WO2007139464A1 - Dérivés d'isoindole utilisés pour traiter la douleur, les maladies du tube digestif et le cancer - Google Patents

Dérivés d'isoindole utilisés pour traiter la douleur, les maladies du tube digestif et le cancer Download PDF

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Publication number
WO2007139464A1
WO2007139464A1 PCT/SE2007/000503 SE2007000503W WO2007139464A1 WO 2007139464 A1 WO2007139464 A1 WO 2007139464A1 SE 2007000503 W SE2007000503 W SE 2007000503W WO 2007139464 A1 WO2007139464 A1 WO 2007139464A1
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alkyl
alkoxy
oxo
amino
halogenated
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PCT/SE2007/000503
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Yun-Xing Cheng
Miroslaw Tomaszewski
Hua Yang
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Astrazeneca Ab
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Priority to EP07748167A priority Critical patent/EP2029535A1/fr
Priority to JP2009511980A priority patent/JP2009538296A/ja
Publication of WO2007139464A1 publication Critical patent/WO2007139464A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • Isoindole derivatives useful for treating pain, gastrointestinal diseases and cancer are useful for treating pain, gastrointestinal diseases and cancer.
  • the invention is related to therapeutic compounds, pharmaceutical compositions containing these compounds, manufacturing processes thereof and uses thereof. Particularly, the present invention is related to compounds that may be effective in treating pain, cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, anxiety disorders, gastrointestinal disorders and/or cardiovascular disorders. 2. Discussion of Relevant Technology
  • Pain management has been an important field of study for many years. It has been well known that cannabinoid receptor (e.g., CBi receptor, CB 2 receptor) ligands including agonists, antagonists and inverse agonists produce relief of pain in a variety of animal models by interacting with CBi and/or CB 2 receptors.
  • cannabinoid receptor e.g., CBi receptor, CB 2 receptor
  • CBi receptors are located predominately in the central nervous system
  • CB 2 receptors are located primarily in the periphery and are primarily restricted to the cells and tissues derived from the immune system.
  • CBi receptor agonists such as ⁇ 9 -tetrahydrocannabinol ( ⁇ 9 -THC) and anadamide
  • CNS side effects e.g., psychoactive side effects, the abuse potential, drug dependence and tolerance, etc.
  • CBi receptors located in CNS There are lines of evidence, however, suggesting that CBl agonists acting at peripheral sites or with limited CNS exposure can manage pain in humans or animals with much improved overall in vivo profile. Therefore, there is a need for new CBi receptor ligands such as agonists that may be useful in managing pain or treating other related symptoms or diseases with reduced or minimal undesirable CNS side effects.
  • the present invention provides CBi receptor ligands which may be useful in treating pain and/or other related symptoms or diseases.
  • C m-n or "C m-n group” used alone or as a prefix, refers to any group having m to n carbon atoms.
  • hydrocarbon used alone or as a suffix or prefix, refers to any structure comprising only carbon and hydrogen atoms up to 14 carbon atoms.
  • hydrocarbon radical or “hydrocarbyl” used alone or as a suffix or prefix, refers to any structure as a result of removing one or more hydrogens from a hydrocarbon
  • alkyl used alone or as a suffix or prefix, refers to a saturated monovalent straight or branched chain hydrocarbon radical comprising 1 to about 12 carbon atoms.
  • alkyls include, but are not limited to, C 1-6 alkyl groups, such as methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3-methyl-l -butyl, 2-methyl-3-butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3-methyl-l- pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2- dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl, and longer alkyl groups, such as
  • alkylene used alone or as suffix or prefix, refers to divalent straight or branched chain hydrocarbon radicals comprising 1 to about 12 carbon atoms, which serves to links two structures together.
  • alkenyl used alone or as suffix or prefix, refers to a monovalent straight or branched chain hydrocarbon radical having at least one carbon-carbon double bond and comprising at least 2 up to about 12 carbon atoms.
  • the double bond of an alkenyl can be unconjugated or conjugated to another unsaturated group.
  • Suitable alkenyl groups include, but are not limited to C ⁇ - ⁇ alkenyl groups, such as vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2-methyl-3- butene)-pentenyl.
  • An alkenyl can be unsubstituted or substituted with one or two suitable substituents.
  • alkynyl used alone or as suffix or prefix, refers to a monovalent straight or branched chain hydrocarbon radical having at least one carbon-carbon triple bond and comprising at least 2 up to about 12 carbon atoms.
  • the triple bond of an alkynyl group can be unconjugated or conjugated to another unsaturated group.
  • Suitable alkynyl groups include, but are not limited to, C 2 - 6 alkynyl groups, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-l -butynyl, 4-propyl-2-pentynyl, and 4-butyl- 2-hexynyl.
  • An alkynyl can be unsubstituted or substituted with one or two suitable substituents.
  • cycloalkyl refers to a saturated monovalent ring-containing hydrocarbon radical comprising at least 3 up to about 12 carbon atoms.
  • cycloalkyls include, but are not limited to, Cs ⁇ cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and saturated cyclic and bicyclic terpenes.
  • a cycloalkyl can be unsubstituted or substituted by one or two suitable substituents.
  • the cycloalkyl is a monocyclic ring or bicyclic ring.
  • cycloalkenyl used alone or as suffix or prefix, refers to a monovalent ring-containing hydrocarbon radical having at least one carbon-carbon double bond and comprising at least 3 up to about 12 carbon atoms.
  • cycloalkynyl used alone or as suffix or prefix, refers to a monovalent ring-containing hydrocarbon radical having at least one carbon-carbon triple bond and comprising about 7 up to about 12 carbon atoms.
  • aryl used alone or as suffix or prefix, refers to a monovalent hydrocarbon radical having one or more polyunsaturated carbon rings having aromatic character, (e.g., 4n + 2 delocalized electrons) and comprising 5 up to about 14 carbon atoms.
  • arylene used alone or as suffix or prefix, refers to a divalent hydrocarbon radical having one or more polyunsaturated carbon rings having aromatic character, ⁇ e.g., 4n + 2 delocalized electrons) and comprising 5 up to about 14 carbon atoms, which serves to link two structures together.
  • heterocycle used alone or as a suffix or prefix, refers to a ring-containing structure or molecule having one or more multivalent heteroatoms, independently selected from N, O, P and S, as a part of the ring structure and including at least 3 and up to about 20 atoms in the ring(s).
  • Heterocycle may be saturated or unsaturated, containing one or more double bonds, and heterocycle may contain more than one ring. When a heterocycle contains more than one ring, the rings may be fused or tmfused. Fused rings generally refer to at least two rings share two atoms therebetween. Heterocycle may have aromatic character or may not have aromatic character.
  • heteromatic used alone or as a suffix or prefix, refers to a ring- containing structure or molecule having one or more multivalent heteroatoms, independently selected from N, O, P and S, as a part of the ring structure and including at least 3 and up to about 20 atoms in the ring(s), wherein the ring-containing structure or molecule has an aromatic character (e.g., 4n + 2 delocalized electrons).
  • heterocyclic group refers to a radical derived from a heterocycle by removing one or more hydrogens thereftom.
