WO2003084931A1 - Antagonistes 5h-benzo[4,5]cyclohepta[1,2-b]pyridines de nmda/nr2b - Google Patents

Antagonistes 5h-benzo[4,5]cyclohepta[1,2-b]pyridines de nmda/nr2b Download PDF

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WO2003084931A1
WO2003084931A1 PCT/US2003/009689 US0309689W WO03084931A1 WO 2003084931 A1 WO2003084931 A1 WO 2003084931A1 US 0309689 W US0309689 W US 0309689W WO 03084931 A1 WO03084931 A1 WO 03084931A1
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group
6alkyl
compound
pharmaceutically acceptable
acceptable salt
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PCT/US2003/009689
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English (en)
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John A. Mccauley
John W. Butcher
David A. Claremon
Nigel J. Liverton
Charles Mcintyre
Joseph J. Romano
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Merck & Co., Inc.
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Priority to AU2003230758A priority Critical patent/AU2003230758A1/en
Publication of WO2003084931A1 publication Critical patent/WO2003084931A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered

Definitions

  • This invention relates to novel 5H-benzo [4,5]cyclohepta[l,2- b]pyridine compounds.
  • this invention relates to novel 5H-benzo [4,5]cyclohepta[l,2-b]pyridine compounds that are effective as NMD A NR2B antagonists useful for relieving pain.
  • Ions such as glutamate play a key role in processes related to chronic pain and pain-associated neurotoxicity - primarily by acting through N-methyl-D- aspartate ("NMD A") receptors.
  • NMD A N-methyl-D- aspartate
  • inhibition of such action - by employing ion channel antagonists, particularly NMDA antagonists - can be beneficial in the treatment and control of pain.
  • NMDA antagonists include etamine, dextromophan, and 3-(2- carboxypiperazin-4-yl)-propyl-l-phosphonic acid ("CPP"). Although these compounds have been reported (LD.Kristensen, et al., Pain, 51:249-253 (1992); K.Eide, et al., Pain, 61:221-228 (1995); DJ.Knox, et al., Anaesth. Intensive Care 23:620-622 (1995); and M.B.Max, et al, Clin. Neuropharmacol.
  • CPP 3-(2- carboxypiperazin-4-yl)-propyl-l-phosphonic acid
  • NMDA receptors are heteromeric assemblies of subunits, of which two major subunit families designated NR1 and NR2 have been cloned. Without being bound by theory, it is generally believed that the various functional NMDA receptors in the mammalian central nervous system ("CNS") are only formed by combinations of NR1 and NR2 subunits, which respectively express glycine and glutamate recognition sites.
  • the NR2 subunit family is in turn divided into four individual subunit types: NR2A, NR2B, NR2C, and NR2D. I. Ishii, et al., J. Biol.
  • Chem., 268:2836-2843 (1993), A.Wenel, et al., Neural Report, 7:45-48 (1995), and DJ Why et al., Mol. Brain Res., 51:23-32 (1997) describe how the various resulting combinations produce a variety of NMDA receptors differing in physiological and pharmacological properties such as ion gating properties, magnesium sensitivity, pharmacological profile, as well as in anatomical distribution.
  • NR2 subunits are differentially distributed.
  • the distribution map for NR2B lowers the probability of side effects while producing pain relief.
  • S.Boyce, et al., Neuropharniacology, 38:611-623(1999) describes the effect of selective NMDA NR2B antagonists on pain with reduced side-effects.
  • the present invention relates to novel benzo [4,5]cyclohepta[l,2- bjpyridines.
  • the present invention also forms novel pharmaceutical compositions utilizing these novel compounds. Further, this invention includes novel methods to treat pain by utilizing the novel compounds.
  • Rl is hydrogen, CI, or C ⁇ _6alkyl group, C2-6*alkenyl group, C2-6 a lkynyl group, C3_8cycloalkyl group, aryl group, heteroaryl group, heterocyclic group, or NR9R1C* group; each group optionally substituted with one to five substituents, each substituent independently being halogen, -CN, C ⁇ _6alkyl, hydroxyC ⁇ _6alkyl, haloC ⁇ _6alkyl, Ci- ⁇ alkoxy, -CHO, C3_6cycloalkenyl, Ci_6alkyl- S-, -NH2, -C(O)NH2 > phenyl, halophenyl, phenylC ⁇ _6alkyl, phenylCi_6alkyl-O-, phenylC i _6alkyl-O-C i _6alkyl ;
  • R5 and R55 are each independently hydrogen, chloro, amino, phenyl, aryl, C ⁇ _6alkylamino, Ci_6alkyl(C ⁇ _6alkyl)amino, or arylamino;
  • R8 is Ci_6alkyl, phenyl, or heterocyclic
  • R9 and RlO are each independently hydrogen, Ci_6alkyl group, C3_7cycloalkyl group, aryl group, or heterocylic group each group optionally substituted with one to five substituents, each substituent independently being C ⁇ _ 6alkoxy, -N(C ⁇ -6*alkyl)(C ⁇ -6alkyl), or C3-7cycloalkyl; and
  • X is O or CH2; but excluding compounds represented by the following exclusion table wherein other R are H:
  • the compounds of this invention are represented by Formula (I), excluding compounds in the exclusion table above:
  • Rl is hydrogen, CI, or Ci- ⁇ alkyl group, C2-6 a lkenyl group, C2-6*alkynyl group, C3-8cycloalkyl group, aryl group, heteroaryl group, heterocyclic group, or NR9R10 group; each group optionally substituted with one to five substituents, each substituent independently being halogen, -CN, Ci- ⁇ alkyl, hydroxyC ⁇ _6alkyl, haloCi-6alkyl, C ⁇ _6alkoxy, -CHO, C3-6cycloalkenyl, C ⁇ _6alkyl- S-, -NH2, -C(O)NH2, phenyl, halophenyl, phenylC ⁇ _6alkyl, phenylC ⁇ _6alkyl-O-, phenylC i _6alkyl-O-C i -6alkyl;
  • R2, R3 ; R6 5 and R7 are each independently hydrogen, OH, -O-Ci_6alkyl group, -O-acyl group, -O-aryl group, -NH2, -NH(C ⁇ _6alkyl) group, -N(C ⁇ _6alkyl)(Ci_6alkyl) group, -NH(aryl) group, each group optionally substituted with one to five substituents, each substituent independently being C ⁇ _6alkyl;
  • R-5 and R5 are each independently hydrogen, chloro, amino, phenyl, aryl, C ⁇ _6alkylamino, C ⁇ _6alkyl(C ⁇ _6alkyl)amino, or arylamino;
  • R8 is Ci-.6alkyl, phenyl, or heterocyclic;
  • R9 and RlO are each independently hydrogen, Ci- ⁇ alkyl group, C3_7cycloalkyl group, aryl group, or heterocylic group each group optionally substituted with one to five substituents, each substituent independently being C ⁇ - ⁇ alkoxy, -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), or C3_7cycloalkyl.
