WO2003051275A2 - Benzodiazepine derivatives, preparation thereof and use thereof - Google Patents

Benzodiazepine derivatives, preparation thereof and use thereof Download PDF

Info

Publication number
WO2003051275A2
WO2003051275A2 PCT/SE2002/002309 SE0202309W WO03051275A2 WO 2003051275 A2 WO2003051275 A2 WO 2003051275A2 SE 0202309 W SE0202309 W SE 0202309W WO 03051275 A2 WO03051275 A2 WO 03051275A2
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
alkyl
mmol
methyl
heterocyclyl
Prior art date
Application number
PCT/SE2002/002309
Other languages
French (fr)
Other versions
WO2003051275A3 (en
Inventor
Carmen Leung
Vijayaratnam Santhakumar
Miroslaw Tomaszewski
Simon Woo
Original Assignee
Astrazeneca Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to AU2002359126A priority Critical patent/AU2002359126A1/en
Publication of WO2003051275A2 publication Critical patent/WO2003051275A2/en
Publication of WO2003051275A3 publication Critical patent/WO2003051275A3/en

Links

Classifications

    • 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
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C07D243/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention is directed to methods of treating or preventing pain, septic shock, pancreatitis, edema, rhinitis, asthma, colitis, arthritis, hepatorenal syndrome, cancer, bacterial and viral infections, ulcerative colitis, and Alzheimer's Disease. More particularly, the present invention is directed to the methods of treating pain.
  • bradykinin receptor Two types are known: The Bl receptor and the B2 receptor.
  • compounds that are B2 antagonists are useful in the relief of pain, including chronic pain and acute pain, e.g., chronic inflammatory pain, neuropathic pain, back pain, migraine, cancer pain, visceral pain, arthritis pain and postoperative pain.
  • the problem underlying the present invention was to develop new methods of treating pain by administering novel kinin B2 antagonists to a warm-blooded animal such as a human. Accordingly, in one aspect, the present invention provides methods of treating pain.
  • C m . n or "C m . n group” used alone or as a prefix, refers to any group having m to n carbon atoms, and having 0 to n multivalent heteroatoms selected from O, S, N and P, wherein m and n are 0 or positive integers, and n>m.
  • C ⁇ . 6 would refer to a chemical group having 1 to 6 carbon atoms, and having 0 to 6 multivalent heteroatoms selected from O, S, N and P.
  • 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 monovalent straight or branched chain hydrocarbon radicals comprising 1 to about 12 carbon atoms. Unless otherwise specified, “alkyl” general includes both saturated alkyl and unsaturated alkyl.
  • 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.
  • 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.
  • cycloalkyl used alone or as suffix or prefix, refers to a monovalent ring-containing hydrocarbon radical comprising at least 3 up to about 12 carbon atoms.
  • 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 links 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.
  • the rings may be fused or unfused.
  • Fused rings generally refer to at least two rings share two atoms therebetween.
  • Heterocycle may have aromatic character or may not have aromatic character.
  • heteroalkyl used alon or as a suffix or prefix, refers to a radical formed as a result of replacing one or more carbon atom of an alkyl with one or more heteroatoms selected from N, O, P and S.
  • 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 formed as a result of replacing one or more carbon atom of an alkyl with one or more heteroatoms selected from N, O, P and S.
  • heteromatic used alone or as a suffix or prefix, refers to a ring- containing structure or molecule having one or more multivalent heteroatom
  • heterocyclo used alone or as a suffix or prefix, refers to a radical derived from a heterocycle by removing one or more hydrogens therefrom.
  • 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.
  • heteroaryl used alone or as a suffix or prefix, refers to a heterocyclyl having aromatic character.
  • heterocyclylcoalkyl used alone or as a suffix or prefix, refers to a heterocyclyl that does not have aromatic character.
  • heteroarylene used alone or as a suffix or prefix, refers to a heterocyclylene having aromatic character.
  • heterocycloalkylene used alone or as a suffix or prefix, refers to a heterocyclylene that does not have aromatic character.
  • f ⁇ ve-membered 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.
  • Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.
  • substituted refers to a structure, molecule or group, wherein one or more hydrogens are replaced with one or more Cj- ⁇ hydrocarbon groups, or one or more chemical groups containing one or more heteroatoms selected from N, O, S, F, Cl, Br, I, and P.
  • substituted phenyl may refer to nitrophenyl, pyridylphenyl, methoxyphenyl, chlorophenyl, aminophenyl, etc., wherein the nitro, pyridyl, methoxy, chloro, and amino groups may replace any suitable hydrogen on the phenyl ring.
  • substituted used as a suffix of a first structure, molecule or group, followed by one or more names of chemical groups refers to a second structure, molecule or group, which is a result of replacing one or more hydrogens of the first structure, molecule or group with the one or more named chemical groups.
  • a "phenyl substituted by nitro" refers to nitrophenyl.
  • Heterocycle includes, for example, monocyclic heterocycles such as: aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazoline, 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 homopiperazine,
  • heterocycle includes aromatic heterocycles, for example, pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, furazan, pyrrole, imidazole, thiazole, oxazole, pyrazole, isothiazole, isoxazole, 1,2,3-triazole, 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, phenoxazine, 1,2-benzisoxazole, benzothiophene, benzoxazole,
  • 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, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, dioxolanyl, sulfolanyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, tetrahydrofuranyl, thiophanyl, piperidinyl, 1,2,3,6-tetrahydro-pyridinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, 2,3-dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridinyl, 1,4-di
  • 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, cirmolinyl, pteridin
  • 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” used alone or as a suffix or prefix, refers to radicals of the general formula -NRR', wherein R and R' are independently selected from hydrogen or a hydrocarbon radical.
  • Acyl groups include, for example, acetyl, propionyl, benzoyl, phenyl acetyl, carboethoxy, and dimethylcarbamoyl.
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • Halogenated used as a prefix of a group, means one or more hydrogens on the group is replaced with one or more halogens.
  • RT room temperature
  • a first ring group being "fused" with a second ring group means the first ring and the second ring share at least two atoms therebetween.
  • Link means covalently linked or bonded.
  • the present invention provides a method of treating pain in a warm- blooded animal, comprising the step of administering to said animal a therapeutically effective amount of a compound of Formula (I), pharmaceutically acceptable salts thereof, diasteriomers thereof, enantiomers thereof, or mixtures thereof:
  • R 1 is selected from optionally substituted acyl, optionally substituted alkyl- oxycarbonyl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted aryl; optionally substituted heterocyclyl; optionally substituted aryl-C ⁇ . 6 alkyl, and optionally substituted heterocyclyl-C ⁇ . 6 alkyl; or a divalent CM 2 group that together with a second nitrogen of X to form a ring;
  • X is a divalent group including a first nitrogen atom and the second nitrogen atom, wherein a first group (e.g., the 2H-l,4-benzodiazepin-2-one group of formula (I)) is linked to the first nitrogen atom and R 1 is linked to the second nitrogen atom, and wherein the first and second nitrogen atoms are separated by either one carbon atom, or two carbon atoms wherein said two carbon atoms have a double bond therebetween;
  • a first group e.g., the 2H-l,4-benzodiazepin-2-one group of formula (I)
  • R 3 is optionally substituted aryl, optionally substituted C ⁇ _ ⁇ 2 alkyl, optionally substituted C 3 . ⁇ 2 cycloalkyl, or optionally substituted heterocyclyl;
  • R 5 , R 6 and R 7 are independently -H, optionally substituted C ⁇ _ 6 alkyl.
  • the compounds used in the methods of the present invention are those of formula (I), pharmaceutically acceptable salts thereof, diasteriomers thereof, enantiomers thereof, or mixtures thereof, wherein
  • R 1 is selected from optionally substituted acyl, optionally substituted alkyl- oxycarbonyl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted aryl; optionally substituted heterocyclyl; optionally substituted aryl-C ⁇ profession 6 alkyl, and optionally substituted heterocyclyl-C ⁇ _ 6 alkyl; or a divalent C ⁇ . 12 group that together with a divalent R 2 of X forms a portion of a ring;
  • X is represented by (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), (xi), (xii), (xi ⁇ ), (xiv), (xv), (xvi), or (xvii) below:
  • R 2 is selected from -H, optionally substituted C ⁇ _ ⁇ 2 alkyl, optionally substituted C ⁇ - ⁇ 2 heteroalkyl, optionally substituted aryl, optionally substituted heterocyclyl, and a divalent C 0 - 6 group together with a divalent R 1 to form the portion of the ring, wherein said divalent Co- 6 group optionally includes one or more heteroatoms;
  • R 3 is optionally substituted aryl, optionally substituted C ⁇ _ ⁇ 2 alkyl, optionally substituted C 3 - ⁇ 2 cycloalkyl, or optionally substituted heterocyclyl;
  • the compound used in the method of the present invention is a compound of formula (I), wherein
  • R 1 is optionally substituted phenyl, optionally substituted naphthyl, optionally substituted isoquinolyl, optionally substituted acridinyl, optionally substituted coumarinyl, optionally substituted carbazolyl, or a first divalent group selected from optionally substituted C ⁇ .j 2 alkylene and optionally substituted C ⁇ _ ⁇ 2 heteroalkylene; wherein said phenyl, naphthyl, isoquinolyl, acridinyl, coumarinyl, and carbazolyl are optionally substituted by C ⁇ _ 6 alkyl, C]. 6 heterocyclyl or amino, wherein said d. ⁇ alkylene and C ⁇ - ⁇ 2 heteroalkylene are optionally substituted by C ⁇ - 6 alkyl, aryl-C ⁇ . 6 alkyl, aryl or heterocyclyl;
  • X is selected from formulas (i), (ii), (iii), (vi) and (xvii) below:
  • R is -H, C ⁇ _ 3 alkyl, or a second divalent group selected from a single bond, an optionally substituted alkylene and an optionally substituted heteroalkylene; wherein said second divalent group together with said first divalent group forms a portion of a ring; R is optionally substituted aryl, optionally substituted heteroaryl or optionally substituted cycloalkyl;
  • R 4 is halogen, or C ⁇ _ 3 alkyl; and R 5 is C ⁇ _ 3 alkyl.
  • the compound used in the method of the present invention is a compound of formula (I), wherein
  • -X-R 1 of formula (I) is selected from formulas (a), (b), (c), (d), (e), (f) and (g) below:
  • R 1 is optionally substituted phenyl, optionally substituted naphthyl, optionally substituted isoquinolyl, wherein said phenyl, naphthyl and isoquinolyl are optionally substituted by C ⁇ . 6 alkyl, C ⁇ . 6 heterocyclyl or amino;
  • R 2 is -H, or C ⁇ . 3 alkyl;
  • — is a nitrogen containing heterocyclyl, which may be optionally substituted by one or more -R 8 , and which includes a bond on the nitrogen that links to other group of formula (I).
  • exemplary nitrogen containing heterocyclyls include, but is not limited to, piperazinyl, morpholinyl, poperidyl, and pyrrolidinyl.
  • R 8 is -H, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted Cj. 6 alkyl, -OH, or C ⁇ - 6 alkoxy, wherein R 8 is optionally fused with
  • R 3 is optionally substituted cyclohexyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted thienyl, or optionally substituted pyrimidinyl, wherein said cyclohexyl, phenyl, pyridyl, thienyl and pyrimidinyl are optionally substituted by halogen, methoxy, or Cj. 3 alkyl;
  • R 4 is halogen
  • R 5 is methyl
  • Table 1 Spreadsheet of combinatorially prepared compounds with LCMS analysis of the reaction product.
  • the compounds listed in Table 1, or their pharmaceutically acceptable salts, may be used in the methods described herein to treat or prevent pain.
  • 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, HC1 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 -toluenesulphonate.
  • an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate or -toluenesulphonate.
  • novel compounds of the present invention are useful in therapy, especially for the treatment 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.
  • Compounds of the invention are useful in disease states where degeneration or dysfunction of Bradykinin 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 septic shock, pancreatitis, edema, rhinitis, asthma, colitis, arthritis, hepatorenal syndrome, cancer, (including but not restricted to SCLC, prostrate cancer), bacterial and viral infections, ulcerative colitis, and Alzheimer's Disease.
  • Compounds of the invention are useful as an analgesic agent for use during general anesthesia and monitored anesthesia 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.
  • 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.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the term “therapeutic” and “therapeutically” 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, acute 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 inj ection into the j oints .
  • the route of administration may be orally, intravenously or intramuscularly.
  • 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 substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or table 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 moulds 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.
  • Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
  • 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.
  • the pharmaceutical composition will preferably include from 0.05% to 99%w (per cent 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.
  • the use of any compound of formula I as defined above for the manufacture of a medicament is the use of any compound of formula I as defined above for the manufacture of a medicament.
  • 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, acute 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.
  • a pharmaceutical 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.
  • the present invention provides a method of preparing a compound of formula I.
  • the compounds listed in Table 1 were prepared as single compounds in a combinatorial array.
  • the Table 1, column 4 designation of "yes” indicates that the target mass of the designated compound was found in >50% abundance in the MS spectrum.
  • the designation of “tentative” indicates that that the target mass of the designated compound was found in 15-50% abundance in the MS spectrum.
  • the designation “no” indicates that the target mass of the designated compound was found in ⁇ 15% abundance in MS spectrum.
  • Y is a protecting group such as CBZ or FMOC, with an alkyl or alkenyl halide, such as allyl bromide in the presence of a base such as cesium carbonate to give compounds of general formula III; 147
  • b is 0, 1, or 2; R 1 , R 2 , R 3 , R 4 , and R 5 are as defined above.
  • certain compounds of the present invention and certain intermediates used in the preparation of the compounds of the present invention may be prepared according to one or more of the following general procedures, wherein, unless specified otherwise, b, R 1 , R 2 , R 3 , R 4 and R 5 are defined as above.
  • the products were purified by flash chromatography using dichloromethane as the eluent.
  • the products (8mmol) were added with cone ⁇ Br (33% in acetic acid) (50ml) and were stirred at room temperature for 3 hours.
  • the reaction mixture was poured into ether (300 ml), the precipitate was collected, and then taken in dichloromethane (250 ml) and washed with 2N NaO ⁇ (2x50ml).
  • the organic phase was dried over MgSO4, filtered and concentrated in vacuo to provide the desired compound.
  • N 2 gas was bubbled through both DME and water for at least 3 hours.
  • a solution of the imidoyl chloride (1 equiv.) in DME (1.5 mL/mmol imidoyl chloride) was placed in a N 2 purged flask.
  • PdCl 2 (dppf) 0.05 equiv.
  • boronic acid 0.05 equiv.
  • water 0.5 mL/mmol imidoyl chloride
  • the reaction was then cooled, diluted with CH 2 C1 2 and water, and the layers were separated.
  • the aqueous phase was extracted with CH 2 C1 2 (3x), and the combined organic phases were dried over Na 2 SO , filtered, and concentrated in vacuo.
  • the crude product was purified by silica gel column chromatography to provide the desired compound.
  • boronic acid (1.15 equiv.), Pd 2 (dba) 3 (0.015 equiv.), and dry KF (3.3 equiv.) were placed in an oven-dried, N 2 purged flask.
  • the resulting mixture was heated at reflux until the imidoyl chloride was consumed (typically 16 h).
  • the reaction was then cooled, diluted with EtOAc, and filtered through a small pad of silica gel.
  • the silica was washed well with EtOAc, and the combined organic phases were concentrated in vacuo.
  • the product was purified by silica gel column chromatography to provide the desired compound.
  • Glacial acetic acid (4.4 equiv) was then added, and the mixture was warmed to 30 °C for 2 h. Saturated NaHCO 3 was added, the layers were separated, and the aqueous phase was extracted with CH 2 C1 2 (4x). The combined organic phases were dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The product was purified by silica gel column chromatography to provide the corresponding azide compound.
  • polymer supported triphenylphosphine (Argonaut Technologies, 5-10 equiv) was added to a solution of the azide (1 equiv.) in THF (10 mL/g polymer) and water (0.8 mL/g polymer). The resulting mixture was stirred at room temperature until all of the azide had been consumed (typically overnight). The polymer resin was then removed by filtration, and was washed well with CH C1 2 and MeOH (3x each). The filtrate was concentrated in vacuo, and the residue was redissolved in CH 2 C1 2 . Any remaining water was removed with the aid of a separatory funnel, and the organic phase was dried over Na 2 SO 4 , filtered, and concentrated in vacuo.
  • the amine was purified using a "catch and release” strategy with MP-TsOH resin (Argonaut Technologies): The product was dissolved in CH 2 C1 2 (10 mL/mmol product), and MP- TsOH resin (2.3 equiv) was added. The mixture was stirred for 1 h, and the solvent was removed by filtration and discarded. The resin was rinsed with CH 2 C1 2 and MeOH (3x each), and the washings were discarded as well. The product was then released from the resin by washing with 2M NH in MeOH and CH 2 C1 2 (3x each). Concentration of the filtrate in vacuo provided the corresponding amine compound.
  • Additional compounds of the present invention may also be prepared according to the m neetthhooddss rreepprreesseennted in Schemes 2-4 below, wherein, unless specified otherwise, b, R , R 2 , R 3 , R 4 and R 5 are defined as above.
  • hB2 receptor expression and membrane preparation The cloned human Bradykinin B2 (hB2) receptor in the pCIN vector was purchased from Receptor Biology. The hB2 receptor was stably transfected into HEK 293 S cells and a clonal cell line was generated. Cells were grown in T-flasks with DMEM culture media containing 10% FBS, 2 mM glutamine, 600 ⁇ g/ml neomycin and an antibiotic cocktail (100 IU penicillin, lOO ⁇ g/ml streptomycin, 0.25 ⁇ g/ml amphotericin B).
  • Membranes expressing the hB2 receptor, were prepared from this cell line according to this protocol: Cells are harvested at 1 to 1.2 million cells/ml, pelleted, and resuspended in ice-cold lysis buffer (50 mM Tris, pH 7.0, 2.5 mM EDTA, with PMSF added just prior to use to 0.5 mM from a 0.5 M stock in DMSO. After lysis on ice for 15 min, the cells are homogenized with a polytron for 10 sec. The suspension is spun at lOOOg for 10 min at 4°C. The supernatant is saved on ice and the pellets resuspended and spun as before.
  • ice-cold lysis buffer 50 mM Tris, pH 7.0, 2.5 mM EDTA, with PMSF added just prior to use to 0.5 mM from a 0.5 M stock in DMSO. After lysis on ice for 15 min, the cells are homogenized with a polytron for 10 sec. The suspension
  • the supematants from both spins are combined and spun at 46,000g for 10-30 min.
  • the pellets are resuspended in cold Tris buffer (50 mM Tris/Cl, pH 7.0) at a dilution of 0.2 - 1 ml per 40 million cells and spun again.
  • the final pellets are resuspended in membrane buffer (50 mM Tris, 0.32 M sucrose, pH 7.0). Aliquots are frozen in dry ice/ethanol and stored at -70°C until use.
  • the protein concentrations are determined by a modified Lowry with SDS.
  • hB2 receptor binding Membranes expressing the hB2 receptor are thawed at 37°C, passed 3 times through a 25- gauge blunt-end needle, diluted in the bradykinin binding buffer (50 mM Tris, 3mM MgCl 2 , and 1 mg/ml BSA, pH 7.4, 0.02 mg/ml Phenanthroline, 0.25 mg/ml Pefabloc) and 80 ⁇ L aliquots containing the appropriate amount of protein (final concentration of 0.25 ⁇ g/ml) are distributed in 96-well polystyrene plates (Treff Lab).
  • bradykinin binding buffer 50 mM Tris, 3mM MgCl 2 , and 1 mg/ml BSA, pH 7.4, 0.02 mg/ml Phenanthroline, 0.25 mg/ml Pefabloc
  • Kd 0.05
  • 50,000 to 60,000 dpm per well 0.03-0.04nM
  • the total and non-specific binding are determined in the absence and presence of 0.1 ⁇ M (150 ⁇ L) of Bradykinin respectively.
  • the plates are vortexed and incubated for 60 minutes at room temperature, filtered through Unifilters-96 GF/B (Canberra Packard), which were presoaked in 0.1 % polyethyleneimine, with a harvester using 3ml of wash buffer (50 mM Tris, pH 7.0, 3mM MgCl 2 ). The filters are dried for 1 hour at 55°C. The radioactivity (cpm) is counted in a TopCount (Canberra Packard) after adding 65 ⁇ l/well of MS-20 scintillation liquid (Canberra Packard). Compounds of the present invention have demonstrated hB2 receptor binding at concentrations less than 10 ⁇ M.
  • the dissociation constant (Ki) for a particular compound of the invention towards a particular receptor is determined using the following equation:
  • Ki IC 50 /(l+[rad]/Kd)
  • IC 5 o is the concentration of the compound of the invention at which 50%) displacement has been observed
  • [rad] is a standard or reference radioactive ligand concentration at that moment
  • Kd is the dissociation constant of the radioactive ligand towards the particular receptor.
  • Human Bradykinin-2 membranes (hB2 293s) are thawed at 37°C, passed 3 times through a 25-gauge blunt-end needle and diluted in the GTP ⁇ S binding buffer for the assay (50 mM Hepes, pH 7.4; 200 mM NaCl; 1 mM EDTA; 5 mM MgCl 2 . To this added freshly prepared 1 mM DTT, 0.5% BSA, 1 ⁇ M GDP. The EC50 and Emax of compounds are evaluated from 10-point dose-response curves done in 300 ⁇ l with the appropriate amount of membrane protein and 100,000-120,000 dpm of GTP ⁇ 35 S per well (0.11 - 0.14 nM). Bradykinin (1-9) is used as the standard agonist at hB2. The ranges of concentrations tested should include a maximal concentration of O.l ⁇ M bradykinin in order to establish the E max .
  • the plates are vortexed and incubated for 60 minutes at room temperature, filtered on GF/B Unifilters (presoaked in water) with the Packard harvester using 4 ml/well of wash buffer (50 mM Tris, 5 mM MgCl 2 , 50 mM NaCl, pH 7.0), minimum. The filters are dried for 1 hour at 55°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 a similar manner except that the compound dose-response curve's are performed in the presence of a constant concentration of agonist (approx. 80%> bradykinin E max ; ⁇ 5 nM).
  • a standard B2 Antagonist is used as the reference antagonist at hB2.
  • the ranges of antagonist concentrations tested should include a maximal concentration of 3 ⁇ M of the standard B2 Antagonist in order to establish the maximal displacement (D max ).
  • GTP[ ⁇ ]35s is acquired from Perkin-Elmer (250 ⁇ Ci/20 ⁇ l) . It is diluted from with 10 mM DTT, 50 mM Tris, pH 7 (dilute in 2 ml, 1.0 mCI/20 ⁇ ). Sonicate the solution, filter through a 0.45 ⁇ m filter, and freeze aliquots at -70°C. For the experiment, use ⁇ 0.3 nM dilution of this tracer in the GTP binding buffer.
  • the EC 50 and E max of compounds are evaluated from 10-point dose-response curves done in 300 ⁇ l with the appropriate amount of membrane protein and GTP ⁇ 35 S per well and are calculated in Activity base with ExcelFit. The basal and maximal stimulated binding are determined in the absence and presence of standard reference compounds, respectively.
  • the stimulation (Stim) in the presence of compounds is expressed as the percentage of D max of the reference antagonist. Values of IC 50 , Ki' and D max for ligands capable of competing for agonist stimulated binding are calculated in Activity Base.
  • Table 2 List of the test samples used in the Biological Evaluation
  • Test Sample Nos Structure of the Test Sample
  • INTERMEDIATE 2 3-amino-5-(2-bromophenyl)-7-fluoro-l,3-dihydro-l-methyl- 2H-l,4-benzodiazepin-2-one.
  • INTERMEDIATE 2 was obtained as a thick pale brown oil (0.5g, 17%) and used for the subsequent reaction without further purification.
  • INTERMEDIATE 3 3-amino-5-cycIohexyl-l,3-dihydro-l-methyl-2H-l,4- benzodiazepin-2-one.
  • INTERMEDIATE 4 3-amino-7-chloro-5-(2-chloropl ⁇ enyl)-l,3-dihydro-l-methyl- 2J ⁇ -l,4-benzodiazepin-2-one.
  • INTERMEDIATE 7 7-chloro-l,3-dihydro-3-isothiocyanato-l-methyl-5-phenyl-2H- l,4-benzodiazepin-2-one.
  • EXAMPLE 4 N-[7-chloro-5-(2-chlorophenyl)-2,3-dil ⁇ ydro-l-metl ⁇ yl-2-oxo-lH-l,4- benzodiazepin-3-yl]-N'-[4-(dimethylamino)-l-naphthalenyl]- thiourea.
  • EXAMPLE 7 N-(7-chloro-2,3-dihydro-l-methyl-2-oxo-5-phenyl-lH-l,4- benzodiazepin-3-yl)-iV-(4-methoxy-2-methylpheny )- urea.
  • EXAMPLE 10 N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-l-methyl-2-oxo-lJ3-l,4- benzo-diazepin-3-yl]-iV , -cyano-N'-[4-(4-morpholinyI)-l-naphthalenyl]- guanidine (E and Z isomers separated but not identified).
  • EXAMPLE 10A N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-l-methyl-2-oxo-lH- l,4-benzo-diazepin-3-yl]-N"-cyano--V-[4-(4-morpholinyl)-l-naphthalenyl]- guanidine (polar isomer)
  • EXAMPLE 12 N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-l-methyl-2-oxo-lH-l,4- benzo-diazepin-3-yl]- ⁇ -[4-(4-morpholinyl)-l-naphthalenyl]- uanidine.
  • EXAMPLE 13 N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-l-methyl-2-oxo-lH-l,4- benzo-diazepin-3-yl]-iV-[2-methyl-4-(4-morpholinyl)phenyl]- thiourea.
  • EXAMPLE 14 N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-l-methyl-2-oxo-lH-l,4- benzo-diazepin-3-yl]-iV-[4-(dimethylamino)-2-methylphenyl]- thiourea.
  • EXAMPLE 15 N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-l-methyl-2-oxo-lH-l,4- benzo-diazepin-3-yl]-/Y-[4-(dimethylamino)-3-methylphenyl]- thiourea.
  • EXAMPLE 16 N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-l-methyl-2-oxo-lH-l,4- benzo-diazepin-3-yl]-iV-[3-chloro-4-(dimethylamino)phenyl]- thiourea.
  • EXAMPLE 17 N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-l-methyl-2-oxo-lH-l,4- benzo-diazepin-3-yl]-iV-[4-(dimethylamino)-3-(trifluoromethyl)phenyl]- thiourea.
  • EXAMPLE 18 N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-l-methyl-2-oxo-lH-l,4- benzo-diazepin-3-yl]-iV-[4-chloro-2-(dimethylamino)phenyl]-thiourea.
  • EXAMPLE 20 N-[(lE)-[[7-Chloro-5-(2-chlorophenyl)-2,3-dihydro-l-methyl-2-oxo- lH r -l,4-benzodiazepin-3-yl]amino][[4-(4-morpholmyl)-l- naphthalenyl]amino]methylene]urea
  • 3-thienylboronic acid (1.15 g, 9.01 mmol), Pd 2 (dba) 3 (0.113 g, 0.123 mmol), dry KF (1.57 g, 27.0 mmol), 5,7-dichloro-l,3-dihydro-l-methyl-2H-l,4-benzodiazepin-2-one (1.98 g, 8.15 mmol) and P(t-Bu) 3 (0.75 mL of a 10 % solution in hexanes, 0.37 mmol) were combined and heated for 16 h.
  • This reaction was carried out in a multiwell plate. As illustrated in the scheme above, aA mixture of 7-chloro- 1 ,3 -dihydro-3 -isothiocyanato- 1 -methyl-5-(3 -thienyl)-2H- 1 ,4- benzodiazepin-2-one (156 ⁇ L of a 0.128 M solution in (C ⁇ 2 C1) 2 , 0.020 mmol), 4-(4- morpholinyl)- 1-naphthalenamine (44 ⁇ L of a 0.5 M solution in DMA, 0.022 mmol), and (CH 2 C1) 2 (300 ⁇ L) was agitated and heated at 70 °C for 22 h. The reaction was cooled and concentrated.