  • heterocyclyl used alone or as a suffix or prefix, refers a monovalent radical derived from a heterocycle by removing one hydrogen therefrom.
  • heterocyclylene used alone or as a suffix or prefix, refers to a divalent radical derived from a heterocycle by removing two hydrogens therefrom, which serves to links two structures together.
  • five-membered used as prefix refers to a group having a ring that contains five ring atoms.
  • a five-membered ring heteroaryl is a heteroaryl with a ring having five ring atoms ⁇ wherein 1, 2 or 3 ring atoms are independently selected from N, O and S.
  • Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3- thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4- triazolyl, 1,3,4-thiadiazolyl, and 1,3,4- oxadiazolyl.
  • a six-membered ring heteroaryl is a heteroaryl with a ring having six ring atoms wherein 1, 2 or 3 ring atoms are independently selected from N, O and S.
  • heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.
  • heteroaryl used alone or as a suffix or prefix, refers to a heterocyclyl having aromatic character.
  • heterocycloalkyl used alone or as a suffix or prefix, refers to a monocyclic or polycyclic ring comprising carbon and hydrogen atoms and at least one heteroatom, preferably, 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and having no unsaturation.
  • heterocycloalkyl groups include pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, and pyranyl.
  • a heterocycloalkyl group can be unsubstituted or substituted with one or two suitable substituents.
  • the heterocycloalkyl group is a monocyclic or bicyclic ring, more preferably, a monocyclic ring, wherein the ring comprises from 3 to 6 carbon atoms and form 1 to 3 heteroatoms, referred to herein as C 3-6 heterocycloalkyl.
  • Heterocycle includes, for example, monocyclic heterocycles such as: aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazol ne, dioxolane, sulfolane 2,3-dihydrofuran, 2,5-dihydrofuran tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydro-pyridine, piperazine, morpholine, thiomorpholine, pyran, thiopyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dihydropyridine, 1,4-dioxane, 1,3-dioxane, dioxane, homopiperidine, 2,3,4,7-tetrahydro-lH-azepine homopipe
  • heterocycle includes aromatic heterocycles, for example, pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, furazan, pyrrole, imidazole, thiazole, oxazole, pyrazole, isothiazole, isoxazole, 1,2,3-triazoIe, tetrazole, 1,2,3-thiadiazole, 1,2,3- oxadiazole, 1,2,4-triazole, 1,2,4-thiadiazole, 1,2,4-oxadiazole, 1,3,4-triazole, 1,3,4- thiadiazole, and 1,3,4- oxadiazole.
  • aromatic heterocycles for example, pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, furazan, pyrrole, imidazole, thiazole, oxazole, pyrazole, isothiazole
  • heterocycle encompass polycyclic heterocycles, for example, indole, indoline, isoindoline, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, 1,4-benzodioxan, coumarin, dihydrocoumarin, benzofuran, 2,3-dihydrobenzofuran, isobenzofuran, chromene, chroman, isochroman, xanthene, phenoxathiin, thianthrene, indolizine, isoindole, indazole, purine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, phenanthridine, perimidine, phenanthroline, phenazine, phenothiazine, phenoxazi ⁇ e, 1,2-benzisoxazole, benzothiophene, benzoxazo
  • heterocycle includes polycyclic heterocycles wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings.
  • bridged heterocycles include quinuclidine, diazabicyclo[2.2.1]heptane and 7-oxabicyclo[2.2.1]heptane.
  • Heterocyclyl includes, for example, monocyclic heterocyclyls, such as: aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyi, imidazolidinyl, pyrazolidinyl, pyrazolinyl, dioxolanyl, sulfolanyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, tetrahydrofuranyl, thiophanyl, piperidinyl, 1,2,3,6-tetrahydro-pyridinyl, piperazinyl, morpholinyl, thiomo ⁇ holinyl, pyranyl, thiopyranyl, 2,3-dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridinyl, 1,4
  • heterocyclyl includes aromatic heterocyclyls or heteroaryl, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, furazanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3- thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4- triazolyl, 1,3,4-thiadiazolyl, and 1,3,4 oxadiazolyl.
  • heterocyclyl encompasses polycyclic heterocyclyls (including both aromatic or non-aromatic), for example, indolyl, indolinyl, isoindolinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, 1,4-benzodioxanyl, coumarinyl, dihydrocoumarinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, isobenzofuranyl, chromenyl, chromanyl, isochromanyl, xanthenyl, phenoxathiinyl, thianthrenyl, indolizinyl, isoindolyl, indazolyl, purinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteri
  • heterocyclyl includes polycyclic heterocyclyls wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings.
  • bridged heterocycles include quinuclidinyl, diazabicyclo[2.2.1]heptyl; and 7-oxabicyclo[2.2.1]heptyl.
  • alkoxy used alone or as a suffix or prefix, refers to radicals of the general formula -O-R, wherein R is selected from a hydrocarbon radical.
  • exemplary alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, cyclopropylmethoxy, allyloxy, and propargyloxy.
  • amine or “amino” refers to -NH 2 .
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • Halogenated used as a prefix of a group, means one or more hydrogens on the group are replaced with one or more halogens.
  • RT room temperature
  • DMF dimethyl formamide
  • DIPEA N,N-diisopropylethylamine
  • HATU refers to 2-(7-Aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate.
  • One aspect of the invention is a compound of formula I, a pharmaceutically acceptable salt thereof, a diastereomer, an enantiomer, or a mixture thereof:
  • R 2 is selected from
  • said group used in defining R ⁇ is optionally substituted by one or more groups selected from halogen, halogenated C 1-6 alkyl, C 1-6 alkyl, halogenated C 1-6 alkoxy, cyano, nitro, C 1-6 alkoxy, hydroxy, hydroxy-C 1-6 alkyl, amino, C 1-6 alkyl-C 6-10 aryl, C 1-6 alkoxy-Ci. ealkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylamino, di-C 1-6 alkylamino, di-Cj.
  • R 3 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, C ⁇ cycloalkenyl, C 1 . ⁇ alkoxy, and C 2-5 heterocycloalkyl; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, C 4- ecycloalkenyl, C 1-6 alkoxy, and C 2-5 heterocycloalkyl used in defining R 3 is optionally substituted by one or more groups selected from halogen, halogenated C h alky!, C 1-6 alkyl, halogenated C 1-6 alkoxy, cyano, nitro, C ⁇ galkoxy, hydroxy, hydroxy-C 1-6 alkyl, amino, Q.
