WO1997030054A1 - Pharmaceutically active compounds and methods of use - Google Patents

Pharmaceutically active compounds and methods of use Download PDF

Info

Publication number
WO1997030054A1
WO1997030054A1 PCT/US1997/002678 US9702678W WO9730054A1 WO 1997030054 A1 WO1997030054 A1 WO 1997030054A1 US 9702678 W US9702678 W US 9702678W WO 9730054 A1 WO9730054 A1 WO 9730054A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
unsubstituted
carboximidamide
carbon atoms
indolinyl
Prior art date
Application number
PCT/US1997/002678
Other languages
French (fr)
Inventor
N. Laxma Reddy
Michael Maillard
David Berlove
Sharad Magar
Graham J. Durant
Original Assignee
Cambridge Neuroscience, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cambridge Neuroscience, Inc. filed Critical Cambridge Neuroscience, Inc.
Priority to JP9529602A priority Critical patent/JP2000504730A/en
Priority to EP97906923A priority patent/EP0925300A1/en
Priority to AU22780/97A priority patent/AU733475B2/en
Publication of WO1997030054A1 publication Critical patent/WO1997030054A1/en
Priority to US09/425,582 priority patent/US6358993B1/en
Priority to US10/038,178 priority patent/US6514990B2/en
Priority to US10/321,402 priority patent/US6770668B2/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/90—Benzo [c, d] indoles; Hydrogenated benzo [c, d] indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/90—Benzo [c, d] indoles; Hydrogenated benzo [c, d] indoles
    • C07D209/92—Naphthostyrils
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/08—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms with acylated ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • 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
    • C07D221/10—Aza-phenanthrenes
    • C07D221/12—Phenanthridines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
    • C07D225/04—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D225/08—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/16—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to pharmaceuticially active compounds, including certain substituted indolinyl (and derivatives thereof), 1,2,3,4-tetrahydroquinolinyl (and derivatives thereof), 1,2,3,4-tetrahydroisoquinolinyl, benz[cd] indolinyl and 5,6-dihydrophenanthridinyl compounds, and methods of treatment and pharmaceutical compositions that utilize or comprise one or more such compounds.
  • Compounds of the invention are particularly useful for the treatment or prophylaxis of neurological injury and neurodegenerative disorders.
  • Nerve cell death can cause potentially devastating and irreversible effects for an individual and may occur e.g. as a result of stroke, heart attack or other brain or spinal chord ischemia or trauma. Additionally,
  • nerve cell death such as nerve cell death
  • Alzheimer's disease Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, Down's Syndrome and Korsakoff s disease.
  • MK-801 has exhibited good results in a variety of in vivo models of stroke. See B. Meldrum, Cerbrovascular Brain Metab. Rev. , 2:27-57 (1990); D. Choi, Cerbrovascular Brain Metab. Rev. , 2: 105-147 (1990). See also Merck Index, monograph 3392, 11th ed., 1989.
  • MK-801 exhibits good activity in mouse audiogenic tests, a recognized model for evaluation of
  • MK-801 also has shown toxicity and further clinical development of the compound is currently uncertain. See J. W. Olney et al., Science, 244: 1360-1362 (1989); W. Koek et al., J. Pharmacol. Exp. Ther. , 252:349-357 (1990); F.R. Sharp et al. , Society for Neuroscience Abstr. , abstr. no. 482.3 (1992).
  • neurodegeneration such as may occur with stroke, heart attack or brain or spinal cord trauma, or to treat neurodegenerative disorders such as Alzheimer's disease,
  • Parkinson's disease Huntington's disease, Amyotrophic Lateral Sclerosis, Down's Syndrome and Korsakoffs disease.
  • the present invention provides substituted indolinyl and indolinyl derivative compounds of the following Formula I:
  • R and R 1 are each independently hydrogen; substituted or
  • each R 2 and each R 3 are each independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or
  • unsubstituted alkenyl having from 2 to about 20 carbon atoms substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms, or substituted or unsubstituted aralkyl having at least about 6 ring carbon atoms;
  • X is substituted or unsubstituted methylene (-CH 2 -), -S- (i.e. 3-benzothiazolinylcarboximidamide compounds), -O- or substituted or unsubstituted -N-, and preferably is substituted or unsubstituted methylene;
  • n 0, 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
  • the invention provides compounds of the following
  • R and R 1 are each independently hydrogen; substituted or
  • each R 2 i.e. substituent of the 2 and 3 ring positions
  • each R 3 i.e.
  • substituent of the 5, 6, 7 and 8 aromatic ring positions are each independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 6 ring
  • X is -O- (i.e. 2,3-benzmorpholinyl compounds), -S- (i.e. 2,3-benzthiomorpholinyl compounds), substituted or unsubstituted -N-, or substituted or unsubstituted methylene (-CH r );
  • n and n are each independently 0 (i.e. the available ring are each hydrogen-substituted), 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
  • the invention provides tetrahydroisoquinolinyl compounds of the following Formula III:
  • R and R 1 are each independently hydrogen; substituted or
  • each R 2 (i.e. substituent of the 1, 3 and 4 tetrahydroisoquinolinyl ring positions) and each R 3 (i.e. substituent of the 5, 6, 7 and 8 tetrahydroisoquinolinyl ring positions) are each independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1
  • n 0 (i.e. the 5, 6, 7 and 8
  • tetrahydroisoquinolinyl ring positions are each hydrogen-substituted), 1 , 2, 3 or 4; and pharmaceutically acceptable salts thereof.
  • R and R 1 are each independently hydrogen; substituted or
  • each R 2 and each R 3 are each independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having
  • n 0 (i.e. the available ring are each hydrogen-substituted), 1, 2, 3, 4, 5 or 6; and pharmaceutically acceptable salts thereof.
  • R and R 1 are each independently hydrogen; substituted or
  • each R 4 i.e. substituent of the aromatic positions 7-10 are each independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted
  • n and r are each independently 0 (i.e. the ring positions are each hydrogen-substituted), 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
  • R, R 1 , X, R 2 , R 3 and n are the same as defined above for Formula II, but where X can also be sulfinyl (i.e.-S(O)-) or sulfonyl (i.e. -S(O 2 )-), and m of Formula VI is an integer equal to 0-6, and preferably m is 0, 1 or 2; and
  • R, R 1 , R 2 , R 3 and m are the same as defined above for Formula IV, and n of Formula VII is an integer equal to 0-9, and preferably n is 0, 1 or 2; and pharmaceutically acceptable salts thereof. It is understood that an R 3 substituent can be the same or different and may be present on either the non-aromatic or aromatic fused ring. Preferred substituents of Formula IV also will be preferred substituents at corresponding positions of compounds of Formula VI.
  • the invention also provides compounds of the following Formula VIII:
  • R, R 1 , R 2 , R 3 , n and r are the same as defined above for Formula V, except R and R 1 each may be hydrogen, although preferably at least one of R and R 1 will be other than hydrogen, and m of Formula VIII is an integer equal to 0-4, and preferably m is 0, 1 or 2, and the dotted line in Formula VIII represents an optional carbon-carbon double bond (endocyclic bond); and pharmaceutically acceptable salts thereof.
  • Preferred substituents of Formula V also will be preferred substituents at corresponding positions of compounds of Formula VIII.
  • the invention also provides compounds of the following Formula IX: wherein R 2 , R 3 , n and r are the same as defined above for Formula V; R and
  • R 1 are also the same as defined above for Formula V, except R and R 1 each may be hydrogen, although preferably at least one of R and R 1 will be other than hydrogen; m of Formula IX is an integer equal to 0-6 (i.e. R 2 may be a substituent at any of the available three saturated ring positions), and preferably m is 0, 1 or 2
  • R and R 1 are a carbocyclic aryl, aralkyl, or heteroaromatic or heteroalicyclic group, particularly substituted or unsubstituted phenyl or naphthyl. More preferably, for each of Formulae I through IX (which includes Formulae I" and II"), R is a carbocyclic aryl, heteroaromatic or heteroalicyclic group, and R 1 is a non-aryl group, particularly hydrogen or substituted or unsubstituted alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, or aminoalkyl. Substimted or unsubstituted phenyl or naphthyl are preferred R groups of Formulae I through IX (including Formulae I" and II"). Generally more preferred R 1 groups are hydrogen and substituted or
  • unsubstituted alkyl such as substituted or unsubstituted alkyl having 1 to about 6 carbon atoms or 1 to about 3 carbon atoms.
  • the compounds of the invention i.e. compounds of Formulae I, II, III, IV and V as well as compounds of Formulae I', I" , la, laa, lb, II", IIa, IIaa, IIb, IIIa, IIIaa, IIIb, IVa, IVaa, IVb, Va, Vaa and Vb as discussed below, and as well as compounds of Formulae VI, VII, VIII and IX above
  • the invention includes methods for treatment and/or prophylaxis of neurological conditions/injuries such as epilepsy, neurodegenerative conditions and/or nerve cell death (degeneration) resulting from e.g.
  • the compounds of the invention are especially useful for treatment of a person susceptible or suffering from stroke or heart attack or neurological deficits relating to cardiac arrest, a person suffering or susceptible to brain or spinal cord injury, or a person suffering from the effects of retinal ischemica or
  • Compounds of the invention also are useful to treat and/or prevent various neurodegenerative diseases such as Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, Alzheimer's disease, Down's Syndrome, Korsakoff s disease, cerebral palsy and/or age-dependent dementia.
  • Compounds of the invention will be further useful to treat and/or prevent migraines, shingles (herpes zoster), epilepsy, emesis and/or narcotic withdrawal symptoms.
  • the treatment methods of the invention in general comprise administration of a therapeutically effective amount of one or more compounds of the invention to an animal, including a mammal, particularly a human.
  • Particularly preferred compounds of the invention exhibit good activity in an anticonvulsant in vivo mouse audiogenic assay e.g. as disclosed in Example 48 which follows, preferably about 20% or more inhibition at a dose of a compound of the invention of 20 mg/kg, more preferably about 50% or more or 70% or more inhibition at a dose of 20 mg/kg in such an anticonvulsant in vivo audiogenic assay.
  • the invention also provides pharmaceutical compositions that comprise one or more compounds of the invention and a suitable carrier for the compositions.
  • preferred compounds of Formula I include those where the group X is substituted or unsubstituted methylene, i.e. indolinyl compounds of the following Formula I':
  • R, R 1 , R 2 , R 3 and n are each the same as defined above for Formula I; m is 0, 1 , 2, 3 or 4; and pharmaceutically acceptable salts thereof.
  • Preferred compounds of Formula I as defined above include those where R is substituted or unsubstituted carbocyclic aryl, particularly substituted or unsubstituted phenyl, naphthyl and acenaphthyl.
  • Substimted and unsubstituted phenyl and naphthyl are particularly preferred R group of compounds of Formula I, such as compounds of the following Formulae la and Iaa:
  • each R" is independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl, substituted or
  • alkylsulfinyl substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, or substituted or
  • p is an integer of 0 (where the phenyl ring is fully hydrogen substituted), 1 , 2,
  • s is an integer of from 0 to 7, and more preferably is 0 (where the naphthyl ring is fully hydrogen- substituted), 1, 2, 3 or 4;
  • R 1 , R 2 , R 3 , X, m and n are each the same as defined above for Formula I; and pharmaceutically acceptable salts thereof.
  • Particularly preferred compounds of Formula la include those where p is 1 or greater, e.g. compounds that are substituted at the ortho, meta and/or para phenyl ring positions by R" group(s) other than hydrogen, or 2,5-phenyl ring substituted, 2,3,5-phenyl ring substituted or 2,4,5-phenyl ring substituted by R" groups other than hydrogen(s) such as halogen, substituted or unsubstituted alkyl having 1 to about 6 carbon atoms, substituted or unsubstituted alkoxy having 1 to about 6 carbon atoms, or substituted or unsubstituted alkylthio having 1 to about 6 carbon atoms.
