WO2002099388A2 - Benzodiazepine bradykinin antagonists - Google Patents

Benzodiazepine bradykinin antagonists Download PDF

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WO2002099388A2
WO2002099388A2 PCT/US2002/021065 US0221065W WO02099388A2 WO 2002099388 A2 WO2002099388 A2 WO 2002099388A2 US 0221065 W US0221065 W US 0221065W WO 02099388 A2 WO02099388 A2 WO 02099388A2
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Prior art keywords
pharmaceutically acceptable
acceptable salt
compound according
aryl
dihydro
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PCT/US2002/021065
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French (fr)
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WO2002099388A3 (en
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Michael R. Wood
Mark G. Bock
Dai-Shi Su
Scott D. Kuduk
Wei Han
Bruce D. Dorsey
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Merck & Co., Inc.
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Priority to AU2002346048A priority Critical patent/AU2002346048A1/en
Publication of WO2002099388A2 publication Critical patent/WO2002099388A2/en
Publication of WO2002099388A3 publication Critical patent/WO2002099388A3/en

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention is directed to benzodiazepine compounds.
  • this invention is directed to benzodiazepine compounds that are bradykinin Bl antagonists or inverse agonists having selectivity against the bradykinin B2 receptor.
  • Bradykinin is a kinin that plays an important role in the pathophysiological processes accompanying acute and chronic pain and inflammation. Bradykinins, like other related kinins, are autocoid peptides produced by the catalytic action of kallikrein enzymes on plasma and tissue precursors termed kininogens. Inhibition of bradykinin Bl receptors by compounds that are bradykinin Bl antagonists or inverse agonists would provide relief from maladies that mediate undesirable symptoms through a BK Bl receptor pathway. Accordingly, there is a need for novel compounds that are effective bradykinin B 1 antagonists or inverse agonists.
  • U.S. Patent Nos. 5,220,018, 5,302,591, 5,360,802, 5,451,582, 5,478,933, 5,521,175, 5,556,969, 5,696,110, and 5,728,829 describe compounds that are cholecystokinin ("CCK") and gastrin antagonists.
  • European Patent Nos. EP 434364, EP 514133, and EP 538945 describe compounds that are CCK and gastrin antagonists.
  • British Patent No. GB 2271354 describes compounds that are CCK and gastrin antagonists.
  • WO 9302078 WO 9307131, WO 9319052, WO 9400438, WO 9403437, WO 9403447, WO 9506041, and WO 9815535 describe compounds that are CCK and gastrin antagonists.
  • bradykinin B 1 antagonists to treat chronic pain and inflammation.
  • Such compounds would be effective in the treatment or prevention of pain including, for example, bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia), perioperative pain (general surgery, gynecological) and chronic pain.
  • inflammatory pain such as, for example, inflammatory airways disease (chronic obstructive pulmonary disease) would be effectively treated by bradykinin Bl antagonist compounds.
  • such compounds may additionally be used to treat asthma, inflammatory bowel disease, rhinitis, pancreatitis, cystitis (interstitial cystitis), uveitis, inflammatory skin disorders, rheumatoid arthritis and edema resulting from trauma associated with burns, sprains or fracture. They may be used subsequent to surgical intervention (e.g. as post-operative analgesics) and to treat inflammatory pain of varied origins (e.g. osteoarthritis, rheumatoid arthritis, rheumatic disease, teno- synovitis and gout) as well as for the treatment of pain associated with angina, menstruation or cancer.
  • surgical intervention e.g. as post-operative analgesics
  • inflammatory pain of varied origins e.g. osteoarthritis, rheumatoid arthritis, rheumatic disease, teno- synovitis and gout
  • diabetic vasculopathy post capillary resistance or diabetic symptoms associated with insulitis (e.g. hyperglycemia, diuresis, proteinuria and increased nitrite and kallikrein urinary excretion). They may be used to treat inflammatory skin disorders such as psoriasis and eczema. They may be used as smooth muscle relaxants for the treatment of spasm of the gastrointestinal tract or uterus or in the therapy of Crohn's disease, ulcerative colitis or pancreatitis. Such compounds may be used therapeutically to treat hyperreactive airways and to treat inflammatory events associated with airways disease e.g. asthma, and to control, restrict or reverse airways hyperreactivity in asthma.
  • insulitis e.g. hyperglycemia, diuresis, proteinuria and increased nitrite and kallikrein urinary excretion.
  • insulitis e.g. hyperglycemia, diuresis, proteinuria and increased nitrite and kallik
  • They may be used to treat intrinsic and extrinsic asthma including allergic asthma (atopic or non-atopic) as well as exercise-induced asthma, occupational asthma, asthma post-bacterial infection, other non-allergic asthmas and "whez- infant syndrome". They may also be effective against pneumoconiosis, including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis was well as adult respiratory distress syndrome, chronic obstructive pulmonary or airways disease, bronchitis, allergic rhinitis, and vasomotor rhinitis.
  • pneumoconiosis including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis was well as adult respiratory distress syndrome, chronic obstructive pulmonary or airways
  • liver disease multiple sclerosis, atherosclerosis, Alzheimer's disease, septic shock e.g. as anti-hypovolemic and/or anti-hypotensive agents, cerebral edema, headache, migraine, closed head trauma, irritable bowel syndrome and nephritis.
  • septic shock e.g. as anti-hypovolemic and/or anti-hypotensive agents
  • cerebral edema headache, migraine, closed head trauma, irritable bowel syndrome and nephritis.
  • such compounds are also useful as research tools (in vivo and in vitro).
  • bradykinin Bl antagonist compounds useful in the treatment or prevention of symptoms such as pain and inflammation associated with the bradykinin Bl pathway.
  • Rl is H, C ⁇ _8alkyl (optionally substituted with 1-9 independent halogens), C ⁇ _6alkyloxy- -C ⁇ -loalkylaryl, -C ⁇ -2alkyl-C3-i ocycloalkyl or C2-6alkenyl;
  • R2 is -NHC(O)NR22R23, -OC(O)NR22R23, -C ⁇ _3alkyl- C(O)NR22R23 or -NHC(O)R23 ; or
  • R2 is H and Rl is -C ⁇ _7alkyl-C(O)-NH-Rl2;
  • Rl2 is -C2-4alkyl-Rl3 0 r
  • Rl4 is aryl or heteroaryl wherein the aryl or heteroaryl is optionally substituted with 1-2 substituents, each substituent independently is C ⁇ _6alkyl, C ⁇ _6alkyloxy, Ci-6alkylcarboxy-, Ci-6alkylamido, OH, halogen, nitro, amino or cyano;
  • R22 is H, C ⁇ _8alkyl (optionally substituted with 1-9 independent halogens), Ci- ⁇ alkyloxy- -Ci-ioalkylaryl, -C ⁇ -2alkyl-C3_ ⁇ ocycloalkyl, or C2-6alkenyl;
  • R23 is -C2-6alkyl-R25, -C ⁇ _6alkyl-R31, -C ⁇ -4alkylaryl, or -C ⁇ -4alkylheteroaryl, wherein the aryl or heteroaryl is substituted with a group selected from -C ⁇ C-R44, -(CH2) ⁇ -4-R 25 and -C(O)-R25;
  • R44 1S aryl or heteroaryl wherein the aryl or heteroaryl is optionally substituted with 1-2 substituents, each substituent independently is C ⁇ _6alkyl (optionally substituted with 1-9 independent halogens), Ci_6alkyloxy-, Ci- ⁇ alkyl- carboxy-, Ci- ⁇ alkylamido- OH, halogen, nitro, amino or cyano;
  • R26 is H, -NR66R67, _c(O)-O-R66, -C(O)-NR66R67 OH,
  • aryl or heteroaryl wherein the aryl or heteroaryl is optionally substituted with 1-2 substituents, each substituent independently is C ⁇ _6alkyl (optionally substituted with 1-9 independent halogens), Cl-6alkyloxy-, C ⁇ _6alkylcarboxy-, Ci ⁇ alkylamido-, OH, halogen, nitro, amino, or cyano;
  • R6 and R67 are each independently H, OH, C ⁇ -salkyl (optionally substituted with 1-9 independent halogens), Ci-6a ⁇ kyloxy- -C ⁇ _ ⁇ oalkylaryl, -Co-2alkyl-C3_iocycloalkyl, or C2-6alkenyl;
  • R27 is -C ⁇ -2alkyl-C3-iocycloalkyl, -C ⁇ -2alkylaryl, or -C ⁇ -2 a lkylheteroaryl, wherein the aryl or heteroaryl is optionally substituted with 1-2 substituents, each substituent independently is Ci-6alkyl (optionally substituted with 1-9 independent halogens), Ci_6alkyloxy-, C ⁇ _6alkylcarboxy-, Ci_6alkylamido-, OH, halogen, nitro, amino or cyano;
  • R4 is Ci-8alkyl (optionally substituted with 1-9 independent halogens), Ci_6alkyloxy-, -Co-3alkyl-C3_iocycloalkyl, C2-8 a lkenyl, -C ⁇ -3alkylaryl, or -C -3alkylheteroaryl, wherein the aryl or heteroaryl is optionally substituted with 1-3 substituents, each substituent independently is C ⁇ _6alkyl (optionally substituted with 1-9 independent halogens), Cj-jalkyloxy- Ci- ⁇ alkylcarboxy- Ci_6alkylamido-, OH, halogen, nitro, amino, or cyano, or
  • R41 and R42 are each independently H, C ⁇ _8alkyl (optionally substituted with 1-9 independent halogens), Ci_6alkyloxy- -Ci-ioalkylaryl, -C ⁇ -2 a lkyl-C3_ ⁇ ocycloalkyl, or C2-6alkenyl;
  • R5 is H, nitro, halogen, cyano, OH, amino, Ci - ⁇ alkylthio- Ci-8alkyl (optionally substituted with 1-9 independent halogens), C ⁇ _8alkyloxy- -Co-10alkylaryl, -C0-10alkylheteroaryl, -C(O)-C ⁇ -2alkylaryl, -C(O)-Co-2alkylheteroaryl, -C(O)-O-aryl, -C(O)-O-heteroaryl, -C(O)-NH-
  • the compounds of the present application are represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein: R2 is -NHC(O)NR22R23.
  • R 3 is -C ⁇ -4alkylaryl, wherein the aryl is substituted with
  • R27 is -C0-2alkylaryl, or -C ⁇ -2alkylheteroaryl, wherein the aryl or heteroaryl is optionally substituted with 1-2 substituents, each substituent independently is Ci_6alkyl (optionally substituted with 1-9 independent halogens), C ⁇ _6alkyloxy-, C ⁇ _6alkylcarboxy-, Ci_6alkylamido- OH, halogen, nitro, amino or cyano;
  • R23 is -C ⁇ -4alkylaryl, wherein the aryl is substituted with -(CH2) ⁇ -4-R 2 ⁇ or -C(O)-R25;
  • R23 is -C ⁇ -4alkylaryl, wherein the aryl is substituted with -(CH2) ⁇ -4-R 2 ⁇ or -C(O)-R25 ;
  • R23 is -C ⁇ -4alkylaryl, wherein the aryl is substituted with -(CH2)0-4-R 2 5, or -C(O)-R25;
  • R23 is -C ⁇ -4alkylaryl, wherein the aryl is substituted with -(CH2)0-4-R 25 or -C(O)-R25;
  • R23 is -C ⁇ -4alkylaryl, wherein the aryl is substituted with -(CH2) ⁇ -4 ⁇ R 2 ⁇ or-C(O)-R25 ; R25 is
  • R26 is aryl, wherein the aryl is optionally substituted with 1-2 substituents, each substituent independently is C ⁇ _6alkyl (optionally substituted with 1-9 independent halogens), Ci_6alkyloxy- C ⁇ _6alkylcarboxy- C ⁇ _6alkylamido-, OH, halogen, nitro, amino, or cyano;
  • R23 is -C ⁇ -4alkylaryl, wherein the aryl is substituted with -(CH2) ⁇ -4 ⁇ 2 ⁇ or-C(O)-R25;
  • R23 is
  • R23 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R26 is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with 1-2 substituents, each substituent independently is Ci-6alkyl (optionally substituted with 1-9 independent halogens), C ⁇ -6alkyloxy-, Ci-6alkylcarboxy- C ⁇ _.6alkylamido-, OH, halogen, nitro, amino, or cyano.
  • R23 is
  • R23 is -C ⁇ -4alkylaryl, wherein the aryl is substituted with
  • the compounds of the present application are represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein: R2 is -O-C(O)NR22R23 0 r -Ci -3alkyl-C(O)NR22R23.
  • R2 is -O-C(O)NR22R23 ;
  • R23 is -C ⁇ -4alkylaryl, wherein the aryl is optionally substituted with 1-2 substituents, each substituent independently is -(CH2)0-4-R 2 5, or-C(O)-R25;
  • R25 is
  • R2 is -Ci-3alkyl-C(O)NR22R23 ; R23 i s -C ⁇ -4alkylaryl, wherein the aryl is substituted with -(CH2)0-4-R 25 or -C(O)-R25 ; R25 is
  • R is -Ci-3alkyl-C(O)NR22R23 ; R23 1S -C ⁇ -4alkylaryl, wherein the aryl is substituted with -(CH2)0-4-R 25 or-C(O)-R25 ;
  • the compounds of the present application are represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein: R2 is H and Rl is -C ⁇ _7alkyl-C(O)-NH-Rl2.