  • alkyl-C ⁇ -ioaryl C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, Ci- 6alkylamino, di-Ci -e alkylamino, di-C 1-6 alkylammo-C 1-6 alkyL, amino-C 1-6 alkyl, d- ⁇ alkyl- arnino-carbonyl, C 2-5 heteroaryl-carbonyl, C 2-5 heterocycloalkyl-carbonyl, C ⁇ -ioarylcarbonyl, C 2-5 heterocycloalkyl, Cs ⁇ cycloalkyl, C3-6cycloalkyl-Ci -6 alkyl, C 2-5 heteroaryl, C 2- sheteroaryl-C 1-6 alkyl, C 6-10 aryl, and C 6 -ioaryl-C 1-6 alkyl;
  • R 4 is selected from Ci -6 alkyl, halogenated C 1-6 alkyl, hydroxy, hydroxy-Cj. ⁇ alkylamino, amino, C 1-6 alkoxy, C 1-6 alkylamino, di-C 1-6 alkylamino, hydroxyamino, Q. 6 alkoxyamino, benzylamino, C 2-5 heterocycloalkyl, C 2-5 heteroaryl, and C 2-5 heteroaryl-Q. ⁇ alkyl;
  • R 1 is selected from hydrogen, methoxy, 2- hydroxyethoxy, benzyloxy, acetoxy and acetylamino.
  • R 1 is selected from ethylsulfonyloxy, and 3- trifluoropropylsulfonyloxy.
  • R 4 is selected from hydroxy, methoxy, amino, methylamino, dimethylamino, hydroxyamino, methoxyamino, beirzylamino, morpholinyl, 2-hydroxyethylamino, and pyridinylmethyl.
  • certain compounds of the present invention are those of fo ⁇ nula I as defined above, wherein R 1 is independently selected from hydrogen, halogen, hydroxyl, C 1-6 alkoxy, C 1 . ⁇ alkyl, halogenated C 1-6 alkoxy, halogenated Q.galkyl, amino, and C 1-6 alkylamino and di-Q. ⁇ alkylamino;
  • R 2 is selected from
  • R 2 wherein said group used in defining R 2 is optionally substituted by one or more groups selected from halogen, halogenated C h alky!, C h alky!, halogenated C 1-6 aUcoxy, cyano, nitro, C 1-6 alkoxy, hydroxy, hydroxy-C 1-6 alkyl, amino, C 1-6 alkyl-C 6-10 aryl, C 1-6 alkoxy-Ci. ⁇ alkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylair ⁇ io, di-C 1-6 alkylamino, di-Ci.
  • R 3 is selected from C 1-6 alkyl, C 2-6 alkenyl, C3.6cycloalkyl, C ⁇ cycloalkenyl, Q. ⁇ alkoxy, and C 2-5 heterocycloalkyl; wherein said C 1-6 alkyl, C 2 - 6 alkenyl, C 3-6 cycloalkyl, C 4 .
  • ⁇ cycloalkenyl, C 1-6 alkoxy, and C 2-5 heterocycloalkyl used in defining R 3 is optionally substituted by one or more groups selected from halogen, halogenated C ⁇ aHcyl, C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1-6 alkoxy, hydroxy, hydroxy-C 1-6 alkyl, amino, C 1-6 alkoxy-Ci. ealkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylamino, and di-C 1-6 alkylamino;
  • R 1 is hydrogen
  • R 2 is selected from
  • said group used in defining R is optionally substituted by one or more groups selected from halogen, halogenated C 1-6 alkyl, C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1-6 alkoxy, hydroxy, hydroxy-C 1-6 alkyl, amino, C 1-6 alkoxy-C 1-6 alkyl, C 2- sheteroaryl-Ci-6alkyl, Ci- 6 alkylamino, di-C 1-6 alkylamino, di-C 1-6 alkylamino-Ci-salkyl;
  • R 3 is selected from C h alky!, C2. ⁇ alkenyl, Ca- ⁇ cycloalkyl, piperidinyl, morpholinyl, tetrahydrofuranyl and tetrahydropyranyl; wherein said C h alky!, C 2-6 alkenyl, C3.
  • 6 cycloalkyl ; piperdinyl, morpholinyl, and tetrahydropyranyl used in defining R 3 is optionally substituted by one or more groups selected from halogen, halogenated C h alky!, d- ⁇ alkyl, halogenated C 1-6 alkoxy, Ci -6 alkoxy, hydroxy, hydroxy-C 1-6 alkyI, amino, C 1-6 alkoxy-C 1-6 alkyl, Ci- galkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylamino, and di-C 1-6 alkylamino;
  • R 1 is hydrogen
  • R 2 is selected from
  • R 2 is optionally substituted by one or more groups selected from halogen, methyl, ethyl, methoxy, methoxymethyl, benzyloxy, dimethylamino, hydroxy, and triazolylmethyl.
  • R 2 is selected from cyclohexyl, phenyl and naphtbyl, wherein said cyclohexyl, phenyl and naphthyl are optionally substituted by one or more groups selected from halogen, methyl, ethyl, methoxy, methoxymethyl, benzyloxy, dimethylamino, hydroxy, and triazolylmethyl.
  • R 2 is selected from cyclohexyl, phenyl and 1- naphthyl, wherein said cyclohexyl, phenyl and 1 -naphthyl are optionally substituted by one or more groups selected from halogen, methyl, ethyl, methoxy, methoxymethyl, benzyloxy, dimethylamino, hydroxy, and triazolylmethyl.
  • R 2 is selected from phenyl and 1 -naphthyl, wherein said phenyl and 1 -naphthyl are optionally substituted by one or more groups selected from halogen, methyl, ethyl, methoxy, methoxymethyl, benzyloxy, dimethylamino, hydroxy, and triazolylmethyl.
  • R 3 is selected from C 1-6 alkyl, C 2-6 alkenyl, Cs-gcycloalkyl and C 2- 5heterocycIoalkyl, wherein said Q-ealkyl, C 2 - 6 alkenyl, C3- 6 cycloalkyl and C 2- 5 heterocycloalkyl are optionally substituted by one or more groups selected from halogen, halogenated Q.ealkyl, C h alky!, t-butoxycarbonyl, amino, C 1-6 alkoxy-C 1-6 alkyl, Ci. ⁇ alkylamino, and di-C 1-6 alkylamino with a proviso that R 3 is not an optionally substituted 2,6-dioxopiperidi ⁇ -3-yl.
  • R 3 is. selected from Q.ealkyl, C 2 - 6 alkenyl, Cs-gcycloalkyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrrolidinyl, wherein said C 1-6 alkyl, C 2- 6alkenyl, Ca- ⁇ cycloalkyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrrolidinyl are optionally substituted by one or more groups selected from halogen, halogenated C 1-6 alkyl, C ⁇ aUcyl, t-butoxycarbonyl, amino, Cj- ⁇ alkoxy-C 1-6 alkyl, Ci -5 alkylamino, and di-C 1-6 alkylamino.
  • R 3 is selected from C 3-6 cycloalkyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrrolidinyl, wherein said C 3 .. ⁇ cycloalkyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrrolidinyl are optionally substituted by one or more groups selected from halogen, halogenated Q- ealkyl, C 1-6 alkyl, t-butoxycarbonyl, amino, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkylamino, and di-Ci. galkylamino.
  • the compounds of the invention may exist in, and be isolated as, enantiomeric or diastereomeric forms, or as a racemic mixture.
  • the present invention includes any possible enantiomers, diastereomers, racemates or mixtures thereof, of a compound of Formula I.
  • the optically active forms of the compound of the invention may be prepared, for example, by chiral chromatographic separation of a racemate, by synthesis from optically active starting materials or by asymmetric synthesis based on the procedures described thereafter.
