WO2007017093A1 - Substituted 2-benzyloxy-benzoic acid amide derivatives - Google Patents

Substituted 2-benzyloxy-benzoic acid amide derivatives Download PDF

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WO2007017093A1
WO2007017093A1 PCT/EP2006/007298 EP2006007298W WO2007017093A1 WO 2007017093 A1 WO2007017093 A1 WO 2007017093A1 EP 2006007298 W EP2006007298 W EP 2006007298W WO 2007017093 A1 WO2007017093 A1 WO 2007017093A1
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alkyl
represents hydrogen
group
halogen
general formula
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PCT/EP2006/007298
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French (fr)
Inventor
Thomas Lampe
Cristina Alonso-Alija
Hartmut Beck
Ulrich Rosentreter
Peter Sandner
Elke Stahl
Beatrix Stelte-Ludwig
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Bayer Healthcare Ag
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Publication of WO2007017093A1 publication Critical patent/WO2007017093A1/en

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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C07C323/40—Y being a hydrogen or a carbon atom
    • C07C323/42—Y being a carbon atom of a six-membered aromatic ring
    • 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
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/66—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings being part of condensed ring systems and singly-bound oxygen atoms, bound to the same carbon skeleton
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/16—Halogen atoms or nitro radicals
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
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    • 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
    • C07D333/06—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
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    • 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
    • C07D333/28—Halogen atoms
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • the present invention relates to novel substituted 2-benzyloxy-benzoic acid amide 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 (UI) such as urge urinary incontinence (UUI), and/or overactive bladder, Lower urinary tract symptoms secondary to or independent of benign prostatic hyperplasia.
  • UI urinary incontinence
  • UUI urge urinary incontinence
  • overactive bladder Lower urinary tract symptoms secondary to or independent of benign prostatic hyperplasia.
  • 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)
  • A represents a group of the formula
  • R 8 represents hydrogen, chlorine, fluorine, nitro, trifluoromethyl, trifluoromethoxy
  • R 9 represents hydrogen or halogen
  • R 1 represents hydrogen, halogen, cyano, trifluoromethyl or Ci-Gralkyl
  • R 2 represents hydrogen or halogen
  • R 3 represents hydrogen or halogen
  • R 4 represents hydrogen or Ci-G t -alkyl
  • R 5 represents C 3 -C 8 -alkyl, C 3 -C 8 -alkenyl, C 3 -Cio-cycloalkyl, C 6 -Ci 0 -aryl or 5- to 10-membered heteroaryl,
  • alkyl can be further substituted with one radical selected from the group consisting of 5- to 10-membered heteroaryl,
  • cycloalkyl can be further substituted with one to three identical or different radicals selected from the group consisting of C r 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, trifluoromethoxy, trifluoromethylthio, C r C 6 -alkyl, Ci-C ⁇ -alkoxy, Ci-C 6 -alkylthio, C]-C 6 -alkylamino, phenoxy, benzyloxy, phenylthio, benzylthio, phenylcarbonyl, C r C 6 -aIkoxycarbonyl and optionally halogen substituted phenyl,
  • phenoxy, benzyloxy, phenylthio and benzylthio can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, nitro, amino, hydroxy, trifluoromethyl, trifluoromethoxy, Ci-C 6 -alkyl, Ci-C 6 -alkoxy and Ci-C ⁇ -alkylamino,
  • R 6 represents hydrogen or
  • R 7 represents CpC ⁇ -alkyl
  • alkyl is further substituted with one radical selected from the group consisting of amino, mono-alkylamino, Ci-C 4 -alkylcarbonylamino or CrC 4 -alkoxycarbonylamino,
  • 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-buty ⁇ , pentyl, isopentyl, hexyl, isohexyl.
  • radicals such as alkoxy, alkylthio, alkylamino, alkylcarbonylamino, alkoxycarbonyl, 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-l-yl and 2-methylprop-2-en-l-yl.
  • Alkoxy illustratively and preferably represents methoxy, ethoxy, n-propoxy, isopropoxy, ter/-butoxy, n-pentoxy and n-hexoxy.
  • a Iky lth io illustratively and preferably represents methylthio, ethylthio, n-propylthio, isopropylthio, ter/-butylthio, n-pentylthio and n-hexylthio.
  • 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.
  • Alkoxycarbonyl illustratively and preferably represents methoxycarbonyl, ethoxycarbonyl, n- propoxycarbonyl, isopropoxycarbonyl, /er ⁇ -butoxycarbonyl, n-pentoxycarbonyl and n-hexoxy- carbonyl.
  • Alkoxycarbonylamino illustratively and preferably represents methoxycarbonylamino, ethoxy- carbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, te/7-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, tert-butylamino, n-pentylamino, n-hexylamino, N,N-dimethylamino, NN-diethyl- amino, N-ethyl-N-methylamino, N-methyl- ⁇ r -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, tert-butylamino, n-pentylamino and n-hexylamino.
  • Cvcloalkyl in general represents a mono- or bicyclic saturated or one or more double bonds comprising non aromatic hydrocarbon radical having 3 to 10, preferably 3 to 6 carbon atoms.
  • ⁇ on- limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and indanyl.
  • 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 ⁇ , 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
  • A represents a group of the formula
  • R 8 represents hydrogen, methoxy or ethoxy
  • R 9 represents hydrogen
  • R 1 represents hydrogen, halogen, cyano, trifluoromethyl or methyl
  • R 2 represents hydrogen or halogen
  • R 3 represents hydrogen
  • R 4 represents hydrogen
  • R 5 represents C 3 -C 8 -alkyl, C 3 -C 7 -cycloalkyl, C 6 -Ci 0 -aryl 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 Ci-G t -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, trifluoromethoxy, trifluoromethylthio, Ci-C ⁇ -alkyl, Ci-C 6 -alkoxy, Ci-C 6 -alkylthio, Ci-C 6 -alkylamino, phenoxy, benzyloxy, phenylthio, benzylthio, Ci-C ⁇ -alkoxycarbonyl and optionally halogen substituted phenyl,
  • phenoxy, benzyloxy, phenylthio and benzylthio can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, nitro, amino, hydroxy, trifluoromethyl, trifluoromethoxy, Ci-C 6 -alkyl, C]-C 6 -alkoxy and Ci-C 6 -alkylamino,
  • R 6 represents hydrogen
  • R 7 represents Ci-Gi-alkyl
  • alkyl is further substituted with one radical selected from the group consisting of amino or Ci-C 4 -alkoxycarbonylamino,
  • the present invention relates to compounds of general formula (I), wherein
  • A represents a group of the formula
  • R 8 represents hydrogen
  • R 9 represents hydrogen
  • R 1 represents hydrogen, fluorine, chlorine, cyano, trifluoromethyl or methyl
  • R 2 represents hydrogen or fluorine
  • R 3 represents hydrogen
  • R 4 represents hydrogen
  • R 5 represents C 3 -C 6 -alkyl, cyclohexyl, cyclopentyl, phenyl, naphthyl, pyridyl, pyrimidyl, thienyl or furyl,
  • phenyl, naphthyl, pyridyl, pyrimidyl, thienyl and furyl can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, C r C 4 -alkyl, methoxy, ethoxy, methylthio, ethylthio, phenoxy, benzyloxy, phenylthio, benzylthio, methoxycarbonyl and optionally halogen substituted phenyl,
  • phenoxy, benzyloxy, phenylthio and benzylthio can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, nitro, trifluoromethyl, trifluoromethoxy, Ci-C 4 -alkyl, methoxy and ethoxy,
  • R 6 represents hydrogen
  • R 7 represents Ci-C 2 -alkyl
  • alkyl is further substituted with one radical selected from the group consisting of amino or te/V-butoxycarbonylamino,
  • the present invention relates to compounds of general formula (I), wherein A represents a group of the formula
  • the present invention relates to compounds of general formula (T), 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 or chlorine, R 2 represents hydrogen or fluorine and R 3 represents hydrogen.
  • the present invention relates to compounds of general formula (I), wherein R 4 represents hydrogen.
  • the present invention relates to compounds of general formula (I), wherein R 5 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 hydrogen.
  • the present invention relates to compounds of general formula (T), 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 8 represents hydrogen or C r C 4 -alkoxy and R 9 represents hydrogen.
  • R 4 , R 5 , R 6 and R 7 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 in the presence of a base.
  • 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 RPl 8 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 +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 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 hydrogen carbonate, cyclic amines such as, for example, N-methylmorpholine, N-methylpiperidine, pyridine or 4-NN-dimethylamino- pyridine, or (Ci-CO-trialkylamines such as, for example, triethylamine or diisopropylethylamine. Preference is given to triethylamine.
  • alkali carbonates such as sodium or potassium carbonate or hydrogen carbonate
  • cyclic amines such as, for example, N-methylmorpholine, N-methylpiperidine, pyridine or 4-NN-dimethylamino- pyridine
  • Ci-CO-trialkylamines such as, for example, triethylamine or diisopropylethylamine. Preference is given to triethylamine.
  • the process [B] 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-NN-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-NN-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 (VI)
  • the process is in general carried out in a temperature range from -20°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-butanol, 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-butanol, 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.
  • the compounds of general formula (FV) can be synthesized by treating compounds of general formula (Ia)
  • the process is in general carried out in a temperature range from -2O 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 alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol or 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].
  • 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 HTV 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 H
  • 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, transdermal Iy, 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, intracutaneous Iy, percutaneously or intraperitoneally).
  • 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 Instrument: Micromass Quattro LCZ; Instrument HPLC: Agilent Serie 1100; 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: 208- 400 nm.
  • LC-MS Instrument MS: Micromass TOF (LCT); Instrument HPLC: 2-column-method, Waters2690; column: YMC-ODS-AQ, 50 mm x 4.6 mm, 3.0 ⁇ m; eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1 % formic acid; gradient: 0.0 min 100% A -> 0.2 min 95% A -> 1.8 min 25% A -> 1.9 min 10% A -> 2.0 min 5% A -> 3.2 min 5% A; flow: 3.0 ml/min; oven: 40 0 C; UV detection: 210 nm.
  • the residue is purified in 5 portions by preparative HPLC (column: YMC-GeI ODS-AQ S-5 15 ⁇ m, 250 mm x 30 mm; eluent A: acetonitrile, eluent B: water + 0.1% formic acid, gradient: 0 min 10% A, 5 min 10% A, 23 min 90% A, 28 min 90% A, 28.2 min 10% A, 33 min 10% A; flow rate: 25 ml/min; UV detection: 220 nm).