  • Rl2 is
  • Rl4 is heteroaryl, wherein the heteroaryl is optionally substituted with 1-2 substituents, each substituent independently is C ⁇ _6alkyl, Ci _6alkyloxy- Ci_6alkylcarboxy-, C ⁇ _6alkylamido-, OH, halogen, nitro, amino, or cyano;
  • R2 is -NH-C(O)-NHR23 and Rl is propyl, cyclopropylmethyl or 2,2,2-trifluoroethyl,
  • R23 is aryl or heteroaryl, wherein the aryl or heteroaryl is substituted with
  • R26 is NR66R67 ; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with 1-2 substituents, each substituent independently is C ⁇ _6alkyl (optionally substituted with 1-9 independent halogens), C ⁇ _6alkyloxy, Ci_6alkylcarboxy, Ci_6alkylamido, OH, halogen, nitro, amino, or cyano, or,
  • R66 and R67 are each independently H, Ci_8alkyl (optionally substituted with 1-9 independent halogens), Ci -6aIkyloxy, Ci-ioalkylaryl, -C ⁇ -2alkyl-C3-6cycloalkyl, C2-6alkenyl;
  • R27 is -Co-2alkyl-C3_6cycloalkyl, C ⁇ -2 a lkylaryl, C ⁇ -2alkylheteroaryl, wherein the aryl or heteroaryl is optionally substituted with 1-2 substituents, each substituent independently is C ⁇ _6alkyl (optionally substituted with 1-9 independent halogens), Ci-6alkyloxy, C ⁇ _6alkylcarboxy, Ci-6alkylamido, OH, halogen, nitro, amino or cyano;
  • R4 is C ⁇ -3alkyl-C3_iocycloalkyl, C ⁇ -3alkyIaryl, C ⁇ -3alkylheteroaryl, wherein the aryl or heteroaryl is optionally substituted with 1-3 substituents, each substituent independently is Ci-6alkyl (optionally substituted with 1-9 independent halogens), C ⁇ _6alkoxy, C ⁇ _6alkylcarboxy, Ci-6alkylamido, OH, halogen, nitro, amino, or cyano, or R4 is
  • R5 is H or a single substituent, at the 7-position of the benzodiazepine core, chosen from among the following list: nitro, halogen, cyano, OH, amino, Ci_6alkylthio, Ci_8alkyl (optionally substituted with 1-9 independent halogens), Ci -8alkoxy, -Cfj-ioalkylaryl, -Co-lOalkylheteroaryl, -C(O) -C ⁇ -2alkylaryl, -C(O)- C ⁇ -2alkylheteroaryl, -C(O)-O-aryl, -C(O)-O-heteroaryl, -C(O)-NH-C ⁇ -2alkylaryl, -C(O)-NH-Co-2alkylheteroaryl, -C(O)-N(C ⁇ _8alkyl)-C ⁇ -2alkylaryl, -C(O)- N(C ⁇ _8alkyl
  • Rl is propyl and R is
  • R27 is 4-pyridyl
  • R4 is cyclohexyl, -CH2-CH2-phenyl, or 4-methylphenyl
  • R5 is H.
  • Another aspect of the present application provides a compound selected from the group and pharmaceutically acceptable salts thereof:
  • Preferred compounds are:
  • alkyl as well as other groups having the prefix “alk” such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like, means carbon chains which may be linear or branched or combinations thereof.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and the like.
  • alkenyl alkynyl and other like terms include carbon chains containing at least one unsaturated C-C bond.
  • cycloalkyl means carbocycles containing no heteroatoms, and includes mono-, bi- and tricyclic saturated carbocycles, as well as fused ring systems.
  • fused ring systems can include one ring that is partially or fully unsaturated such as a benzene ring to form fused ring systems such as benzofused carbocycles.
  • Cycloalkyl includes such fused ring systems as spirofused ring systems.
  • cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, indenyl, fluorenyl, 1,2,3,4- tetrahydronaphthalene and the like.
  • cycloalkenyl means carbocycles containing no heteroatoms and at least one non-aromatic C-C double bond, and include mono-, bi- and tricyclic partially saturated carbocycles, as well as benzofused cycloalkenes.
  • Examples of cycloalkenyl examples include cyclohexenyl, indenyl, and the like.
  • Co means that the carbon is not present.
  • C0-C5 means that there are from none to five carbons present - that is, five, four, three, two, one, or no carbons present.
  • the link is a direct bond.
  • the terminus is hydrogen.
  • aryl is an aromatic mono- or bicyclic carbocycle having from 6 to 10 carbon atoms, optionally fused to a 4- to 6-membered non-aromatic ring containing 0-3 heteroatoms selected from N, O and S(O)m. Examples include phenyl and naphthyl.
  • Heteroaryl is a mono-or bicyclic aromatic ring containing from 1 to 6 heteroatoms independently selected from N, O and S wherein each ring has five or six ring atoms.
  • heteroaryl include pyridyl, pyrimidinyl, pyrrolyl, furyl, thienyl, imidazolyl, thiazolyl, fhiadiazolyl, triazolyl, tetrazolyl, oxadiazolyl, oxazolyl, imidazolidinyl, pyrazolyl, isoxazolyl, benzothiadiazolyl, indolyl, indolinyl, benzodioxolyl, benzodioxanyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl, benzotriazolyl, benzoxazolyl, purin
  • composition as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • optionally substituted is intended to include both substituted and unsubstituted.
  • optionally substituted aryl could represent a pentafluorophenyl or a phenyl ring.
  • Compounds described herein may contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
  • the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
  • the above Formula I is shown without a definitive stereochemistry at certain positions.
  • the present invention includes all stereoisomers of Formula I, and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases.
  • Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines.
  • Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N,N -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine,
  • the compound of the present invention When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.
  • compositions of the present invention comprise a compound of the present invention (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants.
  • the compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • the compounds of this invention or pharmaceutically acceptable salts thereof can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
  • compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion.
  • the compounds of the present invention or pharmaceutically acceptable salts thereof may also be administered by controlled release means and/or delivery devices.
  • the compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both.
  • the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound of the present invention or a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention or pharmaceutically acceptable salts thereof can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
  • the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers are sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers include carbon dioxide and nitrogen.
  • any convenient pharmaceutical media may be employed.
  • water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets.
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets.
  • tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
  • tablets may be coated by standard aqueous or nonaqueous techniques
  • a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • Each tablet preferably contains from about O.lmg to about 500mg of the active ingredient and each cachet or capsule preferably containing from about 0.1 to about 500mg of the active ingredient.
  • the tablet, cachet, or capsule can each contain, for example, O.lmg, 0.5mg, lmg, 3mg, 5mg, lOmg, 25mg, 50mg, lOOmg, 125mg, 250mg, or 500mg of active ingredient.
  • compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
  • a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
  • Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
  • Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices.
  • formulations may be prepared, utilizing a compound of this invention, or pharmaceutically acceptable salts thereof, via conventional processing methods.
  • a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.
  • compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds.
  • the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient
  • Radioligand binding assays are performed using membranes from CHO cells that stably express the human, rabbit, rat, or dog B 1 receptors or CHO cells that express the human B2 receptor.
  • cells are harvested from culture flasks in PBS/lmM EDTA and centrifuged at lOOOxg for 10 minutes. The cell pellets are homogenized with a polytron in ice cold 20mM HEPES, ImM EDTA, pH 7.4 (lysis buffer) and centrifuged at 20,000xg for 20 minutes.
  • the membrane pellets are rehomogenized in lysis buffer, centrifuged again at 20,000xg and the final pellets are resuspended at 5mg protein/ml in assay buffer (120mM NaCl, 5mM KC1, 20mM HEPES, pH 7.4) supplemented with 1% BSA and frozen at -80°C.
  • membranes are centrifuged at 14,000xg for 5 minutes and resuspended to the desired protein concentration in assay buffer containing lOOnM enaliprilat, 140/ig/mL bacitracin and 0.1% BSA.
  • 3H-des-arglO, leu9 kallidin is the radioligand used for the human and rabbit Bl receptors
  • 3H-des- arglO kallidin is used for the rat and dog Bl receptors
  • 3H-bradykinin is used to label the human B2 receptor.
  • Radioactivity retained by the filter is counted using a Wallac Beta-plate scintillation counter.
  • the compounds of this invention have potency in the above assay as demonstrated by results of less than 5 ⁇ M. It is advantageous that the assay results be less than l ⁇ ,M, even more advantageous for the results be less than 0.5 ⁇ M. Accordingly, the compounds of this invention are useful in the treatment of pain and inflammation.
  • the compounds would be effective in the treatment or prevention of pain including, for example, bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia), perioperative pain (general surgery, gynecological) and chronic pain.
  • inflammatory pain such as, for example, inflammatory airways disease (chronic obstructive pulmonary disease) would be effectively treated by the bradykinin Bl antagonist compounds of this invention.
  • the compounds of this invention - by being bradykinin Bl antagonists - can additionally be used to treat asthma, inflammatory bowel disease, rhinitis, pancreatitis, cystitis (interstitial cystitis), uveitis, inflammatory skin disorders, rheumatoid arthritis and edema resulting from trauma associated with bums, sprains or fracture. They may be used subsequent to surgical intervention (e.g. as postoperative analgesics) and to treat inflammatory pain of varied origins (e.g.
  • osteoarthritis rheumatoid arthritis, rheumatic disease, teno-synovitis and gout
  • They may be used to treat diabetic vasculopathy, post capillary resistance or diabetic symptoms associated with insulitis (e.g. hyperglycemia, diuresis, proteinuria and increased nitrite and kallikrein urinary excretion).
  • insulitis e.g. hyperglycemia, diuresis, proteinuria and increased nitrite and kallikrein urinary excretion.
  • They may be used to treat inflammatory skin disorders such as psoriasis and eczema.
  • They may be used as smooth muscle relaxants for the treatment of spasm of the gastrointestinal tract or uterus or in the therapy of Crohn's disease, ulcerative colitis or pancreatitis.
  • Such compounds may be used therapeutically to treat hyperreactive airways and to treat inflammatory events associated with airways disease e.g. asthma, and to control, restrict or reverse airways hyperreactivity in asthma.
  • They may be used to treat intrinsic and extrinsic asthma including allergic asthma (atopic or non-atopic) as well as exercise-induced asthma, occupational asthma, asthma post-bacterial infection, other non-allergic asthmas and "whez-infant syndrome".
  • They may also be effective against pneumoconiosis, including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis was well as adult respiratory distress syndrome, chronic obstructive pulmonary or airways disease, bronchitis, allergic rhinitis, and vasomotor rhinitis. Additionally, they may be effective against liver disease, multiple sclerosis, atherosclerosis, Alzheimer's disease, septic shock e.g.
  • anti-hypovolemic and/or anti-hypotensive agents cerebral edema
  • headache including cluster headache, migraine including prophylactic and acute use, closed head trauma, irritable bowel syndrome and nephritis.
  • such compounds are also useful as research tools (in vivo and in vitro).
  • the compounds of this invention are useful in the treatment of pain and inflammation by the administration of a tablet, cachet, or capsule each containing, for example, O.lmg, 0.5mg, lmg, 3mg, 5mg, lOmg, 25mg, 50mg, lOOmg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.
  • a tablet, cachet, or capsule each containing, for example, O.lmg, 0.5mg, lmg, 3mg, 5mg, lOmg, 25mg, 50mg, lOOmg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.
  • the compounds would be effective in the treatment or prevention of pain including, for example, bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia), perioperative pain (general surgery, gynecological) and chronic pain by the administration of a tablet, cachet, or capsule each containing, for example, O.lmg, 0.5mg, lmg, 3mg, 5mg, lOmg, 25mg, 50mg, lOOmg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.
  • pain including, for example, bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia), perioperative pain (general surgery,
  • inflammatory pain such as, for example, inflammatory airways disease (chronic obstructive pulmonary disease) would be effectively treated by the bradykinin B 1 antagonist compounds of this invention by the administration of a tablet, cachet, or capsule each containing, for example, O.lmg, 0.5mg, lmg, 3mg, 5mg, lOmg, 25mg, 50mg, lOOmg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.
  • a tablet, cachet, or capsule each containing, for example, O.lmg, 0.5mg, lmg, 3mg, 5mg, lOmg, 25mg, 50mg, lOOmg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once,
  • the compounds of this invention - by being bradykinin Bl antagonists - can additionally be used to treat asthma, inflammatory bowel disease, rhinitis, pancreatitis, cystitis (interstitial cystitis), uveitis, inflammatory skin disorders, rheumatoid arthritis and edema resulting from trauma associated with burns, sprains or fracture by the administration of a tablet, cachet, or capsule each containing, for example, O.lmg, 0.5mg, lmg, 3mg, 5mg, lOmg, 25mg, 50mg, lOOmg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.
  • a tablet, cachet, or capsule each containing, for example, O.lmg, 0.5mg, lmg, 3mg, 5mg, lOmg, 25mg, 50mg, lOOmg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.
  • diabetic vasculopathy post capillary resistance or diabetic symptoms associated with insulitis (e.g. hyperglycemia, diuresis, proteinuria and increased nitrite and kallikrein urinary excretion) by the administration of a tablet, cachet, or capsule each containing, for example, O.lmg, 0.5mg, lmg, 3mg, 5mg, lOmg, 25mg, 50mg, lOOmg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.
  • insulitis e.g. hyperglycemia, diuresis, proteinuria and increased nitrite and kallikrein urinary excretion
  • a tablet, cachet, or capsule each containing, for example, O.lmg, 0.5mg, lmg, 3mg
  • a tablet, cachet, or capsule each containing, for example, O.lmg, 0.5mg, lmg, 3mg, 5mg, lOmg, 25 mg, 50mg, lOOmg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.
  • They may be used as smooth muscle relaxants for the treatment of spasm of the gastrointestinal tract or uterus or in the therapy of Crohn' s disease, ulcerative colitis or pancreatitis by the administration of a tablet, cachet, or capsule each containing, for example, O.lmg, 0.5mg, lmg, 3mg, 5mg, lOmg, 25mg, 50mg, lOOmg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.
  • O.lmg 0.5mg, lmg, 3mg, 5mg, lOmg, 25mg, 50mg, lOOmg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release
  • Such compounds may be used therapeutically to treat hyperreactive airways and to treat inflammatory events associated with airways disease e.g. asthma, and to control, restrict or reverse airways hyperreactivity in asthma by the administration of a tablet, cachet, or capsule each containing, for example, O.lmg, 0.5mg, lmg, 3mg, 5mg, lOmg, 25mg, 50mg, lOOmg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.
  • a tablet, cachet, or capsule each containing, for example, O.lmg, 0.5mg, lmg, 3mg, 5mg, lOmg, 25mg, 50mg, lOOmg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours,
  • a tablet, cachet, or capsule each containing, for example, O.lmg, 0.5mg, lmg, 3mg, 5mg, lOmg, 25mg, 50mg, lOOmg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.
  • pneumoconiosis including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis was well as adult respiratory distress syndrome, chronic obstructive pulmonary or airways disease, bronchitis, allergic rhinitis, and vasomotor rhinitis by the administration of a tablet, cachet, or capsule each containing, for example, O.lmg, 0.5mg, lmg, 3mg, 5mg, lOmg, 25mg, 50mg, lOOmg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.
  • pneumoconiosis including aluminosis, anthracosis, asbestosis, chal
  • liver disease multiple sclerosis, atherosclerosis, Alzheimer's disease, septic shock e.g. as anti-hypovolemic and/or anti-hypotensive agents, cerebral edema, headache, migraine, closed head trauma, irritable bowel syndrome and nephritis by the administration of a tablet, cachet, or capsule each containing, for example, O.lmg, 0.5mg, lmg, 3mg, 5mg, lOmg, 25mg, 50mg, lOOmg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.
  • septic shock e.g. as anti-hypovolemic and/or anti-hypotensive agents, cerebral edema, headache, migraine, closed head trauma, irritable bowel syndrome and nephritis by the
  • the benzodiazepine core (1) obtained commercially or prepared according to J. Org. Chem., 52:3232-3239(1987), is alkylated with an appropriate alkylating agent, like propyl iodide, in an aprotic solvent, like DMF, using a base, like sodium hydride, to provide (2).