  • Formula Iaa includes compounds that have either a 1-naphthyl or 2-naphthyl amino (-N(R')-) substituent, compounds having a 1-naphthyl group are generally more preferred.
  • Compounds of Formula Iaa that have a non-hydrogen R" substituent at the 4-naphthyl position are also particularly preferred.
  • Compounds of Formula I may suitably contain one or more indolinyl (or derivative) ring substituents, i.e. the sum of the values of m and n of Formula I is one or more. It is understood that references herein to "derivatives" of indolinyl compounds of Formula I refer to those compounds where the group X is other than substituted or unsubstituted methylene.
  • substituents such as compounds that contain 0 (i.e. ring position 2 is -CH 2 -) or 1 (i.e. ring position 2 is -CH 2 -) non-hydrogen R 2 substituents.
  • generally preferred compounds of Formula I' that include indolinyl ring substimtents contain no more than two or three non-hydrogen R 2 substitutents, such as compounds that contain 0 (i.e. each of ring positions 2 and 3 is -CH 2 -) or 1 (i.e. one indolinyl ring position is -CH 2 - and the other is -CH(R 2 )-) non-hydrogen R 2 substituents.
  • Generally preferred compounds of Formula I also include those that contain 0 (ring positions 4-7 each hydrogen substituted), and 1 or 2 R 3 ring substituents.
  • Preferred compounds of Formula I also include those compounds that are unsubstituted on the ring (each m and n as defined above for Formula I is 0), i.e. compounds of the following Formula lb:
  • R, R 1 and X are the same as defined above for Formula I; and pharmaceutically salts thereof.
  • the above noted preferred R and R 1 groups of Formula I are also preferred groups of compounds of Formula lb.
  • compounds of Formula I are provided, which is defined the same as Formula I above, but where X is sulfinyl (i.e.-S(O)-) or sulfonyl (i.e. -S(O 2 )-).
  • X is sulfinyl (i.e.-S(O)-) or sulfonyl (i.e. -S(O 2 )-).
  • Preferred substitutents of compounds of Formula I as noted herein are also preferred substituents for corresponding positions for compounds of Formula I".
  • Preferred compounds of Formula II include those where R is substituted or unsubstituted carbocyclic aryl such as substituted or unsubstituted phenyl, naphthyl or acenaphthyl, particularly substituted or unsubstituted phenyl or naphthyl, i.e.
  • each R" is independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl, substituted or
  • alkylsulfinyl substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, or substituted or
  • p is an integer of 0 (where the phenyl ring is fully hydrogen substituted), 1, 2, 3, 4 or 5, and more preferably is 1, 2 or 3;
  • s is an integer of from 0 to 7, and more preferably is 0 (i.e. where the naphthyl ring is fully hydrogen-substituted), 1, 2, 3 or 4;
  • R 1 , R 2 , R 3 , X, m and n are each the same as defined above for Formula II; and pharmaceutically acceptable salts thereof.
  • Particularly preferred compounds of Formula IIa include those where p is 1 or greater, e.g. compounds that are substituted at the ortho, meta and/or para phenyl ring positions by R" group(s) other than hydrogen, or 2,5-phenyl ring substituted, 2,3,5-phenyl ring substituted or 2,4,5-phenyl ring substituted by non-hydrogen R" groups such as halogen, substituted or unsubstituted alkyl having 1 to about 6 carbon atoms, substituted or unsubstituted alkoxy having 1 to about 6 carbon atoms, or substituted or unsubstituted alkylthio having 1 to about 6 carbon atoms.
  • Formula IIaa includes compounds that have either a 1-naphthyl or 2-naphthyl amino (-N(R 1 )-) substituent, compounds having a 1-naphthyl group are generally more preferred.
  • Compounds of Formula IIaa that have a non-hydrogen R" substituent at the 4-naphthyl position are also particularly preferred.
  • Compounds of Formula II may suitably contain one or more
  • tetrahydroquinolinyl (or derivative thereof) ring substituents i.e. the sum of the values of m and n of Formula II is one or more. It is understood that references herein to "derivatives" of tetrahydroquinolinyl compounds of Formula II refer to those compounds where the group X is other than substituted or unsubstituted methylene.
  • Generally preferred compounds of Formula II that include tetrahydroquinolinyl (or derivative thereof) ring substituents contain no more than about three non-hydrogen R 2 substituents, including compounds that contain 0 (i.e. each of
  • tetrahydroquinolinyl ring positions 2, 3 and 4 is -CH 2 -) or 1 (i.e. two ring positions is -CH 2 - and the other is -CH(R 2 )-) R 2 substituents.
  • preferred compounds also include those that contain 0 (ring positions 5-8 each hydrogen substituted), 1 or 2 non-hydrogen R 3 ring substituents.
  • Preferred compounds of Formula II also include those that are unsubstituted on the tetrahydroquinolinyl (or derivative thereof) ring, i.e. m and n or Formula II are each 0, particularly compounds of the following Formula lib:
  • R and R 1 are the same as defined above for Formula II;
  • compounds of Formula II are provided, which is defined the same as Formula II above, but where X is sulfinyl (i.e.-S(O)-) or sulfonyl (i.e. -S(O 2 )-).
  • Preferred substimtents of compounds of Formula II as noted herein are also preferred substituents for corresponding positions for compounds of Formula II".
  • Preferred compounds of Formula III include those where R is substituted or unsubstituted carbocyclic aryl such as substituted or unsubstituted phenyl, naphthyl or acenaphthyl, particularly substituted or unsubstituted phenyl or naphthyl, i.e.
  • each R" is independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted
  • alkylsulfinyl substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, or substituted or
  • p is an integer of 0 (where the phenyl ring is fully hydrogen substituted), 1, 2, 3, 4 or 5, and more preferably is 1, 2 or 3;
  • s is an integer of from 0 to 7, and more preferably is 0 (i.e. where the naphthyl ring is fully hydrogen-substituted), 1, 2, 3 or 4;
  • R 1 , R 2 , R 3 , m and n are each the same as defined above for Formula III; and pharmaceutically acceptable salts thereof.
  • Particularly preferred compounds of Formula IIIa include those where p is 1 or greater, e.g. compounds that are substituted at the ortho, meta and/or para phenyl ring positions by R" group(s) other than hydrogen, or 2,5-phenyl ring substituted, 2,3,5-phenyl ring substituted or 2,4,5-phenyl ring substituted by non-hydrogen R" groups such as halogen, substituted or unsubstituted alkyl having 1 to about 6 carbon atoms, substituted or unsubstituted alkoxy having 1 to about 6 carbon atoms, or substituted or unsubstituted alkylthio having 1 to about 6 carbon atoms.
  • Formula IIIaa includes compounds that have either a 1-naphthyl or 2-naphthyl amino (-N(R 1 )-) substituent, compounds having a 1-naphthyl group are generally more preferred.
  • Compounds of Formula IIIaa that have a nonhydrogen R" substituent at the 4-naphthyl position are also particularly preferred.
  • Compounds of Formula III may suitably contain one or more
  • tetrahydroisoquinolinyl ring substituents i.e. the sum of the values of m and n of Formula III is one or more.
  • tetrahydroisoquinolinyl ring substituents contain no more than about three nonhydrogen R 2 substituents, including compounds that contain 0 (i.e. each of tetrahydroisoquinolinyl ring positions 1, 3 and 4 is -CH 2 -) or 1 (i.e. two ring positions are -CH 2 - and the other is -CH(R 2 )-) non-hydrogen R 2 substituents.
  • Generally preferred compounds also include those that contain 0 (ring positions 5-8 each hydrogen substituted), 1 or 2 non-hydrogen R 3 ring substituents.
  • Preferred compounds of Formula III also include those that are unsubstituted on the tetrahydroisoquinolinyl ring, i.e. m and n or Formula III are each 0, particularly compounds of the following Formula IIIb:
  • R and R 1 are the same as defined above for Formula II;
  • Preferred compounds of Formula IV as defined above include those where R is substituted or unsubstituted carbocyclic aryl, particularly substituted or
  • Substimted and unsubstituted phenyl and naphthyl are particularly preferred R groups of compounds of Formula IV, such as compounds of the following Formulae IVa and IVaa:
  • each R" is independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted
  • alkylsulfinyl substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, or substituted or
  • p is an integer of 0 (where the phenyl ring is fully hydrogen substituted), 1, 2, 3, 4 or 5, and more preferably is 1, 2 or 3;
  • s is an integer of from 0 to 7, and more preferably is 0 (i.e. where the naphthyl ring is fully hydrogen-substituted), 1, 2, 3 or 4;
  • R 1 , R 2 , R 3 , m and n are each as defined above for Formula IV; and pharmaceutically acceptable salts thereof.
  • Preferred compounds of Formula IVa include those where p is 1 or greater, e.g. compounds that are substituted at the ortho, meta and/or para phenyl ring positions by R" group(s) other than hydrogen, or 2,5-phenyl ring substituted, 2,3,5-phenyl ring substituted or 2,4,5-phenyl ring substituted by non-hydrogen R" groups such as halogen, substituted or unsubstituted alkyl having 1 to about 6 carbon atoms, substituted or unsubstituted alkoxy having 1 to about 6 carbon atoms, or substituted or unsubstituted alkylthio having 1 to about 6 carbon atoms.
  • Compounds of Formula IV may suitably contain one or more benzindolinyl ring substituents, i.e. the sum of the values of m and n of Formula IV is one or more.
  • benzindolinyl ring substituents contain 0 R 2 substituents (i.e. the 2 benz[cd]indolinyl positions is -CH 2 -), or 1 non-hydrogen R 2 substiment.
  • Generally preferred compounds of Formula IV also include those that contain 0 (i.e. benz[cd]indolinyl ring positions 3-8 each hydrogen substituted), 1 or 2 R 3 ring substituents.
  • Preferred compounds of Formula IV also include those compounds that are unsubstituted on the benzindolinyl ring (each m and n as defined above for Formula IV is 0), i.e. compounds of the following Formula IVb: wherein the groups R and R 1 are the same as defined above for Formula III; and pharmaceutically salts thereof.
  • the above noted preferred R and R 1 groups of Formula IV are also preferred R and R 1 groups of compounds of Formula IVb.
  • Preferred compounds of Formula V include those where R is substituted or unsubstituted carbocyclic aryl such as substituted or unsubstituted phenyl, naphthyl or acenaphthyl, particularly substituted or unsubstituted phenyl or naphthyl, such as compounds of the following Formulae Va and Vaa:
  • each R" is independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted
  • alkylsulfinyl substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, or substituted or
  • p is an integer of 0 (where the phenyl ring is fully hydrogen substituted), 1, 2, 3, 4 or 5, and more preferably is 1, 2 or 3;
  • s is an integer from 0 to 7, and more preferably is 0 (i.e. where the naphthyl ring is fully hydrogen-substituted), 1 , 2, 3 or 4;
  • R 1 , R 2 , R 3 , R 4 , m, n and r are each as defined above for Formula V; and pharmaceutically acceptable salts thereof.
  • Preferred compounds of Formula Va include those where p is 1 or greater, e.g. compounds that are substituted at the ortho and/or meta phenyl ring positions by R" groups other than hydrogen, or 2,5-phenyl ring substituted, 2,3,5-phenyl ring substituted or 2,4,5-phenyl ring substituted by R" groups other than hydrogen such as halogen, substituted or unsubstituted alkyl having 1 to about 6 carbon atoms, substituted or unsubstituted alkoxy having 1 to about 6 carbon atoms, or substituted or unsubstituted alkylthio.