Abstract

A method of treating pain in a warm-blooded animal, comprising the step ofadministering to said animal a therapeutically effective amount of a compound of formula(I), pharmaceutically acceptable salts thereof, diasteriomers thereof, enantiomers thereof, or mixtures thereof:[Chemical formula should be inserted here. Please see paper copy]wherein R 1 , R 3 , R 4 , R 5 and X are as defined in the specification.

Description

BENZODIAZEPΓNE DERIVATIVES, PREPARATION THEREOF AND USE THEREOF
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is directed to methods of treating or preventing pain, septic shock, pancreatitis, edema, rhinitis, asthma, colitis, arthritis, hepatorenal syndrome, cancer, bacterial and viral infections, ulcerative colitis, and Alzheimer's Disease. More particularly, the present invention is directed to the methods of treating pain.
2. Discussion of Relevant Art
Two types of bradykinin receptor are known: The Bl receptor and the B2 receptor. A number of reports indicate an important role for the B2 receptor in the pathophysiology of pain. [e.g. Hall, J.M., Morton, I.K.M. The pharmacology and immunopharmacology of kinin receptors. In: Farmer SG (Ed). The kinin system. London: Academic Press, 1997; 9-44]. Hence, compounds that are B2 antagonists are useful in the relief of pain, including chronic pain and acute pain, e.g., chronic inflammatory pain, neuropathic pain, back pain, migraine, cancer pain, visceral pain, arthritis pain and postoperative pain.
DETAILED DESCRIPTION OF THE INVENTION
Thus, the problem underlying the present invention was to develop new methods of treating pain by administering novel kinin B2 antagonists to a warm-blooded animal such as a human. Accordingly, in one aspect, the present invention provides methods of treating pain.
Definitions
Unless specified otherwise within this specification, the nomenclature used in this specification generally follows the examples and rules stated in Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, and H, Pergamon Press, Oxford, 1979, which is incorporated by references herein for its exemplary chemical structure names and rules on naming chemical structures. Optionally, a name of a compound may be generated using a chemical naming program: ACD/ChemSketch, Version 5.09/September 2001, Advanced Chemistry Development, Inc., Toronto, Canada.
The term "Cm.n" or "Cm.n group" used alone or as a prefix, refers to any group having m to n carbon atoms, and having 0 to n multivalent heteroatoms selected from O, S, N and P, wherein m and n are 0 or positive integers, and n>m. For example, "Cι.6" would refer to a chemical group having 1 to 6 carbon atoms, and having 0 to 6 multivalent heteroatoms selected from O, S, N and P.
The term "hydrocarbon" used alone or as a suffix or prefix, refers to any structure comprising only carbon and hydrogen atoms up to 14 carbon atoms. The term "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.
The term "alkyl" used alone or as a suffix or prefix, refers to monovalent straight or branched chain hydrocarbon radicals comprising 1 to about 12 carbon atoms. Unless otherwise specified, "alkyl" general includes both saturated alkyl and unsaturated alkyl.
The term "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.
The term "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 term "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 term "cycloalkyl," used alone or as suffix or prefix, refers to a monovalent ring-containing hydrocarbon radical comprising at least 3 up to about 12 carbon atoms.
The term "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. The term "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. The term "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. The term "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 links two structures together.
The term "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 unfused. Fused rings generally refer to at least two rings share two atoms therebetween. Heterocycle may have aromatic character or may not have aromatic character.
The term "heteroalkyl" used alon or as a suffix or prefix, refers to a radical formed as a result of replacing one or more carbon atom of an alkyl with one or more heteroatoms selected from N, O, P and S. The term "heteroaromatic" 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). The term "heterocyclic group," "heterocyclic moiety," "heterocyclic," or
"heterocyclo" used alone or as a suffix or prefix, refers to a radical derived from a heterocycle by removing one or more hydrogens therefrom.
The term "heterocyclyl" used alone or as a suffix or prefix, refers a monovalent radical derived from a heterocycle by removing one hydrogen therefrom. The term "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. The term "heteroaryl" used alone or as a suffix or prefix, refers to a heterocyclyl having aromatic character.
The term "heterocylcoalkyl" used alone or as a suffix or prefix, refers to a heterocyclyl that does not have aromatic character. The term "heteroarylene" used alone or as a suffix or prefix, refers to a heterocyclylene having aromatic character.
The term "heterocycloalkylene" used alone or as a suffix or prefix, refers to a heterocyclylene that does not have aromatic character.
The term "six-membered" used as prefix refers to a group having a ring that contains six ring atoms.
The term "fϊve-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.
Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.
The term "substituted" used as a prefix refers to a structure, molecule or group, wherein one or more hydrogens are replaced with one or more Cj-πhydrocarbon groups, or one or more chemical groups containing one or more heteroatoms selected from N, O, S, F, Cl, Br, I, and P. Exemplary chemical groups containing one or more heteroatoms include heterocyclyl, -NO2, -OR, -Cl, -Br, -I, -F, -CF3, -C(=O)R, -C(=O)OH, -NH2, -SH, -NHR, -NR2, -SR, -SO3H, -SO2R, -S(=O)R, -CN, -OH, -C(=O)OR, -C(=O)NR2, - NRC(=O)R, oxo (=O), imino (=NR), thio (=S), and oximino (=N-OR), wherein each "R" is a Cι-ι2hydrocarbyl. For example, substituted phenyl may refer to nitrophenyl, pyridylphenyl, methoxyphenyl, chlorophenyl, aminophenyl, etc., wherein the nitro, pyridyl, methoxy, chloro, and amino groups may replace any suitable hydrogen on the phenyl ring. The term "substituted" used as a suffix of a first structure, molecule or group, followed by one or more names of chemical groups refers to a second structure, molecule or group, which is a result of replacing one or more hydrogens of the first structure, molecule or group with the one or more named chemical groups. For example, a "phenyl substituted by nitro" refers to nitrophenyl.
The term "optionally substituted" refers to both groups, structures, or molecules that are substituted and those that are not substituted.
Heterocycle includes, for example, monocyclic heterocycles such as: aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazoline, 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 homopiperazine, 1,3-dioxepane, 4,7-dihydro-l,3-dioxepin, and hexamethylene oxide.
In addition, heterocycle includes aromatic heterocycles, for example, pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, furazan, pyrrole, imidazole, thiazole, oxazole, pyrazole, isothiazole, isoxazole, 1,2,3-triazole, 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.
Additionally, 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, phenoxazine, 1,2-benzisoxazole, benzothiophene, benzoxazole, benzthiazole, benzimidazole, benztriazole, thioxanthine, carbazole, carboline, acridine, pyrolizidine, and quinolizidine. In addition to the polycyclic heterocycles described above, 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. Examples of such 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, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, dioxolanyl, sulfolanyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, tetrahydrofuranyl, thiophanyl, piperidinyl, 1,2,3,6-tetrahydro-pyridinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, 2,3-dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridinyl, 1,4-dioxanyl, 1,3-dioxanyl, dioxanyl, homopiperidinyl, 2,3,4,7-tetrahydro-lH-azepinyl, homopiperazinyl, 1,3-dioxepanyl, 4,7- dihydro- 1 ,3 -dioxepinyl, and hexamethylene oxidyl .
In addition, 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.
Additionally, 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, cirmolinyl, pteridinyl, phenanthridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, 1,2-benzisoxazolyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, benztriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrolizidinyl, and quinolizidinyl.
In addition to the polycyclic heterocyclyls described above, 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. Examples of such bridged heterocycles include quinuclidinyl, diazabicyclo[2.2.1]heptyl; and 7-oxabicyclo[2.2.1]heptyl.
The term "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.
The term "amine" or "amino" used alone or as a suffix or prefix, refers to radicals of the general formula -NRR', wherein R and R' are independently selected from hydrogen or a hydrocarbon radical.
"Acyl" used alone, as a prefix or suffix, means -C(=O)-R, wherein R is an optionally substituted hydrocarbyl, hydrogen, amino or alkoxy. Acyl groups include, for example, acetyl, propionyl, benzoyl, phenyl acetyl, carboethoxy, and dimethylcarbamoyl.
Halogen includes fluorine, chlorine, bromine and iodine. "Halogenated," used as a prefix of a group, means one or more hydrogens on the group is replaced with one or more halogens.
"RT" or "rt" means room temperature.
A first ring group being "fused" with a second ring group means the first ring and the second ring share at least two atoms therebetween. "Link," "linked," or "linking," unless otherwise specified, means covalently linked or bonded.
Description of Preferred Embodiments
In one aspect, the present invention provides a method of treating pain in a warm- blooded animal, comprising the step of administering to said animal a therapeutically effective amount of a compound of Formula (I), pharmaceutically acceptable salts thereof, diasteriomers thereof, enantiomers thereof, or mixtures thereof:
Figure imgf000008_0001
wherein
R1 is selected from optionally substituted acyl, optionally substituted alkyl- oxycarbonyl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted aryl; optionally substituted heterocyclyl; optionally substituted aryl-Cι.6alkyl, and optionally substituted heterocyclyl-Cι.6alkyl; or a divalent CM2 group that together with a second nitrogen of X to form a ring;
X is a divalent group including a first nitrogen atom and the second nitrogen atom, wherein a first group (e.g., the 2H-l,4-benzodiazepin-2-one group of formula (I)) is linked to the first nitrogen atom and R1 is linked to the second nitrogen atom, and wherein the first and second nitrogen atoms are separated by either one carbon atom, or two carbon atoms wherein said two carbon atoms have a double bond therebetween;
R3 is optionally substituted aryl, optionally substituted Cι_ι2alkyl, optionally substituted C3.ι2cycloalkyl, or optionally substituted heterocyclyl; R4 is, at each position, independently -H, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, nitro, cyano, hydroxy, -OR6, -SR6, -S(=O)R6, -S(=O)2R6, -C(=O)R6, -C(=S)R6, -NR7R6, -C(=O)NR7R6, -NR7C(=O)R6, -SO2NR7R6, -NR7SO2R6, or -C(=O)OR6; and
R5, R6 and R7 are independently -H, optionally substituted Cι_6alkyl.
In another aspect, the compounds used in the methods of the present invention are those of formula (I), pharmaceutically acceptable salts thereof, diasteriomers thereof, enantiomers thereof, or mixtures thereof, wherein
R1 is selected from optionally substituted acyl, optionally substituted alkyl- oxycarbonyl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted aryl; optionally substituted heterocyclyl; optionally substituted aryl-Cι„6alkyl, and optionally substituted heterocyclyl-Cι_6alkyl; or a divalent Cι.12 group that together with a divalent R2 of X forms a portion of a ring;
X is represented by (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), (xi), (xii), (xiϋ), (xiv), (xv), (xvi), or (xvii) below:
Figure imgf000010_0001
(i) (iii) (iv)
Figure imgf000010_0002
(v) (vi) (vii) (viii)
Figure imgf000010_0003
(ix) (x) (xi) (xϋ)
Figure imgf000010_0004
(xiii) (xiv) (XV) (xvi)
Figure imgf000010_0005
(xvii) wherein R2 is selected from -H, optionally substituted Cι_ι2alkyl, optionally substituted Cι-ι2heteroalkyl, optionally substituted aryl, optionally substituted heterocyclyl, and a divalent C0-6group together with a divalent R1 to form the portion of the ring, wherein said divalent Co-6 group optionally includes one or more heteroatoms; R3 is optionally substituted aryl, optionally substituted Cι_ι2alkyl, optionally substituted C3-ι2cycloalkyl, or optionally substituted heterocyclyl;
R4 is, at each position, independently, -H, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, nitro, cyano, hydroxy, -OR6, -SR6, -S(=O)R6, -S(=O)2R6, -C(=O)R6, -C(=S)R6, -NR7R6, -C(=O)NR7R6, -NR7C(=O)R6, -SO2NR7R6, -NR7SO2R6, or -C(=O)OR6; and R5, R6 and R7 are independently -H, optionally substituted Cj.6alkyl.
More particularly, the compound used in the method of the present invention is a compound of formula (I), wherein
R1 is optionally substituted phenyl, optionally substituted naphthyl, optionally substituted isoquinolyl, optionally substituted acridinyl, optionally substituted coumarinyl, optionally substituted carbazolyl, or a first divalent group selected from optionally substituted Cι.j2alkylene and optionally substituted Cι_ι2heteroalkylene; wherein said phenyl, naphthyl, isoquinolyl, acridinyl, coumarinyl, and carbazolyl are optionally substituted by Cι_6alkyl, C].6heterocyclyl or amino, wherein said d.^alkylene and Cι-ι2heteroalkylene are optionally substituted by Cι-6alkyl, aryl-Cι.6alkyl, aryl or heterocyclyl;
X is selected from formulas (i), (ii), (iii), (vi) and (xvii) below:
Figure imgf000011_0001
(0 (ϋ) (iϋ) (vi) (xvii)
R is -H, Cι_3alkyl, or a second divalent group selected from a single bond, an optionally substituted alkylene and an optionally substituted heteroalkylene; wherein said second divalent group together with said first divalent group forms a portion of a ring; R is optionally substituted aryl, optionally substituted heteroaryl or optionally substituted cycloalkyl;
R4 is halogen, or Cι_3alkyl; and R5 is Cι_3alkyl.
Most particularly, the compound used in the method of the present invention is a compound of formula (I), wherein
-X-R1 of formula (I) is selected from formulas (a), (b), (c), (d), (e), (f) and (g) below:
Figure imgf000011_0002
(a) (b) (c) (d) (e) 11
Figure imgf000012_0001
( ) (g)
R1 is optionally substituted phenyl, optionally substituted naphthyl, optionally substituted isoquinolyl, wherein said phenyl, naphthyl and isoquinolyl are optionally substituted by Cι.6alkyl, Cι.6heterocyclyl or amino; R2 is -H, or Cι.3alkyl;
Figure imgf000012_0002
" — " is a nitrogen containing heterocyclyl, which may be optionally substituted by one or more -R8, and which includes a bond on the nitrogen that links to other group of formula (I). Exemplary nitrogen containing heterocyclyls include, but is not limited to, piperazinyl, morpholinyl, poperidyl, and pyrrolidinyl. R8 is -H, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted Cj.6alkyl, -OH, or Cι-6alkoxy, wherein R8 is optionally fused with
Figure imgf000012_0003
R3 is optionally substituted cyclohexyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted thienyl, or optionally substituted pyrimidinyl, wherein said cyclohexyl, phenyl, pyridyl, thienyl and pyrimidinyl are optionally substituted by halogen, methoxy, or Cj.3alkyl;
R4 is halogen; and
R5 is methyl.
Specific examples of compounds of the present invention that may be used in practicing the present invention are listed in Table 1, below.
Table 1: Spreadsheet of combinatorially prepared compounds with LCMS analysis of the reaction product. 30
12
Figure imgf000013_0001
Figure imgf000014_0001
14
Figure imgf000015_0001
Figure imgf000016_0001
16
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
19
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
3
22
Figure imgf000023_0001
/051275
23
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
26
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
32
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
35
Figure imgf000036_0001
Figure imgf000037_0001
37
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
/051
43
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
3/051275
46
Figure imgf000047_0001
47
Figure imgf000048_0001
48
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
52
Figure imgf000053_0001
Figure imgf000054_0001
54
Figure imgf000055_0001
55
Figure imgf000056_0001
56
Figure imgf000057_0001
Figure imgf000058_0001
58
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
61
Figure imgf000062_0001
Figure imgf000063_0001
63
Figure imgf000064_0001
64
Figure imgf000065_0001
65
Figure imgf000066_0001
Figure imgf000067_0001
67
Figure imgf000068_0001
Figure imgf000069_0001
/051275
69
Figure imgf000070_0001
/051275
70
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
73
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
/051275
77
Figure imgf000078_0001
Figure imgf000079_0001
/05127
79
Figure imgf000080_0001
80
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
83
Figure imgf000084_0001
3/05127
84
Figure imgf000085_0001
/051275
85
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
88
Figure imgf000089_0001
89
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
95
Figure imgf000096_0001
Figure imgf000097_0001
97
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
103
Figure imgf000104_0001
/051
