WO2007080109A1 - Dérivés de benzyloxyphénylméthylurée substitués - Google Patents

Dérivés de benzyloxyphénylméthylurée substitués Download PDF

Info

Publication number
WO2007080109A1
WO2007080109A1 PCT/EP2007/000192 EP2007000192W WO2007080109A1 WO 2007080109 A1 WO2007080109 A1 WO 2007080109A1 EP 2007000192 W EP2007000192 W EP 2007000192W WO 2007080109 A1 WO2007080109 A1 WO 2007080109A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
group
general formula
further substituted
represents hydrogen
Prior art date
Application number
PCT/EP2007/000192
Other languages
English (en)
Inventor
Thomas Lampe
Cristina Alonso-Alija
Hartmut Beck
Ulrich Rosentreter
Peter Sandner
Elke Stahl
Beatrix Stelte-Ludwig
Original Assignee
Bayer Healthcare Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Healthcare Ag filed Critical Bayer Healthcare Ag
Publication of WO2007080109A1 publication Critical patent/WO2007080109A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/36—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
    • C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/26—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups

Definitions

  • the present invention relates to novel substituted benzyloxy-phenylmethylurea derivatives, processes for their preparation, and their use in medicaments, especially for the prophylaxis and treatment of diseases associated with Cold Menthol Receptor 1 (CMR-I) activity, in particular for the treatment of urological diseases or disorders, such as detrusor overactivity (overactive bladder), urinary incontinence, neurogenic detrusor overactivity (detrusor hyperflexia), idiopathic detrusor overactivity (detrusor instability), benign prostatic hyperplasia, and lower urinary tract symptoms; chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritic pain, neuralgia, neuropathies, algesia, nerve injury, ischaemia, neurodegeneration, stroke, and inflammatory disorders such as asthma and chronic obstructive pulmonary (or airways) disease (COPD).
  • COPD chronic obstructive pulmonary
  • TRP Transient Receptor Potential
  • CMR-I cold menthol receptor - 1
  • This receptor which is activated by 8 - 28°C temperature is expressed on the bladder urothelium and DRG (Dorsal Root Ganglia) and C-fibers.
  • DRG Dorsal Root Ganglia
  • C-fibers The intravesical ice water or menthol also induce C-fiber mediated spinal micturition reflex in patients with urgency and urinary incontinence (UI).
  • Clinically CMR-I is supposed to mediate the bladder cooling reflex seen after ice water test in overactive patients.
  • antagonism of the CMR-I receptor leads to the blockage of neurotransmitter release, resulting in prophylaxis and treatment of the conditions and diseases associated with CMR-I activity.
  • Antagonists of the CMR-I receptor can be used for prophylaxis and treatment of the conditions and diseases including chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritic pain, neuralgia, neuropathies, algesia, nerve injury, ischaemia, neurodegeneration, stroke, inflammatory disorders, urinary incontinence (Ul) such as urge urinary incontinence (UUI), and/or overactive bladder, Lower urinary tract symptoms secondary to or independent of benign prostatic hyperplasia.
  • Ul urinary incontinence
  • UUI urge urinary incontinence
  • UUI urge urinary incontinence
  • overactive bladder Lower urinary tract symptoms secondary to or independent of benign prostatic hyperplasia.
  • UI is the involuntary loss of urine.
  • UUl is one of the most common types of UI together with stress urinary incontinence (SUI) which is usually caused by a defect in the urethral closure mechanism.
  • UUl is often associated with neurological disorders or diseases causing neuronal damages such as dementia, Parkinson's disease, multiple sclerosis, stroke and diabetes, although it also occurs in individuals with no such disorders.
  • UUI is overactive bladder (OAB) which is a medical condition referring to the symptoms of frequency and urgency derived from abnormal contractions and instability of the detrusor muscle.
  • OAB overactive bladder
  • the present invention relates to compounds of the general formula (I)
  • R 1 represents hydrogen or halogen
  • R 2 represents hydrogen or halogen
  • R 3 represents hydrogen or halogen
  • R 4 represents chlorine, fluorine, nitro, trifluoromethyl, trifluoromethoxy, C
  • R 5 represents hydrogen or halogen
  • R 6 represents C 3 -C 8 -alkyl, C 3 -C 7 -cycloalkyl, C 6 -Ci 0 -aryl, 5- to 10-membered heteroaryl or a group of the formula -Y-R 9 ,
  • cycloalkyl can be further substituted with one to three identical or different radicals selected from the group consisting of trifluoromethyl and Ci-C 4 - alkyl,
  • aryl and heteroaryl can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, nitro, amino, hydroxy, trifluoromethyl, Ci-C 6 -alkyl, Ci-C 6 -alkoxy and C
  • Y represents Ci -C 4 -alkandiyl
  • R 9 represents C 3 -C 7 -cycloalkyl, phenyl or 5- to 10-membered heteroaryl,
  • cycloalkyl can be further substituted with one to three identical or different radicals selected from the group consisting of trifluoromethyl and
  • phenyl and heteroaryl can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, nitro, amino, hydroxy, trifluoromethyl, C
  • R 7 represents C
  • R 8 represents hydrogen or C
  • Physiologically acceptable salts are preferred in the context of the present invention.
  • Physiologically acceptable salts according to the invention are non-toxic salts which in general are accessible by reaction of the compounds (I) with an inorganic or organic base or acid conventionally used for this purpose.
  • Non-limiting examples of pharmaceutically acceptable salts of compounds (I) include the alkali metal salts, e.g.
  • the alkaline earth metal salts such as magnesium and calcium salts
  • the quaternary ammonium salts such as, for example, triethyl ammonium salts, acetates, benzene sulphonates, benzoates, dicarbonates, disulphates, ditartrates, borates, bromides, carbonates, chlorides, citrates, dihydrochlorides, fumarates, gluconates, glutamates, hexyl resorcinates, hydrobromides, hydrochlorides, hydroxy- naphthoates, iodides, isothionates, lactates, laurates, malates, maleates, mandelates, mesylates, methylbromides, methylnitrates, methylsulphates, nitrates, oleates, oxalates, palmitates, pantothenates, phosphates, diphosphates, polygalacturonates, sal
  • Hydrates of the compounds of the invention or their salts are stoichiometric compositions of the compounds with water, such as for example hemi-, mono-, or dihydrates.
  • Solvates of the compounds of the invention or their salts are stoichiometric compositions of the compounds with solvents.