  • Compound (2) can then be converted into the 3-amino-benzodiazapine (3) in accordance with J. Org. Chem., 52:3232-3239 (1987).
  • This amine derivative (3) is then reacted with a carboxylic acid or carboxylic acid equivalent, using an appropriate set of peptide coupling reagents, like EDCI/HOBt, in and appropriate solvent, like DMF to yield title compounds (la).
  • an amine like l-pyridin-4- ylpiperazine, is reacted with l-fluoro-4-nitrobenzene in an appropriate solvent, like THF, in the presence of a base, like triethylamine, to provide adduct (4).
  • This nitroaromatic intermediate (4) is then reduced to the aniline (5) using standard catalytic hydrogenation conditions, with palladium on carbon in a suitable solvent, like methanol.
  • a urea linkage between aniline (5) and 3-amino-benzodiazapine (3), prepared according to Scheme 1, can be formed using standard conditions, such as triphosgene and triethylamine in THF to provide title compounds (lb).
  • the benzodiazepine (1) is alkylated with an ester-containing alkylhalide (7), using a strong base, like sodium hydride, in an aprotic solvent, like DMF, to provide ester (8).
  • This ester (8) is then hydrolyzed by the action of an appropriate base, like sodium hydroxide, in a mixture of water and an organic solvent, like THF, to provide carboxylic acid (9), after acidification.
  • Carboxylic acid (9) is then coupled to the amine (5), prepared according to Scheme 2, using an appropriate set of peptide coupling reagents, like EDCI/HOBt, in and appropriate solvent, like DMF, to provide title compounds (Ic).
  • the title compound was prepared by the acylation of the 3-amino benzodiazepine core, according to /. Med. Chem., 31:2235-2246(1988), with the carboxylic acid prepared according to International Patent Publication No. WO 9931061.
  • the benzodiazepine portion was either prepared according to J. Org. Chem., 52:3232-3239(1987) or obtained commercially and alkylated at the N-l position with the appropriate electrophile (in this example, propyl iodide) in DMF using sodium hydride as the base, applying conventional procedures as known in the art.
  • the compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (ES+) of 516.3 for M+H+.
  • the title compound was prepared according to the general method of Example 1, with the exception that the acyl side chain, (4-[l,4]Bipiperidinyl-l -yl- phenyl)-acetic acid, was prepared starting from ethyl (4-aminophenyl)acetate. This starting aniline was homologated to the ketone, ethyl [4-(4-oxopiperidin-l-yl)phenyl]- acetate, according to Org. Lett, 1:1261-1262(1999).
  • the ketone was then reductively animated with piperidine using Pd/C and hydrogen to provide the required ester, which was hydrolyzed under basic conditions to (4-[l,4 Bipiperidinyl-l'-yl-phenyl)- acetic acid.
  • the title compound gave proton NMR spectra consistent with theory and a mass ion (ES+) of 584.5 for M+H+.
  • the title compound was prepared similarly to Example 2, with the exception that the acyl side chain, S-fl ⁇ 'jbipiperidinyl-l'-yl-benzoic acid, was prepared using ethyl 3-aminobenzoate instead of ethyl (4-aminophenyl)acetate.
  • the title compound gave proton NMR spectra consistent with theory and a mass ion (ES+) of 570.4 for M+H+.
  • the title compound was prepared by formation of the urea between the benzodiazepine core, 3-amino-5-(2-phenylethyl)-l-propyl-l,3-dihydro-2H-l,4- benzodiazepin-2-one, and the amine side chain, 4-(4-pyridin-4-ylpiperazin-l- yl)aniline, according to J. Med. Chem., 36:4276-4292(1993).
  • the benzodiazepine portion was prepared in accordance with J. Org. Chem., 52:3232-3239(1987).
  • Example 4 using l,4'-bipiperidine instead of l-pyridin-4-yl-piperazine.
  • Example 7.1 The title compound was prepared by the alkaline hydrolysis of Example 7.1 in an ethanol/water mixture with sodium hydroxide, applying conventional procedures as known in the art.
  • the compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (FT/ICR+) of 540.3 for M+H+.
  • the title compound was prepared by standard peptide coupling conditions using isobutyl chloroformate/triethylamine/ammonia, using Example 10 as the starting material.
  • the compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (FT/ICR+) of 539.3 for M+H+.
  • the title compound was prepared by analogy to Example 4 after the preparation of 3-(l,4 '-bipiperidin-l'-ylmethyl)aniline. This aniline was prepared in two steps from 3-nitrobenzyl bromide and l,4'-bipiperidine. The title compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (FT/ICR+) of 599.4 for M+H+.
  • the title compound was prepared by analogy to Example 4 after the preparation of 3-[4-(4-fIuorophenyI)piperidin-l-yl]propan-l-amine. This amine was prepared in two steps from 2-(3-bromopropyl)-lH-isoindole-l,3(2H)-dione and 4-(4- fluorophenyl)piperidine. The title compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (ES+) of 562.4 for M+H+.
  • the title compound was prepared by analogy to Example 4 after the preparation of 3-(l,4-bipiperidin-l'-yl)propan-l-amine. This amine was prepared in two steps from 2-(3-bromopropyl)-lH-isoindole-l,3(2H)-dione and 1,4-bipiperidine. The title compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (ES+) of 551.5 for M+H+.
  • the title compound was prepared by analogy to Example 17 using 2- (4-bromobutyl)-lH-isoindole-l,3(2H)-dione instead of using 2-(3-bromopropyl)-lH- isoindole-l,3(2H)-dione.
  • the title compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (ES+) of 565.4 for M+H+.
  • the title compound was prepared by analogy to Example 4 after the preparation of l-[4-(l,4'-bipi ⁇ eridin- -yl)phenyl]methanamine. This amine was prepared in two steps from 4-fluorobenzonitrile and 1,4-bipiperidine. The title compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (ES+) of 599.4 for M+H+.
  • the title compound was prepared by analogy to Example 4 after the preparation of 4-(pyridin-4-ylethynyl)aniline.
  • This aniline was prepared in one step from 4-bromopyridine and 4-efhynylaniline according to Ada. Chem. Scand., SerB, 42:448(1988).
  • the title compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (ES+) of 520.3 for M+H+.
  • the title compound was prepared by analogy to Example 4, after the preparation of 3-(4-pyridin-4-ylpiperazin-l-yl)aniline.
  • This aniline was prepared using 3-fluoronitrobenzene and l-pyridin-4-ylpi ⁇ erazine in DMSO, at 90°C, for 60h with potassium carbonate; followed by hydrogenation of the nitro group.
  • the title compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (EI+) of 579.4 for M+.
  • the title compound was prepared by analogy to Example 4, after the preparation of 3-bromo-4-[4-(3-bromopyridin-4-yl)piperazin-l-yl]aniline.
  • This aniline was prepared in 3 steps from 4-fluoronitrobenzene and l-pyridin-4- ylpiperazine. After these two starting materials were allowed to react according to Tetrahedron Lett., 39:2471-2474(1998), the resulting product was bis-brominated with NBS in methylene chloride, and then the nitro group was reduced with iron(0) in acetic acid / ethanol / aqueous HCl, applying conventional procedures as l ⁇ iown in the art.
  • the title compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (ES+) of 757.8 for M+H+(79Br2) .
  • the title compound was prepared by analogy to Example 3.4.
  • the benzodiazepine core 5-cyclohexyl -l-propyl-l,3-dihydro-2H-l,4-benzodiazepin-2- one, was prepared according to J.O.C., 52:3232-3239(1987).
  • This benzodiazepine was then oxidized at N-4 with mCPBA, rearranged to the C-3 acetate with acetic anhydride at 100°C, and then hydrolyzed to the C-3 hydroxyl. This was then coupled to the aniline used in Table 3.
  • the title compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (FT/ICR+) of 293.7 for M+2H+.
  • the title compound was prepared according to J. Med. Chem., 36:4276-4292(1993), using l-(2-aminophenyl)-2,2-dimethylpropan-l-one and ⁇ [(benzyIoxy)carbonyl]amino ⁇ [(tert-butoxycarbonyl)amino]acetic acid as starting materials.
  • the title compound was prepared by analogy to Example 30, using the aniline of Example 3.1, after the preparation of 3-amino-5-piperidin-l-yl-l-propyl- l,3-dihydro-2H-l,4-benzodiazepin-2-one, which was prepared according to J. Med. Chem., 37:719-721(1994).
  • the title compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (FAB+) of 586.4 for M+H+.
  • the title compound was prepared from the benzodiazepine core, 5- cyclohexyl-l-propyl-l,3-dihydro-2H-l,4-benzodiazepin-2-one, and the aniline used in Table 4.
  • the benzodiazepine was alkylated at the C-3 position with tert-butyl bromoacetate and potassium tert-butoxide. After aqueous acidic removal of the tert- butyl group, the resulting acid was coupled with l-(4-aminophenyl)-N,N- dimethylpiperidin-4-amine, employing standard N,N'-dicyclohexylcarbodiimide/N,N- dimethylpyridin-4-amine techniques.
  • the title compound was synthesized from the core benzodiazepine, 5- cyclohexyl-l,3-dihydro-2H-l,4-benzodiazepin-2-one, prepared according to J.O.C, 52:3232-3239(1987).
  • This benzodiazepine was alkylated at the N-l position using ethyl 4-bromobutanoate and sodium hydride.
  • the resulting acid was coupled with 4-(4-pyridin-4-ylpiperazin-l- yl)aniline, described in Example 4, using standard EDCI/HOBt techniques.

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Abstract

Compounds disclosed here or a pharmaceutically acceptable salt thereof, are bradykinin B1 antagonist compounds useful in the treatment or prevention of symptoms such as pain and inflammation associated with the bradykinin B1 pathway.

Description

TITLE OF TEE INVENTION
BENZODIAZEPINE BRADYKININ ANTAGONISTS
BACKGROUND OF THE INVENTION This invention is directed to benzodiazepine compounds. In particular, this invention is directed to benzodiazepine compounds that are bradykinin Bl antagonists or inverse agonists having selectivity against the bradykinin B2 receptor.
Bradykinin ("BK") is a kinin that plays an important role in the pathophysiological processes accompanying acute and chronic pain and inflammation. Bradykinins, like other related kinins, are autocoid peptides produced by the catalytic action of kallikrein enzymes on plasma and tissue precursors termed kininogens. Inhibition of bradykinin Bl receptors by compounds that are bradykinin Bl antagonists or inverse agonists would provide relief from maladies that mediate undesirable symptoms through a BK Bl receptor pathway. Accordingly, there is a need for novel compounds that are effective bradykinin B 1 antagonists or inverse agonists.
U.S. Patent Nos. 5,220,018, 5,302,591, 5,360,802, 5,451,582, 5,478,933, 5,521,175, 5,556,969, 5,696,110, and 5,728,829 describe compounds that are cholecystokinin ("CCK") and gastrin antagonists. European Patent Nos. EP 434364, EP 514133, and EP 538945 describe compounds that are CCK and gastrin antagonists. British Patent No. GB 2271354 describes compounds that are CCK and gastrin antagonists. International Patent Publication Nos. WO 9302078, WO 9307131, WO 9319052, WO 9400438, WO 9403437, WO 9403447, WO 9506041, and WO 9815535 describe compounds that are CCK and gastrin antagonists. G. Semple et al., J. Med. Chem., 40:331-341(1997), M. Satoh et al.,
Chem. Pharm. Bull., 44:1412-1414(1996) describe compounds that are CCK and gastrin antagonists. M.G. Bock and I. Longmore, Current Opinion in Chem. Biol, 4:401-406(2000) describes bradykinin antagonists.
Nevertheless, there remains a need for new effective bradykinin B 1 antagonists to treat chronic pain and inflammation. Such compounds would be effective in the treatment or prevention of pain including, for example, bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia), perioperative pain (general surgery, gynecological) and chronic pain. In particular, inflammatory pain such as, for example, inflammatory airways disease (chronic obstructive pulmonary disease) would be effectively treated by bradykinin Bl antagonist compounds.
Further, such compounds may additionally be used to treat asthma, inflammatory bowel disease, rhinitis, pancreatitis, cystitis (interstitial cystitis), uveitis, inflammatory skin disorders, rheumatoid arthritis and edema resulting from trauma associated with burns, sprains or fracture. They may be used subsequent to surgical intervention (e.g. as post-operative analgesics) and to treat inflammatory pain of varied origins (e.g. osteoarthritis, rheumatoid arthritis, rheumatic disease, teno- synovitis and gout) as well as for the treatment of pain associated with angina, menstruation or cancer. They may be used to treat diabetic vasculopathy, post capillary resistance or diabetic symptoms associated with insulitis (e.g. hyperglycemia, diuresis, proteinuria and increased nitrite and kallikrein urinary excretion). They may be used to treat inflammatory skin disorders such as psoriasis and eczema. They may be used as smooth muscle relaxants for the treatment of spasm of the gastrointestinal tract or uterus or in the therapy of Crohn's disease, ulcerative colitis or pancreatitis. Such compounds may be used therapeutically to treat hyperreactive airways and to treat inflammatory events associated with airways disease e.g. asthma, and to control, restrict or reverse airways hyperreactivity in asthma. They may be used to treat intrinsic and extrinsic asthma including allergic asthma (atopic or non-atopic) as well as exercise-induced asthma, occupational asthma, asthma post-bacterial infection, other non-allergic asthmas and "wheezy- infant syndrome". They may also be effective against pneumoconiosis, including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis was well as adult respiratory distress syndrome, chronic obstructive pulmonary or airways disease, bronchitis, allergic rhinitis, and vasomotor rhinitis. Additionally, they may be effective against liver disease, multiple sclerosis, atherosclerosis, Alzheimer's disease, septic shock e.g. as anti-hypovolemic and/or anti-hypotensive agents, cerebral edema, headache, migraine, closed head trauma, irritable bowel syndrome and nephritis. Finally, such compounds are also useful as research tools (in vivo and in vitro).