  • Formula Vaa includes compounds that have either a 1-naphthyl or 2-naphthyl amino substituent, compounds having a 1-naphthyl group are generally more preferred.
  • Compounds of Formula Vaa that have a non-hydrogen R" substituent at the 4-naphthyl position are also present.
  • Compounds of Formula V may suitably contain one or more 5,6-dihydrophenanthridinyl ring substituents, i.e. the sum of the values of m and n of Formula V is one or more.
  • Generally preferred compounds of Formula V include those compounds that contain 0 (i.e. the 6-hydrophenanthridinyl ring position is -CH 2 -), or 1 (i.e. the 6-hydrophenanthridinyl ring position is -CH(R 2 )-) non-hydrogen R 2 substituents.
  • preferred compounds also include those that contain 0 (ring positions 5-8 each hydrogen substituted), 1 or 2 R 3 and/or R 4 ring substituents.
  • Preferred compounds of Formula V include those that are unsubstituted on the 5,6-dihydrophenanthridinyl ring (m, n and r each zero), particularly compounds of the following Formula Vb:
  • R and R 1 are each the same as defined above for Formula V; and pharmaceutically acceptable salts thereof.
  • the above noted preferred R and R 1 groups of Formula V are also preferred R and R 1 groups of compounds of Formula Vb.
  • Suitable halogen substituent groups of compounds of Formulae I, I', I", la, Iaa, lb, II, II” , IIa, IIaa, IIb, III, IIIa, IIIaa, nib, IV, IVa, IVaa, IVb, V, Va, Vaa, Vb, VI, VII, VIII or IX, as defined above include F, Cl, Br and I.
  • Alkyl groups of compounds Formulae I, I", II, II", III, IV, V, VI, VII, VIII or IX preferably have from 1 to about 12 carbon atoms, more preferably 1 to about 8 carbon atoms, still more preferably 1 to about 6 carbon atoms, even more preferably 1, 2, 3 or 4 carbon atoms.
  • Methyl, ethyl and propyl including isopropyl are particularly preferred alkyl groups of compounds of the invention.
  • alkyl unless otherwise modified refers to both cyclic and noncyclic groups, although of course cyclic groups will comprise at least three carbon ring members.
  • Preferred alkenyl and alkynyl groups of compounds of the invention have one or more unsaturated linkages and from 2 to about 12 carbon atoms, more preferably 2 to about 8 carbon atoms, still more preferably 2 to about 6 carbon atoms, even more preferably 1 , 2, 3 or 4 carbon atoms.
  • alkenyl and alkynyl refer to both cyclic and noncyclic groups, although straight or branched noncyclic groups are generally more preferred.
  • V, VI, VII, VIII or IX include groups having one or more oxygen linkages and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms, even more preferably 1, 2, 3 or 4 carbon atoms.
  • Preferred alkylthio groups of compounds of Formulae I through IX include those groups having one or more thioether linkages and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms. Alkylthio groups having 1, 2, 3 or 4 carbon atoms are particularly preferred.
  • Preferred alkylsulfinyl groups of compounds of the invention include those groups having one or more sulfoxide (SO) groups and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms. Alkylsulfinyl groups having 1, 2, 3 or 4 carbon atoms are particularly preferred. Preferred alkylsulfonyl groups of compounds of the invention include those groups having one or more sulfonyl (SO 2 ) groups and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms.
  • SO sulfoxide
  • Alkylsulfonyl groups having 1, 2, 3 or 4 carbon atoms are particularly preferred.
  • Preferred aminoalkyl groups include those groups having one or more primary, secondary and/or tertiary amine groups, and from 1 to about 12 carbon atoms, more preferably 1 to about 8 carbon atoms, still more preferably 1 to about 6 carbon atoms, even more preferably 1, 2, 3 or 4 carbon atoms.
  • Secondary and tertiary amine groups are generally more preferred than primary amine moieties.
  • VI, VII, VIII or IX contain one or more N, O or S atoms and include, e.g., coumarinyl including 8-coumarinyl, quinolinyl including 8-quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl and benzothiazol.
  • Suitable heteroalicyclic groups of compounds of Formulae I, I", II, II", III, IV, V, VI, VII, VIII or IX contain one or more N, O or S atoms and include, e.g., tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholino and pyrrolindinyl groups.
  • Suitable carbocyclic aryl groups of compounds of Formulae I, I", II, II", III, IV, V, VI, VII, VIII or IX include single and multiple ring compounds, including multiple ring compounds that contain separate and/or fused aryl groups. Typical carbocyclic aryl groups contain 1 to 3 separate or fused rings and from 6 to about 18 carbon ring atoms.
  • carbocyclic aryl groups include phenyl including substituted phenyl, such as 2-substituted phenyl, 3-substituted phenyl, 2,3-substituted phenyl, 2,5-substituted phenyl, 2,3,5-substituted and 2,4,5-substituted phenyl, including where the phenyl substituents are selected from the same group as defined above in Formulae I-V for R 3 ; naphthyl including 1-naphthyl and 2-naphthyl; biphenyl; phenanthryl; and anthracyl.
  • substituted phenyl such as 2-substituted phenyl, 3-substituted phenyl, 2,3-substituted phenyl, 2,5-substituted phenyl, 2,3,5-substituted and 2,4,5-substituted phenyl, including where the phenyl
  • Suitable aralkyl groups of compounds of Formulae I, I", II, n", III, IV, V, VI, VII, VIII or IX include single and multiple ring compounds, including multiple ring compounds that contain separate and/or fused aryl groups.
  • Typical aralkyl groups contain 1 to 3 separate or fused rings and from 6 to about 18 carbon ring atoms.
  • Preferred aralkyl groups include benzyl and methylenenaphthyl (-CH 2 -naphthyl).
  • references herein to substituted R, R 1 , R 2 , R 3 , R 4 , R" and X groups of compounds of the invention refer to the specified moiety that may be substituted at one or more available positions by one or more suitable groups such as, e.g.
  • halogen such as fluoro, chloro, bromo and iodo
  • cyano hydroxyl; nitro; azido
  • alkanoyl such as a C 1-6 alkanoyl group such as acyl and the like
  • carboxamido alkyl groups including those groups having 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms and more preferably 1-3 carbon atoms
  • alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 12 carbon or from 2 to about 6 carbon atoms
  • alkoxy groups having those having one or more oxygen linkages and from 1 to about 12 carbon atoms or 1 to about 6 carbon atoms
  • aryloxy such as phenoxy
  • alkylthio groups including those moieties having one or more thioether linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms
  • alkylsulfinyl groups including those moieties having
  • R being a substituted or unsubstituted biphenyl moiety); and aralkyl such as benzyl.
  • Generally preferred substituents of substituted nitrogen and methylene X groups of compounds of Formulae I, II and VI include the groups from which R 2 is selected in Formulae I, II and VI. More typical substituents of substituted nitrogen and methylene X groups of compounds of Formulae I, II and VI include substituted and unsubstituted alkyl, including C 1-4 alkyl and halosubstituted C 1-4 alkyl, particularly fluoro-substituted C 1-4 alkyl such as trifluoromethyl, and in the case of a substituted methylene group, halogen and alkylthio.
  • alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl and aminoalkyl substituent groups described above include groups where a hetero atom is directly bonded to a ring system, such as a carbocyclic aryl group or a heterocyclic group, as well as groups where a hetero atom of the group is spaced from such ring system by an alkylene linkage, e.g. of 1 to about 4 carbon atoms.
  • Preferred carbocyclic ring substituents of compounds of Formulae I, I" , II, II", III, IV, V, VI, VII, VIII or IX including substituents of the group R where R is a carbocyclic ring such as phenyl or naphthyl, i.e.
  • compounds of Formula la Iaa, IIa, IIaa, IIIa, IIIaa, IVa, IVaa, Va and Vaa where p or s ⁇ 1 and R" is other than hydrogen
  • halogen particularly F, Cl and Br
  • hydroxyl azido
  • substituted or unsubstituted alkyl having 1 to about 6 carbons such as methyl, ethyl, propyl and butyl, and including halogenated alkyl, particularly fluoro-alkyl having 1 to about 6 carbon atoms; substituted and unsubstituted alkoxy having 1 to about 6 carbons and including halogenated alkoxy, particularly fluoro-alkoxy having 1 to about 6 carbon atoms; substituted and unsubstituted alkylthio having 1 to about 6 carbons; substituted and unsubstituted alkylsulfinyl having 1 to about 6 carbons; substituted and
  • unsubstituted alkylsulfonyl having 1 to about 6 carbons and carbocylic aryl, particularly phenyl to provide a substituted phenyl R group that is bi-phenyl.
  • phenyl ring substituents typically have 1 to 4 carbon atoms with methyl, ethyl, propyl including isopropyl and butyl including sec-butyl being particularly preferred.
  • Halogen-substituted alkyl and alkoxy groups are also particularly preferred including fluoroalkyl having 1 , 2, 3 or 4 carbon atoms such as trifluoromethyl and fluoro-substituted alkoxy having 1, 2, 3 or 4 carbon atoms such as trifluoromethoxy (-OCF 3 ).
  • Methylthio (-SCH 3 ) and ethylthio (-SCH 2 CH 3 ) are also particularly preferred phenyl ring substituents.
  • Preferred alkylsulfinyl ring substituents of carbocyclic aryl groups of compounds of the invention typically have one or more sulfoxide groups, more typically, one or two sulfoxide groups and from 1 to about 8 carbon atoms, more preferably 1 to about 6 carbon atoms, even more preferably 1 to about 3 carbon atoms.
  • Methylsulfinyl (-S(O)CH 3 ) and ethylsulfinyl (-S(O)CH 2 CH 3 ) are particularly preferred R 2 , R 3 and R 4 alkylsulfinyl ring substituents as well as preferred ring substituents of a substituted carbocyclic R group.
  • methylsulfinylphenyl and ethylsulfinylphenyl are preferred R groups.
  • Preferred substituted alkylsulfinyl substituents include haloalkylsulfinyl groups that contain one or more F, Cl, Br or I atoms, preferably one or more F atoms, and preferably 1 to about 3 carbon atoms, more preferably one or two carbon atoms.
  • Specifically preferred groups include fluoromethylsulfinyl, particularly trifluoromethylsulfinyl (-S(O)CF 3 ), and
  • fluoroethylsulfinyl such as 2-trifluoroethylsulfinyl (-S(O)CH 2 CF 3 ) and
  • Preferred alkylsulfonyl ring substituents of carbocyclic aryl group compounds of the invention have one or more sulfono (SO 2 ) groups, more typically one sulfono group, and from 1 to about 8 carbon atoms, still more preferably 1 to about 6 carbon atoms, even more preferably 1 to about 3 carbon atoms.
  • SO 2 sulfono
  • Methylsulfonyl (-S(O) 2 CH 3 ) and ethylsulfonyl (-S(O) 2 CH 2 CH 3 ) are
  • alkylsulfonyl substituents include haloalkylsulfonyl groups that contain one or more F, Cl, Br or I atoms, preferably one or more F atoms, and preferably 1 to about 3 carbon atoms, more preferably one or two carbon atoms.
  • Specifically preferred groups include fluoromethylsulfonyl, particularly trifluoromethylsulfonyl (-S(O) 2 CF 3 ), and fluoroethylsulfonyl such as 2-trifluoroethylsulfonyl (-S(O) 2 CH 2 CF 3 ) and
  • compounds of the invention that contain an alkylsulfinyl and/or alkylsulfonyl group may be, in effect, "pro-drugs" wherein after administration of the compound to a subject the sulfinyl or sulfonyl group(s) are metabolized (reduced) in vivo to the corresponding sulfide moiety.