104
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
108
Figure imgf000109_0001
109
Figure imgf000110_0001
Figure imgf000111_0001
ill
Figure imgf000112_0001
3/0512
112
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
124
Figure imgf000125_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
129
Figure imgf000130_0001
0
130
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
137
Figure imgf000138_0001
Figure imgf000139_0001
0
139
Figure imgf000140_0001
140
Figure imgf000141_0001
O 03/051
141
Figure imgf000142_0001
The compounds listed in Table 1, or their pharmaceutically acceptable salts, may be used in the methods described herein to treat or prevent pain.
It will be understood that when compounds of the present invention contain one or more chiral centers, 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.
It will also be appreciated that 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.
It will also be understood that certain compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms. It will further be understood that the present invention encompasses all such solvated forms of the compounds of the formula I.
Within the scope of the invention are also salts of the compounds of the formula I. Generally, 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, HC1 or acetic acid, to afford a physiologically acceptable anion. It may also be possible to make a corresponding alkali metal (such as sodium, potassium, or lithium) or an alkaline earth metal (such as a calcium) salt by treating 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.
In one embodiment, 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 -toluenesulphonate.
The novel compounds of the present invention are useful in therapy, especially for the treatment 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.
Compounds of the invention are useful in disease states where degeneration or dysfunction of Bradykinin 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).
Compounds of the invention are useful for the treatment of septic shock, pancreatitis, edema, rhinitis, asthma, colitis, arthritis, hepatorenal syndrome, cancer, (including but not restricted to SCLC, prostrate cancer), bacterial and viral infections, ulcerative colitis, and Alzheimer's Disease.
Compounds of the invention are useful as an analgesic agent for use during general anesthesia and monitored anesthesia 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.
Also within the scope of the invention is the use of any of the compounds according to the formula I above, for the manufacture of a medicament for the treatment of any of the conditions discussed above.
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.
Thus, the invention provides a compound of formula I, or pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.
In a further aspect, 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.
In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The term "therapeutic" and "therapeutically" 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, acute pain, back pain, cancer pain, and visceral pain.
In use for therapy in a warm-blooded animal such as a human, 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 inj ection into the j oints .
In one embodiment of the invention, the route of administration may be orally, intravenously or intramuscularly. 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. For preparing pharmaceutical compositions from the compounds of this invention, 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 substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or table disintegrating agents; it can also be an encapsulating material.
In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided compound of the invention, or the active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
For preparing suppository compositions, 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 moulds 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.
The term 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.
Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
Liquid form compositions include solutions, suspensions, and emulsions. For example, 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.
Depending on the mode of administration, the pharmaceutical composition will preferably include from 0.05% to 99%w (per cent 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. Within the scope of the invention is the use of any compound of formula I as defined above for the manufacture of a medicament.
Also within the scope of the invention is the use of any compound of formula I for the manufacture of a medicament for the therapy of pain.
Additionally provided is the use of 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, acute 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. Additionally, there is provided a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
Particularly, there is provided 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. Further, there is provided a pharmaceutical 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. In a further aspect, the present invention provides a method of preparing a compound of formula I.
Methods of preparation
The compounds listed in Table 1 were prepared as single compounds in a combinatorial array. The Table 1, column 4 designation of "yes" indicates that the target mass of the designated compound was found in >50% abundance in the MS spectrum. Similarly, the designation of "tentative" indicates that that the target mass of the designated compound was found in 15-50% abundance in the MS spectrum. Likewise the designation "no" indicates that the target mass of the designated compound was found in <15% abundance in MS spectrum. It will be understood by those of ordinary skill in the art that a chemical reaction which fails to efficiently yield the desired product within the context of a combinatorial protocol may nonetheless efficiently yield the desired product when the reaction is performed in a single reaction or parallel reaction format, without undue experimentation on the part of the chemist. In this regard, several of the compounds which were not prepared efficiently in the combinatorial array, were subsequently prepared in separate syntheses as shown in the Examples.
The reaction sequence depicted in Scheme 1, infra, describes a process for preparing compounds of formula (I) wherein X is represented by formula (i) or (ii), comprising reacting a compound of general formula II
Figure imgf000147_0001
wherein Y is a protecting group such as CBZ or FMOC, with an alkyl or alkenyl halide, such as allyl bromide in the presence of a base such as cesium carbonate to give compounds of general formula III; 147
Figure imgf000148_0001
deprotecting the compounds of formula III under standard conditions and then acylated the deprotected products of formula IN with thiophosgene or phosgene to yield isothiocyanates or isocyanates of formula N, respectively:
Figure imgf000148_0002
and subsequently aminating the compounds of formula V combinatorially in a multiwell plate with a selection of different amines to yield compounds of formula I wherein X is represented by formula (i) or (ii) as defined above.
The general protocol for the preparation of the combinatorial library is depicted in Scheme 1 and specific experimental details are provided in the Examples below.
Scheme 1
Figure imgf000148_0003
b is 0, 1, or 2; R1, R2, R3, R4, and R5 are as defined above. In addition, certain compounds of the present invention and certain intermediates used in the preparation of the compounds of the present invention may be prepared according to one or more of the following general procedures, wherein, unless specified otherwise, b, R1, R2, R3, R4 and R5 are defined as above.
General Procedure 1 :
Figure imgf000149_0001
As illustrated in the scheme above, to a stirred solution of (7-chloro-2,3-dihydro-2-oxo-5- phenyl-lH-l,4-benzodiazepin-3-yl)-, phenylmethyl ester- carbamic acid (lOmmol) in DMF (140ml) was added cesium carbonate (3.72g, 11.4mmol) followed by methyl iodide (2.0g, 14mmol). The reaction mixture was stirred at room temperature for 5 hours then concentrated in vacuo. The residue was taken in EtOAc (200ml) and washed with brine (2x30ml). The organic phase was then dried over MgSO4, filtered and concentrated in vacuo. The products were purified by flash chromatography using dichloromethane as the eluent. The products (8mmol) were added with cone ΗBr (33% in acetic acid) (50ml) and were stirred at room temperature for 3 hours. The reaction mixture was poured into ether (300 ml), the precipitate was collected, and then taken in dichloromethane (250 ml) and washed with 2N NaOΗ (2x50ml). The organic phase was dried over MgSO4, filtered and concentrated in vacuo to provide the desired compound.
General Procedure 2:
Figure imgf000149_0002
As illustrated in the scheme above, to a solution of 3-aminobenzodiazepines (3 mmol) in dichloroethane (20ml) and saturated aqueous Na2CO3 (20ml) was added dropwise thiophosgene (0.7g, 6 mmol). and the The reaction mixture was stirred at room temperature for 3 hours. The organic phase was separated and the aqueous phase was extracted with dichloromethane (50ml). The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. The product was purified by flash chromatography (100% CH2C12) to yield a compound of formula N.
General Procedure 3:
RaRb
Figure imgf000150_0002
Figure imgf000150_0001
FTNRaRb
Figure imgf000150_0004
Figure imgf000150_0003
Figure imgf000150_0005
As illustrated in the scheme above, to a solution of 4-fluoro-2 -methyl- 1 -nitro- benzene (0.155g, lmmol) in a 1:1 mixture of ethanol and water (20 ml) was added morpholine (0.435g, 5 mmol). The reaction mixture was heated at 90°C for 16 h. The solvent was evaporated in vacuo, the residue was taken in dichloromethane (50 ml) and washed with brine (3x 10ml). The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The product was taken up in ethanol (20 ml) and heated at reflux. A solution of tin chloride (2M, 2.5 ml) in cone. HC1 was added dropwise and heated at reflux for another 30 minutes. The solvent was then evaporated in vacuo, and the residue was treated with a 2M solution of sodium hydroxide until the pH of the solution was >10. The mixture was extracted with dichloromethane (50 ml) and the organic phase was dried over MgSO , filtered, and concentrated in vacuo. The product (0.032g, 0.2 mmol) ((ESI) (M+H) =192) was taken up in dichloroethane (5 ml), and 7-chloro-5-(2-chlorophenyl)-l,3-dihydro-3- isothiocyanato-1 -methyl- 2H-l,4-benzodiazepin-2-one(0.075g, 0.2 mmol) was added. The reaction mixture was heated at 70C for 16 h. The solvent was evaporated in vacuo, and the residue was washed with ether (2 x 10 ml) to yield the desired compound.
General Procedure 4:
Figure imgf000151_0001
As illustrated in the scheme above, N2 gas was bubbled through both DME and water for at least 3 hours. A solution of the imidoyl chloride (1 equiv.) in DME (1.5 mL/mmol imidoyl chloride) was placed in a N2 purged flask. Na2CO3 (1 equiv.), PdCl2(dppf) (0.05 equiv.), boronic acid (1 equiv.) and water (0.5 mL/mmol imidoyl chloride) were added sequentially, and the resulting mixture was heated at 100 °C until the imidoyl chloride was consumed (typically 16 h). The reaction was then cooled, diluted with CH2C12 and water, and the layers were separated. The aqueous phase was extracted with CH2C12 (3x), and the combined organic phases were dried over Na2SO , filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography to provide the desired compound.
General Procedure 5:
Figure imgf000151_0002
As illustrated in the scheme above, boronic acid (1.15 equiv.), Pd2(dba)3 (0.015 equiv.), and dry KF (3.3 equiv.) were placed in an oven-dried, N2 purged flask. A solution of the imidoyl chloride (1 equiv.) in dry THF (2 mL/mmol imidoyl chloride) was added followed by a solution of P(t-Bu)3 (0.045 equiv., 10 % solution in hexanes) in dry THF (1.6 mL/mmol imidoyl chloride). The resulting mixture was heated at reflux until the imidoyl chloride was consumed (typically 16 h). The reaction was then cooled, diluted with EtOAc, and filtered through a small pad of silica gel. The silica was washed well with EtOAc, and the combined organic phases were concentrated in vacuo. The product was purified by silica gel column chromatography to provide the desired compound.
General Procedure 6:
Figure imgf000152_0001
As illustrated in the scheme above, a solution of the benzodiazepine compound (1 equiv.) in dry THF (4 mL/mmol benzodiazepine, or slightly more if solubility was low) was added to a mixture of KΗMDS (1.05 equiv., 0.5 M in toluene) and dry THF (2 mL/mmol benzodiazepine) immersed in a -78 °C cooling bath. After stirring for 5 min., a solution of trisyl azide (2.5 equiv) in dry THF (4 mL/mmol benzodiazepine) was added to the reaction, and stirring was continued until all the starting benzodiazepine had been consumed (typically 10 min.). Glacial acetic acid (4.4 equiv) was then added, and the mixture was warmed to 30 °C for 2 h. Saturated NaHCO3 was added, the layers were separated, and the aqueous phase was extracted with CH2C12 (4x). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. The product was purified by silica gel column chromatography to provide the corresponding azide compound.
General Procedure 7:
Figure imgf000153_0001
As illustrated in the scheme above, polymer supported triphenylphosphine (Argonaut Technologies, 5-10 equiv) was added to a solution of the azide (1 equiv.) in THF (10 mL/g polymer) and water (0.8 mL/g polymer). The resulting mixture was stirred at room temperature until all of the azide had been consumed (typically overnight). The polymer resin was then removed by filtration, and was washed well with CH C12 and MeOH (3x each). The filtrate was concentrated in vacuo, and the residue was redissolved in CH2C12. Any remaining water was removed with the aid of a separatory funnel, and the organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The amine was purified using a "catch and release" strategy with MP-TsOH resin (Argonaut Technologies): The product was dissolved in CH2C12 (10 mL/mmol product), and MP- TsOH resin (2.3 equiv) was added. The mixture was stirred for 1 h, and the solvent was removed by filtration and discarded. The resin was rinsed with CH2C12 and MeOH (3x each), and the washings were discarded as well. The product was then released from the resin by washing with 2M NH in MeOH and CH2C12 (3x each). Concentration of the filtrate in vacuo provided the corresponding amine compound.
Additional compounds of the present invention may also be prepared according to the m neetthhooddss rreepprreesseennted in Schemes 2-4 below, wherein, unless specified otherwise, b, R , R2, R3, R4 and R5 are defined as above.
Scheme 2
Figure imgf000154_0001
Scheme 3
Figure imgf000155_0001
Scheme 4
Figure imgf000155_0002
Biological Evaluation
I. B2 bradykinin Binding Assay
A. Human Bradykinin B2 (hB2) receptor expression and membrane preparation The cloned human Bradykinin B2 (hB2) receptor in the pCIN vector was purchased from Receptor Biology. The hB2 receptor was stably transfected into HEK 293 S cells and a clonal cell line was generated. Cells were grown in T-flasks with DMEM culture media containing 10% FBS, 2 mM glutamine, 600μg/ml neomycin and an antibiotic cocktail (100 IU penicillin, lOOμg/ml streptomycin, 0.25μg/ml amphotericin B). Membranes, expressing the hB2 receptor, were prepared from this cell line according to this protocol: Cells are harvested at 1 to 1.2 million cells/ml, pelleted, and resuspended in ice-cold lysis buffer (50 mM Tris, pH 7.0, 2.5 mM EDTA, with PMSF added just prior to use to 0.5 mM from a 0.5 M stock in DMSO. After lysis on ice for 15 min, the cells are homogenized with a polytron for 10 sec. The suspension is spun at lOOOg for 10 min at 4°C. The supernatant is saved on ice and the pellets resuspended and spun as before. The supematants from both spins are combined and spun at 46,000g for 10-30 min. The pellets are resuspended in cold Tris buffer (50 mM Tris/Cl, pH 7.0) at a dilution of 0.2 - 1 ml per 40 million cells and spun again. The final pellets are resuspended in membrane buffer (50 mM Tris, 0.32 M sucrose, pH 7.0). Aliquots are frozen in dry ice/ethanol and stored at -70°C until use. The protein concentrations are determined by a modified Lowry with SDS.
B. hB2 receptor binding Membranes expressing the hB2 receptor are thawed at 37°C, passed 3 times through a 25- gauge blunt-end needle, diluted in the bradykinin binding buffer (50 mM Tris, 3mM MgCl2, and 1 mg/ml BSA, pH 7.4, 0.02 mg/ml Phenanthroline, 0.25 mg/ml Pefabloc) and 80 μL aliquots containing the appropriate amount of protein (final concentration of 0.25μg/ml) are distributed in 96-well polystyrene plates (Treff Lab). The IC5o of compounds are evaluated from 10-point dose-response curves, where the serial dilutions are done on a final volume of 150μL, with 70μL of 125I-Desamino-TyrHOE140 (Kd=0.05) at 50,000 to 60,000 dpm per well (0.03-0.04nM) in a final volume of 300μl. The total and non-specific binding are determined in the absence and presence of 0.1 μM (150μL) of Bradykinin respectively. The plates are vortexed and incubated for 60 minutes at room temperature, filtered through Unifilters-96 GF/B (Canberra Packard), which were presoaked in 0.1 % polyethyleneimine, with a harvester using 3ml of wash buffer (50 mM Tris, pH 7.0, 3mM MgCl2). The filters are dried for 1 hour at 55°C. The radioactivity (cpm) is counted in a TopCount (Canberra Packard) after adding 65 μl/well of MS-20 scintillation liquid (Canberra Packard). Compounds of the present invention have demonstrated hB2 receptor binding at concentrations less than 10 μM.