SUMMARY OF THE INVENTION
Compounds of this invention represented by Formula I:
Figure imgf000004_0001
(I) or a pharmaceutically acceptable salt thereof, are bradykinin Bl antagonist compounds useful in the treatment or prevention of symptoms such as pain and inflammation associated with the bradykinin Bl pathway.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention are represented by Formula I:
Figure imgf000004_0002
(I) or a pharmaceutically acceptable salt thereof, wherein:
Rl is H, Cι _8alkyl (optionally substituted with 1-9 independent halogens), Cι _6alkyloxy- -Cι -loalkylaryl, -Cθ-2alkyl-C3-i ocycloalkyl or C2-6alkenyl;
R2 is -NHC(O)NR22R23, -OC(O)NR22R23, -Cι _3alkyl- C(O)NR22R23 or -NHC(O)R23; or
R2 is H and Rl is -Cι _7alkyl-C(O)-NH-Rl2;
Rl2 is -C2-4alkyl-Rl3 0r
Figure imgf000004_0003
Figure imgf000005_0001
Rl4 is aryl or heteroaryl wherein the aryl or heteroaryl is optionally substituted with 1-2 substituents, each substituent independently is Cι_6alkyl, Cι_6alkyloxy, Ci-6alkylcarboxy-, Ci-6alkylamido, OH, halogen, nitro, amino or cyano;
R22 is H, Cι_8alkyl (optionally substituted with 1-9 independent halogens), Ci-όalkyloxy- -Ci-ioalkylaryl, -Cθ-2alkyl-C3_ιocycloalkyl, or C2-6alkenyl;
R23 is -C2-6alkyl-R25, -Cι_6alkyl-R31, -Cθ-4alkylaryl, or -Cθ-4alkylheteroaryl, wherein the aryl or heteroaryl is substituted with a group selected from -C≡C-R44, -(CH2)θ-4-R25 and -C(O)-R25;
R441S aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with 1-2 substituents, each substituent independently is Cι_6alkyl (optionally substituted with 1-9 independent halogens), Ci_6alkyloxy-, Ci-βalkyl- carboxy-, Ci-όalkylamido- OH, halogen, nitro, amino or cyano;
R25 is
Figure imgf000005_0002
R26 is H, -NR66R67, _c(O)-O-R66, -C(O)-NR66R67 OH,
Figure imgf000005_0003
aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with 1-2 substituents, each substituent independently is Cι _6alkyl (optionally substituted with 1-9 independent halogens), Cl-6alkyloxy-, Cι_6alkylcarboxy-, Ci^alkylamido-, OH, halogen, nitro, amino, or cyano; R6 and R67 are each independently H, OH, Cι -salkyl (optionally substituted with 1-9 independent halogens), Ci-6aιkyloxy- -Cι_ιoalkylaryl, -Co-2alkyl-C3_iocycloalkyl, or C2-6alkenyl;
R27 is -Cθ-2alkyl-C3-iocycloalkyl, -Cθ-2alkylaryl, or -Cθ-2alkylheteroaryl, wherein the aryl or heteroaryl is optionally substituted with 1-2 substituents, each substituent independently is Ci-6alkyl (optionally substituted with 1-9 independent halogens), Ci_6alkyloxy-, Cι_6alkylcarboxy-, Ci_6alkylamido-, OH, halogen, nitro, amino or cyano;
R31 is
H
Figure imgf000006_0001
R4 is Ci-8alkyl (optionally substituted with 1-9 independent halogens), Ci_6alkyloxy-, -Co-3alkyl-C3_iocycloalkyl, C2-8alkenyl, -Cθ-3alkylaryl, or -C -3alkylheteroaryl, wherein the aryl or heteroaryl is optionally substituted with 1-3 substituents, each substituent independently is Cι_6alkyl (optionally substituted with 1-9 independent halogens), Cj-jalkyloxy- Ci-βalkylcarboxy- Ci_6alkylamido-, OH, halogen, nitro, amino, or cyano, or
R4 is
Figure imgf000006_0002
R41 and R42 are each independently H, Cι_8alkyl (optionally substituted with 1-9 independent halogens), Ci_6alkyloxy- -Ci-ioalkylaryl, -Cθ-2alkyl-C3_ιocycloalkyl, or C2-6alkenyl;
R5 is H, nitro, halogen, cyano, OH, amino, Ci -βalkylthio- Ci-8alkyl (optionally substituted with 1-9 independent halogens), Cι_8alkyloxy- -Co-10alkylaryl, -C0-10alkylheteroaryl, -C(O)-Cθ-2alkylaryl, -C(O)-Co-2alkylheteroaryl, -C(O)-O-aryl, -C(O)-O-heteroaryl, -C(O)-NH-
Cθ-2alkylaryl, -C(O)-NH-Co-2alkylheteroaryl, -C(O)-N(Ci_8alkyl)-CO-2alkylaryl, or -C(O)-N(Ci-8alkyl)-Cθ-2alkylheteroaryl, wherein the aryl or heteroaryl is optionally substituted with 1-2 substituents, each substituent independently is Cι_6alkyl, Ci-6alkyloxy-, Ci-6alkylcarboxy-, Ci-6alkylamido- OH, halogen, nitro, amino, or cyano. In one aspect, the compounds of the present application are represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein: R2 is
Figure imgf000007_0001
In a second aspect, the compounds of the present application are represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein: R2 is -NHC(O)NR22R23.
In an embodiment of the second aspect, R 3 is -Cθ-4alkylaryl, wherein the aryl is substituted with
Figure imgf000007_0002
R27 is -C0-2alkylaryl, or -Cθ-2alkylheteroaryl, wherein the aryl or heteroaryl is optionally substituted with 1-2 substituents, each substituent independently is Ci_6alkyl (optionally substituted with 1-9 independent halogens), Cι_6alkyloxy-, Cι_6alkylcarboxy-, Ci_6alkylamido- OH, halogen, nitro, amino or cyano; In another embodiment of the second aspect R23 is -Cθ-4alkylaryl, wherein the aryl is substituted with -(CH2)θ-4-R2^ or -C(O)-R25;
R25 is
Figure imgf000007_0003
In still another embodiment of the second aspect, R23 is -Cθ-4alkylaryl, wherein the aryl is substituted with -(CH2)θ-4-R2^ or -C(O)-R25;
R25 is
Figure imgf000008_0001
In yet still another embodiment of the second aspect R23 is -Cθ-4alkylheteroaryl, wherein the heteroaryl is substituted with -(CH2)θ-4-R25, or -C(O)-R25;
R25 is
In an embodiment of the second aspect, R23 is -Cθ-4alkylaryl, wherein the aryl is substituted with -(CH2)0-4-R25, or -C(O)-R25;
R25 is
Figure imgf000008_0003
In still another embodiment of the second aspect R23 is -Cθ-4alkylaryl, wherein the aryl is substituted with -(CH2)0-4-R25 or -C(O)-R25;
R25 is
Figure imgf000008_0004
In still another embodiment of the second aspect, R23 is -Cθ-4alkylaryl, wherein the aryl is substituted with -(CH2)θ-4~R2^ or-C(O)-R25; R25 is
Figure imgf000009_0001
R26 is aryl, wherein the aryl is optionally substituted with 1-2 substituents, each substituent independently is Cι_6alkyl (optionally substituted with 1-9 independent halogens), Ci_6alkyloxy- Cι _6alkylcarboxy- Cι_6alkylamido-, OH, halogen, nitro, amino, or cyano;
In yet still another embodiment of the second aspect, R23 is -Cθ-4alkylaryl, wherein the aryl is substituted with -(CH2)θ-4~ 2^ or-C(O)-R25;
R25 is
Figure imgf000009_0002
In still another further embodiment of the second aspect, R23 is
-Cθ-4alkylaryl, wherein the aryl is substituted with -(CH2)θ-4~R2^ or -C(O)-R25; R25 is
Figure imgf000009_0003
In another further embodiment of the second aspect, R23 is
Figure imgf000009_0004
R26 is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with 1-2 substituents, each substituent independently is Ci-6alkyl (optionally substituted with 1-9 independent halogens), Cχ-6alkyloxy-, Ci-6alkylcarboxy- Cι_.6alkylamido-, OH, halogen, nitro, amino, or cyano. In yet another further embodiment of the second aspect, R23 is
Figure imgf000010_0001
In still yet another embodiment of the second aspect, R23 is -Cθ-4alkylaryl, wherein the aryl is substituted with
Figure imgf000010_0002
In a third aspect, the compounds of the present application are represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein: R2 is -O-C(O)NR22R23 0r -Ci -3alkyl-C(O)NR22R23.
In one embodiment of the third aspect, R2 is -O-C(O)NR22R23; R23 is -Cθ-4alkylaryl, wherein the aryl is optionally substituted with 1-2 substituents, each substituent independently is -(CH2)0-4-R25, or-C(O)-R25; R25 is
Figure imgf000010_0003
In another embodiment of the third aspect, R2 is -Ci-3alkyl-C(O)NR22R23; R23 is -Cθ-4alkylaryl, wherein the aryl is substituted with -(CH2)0-4-R25 or -C(O)-R25; R25 is
Figure imgf000010_0004
In still another embodiment of the third aspect, R is -Ci-3alkyl-C(O)NR22R23; R23 1S -Cθ-4alkylaryl, wherein the aryl is substituted with -(CH2)0-4-R25 or-C(O)-R25;
R25 i is
Figure imgf000011_0001
In a fourth aspect, the compounds of the present application are represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein: R2 is H and Rl is -Cι_7alkyl-C(O)-NH-Rl2.
In an embodiment of the fourth aspect, Rl2 is
Figure imgf000011_0002
Rl4 is heteroaryl, wherein the heteroaryl is optionally substituted with 1-2 substituents, each substituent independently is Cι_6alkyl, Ci _6alkyloxy- Ci_6alkylcarboxy-, Cι_6alkylamido-, OH, halogen, nitro, amino, or cyano;
In another embodiment of the fourth aspect, Rl js
Figure imgf000011_0003
In still another embodiment of the fourth aspect, Rl2 is
Figure imgf000011_0004
It is advantageous that for compounds of Formula I R is H and Rl is
Figure imgf000012_0001
R2 is -NH-C(O)-NHR23 and Rl is propyl, cyclopropylmethyl or 2,2,2-trifluoroethyl,
R23 is aryl or heteroaryl, wherein the aryl or heteroaryl is substituted with
Figure imgf000012_0002
, or ;
R26 is NR66R67; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with 1-2 substituents, each substituent independently is Cι_6alkyl (optionally substituted with 1-9 independent halogens), Cι_6alkyloxy, Ci_6alkylcarboxy, Ci_6alkylamido, OH, halogen, nitro, amino, or cyano, or,
R26 is
Figure imgf000012_0003
R66 and R67 are each independently H, Ci_8alkyl (optionally substituted with 1-9 independent halogens), Ci -6aIkyloxy, Ci-ioalkylaryl, -Cθ-2alkyl-C3-6cycloalkyl, C2-6alkenyl;
R27 is -Co-2alkyl-C3_6cycloalkyl, Cθ-2alkylaryl, Cθ-2alkylheteroaryl, wherein the aryl or heteroaryl is optionally substituted with 1-2 substituents, each substituent independently is Cι_6alkyl (optionally substituted with 1-9 independent halogens), Ci-6alkyloxy, Cι_6alkylcarboxy, Ci-6alkylamido, OH, halogen, nitro, amino or cyano;
R4 is Cθ-3alkyl-C3_iocycloalkyl, Cθ-3alkyIaryl, Cθ-3alkylheteroaryl, wherein the aryl or heteroaryl is optionally substituted with 1-3 substituents, each substituent independently is Ci-6alkyl (optionally substituted with 1-9 independent halogens), Cι_6alkoxy, Cι_6alkylcarboxy, Ci-6alkylamido, OH, halogen, nitro, amino, or cyano, or R4 is
Figure imgf000013_0001
R5 is H or a single substituent, at the 7-position of the benzodiazepine core, chosen from among the following list: nitro, halogen, cyano, OH, amino, Ci_6alkylthio, Ci_8alkyl (optionally substituted with 1-9 independent halogens), Ci -8alkoxy, -Cfj-ioalkylaryl, -Co-lOalkylheteroaryl, -C(O) -Cθ-2alkylaryl, -C(O)- Cθ-2alkylheteroaryl, -C(O)-O-aryl, -C(O)-O-heteroaryl, -C(O)-NH-Cθ-2alkylaryl, -C(O)-NH-Co-2alkylheteroaryl, -C(O)-N(Cι_8alkyl)-Cθ-2alkylaryl, -C(O)- N(Cι_8alkyl)-Cθ-2alkylheteroaryl, wherein the aryl or heteroaryl is optionally substituted with 1-2 substituents, each substituent independently is Ci_6alkyl, Cι_6alkoxy, Ci_6alkylcarboxy, Cι_6alkylamido, OH, halogen, nitro, amino, or cyano. More advantageously, R2 is H and Rl is
Figure imgf000013_0002
Rl is propyl and R is
Figure imgf000013_0003
R25 i is
Figure imgf000013_0004
or
R26 i is
Figure imgf000013_0005
R27 is 4-pyridyl;
R4 is cyclohexyl, -CH2-CH2-phenyl, or 4-methylphenyl; and
R5 is H.
Another aspect of the present application provides a compound selected from the group and pharmaceutically acceptable salts thereof:
N-(l-methyl-5-phenyl-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)- 4-(n-pentyl)benzamide (Example 1.1);
N-(l-methyl-5-(2-fluorophenyl)-2-oxo-2,3-dihydro-lH-l,4- benzodiazepin-3-yl)-4-(n-pentyl)benzamide (Example 1.2); N-(l-isopropyl-5-phenyl-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin-3- yl)-3-bromobenzamide (Example 1.3);
N-(l-isopropyl-5-phenyl-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin-3- yl)-3-(trifluoromethyl)benzeneacetamide (Example 1.4);
N-(5-cyclohexyl-2-oxo-2,3-dihydro-lH-l,4~benzodiazepin-3-yl)-2- (phenoxy)benzeneacetamide (Example 1.5);
N-(5-(2-flurophenyl)-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)- 3-methyl-2-indencarboxamide (Example 1.6);
N-(5-(2-fluorophenyl)-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)- benzamide (Example 1.7); N-(l-methyl-5-phenyl-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)- cyclohexanecarboxamide (Example 1.8);
N-(l-propyl-5-cyclohexyl-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin-3- yl)-4-(dimethylamino)benzamide (Example 1.9);
N-(l-propyl-5-cyclohexyl-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin-3- yl)-lH-5-indolecarboxamide (Example 1.10);
N-[2-oxo-5-phenyl-l-isopropyl-2,3-dihydro-lH-l,4-benzodiazepin-3- yl]-N'-[4-((3-(dimethyIamino)propyl(methyl)amino)phenyljurea, (Example 5.1);
N-[2-oxo-5-isopropyl-l-propyl-2,3-dihydro-lH-l,4-benzodiazepin-3- yl]-N'-[4-((3-(dimethylamino)propyl(methyl)amino)phenyl]urea, (Example 5.2); N~[2-oxo-5-cyclohexyl-l-propyl-2,3-dihydro-lH-l,4-benzodiazepin-3- yl]-N'-[4-((3-(dimethylamino)propyl(methyl)amino)phenyl]urea, (Example 5.3);
N-[2-oxo-5-cyclohexyl-l-propyl-2,3-dihydro-lH-l,4-benzodiazepin-3- yl]-N'-[4-(2-(piperidin-l-yl)ethoxy)phenyl]urea, (Example 7.6); N-[2-oxo-5-phenyl-l-ethyl-2,3-dihydro-lH-l,4-benzodiazepin-3-yl]- N'-(3-methoxyphenyl)urea, (Example 8.1);
N-[2-oxo-5-isopropyl-l-propyl-2,3-dihydro-lH-l,4-benzodiazepin-3- yl]-N-[4-(morpholin-4-yl)phenyl]urea, (Example 8.2); N-[2-oxo-5-cyclohexyl-l-propyl-2,3-dihydro-lH-l,4-benzodiazepin~3- yl]-N-[4-(morpholin-4-yl)phenyl]urea, (Example 8.3);
N-[2-oxo-5-cyclohexyl-l-propyl-2,3-dihydro-lH-l,4-benzodiazepin-3- yl]-N'-[4-(piperidin-l-yl)phenyl]urea, (Example 8.4);
N-[2-oxo-5-cyclohexyl-l-propyl-2,3-dihydro-lH-l,4-benzodiazepin-3- yl]-N'-(3-pyridyl)urea, (Example 8.5);
Benzyl 5-tert-butyl-l-isobutyl-2-oxo-2,3-dihydro-lH-l,4- benzodiazepin-3-ylcarbamate (Example 29);
N-[5-(4-methylpiperazin-l-yl)-2-oxo-l-propyl-2,3-dihydro-lH-l,4- benzodiazepin-3-yl]-N'-(5-methyl-l,3,4-thiadiazol-2-yl)urea (Example 30); and N-(5-azepan-l-yl-I-methyl-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin-
3-yl)-4-phenylbutanamide (Example 32).