  • Specifically preferred compounds of Formula I include the following: N-(4-benzyloxyphenyl)-1-indolinylcarboximidamide;
  • N-(1-naphthyl)-1-indolinylcarboximidamide and pharmaceutically acceptable salts thereof are particularly preferred compounds of Formula I.
  • Additional preferred compounds of Formula I include the following where the compound is structurally depicted above the chemical name thereof, and
  • Specifically preferred compounds of Formula II include the following:
  • N-(2,5-dibromophenyl)-1-(7-trifluoromethyl)-(1,2,3,4-tetrahydroquinolinyl) carboximidamide and pharmaceutically acceptable salts thereof are particularly preferred compounds of Formula II, i.e. the compound of the following structure and pharmaceutically acceptable salts thereof:
  • Additional preferred compounds of Formulae II and IF include the following where the compound is structurally depicted above the chemical name thereof, and pharmaceutically acceptable salts of these depicted compounds.
  • Specifically preferred compounds of Formula III include the following: N-(1-naphthyl)-1-(1,2,3,4-tetrahydroisoqumolmyl)carboximidamide;
  • Specifically preferred compounds of Formula IV include the following:
  • N-(2-methylphenyl)-1-(benz[cd]indolinyl)carboximidamide is a particularly preferred compound of Formula IV.
  • Additional preferred compounds of Formula IV include the following where the compound is structurally depicted above the chemical name thereof, and pharmaceutically acceptable salts of these depicted compounds.
  • Specifically preferred compounds of Formula V include the following:
  • Specifically preferred compounds of Formula VI include the following where the where the compound is structurally depicted above the chemical name thereof, and pharmaceutically acceptable salts of these depicted compounds:
  • Specifically preferred compounds of Formula VII include the following where the where the compound is structurally depicted above the chemical name thereof, and pharmaceutically acceptable salts of these depicted compounds:
  • Specifically preferred compounds of Formulae VIII and IX include the following where the where the compound is structurally depicted above the chemical name thereof, and pharmaceutically acceptable salts of these depicted compounds:
  • N-(alkylphenyl)-1-indolinylcarboximidamide compounds i.e. compounds of Formula I where X is CH 2 and R is alkyl-substituted phenyl, particularly where R 1 is H
  • N-(monoalkylphenyl)-1-mdolinylcarboximidamide such as N-(m-ethylphenyl)-1-indolinyl carboximidamide
  • R is acenaphthyl, particularly where R is unsubstituted acenaphthyl and/or ring substituents R 2 and R 3 are each only hydrogen, and/or where X is CH 2 in the case of Formulae I and II, and/or one of R and R 1 is hydrogen
  • compounds of Formula III where R or R 1 is aralkyl, particularly where ring substituents R 2 and R 3 are each only hydrogen, and/or R and R 1
  • Compounds of the invention can be prepared by the reaction of a suitable precursor compound, e.g. indolinyl (or derivative thereof) compound, 1,2,3,4-tetrahydroquinolinyl (or derivative thereof) compound, 1,2,3,4-tetrahydroisoquinolinyl compound, benz[cd]indolinyl compound, 5,6-dihydrophenanthridinyl compound, 2,3,4,5-tetrahydro-[1,5]-benzothiazepine compounds (or derviative thereof, e.g.
  • compounds the invention can be suitably prepared by reaction of an appropriate indolinyl (or derivative thereof) salt (to prepare compounds of Formulae I, I', I", la, Iaa or Ib), 1,2,3, 4-tetrahydroquinolinyl (or derivative thereof) salt (to prepare compounds of Formulae II, II", IIa, IIaa or lIb), 1,2,3,4-tetrahydroisoquinolinyl salt (to prepare compounds of Formulae III, IIIa, IIIaa or IIIb), benz[cd]indolinyl salt (to prepare compounds of Formulae IV, IVa, IVaa or IVb), or 5,6-dihydrophenanthridinyl salt (to prepare compounds of Formulae V, Va, Vaa or Vb) or other appropriate salt such as salts of above mentioned precursor compounds (to form compounds of Formulae VI-IX) with a substituted cyanamide in a suitable solvent such as toluene, chlorobenzene or the like under an inert
  • reaction solution is then heated e.g. from about 110° to 120°C for 2 to about 16 hours until reaction completion, e.g. as indicated by thin layer chromatography.
  • reaction solution is then cooled to room temperature, and the solvent is then removed under reduced pressure to provide the desired compound of the invention.
  • the crude product then can be purified by recrystallization and/or column chromatography, e.g. by elution one or more times on silica gel (e.g., 60-200 mesh, 50x w/w) with suitable solvents. See Example 2 which follows for exemplary conditions.
  • indolinyl or derivative thereof
  • 1,2,3,4-tetrahydroquinoline or derivative thereof
  • 1,2,3,4-tetrahydroisoquinoline benz[cd] indolinyl or 5,6-dihydrophenanthridinyl ot other presursor such as those mentioned above (for
  • the cyanamide starting material can be synthesized from the correspondingly substituted amine by treatment with cyanogen bromide (BrCN) in a suitable solvent such as dry ethyl ether or toluene at reduced temperatures (e.g. 0°C) or room temperature.
  • cyanogen bromide BrCN
  • a suitable solvent such as dry ethyl ether or toluene at reduced temperatures (e.g. 0°C) or room temperature.
  • the amine to be reacted with cyanogen bromide is substituted with the R moiety as defined above for Formulae I, I" , II, II", III, IV, V, VI, VII, VIII or IX (in the Scheme, that R moiety is exemplified as phenyl which may be ring-substituted by groups R 1 and R 2 ).
  • R groups of compounds of Formula I through IX can be provided by use of suitable substituted amines that are reacted with BrCN, such as e.g. substituted and unsubstituted anilines as shown in the Scheme, substituted and unsubstituted 1-naphmylamine, 2-naphthylamine, acenaphthylamine, etc.
  • R 1 groups other than hydrogen of compounds of Formulae I through IX can be readily provided by reaction of a substituted cyanamide with a suitable nucleophile such as a halide reagent (e.g., a substituted or unsubstituted alkyl or alkenyl iodide or bromide).
  • a suitable nucleophile such as a halide reagent (e.g., a substituted or unsubstituted alkyl or alkenyl iodide or bromide).
  • a suitable nucleophile such as a halide reagent (e.g., a substituted or unsubstituted alkyl or alkenyl iodide or bromide).
  • a suitable nucleophile such as a halide reagent (e.g., a substituted or unsubstituted alkyl or alkenyl iodide or bromide).
  • the aryl cyanamide is
  • alkylsulfinyl-substituted or alkylsulfonyl-substituted reagents that can provide correspondingly substituted compounds of the invention as described above, can be provided by oxidation (e.g. , H 2 O 2 ) of alkylthio-substituted reagents. See for instance Example 46 which follows.
  • R and R 1 are each hydrogen can be prepared by reaction of 1,2,3,4-tetrahydroquinoline compound with cyanamide.
  • R 2 substituents can be provided by reaction of a substituted or unsubstituted quinoline compound with a Grignard reagent followed by hydrogenation to provide the substituted 1,2,3,4-tetrahydroquinoline compound. See Example 3 which follows for an exemplary procedure. See also Examples 41 and 42 which follow.
  • Compounds of Formulae I", H" and VI where X is -S(O)- or -S(O) 2 - can be prepared by oxidation (e.g.
  • benz[cd]indoline and 5,6-dihydrophenanthridine reagents can be prepared treatment of a benz[cd]indo-2(1H)-one compound or 5,6-dihydrophenanthridinone compound with a base such as diborane in a suitable solvent such as tetrahydrofuran. See Example 1 which follows for exemplary conditions.
  • Chiral compounds of the invention may be used as optically enriched or racemic mixtures.
  • An optically enriched mixture contains substantially more (e.g. about 60%, 70%, 80% or 90% or more) of one enantiomer or diastereoisomer than the other stereoisomers.
  • Optically enriched mixtures can be obtained by known procedures, e.g. , column chromatography using an optically active binding material or formation of a salt using an optically active material, particularly an optically active acid.
  • optically enriched mixtures include sulfinyl-containing compound of the invention, e.g. compounds of Formulae I", II" or VI where X is -S(O)-, or compounds having having an alkylsulfinyl or other sulfinyl substituent.
  • sulfinyl-containing compound of the invention e.g. compounds of Formulae I", II" or VI where X is -S(O)-, or compounds having having an alkylsulfinyl or other sulfinyl substituent.
  • Such optically active mxtures of sulfinyl-containing compounds can be readily prepared, e.g. by column chromatography using an optically active binding material.
  • the present invention includes methods for treating preventing certain neurological disorders, including the consequences of stroke, heart attack and traumatic head or brain injury, epilepsy or neurodegenerative diseases comprising the administration of an effective amount of one or more compounds of the invention to a subject including a mammal, particularly a human, in need of such treatment.
  • the invention provides methods for treatment and/or prophylaxis of nerve cell death (degeneration) resulting e.g. from hypoxia,
  • hypoglycemia brain or spinal cord ischemia, brain or spinal cord trauma, stroke, heart attack or drowning.
  • candidates for treatment include e.g. heart attack, stroke and/ or persons suffering from cardiac arrest neurological deficits, brain or spinal cord injury patients, patients undergoing major surgery such as heart surgery where brain ischemia is a potential complication and patients such as divers suffering from decompression sickness due to gas emboli in the blood stream.
  • Candidates for treatment also will include those patients undergoing a surgical procedure involving extra- corporal circulation such as e.g. a bypass procedure.
  • the invention in particular provides methods for treatment which comprise administration of one or more compounds of the invention to a patient that is undergoing surgery or other procedure where brain or spinal cord ischemia is a potential risk.
  • carotid endarterectomy is a surgical procedure employed to correct atherosclerosis of the carotid arteries.
  • Major risks associated with the procedure include intraoperative embolization and the danger of hypertension in the brain following increased cerebral blood flow, which may result in aneurism or hemorrhage.
  • an effective amount of one or more compounds of the present invention could be administered pre-operatively or peri-operatively to reduce such risks associated with carotid endarterectomy, or other post-surgical neuorological deficits.
  • the invention further includes methods for prophylaxis against neurological deficits resulting from e.g. coronary artery bypass graft surgery and aortic valve replacement surgery, or other procedure involving extra-corporal circulation. Those methods will comprise administering to a patient undergoing such surgical procedures an effective amount of one or more compounds of the invention, typically either pre- operatively or peri-operatively.
  • the invention also provides methods for prophylaxis and treatment against neurological injury for patients undergoing myocardial infarction, a procedure that can result in ischemic insult to the patient. Such methods will comprise administering to a patient undergoing such surgical procedure an effective amount of one or more compounds of the invention, typically either pre-operatively or peri-operatively.
  • the invention also provides methods for treatment and prophylaxis against retinal ischemia or degeneration and resulting visual loss.
  • a compound of the invention can be administered parenterally or by other procedure as described herein to a subject a suffering from or susceptible to ischemic insult that may adversely affect retinal function, e.g. , significantly elevated intraocular pressures, diseases such as retinal artery or vein occlusion, diabetes or other ischemic ocularrelated diseases.
  • Post- ischemic administration also may limit retinal damage.
  • the invention also includes methods for treating and prophylaxis against decreased blood flow or nutrient supply to retinal tissue or optic nerve, or treatment or prophylaxis against retinal trauma or optic nerve injury.
  • Subjects for treatment according to such therapeutic methods of the invention may be suffering or susceptible to retinal ischemia that is associated with atherosclerosis, venous capillary insufficiency, obstructive arterial or venous retinopthies, senile macular degeneration, cycstoid macular edema or glaucoma, or the retinal ischemia may be associated with a tumor or injury to the mammal.