  • certain compounds of the present invention may exist as geometrical isomers, for example E and Z isomers of alkenes.
  • the present invention includes any geometrical isomer of a compound of Formula I. It will further be understood that the present invention encompasses tautomers of the compounds of the formula I.
  • salts of the compounds of the formula I are also salts of the compounds of the formula I.
  • pharmaceutically acceptable salts of compounds of the present invention may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound, for example an alkyl amine with a suitable acid, for example, HCI or acetic acid, to afford a physiologically acceptable anion.
  • a corresponding alkali metal such as sodium, potassium, or lithium
  • an alkaline earth metal such as a calcium
  • a compound of the present invention having a suitably acidic proton, such as a carboxylic acid or a phenol with one equivalent of an alkali metal or alkaline earth metal hydroxide or alkoxide (such as the ethoxide or methoxide), or a suitably basic organic amine (such as choline or meglumine) in an aqueous medium, followed by conventional purification techniques.
  • a suitably acidic proton such as a carboxylic acid or a phenol
  • an alkali metal or alkaline earth metal hydroxide or alkoxide such as the ethoxide or methoxide
  • a suitably basic organic amine such as choline or meglumine
  • the compound of formula I above may be converted to a pharmaceutically acceptable salt or solvate thereof, particularly, an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate or p-toluenesulphonate.
  • an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate or p-toluenesulphonate.
  • the compounds of the invention exhibit activity as agonist of the CBi receptors and are useful in therapy, especially for relief of various pain conditions such as chronic pain, neuropathic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain etc. This list should however not be interpreted as exhaustive. Additionally, compounds of the present invention are useful in other disease states in which dysfunction of CBi receptors is present or implicated. Furthermore, the compounds of the invention may be used to treat cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, anxiety disorders, gastrointestinal disorders and cardiavascular disorders.
  • Compounds of the invention are useful as immunomodulators, especially for autoimmune diseases, such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases, various allergies, for use as anti-tumour agents and anti viral agents.
  • Compounds of the invention are useful in disease states where degeneration or dysfunction of cannabinoid receptors is present or implicated in that paradigm. This may involve the use of isotopically labeled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET).
  • PET positron emission tomography
  • Compounds of the invention are useful for the treatment of diarrhea, depression, anxiety and stress-related disorders such as post-traumatic stress disorders, panic disorder, generalized anxiety disorder, social phobia, and obsessive compulsive disorder, urinary incontinence, premature ejaculation, various mental illnesses, cough, lung edema, various gastro-intestinal disorders, e.g. constipation, functional gastrointestinal disorders such as Irritable Bowel Syndrome and Functional Dyspepsia, Parkinson's disease and other motor disorders, traumatic brain injury, stroke, cardioprotection following miocardial infarction, spinal injury and drug addiction, including the treatment of alcohol, nicotine, opioid and other drug abuse and for disorders of the sympathetic nervous system for example hypertension.
  • stress-related disorders such as post-traumatic stress disorders, panic disorder, generalized anxiety disorder, social phobia, and obsessive compulsive disorder, urinary incontinence, premature ejaculation, various mental illnesses, cough, lung edema, various gastro-intestinal disorders, e
  • Compounds of the invention are useful as an analgesic agent for use during general anaesthesia and monitored anaesthesia care.
  • Combinations of agents with different properties are often used to achieve a balance of effects needed to maintain the anesthetic state (e.g. amnesia, analgesia, muscle relaxation and sedation). Included in this combination are inhaled anesthetics, hypnotics, anxiolytics, neuromuscular blockers and opioids.
  • Another aspect of the present invention is the use of a compound according to Formula I, for the inhibition of transient lower esophageal sphincter relaxations (TLESRs) and thus for treatment or prevention of gastroesophageal reflux disorder (GERD).
  • TLESRs transient lower esophageal sphincter relaxations
  • GERD gastroesophageal reflux disorder
  • the major mechanism behind reflux has been considered to depend on a hypotonic lower esophageal sphincter.
  • TLESRs transient lower esophageal sphincter relaxations
  • the compound according to Formula I are useful for the prevention of reflux, treatment or prevention of regurgitation, treatment or prevention of asthma, treatment or prevention of laryngitis, treatment or prevention of lung disease and for the management of failure to thrive.
  • a further aspect of the present invention is the use of a compound according to Formula I, for the manufacture of a medicament for the inhibition of transient lower esophageal sphincter relaxations, for the treatment or prevention of GERD, for the prevention of reflux, for the treatment or prevention of regurgitation, treatment or prevention of asthma, treatment or prevention of laryngitis, treatment or prevention of lung disease and for the management of failure to thrive.
  • Still another aspect of the present invention is the use of a compound according to Formula I, for the manufacture of a medicament for the inhibition of transient lower esophageal sphincter relaxations, for the treatment or prevention of GERD, for the prevention of reflux, for the treatment or prevention of regurgitation, treatment or prevention of asthma, treatment or prevention of laryngitis, treatment or prevention of lung disease and for the management of failure to thrive.
  • Still another aspect of the present invention is the use of a compound according to Formula I, for the manufacture of a medicament for the inhibition of transient lower esophageal sphin
  • Formula I for the manufacture of a medicament for the treatment or prevention of functional gastrointestinal disorders such as functional dyspepsia (FD).
  • a compound according to Formula I for the manufacture of a medicament for the treatment or prevention of irritable bowel syndrome (IBS) such as constipation predominant IBS, diarrhea predominant IBS or alternating bowel movement predominant IBS.
  • IBS irritable bowel syndrome
  • FGD functional gastrointestinal disorders
  • a further aspect of the invention is a method for the treatment of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the formula I above, is administered to a patient in need of such treatment.
  • the invention provides a compound of formula I, or pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.
  • the present invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
  • therapy also includes “prophylaxis” unless there are specific indications to the contrary.
  • therapeutic and
  • terapéuticaally should be construed accordingly.
  • the term "therapy” within the context of the present invention further encompasses to administer an effective amount of a compound of the present invention, to mitigate either a pre-existing disease state, acute or chronic, or a recurring condition.
  • This definition also encompasses prophylactic therapies for prevention of recurring conditions and continued therapy for chronic disorders.
  • the compounds of the present invention are useful in therapy, especially for the therapy of various pain conditions including, but not limited to: acute pain, chronic pain, neuropathic pain, back pain, cancer pain, and visceral pain.
  • the compound of the invention may be administered in the form of a conventional pharmaceutical composition by any route including orally, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints.
  • the route of administration may be oral, intravenous or intramuscular.
  • the dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level at the most appropriate for a particular patient.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • a solid carrier can be one or more substance, which may also act as diluents, flavoring agents, sohibilizers, lubricants, suspending agents, binders, or tablet-disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid, which is in a mixture with the finely divided compound of the invention, or the active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture in then poured into convenient sized molds and allowed to cool and solidify.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low- melting wax, cocoa butter, and the like.
  • composition is also intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it. Similarly, cachets are included.
  • Liquid form compositions include solutions, suspensions, and emulsions.
