyl]-1H-pyridin-2-one is prepared following example 13.2a from 4-benzyloxy-1- ⁇ 2-[3-methyl-2-(2,2,2-trifluoro- acetyl)-1 ,2, 3,4-tetrahydro-isoquinolin-7-yl]-2-oxo-ethyl ⁇ -1 /-/-pyridin-2-one (preparation 19, 80 mg, 0.17 mmol).
  • 5-Benzyloxy-2-[2-(2,3-dimethyl-1 ,2,3 l 4-tetrahydro-isoquinolin-7-yl)-2-oxo-ethyl]-2/-/-pyridazin- 3-one is prepared following example 18.2 from 5-benzyloxy-2-[2-(3-methyl-1,2,3,4-tetrahydro- isoquinolin-7-yl)-2-oxo-ethyl]-2/-/-pyridazin-3-one (example 25.1 , 88 mg, 0.23 mmol) and 37% aqueous formaldehyde solution (28 ⁇ L, 0.34 mmol).
  • 6- ⁇ 2-[4-(5-Chloro-pyridin-2-ylmethoxy)-6-oxo-6H-pyridazin-1-yl]-ethyl ⁇ -3,4-dihydro-1H- isoquinoline-2-carboxylic acid terf-butyl ester is prepared following preparation 1b from 5-(5- chloro-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 10.4, 238 mg, 1.00 mmol) and 6- [2-(toluene-4-sulfonyloxy)-ethyl]-3,4-dihydro-1/-/-isoquinoline-2-carboxylic acid terf-butyl ester (preparation 26, 432 mg, 1.00 mmol).
  • 4-(4-Fluoro-benzyloxy)-1-[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl)-1H-pyridin-2-one is prepared following example 13.2a from 4-(4-fluoro-benzyloxy)-1- ⁇ 2-oxo-2-[2-(2,2,2-trifluoro- acetyl)-1 ,2,3,4-tetrahydro-isoquinolin-7-yl]-ethyl ⁇ -1H-pyridin-2-one (example 31.1a, 0.40 g, 0.82 mmol).
  • 4-(4-Fluoro-benzyloxy)-1-[2-(2-isopropyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo-ethyl]-1/-/- pyridin-2-one is prepared following example 14.2 from 4-(4-fluoro-benzyloxy)-1-[2-oxo-2- (1,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1A7-pyridin-2-one (example 31.1 b, 70 mg, 0.18 mmol) and 14 ⁇ l_ acetone instead of acetaldehyde. Yield: 6 mg (8% of theory)
  • 5-(4-Fluoro-benzyloxy)-2-[2-(2-isopropyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo-ethyl]-2/-/- pyridazin-3-one is prepared following example 14.2 from 5-(4-fluoro-benzyloxy)-2-[2-oxo-2- (1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-2H-pyridazin-3-one (example 32.1b, 100 mg, 0.25 mmol) and 21 ⁇ l_ acetone instead of acetaldehyde. Yield: 20 mg (18% of theory)
  • Example 34 1-[2-Oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-4-(5-trifluoromethyl-pyridin-2- ylmethoxy)-1 /-/-pyridin-2-one
  • Example 35.4 The following examples are prepared as described for Example 35.4 starting from 5-(5- bromo-pyridin-2-ylmethoxy)-2-[2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-2H-pyridazin-3- one (for preparation see WO 08/022979).
  • Example 35.4 The following examples are prepared as described for Example 35.4 starting from 4-(5- chloro-pyridin-2-ylmethoxy)-1-[2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1H-pyridin-2-one (example 36.1 ).

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Abstract

La présente invention porte sur des dérivés de pyridone et de pyridazinone tels qu'énumérés dans la revendication 1, y compris leurs sels. De plus, l'invention porte sur des compositions pharmaceutiques contenant au moins un composé selon l'invention. En vertu de leur activité antagoniste du récepteur de la MCH, les compositions pharmaceutiques selon l'invention sont appropriées pour le traitement de troubles métaboliques et/ou de troubles de l'alimentation, en particulier l'obésité, la boulimie, l'anorexie, l'hyperphagie et le diabète.
PCT/EP2009/001081 2008-02-19 2009-02-17 Dérivés de pyridone et de pyridazinone comme antagonistes de la mch WO2009103478A1 (fr)

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WO2014026079A2 (fr) 2012-08-10 2014-02-13 Lantheus Medical Imaging, Inc. Compositions, procédés et systèmes de synthèse, et utilisation d'agents d'imagerie
CN104211565A (zh) * 2013-05-31 2014-12-17 浙江九洲药业股份有限公司 一种抗丙型肝炎药物中间体的制备方法
US9550000B2 (en) 2011-09-09 2017-01-24 Lantheus Medical Imaging, Inc. Compositions, methods, and systems for the synthesis and use of imaging agents
US9603951B2 (en) 2010-02-08 2017-03-28 Lantheus Medical Imaging, Inc. Methods and apparatus for synthesizing imaging agents, and intermediates thereof
US9718786B2 (en) 2004-02-13 2017-08-01 Lantheus Medical Imaging, Inc. Contrast agents for myocardial perfusion imaging
US10245332B2 (en) 2008-02-29 2019-04-02 Lantheus Medical Imaging, Inc. Contrast agents for applications including perfusion imaging
CN112707809A (zh) * 2020-12-30 2021-04-27 丽珠集团新北江制药股份有限公司 一种制备噁唑啉杀虫剂氟雷拉纳中间体的方法