Preferred compounds are:
N-[4-(l,4'-bipiρeridin-r-yl)phenyl]-4-(5-cyclohexyl-2-oxo-2,3- dihydro- 1H-1 ,4-benzodiazepin- 1 -yl)butanamide, N-[2-oxo-5-(2-phenylethyl)-l-propyl-2,3-dihydro-lH-l,4-benzo- diazepin-3-yl]-N'-[4-(4-pyridin-4-ylpiperazin-l-yl)phenyl]urea,
N-[4-(l,4-bipiperidin- -yl)phenyl]-N'-(5-cyclohexyl-2-oxo-l-propyl- 2,3-dihydro-lH-l,4-benzodiazepin-3-yl)urea,
N-[4-(l,4'-bipiρeridin- -yl)phenyl]-N-[5-(4-methylphenyl)-2-oxo-l- propyl-2,3-dihydro-lH-l,4-benzodiazepin-3-yl]urea, or pharmaceutically acceptable salts thereof.
As used herein, "alkyl" as well as other groups having the prefix "alk" such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like, means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and the like. "Alkenyl", "alkynyl" and other like terms include carbon chains containing at least one unsaturated C-C bond.
The term "cycloalkyl" means carbocycles containing no heteroatoms, and includes mono-, bi- and tricyclic saturated carbocycles, as well as fused ring systems. Such fused ring systems can include one ring that is partially or fully unsaturated such as a benzene ring to form fused ring systems such as benzofused carbocycles. Cycloalkyl includes such fused ring systems as spirofused ring systems. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, indenyl, fluorenyl, 1,2,3,4- tetrahydronaphthalene and the like. Similarly, "cycloalkenyl" means carbocycles containing no heteroatoms and at least one non-aromatic C-C double bond, and include mono-, bi- and tricyclic partially saturated carbocycles, as well as benzofused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl, indenyl, and the like. The term "Co" means that the carbon is not present. Thus, "C0-C5" means that there are from none to five carbons present - that is, five, four, three, two, one, or no carbons present. When no carbons are present in a linking alkyl group, the link is a direct bond. When no carbons are present in a terminal alkyl group, the terminus is hydrogen.
The term "aryl" is an aromatic mono- or bicyclic carbocycle having from 6 to 10 carbon atoms, optionally fused to a 4- to 6-membered non-aromatic ring containing 0-3 heteroatoms selected from N, O and S(O)m. Examples include phenyl and naphthyl.
"Heteroaryl" is a mono-or bicyclic aromatic ring containing from 1 to 6 heteroatoms independently selected from N, O and S wherein each ring has five or six ring atoms. Examples of heteroaryl include pyridyl, pyrimidinyl, pyrrolyl, furyl, thienyl, imidazolyl, thiazolyl, fhiadiazolyl, triazolyl, tetrazolyl, oxadiazolyl, oxazolyl, imidazolidinyl, pyrazolyl, isoxazolyl, benzothiadiazolyl, indolyl, indolinyl, benzodioxolyl, benzodioxanyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl, benzotriazolyl, benzoxazolyl, purinyl, furopyridine and thienopyridine.
The term "composition", as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier. The term "optionally substituted" is intended to include both substituted and unsubstituted. Thus, for example, optionally substituted aryl could represent a pentafluorophenyl or a phenyl ring.
Compounds described herein may contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. The above Formula I is shown without a definitive stereochemistry at certain positions. The present invention includes all stereoisomers of Formula I, and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N,N -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids. The pharmaceutical compositions of the present invention comprise a compound of the present invention (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
In practice, the compounds of this invention or pharmaceutically acceptable salts thereof can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compounds of the present invention or pharmaceutically acceptable salts thereof, may also be administered by controlled release means and/or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation. Thus, the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound of the present invention or a pharmaceutically acceptable salt thereof. The compounds of the present invention or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.
In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques
A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about O.lmg to about 500mg of the active ingredient and each cachet or capsule preferably containing from about 0.1 to about 500mg of the active ingredient. The tablet, cachet, or capsule can each contain, for example, O.lmg, 0.5mg, lmg, 3mg, 5mg, lOmg, 25mg, 50mg, lOOmg, 125mg, 250mg, or 500mg of active ingredient.
Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms. Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof. Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound of this invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.
Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds.
In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound described by Formula I, or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.
Experimental Protocols
Assessing the Activity of Selected Compounds to Bind to the Bradykinin Bl and B2 Receptors
Radioligand binding assays are performed using membranes from CHO cells that stably express the human, rabbit, rat, or dog B 1 receptors or CHO cells that express the human B2 receptor. For all receptor types, cells are harvested from culture flasks in PBS/lmM EDTA and centrifuged at lOOOxg for 10 minutes. The cell pellets are homogenized with a polytron in ice cold 20mM HEPES, ImM EDTA, pH 7.4 (lysis buffer) and centrifuged at 20,000xg for 20 minutes. The membrane pellets are rehomogenized in lysis buffer, centrifuged again at 20,000xg and the final pellets are resuspended at 5mg protein/ml in assay buffer (120mM NaCl, 5mM KC1, 20mM HEPES, pH 7.4) supplemented with 1% BSA and frozen at -80°C.
On the day of assay, membranes are centrifuged at 14,000xg for 5 minutes and resuspended to the desired protein concentration in assay buffer containing lOOnM enaliprilat, 140/ig/mL bacitracin and 0.1% BSA. 3H-des-arglO, leu9 kallidin is the radioligand used for the human and rabbit Bl receptors, 3H-des- arglO kallidin is used for the rat and dog Bl receptors, and 3H-bradykinin is used to label the human B2 receptor.
For all assays, compounds are diluted from DMSO stock solutions with 4μ,L added to assay tubes for a final DMSO concentration of 2%. This is followed by the addition of 100j L radioligand and lOOμL of the membrane suspension. Nonspecific binding for the Bl receptor binding assays is determined using lμ.M des-arglO kallidin and nonspecific binding for the B2 receptor is determined with lμM bradykinin. Tubes are incubated at room temperature (22°C) for 60 minutes followed by filtration using a Tomtec 96-well harvesting system.
Radioactivity retained by the filter is counted using a Wallac Beta-plate scintillation counter.
The compounds of this invention have potency in the above assay as demonstrated by results of less than 5μM. It is advantageous that the assay results be less than lμ,M, even more advantageous for the results be less than 0.5μM. Accordingly, the compounds of this invention are useful in the treatment of pain and inflammation. The compounds would be effective in the treatment or prevention of pain including, for example, bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia), perioperative pain (general surgery, gynecological) and chronic pain. In particular, inflammatory pain such as, for example, inflammatory airways disease (chronic obstructive pulmonary disease) would be effectively treated by the bradykinin Bl antagonist compounds of this invention.
Further, the compounds of this invention - by being bradykinin Bl antagonists - can additionally be used to treat asthma, inflammatory bowel disease, rhinitis, pancreatitis, cystitis (interstitial cystitis), uveitis, inflammatory skin disorders, rheumatoid arthritis and edema resulting from trauma associated with bums, sprains or fracture. They may be used subsequent to surgical intervention (e.g. as postoperative analgesics) and to treat inflammatory pain of varied origins (e.g. osteoarthritis, rheumatoid arthritis, rheumatic disease, teno-synovitis and gout) as well as for the treatment of pain associated with angina, menstruation or cancer. They may be used to treat diabetic vasculopathy, post capillary resistance or diabetic symptoms associated with insulitis (e.g. hyperglycemia, diuresis, proteinuria and increased nitrite and kallikrein urinary excretion). They may be used to treat inflammatory skin disorders such as psoriasis and eczema. They may be used as smooth muscle relaxants for the treatment of spasm of the gastrointestinal tract or uterus or in the therapy of Crohn's disease, ulcerative colitis or pancreatitis. Such compounds may be used therapeutically to treat hyperreactive airways and to treat inflammatory events associated with airways disease e.g. asthma, and to control, restrict or reverse airways hyperreactivity in asthma. They may be used to treat intrinsic and extrinsic asthma including allergic asthma (atopic or non-atopic) as well as exercise-induced asthma, occupational asthma, asthma post-bacterial infection, other non-allergic asthmas and "wheezy-infant syndrome". They may also be effective against pneumoconiosis, including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis was well as adult respiratory distress syndrome, chronic obstructive pulmonary or airways disease, bronchitis, allergic rhinitis, and vasomotor rhinitis. Additionally, they may be effective against liver disease, multiple sclerosis, atherosclerosis, Alzheimer's disease, septic shock e.g. as anti-hypovolemic and/or anti-hypotensive agents, cerebral edema, headache including cluster headache, migraine including prophylactic and acute use, closed head trauma, irritable bowel syndrome and nephritis. Finally, such compounds are also useful as research tools (in vivo and in vitro).
The compounds of this invention are useful in the treatment of pain and inflammation by the administration of a tablet, cachet, or capsule each containing, for example, O.lmg, 0.5mg, lmg, 3mg, 5mg, lOmg, 25mg, 50mg, lOOmg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.
The compounds would be effective in the treatment or prevention of pain including, for example, bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia), perioperative pain (general surgery, gynecological) and chronic pain by the administration of a tablet, cachet, or capsule each containing, for example, O.lmg, 0.5mg, lmg, 3mg, 5mg, lOmg, 25mg, 50mg, lOOmg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.
In particular, inflammatory pain such as, for example, inflammatory airways disease (chronic obstructive pulmonary disease) would be effectively treated by the bradykinin B 1 antagonist compounds of this invention by the administration of a tablet, cachet, or capsule each containing, for example, O.lmg, 0.5mg, lmg, 3mg, 5mg, lOmg, 25mg, 50mg, lOOmg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.
Further, the compounds of this invention - by being bradykinin Bl antagonists - can additionally be used to treat asthma, inflammatory bowel disease, rhinitis, pancreatitis, cystitis (interstitial cystitis), uveitis, inflammatory skin disorders, rheumatoid arthritis and edema resulting from trauma associated with burns, sprains or fracture by the administration of a tablet, cachet, or capsule each containing, for example, O.lmg, 0.5mg, lmg, 3mg, 5mg, lOmg, 25mg, 50mg, lOOmg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.
They may be used subsequent to surgical intervention (e.g. as postoperative analgesics) and to treat inflammatory pain of varied origins (e.g. osteoarthritis, rheumatoid arthritis, rheumatic disease, teno-synovitis and gout) as well as for the treatment of pain associated with angina, menstruation or cancer by the administration of a tablet, cachet, or capsule each containing, for example, O.lmg, 0.5mg, lmg, 3mg, 5mg, lOmg, 25mg, 50mg, lOOmg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week. They may be used to treat diabetic vasculopathy, post capillary resistance or diabetic symptoms associated with insulitis (e.g. hyperglycemia, diuresis, proteinuria and increased nitrite and kallikrein urinary excretion) by the administration of a tablet, cachet, or capsule each containing, for example, O.lmg, 0.5mg, lmg, 3mg, 5mg, lOmg, 25mg, 50mg, lOOmg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.
They may be used to treat inflammatory skin disorders such as psoriasis and eczema by the administration of a tablet, cachet, or capsule each containing, for example, O.lmg, 0.5mg, lmg, 3mg, 5mg, lOmg, 25 mg, 50mg, lOOmg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.
They may be used as smooth muscle relaxants for the treatment of spasm of the gastrointestinal tract or uterus or in the therapy of Crohn' s disease, ulcerative colitis or pancreatitis by the administration of a tablet, cachet, or capsule each containing, for example, O.lmg, 0.5mg, lmg, 3mg, 5mg, lOmg, 25mg, 50mg, lOOmg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.
Such compounds may be used therapeutically to treat hyperreactive airways and to treat inflammatory events associated with airways disease e.g. asthma, and to control, restrict or reverse airways hyperreactivity in asthma by the administration of a tablet, cachet, or capsule each containing, for example, O.lmg, 0.5mg, lmg, 3mg, 5mg, lOmg, 25mg, 50mg, lOOmg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week. They may be used to treat intrinsic and extrinsic asthma including allergic asthma (atopic or non-atopic) as well as exercise-induced asthma, occupational asthma, asthma post-bacterial infection, other non-allergic asthmas and "wheezy-infant syndrome" by the administration of a tablet, cachet, or capsule each containing, for example, O.lmg, 0.5mg, lmg, 3mg, 5mg, lOmg, 25mg, 50mg, lOOmg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.
They may also be effective against pneumoconiosis, including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis was well as adult respiratory distress syndrome, chronic obstructive pulmonary or airways disease, bronchitis, allergic rhinitis, and vasomotor rhinitis by the administration of a tablet, cachet, or capsule each containing, for example, O.lmg, 0.5mg, lmg, 3mg, 5mg, lOmg, 25mg, 50mg, lOOmg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week. Additionally, they may be effective against liver disease, multiple sclerosis, atherosclerosis, Alzheimer's disease, septic shock e.g. as anti-hypovolemic and/or anti-hypotensive agents, cerebral edema, headache, migraine, closed head trauma, irritable bowel syndrome and nephritis by the administration of a tablet, cachet, or capsule each containing, for example, O.lmg, 0.5mg, lmg, 3mg, 5mg, lOmg, 25mg, 50mg, lOOmg, 125mg, 250mg, or 500mg of a compound of this invention once every three to four hours, once, twice or three times a day, or (in an extended release formulation) once, twice or three times a week.