  • the compound of the invention is represented by Formula (I), or pharmaceutically acceptable salts thereof, excluding compounds in the exclusion table above, wherein
  • Rl is hydrogen, CI, or C ⁇ _6alkyl group, C2-6*alkenyl group, C2-6 a lkynyl group, C3_8cycloalkyl group, aryl group, heteroaryl group, heterocyclic group, or NR9R10 group; each group optionally substituted with one to five substituents, each substituent independently being halogen, -CN, Ci_6alkyl, hydroxyC ⁇ _6alkyl, haloC ⁇ _6alkyl, Ci-6alkoxy, -CHO, C3_6cycloalkenyl, C ⁇ _6alkyl- S-, -NH2, -C(O)NH2, phenyl, halophenyl, phenylCi-6alkyl, phenylC ⁇ _6alkyl-O-, phenylCi-6alkyl-O-Ci-6alkyl;
  • R4, R41 5 R42 ; and R43 are each independently -CN, hydrogen, bromo, chloro, fluoro, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, amino, nitro, Ci_6alkyl, aryl, R8SO2NH-, or -CHO;
  • R5 and R55 are each independently hydrogen, chloro, amino, phenyl, aryl, Ci-6alkylamino, C ⁇ _6alkyl(Ci-6alkyl)amino, or arylamino;
  • R8 is C _6alkyl, phenyl, or heterocyclic;
  • R9 and RlO are each independently hydrogen, C _6alkyl group, C3-7cycloalkyl group, aryl group, or heterocylic group each group optionally substituted with one to five substituents, each substituent independently being Ci_ 6alkoxy, -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), or C3-7cycloalkyl.
  • the compound of the invention is represented by Formula (I), or pharmaceutically acceptable salts thereof, excluding compounds in the exclusion table above, wherein
  • Rl is hydrogen, CI, or Ci_6alkyl group, C2-6alkenyl group, C2-6alkynyl group, C3_8cycloalkyl group, aryl group, heteroaryl group, heterocyclic group, or NR9R10 group; each group optionally substituted with one to five substituents, each substituent independently being halogen, -CN, Ci- ⁇ alkyl, hydroxyCi_6alkyl, haloCi_6alkyl, Ci_6alkoxy, -CHO, C3_6cycloalkenyl, C ⁇ -.6alkyl- S-, -NH2, -C(O)NH2, phenyl, halophenyl, phenylCi-6alkyl, phenylCi_6alkyl-O-, phenylC ⁇ _6alkyl-O-Ci_6alkyl;
  • R6, and R7 are each independently hydrogen, OH, -O-Ci_6alkyl group, -O-acyl group, -O-aryl group, -NH2, -NH(C ⁇ _6alkyl) group, -N(Ci-6alkyl)(C ⁇ _ ⁇ alkyl) group, -NH(aryl) group, each group optionally substituted with one to five substituents, each substituent independently being C ⁇ _6alkyl;
  • R77 is hydrogen
  • R4, R41 S R42 ; and R43 are each independently -CN, hydrogen, bromo, chloro, fluoro, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, amino, nitro, C ⁇ _6alkyl, aryl, R8SO2NH-, or -CHO;
  • R5 and R-55 are each independently hydrogen, chloro, amino, phenyl, aryl, C ⁇ _6alkylamino, C ⁇ _6alkyl(C ⁇ _6alkyl)amino, or arylamino;
  • R8 is Ci_6alkyl, phenyl, or heterocyclic; and
  • R and RlO are each independently hydrogen, Ci-6alkyl group, C3_7cycloalkyl group, aryl group, or heterocylic group each group optionally substituted with one to five substituents, each substituent independently being Ci_ 6alkoxy, -N(CQ-6alkyl)(C ⁇ -6alkyl),
  • Rl is hydrogen, CI, or C ⁇ _6alkyl group, C2-6alkenyl group, C2-6alkynyl group, C3_8cycloalkyl group, aryl group, heteroaryl group, heterocyclic group, or NR9R10 group; each group optionally substituted with one to five substituents, each substituent independently being halogen, -CN, C ⁇ _6alkyl, hydroxyCi-6alkyl, haloC ⁇ _6alkyl, C ⁇ _6alkoxy, -CHO, C3_6cycloalkenyl, C ⁇ _6alkyl- S-, -NH2, -C(O)NH2, phenyl, halophenyl, phenylC ⁇ _6alkyl, phenylCi-6alkyl-O-, phenylCi-6alkyl-O-C ⁇ _6alkyl;
  • R4, R41 5 R42 ; and R43 are each independently -CN, hydrogen, bromo, chloro, fluoro, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, amino, nitro, C ⁇ _6alkyl, aryl, R8SO2NH-, or -CHO;
  • R5 and R-55 are each independently hydrogen, chloro, amino, phenyl, aryl, Ci-6alkylamino, Ci-6alkyl(Ci-6alkyl)amino, or arylamino;
  • R8 is C ⁇ _6alkyl, phenyl, or heterocyclic; and
  • R9 and RlO are each independently hydrogen, Ci_6alkyl group, C3_7cycloalkyl group, aryl group, or heterocylic group each group optionally substituted with one to five substituents, each substituent independently being Ci- 6alkoxy, -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), or C
  • the compound of the invention is represented by Formula (II), or pharmaceutically acceptable salts thereof, excluding compounds in the exclusion table above, wherein
  • Rl is hydrogen, CI, or C ⁇ _6alkyl group, C2-6 a lkenyl group, C2-6alkynyl group, C3-8cycloalkyl group, aryl group, heteroaryl group, heterocyclic group, or NR9R10 group; each group optionally substituted with one to five substituents, each substituent independently being halogen, -CN, Ci_6alkyl, hydroxyCi-6alkyl, haloCi_6alkyl, Ci_6alkoxy, -CHO, C3_6cycloalkenyl, C ⁇ _6alkyl-