Based on the above assays, the dissociation constant (Ki) for a particular compound of the invention towards a particular receptor is determined using the following equation:
Ki = IC50/(l+[rad]/Kd),
Wherein IC5o is the concentration of the compound of the invention at which 50%) displacement has been observed;
[rad] is a standard or reference radioactive ligand concentration at that moment; and
Kd is the dissociation constant of the radioactive ligand towards the particular receptor.
II. GTPM-^S binding experiments on Bradykinin (B2) receptors A. General Information
The procedures below describe how to perform and interpret GTP[γ]35$ binding experiments designed to determine the activity of new compounds on the human B2 receptor.
B. General procedure of the assay
Human Bradvkinin-2 GTPfγ135S Binding
Human Bradykinin-2 membranes (hB2 293s) are thawed at 37°C, passed 3 times through a 25-gauge blunt-end needle and diluted in the GTPγS binding buffer for the assay (50 mM Hepes, pH 7.4; 200 mM NaCl; 1 mM EDTA; 5 mM MgCl2. To this added freshly prepared 1 mM DTT, 0.5% BSA, 1 μM GDP. The EC50 and Emax of compounds are evaluated from 10-point dose-response curves done in 300μl with the appropriate amount of membrane protein and 100,000-120,000 dpm of GTPγ35S per well (0.11 - 0.14 nM). Bradykinin (1-9) is used as the standard agonist at hB2. The ranges of concentrations tested should include a maximal concentration of O.lμM bradykinin in order to establish the Emax.
The plates are vortexed and incubated for 60 minutes at room temperature, filtered on GF/B Unifilters (presoaked in water) with the Packard harvester using 4 ml/well of wash buffer (50 mM Tris, 5 mM MgCl2, 50 mM NaCl, pH 7.0), minimum. The filters are dried for 1 hour at 55°C. The radioactivity (cpm) is counted in a TopCount (Packard) after adding 65 μl/well of MS-20 scintillation liquid.
Antagonist reversal studies are done in a similar manner except that the compound dose-response curve's are performed in the presence of a constant concentration of agonist (approx. 80%> bradykinin Emax ; ~ 5 nM). A standard B2 Antagonist is used as the reference antagonist at hB2. The ranges of antagonist concentrations tested should include a maximal concentration of 3μM of the standard B2 Antagonist in order to establish the maximal displacement (Dmax).
C. Radioligand: Preparation of GTP[γ]35S
GTP[γ]35s is acquired from Perkin-Elmer (250 μCi/20 μl) . It is diluted from with 10 mM DTT, 50 mM Tris, pH 7 (dilute in 2 ml, 1.0 mCI/20μ). Sonicate the solution, filter through a 0.45 μm filter, and freeze aliquots at -70°C. For the experiment, use ~ 0.3 nM dilution of this tracer in the GTP binding buffer.
D. Data analysis
The EC50 and Emax of compounds are evaluated from 10-point dose-response curves done in 300μl with the appropriate amount of membrane protein and GTPγ35S per well and are calculated in Activity base with ExcelFit. The basal and maximal stimulated binding are determined in the absence and presence of standard reference compounds, respectively.
The stimulation (Stim) in the presence of compounds is expressed as the percentage of Dmax of the reference antagonist. Values of IC50, Ki' and Dmax for ligands capable of competing for agonist stimulated binding are calculated in Activity Base.
Mean ± S.E.M. values of IC50 , Ki' and % Dmax are reported for ligands tested in at least three dose-response curves.
Biological data for particular testing samples (as listed in Table 2) of the compounds of the invention are listed in Table 3 below.
Table 2: List of the test samples used in the Biological Evaluation
Test Sample Nos: Structure of the Test Sample
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0003
Table 3 Biological Data for the testing samples as listed in Table 2
Figure imgf000163_0004
EXAMPLES
The invention will further be described in more detail by the following Examples which describe methods whereby compounds of the present invention may be prepared, purified, analyzed and biologically tested, and which are not to be construed as limiting the invention.
INTERMEDIATE 1 : 3-amino-7-chloro-l,3-dihydro-l-methyl-5-phenyl-2H-l,4- benzodiazepin-2-one.
Figure imgf000163_0001
Following General Procedure 1, INTERMEDIATE 1 was obtained as pale brown solid (2.5g, 11%) and used for the subsequent reaction without further purification. MS (ESI) (M+H)+=300.
INTERMEDIATE 2: 3-amino-5-(2-bromophenyl)-7-fluoro-l,3-dihydro-l-methyl- 2H-l,4-benzodiazepin-2-one.
Figure imgf000163_0002
Following General procedure 1, INTERMEDIATE 2 was obtained as a thick pale brown oil (0.5g, 17%) and used for the subsequent reaction without further purification. INTERMEDIATE 3: 3-amino-5-cycIohexyl-l,3-dihydro-l-methyl-2H-l,4- benzodiazepin-2-one.
Figure imgf000164_0001
Following General Procedure 1, after flash chromatography (100% EtOAc), INTERMEDIATE 3 was obtained as a pale brown solid ( 1.25g, 45%). MS (ESI) (M+H)+=272
INTERMEDIATE 4: 3-amino-7-chloro-5-(2-chloroplιenyl)-l,3-dihydro-l-methyl- 2JΪ-l,4-benzodiazepin-2-one.
Figure imgf000164_0002
Following General Procedure 1, INTERMEDIATE 4 was obtained as a thick pale brown oil (1.8g, 65%) and used for the subsequent reaction without further purification. MS
(ESI) (M+H)+=334
INTERMEDIATE 5 : 3-amino-l,3-dihydro-l-methyl-5-phenyl-2H-l,4- benzodiazepin-2-one.
Figure imgf000164_0003
To a stirred solution of (2,3-dihydro-2-oxo-5-phenyl-lH-l,4-benzodiazepin-3-yl)-, phenylmethyl ester-carbamic acid, (4.0g, 10.3mmol) in toluene (100ml) was added Aliquat336 (l.Og) and 50% aqueous sodium hydroxide (20ml) followed by methyl iodide (5.0g, 35mmol) . The reaction mixture was stirred at room temperature for 17 hours. The solvent was evaporated in vacuo and the residue was taken in dichloromethane (150ml). The organic phase was washed with 2N sodium hydroxide (50ml) and brine (50ml); the organic phase was dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with hexane and the precipitate was treated with cone. ΗBr as in General Procedure 1. INTERMEDIATE 5 was obtained as a pale brown solid (1.63g, 59%) and used for the subsequent reaction without further purification. MS (ESI) (M+H) A266
INTERMEDIATE 6: 3-amino-7-chloro-l,3-dihydro-5-phenyl-l-(2-propenyl)- 2H- l,4-benzodiazepin-2-one.
Figure imgf000165_0001
To a stirred solution of (7-chloro-2,3-dihydro-2-oxo-5-phenyl-lH-l,4-benzodiazepin-3- yl)-, phenylmethyl ester- carbamic acid (lmmol) in DMF (10ml) was added cesium carbonate (0.370g, 1.14mmol) followed by allyl bromide (0.134g, 1. lmmol). The reaction mixture was stirred at room temperature for 5 hours. The solvent was evaporated in vacuo and the residue was taken in EtOAc (50ml). The organic phase was washed with brine (2x10ml); the organic phase was dried over MgSO4, filtered and concentrated in vacuo. The crude products were purified by flash chromatography using dichloromethane as the eluent. The crude product was added to cone. ΗBr (33% in acetic acid) (10ml) and stirred at room temperature for 3 hours. The reaction mixture was poured into ether (100 ml), the precipitate was collected and then taken in dichloromethane (50 ml) and washed with 2N NaOΗ (2x10ml). The organic phase dried over MgSO4, filtered and concentrated in vacuo. The title compound was obtained as a pale yellow solid (0.19g, 60%) and used for the subsequent reaction without further purification. MS (ESI) (M+Η)+=326
INTERMEDIATE 7: 7-chloro-l,3-dihydro-3-isothiocyanato-l-methyl-5-phenyl-2H- l,4-benzodiazepin-2-one.
Figure imgf000165_0002
Following General Procedure 2, INTERMEDIATE 7 was obtained as a pale yellow solid (0.7g, 69%). Η-NMR (CDC13): δ 7.66-7.64 (m, 2H), 7.60-7.57 (dd, J=2.4Hz and 8.8Hz, 1H), 7.55-7.51 (m, 1H), 7.47-7.43 (m, 2H), 7.36-7.34 (m, 2H) and 3.48 (s, 4H) MS (ESI) (M+H)+=342 INTERMEDIATE S: 7-chloro-5-(2-chlorophenyl)-l,3-dihydro-3-isothiocyanato-l- methyl-2iϊ-l,4-benzodiazepin-2-one.
Figure imgf000166_0001
Following General Procedure 2, after flash chromatography (dichloromethane), the title compound was obtained as pale yellow solid (2.2g, 65%). 1H-NMR (CDC13): δ 7.66-7.64 (m, IH), 7.56-7.53 (dd, J=2.4Hz and 8.8Hz, IH), 7.46-7.43 (m, 2H), 7.39-7.37 (m, IH), 7.05 (d, J=2.0Hz, IH), 3.73 (s, IH) and 3.51 (s, 3H). MS (ESI) (M+H)+=376
EXAMPLE 1 : N-(7-chloro-2,3-dihydro-l-methyl-2-oxo-5-phenyl-lH-l,4- benzodiazepin-3-yl)-iV-(5-isoquinolinyl)- thiourea.
Figure imgf000166_0002
Scheme:
Figure imgf000166_0003
X= H, halogen
As illustrated in the scheme above, to a solution of 7-chloro-l,3-dihydro-3- isothiocyanato-l-methyl-5-phenyl-2H-l,4-benzodiazeρin-2-one (INTERMEDIATE 7) (0.035g, 0. lmmol) in dichloromethane (5ml) was added 5-isoquinolinamine (0.015g, 0. lmmol). The reaction mixture was heated at reflux for 17 hours. The solvent was evaporated in vacuo, the residue was triturated with ether and the title compound was obtained as a colorless solid (20mg, 40%). Η-NMR (CDC13): δ 9.33 and 9.19 (2xs, 1Η), 8.63 and 8.49 (2xd, A5.6Ηz and A6.0Hz, IH), 8.34 (br s, IH), 8.02 (d, A8.4Hz, IH), 7.92 (t, J=l 1.6Hz, 2H), 7.58-7.32 (m, 10H), 6.03 (d, A7.6Hz, IH) and 3.3 (s, 3H). MS (ESI) (M+H)+= 486 EXAMPLE 2 : N-(7-chloro-2,3-dihydro-l-methyl-2-oxo-5-phenyl-lH-l,4- benzodiazepin-3-yl)-iV-[4-(dimetlιylamino)phenyl]- thiourea.
Figure imgf000167_0001
To a solution of 7-chloro-l,3-dihydro-3-isothiocyanato-l-methyl-5-phenyl-2H-l,4- benzodiazepin-2-one (INTERMEDIATE 7) (0.342g, lmmol) in dichloromethane (20ml) was added N,N-dimethyl-l,4-benzenediamine (0.136g, lmmol). The reaction mixture was heated at reflux for 17 hours. The solvent was evaporated in vacuo, the residue was triturated with ether and the title compound was obtained as a colorless solid (0.167g, 35%). 1H-ΝMR (CDC13): δ 7.70-7.22 (m, 10Η), 6.75 (d, A8.8Ηz, 2H), 6.05 (d, A7.6Hz, IH), 3.42 (s, 3H) and 2.98 (s, 6H). MS (ESI) (M+H)+= 478.
EXAMPLE 3: N-(7-chloro-2,3-dihydro-l-methyl-2-oxo-5-phenyl-lJΪ-l,4- benzodiazepin-3-yl)-iV-[4-(dimethylamino)-l-naphthalenyl]-N-methyl- thiourea.
Figure imgf000167_0002
To a stirred solution of carboxybenzyl-3-amino-7-chloro-5-phenyl-2-oxo-l,4- benzodiazepine (EXAMPLE 6) (lmmol) in DMF (10ml) was added cesium carbonate (5mmol) followed by methyl iodide (2.2mmol). The reaction mixture was stirred at room temperature for 5 hours. The solvent was evaporated in vacuo and the residue was taken in EtOAc (50ml). The organic phase was washed with brine (2x10ml); the organic phase was dried over MgSO , filtered and concentrated in vacuo. The product (O.δmmol) was added to cone. HBr (35% in acetic acid) (10ml) and was stirred at room temperature for 3 hours. The reaction mixture was poured into ether (30ml), the precipitate was collected, and taken in dichloromethane (25 ml) and washed with 2N NaOH (2x10ml). The organic phase was dried over MgSO , filtered and concentrated in vacuo. The product was used for the subsequent steps without further purification.
To a solution of the product above (0.03g, lmmol) in dichloroethane (5ml) was added 4- isothiocyanato-N,N-dimethyl-l-naphthalenamine (0.025g, lmmol). The reaction mixture was stirred at 70C for 4 hours. The solvent was evaporated in vacuo, the residue was triturated with ether and the title compound was obtained as a colorless solid (28mg, 52%). 1H-NMR (CDC13): δ 8.24 (m, IH), 7.92 (m, IH), 7.67 (d, J=7.2Hz, 2H), 7.52-7.40 (m, 8H), 7.31 (d, A1.6Hz, IH), 7.05 (d, J=8.0Hz, 2H), 3.78 (s, 3H), 3.41 (s, 3H) and 2.91 (s, 6H). MS (ESI) (M+H)+=542.
EXAMPLE 4: N-[7-chloro-5-(2-chlorophenyl)-2,3-dilιydro-l-metlιyl-2-oxo-lH-l,4- benzodiazepin-3-yl]-N'-[4-(dimethylamino)-l-naphthalenyl]- thiourea.
Figure imgf000168_0001
To a solution of 3-amino-7-chloro-5-(2-chlorophenyl)-l,3-dihydro-l-methyl-2H-l,4- benzodiazepin-2-one (LNTERMEDIATE 8) (0.03g, lmmol) in dichloroethane (5ml) was added 4-isothiocyanato-N,N-dimethyl-l-naphthalenamine (0.025g, lmmol). The reaction mixture was stirred at 70°C for 4 hours. The solvent was evaporated in vacuo, the residue was triturated with ether and the title compound was obtained as a colorless solid (35mg, 60%). 1H-ΝMR (CDCI3): δ 8.26 (d, A8.4Ηz, IH), 8.03 (d, J=7.6Hz, IH), 7.93 (br s, IH), 7.73-7.06 (m, 1 IH) 6.10 (d, J=7.6Hz, IH), 3.40 (s, 3H) and 2.92 (s, 6H). MS (ESI) (M+H)+= 562.
EXAMPLE 5: N-[7-chloro-2,3-dihydro-2-oxo-5-phenyl-l-(2-propenyl)-lH-l,4- benzodiazepin-3-yI]-7Y-[4-(dimethylamino)-l-naphthaIenyl]- thiourea.
Figure imgf000168_0002
A solution of 3-amino-7-chloro-l,3-dihydro-5-phenyl-l-(2-propenyl)- 2H-1,4- benzodiazepin-2-one (INTERMEDIATE 6) (0.162g, 0.5mmol) in dichloroethane (5ml) was added 4-isothiocyanato-N,N-dimethyl-l-naphthalenamine (0.115g, 0.5mmol). The reaction mixture was stirred at 70°C for 4 hours. The solvent was evaporated in vacuo, the residue was triturated with ether and the title compound was obtained as a colorless solid (0.152g, 55%). 1H-ΝMR (CDCI3): δ 8.29-8.27 (m, 1Η), 8.08-8.06 (m, 1Η), 7.90 (s, 1H), 7.60-7.36 (m, 10H), 7.32 (d, J=2.4Hz, IH), 7.09 (d, J=8Hz, IH), 6.14 (d, J=7.6Hz, IH), 5.76-5,69 (m, IH), 5,15 (s, IH), 5.12 (dd, A1.2 and 7.0 Hz, IH), 4.57-4.39 (m, 2H) and 2.93 (s, 6H). MS (ESI) (M+H)+=554.
EXAMPLE 6: N-(7-chloro-2,3-dihydro-l-methyl-2-oxo-5-phenyl-lH-l,4- benzodiazepin-3-yl)--V-[4-(dimethylamino)-l-naphthalenyl]- thiourea.
Figure imgf000169_0001
To a solution of 3-amino-7-chloro-5-phenyl-l,3-dihydro-l-methyl-2H-l,4-benzodiazepin- 2-one (INTERMEDIATE 1) (0.299g, lmmol) in dichloroethane (15ml) was added 4- isothiocyanato-N,N-dimethyl-l-naphthalenamine (0.230g, lmmol). The reaction mixture was stirred at room temperature for 17 hours. The solvent was evaporated in vacuo, the residue was triturated with ether and the title compound was obtained as a colorless solid (0.345g, 65%). 1H-ΝMR (CD3OD): δ 8.25 (d, 8.4Ηz, 2H), 8.00 (d, J=8.4Hz, IH), 7.88 (d, J=8.4Hz, IH), 7.85-7.81 (m, 2H), 7.77-7.72 (m, 2H), 7.65 (d, J=8.8Hz, IH), 7.61-7.58 (m, 4H), 7.51-7.47 (m, 2H), 7.29 (d, J=2.4Hz, IH), 6.01 (s, IH) and 3.49 (s, 9H). MS (ESI) (M+H)+= 528.
EXAMPLE 7: N-(7-chloro-2,3-dihydro-l-methyl-2-oxo-5-phenyl-lH-l,4- benzodiazepin-3-yl)-iV-(4-methoxy-2-methylpheny )- urea.
Figure imgf000169_0002
To a solution of 3-amino-7-chloro-5-phenyl-l,3-dihydro-l-methyl-2H-l,4-benzodiazepin-
2-one (INTERMEDIATE 1) (0.299g, lmmol) in dichloromethane (15ml) was added 1- isocyanato-4-methoxy-2-methyl- benzene (0.163g, lmmol). The reaction mixture was stirred at room temperature for 17 hours. The solvent was evaporated in vacuo, the residue was triturated with ether and the title compound was obtained as a colorless solid
(0.197g, 42%). 1H-NMR (CDC13): δ 7.57-7.48 (m, 3Η), 7.47-7.44 (m, IH), 7.39-7.38 (m,
3H), 7.36-7.29 (m, 2H), 6.77-6.73 (m, 2H), 6.71 (d, A2.8Hz, IH), 6.61 (s, IH), 5.51 (d,
A8.4Hz, IH), 3.78 (s, 3H), 3.39 (s, 3H) and 2.29 (s, 3H). MS (ESI) (M+H)+ = 463. EXAMPLE 8: N-(7-chloro-2,3-dihydro-l-methyl-2-oxo-5-phenyl-lH-l,4- benzodiazepin-3-yl)-iV-[4-(dimethylamino)-l-naplιtlιalenyl]- urea.
Figure imgf000170_0001
Figure imgf000170_0002
As illustrated in the scheme above, a mixture of 4-(dimethylamino)- 1- naphthalenecarboxylic acid (0. lmmol), diphenylphosphoryl azide (0.15mmol) and triethylamine (0.3mmol) in toluene (10ml) was heated at reflux overnight. The solvent was evaporated in vacuo, and then the residue was redissolved in dichloroethane, added to INTERMEDIATE 1 (0.08mmol) and heated at 70°C for 4 hours. The solvent was evaporated in vacuo and the residue was taken in dichloromethane (50ml). The organic phase was washed with brine (2x10ml); the organic phase was dried over MgSO , filtered and concentrated in vacuo. The residue was triturated with ether and the title compound was obtained as a colorless solid (9mg, 22%); 1H-NMR (CDC13): δ 8.27 (m, IH), 8.11 (m, IH), 7.60 (d, J=8Hz, IH), 7.77-7.29 (m, 10H), 7.08 (d, J=8.4Hz, IH), 6.75 (br s, 2H), 5.56 (d, J=8.4Hz, IH), 3.39 (s, 3H) and 2.90 (s, 6H); MS (ESI) (M+H)+= 512.
EXAMPLE 9: N-[5-(2-bromophenyl)-7-fluoro-2,3-dihydro- Amethyl-2-oxo-lH-l,4- benzo-diazepin-3-yl]-iY-[4-(dimethylamino)-l-naphthalenyl]- thiourea.
Figure imgf000170_0003
Scheme:
Figure imgf000171_0001
As illustrated in the scheme above, INTERMEDIATE 2 (0.018g, 0.05mmol) and 4- isothiocyanato-N,N-dimethyl-l-naphthalenamine (0.01 lg, 0.05mmol) was heated in dichloroethane (4 mL) at 70°C overnight. The solvent was evaporated in vacuo and the residue was trituated with ether (2 x 10 ml). The title compound (0.021g, 72%) was obtained as a colorless solid. 1H-ΝMR (CDC13): δ 8.26 (m, IH), 8.06 (m, IH), 7.85 (s, IH), 7.79 (m, IH), 7.69 - 7.24 (m, 8H), 7.08 (d, J=8.0Hz, IH), 7.02 (t, J=8.4Hz, IH), 6.06 (d, J=8.0 Hz, IH), 3.39 (s, 3H), 2.93 (s, 6H). (ESI) (M+H)X9i.
EXAMPLE 10: N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-l-methyl-2-oxo-lJ3-l,4- benzo-diazepin-3-yl]-iV ,-cyano-N'-[4-(4-morpholinyI)-l-naphthalenyl]- guanidine (E and Z isomers separated but not identified).
Figure imgf000171_0002
Scheme:
Figure imgf000172_0001
As illustrated in the scheme above, a solution of N-[7-chloro-5-(2-chlorophenyl)-2,3- dihydro-l-methyl-2-oxo-lH-l,4-benzodiazepin-3-yl]-N-[4-(4-morpholinyl)-l- naphthalenyl]- thiourea (EXAMPLE 11, made according toGeneral Procedure 3) (0.058g, 0.1 mmol) and silver triflate (0.077g, 0.3 mmol) in dichloromethane (2 ml) was combined with cyanamide disodium salt (1 mmol) and stirred at room temperature for 3h. The reaction mixture was then diluted with dichloromethane (10 ml) and washed with brine (2x5 ml). The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The residue was washed with ether (2 10 ml) and the polar isomer of the title compound (0.023g, 38%) was obtained as pale yellow solid. The ether layer was concentrated in vacuo and purified by column chromatography (1:1 EtOAc :CΗ2C12) to give the non-polar isomer of the title compound (0.009g, 15%) as a colorless solid.
EXAMPLE 10A: N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-l-methyl-2-oxo-lH- l,4-benzo-diazepin-3-yl]-N"-cyano--V-[4-(4-morpholinyl)-l-naphthalenyl]- guanidine (polar isomer)