  • the present invention includes both the individual enantiomers or diastereomers and the corresponding racemates or diastereomeric mixtures of the compounds according to the invention and their respective salts.
  • all possible tautomeric forms of the compounds described above are included according to the present invention.
  • the diastereomeric mixtures can be separated into the individual isomers by chromatographic processes.
  • the racemates can be resolved into the respective enantiomers either by chromatographic processes on chiral phases or by resolution.
  • Alkyl in general represents a straight-chain or branched saturated hydrocarbon radical having 1 to 6, preferably 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, iso- propyl, n-butyl, isobutyl, sec-butyl, tert-bulyl, pentyl, isopentyl, hexyl, isohexyl.
  • radicals such as alkoxy, alkylamino, alkylcarbonylamino, alkoxycarbonylamino and the like.
  • Alkandiyl in general represents a straight-chain or branched saturated alkandiyl radical having 1 to 4 carbon atoms.
  • Non-limiting examples include methylen, ethan-l ,2-diyl, ethan-l .l-diyl, propan- 1 ,3-diyl, propan-l ,2-diyl, propan-2,2-diyl, butan-l ,4-diyl, butan-l ,3-diyl and butan-2,4-diyl.
  • Alkenyl in general represents a straight-chain or branched alkenyl radical having 2 to 6, preferably 2 to 4 carbon atoms.
  • Non-limiting examples include vinyl, allyl, n-prop-1-en-l-yl, n-but-2-en-l-yl, 2-methylprop-l -en-1 -yl and 2-methylprop-2-en-l -yl.
  • Alkinyl in general represents a straight-chain or branched alkinyl radical having 2 to 6, preferably 2 to 4 carbon atoms.
  • Non-limiting examples include ethinyl, propargyl (2-propinyl), 1-propinyl, but- 1-inyl, but-2-inyl.
  • Alkoxy illustratively and preferably represents methoxy, ethoxy, n-propoxy, isopropoxy, /er/-butoxy, n-pentoxy and n-hexoxy.
  • Alkylcarbonylamino in general represents a straight-chain or branched hydrocarbon radical having 1 to 6, preferably 1 to 4 carbon atoms which has a carbonylamino (-CO-NH-) function at the position of attachment and which is bonded to the carbonyl group.
  • Non-limiting examples include formylamino, acetylamino, n-propionylamino, n-butyrylamino, isobutyrylamino, pivaloylamino, n- hexanoylamino.
  • Alkoxycarbonylamino illustratively and preferably represents methoxycarbonylamino, ethoxy- carbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, tert-butoxycarbonylamino, n-pentoxycarbonylamino and n-hexoxycarbonylamino.
  • Alkylamino represents an alkylamino radical having one or two (independently selected) alkyl substituents, illustratively and preferably representing methylamino, ethylamino, n-propylamino, isopropylamino, t ⁇ rt-butylamino, n-pentylamino, n-hexylamino, N,N-dimethylamino, N,N-diethyl- amino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino, N-tert- butyl-N-methylamino, N-ethyl-N-n-pentylamino and N-n-hexyl-N-methylamino.
  • Mono-alkylamino represents an alkylamino radical having one alkyl substituents, illustratively and preferably representing methylamino, ethylamino, n-propylamino, isopropylamino, fert-butylamino, n-pentylamino and n-hexylamino.
  • Cvcloalkyl in general represents a cyclic saturated hydrocarbon radical having 3 to 8, preferably 3 to 6 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclo- hexyl and cycloheptyl.
  • Aryl in general represents an aromatic mono- or bicyclic radical having 6 to 10 ring atoms, illustratively and preferably representing phenyl and naphthyl.
  • Heteroaryl per se and in heteroarylmethyl in general represents an aromatic mono- or bicyclic radical having 5 to 10 and preferably 5 or 6 ring atoms, and up to 5 and preferably up to 4 hetero- atoms selected from the group consisting of S, O and N, illustratively and preferably representing thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzo- thienyl, benzothiazolyl, quinolinyl, isoquinolinyl.
  • Halogen represents fluorine, chlorine, bromine and iodine.
  • the present invention relates to compounds of general formula (I), wherein
  • R 1 represents hydrogen or halogen
  • R 2 represents hydrogen or halogen
  • R 3 represents hydrogen
  • R 4 represents chlorine, nitro, trifluoromethoxy, Ci-C 3 -alkyl or Ci-C 3 -alkoxy,
  • R 5 represents hydrogen
  • R 6 represents C 3 -C 8 -alkyl, C 3 -C 7 -cycloalkyl, phenyl, 5- or 6-membered heteroaryl or a group of the formula -Y-R 9 ,
  • cycloalkyl can be further substituted with one to three identical or different radicals selected from the group consisting of trifluoromethyl and C 1 -C 4 - alkyl.
  • phenyl and heteroaryl can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, nitro, trifluoromethyl, Ci-C 6 -alkyl and C
  • Y represents CpGj-alkandiyl
  • R 9 represents C 3 -C 7 -cycloalkyl, phenyl or 5- or 6-membered heteroaryl
  • cycloalkyl can be further substituted with one to three identical or different radicals selected from the group consisting of trifluoromethyl and C,-C 4 -alkyl,
  • phenyl and heteroaryl can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, nitro, trifluoromethyl, Ci-C ⁇ -alkyl and Ci-C 6 -alkoxy,
  • R 7 represents Ci-C 3 -alkyl
  • alkyl is further substituted with one radical selected from the group consisting of amino, mono-alkylamino or C,-C 4 -alkoxycarbonylamino,
  • R 8 represents hydrogen
  • the present invention relates to compounds of general formula (I), wherein
  • R 1 represents hydrogen or fluorine
  • R 2 represents hydrogen or fluorine
  • R 3 represents hydrogen
  • R 4 represents chlorine or methoxy
  • R 5 represents hydrogen
  • R 6 represents C 3 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, phenyl, thienyl or a group of the formula -Y-R 9 ,
  • cycloalkyl can be further substituted with one trifluoromethyl group
  • phenyl and thienyl can be further substituted with one to three identical or different radicals selected from the group consisting of fluorine, chlorine, nitro, trifluoromethyl, methyl and methoxy,
  • Y represents methylen or ethan- 1 , 1 -diyl
  • R 9 represents phenyl
  • phenyl can be further substituted with one to three identical or different radicals selected from the group consisting of fluorine, chlorine, nitro, trifluoromethyl, methyl and methoxy,
  • R 7 represents Ci-C 2 -alkyl
  • alkyl is further substituted with one radical selected from the group consisting of amino or tert-butoxycarbonylamino,
  • R 8 represents hydrogen
  • the present invention relates to compounds of general formula (I), wherein R 7 represents -CH 2 NH 2 or -CH 2 CH 2 NH 2 .
  • the present invention relates to compounds of general formula (I), wherein R 1 , R 2 and R 3 represent hydrogen.