  • R2, R3 ; and R6 are each independently hydrogen, OH, -O-Ci- ⁇ alkyl group, -O-acyl group, -O-aryl group, -NH2, -NH(C ⁇ _6alkyl) group, -N(Ci_
  • R4, R41 5 R42 ; and R43 are each independently -CN, hydrogen, bromo, chloro, fluoro, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, amino, nitro, C ⁇ _6alkyl, aryl, R8SO2NH-, or -CHO;
  • R5 and R55 are each independently hydrogen, chloro, amino, phenyl, aryl, C ⁇ _6alkylamino, Ci_6alkyl(Ci-6alkyl)amino, or arylamino;
  • R8 is Ci_6alkyl, phenyl, or heterocyclic;
  • R9 and RlO are each independently hydrogen, C ⁇ _6alkyl group, C3_7cycloalkyl group, aryl group, or heterocylic group each group optionally substituted with one to five substituents, each substituent independently being Ci_ 6alkoxy, -N(C ⁇ -6alkyl)(C()-6alkyl), or C3_7cycloalkyl.
  • the compound of the invention is represented by Formula (II), or pharmaceutically acceptable salts thereof, excluding compounds in the exclusion table above, wherein
  • Rl is hydrogen, CI, or Ci-6alkyl group, C2-6alkenyl group, C2-6 a lkynyl group, C3_8cycloalkyl group, aryl group, heteroaryl group, heterocyclic group, or NR9R10 group; each group optionally substituted with one to five substituents, each substituent independently being halogen, -CN, Ci- ⁇ alkyl, hydroxyCi-6alkyl, haloC ⁇ _6alkyl, Ci-6alkoxy, -CHO, C3_6cycloalkenyl, Ci_6alkyl- S-, -NH2, -C(O)NH2, phenyl, halophenyl, phenylC ⁇ _6alkyl, phenylC ⁇ _6alkyl-O-, phenylCi-6alkyl-O-Ci-6alkyl;
  • R4, R41 s R42 ; and R43 are each independently -CN, hydrogen, bromo, chloro, fluoro, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, amino, nitro, Ci_6alkyl, aryl, R8SO2NH-, or -CHO;
  • R5 and R-5 are each independently hydrogen, chloro, amino, phenyl, aryl, C ⁇ _6alkylamino, C ⁇ _6alkyl(Ci_6alkyl)amino, or arylamino;
  • R8 is C ⁇ _6alkyl, phenyl, or heterocyclic;
  • R9 and RlO are each independently hydrogen, Ci_6alkyl group, C3-7cycloalkyl group, aryl group, or heterocylic group each group optionally substituted with one to five substituents, each substituent independently being C ⁇ _ 6alkoxy, -N(C ⁇ -6alkyl)(C()-6alkyl), or C3_7cycloalkyl.
  • Rl is hydrogen, CI, or Ci_6alkyl group, C2-6alkenyl group, C2-6alkynyl group, C3_8cycloalkyl group, aryl group, heteroaryl group, heterocyclic group, or NR9R10 group; each group optionally substituted with one to five substituents, each substituent independently being halogen, -CN, C ⁇ _6alkyl, hydroxyCi_6alkyl, haloCi-6alkyl, C ⁇ _6alkoxy, -CHO, C3_6cycloalkenyl, Ci-6alkyl- S-, -NH2, -C(O)NH2, phenyl, halophenyl, phenylC ⁇ _6alkyl, phenylCi-6alkyl-O-, phenylC 1 _6alkyl-O-C i _6alkyl ;
  • R4, R41, R42, and R43 are each independently -CN, hydrogen, bromo, chloro, fluoro, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, amino, nitro, C ⁇ _6alkyl, aryl, R8SO2NH-, or -CHO;
  • R5 and R-55 are each independently hydrogen, chloro, amino, phenyl, aryl, C ⁇ _6alkylamino, C ⁇ _6alkyl(Ci-6alkyl)amino, or arylamino;
  • R8 is Ci_6alkyl, phenyl, or heterocyclic; R9 and RlO are each independently hydrogen, Ci-6alkyl group,
  • C3_7cycloalkyl group, aryl group, or heterocylic group each group optionally substituted with one to five substituents, each substituent independently being Ci_ 6alkoxy, -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), or C3_7cycloalkyl;
  • X is O or CH2.
  • the compound of the invention is represented by Formula (HI), or pharmaceutically acceptable salts thereof, wherein
  • Rl is hydrogen, CI, or Ci_6alkyl group, C2-6 a lkenyl group, C2-6alkynyl group, C3_8cycloalkyl group, aryl group, heteroaryl group, heterocyclic group, or NR9R10 group; each group optionally substituted with one to five substituents, each substituent independently being halogen, -CN, Ci- ⁇ alkyl, hydroxyCi_6alkyl, haloCl_6alkyl, Ci-6alkoxy, -CHO, C3_6cycloalkenyl, C ⁇ _6alkyl- S-, -NH2, -C(O)NH2, phenyl, halophenyl, phenylC ⁇ _6alkyl, phenylCi-6alkyl-O-, phenylC i_6alkyl-O-C i-.6alkyl; R2, and R3 are each independently hydrogen, OH, -O-C
  • R5 and R55 are each independently hydrogen, chloro, amino, phenyl, aryl, C ⁇ _6alkylamino, Ci-6alkyl(Ci_6alkyl)amino, or arylamino;
  • R8 is C ⁇ _6alkyl, phenyl, or heterocyclic;
  • R9 and RlO are each independently hydrogen, C ⁇ _6alkyl group, C3-7cycloalkyl group, aryl group, or heterocylic group each group optionally substituted with one to five substituents, each substituent independently being Ci_ 6alkoxy, -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), or C3_7cycloalkyl; and X is O or CH2.