1H-ΝMR (CDC13): δ 8.26 (m, IH), 7.9 (m, 2H), 7.69 (d, J=12.0Hz, 2H), 7.53 - 7.46 (m, 4H), 7.39 (m, IH), 7.30 - 7.23 (m, 4H), 7.11 (m, 2H), 3.98 (t, J=9.2Hz, 2H), 3.48 (s, 3H) and 3.12 (br.s, 6H). (ESI) (M+H)A612 EXAMPLE 10B: N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-l-methyl-2-oxo-lH- l,4-benzo-diazepin-3-yl]-NM-cyano--V-[4-(4-morpholinyl)-l-naphtlialenyl]- guanidine (nonpolar isomer).
1H-NMR (CDCI3): δ 8.25 (m, IH), 8.03 (m, IH), 7.66 - 7.53 (m, 5H), 7.44 - 7.40 (m, 3H), 7.39 - 7.30 (m, 2H), 7.09 (m, 2H), 6.54 (d, J=7.6Hz, IH), 5.48 (d, J=7.6Hz, IH), 3.99 (t, J=9.2Hz, 4H), 3.39 (s, 3H) and 3.15' (br.s, 4H). (ESI) (M+H)+=612.
EXAMPLE 11: N-[7-chIoro-5-(2-chlorophenyl)-2,3-dihydro-l-methyl-2-oxo-lH-l,4- benzodiazepin-3-yI]-N'-[4-(4-morpholinyl)-l-naplιthalenyl]-thiourea
Figure imgf000173_0001
Following General Procedure 3, the title compound (0.078g, 65%) was obtained as a white solid. 1H-NMR (CDC13): δ 8.4 (m, IH), 8.08 (m, 2H), 7.72 (m, IH), 7.64 (d,
J=8Hz, IH), 7.6-7.5 (m, 4H), 7.39 (t, J=4.4Hz, 2H), 7.30 (d, J=8.8Hz, 2H), 7.10 (m, 2H),
6.09 (d, J=7.6 Hz, IH), 3.98 (t, J=4.4Hz, 4H) 3.40 (s, 3H), and 3.13 (m, 4H). (ESI) (M+H)+=604.
EXAMPLE 12: N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-l-methyl-2-oxo-lH-l,4- benzo-diazepin-3-yl]-Λ^-[4-(4-morpholinyl)-l-naphthalenyl]- uanidine.
Figure imgf000173_0002
As illustrated in the scheme above, to a solution of N-[7-chloro-5-(2-chlorophenyl)-2,3-- dihydro- 1 -methyl-2-oxo- IH- 1 ,4-benzodiazepin-3 -yl]-N-[4-(4-morpholinyl)- 1 - naphthalenyl]- thiourea (EXAMPLE 11) (0.029g, 0.05 mmol) and silver triflate (0.038g, 0.15 mmol) in dichloromethane (2 ml) was added a solution of ammonia (0.25ml, 2M in methanol). Thereactiomn mixture was stirred at room temperature for 3h, diluted with dichloromethane (10 ml) and washed with brine (2x5 ml). The organic layer was dried with MgSO4 filtered, concentrated in vacuo. The residue was triturated with ether to give the title compound (0.008g, 28%) as a pale yellow solid. 1H-ΝMR (CDC13): δ 8.22 (d, J= 9.2Ηz, IH), 8.11 (d, J=8.4Hz, IH), 7.75 (br.s, IH), 7.50 - 7.41 (m, IK), 7.31 (d, J=8.8Hz, IH), 7.04 (m, 2H), 5.8 (br.s, IH), 3.96 (t, J=9.2Hz, 4H) 3.51 (s, 3H) and 3.05 (br.s, 4H). ). (ESI) (M+H)+=587.
EXAMPLE 13: N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-l-methyl-2-oxo-lH-l,4- benzo-diazepin-3-yl]-iV-[2-methyl-4-(4-morpholinyl)phenyl]- thiourea.
Figure imgf000174_0001
Following General Procedure 3, the title compound (0.096g, 85%) was obtained as a colorless solid. 1H-ΝMR (CDC13): δ 7.74 (m, IH), 7.54 (s, IH), 7.51 (m, IH), 7.42 - 7.39 (m, 3H), 7.34 - 7.31 (m, 2H), 7.24 (d, J=8.8Hz, IH), 7.09 (d, J=2.4Hz, IH), 6.80 - 6.76 (m, 2H), 6.09 (d, A7.6Hz, IH), 3.85 (t, J=9.6Hz, 4H), 3.44 (s, 3H), 3.17 (t, AlO.OHz, 4H) and 2.32 (s, 3H). (ESI) (M+H)+=568.
EXAMPLE 14: N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-l-methyl-2-oxo-lH-l,4- benzo-diazepin-3-yl]-iV-[4-(dimethylamino)-2-methylphenyl]- thiourea.
Figure imgf000174_0002
Following the General Procedure 3, the title compound (0.052g, 51%) was obtained as a pale brown solid. 1H-NMR (CDC13): δ 7.75 (m, IH), 7.52 (dd, J=8.8Hz, IH), 7.47 (s, IH), 7.42 - 7.40 (m, 3H), 7.34 - 7.31 (m, 2H), 7.19 (d, J=8.0Hz, IH), 7.09 (d, J=2.0Hz, IH), 6.60 (br.s, IH), 6.58 (br.s, IH), 6.09 (d, J=8.0Hz, IH), 3.44 (s, 3H), 2.97 (s, 6H) and 2.30 (s, 3H). (ESI) (M+H)+=526.
EXAMPLE 15: N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-l-methyl-2-oxo-lH-l,4- benzo-diazepin-3-yl]-/Y-[4-(dimethylamino)-3-methylphenyl]- thiourea.
Figure imgf000174_0003
Following General Procedure 3, the title compound (0.034g, 35%) was obtained as a pale brown solid. 1H-NMR (CDC13): δ 7.86 (d, J=7.6Hz, IH), 7.76 (m, IH), 7.53 (dd, J=8.8Hz, IH), 7.42 - 7.39 (m, 2H), 7.36 - 7.32 (m, 2H), 7.17 (dd, J=8.8Hz, IH), 7.12 (d, J=2.0Hz, IH), 7.10 (d, J=2.4Hz, IH), 7.06 (d, J=8.4Hz, IH), 6.09 (d, J=7.6Hz, IH), 3.46 (s, 3H), 2.71 (s, 6H) and 2.33 (s, 3H). (ESI) (M+H)+=526.
EXAMPLE 16: N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-l-methyl-2-oxo-lH-l,4- benzo-diazepin-3-yl]-iV-[3-chloro-4-(dimethylamino)phenyl]- thiourea.
Figure imgf000175_0001
Following the General Procedure 3, the title compound (0.025g, 23%) was obtained as a pale brown solid. 1H-NMR (CDC13): δ 7.86 (s, IH), 7.83 (d, J=7.2Hz, IH), 7.5 (m, IH), 7.53 (dd, J=8.8Hz, IH), 7.43 - 7.40 (m, 2H), 7.35 - 7.33 (m, 2H), 7.28 (m, IH), 7.10 (s, A2.0Hz, IH), 7.05 (d, J=7.2Hz, IH), 6.06 (d, J=7.2Hz, IH), 3.47 (s, 3H) and 2.82 (s, 6H). (ESI) (M+H)+=546.
EXAMPLE 17: N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-l-methyl-2-oxo-lH-l,4- benzo-diazepin-3-yl]-iV-[4-(dimethylamino)-3-(trifluoromethyl)phenyl]- thiourea.
Figure imgf000175_0002
Following General Procedure 3, the title compound (0.017g, 18%>) was obtained as a pale brown solid. 1H-NMR (CDC13): δ 7.93 (s, IH), 7.85 (d, J=7.2Hz, IH), 7.38 (m, IH), 7.58 (d, J=8.4Hz, IH), 7.55 - 7.53 (m, 2H), 7.42 - 7.40 (m, 2H), 7.34 (m, 3H), 7.10 (s, J=2.0Hz, IH), 6.06 (d, J=7.6Hz, IH), 3.47 (s, 3H) and 2.76 (s, 6H). (ESI) (M+H)+=580.
EXAMPLE 18: N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-l-methyl-2-oxo-lH-l,4- benzo-diazepin-3-yl]-iV-[4-chloro-2-(dimethylamino)phenyl]-thiourea.
Figure imgf000176_0001
Following the General Procedure 3, the title compound (0.024g, 22%) was obtained as a pale brown solid. 1H-NMR (CDC13): δ 8.55 (d, J=7.2Hz, IH), 7.84 (s, IH), 7.77 (t, J= .8Hz, IH), 7.53 (dd, J=8.8Hz, IH), 7.46 (d, J=8.4Hz, IH), 7.42 - 7.41 (m, 2H), 7.36 - 7.34 (m, 3H), 7.11 - 7.02 (m, 2H), 60.6 (d, A7.2Hz, IH), 3.48 (s, 3H) and 2.75 (s, 6H). (ESI) (M+H)+=546.
EXAMPLE 19: N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-l-methyl-2-oxo-lH-l,4- benzo-diazepin-3-yl]-iV-[4-(diethylamino)-2-(dimethylamino)phenyl]- thiourea.
Figure imgf000176_0002
Following the General Procedure 3, the title compound (0.040g, 35%) was obtained as a pale gray solid. 1H-NMR (CDC13): δ 9.4 (s, IH), 8.22 (s, IH), 7.76 (m, IH), 7.52 (dd, J=8.8Hz, IH), 7.40 (m, 2H), 7.35 (m, 2H), 7.10 (d, J=2.4Hz, IH), 7.03 (d, J=8.8 Hz, IH), 6.84 (s, IH), 6.49 (dd, J=8.8 Hz, IH), 6.11 (d, J=7.2Hz, IH), 3.47 (s, 3H) 3.33 (m, 4H), 2.65 (s, 6H) and 1.38 (t, J=14.0 Hz, 6H). (ESI) (M+H)+=583.
EXAMPLE 20: N-[(lE)-[[7-Chloro-5-(2-chlorophenyl)-2,3-dihydro-l-methyl-2-oxo- lHr-l,4-benzodiazepin-3-yl]amino][[4-(4-morpholmyl)-l- naphthalenyl]amino]methylene]urea
Figure imgf000176_0003
A mixture of N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-l-methyl-2-oxo-lH-l,4- benzodiazepin-3-yl]-N'-cyano-N-[4-(4-mo holinyl)-l-naphthalenyl]guanidine (EXAMPLE 10) (21.9 mg, 35.8 μmol), water (4.6 μL, 260 μmol) and trifluoroacetic acid (19.8 μL, 257 μmol) in TΗF (3 mL) was heated to reflux for 43 h. The reaction was concentrated in vacuo, and the residue was purified by reverse phase ΗPLC (gradient 20- 70% CΗ3CΝ in H2O) to provide the title compound (0.0092 g, 35%) as its TFA salt. 1H- NMR (CD3OD): δ 8.37 (br s, IH), 8.06 (br s, IH), 7.75-7.41 (br m, 9H), 7.26 (br s, IH), 7.04 (br s, IH), 5.66 (br s, IH), 4.00 (br s, 4H), 3.58 (br s, 3H), 3.17 (br s, 4H). HRMS calculated for (C32H29Cl2N7O3+H) (M+H)+: 630.1787. Found (ESI): 630.1800.
EXAMPLE 21 : N,-[7-Chloro-5-(2-chlorophenyl)-2,3-dihydro-l-methyl-2-oxo-lH- l,4-benzodiazepin-3-yl]-N-methyl-N-[2-methyl-4-(4-morpholinyl)phenyl]thiourea
Figure imgf000177_0001
(CH2CI)a, Δ A solution of 2-methyl-4-(4-morpholinyl)benzenamine (53.3 mg, 0.277 mmol) and diisopropylethylamine (0.063 mL, 0.36 mmol) in CH2C12 (1 mL) was cooled to 0 °C. Methyl chloroformate (0.024 mL, 0.31 mmol) was added dropwise, and then the reaction was allowed to warm to room temperature and stir overnight. The reaction was diluted with CH2C12 (20 mL) and washed with brine (10 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was then suspended in a 1:2 mixture of Et2O:THF (6 mL). A solution of LiAlH4 in Et2O (0.34 mL of a 1 M solution, 0.34 mmol) was added dropwise, and then the reaction mixture was heated to reflux for 1.5 h. The reaction was cooled, diluted with additional Et O (8 mL), and quenched with Na2SO 5H2O (0.98 g, 4.2 mmol). After stirring for 15 minutes, the mixture was filtered and the reaction was concentrated in vacuo. A portion of this crude aniline (0.0580 g, 0.281 mmol) was dissolved in (CH2C1)2 (8 mL), and 7-chloro-5-(2- chlorophenyl)- 1 ,3-dihydro-3-isothiocyanato-l -methyl-2H- 1 ,4-benzodiazepin-2-one (0.106 g, 0.281 mmol) was added. The resulting mixture was heated at 70 °C for 14 h. The reaction was cooled and concentrated in vacuo, and the residue was purified by silica gel column chromatography (7:1 CΗ2C12: EtOAc) to provide the title compound (0.1211 g, 74%). Due to hindered rotation about one of the bonds, rotamers were observed in the 1H-NMR spectrum. 1H-NMR (CDC13): δ 7.77-7.68 (m, IH), 7.51 (dd, J=2.4 Hz, J=8.8 Hz, IH), 7.43-7.36 (m, 2H), 7.34-7.28 (m, 2H), 7.16 (t, J=8.4 Hz, IH), 7.10-7.01 (m, 2H), 6.86-6.76 (m, 2H), 6.14 and 6.10 (2 x d, J=8.0 Hz, J=7.6 Hz, IH), 3.88-3.82 (br m, 4H), 3.60 and 3.59 (2 x s, 3H), 3.41 (s, 3H), 3.19 (br s, 4H), 2.24 and 2.23 (2 x s, 3H). MS (ESI) (M+H)+ = 582. HRMS calculated for (C29H29Cl2N5O2S+H) (M+H)+: 582.1497. Found (ESI): 582.1448.
INTERMEDIATE 9: 6-Chloro-l-methyl-2H-3,l-benzoxazine-2,4(lH)-dione
Figure imgf000178_0001
As illustrated in the scheme above, NaH (2.43 g of a 60%> dispersion, 60.8 mmol) was added to a solution of 6-chloro-2H-3,l-benzoxazine-2,4(lH)-dione (10.0 g, 50.6 mmol) dissolved in DMF (200 mL). The resulting mixture was stirred at room temperature for 30 min., and then methyl iodide (6.3 mL, 101 mmol) was added dropwise. After the reaction had stirred at room temperature overnight, it was concentrated in vacuo. Water and brine were added to the residue, and the aqueous layer was extracted with CΗ2C12 (2x). The combined organic phases were dried over Na2SO , filtered, and concentrated in vacuo. The crude product was triturated with 3:1 hexanes:EtOAc. The solvent was removed by filtration, and the resulting solid was washed with additional 3 : 1 hexanes:EtOAc, followed by 100%) hexanes. The product was dried briefly under vacuum to produce the title compound as a pale yellow solid (8.59 g, 80 %). 1H-NMR (DMSO-d6): δ 7.96 (d, J=2.6 Hz, IH), 7.89 (dd, J=2.6 Hz, J=9.0 Hz, IH), 7.48 (d, J=9.0 Hz, IH), 3.45 (s, 3H). MS (ESI) (M+H)+ = 212. INTERMEDIATE 10: 7-Chloro-3,4-dihydro-l-methyl-lH-l,4-benzodiazepine-2,5- dione
glycine, AcOH
Figure imgf000179_0002
Figure imgf000179_0001
As illustrated in the scheme above, a mixture of 6-chloro-l-methyl-2H-3,l-benzoxazine- 2,4(lH)-dione (6.00 g, 28.4 mmol) and glycine (2.14 g, 28.4 mmol) in glacial acetic acid (72 mL) was heated at reflux for 4 h. The reaction was cooled and concentrated in vacuo. Water was added to the residue, and the mixture was cooled to 0 °C. NaΗCO3 was added to adjust the pH of the aqueous layer to approximately 8, and then the aqueous layer was extracted with CH2C12 (3x). The combined organic phases were dried over Na2SO , filtered, and concentrated in vacuo. The crude product was triturated with Et2O, the solvent was removed by filtration, and the resulting solid was washed with additional Et2O to provide the title compound as a slightly yellow solid (5.657 g, 89%). 1H-NMR (CDC13): δ 7.88 (d, J=2.5 Hz, IH), 7.57 (br s, IH), 7.53 (dd, J=2.6 Hz, J=8.7 Hz, IH), 7.19 (d, J=8.6 Hz, IH), 3.84 (d, J=6.1 Hz, 2H), 3.39 (s, 3H). MS (ESI) (M+H)+ = 225.
INTERMEDIATE 11 : 5,7-Dichloro-l,3-dihydro-l-methyl-2H-l,4-benzodiazepin-2- one
Figure imgf000179_0003
As illustrated in the scheme above, 7-chloro-3 ,4-dihydro- 1 -methyl- IH- 1 ,4- benzodiazepine-2,5-dione (5.00 g, 22.3 mmol) was suspended in POCl3 (100 L) and heated at 100 °C for 30 min. The reaction was cooled and concentrated in vacuo. Traces of POCI3 were removed by adding toluene and concentrating the mixture in vacuo (2x). The residue was dissolved in CΗ2C12, the solution was cooled to 0 °C, and Et3N (6.8 mL, 48.8 mmol) was added dropwise. The mixture was stirred for 1 h and allowed to slowly warm to room temperature, and was then concentrated in vacuo once again. The residue was purified by silica gel column chromatography (5:1 CH2Cl2:EtOAc + 0.5% Et3N) to provide the title compound as an orange solid (4.68 g, 86%). 1H-NMR (CDC13): δ 7.79 (d, J=2.5 Hz, IH), 7.55 (dd, J=2.4 Hz, J=8.9 Hz, IH), 7.23 (d, J=8.8 Hz, IH), 4.67 (br s, IH), 3.72 (br s, IH), 3.39 (s, 3H). MS (ESI) (M+H)+ = 243.
INTERMEDIATE 12: 7-Chloro-5-(2,4-dimethoxy-5-pyrimidinyl)-l,3-dihydro-l- methyl-2H-l,4-benzodiazepin-2-one
Figure imgf000180_0001
As illustrated in the scheme above and following General Procedure 5, (2,4-dimethoxy-5- pyrimidinyl)boronic acid (0.939 g, 5.10 mmol), Pd2(dba)3 (0.064 g, 0.07 mmol), dry KF (0.890 g, 15.3 mmol), 5,7-dichloro-l,3-dihydro-l-methyl-2H-l,4-benzodiazepin-2-one (1.12 g, 4.61 mmol) and P(t-Bu)3 (0.42 mL of a 10 % solution in hexanes, 0.21 mmol) were combined and heated for 20 h. After workup, purification of the crude product by silica gel column chromatography (1:3 hexanes :EtO Ac) provided the title compound as a pale orange solid (1.20 g, 75%). 1H-NMR (CDC13): δ 8.50 (s, 1Η), 7.49 (dd, J=2.4 Ηz, J=8.8 Ηz, 1Η), 7.29 (d, J=8.8 Ηz, 1Η), 7.13 (d, J=2.4 Ηz, 1Η), 4.84 (d, J=10.8 Ηz, 1Η), 4.06 (s, 3Η), 3.79 (s, 3H), 3.76 (d, J=10.8 Hz, IH), 3.42 (s, 3H). MS (ESI) (M+H)+ = 347.
INTERMEDIATE 13 : 3-Azido-7-chloro-5-(2,4-dimethoxy-5-pyrimidinyl)-l,3- dihydro-l-methyl-2H-l,4-benzodiazepin-2-one
Figure imgf000181_0001
As illustrated in the scheme above and following General Procedure 6, KHMDS (7.0 mL of 0.5 M in toluene, 3.5 mmol), 7-chloro-5-(2,4-dimethoxy-5-pyrimidinyl)-l,3-dihydro- l-methyl-2H-l,4-benzodiazepin-2-one (1.16 g, 3.35 mmol), trisyl azide (2.60 g, 8.40 mmol) and acetic acid (0.85 mL, 14.8 mmol) were combined. After workup, purification of the crude product by silica gel column chromatography (2:3 hexanes :EtO Ac) provided the title compound as a pale yellow solid (1.23 g, 95%). 1H-NMR (CDC13): δ 8.64 (s, 1Η), 7.54 (dd, J=2.3 Ηz, J=8.8 Ηz, 1Η), 7.33 (d, J=8.8 Ηz, 1Η), 7.19 (d, J=2.3 Ηz, 1Η), 4.51 (s, 1Η), 4.08 (s, 3Η), 3.78 (s, 3H), 3.47 (s, 3H). MS (ESI) (M+H)+ = 388.
INTERMEDIATE 14: 3-Amino-7-chloro-5-(2,4-dimethoxy-5-pyrimidinyl)-l,3- dihydro-l-methyl-2H-l,4-benzodiazepin-2-one
Figure imgf000181_0002
As illustrated in the scheme above and following General Procedure 7, 3-azido-7-chloro- 5-(2,4-dimethoxy-5-pyrimidinyl)-l,3-dihydro-l-methyl-2H-l,4-benzodiazepin-2-one (1.22 g, 3.15 mmol) and PS-PPh3 (23.0 g of 1.37 mmol/g, 31.5 mmol) were combined. After workup and purification by "catch and release," the title compound was obtained as a brown solid (1.15 g, quantitative). 1H-NMR (CDC13): δ 8.56 (s, 1Η), 7.50 (dd, J=2.4 Ηz, J=8.9 Ηz, 1Η), 7.30 (d, J=8.8 Ηz, 1Η), 7.15 (d, J=2.5 Ηz, 1Η), 4.46 (s, 1Η), 4.06 (s, 3Η), 3.77 (s, 3H), 3.46 (s, 3H), 2.85-2.12 (br s, 2H). MS (ESI) (M+H)+ = 362. INTERMEDIATE 15: 7-Chloro-5-(2,4-dimethoxy-5-pyrimidinyl)-l,3-dihydro-3- isothiocyanato-l-methyl~2H-l,4-benzodiazepin-2-one
Figure imgf000182_0001
As illustrated in the scheme above and following General Procedure 2, 3-amino-7-chloro-
5-(2,4-dimethoxy-5-pyrimidinyl)- 1 ,3 -dihydro- 1 -methyl-2H- 1 ,4-benzodiazepin-2-one (1.15 g, 3.18 mmol) and thiophosgene (0.49 mL, 6.4 mmol) were combined. Purification of the crude product by silica gel column chromatography (9:1 CΗ2Cl2:EtOAc) provided the title compound as a viscous dark yellow oil (0.560 g, 44%). 1H-NMR (CDC13): δ 8.60 (s, IH), 7.55 (dd, J=2.5 Hz, J=8.8 Hz, IH), 7.33 (d, J=8.8 Hz, IH), 7.17 (d, J=2.5 Hz, IH), 5.16 (s, IH), 4.07 (s, 3H), 3.78 (s, 3H), 3.49 (s, 3H). MS (ESI) (M+H)+ = 404.
EXAMPLE 22 : N-[7-chloro-5-(2,4-dimethoxy-5-pyrimidinyl)-2,3-dihydro-l-methyl- 2-oxo-lH-l,4-benzodiazepin-3-yl]-iV-[4-(diethylamino)-2-methylphenyl]- thiourea
Figure imgf000182_0002
As illustrated in the scheme above, a solution of 7-chloro-5-(2,4-dimethoxy-5- ρyrimidinyl)-l,3-dihydro-3-isothiocyanato-l-methyl-2H-l,4-benzodiazepin-2-one (0.069 g, 0.146 mmol) and N\ΛAdiemyl-2-methyl-l,4-benzenediamine (0.029 g, 0.161 mmol) in (CH2C1) (5.0 mL) was heated at 70 °C for 16 h. The reaction was cooled and concentrated in vacuo, and the residue was purified by silica gel column chromatography (7:3 CH2C1 : EtOAc) to provide the title compound as a light orange solid (0.074 g, 87%>). 1H-NMR (CDC13): δ 8.64 (s, IH), 7.52 (dd, J=2.5 Hz, J=8.8 Hz, IH), 7.40 (s, IH), 7.35 (d, A=7.8 Hz, IH), 7.32 (d, J=9.0 Hz, IH), 7.20 (d, J=2.2 Hz, IH), 7.17-7.13 (m, IH), 6.54-6.51 (m, 2H), 6.06 (d, J=8.0 Hz, IH), 4.05 (s, 3H), 3.74 (s, 3H), 3.42 (s, 3H), 3.40- 3.27 (m, 4H), 2.30 (s, 3H), 1.17 (t, J=7.1 Hz, 6H). HRMS calculated for (C28H32ClN7O3S+H) (M+H)+: 582.2054. Found (ESI): 582.2076.
INTERMEDIATE 16: 7-Chloro-l,3-dihydro-l-methyl-5-(3-thienyl)-2H-l,4- benzodiazepin-2-one
Figure imgf000183_0001
As illustrated in the scheme above and following General Procedure 5, 3-thienylboronic acid (1.15 g, 9.01 mmol), Pd2(dba)3 (0.113 g, 0.123 mmol), dry KF (1.57 g, 27.0 mmol), 5,7-dichloro-l,3-dihydro-l-methyl-2H-l,4-benzodiazepin-2-one (1.98 g, 8.15 mmol) and P(t-Bu)3 (0.75 mL of a 10 % solution in hexanes, 0.37 mmol) were combined and heated for 16 h. After workup, purification of the crude product by silica gel column chromatography (9:1 CΗ2Cl2:EtOAc) provided the title compound as a yellow solid (1.44 g, 61%). 'H-NMR (CDC13): δ 7.54-7.49 (m, 4H), 7.37 (dd, J=3.0 Hz, J=5.0 Hz, IH), 7.29 (d, J=9.4 Hz, IH), 4.76 (d, J=10.9 Hz, IH), 3.77 (d, J=10.9 Hz, IH), 3.38 (s, 3H). MS (ESI) (M+H)+ = 291.
INTERMEDIATE 17: 3-Azido-7-chloro-l,3-dihydro-l-methyl-5-(3-thienyl)-2H-l,4- benzodiazepin-2-one
Figure imgf000184_0001
As illustrated in the scheme above and following General Procedure 6, KHMDS (10.4 mL of 0.5 M in toluene, 5.20 mmol), 7-chloro-l,3-dihydro-l-methyl-5-(3-thienyl)-2H- l,4-benzodiazepin-2-one (1.44 g, 4.95 mmol), trisyl azide (3.83 g, 12.4 mmol) and acetic acid (1.25 mL, 21.8 mmol) were combined. After workup, purification of the crude product by silica gel column chromatography (7:3 hexanes :EtO Ac) provided the title compound as a pale yellow solid (1.60 g, 98%). 1H-NMR (CDC13): δ 7.61-7.55 (m, 4Η), 7.40 (dd, J=2.9 Hz, J=5.1 Hz, IH), 7.33 (dd, J=1.0 Hz, J=8.2 Hz, IH), 4.54 (s, IH), 3.44 (s, 3H). MS (ESI) (M+H)+ = 332.