  • the desired fractions are combined, neutralized with IN sodium hydroxide solution and concentrated in vacuo.
  • the concentrate is extracted several times with dichloromethane.
  • the combined extracts are washed with sodium hydrogen carbonate solution, dried with magnesium sulfate and evaporated in vacuo. Yield: 3.23 g (83% of th.).
  • the residue is purified in 5 portions by preparative HPLC (column: YMC-GeI ODS-AQ S-5 15 ⁇ m, 250 mm x 30 mm; eluent A: acetonitrile, eluent B: water + 0.1% formic acid, gradient: 0 min 10% A, 5 min 10% A, 23 min 90% A, 28 min 90% A, 28.2 min 10% A, 33 min 10% A; flow rate: 25 ml/min; UV detection: 220 nm).
  • the desired fractions are combined, neutralized with IN sodium hydroxide solution and concentrated in vacuo.
  • the concentrate is extracted several times with dichloromethane.
  • the combined extracts are washed with sodium hydrogen carbonate solution, dried with magnesium sulfate and evaporated in vacuo. Yield: 3.33 g (69% of th.).
  • the title compound is prepared in analogy to 2-[(2,4-difluorobenzyl)oxy]benzoyl chloride from commercially available 2-(benzyloxy)benzoic acid and used without further purification.
  • the title compound is prepared in analogy to 2-[(2,4-difluorobenzyl)oxy]benzoyl chloride from commercially available 2-[4-methylbenzyl)oxy]benzoic acid and used without further purification.
  • reaction solution After stirring over night the reaction solution is filtered and purified by preparative HPLC (column: Merck SelfPackColumn Cromsil ODS 4 HE 10 ⁇ m, 50 mm x 200 mm, eluent A: acetonitrile, eluent B: water + 0.1% formic acid, gradient: 0 min 10% A, 5.00 min 10% A, 23 min 90% A, 28 min 90% A, 28.2 min 10% A, 33 min 10% A; flow rate: 1 10 ml/min, UV detection: 220 nm).
  • the desired fractions are combined, neutralized with IN sodium hydroxide solution and concentrated in vacuo.
  • the concentrate is extracted several times with dichloromethane. The combined extracts are washed with sodium hydrogen carbonate solution, dried with magnesium sulfate and evaporated in vacuo. Yield: 4.72 g (78% of th.).
  • the residue is purified in 5 portions by preparative HPLC (column: YMC- GeI ODS-AQ S-5 15 ⁇ m, 250 mm x 30 mm; eluent A: acetonitrile, eluent B: water + 0.1% formic acid, gradient: 0 min 10% A, 5 min 10% A, 23 min 90% A, 28 min 90% A, 28.2 min 10% A, 33 min 10% A; flow rate: 25 ml/min; UV detection: 220 nm).
  • the desired fractions are combined, neutralized with IN sodium hydroxide solution and concentrated in vacuo.
  • the concentrate is extracted several times with dichloromethane.
  • the combined extracts are washed with sodium hydrogen carbonate solution, dried with magnesium sulfate and evaporated in vacuo. Yield: 6.02 g (62% of th.).
  • reaction mixture is stirred for 1 h at room temperature, filtrated and purified by preparative HPLC (column: Machery Nagel VP50/21 Nucleosil 100-5 Cl 8 Nautilus, 5 ⁇ m, 21 mm x 50 mm; eluent A: water + 0.1 % formic acid, eluent B: acetonitrile, gradient: 0 min 10% B, 2 min 10% B, 6 min 90% B, 9 min 90% B, 9.1 min 10% B, 10 min 10% B; flow rate: 25 ml/min; UV detection: 220 nm).
  • the desired fractions are combined and concentrated in vacuo.
  • One half of the residue is dissolved in a 4M solution of hydrogen chloride in dioxane. After standing for 1 h at room temperature the solution is evaporated in vacuo. Yield: 19.3 mg (43% of th.).
  • the resin is washed three times with DMF, twice with water, once with a l : l-mixture of DMF and DIEA, and then consecutively once with methanol, dichloromethane and diethylether.
  • the resin is dried in vacuo.
  • the resin is suspended in 5 ml DMF and treated with 2.28 g 2-(benzyloxy)benzoic acid (10.0 mmol, 5 eq) and 2.52 g (20.0 mmol, 10 eq.) DIC overnight at rt.
  • the resin is washed three times with DMF, and alternately three times with methanol and dichloromethane.
  • Hydrochloric salts in examples 49-62 are prepared by treatment of the purified sample with 0.5 ml dichloromethane and a 0.5 M solution of hydrogen chloride in dioxane followed by evaporation of the solvent.
  • 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.
  • Preparation of primary cultured rat DRG neurons DRG are prepared from Zucker rats (30 days in age) and neuronal cells are dispersed in 0.1% collagenase.
  • non-adherent neuronal cells 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- fluorodeoxyuridine.
  • 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.

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Abstract

The present invention relates to novel substituted 2-benzyloxy-benzoic acid amide 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-1) 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; 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).

Description

Substituted 2-benzγloxy-benzoic acid amide derivatives Technical field of the invention
The present invention relates to novel substituted 2-benzyloxy-benzoic acid amide 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).
There is abundant direct or indirect evidence that shows the relation between Transient Receptor Potential (TRP) channel activity and diseases such as pain, ischaemia, and inflammatory disorders. Further, it has been demonstrated that TRP channels transduce reflex signals that are involved in the overactive bladder of patients who have damaged or abnormal spinal reflex pathways [De Groat WC: A neurologic basis for the overactive bladder. Urology 50 (6A Suppl): 36-52, 1997]. CMR-I, a nonselective cation channel is such a member of the TRP channel family (TRPM8). Recently, in 2002 the receptor was cloned and it was found to be sensitive to cold temperature and menthol and therefore named as cold menthol receptor - 1 (CMR-I) (McKemy et al, 2002; Peier et al., 2002). This receptor which is activated by 8 - 28°C temperature is expressed on the bladder urothelium and DRG (Dorsal Root Ganglia) and 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.
Therefore 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 (UI) such as urge urinary incontinence (UUI), and/or overactive bladder, Lower urinary tract symptoms secondary to or independent of benign prostatic hyperplasia. UI is the involuntary loss of urine. UUI 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. One of the usual causes of 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.
There are several medications for urinary incontinence on the market today mainly to help treating UUI. Therapy for OAB is focused on drugs that affect peripheral neural control mechanisms or those that act directly on bladder detrusor smooth muscle contraction, with a major emphasis on development of anticholinergic agents. These agents can inhibit the parasympathetic nerves which control bladder voiding or can exert a direct spasmolytic effect on the detrusor muscle of the bladder. This results in a decrease in intravesicular pressure, an increase in capacity and a reduction in the frequency of bladder contraction. Orally active anticholinergic drugs which are commonly prescribed have serious drawbacks such as unacceptable side effects such as dry mouth, abnormal visions, constipation, and central nervous system disturbances. These side effects lead to poor compliance. Dry mouth symptoms alone are responsible for a 70% non-compliance rate with oxybutynin. The inadequacies of present therapies highlight the need for novel, efficacious, safe, orally available drugs that have fewer side effects.
In WO 03/037865 and Y. Lu, et al., Bioorg. Med. Chem. Lett. 2004, 14, 3957-3962 related benzyloxy-phenyl amide derivatives for the treatment of cancer are described generically.
The present invention relates to compounds of the general formula (I)
Figure imgf000003_0001
wherein
A represents a group of the formula
Figure imgf000004_0001
wherein
represents the linkage to the oxygen atom,
# represents the linkage to the carbonyl group,
R8 represents hydrogen, chlorine, fluorine, nitro, trifluoromethyl, trifluoromethoxy,
Ci-C4-alkyl or CrC4-alkoxy,
and
R9 represents hydrogen or halogen,
R1 represents hydrogen, halogen, cyano, trifluoromethyl or Ci-Gralkyl,
R2 represents hydrogen or halogen,
R3 represents hydrogen or halogen,
R4 represents hydrogen or Ci-Gt-alkyl,
R5 represents C3-C8-alkyl, C3-C8-alkenyl, C3-Cio-cycloalkyl, C6-Ci0-aryl or 5- to 10-membered heteroaryl,
wherein alkyl can be further substituted with one radical selected from the group consisting of 5- to 10-membered heteroaryl,
and
wherein cycloalkyl can be further substituted with one to three identical or different radicals selected from the group consisting of CrC4-alkyl,
and wherein 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, trifluoromethoxy, trifluoromethylthio, CrC6-alkyl, Ci-Cδ-alkoxy, Ci-C6-alkylthio, C]-C6-alkylamino, phenoxy, benzyloxy, phenylthio, benzylthio, phenylcarbonyl, CrC6-aIkoxycarbonyl and optionally halogen substituted phenyl,
wherein phenoxy, benzyloxy, phenylthio and benzylthio can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, nitro, amino, hydroxy, trifluoromethyl, trifluoromethoxy, Ci-C6-alkyl, Ci-C6-alkoxy and Ci-Cβ-alkylamino,
R6 represents hydrogen or
Figure imgf000005_0001
R7 represents CpCβ-alkyl,
wherein alkyl is further substituted with one radical selected from the group consisting of amino, mono-alkylamino, Ci-C4-alkylcarbonylamino or CrC4-alkoxycarbonylamino,
and their salts, hydrates and/or solvates.
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. lithium, potassium and sodium salts, 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, salicylates, stearates, sulphates, succinates, tartrates, tosylates, valerates, and other salts used for medicinal purposes.
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. In addition, 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.
In the context of the present invention, the substituents, if not stated otherwise, in general have the following meaning:
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-buty\, pentyl, isopentyl, hexyl, isohexyl. The same applies to radicals such as alkoxy, alkylthio, alkylamino, alkylcarbonylamino, alkoxycarbonyl, 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-l-yl and 2-methylprop-2-en-l-yl.
Alkoxy illustratively and preferably represents methoxy, ethoxy, n-propoxy, isopropoxy, ter/-butoxy, n-pentoxy and n-hexoxy.
A Iky lth io illustratively and preferably represents methylthio, ethylthio, n-propylthio, isopropylthio, ter/-butylthio, n-pentylthio and n-hexylthio.
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. Alkoxycarbonyl illustratively and preferably represents methoxycarbonyl, ethoxycarbonyl, n- propoxycarbonyl, isopropoxycarbonyl, /erΛ-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxy- carbonyl.