  • the present invention relates to compounds of general formula (I), wherein R 1 represents halogen, R 2 represents hydrogen or halogen and R 3 represents hydrogen or halogen.
  • the present invention relates to compounds of general formula (I), wherein R 1 represents halogen, R 2 represents hydrogen or halogen and R 3 represents hydrogen.
  • the present invention relates to compounds of general formula (I), wherein R 1 represents fluorine, R 2 represents hydrogen or fluorine and R 3 represents hydrogen.
  • the present invention relates to compounds of general formula (0, wherein R 4 represents chlorine or methoxy.
  • the present invention relates to compounds of general formula (I), wherein R 6 represents phenyl, wherein phenyl can be further substituted with one to three identical or different radicals selected from the group consisting of fluorine, chlorine, nitro, trifluoromethyl, methyl and methoxy.
  • the present invention relates to compounds of general formula (I), wherein R 6 represents a group of the formula -Y-R 9 , wherein Y represents methylen or ethan- 1 ,1-diyl, and R 9 represents phenyl, wherein phenyl can be further substituted with one to three identical or different radicals selected from the group consisting of fluorine, chlorine, nitro, trifluoromethyl, methyl and methoxy.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 7 and R 8 have the meaning indicated above,
  • R 6 has the meaning indicated above
  • R 6 has the meaning indicated above
  • R 4 , R 5 , R 6 , R 7 and R 8 have the meaning indicated above,
  • R 1 , R 2 and R 3 have the meaning indicated above, and
  • X 1 represents a leaving group, such as halogen, preferably chlorine or bromine,
  • a base can be added to the reaction mixture.
  • Amino groups in R 7 of compounds of general formula (II) are protected with acid labile groups, preferred is a boc-group. After the synthesis of compounds of general formula (I) this acid labile group can be cleaved via standard procedures known by a person skilled in the art. Compounds of general formula (I) are obtained. Preferred are acidic cleavage conditions.
  • the free base can be obtained by reversed phase chromatography of the salt using a mixture of acetonitile and water as eluent in the presence of a base.
  • a RP 18 Phenomenex Luna C 18(2) column is used in the presence of diethylamine as base.
  • the free base of a compound of general formula (I) can be obtained by neutralizing with a base and extraction.
  • the process [A] is in general carried out in a temperature range from -20 0 C to boiling point of the solvent, preferably from O 0 C to +40 0 C.
  • the process is generally carried out at normal pressure. However, it is also possible to carry it out at elevated pressure or at reduced pressure (for example in a range from 0.5 to 5 bar).
  • Suitable solvents for the process are ethers such as dioxan or tetrahydrofuran, or halogeno-hydro- carbons such as dichloromethane, dichloroethane or trichloromethane, or other solvents such as dimethylformamide, ethyl acetate or acetonitrile. It is also possible to use mixtures of the above- mentioned solvents. Preferred for the process is tetrahydrofuran or dichloromethane.
  • Suitable bases for the process are generally inorganic or organic bases. These preferably include alkali carbonates such as sodium or potassium carbonate or hydrogencarbonate, cyclic amines such as, for example, N-methylmorpholine, N-methylpiperidine, pyridine or 4-N,N-dimethylamino- pyridine, or (C
  • alkali carbonates such as sodium or potassium carbonate or hydrogencarbonate
  • cyclic amines such as, for example, N-methylmorpholine, N-methylpiperidine, pyridine or 4-N,N-dimethylamino- pyridine
  • -C 4 )-trialkylamines such as, for example, triethylamine or diisopropylethylamine
  • the process [B] is in general carried out in a temperature range from room temperature to +40 0 C.
  • the process is generally carried out at normal pressure. However, it is also possible to carry it out at elevated pressure or at reduced pressure (for example in a range from 0.5 to 5 bar).
  • Suitable carbonic acid derivatives for the process are ⁇ . ⁇ -carbonyldiimidazole, phosgene, diphosgene, triphosgene, chloroformic acid phenyl ester or chloroformic acid 4-nitrophenyl ester. Preference is given to ⁇ , ⁇ -carbonyldiimidazole.
  • Suitable solvents for the process are ethers such as dioxan or tetrahydrofuran, or halogeno-hydro- carbons such as dichloromethane, dichloroethane or trichloromethane, or other solvents such as dimethylformamide, ethyl acetate or acetonitrile. It is also possible to use mixtures of the above- mentioned solvents. Preferred for the process is tetrahydrofuran or dichloromethane.
  • Suitable bases for the process are generally organic bases. These preferably include cyclic amines such as, for example, N-methylmorpholine, N-methylpiperidine, pyridine or 4-NN-dimethylamino- pyridine, or (C ⁇ -Gi)-trialkylamines such as, for example, triethylamine or diisopropylethylamine. Preference is given to diisopropylethylamine.
  • the process [C] is in general carried out in a temperature range from 0 0 C to boiling point of the solvent, preferably from 20 0 C to boiling point of the solvent.
  • the process is generally carried out at normal pressure. However, it is also possible to carry it out at elevated pressure or at reduced pressure (for example in a range from 0.5 to 5 bar).
  • an alkali iodide such as sodium or potassium iodide can be added to the reaction mixture.
  • Suitable solvents for the process are ethers such as dioxan or tetrahydrofuran, or halogeno-hydro- carbons such as dichloromethane, dichloroethane or trichloromethane, or other solvents such as dimethylformamide, dimethylsulfoxide, ethyl acetate or acetonitrile. It is also possible to use mixtures of the above-mentioned solvents. Preferred for the process is acetonitrile.
  • Suitable bases for the process are generally inorganic or organic bases. These preferably include alkali carbonates such as sodium or potassium carbonate or hydrogen carbonate, cyclic amines such as, for example, N-methylmorpholine, N-methylpiperidine, pyridine or 4-N,N-dimethylamino- pyridine, or (Ci-GO-trialkylamines such as, for example, triethylamine or diisopropylethylamine. Preference is given to potassium carbonate.
  • alkali carbonates such as sodium or potassium carbonate or hydrogen carbonate
  • cyclic amines such as, for example, N-methylmorpholine, N-methylpiperidine, pyridine or 4-N,N-dimethylamino- pyridine
  • Ci-GO-trialkylamines such as, for example, triethylamine or diisopropylethylamine.
  • Preference is given to potassium carbonate.
  • the compounds of general formula (II) can be synthesized by condensing compounds of general formula (VII)
  • R 7 and R 8 have the meaning indicated above
  • the process is in general carried out in a temperature range from -20 0 C to boiling point of the solvent, preferably from 0 0 C to +40 0 C.
  • the process is generally carried out at normal pressure. However, it is also possible to carry it out at elevated pressure or at reduced pressure (for example in a range from 0.5 to 5 bar).
  • Suitable solvents for the process are halogeno-hydrocarbons such as dichloromethane, dichloro- ethane or trichloromethane, or alcohols such as methanol, ethanol, n-propanol, iso-propanol, n- butanol or tert-butano ⁇ , or a mixture of alcohol and water.
  • halogeno-hydrocarbons such as dichloromethane, dichloro- ethane or trichloromethane
  • alcohols such as methanol, ethanol, n-propanol, iso-propanol, n- butanol or tert-butano ⁇ , or a mixture of alcohol and water.
  • Preferred for the process is methanol or a mixture of methanol and water.
  • Suitable reducing agents for the process are sodium borohydride or triacetoxyborohydride.
  • R 1 , R 2 and R 3 have the meaning indicated above, and
  • X 2 represents a leaving group, such as halogen, preferably chlorine or bromine,
  • an alkali iodide such as sodium or potassium iodide can be added to the reaction mixture.
  • the process is in general carried out in a temperature range from 0 0 C to boiling point of the solvent, preferably from 20 0 C to boiling point of the solvent.
  • the process is generally carried out at normal pressure. However, it is also possible to carry it out at elevated pressure or at reduced pressure (for example in a range from 0.5 to 5 bar).
  • Suitable solvents for the process are ethers such as dioxan or tetrahydrofuran, or halogeno-hydro- carbons such as dichloromethane, dichloroethane or trichloromethane, or other solvents such as dimethylformamide, dimethylsulfoxide, ethyl acetate or acetonitrile. It is also possible to use mixtures of the above-mentioned solvents. Preferred for the process is acetonitrile.
  • Suitable bases for the process are generally inorganic or organic bases. These preferably include alkali carbonates such as caesium, sodium or potassium carbonate or hydrogencarbonate, cyclic amines such as, for example, N-methylmorpholine, N-methylpiperidine, pyridine or 4-N 1 N- dimethylaminopyridine, or (Ci-C 4 )-trialkylamines such as, for example, triethylamine or diiso- propylethylamine. Preference is given to potassium carbonate.
  • alkali carbonates such as caesium, sodium or potassium carbonate or hydrogencarbonate
  • cyclic amines such as, for example, N-methylmorpholine, N-methylpiperidine, pyridine or 4-N 1 N- dimethylaminopyridine
  • (Ci-C 4 )-trialkylamines such as, for example, triethylamine or diiso- propylethylamine.
  • the compounds of general formula (V) can be synthesized by treating compounds of general formula (Ia)
  • R 4 , R 5 , R 6 , R 7 and R 8 have the meaning indicated above,
  • the process is in general carried out in a temperature range from -20 0 C to boiling point of the solvent, preferably from 0 0 C to +4O 0 C.
  • the process is generally carried out at normal pressure. However, it is also possible to carry it out at elevated pressure or at reduced pressure (for example in a range from 0.5 to 5 bar).
  • Suitable solvents for the process are alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol or tert-butanol, or tetrahydrofuran, or a mixture of alcohol and water.
  • Preferred for the process is methanol, ethanol, tetrahydrofuran or a mixture of ethanol and water.
  • Suitable reducing agents for the process are metals such as palladium, platin, nickel or ruthenium or oxides thereof in the presence of hydrogen such as palladium on charcoal and hydrogen.
  • Preferred for the process is palladium on charcoal and hydrogen.
  • the compounds of general formula (Ia) can be synthesized via process [A] or [B] or [C].
  • the compounds according to the invention exhibit an unforeseeable, useful pharmacological activity spectrum. They are therefore suitable for use as medicaments for the treatment and/or prophylaxis of disorders in humans and animals.
  • the compounds of the present invention show excellent CMR-I antagonistic activity. They are, therefore suitable especially for the prophylaxis and treatment of diseases associated with CMR-I activity, in particular for the treatment of urological diseases or disorders, such as detrusor overactivity (overactive bladder), urinary incontinence, neurogenic detrusor oeractivity (detrusor hyperflexia), idiopathic detrusor overactivity (detrusor instability), benign prostatic hyperplasia, and lower urinary tract symptoms.
  • urological diseases or disorders such as detrusor overactivity (overactive bladder), urinary incontinence, neurogenic detrusor oeractivity (detrusor hyperflexia), idiopathic detrusor overactivity (detrusor instability), benign prostatic hyperplasia, and lower urinary tract symptoms.
  • the compounds of the present invention are also effective for treating or preventing a disease selected from the group consisting of chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritic pain, neuralgia, neuropathies, algesia, nerve injury, ischaemia, neuro- degeneration and/or stroke, as well as respiratory diseases and inflammatory diseases such as asthma, COPD and allergic rhinitis since the diseases also relate to CMR-I activity.
  • a disease selected from the group consisting of chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritic pain, neuralgia, neuropathies, algesia, nerve injury, ischaemia, neuro- degeneration and/or stroke, as well as respiratory diseases and inflammatory diseases such as asthma, COPD and allergic rhinitis since the diseases also relate to CMR-I activity.
  • the compounds of the present invention are also useful for the treatment and prophylaxis of neuropathic pain, which is a form of pain often associated with herpes zoster and post-herpetic neuralgia, painful diabetic neuropathy, neuropathic low back pain, posttraumatic and postoperative neuralgia, neuralgia due to nerve compression and other neuralgias, phantom pain, complex regional pain syndromes, infectious or parainfectious neuropathies like those associated with HIV infection, pain associated with central nervous system disorders like multiple sclerosis or Parkinson disease or spinal cord injury or traumatic brain injury, and post-stroke pain.