INTERMEDIATE 18: 3-Amino-7-chloro-l,3-dihydro-l-methyl-5-(3-thienyl)-2H-l,4- benzodiazepin-2-one
Figure imgf000184_0002
As illustrated in the scheme above and following General Procedure 7, 3-azido-7-chloro- l,3-dihydro-l-methyl-5-(3-thienyl)-2H-l,4-benzodiazepin-2-one (1.60 g, 4.82 mmol) and PS-PPI13 (30.0 g of 1.37 mmol/g, 41.1 mmol) were combined. After workup and purification by "catch and release," the title compound was obtained as a brown solid (1.35 g, 92%). 1H-NMR (CDCI3): δ 7.56-7.50 (m, 4Η), 7.36 (dd, J=3.1 Hz, J=4.9 Hz, IH), 7.29 (d, J=8.8 Hz, IH), 4.46 (s, IH), 3.43 (s, 3H), 2.35-2.15 (br s, 2H). MS (ESI) (M+H)+ = 306. INTERMEDIATE 19: 7-Chloro-l,3-dihydro-3-isothiocyanato-l-methyl-5-(3- thienyl)-2H-l,4-benzodiazepin-2-one
Figure imgf000185_0001
As illustrated in the scheme above and following General Procedure 2, 3-amino-7-chloro- l,3-dihydro-l-methyl-5-(3-thienyl)-2H-l,4-benzodiazepin-2-one (1.35 g, 4.41 mmol) and thiophosgene (0.67 mL, 8.8 mmol) were combined. Purification of the crude product by silica gel column chromatography (100% CΗ C12) provided the title compound as a yellow solid (1.04 g, 68%). 1H-NMR (CDC13): δ 7.61-7.54 (m, 4H), 7.39 (dd, J=2.9 Hz, J=5.3 Hz, IH), 7.33 (d, 7=8.8 Hz, IH), 5.20 (s, IH), 3.46 (s, 3H). MS (ESI) (M+H)+ = 348.
Example 23: N-[7-Chloro-2,3-dihydro-l-methyl-2-oxo-5-(3-thienyl)-lH-l,4- benzodiazepin-3-yl]-N'-[4-(4-morpholinyl)-l-naphthalenyl]thiourea
Figure imgf000185_0002
This reaction was carried out in a multiwell plate. As illustrated in the scheme above, aA mixture of 7-chloro- 1 ,3 -dihydro-3 -isothiocyanato- 1 -methyl-5-(3 -thienyl)-2H- 1 ,4- benzodiazepin-2-one (156 μL of a 0.128 M solution in (CΗ2C1)2, 0.020 mmol), 4-(4- morpholinyl)- 1-naphthalenamine (44 μL of a 0.5 M solution in DMA, 0.022 mmol), and (CH2C1)2 (300 μL) was agitated and heated at 70 °C for 22 h. The reaction was cooled and concentrated. in vacuo, and the residue was redissolved in DMA (25 μL) and (CH2C1)2 (275 μL). Polyamine resin HL (NovaBiochem) was added (20 mg of 4.53 mmol/g, 0.091 mmol), and the mixture was agitated at room temperature overnight. The resin was removed by filtration and washed with additional (CH2C1)2 and MeOH. The filtrate was concentrated in vacuo to provide the title compound. MS (ESI) (M+H)+ = 576.
INTERMEDIATE 20: 7-Chloro-l,3-dihydro-l-methyl-5-(3-pyridinyl)-2H-l,4- benzodiazepin-2-one
Figure imgf000186_0001
As illustrated in the scheme above and following General Procedure 4, 5,7-dichloro-l,3- dihydro-l-methyl-2H-l,4-benzodiazepin-2-one (1.99 g, 8.19 mmol), Na2CO3 (0.868 g, 8.19 mmol), PdCl2(dppf) (0.335 g, 0.410 mmol) and (3-pyridinyl)boronic acid (1.01 g, 8.19 mmol) were combined and heated for 14 h. After workup, purification of the crude product by silica gel column cliromatography (100%) EtOAc) provided the title compound (1.51 g, 64%). 1H-NMR (CDC13): δ 8.78 (d, J=1.6 Ηz, 1Η), 8.72 (dd, 7=1.6 Ηz, J=4.8 Ηz, 1Η), 8.02 (dt, 7=1.6 Ηz, 7=8.0 Ηz, 1Η), 7.56 (dd, 7=2.4 Ηz, 7=8.8 Ηz, 1Η), 7.39 (dd, 7=4.8 Ηz, 7=8.0 Ηz, 1Η), 7.34 (d, 7=8.8 Ηz, 1Η), 7.28 (d, 7=2.4 Ηz, 1Η), 4.89 (d, 7=10.4 Ηz, 1Η), 3.80 (d, 7=10.8 Ηz, 1Η), 3.41 (s, 3Η). MS (ESI) (M+H)+ = 286.
INTERMEDIATE 21: 3-Azido-7-chloro-l,3-dihydro-l-methyl-5-(3-pyridinyl)-2H- l,4-benzodiazepin-2-one
Figure imgf000186_0002
As illustrated in the scheme above and following General Procedure 6, KHMDS (10.5 mL of 0.5 M in toluene, 5.25 mmol), 7-chloro-l,3-dihydro-l-methyl-5-(3-pyridinyl)-2H- l,4-benzodiazepin-2-one (1.43 g, 4.99 mmol), trisyl azide (3.86 g, 12.5 mmol) and acetic acid (1.26 mL, 22.0 mmol) were combined. After workup, purification of the crude product by silica gel column chromatography (1:1 CΗ2Cl2:EtOAc) provided the title compound as a yellow foam (1.47 g, 90%). 1H-NMR (CDC13): δ 8.80 (s, IH), 8.76 (d, 7=3.6 Hz, IH), 8.14 (dt, 7=1.6 Hz, 7=8.0 Hz, IH), 7.61 (dd, 7=2.0 Hz, 7=8.4 Hz, IH), 7.44 (ddd, 7=0.8 Hz, 7=4.8 Hz, 7=8.0 Hz, IH), 7.38 (d, 7=8.8 Hz, IH), 7.35 (d, 7=2.4 Hz, IH), 4.56 (s, IH), 3.48 (s, 3H). MS (ESI) (M+H)+ = 327.
INTERMEDIATE 22 : 3-Amino-7-chloro-l,3-dihydro-l-methyl-5-(3-pyridinyl)-2H- 1 ,4-benzodiazepin-2-one
Figure imgf000187_0001
As illustrated in the scheme above and following General Procedure 7, 3-azido-7-chloro- l,3-dihydro-l-methyl-5-(3-pyridinyl)-2H-l,4-benzodiazepin-2-one (1.47 g, 4.49 mmol) and PS-PPh3 (16.4 g of 1.37 mmol/g, 22.4 mmol) were combined. After workup and purification by "catch and release," the title compound was obtained as a slightly brown solid (1.46 g, quantitative). 1H-NMR (CDC13): δ 8.76 (d, 7=2.4 Ηz, 1Η), 8.72 (dd, 7=1.6 Ηz, 7=5.2 Ηz, 1Η), 8.06 (dt, 7=2.4 Ηz, 7=7.6 Ηz, 1Η), 7.58 (dd, 7=2.4 Ηz, 7=8.8 Ηz, 1Η), 7.40 (dd, 7=4.8 Ηz, 7=8.0 Ηz, 1Η), 7.35 (d, 7=8.8 Ηz, 1Η), 7.29 (d, 7=2.4 Ηz, 1Η), 4.51 (s, 1Η), 3.46 (s, 3Η), 2.41 (br s, 2H). MS (ESI) (M+H)+ = 301.
INTERMEDIATE 23 : 7-Chloro-l,3-dihydro-3-isothiocyanato-l-methyl-5-(3- pyridinyl)-2H-l,4-benzodiazepin-2-one
Figure imgf000188_0001
As illustrated in the scheme above, a solution of 3-amino-7-chloro-l,3-dihydro-l-methyl- 5-(3-pyridinyl)-2H-l,4-benzodiazepin-2-one (1.36 g, 4.52 mmol) in dry TΗF (55 mL) was cooled to -15 °C. Carbon disulfide (2.7 mL, 45 mmol) was added, followed by EDCI (1.73 g, 9.03 mmol). The mixture was stirred for 10 min., and then Et3N (1.26 mL, 9.04 mmol) was added. The reaction was stirred for 16 h while it was allowed to slowly warm to room temperature. The precipitated solid was removed by filtration and was washed well with CΗ2C12 and then discarded. The filtrate was concentrated in vacuo, and the residue was dissolved in CH2C12. The organic phase was washed with water, saturated NaHCO3, and brine, and was then dried over Na SO4, filtered, and concentrated in vacuo. Purification of the crude product by silica gel column chromatography (3:1 CH2Cl2:EtOAc) provided the title compound as a solid (0.652 g, 42%). 1H-NMR (CDC13): δ 8.75 (s, 2H), 8.12 (dt, 7=2.0 Hz, 7=8.0 Hz, IH), 7.63 (dd, 7=2.0 Hz, 7=8.8 Hz, IH), 7.43 (dd, 7=4.8 Hz, 7=8.0 Hz, IH), 7.39 (d, 7=8.8 Hz, IH), 7.33 (d, 7=2.4 Hz, IH), 5.22 (s, IH), 3.50 (s, 3H). MS (ESI) (M+H)+ = 343.
EXAMPLE 24: N-[7-Chloro-2,3-dihydro-l-methyl-2-oxo-5-(3-pyridinyl)-lH-l,4- benzodiazepin-3-yl]-iV-[4-(4-morpholmyl)-l-naphthalenyl]thiourea
Figure imgf000188_0002
A solution of 7-chloro-l,3-dihydro-3-isothiocyanato-l-methyl-5-(3-pyridinyl)-2H-l,4- benzodiazepin-2-one (0.0282 g, 0.0823 mmol) and 4-(4-morpholinyι)- 1-naphthalenamine (0.0188 g, 0.0823 mmol) in (CΗ2C1)2 (2.5 mL) was heated at 70 °C for 24 h. The reaction was cooled and concentrated in vacuo, and the residue was purified by silica gel column chromatography (1 :2 CH2C12: EtOAc) to provide the title compound (0.0263 g, 56%). 1H-NMR (CDC13): δ 8.72-8.68 (m, 2H), 8.29-8.25 (m, IH), 8.11-8.07 (m, IH), 8.05-8.00 (m, 2H), 7.64-7.55 (m, 5H), 7.38-7.33 (m, 3H), 7.15 (d, 7=8.0 Hz, IH), 6.08 (d, 7=7.6 Hz, IH), 4.03-3.96 (br m, 4H), 3.39 (s, 3H), 3.15 (br s, 4H). HRMS calculated for (C30H27C1N6O2S+H) (M+H)+: 571.1683. Found (ESI): 571.1699. Anal. Calcd for C30H27C1N6O2S + 0.7 H2O: C, 61.73; H, 4.90; N, 14.40. Found: C, 61.93; H, 4.79; N, 13.87.
INTERMEDIATE 24: 6-Fluoro-l-methyl-2H-3,l-benzoxazine-2,4(lET)-dione
Figure imgf000189_0001
As illustrated in the scheme above, NaH (0.312 g of a 60%> dispersion, 7.80 mmol) was added to a solution of 6-fluoro-2H-3,l-benzoxazine-2,4(lH)-dione (1.176 g, 6.49 mmol) dissolved in DMF (60 mL). The resulting mixture was stirred at room temperature for 30 min., and then methyl iodide (0.81 mL, 13 mmol) was added dropwise. After the reaction had stirred at room temperature overnight, it was concentrated in vacuo. Water and brine were added to the residue, and the aqueous layer was extracted with CΗ2C12 (3x). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was triturated with Et2O. The solvent was removed by filtration, and the resulting solid was washed with additional Et2O. The product was dried briefly under vacuum to produce the title compound as a white solid (1.00 g, 79%). 1H-NMR (CDC13): δ 7.86-7.82 (m, IH), 7.55-7.48 (m, IH), 7.22-7.17 (m, IH), 3.61 (s, 3H). MS (ESI) (M+H)+ = 196.
INTERMEDIATE 25: 7-Fluoro-3,4-dihydro-l-methyl-lH-l,4-benzodiazepine-2,5- dione
Figure imgf000190_0001
As illustrated in the scheme above, a mixture of 6-fluoro-l-methyl-2H-3,l-benzoxazine- 2,4(lH)-dione (1.00 g, 5.12 mmol) and glycine (0.385 g, 5.13 mmol) in glacial acetic acid (13 mL) was heated at reflux for 4 h. The reaction was cooled and concentrated in vacuo. Water was added to the residue, and the mixture was cooled to 0 °C. NaΗCO3 was added to adjust the pH of the aqueous layer to approximately 8, and then the aqueous layer was extracted with CH2C1 (4x). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was triturated with Et2O, the solvent was removed by filtration, and the resulting solid was washed with additional Et2O to provide the title compound as a slightly yellow solid (0.560 g, 52%>). 1H-NMR (DMSO-d6): δ 8.80 (br s, IH), 7.49-7.38 (m, 3H), 3.76 (br d, IH), 3.47 (br d, IH), 3.26 (s, 3H). MS (ESI) (M+H)+ = 209.
INTERMEDIATE 26: 5-Chloro-7-fluoro-l,3-dihydro-l-methyl-2H-l,4- b enzo diazepin-2-one
Figure imgf000190_0002
As illustrated in the scheme above, 7-fluoro-3,4-dihydro-l-methyl-lH-l,4- benzodiazepine-2,5-dione (0.495 g, 2.38 mmol) was suspended in POCl3 (10.6 mL) and heated at 100 °C for 30 min. The reaction was cooled and concentrated in vacuo. Traces of POCl3 were removed by adding toluene and concentrating the mixture in vacuo (2x). The residue was dissolved in CΗ2C12, the solution was cooled to 0 °C, and Et3N (0.75 mL, 5.4 mmol) was added dropwise. The mixture was stirred for 0.5 h and allowed to slowly warm to room temperature, and was then concentrated in vacuo once again. The residue was purified by silica gel column chromatography (9:1 CH2Cl2:EtOAc + 0.5% Et3N) to provide the title compound as a light tan solid (0.422 g, 78%). 1H-NMR (CDC13): δ 7.53- 7.48 (m, IH), 7.34-7.24 (m, 2H), 4.66 (br s, IH), 3.72 (br s, IH), 3.39 (s, 3H). MS (ESI) (M+H)+ = 227.
INTERMEDIATE 27: 7-Fluoro-l53-dihydro-l-methyl-5-phenyl-2H-l,4- benzodiazepin-2-one
Figure imgf000191_0001
As illustrated in the scheme above and following General Procedure 4, 5-chloro-7-fluoro- l,3-dihydro-l-methyl-2H-l,4-benzodiazepin-2-one (0.201 g, 0.887 mmol), Na2CO3 (0.0940 g, 0.887 mmol), PdCl2(dppf) (0.0362 g, 0.0443 mmol) and phenylboronic acid (0.108 g, 0.886 mmol) were combined and heated for 13 h. After workup, purification of the crude product by silica gel column chromatography (3:1 CΗ2Cl2:EtOAc) provided the title compound (0.180 g, 16%). 1H-NMR (CDC13): δ 7.64-7.60 (m, 2H), 7.51-7.45 (m, IH), 7.44-7.39 (m, 2H), 7.34 (dd, 7=4.8 Hz, 7=9.2 Hz, IH), 7.31-7.25 (m, IH), 7.02 (dd, 7=2.8 Hz, 7=8.8 Hz, IH), 4.84 (d, 7=10.8 Hz, IH), 3.78 (d, 7=10.8 Hz, IH), 3.40 (s, 3H). MS (ESI) (M+H)+ = 269.
INTERMEDIATE 28: 3-Azido-7-fluoro-l,3-dihydro-l-methyl-5-phenyl-2H-l,4- benzodiazepin-2-one
Figure imgf000191_0002
As illustrated in the scheme above and following General Procedure 6, KHMDS (1.34 mL of 0.5 M in toluene, 0.670 mmol), 7-fluoro-l,3-dihydro-l-methyl-5-phenyl-2H-l,4- benzodiazepin-2-one (0.171 g, 0.637 mmol), trisyl azide (0.493 g, 1.59 mmol) and acetic acid (0.16 mL, 2.8 mmol) were combined. After workup, purification of the crude product by silica gel column chromatography (100% CH2C12 to 9:1 CH2Cl :EtOAc) provided the title compound as a pale yellow solid (0.163 g, 83%). 1H-NMR (CDC13): δ 7.72-7.67 (m, 2H), 7.54-7.49 (m, IH), 7.47-7.42 (m, 2H), 7.39 (dd, 7=4.8 Hz, 7=9.2 Hz, IH), 7.36-7.30 (m, IH), 7.08 (dd, 7=2.8 Hz, 7=8.4 Hz, IH), 4.55 (s, IH), 3.45 (s, 3H). MS (ESI) (M+H)+ = 310.
INTERMEDIATE 29: S-Amino^-fluoro-l^-dihydro-l-methyl-S-phenyl^H-l^- benzodiazepin-2-one
Figure imgf000192_0001
As illustrated in the scheme above and following General Procedure 7, 3-azido-7-fluoro- l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one (0.0826 g, 0.267 mmol) and PS-PPh3 (1.63 g of 1.64 mmol/g, 2.67 mmol) were combined. After workup and purification by "catch and release," the title compound was obtained as a slightly yellow solid (0.0450 g, 59%). 1H-NMR (CDCI3): δ 7.65-7.60 (m, 2Η), 7.51-7.46 (m, IH), 7.44- 7.39 (m, 2H), 7.36 (dd, 7=4.8 Hz, 7=9.2 Hz, IH), 7.33-7.26 (m, IH), 7.03 (dd, 7=2.4 Hz, 7=8.4 Hz, IH), 4.48 (s, IH), 3.45 (s, 3H), 2.30-1.60 (br s, 2H). MS (ESI) (M+H)+ = 284.
EXAMPLE 25: N-(7-Fluoro-2,3-dihydro-l-methyl-2-oxo-5-phenyl-lH-l,4- benzodiazepin-3-yl)--V-[2-methyl-4-(4-morpholinyl)phenyl]thiourea
Figure imgf000192_0002
As illustrated in the scheme above, a solution of 3-amino-7-fluoro-l,3-dihydro-l-methyl- 5-phenyl-2H-l,4-benzodiazepin-2-one (0.0056 g, 0.020 mmol) and 4-(4-isothiocyanato-3- methylphenyl)morpholine (0.0048 g, 0.020 mmol) in DMA (0.5 mL) was heated at 70 °C for 16 h. The reaction was cooled and concentrated in vacuo, and the residue was lyophilized to provide the title compound (0.0104 g, quantitative). 1H-NMR (CDC13): δ 7.63-7.58 (m, 2Η), 7.50-7.45 (m, IH), 7.44-7.36 (m, 4H), 7.36-7.26 (m, 3H), 7.09 (dd, 7=2.4 Hz, 7=8.4 Hz, IH), 6.85-6.78 (m, 2H), 6.09-6.05 (m, IH), 3.90-3.83 (br m, 4H), 3.41 (s, 3H), 3.21-3.15 (br s, 4H), 2.36 (s, 3H). MS (ESI) (M+H)+ = 518. HRMS calculated for (C28H28FN5O2S+H) (M+H)+: 518.2026. Found (ESI): 518.2117. -
INTERMEDIATE 30: 7-Chloro-l,3-dihydro-5-(6-methoxy-2-pyridinyl)-l-methyl- 2H-l,4-benzodiazepin-2-one
Figure imgf000193_0001
As illustrated in the scheme above, a solution of 2-bromo-6-methoxypyridine (0.022 mL, 0.18 mmol) in dry Et2O (0.3 mL) was added to a solution of n-BuLi (0.12 mL of 1.6 M in hexanes, 0.19 mmol) maintained at -40 °C. The reaction was stirred at -40 °C for 20 min., and then B(OMe)3 (0.022 mL, 0.19 mmol) was added dropwise. The reaction was stirred at -40 °C for 30 min., and then at room temperature for 3.5 h. The reaction was concentrated in vacuo, anhydrous MeOH was added to the residue, and the reaction was concentrated in vacuo once again. Dry DME (0.8 mL), 5,7-dichloro-l,3-dihydro-l- methyl-2H-l,4-benzodiazepin-2-one (0.0392 g, 0.161 mmol), Pd(PPh3)4 (0.0093 g, 0.0080 mmol) and CsF (0.0612 g, 0.403 mmol) were added to the residue, and the mixture was heated to reflux for 15 h. Water (5 mL) and CΗ2C12 (5 mL) were added to the reaction mixture, and the layers were separated. The aqueous phase was extracted with additional CH2C12 (3x), and the combined organic phases were dried over Na2SO , filtered, and concentrated in vacuo. Purification of the crude product by silica gel column 193 chromatography (2:1 CH2Cl2:EtOAc) provided the title compound (0.029 g, 57%). 1H- NMR (CDC13): δ 7.77 (d, 7=7.6 Hz, IH), 7.71-7.64 (m, 2H), 7.49 (dd, 7=2.4 Hz, 7=8.8 Hz, IH), 7.27 (d, 7=8.8 Hz, IH), 6.83 (d, 7=8.0 Hz, IH), 4.85 (d, 7=10.8 Hz, IH), 3.86 (d, 7=10.4 Hz, IH), 3.81 (s, 3H), 3.39 (s, 3H). MS (ESI) (M+H)+ = 316.
INTERMEDIATE 31 : 3-Azido-7-chloro-l,3-dihydro-5-(6-methoxy-2-pyridinyl)-l- methyl-2H,-l!,4-benzodiazepm-2-one
Figure imgf000194_0001
As illustrated in the scheme above and following General Procedure 6, KHMDS (0.19 mL of 0.5 M in toluene, 0.095 mmol), 7-chloro-l,3-dihydro-5-(6-methoxy-2-pyridinyl)-l- methyl-2H-l,4-benzodiazepin-2-one (0.0290 g, 0.0918 mmol), trisyl azide (0.0710 g, 0.229 mmol) and acetic acid (0.023 mL, 0.40 mmol) were combined. After workup, purification of the crude product by silica gel column chromatography (49: 1 CΗ2Cl2:EtOAc) provided the title compound (0.0204 g, 62%). 1H-NMR (CDCI3): δ7.95 (d, 7=7.2 Hz, IH), 7.78-7.70 (m, 2H), 7.54 (dd, 7=2.4 Hz, 7=8.8 Hz, IH), 7.31 (d, 7=8.8 Hz, IH), 6.87 (d, 7=8.4 Hz, IH), 4.64 (s, IH), 3.80 (s, 3H), 3.44 (s, 3H). MS (ESI) (M+H)+ = 357.
INTERMEDIATE 32 : 3-Amino-7-chloro-l,3-dihydro-5-(6-methoxy-2-pyridinyl)-l- methyl-2H-l ,4-b enzo diazepin-2-one
Figure imgf000194_0002
As illustrated in the scheme above, a suspension of Pd/C (0.005 g of 10% on C) in MeOH (0.5 mL) under N2 was treated with ammonium formate (0.0252 g, 0.400 mmol). The mixture was stirred for 10 min. and then transferred via Pasteur pipette to a suspension of 3 -azido-7-chloro- 1 ,3 -dihydro-5-(6-methoxy-2 -pyridinyl)- 1 -methyl-2H- 1 ,4- benzodiazepin-2-one (0.0204 g, 0.0572 mmol) in MeOΗ (1.2 mL). The resulting mixture was stirred at room temperature for 3h and was then filtered through a small pad of Celite. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (100%) EtOAc, followed by 4:1 CΗ2Cl2:EtOAc) to provide the title compound (0.0148 g, 78%). 1H-NMR (CDC13): δ 7.82 (dd, 7=0.8 Hz, 7=7.6 Hz, IH), 7.71-7.66 (m, 2H), 7.51 (dd, 7=2.4 Hz, 7=8.8 Hz, IH), 7.28 (d, 7=8.8 Hz, IH), 6.83 (dd, 7=0.8 Hz, 7=8.4 Hz, IH), 4.56 (s, IH), 3.80 (s, 3H), 3.44 (s, 3H), 2.53 (br s, 2H). MS (ESI) (M+H)+ = 331.
EXAMPLE 26: N-[7-Chloro-2,3-dihydro-5-(6-methoxy-2-pyridinyl)-l-methyl-2-oxo- lH-l,4-benzodiazepin-3-yl]-iV-[2-methyl-4-(4-morpholinyl)phenyl]thiourea
Figure imgf000195_0001
As illustrated in the scheme above, a solution of 3-amino-7-chloro-l,3-dihydro-5-(6- methoxy-2 -pyridinyl)- l-methyl-2H-l,4-benzodiazepin-2-one (0.0113 g, 0.0342 mmol) and 4-(4-isothiocyanato-3-methylphenyl)morpholine (0.0080 g, 0.034 mmol) in (CΗ2C1)2 (0.9 mL) was heated at 70 °C for 20 h. The reaction was cooled and concentrated in vacuo, and the residue was purified by silica gel column chromatography (2:1 CH2C12: EtOAc) to provide the title compound (0.0172 g, 89%>) as a slightly yellow solid. 1H- NMR (CDC13): δ 7.79 (dd, 7=0.8 Hz, 7=7.2 Hz, IH), 7.70-7.65 (m, 2H), 7.54 (dd, 7=2.4 Hz, 7=8.8 Hz, IH), 7.42 (br s, IH), 7.30 (d, 7=8.8 Hz, IH), 7.28-7.25 (m partially hidden under CHC13, 2H), 6.85-6.80 (m, 3H), 6.14 (m, IH), 3.88-3.85 (m, 4H), 3.78 (s, 3H), 3.40 (s, 3H), 3.22-3.18 (m, 4H), 2.36 (s, 3H). MS (ESI) (M+H)+ = 565.