  • sterile water or water propylene glycol solutions of the active compounds may be liquid preparations suitable for parenteral administration.
  • Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired.
  • Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
  • a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
  • the pharmaceutical composition will preferably include from 0.05% to 99%w (percent by weight), more preferably from 0.10 to 50%w, of the compound of the invention, all percentages by weight being based on total composition.
  • a therapeutically effective amount for the practice of the present invention may be determined, by the use of known criteria including the age, weight and response of the individual patient, and interpreted within the context of the disease which is being treated or which is being prevented, by one of ordinary skills in the art.
  • any compound according to Formula I for the manufacture of a medicament for the therapy of various pain conditions including, but not limited to: acute pain, chronic pain, neuropathic pain, back pain, cancer pain, and visceral pain.
  • a further aspect of the invention is a method for therapy of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the formula I above, is administered to a patient in need of such therapy.
  • a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier for therapy, more particularly for therapy of pain.
  • composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier use in any of the conditions discussed above.
  • Another aspect of the invention is a method of preparing the compounds of the present invention.
  • the method of the invention is a method for preparing a compound of formula I,
  • R 2 -X-Y optionally in the presence of a base, such as diisopropylethylamine, a solvent such as dichloromethane, wherein Y is selected from Cl, Br, F, and OH; and X, R 1 , R 2 and R 3 are defined as above.
  • a base such as diisopropylethylamine
  • a solvent such as dichloromethane
  • Methyl-2-bromoethyl-6-nitro-benzoate (1 equiv.) and the corresponding primary amine (1.8 equiv.) are dissolved in a minimum amount of DMF.
  • Diisopropyl ethylamine (2 equiv.) is added and the mixture is heated at 80°C overnight. Volatiles are evaporated under vacuum, leaving 2-alkyl-7-nitroisoindolin-l-one as a yellow oil (used without further purification). Reactions are performed on 0.5 to 15 mmol scale.
  • 2-Alkyl-7-nitroisoindolin-l-one (-0.5 mmol) is dissolved in 20 ml of methanol. FeClj. ⁇ HaO (200 mg) is added and the mixture is heated to 65°C. Hydrazine hydrate (0.6 ml) is added dropwise. Heating is continued for 15h. After cooling to rt, the mixture is diluted with diethylether (80 ml) and filtered over Celite. Evaporation of solvents leaves an intermediate (2-(alkyl)isoindolin-4-amine) as white to yellow solids. The intermediate is used without further purification.
  • Human CBi receptor from Receptor Biology (hCBi) or human CB 2 receptor from BioSignal (I1CB2) membranes are thawed at 37 °C, passed 3 times through a 25-gauge blunt-end needle, diluted in the cannabinoid binding buffer (50 mM Tris, 2.5 mM EDTA, 5 mM MgCl 2 , and 0.5 mg/mL BSA fatty acid free, pH 7.4) and aliquots containing the appropriate amount of protein are distributed into 96-well plates.
  • cannabinoid binding buffer 50 mM Tris, 2.5 mM EDTA, 5 mM MgCl 2 , and 0.5 mg/mL BSA fatty acid free, pH 7.4
  • the IC 50 of the compounds of the invention at hCBi and I1CB 2 are evaluated from 10-point dose-response curves done with 3 H-CP55,940 at 20000 to 25000 dpm per well (0.17-0.21 nM) in a final volume of 300 ⁇ l.
  • the total and non-specific binding are determined in the absence and presence of 0.2 ⁇ M of HU210 respectively.
  • the plates are vortexed and incubated for 60 minutes at room temperature, filtered through Unifilters GFfB (presoaked in 0.1% polyethyleneimine) with the Tomtec or Packard harvester using 3 mL of wash buffer (50 mM Tris, 5 mM MgCl 2 , 0.5 mg BSA pH 7.0).
  • the filters are dried for 1 hour at 55 0 C.
  • the radioactivity (cpm) is counted in a TopCount (Packard) after adding 65 ⁇ l/well of MS-20 scintillation liquid.
  • Human CBi receptor from Receptor Biology (hCBi) or human CB 2 receptor membranes (BioSignal) are thawed at 37 0 C, passed 3 times through a 25-gauge blunt-end needle and diluted in the GTP ⁇ S binding buffer (50 mM Hepes, 20 mM NaOH, 100 mM NaCl, 1 mM EDTA, 5 mM MgCl 2 , pH 7.4, 0.1% BSA).
  • the EC 50 and E max of the compounds of the invention are evaluated from 10-point dose-response curves done in 300 ⁇ l with the appropriate amount of membrane protein and 100000-130000 dpm of GTPg 35 S per well (0.11 -0.14 nM).
  • the basal and maximal stimulated binding is determined in absence and presence of 1 ⁇ M (hCB 2 ) or 10 ⁇ M (hCBi) Win 55,212-2 respectively.
  • the membranes are pre-incubated for 5 minutes with 56.25 ⁇ M (hCB2) or 112.5 ⁇ M (hCBi) GDP prior to distribution in plates (15 ⁇ M (hCB 2 ) or 30 ⁇ M (hCBi) GDP final).
  • the plates are vortexed and incubated for 60 minutes at room temperature, filtered on Unifilters GF/B (presoaked in water) with the Tomtec or Packard harvester using 3 ml of wash buffer (50 mM Tris, 5 mM MgCl 2 , 50 mM NaCl, pH 7.0). The filters are dried for 1 hour at 55 0 C. The radioactivity (cpm) is counted in a TopCount (Packard) after adding 65 ⁇ l/well of MS-20 scintillation liquid.
  • wash buffer 50 mM Tris, 5 mM MgCl 2 , 50 mM NaCl, pH 7.0.
  • Antagonist reversal studies are done in the same way except that (a) an agonist dose-response curve is done in the presence of a constant concentration of antagonist, or (b) an antagonist dose-response curve is done in the presence of a constant concentration of agonist.
  • Kd is the dissociation constant of the radioactive ligand towards the particular receptor.
  • Certain compounds of the invention's activities towards certain human CBl receptors are tested using the above-mentioned assays and are found to be active.
  • Step B The preparation of 7-amino-2-(cyclobutylmethyl)isoindolin-l-one
  • Step C The preparation of N-[2-(cyclobutylmethyl)-3-oxo-2,3-dihydro-lH-isoindol-4-yl]- 1-naphthamide
  • Step A The preparation of 2-allyl-7-nitroisoindoIin- 1 -one
  • Step B 2-allyl-7-nitroisoindolin-l-one (206 mg, 0.944 mmol) was reduced with Zinc (300 mg) in HOAc (5 ml) and MeOH (5 ml). The crude product was used without purification.
  • Step C The preparation of N-(2-allyl-3-oxo-2,3-dihydro-lH-isoindol-4-yl)-l-naphthamide
  • Step A The preparation of 7-nitro-2-propylisoi ⁇ dolin-l-one
  • Step B The preparation of 2-propyl-7-aminoisoindoIi ⁇ -l-one
  • 2-Propyl-7-aminoisoindolin-l-one was prepared from 7-nitro-2-propylisoindolin-l-one following General Procedure B. MS (M+l):191, 78% purity (UV detection at 254 nm).