  • the compound of the invention is represented by Formula (DI), or pharmaceutically acceptable salts thereof, wherein Rl is hydrogen, CI, or C ⁇ _6alkyl group, C2-6 a lkenyl group, C2-6*alkynyl group, C3-8cycloalkyl group, aryl group, heteroaryl group, heterocyclic group, or NR9R10 group; each group optionally substituted with one to five substituents, each substituent independently being halogen, -CN, Ci- ⁇ alkyl, hydroxyCi-6alkyl, haloC ⁇ _6alkyl, C ⁇ _6alkoxy, -CHO, C3_6cycloalkenyl, C ⁇ _6alkyl- S-, -NH2, -C(O)NH2, phenyl, halophenyl, phenylC i-6alkyl, phenylCi- ⁇ alkyl-O-, phenylCi-6alkyl-
  • R4, R41, R42, and R43 are each independently -CN, hydrogen, bromo, chloro, fluoro, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, amino, nitro, Ci_6alkyl, aryl, R8SO2NH-, or -CHO;
  • R-5 and R55 are each independently hydrogen, chloro, amino, phenyl, aryl, C ⁇ _6alkylamino, C ⁇ _6alkyl(C ⁇ _6alkyl)amino, or arylamino;
  • R8 is C ⁇ _6alkyl, phenyl, or heterocyclic;
  • R9 and RlO are each independently hydrogen, C ⁇ _6alkyl group, C3-7cycloalkyl group, aryl group, or heterocylic group each group optionally substituted with one to five substituents, each substituent independently being Ci- 6alkoxy, -N(C ⁇ -6alkyl)(C ⁇ -6alkyl), or
  • the compound of the invention is represented by Formula (DI), or pharmaceutically acceptable salts thereof, wherein
  • Rl is hydrogen, CI, or Ci- ⁇ alkyl group, C2-6 lkenyl group, C2-6 a lkynyl group, C3_8cycloalkyl group, aryl group, heteroaryl group, heterocyclic group, or NR9R10 group; each group optionally substituted with one to five substituents, each substituent independently being halogen, -CN, C ⁇ _6alkyl, hydroxyCi- ⁇ alkyl, haloC ⁇ _6alkyl, C ⁇ _6alkoxy, -CHO, C3_6cycloalkenyl, Ci-6alkyl- S-, -NH2, -C(O)NH2, phenyl, halophenyl, phenylC i_6alkyl, phenylC i-6alkyl-O-, phenylC i-6alkyl-O-C ⁇ _6alkyl; R2, and R3 are each independently hydrogen, OH, -O-
  • R2 and R3 together form O;
  • R4, R41 ; R42 ; and R43 are each independently -CN, hydrogen, bromo, chloro, fluoro, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, amino, nitro, Ci_6alkyl, aryl, R8SO2NH-, or -CHO;
  • R-5 and R5 are each independently hydrogen, chloro, amino, phenyl, aryl, C ⁇ _6alkylamino, C ⁇ _6alkyl(Ci-6alkyl)amino, or arylamino;
  • R8 is C ⁇ -.6alkyl, phenyl, or heterocyclic;
  • R9 and RlO are each independently hydrogen, C ⁇ _6alkyl group, C3_7cycloalkyl group, aryl group, or heterocylic group each group optionally substituted with one to five substituents, each substituent independently being Ci_ 6alkoxy, -N(C ⁇ -6alkyl)(C ⁇ -6 lkyl), or C3_7cycloalkyl; and X is O.
  • the compound of the invention is represented by Formula (III), or pharmaceutically acceptable salts thereof, wherein Rl is hydrogen, CI, or Ci_6alkyl group, C2-6alkenyl group, C2-6alkynyl group, C3_8cycloalkyl group, aryl group, heteroaryl group, heterocyclic group, or NR9R10 group; each group optionally substituted with one to five substituents, each substituent independently being halogen, -CN, Ci-6alkyl, hydroxyCi-6alkyl, haloCi- ⁇ alkyl, C ⁇ _6alkoxy, -CHO, C3_6cycloalkenyl, Ci_6alkyl- S-, -NH2, -C(O)NH2, phenyl, halophenyl, phenylC i_6alkyl, phenylC ⁇ _6alkyl-O-, phenylC i _6alkyl-O-
  • R4, R41 5 R42 5 and R43 are each independently -CN, hydrogen, bromo, chloro, fluoro, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, amino, nitro, Ci-6al yl, aryl, R8SO2NH-, or -CHO;
  • R-5 and R55 are each independently hydrogen, chloro, amino, phenyl, aryl, C ⁇ _6alkylamino, C ⁇ _6alkyl(Ci_6alkyl)amino, or arylamino;
  • R8 is Ci- ⁇ alkyl, phenyl, or heterocyclic
  • R9 and RlO are each independently hydrogen, Ci-6alkyl group, C3_7cycloalkyl group, aryl group, or heterocylic group each group optionally substituted with one to five substituents, each substituent independently being Ci- 6alkoxy, -N(C ⁇ -6 a lkyl)(C ⁇ -6 a lkyl), or C3_7cycloalkyl; and
  • X is CH2.
  • 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- tetrahydronaphalene 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.
  • aryl includes phenyl and napthyl.
  • heteroaryl includes pyridyl, thiazolyl, thiophenyl, furanyl, terazolyl, and isoquinolinyl. Generally, heteroaryls are connected through a carbon unless the nomenclature indicates otherwise (such as N-, or N-yl). Substituents on heteroaryls can be attached to the hetero ring atom as well as to the carbon ring atoms.
  • heterocyclic includes piperidinyl, piperidin-N-yl, perhydroazepinyl, perhydroazepin-N-yl, pyrrolidinyl, pyrrolidin-N-yl, piperazinyl, piperazin-N-yl, morpholinyl, morpholin-N-yl, oxazin-N-yl, tetrahydropyridyl, l-azabicyclo[2.2.2]octenyl, and l-aza[1.1.3]octan-N-yl.
  • a pyridyl nitrogen includes the ⁇ -oxide form.
  • carbonyl and aminocarbonyl include short C1-C2 termini.
  • the terms include, for example, -CH2CO ⁇ H-, -CH2CO-, -C2H4CONHCH2-, and -CH2COC2H4-.
  • carboxylate is used to include -NHCOOCi-C4alkyl, and -OCONHCj . -C4alkyl.
  • amino refers to -N(Co-C4alkyl) (C 0 -C 4 alkyl).
  • halogen includes fluorine, chlorine, bromine and iodine atoms.
  • C0-C5 means that there are from none to five carbons present - that is, five, four, three, two, one, or no carbons present.
  • a bridging alkyl without a carbon present is a direct bond.
  • a terminal alkyl without a carbon present is a hydrogen.
  • optionally substituted is intended to include both substituted and unsubstituted.
  • optionally substituted aryl could represent a pentafluorophenyl or a phenyl ring.
  • substitution may be at any site as determined by a chemist. That is, substituted alkylaryl may be substituted at the alkyl, the aryl, or at both. If substitution is limited, such limitation will be stated as in, for example, "alkylaryl substituted at the alkyl” is not substituted at the aryl.
  • 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 and Formula D are shown without a definitive stereochemistry at certain positions.
  • the present invention includes all stereoisomers of Formula I and Formula D or 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 represented by Formula I, Formula It, or Formula HI (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 represented by Formula I, Formula D, or Formula ID, or pharmaceutically acceptable salts thereof, of this invention 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 compound represented by Formula I, Formula E, or Formula DI, 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.
  • 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.
  • the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of Formula I, Formula ⁇ , or Formula HI.
  • the compounds of Formula Formula I, Formula -3, or Formula IE, 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 lmg to about 500mg of the active ingredient and each cachet or capsule preferably containing from about 1 to about 500mg of the 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.
  • compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.
  • the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
  • 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.
  • 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 represented by Formula I or Formula H 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.
  • 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
  • NR1A/2B receptor transfected L(tk) cells are plated in 96-well format at 3 x 10 6 cells per plate and grown for one - two days in normal growth media
  • NRlA/2B-expression in these cells is induced by the addition of 4nM dexamethasone in the presence of 500 ⁇ M ketamine for 16 - 24 hours. After receptor induction cells are washed using a Labsystem Cellwasher two times with assay buffer (Hanks balanced salt solution (HBSS-Mg ++ free) containing 20mM HEPES, 0.1% BSA, 2mM CaCl 2 and 250 ⁇ M probenecid).
  • assay buffer Hanks balanced salt solution (HBSS-Mg ++ free) containing 20mM HEPES, 0.1% BSA, 2mM CaCl 2 and 250 ⁇ M probenecid).
  • the cells of each 96 well cell plate are loaded with the Ca ++ sensitive dye Fluo-3 (Molecular Probes, Inc.) at 4 ⁇ M in assay buffer containing 0.5% FBS, and 0.04% pluronic F-127 (Molecular Probes, Inc.) for lh at 37 °C avoiding light.
  • the cells are then washed with the Cellwasher four times with assay buffer leaving them in 1 OO ⁇ l buffer.
  • Test compounds in solution are pipetted by FLIPR (Fluorometric Imaging Plate Reader) into each test well for a 2min pretreatment. During this time the fluorescence intensity is recorded (excitation at 488nm and emission at 530nm).
  • the glutamate/glycine 50 ⁇ L agonist solution (final concentration l ⁇ M/l ⁇ M) is then added by FLIPR into each well already containing 150 ⁇ L of buffer (containing the test compound or vehicle) and the fluorescence is continuously monitored for lOmin.
  • the endpoint fluorescence values are used to determine an IC 50 value comparing the agonist-stimulated signal for the vehicle alone sample and that for the cells incubated with each concentration of test compound. Determining the Apparent Dissociation Constant (Ki) of Compounds for Human NR1A/NR2B Receptors (Binding Assay):
  • the radioligand binding assay is performed at room temperature in 96-well microtiter plates with a final assay volume of l.OmL in 20mM Hepes buffer (pH 7.4) containing 150mM NaCI. Solutions of test compounds were prepared in DMSO and serially diluted with DMSO to yield 20 ⁇ L of each of 10 solutions differing by 3-fold in concentration. Non-specific binding (NSB) using hot AMD-1 (lO ⁇ M final concentration) and total binding (TB) by using DMSO (2% final concentration). A solution of NR1 A/NR2B receptors (40pM final concentration) and tritiated AMD-2 (InM final concentration) were added to the test compounds.
  • Kp is the apparent dissociation constant for the radioligand for the receptor as determined by hot saturation and SB is the specifically bound CPM determined from the difference of TB and NSB .
  • Tritiated AMD-1 was prepared by the following procedure: A mixture of AMD-1, hydrochloride salt, (5mg, 0.012mmol) in dioxane (0.2mL) containing triethylamine (4 ⁇ L) was treated with hexamethylditin (5 ⁇ L), a catalytic amount of palladium catalyst and heated at 100°C for 45 minutes. The reaction was cooled to room temperature, filtered through a glass wool plug, rinsed with methanol and concentrated in vacuo to give 10.7mg of a brown oil. The oil was dissolved in methylene chloride and passed through a small silica column eluting with methylene chloride followed by 5% methanol/methylene chloride.
  • Tritiated AMD-2 was prepared by the following procedure: The phenol of AMD-2 (2mg, 0.008mmol) dissolved in dimethylformamide (0.6mL) and potasium carbonate (1.2mg) for lhr. High specific activity tritiated methyl iodide (50mCi, 0.0006mmol, in toluene ImL, American Radiolabeled Chemicals) was added at room temperature and stirred for 2 hours. The reaction mixture was filtered using a Whatman PTFE 0.45 ⁇ m syringeless filter device to remove any insoluable potassium carbonate, washed with Abs.
  • the compounds of this invention exhibit 25 ⁇ M or less in the FLIPR and binding assays. It is advantageous that the compounds of this invention exhibit less than 5 ⁇ M in the FLIPR and binding assays. It is still more advantageous that the compounds of this invention exhibit less than l ⁇ M in the FLIPR and binding assays. It is most advantageous that the compounds of this invention exhibit less than 0.05 ⁇ M in the FLIPR and binding assays.
  • the compounds and pharmaceutical compositions of this invention have been found to exhibit biological activity as NMDA NR2B antagonists. Accordingly, another aspect of the invention is the treatment of pain, migraine, depression, anxiety, schizophrenia, Parkinson's disease, or stroke - maladies that are amenable to amelioration through inhibition of NMDA NR2B receptors - by the administration of an effective amount of the compounds of this invention.
  • Examples 1 and 3 were prepared by the following procedure: COMPOUND 11: (Dimethylamino-phenyl-allylidene)-dimethyl-ammonium; perchlorate
  • COMPOUND 13 2-Methyl-5-phenyl-nicotinic acid hydrochloride
  • COMPOUND 14 2-Methyl-5-phenyl-nicotinic acid methyl ester hydrochloride
  • COMPOUND 15 2-[2-(2-Bromo-phenyl)-vinyl]-5-phenyl-nicotinic acid hydrochloride
  • Example 3 A suspension of Example 3 (50mg, 0.137mmol), zinc (22mg, 0.343mmol) and acetic acid (0.5mL) was heated at reflux for 24h. The solvent was removed in vacuo and saturated sodium bicarbonate was added. The resulting suspension was extracted with methylene chloride (4x). The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (gradient, 100% hexane to hexane:ethyl acetate 50:50). Trituration with hexane/ether gave Example 1 as a white solid. 1H NMR (CDC1 3 , 400MHz) ⁇ 8.74 (d, IH); 7.79 (m, IH); 7.62-7.24 (m, 9H); 7.16 (m, IH), 3.80 (s, 2H).
  • Examples 9-13 were prepared by procedures similar to that described for Example 3. These Examples are summarized in Table 2 below.
  • EXAMPLE 10 3-Phenvl-5H-benzor4.51cvcloheptan,2-blpvridine-9-carbonitrile
  • EXAMPLE 11 3-Phenyl-10,ll-dihydro-5H-benzo[4,5]cyclo hepta[l,2- b]pyridine-9-carbonitrile
  • Aqueous lithium hydroxide (1M, 0.676mL, 0.676mmol) was added to a methanol (15mL) solution of EXAMPLE 12 (250mg, 0.676mmol) under nitrogen. After lh, the mixture was concentrated in vacuo and water was added. The mixture was extracted with methylene chloride (3x). The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. A white solid remained which was added to ethyl acetate (lOOmL). To this was added IN hydrogen chloride/ether (4ml). After lOrnin the solvent was removed in vacuo and the remaining residue was triturated with ether to give EXAMPLE 13 as a white solid.
  • Zinc (600mg, 9.23mmol) was added to an acetic acid (lOmL) solution of EXAMPLE 12 (357mg, 0.965mmol) under nitrogen and the resulting suspension was heated to reflux for 6h. The acetic acid was removed in vacuo and sat. sodium bicarbonate was added to the residue. The mixture was extracted with ethyl acetate (3x) and the combined organic extracts were dried with sodium sulfate, filtered and concentrated. The crude product was purified y silica gel chromatography (gradient, hexane:ethyl acetate 90: 10 to 50:50) to afford a white foam.
  • Examples 30-55 were prepared using an approach similar to that described for EXAMPLE 13. These Examples are summarized in Table 5 below.
  • EXAMPLE 57 was prepared via the procedure for EXAMPLE 56 except using Intermediate 11 instead of Intermediate 10. MS m/z 369.22 (MET 1" )
  • EXAMPLE 58 was prepared via the procedure for EXAMPLE 56 except using Intermediate 12 instead of Intermediate 10. MS m/z 369.22 (MH0)
  • EXAMPLE 59 was prepared from EXAMPLE 56 using an approach like that described for EXAMPLE 13. MS m/z 327.23 (ME0)
  • EXAMPLE 60 was prepared from EXAMPLE 57 using an approach like that described for EXAMPLE 13. MS m/z 327.23 (MET 1" )
  • EXAMPLE 61 was prepared from EXAMPLE 58 using an approach like that described for EXAMPLE 13.
  • Examples 62-82 were prepared using an approach similar to that described for EXAMPLE 14. These substances are summarized in Table 6 below.
  • Examples 89-97 were prepared using an approach similar to that described for EXAMPLE 85. These Examples are summarized in Table 8 below.
  • EXAMPLE 98 was prepared from EXAMPLE 85 using an approach like that described for EXAMPLE 9. MS m/z 360.36 (MH*)
  • EXAMPLE 99 was prepared from EXAMPLE 98 using an approach like that described for EXAMPLE 10. MS m/z 302.32 (MfT) EXAMPLE 100 to EXAMPLE 102 were prepared according to Scheme 10 below:
  • EXAMPLE 102 4-Chloro-3 -phenyl- 10, 1 l-dihydro-5H- benzo[4,5]cyclohepta[l,2-b]pyridine-9-carbonitrile: 1H NMR (300 MHz, CDC1 3 ) ⁇ 8.30 (s, IH), 7.60-7.20 (m, 8 H), 4.42 (s, 2 H), 3.50 (m, 4 H) ppm. Mass spectrum m/z 331.34 [(M+H) + ,C 21 H 16 N 2 CTJ.
  • EXAMPLE 103 4-Phenyl-6,10b-dihydro-laH- benzo[4,5joxireno[6,7]cyclohepta[l,2-b]pyridine-10-carbonitrile.
  • EXAMPLE 104 was prepared via the procedure for Intermediate 18 except starting with EXAMPLE 10 instead of EXAMPLE 11.
  • EXAMPLE 105and Intermediate 20 were prepared via a similar procedure used for EXAMPLE 102 and Intermediate 19 except staring with EXAMPLE 104 instead of Intermediate 18.
  • EXAMPLE 105 4-Chloro-3-phenyl-5H-benzo[4,5]cyclohepta[l,2-b]pyridine-9- carbonitrile: 1H NMR (300 MHz, CDC1 3 ) ⁇ 8.40 (s, IH), 7.70-7.40 (m, 10 H), 4.01 (s, 2 H) ppm. Mass spectrum m/z 329.42 [(M+H) + ,C 21 Hi 4 N 2 Cl].
  • m-Chloroperoxybenzoic acid (627mg, 3.63mmol) was added to a stirred solution of pyridine Intermediate 21 (400mg, 1.82mmol) in 70mL of dichloromethane under nitrogen. After lh, lOOmL of sat'd sodium bicarbonate solution was added, the organic layer separated and the resulting aqueous layer was extracted 2x75mL dichloromethane. The combined organic extracts were dried with magnesium sulfate (anh.), filtered, and evaporated in vacuo to yield a white solid.
  • N-oxide Intermediate 22 (309mg, 1.31mmol) was added to phosphorous oxychloride (15mL) and heated at 90°C under nitrogen for 2h, and 18h at 25°C. Ice and 500mL sat'd sodium bicarbonate solution were slowly added and the solution was extracted with 2x200mL of dichloromethane. The combined organic extracts were dried with magnesium sulfate (anh.), filtered and evaporated in vacuo to yield a white solid. The product was pre-absorbed on silica and purified by flash column chromatography (ethyl acetate:hexanes 1:20 to 1:1), yielding a white solid of desired product Intermediate 23 and the 2-chloro isomer as a minor product.
  • Step 4 EXAMPLE 106: 4-Phenethylamino-10,ll-dihydro-5H- benzo[4,5]cyclohepta[l,2-b]pyridine-9-carbonitrile.
  • EXAMPLE 107 4-(3-Phenyl-propylamino)-10,ll-dihydro-5H- benzo[4,5]cyclohepta[l,2-b]pyridine-9-carbonitrile.
  • Example 110 Example 111
  • EXAMPLE 109 2-Indol-l-yl-3-phenyl-10,ll-dihydro-5H- benzo[4,5]cyclohepta[l,2-b]pyridine-9-carbonitrile.
  • EXAMPLE 110 4-(2.6-Dimethoxv-benzvIamino)-3-phenvl-10,ll-dihvdro-5H- benzo[4,5]cyclohepta[l,2-b]pyridine-9-carbonitrile.
  • EXAMPLE 111 4-Amino-3-phenyl-10,ll-dihydro-5H-benzo[4,5]cyclohepta[l,2- b]pyridine-9-carbonitrile.
  • EXAMPLE 110 To a stirring solution of EXAMPLE 110 in 5mL of dichloromethane was added trifloroacetic acid. The solution was stirred 30min then basified with sat'd sodium bicarbonate, the organic layer was separated, dried with magnesium sulfate, filtered and evaporated to a yellow oil. Purification by flash column chromatography (dichloromethane to dichloromethane:methanol:ammonium hydroxide, 80:20:1) and evaporation of solvents in vacuo yielded EXAMPLE 111 as a yellow solid. MS: 312.35 m/z.
  • Lithium aluminum hydride solution (l.OM in THF, 0.81mL, 0.81 mmol) was added in a slow stream to a THF solution of EXAMPLE 6 (50mg, 0.16 mmol) at -78°C under a nitrogen atmosphere. After 0.5h the reaction flask was warmed to 0°C and aged 18h. The contents of the reaction flask were quenched with water and extracted with methylene chloride (3 x 50mL). The combined organic extracts were washed with brine and dried with sodium sulfate. Flash column chromatography (methylene chloride:methanol:ammonium hydroxide 98:2:0.2) gave after trituration with methanol EXAMPLE 112 as a yellow solid.
  • EXAMPLE 101 A solution of EXAMPLE 101 (50.0mg, O.l ⁇ Ommol), diethyl azodicarboxylate (0.025mL, 0.160mmol), triphenylphosphine (46mg, 0.176mmol), diphenylphosphoryl azide (0.038mL, 0.176mmol) and THF (ImL) was stirred 24h under Nitrogen. The contents of the reaction flask were poured into water. Extracted with methylene chloride (4x); dried with sodium sulfate, filtered. Removal of the solvent in vacuo followed by Gilson reverse phase preparative HPLC gave EXAMPLE 116 as a white foam.
  • EXAMPLE 116 (lO.Omg, 0.029mmol), triphenylphosphine (9.0mg, 0.032mmol), THF (0.5mL) and water (0.5mL) were combined under Nitrogen and stirred at rt 48h. To this was added aqueous sodium hydroxide and methanol. After 2h the contents of the reaction flask were evaporated in vacuo and the remaining residue was subjected to Gilson reverse phase preparative HPLC to give EXAMPLE 117 as a white solid. MS ESI m/z [M+H] + 312.25
  • EXAMPLE 118 (50 mg, 0.167 mmole) was dissolved in 0.5 M sodium methoxide (l.lmL) and allowed to stir at rt for 5min. 4- Toluenesulfonylmethylisocyanide (40mg, 0.20mmole) was added and the mixture stirred at 40°C for 3h. The reaction was diluted with water (20mL) and extracted with ethyl acetate (30mL). The ethyl acetate extract was dried over sodium sulfate, filtered, concentrated and chromatographed on silica using 30-100% ethyl acetate/hexane to give EXAMPLE 119 as a foam. M.S.(M+1): 339.
  • EXAMPLE 120 2,2-Dimethyl-propionic acid 9-cyano-3-phenyl-5H- benzo[4,5]cyclohepta[l,2-b]pyridin-5-yl ester.