  • Intravitreal injection of a compound of the invention also may be a preferred administration route to provide more direct treatment to the ischemic retina.
  • the invention also provides methods for treatment of a subject suffering from shingles as well as treatment of a person suffering from or susceptible to migraines, particularly to alleviate the pain and discomfort associated with those disorders.
  • These methods comprise administration of an effective amount of one or more compounds of the invention to a patient in need of treatment.
  • the invention further provides a method of treating Korsakoff s disease, a chronic alcoholism-induced condition, comprising administering to a subject including a mammal, particularly a human, one or more compounds of the invention in an amount effective to treat the disease.
  • Compounds of the invention are anticipated to have utility for the attenuation of cell loss, hemorrhages and/or amino acid changes associated with Korsakoff s disease.
  • the invention also includes methods for treating a person suffering from or susceptible to cerebral palsy, emesis, narcotic withdrawal symptoms and age-dependent dementia, comprising administering to a subject including a mammal, particularly a human, one or more compounds of the invention in an amount effective to treat the condition.
  • preferred compounds of the invention in a standard anticonvulsant in vivo audiogenic test such as the audiogenic mouse assay of
  • Example 48 which follows, where DBA/2 mice about 20-23 days old are injected intraperitoneally with a test compound 30 minutes prior to being placed in a bell jar with exposure to auditory stimulus of 12KHz sine wave at 110-120 db.
  • References herein in vivo "audiogenic assay” are intended to refer to that protocol.
  • Generally preferred compounds exhibit 20% or more inhibition (relative to subjects treated with vehicle control only) at a dose of 20 mg/kg, more preferably about 50% or more or 70% or more inhibition at a dose of 20 mg/kg in such an in vivo audiogenic assay.
  • activity in the audiogenic assay has been recognized as indicative that a test compound has neuroprotective properties. See, e.g. , M. Tricklebank et al., European Journal of Pharmacology, supra; T. Seyfried, Federation Proceedings, supra.
  • the invention also provides methods for determining binding activity of compounds of the invention as well as in vitro and in vivo binding activity diagnostic methods using one or more radiolabelled compounds of the invention, e.g., a compound of the invention that is labeled with 125 I, tritium, 32 P, 99 Tc, or the like, preferably 125 I.
  • a compound of the invention having a phenyl or other aryl substituent that is ring substituted with one or more 125 I groups can be
  • SPECT single photon emission computed tomography
  • a labeled compound of the invention will selectively bind to ischemic tissue of e.g. a subject's brain to differentiate between ischemic and non- ischemic tissue and thereby assess trauma or other injury to the brain.
  • the invention includes compounds of the invention that contain a radiolabel such as 125 I, tritium, 32 P, 99 Tc, or the like, preferably 125 I.
  • a radiolabel such as 125 I, tritium, 32 P, 99 Tc, or the like, preferably 125 I.
  • radiolabelled compounds can be suitably prepared by procedures known in the synthesis art.
  • a compound of the invention having an aromatic group, such as phenyl, that has a bromo or chloro ring substituent can be employed in an exchange labeling reaction to provide the corresponding compound having an 125 I ring substiment.
  • Compounds of the invention may be used in therapy in conjunction with other medicaments.
  • one or more compounds of Formulae I, II, III, IV or V, or one or compounds of Formulae I", II", VI, VII, VIII or IX may be suitably administered together with a pharmaceutical targeted for interaction in the blood clotting mechanism such as streptokinase, tPA, urokinase and other agents that lyse clots.
  • a pharmaceutical targeted for interaction in the blood clotting mechanism such as streptokinase, tPA, urokinase and other agents that lyse clots.
  • one or more compounds of the invention may be administered together with agents such as heparin and related heparin-based compounds, acenocoumarol or other known anticoagulants.
  • the compounds of this invention can be administered intranasally, orally or by injection, e.g. , intramuscular, intraperitoneal, subcutaneous or intravenous injection, or by transdermal, intraocular or enteral means.
  • the optimal dose can be determined by conventional means.
  • Compounds of the present invention are suitably
  • a pharmaceutically acceptable salt of an organic or inorganic acid e.g., hydrochloride, sulfate, hemi-sulfate, phosphate, nitrate, acetate, oxalate, citrate, maleate, mesylate, etc.
  • Compounds of the invention can be employed, either alone or in combination with one or more other therapeutic agents as discussed above, as a pharmaceutical composition in mixture with conventional excipient, i.e. , pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, enteral or intranasal application which do not deleteriously react with the active compounds and are not deleterious to the recipient thereof.
  • conventional excipient i.e. , pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, enteral or intranasal application which do not deleteriously react with the active compounds and are not deleterious to the recipient thereof.
  • Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, etc.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously react with the active compounds.
  • solutions preferably oily or aqueous solutions as well as suspensions, emulsions, or implants, including suppositories.
  • Ampules are convenient unit dosages.
  • enteral application particularly suitable are tablets, dragees or capsules having talc and/or carbohydrate carrier binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch.
  • a syrup, elixir or the like can be used wherein a sweetened vehicle is employed.
  • Sustained release compositions can be formulated including those wherein the active component is protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, etc.
  • Intravenous or parenteral administration e.g., sub-cutaneous, intraperitoneal or intramuscular administration are preferred.
  • the compounds of this invention are particularly valuable in the treatment of mammalian subjects, e.g. , humans, to provide neuroprotective therapy and/or prophylaxis.
  • mammalian subjects e.g. , humans
  • neurodegenerative diseases such as Parkinson's disease
  • Huntington's disease Amyotrophic Lateral Sclerosis, Alzheimer's disease, Down's Syndrome and Korsakoff s disease.
  • Also suitable for treatment are those subjects suffering from or likely to suffer from nervous system dysfunctions resulting from, for example, epilepsy or nerve cell degeneration which is the result of hypoxia, hypoglycemia, brain or spinal chord ischemia or brain or spinal chord trauma.
  • typical candidates for treatment include heart attack, stroke, brain or spinal cord injury patients, patients undergoing major surgery where brain or spinal cord ischemia is a potential complication and patients such as divers suffering from decompression sickness due to gas emboli in the blood stream.
  • a suitable effective dose of one or more compounds of Formulae I, II, III, IV or V, or one or compounds of Formulae I", II", VI, VII, VIII or IX will be in the range of from 0.01 to 100 milligrams per kilogram of bodyweight of recipient per day, preferably in the range of from 0.01 to 20 milligrams per kilogram bodyweight of recipient per day, more preferably in the range of 0.05 to 4 milligrams per kilogram bodyweight of recipient per day.
  • the desired dose is suitably administered once daily, or several sub-doses, e.g. 2 to 4 sub-doses, are administered at appropriate intervals through the day, or other appropriate schedule.
  • sub-doses may be administered as unit dosage forms, e.g. , containing from 0.05 to 10 milligrams of compound(s) of
  • Benz[cd]indoline (5.58 g, 67.6%).
  • Benz[cd]indoline (1.0g, 6.44 mmol) was then dissolved in a minimum amount of diethyl ether and 15 ml of 1M HCl diethyl ether solution was added. The precipitate was collected by filtration, washed with diethyl ether and dried to afford Benz[cd]indoline HCl (1.21 g, 98%) as a white solid.
  • R 3 methoxy (at 5-indoline position)
  • the title compound was prepared by oxidiation of the corresponding sulfide precursor (i.e. N-(1-naphthyl)-1-(2,3-dihydro-6-trifluoromethylbenzo[1,4]thiazin-4-yl)carboximidamide) with sodium periodate in acetonitrile: water (1: 1) at room
  • EXAMPLE 48 In vivo Anticonvulsant activity in the DBA/2 mouse model
  • mice were injected intraperitoneally with the compound specified in Table I below or with vehicle control, 30 minutes prior to being placed in a bell jar and turning on the auditory stimulus (12 KHz sine wave at 110-120 db).
  • Administered doses are specified in Table I as milligram of compound per kilogram bodyweight of mouse. The auditory stimulus was left on for 60 seconds and mice reactions were timed and recorded. Percentage inhibition was determined with reference to vehicle controls. Results are shown in the Table I below. "FB" refers to free base.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention relates to pharmaceutically acceptable compounds, including certain substituted indolinyl and derivatives thereof, 1,2,3,4-tetrahydroquinolinyl and derivatives thereof, 1,2,3,4-tetrahydroisoquinolinyl, benz[cd]indolinyl and 5,6-dihydrophenanthridinyl compounds, and methods of treatment and pharmaceutical compositions that utilize or comprise one or more such compounds. Compounds of the invention are particularly useful for the treatment or prophylaxis of neurological injury and neurodegenerative disorders.

Description

PHARMACEUTICALLY ACTIVE COMPOUNDS AND METHODS OF USE
This application is a continuation-in-part of copending U.S. application serial number 08/601 ,992, filed February 15, 1996, which application is incorporated herein by reference.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to pharmaceuticially active compounds, including certain substituted indolinyl (and derivatives thereof), 1,2,3,4-tetrahydroquinolinyl (and derivatives thereof), 1,2,3,4-tetrahydroisoquinolinyl, benz[cd] indolinyl and 5,6-dihydrophenanthridinyl compounds, and methods of treatment and pharmaceutical compositions that utilize or comprise one or more such compounds. Compounds of the invention are particularly useful for the treatment or prophylaxis of neurological injury and neurodegenerative disorders.
2. Background
Nerve cell death (degeneration) can cause potentially devastating and irreversible effects for an individual and may occur e.g. as a result of stroke, heart attack or other brain or spinal chord ischemia or trauma. Additionally,
neurodegenerative disorders involve nerve cell death (degeneration) such as
Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, Down's Syndrome and Korsakoff s disease.
Therapies have been investigated to treat nerve cell degeneration and related disorders, e.g. , by limiting the extent of nerve cell death that may otherwise occur to an individual. See, e.g., N. L. Reddy et al., J. Med. Chem. , 37:260-267 (1994); and WO 95/20950.
The compound MK-801 has exhibited good results in a variety of in vivo models of stroke. See B. Meldrum, Cerbrovascular Brain Metab. Rev. , 2:27-57 (1990); D. Choi, Cerbrovascular Brain Metab. Rev. , 2: 105-147 (1990). See also Merck Index, monograph 3392, 11th ed., 1989. For example, MK-801 exhibits good activity in mouse audiogenic tests, a recognized model for evaluation of
neuroprotective drugs. See, e.g., M. Tricklebank et al., European Journal of Pharmacology, 167: 127-135 (1989); T. Seyfried, Federation Proceedings,
38(10):2399-2404 (1979).
However, MK-801 also has shown toxicity and further clinical development of the compound is currently uncertain. See J. W. Olney et al., Science, 244: 1360-1362 (1989); W. Koek et al., J. Pharmacol. Exp. Ther. , 252:349-357 (1990); F.R. Sharp et al. , Society for Neuroscience Abstr. , abstr. no. 482.3 (1992).
It thus would be highly desirable to have new neuroprotective agents, particularly agents to limit the extent or otherwise treat nerve cell death
(degeneration) such as may occur with stroke, heart attack or brain or spinal cord trauma, or to treat neurodegenerative disorders such as Alzheimer's disease,
Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, Down's Syndrome and Korsakoffs disease.