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WO2007018248A1 (fr) * 2005-08-10 2007-02-15 Banyu Pharmaceutical Co., Ltd. Composé de pyridone
WO2008022979A1 (fr) * 2006-08-25 2008-02-28 Boehringer Ingelheim International Gmbh NOUVEAUX DÉRIVÉS DE LA PYRIDONE PRÉSENTANT UNE ACTIVITÉ ANTAGONISTE de MCH ET MÉDICAMENTS COMPRENANT CES COMPOSÉS

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US10889550B2 (en) 2004-02-13 2021-01-12 Lantheus Medical Imaging, Inc. Contrast agents for myocardial perfusion imaging
US10125106B2 (en) 2004-02-13 2018-11-13 Lantheus Medical Imaging, Inc. Contrast agents for myocardial perfusion imaging
US10245332B2 (en) 2008-02-29 2019-04-02 Lantheus Medical Imaging, Inc. Contrast agents for applications including perfusion imaging
US10842892B2 (en) 2010-02-08 2020-11-24 Lantheus Medical Imaging, Inc. Methods and apparatus for synthesizing imaging agents, and intermediates thereof
US9603951B2 (en) 2010-02-08 2017-03-28 Lantheus Medical Imaging, Inc. Methods and apparatus for synthesizing imaging agents, and intermediates thereof
US10022462B2 (en) 2010-02-08 2018-07-17 Lantheus Medical Imaging, Inc. Methods and apparatus for synthesizing imaging agents, and intermediates thereof
US9550000B2 (en) 2011-09-09 2017-01-24 Lantheus Medical Imaging, Inc. Compositions, methods, and systems for the synthesis and use of imaging agents
US8933079B2 (en) 2012-03-07 2015-01-13 Boehringer Ingelheim International Gmbh Pyridone and pyridazinone derivatives as anti-obesity agents
JP2015509517A (ja) * 2012-03-07 2015-03-30 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｍｃｈ−受容体モジュレーターとしてのピリジノン誘導体及びピリダジノン誘導体
WO2013131935A1 (fr) 2012-03-07 2013-09-12 Boehringer Ingelheim International Gmbh Dérivés de pyridinone et pyridazinone en tant que modulateurs du récepteur de mch
JP2015531760A (ja) * 2012-08-10 2015-11-05 ランセウス メディカル イメージング， インコーポレイテッド 造影剤の合成および使用のための組成物、方法およびシステム
US9919064B2 (en) 2012-08-10 2018-03-20 Lantheus Medical Imaging, Inc. Compositions, methods, and systems for the synthesis and use of imaging agents
US9713651B2 (en) 2012-08-10 2017-07-25 Lantheus Medical Imaging, Inc. Compositions, methods, and systems for the synthesis and use of imaging agents
JP2018123134A (ja) * 2012-08-10 2018-08-09 ランセウス メディカル イメージング， インコーポレイテッド 造影剤の合成および使用のための組成物、方法およびシステム
EP2882719A4 (fr) * 2012-08-10 2016-10-05 Lantheus Medical Imaging Inc Compositions, procédés et systèmes de synthèse, et utilisation d'agents d'imagerie
KR20150040348A (ko) * 2012-08-10 2015-04-14 랜티우스 메디컬 이메징, 인크. 영상화제의 합성 및 사용을 위한 조성물, 방법 및 시스템
US10500293B2 (en) 2012-08-10 2019-12-10 Lantheus Medical Imaging, Inc. Compositions, methods, and systems for the synthesis and use of imaging agents
WO2014026079A2 (fr) 2012-08-10 2014-02-13 Lantheus Medical Imaging, Inc. Compositions, procédés et systèmes de synthèse, et utilisation d'agents d'imagerie
KR102223883B1 (ko) * 2012-08-10 2021-03-08 랜티우스 메디컬 이메징, 인크. 영상화제의 합성 및 사용을 위한 조성물, 방법 및 시스템
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CN112707809A (zh) * 2020-12-30 2021-04-27 丽珠集团新北江制药股份有限公司 一种制备噁唑啉杀虫剂氟雷拉纳中间体的方法
CN112707809B (zh) * 2020-12-30 2023-08-29 丽珠集团新北江制药股份有限公司 一种制备噁唑啉杀虫剂氟雷拉纳中间体的方法

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