  • EXAMPLE 122 6-Chloro-5-hvdroxv-3-phenvl-5H-benzor4,51cycloheptan,2- b]pyridine-9-carbonitrile.
  • EXAMPLE 123 was prepared according to the procedure for preparing EXAMPLE 12 except using Intermediate 25 instead of Example 23. MS m/z 311.3 (Mtf)
  • EXAMPLE 124 was prepared from EXAMPLE 101 using an approach like that described for EXAMPLE 13. MS m/z 313.28 (MH + )
  • Oxalyl chloride (31 ⁇ L, 0.353mmol) was added to methylene chloride (4mL) and cooled under nitrogen to -70°C. To this was added a solution of DMSO (60 ⁇ L, 0.847mmol) in methylene chloride. After lOmin. a solution of EXAMPLE 124 (lOOmg, 0.321mmol) in methylene chloride was added. After lOmin. triethylamine (223 ⁇ L, l. ⁇ lmmol) was added and the reaction was warmed to it. Water and 5% potassium bisulfate were added and the layers were separated.
  • EXAMPLE 125 (5rng, O.Ol ⁇ rnrnol), methanol (50 ⁇ L) and (trimethylsilyl)diazomethane (2.0M in hexane, lOO ⁇ L) were combined and stirred 24h under nitrogen. The contents of the reaction flask were quenched with 6N hydrochloric acid, evaporated and subjected to Gilson reverse phase preparative HPLC to give EXAMPLE 126 as a yellow solid. MS m/z 325.25 (MH " )

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Abstract

L'invention concerne des benzo[4,5]cyclohepta[1,2-b]pyridines représentées par la formule (I), ou des sels pharmaceutiquement acceptables desdits composés, efficaces comme antagonistes de NMDA NR2B destinés à atténuer la douleur.
PCT/US2003/009689 2002-04-02 2003-03-28 Antagonistes 5h-benzo[4,5]cyclohepta[1,2-b]pyridines de nmda/nr2b WO2003084931A1 (fr)

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WO2007002258A2 (fr) * 2005-06-23 2007-01-04 Merck & Co., Inc. Inhibiteurs de tyrosine kinase
WO2007002254A3 (fr) * 2005-06-23 2007-05-18 Merck & Co Inc Benzocycloheptapyridines utilises comme inhibiteurs de la tyrosine kinase receptrice met
EP1951252A2 (fr) * 2005-10-21 2008-08-06 Merck & Co., Inc. Inhibiteurs des tyrosine kinases
JP2009173622A (ja) * 2006-07-10 2009-08-06 Merck & Co Inc チロシンキナーゼインヒビター
US7790739B2 (en) 2005-10-21 2010-09-07 Merck & Co., Inc. and Merck Sharp & Dohme Corp. Tyrosine kinase inhibitors
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CN101203495B (zh) * 2005-06-23 2013-07-17 默沙东公司 作为受体酪氨酸激酶met抑制剂的苯并环庚三烯并吡啶化合物
WO2013156614A1 (fr) 2012-04-20 2013-10-24 Ucb Pharma S.A. Méthodes de traitement de la maladie de parkinson
US8674105B2 (en) 2009-09-30 2014-03-18 Merck Sharp & Dohme Limited Crystalline hydrochloride salts of c-Met kinase inhibitors
US9238571B2 (en) 2009-09-30 2016-01-19 Merck Sharp & Dohme Limited Formulations for c-Met kinase inhibitors

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007002258A2 (fr) * 2005-06-23 2007-01-04 Merck & Co., Inc. Inhibiteurs de tyrosine kinase
WO2007002254A3 (fr) * 2005-06-23 2007-05-18 Merck & Co Inc Benzocycloheptapyridines utilises comme inhibiteurs de la tyrosine kinase receptrice met
WO2007002258A3 (fr) * 2005-06-23 2007-06-07 Merck & Co Inc Inhibiteurs de tyrosine kinase
JP2008156336A (ja) * 2005-06-23 2008-07-10 Merck & Co Inc チロシンキナーゼインヒビター
CN101203495B (zh) * 2005-06-23 2013-07-17 默沙东公司 作为受体酪氨酸激酶met抑制剂的苯并环庚三烯并吡啶化合物
US7550478B2 (en) 2005-06-23 2009-06-23 Merck & Co. Inc. Tyrosine kinase inhibitors
US8207186B2 (en) 2005-06-23 2012-06-26 Merck Sharp & Dohme Corp. Benzocycloheptapyridines as inhibitors of the receptor tyrosine kinase MET
US7790739B2 (en) 2005-10-21 2010-09-07 Merck & Co., Inc. and Merck Sharp & Dohme Corp. Tyrosine kinase inhibitors
EP1951252A4 (fr) * 2005-10-21 2010-03-17 Merck Sharp & Dohme Inhibiteurs des tyrosine kinases
EP1951252A2 (fr) * 2005-10-21 2008-08-06 Merck & Co., Inc. Inhibiteurs des tyrosine kinases
US8101603B2 (en) 2006-07-10 2012-01-24 Merck Sharp & Dohme Corp. Tyrosine kinase inhibitors
JP2009173622A (ja) * 2006-07-10 2009-08-06 Merck & Co Inc チロシンキナーゼインヒビター
US8222269B2 (en) 2006-07-10 2012-07-17 Merck Sharp & Dohme Corp. Tyrosine kinase inhibitors
US7893081B2 (en) 2007-12-20 2011-02-22 Merck & Co., Inc. Tyrosine kinase inhibitors
US8674105B2 (en) 2009-09-30 2014-03-18 Merck Sharp & Dohme Limited Crystalline hydrochloride salts of c-Met kinase inhibitors
US9238571B2 (en) 2009-09-30 2016-01-19 Merck Sharp & Dohme Limited Formulations for c-Met kinase inhibitors
WO2013156614A1 (fr) 2012-04-20 2013-10-24 Ucb Pharma S.A. Méthodes de traitement de la maladie de parkinson

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