SUMMARY OF THE INVENTION
In a first aspect, the present invention provides substituted indolinyl and indolinyl derivative compounds of the following Formula I:
Figure imgf000004_0001
wherein R and R1 are each independently hydrogen; substituted or
unsubstituted alkyl having from 1 to about 20 carbon atoms; substituted or
unsubstituted alkenyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms; substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfinyl having 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfonyl having 1 to about 20 carbon atoms; substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms; or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms, with at least one of R and R1 being other than hydrogen;
each R2 and each R3 (i.e. substituent of the 4, 5, 6 and 7 aromatic ring positions) are each independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or
unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms, or substituted or unsubstituted aralkyl having at least about 6 ring carbon atoms;
X is substituted or unsubstituted methylene (-CH2-), -S- (i.e. 3-benzothiazolinylcarboximidamide compounds), -O- or substituted or unsubstituted -N-, and preferably is substituted or unsubstituted methylene;
m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
In a further aspect, the invention provides compounds of the following
Formula II:
Figure imgf000005_0001
wherein R and R1 are each independently hydrogen; substituted or
unsubstituted alkyl having from 1 to about 20 carbon atoms; substituted or
unsubstituted alkenyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms; substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfinyl having 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfonyl having 1 to about 20 carbon atoms; substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms; or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms;
each R2 (i.e. substituent of the 2 and 3 ring positions) and each R3 (i.e.
substituent of the 5, 6, 7 and 8 aromatic ring positions) are each independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms, or substituted or unsubstituted aralkyl having at least about 6 ring carbon atoms;
X is -O- (i.e. 2,3-benzmorpholinyl compounds), -S- (i.e. 2,3-benzthiomorpholinyl compounds), substituted or unsubstituted -N-, or substituted or unsubstituted methylene (-CHr);
m and n are each independently 0 (i.e. the available ring are each hydrogen-substituted), 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
In a still further aspect, the invention provides tetrahydroisoquinolinyl compounds of the following Formula III:
Figure imgf000007_0001
wherein R and R1 are each independently hydrogen; substituted or
unsubstituted alkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms; substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfinyl having 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfonyl having 1 to about 20 carbon atoms; substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms; or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms;
each R2 (i.e. substituent of the 1, 3 and 4 tetrahydroisoquinolinyl ring positions) and each R3 (i.e. substituent of the 5, 6, 7 and 8 tetrahydroisoquinolinyl ring positions) are each independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms, or substituted or unsubstituted aralkyl having at least about 6 ring carbon atoms;
m is 0 (i.e. the 1, 3 and 4 tetrahydroisoquinolinyl ring positions are each hydrogen-substituted), 1, 2, 3, 4, 5 or 6; n is 0 (i.e. the 5, 6, 7 and 8
tetrahydroisoquinolinyl ring positions are each hydrogen-substituted), 1 , 2, 3 or 4; and pharmaceutically acceptable salts thereof.
In a yet further aspect, the invention provides compounds of the following Formula IV:
Figure imgf000008_0001
wherein R and R1 are each independently hydrogen; substituted or
unsubstituted alkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms; substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfinyl having 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfonyl having 1 to about 20 carbon atoms; substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms; or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms, with at least one of R and R1 being other than hydrogen;
each R2 and each R3 (i.e. substituent of the aromatic positions 3-8) are each independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms, or substituted or unsubstituted aralkyl having at least about 6 ring carbon atoms;
m is 0 (i.e. the 2-benz[cd]indolinyl position is hydrogen- substituted), 1 or 2; and n is 0 (i.e. the available ring are each hydrogen-substituted), 1, 2, 3, 4, 5 or 6; and pharmaceutically acceptable salts thereof.
Still further, the invention provides compounds of the following Formula V:
Figure imgf000009_0001
wherein R and R1 are each independently hydrogen; substituted or
unsubstituted alkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms; substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfinyl having 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfonyl having 1 to about 20 carbon atoms; substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms; or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms, with at least one of R and R1 being other than hydrogen; each R2, each R3 (i.e. substiment of the aromatic positions 1-4) and each R4 (i.e. substituent of the aromatic positions 7-10) are each independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms, or substituted or unsubstituted aralkyl having at least about 6 ring carbon atoms;
m is 0 (i.e. the 5,6-dihydrophenanthridinyl ring position is hydrogen-substituted), 1 or 2; and n and r are each independently 0 (i.e. the ring positions are each hydrogen-substituted), 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
In a yet further aspect the invention provides compounds of the following Formulae VI:
Figure imgf000010_0001
wherein R, R1, X, R2, R3 and n are the same as defined above for Formula II, but where X can also be sulfinyl (i.e.-S(O)-) or sulfonyl (i.e. -S(O2)-), and m of Formula VI is an integer equal to 0-6, and preferably m is 0, 1 or 2; and
pharmaceutically acceptable salts thereof. Preferred substituents of Formula II also will be preferred substituents at corresponding positions of compounds of of Formula VI. The invention also provides compounds of the following Formula VII:
Figure imgf000011_0001
wherein R, R1, R2, R3 and m are the same as defined above for Formula IV, and n of Formula VII is an integer equal to 0-9, and preferably n is 0, 1 or 2; and pharmaceutically acceptable salts thereof. It is understood that an R3 substituent can be the same or different and may be present on either the non-aromatic or aromatic fused ring. Preferred substituents of Formula IV also will be preferred substituents at corresponding positions of compounds of Formula VI.
The invention also provides compounds of the following Formula VIII:
Figure imgf000011_0002
wherein R, R1, R2, R3, n and r are the same as defined above for Formula V, except R and R1 each may be hydrogen, although preferably at least one of R and R1 will be other than hydrogen, and m of Formula VIII is an integer equal to 0-4, and preferably m is 0, 1 or 2, and the dotted line in Formula VIII represents an optional carbon-carbon double bond (endocyclic bond); and pharmaceutically acceptable salts thereof. Preferred substituents of Formula V also will be preferred substituents at corresponding positions of compounds of Formula VIII.
The invention also provides compounds of the following Formula IX:
Figure imgf000012_0001
wherein R2, R3, n and r are the same as defined above for Formula V; R and
R1 are also the same as defined above for Formula V, except R and R1 each may be hydrogen, although preferably at least one of R and R1 will be other than hydrogen; m of Formula IX is an integer equal to 0-6 (i.e. R2 may be a substituent at any of the available three saturated ring positions), and preferably m is 0, 1 or 2
For each of Formulae I, II, III, IV and V, as well as for each of Formulae VI,
VII, VII and IX and Formulae I" and II" as defined below, preferably at least one of R and R1 is a carbocyclic aryl, aralkyl, or heteroaromatic or heteroalicyclic group, particularly substituted or unsubstituted phenyl or naphthyl. More preferably, for each of Formulae I through IX (which includes Formulae I" and II"), R is a carbocyclic aryl, heteroaromatic or heteroalicyclic group, and R1 is a non-aryl group, particularly hydrogen or substituted or unsubstituted alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, or aminoalkyl. Substimted or unsubstituted phenyl or naphthyl are preferred R groups of Formulae I through IX (including Formulae I" and II"). Generally more preferred R1 groups are hydrogen and substituted or
unsubstituted alkyl such as substituted or unsubstituted alkyl having 1 to about 6 carbon atoms or 1 to about 3 carbon atoms.
The compounds of the invention (i.e. compounds of Formulae I, II, III, IV and V as well as compounds of Formulae I', I" , la, laa, lb, II", IIa, IIaa, IIb, IIIa, IIIaa, IIIb, IVa, IVaa, IVb, Va, Vaa and Vb as discussed below, and as well as compounds of Formulae VI, VII, VIII and IX above) are useful for a number of therapeutic applications. In particular, the invention includes methods for treatment and/or prophylaxis of neurological conditions/injuries such as epilepsy, neurodegenerative conditions and/or nerve cell death (degeneration) resulting from e.g. hypoxia, hypoglycemia, brain or spinal chord ischemia, retinal ischemia, brain or spinal chord trauma or post-surgical neurological deficits and the like as well as neuropathic pain. The compounds of the invention are especially useful for treatment of a person susceptible or suffering from stroke or heart attack or neurological deficits relating to cardiac arrest, a person suffering or susceptible to brain or spinal cord injury, or a person suffering from the effects of retinal ischemica or
degeneration, or a person suffering from decreased blood flow or nutrient supply to retinal tissue or optic nerve or retinal trauma or optic nerve injury. Compounds of the invention also are useful to treat and/or prevent various neurodegenerative diseases such as Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, Alzheimer's disease, Down's Syndrome, Korsakoff s disease, cerebral palsy and/or age-dependent dementia. Compounds of the invention will be further useful to treat and/or prevent migraines, shingles (herpes zoster), epilepsy, emesis and/or narcotic withdrawal symptoms. The treatment methods of the invention in general comprise administration of a therapeutically effective amount of one or more compounds of the invention to an animal, including a mammal, particularly a human.
Particularly preferred compounds of the invention exhibit good activity in an anticonvulsant in vivo mouse audiogenic assay e.g. as disclosed in Example 48 which follows, preferably about 20% or more inhibition at a dose of a compound of the invention of 20 mg/kg, more preferably about 50% or more or 70% or more inhibition at a dose of 20 mg/kg in such an anticonvulsant in vivo audiogenic assay.
The invention also provides pharmaceutical compositions that comprise one or more compounds of the invention and a suitable carrier for the compositions.
Other aspects of the invention are disclosed infra.
DETAILED DESCRIPTION OF THE INVENTION
As mentioned above, preferred compounds of Formula I include those where the group X is substituted or unsubstituted methylene, i.e. indolinyl compounds of the following Formula I':
Figure imgf000014_0001
where R, R1, R2, R3 and n are each the same as defined above for Formula I; m is 0, 1 , 2, 3 or 4; and pharmaceutically acceptable salts thereof.
Preferred compounds of Formula I as defined above include those where R is substituted or unsubstituted carbocyclic aryl, particularly substituted or unsubstituted phenyl, naphthyl and acenaphthyl.
Substimted and unsubstituted phenyl and naphthyl are particularly preferred R group of compounds of Formula I, such as compounds of the following Formulae la and Iaa:
Figure imgf000014_0002
Figure imgf000014_0003
wherein for each of Formulae la and Iaa each R" is independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted
alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, or substituted or
unsubstituted aralkyl;
p is an integer of 0 (where the phenyl ring is fully hydrogen substituted), 1 , 2,
3, 4 or 5, and more preferably is 1, 2 or 3;
s is an integer of from 0 to 7, and more preferably is 0 (where the naphthyl ring is fully hydrogen- substituted), 1, 2, 3 or 4;
R1, R2, R3, X, m and n are each the same as defined above for Formula I; and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of Formula la include those where p is 1 or greater, e.g. compounds that are substituted at the ortho, meta and/or para phenyl ring positions by R" group(s) other than hydrogen, or 2,5-phenyl ring substituted, 2,3,5-phenyl ring substituted or 2,4,5-phenyl ring substituted by R" groups other than hydrogen(s) such as halogen, substituted or unsubstituted alkyl having 1 to about 6 carbon atoms, substituted or unsubstituted alkoxy having 1 to about 6 carbon atoms, or substituted or unsubstituted alkylthio having 1 to about 6 carbon atoms. It is of course understood that where a phenyl or napthyl group of Formulae la or Iaa is not substituted by an R" group, the ring position is hydrogen-substituted. While as shown by the above structure Formula Iaa includes compounds that have either a 1-naphthyl or 2-naphthyl amino (-N(R')-) substituent, compounds having a 1-naphthyl group are generally more preferred. Compounds of Formula Iaa that have a non-hydrogen R" substituent at the 4-naphthyl position are also particularly preferred.
Compounds of Formula I may suitably contain one or more indolinyl (or derivative) ring substituents, i.e. the sum of the values of m and n of Formula I is one or more. It is understood that references herein to "derivatives" of indolinyl compounds of Formula I refer to those compounds where the group X is other than substituted or unsubstituted methylene.