Alkoxycarbonylamino illustratively and preferably represents methoxycarbonylamino, ethoxy- carbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, te/7-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, tert-butylamino, n-pentylamino, n-hexylamino, N,N-dimethylamino, NN-diethyl- amino, N-ethyl-N-methylamino, N-methyl-Λr-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, tert-butylamino, n-pentylamino and n-hexylamino.
Cvcloalkyl in general represents a mono- or bicyclic saturated or one or more double bonds comprising non aromatic hydrocarbon radical having 3 to 10, preferably 3 to 6 carbon atoms. Νon- limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and indanyl.
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 Ν, 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.
In the group of the formula representing A the end point of a bond, denoted by the * or # symbol next to the bond, does not stand for a carbon atom or a CH2-group, but it is part of the bond to the oxygen atom or the carbonyl group. In another preferred embodiment, the present invention relates to compounds of general formula (I), wherein
A represents a group of the formula
Figure imgf000008_0001
wherein
* represents the linkage to the oxygen atom,
# represents the linkage to the carbonyl group,
R8 represents hydrogen, methoxy or ethoxy,
and
R9 represents hydrogen,
R1 represents hydrogen, halogen, cyano, trifluoromethyl or methyl,
R2 represents hydrogen or halogen,
R3 represents hydrogen,
R4 represents hydrogen,
R5 represents C3-C8-alkyl, C3-C7-cycloalkyl, C6-Ci0-aryl or 5- to 10-membered heteroaryl,
wherein cycloalkyl can be further substituted with one to three identical or different radicals selected from the group consisting of Ci-Gt-alkyl,
and
wherein 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, trifluoromethoxy, trifluoromethylthio, Ci-Cβ-alkyl, Ci-C6-alkoxy, Ci-C6-alkylthio, Ci-C6-alkylamino, phenoxy, benzyloxy, phenylthio, benzylthio, Ci-Cβ-alkoxycarbonyl and optionally halogen substituted phenyl,
wherein phenoxy, benzyloxy, phenylthio and benzylthio can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, nitro, amino, hydroxy, trifluoromethyl, trifluoromethoxy, Ci-C6-alkyl, C]-C6-alkoxy and Ci-C6-alkylamino,
R6 represents hydrogen,
R7 represents Ci-Gi-alkyl,
wherein alkyl is further substituted with one radical selected from the group consisting of amino or Ci-C4-alkoxycarbonylamino,
and their salts, hydrates and/or solvates.
In another particularly preferred embodiment, the present invention relates to compounds of general formula (I), wherein
A represents a group of the formula
Figure imgf000009_0001
wherein
represents the linkage to the oxygen atom,
represents the linkage to the carbonyl group,
R8 represents hydrogen,
and
R9 represents hydrogen,
R1 represents hydrogen, fluorine, chlorine, cyano, trifluoromethyl or methyl, R2 represents hydrogen or fluorine,
R3 represents hydrogen,
R4 represents hydrogen,
R5 represents C3-C6-alkyl, cyclohexyl, cyclopentyl, phenyl, naphthyl, pyridyl, pyrimidyl, thienyl or furyl,
wherein phenyl, naphthyl, pyridyl, pyrimidyl, thienyl and furyl can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, CrC4-alkyl, methoxy, ethoxy, methylthio, ethylthio, phenoxy, benzyloxy, phenylthio, benzylthio, methoxycarbonyl and optionally halogen substituted phenyl,
wherein phenoxy, benzyloxy, phenylthio and benzylthio can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, nitro, trifluoromethyl, trifluoromethoxy, Ci-C4-alkyl, methoxy and ethoxy,
R6 represents hydrogen,
R7 represents Ci-C2-alkyl,
wherein alkyl is further substituted with one radical selected from the group consisting of amino or te/V-butoxycarbonylamino,
and their salts, hydrates and/or solvates.
In another preferred embodiment, the present invention relates to compounds of general formula (I), wherein A represents a group of the formula
Figure imgf000010_0001
wherein * represents the linkage to the oxygen atom, # represents the linkage to the carbonyl group and R8 and R9 represent hydrogen. In another preferred embodiment, the present invention relates to compounds of general formula (T), wherein R1, R2 and R3 represent hydrogen.
In another preferred embodiment, the present invention relates to compounds of general formula (I), wherein R1 represents halogen, R2 represents hydrogen or halogen and R3 represents hydrogen or halogen.
In another preferred embodiment, the present invention relates to compounds of general formula (I), wherein R1 represents halogen, R2 represents hydrogen or halogen and R3 represents hydrogen.
In another preferred embodiment, the present invention relates to compounds of general formula (I), wherein R1 represents fluorine or chlorine, R2 represents hydrogen or fluorine and R3 represents hydrogen.
In another preferred embodiment, the present invention relates to compounds of general formula (I), wherein R4 represents hydrogen.
In another preferred embodiment, the present invention relates to compounds of general formula (I), wherein R5 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.
In another preferred embodiment, the present invention relates to compounds of general formula (I), wherein R6 represents hydrogen.
In another preferred embodiment, the present invention relates to compounds of general formula (T), wherein R7 represents -CH2NH2 or -CH2CH2NH2.
In another preferred embodiment, the present invention relates to compounds of general formula (I), wherein R8 represents hydrogen or CrC4-alkoxy and R9 represents hydrogen.
Very particular preference is given to combinations of two or more of the abovementioned preference ranges.
The compounds of general formula (I) can be synthesized by
[A] condensing compounds of general formula (II)
Figure imgf000012_0001
wherein R4, R5, R6 and R7 have the meaning indicated above,
with compounds of general formula (III)
Figure imgf000012_0002
wherein A, R1, R2 and R3 have the meaning indicated above,
in the presence of a base
or
[B] condensing compounds of general formula (FV)
Figure imgf000012_0003
wherein A, R4, R5, R6 and R7 have the meaning indicated above,
with compounds of general formula (V)
Figure imgf000012_0004
wherein R1, R2 and R3 have the meaning indicated above, and
X1 represents a leaving group, such as halogen, preferably chlorine or bromine in the presence of a base.
Amino groups in R7 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.
If a salt of a compound of general formula (I), for example a hydrochloride or trifluoroacetate, is isolated 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. Preferably a RPl 8 Phenomenex Luna C 18(2) column is used in the presence of diethylamine as base. Or 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 -200C to boiling point of the solvent, preferably from O0C to +4O0C.
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 hydrogen carbonate, cyclic amines such as, for example, N-methylmorpholine, N-methylpiperidine, pyridine or 4-NN-dimethylamino- pyridine, or (Ci-CO-trialkylamines such as, for example, triethylamine or diisopropylethylamine. Preference is given to triethylamine.
The process [B] is in general carried out in a temperature range from 00C to boiling point of the solvent, preferably from 200C 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).
Optionally 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-NN-dimethylamino- pyridine, or (Ci-GO-trialkylamines such as, for example, triethylamine or diisopropylethylamine. Preference is given to potassium carbonate.
The compounds of the general formulas (HI) and (V) are known per se, or they can be prepared by customary methods.
The compounds of general formula (II) can be synthesized by condensing compounds of general formula (VI)
Figure imgf000014_0001
wherein R4 and R5 have the meaning indicated above,
with compounds of general formula (VII)
Figure imgf000014_0002
wherein R6 and R7 have the meaning indicated above,
under conditions of a reductive animation.
The process is in general carried out in a temperature range from -20°C to boiling point of the solvent, preferably from 00C to +400C.
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-butanol, 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.
The compounds of the general formulas (VI) and (VIl) are known per se, or they can be prepared by customary methods.
The compounds of general formula (FV) can be synthesized by treating compounds of general formula (Ia)
Figure imgf000015_0001
wherein A, R4, R5, R6 and R7 have the meaning indicated above,
under reducing conditions.
The process is in general carried out in a temperature range from -2O0C to boiling point of the solvent, preferably from 00C to +400C.
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
Figure imgf000015_0002
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].
The above-mentioned process can be illustrated by the following scheme: Scheme 1
Figure imgf000016_0001
tnethylamine
Figure imgf000016_0002
potassium carbonate
Figure imgf000016_0004
Figure imgf000016_0003
isolation as free base or salt (TFA or HCI)
Figure imgf000016_0005
isolation as free base or salt (TFA or HCI)
Alternatively above mentioned process can be conducted on solid support using polymer bound diamines. Initially the diamines are attached to the resin via an acid labile linkage. In the final step of the synthesis the products are released from the solid support. The following scheme illustrates the process on solid phase: Scheme 2
Figure imgf000017_0001
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.
Surprisingly, 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.
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.
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 HTV 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.
Furthermore, 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.
In addition, 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.
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. For this purpose, it can be applied in a suitable manner, for example orally, parenterally, pulmonally, nasally, sublingually, lingually, buccally, rectally, transdermal Iy, conjunctivally, otically or as an implant.
For these application routes, 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, intracutaneous Iy, percutaneously or intraperitoneally). 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.
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. These 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.
For human use, 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. In the case of 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.
In spite of this, it can be necessary in certain circumstances to depart from the amounts mentioned, namely as a function of body weight, application route, individual behaviour towards the active component, manner of preparation and time or interval at which application takes place. It can for instance be sufficient in some cases to use less than the aforementioned minimum amount, while in other cases the upper limit mentioned will have to be exceeded. In the case of the application of larger amounts, it can be advisable to divide them into a plurality of individual doses spread through the day.