  • neuropathic pain which is a form of pain often associated with herpes zoster and post-herpetic neuralgia, painful diabetic neuropathy, neuropathic low back pain, posttraumatic and postoperative neuralgia, neuralgia due to nerve compression and other neuralgias, phantom pain, complex regional pain syndromes, infectious or parainfectious neuropathies like those associated with HIV infection
  • the compounds of the present invention are useful for the treatment of musculoskeletal pain, forms of pain often associated with osteoarthritis or rheumatoid arthritis or other forms of arthritis, and back pain.
  • the compounds of the present invention are useful for the treatment of pain associated with cancer, including visceral or neuropathic pain associated with cancer or cancer treatment.
  • the compounds of the present invention are furthermore useful for the treatment of visceral pain, e.g. pain associated with obstruction of hollow viscus like gallstone colik, pain associated with irritable bowel syndrome, pelvic pain, vulvodynia, orchialgia or prostatodynia, pain associated with inflammatory lesions of joints, skin, muscles or nerves, and orofascial pain and headache, e.g. migraine or tension-type headache.
  • visceral pain e.g. pain associated with obstruction of hollow viscus like gallstone colik
  • pain associated with irritable bowel syndrome pelvic pain
  • vulvodynia orchialgia or prostatodynia
  • pain associated with inflammatory lesions of joints, skin, muscles or nerves e.g. migraine or tension-type headache.
  • the present invention further provides medicaments containing at least one compound according to the invention, preferably together with one or more pharmacologically safe excipient or carrier substances, and also their use for the above-mentioned purposes.
  • the active component can act systemically and/or locally.
  • it can be applied in a suitable manner, for example orally, parenterally, pulmonally, nasally, sublingually, lingually, buccally, rectally, transdermally, conjunctivally, otically or as an implant.
  • the active component can be administered in suitable application forms.
  • Useful oral application forms include application forms which release the active component rapidly and/or in modified form, such as for example tablets (non-coated and coated tablets, for example with an enteric coating), capsules, sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, solutions and aerosols.
  • Parenteral application can be carried out with avoidance of an absorption step (intravenously, intraarterially, intracardially, intraspinally or intralumbarly) or with inclusion of an absorption (intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneal ⁇ ).
  • Useful parenteral application forms include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders.
  • Forms suitable for other application routes include for example inhalatory pharmaceutical forms (including powder inhalers, nebulizers), nasal drops/solutions, sprays; tablets or capsules to be administered lingually, sublingually or buccally, suppositories, ear and eye preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, milk, pastes, dusting powders or implants.
  • inhalatory pharmaceutical forms including powder inhalers, nebulizers
  • nasal drops/solutions, sprays including lingually, sublingually or buccally, suppositories, ear and eye preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, milk, pastes, dusting powders or implants.
  • the active components can be converted into the recited application forms in a manner known per se. This is carried out using inert non-toxic, pharmaceutically suitable excipients.
  • inert non-toxic, pharmaceutically suitable excipients include inter alia carriers (for example microcrystalline cellulose), solvents (for example liquid polyethylene glycols), emulsifiers (for example sodium dodecyl sulphate), dispersing agents (for example polyvinylpyrrolidone), synthetic and natural biopolymers (for example albumin), stabilizers (for example antioxidants such as ascorbic acid), colorants (for example inorganic pigments such as iron oxides) or taste and/or odor corrigents.
  • carriers for example microcrystalline cellulose
  • solvents for example liquid polyethylene glycols
  • emulsifiers for example sodium dodecyl sulphate
  • dispersing agents for example polyvinylpyrrolidone
  • synthetic and natural biopolymers for example albumin
  • stabilizers for example antioxidant
  • oral administration in the case of oral administration, it is recommendable to administer doses of from 0.001 to 50 mg/kg, preferably of 0.01 mg/kg to 20 mg/kg.
  • parenteral administration such as, for example, intravenously or via mucous membranes nasally, buccally or inhalationally, it is recommendable to use doses of 0.001 mg/kg to 0.5 mg/kg.
  • LC-MS / HPLC methods method 1 (LC-MS): Instrument MS: Micromass ZQ; Instrument HPLC: Waters Alliance 2795; column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20 mm x 4 mm; eluent A: 1 1 water + 0.5 ml 50% formic acid, eluent B: 1 1 acetonitrile + 0.5 ml 50% formic acid; gradient: 0.0 min 90% A — > 2.5 min 30% A ⁇ 3.0 min 5% A -» 4.5 min 5% A; flow: 0.0 min 1 ml/min ⁇ 2.5 min/3.0 min/4.5 min 2 ml/min; oven: 50 0 C; UV detection: 210 nm.
  • LC-MS Instrument MS: Micromass Quattro LCZ; Instrument HPLC: HP 1 100 Series; UV DAD; column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20 mm x 4 mm; eluent A: 1 1 water + 0.5 ml 50% formic acid, eluent B: 1 1 acetonitrile + 0.5 ml 50% formic acid; gradient: 0.0 min 90% A ⁇ 2.5 min 30% A ⁇ 3.0 min 5% A ⁇ 4.5 min 5% A; flow: 0.0 min 1 ml/min ⁇ 2.5 min/3.0 min/4.5 min 2 ml/min; oven: 50 0 C; UV detection: 210 nm.
  • the resin can be used without further purification, drying to constant weight can be achieved in high vacuum.
  • the mixture is filtered and the remaining resin is washed three times with DMF, and then successively twice with water, with a mixture of DMF and N-ethyl-N-isopropylpropan-2 -amine (1 : 1), with methanol and with dichloromethane.
  • the resin is dried in vacuo.
  • the amine (1.0 eq.) is dissolved in dichloromethane (approx. 0.2 g/ml).
  • Isocyanate (1.2 to 2 eq.) is added at rt.
  • an excess of polymer bound tris-amine and dichloromethane are added to the mixture, the suspension is agitated for approx. 1 h, then filtrated.
  • the resin is washed with dichloromethane and the combined filtrates are concentrated in vacuo. Further purification of the product can be achieved by preparative reverse phase HPLC (water/acetonitril).
  • the amine (1.0 eq.) is dissolved in dichloromethane (approx. 0.2 g/ml).
  • Isocyanate (1.2 to 1.5 eq.) is added at rt. The mixture is stirred over night, while the product gradually precipitates. The crystalline solid is collected by filtration, washed with ethanol and dried in vacuo.