  • Step C The preparation of N-(2-propyl-3-oxo-2,3-dihydro-lH-isoindol-4-yl)-l- naphthamide
  • N-(2-propyl-3-oxo-2,3-dihydro-lH-isoindol-4-yl)-l-naphthamide (25.6 mg, 74% yield in 3 steps) as white solid was prepared .from 2-propyl-7-aminoisoindolin-l-one and 1-naphthoyl chloride following General Procedure C. MS (M+l): 345.
  • Step A The preparation of 7-nitro-2-butyl-isoindolin-l-one
  • Step B The preparation of 2-butyl-7-aminoisoindoKn-l-one
  • Step C The preparation of N-(2-butyl-3-oxo-2,3-dihydro-lH-isoi ⁇ dol-4-yl)-l-naphthamide
  • N-(2-buryl-3-oxo-2 3 3-diliydro-lH-isoindol-4-yl)-l-naphthamide (18.1 mg, 50% yield in 3 steps) as white solid was prepared from 2-butyl-7-aminoisoindolin-l-one and 1-naphthoyl chloride following General Procedure C. MS (M+l): 359 (M+l).
  • Step A The preparation of 2-[2-(dirnethylarnino)ethyl]-7-mtroisoindolin-l-one
  • Step B The preparation of 7-amino-2-[2-(dimethylar ⁇ ino)ethyl]isoindolm-l-one
  • Step C The preparation ofN- ⁇ 2-[2-(dimethylamino)ethyl]-3-oxo-2 ; 3-dihydro-lH-isoindol- 4-yl ⁇ -1 -naphthamide
  • Step A The preparation of 2-(cyclohexylmethyl)-7-nitroisoindolin-l-one
  • Step B The preparation of 7-amino-2-(cyclohexylmethyl)isoindolin-l-one
  • Step C The preparation of N-[2-(cyclohexylmethyl)-3-oxo-2,3-dihydro-lH-isoindol-4-yl]- 1- naphthamide
  • Step A The preparation of 2-(tetrahydro-2H-pyran-4-ylmethyl)-7-nitroisoindolin-l-one
  • Step B The preparation of 7-amino-2-(tetrahydro-2H-pyran-4-yhnethyl)isoindolin-l-one
  • Step C The preparation of N-[2-( tetrahydro-2H-pyran-4-ylmethyl)-3-oxo-2,3-dihydro-lH- isoindol-4-yl]-l- naphthamide
  • Step 2 The preparation of tert-butyl 3-(7-nitro-l-oxo-l,3-dihydro-2H-isoindol-2- yl)piperidine-l -carboxylate
  • Step B The preparation of tert-butyl 3-(7-amino-l-oxo-l 3 3-dihydro-2H-isoindol-2- yl)piperidine-l -carboxylate
  • Step C The preparation of tert-butyl 3-[7-(l-naphthoylamino)-l-oxo-l,3-dihydro-2H- isoindol-2-yl]piperidine-l-carboxylate
  • Step D The preparation of N-(3-oxo-2-piperidin-3-yl-2,3-dihydro-lH-isoindol-4-yl)-l- naphthamide
  • Step A The preparation of tert-butyl 2-[(7-mtro-l-oxo-l,3-dlhydro-2H-isoindol-2- yl)methyl]piperidine-l -carboxylate
  • Step B The preparation of tert-butyl 2-[(7-amino-l-oxo-l,3-dihydro-2H-isoindol-2- yl)methyl]piperidine-l-carboxylate
  • Step C The preparation of tert-butyl 2- ⁇ [7-(l-naphthoylamino)-l-oxo-l,3-dihydro-2H- isoindol-2-yl]methyl ⁇ piperidine- 1 -carboxylate
  • Step D The preparation of N-[3-oxo-2-(piperidin-2-ylmethyl)-2,3-dihydro-lH-isoindol-4- yl]-l-naphthamide
  • Step A The preparation of tert-butyl 2-( ⁇ 7-[(4-methoxy-l-naphthoyl)amino]-l-oxo-l,3- dihydro-2H-isoindol-2-yl ⁇ methyl)piperidine-l-carboxylate
  • Step B The preparation of 4-methoxy-N-[3-oxo-2-( ⁇ iperidin-2-ylmethyl)-2,3-dihydro-lH- isoindol-4-yl]- 1-naphthamide
  • Step B Preparation of 7-amino-2-(2-mo ⁇ holin-4-ylethyl)isoindolin-l-one hydrate
  • Step A The preparation of 4-(bromomethy I)-I -naphthoic acid
  • Step B The preparation of 4-(methoxymethyl)-l-naphthoic acid
  • Step C The preparation of 4-(methoxymethyl)-N-[3-oxo-2-(tetrahydro-2H-pyran-4- ylmethyl)-2,3 -dihydro- 1 H-isoindol-4-yl]- 1 -naphthamide
  • Step A The preparation of 4-(lH-l,2,3-triazol-l-yhnethyl)-l-naphthoic acid
  • Step B The preparation of N-[3-oxo-2-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-lH- isoindol-4-yl]-4-(lH-l,2,3-triazol-l-yhnethyl)-l-naphthamide
  • N-(2-Allyl-3-oxo-2,3-dihydro-lH-isokidol-4-yl)-2,3-dichlorobenzamide (57 mg, 45% yield in 3 steps) as white solid was prepared from 2-allyl-7-aminoisoindolin-l-one and 2,3- dichlorolbenzoyl chloride following General Procedure C. MS (M+l): 361.1 (M+l).
  • Step A N-[2-(Cyclohexylmethyl)-3-oxoisoindolin-4-yl]naphthylcarboxamide
  • Step B 2-(Cyclohexylmethyl)-7-nitroisoindoli ⁇ -l-one
  • Step C 7-Ammo-2-(cyclohexyhnethyl)isomdolin-l-one
  • Step A N-[2-(Cyclohexylmethyl)-3-oxoisoindolin-4-yl](4-me1hylnaphthyl)carboxaniide
  • Step B 4-Methylnaphthalenecarbonyl chloride
  • Step A N-[2-(Cyclohexymiethyl)-3-oxoisoindolin-4-yl](4-methoxylnaphthyl)carboxamide
  • step A reaction of 7-amino-2- (cyclohexylmethyl) isoindolin-1-one (0.122 g, 0.500 mmol) with 4- methoxynaphthalenecarbonyl chloride (0.202 g, 1.00 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.21 mL, 1.5 mmol) in CHzCl 2 (10 mL), after purification by flash chromatography over silica gel, using EtO Ac/hexanes (1:10 to 1:5), gave the title compound as a white foam, which was crystallized from EtOAc to afford a white solid, 0.11 g (52%).
  • Step A N-[2-(Cyclohexybnethyl)-3-oxoisoindolin-4-yl](4-fluoronaphthyl)carboxamide
  • step A reaction of 7-amino-2- (cyclohexylmethyl)isoindolin-l-one (0.147 g, 0.600 mmol) with 4- fluoronaphthalenecarbonyl chloride (0.170 g, 0.900 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.26 mL, 1.8 mmol) in CH 2 Cl 2 (10 mL), after purification by flash chromatography over silica gel, using EtO Ac/hexanes (1:10 to 1:5) gave the title compound, as a white foam.