The percentages in the tests and examples which follows are, unless otherwise stated, by weight; parts are by weight. Solvent ratios, dilution ratios and concentrations reported for liquid/liquid solutions are each based on the volume. A. Examples
Abbreviations:
aq. aqueous boc terf-butoxycarbonyl
CDCl3 deutero chloroform cone. concentrated
DCI direct chemical ionisation (for MS)
DIC diisopropylcarbodiimid
DIEA diisopropylethylamine (Hϋnig's base)
DMAP 4-NN-dimethylaminopyridine
DMF NN-dimethylformamide
DMSO dimethylsulfoxide
EI electron impact ionisation (for MS)
ESI electro-spray ionisation (for MS) h hour(s)
HBTU 2-(lH-benzotriazole-l-yl)-l ,l,3,3-tetramethyluronium hexafluorophosphate
HOBT hydroxybenzotriazole
HPLC high pressure liquid chromatography
LC-MS liquid chromatography coupled with mass spectroscopy min minute(s)
Mp. melting point
MS mass spectroscopy
NMR nuclear magnetic resonance spectroscopy of th. of theoretical (yield)
RP reverse phase (for HPLC) rt room temperature
Rt retention time (for HPLC) sat. saturated
TBABH tetrabutylammonium borohydride
TMOF trimehtylorthoformiate
TFA Trifluoroacetic acid
THF tetrahydrofuran LC-MS / HPLC methods:
method 1 (LC-MSt: Instrument MS: Micromass ZQ; Instrument HPLC: Waters Alliance 2795; column: Phenomenex Synergi 2μ 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°C; UV detection: 210 nm.
method 2 (HPLC): Instrument: HP 1 100 with DAD detection; column: Kromasil 100 RP-18, 60 mm x 2.1 mm, 3.5 μm; eluent A: 5 ml HClO4 (70%) /1 water, eluent B: acetonitrile; gradient: 0 min 2% B → 0.5 min 2% B -> 4.5 min 90% B → 15.0 min 90%B → 15.2 min 2% B → 16 min 2% B; flow: 0.75 ml/min; oven: 300C; UV detection: 210 nm.
method 3 (LC-MS): Instrument MS: Micromass Quattro LCZ; Instrument HPLC: HP 1100 Series; UV DAD; column: Phenomenex Synergi 2μ 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: 500C; UV detection: 210 nm.
method 4 (LC-MS): Instrument MS: Micromass ZQ; Instrument HPLC: Waters Alliance 2795; column: Merck Chromolith SpeedROD RP-18e 50 mm x 4.6 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 10% B-> 3.0 min 95% B-> 4.0 min 95% B; flow: 0.0 min 1.0 ml/min-> 3.0 min 3.0 ml/min-> 4.0 min 3.0 ml/min; oven: 35°C; UV detection: 210 nm.
method 5 (LC-MS): Instrument: Micromass Quattro LCZ; Instrument HPLC: Agilent Serie 1100; column: Phenomenex Synergi 2μ 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: 500C; UV detection: 208- 400 nm.
method 6 (HPLC): Instrument: HP 1 100 with DAD-detection, column: Kromasil 100 RP-18, 60 mm x 2.1 mm, 3.5 μm; eluent A: 5 ml HClO4 (70 %) /1 water, eluent B: acetonitrile; gradient: 0 min 2% B -» 0.5 min 2% B -> 4.5 min 90% B -» 6.5 min 90% B -> 6.7 min. 2% B -> 7.5 min 2 % B; flow: 0.75 ml/min; column temperature: 300C; UV detection: 210 nm.
method 7 (HPLC): Instrument: HP 1 100 with DAD-detection; column: Kromasil 100 RP-18, 60 mm x 2.1 mm, 3.5 μm; eluent A: 5 ml HClO4 (70 %) /1 water, eluent B: acetonitrile; gradient: 0 min 2% B -> 0.5 min 2% B -> 4.5 min 90% B -> 9 min 90% B -> 9.2 min. 2% B -* 10 min 2 % B; flow: 0.75 ml/min; column temperature: 30 0C; UV detection: 210 nm.
method 8 (LC-MS): Instrument MS: Micromass TOF (LCT); Instrument HPLC: 2-column-method, Waters2690; column: YMC-ODS-AQ, 50 mm x 4.6 mm, 3.0 μm; eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1 % formic acid; gradient: 0.0 min 100% A -> 0.2 min 95% A -> 1.8 min 25% A -> 1.9 min 10% A -> 2.0 min 5% A -> 3.2 min 5% A; flow: 3.0 ml/min; oven: 400C; UV detection: 210 nm.
Starting Materials and Intermediates:
Example IA
tert-butyl {3-[(2-thienylmethyl)amino]propyl}carbamate
Figure imgf000023_0001
3.48 g (20 mmol) tert-butyl (3-aminopropyl)carbamate and 2.47 g (20 mmol) thiophene-2- carbaldehyde are dissolved in 60 ml methanol and stirred for 2 h at room temperature. After cooling to 00C 3.78 g (100 mmol) sodium borohydride are added in several portions and stirring is continued for 16 h at room temperature. The reaction solution is concentrated in vacuo and taken up in dichloromethane. The solution is washed with brine, dried with magnesium sulfate and evaporated in vacuo. The residue is purified by chromatography on silica gel (eluent: cyclohexane- ethyl acetate 1 : 1 -> ethyl acetate -> ethyl acetate-methanol 9:1). Yield: 4.75 g (88% of th.).
LC-MS (method 1): R, = 0.87 min, m/z = 271 (M+H)+
1H-NMR (300 MHz, DMSOd6): δ = 7.45 (dd, IH), 6.95 (m, 2H), 6.80 (tr, IH), 3.85 (s, 2H), 2.95 (q, 2H), 2.50 (tr, 2H), 1.55 (quintett, 2H), 1.40 (s, 9H).
Example 2A
2-{[{3-[(tert-butoxycarbonyl)amino]propyl}(2-thienylmethyl)amino]carbonyl}phenyl acetate
Figure imgf000023_0002
To a solution of 4.39 g (16.2 mmol) tert-butyl {3-[(2-thienylmethyl)amino]propyl}carbamate in 32.5 ml pyridine are added 3.22 g (16.2 mmol) 2-(chlorocarbonyl)phenyl acetate at 00C. After stirring for 30 min at 00C the reaction mixture is warmed to room temperature and stirred for an additional 2 h. The reaction mixture is poured into brine and extracted several times with dichloromethane. The combined organic phases are dried with magnesium sulfate and evaporated in vacuo. The residue is purified by chromatography on silica gel (eluent: dichloromethane). Yield: 4.03 g (57% of th.).
LC-MS (method 5): R, = 2.34 min, m/z = 433 (M+H)+
1H-NMR (300 MHz, DMSO-d6): δ = 7.5 - 6.95 (m, 7H), 6.85 and 6.65 (2 tr, IH), 4.75 and 4.45 (2 s, 2H), 3.0 (q, 2H), 2.75 (q, 2H), 2.25 and 2.0 (2 s, 3H), 1.65 (m, 2H), 1.35 and 1.30 (2 s, 9H).
Example 3A
tert-buty 1 { 3 - [(2-hy droxy benzoy l)(2-th ieny lmethy l)amino] propy 1 } carbamate
Figure imgf000024_0001
To a solution of 4.16 g (9.63 mmol) 2-{[{3-[(tert-butoxycarbonyl)amino]propyl}(2-thienylmethyl)- amino]carbonyl} phenyl acetate in 48 ml ethanol are added 9.6 ml (19.25 mmol) 2N aq. sodium hydroxide solution. After stirring for 1 h at room temperature the solution is diluted with brine and extracted several times with dichloromethane. The combined extracts are dried with magnesium sulfate and evaporated in vacuo. Yield: 3.54 g (84% of th.).
LC-MS (method 5): R, = 2.20 min, m/z = 391 (M+H)+
1H-NMR (300 MHz, DMSO-d6): δ = 7.5 - 6.6 (m, 8H), 4.8 and 4.5 (2 s, 2H), 4.35 and 3.1 (2 m, 2H), 3.0 and 2.70 (2 m, 2H), 1.65 (m, 2H), 1.40 and 1.3 (2 s, 9H).
Example 4A
tert-butyl {3-[(4-chlorobenzyl)amino]propyl}carbamate
Figure imgf000025_0001
3.48 g (20 mmol) tert-butyl (3-aminopropyl)carbamate and 3.09 g (22 mmol) 4-chlorobenz- aldehyde are dissolved in 60 ml methanol and stirred for 2 h at room temperature. After cooling to 00C 3.78 g (100 mmol) sodium borohydride are added in several portions and stirring is continued for 16 h at room temperature. The reaction solution is concentrated in vacuo and taken up in dichloromethane. The solution is washed with brine, dried with magnesium sulfate and evaporated in vacuo. The residue is purified by chromatography on silica gel (eluent: cyclohexane-ethyl acetate 1 : 1 -> ethyl acetate -> ethyl acetate-methanol 9:1). Yield: 3.7 g (62% of th.).
LC-MS (method 1): R, = 1.1 min, m/z = 299 (M+H)+
1H-NMR (300 MHz, DMSOd6): δ = 7.35 (m, 4H), 6.8 (tr, IH), 3.65 (s, 2H), 2.95 (q, 2H), 2.45 (tr, 2H), 1.55 (quintett, 2H), 1.40 (s, 9H).
Example 5A
tert-butyl {3-[(4-chlorobenzyl)(2-hydroxybenzoyl)amino]propyl} carbamate
Figure imgf000025_0002
To a solution of 4.72 g (9.27 mmol) tert-butyl {3-[[2-(benzyloxy)benzoyl](4-chlorobenzyl)- amino]propyl} carbamate (example 1) in 83 ml THF are added ca. 100 mg 10% palladium on charcoal. After hydrogenation under normal pressure at room temperature for 1 h the reaction mixture is filtered and evaporated in vacuo. The residue is purified in 5 portions by preparative HPLC (column: YMC-GeI ODS-AQ S-5 15 μm, 250 mm x 30 mm; eluent A: acetonitrile, eluent B: water + 0.1% formic acid, gradient: 0 min 10% A, 5 min 10% A, 23 min 90% A, 28 min 90% A, 28.2 min 10% A, 33 min 10% A; flow rate: 25 ml/min; UV detection: 220 nm). The desired fractions are combined, neutralized with IN sodium hydroxide solution and concentrated in vacuo. The concentrate is extracted several times with dichloromethane. The combined extracts are washed with sodium hydrogen carbonate solution, dried with magnesium sulfate and evaporated in vacuo. Yield: 3.23 g (83% of th.).
LC-MS (method 5): R, = 2.42 min, m/z = 419 (M+H)+
'H-NMR (300 MHz, DMSOd6): δ = 7.5 - 6.8 (m, 8H), 6.75 and 6.6 (2 s, IH), 4.7 and 4.35 (2 s, 2H), 3.3 and 3.05 (2 m, 2H), 3.0 and 2.7 (2 m, 2H), 1.65 and 1.5 (2 m, 2H), 1.35 and 1.30 (2 s, 9H).
Example 6A
tert-butyl {3-[(4-fluorobenzyl)amino]propyl}carbamate
Figure imgf000026_0001
3.48 g (20 mmol) tert-butyl (3-aminopropyl)carbamate and 2.73 g (22 mmol) 4-fluorobenzaldehyde are dissolved in 60 ml methanol and stirred for 2 h at room temperature. After cooling to 00C 3.78 g (100 mmol) sodium borohydride are added in several portions and stirring is continued for 16 h at room temperature. The reaction solution is concentrated in vacuo and taken up in dichloromethane. The solution is washed with brine, dried with magnesium sulfate and evaporated in vacuo. The residue is purified by chromatography on silica gel (eluent: cyclohexane-ethyl acetate 1 : 1 -> ethyl acetate -> ethyl acetate-methanol 9:1). Yield: 5.59 g (99% of th.).