Claims

What is claimed is:
1. A method of treating pain in a warm-blooded animal, comprising the step of administering to said animal a therapeutically effective amount of a compound of Formula (I), pharmaceutically acceptable salts thereof, diasteriomers thereof, enantiomers thereof, or mixtures thereof:
Figure imgf000197_0001
wherein R1 is selected from optionally substituted acyl, optionally substituted alkyl- oxycarbonyl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted aryl; optionally substituted heterocyclyl; optionally substituted aryl-Cι-6alkyl, and optionally substituted heterocyclyl-Cι-6alkyl; or a divalent CM2 group that together with a second nitrogen of X to form a ring; X is a divalent group including a first nitrogen atom and the second nitrogen atom, wherein a first group is linked to the first nitrogen atom and R1 is linked to the second nitrogen atom, and wherein the first and second nitrogen atoms are separated by either one carbon atom, or two carbon atoms wherein said two carbon atoms have a double bond therebetween; R3 is optionally substituted aryl, optionally substituted Cι-ι2alkyl, optionally substituted C3_ι2cycloalkyl, or optionally substituted heterocyclyl;
R4 is, at each position, independently -H, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, nitro, cyano, hydroxy, -OR6, -SR6, -S(=O)R6, -S(=O)2R6, -C(=O)R6, -C(=S)R6, -NR7R6, -C(=O)NR7R6, -NR7C(=O)R6, -SO2NR7R6, -NR7SO2R6, or -C(=O)OR6; and
R5, R6 and R7 are independently -H, optionally substituted Cj.6alkyl.
2. A method of treating pain in a warm-blooded animal, comprising the step of administering to said animal a therapeutically effective amount of a compound of Formula (I), pharmaceutically acceptable salts thereof, diasteriomers thereof, enantiomers thereof, or mixtures thereof:
Figure imgf000198_0001
wherein
R1 is selected from optionally substituted acyl, optionally substituted alkyl- oxycarbonyl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted aryl; optionally substituted heterocyclyl; optionally substituted aryl-Cι.6alkyl, and optionally substituted heterocyclyl-Cι.6alkyl; or a divalent CM2 group that together with a divalent R2 of X forms a portion of a ring;
X is selected from groups of formulae (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), (xi), (xii), (xiii), (xiv), (xv), (xvi) and (xvii),
Figure imgf000199_0001
(i) (ϋ) (iϋ) (iv)
Figure imgf000199_0002
(v) ( i) ( ii) (viii)
Figure imgf000199_0003
(ix) (x) (xi) (χii)
Figure imgf000199_0004
(xiii) (xiv) (XV) (xvi)
Figure imgf000199_0005
(xvii) wherein R2 is selected from -H, optionally substituted Cι_ι alkyl, optionally substituted Cι-ι2heteroalkyl, optionally substituted aryl, optionally substituted heterocyclyl, and a divalent Co-6group together with a divalent R1 to form the portion of the ring, wherein said divalent Co-6 group optionally includes one or more heteroatoms;
R is optionally substituted aryl, optionally substituted Cj.πalkyl, optionally substituted C3-j2cycloalkyl, or optionally substituted heterocyclyl;
R is, at each position, independently, -H, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, nitro, cyano, hydroxy, -OR6, -SR6, -S(=O)R6, -S(=O)2R6, -C(=O)R6, -C(=S)R6, -NR7R6, -C(=O)NR7R6, -NR7C(=O)R6, -SO2NR7R6,
-NR7SO2R6, or -C(=O)OR6; and R5, R6 and R7 are independently -H, optionally substituted Cι.6alkyl.
3. A method according to claim 2, wherein
R1 is optionally substituted phenyl, optionally substituted naphthyl, optionally substituted isoquinolyl, optionally substituted acridinyl, optionally substituted coumarinyl, optionally substituted carbazolyl, or a first divalent group selected from optionally substituted C]-ι2alkylene and optionally substituted Cι_ι2heteroalkylene; wherein said phenyl, naphthyl, isoquinolyl, acridinyl, coumarinyl, and carbazolyl are optionally substituted by Cι_6alkyl, Cι.6heterocyclyl or amino, wherein said Cι-ι2alkylene and Cι-ι2heteroalkylene are optionally substituted by Cj.6alkyl, aryl-C .6alkyl, aryl or heterocyclyl;
X is selected from groups of formulas (i), (ii), (iii), (vi) and (xvii):
Figure imgf000200_0001
(') (ϋ) (iϋ) (vi) (xvii)
R2 is -H, Cj.3alkyl, or a second divalent group selected from a single bond, an optionally substituted alkylene and an optionally substituted heteroalkylene; wherein said second divalent group together with said first divalent group forms a portion of a ring; R is optionally substituted aryl, optionally substituted heteroaryl or optionally substituted cycloalkyl;
R4 is halogen, or Cj.3alkyl; and R5 is Cι.3alkyl.
4. A method according to claim 2, wherein
-X-R1 of formula (I) is selected from groups of formulas (a), (b), (c), (d), (e), (f) and (g):
Figure imgf000200_0002
(a) (b) (c) (d) (e)
Figure imgf000201_0001
(f) (g)
R1 is optionally substituted phenyl, optionally substituted naphthyl, optionally substituted isoquinolyl, wherein said phenyl, naphthyl and isoquinolyl are optionally substituted by Ci-βalkyl, Cι.6heterocyclyl or amino; R2 is -H, or Cι.3alkyl;
Figure imgf000201_0002
is a nitrogen containing heterocyclyl, which is be optionally substituted by one or more -R8, and which includes a bond on the nitrogen that links to other group of formula (I);
R8 is -H, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted Cι.6alkyl, -OH, or Cι-6alkoxy, wherein R is optionally fused with
Figure imgf000201_0003
R3 is optionally substituted cyclohexyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted thienyl, or optionally substituted pyrimidinyl, wherein said cyclohexyl, phenyl, pyridyl, thienyl and pyrimidinyl are optionally substituted by halogen, methoxy, or Cι-3alkyl;
R4 is halogen; and
R5 is methyl.
5. A method according to claim 4, wherein said nitrogen containing heterocyclyl is selected from piperazinyl, morpholinyl, poperidyl, and pyrrolidinyl.
6. A method of treating pain in a warm-blooded animal, comprising the step of administering to said animal a therapeutically effective amount of a compound selected from: 201
Figure imgf000202_0001
Figure imgf000203_0001
and pharmaceutically acceptable salts thereof.
7. A compound of formula (I) according to any one of claims 1-5 for use as a medicament.
8. The use of a compound of formula (I) according to any one of claims 1-5 in the manufacture of a medicament for the therapy of pain.
9. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1-5 and a pharmaceutically acceptable carrier.
10. The use of a compound of formula (I) according to any one of claims 1-5 as an antagonist of bradykinin at the B2 receptor.
PCT/SE2002/002309 2001-12-14 2002-12-11 Benzodiazepine derivatives, preparation thereof and use thereof WO2003051275A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002359126A AU2002359126A1 (en) 2001-12-14 2002-12-11 Benzodiazepine derivatives, preparation thereof and use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0104248-0 2001-12-14
SE0104248A SE0104248D0 (en) 2001-12-14 2001-12-14 Method of treatment