  • the product is isolated from the crude mixture by chromatography on silica gel (gradient dichloromethane to dichloromethane/methanol 100:1) followed by chromatography on silica gel (gradient cyclohexane / ethyl acetate 5:1 - 3: 1 - 2: 1) to yield 2.5 g (44% of th.) of the title compound.
  • a stirred solution of a BOC derivative in 1 ,4-dioxane (approx. lg/ml) is treated with approx. 10 equivalents of hydrochloric acid in 1 ,4-dioxane (4 molar solution) at rt for approx. 1 h.
  • Methanol is added to the mixture until a homogeneous solution is obtained.
  • the product is isolated from the crude solution after purification by reverse phase HPLC (water-acetonitrile gradient) and concentration in vacuo as a hydrochloric acid salt.
  • N-[4-(benzyloxy)-3-chlorobenzyl]-l ,2-diaminoethane trityl resin (approx. 0.8 mmol loading on resin) is suspended in dichloromethane and treated at rt with 0.175 ml (1.52 mmol) 4- fluorophenylisocyante. The mixture is gentlye agitated for 1 h at rt until more dichloromethane is added. The mixture is filtrated and the resin washed three times with dichloromethane.
  • the mixture is filtered and the remaining resin is washed five times with dichloromethane.
  • the resin is suspended in 10 ml dichloromethane, treated with 2 ml TFA (resin turns dark-red) at rt with stricte shaking and further agitated for 10 min.
  • the cleavage mixture is filtrated and the resin washed four times with dichloromethane.
  • the filtrates are collected and combined.
  • the cleavage procedure is repeated once and all filtrates are combined and washed three times with saturated sodium carbonate solution, water and brine, dried over magnesium sulfate and concentrated in vacuo to yield after evaporation of solvents 687 mg (84% of th. based on calculated initial loading) of the title compound.
  • the product is used without further purification.
  • CMR-I Cold Menthol Receptor - 1
  • a cell-based calcium influx assay using HEK293 cells stably expressing human CMR-I is used to identify CMR-I receptor-antagonists.
  • Menthol a CMR-I specific agonist, is used for stimulation of these cells, inducing an increase in intracellular calcium. This menthol-induced Ca 2+ increase is traced by fluorescence measurement. Therefore the cells are loaded with fluo4-AM prior to stimulation. For testing inhibitors the cells are preincubated with various concentrations of the compound before menthol stimulation. The potency of potential CMR-I inhibitors is quantified by measuring decrease of fluorescence .
  • CMR-I is expressed on DRG (C-fibers), in which this receptor mediates the altered afferent information in overactive bladder; primary cultures of rat DRG are used as functional in vitro test. Stimulation of the cells is done with menthol and cold and the induced calcium influx is quantified by fluorescence in the presence or absence of CMR-I inhibitors.
  • DRG are prepared from Zucker rats (30 days in age) and neuronal cells are dispersed in 0.1% collagenase. After removal of Schwann cells by adhering to a culture plate, non-adherent neuronal cells are recovered and cultured on laminin- and poly-D-lysine coated 384 well plates for 2 days in the presence of 50 ng/ml rat NGF and 50 ⁇ M 5- fiuorodeoxyuridine.
  • Rat DRG neurons are suspended in a culture medium and seeded into 384- well plates (black walled clear-base / Nalge Nunc International). Following the culture for 48 hrs the medium is changed to 2 ⁇ M Fluo-4 AM (Molecular Probes) and 0.02% Puronic F-127 in assay buffer (Hank's balanced salt solution (HBSS), 17 mM HEPES (pH7.4), 1 mM Probenecid, 0.1% bovine serum albumin (BSA)) and the cells are incubated for 60 min at 25°C. After washing twice with assay buffer the cells are incubated with a test compound or vehicle (dimethylsulfoxide) for 20 min at 25°C.
  • assay buffer Hort's balanced salt solution (HBSS), 17 mM HEPES (pH7.4), 1 mM Probenecid, 0.1% bovine serum albumin (BSA)
  • the fluorescence change indicating mobilization of cytoplasmic Ca 2+ is measured for 60 sec after the stimulation with 50 ⁇ M menthol.
  • the fluorescence change is calculated in the samples treated with a test compound and vehicle respectively.
  • Inhibitory effect of the compound is calculated by a comparison of the values.
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • Example 1 100 mg of the compound of Example 1 , 50 mg of lactose (monohydrate), 50 mg of maize starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.
  • the mixture of active component, lactose and starch is granulated with a 5% solution (m/m) of the PVP in water. After drying, the granules are mixed with magnesium stearate for 5 min. This mixture is moulded using a customary tablet press (tablet format, see above). The moulding force applied is typically 15 kN.
  • a single dose of 100 mg of the compound according to the invention is provided by 10 ml of oral suspension.
  • Rhodigel is suspended in ethanol and the active component is added to the suspension. The water is added with stirring. Stirring is continued for about 6h until the swelling of the Rhodigel is complete.
  • Solution for intravenous administration :
  • Example 1 The compound of Example 1 is dissolved with polyethylene glycol 400 in the water with stirring., The solution is sterilized by filtration (pore diameter 0.22 ⁇ m) and dispensed under aseptic conditions into heat-sterilized infusion bottles. These are closed with infusion stoppers and crimped caps.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux dérivés de benzyloxyphénylméthylurée substitués, des procédés pour leur préparation et leur utilisation dans des médicaments, notamment pour la prévention et le traitement de maladies associées à l'activité du récepteur 1 du menthol froid (CMR-1), en particulier pour le traitement de maladies ou de troubles urologiques tels que l'hyperactivité du détrusor (vessie hyperactive), l'incontinence urinaire, l'hyperactivité neurogène du détrusor (hyperflexie du détrusor), l'hyperactivité idiopathique du détrusor (instabilité du détrusor), l'hyperplasie prostatique bénigne et les symptômes du système urinaire inférieur ; la douleur chronique, la douleur neuropathique, la douleur post-opératoire, la douleur liée à la polyarthrite rhumatoïde, la névralgie, les neuropathies, l'algésie, les lésions nerveuses, l'ischémie, la neurodégénérescence, l'accident vasculaire cérébral et des troubles inflammatoires tels que l'asthme et la broncho-pneumopathie chronique obstructive (BPCO).
PCT/EP2007/000192 2006-01-16 2007-01-11 Dérivés de benzyloxyphénylméthylurée substitués WO2007080109A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP06075086.6 2006-01-16
EP06075086 2006-01-16

Publications (1)

Publication Number Publication Date
WO2007080109A1 true WO2007080109A1 (fr) 2007-07-19

Family

ID=38009413

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2007/000192 WO2007080109A1 (fr) 2006-01-16 2007-01-11 Dérivés de benzyloxyphénylméthylurée substitués

Country Status (1)

Country Link
WO (1) WO2007080109A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2481727A1 (fr) 2011-01-28 2012-08-01 Dompe S.p.A. Antagonistes du récepteur TRPM8
EP2606888A1 (fr) 2011-12-19 2013-06-26 Dompe' S.P.A. Antagonistes du TRPM8
WO2013092711A1 (fr) 2011-12-19 2013-06-27 Dompe' S.P.A. Antagonistes de trpm8
WO2015197640A1 (fr) 2014-06-23 2015-12-30 Dompe' Farmaceutici S.P.A. Dérivés du 2-aryl-4-hydroxy-1,3-thiazole utilisables comme inhibiteurs du trpm8 dans le traitement de la névralgie, de la douleur, de la broncho-pneumopathie chronique obstructive et de l'asthme
EP3115045A3 (fr) * 2008-08-26 2017-05-17 Basf Se Verification et utilisation de modulateurs sous-moleculaires du recepteur de froid et de menthol trpm8
EP3184524A1 (fr) 2015-12-21 2017-06-28 Dompé farmaceutici S.p.A. Dérivés de 4-hydroxy-2-phenyl-1,3-thiazole-méthanone en tant qu'antagonistes du trpm8
CN113354621A (zh) * 2021-06-04 2021-09-07 沈阳药科大学 含有吡啶基团的1-取代苄基-3-芳基脲类化合物及其制备方法和应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006040136A1 (fr) * 2004-10-13 2006-04-20 Bayer Healthcare Ag Derives de 4-benzyloxy-phenylmethylamide substitues utilises comme antagonistes de recepteur 1 au froid active par menthol (cmr-1) pour traiter des troubles urologiques

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006040136A1 (fr) * 2004-10-13 2006-04-20 Bayer Healthcare Ag Derives de 4-benzyloxy-phenylmethylamide substitues utilises comme antagonistes de recepteur 1 au froid active par menthol (cmr-1) pour traiter des troubles urologiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
D'AGOSTINO G ET AL: "An appraisal or recently patented compounds for bladder overactivity and urinary incontinence", EXPERT OPINION ON THERAPEUTIC PATENTS, ASHLEY PUBLICATIONS, GB, vol. 14, no. 7, 2004, pages 1041 - 1060, XP002408785, ISSN: 1354-3776 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3115045A3 (fr) * 2008-08-26 2017-05-17 Basf Se Verification et utilisation de modulateurs sous-moleculaires du recepteur de froid et de menthol trpm8
EP3698779A1 (fr) * 2008-08-26 2020-08-26 Basf Se Vérification et utilisation de modulateurs sous-moléculaires du récepteur de froid et de menthol trpm8
WO2012101244A1 (fr) 2011-01-28 2012-08-02 Dompe' S.P.A. Antagonistes des récepteurs trpm8
EP2481727A1 (fr) 2011-01-28 2012-08-01 Dompe S.p.A. Antagonistes du récepteur TRPM8
US8906946B2 (en) 2011-01-28 2014-12-09 Dompe' S.P.A. TRPM8 receptor antagonists
WO2013092711A1 (fr) 2011-12-19 2013-06-27 Dompe' S.P.A. Antagonistes de trpm8
EP2606888A1 (fr) 2011-12-19 2013-06-26 Dompe' S.P.A. Antagonistes du TRPM8
WO2015197640A1 (fr) 2014-06-23 2015-12-30 Dompe' Farmaceutici S.P.A. Dérivés du 2-aryl-4-hydroxy-1,3-thiazole utilisables comme inhibiteurs du trpm8 dans le traitement de la névralgie, de la douleur, de la broncho-pneumopathie chronique obstructive et de l'asthme
US10196368B2 (en) 2014-06-23 2019-02-05 Dompé Farmaceutici S.P.A. 2-aryl-4-hydroxy-1,3-thiazole derivatives useful as TRPM8-inhibitors in treatment of neuralgia, pain, COPD and asthma
US11046662B2 (en) 2014-06-23 2021-06-29 Dompé Farmaceutici S.P.A. 2-aryl-4-hydroxy-1,3-thiazole derivatives useful as TRPM8-inhibitors in treatment of neuralgia, pain, COPD and asthma
EP3184524A1 (fr) 2015-12-21 2017-06-28 Dompé farmaceutici S.p.A. Dérivés de 4-hydroxy-2-phenyl-1,3-thiazole-méthanone en tant qu'antagonistes du trpm8
US10246448B2 (en) 2015-12-21 2019-04-02 Dompé Farmaceutici S.P.A. 4-hydroxy-2-phenyl-1,3-thiazol-5-yl methanone derivatives as TRPM8 antagonists
CN113354621A (zh) * 2021-06-04 2021-09-07 沈阳药科大学 含有吡啶基团的1-取代苄基-3-芳基脲类化合物及其制备方法和应用

Similar Documents

Publication Publication Date Title
US20080214654A1 (en) Substituted Benzyloxy-Phenylmethylamide Derivatives
WO2007017093A1 (fr) Derives amides d'acide 2-benzyloxy-benzoique substitue
WO2007017092A1 (fr) Derives amides d'acide 4-benzyloxy-benzoique substitue
WO2007017094A1 (fr) Dérivés benzyloxyphénylméthylcarbamate substitués
KR101866858B1 (ko) Lsd1의 아릴사이클로프로필아민 기반 디메틸라아제 억제제 및 이의 의학적 이용
US5705640A (en) O-carbamoyl-(d)-phenylalaninol compounds, their pharmaceutically useful salts and process for preparing the same
WO2007080109A1 (fr) Dérivés de benzyloxyphénylméthylurée substitués
US20100240635A1 (en) Benzothiadiazepine compounds, a process for their preparation and pharmaceutical compositions containing them
KR20180134675A (ko) 시클로프로필아민 유도체 화합물 및 이의 용도
EP0873308A1 (fr) Composes de o-carbamoyl-phenylalaninol, sels de ces composes utiles sur le plan pharmaceutique, et procede de preparation de ces derniers
DK163181B (da) Analogifremgangsmaade til fremstilling af n,n'-di(arylalkylen)alkylendiaminer eller farmaceutisk acceptable salte deraf
UA116542C2 (uk) Сполуки сечовини та їх застосування як інгібіторів ферментів
CN110582480B (zh) 治疗化合物和方法
DE602004005016T2 (de) Biphenylcarboxamidderivate und ihre verwendung als p38 kinase inhibitoren
KR20000052921A (ko) 뉴로키닌 길항제로서의 피페라지노 유도체
CN112759545A (zh) 3-(二甲氨基甲基)哌啶-4-醇类衍生物及其制备方法和药物用途
CA3215210A1 (fr) Composes macrocycliques d'amide substitues ayant une activite agoniste du recepteur de l'orexine 2
CA2136837A1 (fr) Derives 1-azaadamantane utilises comme agonistes ou antagonistes du 5-ht
EP0367040B1 (fr) Composés pour le traitement de l'incontinence d'urine
KR20110133033A (ko) 모틸린 수용체에 대해 작용제 활성을 가진 옥시인돌 유도체
SK285679B6 (sk) Derivát benzamidu, liečivo s jeho obsahom a ich použitie
US9856250B2 (en) Substituted tropane derivatives
US20230285372A1 (en) Pharmaceutical use of (E)-3-arylheterocyclylprop-2-enoic acid derivatives
US10494346B2 (en) Substituted pyrimidine-4-carboxylic acids having anticancer activity
JP2008001596A (ja) ナトリウムチャネル阻害剤

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07702678

Country of ref document: EP

Kind code of ref document: A1