  • step A reaction of 7-amino-2- (cyclohexylmethyl)isoindolm-l-one (0.147 g, 0.600 mmol) with 4,7- (dimethoxy) ⁇ aphthalenecarbonyl chloride (0.210 g, 0.900 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.26 mL, 1.8 mmol) in CH 2 CI 2 (10 mL), after purification by flash chromatography over silica gel, using EtOAc/hexanes (1:10 to 1:5), followed by preparative tic (CE ⁇ Gb/hexanes, 2: 1), gave the title compound as a pale yellow foam, which was crystallized from EtOAc/hexanes (1 :3) to afford a pale yellow solid, 0.2 g (73%).
  • Step A Naphthyl-N-[3-oxo-2-(2H-3,4,5,6-tetrahydropyran-4-yhnethyl)isoindolin-4- yl)carboxamide
  • Step B 7-Nitro-2-(2H-3,4,5,6-tetrahydropyran-4-ylmethyl)isoindolin-l-one
  • Step C 7-Ami ⁇ o-2-(2H-3,4,5,6-tetrah.ydropyran-4-ylmethyl)isoindolij ⁇ -l-one Compound 6
  • step B reaction of 7-amino-2-(2H- 3,4,5,6-tetrahydropyran-4-ylmethyl)isoindolin-l-one (0.148 g, 0.600 mmol) with 4- methylnaphthalenecarbonyl chloride (0.223 g, 1.20 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.26 mL, 1.8 mmol) in CH 2 CI 2 (10 mL), after purification by flash chromatography over silica gel, using EtOAc/hexanes (1:1 to 2:1), gave the title compound, as a white foam, which was crystallized from EtOAc/hexanes (1:1) to afford a white solid, 0.18 g (72%).
  • 1 H NMR 400 MHz,
  • step B reaction of 7-amino-2-(2H- 3,4,5,6-tetrahydropyran-4-ylmethyl)isoindolin-l-one (0.123 g, 0.500 mmol) with 4- methoxynaphthalenecarbonyl chloride (0.202 g, 1.00 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.21 mL, 1.5 mmol) in CH 2 Cl 2 (10 mL), after purification by flash chromatography over silica gel, using EtOAc/hexanes (1:1 to 2:1), gave the title compound, as a white foam, which was crystallized from EtOAc/hexanes (1:1) to afford a white solid, 0.17 g (79%).
  • step A reaction of 7-amino-2-(2H- 3,4,5,6-tetrahydropy ⁇ an-4-ylmeth.yl)isoindolm-l-one (0.148 g, 0.600 mmol) with 4- fluoronaphthalenecarbonyl chloride (0.170 g, 0.900 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.26 mL, 1.8 mmol) in CH 2 Cl 2 (10 mL), after purification by flash chromatography over silica gel, using EtOAc/hexanes (1:1 to 2:1), gave the title compound, as a white foam, which was crystallized from EtOAc to afford a white solid, 0.18 g (72%).
  • step A reaction of 7-amino-2-(2H- 3,4,5,6-tetrahydropyran-4-ylmethyl)isoindolin-l-one (0.148 g, 0.600 mmol) with 4,7- dimethoxynaphthalenecarbonyl chloride (0.210 g, 0.900 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.26 mL, 1.8 mmol) in CH 2 CI 2 (10 mL), after purification by flash chromatography over silica gel, using EtOAc/hexanes (1:1 to 2:1), gave the title compound, as a white foam.
  • Step A N-[2-(Morpholin-4-ylethyl)-3-oxoisoindolin-4-yl]naphthylcarboxamide
  • Step B 2-(2-Morpholin-4-yIethyl)-7-nitroisoindolin-l-one
  • step B reaction of 7-amino-2-(2- morpholin-4-ylethyl)isoindolin-l-one (0.15 g, 0.57 mmol) with 4- methylnaphthalenecarbonyl chloride (0.40 g, 1.14 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.16 mL), 1.14 mmol) in CH 2 CI 2 (20 mL) gave the crude product, which was purified by crystallization from C ⁇ Cyhexanes. The title compound was an off-white solid 0.085 g (34%).
  • step B reaction of 7-amino-2-(2- morpholin-4-ylethyl)isomdolin-l-one (0.150 g, 0.57 mmol) with 4- methoxynaphthalenecarbonyl chloride (0.250 g, 1.14 mmol) (prepared according to the procedure of Step B in example 2) and triethylamine (0.16 mL, 1.14 mmol), in dry CH 2 CI 2 (20 mL), after chromatography over silica gel using EtOAc/hexanes (3:7), gave the title compound as a solid. Crystallization from CHaCb/hexanes gave a solid 0.095 g (38%).
  • Step A (4-Methoxynaphthyl)-iV-[3-oxo-2-(2-piperidylethyl)isoindolin-4- yl]carboxamide
  • step B reaction of 7-amino-2-(2- (piperidin-l-ylemyl)isoindolin-l-one (0.150 g, 0.58 mnaol) (for preparation, see the following steps B and C) with 4-methoxynaphthalenecarbonyl chloride (0.250 g, 1.14 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.16 mL, 1.14 mmol) in CH2CI 2 (20 mL), after purification by chromatography over silica gel using CH 2 Cl 2 MeOH (9:1) gave the title compound.
  • Step B 7-Nitro-2-(2-(piperidin-l-ylethyl)isoindolin-l-one
  • Step C 7-Amino-2-(2-(piperidin-l-ylethyl)isoindolm-l-one
  • step B reaction of 7-amino-2-(2- (piperidin-l-ylethyl)isoindolin-l-one (0.200 g, 0.77 mmol) with 4- fluoronaphthalenecarbonyl chloride (0.240 g, 1.15 mmol) (prepared according to the procedure of Step B in example 22.) in CH2CI2 (30 mL), after chromatography over silica gel using CH 2 Cl 2 ZMeOH (98:2 to 95:5) gave the title compound as a solid 0.195 g (57%).
  • Step B N-[2-(cyclohexylmethyl)-3-oxoisoindolin-4-yI][4- (phenylmethoxy)naphthyl] carboxamide
  • step A reaction of 7-amino-2 ⁇ (cyclohexyhnethyl)isoindolin-l-one (0.135 g, 0.550 mmol) with 4- (phenylmethoxy)naphthalenecarbonyl chloride (0.230 g, 0.827 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.24 mL, 1.7 mmol) in CH 2 Cl 2 (10 mL), after purification by flash chromatography over silica gel, using CH 2 Cl 2 /hexanes (1:3 to 1:1) gave the title compound , 0.26 g (94%) as a pale white solid.
  • Step A [4-(Hydroxy)naphthyl)]-N-[3-oxo-2-(2H-3,4,5,6-tetrahydropyran-4- ylmethyl)isoindolm-4-yl]carboxamide
  • Step B N-[3-oxo-2-(2H-3,4,5,6-tetrahydropyran-4-ylmethyl)isoindoIinyl] [4- (phenylmethoxy)naphthyl]carboxamide
  • step B reaction of 7-amino-2-(2H- 3,4,5,6-tetrahydropyran-4-ylmethyl)isoindolin-l-one (0.136 g, 0.550 mmol) with 4- (phenylmethoxy)naphthalenecarbonyl chloride (0.230 g, 0.827 mmol) (prepared according to the procedure of Step B in example 22) and triethylamine (0.24 mL, 1.6 mmol) in CH 2 Cl 2 (10 ⁇ iL), after purification by flash chromatography over silica gel, using EtOAc/CH 2 Cl 2 (1:10 to 1:5), gave the title compound, 0.26 g (94%) as a white solid.

Abstract

L'invention concerne des composés de formule (I) ou leurs sels pharmaceutiquement acceptables. Dans cette formule, X, R1, R2, R3, m and n sont spécifiés dans la description, de même que la préparation des sels et des compositions pharmaceutiques contenant lesdits composés. Les composés de l'invention sont utilisés dans le cadre d'une thérapie, en particulier dans la gestion de la douleur.
PCT/SE2007/000503 2006-05-26 2007-05-24 Dérivés d'isoindole utilisés pour traiter la douleur, les maladies du tube digestif et le cancer WO2007139464A1 (fr)

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JP2009511980A JP2009538296A (ja) 2006-05-26 2007-05-24 疼痛、胃腸疾患及びがんの処置に有用なイソインドール誘導体

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WO2014077401A1 (fr) 2012-11-19 2014-05-22 武田薬品工業株式会社 Composé hétérocyclique contenant de l'azote
WO2015163485A1 (fr) 2014-04-23 2015-10-29 Takeda Pharmaceutical Company Limited Dérivés i isoindoline-1-one à activité de modulateur alloestérique positif du récepteur m1 muscarinique cholinergique pour le traitement de la maladie d'alzheimer
US9403802B2 (en) 2012-03-02 2016-08-02 Takeda Pharmaceutical Company Limited Heterocyclic compound and use therefor
US9856216B2 (en) 2015-04-27 2018-01-02 Green Cross Corporation Compounds as TNIK, IKKε and TBK1 inhibitors and pharmaceutical composition comprising same
US9938269B2 (en) 2011-06-30 2018-04-10 Abbvie Inc. Inhibitor compounds of phosphodiesterase type 10A
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WO2003011858A1 (fr) * 2001-07-30 2003-02-13 Bayer Healthcare Ag Isoindoles substitues et leur utilisation
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Publication number Priority date Publication date Assignee Title
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2010077686A1 (fr) * 2008-12-08 2010-07-08 Sirtris Pharmaceuticals, Inc. Isoindolinone et analogues apparentés comme modulateurs de sirtuine
EP2632461A1 (fr) * 2010-10-29 2013-09-04 Merck Sharp & Dohme Corp. Composés d'isoindolinone utiles comme inhibiteurs de pde 10
EP2632461A4 (fr) * 2010-10-29 2014-04-02 Merck Sharp & Dohme Composés d'isoindolinone utiles comme inhibiteurs de pde 10
US9938269B2 (en) 2011-06-30 2018-04-10 Abbvie Inc. Inhibitor compounds of phosphodiesterase type 10A
US9403802B2 (en) 2012-03-02 2016-08-02 Takeda Pharmaceutical Company Limited Heterocyclic compound and use therefor
WO2014077401A1 (fr) 2012-11-19 2014-05-22 武田薬品工業株式会社 Composé hétérocyclique contenant de l'azote
US9777005B2 (en) 2012-11-19 2017-10-03 Takeda Pharmaceutical Company Limited Bicyclic heterocyclic compound containing a substituted pyrrole ring
US9662316B2 (en) 2014-04-23 2017-05-30 Takeda Pharmaceutical Company Limited Nitrogen-containing heterocyclic compound
US9789083B2 (en) 2014-04-23 2017-10-17 Takeda Pharmaceutical Company Limited Nitrogen-containing heterocyclic compound
KR20160143852A (ko) 2014-04-23 2016-12-14 다케다 야쿠힌 고교 가부시키가이샤 알츠하이머 병의 치료를 위한 콜린작동성 무스카린 ｍ１ 수용체 양성 알로스테릭 조절인자 활성을 갖는 이소인돌린-1-온 유도체
US9655881B2 (en) 2014-04-23 2017-05-23 Takeda Pharmaceutical Company Limited Nitrogen-containing heterocyclic compound
US9499516B2 (en) 2014-04-23 2016-11-22 Takeda Pharmaceutical Company Limited Nitrogen-containing heterocyclic compound
US9675597B2 (en) 2014-04-23 2017-06-13 Takeda Pharmaceutical Company Limited Nitrogen-containing heterocyclic compound
US9315458B2 (en) 2014-04-23 2016-04-19 Takeda Pharmaceutical Company, Limited Nitrogen-containing heterocyclic compound
US9775827B2 (en) 2014-04-23 2017-10-03 Takeda Pharmaceutical Company Limited Nitrogen-containing heterocyclic compound
US9789084B2 (en) 2014-04-23 2017-10-17 Takeda Pharmaceutical Company Limited Nitrogen-containing heterocyclic compound
US9518042B2 (en) 2014-04-23 2016-12-13 Takeda Pharmaceutical Company Limited Nitrogen-containing heterocyclic compound
US10865200B2 (en) 2014-04-23 2020-12-15 Takeda Pharmaceutical Company Limited Nitrogen-containing heterocyclic compound
US9868725B2 (en) 2014-04-23 2018-01-16 Takeda Pharmaceutical Company Limited Isoindoline-1-one derivatives as cholinergic muscarinic M1 receptor positive alloesteric modulator activity for the treatment of Alzheimer's disease
US10457670B2 (en) 2014-04-23 2019-10-29 Takeda Pharmaceutical Company Limited Isoindoline-1-one derivatives as cholinergic muscarinic M1 receptor positive alloesteric modulator activity for the treatment of Alzheimers disease
WO2015163485A1 (fr) 2014-04-23 2015-10-29 Takeda Pharmaceutical Company Limited Dérivés i isoindoline-1-one à activité de modulateur alloestérique positif du récepteur m1 muscarinique cholinergique pour le traitement de la maladie d'alzheimer
US10208046B2 (en) 2014-05-16 2019-02-19 Takeda Pharmaceutical Company Limited Nitrogen-containing heterocyclic compound
KR101846475B1 (ko) * 2015-04-27 2018-04-09 주식회사 녹십자 TNIK, IKKε 및 TBK1 억제제로서의 화합물 및 이를 포함하는 약학적 조성물
US9856216B2 (en) 2015-04-27 2018-01-02 Green Cross Corporation Compounds as TNIK, IKKε and TBK1 inhibitors and pharmaceutical composition comprising same

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CL2007001517A1 (es) 2008-01-25
CN101495450A (zh) 2009-07-29
TW200806625A (en) 2008-02-01

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