WO2013131935A1 - Pyridinone and pyridazinone derivatives as mch - receptor modulators - Google Patents

Pyridinone and pyridazinone derivatives as mch - receptor modulators Download PDF

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Publication number
WO2013131935A1
WO2013131935A1 PCT/EP2013/054465 EP2013054465W WO2013131935A1 WO 2013131935 A1 WO2013131935 A1 WO 2013131935A1 EP 2013054465 W EP2013054465 W EP 2013054465W WO 2013131935 A1 WO2013131935 A1 WO 2013131935A1
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methyl
pyridin
ethyl
phenyl
oxo
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PCT/EP2013/054465
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French (fr)
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Thorsten Oost
Ralf Lotz
Dirk Stenkamp
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Boehringer Ingelheim International Gmbh
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Priority to JP2014560346A priority Critical patent/JP5950239B2/en
Priority to EP13710316.4A priority patent/EP2822937B1/en
Publication of WO2013131935A1 publication Critical patent/WO2013131935A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • C07D401/10—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to new compounds, in particular a compound of the formula I
  • R 1 , R 2 , L 1 , L 2 , U and B are defined as hereinafter, to processes for preparing such compounds, to pharmaceutical compositions, to their use as MCH antagonists, to methods for their therapeutic use, in particular in diseases and conditions mediated by the modulation of the melanin-concentrating hormone (MCH) receptor, and to pharmaceutical compositions comprising them.
  • MCH melanin-concentrating hormone
  • obesity means an excess of adipose tissue in the body.
  • obesity is fundamentally to be seen as the increased level of fatness which leads to a health risk.
  • the health risk accompanying obesity is presumed to rise continuously as the level of fatness increases.
  • transgenic rats which produce more MCH than control animals, when given a high-fat diet, responded by gaining significantly more weight than animals without an experimentally altered MCH level. It was also found that there is a positive correlation between phases of increased desire for food and the quantity of MCH mRNA in the hypothalamus of rats. On the other hand, experiments with MCH knock-out mice are particularly important in showing the function of MCH. Loss of the neuropeptide results in lean animals with a reduced fat mass, which take in significantly less food than control animals.
  • MCH-1 R Gas- coupled MCH-1 receptor
  • MCH MCH1R Antagonists
  • the aim of the present invention is to provide new compounds, in particular new pyridone and pyridazinone derivatives, which are active against the MCH receptor, in particular against the MCH receptor 1 (MCH-1 R).
  • Another aim of the present invention is to provide new compounds, in particular new pyridone and pyridazinone derivatives, which are antagonists of the MCH-1 R.
  • a further aim of the present invention is to provide new compounds, in particular pyridone and pyridazinone derivatives, which have a greater metabolic stability than pyridone and pyridazinone derivatives of the prior art.
  • a further aim of the present invention is to provide new compounds, in particular pyridone and pyridazinone derivatives, which are MCH-1 R antagonists with suitable pharmacological and pharmacokinetic properties to use them as medicaments.
  • a further aim of the present invention is to provide methods for treating a disease or condition mediated by the MCH receptor in a patient.
  • a further aim of the present invention is to provide a pharmaceutical composition comprising at least one compound according to the invention.
  • a further aim of the present invention is to provide methods for the synthesis of the new compounds, in particular pyridone and pyridazinone derivatives.
  • a further aim of the present invention is to provide starting and/or intermediate compounds suitable in methods for the synthesis of the new compounds.
  • the compounds according to the invention described in more detail hereinafter have surprising and particularly advantageous properties, and in particular as MCH-1 R antagonists. Furthermore the compounds according to the invention have a good metabolic stability. It has been found that compounds according to this invention with a methyl substituent at the ortho-position (with respect to the carbonyl group) at the central phenyl ring have an improved metabolic stability compared with corresponding known compounds without such a methyl substituent.
  • R 1 , R 2 independently of each other are selected from the group R 1 -G1
  • alkyl groups may be straight- chain or branched, including any tautomers and stereoisomers thereof, or a salt thereof or a solvate or hydrate thereof.
  • the present invention relates to processes for preparing a compound of general formula I and to new intermediate compounds in these processes.
  • a further aspect of the invention relates to a salt of the compounds of general formula I according to this invention, in particular to a pharmaceutically acceptable salt thereof.
  • this invention relates to a pharmaceutical composition, comprising one or more compounds of general formula I or one or more pharmaceutically acceptable salts thereof according to the invention, optionally together with one or more excipients.
  • this invention relates to a method for treating a disease or condition which is mediated by modulating the activity of the MCH receptor in a patient in need thereof characterized in that a compound of general formula I or a pharmaceutically acceptable salt thereof is administered to the patient.
  • a method for treating a disease or condition which is mediated by blocking the MCH receptor in a patient in need thereof characterized in that a compound of general formula I or a
  • the groups, residues, and substituents particularly R 1 , R 2 , R 11 , R 12 , R 13 , R 14 , R 20 , L 1 , L 2 , U and B are defined as above and hereinafter. If residues, substituents, or groups occur several times in a compound, as for example R 11 or R 20 , they may have the same or different meanings. Some preferred meanings of individual groups and substituents of the compounds according to the invention will be given hereinafter. Any and each of these definitions may be combined with each other.
  • R 1 and R 2 are independently of each other preferably selected from the group R 1 -G1 as defined hereinbefore and hereinafter.
  • R 1 denotes H
  • R 2 preferably has a meaning different than H.
  • R 1 R 2 N- wherein R 1 and R 2 are linked to each other such that the R 1 R 2 N- group forms a bridged cyclic ring system with 5 to 8 C-atoms, in particular 6 or 7 C-atoms are:
  • H atoms may be replaced by identical or different groups R 11 .
  • the groups R 1 and R 2 independently of each other are selected from the group R 1 -G2 consisting of H, Ci -4 -alkyl and C3-6-cycloalkyl, while the alkyl or cydoalkyi group may be mono- or polysubstituted by identical or different groups R 11 , and a -CH 2 - group in position 3 or 4 of a 5- or 6-membered cydoalkyi group may be replaced by -O- or -NR 12 -.
  • R 1 denotes H
  • R 2 preferably has a meaning different than H.
  • the groups R 1 and R 2 independently of each other are selected from the group R 1 -G3 consisting of H and Ci -4 -alkyl, while the alkyl group may be mono- or polysubstituted by identical or different groups R 11 .
  • Preferred examples of the group R 1 -G3 are H, methyl, ethyl, n-propyl and i-propyl.
  • R 1 denotes H
  • R 2 preferably has a meaning different than H.
  • the groups R 1 and R 2 are linked to each other and together form a group which is selected from the group R 1 -R 2 -G1 as defined hereinbefore and hereinafter or R 1 and R 2 are linked to each other such that the R 1 R 2 N- group forms a bridged cyclic ring system with 5 to 8 C-atoms wherein one or more H atoms of the bridged cyclic ring system may be replaced by identical or different groups R 11 .
  • R 1 -R 2 -G2 the groups R 1 and R 2 are linked to each other and together form a group which is selected from the group R 1 -R 2 -G2 consisting of a alkylene bridge, wherein a -CH 2 - group not adjacent to the N atom of the R 1 R 2 N- group may be replaced by -O- or -NR 12 -, and wherein 1 or 2 H atoms of the alkylene bridge may be replaced by identical or different groups R 11 , or R 1 and R 2 are linked to each other such that the R 1 R 2 N- group forms a bridged cyclic ring system with 5, 6 or 7 C-atoms wherein one or more, in particular one or two, H atoms of the bridged cyclic ring system may be replaced by identical or different groups R 11 .
  • R 1 such that the group is selected from the group R 1 -R 2 -G3 consisting of the cyclic groups
  • R 1 and R 2 are linked to each other such that the R 1 R 2 N- group forms the bridged
  • each cyclic group may be substituted with an additional -CH 3 group.
  • the groups L 1 and L 2 are independently of each other preferably selected from the group L 1 -G1 as defined hereinbefore and hereinafter.
  • the groups L 1 and L 2 are independently of each other selected from the group L 1 -G2 consisting of H and CH 3 .
  • L 1 and L 2 denote H.
  • L 1 denotes H and L 2 denotes CH 3 .
  • the group U is preferably selected from the group U-G1 as defined hereinbefore and hereinafter.
  • the group U is selected from the group U-G2 consisting of CH.
  • the group U is selected from the group U-G3 consisting of N.
  • the group B is preferably selected from the group B-G1 as defined hereinbefore and hereinafter.
  • the group B is selected from the group B-G2 consisting of phenyl which may be substituted by 1 , 2 or 3 identical or different substituents R 20 .
  • the group B is selected from the group B-G3 consisting of pyridinyl which may be substituted by 1 , 2 or 3 identical or different substituents R 20 .
  • the group R 11 is preferably selected from the group R 11 -G1 as defined hereinbefore and hereinafter.
  • R 11 -G2 the group R 11 is selected from the group R 11 -G2 consisting of OH, F, Ci -4 -alkyl, Ci-3-alkyl-O-, C3-6-cycloalkyl and C3-6-cycloalkyl-O-, while each of the above mentioned alkyl and cydoalkyi groups may be substituted by one or more substituents independently of each other selected from F, OH and Ci-3- alkyl-O.
  • the group R 11 is selected from the group R 11 -G3 consisting of OH and Ci-3-alkyl, wherein alkyl may be substituted by OH.
  • Preferred examples of the group R 11 -G3 are OH, CH 3 and HO-CH 2 -,
  • the group R 12 is preferably selected from the group R 12 -G1 as defined hereinbefore and hereinafter.
  • the group R 12 is selected from the group R 12 -G2 consisting of H and Ci-3-alkyl.
  • Preferred examples of the group R 12 -G2 are H, CH 3 and H 3 C-CH 2 -,
  • the groups R 13 and R 14 are independently of each other preferably selected from the group R 13 -G1 as defined hereinbefore and hereinafter.
  • the groups R 13 and R 14 are independently of each other selected from the group R 14 -G2 consisting of H and CH 3 .
  • R 20 The group R is preferably selected from the group R -G1 as defined hereinbefore and hereinafter.
  • the group R 20 is selected from the group R 20 -G2 consisting of F, CI, Br, OH, CN, Ci -4 -alkyl and Ci -4 -alkyl-O-, wherein each alkyl group may be substituted with one or more substituents independently of each other selected from F, OH, CN and Ci -4 -alkyl-O-.
  • Preferred examples of the group R 20 -G3 are F, CI, Br, H3C-O-.
  • R 1 -R 2 -G3 Particularly preferred compounds, including their tautomers and stereoisomers, the salts thereof, or any solvates or hydrates thereof, are described in the experimental section hereinafter.
  • the following compounds are mentioned as examples of compounds according to the invention:
  • a compound of general formula (1 -1 ) is reacted with a compound of general formula (1 -2) in the presence of a base.
  • Suitable bases are particularly inorganic bases such as carbonates, especially cesium carbonate and potassium carbonate.
  • Suitable leaving groups (LG) are preferably selected from bromide, chloride, iodide, trifluoroacetate, tnfluoromethanesulfonate, methanesulfonate and toluenesulfonate and the like.
  • the reaction is preferably carried out in an inert organic solvent such as DMF, N,N- dimethylacetamide, DMSO, acetonitrile, THF, methylene chloride or a mixture of solvents.
  • the reaction usually takes place within 2 to 48 hours.
  • Preferred reaction temperatures are between 0°C and 150°C.
  • Ortho-methyl acetophenone precursors for the synthesis of a compounds of general formula (1 -1 ) can be prepared from the corresponding ortho-methyl aryl iodides or bromides via Heck reaction with alkyl vinyl ethers followed by hydrolysis of the vinyl ether, for instance as described in J. Org. Chem. 2001 , 66, 4340-4343.
  • Suitable leaving groups are preferably selected from bromide, chloride, iodide, trifluoroacetate, trifluoromethanesulfonate, methanesulfonate and toluenesulfonate and the like.
  • the methods for preparing the mentioned leaving groups are known to the one skilled in the art and are described in the literature of organic synthesis.
  • a compound of general formula (1 -4) is reacted with an amine HNR 1 R 2 .
  • the amine HNR 1 R 2 is used in excess (about 2 to 4 mol equivalents based on the compound 1 -4).
  • a non nucleophilic organic base preferably triethylamine, diisopropyl-ethylamine, potassium carbonate or cesium carbonate, can be added, so that only 1 .0 equivalent of HNR 1 R 2 has to be used.
  • the reactions are preferably carried out in an inert organic solvent like DMF, ⁇ , ⁇ -dimethylacetamide, methylene chloride, acetonitrile or THF, or mixtures thereof.
  • DMF and N,N-dimethylacetamide are preferred solvents.
  • the reaction usually takes place within 2 to 48 hours.
  • a preferred temperature range for this reaction is 20°C to 150°C, preferably 20°C to 80°C.
  • a compound of general formula (2-1 ) is reacted with a compound of general formula (2-2) in the presence of a base.
  • Suitable bases are particularly inorganic bases such as carbonates, especially potassium carbonate.
  • Suitable leaving groups (LG) are preferably selected from bromide, chloride, iodide, trifluoroacetate, trifluoromethanesulfonate, methanesulfonate and toluenesulfonate and the like.
  • the reaction is preferably carried out in an inert organic solvent such as DMF, acetonitrile, THF, methylene chloride or a mixture of solvents. DMF is the preferred solvent.
  • DMF is the preferred solvent.
  • the reaction usually takes place within 2 to 48 hours. Preferred reaction temperatures are between -20°C and 120°C, preferably 0°C to 60°C.
  • Suitable leaving groups (LG) are preferably selected from bromide, chloride, iodide, trifluoroacetate, trifluoromethanesulfonate, methanesulfonate and toluenesulfonate and the like.
  • the methods for preparing the mentioned leaving groups are known to the one skilled in the art and are described in the literature of organic synthesis.
  • a compound of general formula (2-4) is reacted with an amine HNR 1 R 2 .
  • the amine HNR 1 R 2 is used in excess (about 2 to 4 mol equivalents based on the compound 2-4).
  • a non nucleophilic organic base preferably triethylamine, diisopropyl-ethylannine, potassium carbonate or cesium carbonate, can be added, so that only 1 .0 equivalent of HNR 1 R 2 has to be used.
  • the reactions are preferably carried out in an inert organic solvent like DMF, ⁇ , ⁇ -dimethylacetamide, methylene chloride, acetonitrile or THF, or mixtures thereof. DMF is the preferred solvent.
  • the reaction usually takes place within 2 to 48 hours.
  • a preferred temperature range for this reaction is 0°C to 150°C, preferably 20°C to 80°C.
  • the synthetic routes presented may rely on the use of protecting groups.
  • reactive groups present such as hydroxy, carbonyl, carboxy, amino, alkylamino, or imino, may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
  • Suitable protecting groups for the respective functionalities and their removal are well known to the one skilled in the art and are described in the literature of organic synthesis.
  • the compounds of general formula I may be resolved into their enantiomers and/or diastereomers as mentioned before.
  • cis/trans mixtures may be resolved into their cis and trans isomers and racemic compounds may be separated into their enantiomers.
  • the cis/trans mixtures may be resolved, for example, by chromatography into the cis and trans isomers thereof.
  • the compounds of general formula I which occur as racemates may be separated by methods known per se into their optical antipodes and diastereomeric mixtures of compounds of general formula I may be resolved into their diastereomers by taking advantage of their different physico-chemical properties using methods known per se, e.g. chromatography and/or fractional crystallization; if the compounds obtained thereafter are racemates, they may be resolved into the enantiomers as mentioned above.
  • racemates are preferably resolved by column chromatography on chiral phases or by crystallization from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as esters or amides with the racemic compound.
  • Salts may be formed with enantiomerically pure acids for basic compounds and with enantiomerically pure bases for acidic compounds.
  • Diastereomeric derivatives are formed with enantiomerically pure auxiliary
  • the compounds of formula I may be converted into salts, particularly for pharmaceutical use into the pharmaceutically acceptable salts, for example into the chlorides.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof, for example salts with hydrochloric acid.
  • treatment and “treating” embraces both preventative, i.e. prophylactic, or therapeutic, i.e. curative and/or palliative, treatment.
  • treatment and “treating” comprise therapeutic treatment of patients having already developed said condition, in particular in manifest form.
  • Therapeutic treatment may be symptomatic treatment in order to relieve the symptoms of the specific indication or causal treatment in order to reverse or partially reverse the conditions of the indication or to stop or slow down progression of the disease.
  • compositions and methods of the present invention may be used for instance as therapeutic treatment over a period of time as well as for chronic therapy.
  • treatment and “treating” comprise prophylactic treatment, i.e. a treatment of patients at risk to develop a condition mentioned hereinbefore, thus reducing said risk.
  • this invention refers to patients requiring treatment, it relates primarily to treatment in mammals, in particular humans.
  • terapéuticaally effective amount means an amount of a compound of the present invention that (i) treats or prevents the particular disease or condition, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease or condition, or (iii) prevents or delays the onset of one or more symptoms of the particular disease or condition described herein.
  • modulated refers to the deactivation of the melanin-concentrating hormone (MCH), in particular blockade or antagonism of the MCH receptor 1 with one or more compounds of the present invention.
  • MCH melanin-concentrating hormone
  • mediated refers to the (i) treatment, including prevention of the particular disease or condition, (ii) attenuation, amelioration, or elimination of one or more symptoms of the particular disease or condition, or (iii) prevention or delay of the onset of one or more symptoms of the particular disease or condition described herein.
  • body mass index or "BMI” of a human patient is defined as the weight in kilograms divided by the square of the height in meters, such that BMI has units
  • overweight is defined as the condition wherein the individual has a BMI greater than or 25 kg/m 2 and less than 30 kg/m 2 .
  • overweight and “pre-obese” are used interchangeably.
  • obesity is defined as the condition wherein the individual has a BMI equal to or greater than 30 kg/m 2 .
  • the term obesity may be categorized as follows: the term “class I obesity” is the condition wherein the BMI is equal to or greater than 30 kg/m 2 but lower than 35 kg/m 2 ; the term “class II obesity” is the condition wherein the BMI is equal to or greater than 35 kg/m 2 but lower than 40 kg/m 2 ; the term “class III obesity” is the condition wherein the BMI is equal to or greater than 40 kg/m 2 .
  • visceral obesity is defined as the condition wherein a waist-to-hip ratio of greater than or equal to 1.0 in men and 0.8 in women is measured. It defines the risk for insulin resistance and the development of pre-diabetes.
  • abdominal obesity is usually defined as the condition wherein the waist circumference is > 40 inches or 102 cm in men, and is > 35 inches or 94 cm in women. With regard to a Japanese ethnicity or Japanese patients abdominal obesity may be defined as waist circumference ⁇ 85 cm in men and ⁇ 90 cm in women (see e.g. investigating committee for the diagnosis of metabolic syndrome in Japan).
  • substituted means that any one or more hydrogens on the designated atom, radical or moiety is replaced with a selection from the indicated group, provided that the atom's normal valence is not exceeded, and that the substitution results in an acceptably stable compound.
  • Ci-6-alkyl means an alkyl group or radical having 1 to 6 carbon atoms.
  • the last named subgroup is the radical attachment point, for example, the substituent "aryl-Ci-3-alkyl-" means an aryl grou p wh ich is bound to a Ci-3-alkyl- group, the latter of which is bound to the core or to the group to which the substituent is attached.
  • aryl-Ci-3-alkyl- means an aryl grou p wh ich is bound to a Ci-3-alkyl- group, the latter of which is bound to the core or to the group to which the substituent is attached.
  • An asterisk may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.
  • the numeration of the atoms of a substituent starts with the atom which is closest to the core or the group to which the substituent is attached.
  • 3-carboxypropyl-group represents the following substituent:
  • the asterisk may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.
  • each X, Y and Z group is optionally substituted with
  • each X, Y and Z group may be substituted with
  • the like denotes that each group X, each group Y and each group Z either each as a separate group or each as part of a composed group may be substituted as defined.
  • R ex denotes H, Ci-3-alkyl, C3-6- cycloalkyl, C3-6-cycloalkyl-Ci-3-alkyl or Ci-3-alkyl-O-, wherein each alkyl group is optionally substituted with one or more L ex " or the like means that in each of the beforementioned groups which comprise the term alkyl, i.e. in each of the groups Ci- 3-alkyl, C3-6-cycloalkyl-Ci-3-alkyl and Ci-3-alkyl-O-, the alkyl moiety may be substituted with L ex as defined.
  • a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers etc ..) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • a preferred example are chlorides of the compound according to the invention.
  • Salts of acids which for example are useful for purifying or isolating the compounds of the present invention (e.g. trifluoro acetate salts) also comprise a part of the invention.
  • halogen generally denotes fluorine, chlorine, bromine and iodine.
  • n is an integer from 1 to n, either alone or in
  • Ci -5 -alkyl embraces the radicals H 3 C-, H 3 C-CH 2 -, H 3 C-CH 2 -CH 2 -, H 3 C-CH(CH 3 )-, H 3 C-CH2-CH 2 -CH 2 -, H 3 C-CH 2 -CH(CH 3 )-, H 3 C-CH(CH 3 )-CH 2 -, H 3 C-C(CH 3 ) 2 -, H 3 C-CH 2 -CH 2 -CH 2 -CH 2 -, H 3 C-CH 2 -CH 2 -CH(CH 3 )-, H 3 C-CH 2 -CH(CH 3 )-, H 3 C-CH 2 -CH(CH 3 )-CH 2 -, H 3 C-CH(CH 3 )-CH 2 -, H 3 C-CH(CH 3 )-CH 2 -, H 3 C-CH(CH 3 )-CH 2 -, H 3 C-CH(CH 3 )-CH 2 -,
  • n is an integer 1 to n, either alone or in combination with another radical, denotes an acyclic, straight or branched chain divalent alkyl radical containing from 1 to n carbon atoms.
  • Ci -4 -alkylene includes -(CH 2 )-, -(CH 2 -CH 2 )-, -(CH(CH 3 ))-, -(CH 2 -CH 2 -CH 2 )-, -(C(CH 3 ) 2 )-, - (CH(CH 2 CH 3 ))-, -(CH(CH 3 )-CH 2 )-, -(CH 2 -CH(CH 3 ))-, -(CH 2 -CH 2 -CH 2 -CH 2 )-, -(CH 2 - CH 2 -CH(CH 3 ))-, -(CH(CH 3 )-CH 2 -CH 2 )-, -(CH 2 -CH(CH 3 )-CH 2 )-, -(CH 2 -CH(CH 3 )-CH 2 )-, -(CH 2 -C(CH 3 ) 2 )-, -(C (CH 3 ) 2 -CH 2
  • C 3-n -cycloalkyl wherein n is an integer 4 to n, either alone or in
  • the cyclic group may be mono-, bi-, tri- or spirocyclic, most preferably monocyclic.
  • Examples of such cycloalkyi groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo[3.2.1 .]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl, etc.
  • the compounds according to the present invention are effective as antagonists of the MCH receptor, particularly the MCH-1 receptor, and exhibit good affinity in MCH receptor binding studies.
  • the compounds according to the invention have an improved metabolic stability.
  • An improved metabolic stability in an in vitro test system typically results in a reduced total body clearance (CL).
  • AUC area under the curve
  • the drug can typically be dosed in a lower amount.
  • CL/F Dose / AUC (F corresponds to oral bioavailability).
  • Lower dosages have the advantages of lower drug load of parent drug and metabolites for the patient and lower production costs for the drug product.
  • Pharmacological test systems for MCH-antagonistic properties as well as for metabolic stability are described in the following experimental section.
  • the compounds according to the invention are advantageously suitable as pharmaceutical active substances for the treatment of conditions 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.
  • MCH antagonists which contain at least one compound according to the invention are particularly suitable in mammals, in particular humans, for the treatment of conditions or diseases which are caused by MCH or are otherwise causally connected with MCH, in particular conditions or diseases which are mediated by blocking the MCH receptor, in particular MCH-1 R.
  • Diseases or conditions caused by MCH or otherwise causally connected with MCH are particularly metabolic disorders, such as for example overweight, obesity, and eating disorders, such as for example bulimia, including bulimia nervosa.
  • the indication obesity includes in particular class I obesity, class II obesity, class III obesity, visceral obesity, abdominal obesity, 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. In particular compounds according to the invention may be suitable to reduce food consumption in overweigth or obese patients.
  • 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 treatment of other illnesses and/or disorders, particularly those which accompany obesity, such as for example diabetes, diabetes mellitus, particularly type II diabetes mellitus, 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.
  • compounds according to the invention may be suitable in the treatment of obesity in conjunction with a calorie-reduced diet.
  • compounds according to the invention may be suitable for inducing weight loss and/or maintaining of weight loss in in conjunction with a calorie-reduced diet, in particular in obese or overweight patients.
  • compounds according to the invention may be suitable for reducing body weight in overweight or obese patients, in particular in conjunction with a calorie-reduced diet.
  • the treatment with one or more compounds according to the invention is preferred in obese patients with an initial body mass index (BMI) greater or equal 30 kg/m 2 , or in overweight patients with an initial BMI greater or equal 27 kg/m 2 , in particular in obese or overweight patients in the presence of weight-related comorbidities.
  • BMI body mass index
  • Another range of indications for which the compounds according to the invention are advantageously suitable is the 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.
  • 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 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 such as for example alcohol and/or nicotine dependency
  • 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.
  • dependency is used here to denote a dependency on an addictive substance.
  • drawal 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 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, cocaine, amphetamine, opiates, benzodiazepines and barbiturates.
  • compounds according to the invention may be suitable in the treatment of intestinal inflammation such as cause by inflammatory bowel disease, colitis and/or Crohn's disease.
  • intestinal inflammation such as cause by inflammatory bowel disease, colitis and/or Crohn's disease.
  • the assessment of activity of compounds of formula I may be carried out employing the assays as described in Kokkotou, E. et al., "Melanin- concentrating hormone as a mediator of intestinal inflammation", PNAS, 105 (30); 10613-10618.
  • a preferred embodiment is an oral administration once or twice daily.
  • a single dose for a human patient is for example in the range from 1 to 200 mg once or twice daily.
  • the actual therapeutically effective amount or therapeutic dosage will of course depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease. In any case the compound or composition will be administered at dosages and in a manner which allows a therapeutically effective amount to be delivered based upon patient's unique condition.
  • Suitable preparations for administering the compounds of formula I will be apparent to those with ordinary skill in the art and include for example tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injectables, inhalatives and powders etc. Oral formulations, particularly solid forms such as e.g. tablets or capsules are preferred.
  • the content of the pharmaceutically active compound(s) is advantageously in the range from 0.1 to 90 wt.-%, for example from 1 to 70 wt.-% of the composition as a whole.
  • Suitable tablets may be obtained, for example, by mixing one or more compounds according to formula I with known excipients, for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants.
  • the tablets may also consist of several layers.
  • the particular excipients, carriers and/or diluents that are suitable for the desired preparations will be familiar to the skilled man on the basis of his specialist knowledge.
  • the preferred ones are those that are suitable for the particular formulation and method of administration that are desired.
  • preparations or formulations according to the invention may be prepared using methods known per se that are familiar to the skilled man, such as for example by mixing or combining at least one compound of formula I according to the invention, or a pharmaceutically acceptable salt of such a compound, and one or more excipients, for example carriers and/or diluents.
  • the actual therapeutically effective amount or therapeutic dosage will of course depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease. In any case the compound or composition will be administered at dosages and in a manner which allows a therapeutically effective amount to be delivered based upon patient's unique condition.
  • Other features and advantages of the present invention will become apparent from the following more detailed Examples which illustrate, by way of example, the principles of the invention. Examples
  • HPLC data are measured under the following conditions: method A: analytical column: Waters, Xbridge C18, 3.0 x 30 mm, 2.5 ⁇
  • Solvent A 0.1 % NH 3 in water
  • Solvent A 0.1 % HCOOH in water
  • Solvent B 0.1 % HCOOH in acetonitrile
  • Solvent A 0.1 % NH 3 in water
  • Solvent A 0.1 % TFA in water
  • Solvent A 0.1 % NH 3 in water
  • Solvent A 0.1 % TFA in water
  • Solvent B methanol time in min %A %B flow rate in ml/min
  • Solvent A 0.1 % HCOOH in water
  • Solvent B 0.1 % HCOOH in acetonitrile
  • the melting points of crystalline compounds of the invention or salts thereof are determined by Differential Scanning Calorimetry (DSC) and evaluated by the onset temperature.
  • the heating rate of the experiments are 10°C/min.
  • the values are determined using a DSC instrument from the Q-seriesTM of TA Instruments.
  • 4-(5-Fluoro-pyridin-2-ylmethoxy)-1 -[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo- ethyl]-1 H-pyridin-2-one is prepared following preparation 1 c employing 4-(5-fluoro- pyridin-2-ylmethoxy)-1 H-pyridin-2-one (described in WO 09/103478) instead of 4- benzyloxy-1 H-pyridin-2-one.
  • 4-(5-Chloro-pyridin-2-ylmethoxy)-1 -[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo- ethyl]-1 H-pyridin-2-one is prepared following preparation 1 c employing 4-(5-chloro- pyridin-2-ylmethoxy)-1 H-pyridin-2-one (described in WO 09/103478) instead of 4- benzyloxy-1 H-pyridin-2-one.
  • 5-(5-Fluoro-pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo- ethyl]-2H-pyridazin-3-one is prepared following preparation 1 c employing 5-(5-fluoro- pyridin-2-ylmethoxy)-2H-pyridazin-3-one (described in WO 09/103478) instead of 4- benzyloxy-1 H-pyridin-2-one.
  • 2H-pyridazin-3-one is prepared following preparation 1d employing 5-(5-fluoro- pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H- pyridazin-3-one (preparation 6a) instead of preparation 1 c.
  • 5-(5-Chloro-pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo- ethyl]-2H-pyridazin-3-one is prepared following preparation 1 c employing 5-(5-chloro- pyridin-2-ylmethoxy)-2H-pyridazin-3-one (described in WO 09/103478) instead of 4- benzyloxy-1 H-pyridin-2-one.
  • 2H-pyridazin-3-one is prepared following preparation 1d employing 5-(5-chloro- pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H- pyridazin-3-one (preparation 7a) instead of preparation 1 c.
  • 5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo- ethyl]-2H-pyridazin-3-one is prepared following preparation 1 c employing 5-(5-bromo- pyridin-2-ylmethoxy)-2H-pyridazin-3-one (described in WO 09/103478) instead of 4- benzyloxy-1 H-pyridin-2-one.
  • reaction mixture is stirred for 3 h at room temperature.
  • the reaction mixture is filtered and the solvent is evaporated.
  • the residue is purified via reverse phase HPLC chromatography (Waters XBridge 5 ⁇ , gradient 5% -> 90% acetonitrile in water + 0.3% NH 4 OH).
  • Example 1 .1 The following examples are prepared as described for Example 1 .1 , employing the corres onding amines (as free base), respectively.
  • the hydrochloride salt of the compound 1 .3 is prepared by adding a 1 .1 equivalent of HCI (as 10 M solution of HCI in ethanol) to a concentrated solution of the corresponding free base in refluxing ethanol.
  • the hydrochloride salt which precipitates upon cooling, is filtered off and dried under reduced pressure.
  • the hydrochloride salt of the compound 1 .7 is prepared by adding a 1 .1 equivalent of HCI (as 10 M solution of HCI in ethanol) to a concentrated solution of the corresponding free base in refluxing ethanol.
  • HCI as 10 M solution of HCI in ethanol
  • Example 1 4-Benzyloxy-1 - ⁇ 2-[4-(3-hydroxy-3-methyl-pyrrolidin-1 -yl methyl )-2- meth l-phenyl]-2-oxo-ethyl ⁇ -1 H-pyridin-2-one
  • Example 1 The following examples are prepared as described for Example 1 .10, employing the corresponding amines, respectively, and ⁇ , ⁇ -dimethylacetamide (instead of DMF) as solvent.
  • Example 2.1 The following examples are prepared as described for Example 2.1 , employing the corresponding amines, respectively.
  • Example 3.1 The following examples are prepared as described for Example 3.1 , employing the corresponding amines, respectively.
  • Example 4.1 The following examples are prepared as described for Example 4.1 , employing the corresponding amines, respectively.
  • Example 4.7 The following examples are prepared as described for Example 4.7, employing the corresponding amines (as free base), respectively.
  • Example 5.1 The following examples are prepared as described for Example 5.1 , employing the corresponding amines (as free base), respectively.
  • Example 6.1 The following examples are prepared as described for Example 6.1 , employing the corresponding amines, respectively.
  • Example 7.1 The following examples are prepared as described for Example 7.1 , employing the corresponding amines, respectively.
  • the mixture is purified via reverse phase HPLC chromatography (Xbridge C18 5 ⁇ , gradient 5% -» 90% acetonitrile in water + 0.3% NH 4 OH, 120 mL/min) to yield 90 mg of the Boc-protected product (67% of theory).
  • This intermediate is dissolved in CH2CI2 (3 mL), trifluoroacetic acid is added (0.3 mL) and the mixture is stirred overnight at room temperature.
  • the reaction mixture is quenched with aqueous NaHCO3 solution and extracted with CH2CI2.
  • the organic layer is dried over MgSO 4 and concentrated under reduced pressure.
  • the hydrochloride salt of the compound 9.1 is prepared by adding a 1 .1 equivalent of HCI (as 10 M solution of HCI in ethanol) to a concentrated solution of the corresponding free base in refluxing ethanol.
  • the hydrochloride salt which precipitates upon cooling, is filtered off and dried under reduced pressure.
  • the title compound as comparative example can be prepared from 2-bromo-1 -(4- hydroxymethyl-phenyl)-ethanone (preparation described in WO2008/22979) and 5- (5-methoxy-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 9b) in analogy to the preparation of example 9.1 .
  • Example 9.1 The following examples are prepared as described for Example 9.1 , employing the corresponding amines, respectively.
  • 5-(5-Methoxy-pyridin-2-ylmethoxy)-2- ⁇ 2-[2-methyl-4-(1 -methylamino-ethyl)-phenyl]-2- oxo-ethyl ⁇ -2H-pyridazin-3-one is prepared following the procedure for example 10.1 , employing methylamine instead of dimethylamine.
  • Example 1 1 .1 1 - ⁇ 2-[4-(4-Hydroxy-piperidin-1 -ylmethyl)-2-methyl-phenyl]-2-oxo- ethyl ⁇ -4-(5-methoxy-pyridin-2-ylmethoxy)-1 H-pyridin-2-one
  • test methods for determining an MCH-receptor antagonistic activity will now be described.
  • other test methods known to the skilled man may be used, e.g. by inhibiting the MCH-receptor-mediated inhibition of cAMP production, as described by Hoogduijn M et al. in "Melanin-concentrating hormone and its receptor are expressed and functional in human skin", Biochem. Biophys. Res Commun. 296 (2002) 698-701 and by biosensory measurement of the binding of MCH to the MCH receptor in the presence of antagonistic substances by plasmon resonance, as described by Karlsson OP and Lofas S.
  • Test cell hMCH-1 R stably transfected into CHO/Galpha16 cells
  • Membranes from CHO/Galpha16 cells stably transfected with human hMCH-1 R are resuspended using a syringe (needle 0.6 x 25 mm) and diluted in test buffer (50 mM HEPES, 10 mM MgCI 2 , 2 mM EGTA, pH 7.00; 0.1 % bovine serum albumin
  • concentrating hormone 125 I-MCH commercially obtainable from NEN
  • increasing concentrations of the test compound in a final volume of 250 microlitres.
  • the reaction is filtered using a cell harvester through 0.5% PEI treated fibreglass filters (GF/B, Unifilter Packard).
  • the membrane-bound radioactivity retained on the filter is then determined after the addition of scintillator substance (Packard Microscint 20) in a measuring device (TopCount of Packard).
  • the non-specific binding is defined as bound radioactivity in the presence of 1 micromolar MCH during the incubation period.
  • the analysis of the concentration binding curve is carried out on the assumption of one receptor binding site.
  • Non-labelled MCH competes with labelled 125 I-MCH for the receptor binding with an IC50 value of between 0.06 and 0.15 nM.
  • the KD value of the radioligand is 0.156 nM.
  • the compounds according to the invention typically have IC 5 o values in the range from about 1 nM to about 200 nM, preferably from 1 nM to 50 nM.
  • IC 5 o values in the range from about 1 nM to about 200 nM, preferably from 1 nM to 50 nM.
  • Example IC50 Example IC50 Example IC50 Example IC50 Example IC50
  • Example IC50 Example IC50 Example IC50 Example IC50 Example IC50
  • Example IC50 Example IC50 Example IC50 Example IC50 Example IC50
  • Hepatocytes typically cryopreserved
  • an appropriate buffer system e.g. Dulbecco ' s modified eagle medium plus 3.5 g glucagon/500ml_, 2.5mg insulin/500ml_ and 3.75mg/500mL hydrocortison
  • human serum e.g. Dulbecco ' s modified eagle medium plus 3.5 g glucagon/500ml_, 2.5mg insulin/500ml_ and 3.75mg/500mL hydrocortison
  • test compound solution 80 ⁇ ; from 2mM in DMSO stock solution diluted 1 :25 with medium
  • 395 ⁇ hepatocyte suspension cell density in the range 0.25- 5 Mio cells/mL, typically 1 Mio cells/mL; final concentration of test compound 1 ⁇ , final DMSO concentration 0.05%).
  • the cells are incubated for six hours (incubator, orbital shaker) and samples (25 ⁇ ) are taken at 0, 0.5, 1 , 2, 4 and 6 hours. Samples are transferred into acetonitrile and pelleted by centrifugation (5 min).
  • Decline of parent compound is analyzed by HPLC-MS/MS.
  • CO initial concentration in the incubation [ ⁇ ]
  • CD cell density of vital cells [10e6cells/ml_]
  • AUD area under the data [ ⁇ x h]
  • clast concentration of last data point [ ⁇ ]
  • k slope of the regression line for parent decline [h-1 ].
  • the calculated in vitro hepatic intrinsic clearance can be scaled up to the intrinsic in vivo hepatic clearance and used to predict hepatic in vivo blood clearance (CL) by the use of a liver model (well stirred model).
  • CLJNTRINSICJNVIVO [ml/min/kg] (CLJNTRINSIC ⁇ L/min/10e6cells] x hepatocellularity [10e6cells/g liver] x liver factor [g/kg bodyweight]) / 1000
  • CL [ml/min/kg] CLJNTRINSICJNVIVO [ml/min/kg] x hepatic blood flow [ml/min/kg] /(CLJNTRINSICJNVIVO [ml/min/kg] + hepatic blood flow [ml/min/kg])
  • liver factor human: 25.7 g liver / kg bodyweight
  • the animals receive two daily oral administrations of either vehicle alone (0.5% aqueous hydroxyethylcellulose, 0.015% polysorbat 80) or the test compound dissolved in this vehicle. Body weight is measured daily before the second administration. The data are presented as mean ⁇ S.E.M. of baseline- corrected body weight change. Statistical comparison is conducted by repeated measures two-way ANOVA followed by Bonferroni post tests for group-wise comparisons. A p value ⁇ 0.05 is considered to show a statistically significant difference. Control animals are dosed twice daily with vehicle. Animals are dosed with vehicle in the morning and 3, 10, or 30 mg/kg of the compound in the evening (once daily compound dosing; qd). Body weight reduction is observed at least in the groups with higher dosing. Animals which receive 3 or 10 mg/kg of compound in the morning and evening (twice daily dosing; bid) show a higher body weight loss versus control.

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Abstract

The present invention relates to compounds of general formula I, wherein the groups R1, R2, L1, L2, U and B are as defined in the application, which have valuable pharmacological properties, and in particular modulate the activity of the MCH receptor.

Description

PYRIDINONE AND PYRIDAZINONE DERIVATIVES AS MCH - RECEPTOR MODULATORS
Field of the invention
The present invention relates to new compounds, in particular a compound of the formula I
Figure imgf000002_0001
wherein the groups R1, R2, L1, L2, U and B are defined as hereinafter, to processes for preparing such compounds, to pharmaceutical compositions, to their use as MCH antagonists, to methods for their therapeutic use, in particular in diseases and conditions mediated by the modulation of the melanin-concentrating hormone (MCH) receptor, and to pharmaceutical compositions comprising them.
Background of the invention
The intake of food and its conversion in the body is an essential part of life for all living creatures. Therefore, deviations in the intake and conversion of food generally lead to problems and also illness. The changes in the lifestyle and nutrition of humans, particularly in industrialised countries, have promoted morbid overweight (also known as corpulence or obesity) in recent decades. In affected people, obesity leads directly to restricted mobility and a reduction in the quality of life. There is the additional factor that obesity often leads to other diseases such as, for example, diabetes, dyslipidaemia, high blood pressure, arteriosclerosis and coronary heart disease. Moreover, high body weight alone puts an increased strain on the support and mobility apparatus, which can lead to chronic pain and diseases such as arthritis or osteoarthritis. Thus, obesity is a serious health problem for society.
The term obesity means an excess of adipose tissue in the body. In this connection, obesity is fundamentally to be seen as the increased level of fatness which leads to a health risk. There is no sharp distinction between normal individuals and those suffering from obesity, but the health risk accompanying obesity is presumed to rise continuously as the level of fatness increases.
Apart from physical activity and a change in nutrition, there is currently no convincing treatment option for effectively reducing body weight. However, as obesity is a major risk factor in the development of serious and even life-threatening diseases, it is all the more important to have access to pharmaceutical active substances for the prevention and/or treatment of obesity. One approach which has been proposed is the therapeutic use of MCH antagonists.
Investigations into the function of MCH in animal models have provided good indications for a role of the peptide in regulating the energy balance, i.e. changing metabolic activity and food intake. For example, after intraventricular administration of MCH in rats, food intake was increased compared with control animals.
Additionally, transgenic rats which produce more MCH than control animals, when given a high-fat diet, responded by gaining significantly more weight than animals without an experimentally altered MCH level. It was also found that there is a positive correlation between phases of increased desire for food and the quantity of MCH mRNA in the hypothalamus of rats. On the other hand, experiments with MCH knock-out mice are particularly important in showing the function of MCH. Loss of the neuropeptide results in lean animals with a reduced fat mass, which take in significantly less food than control animals.
The anorectic effects of MCH are presumably mediated in rodents through the Gas- coupled MCH-1 receptor (MCH-1 R), as, unlike primates, ferrets and dogs, no second MCH receptor subtype has hitherto been found in rodents. After losing the MCH-1 R, knock-out mice have a lower fat mass, an increased energy conversion and, when fed on a high fat diet, do not put on weight, compared with control animals. Several small-molecule MCH-1 R antagonists have been discribed in the literature which consistently show decreased food intake and body weight reduction in animal models of diet-induced obesity [1 ]. In addition to its anorectic effect, MCH-1 R antagonists also achieve additional anxiolytic and antidepressant effects in behavioural experiments [1 ]. Thus, there are clear indications that the MCH-MCH-1 R system is involved not only in regulating the energy balance but also in affectivity.
Literature:
1 . Chung, S. et al., Recent Updates on the Melanin-Concentrating Hormone
(MCH) and its Receptor System: Lessons from MCH1R Antagonists. J Mol Neurosci, 201 1 . 43: p.1 15-121
In the patent literature (WO 2008/022979) pyridone and pyridazinone derivatives of the formula I
Figure imgf000004_0001
are described as MCH antagonists. In case the group Y denotes phenyl a
substitution with methyl in ortho position is not described therein.
In the patent literature (WO 2009/103478) specific pyridone and pyridazinone derivatives are described as MCH antagonists.
In the atent literature (EP 1916239) pyridone derivatives of the formula
Figure imgf000004_0002
are described as MCH antagonists. Aim of the present invention
The aim of the present invention is to provide new compounds, in particular new pyridone and pyridazinone derivatives, which are active against the MCH receptor, in particular against the MCH receptor 1 (MCH-1 R).
Another aim of the present invention is to provide new compounds, in particular new pyridone and pyridazinone derivatives, which are antagonists of the MCH-1 R.
A further aim of the present invention is to provide new compounds, in particular pyridone and pyridazinone derivatives, which have a greater metabolic stability than pyridone and pyridazinone derivatives of the prior art.
A further aim of the present invention is to provide new compounds, in particular pyridone and pyridazinone derivatives, which are MCH-1 R antagonists with suitable pharmacological and pharmacokinetic properties to use them as medicaments.
A further aim of the present invention is to provide methods for treating a disease or condition mediated by the MCH receptor in a patient.
A further aim of the present invention is to provide a pharmaceutical composition comprising at least one compound according to the invention.
A further aim of the present invention is to provide methods for the synthesis of the new compounds, in particular pyridone and pyridazinone derivatives.
A further aim of the present invention is to provide starting and/or intermediate compounds suitable in methods for the synthesis of the new compounds.
Further aims of the present invention become apparent to the one skilled in the art by the description hereinbefore and in the following and by the examples. Object of the Invention
It has now been found that the compounds according to the invention described in more detail hereinafter have surprising and particularly advantageous properties, and in particular as MCH-1 R antagonists. Furthermore the compounds according to the invention have a good metabolic stability. It has been found that compounds according to this invention with a methyl substituent at the ortho-position (with respect to the carbonyl group) at the central phenyl ring have an improved metabolic stability compared with corresponding known compounds without such a methyl substituent.
In a first aspect the invention thus relates to a compound of formula I
Figure imgf000006_0001
wherein
R1 , R2 independently of each other are selected from the group R1-G1
consisting of H, Ci-6-alkyl and C3-7-cycloalkyl, while the alkyl or cycloalkyl group may be mono- or polysubstituted by identical or different groups R1 1 , and a -CH2- group in position 3 or 4 of a 5-, 6- or 7- membered cycloalkyl group may be replaced by -O-, -S-, -S(=O)-, -S(=O)2- or -NR12-; or
R1 and R2 are linked to each other and together form a group which is selected from the group R1-R2-G1 consisting of a C3-6-alkylene bridge, wherein a -CH2- group not adjacent to the N atom of the R1 R2N- group may be replaced by -O-, -S-, -S(=O)-, -S(=O)2- or -NR12-, and wherein one or more H atoms of the alkylene bridge may be replaced by identical or different groups R1 1 ; or R1 and R2 are linked to each other such that the R1 R2N- group forms a bridged cyclic ring system with 5 to 8 C-atoms wherein one or more H atoms of the bridged cyclic ring system may be replaced by identical or different groups R1 1 ; and independently of each other are selected from the group L1-G1 consisting of H and Ci-3-alkyl, or L1 and L2 are linked to each other and together form a group which is selected from the group L1-L2-G1 consisting of a C2-5-alkylene bridge; and is selected from the group U-G1 consisting of CH and N; and is selected from the group B-G1 consisting of phenyl and pyridinyl each of which may be mono- or polysubstituted by identical or different substituents R20; and is selected from the group R11-G1 consisting of OH, F, CI, Br, CN, Ci-6- alkyl, C3-6-cycloalkyl, Ci-4-alkyl-O- and R13R14N-, while each of the above mentioned alkyl or cycloalkyl groups may be substituted independently of one another by one or more substituents selected from F, CI, Br, OH, CN, CF3, Ci-3-alkyl, Ci-3-alkyl-O- and HO-Ci-3-alkyl; and is selected from the group R12-G1 consisting of H, Ci-4-alkyl and Ci-4- alkyl-C(=O)-; and independently of each other are selected from the group R13-G1 consisting of H and Ci-4-alkyl; and is selected from the group R20-G1 consisting of F, CI, Br, OH, CN, NO2, Ci-4-alkyl and Ci-4-alkyl-O-, wherein each alkyl group may be
substituted with one or more substituents independently of each other selected from F, CI, Br, OH, CN, NO2 and Ci-4-alkyl-O-; and while, unless otherwise stated, the above-mentioned alkyl groups may be straight- chain or branched, including any tautomers and stereoisomers thereof, or a salt thereof or a solvate or hydrate thereof.
In a further aspect the present invention relates to processes for preparing a compound of general formula I and to new intermediate compounds in these processes.
A further aspect of the invention relates to a salt of the compounds of general formula I according to this invention, in particular to a pharmaceutically acceptable salt thereof.
In a further aspect this invention relates to a pharmaceutical composition, comprising one or more compounds of general formula I or one or more pharmaceutically acceptable salts thereof according to the invention, optionally together with one or more excipients.
In a further aspect this invention relates to a method for treating a disease or condition which is mediated by modulating the activity of the MCH receptor in a patient in need thereof characterized in that a compound of general formula I or a pharmaceutically acceptable salt thereof is administered to the patient.
According to another aspect of the invention, there is provided a method for treating a disease or condition which is mediated by blocking the MCH receptor in a patient in need thereof characterized in that a compound of general formula I or a
pharmaceutically acceptable salt thereof is administered to the patient. According to another aspect of the invention, there is provided the use of a
compound of the general formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for a therapeutic method as described
hereinbefore and hereinafter.
According to another aspect of the invention, there is provided a compound of the general formula I or a pharmaceutically acceptable salt thereof for use in a
therapeutic method as described hereinbefore and hereinafter.
Other aspects of the invention become apparent to the one skilled in the art from the specification and the experimental part as described hereinbefore and hereinafter.
Detailed Description
Unless otherwise stated, the groups, residues, and substituents, particularly R1, R2, R11, R12, R13, R14, R20, L1, L2, U and B are defined as above and hereinafter. If residues, substituents, or groups occur several times in a compound, as for example R11 or R20, they may have the same or different meanings. Some preferred meanings of individual groups and substituents of the compounds according to the invention will be given hereinafter. Any and each of these definitions may be combined with each other.
R1. R2:
R1-G1 :
The groups R1 and R2 are independently of each other preferably selected from the group R1-G1 as defined hereinbefore and hereinafter. In case R1 denotes H, then R2 preferably has a meaning different than H.
Examples of the group R1R2N- wherein R1 and R2 are linked to each other such that the R1R2N- group forms a bridged cyclic ring system with 5 to 8 C-atoms, in particular 6 or 7 C-atoms are:
Figure imgf000010_0001
In each of the above bridged cyclic ring systems one or more, in particular one or two, H atoms may be replaced by identical or different groups R11.
R1-G2:
According to one embodiment the groups R1 and R2 independently of each other are selected from the group R1-G2 consisting of H, Ci-4-alkyl and C3-6-cycloalkyl, while the alkyl or cydoalkyi group may be mono- or polysubstituted by identical or different groups R11, and a -CH2- group in position 3 or 4 of a 5- or 6-membered cydoalkyi group may be replaced by -O- or -NR12-. In case R1 denotes H, then R2 preferably has a meaning different than H.
R1-G3:
According to one embodiment the groups R1 and R2 independently of each other are selected from the group R1-G3 consisting of H and Ci-4-alkyl, while the alkyl group may be mono- or polysubstituted by identical or different groups R11.
Preferred examples of the group R1-G3 are H, methyl, ethyl, n-propyl and i-propyl.
In case R1 denotes H, then R2 preferably has a meaning different than H.
R1-R2-G1 :
According to another embodiment the groups R1 and R2 are linked to each other and together form a group which is selected from the group R1-R2-G1 as defined hereinbefore and hereinafter or R1 and R2 are linked to each other such that the R1R2N- group forms a bridged cyclic ring system with 5 to 8 C-atoms wherein one or more H atoms of the bridged cyclic ring system may be replaced by identical or different groups R11.
R1-R2-G2: According to another embodiment the groups R1 and R2 are linked to each other and together form a group which is selected from the group R1-R2-G2 consisting of a alkylene bridge, wherein a -CH2- group not adjacent to the N atom of the R1R2N- group may be replaced by -O- or -NR12-, and wherein 1 or 2 H atoms of the alkylene bridge may be replaced by identical or different groups R11, or R1 and R2 are linked to each other such that the R1R2N- group forms a bridged cyclic ring system with 5, 6 or 7 C-atoms wherein one or more, in particular one or two, H atoms of the bridged cyclic ring system may be replaced by identical or different groups R11.
R1-R2-G3:
According to another embodiment the groups R1 and R2 are linked to each other
R1 such that the group is selected from the group R1-R2-G3 consisting of the cyclic groups
Figure imgf000011_0001
or R1 and R2 are linked to each other such that the R1R2N- group forms the bridged
Figure imgf000011_0002
cyclic ring system
wherein in each cyclic group or in the bridged cyclic ring system one or more, in particular one or two, H atoms may be replaced by identical or different groups R11.
Preferred examples according to this embodiment are
Figure imgf000012_0001
wherein each cyclic group may be substituted with an additional -CH3 group.
L1-G1 :
The groups L1 and L2 are independently of each other preferably selected from the group L1-G1 as defined hereinbefore and hereinafter.
L1-G2:
According to one embodiment the groups L1 and L2 are independently of each other selected from the group L1-G2 consisting of H and CH3.
According to a preferred example L1 and L2 denote H.
According to another preferred example L1 denotes H and L2 denotes CH3.
Ui
U-G1 : The group U is preferably selected from the group U-G1 as defined hereinbefore and hereinafter.
U-G2:
According to one embodiment the group U is selected from the group U-G2 consisting of CH.
U-G3:
According to another embodiment the group U is selected from the group U-G3 consisting of N.
§1
B-G1 :
The group B is preferably selected from the group B-G1 as defined hereinbefore and hereinafter.
B-G2:
According to one embodiment the group B is selected from the group B-G2 consisting of phenyl which may be substituted by 1 , 2 or 3 identical or different substituents R20.
B-G3:
According to another embodiment the group B is selected from the group B-G3 consisting of pyridinyl which may be substituted by 1 , 2 or 3 identical or different substituents R20.
R^:
R11-G1 :
The group R11 is preferably selected from the group R11-G1 as defined hereinbefore and hereinafter.
R11-G2: According to one embodiment the group R11 is selected from the group R11-G2 consisting of OH, F, Ci-4-alkyl, Ci-3-alkyl-O-, C3-6-cycloalkyl and C3-6-cycloalkyl-O-, while each of the above mentioned alkyl and cydoalkyi groups may be substituted by one or more substituents independently of each other selected from F, OH and Ci-3- alkyl-O.
R11-G3:
According to one embodiment the group R11 is selected from the group R11-G3 consisting of OH and Ci-3-alkyl, wherein alkyl may be substituted by OH.
Preferred examples of the group R11-G3 are OH, CH3 and HO-CH2-,
R12-G1 :
The group R12 is preferably selected from the group R12-G1 as defined hereinbefore and hereinafter.
R12-G2:
According to one embodiment the group R12 is selected from the group R12-G2 consisting of H and Ci-3-alkyl.
Preferred examples of the group R12-G2 are H, CH3 and H3C-CH2-,
R13-G1 :
The groups R13 and R14 are independently of each other preferably selected from the group R13-G1 as defined hereinbefore and hereinafter.
R13-G2:
According to one embodiment the groups R13 and R14 are independently of each other selected from the group R14-G2 consisting of H and CH3.
R20: The group R is preferably selected from the group R -G1 as defined hereinbefore and hereinafter.
R20-G2:
According to one embodiment the group R20 is selected from the group R20-G2 consisting of F, CI, Br, OH, CN, Ci-4-alkyl and Ci-4-alkyl-O-, wherein each alkyl group may be substituted with one or more substituents independently of each other selected from F, OH, CN and Ci-4-alkyl-O-.
Preferred examples of the group R20-G3 are F, CI, Br, H3C-O-.
The following preferred embodiments of compounds of the formula I are described using generic formulae 1.1 and I.2 wherein any tautomers and stereoisomers, solvates and hydrates thereof, and salts thereof, in particular the pharmaceutically acceptable salts thereof, are encompassed.
Figure imgf000015_0001
wherein the groups R1, R2, L1, L2 and B are defined as hereinbefore and hereinafter. Examples of preferred subgeneric embodiments according to the present invention are set forth in the following table, wherein each substituent group of each embodiment is defined according to the definitions set forth hereinbefore and wherein all other substituents are defined according to the definitions set forth hereinbefore:
Figure imgf000016_0001
The following particularly preferred embodiments of compounds of the formula I are described using generic formulae 1.1 .1 , 1.1 .2, 1.2.1 and I.2.2 wherein any tautomers and stereoisomers, solvates and hydrates thereof, and salts thereof, in particular the pharmaceutically acceptable salts thereof, are encompassed. 1.1 .1
1.1 .2
1.2.1
I.2.2
Examples of preferred subgeneric embodiments according to the present invention are set forth in the following table, wherein each substituent group of each embodiment is defined according to the definitions set forth hereinbefore and wherein all other substituents are defined according to the definitions set forth hereinbefore: Embodi¬
Formula R1, R2 L1, L2 R20 ment
R1-G1
E-17 1.1 .1 or L1-G1 R20-G1
R1-R2-G1
R1-G2
E-18 1.1 .1 or L1-G1 R20-G1
R1-R2-G2
R1-G3
E-19 1.1 .1 or L1-G2 R20-G2
R1-R2-G3
R1-G1
E-20 1.1 .2 or L1-G1 R20-G1
R1-R2-G1
R1-G2
E-21 1.1 .2 or L1-G1 R20-G1
R1-R2-G2
R1-G3
E-22 1.1 .2 or L1-G2 R20-G2
R1-R2-G3
R1-G1
E-23 1.2.1 or L1-G1 R20-G1
R1-R2-G1
R1-G2
E-24 1.2.1 or L1-G1 R20-G1
R1-R2-G2
R1-G3
E-25 1.2.1 or L1-G2 R20-G2
R1-R2-G3
R1-G1
E-26 I.2.2 or L1-G1 R20-G1
R1-R2-G1
R1-G2
E-27 I.2.2 or L1-G1 R20-G1
R1-R2-G2
R1-G3
E-28 I.2.2 or L1-G2 R20-G2
R1-R2-G3 Particularly preferred compounds, including their tautomers and stereoisomers, the salts thereof, or any solvates or hydrates thereof, are described in the experimental section hereinafter. The following compounds are mentioned as examples of compounds according to the invention:
Example Name
1 .1 4-Benzyloxy-1 -{2-[4-(3-hydroxy-azetidin-1 -ylmethyl)-2-methyl-phenyl]- 2-oxo-ethyl}-1 H-pyridin-2-one
1 .2 4-Benzyloxy-1 -[2-(2-methyl-4-methylaminomethyl-phenyl)-2-oxo- ethyl]-1 H-pyridin-2-one
1 .3 4-Benzyloxy-1 -{2-[4-(4-hydroxy-piperidin-1 -ylmethyl)-2-methyl- phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
1 .5 4-Benzyloxy-1 -{2-[2-methyl-4-(4-methyl-piperazin-1 -yl methyl )-phenyl]- 2-oxo-ethyl}-1 H-pyridin-2-one
1 .6 4-Benzyloxy-1 -{2-[4-(4-hydroxymethyl-piperidin-1 -yl methyl )-2-methyl- phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
1 .7 4-Benzyloxy-1 -[2-(2-methyl-4-pyrrolidin-1 -ylmethyl-phenyl)-2-oxo- ethyl]-1 H-pyridin-2-one
1 .8 4-Benzyloxy-1 -[2-(4-dimethylaminomethyl-2-methyl-phenyl)-2-oxo- ethyl]-1 H-pyridin-2-one
1 .1 1 (S)-4-Benzyloxy-1 -{2-[4-(3-hydroxy-pyrrolidin-1 -ylmethyl)-2-methyl- phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
1 .12 4-Benzyloxy-1 -[2-(4-ethylaminomethyl-2-methyl-phenyl)-2-oxo-ethyl]- 1 H-pyridin-2-one
1 .13 (S)-4-Benzyloxy-1 -{2-[4-(3-hydroxy-piperidin-1 -yl methyl )-2-methyl- phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
1 .15 (R)-4-Benzyloxy-1 -{2-[4-(3-hydroxy-piperidin-1 -ylmethyl)-2-methyl- phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
1 .17 (S)-4-Benzyloxy-1 -{2-[4-(2-hydroxymethyl-pyrrolidin-1 -yl methyl )-2- methyl-phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one 4-(5-Chloro-pyridin-2-ylmethoxy)-1 -{2-[4-((S)-2-hydroxymethyl- pyrrolidin-1 -yl methyl )-2-methyl-phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
(R)-4-(5-Chloro-pyridin-2-ylmethoxy)-1 -{2-[4-(3-hydroxy-pyrrolidin-1 - yl methyl )-2-methyl-phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
4-(5-Chloro-pyridin-2-ylmethoxy)-1 -[2-(2-methyl-4-pyrrolidin-1 - ylmethyl-phenyl)-2-oxo-ethyl]-1 H-pyridin-2-one
4-(5-Chloro-pyridin-2-ylmethoxy)-1 -[2-(4-dimethylaminomethyl-2- methyl-phenyl)-2-oxo-ethyl]-1 H-pyridin-2-one
4-(5-Chloro-pyridin-2-ylmethoxy)-1 -[2-(4-ethylaminomethyl-2-methyl- phenyl)-2-oxo-ethyl]-1 H-pyridin-2-one
(R)-4-(5-Chloro-pyridin-2-ylmethoxy)-1 -{2-[4-(3-hydroxy-piperidin-1 - yl methyl )-2-methyl-phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
4-(5-Chloro-pyridin-2-ylmethoxy)-1 -{2-[4-(3-hydroxy-azetidin-1 - yl methyl )-2-methyl-phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
4-(5-Bromo-pyridin-2-ylmethoxy)-1 -[2-(4-dimethylaminomethyl-2- methyl-phenyl)-2-oxo-ethyl]-1 H-pyridin-2-one
4-(5-Bromo-pyridin-2-ylmethoxy)-1 -{2-[4-(4-hydroxy-piperidin-1 - yl methyl )-2-methyl-phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
4-(5-Bromo-pyridin-2-ylmethoxy)-1 -{2-[4-(4-hydroxymethyl-piperidin-1 - yl methyl )-2-methyl-phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
(S)-4-(5-Bromo-pyridin-2-ylmethoxy)-1 -{2-[4-(3-hydroxy-piperidin-1 - yl methyl )-2-methyl-phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
(S)-4-(5-Bromo-pyridin-2-ylmethoxy)-1 -{2-[4-(2-hydroxymethyl- pyrrolidin-1 -yl methyl )-2-methyl-phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
4-(5-Bromo-pyridin-2-ylmethoxy)-1 -[2-(4-ethylaminomethyl-2-methyl- phenyl)-2-oxo-ethyl]-1 H-pyridin-2-one
4-(5-Bromo-pyridin-2-ylmethoxy)-1 -[2-(2-methyl-4-pyrrolidin-1 -yl methyl -phenyl )-2-oxo-ethyl]-1 H-pyridin-2-one
(R)-4-(5-Bromo-pyridin-2-ylmethoxy)-1 -{2-[4-(3-hydroxy-pyrrolidin-1 - yl methyl )-2-methyl-phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
(R)-4-(5-Bromo-pyridin-2-ylmethoxy)-1 -{2-[4-(3-hydroxy-piperidin-1 - yl methyl )-2-methyl-phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
4-(5-Bromo-pyridin-2-ylmethoxy)-1 -[2-(2-methyl-4-methylaminomethyl- phenyl )-2-oxo-ethyl]-1 H-pyridin-2-one
4-(5-Bromo-pyridin-2-ylmethoxy)-1 -{2-[4-(isopropylamino-methyl)-2- methyl-phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
4-(5-Bromo-pyridin-2-ylmethoxy)-1 -(2-{4-[(isopropyl-methyl-amino)- methyl]-2-methyl-phenyl}-2-oxo-ethyl)-1 H-pyridin-2-one
4-(5-Bromo-pyridin-2-ylmethoxy)-1 -(2-{4-[(ethyl-methyl-amino)- methyl]-2-methyl-phenyl}-2-oxo-ethyl)-1 H-pyridin-2-one
4-(5-Bromo-pyridin-2-ylmethoxy)-1 -[2-(4-diethylaminomethyl-2-methyl- phenyl)-2-oxo-ethyl]-1 H-pyridin-2-one
1 -[2-(4-Azetidin-1 -ylmethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-bromo- pyridin-2-ylmethoxy)-1 H-pyridin-2-one
5-Benzyloxy-2-[2-(4-dimethylaminomethyl-2-methyl-phenyl)-2-oxo- ethyl]-2H-pyridazin-3-one
(S)-5-Benzyloxy-2-{2-[4-(2-hydroxymethyl-pyrrolidin-1 -yl methyl )-2- methyl-phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one
(R)-5-Benzyloxy-2-{2-[4-(3-hydroxy-pyrrolidin-1 -ylmethyl)-2-nnethyl- phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one
5-Benzyloxy-2-[2-(4-ethylaminonnethyl-2-nnethyl-phenyl)-2-oxo-ethyl]- 2H-pyridazin-3-one
5-Benzyloxy-2-{2-[4-(3-hydroxy-azetidin-1 -ylmethyl)-2-nnethyl-phenyl]- 2-oxo-ethyl}-2H-pyridazin-3-one
5-Benzyloxy-2-{2-[2-methyl-4-(2-nnethyl-nnorpholin-4-yl methyl )- phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one
5-Benzyloxy-2-{2-[4-(4-hydroxymethyl-piperidin-1 -yl methyl )-2-methyl- phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one
(R)-5-Benzyloxy-2-{2-[4-(2-hydroxymethyl-piperidin-1 -yl methyl )-2- methyl-phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one
(S)-5-Benzyloxy-2-{2-[4-(3-hydroxy-piperidin-1 -yl methyl )-2-methyl- phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one
5-Benzyloxy-2-{2-[4-(3-hydroxy-3-methyl-pyrrolidin-1 -yl methyl )-2- methyl-phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one
5-(5-Fluoro-pyridin-2-ylmethoxy)-2-[2-(2-methyl-4-pyrrolidin-1 -ylmethy l-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one 5-(5-Fluoro-pyndin-2-ylmethoxy)-2-[2-(2-methyl-4-piperidin-1 -ylmethy l-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one
(S)-5-(5-Chloro-pyridin-2-ylmethoxy)-2-{2-[4-(2-hydroxymethyl- pyrrolidin-1 -yl methyl )-2-methyl-phenyl]-2-oxo-ethyl}-2H-pyridazin-3- one
5-(5-Chloro-pyridin-2-ylmethoxy)-2-[2-(2-methyl-4-methylaminomethyl- phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one
5-(5-Chloro-pyndin-2-ylmethoxy)-2-[2-(4-ethylaminomethyl-2-methyl- phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one
(R)-5-(5-Chloro-pyridin-2-ylmethoxy)-2-{2-[4-(2-hydroxymethyl- piperidin-1 -yl methyl )-2-methyl-phenyl]-2-oxo-ethyl}-2H-pyridazin-3- one
5-(5-Chloro-pyridin-2-ylmethoxy)-2-{2-[4-(4-hydroxy-piperidin-1 - yl methyl )-2-methyl-phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one
5-(5-Chloro-pyridin-2-ylmethoxy)-2-[2-(2-methyl-4-pyrrolidin-1 - ylmethyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one
5-(5-Chloro-pyridin-2-ylmethoxy)-2-[2-(4-dimethylaminomethyl-2- methyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one
5-(5-Bromo-pyridin-2-ylmethoxy)-2-{2-[4-(3-hydroxy-azetidin-1 - yl methyl )-2-methyl-phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one
5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(4-dimethylaminomethyl-2- methyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one
(R)-5-(5-Bromo-pyridin-2-ylmethoxy)-2-{2-[4-(3-hydroxy-piperidin-1 - yl methyl )-2-methyl-phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one
(R)-5-(5-Bromo-pyridin-2-ylmethoxy)-2-{2-[4-(2-hydroxymethyl- piperidin-1 -yl methyl )-2-methyl-phenyl]-2-oxo-ethyl}-2H-pyridazin-3- one
5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(4-ethylaminomethyl-2-methyl- phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one
5-(5-Bromo-pyridin-2-ylmethoxy)-2-{2-[4-(4-hydroxy-piperidin-1 - yl methyl )-2-methyl-phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one
5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(2-methyl-4-methylaminomethyl- phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one 9.1 2-[2-(4-Dimethylaminomethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5- methoxy-pyridin-2-ylmethoxy)-2H-pyridazin-3-one
9.2 2-{2-[4-(4-Hydroxy-piperidin-1 -yl methyl )-2-methyl-phenyl]-2-oxo- ethyl}-5-(5-methoxy-pyridin-2-ylmethoxy)-2H-pyridazin-3-one
9.3 5-(5-Methoxy-pyridin-2-ylmethoxy)-2-[2-(2-methyl-4-pyrrolidin-1 - ylmethyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one
9.4 5-(5-Methoxy-pyridin-2-ylmethoxy)-2-[2-(2-methyl-4- methylaminomethyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one
9.5 2-[2-(4-Ethylaminomethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-methoxy- pyridin-2-ylmethoxy)-2H-pyridazin-3-one
10.1 2-{2-[4-(1 -Dimethylamino-ethyl)-2-methyl-phenyl]-2-oxo-ethyl}-5-(5- methoxy-pyridin-2-ylmethoxy)-2H-pyridazin-3-one
10.2 5-(5-Methoxy-pyridin-2-ylmethoxy)-2-{2-[2-methyl-4-(1 -methylamino- ethyl)-phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one including any tautomers and stereoisomers thereof, or a salt thereof or a solvate or hydrate thereof. The compounds according to the invention and their intermediates 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 analogously to the methods of preparation explained more fully hereinafter, in particular as described in the experimental section. In some cases the sequence adopted in carrying out the reaction schemes may be varied. Variants of these reactions that are known to the skilled man but are not described in detail here may also be used. The general processes for preparing the compounds according to the invention will become apparent to the skilled man on studying the schemes that follow. Starting compounds are commercially available or may be prepared by methods that are described in the literature or herein, or may be prepared in an analogous or similar manner. Before the reaction is carried out any corresponding functional groups in the compounds may be protected using conventional protecting groups. These protecting groups may be cleaved again at a suitable stage within the reaction sequence using methods familiar to the skilled man. Scheme 1 :
Figure imgf000024_0001
Figure imgf000024_0002
To obtain a compound of general formula (1 -3) according to scheme 1 , a compound of general formula (1 -1 ) is reacted with a compound of general formula (1 -2) in the presence of a base. Suitable bases are particularly inorganic bases such as carbonates, especially cesium carbonate and potassium carbonate. Suitable leaving groups (LG) are preferably selected from bromide, chloride, iodide, trifluoroacetate, tnfluoromethanesulfonate, methanesulfonate and toluenesulfonate and the like. The reaction is preferably carried out in an inert organic solvent such as DMF, N,N- dimethylacetamide, DMSO, acetonitrile, THF, methylene chloride or a mixture of solvents. The reaction usually takes place within 2 to 48 hours. Preferred reaction temperatures are between 0°C and 150°C. Ortho-methyl acetophenone precursors for the synthesis of a compounds of general formula (1 -1 ) can be prepared from the corresponding ortho-methyl aryl iodides or bromides via Heck reaction with alkyl vinyl ethers followed by hydrolysis of the vinyl ether, for instance as described in J. Org. Chem. 2001 , 66, 4340-4343. To obtain a compound of general formula (1 -4) according to scheme 1 , the alcohol function in compounds of the general formula (1 -3) is transferred into a leaving group. Suitable leaving groups (LG) are preferably selected from bromide, chloride, iodide, trifluoroacetate, trifluoromethanesulfonate, methanesulfonate and toluenesulfonate and the like. The methods for preparing the mentioned leaving groups are known to the one skilled in the art and are described in the literature of organic synthesis.
To obtain a compound of general formula (1 -5) according to scheme 1 , a compound of general formula (1 -4) is reacted with an amine HNR1R2. The amine HNR1R2 is used in excess (about 2 to 4 mol equivalents based on the compound 1 -4). In case of valuable amines HNR1R2 or amines HNR1R2 being present as salts, for instance as the hydrochloride salts, a non nucleophilic organic base, preferably triethylamine, diisopropyl-ethylamine, potassium carbonate or cesium carbonate, can be added, so that only 1 .0 equivalent of HNR1R2 has to be used. The reactions are preferably carried out in an inert organic solvent like DMF, Ν,Ν-dimethylacetamide, methylene chloride, acetonitrile or THF, or mixtures thereof. DMF and N,N-dimethylacetamide are preferred solvents. The reaction usually takes place within 2 to 48 hours. A preferred temperature range for this reaction is 20°C to 150°C, preferably 20°C to 80°C.
heme 2:
Figure imgf000026_0001
To obtain a compound of general formula (2-3) according to scheme 2, a compound of general formula (2-1 ) is reacted with a compound of general formula (2-2) in the presence of a base. Suitable bases are particularly inorganic bases such as carbonates, especially potassium carbonate. Suitable leaving groups (LG) are preferably selected from bromide, chloride, iodide, trifluoroacetate, trifluoromethanesulfonate, methanesulfonate and toluenesulfonate and the like. The reaction is preferably carried out in an inert organic solvent such as DMF, acetonitrile, THF, methylene chloride or a mixture of solvents. DMF is the preferred solvent. The reaction usually takes place within 2 to 48 hours. Preferred reaction temperatures are between -20°C and 120°C, preferably 0°C to 60°C.
To obtain a compound of general formula (2-4) according to scheme 2, the alcohol function in compounds of the general formula (2-3) is transferred into a leaving group. Suitable leaving groups (LG) are preferably selected from bromide, chloride, iodide, trifluoroacetate, trifluoromethanesulfonate, methanesulfonate and toluenesulfonate and the like. The methods for preparing the mentioned leaving groups are known to the one skilled in the art and are described in the literature of organic synthesis. To obtain a compound of general formula (2-5) according to scheme 2, a compound of general formula (2-4) is reacted with an amine HNR1R2. The amine HNR1R2 is used in excess (about 2 to 4 mol equivalents based on the compound 2-4). In case of valuable amines HNR1R2 or amines HNR1R2 being present as salts, for instance the hydrochloride salts, a non nucleophilic organic base, preferably triethylamine, diisopropyl-ethylannine, potassium carbonate or cesium carbonate, can be added, so that only 1 .0 equivalent of HNR1R2 has to be used. The reactions are preferably carried out in an inert organic solvent like DMF, Ν,Ν-dimethylacetamide, methylene chloride, acetonitrile or THF, or mixtures thereof. DMF is the preferred solvent. The reaction usually takes place within 2 to 48 hours. A preferred temperature range for this reaction is 0°C to 150°C, preferably 20°C to 80°C.
The synthetic routes presented may rely on the use of protecting groups. For example reactive groups present, such as hydroxy, carbonyl, carboxy, amino, alkylamino, or imino, may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction. Suitable protecting groups for the respective functionalities and their removal are well known to the one skilled in the art and are described in the literature of organic synthesis. The compounds of general formula I may be resolved into their enantiomers and/or diastereomers as mentioned before. Thus, for example, cis/trans mixtures may be resolved into their cis and trans isomers and racemic compounds may be separated into their enantiomers. The cis/trans mixtures may be resolved, for example, by chromatography into the cis and trans isomers thereof. The compounds of general formula I which occur as racemates may be separated by methods known per se into their optical antipodes and diastereomeric mixtures of compounds of general formula I may be resolved into their diastereomers by taking advantage of their different physico-chemical properties using methods known per se, e.g. chromatography and/or fractional crystallization; if the compounds obtained thereafter are racemates, they may be resolved into the enantiomers as mentioned above. The racemates are preferably resolved by column chromatography on chiral phases or by crystallization from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as esters or amides with the racemic compound. Salts may be formed with enantiomerically pure acids for basic compounds and with enantiomerically pure bases for acidic compounds.
Diastereomeric derivatives are formed with enantiomerically pure auxiliary
compounds, e.g. acids, their activated derivatives, or alcohols. Separation of the diastereomeric mixture of salts or derivatives thus obtained may be achieved by taking advantage of their different physico-chemical properties, e.g. differences in solubility; the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents.
As mentioned above, the compounds of formula I may be converted into salts, particularly for pharmaceutical use into the pharmaceutically acceptable salts, for example into the chlorides. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof, for example salts with hydrochloric acid.
Terms and definitions
Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to. The terms "compound(s) according to this invention", "compound(s) of formula I", "compound(s) of the invention" and the like denote the compounds of the formula I according to the present invention including their tautomers, stereoisomers and mixtures thereof and the salts thereof, in particular the pharmaceutically acceptable salts thereof, and the solvates and hydrates of such compounds, including the solvates and hydrates of such tautomers, stereoisomers and salts thereof.
The terms "treatment" and "treating" embraces both preventative, i.e. prophylactic, or therapeutic, i.e. curative and/or palliative, treatment. Thus the terms "treatment" and "treating" comprise therapeutic treatment of patients having already developed said condition, in particular in manifest form. Therapeutic treatment may be symptomatic treatment in order to relieve the symptoms of the specific indication or causal treatment in order to reverse or partially reverse the conditions of the indication or to stop or slow down progression of the disease. Thus the compositions and methods of the present invention may be used for instance as therapeutic treatment over a period of time as well as for chronic therapy. In addition the terms "treatment" and "treating" comprise prophylactic treatment, i.e. a treatment of patients at risk to develop a condition mentioned hereinbefore, thus reducing said risk. When this invention refers to patients requiring treatment, it relates primarily to treatment in mammals, in particular humans.
The term "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats or prevents the particular disease or condition, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease or condition, or (iii) prevents or delays the onset of one or more symptoms of the particular disease or condition described herein.
The terms "modulated" or "modulating", or "modulate(s)", as used herein, unless otherwise indicated, refers to the deactivation of the melanin-concentrating hormone (MCH), in particular blockade or antagonism of the MCH receptor 1 with one or more compounds of the present invention.
The terms "mediated" or "mediating" or "mediate", as used herein, unless otherwise indicated, refers to the (i) treatment, including prevention of the particular disease or condition, (ii) attenuation, amelioration, or elimination of one or more symptoms of the particular disease or condition, or (iii) prevention or delay of the onset of one or more symptoms of the particular disease or condition described herein. The term "body mass index" or "BMI" of a human patient is defined as the weight in kilograms divided by the square of the height in meters, such that BMI has units
of kg/m2. The term "overweight" is defined as the condition wherein the individual has a BMI greater than or 25 kg/m2 and less than 30 kg/m2. The terms "overweight" and "pre-obese" are used interchangeably. The term "obesity" is defined as the condition wherein the individual has a BMI equal to or greater than 30 kg/m2. According to a WHO definition the term obesity may be categorized as follows: the term "class I obesity" is the condition wherein the BMI is equal to or greater than 30 kg/m2 but lower than 35 kg/m2; the term "class II obesity" is the condition wherein the BMI is equal to or greater than 35 kg/m2 but lower than 40 kg/m2; the term "class III obesity" is the condition wherein the BMI is equal to or greater than 40 kg/m2.
The term "visceral obesity" is defined as the condition wherein a waist-to-hip ratio of greater than or equal to 1.0 in men and 0.8 in women is measured. It defines the risk for insulin resistance and the development of pre-diabetes.
The term "abdominal obesity" is usually defined as the condition wherein the waist circumference is > 40 inches or 102 cm in men, and is > 35 inches or 94 cm in women. With regard to a Japanese ethnicity or Japanese patients abdominal obesity may be defined as waist circumference≥ 85 cm in men and≥ 90 cm in women (see e.g. investigating committee for the diagnosis of metabolic syndrome in Japan).