Generally preferred compounds of Formula I that include indolinyl (or derivative) substituents contain no more than one or two non-hydrogen R2
substituents, such as compounds that contain 0 (i.e. ring position 2 is -CH2-) or 1 (i.e. ring position 2 is -CH2-) non-hydrogen R2 substituents. Similarly, generally preferred compounds of Formula I' that include indolinyl ring substimtents contain no more than two or three non-hydrogen R2 substitutents, such as compounds that contain 0 (i.e. each of ring positions 2 and 3 is -CH2-) or 1 (i.e. one indolinyl ring position is -CH2- and the other is -CH(R2)-) non-hydrogen R2 substituents.
Generally preferred compounds of Formula I also include those that contain 0 (ring positions 4-7 each hydrogen substituted), and 1 or 2 R3 ring substituents.
Preferred compounds of Formula I also include those compounds that are unsubstituted on the ring (each m and n as defined above for Formula I is 0), i.e. compounds of the following Formula lb:
Figure imgf000016_0001
wherein the groups R, R1 and X are the same as defined above for Formula I; and pharmaceutically salts thereof. The above noted preferred R and R1 groups of Formula I are also preferred groups of compounds of Formula lb.
In another aspect, compounds of Formula I" are provided, which is defined the same as Formula I above, but where X is sulfinyl (i.e.-S(O)-) or sulfonyl (i.e. -S(O2)-). Preferred substitutents of compounds of Formula I as noted herein are also preferred substituents for corresponding positions for compounds of Formula I".
Preferred compounds of Formula II include those where R is substituted or unsubstituted carbocyclic aryl such as substituted or unsubstituted phenyl, naphthyl or acenaphthyl, particularly substituted or unsubstituted phenyl or naphthyl, i.e.
compounds of the following Formulae Ha and IIaa:
Figure imgf000016_0002
Figure imgf000017_0001
wherein for each of Formulae IIa and IIaa each R" is independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted
alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, or substituted or
unsubstituted aralkyl;
p is an integer of 0 (where the phenyl ring is fully hydrogen substituted), 1, 2, 3, 4 or 5, and more preferably is 1, 2 or 3;
s is an integer of from 0 to 7, and more preferably is 0 (i.e. where the naphthyl ring is fully hydrogen-substituted), 1, 2, 3 or 4;
R1, R2, R3, X, m and n are each the same as defined above for Formula II; and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of Formula IIa include those where p is 1 or greater, e.g. compounds that are substituted at the ortho, meta and/or para phenyl ring positions by R" group(s) other than hydrogen, or 2,5-phenyl ring substituted, 2,3,5-phenyl ring substituted or 2,4,5-phenyl ring substituted by non-hydrogen R" groups such as halogen, substituted or unsubstituted alkyl having 1 to about 6 carbon atoms, substituted or unsubstituted alkoxy having 1 to about 6 carbon atoms, or substituted or unsubstituted alkylthio having 1 to about 6 carbon atoms. It is of course understood that where a phenyl or napthyl group of Formulae IIa or IIaa is not substituted by an R" group, the ring position is hydrogen-substituted. While as shown by the above structure Formula IIaa includes compounds that have either a 1-naphthyl or 2-naphthyl amino (-N(R1)-) substituent, compounds having a 1-naphthyl group are generally more preferred. Compounds of Formula IIaa that have a non-hydrogen R" substituent at the 4-naphthyl position are also particularly preferred.
Compounds of Formula II may suitably contain one or more
tetrahydroquinolinyl (or derivative thereof) ring substituents, i.e. the sum of the values of m and n of Formula II is one or more. It is understood that references herein to "derivatives" of tetrahydroquinolinyl compounds of Formula II refer to those compounds where the group X is other than substituted or unsubstituted methylene.
Generally preferred compounds of Formula II that include tetrahydroquinolinyl (or derivative thereof) ring substituents contain no more than about three non-hydrogen R2 substituents, including compounds that contain 0 (i.e. each of
tetrahydroquinolinyl ring positions 2, 3 and 4 is -CH2-) or 1 (i.e. two ring positions is -CH2- and the other is -CH(R2)-) R2 substituents. Generally preferred compounds also include those that contain 0 (ring positions 5-8 each hydrogen substituted), 1 or 2 non-hydrogen R3 ring substituents.
Preferred compounds of Formula II also include those that are unsubstituted on the tetrahydroquinolinyl (or derivative thereof) ring, i.e. m and n or Formula II are each 0, particularly compounds of the following Formula lib:
Figure imgf000018_0001
where R and R1 are the same as defined above for Formula II; and
pharmaceutically acceptable salts thereof. The above noted preferred R and R1 groups of Formula II are also preferred groups of compounds of Formula lib.
In another aspect, compounds of Formula II" are provided, which is defined the same as Formula II above, but where X is sulfinyl (i.e.-S(O)-) or sulfonyl (i.e. -S(O2)-). Preferred substimtents of compounds of Formula II as noted herein are also preferred substituents for corresponding positions for compounds of Formula II". Preferred compounds of Formula III include those where R is substituted or unsubstituted carbocyclic aryl such as substituted or unsubstituted phenyl, naphthyl or acenaphthyl, particularly substituted or unsubstituted phenyl or naphthyl, i.e.
compounds of the following Formulae IIIa and IIIaa:
Figure imgf000019_0001
Figure imgf000019_0002
wherein for each of Formulae IIIa and IIIaa each R" is independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted
alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, or substituted or
unsubstituted aralkyl;
p is an integer of 0 (where the phenyl ring is fully hydrogen substituted), 1, 2, 3, 4 or 5, and more preferably is 1, 2 or 3;
s is an integer of from 0 to 7, and more preferably is 0 (i.e. where the naphthyl ring is fully hydrogen-substituted), 1, 2, 3 or 4;
R1, R2, R3, m and n are each the same as defined above for Formula III; and pharmaceutically acceptable salts thereof. Particularly preferred compounds of Formula IIIa include those where p is 1 or greater, e.g. compounds that are substituted at the ortho, meta and/or para phenyl ring positions by R" group(s) other than hydrogen, or 2,5-phenyl ring substituted, 2,3,5-phenyl ring substituted or 2,4,5-phenyl ring substituted by non-hydrogen R" groups such as halogen, substituted or unsubstituted alkyl having 1 to about 6 carbon atoms, substituted or unsubstituted alkoxy having 1 to about 6 carbon atoms, or substituted or unsubstituted alkylthio having 1 to about 6 carbon atoms. It is of course understood that where a phenyl or napthyl group of Formulae IIIa or IIIaa is not substituted by an R" group, the ring position is hydrogen-substituted. While as shown by the above structure Formula IIIaa includes compounds that have either a 1-naphthyl or 2-naphthyl amino (-N(R1)-) substituent, compounds having a 1-naphthyl group are generally more preferred. Compounds of Formula IIIaa that have a nonhydrogen R" substituent at the 4-naphthyl position are also particularly preferred.
Compounds of Formula III may suitably contain one or more
tetrahydroisoquinolinyl ring substituents, i.e. the sum of the values of m and n of Formula III is one or more.
Generally preferred compounds of Formula III that include
tetrahydroisoquinolinyl ring substituents contain no more than about three nonhydrogen R2 substituents, including compounds that contain 0 (i.e. each of tetrahydroisoquinolinyl ring positions 1, 3 and 4 is -CH2-) or 1 (i.e. two ring positions are -CH2- and the other is -CH(R2)-) non-hydrogen R2 substituents.
Generally preferred compounds also include those that contain 0 (ring positions 5-8 each hydrogen substituted), 1 or 2 non-hydrogen R3 ring substituents.
Preferred compounds of Formula III also include those that are unsubstituted on the tetrahydroisoquinolinyl ring, i.e. m and n or Formula III are each 0, particularly compounds of the following Formula IIIb:
Figure imgf000020_0001
where R and R1 are the same as defined above for Formula II; and
pharmaceutically acceptable salts thereof. The above noted preferred R and R1 groups of Formula III are also preferred groups of compounds of Formula IIIb.
Preferred compounds of Formula IV as defined above include those where R is substituted or unsubstituted carbocyclic aryl, particularly substituted or
unsubstituted phenyl, naphthyl and acenaphthyl.
Substimted and unsubstituted phenyl and naphthyl are particularly preferred R groups of compounds of Formula IV, such as compounds of the following Formulae IVa and IVaa:
Figure imgf000021_0001
Figure imgf000021_0002
wherein for each of Formulae IVa and IVaa each R" is independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted
alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, or substituted or
unsubstituted aralkyl;
p is an integer of 0 (where the phenyl ring is fully hydrogen substituted), 1, 2, 3, 4 or 5, and more preferably is 1, 2 or 3; s is an integer of from 0 to 7, and more preferably is 0 (i.e. where the naphthyl ring is fully hydrogen-substituted), 1, 2, 3 or 4;
R1, R2, R3, m and n are each as defined above for Formula IV; and pharmaceutically acceptable salts thereof.
Preferred compounds of Formula IVa include those where p is 1 or greater, e.g. compounds that are substituted at the ortho, meta and/or para phenyl ring positions by R" group(s) other than hydrogen, or 2,5-phenyl ring substituted, 2,3,5-phenyl ring substituted or 2,4,5-phenyl ring substituted by non-hydrogen R" groups such as halogen, substituted or unsubstituted alkyl having 1 to about 6 carbon atoms, substituted or unsubstituted alkoxy having 1 to about 6 carbon atoms, or substituted or unsubstituted alkylthio having 1 to about 6 carbon atoms. It is of course understood that where a phenyl or napthyl group of Formulae IVa or IVaa is not substituted by an R" group, the ring position is hydrogen- substituted. While as shown by the above strucmre Formula IVaa includes compounds that have either a 1-naphthyl or 2-naphthyl amino substiment, compounds having a 1-naphthyl group are generally more preferred. Compounds of Formula IVaa that have a non-hydrogen R" substiment at the 4-naphthyl position are also particularly preferred.
Compounds of Formula IV may suitably contain one or more benzindolinyl ring substituents, i.e. the sum of the values of m and n of Formula IV is one or more.
Generally preferred compounds of Formula IV that include benzindolinyl ring substituents contain 0 R2 substituents (i.e. the 2 benz[cd]indolinyl positions is -CH2-), or 1 non-hydrogen R2 substiment.
Generally preferred compounds of Formula IV also include those that contain 0 (i.e. benz[cd]indolinyl ring positions 3-8 each hydrogen substituted), 1 or 2 R3 ring substituents.
Preferred compounds of Formula IV also include those compounds that are unsubstituted on the benzindolinyl ring (each m and n as defined above for Formula IV is 0), i.e. compounds of the following Formula IVb:
Figure imgf000023_0001
wherein the groups R and R1 are the same as defined above for Formula III; and pharmaceutically salts thereof. The above noted preferred R and R1 groups of Formula IV are also preferred R and R1 groups of compounds of Formula IVb.
Preferred compounds of Formula V include those where R is substituted or unsubstituted carbocyclic aryl such as substituted or unsubstituted phenyl, naphthyl or acenaphthyl, particularly substituted or unsubstituted phenyl or naphthyl, such as compounds of the following Formulae Va and Vaa:
Figure imgf000023_0002
Figure imgf000023_0003
wherein for each of Formulae Va and Vaa each R" is independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted
alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, or substituted or
unsubstituted aralkyl;
p is an integer of 0 (where the phenyl ring is fully hydrogen substituted), 1, 2, 3, 4 or 5, and more preferably is 1, 2 or 3;
s is an integer from 0 to 7, and more preferably is 0 (i.e. where the naphthyl ring is fully hydrogen-substituted), 1 , 2, 3 or 4;
R1, R2, R3, R4, m, n and r are each as defined above for Formula V; and pharmaceutically acceptable salts thereof.