LC-MS (method 1): R, = 1.1 1 min, m/z = 283 (M+H)+
1H-NMR (300 MHz, DMSOd6): δ = 7.35 (dd, 2H), 7.1 (tr, 2H), 6.8 (tr, IH), 3.65 (s, 2H), 2.95 (q, 2H), 2.45 (tr, 2H), 1.55 (quintett, 2H), 1.40 (s, 9H).
Example 7A
tert-butyl {3-[(4-fiuorobenzyl)(2-hydroxybenzoyi)amino]propyl}carbamate
Figure imgf000027_0001
To a solution of 5.95 g (12.09 mmol) tert-butyl {3-[[2-(benzyloxy)benzoyl](4-fluorobenzyl)- amino]propyl}carbamate (example 2) in 120 ml THF are added ca 100 mg 10% palladium on charcoal. After hydrogenation under normal pressure at room temperature for 1 h the reaction mixture is filtered and evaporated in vacuo. The residue is purified in 5 portions by preparative HPLC (column: YMC-GeI ODS-AQ S-5 15 μm, 250 mm x 30 mm; eluent A: acetonitrile, eluent B: water + 0.1% formic acid, gradient: 0 min 10% A, 5 min 10% A, 23 min 90% A, 28 min 90% A, 28.2 min 10% A, 33 min 10% A; flow rate: 25 ml/min; UV detection: 220 nm). The desired fractions are combined, neutralized with IN sodium hydroxide solution and concentrated in vacuo. The concentrate is extracted several times with dichloromethane. The combined extracts are washed with sodium hydrogen carbonate solution, dried with magnesium sulfate and evaporated in vacuo. Yield: 3.33 g (69% of th.).
LC-MS (method 3): R1 = 2.42 min, m/z = 403 (M+H)+
1H-NMR (300 MHz, DMSOd6): δ = 7.5 - 6.8 (m, 8H), 6.75 and 6.6 (2 s, IH), 4.7 and 4.35 (2 s, 2H), 3.3 and 3.05 (2 m, 2H), 3.0 and 2.7 (2 m, 2H), 1.65 and 1.5 (2 m, 2H), 1.35 and 1.30 (2 s, 9H).
Example 8 A
tert-butyl {2-[(2-thienylmethyl)amino]ethyl} carbamate
Figure imgf000027_0002
5 g (43.7 mmol) 2-thiophencarboxaldehyde and 7.7 g (48.1 mmol) tert-butyl (2-aminoethyl)- carbamate are dissolved in 100 ml methanol and stirred for 2 h at room temperature. The solution is cooled to 00C and 8.27 g (218.5 mmol) sodium borohydride are carefully added. Water is added until a clear solution is formed and the mixture is stirred at room temperature overnight. The mixture is concentrated under vacuum, the residue is diluted with dichloromethane and the organic phase is washed with brine, dried over magnesium sulfate and concentrated under vacuum. The crude is purified by column chromatography over silicagel (cyclohexane/ethyl acetate 7/3) to yield 6.7 g (62% of th.) of the title compound.
HPLC (method 6): R, = 3.59 min; MS (ESIpos): m/z = 257 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ = 7.30 (m, IH), 6.90 (m, 2H), 6.70 (m, IH), 3.80 (s, 2H), 3.00 (m, 2H), 2.55 (m, 2H), 2.20 (bs, IH), 1.40 (s, 9H)
Example 9A
tert-butyl {2-[(4-chiorobenzyl)amino]ethyl}carbamate
Figure imgf000028_0001
5 g (35.6 mmol) 4-chlorobenzaldehyde and 6.3 g (39.2 mmol) tert-butyl (2-aminoethyl)carbamate are dissolved in 120 ml methanol and stirred for 2 h at room temperature. The solution is cooled to 00C and 6.73 g (177.9 mmol) sodium borohydride are carefully added. Water is added until a clear solution is formed and the mixture is stirred at room temperature overnight. The mixture is concentrated under vacuum, the residue is diluted with dichloromethane and the organic phase is washed with brine, dried over magnesium sulfate and concentrated under vacuum. The crude product is re-crystallized from petroleum ether to yield 5.8 g (57% of th.) of the title compound as a solid.
HPLC (method 6): R, = 3.97 min; MS (ESIpos): m/z = 285 (M+H)+
1H-NMR (300 MHz, DMSOd6): δ = 7.35 (m, 4H), 6.70 (m, IH), 3.60 (s, 2H), 3.00 (m, 2H), 2.55 (m, 2H), 2.20 (bs, IH), 1.40 (s, 9H).
Example 1OA
tert-butyl {3-[(4-chlorobenzyl)amino]propyl}carbamate
Figure imgf000028_0002
10 g (71.1 mmol) 4-chlorobenzaldehyde and 13.6 g (78.3 mmol) tert-butyl (2-aminopropyl)- carbamate are dissolved in 200 ml methanol and stirred for 2 h at room temperature. The solution is cooled to O0C and 13.5 g (355.7 mmol) sodium borohydride are carefully added. Water is added until a clear solution is formed and the mixture is stirred at room temperature overnight. The mixture is concentrated under vacuum, the residue is diluted with dichloromethane and the organic phase is washed with brine, dried over magnesium sulfate and concentrated under vacuum. The crude product is re-crystallized from petroleum ether to yield 8.9 g (42% of th.) of the title compound as a solid.
HPLC (method 6): R, = 4.03 min; MS (ESIpos): m/z = 299 (M+H)+
1H-NMR (300 MHz, DMSOd6): δ = 7.35 (m, 4H), 6.70 (m, IH), 3.60 (s, 2H), 2.95 (m, 2H), 2.40 (m, 2H), 2.10 (bs, IH), 1.50 (m, 2H), 1.40 (s, 9H).
Example HA
methyl 2-[(2,4-difluorobenzyl)oxy]benzoate
Figure imgf000029_0001
1 0 g (6.57 mmol) methyl salicylate and 1.47 g (7.23 mmol) 2,4-difluorobenzyl bromide are dissolved in 10 ml DMF. 4.54 g (32.9 mmol) potassium carbonate are added and the mixture is stirred at room temperature overnight. Ethyl acetate is added and the mixture is washed with water, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue is re- crystallized from petroleum ether to yield 1.32 g (71% of th.) of the title compound.
HPLC (method 6): R4 = 4.90 min; MS (DCI): m/z = 279 (M+H)+
1H-NMR (400 MHz, DMSOd6): δ = 7.70-7.00 (m, 7H), 5.50 (s, 2H), 4.00 (s, 3H). Example 12A
2-[(2,4-difluorobenzyl)oxy]benzoic acid
Figure imgf000030_0001
500 mg (1.80 mmol) methyl 2-[(2,4-difluorobenzyl)oxy]benzoate are suspended in 5 ml water and 10 ml methanol and 201 mg (3.59 mmol) potassium hydroxide are added and is heated overnight to reflux. The methanol is evaporated under vacuum and the aqueous residue is extracted with dichloromethane. The aqueous phase is acidified with hydrochloric acid, extracted with dichloromethane, dried over magnesium sulfate, filtered and concentrated to yield 140 mg (30% of th.) of the title acid as a solid.
HPLC (method 6): R1 = 4.35 min; MS (DCI): m/z = 282 (M+NH4)+
1H-NMR (400 MHz, DMSOd6): δ = 12.5 (bs, IH), 7.70-7.00 (m, 7H), 5.20 (s, 2H).
Example 13A
2-[(2,4-difluorobenzyl)oxy]benzoyl chloride
Figure imgf000030_0002
190 mg (0.71 mmol) 2-[(2,4-difluorobenzyl)oxy]benzoic acid are dissolved in 5 ml dichloromethane and one drop DMF is added. 335 mg (2.82 mmol) thionyl chloride are added and the reaction mixture is stirred at room temperature for 1 h. After this period, the mixture is heated to 400C until no further gas formation is observed. The solvent is evaporated under vacuum, petroleum ether is added to the residue and the precipitated product is collected and dried. 135 mg (61% of th.) of the title compound are obtained.
1H-NMR (300 MHz, DMSO-d6): δ = 7.70-7.00 (m, 7H), 5.20 (s, 2H).
Example 14A
Methyl 2-[(4-fluorobenzyl)oxy]benzoate
Figure imgf000031_0001
1.0 g (6.57 mmol) methyl salicylate and 1.37 g (7.23 mmol) 2,4-difluorobenzyl bromide are dissolved in 10 ml DMF. 4.54 g (32.9 mmol) potassium carbonate are added and the mixture is stirred at room temperature overnight. Ethyl acetate is added and the mixture is washed with water, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue is re- crystallized from petroleum ether to yield 0.4 g (23% of th.) of the title compound.
HPLC (method 6): R1 = 4.80 min; MS (DCI): m/z = 261 (M+H)+
1H-NMR (400 MHz, DMSOd6): δ = 7.70 (m, IH), 7.50 (m, 2H), 7.20 (m, 2H), 7.00 (t, IH), 5.20 (s, 2H), 3.80 (s, 3H). Example 15A
2-[(4-fluorobenzyl)oxy]benzoic acid
Figure imgf000032_0001
300 mg (1.15 mmol) methyl 2-[(4-fluorobenzyi)oxy]benzoate are suspended in 4 ml water and 8 ml methanol and 129 mg (2.31 mmol) potassium hydroxide are added and is heated overnight to reflux. The methanol is evaporated under vacuum and the aqueous residue is extracted with dichloromethane. The aqueous phase is acidified with hydrochloric acid, extracted with dichloromethane, dried over magnesium sulfate, filtered and concentrated to yield 190 mg (67% of th.) of the title acid as a solid .
HPLC (method 6): R, = 4.26 min; MS (DCI): m/z = 264 (M+NH,)+
1H-NMR (400 MHz, DMSO-d6): δ = 12.60 (bs, IH), 7.60 (m, IH), 7.50 (m, 2H), 7.20 (m, 2H), 7.00 (t, IH), 5.20 (s, 2H).
Example 16A
2-[(4-difluorobenzyl)oxy]benzoyl chloride
Figure imgf000032_0002
32 mg (0.12 mmol) 2-[(4-difluorobenzyl)oxy]benzoic acid are dissolved in 5 ml dichloromethane and one drop DMF is added. 60 mg (0.50 mmol) thionyl chloride are added and the reaction mixture is stirred at room temperature for 1 h. After this period, the mixture is heated to 400C until no further gas formation is observed. The solvent is evaporated under vacuum, petroleum ether is added to the residue and the precipitated product is collected and dried. 38 mg (100% of th.) of the title compound are obtained.