Publications (2)

Publication Number Publication Date
WO2003051275A2 true WO2003051275A2 (en) 2003-06-26
WO2003051275A3 WO2003051275A3 (en) 2003-10-30

Family

ID=20286350

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE2002/002309 WO2003051275A2 (en) 2001-12-14 2002-12-11 Benzodiazepine derivatives, preparation thereof and use thereof

Country Status (3)

Country Link
AU (1) AU2002359126A1 (en)
SE (1) SE0104248D0 (en)
WO (1) WO2003051275A2 (en)

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007063418A2 (en) * 2005-04-13 2007-06-07 Neuraxon, Inc. Substituted indole compounds having nos inhibitory activity
JP2007516183A (en) * 2003-06-26 2007-06-21 メルク　エンド　カムパニー　インコーポレーテッド Benzodiazepine CGRP receptor antagonist
JP2007516182A (en) * 2003-06-26 2007-06-21 メルク　エンド　カムパニー　インコーポレーテッド Benzodiazepine CGRP receptor antagonist
JP2007519729A (en) * 2004-01-29 2007-07-19 メルク　エンド　カムパニー　インコーポレーテッド CGRP receptor antagonist
JP2007525450A (en) * 2003-04-15 2007-09-06 メルク　エンド　カムパニー　インコーポレーテッド CGRP receptor antagonist
WO2008079683A2 (en) 2006-12-20 2008-07-03 Abbott Laboratories N- (5, 6, 7, 8-tetrahydronaphthalen-1-yl) urea derivatives and related compounds as trpv1 vanilloid receptor antagonists for the treatment of pain
US7989447B2 (en) 2006-04-13 2011-08-02 Neuraxon, Inc. 1,5 and 3,6-substituted indole compounds having NOS inhibitory activity
WO2012177896A1 (en) * 2011-06-24 2012-12-27 Amgen Inc. Trpm8 antagonists and their use in treatments
US8673909B2 (en) 2007-11-16 2014-03-18 Neuraxon, Inc. Indole compounds and methods for treating visceral pain
US8710043B2 (en) 2011-06-24 2014-04-29 Amgen Inc. TRPM8 antagonists and their use in treatments
WO2014078454A1 (en) * 2012-11-13 2014-05-22 Array Biopharma Inc. Bicyclic urea, thiourea, guanidine and cyanoguanidine compounds useful for the treatment of pain
US8952009B2 (en) 2012-08-06 2015-02-10 Amgen Inc. Chroman derivatives as TRPM8 inhibitors
US20160229804A1 (en) * 2013-09-22 2016-08-11 Merck Sharp & Dohme Corp. TrkA KINASE INHIBITORS, COMPOSITIONS AND METHODS THEREOF
US9546156B2 (en) 2012-11-13 2017-01-17 Array Biopharma Inc. N-bicyclic aryl,N'-pyrazolyl urea, thiourea, guanidine cyanoguanidine compounds as TrkA kinase inhibitors
US9562055B2 (en) 2011-05-13 2017-02-07 Array Biopharma Inc. Pyrrolidinyl urea, pyrrolidinyl thiourea and pyrrolidinyl guanidine compounds as TrkA kinase inhibitors
US9790210B2 (en) 2012-11-13 2017-10-17 Array Biopharma Inc. N-(monocyclic aryl),N'-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9790178B2 (en) 2012-11-13 2017-10-17 Array Biopharma Inc. Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9809578B2 (en) 2012-11-13 2017-11-07 Array Biopharma Inc. Pyrazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trkA kinase inhibitors
US9822118B2 (en) 2012-11-13 2017-11-21 Array Biopharma Inc. Bicyclic heteroaryl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9828360B2 (en) 2012-11-13 2017-11-28 Array Biopharma Inc. Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9896435B2 (en) 2012-11-13 2018-02-20 Array Biopharma Inc. N-pyrrolidinyl,N′-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9969694B2 (en) 2012-11-13 2018-05-15 Array Biopharma Inc. N-(arylalkyl)-N′-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9981959B2 (en) 2012-11-13 2018-05-29 Array Biopharma Inc. Thiazolyl and oxazolyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US10835533B2 (en) 2014-05-15 2020-11-17 Array Biopharma Inc. 1 -((3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-yl)urea as a TrkA kinase inhibitor
US11304956B2 (en) * 2016-10-03 2022-04-19 Anatoly Semenovich REDER Use of 7-bromo-5-(O-chlorophenyl)-3-propoxy-1,2-dihydro-3H-1,4-benzodiazepin-2-one for inhibition of neuropathic pain and seizures of different etiology

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0434364A2 (en) * 1989-12-18 1991-06-26 Merck & Co. Inc. Benzodiazepine analogs for treating panic syndrome and for directly inducing analgesia
US5218114A (en) * 1991-04-10 1993-06-08 Merck & Co., Inc. Cholecystokinin antagonists
EP0549039A1 (en) * 1991-12-20 1993-06-30 MERCK SHARP &amp; DOHME LTD. 3-Phenylureido-1,4-Benzodiazepinones and their use as cholecystokinin or gastrin antagonists
WO1993019052A1 (en) * 1992-03-24 1993-09-30 Merck Sharp & Dohme Limited 3-ureido substituted benzodiazepin-2-ones having cholecystokinin and/or gastrin antagonistic activity and their use in therapy
US5378838A (en) * 1993-01-13 1995-01-03 Merck & Co., Inc. Benzodiazepine cholecystokinin antagonists
US5478933A (en) * 1991-10-10 1995-12-26 Merck Sharpe & Dohme Ltd. Benzodiazepine derivatives and their use as antagonists of cholecystokinin and/or gastrin receptors
WO1996004254A2 (en) * 1994-07-29 1996-02-15 Fujisawa Pharmaceutical Co., Ltd. Benzodiazepine derivatives
US5521175A (en) * 1992-07-29 1996-05-28 Merck Sharp & Dohme Ltd. Benzodiazepine derivatives
US5696110A (en) * 1991-10-24 1997-12-09 Merck, Sharp & Dohme, Ltd. Benzodiazepine derivatives and their use as antagonists of cholecystokinin and/or gastrin receptors

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0434364A2 (en) * 1989-12-18 1991-06-26 Merck & Co. Inc. Benzodiazepine analogs for treating panic syndrome and for directly inducing analgesia
US5218114A (en) * 1991-04-10 1993-06-08 Merck & Co., Inc. Cholecystokinin antagonists
US5478933A (en) * 1991-10-10 1995-12-26 Merck Sharpe & Dohme Ltd. Benzodiazepine derivatives and their use as antagonists of cholecystokinin and/or gastrin receptors
US5696110A (en) * 1991-10-24 1997-12-09 Merck, Sharp & Dohme, Ltd. Benzodiazepine derivatives and their use as antagonists of cholecystokinin and/or gastrin receptors
EP0549039A1 (en) * 1991-12-20 1993-06-30 MERCK SHARP &amp; DOHME LTD. 3-Phenylureido-1,4-Benzodiazepinones and their use as cholecystokinin or gastrin antagonists
WO1993019052A1 (en) * 1992-03-24 1993-09-30 Merck Sharp & Dohme Limited 3-ureido substituted benzodiazepin-2-ones having cholecystokinin and/or gastrin antagonistic activity and their use in therapy
US5521175A (en) * 1992-07-29 1996-05-28 Merck Sharp & Dohme Ltd. Benzodiazepine derivatives
US5378838A (en) * 1993-01-13 1995-01-03 Merck & Co., Inc. Benzodiazepine cholecystokinin antagonists
WO1996004254A2 (en) * 1994-07-29 1996-02-15 Fujisawa Pharmaceutical Co., Ltd. Benzodiazepine derivatives

Cited By (52)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007525450A (en) * 2003-04-15 2007-09-06 メルク　エンド　カムパニー　インコーポレーテッド CGRP receptor antagonist
JP2007516183A (en) * 2003-06-26 2007-06-21 メルク　エンド　カムパニー　インコーポレーテッド Benzodiazepine CGRP receptor antagonist
JP2007516182A (en) * 2003-06-26 2007-06-21 メルク　エンド　カムパニー　インコーポレーテッド Benzodiazepine CGRP receptor antagonist
JP2007519729A (en) * 2004-01-29 2007-07-19 メルク　エンド　カムパニー　インコーポレーテッド CGRP receptor antagonist
EA013123B1 (en) * 2005-04-13 2010-02-26 Ньюрэксон, Инк. Substituted indole compounds having nos inhibitory activity
WO2007063418A3 (en) * 2005-04-13 2007-12-21 Neuraxon Inc Substituted indole compounds having nos inhibitory activity
US7375219B2 (en) 2005-04-13 2008-05-20 Neuraxon, Inc. Substituted indole compounds having NOS inhibitory activity
JP2015199745A (en) * 2005-04-13 2015-11-12 ニューラクソン，インコーポレーテッド Substituted indole compounds having nos inhibitory activity
US8586620B2 (en) 2005-04-13 2013-11-19 Neuraxon, Inc. Substituted indole compounds having NOS inhibitory activity
JP2008535908A (en) * 2005-04-13 2008-09-04 ニューラクソン，インコーポレーテッド Substituted indole compounds having NOS inhibitory activity
WO2007063418A2 (en) * 2005-04-13 2007-06-07 Neuraxon, Inc. Substituted indole compounds having nos inhibitory activity
AU2006321284B2 (en) * 2005-04-13 2012-06-21 Neuraxon, Inc. Substituted indole compounds having NOS inhibitory activity
US7951940B2 (en) 2005-04-13 2011-05-31 Neuraxon, Inc. Substituted indole compounds having NOS inhibitory activity
US7989447B2 (en) 2006-04-13 2011-08-02 Neuraxon, Inc. 1,5 and 3,6-substituted indole compounds having NOS inhibitory activity
US8030504B2 (en) 2006-12-20 2011-10-04 Abbott Laboratories Antagonists of the TRPV1 receptor and uses thereof
JP2010513557A (en) * 2006-12-20 2010-04-30 アボット・ラボラトリーズ N- (5,6,7,8-tetrahydronaphthalen-1-yl) urea derivatives and related compounds as TRPV1 vanilloid receptor antagonists for the treatment of pain
US8350083B2 (en) 2006-12-20 2013-01-08 Abbvie Inc. Antagonists of the TRPV1 receptor and uses thereof
WO2008079683A3 (en) * 2006-12-20 2008-08-28 Abbott Lab N- (5, 6, 7, 8-tetrahydronaphthalen-1-yl) urea derivatives and related compounds as trpv1 vanilloid receptor antagonists for the treatment of pain
WO2008079683A2 (en) 2006-12-20 2008-07-03 Abbott Laboratories N- (5, 6, 7, 8-tetrahydronaphthalen-1-yl) urea derivatives and related compounds as trpv1 vanilloid receptor antagonists for the treatment of pain
US8673909B2 (en) 2007-11-16 2014-03-18 Neuraxon, Inc. Indole compounds and methods for treating visceral pain
US10323022B2 (en) 2011-05-13 2019-06-18 Array Biopharma Inc. Pyrrolidinyl urea, pyrrolidinyl thiourea and pyrrolidinyl guanidine compounds as TrkA kinase inhibitors
US9878997B2 (en) 2011-05-13 2018-01-30 Array Biopharma Inc. Pyrrolidinyl urea, pyrrolidinyl thiourea and pyrrolidinyl guanidine compounds as TrkA kinase inhibitors
US9562055B2 (en) 2011-05-13 2017-02-07 Array Biopharma Inc. Pyrrolidinyl urea, pyrrolidinyl thiourea and pyrrolidinyl guanidine compounds as TrkA kinase inhibitors
US9096527B2 (en) 2011-06-24 2015-08-04 Amgen Inc. TRPM8 antagonists and their use in treatments
WO2012177896A1 (en) * 2011-06-24 2012-12-27 Amgen Inc. Trpm8 antagonists and their use in treatments
US8710043B2 (en) 2011-06-24 2014-04-29 Amgen Inc. TRPM8 antagonists and their use in treatments
US8778941B2 (en) 2011-06-24 2014-07-15 Amgen Inc. TRPM8 antagonists and their use in treatments
US8952009B2 (en) 2012-08-06 2015-02-10 Amgen Inc. Chroman derivatives as TRPM8 inhibitors
US9896435B2 (en) 2012-11-13 2018-02-20 Array Biopharma Inc. N-pyrrolidinyl,N′-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US10851080B2 (en) 2012-11-13 2020-12-01 Array Biopharma Inc. Methods of treatment using pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds
WO2014078454A1 (en) * 2012-11-13 2014-05-22 Array Biopharma Inc. Bicyclic urea, thiourea, guanidine and cyanoguanidine compounds useful for the treatment of pain
AU2013344886B2 (en) * 2012-11-13 2017-06-29 Array Biopharma Inc. Bicyclic urea, thiourea, guanidine and cyanoguanidine compounds useful for the treatment of pain
US10889589B2 (en) 2012-11-13 2021-01-12 Array Biopharma Inc. Bicyclic urea, thiourea, guanidine and cyanoguanidine compounds useful for the treatment of pain
US9790210B2 (en) 2012-11-13 2017-10-17 Array Biopharma Inc. N-(monocyclic aryl),N'-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9790178B2 (en) 2012-11-13 2017-10-17 Array Biopharma Inc. Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9809578B2 (en) 2012-11-13 2017-11-07 Array Biopharma Inc. Pyrazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trkA kinase inhibitors
US9822118B2 (en) 2012-11-13 2017-11-21 Array Biopharma Inc. Bicyclic heteroaryl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9828360B2 (en) 2012-11-13 2017-11-28 Array Biopharma Inc. Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
CN104903310A (en) * 2012-11-13 2015-09-09 阵列生物制药公司 Bicyclic urea, thiourea, guanidine and cyanoguanidine compounds useful for the treatment of pain
US9546156B2 (en) 2012-11-13 2017-01-17 Array Biopharma Inc. N-bicyclic aryl,N'-pyrazolyl urea, thiourea, guanidine cyanoguanidine compounds as TrkA kinase inhibitors
CN104903310B (en) * 2012-11-13 2018-08-14 阵列生物制药公司 It can be used for treating bicyclic urea, thiocarbamide, guanidine and the cyanoguandine compounds of pain
US9981959B2 (en) 2012-11-13 2018-05-29 Array Biopharma Inc. Thiazolyl and oxazolyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9969694B2 (en) 2012-11-13 2018-05-15 Array Biopharma Inc. N-(arylalkyl)-N′-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
RU2664541C2 (en) * 2012-11-13 2018-08-20 Эррэй Биофарма Инк. Bicyclic urea, thiourea, guanidine and cyanohuanidine compounds, useful for the treatment of pain
AU2017221802B2 (en) * 2012-11-13 2019-04-04 Array Biopharma Inc. Bicyclic urea, thiourea, guanidine and cyanoguanidine compounds useful for the treatment of pain
KR20150082603A (en) * 2012-11-13 2015-07-15 어레이 바이오파마 인크. Bicyclic urea, thiourea, guanidine and cyanoguanidine compounds useful for the treatment of pain
US10351575B2 (en) 2012-11-13 2019-07-16 Array Biopharma Inc. Bicyclic urea, thiourea, guanidine and cyanoguanidine compounds useful for the treatment of pain
KR102181913B1 (en) 2012-11-13 2020-11-23 어레이 바이오파마 인크. Bicyclic urea, thiourea, guanidine and cyanoguanidine compounds useful for the treatment of pain
US9718782B2 (en) * 2013-09-22 2017-08-01 Merck Sharp & Dohme Corp. TrkA kinase inhibitors, compositions and methods thereof
US20160229804A1 (en) * 2013-09-22 2016-08-11 Merck Sharp & Dohme Corp. TrkA KINASE INHIBITORS, COMPOSITIONS AND METHODS THEREOF
US10835533B2 (en) 2014-05-15 2020-11-17 Array Biopharma Inc. 1 -((3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-yl)urea as a TrkA kinase inhibitor
US11304956B2 (en) * 2016-10-03 2022-04-19 Anatoly Semenovich REDER Use of 7-bromo-5-(O-chlorophenyl)-3-propoxy-1,2-dihydro-3H-1,4-benzodiazepin-2-one for inhibition of neuropathic pain and seizures of different etiology

Also Published As

Publication number Publication date
WO2003051275A3 (en) 2003-10-30
AU2002359126A1 (en) 2003-06-30
SE0104248D0 (en) 2001-12-14
AU2002359126A8 (en) 2003-06-30

Similar Documents

Publication Publication Date Title
WO2003051275A2 (en) Benzodiazepine derivatives, preparation thereof and use thereof
US7375101B2 (en) Benzodiazepine derivatives, preparation thereof and use thereof
CA2575853C (en) Isoindolone compounds and their use as metabotropic glutamate receptor potentiators
WO2006052190A1 (en) Indazole sulphonamide derivatives
JPH07118244A (en) 1,5-benzodiazepine derivative
ZA200602446B (en) Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof
US7384955B2 (en) Azaindole derivatives, preparations thereof, uses thereof and compositions containing them
US7501447B2 (en) Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof
EP0309422A2 (en) New amidino tricycle derivatives
AU2004245296B2 (en) Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof
EP1670770B1 (en) Benzimidazole derivatives, compositions containing them, preparation therof and uses thereof
US20070161619A1 (en) Pyrroloquinoline and piperidoquinoline derivatives, preparation thereof, compositions containing them and uses thereof
US20070265325A1 (en) Nitro Indazole Derivatives
EP1458684B1 (en) Therapeutic heterocycles as bradykinin b2 receptor antagonists
US7244850B2 (en) Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof
MXPA06008941A (en) Pyrroloquinoline and piperidoquinoline derivatives, preparation thereof, compositions containing them and uses thereof

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LU MC NL PT SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase in:

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP