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WO2001064675A1 - Thiazolamines condensees et leur utilisation comme antagonistes du neuropeptide y5 - Google Patents

Thiazolamines condensees et leur utilisation comme antagonistes du neuropeptide y5 Download PDF

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Publication number
WO2001064675A1
WO2001064675A1 PCT/EP2001/002339 EP0102339W WO0164675A1 WO 2001064675 A1 WO2001064675 A1 WO 2001064675A1 EP 0102339 W EP0102339 W EP 0102339W WO 0164675 A1 WO0164675 A1 WO 0164675A1
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Prior art keywords
alkyl
signifies
alkoxy
halogen
formula
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Inventor
Tibur Schmidlin
Heinrich RÜEGER
Marc Gerspacher
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Novartis Pharma GmbH Austria
Novartis AG
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Novartis Erfindungen Verwaltungs GmbH
Novartis AG
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Priority to AU2001246494A priority Critical patent/AU2001246494A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
    • C07F9/6539—Five-membered rings
    • C07F9/6541—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the invention relates to compounds of formula
  • R1 signifies C C -alkyl or which is substituted by C C 7 -alkoxy, halogen, C 3 -
  • R2 signifies hydrogen, SO 3 H or P(O)(OH) 2 ;
  • R3 is hydrogen or one or more substituents selected from the group consisting d-C 7 - alkyl, C ⁇ -C 7 -alkoxy, halogen, trifluoromethyl, cyano and nitro;
  • R4 and R5 independently of one another, signify hydrogen, C C 7 -alkyl or C C 7 -alkyl which is substituted by C* ⁇ -C 7 -alkoxy, halogen, trifluoromethyl, a monocyclic heterocyclyl radical with one or two hetero atoms selected from O, S or N or by C 3 -C 7 -cycloalkyl; or
  • R4 and R5 together signify C 3 -C 7 -alkylene or C 4 -C 7 -alkylene, which is interrupted by O, S or
  • R6 signifies hydrogen or C* ⁇ -C 7 -alkyl
  • X signifies CH or O
  • X-i signifies CO or SO 2 ;
  • X 2 signifies C C 4 -alkylene; whereby phenyl and a heterocyclyl radical are respectively unsubstituted or substituted once or more by a substituent selected from the group consisting C-i-C-ralkyl, CrC-ralkoxy, halogen, trifluoromethyl, cyano and nitro; or a salt, especially a pharmaceutically acceptable salt, thereof, pharmaceutical preparations containing these compounds, their usage and a method for preparing these compounds.
  • the compounds of formula (I) may be present especially in the form of pharmaceutically acceptable salts. Acid addition salts may be formed with each basic amino group.
  • the acid component may be, for example, strong inorganic acids, such as mineral acids, e.g. hydrohalic acids, e.g.
  • hydrochloric acid or strong organic carboxylic acids, e.g. acetic acid or trifluoroacetic acid, or organic sulfonic acids, e.g. methanesulfonic acid or p-toluene- sulfonic acid.
  • compounds of formula (I) with at least one acid group can form salts with bases.
  • Suitable salts with bases are, for example metal salts, such as alkali or alkaline earth metal salts, e.g. sodium, potassium or magnesium salts, or salts with ammonia or an organic amine.
  • salts which are not suitable for therapeutic application and which may be used for example to isolate or purify free compounds of formula (I) or the pharmaceutically acceptable salts thereof. Only salts that are pharmaceutically acceptable and non-toxic are used therapeutically and those salts are therefore preferred.
  • compounds according to the invention may accordingly be present in the form of stereoisomers, stereoisomer mixtures and also in the form of (essentially) pure diastereoisomers.
  • Corresponding compounds with an optically active carbon atom are present as racemates, primarily as (essentially pure) enantiomers.
  • Corresponding stereoisomers are similarly embraced by the present invention.
  • C ⁇ -C 7 -alkyl is e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or a corresponding pentyl, hexyl or heptyl radical.
  • CrC 4 -alkyl is preferred, especially methyl.
  • C- ⁇ -C 7 -alkoxy is e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy or a corresponding pentyloxy, hexyloxy or heptyloxy radical.
  • C**- C 4 -alkoxy is preferred.
  • Methoxy is especially preferred.
  • Halogen is in particular halogen with an atomic number up to and including 35, i.e. fluorine, chlorine, bromine, and also includes iodine. Chlorine is preferred.
  • C 3 -C 8 -cycloalkyl is in particular C 3 -C 6 -cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Cyclopropyl or cyclohexyl is especially preferred.
  • a monocyclic heterocyclyl radical with one or two hetero atoms selected from O, S or N may be of aromatic or non-aromatic nature, and is especially 5- or 6-membered.
  • Examples of corresponding heteroaryl radicals are furyl, e.g. 2- or 3-furyl, thienyl, e.g. 2- or 3-thienyl, pyrrolyl, e.g. 1 -, 2- or 3-pyrrolyl, 1 -C ⁇ -C 7 -alkyl-pyrrolyl, e.g. 1-CrC7-alkyl-2- or 1-CrC ⁇ -alkyl- 3-pyrrolyl, pyrazolyl, e.g.
  • heteroaryl radicals may be partly or wholly hydrogenated.
  • a partly or wholly hydrogenated monocyclic heterocyclyl radical signifies e.g. tetrahydrofuranyl, e.g. 2- or 3- tetrahydrofuranyl, oxo-tetrahydrofuranyl, e.g.
  • Corresponding aromatic or non-aromatic hetercyclyl radicals are unsubstituted or substituted once or more, e.g. two or three times, by substituents selected from the group consisting C ⁇ -C 7 -alkyl, C ⁇ C 7 -aikoxy, halogen, trifluoromethyl, cyano and nitro.
  • CrC 7 -alkoxy-CrC 7 -alkoxy is especially C- ⁇ -C -alkoxy-C ⁇ -C -alkoxy, such as methoxyethoxy, 2-ethoxyethoxy, 2-n-propyloxyethoxy or ethoxymethoxy.
  • C 3 -C 7 -alkylene is especially 1 ,3-propylene, 1 ,4-butylene, 1 ,5-pentylene or 2,4,-dimethyl-1 ,5- propylene.
  • C -C 7 -alkylene which is interrupted by O, S or NR6, is e.g. C 2 -C3-alkylen-oxy-C 2 -C 3 -alkylene, such as ethylenoxyethylene or 2-methyl-ethylene-oxy-ethylene, C 2 -C 3 -alkylene-oxy-C 2 -C 3 - alkylene, such as ethylenethioethylene or 2-methyl-ethylene-thio-ethylene, or ethylene-NR 6 - ethylene.
  • C 4 -C 7 -alkylene substituted by C ⁇ -C 7 -alkoxy is for example 1-CrC 7 -alkoxy-C 4 -C 6 -alkylene, e.g. 1 -methoxymethyl-1 ,4-butylene.
  • CrC-alkylene is especially methylene, but can also signify ethylene, 1 ,2- or 1 ,3-propylene, 2-methyl-1 ,3-propylene or 2,2-dimethyl-1 ,2-ethylene.
  • Adiposity is a widespread phenomenon which is responsible for a whole series of illness symptoms and has a negative affect overall on health. It has emerged that eating habits can be regulated by modulating the neuropeptide-Y(NPY)-receptor subtype Y5.
  • the compounds of formula (I) and their pharmaceutically acceptable salts have a marked, selective affinity for the receptor subtype Y5 (demonstrated in Y5-binding studies) and have in vitro and in vivo antagonising properties. These properties are manifested in vitro by their ability to inhibit the NPY-induced calcium increase in stably transfected cells which express the Y5-receptor.
  • the antagonistic effect is demonstrated in vivo on wake rats by the ability to inhibit food intake induced by intraventricular application of NPY or withdrawal of food for 24 hours.
  • one hour after administering 30 mg p.o. a reduction in food intake of 57% was established for the compound of example 1 , and an inhibition of 25% for the compound of example 7.
  • the selective affinity for the receptor subtype Y5 may be determined for example using the method described in WO 99/62892. Reference is made in particular to the passages on page 4, paragraph 4, to the end of page 5 of WO 99/62892. The subject matter of this description is incorporated into the present application by reference to this publication.
  • the compounds according to the present invention may inhibit the food intake induced either by cerebroventricular application of NPY or by withdrawal of food, as well as the spontaneous food intake of adipose Zucker rats and ob/ob mice.
  • These in vivo antagonising properties of the compounds according to the invention may be determined, for example, by the methods described in WO 99/62892. Reference is made in particular to the passages on page 7, paragraph 3, to page 10, paragraph 3, of WO 99/62892. The subject matter of this description is incorporated into the present application by reference to this publication.
  • an IC 50 of 6 nM was established for the compound of example 1 , an IC 50 of 7.4 nM for the compound of example 44, and an IC 50 of 4.6 nM for the compound of example 68.
  • the compounds act against the binding of the neuropeptide Y (NPY) to the Y5-receptor subtype (NPY-antagonism), and might be used in particular for the treatment and prevention of disorders or conditions associated with the Y5-receptor subtype, i.e. in which the NPY-Y5-receptor subtype takes part. They may be used preferably for the treatment of illnesses caused by eating disorders, such as adiposity, bulimia nervosa, diabetes, dyslipidemia and hypertension.
  • they may be used to treat loss of memory, epileptic convulsions, migraine, sleeping disorders and pain, and in addition, to treat sexual disorders, depression, psychic distress, cerebral bleeding, shock, decompensated cardiac insufficiency, nasal congestion and diarrhoea.
  • the invention relates to a treatment method of illnesses and disorders associated with the NPY-Y5-receptor subtype, which may be used in particular for the prophylaxis and treatment of disorders and illnesses in which the NPY-Y5-receptor subtype takes part, preferably for the treatment of illnesses caused by eating disorders, such as adiposity, bulimia nervosa, diabetes, dyslipidemia and hypertension. Moreover, they may be used to treat loss of memory, epileptic convulsions, migraine, sleeping disorders and pain, and in addition, to treat sexual disorders, depression, psychic distress, cerebral bleeding, shock, decompensated cardiac insufficiency, nasal congestion and diarrhoea. In this method, warm-blooded animals, including humans, requiring such treatment are given a therapeutically effective amount of a compound of formula (I) or of the pharmaceutically acceptable salt of this compound.
  • the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt of this compound, as described above, and as is described in the following for the preparation of a medicament for the prophylaxis and treatment of corresponding illnesses or disorders.
  • the invention further relates to a medicament which contains a compound of formula (I) or a pharmaceutically acceptable salt of this compound, as described above, and as is described in the following for the treatment of corresponding illnesses or disorders
  • R1 is preferably C- ⁇ -C 4 -alkyl, C C 4 -alkoxy, tetrahydrofuranyl or halogen-substituted phenyl.
  • R2 is preferably hydrogen.
  • R3 is preferably halogen, such as fluorine or chlorine, or C C 4 - alkyl, such as methyl.
  • X is preferably CO.
  • X 2 is preferably methylene.
  • the invention relates in particular to a compound of formula (I), wherein
  • R1 signifies CrC 7 -alkyl or C C 7 -alkyl which is substituted by C C 7 -alkoxy or by a group of formula -NR4R5; or CrC-7-alkoxy, C ⁇ -C 7 -alkoxy-C- ⁇ -C 7 -alkoxy, a group of formula -NR4R5,
  • R4 signifies hydrogen or C- ⁇ -C 7 -alkyl and R5 signifies CrC 7 -alkyl, d-C 7 -alkyl which is substituted by CrC 7 -alkoxy, C 3 -C 7 -cycloalkyl, tetrahydrofuranyl or furyl; or C 3 -C 7 -cycloalkyl or tetrahydrofuranyl; or
  • R4 and R5 together signify C 3 -C 7 -alkylene, C 4 -C -alkylene which is interrupted by O, S or
  • R6 signifies hydrogen or C ⁇ -C 7 -alkyl
  • R2 signifies hydrogen
  • R3 is hydrogen or one or more substituents selected from the group consisting C ⁇ -C 7 - alkyl, C C 7 -alkoxy, halogen, trifluoromethyl, cyano and nitro;
  • X signifies CH or O
  • X-i signifies CO or SO 2 ;
  • X 2 signifies C C 4 -alkylene, especially methylene; whereby phenyl and the heterocyclyl radical are respectively unsubstituted or substituted once or more by a substituent selected from the group consisting C ⁇ -C 7 -alkyl, C C -alkoxy, halogen, trifluoromethyl, cyano and nitro; or a salt, especially a pharmaceutically acceptable salt, thereof.
  • the invention relates in particular to a compound of formula (I), wherein
  • R1 signifies C ⁇ -C 7 -alkyl or C* ⁇ -C 7 -alkyl which is substituted by C- ⁇ -C 7 -alkoxy or by a group of formula -NR4R5; or C* ⁇ -C 7 -alkoxy, C 1 -C 7 -alkoxy-C ⁇ -C 7 -alkoxy, C 3 -C 7 -cycloalkyl, phenyl, furyl, pyrrolyl, N-CrC ⁇ alkyl-pyrrolyl, thienyl, isoxazolyl, N-C 1 -C 7 -alkyl-pyrazolyl, N-C ⁇ -C 7 - alkyl-pyrrolidinyl, oxopyrrolidinyl, tetrahydrofuranyl, oxo-thiazolidinyl or thiazolidinyl; and
  • R4 signifies hydrogen or C* ⁇ -C 7 -alkyl and R5 signifies C C 7 -alkyl, C C 7 -alkyl which is substituted by C ⁇ -C 7 -alkoxy, C 3 -C 7 -cycloalkyl, tetrahydrofuranyl or furyl; or C 3 -C 7 -cycloalkyl; or
  • R4 and R5 together signify C 3 -C 7 -alkylene, C ⁇ C ⁇ alkylene which is interrupted by O or NR6, or C 3 -C 7 -cycloalkyl; and R6 signifies hydrogen or d-C-.-alkyl;
  • R2 signifies hydrogen
  • R3 is hydrogen or one or more substituents selected from the group consisting C C 7 - alkyl, CrC 7 -alkoxy, halogen, trifluoromethyl, cyano and nitro;
  • X signifies CH
  • X-i signifies CO or SO 2 ;
  • X 2 signifies methylene; whereby phenyl and the heterocyclyl radical are respectively unsubstituted or substituted once or more by a substituent selected from the group consisting C C 7 -alkyl, C C 7 -alkoxy, halogen, trifluoromethyl, cyano and nitro; or a salt, especially a pharmaceutically acceptable salt, thereof.
  • the invention relates in particular to a compound of formula (I), wherein
  • R1 signifies C- ⁇ -C 7 -alkyl or C* ⁇ -C 7 -alkyl which is substituted by halogen, C 3 -
  • C ⁇ -cycloalkyl by amino substituted by C C 7 -alkyl and C 3 -C 8 -cycloalkyl-C ⁇ -C 7 -alkyl; or C 1 -C 7 - alkoxy or tetrahydrofuranyl;
  • R2 signifies hydrogen
  • R3 is C ⁇ -C 7 -alkoxy, halogen or trifluoromethyl
  • X signifies O
  • X-i signifies CO
  • X 2 signifies methylene; or a salt, especially a pharmaceutically acceptable salt, thereof.
  • the invention relates in particular to a compound of formula (IA) wherein
  • R3 is halogen, such as fluorine or chlorine; or R3 is C* ⁇ -C 4 -alkyl, such as methyl; and (i) X, is CO and R1 is C C 4 -alkyl such as methyl, C ⁇ -C -alkoxy such as methoxy, tetrahydrofuranyl such as 2-tetrahydrofuranyl; or phenyl which is substituted by halogen such as fluorine; or
  • X! is SO 2 and R ⁇ is C- ⁇ -C 4 -alkyl such as methyl; or a salt, especially a pharmaceutically acceptable salt, thereof.
  • the invention relates in particular to a compound of formula (IB)
  • R1 signifies C C -alkyl, such as n-butyl, or C ⁇ -C 4 -alkoxy-CrC 2 -alkyl, such as ethoxymethyl; and R3 signifies halogen, such as fluorine; or R3 is C* ⁇ -C 4 -alkyl, such as methyl; or a salt, especially a pharmaceutically acceptable salt, thereof.
  • the invention further relates to the compounds according to the invention which are disclosed in the examples.
  • the invention also relates to a method of preparing the compounds according to the invention.
  • a method of preparing a compound of formula (I), is characterised e.g. in that a compound of formula
  • a method of preparing a compound of formula (I), wherein R1 signifies C C 7 -alkyl, which is substituted by a group of formula -NR4R5 and at least one of radicals R4 and R5 is other than hydrogen, is characterised e.g. in that a compound of formula (I), wherein R1 signifies C C 7 -alkyl, which is substituted by a group of formula -NR4R5 and at least one of radicals R4 and R5 is other than hydrogen, is characterised e.g. in that a compound of formula (I), wherein R1 signifies C C 7 -alkyl, which is substituted by a group of formula -NR4R5 and at least one of radicals R4 and R5 is other than hydrogen, is characterised e.g. in that a compound of formula (I), wherein R1 signifies C C 7 -alkyl, which is substituted by a group of formula -NR4R5 and at least one of radicals R4 and R5
  • the reactions described hereinbefore and hereinafter are carried out in a known manner, e.g. in the absence or usually in the presence of a suitable solvent or diluent or a mixture thereof, proceeding as required under conditions of cooling, of ambient temperature, or of heating, e.g. in a temperature range of about -80°C to the boiling temperature of the reaction medium, preferably about -10° to about +200°C, and where appropriate in a closed vessel, under pressure, in an inert gas atmosphere, and/or under non-aqueous conditions.
  • An appropriate leaving group Y ⁇ which is derived from an activated form of an acid of formula RI-X-i-OH, is primarily halogen, such as chlorine, and also fluorine or bromine.
  • Halogen in Y 2 signifies chlorine in particular, but may also be bromine or iodine.
  • the reaction is preferably carried out in the presence of an organic base.
  • This type of base may be e.g. a tri-C 1 -C 7 -alkylamine, such as triethylamine, likewise a tri-C C 7 -alkylamine with voluminous radicals, e.g. ethyl diisopropylamine, or a heterocyclic base, e.g. pyridine, 4- dimethylaminopyridine or N-methylmorpholine.
  • the starting material of formula (II a) is prepared, for example, from a compound of formula
  • the amino protecting group is cleaved e.g. by treating with an acid, such as hydrochloric acid, and a corresponding compound of formula (II a) is obtained.
  • a compound of formula (II e) may be produced e.g. whereby a compound of formula
  • the starting material of formula (III a) may be produced e.g. by reacting a compound of formula (II a) with a compound of formula Y1 -X ⁇ -Y 2 (III c) in the presence of one of the above bases.
  • the starting material of formulae (II b) and (III b) is partly known or may be prepared in known manner.
  • the reactions described hereinbefore and hereinafter are carried out in a known manner, e.g. in the absence or usually in the presence of a suitable solvent or diluent or a mixture thereof, proceeding as required under conditions of cooling, of ambient temperature, or of heating, e.g. in a temperature range of about -80°C to the boiling temperature of the reaction medium, preferably about -10° to about +200°C, and where appropriate in a closed vessel, under pressure, in an inert gas atmosphere, and/or under non-aqueous conditions.
  • the invention is illustrated in particular by the examples and also relates to the new compounds named in the examples and to their usage and to methods for the preparation thereof.
  • Salts of compounds of formula (I) may be prepared in a known manner.
  • acid addition salts of compounds of formula (I) are obtained by treatment with an acid or in an appropriate ion exchanger reagent.
  • Acid addition salts may be converted into the free compounds in the usual way, e.g. by treatment with an appropriate basic agent.
  • the acid addition salts obtained may be converted in known manner into other salts, e.g. by treatment with an appropriate metal salt, such as a sodium, barium or silver salt, of another acid in a suitable solvent in which a resulting inorganic salt is insoluble and thus precipitates out from the reaction equilibrium.
  • an appropriate metal salt such as a sodium, barium or silver salt
  • the compounds of formula I are also obtainable in the form of hydrates, or may include the solvent used for crystallisation (present as solvates).
  • the diastereoisomer mixtures and enantiomer mixtures obtained may be separated into the pure diastereoisomers and enantiomers in known manner, based on the physical-chemical differences in their components, for example by chromatography and/or fractional crystallisation.
  • the new compounds of formula (I) may be used e.g. in the form of pharmaceutical preparations, which contain a therapeutically effective amount of the active substance, optionally together with an inorganic or organic, solid or liquid, pharmaceutically acceptable carriers, which are suitable for enteral, e.g. oral, or parenteral administration.
  • the present pharmaceutical preparations which, if so desired, may contain further pharmacologically active substances, are prepared in a manner known perse, for example by means of conventional mixing, granulating, coating, dissolving or lyophilising processes, and contain from about 0.1% to 100%, especially from about 1 % to about 50%, of lyophilisates up to approximately 100% of the active substance.
  • the invention similarly relates to the usage of the compounds of formula (I), preferably in the preparation of pharmaceutical compositions. Dosaging may depend on various factors, such as mode of application, species, age and/or individual condition. For oral application, the doses to be administered daily are between ca. 0.25 and 300 mg/kg, and for warmblooded animals with a body weight of ca. 70 kg, preferably between ca. 20 mg and 500 mg.
  • the invention similarly relates to combinations, e.g. pharmaceutical combinations, containing a compound of formula (I) or (IA) or (IB) or in each case a pharmaceutically acceptable salt thereof, in combination with at least one composition for the treatment of obesity and related conditions and illnesses as listed above, or in each case a pharmaceutically acceptable salt thereof.
  • compositions for the treatment of obesity and related conditions and illnesses as listed above are those combined with at least one further active ingredient selected from the group consisting, for example, a NPY receptor antagonist, such as a NPY Y ⁇ Y 2 and Y 5 receptor antagonist, a combined serotonin and noradrenaline uptake inhibitor, such as sibutramines, a pancreatic lipase inhibitor, such as orlistat, a melanocortin-4-receptor antagonist, an orexin-2 receptor antagonist, a serotonergic active ingredient, such as a 5-HT 2c -receptor agonist, and a peripherally active adrenergic active ingredient, such as a ⁇ 3-adrenoceptor agonist.
  • a NPY receptor antagonist such as a NPY Y ⁇ Y 2 and Y 5 receptor antagonist
  • a combined serotonin and noradrenaline uptake inhibitor such as sibutramines
  • a pancreatic lipase inhibitor such as orlistat
  • HPLC eluants A) water + 0.1 % by volume of trifluoroacetic acid
  • HPLC column dimension 125 x 4 mm HPLC column packed with: Nucleosil ® 100-5 C ⁇ 8
  • HPLC eluants A) water + 0.1 % by volume of trifluoroacetic acid
  • Example 1 1 - ⁇ 4-[(9-f luoro-5,6-dihydro-4H-3-thia-1 -aza-benzo[e]azulen-2-ylamino)- methyl]-piperidin-1 -yl ⁇ -ethanone
  • the acetyl chloride is added at 0-5°C to a mixture of (9-fluoro-5,6-dihydro-4H-3-thia-1-aza- benzo[e]azulen-2-yl)-piperidin-4-ylmethyl-amine (7.0 g) and diisopropylethylamine (7.17 ml) in dimethylformamide (70 ml). After 15 minutes, the reaction mixture is poured onto ice- water (500 ml) and 10% sodium carbonate solution (50 ml), and the aqueous phase is extracted with ethyl acetate (2 x 200 ml). The combined organic phases are washed with brine, dried over magnesium sulphate and concentrated by evaporation.
  • the starting materials may be prepared for example as follows: 4-(3-benzoyl-thioureidomethyl)-piperidine-1 -carboxylic acid-tert.-butylester: A solution of benzoyl isothiocyanate (56.1 g) in tetrahydrofuran (100 ml) is added to a solution of 4- aminomethyl-piperidine-1 -carboxylic acid-tert. -butyl ester (85 g) [J. Med. Chem. 1996, 39, 487-493] in tetrahydrofuran (500 ml). After 1 hour under reflux, the reaction mixture is concentrated by evaporation and the residue is recrystallised from diethylether and hexane.
  • 4-thioureidomethyl-piperidine-1 -carboxylic acid-tert.-butylester A solution of 4-(3- benzoyl-thioureidomethyl)-piperidine-1 -carboxylic acid-tert.-butylester (196.3 g) in methanol (300 ml) is added to a solution of potassium carbonate (75.9 g) in water (100 ml). After 3 hours under reflux, the reaction mixture is concentrated by evaporation and the residue is mixed with water. The crystalline solid is filtered off and washed with diethylether.
  • Methanesulfonic acid chloride (0.04 ml) is added at 20°C to a mixture of (9-chloro-5,6- dihydro-4.H.-3-thia-1-aza-benzo[e]azulen-2-yl)-piperidin-4-ylmethyl-amine (0.175 g) and pyridine (6.0 ml).
  • the starting materials may be prepared for example as follows: 4-bromo-7-chloro-3,4-dihydro-2H-benzo[b]oxepin-5-one: Bromine (0.54 ml) is added dropwise at 0-5°C over the course of 5 minutes to a solution of 8-chloro-1-benzosuberone [J. Chem. Soc. (C) 1969, 2176-2181] (1.94 g) in ether (20 ml). After stirring for 1 hour at 0- 5°C, the reaction solution is poured onto ice-water, the ether phase separated and the aqueous phase extracted with ether.
  • Examples 3 - 38 The following may be prepared in analogous manner, for example as described in examples 1 and 2:
  • Example 30 1 - ⁇ 4-[(9-fluoro-5,6-dihydro-4H-3-thia-1 -aza-benzo[e]azulen-2-ylamino)- methyl]-piperidin-1 -yl ⁇ -2-piperidin-1 -yl-ethanone
  • the trifluoroacetate salt is converted into the free base with a 10% sodium carbonate solution and extracted with ethyl acetate.
  • a solution of the free base in ethanol with a 5 N hydrochloric acid solution in isopropanol and subsequently adding diethylether the dihydrochloride of the title compound is obtained as white crystals.
  • Rf 0.39 (toluene/ethanol/conc. ammonia 90:20:1 ).
  • the starting material may be prepared for example as follows:
  • the aqueous phase is again extracted with ethyl acetate and the combined organic phases are washed with brine and water, dried over magnesium sulfate and concentrated by evaporation.
  • Examples 31 -43 The following may be prepared in analogous manner, for example as described in example 30:
  • Example 44 1 - ⁇ 4-[(9-f luoro-4,5-dihydro-6-oxa-3-thia-1 -aza-benzo[e]azulen-2-ylamino)- methyl]-piperidin-1 -yl ⁇ -pentan-1 -one
  • the aqueous phase is again extracted with ethyl acetate and the combined organic phases are washed with 10% sodium carbonate solution and 5% citric acid solution, dried over magnesium sulfate and concentrated by evaporation.
  • the residue is crystallised from diethyl ether.
  • the starting materials may be prepared for example as follows:
  • the aqueous phase is again extracted with ethyl acetate and the combined organic phases are washed with 10% sodium carbonate solution, 5% citric acid solution and aqueous 5% sodium bicarbonate solution dried over magnesium sulfate and concentrated by evaporation.
  • Example 58 2-(cyclopropylmethyl-methyl-amino)-1- ⁇ 4-[(9-fluoro-4,5-dihydro-6-oxa- 3-thia-1-aza-benzo[e]azulen-2-ylamino)-methyl]-piperidin-1-yl ⁇ -ethanone
  • the trifluoroacetate salt is converted into the free base with a 10% sodium carbonate solution and extracted with ethyl acetate.
  • a solution of the free base in dichloromethane (5 ml) with a 5 N hydrochloric acid solution in diethylether the dihydrochloride of the title compound is obtained as an amorphous solid.
  • Rf 0.45 (toluene/ethanol/conc. ammonia 90:20:1).
  • the starting material may be prepared for example as follows: a) 2-chloro-1 - ⁇ 4-[(9-f luoro-4,5-dihydro-6-oxa-3-thia-1 -aza-benzo[e]azulen-2-ylamino)- methyl]-piperidin-1-yl ⁇ -ethanone: A solution of chloroacetyl chloride (4.05 ml) in dichloromethane (30 ml) is added at 5°C to a mixture of (9-fluoro-4,5-dihydro-6-oxa-3-thia-1 - aza-benzo[e]azulen-2-yl)-piperidin-4-ylmethyl-amine (15.33 g) and diisopropylethylamine (11.27 ml) in dichloromethane (200 ml).
  • Compounds 67-71 may be prepared in analogous manner, for example as described in example 1, by using e.g. (9-methyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[.e.]azulen-2-yl)- piperidin-4-ylmethyl-amine instead of (9-f luoro-4,5-dihydro-6-oxa-3-thia-1 -aza- benzo[e]azulen-2-yl)-piperidin-4-ylmethyl-amine.
  • (9-MethyI-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[.e.]azulen-2-yl)-piperidin-4-ylmethyl-amine may be prepared by employing the same process conditions as for the preparation of (9-fluoro-4,5-dihydro-6-oxa-3-thia-1 -aza- benzo[.e.]azulen-2-yl)-piperidin-4-ylmethyl-amine (see example 1) and using 4- methylphenol instead of 4-fluorophenol as the starting material.
  • Hard gelatin capsules containing 100 mg of active ingredient e.g. 1- ⁇ 4-[(9-fluoro-5,6-dihydro-4H-3-thia-1-aza-benzo[e]azulen-2-ylamino)-methyl]-piperidin-1-yl ⁇ - ethanone or a salt, e.g. the hydrochloride, thereof, may be prepared e.g. as follows:
  • Composition for 1000 capsules

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Abstract

L'invention concerne des composés représentés par la formule générale (I), dans laquelle X représente un CH2 ou un O, X1 représente un CO ou un SO2 et X2 représente un alkylène C1-C4, ou un sel, et plus particulièrement un sel pharmaceutiquement acceptable de ce composé. Ces composés agissent contre la fixation du neuropeptide Y (NPY) sur le sous-type Y5 du récepteur (antagonisme NPY), et peuvent être utilisés en particulier dans le traitement de l'adiposité.
PCT/EP2001/002339 2000-03-03 2001-03-01 Thiazolamines condensees et leur utilisation comme antagonistes du neuropeptide y5 Ceased WO2001064675A1 (fr)

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Cited By (15)

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EP1194421A4 (fr) * 1999-06-30 2002-09-11 Synaptic Pharma Corp Antagonistes selectifs du npy (y5)
US6569856B2 (en) 1999-04-22 2003-05-27 Synaptic Pharmaceutical Corporation Selective NPY (Y5) antagonists (triazines)
WO2003072577A1 (fr) * 2002-02-28 2003-09-04 F.Hoffmann-La Roche Ag Derives thiazoles utilises comme antagonistes du recepteur npy
WO2003084952A1 (fr) * 2002-04-09 2003-10-16 Laboratorios Del Dr. Esteve S.A. Composes derives de benzoxazinone, leur preparation et utilisation comme medicaments
WO2004014884A1 (fr) * 2002-08-07 2004-02-19 F. Hoffmann-La Roche Ag Derives de thiazole
WO2005014593A1 (fr) * 2003-08-12 2005-02-17 F. Hoffmann-La Roche Ag Derives de thiazole utiles comme antagonistes de npy *
US6989379B1 (en) 1999-04-22 2006-01-24 H. Lundbick A/S Selective NPY (Y5) antagonists
US7189720B2 (en) 1999-04-22 2007-03-13 H. Lundbeck A/S Selective NPY (Y5) antagonists
US7273880B2 (en) 1999-06-30 2007-09-25 H. Lunbeck A/S Selective NPY (Y5) antagonists
WO2011036284A1 (fr) * 2009-09-28 2011-03-31 F. Hoffmann-La Roche Ag Composés de benzoxépine inhibiteurs de pi3k et leurs procédés d'utilisation
US7928248B2 (en) 2008-03-31 2011-04-19 Genentech, Inc. Benzopyran and benzoxepin PI3K inhibitor compounds and methods of use
US8242104B2 (en) 2009-09-28 2012-08-14 F. Hoffman-La Roche Ag Benzoxazepin P13K inhibitor compounds and methods of use
JPWO2010101246A1 (ja) * 2009-03-05 2012-09-10 塩野義製薬株式会社 Ｎｐｙｙ５受容体拮抗作用を有するピペリジンおよびピロリジン誘導体
WO2013120980A1 (fr) 2012-02-17 2013-08-22 F. Hoffmann-La Roche Ag Composés tricycliques et méthodes d'utilisation correspondantes
US9090628B2 (en) 2011-03-21 2015-07-28 Genentech, Inc. Benzoxazepin compounds selective for PI3K P110 delta and methods of use

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Cited By (40)

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Publication number Priority date Publication date Assignee Title
US6989379B1 (en) 1999-04-22 2006-01-24 H. Lundbick A/S Selective NPY (Y5) antagonists
US6569856B2 (en) 1999-04-22 2003-05-27 Synaptic Pharmaceutical Corporation Selective NPY (Y5) antagonists (triazines)
US7189720B2 (en) 1999-04-22 2007-03-13 H. Lundbeck A/S Selective NPY (Y5) antagonists
EP1194421A4 (fr) * 1999-06-30 2002-09-11 Synaptic Pharma Corp Antagonistes selectifs du npy (y5)
US7273880B2 (en) 1999-06-30 2007-09-25 H. Lunbeck A/S Selective NPY (Y5) antagonists
US6686381B2 (en) 2002-02-28 2004-02-03 Hoffmann-La Roche Inc. Thiazole derivatives
WO2003072577A1 (fr) * 2002-02-28 2003-09-04 F.Hoffmann-La Roche Ag Derives thiazoles utilises comme antagonistes du recepteur npy
CN100363362C (zh) * 2002-02-28 2008-01-23 霍夫曼-拉罗奇有限公司 用作npy受体拮抗剂的噻唑衍生物
WO2003084952A1 (fr) * 2002-04-09 2003-10-16 Laboratorios Del Dr. Esteve S.A. Composes derives de benzoxazinone, leur preparation et utilisation comme medicaments
US7056914B2 (en) 2002-04-09 2006-06-06 Esteve Laboratorios Dr. Esteve S.A. Benzoxazinone-derived compounds, their preparation and use as medicaments
US7514429B2 (en) 2002-04-09 2009-04-07 Esteve Laboratorios Dr. Esteve S.A. Benzoxazinone-derived compounds, their preparation and use as medicaments
WO2004014884A1 (fr) * 2002-08-07 2004-02-19 F. Hoffmann-La Roche Ag Derives de thiazole
CN100381429C (zh) * 2002-08-07 2008-04-16 霍夫曼-拉罗奇有限公司 噻唑衍生物
US7253197B2 (en) 2002-08-07 2007-08-07 Hoffmann-La Roche Inc. Aminothiazole derivatives
WO2005014593A1 (fr) * 2003-08-12 2005-02-17 F. Hoffmann-La Roche Ag Derives de thiazole utiles comme antagonistes de npy *
RU2321586C2 (ru) * 2003-08-12 2008-04-10 Ф.Хоффманн-Ля Рош Аг Производные тиазола в качестве антагонистов npy
CN100393718C (zh) * 2003-08-12 2008-06-11 霍夫曼-拉罗奇有限公司 作为npy拮抗剂的噻唑衍生物
US7265109B2 (en) 2003-08-12 2007-09-04 Hoffmann-La Roche Inc. Thiazole derivatives
US9309265B2 (en) 2008-03-31 2016-04-12 Genentech, Inc. Benzopyran and benzoxepin PI3K inhibitor compounds and methods of use
US7928248B2 (en) 2008-03-31 2011-04-19 Genentech, Inc. Benzopyran and benzoxepin PI3K inhibitor compounds and methods of use
US8399690B2 (en) 2008-03-31 2013-03-19 Genentech, Inc. 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene compounds
US8846762B2 (en) 2008-03-31 2014-09-30 Genentech, Inc. Benzopyran and benzoxepin PI3K inhibitor compounds and methods of use
JPWO2010101246A1 (ja) * 2009-03-05 2012-09-10 塩野義製薬株式会社 Ｎｐｙｙ５受容体拮抗作用を有するピペリジンおよびピロリジン誘導体
US8889674B2 (en) 2009-03-05 2014-11-18 Shionogi & Co., Ltd. Piperidine and pyrrolidine derivatives having NPY Y5 receptor antagonism
US8242104B2 (en) 2009-09-28 2012-08-14 F. Hoffman-La Roche Ag Benzoxazepin P13K inhibitor compounds and methods of use
US8343955B2 (en) 2009-09-28 2013-01-01 Genentech, Inc. Benzoxazepin PI3K inhibitor compounds and methods of use
US9670228B2 (en) 2009-09-28 2017-06-06 Genentech, Inc. Benzoxazepin PI3K inhibitor compounds and methods of use
US8586574B2 (en) 2009-09-28 2013-11-19 Genentech, Inc. Benzoxazepin PI3K inhibitor compounds and methods of use
US8673952B2 (en) 2009-09-28 2014-03-18 F. Hoffman-La Roche Ag Benzoxepin PI3K inhibitor compounds and methods of use
US8785626B2 (en) 2009-09-28 2014-07-22 Genentech, Inc. Benzoxazepin PI3K inhibitor compounds and methods of use
JP2014139222A (ja) * 2009-09-28 2014-07-31 F Hoffmann-La Roche Ag ベンゾキセピンｐｉ３ｋ阻害剤化合物及び使用方法
JP2013505920A (ja) * 2009-09-28 2013-02-21 エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト ベンゾキセピンｐｉ３ｋ阻害剤化合物及び使用方法
EP2784078A1 (fr) * 2009-09-28 2014-10-01 F. Hoffmann-La Roche AG Composés inhibiteurs de pi3k benzoxazepine et procédés d'utilisation
US8263633B2 (en) 2009-09-28 2012-09-11 F. Hoffman-La Roche Ag Benzoxepin PI3K inhibitor compounds and methods of use
US8952043B2 (en) 2009-09-28 2015-02-10 Genetech, Inc. Benzoxepin PI3K inhibitor compounds and methods of use
WO2011036284A1 (fr) * 2009-09-28 2011-03-31 F. Hoffmann-La Roche Ag Composés de benzoxépine inhibiteurs de pi3k et leurs procédés d'utilisation
US9175009B2 (en) 2009-09-28 2015-11-03 Genentech, Inc. Benzoxepin PI3K inhibitor compounds and methods of use
US9198918B2 (en) 2009-09-28 2015-12-01 Genentech, Inc. Benzoxazepin PI3K inhibitor compounds and methods of use
US9090628B2 (en) 2011-03-21 2015-07-28 Genentech, Inc. Benzoxazepin compounds selective for PI3K P110 delta and methods of use
WO2013120980A1 (fr) 2012-02-17 2013-08-22 F. Hoffmann-La Roche Ag Composés tricycliques et méthodes d'utilisation correspondantes

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