1H-NMR (300 MHz, DMSO-d6): δ = 7.60 (m, IH), 7.50 (m, 2H), 7.20 (m, 2H), 7.00 (t, IH), 5.20 (s, 2H).
Example 17A
2-(benzyloxy)benzoyl chloride
Figure imgf000033_0001
The title compound is prepared in analogy to 2-[(2,4-difluorobenzyl)oxy]benzoyl chloride from commercially available 2-(benzyloxy)benzoic acid and used without further purification.
Example 18A
2-[4-methylbenzyl)oxy]benzoyl chloride
Figure imgf000033_0002
The title compound is prepared in analogy to 2-[(2,4-difluorobenzyl)oxy]benzoyl chloride from commercially available 2-[4-methylbenzyl)oxy]benzoic acid and used without further purification.
Example 19A
p-nitrophenyl-carbonate Wang resin
Figure imgf000034_0001
30 g (ca. 30 mmol) of Wang-OH resin (Novabiochem, ca. 1 mmol/g) and 35.60 g (450 mmol, 15 eq) pyridine in 300 ml dichloromethane are cooled to 0 0C in an ice bath. A solution of 30.24 g p- nitrophenyl-chloroformiat (150 mmol, 4 eq) in 120 ml dichloromethane are added dropwise during 20 min. The mixture is stirred 3 h at rt afterwards. The resin is washed once with iso-propanol, twice with DMF, once with iso-propanol and three times alternately with methanol and dichloromethane. The resin is dried in vacuo.
Preparation Examples:
Example 1
tert-butyl {3-[[2-(benzyloxy)benzoyl](4-chlorobenzyl)amino]propyl} carbamate
Figure imgf000035_0001
To a solution of 2.73 g (1 1.9 mmol) 2-(benzyloxy)benzoic acid in 20 ml DMF are added 1.66 ml (11.9 mmol) triethylamine and 4.74 g (1 1.9 mmol) HBTU. After stirring for 1 h a solution of 3.57 g (11.9 mmol) tert-butyl {3-[(4-chlorobenzyl)amino]propyl}carbamate (example 4A) in 10 ml DMF is added. After stirring over night the reaction solution is filtered and purified by preparative HPLC (column: Merck SelfPackColumn Cromsil ODS 4 HE 10 μm, 50 mm x 200 mm, eluent A: acetonitrile, eluent B: water + 0.1% formic acid, gradient: 0 min 10% A, 5.00 min 10% A, 23 min 90% A, 28 min 90% A, 28.2 min 10% A, 33 min 10% A; flow rate: 1 10 ml/min, UV detection: 220 nm). The desired fractions are combined, neutralized with IN sodium hydroxide solution and concentrated in vacuo. The concentrate is extracted several times with dichloromethane. The combined extracts are washed with sodium hydrogen carbonate solution, dried with magnesium sulfate and evaporated in vacuo. Yield: 4.72 g (78% of th.).
LC-MS (method 3): R, = 3.07 min, m/z = 509 (M+H)+
1H-NMR (300 MHz, DMSOd6): δ = 7.5 - 6.95 (m, 13H), 6.7 and 6.6 (2 tr, IH), 5.2 (m, 2H), 4.25 (m, 2 H), 3.6 and 2.9 (2 m, 2H), 3.1 and 2.7 (2 m, 2H), 1.6 (m, 2H), 1.35 and 1.30 (2 s, 9H).
Example 2
tert-butyl {3-[[2-(benzyloxy)benzoyl](4-fiuorobenzyl)amino]propyl}carbamate
Figure imgf000036_0001
To a solution of 4.53 g (19.8 mmol) 2-(benzyloxy)benzoic acid in 40 ml DMF are added 2.76 ml (19.8 mmol) triethylamine and 7.87 g (19.8 mmol) HBTU. After stirring for 1 h a solution of 5.6 g (19.8 mmol) tert-butyl {3-[(4-fluorobenzyl)amino]propyl}carbamate (example 6A) in 20 ml DMF is added. After stirring over night the reaction solution is poured into brine and extracted several times with dichloromethane. The combined extracts are dried with magnesium sulfate and evaporated in vacuo. The residue is purified in 5 portions by preparative HPLC (column: YMC- GeI ODS-AQ S-5 15 μm, 250 mm x 30 mm; eluent A: acetonitrile, eluent B: water + 0.1% formic acid, gradient: 0 min 10% A, 5 min 10% A, 23 min 90% A, 28 min 90% A, 28.2 min 10% A, 33 min 10% A; flow rate: 25 ml/min; UV detection: 220 nm). The desired fractions are combined, neutralized with IN sodium hydroxide solution and concentrated in vacuo. The concentrate is extracted several times with dichloromethane. The combined extracts are washed with sodium hydrogen carbonate solution, dried with magnesium sulfate and evaporated in vacuo. Yield: 6.02 g (62% of th.).
LC-MS (method 3): R4 = 2.93 min, m/z = 493 (M+H)+
1H-NMR (300 MHz, DMSOd6): δ = 7.5 - 6.75 (m, 13H), 6.7 and 6.6 (2 tr, IH), 5.2 (m, 2H), 4.25 (m, 2H), 3.6 and 2.9 (2 m, 2H), 3.1 and 2.7 (2 m, 2H), 1.6 (m, 2H), 1.35 and 1.30 (2 s, 9H).
Example 3
tert-butyl {3-[[2-(benzyloxy)benzoyl](2-thienylmethyl)amino]propyl}carbamate
Figure imgf000037_0001
To a solution of 3.5 g (15.3 mmol) 2-(benzyloxy)benzoic acid in 30 ml DMF are added 2.13 ml (15.3 mmol) triethylamine and 6.08 g (15.3 mmol) HBTU. After stirring for 1 h a solution of 4.14 g (15.3 mmol) tert-butyl {3-[(2-thienylmethyl)amino]propyl}carbamate (example IA) in 10 ml DMF is added. After stirring overnight the reaction solution is filtrated and purified in 5 portions by preparative HPLC (column: Merck SelfPackColumn Cromsil ODS 4 HE 10 μm, 50 mm x 200 mm, eluent A: acetonitrile, eluent B: water + 0.1% formic acid, gradient: 0 min 10% A, 5.00 min 10% A, 23 min 90% A, 28 min 90% A, 28.2 min 10% A, 33 min 10% A; flow rate: 1 10 ml/min, UV detection: 220 nm). The desired fractions are combined, neutralized with IN sodium hydroxide solution and concentrated in vacuo. The concentrate is extracted several times with dichloromethane. The combined extracts are washed with sodium hydrogen carbonate solution, dried with magnesium sulfate and evaporated in vacuo. Yield: 5.9 g (80% of th.).
LC-MS (method 1): R, = 2.60 min, m/z = 481 (M+H)+
1H-NMR (300 MHz, DMSOd6): δ = 7.5 - 6.8 (m, 12H), 6.7 and 6.6 (2 tr, IH), 5.2 (m, 2H), 4.5 (m, 2H), 3.7 and 2.9 (2 m, 2H), 3.1 and 2.7 (2 m, 2H), 1.6 (m, 2H), 1.35 and 1.30 (2 s, 9H).
Example 4
N-(3-aminopropyl)-2-(benzyloxy)-N-(2-thienylmethyl)benzamide hydrochloride
Figure imgf000037_0002
5.62 g (1 1.7 mmol) tert-butyl {3-[[2-(benzyloxy)benzoyl](2-thienylmethyl)arnino]propyl}- carbamate are dissolved in a 4M solution of hydrogen chloride in dioxane. After standing for 1 h at room temperature the solution is evaporated in vacuo. Yield: 5.53 g (quant.).
LC-MS (method 5): R, = 1.71 min, m/z = 381 (M+H)+
1H-NMR (300 MHz, DMSOd6): δ = 7.75 (s, 2H), 7.45 - 6.8 (m, 12H), 5.15 (m, 2H), 4.5 (m, 2H), 3.75 and 2.7 (2 m, 2H), 3.15 and 2.55 (2 m, 2H), 1.8 (m, 2H).
Example 5
tert-butyl {2-[[2-(benzyloxy)benzoyl](2-thienylmethyI)amino]ethyl}carbarnate
Figure imgf000038_0001
236.0 mg (0.92 mmol) tert-butyl {2-[(2-thienylmethyl)amino]ethyl}carbamate are dissolved in 5 ml dichloromethane. 249.8 mg (1.01 mmol) 2-(benzyloxy)benzoyl chloride and 140 mg (1.38 mmol) triethylamine are added at room temperature and the solution is stirred at room temperature overnight. A IN sodium hydroxide solution is then carefully added until basic pH, the organic phase is separated and washed with brine, dried over magnesium sulfate, filtered and concentrated under vacuum to yield the crude desired compound. The crude compound is purified by preparative HPLC (acetonitrile/water) to yield 235 mg (56% of th.) of the title compound.
HPLC (method 6): R, = 5.07 min; MS (ESIpos): m/z = 489 (M+Na)+
1H-NMR (300 MHz, DMSOd6): δ = 7.50-6.70 (m, 13H), 5.20-5.10 (m, 2.6H), 4.50-4.40 (m, 1.4H), 3.20-2.80 (m, 4H), 1.40 (m, 9H).
Example 6
tert-butyl [3-((4-chlorobenzyl){2-[(2,4-difluorobenzyl)oxy]benzoyl}amino)propyl]carbamate
Figure imgf000039_0001
47.8 mg (0.16 mmol) tert-butyl {3-[(4-chlorobenzyl)amino]propyl}carbamate are dissolved in 5 ml dichloromethane. 49.7 mg (0.18 mmol) 2-[(2,4-difluorobenzyl)oxy]benzoyl chloride and 24.3 mg (0.24 mmol) triethylamine are added at room temperature and the solution is stirred at room temperature overnight. A IN sodium hydroxide solution is then carefully added until basic pH, the organic phase is separated and washed with brine, dried over magnesium sulfate, filtered and concentrated under vacuum to yield the crude desired compound. The crude compound is purified by preparative HPLC (acetonitrile/water) to yield 74.8 mg (86% of th.) of the title compound.
HPLC (method 6): R, = 5.36 min; MS (ESIpos): m/z = 567 (M+Na)+
1H-NMR (300 MHz, DMSOd6): δ = 7.50-6.95 (m, 1 IH), 6.60 (bs, IH), 5.20-5.00 (m, 2.6H), 4.30- 4.10 (m, 1.4H), 3.60-2.70 (m, 4H), 1.50 (m, 2H), 1.40 (m, 9H).
Example 7
tert-butyl [2-((4-chlorobenzyl){2-[(4-methylbenzyl)oxy]benzoyl}amino)ethyl]carbamate
Figure imgf000039_0002
100.0 mg (0.35 mmol) tert-butyl {2-[(4-chlorobenzyl)amino]ethyl}carbamate are dissolved in 5 ml dichloromethane. 100.7 mg (0.39 mmol) 2-[(4-methylbenzyl)oxy]benzoyl chloride and 53.3 mg (0.53 mmol) triethylamine are added at room temperature and the solution is stirred at room temperature overnight. A IN sodium hydroxide solution is then carefully added until basic pH, the organic phase is separated and washed with brine, dried over magnesium sulfate, filtered and concentrated under vacuum to yield the crude desired compound. The crude compound is purified by preparative HPLC (acetonitrile/water) to yield 79.6 mg (45% of th.) of the title compound.
HPLC (method 7): R, = 5.41 min; MS (ESIpos): m/z = 531 (M+Na)+
1H-NMR (300 MHz, DMSOd6): δ = 7.40-6.70 (m, 13H), 5.25-5.05 (m, 2.6H), 4.30 (s, 0.8H), 4.05 (d, 0.6H), 3.30-2.80 (m, 4H), 2.35 (m, 3H), 1.40 (m, 9H).
Example 8
tert-butyl [2-((4-chlorobenzyl)[2-(benzyl)oxy)benzoyl]amino)ethyl]carbamate
Figure imgf000040_0001
100.0 mg (0.35 mmol) tert-butyl {2-[(4-chlorobenzyl)amino]ethyl}carbamate are dissolved in 5 ml dichloromethane. 95.9 mg (0.39 mmol) 2-(benzyloxy)benzoyl chloride and 53.3 mg (0.53 mmol) triethylamine are added at room temperature and the solution is stirred at room temperature overnight. A IN sodium hydroxide solution is then carefully added until basic pH, the organic phase is separated and washed with brine, dried over magnesium sulfate, filtered and concentrated under vacuum to yield the crude desired compound. The crude compound is purified by preparative HPLC (acetonitrile/water) to yield 63.7 mg (37% of th.) of the title compound.
HPLC (method 7): R, = 5.25 min; MS (ESIpos): m/z = 517 (M+Na)+
1H-NMR (300 MHz, DMSOd6): δ = 7.40-6.70 (m, 14H), 5.20-5.10 (m, 2.6H), 4.30-4.00 (m, 1.4H), 3.20-2.80 (m, 4H), 1.40 (m, 9H).
Using an analogous procedure the following compounds are prepared:
Figure imgf000041_0001
Example 12
N-(2-aminoethyl)-2-(benzyloxy)-N-(2-thienylmethyl)benzamide hydrochloride
Figure imgf000042_0001
100 mg (0.21 mmol) tert-butyl {2-[[2-(benzyloxy)benzoyl](2-thienylmethyl)amino]ethyl}- carbamate are dissolved in 2 ml dioxane and 1 ml of a 4M solution of hydrochloric acid in dioxane are added dropwise. The solution is stirred overnight and concentrated under vacuum. Petroleum ether is added to the residue, stirred and the solid title compound is filtered (72.3 mg, 84% of th.).
HPLC (method 6): R, = 4.12 min; MS (ESIpos): m/z = 367 (M-HC1+H)+
1H-NMR (300 MHz, DMSOd6): δ = 7.80 (br.s, 3H), 7.50-6.80 (m, 12H), 5.15 (m, 2.6H), 4.50 (m, 1.4H), 3.40- 2.90 (m, 4H).
Example 13
N-(3-aminopropyl)-N-(4-chlorobenzyl)-2-[(2,4-difluorobenzyl)oxy]benzamide hydrochloride
Figure imgf000042_0002
65 mg (0.12 mmol) tert-butyl [3-((4-chlorobenzyl){2-[(2,4-difluorobenzyI)oxy]benzoyl}amino)- propyl]carbamate are dissolved in 2 ml dioxane and 1 ml of a 4M solution of hydrochloric acid in dioxane are added dropwise. The solution is stirred overnight and concentrated under vacuum. Petroleum ether is added to the residue, stirred and the solid title compound is filtered (10.8 mg, 19% of th.).
HPLC (method 6): R, = 4.51 min; MS (ESIpos): m/z = 445 (M-HCH-H)+
1H-NMR (300 MHz, DMSOd5): δ = 7.80 (br.s, 3H), 7.70-6.90 (m, HH), 5.25-5.05 (m, 2.4H), 4.35-4.10 (m, 1.6H), 3.70-2.90 (m, 4H), 1.80-1.60 (m, 2H).
Example 14
N-(3-aminopropyl)-N-(4-chlorobenzyl)-2-(benzy!oxy)benzamide hydrochloride
Figure imgf000043_0001
100 mg (0.20 mmol) tert-butyl {3-[[2-(benzyloxy)benzoyl](4-chlorobenzyl)amino]propyl}- carbamate are dissolved in 2 ml dioxane and 1 ml of a 4M solution of hydrochloric acid in dioxane are added dropwise. The solution is stirred overnight and concentrated under vacuum. Petroleum ether is added to the residue, stirred and the solid title compound is filtered (42.7 mg, 46% of th.).
HPLC (method 6): R, = 4.45 min; MS (ESIpos): m/z = 409 (M-HCRH)+
1H-NMR (300 MHz, DMSO-d6): δ = 7.70 (br.s, 3H), 7.50-6.90 (m, 13H), 5.25-5.05 (m, 2.4H), 4.30 (s, 1.2H), 4.20 (d, 0.4H), 3.70- 2.70 (m, 4H), 1.80-1.60 (m, 2H).
Using an analogous procedure the following compounds are prepared: δ =
= (s, (m,
=
δ =
Figure imgf000044_0001
Example 19
iso-butyl {3-[[2-(benzyloxy)benzoyl](2-thienylmethyl)amino]propyl}carbamate
Figure imgf000045_0001
To a solution of 76.1 mg (0.18 mmol) N-(3-aminopropyl)-2-(benzyloxy)-N-(2-thienylmethyl)- benzamide hydrochloride in 0.5 ml pyridine are added 54.6 mg (0.4 mmol) iso-butyl chloridocarbonate. After stirring for 4 h at room temperature 40 mg (0.4 mmol) 1 -methylpiperazine are added to the reaction mixture and stirring is continued for 1 h. The reaction mixture is filtrated and purified by preparative HPLC (column: Machery Nagel VP50/21 Nucleosil 100-5 Cl 8
Nautilus, 5 μm, 21 mm x 50 mm; eluent A: water + 0.1 % formic acid, eluent B: acetonitrile, gradient: 0 min 10% B, 2 min 10% B, 6 min 90% B, 9 min 90% B, 9.1 min 10% B, 10 min 10% B; flow rate: 25 ml/min; UV detection: 220 nm). The desired fractions are combined and concentrated in vacuo. Yield: 74.3 mg (86% of th.).
LC-MS (method 5): R, = 2.56 min, m/z = 481 (M+H)+
1H-NMR (300 MHz, DMSO-d6): δ = 7.45 - 6.8 (m, 13H), 5.2 (m, 2H), 4.5 (m, 2H), 3.75 and 3.65 (2 d, 2H), 3.1 - 2.7 (m, 2H), 1.8 (m, IH), 1.7 (m, 2H), 0.9 and 0.85 (2 d, 6H). Example 20
N-(3-aminopropyl)-N-(4-fluorobenzyl)-2-[(4-fluorobenzyl)oxy]benzamide hydrochloride
Figure imgf000046_0001
To a solution of 80.5 mg (0.2 mmol) tert-butyl {3-[(4-fluorobenzyl)(2-hydroxybenzoyl)amino]- propyl} carbamate in 0.5 ml DMF are added 37.8 mg (0.2 mmol) 1 -(bromomethyl)-4-fluorobenzene and 55.3 mg (0.4 mmol) potassium carbonate. The reaction mixture is stirred for 1 h at room temperature, filtrated and purified by preparative HPLC (column: Machery Nagel VP50/21 Nucleosil 100-5 Cl 8 Nautilus, 5 μm, 21 mm x 50 mm; eluent A: water + 0.1 % formic acid, eluent B: acetonitrile, gradient: 0 min 10% B, 2 min 10% B, 6 min 90% B, 9 min 90% B, 9.1 min 10% B, 10 min 10% B; flow rate: 25 ml/min; UV detection: 220 nm). The desired fractions are combined and concentrated in vacuo. One half of the residue is dissolved in a 4M solution of hydrogen chloride in dioxane. After standing for 1 h at room temperature the solution is evaporated in vacuo. Yield: 19.3 mg (43% of th.).
LC-MS (method 3): R, = 2.03 min, m/z = 41 1 (M-HCRH)+
1H-NMR (300 MHz, DMSOd6): δ = 7.9 (s broad, 3H), 7.45 - 6.8 (m, 12H), 5.2 (m, 2H), 4.3 (m, 2H), 3.7 and 3.5 (2 m, IH), 3.1 (m, 2H), 2.7 (m, IH), 1.8 (m, 2H).
Using an analogous procedure the following compounds are prepared:
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Scheme solid phase synthesis, general procedure:
Figure imgf000053_0001
Example 48
N-(3-aminopropyl)-2-(benzyloxy)-N-(cyclohexylmethyl)benzamide hydrochloride
Figure imgf000053_0002
1. variaton point: diamine
10.00 g of p-nitrophenyl-carbonate Wang resin (ca. 1 mmol/g, 1 eq) is treated with 7.41 g (100 mmol, 10 eq.) propane-l,3-diamine and 12.9 g (100 mmol, 10 eq.) DIEA in 350 ml DMF overnight at rt. The resin is washed three times with DMF and three times alternately with methanol and dichloromethane and dried in vacuo. 2. variation point: aldehyde
2.00 g of this resin is treated with 20 ml of a l :l-mixture of TMOF/dichloromethane and 2.24 g (20.0 mmol, 10 eq.) cyclohexanecarbaldehyde for two days at rt. The resin is washed three times with DMF and suspended again in 20 ml DMF. 2.57 g TBABH (10.0 mmol, 5 eq.) are added. After 30 min at rt the mixture is cooled to -40 0C and 1 1.9 g acetic acid (198 mmol, 99 eq.) are added dropwise while shaking, followed by shaking overnight at rt. The resin is washed three times with DMF, twice with water, once with a l : l-mixture of DMF and DIEA, and then consecutively once with methanol, dichloromethane and diethylether. The resin is dried in vacuo.
3. variation point: acid
The resin is suspended in 5 ml DMF and treated with 2.28 g 2-(benzyloxy)benzoic acid (10.0 mmol, 5 eq) and 2.52 g (20.0 mmol, 10 eq.) DIC overnight at rt. The resin is washed three times with DMF, and alternately three times with methanol and dichloromethane.
Cleavage: the product is cleaved from the resin by treatment with 5 ml TFA/dichloromethane = 1 :1. The cleaving solution is concentrated. The crude product is purified by preparative FIPLC (MS detection).
LC-MS (method 1): R, = 1.70 min, m/z = 381 (M+H)+
1H-NMR (400 MHz, DMSOd6): δ = 7.80-6.95 (m, HH), 5.15-5.10 (d, 2H), 3.35-2.50 (m, 6H), 1.85 (m, IH), 1.75-0.40 (m, 12H).
Using an analogous procedure the following compounds are prepared starting from different diamines, aldehydes and acids:
Hydrochloric salts in examples 49-62 are prepared by treatment of the purified sample with 0.5 ml dichloromethane and a 0.5 M solution of hydrogen chloride in dioxane followed by evaporation of the solvent.
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
B. Evaluation of physiological activity
The potential Cold Menthol Receptor - 1 (CMR-I) antagonistic activity of the compounds of the invention may be demonstrated, for example, using the following assays:
Measurement of the menthol-induced Ca2+ influx in HEK293 Cell expressing CMR-I receptor (Assay 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 Ca2+ 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 .
Table A
Figure imgf000087_0001
Measurement of the menthol-induced Ca2+ influx in primary cultured rat dorsal root ganglia neurons (Assay 2)
Since 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. Preparation of primary cultured rat DRG neurons: 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 μM 5- fluorodeoxyuridine.
Measurement of Ca2+: 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 μM 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. The fluorescence change indicating mobilization of cytoplasmic Ca2+ is measured for 60 sec after the stimulation with 50 μM 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.
Measurement of the micturition frequency in guinea pigs in vivo (Assay 3)
Experiments are performed according to the principles of the national law for the protection of laboratory. Female Guinea Pigs (300-35Og) are anaesthetized with urethane (1 mg/kg i.p.). A midline abdominal incision is performed, both ureters are exposed and ligated, a catheter is implanted in the bladder pole and the abdomen is closed. For administration of the compounds the vena jugularis is exposed and canulated with a catheter. After this surgery the bladder catheter is connected via a t-shaped tube to an infusion pump (Braun Perfusor® compact) and to a pressure transducer (BioResearch Center, MLT0698, Nagoya). Saline is infused and intrabladder pressure is registered. After 1 h of equilibration period and the establishment of constant voiding cycles, menthol (0.6 mM) is added to the infused saline. At this point also vehicle (control group) or CMR-I inhibitors are administered i.v. as bolus injection. The effect of treatment on the micturition interval (corresponding to bladder capacity) and micturition pressure is calculated and compared between vehicle-treated and compound-treated groups. C. Operative examples relating to pharmaceutical compositions
The compounds according to the invention can be converted into pharmaceutical preparations as follows:
Tablet
Composition:
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.
Tablet weight 212 mg, diameter 8 mm, curvature radius 12 mm.
Preparation:
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.
Orally administrable suspension
Composition:
1000 mg of the compound of Example 1, 1000 mg of ethanol (96%), 400 mg of Rhodigel (xanthan gum from FMC, Pennsylvania, USA) and 99 g of water.
A single dose of 100 mg of the compound according to the invention is provided by 10 ml of oral suspension.
Preparation:
The 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:
Composition:
1 mg of the compound of Example 1 , 15 g of polyethylene glycol 400 and 250 g of water for injection.
Production:
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 μm) and dispensed under aseptic conditions into heat-sterilized infusion bottles. These are closed with infusion stoppers and crimped caps.

Claims

We claim
1. A compound of the general formula (I)
Figure imgf000091_0001
wherein
represents a group of the formula
Figure imgf000091_0002
wherein
* represents the linkage to the oxygen atom,
# represents the linkage to the carbonyl group,
R8 represents hydrogen, chlorine, fluorine, nitro, trifluoromethyl, trifluoromethoxy,
Figure imgf000091_0003
or Ci-C4-alkoxy,
and
R represents hydrogen or halogen,
R1 represents hydrogen, halogen, cyano, trifluoromethyl or Ci-G|-alkyl,
R represents hydrogen or halogen,
R3 represents hydrogen or halogen,
R4 represents hydrogen or d-C4-alkyl, R5 represents C3-C8-alkyl, C3-C8-alkenyl, C3-Ci0-cycloalkyl, C6-Ci0-aryl or 5- to 10- membered heteroaryl,
wherein alkyl can be further substituted with one radical selected from the group consisting of 5- to 10-membered heteroaryl,
and
wherein cycloalkyl can be further substituted with one to three identical or different radicals selected from the group consisting of C]-C4-alkyl,
and
wherein 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, trifluoromethoxy, trifluoromethylthio, C,-C6-alkyl, CrC6-alkoxy, CrC6-alkylthio, CpC6- alkylamino, phenoxy, benzyloxy, phenylthio, benzylthio, phenylcarbonyl, Ci-Cό-alkoxycarbonyl and optionally halogen substituted phenyl,
wherein phenoxy, benzyloxy, phenylthio and benzylthio can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, nitro, amino, hydroxy, trifluoromethyl, trifluoromethoxy, Ci-C6-alkyl, Ci-C6- alkoxy and Ci-C6-alkylamino,
R6 represents hydrogen or Ci-C4-alkyl,
R7 represents Ci-C6-alkyl,
wherein alkyl is further substituted with one radical selected from the group consisting of amino, mono-alkylamino, Ci-C4-alkylcarbonylamino or CpC4- alkoxycarbonylamino,
or one of its salts, hydrates and/or solvates.
2. A compound of general formula (I) according to Claim 1 , wherein
A represents a group of the formula
Figure imgf000093_0001
wherein
* represents the linkage to the oxygen atom,
# represents the linkage to the carbυnyl group,
R8 represents hydrogen, methoxy or ethoxy,
and
R9 represents hydrogen,
R1 represents hydrogen, halogen, cyano, trifluoromethyl or methyl,
R2 represents hydrogen or halogen,
R3 represents hydrogen,
R represents hydrogen,
R5 represents C3-C8-alkyl, C3-C7-cycloalkyl, Cβ-Cio-aryl or 5- to 10-membered heteroaryl,
wherein cycloalkyl can be further substituted with one to three identical or different radicals selected from the group consisting of Ci-C-t-alkyl,
and
wherein 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, trifluoromethoxy, trifluoromethylthio, C,-C6-alkyl, CrC6-alkoxy, Ci-C6-alkylthio, C,-C6- alkylamino, phenoxy, benzyloxy, phenylthio, benzylthio, CrC6- alkoxycarbonyl and optionally halogen substituted phenyl, wherein phenoxy, benzyloxy, phenylthio and benzylthio can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, nitro, amino, hydroxy, trifluoromethyl, trifluoromethoxy, Ci-C6-alkyI, CrC6- alkoxy and CrC6-alkylamino,
R6 represents hydrogen,
R7 represents Ci-C4-alkyl,
wherein alkyl is further substituted with one radical selected from the group consisting of amino or Ci-C4-alkoxycarbonylamino,
or one of its salts, hydrates and/or solvates.
A compound of general formula (I) according to Claim 1 or 2, wherein
A represents a group of the formula
Figure imgf000094_0001
wherein
represents the linkage to the oxygen atom,
represents the linkage to the carbonyl group,
R8 represents hydrogen,
and
R9 represents hydrogen,
R represents hydrogen, fluorine, chlorine, cyano, trifluoromethyl or methyl,
R represents hydrogen or fluorine, R3 represents hydrogen,
R4 represents hydrogen,
R5 represents C3-C6-alkyl, cyclohexyl, cyclopentyl, phenyl, naphthyl, pyridyl, pyrimidyl, thienyi or fUryl,
wherein phenyl, naphthyl, pyridyl, pyrimidyl, thienyi and furyl can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, Ci-C4-alkyl, methoxy, ethoxy, methylthio, ethylthio, phenoxy, benzyloxy, phenylthio, benzylthio, methoxycarbonyl and optionally halogen substituted phenyl,
wherein phenoxy, benzyloxy, phenylthio and benzylthio can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, nitro, trifluoromethyl, trifluoromethoxy, Ci-C4-alkyl, methoxy and ethoxy,
R6 represents hydrogen,
R7 represents Ci-C2-alkyl,
wherein alkyl is further substituted with one radical selected from the group consisting of amino or tert-butoxycarbonylamino,
or one of its salts, hydrates and/or solvates.
4. Process for synthesizing a compound of general formula (I) according to Claim 1 , by
[A] condensing a compound of general formula (II)
Figure imgf000095_0001
wherein R4, R5, R6 and R7 have the meaning indicated in Claim 1, with a compound of general formula (III)
Figure imgf000096_0001
wherein A, R1, R2 and R3 have the meaning indicated in Claim 1 ,
in the presence of a base
or
[B] condensing a compound of general formula (FV)
Figure imgf000096_0002
wherein A, R4, R5, R6 and R7 have the meaning indicated in Claim 1,
with a compound of general formula (V)
Figure imgf000096_0003
wherein R1, R2 and R3 have the meaning indicated in Claim 1, and
X1 represents a leaving group, such as halogen, preferably chlorine or bromine
in the presence of a base.
5. A compound of general formula (I) according to Claim 1, 2 or 3 for the treatment of diseases or disorders.
6. Use of a compound of general formula (I) according to Claim 1, 2 or 3 for the preparation of medicaments.
7. Use according to Claim 6 for the preparation of medicaments for the treatment of urological diseases or disorders.
8. The composition containing at least one compound of general formula (I) according to Claim 1, 2 or 3 and a pharmacologically acceptable diluent.
9. A composition according to Claim 8 for the treatment of urological diseases or disorders.
10. The process for the preparation of compositions according to Claim 8 and 9 characterized in that the compounds of general formula (I) according to Claim 1 , 2 or 3 together with customary auxiliaries are brought into a suitable application form.
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