The term "substituted" as used herein, means that any one or more hydrogens on the designated atom, radical or moiety is replaced with a selection from the indicated group, provided that the atom's normal valence is not exceeded, and that the substitution results in an acceptably stable compound.
In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, Ci-6-alkyl means an alkyl group or radical having 1 to 6 carbon atoms. In general, for groups comprising two or more subgroups, the last named subgroup is the radical attachment point, for example, the substituent "aryl-Ci-3-alkyl-" means an aryl grou p wh ich is bound to a Ci-3-alkyl- group, the latter of which is bound to the core or to the group to which the substituent is attached. In case a compound of the present invention is depicted in form of a chemical name and as a formula in case of any discrepancy the formula shall prevail.
An asterisk may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.
The numeration of the atoms of a substituent starts with the atom which is closest to the core or the group to which the substituent is attached.
For example, the term "3-carboxypropyl-group" represents the following substituent:
Figure imgf000031_0001
wherein the carboxy group is attached to the third carbon atom of the propyl group. The terms "1 -methylpropyl-", "2,2-dimethylpropyl-" or "cyclopropylmethyl-" group represent the followin groups:
Figure imgf000031_0002
The asterisk may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.
In a definition of a group the term "wherein each X, Y and Z group is optionally substituted with" or interchangeably "wherein each X, Y and Z group may be substituted with" and the like denotes that each group X, each group Y and each group Z either each as a separate group or each as part of a composed group may be substituted as defined. For example a definition "Rex denotes H, Ci-3-alkyl, C3-6- cycloalkyl, C3-6-cycloalkyl-Ci-3-alkyl or Ci-3-alkyl-O-, wherein each alkyl group is optionally substituted with one or more Lex" or the like means that in each of the beforementioned groups which comprise the term alkyl, i.e. in each of the groups Ci- 3-alkyl, C3-6-cycloalkyl-Ci-3-alkyl and Ci-3-alkyl-O-, the alkyl moiety may be substituted with Lex as defined. Unless specifically indicated, throughout the specification and the appended claims, a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers etc ..) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including
pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.
As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. A preferred example are chlorides of the compound according to the invention.
Salts of acids which for example are useful for purifying or isolating the compounds of the present invention (e.g. trifluoro acetate salts) also comprise a part of the invention.
The term halogen generally denotes fluorine, chlorine, bromine and iodine.
The term "Ci-n-alkyl", wherein n is an integer from 1 to n, either alone or in
combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms. For example, the term Ci-5-alkyl embraces the radicals H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C- CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2- CH(CH2CH3)-.
The term "Ci-n-alkylene" wherein n is an integer 1 to n, either alone or in combination with another radical, denotes an acyclic, straight or branched chain divalent alkyl radical containing from 1 to n carbon atoms. For example, the term Ci-4-alkylene includes -(CH2)-, -(CH2-CH2)-, -(CH(CH3))-, -(CH2-CH2-CH2)-, -(C(CH3)2)-, - (CH(CH2CH3))-, -(CH(CH3)-CH2)-, -(CH2-CH(CH3))-, -(CH2-CH2-CH2-CH2)-, -(CH2- CH2-CH(CH3))-, -(CH(CH3)-CH2-CH2)-, -(CH2-CH(CH3)-CH2)-, -(CH2-C(CH3)2)-, -(C (CH3)2-CH2)-, -(CH(CH3)-CH(CH3))-, -(CH2-CH(CH2CH3))-, -(CH(CH2CH3)-CH2)-, -(CH(CH2CH2CH3))- , -(CHCH(CH3) 2)- and -C(CH3)(CH2CH3)-.
The term "C3-n-cycloalkyl", wherein n is an integer 4 to n, either alone or in
combination with another radical denotes a cyclic, saturated, unbranched
hydrocarbon radical with 3 to n C atoms. The cyclic group may be mono-, bi-, tri- or spirocyclic, most preferably monocyclic. Examples of such cycloalkyi groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo[3.2.1 .]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl, etc.
Many of the terms given above may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another. Pharmacological Activity
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.
Furthermore the compounds according to the invention have an improved metabolic stability. An improved metabolic stability in an in vitro test system, for example incubation with human hepatocytes, typically results in a reduced total body clearance (CL). To achieve a given systemic exposure (area under the curve, AUC) the drug can typically be dosed in a lower amount. The pharmacokinetic relationship describing this relationship is CL/F = Dose / AUC (F corresponds to oral bioavailability). Lower dosages have the advantages of lower drug load of parent drug and metabolites for the patient and lower production costs for the drug product. Pharmacological test systems for MCH-antagonistic properties as well as for metabolic stability are described in the following experimental section.
As antagonists of the MCH receptor the compounds according to the invention are advantageously suitable as pharmaceutical active substances for the treatment of conditions and/or diseases caused by MCH or causally connected with MCH in some other way. Generally the compounds according to the invention have low toxicity, they are well absorbed by oral route and have good intracerebral transitivity, particularly brain accessibility.
Therefore, MCH antagonists which contain at least one compound according to the invention are particularly suitable in mammals, in particular humans, for the treatment of conditions or diseases which are caused by MCH or are otherwise causally connected with MCH, in particular conditions or diseases which are mediated by blocking the MCH receptor, in particular MCH-1 R.
Diseases or conditions caused by MCH or otherwise causally connected with MCH, in particular diseases or conditions mediated by blocking the MCH receptor are particularly metabolic disorders, such as for example overweight, obesity, and eating disorders, such as for example bulimia, including bulimia nervosa. The indication obesity includes in particular class I obesity, class II obesity, class III obesity, visceral obesity, abdominal obesity, 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. In particular compounds according to the invention may be suitable to reduce food consumption in overweigth or obese patients.
In addition, 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 treatment of other illnesses and/or disorders, particularly those which accompany obesity, such as for example diabetes, diabetes mellitus, particularly type II diabetes mellitus, 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.
Furthermore compounds according to the invention may be suitable in the treatment of obesity in conjunction with a calorie-reduced diet.
Furthermore compounds according to the invention may be suitable for inducing weight loss and/or maintaining of weight loss in in conjunction with a calorie-reduced diet, in particular in obese or overweight patients. Furthermore compounds according to the invention may be suitable for reducing body weight in overweight or obese patients, in particular in conjunction with a calorie-reduced diet. The treatment with one or more compounds according to the invention is preferred in obese patients with an initial body mass index (BMI) greater or equal 30 kg/m2, or in overweight patients with an initial BMI greater or equal 27 kg/m2 , in particular in obese or overweight patients in the presence of weight-related comorbidities.
Another range of indications for which the compounds according to the invention are advantageously suitable is the 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.
Generally speaking, the compounds according to the invention are potentially suitable for 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. By "dependency" 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. In particular, the term "dependency" is used here to denote a dependency on an addictive substance. By "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 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. The term addictive substances refers particularly but not exclusively to substances with a psycho-motor activity, such as narcotics or drugs, particularly alcohol, nicotine, cocaine, amphetamine, opiates, benzodiazepines and barbiturates. Furthermore compounds according to the invention may be suitable in the treatment of intestinal inflammation such as cause by inflammatory bowel disease, colitis and/or Crohn's disease. The assessment of activity of compounds of formula I may be carried out employing the assays as described in Kokkotou, E. et al., "Melanin- concentrating hormone as a mediator of intestinal inflammation", PNAS, 105 (30); 10613-10618.
The dosage required to achieve such one or more the effect as described
hereinbefore 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 administration, 0.01 to 50 mg/kg of body weight, preferably 0.05 to 10 mg/kg of body weight, in each case 1 to 3 x daily. A preferred embodiment is an oral administration once or twice daily. A single dose for a human patient is for example in the range from 1 to 200 mg once or twice daily.
The actual therapeutically effective amount or therapeutic dosage will of course depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease. In any case the compound or composition will be administered at dosages and in a manner which allows a therapeutically effective amount to be delivered based upon patient's unique condition.
Pharmaceutical Compositions
Suitable preparations for administering the compounds of formula I will be apparent to those with ordinary skill in the art and include for example tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injectables, inhalatives and powders etc. Oral formulations, particularly solid forms such as e.g. tablets or capsules are preferred. The content of the pharmaceutically active compound(s) is advantageously in the range from 0.1 to 90 wt.-%, for example from 1 to 70 wt.-% of the composition as a whole. Suitable tablets may be obtained, for example, by mixing one or more compounds according to formula I with known excipients, for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants. The tablets may also consist of several layers. The particular excipients, carriers and/or diluents that are suitable for the desired preparations will be familiar to the skilled man on the basis of his specialist knowledge. The preferred ones are those that are suitable for the particular formulation and method of administration that are desired. The
preparations or formulations according to the invention may be prepared using methods known per se that are familiar to the skilled man, such as for example by mixing or combining at least one compound of formula I according to the invention, or a pharmaceutically acceptable salt of such a compound, and one or more excipients, for example carriers and/or diluents.
The actual therapeutically effective amount or therapeutic dosage will of course depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease. In any case the compound or composition will be administered at dosages and in a manner which allows a therapeutically effective amount to be delivered based upon patient's unique condition. Other features and advantages of the present invention will become apparent from the following more detailed Examples which illustrate, by way of example, the principles of the invention. Examples
Preliminary remarks:
As a rule, 1 H-NMR and/or mass spectra have been obtained for the examples of the invention. The Rf values are determined using ready-made silica gel 60 TLC plates F254 (E. Merck, Darmstadt, Item no. 1 .05714) without chamber saturation or using ready-made aluminium oxide 60 F254 TLC plates (E. Merck, Darmstadt, Item no.
1 .05713) without chamber saturation.
The HPLC data given are measured under the following conditions: method A: analytical column: Waters, Xbridge C18, 3.0 x 30 mm, 2.5 μιτι
column temperature: room temperature
Solvent A: 0.1 % NH3 in water
Solvent B: 0.1 % NH3 in acetonitrile
time in min %A %B flow rate in ml/min
0.00 95.0 5.0 1 .40
1 .80 10.0 90.0 1 .40
2.00 10.0 90.0 1 .40
2.20 95.0 5.0 1 .40 method B: analytical column: Waters, Xbridge C18, 3.0 x 30 mm, 2.5 μιτι
column temperature: room temperature
Solvent A: 0.1 % HCOOH in water
Solvent B: 0.1 % HCOOH in acetonitrile
time in min %A %B flow rate in ml/min
0.00 95.0 5.0 1 .60
0.10 95.0 5.0 1 .60
1 .75 5.0 95.0 1 .60
1 .90 5.0 95.0 1 .60
1 .95 95.0 5.0 1 .60
2.00 95.0 5.0 1 .60 method C: analytical column: Waters, Xbridge C18, 4.6 x 30 mm, 3.5 μιτι column temperature: 60°C
Solvent A: 0.1 % NH3 in water
Solvent B: methanol
time in min %A %B flow rate in ml/min
0.00 95.0 5.0 4.0
0.15 95.0 5.0 4.0
1 .70 0.0 100.0 4.0
2.10 0.0 100.0 4.0 method D: analytical column: Waters, Sunfire C18, 3.0 x 30 mm, 2.5 μιτι column temperature: 60°C
Solvent A: 0.1 % TFA in water
Solvent B: methanol
time in min %A %B flow rate in ml/min
0.00 95.0 5.0 2.2
0.05 95.0 5.0 2.2
1 .40 0.0 100.0 2.2
1 .80 0.0 100.0 2.2 method E: analytical column: Waters, Xbridge C18, 3.0 x 30 mm, 2.5 μιτι column temperature: 60°C
Solvent A: 0.1 % NH3 in water
Solvent B: methanol
time in min %A %B flow rate in ml/min
0.00 95.0 5.0 2.2
0.05 95.0 5.0 2.2
1 .40 0.0 100.0 2.2
1 .80 0.0 100.0 2.2
method F: analytical column: Waters, StableBond C18, 3.0 x 30 mm, 1 .8 μιτι column temperature: 60°C
Solvent A: 0.1 % TFA in water
Solvent B: methanol time in min %A %B flow rate in ml/min
0.00 95.0 5.0 2.2
0.05 95.0 5.0 2.2
1 .40 0.0 100.0
1 .80 0.0 100.0 method G: analytical column: Zorbax, StableBond C18, 3.0 x 30 mm, 1 .8 μιτι column temperature: room temperature
Solvent A: 0.1 % HCOOH in water
Solvent B: 0.1 % HCOOH in acetonitrile
time in min %A %B flow rate in ml/min
0.00 95.0 5.0 1 .4
0.10 95.0 5.0 1 .4
1 .75 5.0 95.0 1 .4
1 .90 5.0 95.0 1 .4
The melting points of crystalline compounds of the invention or salts thereof are determined by Differential Scanning Calorimetry (DSC) and evaluated by the onset temperature. The heating rate of the experiments are 10°C/min. The values are determined using a DSC instrument from the Q-series™ of TA Instruments.
The following abbreviations are used above and hereinafter:
BOC terf-Butyl carbonate
cal. Calculated
CDI 1 ,1 '-Carbonyl-di-imidazole
CO Carbon monoxide
DCM Dichloromethane
DMAP Dimethyl-pyridin-4-yl-amine
DMF Λ/,/V-Dimethylformamide
DMSO Dimethylsulfoxide
Ell Electron impact ionisation
ESI Electron spray ionisation
EtOAc Ethyl acetate h Hour
HCI Hydrochloric acid
Hg Mercury
hPa hecto Pascale
HPLC High pressure liquid chromatography
K2CO3 Potassium crabonate
KHSO4 Potassium hydrogen sulfate
MeOH Methanol
MgSO4 Magnesium sulfate
min Minutes
Na2CO3 Sodium carbonate
NaHCOs Sodiumhydrogencarbonate
NH3 Ammonia
NH4OH Ammoniumhydroxide
OMe Methoxy
Pd/C Palladium on charcoal
PE Petrolether
RT Ambient temperature or room temperature (approx. 20°C)
TFA Trifluoro acidic acid
THF Tetrahydrofuran
Preparation of starting materials:
Preparation 1 :
4-Benz loxy-1 -[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-1 H-pyridin-2-one
Figure imgf000042_0001
1 a 1 -(4-Hydroxymethyl-2-methyl-phenyl)-ethanone
To a solution of (4-iodo-3-methylphenyl)methanol (9.70 g, 39.1 mol) in a mixture of water (25 mL) and DMF (100 mL) is added under argon K2CO3 (6.49 g, 46.9 mmol), palladium(ll) acetate (263 mg, 1 .17 mmol), 1 ,3-bis(diphenylphosphino)-propane (1064 mg, 2.58 mmol), LiCI (4.14 g, 97.7 mmol) and butyl vinyl ether (12.7 mL, 97.7 mmol). The mixture is heated at 90°C for 7 h. After cooling to room temperature, 1 N aqueous HCI (50 mL) is added and the mixture is stirred for 30 min. The mixture is diluted with EtOAc and washed with aqueous K2CO3 solution. The organic layer is dried over MgSO4, concentrated under reduced pressure and purified
chromatographically (silica gel, cyclohexane / EtOAc 7:3).
Yield: 3.60 g (56% of theory)
ESI mass spectrum: [M+H]+ = 165
Rf-value: 0.14 (silica gel, cyclohexane / EtOAc 7:3)
1 b 2-Bromo-1 -(4-hydroxymethyl-2-methyl-phenyl)-ethanone
To a solution of 1 -(4-hydroxymethyl-2-methyl-phenyl)-ethanone (preparation 1 a, 600 mg, 3.65 mmol) in CH2CI2 (25 mL) is added tetrabutylammonium tribromide in several portions (1 .76 g, 3.65 mmol). The reaction mixture is stirred for 30 min at room temperature. After washing with water, the organic layer is dried over MgSO4 and concentrated under reduced pressure. The remaining residue is dissolved in hexanes / EtOAc 3:7 and filtered over silica gel.
Yield: 890 mg (quantitative)
ESI mass spectrum: [M+H]+ = 243
1 c 4-Benzyloxy-1 -[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-1 H-pyridin- 2-one
To a solution of 4-benzyloxy-1 H-pyridin-2-one (728 mg, 3.62 mmol) in DMSO (4.00 mL) is added cesium carbonate (2.95 g, 9.05 mmol) and the mixture is stirred 15 min at room temperature. 2-Bromo-1 -(4-hydroxymethyl-2-methyl-phenyl)-ethanone
(preparation 1 b, 880 mg, 3.62 mmol) is added in portions and the mixture and is stirred 2 h at room temperature. After addition of water, the precipitate is collected, washed with water and dried.
Yield: 1 .10 g (84% of theory)
ESI mass spectrum: [M+H]+ = 364
Retention time HPLC: 1 .57 min (METHOD A). 1 d 4-Benzyloxy-1 -[2-(4-bromonnethyl-2-nnethyl-phenyl)-2-oxo-ethyl]-1 H-pyridin-2- one
To a solution of 4-benzyloxy-1 -[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-1 H- pyridin-2-one (preparation 1 c, 1 .10 g, 3.03 mmol) in CH2CI2 (20 mL) is added slowly phosphorus tribromide (199 μΙ_, 2.12 mmol) at 0°C. The cooling bath is removed and the mixture is stirred for 1 h at room temperature. After cooling, the reaction mixture is quenched with aqueous NaHCO3 solution and extracted with CH2CI2. The organic layer is washed with water, dried over MgSO4, and concentrated under reduced pressure.
Yield: 650 mg (50% of theory)
ESI mass spectrum: [M+H]+ = 426
Retention time HPLC: 1 .84 min (METHOD A).
Preparation 2:
1 -[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-fluoro-pyridin-2-ylmethoxy)- -pyridin-2-one
Figure imgf000044_0001
2a 4-(5-Fluoro-pyridin-2-ylmethoxy)-1 -[2-(4-hydroxymethyl-2-methyl-phenyl)-2- oxo-ethyl]-1 H-pyridin-2-one
4-(5-Fluoro-pyridin-2-ylmethoxy)-1 -[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo- ethyl]-1 H-pyridin-2-one is prepared following preparation 1 c employing 4-(5-fluoro- pyridin-2-ylmethoxy)-1 H-pyridin-2-one (described in WO 09/103478) instead of 4- benzyloxy-1 H-pyridin-2-one.
Yield: 90% of theory
ESI mass spectrum: [M+H]+ = 383
Retention time HPLC: 1 .42 min (METHOD A).
2b 1 -[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-fluoro-pyridin-2- ylmethoxy)-1 H-pyridin-2-one 1 - [2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-fluoro-pyridin-2-ylmethoxy)- 1 H-pyridin-2-one is prepared following preparation 1 d employing 4-(5-fluoro-pyridin-
2- ylmethoxy)-1 -[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-1 H-pyridin-2-one (preparation 2a) instead of preparation 1 c.
Yield: 93% of theory
ESI mass spectrum: [M+H]+ = 445
Retention time HPLC: 1 .72 min (METHOD A).
Preparation 3:
1 -[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-chloro-pyridin-2-ylmethoxy)- -pyridin-2-one
Figure imgf000045_0001
3a 4-(5-Chloro-pyridin-2-ylmethoxy)-1 -[2-(4-hydroxymethyl-2-methyl-phenyl)-2- oxo-ethyl]-1 H-pyridin-2-one
4-(5-Chloro-pyridin-2-ylmethoxy)-1 -[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo- ethyl]-1 H-pyridin-2-one is prepared following preparation 1 c employing 4-(5-chloro- pyridin-2-ylmethoxy)-1 H-pyridin-2-one (described in WO 09/103478) instead of 4- benzyloxy-1 H-pyridin-2-one.
Yield: 99% of theory
ESI mass spectrum: [M+H]+ = 399
Retention time HPLC: 1 .50 min (METHOD A).
3b 1 -[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-chloro-pyridin-2- ylmethoxy)-1 H-pyridin-2-one
1 - [2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-chloro-pyridin-2-ylmethoxy)- 1 H-pyridin-2-one is prepared following preparation 1 d employing 4-(5-chloro-pyridin-
2- ylmethoxy)-1 -[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-1 H-pyridin-2-one (preparation 3a) instead of preparation 1 c.
Yield: 90% of theory
ESI mass spectrum: [M+H]+ = 461 Retention time HPLC: 1 .80 min (METHOD A).
Preparation 4:
1 -[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-bromo-pyridin-2-ylmethoxy)- -pyridin-2-one
Figure imgf000046_0001
4a 4-(5-Bromo-pyridin-2-ylmethoxy)-1 -[2-(4-hydroxymethyl-2-methyl-phenyl)-2- oxo-ethyl]-1 H-pyridin-2-one
4- (5-Bromo-pyridin-2-ylmethoxy)-1 -[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo- ethyl]-1 H-pyridin-2-one is prepared following preparation 1 c employing 4-(5-bromo- pyridin-2-ylmethoxy)-1 H-pyridin-2-one (described in WO 09/103478) instead of 4- benzyloxy-1 H-pyridin-2-one.
Yield: 98% of theory
ESI mass spectrum: [M+H]+ = 443
Retention time HPLC: 1 .54 min (METHOD A).
4b 1 -[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-bromo-pyridin-2- ylmethoxy)-1 H-pyridin-2-one
1 - [2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-bromo-pyridin-2-ylmethoxy)- 1 H-pyridin-2-one is prepared following preparation 1 d employing 4-(5-bromo-pyridin-
2- ylmethoxy)-1 -[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-1 H-pyridin-2-one (preparation 4a) instead of preparation 1 c.
Yield: 88% of theory
ESI mass spectrum: [M+H]+ = 505
Retention time HPLC: 1 .81 min (METHOD A).
Preparation 5:
5- Benzyloxy-2-[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one
Figure imgf000047_0001
5a 5-Benzyloxy-2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H- pyridazin-3-one
5-Benzyloxy-2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one is prepared following preparation 1 c employing 5-benzyloxy-2H-pyridazin-3-one
(described in WO 09/103478) instead of 4-benzyloxy-1 H-pyridin-2-one.
Yield: 81 % of theory
ESI mass spectrum: [M+H]+ = 365
Retention time HPLC: 1 .63 min (METHOD A).
5b 5-Benzyloxy-2-[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H-pyridazin- 3-one
5-Benzyloxy-2-[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one is prepared following preparation 1 d employing 5-benzyloxy-2-[2-(4-hydroxymethyl-2- methyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one (preparation 5a) instead of preparation 1 c.
Yield: 93% of theory
ESI mass spectrum: [M+H]+ = 427
Retention time HPLC: 1 .93 min (METHOD A).
Preparation 6:
2-[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-fluoro-pyridin-2-ylmethoxy)- 2H-pyridazin-3-one
Figure imgf000047_0002
6a 5-(5-Fluoro-pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2- oxo-ethyl]-2H-pyridazin-3-one
5-(5-Fluoro-pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo- ethyl]-2H-pyridazin-3-one is prepared following preparation 1 c employing 5-(5-fluoro- pyridin-2-ylmethoxy)-2H-pyridazin-3-one (described in WO 09/103478) instead of 4- benzyloxy-1 H-pyridin-2-one.
Yield: 91 % of theory
ESI mass spectrum: [M+H]+ = 384
Retention time HPLC: 1 .46 min (METHOD A).
6b 2-[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-fluoro-pyridin-2- ylmethoxy)-2H-pyridazin-3-one
2-[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-fluoro-pyridin-2-ylmethoxy)-
2H-pyridazin-3-one is prepared following preparation 1d employing 5-(5-fluoro- pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H- pyridazin-3-one (preparation 6a) instead of preparation 1 c.
Yield: 92% of theory
ESI mass spectrum: [M+H]+ = 446
Retention time HPLC: 1 .78 min (METHOD A).
Preparation 7:
2-[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-chloro-pyridin-2-ylmethoxy)- -pyridazin-3-one
Figure imgf000048_0001
7a 5-(5-Chloro-pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2- oxo-ethyl]-2H-pyridazin-3-one
5-(5-Chloro-pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo- ethyl]-2H-pyridazin-3-one is prepared following preparation 1 c employing 5-(5-chloro- pyridin-2-ylmethoxy)-2H-pyridazin-3-one (described in WO 09/103478) instead of 4- benzyloxy-1 H-pyridin-2-one.
Yield: 91 % of theory
ESI mass spectrum: [M+H]+ = 400
Retention time HPLC: 1 .54 min (METHOD A).
7b 2-[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-chloro-pyridin-2- ylmethoxy)-2H-pyridazin-3-one
2-[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-chloro-pyridin-2-ylmethoxy)-
2H-pyridazin-3-one is prepared following preparation 1d employing 5-(5-chloro- pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H- pyridazin-3-one (preparation 7a) instead of preparation 1 c.
Yield: 83% of theory
ESI mass spectrum: [M+H]+ = 462
Retention time HPLC: 1 .85 min (METHOD A).
Preparation 8:
2-[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-bromo-pyridin-2-ylmethoxy)- -pyridazin-3-one
Figure imgf000049_0001
8a 5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2- oxo-ethyl]-2H-pyridazin-3-one
5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo- ethyl]-2H-pyridazin-3-one is prepared following preparation 1 c employing 5-(5-bromo- pyridin-2-ylmethoxy)-2H-pyridazin-3-one (described in WO 09/103478) instead of 4- benzyloxy-1 H-pyridin-2-one.
Yield: 90% of theory
ESI mass spectrum: [M+H]+ = 444
Retention time HPLC: 1 .58 min (METHOD A). 8b 2-[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-bromo-pyridin-2- ylmethoxy)-2H-pyridazin-3-one
2-[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-bromo-pyridin-2-ylmethoxy)- 2H-pyridazin-3-one is prepared following preparation 1d employing 5-(5-bromo- pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H- pyridazin-3-one (preparation 8a) instead of preparation 1 c.
Yield: 59% of theory
ESI mass spectrum: [M+H]+ = 506
Preparation 9:
2-[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-methoxy-pyridin-2- ylmethoxy)-2H-pyridazin-3-one
Figure imgf000050_0001
9a 5-(5-Methoxy-pyridin-2-ylmethoxy)-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3- one
To a solution of 5-hydroxy-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (described in preparation 5a of WO 08/022979, 705 mg, 3.59 mmol) and (5-methoxy-pyridin-2-yl)- methanol (Milestone Pharmtech, 500 mg, 3.59 mmol) in THF (10 ml_) is added polymer-bound triphenylphosphine (2.40 g, 3 mmol/g, 7.2 mmol). After cooling to 0°C, diisopropyl azodicarboxylate (1 .42 ml_, 7.2 mmol) is added slowly. Afterwards, the reaction mixture is stirred for 3 h at room temperature. The reaction mixture is filtered and the solvent is evaporated. The residue is purified via reverse phase HPLC chromatography (Waters XBridge 5 μιτι, gradient 5% -> 90% acetonitrile in water + 0.3% NH4OH).
Yield: 500 mg (44% of theory)
ESI mass spectrum: [M+H]+ = 318
Retention time HPLC: 1 .49 min (METHOD A). 9b 5-(5-Methoxy-pyridin-2-ylmethoxy)-2H-pyridazin-3-one
A solution of 5-(5-methoxy-pyridin-2-ylmethoxy)-2-(tetrahydro-pyran-2-yl)-2H- pyridazin-3-one (500 mg, 1 .58 mmol) in a mixture of MeOH (5 mL) and concentrated aqueous HCI (0.65 mL) is heated at reflux for 2h. Most of the volatiles are removed under reduced pressure and water is added. The formed precipitate is filtered off and dried.
Yield: 400 mg (quantitative)
ESI mass spectrum: [M+H]+ = 234
Retention time HPLC: 1 .12 min (METHOD A).
9c 2-[2-(4-Hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-methoxy-pyridin-2- ylmethoxy)-2H-pyridazin-3-one
2-[2-(4-Hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-methoxy-pyridin-2- ylmethoxy)-2H-pyridazin-3-one is prepared following preparation 1 c employing 5-(5- methoxy-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 9b) instead of 4- benzyloxy-1 H-pyridin-2-one.
Yield: 70% of theory
ESI mass spectrum: [M+H]+ = 396
Retention time HPLC: 1 .60 min (METHOD A).
9d 2-[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-methoxy-pyridin-2- ylmethoxy)-2H-pyridazin-3-one
2-[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-methoxy-pyridin-2- ylmethoxy)-2H-pyridazin-3-one is prepared following preparation 1 d employing 2-[2-
(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-methoxy-pyridin-2-ylmethoxy)-
2H-pyridazin-3-one (preparation 9c) instead of preparation 1 c. The reaction mixture is stirred overnight. Tert-butyl methyl ether is added and the resulting precipitate is filtered off and dried.
Yield: 97% of theory
ESI mass spectrum: [M+H]+ = 458
Retention time HPLC: 1 .91 min (METHOD A).
Preparation 10: 2-{2-[4-(1 -Bromo-ethyl)-2-methyl-phenyl]-2-oxo-ethyl}-5-(5-methoxy-pyridin-2- ylmethoxy)-2H-pyridazin-3-one
Figure imgf000052_0001
10a 1 -[4-(1 -Hydroxy-ethyl)-2-methyl-phenyl]-ethanone
1 - [4-(1 -Hydroxy-ethyl)-2-methyl-phenyl]-ethanone is prepared following preparation 1 a employing 1 -(4-bromo-3-methyl-phenyl)-ethanol instead of (4-iodo-3-methyl- phenyl)methanol.
Yield: 49% of theory
10b 2-Bromo-1 -[4-(1 -hydroxy-ethyl)-2-methyl-phenyl]-ethanone
2- Bromo-1 -[4-(1 -hydroxy-ethyl)-2-methyl-phenyl]-ethanone is prepared following preparation 1 b employing 1 -[4-(1 -hydroxy-ethyl)-2-methyl-phenyl]-ethanone instead of 1 -(4-hydroxymethyl-2-methyl-phenyl)-ethanone.
Yield: 82% of theory
ESI mass spectrum: [M+H]+ = 257
10c 2-{2-[4-(1 -Hydroxy-ethyl)-2-methyl-phenyl]-2-oxo-ethyl}-5-(5-methoxy-pyridin- 2-ylmethoxy)-2H-pyridazin-3-one
To a solution of 5-(5-methoxy-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 9b, 2.00 g, 8.58 mmol) in DMSO (20 ml_) is added cesium carbonate (5.59 g, 17.2 mmol) and the mixture is stirred 10 min at room temperature. Then 2-bromo-1 -[4-(1 - hydroxy-ethyl)-2-methyl-phenyl]-ethanone (preparation 10b, 2.21 g, 8.58 mmol) is added in portions and the mixture is stirred overnight at room temperature. An additional 0.5 g of the bromoketone is added and the mixture is stirred for 3 h at room temperature. After addition of water, the reaction mixture is extracted with ethyl acetate. The combined organic layer is dried over MgSO4 and evaporated under reduced pressure.
Yield: 2.90 g (74% of theory)
ESI mass spectrum: [M+H]+ = 410 Retention time HPLC: 0.91 min (METHOD E).
10d 2-{2-[4-(1 -Bromo-ethyl)-2-methyl-phenyl]-2-oxo-ethyl}-5-(5-methoxy-pyridin-2- ylmethoxy)-2H-pyhdazin-3-one
2-{2-[4-(1 -Bromo-ethyl)-2-methyl-phenyl]-2-oxo-ethyl}-5-(5-methoxy-pyridin-2- ylmethoxy)-2H-pyhdazin-3-one is prepared following preparation 1 d employing 2-{2-
[4-(1 -Hydroxy-ethyl)-2-methyl-phenyl]-2-oxo-ethyl}-5-(5-methoxy-pyridin-2- ylmethoxy)-2H-pyridazin-3-one instead of preparation 1 c .
Yield: 93% of theory
ESI mass spectrum: [M+H]+ = 472
Retention time HPLC: 1 .58 min (METHOD C).
Preparation 1 1 :
1 -[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-methoxy-pyridin-2- ylmethoxy)-1 H-pyridin-2-one
Figure imgf000053_0001
1 1 a 2-Bromomethyl-5-methoxy-pyridine
To a suspension of (5-methoxypyridin-2-yl)-methanol (1 .00 g, 7.19 mmol) in CH2CI2 (15 mL) is added slowly under cooling phosphorus tribromide (473 μί, 5.03 mmol).
The reaction mixture is stirred overnight at room temperature. Tert-Butyl methyl ether
(50 mL) is added to the mixture. The formed precipitate is filtered off and dried.
Yield: 2.00 g crude material
ESI mass spectrum: [M+H]+ = 202
Retention time HPLC: 0.59 (METHOD D).
1 1 b 4-(5-Methoxy-pyridin-2-ylmethoxy)-1 H-pyridin-2-one
To a solution of 2-bromomethyl-5-methoxy-pyridine (preparation 1 1 a, 2.00 g crude material), 2,4-dihydroxypyridine (1 .06 g, 9.5 mmol) in acetonitrile (20 mL) and DMF (5 mL) is added K2CO3 and the mixture is stirred for 4h at 50°C and overnight at room temperature. The reaction mixture is diluted with water (60 mL) and extracted several times with ethyl acetate. The organic layer is dried over Na2SO4, concentrated under reduced pressure and purified via reverse phase HPLC chromatography (Waters XBridge 5 μπτι, gradient 25% -» 95% methanol in water + 0.3% NH4OH).
Yield: 532 mg (29% of theory)
ESI mass spectrum: [M+H]+ = 233
Retention time HPLC: 0.60 min (METHOD E).
1 1 c 1 -[2-(4-Hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-methoxy-pyridin-2- ylmethoxy)-1 H-pyridin-2-one
1 -[2-(4-Hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-methoxy-pyridin-2- ylmethoxy)-1 H-pyridin-2-one is prepared following preparation 1 c employing 4-(5- methoxy-pyridin-2-ylmethoxy)-1 H-pyridin-2-one (preparation 1 1 b) instead of 4- benzyloxy-1 H-pyridin-2-one.
Yield: 59% of theory
ESI mass spectrum: [M+H]+ = 395
Retention time HPLC: 0.89 min (METHOD F).
1 1 d 1 -[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-methoxy-pyridin-2- ylmethoxy)-1 H-pyridin-2-one
1 - [2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-methoxy-pyridin-2- ylmethoxy)-1 H-pyridin-2-one is prepared following preparation 1 d employing 1 -[2-(4- hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-methoxy-pyridin-2-ylmethoxy)-1 H- pyridin-2-one (preparation 1 1 c) instead of preparation 1 c. The reaction mixture is stirred overnight. Tert-butyl methyl ether is added and the resulting precipitate is filtered off and dried.
Yield: 80% of theory
ESI mass spectrum: [M+H]+ = 457
Retention time HPLC: 1 .12 min (METHOD F).
Preparation of example compounds:
Example 1 .1 4-Benzyloxy-1 -{2-[4-(3-hydroxy-azetidin-1 -ylmethyl)-2-methyl-phenyl]-
2- oxo-ethyl}-1 H-pyridin-2-one
Figure imgf000055_0001
To a solution of 4-benzyloxy-1 -[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-1 H- pyridin-2-one (preparation 1 d, 72 mg, 0.17 mmol) in DMF (2 ml_) is added 3- hydroxyazetidine hydrochloride (56 mg, 0.51 mmol). The reaction mixture is stirred for 30 min at room temperature. The mixture is purified via reverse phase HPLC chromatography (Gilson, Xbridge C18 5 μιτι, gradient 5% -> 90% acetonitrile in water
+ 0.3% NH4OH, 120 mL/min).
Yield: 43 mg (61 % of theory)
ESI mass spectrum: [M+H]+ = 419
Retention time HPLC: 1 .53 min (METHOD A).
The following examples are prepared as described for Example 1 .1 , employing the corres onding amines (as free base), respectively.
Figure imgf000055_0002
Retention
DSC
Yield time HPLC
Example R1R2N- Formula MS (melting
(%) in min
point) (method)
\ C23 H24 N2 377
1 .2 53 1 .62 (A)
03 [M+H]+
C27 H30 N2 447 Onset:
1 .3 62 1 .59 (A)
* 04 [M+H]+ 156°C
C26 H28 N2 433
1 .4 64 1 .67 (A)
* 04 [M+H]+
Figure imgf000056_0001
4-Benzyloxy-1 -{2-[4-(4-hydroxy-pipehdin-1 -ylmethyl)-2-methyl-phenyl]-2-oxo-ethyl}- 1 H- hdin-2-one, monohydrochlohde
Figure imgf000056_0002
The hydrochloride salt of the compound 1 .3 is prepared by adding a 1 .1 equivalent of HCI (as 10 M solution of HCI in ethanol) to a concentrated solution of the corresponding free base in refluxing ethanol. The hydrochloride salt, which precipitates upon cooling, is filtered off and dried under reduced pressure.
DSC (melting point) of the hydrochloride salt of the compound 1 .3: Onset: 217°C
4-Benzyloxy-1 -[2-(2-methyl-4-pyrrolidin-1 -ylmethyl-phenyl)-2-oxo-ethyl]-1 H-pyridin-2- one, monohydrochlohde
Figure imgf000057_0001
The hydrochloride salt of the compound 1 .7 is prepared by adding a 1 .1 equivalent of HCI (as 10 M solution of HCI in ethanol) to a concentrated solution of the corresponding free base in refluxing ethanol. The hydrochloride salt, which
precipitates upon cooling, is filtered off and dried under reduced pressure.
DSC (melting point) of the hydrochloride salt of the compound 1 .7: Onset: 199°C
Example 1 .10 4-Benzyloxy-1 -{2-[4-(3-hydroxy-3-methyl-pyrrolidin-1 -yl methyl )-2- meth l-phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
Figure imgf000057_0002
To a solution of 4-benzyloxy-1 -[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-1 H- pyridin-2-one (preparation 1 d, 100 mg, 0.24 mmol) in DMF (2 ml_) is added 3- hydroxy-3-methylpyrrolidine (28 mg, 0.28 mmol) and K2CO3 (65 mg, 0.47 mmol) . The reaction mixture is stirred overnight at 50°C. The mixture is purified via reverse phase HPLC chromatography (Phenomenex Gemini-C18 10 μιτι, gradient 5% ->
90% acetonitrile in water + 0.3% NH4OH, 120 mL/min).
Yield: 75 mg (72% of theory)
ESI mass spectrum: [M+H]+ = 447
Retention time HPLC: 1 .67 min (METHOD A).
The following examples are prepared as described for Example 1 .10, employing the corresponding amines, respectively, and Ν,Ν-dimethylacetamide (instead of DMF) as solvent.
Figure imgf000058_0001
Figure imgf000059_0001
Example 2.1 4-(5-Fluoro-pyridin-2-ylmethoxy)-1 -[2-(2-methyl-4-pyrrolidin-1 -ylmethyl- phenyl)-2-oxo-ethyl]-1 H-pyridin-2-one
Figure imgf000059_0002
To a solution of 1 -[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-fluoro- pyridin-2-ylmethoxy)-1 H-pyridin-2-one (preparation 2b, 1 1 1 mg, 0.25 mmol) in DMF (2 mL) is added pyrrolidine (63 μΙ_, 0.75 mmol). The reaction mixture is stirred for 60 min at room temperature. The mixture is purified via reverse phase HPLC
chromatography (Gilson Xbridge C18 5 μιτι, gradient 5% -> 90% acetonitrile in water + 0.3% NH OH, 120 mL/min).
Yield: 13 mg (12% of theory)
ESI mass spectrum: [M+H]+ = 436
Retention time HPLC: 0.70 min (METHOD A).
The following examples are prepared as described for Example 2.1 , employing the corresponding amines, respectively.
Figure imgf000059_0003
Figure imgf000060_0001
Example 3.1 4-(5-Chloro-pyridin-2-ylmethoxy)-1 -{2-[4-(4-ethyl-piperazin-1 -yimethyl )- 2-methyl-phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
Figure imgf000060_0002
To a solution of 1 -[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-chloro- pyridin-2-ylmethoxy)-1 H-pyridin-2-one (preparation 3b, 1 10 mg, 0.23 mmol) in N,N- dimethylacetamide (2 ml_) is added CS2CO3 (184 mg, 0.57 mmol) and N- ethylpiperazine (63 μΙ_, 0.75 mmol). The reaction mixture is stirred overnight at room temperature. The mixture is purified via reverse phase HPLC chromatography (Gilson Xb dge C18 5 μητι, gradient 5% -» 90% acetonitrile in water + 0.3% NH4OH, 120 mL/min).
Yield: 60 mg (54% of theory)
ESI mass spectrum: [M+H]+ = 495
Retention time HPLC: 1 .70 min (METHOD A).
The following examples are prepared as described for Example 3.1 , employing the corresponding amines, respectively.
Figure imgf000061_0001
C26 H28 CI 466
48 1 .92 (A)
* N3 03 [M+H]+
C26 H28 CI 482
42 1 .58 (A)
* N3 04 [M+H]+
C25 H26 CI 452
48 1 .82 (A)
N3 03 [M+H]+
\ C23 H24 CI 426 Onset:
- · 46 1 .70 (A)
N3 03 [M+H]+ 136°C
\ C22 H22 CI 412
42 1 .64 (A)
H N3 03 [M+H]+
C23 H24 CI 426
48 1 .71 (A)
N3 03 [M+H]+
H
OH
C27 H30 CI 496
47 1 .63 (A)
N3 04 [M+H]+
*
OH
C26 H28 CI 482
16 1 .55 (A)
N3 04 [M+H]+
*
Figure imgf000063_0001
Example 4.1 4-(5-Bromo-pyridin-2-ylmethoxy)-1 -[2-(4-dimethylaminomethyl-2- methyl-phenyl)-2-oxo-ethyl]-1 H-pyridin-2-one
Figure imgf000063_0002
To a solution of 1 -[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-bromo- pyridin-2-ylmethoxy)-1 H-pyridin-2-one (preparation 4b, 1000 mg, 1 .98 mmol) in N,N- dimethylacetamide (5 mL) is added dimethylamine (3.0 mL of 2M solution in THF, 6.0 mmol). The reaction mixture is stirred 2 h at room temperature. The mixture is purified via reverse phase HPLC chromatography (Gilson Xbridge C18 5 μιτι, gradient 5% -» 90% acetonitrile in water + 0.3% NH4OH, 120 mL/min).
Yield: 300 mg (32% of theory)
ESI mass spectrum: [M+H]+ = 470
Retention time HPLC: 1 .68 min (METHOD A).
DSC (melting point): Onset: 136°C
The following examples are prepared as described for Example 4.1 , employing the corresponding amines, respectively.
Figure imgf000064_0001
Example 4.7 (R)-4-(5-Bromo-pyridin-2-ylmethoxy)-1 -{2-[4-(2-hydroxymethyl-piperidin- 1 -ylmethyl)-2-methyl-phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
Figure imgf000065_0001
To a solution of 1 -[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-bromo- pyridin-2-ylmethoxy)-1 H-pyridin-2-one (preparation 4b, 100 mg, 0.20 mmol) in DMF (2 mL) is added (R)-2-hydroxymethylpiperidine hydrochloride (75 mg, 0.50 mmol) and K2CO3 (55 mg, 0.40 mmol) . The reaction mixture is stirred 2 h at 80°C. The mixture is purified via reverse phase HPLC chromatography (Phenomenex Gemini-C18 10 μπτι, gradient 5% -» 90% acetonitrile in water + 0.3% NH4OH, 120 mL/min).
Yield: 22 mg (21 % of theory)
ESI mass spectrum: [M+H]+ = 540
Retention time HPLC: 1 .69 min (METHOD A).
The following examples are prepared as described for Example 4.7, employing the corresponding amines (as free base), respectively.
Figure imgf000065_0002
Retention
Yield time HPLC
Example R1R2N- Formula MS
(%) in min
(method)
C25 H26 Br 496
4.8 23 1 .75 (A)
N3 03 [M+H]+
C25 H26 Br 512
4.9 41 1 .54 (A)
N3 04 [M+H]+
Figure imgf000066_0001
C26 H28 Br 510
4.19 15 1 .85 (A)
N3 03 [M+H]+
C25 H28 Br 498
4.20 6 1 .85 (A)
* N3 03 [M+H]+
C24 H24 Br 482
4.21 ** 43 1 .67 (A)
N3 03 [M+H]+ preparation according to procedure for example 4.1 employing CH2CI2 as solvent
Example 5.1 (R)-5-Benzyloxy-2-{2-[4-(3-hydroxy-piperidin-1 -ylmethyl)-2-methyl- phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one
Figure imgf000067_0001
To a solution of 5-benzyloxy-2-[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H- pyridazin-3-one (preparation 5b, 100 mg, 0.23 mmol) in DMF (2 mL) is added (R)-3- hydroxypiperidine hydrochloride (96 mg, 0.70 mmol) and N-ethyldiisopropylamine (362 μΙ_, 2.1 mmol). The reaction mixture is stirred overnight at room temperature. The mixture is purified via reverse phase HPLC chromatography (Waters Xbridge C18 5 μηη, gradient 5% -» 90% acetonitrile in water + 0.3% NH4OH, 120 mL/min). Yield: 42 mg (40% of theory)
ESI mass spectrum: [M+H]+ = 448
Retention time HPLC: 1 .70 min (METHOD A).
The following examples are prepared as described for Example 5.1 , employing the corresponding amines (as free base), respectively.
Figure imgf000068_0001
Figure imgf000068_0002
Figure imgf000069_0001
Example 6.1 5-(5-Fluoro-pyridin-2-ylmethoxy)-2-[2-(2-methyl-4-pyrrolidin-1 -ylmethyl- phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one
Figure imgf000069_0002
To a solution of 2-[2-(4-bromonnethyl-2-nnethyl-phenyl)-2-oxo-ethyl]-5-(5-fluoro- pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 6b, 1 12 mg, 0.25 mmol) in DMF (2 mL) is added pyrrolidine (63 μΙ_, 0.75 mmol). The reaction mixture is stirred for 60 min at room temperature. The mixture is purified via reverse phase HPLC chromatography (Gilson Xbridge C18 5 μιτι, gradient 5% -> 90% acetonitrile in water + 0.3% NH OH, 120 mL/min).
Yield: 79 mg (72% of theory)
ESI mass spectrum: [M+H]+ = 437
Retention time HPLC: 1 .78 min (METHOD A).
The following examples are prepared as described for Example 6.1 , employing the corresponding amines, respectively.
R1
Figure imgf000070_0001
Figure imgf000071_0001
Example 7.1 (S)-5-(5-Chloro-pyhdin-2-ylmethoxy)-2-{2-[4-(2-hydroxymethyl- pyrrolidin-1 -yl methyl )-2-methyl-phenyl]-2-oxo-ethyl}-2H-pyhdazin-3-one
Figure imgf000071_0002
To a solution of 2-[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-chloro- pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 7b, 1 10 mg, 0.24 mmol) in N,N- dimethylacetamide (2 mL) is added CS2CO3 (194 mg, 0.60 mmol) and L-prolinol (37 mg, 0.36 mmol). The reaction mixture is stirred for 2 days at room temperature. The mixture is purified via reverse phase HPLC chromatography (Xbridge C18 5 μιτι, gradient 5% -» 90% acetonitrile in water + 0.3% NH4OH, 120 mL/min).
Yield: 81 mg (71 % of theory)
ESI mass spectrum: [M+H]+ = 483
Retention time HPLC: 1 .04 min (METHOD B).
The following examples are prepared as described for Example 7.1 , employing the corresponding amines, respectively.
Figure imgf000071_0003
Figure imgf000072_0001
Figure imgf000073_0001
Example 7.17 5-(5-Chloro-pyridin-2-ylmethoxy)-2-[2-(2-nnethyl-4-piperazin-1 - ylmethyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one
Figure imgf000073_0002
To a solution of 2-[2-(4-bromonnethyl-2-nnethyl-phenyl)-2-oxo-ethyl]-5-(5-chloro- pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 7b, 1 10 mg, 0.24 mmol) in N,N- dimethylacetamide (2 mL) is added CS2CO3 (194 mg, 0.60 mmol) and Boc-piperazine (65 mg, 0.36 mmol). The reaction mixture is stirred for 2 days at room temperature. The mixture is purified via reverse phase HPLC chromatography (Xbridge C18 5 μιτι, gradient 5% -» 90% acetonitrile in water + 0.3% NH4OH, 120 mL/min) to yield 90 mg of the Boc-protected product (67% of theory). This intermediate is dissolved in CH2CI2 (3 mL), trifluoroacetic acid is added (0.3 mL) and the mixture is stirred overnight at room temperature. The reaction mixture is quenched with aqueous NaHCO3 solution and extracted with CH2CI2. The organic layer is dried over MgSO4 and concentrated under reduced pressure.
Yield: 41 mg (55% of theory)
ESI mass spectrum: [M+H]+ = 468
Retention time HPLC: 1 .52 min (METHOD A).
Example 8.1 (R)-5-(5-Bromo-pyridin-2-ylmethoxy)-2-{2-[4-(3-hydroxy-pyrrolidin-1 - yl methyl )-2-methyl-phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one
Figure imgf000074_0001
To a solution of 2-[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-bromo- pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 8b, 100 mg, 0.20 mmol) in N,N- dimethylacetamide (2 mL) is added Cs2CO3 (160 mg, 0.49 mmol) and (R)-3- hydroxypyrrolidine (22 mg, 0.25 mmol). The reaction mixture is stirred overnight at room temperature. The mixture is purified via reverse phase HPLC chromatography (Phenomenex Gemini-C18 10μηη, gradient 5% -> 90% acetonitrile in water + 0.3% NH4OH, 120 mL/min).
Yield: 78 mg (77% of theory)
ESI mass spectrum: [M+H]+ = 513
Retention time HPLC: 0.91 min (METHOD D). The following examples are prepared as described for Example 8.1 , employing the corresponding amines, respectively.
Figure imgf000075_0001
Figure imgf000076_0001
Example 9.1 2-[2-(4-Dimethylaminomethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5- methoxy-pyridin-2-ylmethoxy)-2H-pyridazin-3-one
Figure imgf000076_0002
To a solution of 2-[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-methoxy- pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 9d, 120 mg, 0.26 mmol) in N,N-dimethylacetamide (2 mL) is added dimethylamine (0.76 mmol, 2 M solution in THF). The reaction mixture is stirred for 4 h at 40°C. The mixture is purified via reverse phase HPLC chromatography (Waters XBridge 5μηη, gradient 5% -> 90% acetonitrile in water + 0.3% NH4OH, 120 mL/min).
Yield: 51 mg (46% of theory)
ESI mass spectrum: [M+H]+ = 423
Retention time HPLC: 1 .64 min (METHOD A).
DSC (melting point): Onset: 122°C 2-[2-(4-Dimethylaminomethyl-2-methyl-ph
ylmethoxy)-2H-pyridazin-3-one, monohydrochloride
Figure imgf000077_0001
The hydrochloride salt of the compound 9.1 is prepared by adding a 1 .1 equivalent of HCI (as 10 M solution of HCI in ethanol) to a concentrated solution of the corresponding free base in refluxing ethanol. The hydrochloride salt, which precipitates upon cooling, is filtered off and dried under reduced pressure.
DSC (melting point): Onset: 212°C Example 9.1 c 2-[2-(4-Dimethylaminomethyl-phenyl)-2-oxo-ethyl]-5-(5-methoxy- pyridin-2-ylmethoxy)-2H-pyridazin-3-one
Figure imgf000077_0002
The title compound as comparative example can be prepared from 2-bromo-1 -(4- hydroxymethyl-phenyl)-ethanone (preparation described in WO2008/22979) and 5- (5-methoxy-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 9b) in analogy to the preparation of example 9.1 .
ESI mass spectrum: [M+H]+ = 409
Retention time HPLC: 1 .01 min (METHOD E).
The following examples are prepared as described for Example 9.1 , employing the corresponding amines, respectively.
Figure imgf000077_0003
Figure imgf000078_0001
Example 10.1 2-{2-[4-(1 -Dimethylamino-ethyl)-2-methyl-phenyl]-2-oxo-ethyl}-5- (5-methoxy-pyridin-2-ylmethoxy)-2H-pyridazin-3-one
Figure imgf000078_0002
To a solution of 2-{2-[4-(1 -Bromo-ethyl)-2-methyl-phenyl]-2-oxo-ethyl}-5-(5-methoxy- pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 10d, 1 .55 g, 3.28 mmol) in CH2CI2 (5 mL) is added a solution of dimethylamine (2 M in THF, 4.9 mL, 9.8 mmol). The reaction mixture is stirred overnight at room temperature. After dilution with CH2CI2, the mixture is washed with aqueous NaHCO3 solution. The organic layer is dried over MgSO4 and evaporated under reduced pressure. The crude product is purified via reverse phase HPLC chromatography (Phenomenex Gemini C18, gradient 30% -» 95% methanol in water + 0.1 % NH4OH, 120 mL/min). Yield: 293 mg (21 % of theory)
ESI mass spectrum: [M+H]+ = 437
Retention time HPLC: 1 .48 min (METHOD C) Example 10.2 5-(5-Methoxy-pyridin-2-ylmethoxy)-2-{2-[2-methyl-4-(1 - methylamino-ethyl)-phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one
Figure imgf000079_0001
5-(5-Methoxy-pyridin-2-ylmethoxy)-2-{2-[2-methyl-4-(1 -methylamino-ethyl)-phenyl]-2- oxo-ethyl}-2H-pyridazin-3-one is prepared following the procedure for example 10.1 , employing methylamine instead of dimethylamine.
Yield: 25% of theory
ESI mass spectrum: [M+H]+ = 423
Retention time HPLC: 1 .41 min (METHOD C).
Example 1 1 .1 1 -{2-[4-(4-Hydroxy-piperidin-1 -ylmethyl)-2-methyl-phenyl]-2-oxo- ethyl}-4-(5-methoxy-pyridin-2-ylmethoxy)-1 H-pyridin-2-one
Figure imgf000079_0002
To a mixture of 1 -[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-methoxy- pyridin-2-ylmethoxy)-1 H-pyridin-2-one (preparation 1 1 d, 129 mg, 0.28 mmol) in
CH2CI2 (2 ml_) is added 4-hydroxypiperidine (85 mg, 0.84 mmol). The reaction mixture is stirred overnight at room temperature. The mixture is purified via reverse phase HPLC chromatography (Waters Xbridge C18 5μηη, gradient 50% -> 95% methanol in water + 0.1 % NH4OH, 120 mL/min).
Yield: 25 mg (18% of theory)
ESI mass spectrum: [M+H]+ = 478
Retention time HPLC: 0.95 min (METHOD E). The following examples are prepared as described for Example 1 1 .1 , employing the corresponding amines, respectively.
Figure imgf000080_0001
Figure imgf000080_0002
Some test methods for determining an MCH-receptor antagonistic activity will now be described. In addition, other test methods known to the skilled man may be used, e.g. by inhibiting the MCH-receptor-mediated inhibition of cAMP production, as described by Hoogduijn M et al. in "Melanin-concentrating hormone and its receptor are expressed and functional in human skin", Biochem. Biophys. Res Commun. 296 (2002) 698-701 and by biosensory measurement of the binding of MCH to the MCH receptor in the presence of antagonistic substances by plasmon resonance, as described by Karlsson OP and Lofas S. in "Flow-Mediated On-Surface Reconstitution of G-Protein Coupled Receptors for Applications in Surface Plasmon Resonance Biosensors", Anal. Biochem. 300 (2002), 132-138. Other methods of testing antagonistic activity to MCH receptors are contained in the references and patent documents mentioned hereinbefore, and the description of the test methods used is hereby incorporated in this application. MCH-1 receptor binding test
Method: MCH binding to hMCH-1 R transfected cells
Species: Human
Test cell: hMCH-1 R stably transfected into CHO/Galpha16 cells
Results: IC50 values
Membranes from CHO/Galpha16 cells stably transfected with human hMCH-1 R are resuspended using a syringe (needle 0.6 x 25 mm) and diluted in test buffer (50 mM HEPES, 10 mM MgCI2, 2 mM EGTA, pH 7.00; 0.1 % bovine serum albumin
(protease-free), 0.021 % bacitracin, 1 g/ml aprotinin, 1 g/ml leupeptin and 1 μΜ phosphoramidone) to a concentration of 5 to 15 g/ml.
200 microlitres of this membrane fraction (contains 1 to 3 g of protein) are incubated for 60 minutes at ambient temperature with 100 pM of 125l-tyrosyl melanin
concentrating hormone (125I-MCH commercially obtainable from NEN) and increasing concentrations of the test compound in a final volume of 250 microlitres. After the incubation the reaction is filtered using a cell harvester through 0.5% PEI treated fibreglass filters (GF/B, Unifilter Packard). The membrane-bound radioactivity retained on the filter is then determined after the addition of scintillator substance (Packard Microscint 20) in a measuring device (TopCount of Packard).
The non-specific binding is defined as bound radioactivity in the presence of 1 micromolar MCH during the incubation period.
The analysis of the concentration binding curve is carried out on the assumption of one receptor binding site.
Standard:
Non-labelled MCH competes with labelled 125I-MCH for the receptor binding with an IC50 value of between 0.06 and 0.15 nM.
The KD value of the radioligand is 0.156 nM.
The compounds according to the invention typically have IC5o values in the range from about 1 nM to about 200 nM, preferably from 1 nM to 50 nM. In order to illustrate that compounds according to the invention with different structural elements possess a very good MCH-1 receptor antagonistic activity, the IC5o values of the compounds depicted in the following table are provided.
Example IC50 Example IC50 Example IC50 Example IC50
No. [nM] No. [nM] No. [nM] No. [nM]
1.1 20 2.1 67 3.1 79 4.1 17
1.2 19 2.2 116 3.2 36 4.2 16
1.3 19 2.3 93 3.3 39 4.3 13
1.4 40 2.4 70 3.4 38 4.4 18
1.5 48 2.5 70 3.5 84 4.5 13
1.6 24 2.6 134 3.6 26 4.6 50
1.7 11 3.7 36 4.7 14
1.8 17 3.8 26 4.8 17
1.9 11 3.9 32 4.9 20
1.10 26 3.10 37 4.10 53
1.11 30 3.11 26 4.11 59
1.12 21 3.12 34 4.12 23
1.13 29 3.13 34 4.13 26
1.14 53 3.14 37 4.14 72
1.15 31 3.15 31 4.15 18
1.16 29 3.16 19 4.16 12
1.17 26 4.17 18
1.18 16 4.18 19
4.19 14
4.20 19
4.21 18
Example IC50 Example IC50 Example IC50 Example IC50
No. [nM] No. [nM] No. [nM] No. [nM]
5.1 14 6.1 38 7.1 26 8.1 22
5.2 9 6.2 35 7.2 71 8.2 19 5.3 1 1 6.3 59 7.3 27 8.3 16
5.4 12 6.4 58 7.4 67 8.4 24
5.5 1 1 6.5 50 7.5 16 8.5 18
5.6 10 6.6 49 7.6 28 8.6 21
5.7 10 7.7 18 8.7 20
5.8 15 7.8 26 8.8 17
5.9 30 7.9 32 8.9 18
5.10 35 7.10 25 8.10 25
5.1 1 13 7.1 1 31 8.1 1 21
5.12 13 7.12 30
5.13 13 7.13 35
5.14 10 7.14 30
7.15 19
7.16 24
7.17 83
Example IC50 Example IC50 Example IC50 Example IC50
No. [nM] No. [nM] No. [nM] No. [nM]
9.1 28 10.1 20 1 1 .1 53
9.2 34 10.2 22 1 1 .2 57
9.3 25 1 1 .3 26
9.4 20 1 1 .4 54
9.5 24
Determination of metabolic degradation in human hepatocytes for compounds of the invention
The metabolic degradation of the test compound is determined in a hepatocyte suspension. Hepatocytes (typically cryopreserved) are incubated in an appropriate buffer system (e.g. Dulbecco 's modified eagle medium plus 3.5 g glucagon/500ml_, 2.5mg insulin/500ml_ and 3.75mg/500mL hydrocortison) containing 5% human serum. Following a (typically) 30 min preincubation in an incubator (37°C, 10% CO2), 5 μΙ of test compound solution (80 μΜ; from 2mM in DMSO stock solution diluted 1 :25 with medium) are added into 395 μΙ hepatocyte suspension (cell density in the range 0.25- 5 Mio cells/mL, typically 1 Mio cells/mL; final concentration of test compound 1 μΜ, final DMSO concentration 0.05%). The cells are incubated for six hours (incubator, orbital shaker) and samples (25μΙ) are taken at 0, 0.5, 1 , 2, 4 and 6 hours. Samples are transferred into acetonitrile and pelleted by centrifugation (5 min). The
supernatant is transferred to a new 96-deepwell plate, evaporated under nitrogen and resuspended.
Decline of parent compound is analyzed by HPLC-MS/MS.
CLint is calculated as follows CLJNTRINSIC = Dose / AUC = (CO/CD) / (AUD + clast/k) x 1000/60. CO: initial concentration in the incubation [μΜ], CD: cell density of vital cells [10e6cells/ml_], AUD: area under the data [μΜ x h], clast: concentration of last data point [μΜ], k: slope of the regression line for parent decline [h-1 ].
The calculated in vitro hepatic intrinsic clearance can be scaled up to the intrinsic in vivo hepatic clearance and used to predict hepatic in vivo blood clearance (CL) by the use of a liver model (well stirred model).
CLJNTRINSICJNVIVO [ml/min/kg] = (CLJNTRINSIC ^L/min/10e6cells] x hepatocellularity [10e6cells/g liver] x liver factor [g/kg bodyweight]) / 1000
CL [ml/min/kg] = CLJNTRINSICJNVIVO [ml/min/kg] x hepatic blood flow [ml/min/kg] /(CLJNTRINSICJNVIVO [ml/min/kg] + hepatic blood flow [ml/min/kg]) Hepatocellularity, human: 120x10e6 cells / g liver
Liver factor, human: 25.7 g liver / kg bodyweight
Hepatic blood flow, human: 21 ml/(min x kg)
In the following table the intrinsic clearance CLint is provided for compounds according to this invention with a methyl substituent in ortho-position of the central phenyl ring in comparison with corresponding compounds without said methyl substitution.
Figure imgf000085_0001
Figure imgf000086_0001
From the above comparative data it can be well seen that the compounds according to this invention show a much lower intrinsic clearance than the comparative compounds without a ortho-methyl-substitution and thus compounds according to the invention are metabolically more stable.
Pharmacological Example
The following example shows the effect on body weight development of a compound according to this invention. All experimental protocols concerning the use of laboratory animals are reviewed by a federal Ethics Committee and approved by governmental authorities. The time course of body weight is followed over a treatment period of 8 days in female diet-induced obese Wistar rats (RjHan:Wi) with a mean body weight of about 340 g at the start of the study. In addition to a normal rodent diet, the rats had received a daily changing diet admixture consisting of palatable commercially available supermarket foods (like chocolate bars). From day 1 to day 8, the animals (n = 6/group) receive two daily oral administrations of either vehicle alone (0.5% aqueous hydroxyethylcellulose, 0.015% polysorbat 80) or the test compound dissolved in this vehicle. Body weight is measured daily before the second administration. The data are presented as mean ± S.E.M. of baseline- corrected body weight change. Statistical comparison is conducted by repeated measures two-way ANOVA followed by Bonferroni post tests for group-wise comparisons. A p value < 0.05 is considered to show a statistically significant difference. Control animals are dosed twice daily with vehicle. Animals are dosed with vehicle in the morning and 3, 10, or 30 mg/kg of the compound in the evening (once daily compound dosing; qd). Body weight reduction is observed at least in the groups with higher dosing. Animals which receive 3 or 10 mg/kg of compound in the morning and evening (twice daily dosing; bid) show a higher body weight loss versus control.

Claims

Claims
Figure imgf000088_0001
independently of each other are selected from the group consisting of H, Ci-6-alkyl and C3-7-cycloalkyl, while the alkyl or cycloalkyl group may be mono- or polysubstituted by identical or different groups R11, and a -CH2- group in position 3 or 4 of a 5-, 6- or 7-membered cycloalkyl group may be replaced by -O-, -S-, -S(=O)-, -S(=O)2- or -NR12-; or
R1 and R2 are linked to each other and together form a group which is selected from the group consisting of a C3-6-alkylene bridge, wherein a -CH2- group not adjacent to the N atom of the R1R2N- group may be replaced by -O-, -S-, -S(=O)-, -S(=O)2- or -NR12-, and wherein one or more H atoms of the alkylene bridge may be replaced by identical or different groups R11; or
R1 and R2 are linked to each other such that the R1R2N- group forms a bridged cyclic ring system with 5 to 8 C-atoms wherein one or more H atoms of the bridged cyclic ring system may be replaced by identical or different groups R11; and independently of each other are selected from the group consisting of H and Ci-3-alkyl, or L1 and L2 are linked to each other and together form a group which is selected from the group consisting of a C2-5-alkylene bridge; and U is selected from the group consisting of CH and N; and is selected from the group consisting of phenyl and pyridinyl each of which may be mono- or polysubstituted by identical or different substituents R20; and is selected from the group consisting of OH, F, CI, Br, CN, Ci-6-alkyl, C3-6-cycloalkyl, Ci-4-alkyl-O- and R13R14N-, while each of the above mentioned alkyl or cydoalkyi groups may be substituted independently of one another by one or more substituents selected from F, CI, Br, OH CN, CF3, Ci-s-alkyl, Ci-3-alkyl-O- and HO-Ci-3-alkyl; and is selected from the group consisting of H,
Figure imgf000089_0001
and Ci-4-alkyl- C(=O)-; and independently of each other are selected from the group consisting of H and Ci-4-alkyl; and
R20 is selected from the group consisting of F, CI, Br, OH, CN, NO2, Ci-4- alkyl and Ci-4-alkyl-O-, wherein each alkyl group may be substituted with one or more substituents independently of each other selected from F, CI, Br, OH, CN, NO2 and Ci-4-alkyl-O-; and while, unless otherwise stated, the above-mentioned alkyl groups may be straight- chain or branched, or a salt thereof.
2. A compound according to claim 1 wherein R1 and R2 independently of each other are selected from the group consisting of H, Ci-4-alkyl and C3-6-cycloalkyl, while the alkyl or cydoalkyi group may be mono- or polysubstituted by identical or different groups R1 1 , and a -CH2- group in position 3 or 4 of a 5- or 6-membered cydoalkyi group may be replaced by -O- or -NR12-, or the groups R1 and R2 are linked to each other and together form a group which is selected from the group consisting of a C3-5-alkylene bridge, wherein a -CH2- group not adjacent to the N atom of the R1R2N- group may be replaced by -O- or -NR12-, and wherein 1 or 2 H atoms of the alkylene bridge may be replaced by identical or different groups R11,
wherein R11 and R12 are defined as in claim 1 .
3. A compound according to claim 1 or 2 wherein the groups L1 and L2 are independently of each other selected from the group consisting of H and CH3.
4. A compound according to claim 1 , 2 or 3 wherein the group U denotes CH.
5. A compound according to claim 1 , 2 or 3 wherein the group U denotes N. 6. A compound according to claim 1 , 2 or 3 wherein the compound is selected from the group of formulas 1.1 .1 , 1.1 .2, 1.2.1 and I.2.2
Figure imgf000090_0001
1.1 .2
Figure imgf000090_0002
Figure imgf000091_0001
Figure imgf000091_0002
or a salt thereof,
wherein the groups R1, R2, L1, L2 and R20 are defined as in the claims 1 , 2 or 3.
A compound according to claim 1 , 2, 3, 4, 5 or 6 selected from the group of compounds
1 .1 4-Benzyloxy-1 -{2-[4-(3-hydroxy-azetidin-1 -ylmethyl)-2-methyl-phenyl]-2- oxo-ethyl}-1 H-pyridin-2-one
1 .2 4-Benzyloxy-1 -[2-(2-methyl-4-methylaminomethyl-phenyl)-2-oxo-ethyl]- 1 H-pyridin-2-one
1 .3 4-Benzyloxy-1 -{2-[4-(4-hydroxy-piperidin-1 -ylmethyl)-2-methyl-phenyl]-2- oxo-ethyl}-1 H-pyridin-2-one
1 .5 4-Benzyloxy-1 -{2-[2-methyl-4-(4-methyl-piperazin-1 -yl methyl )-phenyl]-2- oxo-ethyl}-1 H-pyridin-2-one
1 .
6 4-Benzyloxy-1 -{2-[4-(4-hydroxymethyl-piperidin-1 -yl methyl )-2-methyl- phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
1 .7 4-Benzyloxy-1 -[2-(2-methyl-4-pyrrolidin-1 -ylmethyl-phenyl)-2-oxo-ethyl]- 1 H-pyridin-2-one 4-Benzyloxy-1 -[2-(4-dimethylaminomethyl-2-methyl-phenyl)-2-oxo-ethyl]- 1 H-pyridin-2-one
(S)-4-Benzyloxy-1 -{2-[4-(3-hydroxy-pyrrolidin-1 -ylmethyl)-2-nnethyl- phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
4-Benzyloxy-1 -[2-(4-ethylaminomethyl-2-methyl-phenyl)-2-oxo-ethyl]-1 H- pyridin-2-one
(S)-4-Benzyloxy-1 -{2-[4-(3-hydroxy-piperidin-1 -yl methyl )-2-methyl- phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
(R)-4-Benzyloxy-1 -{2-[4-(3-hydroxy-piperidin-1 -ylmethyl)-2-methyl- phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
(S)-4-Benzyloxy-1 -{2-[4-(2-hydroxymethyl-pyrrolidin-1 -yl methyl )-2-methyl- phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
4-(5-Chloro-pyridin-2-ylmethoxy)-1 -{2-[4-((S)-2-hydroxymethyl-pyrrolidin- 1 -ylmethyl)-2-methyl-phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
(R)-4-(5-Chloro-pyridin-2-ylmethoxy)-1 -{2-[4-(3-hydroxy-pyrrolidin-1 - yl methyl )-2-methyl-phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
4-(5-Chloro-pyridin-2-ylmethoxy)-1 -[2-(2-methyl-4-pyrrolidin-1 -ylmethyl- phenyl)-2-oxo-ethyl]-1 H-pyridin-2-one
4-(5-Chloro-pyridin-2-ylmethoxy)-1 -[2-(4-dimethylaminomethyl-2-methyl- phenyl)-2-oxo-ethyl]-1 H-pyridin-2-one
4-(5-Chloro-pyridin-2-ylmethoxy)-1 -[2-(4-ethylaminomethyl-2-methyl- phenyl)-2-oxo-ethyl]-1 H-pyridin-2-one
(R)-4-(5-Chloro-pyridin-2-ylmethoxy)-1 -{2-[4-(3-hydroxy-piperidin-1 - yl methyl )-2-methyl-phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
4-(5-Chloro-pyridin-2-ylmethoxy)-1 -{2-[4-(3-hydroxy-azetidin-1 -yl methyl )- 2-methyl-phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
4-(5-Bromo-pyridin-2-ylmethoxy)-1 -[2-(4-dimethylaminomethyl-2-methyl- phenyl)-2-oxo-ethyl]-1 H-pyridin-2-one
4-(5-Bromo-pyridin-2-ylmethoxy)-1 -{2-[4-(4-hydroxy-piperidin-1 -yl methyl )- 2-methyl-phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
4-(5-Bromo-pyridin-2-ylmethoxy)-1 -{2-[4-(4-hydroxymethyl-piperidin-1 - yl methyl )-2-methyl-phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
(S)-4-(5-Bromo-pyridin-2-ylmethoxy)-1 -{2-[4-(3-hydroxy-piperidin-1 - yl methyl )-2-methyl-phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
(S)-4-(5-Bromo-pyridin-2-ylmethoxy)-1 -{2-[4-(2-hydroxymethyl-pyrrolidin- 1 -ylmethyl)-2-methyl-phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
4-(5-Bromo-pyridin-2-ylmethoxy)-1 -[2-(4-ethylaminomethyl-2-methyl- phenyl)-2-oxo-ethyl]-1 H-pyridin-2-one
4-(5-Bromo-pyridin-2-ylmethoxy)-1 -[2-(2-methyl-4-pyrrolidin-1 -yl methyl -phenyl )-2-oxo-ethyl]-1 H-pyridin-2-one
(R)-4-(5-Bromo-pyridin-2-ylmethoxy)-1 -{2-[4-(3-hydroxy-pyrrolidin-1 - yl methyl )-2-methyl-phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
(R)-4-(5-Bromo-pyridin-2-ylmethoxy)-1 -{2-[4-(3-hydroxy-piperidin-1 - yl methyl )-2-methyl-phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
4-(5-Bromo-pyridin-2-ylmethoxy)-1 -[2-(2-methyl-4-methylaminomethyl- phenyl)-2-oxo-ethyl]-1 H-pyridin-2-one
4-(5-Bromo-pyridin-2-ylmethoxy)-1 -{2-[4-(isopropylamino-methyl)-2- methyl-phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one
4-(5-Bromo-pyridin-2-ylmethoxy)-1 -(2-{4-[(isopropyl-methyl-amino)- methyl]-2-methyl-phenyl}-2-oxo-ethyl)-1 H-pyridin-2-one
4-(5-Bromo-pyridin-2-ylmethoxy)-1 -(2-{4-[(ethyl-methyl-amino)-methyl]-2- methyl-phenyl}-2-oxo-ethyl)-1 H-pyridin-2-one
4-(5-Bromo-pyridin-2-ylmethoxy)-1 -[2-(4-diethylaminomethyl-2-methyl- phenyl)-2-oxo-ethyl]-1 H-pyridin-2-one
1 -[2-(4-Azetidin-1 -ylmethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-bromo- pyridin-2-ylmethoxy)-1 H-pyridin-2-one
5-Benzyloxy-2-[2-(4-dimethylaminomethyl-2-methyl-phenyl)-2-oxo-ethyl]- 2H-pyridazin-3-one
(S)-5-Benzyloxy-2-{2-[4-(2-hydroxymethyl-pyrrolidin-1 -yl methyl )-2-methyl- phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one
(R)-5-Benzyloxy-2-{2-[4-(3-hydroxy-pyrrolidin-1 -ylmethyl)-2-methyl- phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one
5-Benzyloxy-2-[2-(4-ethylaminomethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H- pyridazin-3-one
5-Benzyloxy-2-{2-[4-(3-hydroxy-azetidin-1 -ylmethyl)-2-methyl-phenyl]-2- oxo-ethyl}-2H-pyridazin-3-one 5-Benzyloxy-2-{2-[2-methyl-4-(2-methyl-morpholin-4-yl methyl )-phenyl]-2- oxo-ethyl}-2H-pyridazin-3-one
5-Benzyloxy-2-{2-[4-(4-hydroxymethyl-piperidin-1 -yl methyl )-2-methyl- phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one
(R)-5-Benzyloxy-2-{2-[4-(2-hydroxymethyl-piperidin-1 -yl methyl )-2-methyl- phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one
(S)-5-Benzyloxy-2-{2-[4-(3-hydroxy-piperidin-1 -yl methyl )-2-methyl- phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one
5-Benzyloxy-2-{2-[4-(3-hydroxy-3-methyl-pyrrolidin-1 -yl methyl )-2-methyl- phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one
5-(5-Fluoro-pyridin-2-ylmethoxy)-2-[2-(2-methyl-4-pyrrolidin-1 -ylmethy l-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one
5-(5-Fluoro-pyridin-2-ylmethoxy)-2-[2-(2-methyl-4-piperidin-1 -ylmethy l-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one
(S)-5-(5-Chloro-pyridin-2-ylmethoxy)-2-{2-[4-(2-hydroxymethyl-pyrrolidin- 1 -ylmethyl)-2-methyl-phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one
5-(5-Chloro-pyridin-2-ylmethoxy)-2-[2-(2-methyl-4-methylaminomethyl- phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one
5-(5-Chloro-pyridin-2-ylmethoxy)-2-[2-(4-ethylaminomethyl-2-methyl- phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one
(R)-5-(5-Chloro-pyridin-2-ylmethoxy)-2-{2-[4-(2-hydroxymethyl-piperidin-1 - yl methyl )-2-methyl-phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one
5-(5-Chloro-pyridin-2-ylmethoxy)-2-{2-[4-(4-hydroxy-piperidin-1 -yl methyl )- 2-methyl-phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one
5-(5-Chloro-pyridin-2-ylmethoxy)-2-[2-(2-methyl-4-pyrrolidin-1 -ylmethyl- phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one
5-(5-Chloro-pyridin-2-ylmethoxy)-2-[2-(4-dimethylaminomethyl-2-methyl- phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one
5-(5-Bromo-pyridin-2-ylmethoxy)-2-{2-[4-(3-hydroxy-azetidin-1 -yl methyl )- 2-methyl-phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one
5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(4-dimethylaminomethyl-2-methyl- phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one
(R)-5-(5-Bromo-pyridin-2-ylmethoxy)-2-{2-[4-(3-hydroxy-piperidin-1 - yl methyl )-2-methyl-phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one
8.
7 (R)-5-(5-Bromo-pyridin-2-ylmethoxy)-2-{2-[4-(2-hydroxymethyl-piperidin-1 - yl methyl )-2-methyl-phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one
8.8 5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(4-ethylaminomethyl-2-methyl- phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one
8.9 5-(5-Bromo-pyridin-2-ylmethoxy)-2-{2-[4-(4-hydroxy-piperidin-1 -yl methyl )- 2-methyl-phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one
8.10 5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(2-methyl-4-methylaminomethyl- phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one
9.1 2-[2-(4-Dimethylaminomethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-methoxy- pyridin-2-ylmethoxy)-2H-pyridazin-3-one
9.2 2-{2-[4-(4-Hydroxy-piperidin-1 -yl methyl )-2-methyl-phenyl]-2-oxo-ethyl}-5- (5-methoxy-pyridin-2-ylmethoxy)-2H-pyridazin-3-one
9.3 5-(5-Methoxy-pyridin-2-ylmethoxy)-2-[2-(2-methyl-4-pyrrolidin-1 -ylmethyl- phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one
9.4 5-(5-Methoxy-pyridin-2-ylmethoxy)-2-[2-(2-methyl-4-methylaminomethyl- phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one
9.5 2-[2-(4-Ethylaminomethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-methoxy- pyridin-2-ylmethoxy)-2H-pyridazin-3-one
10.1 2-{2-[4-(1 -Dimethylamino-ethyl)-2-methyl-phenyl]-2-oxo-ethyl}-5-(5- methoxy-pyridin-2-ylmethoxy)-2H-pyridazin-3-one
10.2 5-(5-Methoxy-pyridin-2-ylmethoxy)-2-{2-[2-methyl-4-(1 -methylamino- ethyl)-phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one or a salt thereof.
8. A pharmaceutically acceptable salt of a compound according to one or more of the claims 1 to 7.
9. A pharmaceutical composition comprising one or more compounds according to one or more of the claims 1 to 7 or one or more pharmaceutically acceptable salts thereof, optionally together with one or more excipients.
10. A method for treating a disease or condition which is mediated by blocking the MCH receptor in a patient in need thereof characterized in that a compound according to one or more of the claims 1 to 7 or a pharmaceutically acceptable salt thereof is administered to the patient.
1 1 . A method for treating overweight or obesity in a patient in need thereof characterized in that a compound according to one or more of the claims 1 to 7 or a pharmaceutically acceptable salt thereof is administered to the patient.
12. A method for reducing food consumption in an overweight or obese patient in need thereof characterized in that a compound according to one or more of the claims 1 to 7 or a pharmaceutically acceptable salt thereof is administered to the patient.
PCT/EP2013/054465 2012-03-07 2013-03-06 Pyridinone and pyridazinone derivatives as mch - receptor modulators WO2013131935A1 (en)

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