Compounds of the present invention may be prepared as illustrated in the following schemes:
Scheme 1
Figure imgf000026_0001
In Scheme 1, the benzodiazepine core (1), obtained commercially or prepared according to J. Org. Chem., 52:3232-3239(1987), is alkylated with an appropriate alkylating agent, like propyl iodide, in an aprotic solvent, like DMF, using a base, like sodium hydride, to provide (2). Compound (2) can then be converted into the 3-amino-benzodiazapine (3) in accordance with J. Org. Chem., 52:3232-3239 (1987). This amine derivative (3) is then reacted with a carboxylic acid or carboxylic acid equivalent, using an appropriate set of peptide coupling reagents, like EDCI/HOBt, in and appropriate solvent, like DMF to yield title compounds (la).
Scheme 2
Figure imgf000027_0001
Triphosgene
Figure imgf000027_0002
Alternatively, as illustrated in Scheme 2, an amine, like l-pyridin-4- ylpiperazine, is reacted with l-fluoro-4-nitrobenzene in an appropriate solvent, like THF, in the presence of a base, like triethylamine, to provide adduct (4). This nitroaromatic intermediate (4) is then reduced to the aniline (5) using standard catalytic hydrogenation conditions, with palladium on carbon in a suitable solvent, like methanol. A urea linkage between aniline (5) and 3-amino-benzodiazapine (3), prepared according to Scheme 1, can be formed using standard conditions, such as triphosgene and triethylamine in THF to provide title compounds (lb).
Figure imgf000028_0001
Alternatively, as illustrated in Scheme 3, the benzodiazepine (1), prepared according to Scheme 1, is alkylated with an ester-containing alkylhalide (7), using a strong base, like sodium hydride, in an aprotic solvent, like DMF, to provide ester (8). This ester (8) is then hydrolyzed by the action of an appropriate base, like sodium hydroxide, in a mixture of water and an organic solvent, like THF, to provide carboxylic acid (9), after acidification. Carboxylic acid (9) is then coupled to the amine (5), prepared according to Scheme 2, using an appropriate set of peptide coupling reagents, like EDCI/HOBt, in and appropriate solvent, like DMF, to provide title compounds (Ic).
The following examples are provided to illustrate the invention and are not to be construed as limiting the scope thereof in any manner. Compounds were named using: ACD/Name version 4.53 (Advanced Chemistry Development Inc. © 1994-2000). Address: 90 Adelaide Street West, Toronto, Ontario, M5H 3V9, Canada. EXAMPLE 1 : N-(5-cyclohexyl-2-oxo-l-propyl-2,3-dihydro-lH-l,4-benzo- diazepin-3-yl)-5-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)pentanamide
Figure imgf000029_0001
The title compound was prepared by the acylation of the 3-amino benzodiazepine core, according to /. Med. Chem., 31:2235-2246(1988), with the carboxylic acid prepared according to International Patent Publication No. WO 9931061. The benzodiazepine portion was either prepared according to J. Org. Chem., 52:3232-3239(1987) or obtained commercially and alkylated at the N-l position with the appropriate electrophile (in this example, propyl iodide) in DMF using sodium hydride as the base, applying conventional procedures as known in the art. The compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (ES+) of 516.3 for M+H+.
EXAMPLE 2: 2-[4-(l,4'-bipiperidin-l'-yI)phenyI]-N-(5-cycIohexyI-2-oxo-l- propyl-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)acetamide
Figure imgf000029_0002
The title compound was prepared according to the general method of Example 1, with the exception that the acyl side chain, (4-[l,4]Bipiperidinyl-l -yl- phenyl)-acetic acid, was prepared starting from ethyl (4-aminophenyl)acetate. This starting aniline was homologated to the ketone, ethyl [4-(4-oxopiperidin-l-yl)phenyl]- acetate, according to Org. Lett, 1:1261-1262(1999). The ketone was then reductively animated with piperidine using Pd/C and hydrogen to provide the required ester, which was hydrolyzed under basic conditions to (4-[l,4 Bipiperidinyl-l'-yl-phenyl)- acetic acid. The title compound gave proton NMR spectra consistent with theory and a mass ion (ES+) of 584.5 for M+H+.
EXAMPLE 3: 3-(l,4'-bipiperidin-l '-yl)-N-(5-cyclohexyl-2-oxo-l-propyl-2,3- dihydro-lH-l,4-benzodiazepin-3-yl)benzamide
Figure imgf000030_0001
The title compound was prepared similarly to Example 2, with the exception that the acyl side chain, S-fl^'jbipiperidinyl-l'-yl-benzoic acid, was prepared using ethyl 3-aminobenzoate instead of ethyl (4-aminophenyl)acetate. The title compound gave proton NMR spectra consistent with theory and a mass ion (ES+) of 570.4 for M+H+.
The following compounds in Table 1 were prepared analogously to Example 1 using commercially available carboxylic acids and acid chlorides for the introduction of R30.
Figure imgf000031_0002
EXAMPLE 4: N-[2-oxo-5-(2-phenylethyl)-l-propyl-2,3-dihydro-lΗ-l,4- benzodiazepin-3-yl]-N'-[4-(4-pyridin-4-ylpiperazin-l-yl)phenyl]urea
Figure imgf000031_0001
The title compound was prepared by formation of the urea between the benzodiazepine core, 3-amino-5-(2-phenylethyl)-l-propyl-l,3-dihydro-2H-l,4- benzodiazepin-2-one, and the amine side chain, 4-(4-pyridin-4-ylpiperazin-l- yl)aniline, according to J. Med. Chem., 36:4276-4292(1993). The benzodiazepine portion was prepared in accordance with J. Org. Chem., 52:3232-3239(1987). The amine portion was prepared in accordance with Tetrahedron Lett., 39:2471- 2474(1998) starting with 4-fluoronitrobenzene and l-pyridin-4-yl-piperazine, followed by palladium catalyzed hydrogenation of the nitro group with Pd/C in ethanol, applying conventional procedures as known in the art. Example 4 thus obtained gave proton NMR spectra consistent with theory and a mass ion (FT/ICR+) of 602.3 for M+H+. While this racemate was potent in biological assays, it could be separated by chiral HPLC methods (BioMed. Chem. Lett., 3:1919-1924(1993)) to provide two enantiomers, both potent, with the preferred enantiomer having an optical rotation of +7.85 ° (c=l, in DCM).
The following compounds in Table 2 were prepared analogously to
Example 4.
Figure imgf000032_0001
The following compounds in Table 3 were prepared analogously to
Example 4, using l,4'-bipiperidine instead of l-pyridin-4-yl-piperazine.
Figure imgf000033_0001
The following compounds in Table 4 were prepared analogously to Example 4, using NN-dimethylpiperidin-4-amine instead of l-pyridin-4-yl- piperazine.
Figure imgf000034_0001
The following compounds in Table 5 were prepared analogously to Example 4, using NN,N'-trimethylpropane-l,3-diamine instead of l-pyridin-4-yl- piperazine.
Figure imgf000034_0002
The following compounds in Table 6 were prepared analogously to Example 4, using 1,4 -bipiperi dine instead of l-pyridin-4-yl-piperazine, and 2-chloro- 5-nitropyridine instead of 4-fluoronitrobenzene.
Figure imgf000035_0001
The following compounds in Table 7 where R25 is a commercially available nucleophile introduced in accordance with Example 4 by its reaction with 4-fluoronitrobenzene under basic conditions, applying conventional procedures as known in the art.
Figure imgf000035_0002
Figure imgf000036_0001
The following compounds in Table 8 were prepared analogously to Example 4 using commercially available amines for the introduction of R21.
Figure imgf000036_0002
EXAMPLE 10: l-[4-({[(l-isopropyl-2-oxo-5-phenyl-2,3-dihydro-lH-l,4- benzodiazepin-3-yl)amino]carbonyl}amino)phenyl]piperidine-4-carboxylic acid
Figure imgf000037_0001
The title compound was prepared by the alkaline hydrolysis of Example 7.1 in an ethanol/water mixture with sodium hydroxide, applying conventional procedures as known in the art. The compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (FT/ICR+) of 540.3 for M+H+.
EXAMPLE 11: l-[4-({[(l-isopropyl-2-oxo-5-phenyl-2,3-dihydro-lH-l,4- benzodiazepin-3-yl)amino]carbonyl}amino)phenyl]piperidine-4-carboxamide
Figure imgf000037_0002
The title compound was prepared by standard peptide coupling conditions using isobutyl chloroformate/triethylamine/ammonia, using Example 10 as the starting material. The compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (FT/ICR+) of 539.3 for M+H+.
EXAMPLE 12: l-[4-({[(5-cyclohexyl-2-oxo-l-propyl-2,3-dihydro-lH-l,4- benzodiazepin-3-yl)amino]carbonyl}amino)phenyl]piperidine-4-carboxylic acid
Figure imgf000038_0001
The title compound was prepared by analogy to Example 10, using Example 7.7 as starting material. The compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (FT/ICR+) of 546.3 for M+H+.
EXAMPLE 13: N-[3-(l,4'-bipiperidin-l '-ylmethyl)phenyl]-N'-(5-cycIohexyl-2- oxo-l-propyI-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)urea
Figure imgf000038_0002
The title compound was prepared by analogy to Example 4 after the preparation of 3-(l,4 '-bipiperidin-l'-ylmethyl)aniline. This aniline was prepared in two steps from 3-nitrobenzyl bromide and l,4'-bipiperidine. The title compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (FT/ICR+) of 599.4 for M+H+.
EXAMPLE 14: N-[3-(l,4'-bipiperidin-l'-ylcarbonyl)phenyl]-N'-(5-cycIohexyI-2- oxo-l-propyl-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)urea
Figure imgf000039_0001
The title compound was prepared by analogy to Example 13 employing 3-nitrobenzoyl chloride rather than 3-nitrobenzyl bromide. The final compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (ES+) of 613.4 for M+H+.
EXAMPLE 15: N-(5-cyclohexyI-2-oxo-l-propyl-2,3-dihydro-lH-l,4- benzodiazepin-3-yl)-N'-{3-[(4-hydroxypiperidin-l-yl)methyl]phenyl}urea
Figure imgf000039_0002
The title compound was prepared by analogy to Example 13 employing 4-hydroxypiperidine rather than l,4'-bipiperidine. The final compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (ES+) of 532.3 for M+H+.
EXAMPLE 16: N-(5-cyclohexyl-2-oxo-l-propyl-2,3-dihydro-lH-l,4- benzodiazepin-3-yl)-N'-{3-[4-(4-fluorophenyI)piperidin-l-yl]propyl}urea
Figure imgf000040_0001
The title compound was prepared by analogy to Example 4 after the preparation of 3-[4-(4-fIuorophenyI)piperidin-l-yl]propan-l-amine. This amine was prepared in two steps from 2-(3-bromopropyl)-lH-isoindole-l,3(2H)-dione and 4-(4- fluorophenyl)piperidine. The title compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (ES+) of 562.4 for M+H+.
EXAMPLE 17: N-[3-(l,4'-bipiperidin-l'-yl)propyl]-N'-(5-cyclohexyl-2-oxo-l- propyl-2,3-dihy dro- 1H- 1 ,4-benzodiazepin-3-yl)urea
Figure imgf000040_0002
The title compound was prepared by analogy to Example 4 after the preparation of 3-(l,4-bipiperidin-l'-yl)propan-l-amine. This amine was prepared in two steps from 2-(3-bromopropyl)-lH-isoindole-l,3(2H)-dione and 1,4-bipiperidine. The title compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (ES+) of 551.5 for M+H+.
EXAMPLE 18: N-[4-(l,4'-bipiperidin-l'-yl)butyl]-N'-(5-cyclohexyl-2-oxo-l- propyl-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)urea
Figure imgf000041_0001
The title compound was prepared by analogy to Example 17 using 2- (4-bromobutyl)-lH-isoindole-l,3(2H)-dione instead of using 2-(3-bromopropyl)-lH- isoindole-l,3(2H)-dione. The title compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (ES+) of 565.4 for M+H+.
EXAMPLE 19: N-[4-(l,4'-bipiperidin-l '-yl)benzyl]-N'-(5-cyclohexyl-2-oxo-l- propyl-2,3-dihydro- 1H- 1 ,4-benzodiazepin-3-yl)urea
Figure imgf000041_0002
The title compound was prepared by analogy to Example 4 after the preparation of l-[4-(l,4'-bipiρeridin- -yl)phenyl]methanamine. This amine was prepared in two steps from 4-fluorobenzonitrile and 1,4-bipiperidine. The title compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (ES+) of 599.4 for M+H+.
EXAMPLE 20: N-(5-cyclohexyl-2-oxo-l-propyl-2,3-dihydro-lH-l,4- benzodiazepin-3-yl)-N'-[4-(4-pyridin-3-ylpiperazin-l-yl)phenyl]urea
Figure imgf000042_0001
The title compound was prepared by analogy to Example 4 after the preparation of l-pyridin-3-ylpiperazine. This piperazine was prepared according to Tetrahedron Lett, 39:617-620(1998). The title compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (ES+) of 580.3 for M+H+.
EXAMPLE 21: N-(5-cyclohexyl-2-oxo-l-propyl-2,3-dihydro-lH-l,4- benzodiazepin-3-yl)-N'-[4-(pyridin-4-ylethynyl)phenyl]urea
Figure imgf000042_0002
The title compound was prepared by analogy to Example 4 after the preparation of 4-(pyridin-4-ylethynyl)aniline. This aniline was prepared in one step from 4-bromopyridine and 4-efhynylaniline according to Ada. Chem. Scand., SerB, 42:448(1988). The title compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (ES+) of 520.3 for M+H+.
EXAMPLE 22: N-(5-cyclohexyl-2-oxo-l-propyl-2,3-dihydro-lH-l,4- benzodiazepin-3-yl)-N'-[4-(pyridin-2-yIethynyI)phenyl]urea
Figure imgf000043_0001
The title compound was prepared by analogy to Example 21, using 2- bromopyridine instead of 4-bromopyridine. The title compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (ES+) of 520.2 for M+H+.
EXAMPLE 23: N-(5-cyclohexyI-2-oxo-l-propyl-2,3-dihydro-lH-l,4- benzodiazepin-3-yl)-N'-[4-(pyridin-3-ylethynyl)phenyI]urea
Figure imgf000043_0002
The title compound was prepared by analogy to Example 21, using 3- bromopyridine instead of 4-bromopyridine. The title compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (ES+) of 520.2 for M+H+.
EXAMPLE 24: N-(5-cyclohexyl-2-oxo-l-propyl-2,3-dihydro-lH-l,4- benzodiazepin-3-yl)-N'-[2-(4-pyridin-4-ylpiperazin-l-yl)phenyl]urea
Figure imgf000044_0001
The title compound was prepared by analogy to Example 4, using 2- fluoronitrobenzene instead of 4-fluoronitrobenzene. The title compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (FT/ICR+) of 580.3 for M+H+.
EXAMPLE 25: N-(5-cyclohexyl-2-oxo-l-propyl-2,3-dihydro-lH-l,4- benzodiazepin-3-yl)-N'-[3-(4-pyridin-4-ylpiperazin-l-yl)phenyl]urea
Figure imgf000044_0002
The title compound was prepared by analogy to Example 4, after the preparation of 3-(4-pyridin-4-ylpiperazin-l-yl)aniline. This aniline was prepared using 3-fluoronitrobenzene and l-pyridin-4-ylpiρerazine in DMSO, at 90°C, for 60h with potassium carbonate; followed by hydrogenation of the nitro group. The title compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (EI+) of 579.4 for M+. EXAMPLE 26: N-[2-oxo-5-(2-phenyIethyl)-l-propyI-2,3-dihydro-lH-l,4- benzodiazepin-3-yl]-N'-[4-(4-pyridin-4-ylpiperidin-l-yl)phenyl]urea
Figure imgf000045_0001
The title compound was prepared by analogy to Example 4, after the preparation of 4-piperidin-4-ylpyridrne, which was used instead of l-pyridin-4- ylpiperazine. This pyridine was prepared according to Tetrahedron Lett, 34:5287- 5288(1993). The title compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (ES+) of 601.3 for M+H+.
EXAMPLE 27: N-{3-bromo-4-[4-(3-bromopyridin-4-yl)piperazin-l-yl]phenyl}-
N'-[2-oxo-5-(2-phenylethyl)-l-propyl-2,3-dihydro-lH-l,4-benzodiazepin-3- yljurea
Figure imgf000045_0002
The title compound was prepared by analogy to Example 4, after the preparation of 3-bromo-4-[4-(3-bromopyridin-4-yl)piperazin-l-yl]aniline. This aniline was prepared in 3 steps from 4-fluoronitrobenzene and l-pyridin-4- ylpiperazine. After these two starting materials were allowed to react according to Tetrahedron Lett., 39:2471-2474(1998), the resulting product was bis-brominated with NBS in methylene chloride, and then the nitro group was reduced with iron(0) in acetic acid / ethanol / aqueous HCl, applying conventional procedures as lαiown in the art. The title compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (ES+) of 757.8 for M+H+(79Br2) .
EXAMPLE 28: 5-cyclohexyl-2-oxo-l-propyl-2,3-dihydro-lH-l,4-benzodiazepin- 3-yl 4-(l,4'-bipiperidin-l'-yl)phenylcarbamate
Figure imgf000046_0001
The title compound was prepared by analogy to Example 3.4. The benzodiazepine core, 5-cyclohexyl -l-propyl-l,3-dihydro-2H-l,4-benzodiazepin-2- one, was prepared according to J.O.C., 52:3232-3239(1987). This benzodiazepine was then oxidized at N-4 with mCPBA, rearranged to the C-3 acetate with acetic anhydride at 100°C, and then hydrolyzed to the C-3 hydroxyl. This was then coupled to the aniline used in Table 3. The title compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (FT/ICR+) of 293.7 for M+2H+.
EXAMPLE 29: benzyl 5-tert-butyl-l-isobutyl-2-oxo-2,3-dihydro-lH-l,4- benzodiazepin-3-ylcarbamate
Figure imgf000047_0001
The title compound was prepared according to J. Med. Chem., 36:4276-4292(1993), using l-(2-aminophenyl)-2,2-dimethylpropan-l-one and {[(benzyIoxy)carbonyl]amino}[(tert-butoxycarbonyl)amino]acetic acid as starting materials.
EXAMPLE 30: N-[5-(4-methylpiperazin-l-yl)-2-oxo-l-propyl-2,3-dihydro-lH- l,4-benzodiazepin-3-yl]-N'-(5-methyl-l,3,4-thiadiazol-2-yl)urea
Figure imgf000047_0002
The title compound was prepared by analogy to Example 4, after the preparation of 3-amino-5-(4-methylpiperazin-l-yl)-l-propyl-l,3-dihydro-2H-l ,4- benzodiazepin-2-onedine, which was prepared according to /. Med. Chem., 37:719- 721(1994). EXAMPLE 31: N-[4-(l,4'-bipiperidin-l'-yl)phenyI]-N'-(2-oxo-5-piperidin-l-yI-l- propyl-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)urea
Figure imgf000048_0001
The title compound was prepared by analogy to Example 30, using the aniline of Example 3.1, after the preparation of 3-amino-5-piperidin-l-yl-l-propyl- l,3-dihydro-2H-l,4-benzodiazepin-2-one, which was prepared according to J. Med. Chem., 37:719-721(1994). The title compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (FAB+) of 586.4 for M+H+.
EXAMPLE 32: N-(5-azepan-l-yl-l-methyl-2-oxo-2,3-dihydro-lH-l,4- benzodiazepin-3-yl)-4-phenylbutanamide
Figure imgf000048_0002
The title compound was prepared by analogy to Example 1, after the preparation of 3-amino-5-azepan-l-yl-l-methyl-l ,3-dihydro-2H-l ,4-benzodiazepin-2- one, which was prepared according to J. Med. Chem., 37:719-721(1994).
EXAMPLE 33: N-allyl-N'-(l-allyl-5-cyclohexyl-2-oxo-2,3-dihydro-lH-l,4- benzodiazepin-3-yl)-N-[4-(l,4'-bipiperidin-l'-yl)phenyl]urea
Figure imgf000049_0001
The title compound was prepared by exposing Example 3.6 to excess allyl bromide and sodium hydride in DMF. The title compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (ES+) of 623.4 for M+H+.
EXAMPLE 34: 2-(5-cyclohexyl-2-oxo-l-propyl-2,3-dihydro-lH-l,4- benzodiazepin-3-yl)-N-{4-[4-(dimethylamino)piperidin-l-yl]phenyl}acetamide
Figure imgf000049_0002
The title compound was prepared from the benzodiazepine core, 5- cyclohexyl-l-propyl-l,3-dihydro-2H-l,4-benzodiazepin-2-one, and the aniline used in Table 4. The benzodiazepine was alkylated at the C-3 position with tert-butyl bromoacetate and potassium tert-butoxide. After aqueous acidic removal of the tert- butyl group, the resulting acid was coupled with l-(4-aminophenyl)-N,N- dimethylpiperidin-4-amine, employing standard N,N'-dicyclohexylcarbodiimide/N,N- dimethylpyridin-4-amine techniques. The title compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (ES+) of 584.6 for M+H+. EXAMPLE 35: N-[4-(l,4'-bipiperidin-l'-yl)phenyl]-2-(5-cyclohexyl-2-oxo-l- propyl-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)acetamide
Figure imgf000050_0001
The title compound was prepared by analogy to Example 36 using 4-
(1,4 -bipiperidin-l'-yl)aniline instead of l-(4-aminophenyl)-N,N-dimethylpiperidin-4- amine. The title compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (ES+) of 544.5 for M+H+.
EXAMPLE 36 4-(5-cyclohexyl-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin-l-yl)-N- [4-(4-pyridin-4-ylpiperazin-l-yl)phenyl]butanamide
Figure imgf000050_0002
The title compound was synthesized from the core benzodiazepine, 5- cyclohexyl-l,3-dihydro-2H-l,4-benzodiazepin-2-one, prepared according to J.O.C, 52:3232-3239(1987). This benzodiazepine was alkylated at the N-l position using ethyl 4-bromobutanoate and sodium hydride. After hydrolysis of the ester using THF/water/NaOH, the resulting acid was coupled with 4-(4-pyridin-4-ylpiperazin-l- yl)aniline, described in Example 4, using standard EDCI/HOBt techniques. The title compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (FT/ICR+) of 565.3 for M+H+. The following compounds in Table 9 were prepared analogously to Example 37, using 4-(l,4 -bipiperidin-l'-yl)aniline instead of 4-(4-pyridin-4- ylpiperazin- 1 -yl)aniline.
Figure imgf000051_0002
EXAMPLE 37: N-[3-(l,4'-bipiperidin-l '-yl)propyl]-4-(5-cyclohexyl-2-oxo-2,3- dihydro-lH-l,4-benzodiazepin-l-yl)butanamide
Figure imgf000051_0001
The title compound was prepared by analogy to Example 37 using the amine described in Example 17. The title compound thus obtained gave proton NMR spectra consistent with theory and a mass ion (FT/ICR+) of 536.4 for M+H+.

Claims

WHAT IS CLAIMED IS:
1. A compound represented by Formula I:
Figure imgf000053_0001
(I)
or a pharmaceutically acceptable salt thereof, wherein:
Rl is H, Ci-8alkyl (optionally substituted with 1-9 independent halogens), Ci-6alkyloxy- -Cι_ι oalkylaryl, -Cθ-2alkyl-C3-i ocycloalkyl or C2-6alkenyl;
R2 is -NHC(O)NR22R23, -OC(O)NR22R23, -Cι _3alkyl- C(O)NR22R23 or -NHC(O)R23; 0r
R2 is H and Rl is -Cι -7alkyI-C(O)-NH-Rl2;
Figure imgf000053_0002
Rl3 IS
Figure imgf000053_0003
Rl4 is aryl or heteroaryl wherein the aryl or heteroaryl is optionally substituted with 1-2 substituents, each substituent independently is Ci _6alkyl, Cι_6alkyloxy, Cι_6alkylcarboxy-, Ci -6alkylamido, OH, halogen, nitro, amino or cyano;
R22 is H, Cι_8alkyl (optionally substituted with 1-9 independent halogens), Ci_6alkyloxy- -Ci-ioalkylaryl, -Cθ-2alkyl-C3_χ ocycloalkyl, or C2-6alkenyl; R23 is -C2-6alkyl-R25, -Ci-6alkyl-R31, -Cθ-4alkylaryl, or -Cθ-4alkylheteroaryl, wherein the aryl or heteroaryl is substituted with a group selected from -C≡C-R44, -(CH2)0-4"R25 and -C(O)-R25;
R44 is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with 1-2 substituents, each substituent independently is Ci _6alkyl (optionally substituted with 1-9 independent halogens), Ci-6alkyloxy- Ci _6alkyl- carboxy- Ci_6alkylamido- OH, halogen, nitro, amino or cyano;
R25 is
Figure imgf000054_0001
R26 is H, -NR66R67, -C C -O-Rθό, -C(O)-NR66R67, OH,
Figure imgf000054_0002
aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with 1-2 substituents, each substituent independently is Ci _6alkyl (optionally substituted with 1-9 independent halogens), Ci-6alkyloxy- Ci _6alkylcarboxy- Ci-6alkylamido- OH, halogen, nitro, amino, or cyano;
R66 and R67 are each independently H, OH, Cι_8alkyl (optionally substituted with 1-9 independent halogens), Cχ_6alkyloxy-, -Ci-ioalkylaryl, -Co-2alkyl-C3-iocycloalkyl, or C2-6alkenyl;
R27 is -Cθ-2alkyl-C3_ιocycloalkyl, -Cθ-2alkylaryl, or -Cθ-2alkylheteroaryl, wherein the aryl or heteroaryl is optionally substituted with 1-2 substituents, each substituent independently is Ci_6alkyl (optionally substituted with 1-9 independent halogens), Cι_6alkyloxy- Cι_6alkylcarboxy- Ci-6alkylamido- OH, halogen, nitro, amino or cyano;
R31 is
Figure imgf000055_0001
R4 is Ci_8alkyl (optionally substituted with 1-9 independent halogens), Cι_6alkyloxy- -Cθ-3alkyl-C3_ιocycloalkyl, C2-8alkenyl, -Cθ-3alkylaryl, or-Cθ-3alkylheteroaryl, wherein the aryl or heteroaryl is optionally substituted with 1-3 substituents, each substituent independently is Ci-^alkyl (optionally substituted with 1-9 independent halogens), Ci-6alkyloxy- Ci_6alkylcarboxy-, Cι_6alkylamido-, OH, halogen, nitro, amino, or cyano, or
R4 is
Figure imgf000055_0002
R41 and R42 are each independently H, Ci-8alkyl (optionally substituted with 1-9 independent halogens), Ci-ζalkyloxy- -Cι_ιoalkylaryl, -Co-2alkyl-C3_iocycloalkyl, or C2-6alkenyl;
R5 is H, nitro, halogen, cyano, OH, amino, Ci _6alkylthio- Cι_8alkyl (optionally substituted with 1-9 independent halogens), Ci-8alkyloxy- -Co-lOalkylaryl, -Co-10alkylheteroaryl, -C(O)-Cθ-2alkylaryl,
-C(O)-Co-2alkylheteroaryl, -C(O)-O-aryl, -C(O)-O-heteroaryl, -C(O)-NH- Co-2alkylaryl, -C(O)-NH-Co-2alkylheteroaryl, -C(O)-N(Ci_8alkyl)-Co-2alkylaryl, or -C(O)-N(Ci-8alkyl)-Cθ-2alkylheteroaryl, wherein the aryl or heteroaryl is optionally substituted with 1-2 substituents, each substituent independently is Ci-galkyl, Ci-6alkyloxy- Ci-6alkylcarboxy- Ci-6alkylamido- OH, halogen, nitro, amino, or cyano.
2. The compound according to Claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is -NH-C(O)-Cι_6alkyl-R31.
3. The compound according to Claim 2, represented by
Figure imgf000056_0001
or a pharmaceutically acceptable salt thereof.
4. The compound according to Claim 1, or a pharmaceutically acceptable salt thereof, wherein
R2 is -NH-C(O)-R23.
5. The compound according to Claim 4, or a pharmaceutically acceptable salt thereof, wherein
R23 is -Cθ-4alkylaryl substituted with -(CH2)θ-4-R25; R25 is
Figure imgf000056_0002
6. The compound according to Claim 4 represented by
Figure imgf000056_0003
Figure imgf000057_0001
or a pharmaceutically acceptable salt thereof.
7. The compound according to Claim 1, wherein R2 is -NH-C(O)-NR22R23 ;
R23 is -Cθ-4alkylaryl, wherein the aryl is substituted with
Figure imgf000057_0002
R27 is -Cθ-2alkylaryl, or -Cθ-2alkylheteroaryl, wherein the aryl or heteroaryl is optionally substituted with 1-2 substituents, each substituent independently is Ci -6alkyl (optionally substituted with 1-9 independent halogens), Cι_6alkyloxy-, Ci -6alkylcarboxy-, Cι_6alkylamido-, OH, halogen, nitro, amino or cyano; or a pharmaceutically acceptable salt thereof.
8. The compound according to Claim 1, wherein
R2 is -NH-C(O)-NR22R23;
R23 is -Cθ-4alkylaryl, wherein the aryl is substituted with -(CH2)0-4-R25, or -C(O)-R25; R25 is
Figure imgf000057_0003
and
R26 is
Figure imgf000058_0001
or a pharmaceutically acceptable salt thereof.
9. The compound according to Claim 1, wherein
R2 is -NH-C(O)-NR22R23;
R23 is -Cθ-4alkylaryl, wherein the aryl is substituted with ~(CH2)θ-4-
R25, or-C(O)-R25;
R25 is
Figure imgf000058_0002
or a pharmaceutically acceptable salt thereof.
10. The compound according to Claim 1, wherein R2 is -NH-C(O)-NR22R23;
R23 is -Cθ-4alkylaryl, wherein the aryl is substituted with -(CH2)θ-4~ R25; or-C(O)-R25; R25 is
Figure imgf000058_0003
or a pharmaceutically acceptable salt thereof.
11. The compound according to Claim 1, wherein
R2 is -NH-C(O)-NR22R23;
R23 is -Co-4alkylaryl, wherein the aryl is substituted with -(CH2)θ-4~ R25, 0r -C(O)-R25; R25 is
Figure imgf000059_0001
or a pharmaceutically acceptable salt thereof.
12. The compound according to Claim 1, wherein
R2 is -NH-C(O)-NR22R23;
R23 is -Cθ-4alkylaryl, wherein the aryl is substituted with -(CH2)θ-4~ R25, or-C(O)-R25;
R25 is
Figure imgf000059_0002
or a pharmaceutically acceptable salt thereof.
13. The compound according to Claim 1, wherein R2 is -NH-C(O)-NR22R23;
R23 is -Cθ-4alkylaryl, wherein the aryl is substituted with -(CH2)0-4- R25, or -C(O)-R25; R25 is
Figure imgf000059_0003
R26 is aryl, wherein the aryl is optionally substituted with 1-2 substituents, each substituent independently is Ci-6alkyl (optionally substituted with 1-9 independent halogens), Ci_6alkyloxy- Ci-6alkylcarboxy-, Cι _6alkylamido-, OH, halogen, nitro, amino, or cyano; or a pharmaceutically acceptable salt thereof.
14. The compound according to Claim 1, wherein R2 is -NH-C(O)-NR22R23;
R23 is -Cθ-4alkylaryl, wherein the aryl is substituted with -(CH2)θ-4~ R25) 0r -C(O)-R25; R25 is
Figure imgf000060_0001
or a pharmaceutically acceptable salt thereof.
15. The compound according to Claim 1, wherein R2 is -NH-C(O)-NR22R23; R23 is -Co-4alkylaryl, wherein the aryl is substituted with -(CH2)θ-4-
R25, or -C(O)-R25;
R25 is
Figure imgf000060_0002
or a pharmaceutically acceptable salt thereof.
16. The compound according to Claim 1, wherein R2 is -NH-C(O)-NR22R23; R23 is _C2-6alkyl-R25; R25 is
Figure imgf000060_0003
R26 is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with 1-2 substituents, each substituent independently is Ci-6alkyl (optionally substituted with 1-9 independent halogens), Ci -6alkyloxy- Ci-βalkylcarboxy-, Cι_6alkylamido-, OH, halogen, nitro, amino, or cyano; or a pharmaceutically acceptable salt thereof.
17. The compound according to Claim 1, wherein
R2 is -NH-C(O)-NR22R23;
R23 is _
Figure imgf000061_0001
or a pharmaceutically acceptable salt thereof.
18. The compound according to Claim 1, wherein R2 is -NH-C(O)-NR22R23; R23 is -Cθ-4alkylaryl, wherein the aryl is substituted with
-R 44
or a pharmaceutically acceptable salt thereof.
19. The compound according to Claim 1, represented by
Figure imgf000061_0002
wherein:
Figure imgf000061_0003
Figure imgf000062_0001
or a pharmaceutically acceptable salt thereof.
20. The compound according to Claim 1, wherein R2 is -NH-C(O)-NR22R23;
R23 is 4-(4-pyridin-4-ylpiperazin-l-yl)phenyl; R5 is H; R4 is cyclohexyl and Rl is propyl, cyclopropylmethyl, butyl, isobutyl, or 2,2,2-trifluoro- ethyl, or R is phenyl and Rl is isopropyl; or
R23 is 4-(l,4'-bipiperidin-l'-yl)phenyl; R5 is H; and Rl and R4 are as follows:
Figure imgf000062_0002
Figure imgf000063_0002
or
R23 is 4-[4-(dimethylamino)piperidin-l-yl]phenyl; R5 is H; R is cyclohexyl and Rl is propyl, cyclopropylmethyl, or benzyl, or R is phenyl and Rl is isopropyl, methyl or ethyl; or
R23 is 4-[[3-(dimethylamino)propyl](methyl)amino]phenyl; R5 is H; Rl is isopropyl and R4 is phenyl, or Rl is propyl and R is isopropyl or cyclohexyl; or
R23 is 6-(l,4'-bipiperidin-l -yl)pyridin-3-yl; R4 is cyclohexyl; R5 is H; and Rl is propyl, cyclopropylmethyl, butyl or isobutyl; or
Figure imgf000063_0001
, R5 is H, and Rl, R4, and R25 are as follows:
Figure imgf000063_0003
Figure imgf000064_0003
or a pharmaceutically acceptable salt thereof.
21. The compound according to Claim 1, wherein R2 is -O-C(O)-NR22R23; or a pharmaceutically acceptable salt thereof.
22. The compound according to Claim 21 wherein R23 is -Cθ-4alkylaryl, wherein the aryl is optionally substituted with -2 substituents, each substituent independently is -(CH2)θ-4-R2->> or-C(O)-R25;
R25 is
Figure imgf000064_0001
or a pharmaceutically acceptable salt thereof.
23. The compound according to Claim 21 represented by
Figure imgf000064_0002
or a pharmaceutically acceptable salt thereof.
24. The compound according to Claim 1, wherein R2 is -Ci-3alkyl-C(O)-NR22R23; or a pharmaceutically acceptable salt thereof.
25. The compound according to Claim 24, wherein R23 is -Cθ-4alkylaryl, wherein the aryl is substituted with -(CH2)θ-4- R25, or -C(O)-R25;
R25 is
Figure imgf000065_0001
or a pharmaceutically acceptable salt thereof.
26. The compound according to Claim 24, wherein R23 is -Cθ-4alkylaryl, wherein the aryl is substituted with -(CH2)θ-4~ R25j 0r-C(O)-R25;
R25 is
Figure imgf000065_0002
or a pharmaceutically acceptable salt thereof.
27. The compound according to Claim 24, represented by
Figure imgf000065_0003
Figure imgf000066_0001
or a pharmaceutically acceptable salt thereof.
28. The compound according to Claim 1, wherein Rl is -Ci-7alkyl-C(O)-NH-Rl2; or a pharmaceutically acceptable salt thereof.
29. The compound according to Claim 28, wherein Rl2 is aryl substituted with
Figure imgf000066_0002
Rl4 is heteroaryl, wherein the aryl or heteroaryl is optionally substituted with 1-2 substituents, each substituent independently is Cχ_6alkyl, Cι_ 6alkyloxy- Ci-6alkylcarboxy- Ci-6alkylamido- OH, halogen, nitro, amino, or , cyano; or a pharmaceutically acceptable salt thereof.
30. The compound according to Claim 28, wherein
Rl2 is aryl substituted with
Figure imgf000066_0003
or a pharmaceutically acceptable salt thereof.
31. The compound according to Claim 28, wherein Rl2 is
Figure imgf000067_0001
or a pharmaceutically acceptable salt thereof.
32. The compound according to Claim 28 represented by
Figure imgf000067_0002
Figure imgf000067_0003
or a pharmaceutically acceptable salt thereof.
33. The compound according to Claim 28, wherein Rl is
Figure imgf000068_0001
R5 = H; and n and R4 is cyclohexyl and n is 1 to 5; or n is 3 and R4 is 2-phenylethyl, t-butyl or methyl; or a pharmaceutically acceptable salt thereof.
34. The compound according to Claim 1 selected from N-[4-(l,4'-bipiperidin-l'-yl)phenyl]-4-(5-cyclohexyl-2-oxo-2,3- dihydro-lH-l,4-benzodiazepin-l-yl)butanamide, N-[2-oxo-5-(2-phenyIethyI)-l-propyl-2,3-dihydro-lH-l,4- benzodiazepin-3-yl]-N'-[4-(4-pyridin-4-ylpiperazin-l-yl)phenyl]urea,
N-[4-(l,4'-bipiperidin- -yl)phenyl]-N'-(5-cyclohexyl-2-oxo-l-propyl- 2,3-dihydro-lH-l,4-benzodiazepin-3-yl)urea, and
N-[4-(l,4'-bipiperidin-l'-yl)phenyl]-N'-[5-(4-methylphenyl)-2-oxo-l- propyl-2,3-dihydro-lH-l,4-benzodiazepin-3-yl]urea, or a pharmaceutically acceptable salt thereof.
35. A pharmaceutical composition comprising a compound according to Claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
36. A method of treatment or prevention of pain and inflammation comprising a step of administering, to a subject in need of such treatment or prevention, an effective amount of a compound according to Claim 1 or a pharmaceutically acceptable salt thereof.
37. A method of treatment of osteoarthritis, repetitive motion pain, dental pain, cancer pain, myofascial pain, muscular injury pain, fibromyalgia pain, peri operative pain comprising a step of administering, to a subject in need of such treatment, an effective amount of a compound according to Claim 1 or a pharmaceutically acceptable salt thereof.
38. A method of treatment or prevention of inflammatory pain caused by chronic obstructive pulmonary disease, asthma, inflammatory bowel disease, rhinitis, pancreatitis, cystitis (interstitial cystitis), uveitis, inflammatory skin disorders, rheumatoid arthritis, edema resulting from trauma associated with burns, sprains or fracture, postsurgical intervention, osteoarthritis, rheumatic disease, teno-synovitis, or gout comprising a step of administering, to a subject in need of such treatment or prevention, an effective amount of a compound according to Claim 1 or a pharmaceutically acceptable salt thereof.
39. A method of treatment or prevention of pain associated with angina, menstruation or cancer comprising a step of administering, to a subject in need of such treatment or prevention, an effective amount of a compound according to Claim 1 or a pharmaceutically acceptable salt thereof.
40. A method of treatment of diabetic vasculopathy, post capillary resistance, diabetic symptoms associated with insulitis, psoriasis, eczema, spasms of the gastrointestinal tract or uterus, Crohn's disease, ulcerative colitis, or pancreatitis comprising a step of administering, to a subject in need of such treatment, an effective amount of a compound according to Claim 1 or a pharmaceutically acceptable salt thereof.
41. A method of treatment or prevention of pain caused by pneumoconiosis, including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis, byssinosis, adult respiratory distress syndrome, bronchitis, allergic rhinitis, vasomotor rhinitis, liver disease, multiple sclerosis, atherosclerosis, Alzheimer's disease, septic shock, cerebral edema, headache, migraine, closed head trauma, irritable bowel syndrome, or nephritis comprising a step of administering, to a subject in need of such treatment or prevention of pain, an effective amount of a compound according to Claim 1 or a pharmaceutically acceptable salt thereof.
42. A compound selected from the group: N-(l-methyl-5-phenyl-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin-3-yι)-
4-(n-pentyl)benzamide; N-(l-methyl-5-(2-fluorophenyl)-2-oxo-2,3-dihydro-lH-l,4- benzodiazepin-3-yl)-4-(n-pentyl)benzamide;
N-(l-isopropyl-5-phenyl-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin-3- yl)-3-bromobenzamide; N-(l-isopropyl-5-phenyl-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin-3- yl)-3-(trifluoromethyl)benzeneacetamide;
N-(5-cyclohexyl-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-2- (phenoxy)benzeneacetamide;
N-(5-(2-flurophenyl)-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)- 3-methyl-2-indencarboxamide;
N-(5-(2-fluorophenyl)-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)- benzamide;
N-(l-methyl-5-phenyl-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)- cyclohexanecarboxamide; N-(l-propyl-5-cyclohexyl-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin-3- yl)-4-(dimethylamino)benz amide;
N-(l-propyl-5-cyclohexyl-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin-3- yl)-lH-5-indolecarboxamide;
N-[2-oxo-5-phenyl-l-isopropyl-2,3-dihydro-lH-l,4-benzodiazepin-3- yl]-N'-[4-((3-(dimethylamino)propyl(methyl)amino)phenyl]urea;
N-[2-oxo-5-isopropyl-l-propyl-2,3-dihydro-lH-l,4-benzodiazepin-3- yl]-N'-[4-((3-(dimethylamino)propyl(methyl)amino)phenyl]urea;
N- [2-oxo-5 -cyclohexyl- 1 -propyl -2,3 -dihydro- 1 H- 1 ,4-benzodiazepin-3 - • yl]-N'-[4-((3-(dimethylamino)propyl(methyl)amino)phenyl]urea; N-[2-oxo-5-cyclohexyl-l-propyl-2,3-dihydro-lH-l,4-benzodiazepin-3- yl]-N'-[4-(2-(piperidin-l-yl)ethoxy)phenyl]urea;
N-[2-oxo-5-phenyl-l-ethyl-2,3-dihydro-lH-l,4-benzodiazepin-3-yl]- N'-(3-methoxyphenyl)urea;
N-[2-oxo-5-isopropyl-l-propyl-2,3-dihydro-lH-l,4-benzodiazepin-3- yl]-N'-[4-(morpholin-4-yl)phenyl]urea;
N-[2-oxo-5-cyclohexyl-l-propyl-2,3-dihydro-lH-l,4-benzodiazepin-3- yl]-N'-[4-(morpholin-4-yl)phenyl]urea;
N- [2-oxo-5 -cyclohexyl- 1 -propyl-2,3 -dihydro- 1 H- 1 ,4-benzodiazepin-3 - yl]-N'-[4-(piperidin-l-yl)phenyl]urea; N- [2-oxo-5 -cyclohexyl- 1 -propyl-2 ,3 -dihydro- IH- 1 ,4-benzodiazepin-3 - yl]-N'-(3-pyridyl)urea;
Benzyl 5-tert-butyl-l-isobutyl-2-oxo-2,3-dihydro-lH-l,4- benzodiazepin-3-ylcarbamate;
N- [5 -(4-methylρiperazin- 1 -yl)-2-oxo- 1 -propyl-2 ,3 -dihydro- IH- 1 ,4- benzodiazepin-3-yl]-N-(5-methyl-l,3,4-thiadiazol-2-yl)urea; and
N-(5-azepan- 1 -yl- 1 -methyl-2-oxo-2,3-dihydro- IH- 1 ,4-benzodiazepin- 3-yl)-4-phenylbutanamide; or a pharmaceutically acceptable salt thereof.
PCT/US2002/021065 2001-06-07 2002-06-03 Benzodiazepine bradykinin antagonists WO2002099388A2 (en)

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