Preferred compounds of Formula Va include those where p is 1 or greater, e.g. compounds that are substituted at the ortho and/or meta phenyl ring positions by R" groups other than hydrogen, or 2,5-phenyl ring substituted, 2,3,5-phenyl ring substituted or 2,4,5-phenyl ring substituted by R" groups other than hydrogen such as halogen, substituted or unsubstituted alkyl having 1 to about 6 carbon atoms, substituted or unsubstituted alkoxy having 1 to about 6 carbon atoms, or substituted or unsubstituted alkylthio. It is of course understood that where a phenyl or napthyl group of Formulae Va or Vaa is not substituted by an R" group, the ring position is hydrogen-substituted. While as shown by the above structure Formula Vaa includes compounds that have either a 1-naphthyl or 2-naphthyl amino substituent, compounds having a 1-naphthyl group are generally more preferred. Compounds of Formula Vaa that have a non-hydrogen R" substituent at the 4-naphthyl position are also
particularly preferred.
Compounds of Formula V may suitably contain one or more 5,6-dihydrophenanthridinyl ring substituents, i.e. the sum of the values of m and n of Formula V is one or more.
Generally preferred compounds of Formula V include those compounds that contain 0 (i.e. the 6-hydrophenanthridinyl ring position is -CH2-), or 1 (i.e. the 6-hydrophenanthridinyl ring position is -CH(R2)-) non-hydrogen R2 substituents.
Generally preferred compounds also include those that contain 0 (ring positions 5-8 each hydrogen substituted), 1 or 2 R3 and/or R4 ring substituents. Preferred compounds of Formula V include those that are unsubstituted on the 5,6-dihydrophenanthridinyl ring (m, n and r each zero), particularly compounds of the following Formula Vb:
Figure imgf000025_0001
where R and R1 are each the same as defined above for Formula V; and pharmaceutically acceptable salts thereof. The above noted preferred R and R1 groups of Formula V are also preferred R and R1 groups of compounds of Formula Vb.
Suitable halogen substituent groups of compounds of Formulae I, I', I", la, Iaa, lb, II, II" , IIa, IIaa, IIb, III, IIIa, IIIaa, nib, IV, IVa, IVaa, IVb, V, Va, Vaa, Vb, VI, VII, VIII or IX, as defined above (i.e. compounds of the invention) include F, Cl, Br and I. Alkyl groups of compounds Formulae I, I", II, II", III, IV, V, VI, VII, VIII or IX preferably have from 1 to about 12 carbon atoms, more preferably 1 to about 8 carbon atoms, still more preferably 1 to about 6 carbon atoms, even more preferably 1, 2, 3 or 4 carbon atoms. (It is understood that references herein to Formulae I; I"; II; II"; III; IV; and V apply equally to compounds of Formulae I', la, Iaa and lb; IIa, IIaa and IIb; IIIa, IIIaa and IIIb; IVa, IVaa and IVb; Va, Vaa and Vb, respectively, as those formulae are defined herein. Hence, suitable and preferred substituent groups of Formulae I, I", II, II", III, IV and V are also suitable and preferred substiment groups of compounds of Formulae I', la, Iaa, lb, IIa, IIaa, IIb, IIIa, IIIaa, IIIb, IVa, IVaa, IVb, Va, Vaa and Vb unless otherwise indicated.)
Methyl, ethyl and propyl including isopropyl are particularly preferred alkyl groups of compounds of the invention. As used herein, the term alkyl unless otherwise modified refers to both cyclic and noncyclic groups, although of course cyclic groups will comprise at least three carbon ring members. Preferred alkenyl and alkynyl groups of compounds of the invention have one or more unsaturated linkages and from 2 to about 12 carbon atoms, more preferably 2 to about 8 carbon atoms, still more preferably 2 to about 6 carbon atoms, even more preferably 1 , 2, 3 or 4 carbon atoms. The terms alkenyl and alkynyl as used herein refer to both cyclic and noncyclic groups, although straight or branched noncyclic groups are generally more preferred. Preferred alkoxy groups of compounds of Formulae I, I", II, II", III, IV,
V, VI, VII, VIII or IX include groups having one or more oxygen linkages and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms, even more preferably 1, 2, 3 or 4 carbon atoms. Preferred alkylthio groups of compounds of Formulae I through IX (which includes Formulae I" and II") include those groups having one or more thioether linkages and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms. Alkylthio groups having 1, 2, 3 or 4 carbon atoms are particularly preferred. Preferred alkylsulfinyl groups of compounds of the invention include those groups having one or more sulfoxide (SO) groups and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms. Alkylsulfinyl groups having 1, 2, 3 or 4 carbon atoms are particularly preferred. Preferred alkylsulfonyl groups of compounds of the invention include those groups having one or more sulfonyl (SO2) groups and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms. Alkylsulfonyl groups having 1, 2, 3 or 4 carbon atoms are particularly preferred. Preferred aminoalkyl groups include those groups having one or more primary, secondary and/or tertiary amine groups, and from 1 to about 12 carbon atoms, more preferably 1 to about 8 carbon atoms, still more preferably 1 to about 6 carbon atoms, even more preferably 1, 2, 3 or 4 carbon atoms. Secondary and tertiary amine groups are generally more preferred than primary amine moieties. Suitable heteroaromatic groups of compounds of Formulae I, I", II, II", III, IV, V,
VI, VII, VIII or IX contain one or more N, O or S atoms and include, e.g., coumarinyl including 8-coumarinyl, quinolinyl including 8-quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl and benzothiazol. Suitable heteroalicyclic groups of compounds of Formulae I, I", II, II", III, IV, V, VI, VII, VIII or IX contain one or more N, O or S atoms and include, e.g., tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholino and pyrrolindinyl groups. Suitable carbocyclic aryl groups of compounds of Formulae I, I", II, II", III, IV, V, VI, VII, VIII or IX include single and multiple ring compounds, including multiple ring compounds that contain separate and/or fused aryl groups. Typical carbocyclic aryl groups contain 1 to 3 separate or fused rings and from 6 to about 18 carbon ring atoms. Specifically preferred carbocyclic aryl groups include phenyl including substituted phenyl, such as 2-substituted phenyl, 3-substituted phenyl, 2,3-substituted phenyl, 2,5-substituted phenyl, 2,3,5-substituted and 2,4,5-substituted phenyl, including where the phenyl substituents are selected from the same group as defined above in Formulae I-V for R3; naphthyl including 1-naphthyl and 2-naphthyl; biphenyl; phenanthryl; and anthracyl. Suitable aralkyl groups of compounds of Formulae I, I", II, n", III, IV, V, VI, VII, VIII or IX include single and multiple ring compounds, including multiple ring compounds that contain separate and/or fused aryl groups. Typical aralkyl groups contain 1 to 3 separate or fused rings and from 6 to about 18 carbon ring atoms. Preferred aralkyl groups include benzyl and methylenenaphthyl (-CH2-naphthyl).
References herein to substituted R, R1, R2, R3, R4, R" and X groups of compounds of the invention refer to the specified moiety that may be substituted at one or more available positions by one or more suitable groups such as, e.g. , halogen such as fluoro, chloro, bromo and iodo; cyano; hydroxyl; nitro; azido; alkanoyl such as a C1-6 alkanoyl group such as acyl and the like; carboxamido; alkyl groups including those groups having 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms and more preferably 1-3 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 12 carbon or from 2 to about 6 carbon atoms; alkoxy groups having those having one or more oxygen linkages and from 1 to about 12 carbon atoms or 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those moieties having one or more thioether linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; alkylsulfinyl groups including those moieties having one or more sulfinyl linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; alkylsulfonyl groups including those moieties having one or more sulfonyl linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; aminoalkyl groups such as groups having one or more N atoms and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; carbocylic aryl having 6 or more carbons, particularly phenyl (e.g. R being a substituted or unsubstituted biphenyl moiety); and aralkyl such as benzyl. Generally preferred substituents of substituted nitrogen and methylene X groups of compounds of Formulae I, II and VI include the groups from which R2 is selected in Formulae I, II and VI. More typical substituents of substituted nitrogen and methylene X groups of compounds of Formulae I, II and VI include substituted and unsubstituted alkyl, including C1-4 alkyl and halosubstituted C1-4 alkyl, particularly fluoro-substituted C1-4 alkyl such as trifluoromethyl, and in the case of a substituted methylene group, halogen and alkylthio.
It should be understood that alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl and aminoalkyl substituent groups described above include groups where a hetero atom is directly bonded to a ring system, such as a carbocyclic aryl group or a heterocyclic group, as well as groups where a hetero atom of the group is spaced from such ring system by an alkylene linkage, e.g. of 1 to about 4 carbon atoms.
Preferred carbocyclic ring substituents of compounds of Formulae I, I" , II, II", III, IV, V, VI, VII, VIII or IX (including substituents of the group R where R is a carbocyclic ring such as phenyl or naphthyl, i.e. compounds of Formula la, Iaa, IIa, IIaa, IIIa, IIIaa, IVa, IVaa, Va and Vaa where p or s≥ 1 and R" is other than hydrogen) include halogen, particularly F, Cl and Br; hydroxyl; azido; substituted or unsubstituted alkyl having 1 to about 6 carbons such as methyl, ethyl, propyl and butyl, and including halogenated alkyl, particularly fluoro-alkyl having 1 to about 6 carbon atoms; substituted and unsubstituted alkoxy having 1 to about 6 carbons and including halogenated alkoxy, particularly fluoro-alkoxy having 1 to about 6 carbon atoms; substituted and unsubstituted alkylthio having 1 to about 6 carbons; substituted and unsubstituted alkylsulfinyl having 1 to about 6 carbons; substituted and
unsubstituted alkylsulfonyl having 1 to about 6 carbons; and carbocylic aryl, particularly phenyl to provide a substituted phenyl R group that is bi-phenyl.
Typically preferred phenyl ring substituents have 1 to 4 carbon atoms with methyl, ethyl, propyl including isopropyl and butyl including sec-butyl being particularly preferred. Halogen-substituted alkyl and alkoxy groups are also particularly preferred including fluoroalkyl having 1 , 2, 3 or 4 carbon atoms such as trifluoromethyl and fluoro-substituted alkoxy having 1, 2, 3 or 4 carbon atoms such as trifluoromethoxy (-OCF3). Methylthio (-SCH3) and ethylthio (-SCH2CH3) are also particularly preferred phenyl ring substituents. Preferred alkylsulfinyl ring substituents of carbocyclic aryl groups of compounds of the invention typically have one or more sulfoxide groups, more typically, one or two sulfoxide groups and from 1 to about 8 carbon atoms, more preferably 1 to about 6 carbon atoms, even more preferably 1 to about 3 carbon atoms. Methylsulfinyl (-S(O)CH3) and ethylsulfinyl (-S(O)CH2CH3) are particularly preferred R2, R3 and R4 alkylsulfinyl ring substituents as well as preferred ring substituents of a substituted carbocyclic R group. In particular, methylsulfinylphenyl and ethylsulfinylphenyl are preferred R groups. Preferred substituted alkylsulfinyl substituents include haloalkylsulfinyl groups that contain one or more F, Cl, Br or I atoms, preferably one or more F atoms, and preferably 1 to about 3 carbon atoms, more preferably one or two carbon atoms. Specifically preferred groups include fluoromethylsulfinyl, particularly trifluoromethylsulfinyl (-S(O)CF3), and
fluoroethylsulfinyl such as 2-trifluoroethylsulfinyl (-S(O)CH2CF3) and
pentafluoroethylsulfinyl (-S(O)CF2CF3). Preferred alkylsulfonyl ring substituents of carbocyclic aryl group compounds of the invention have one or more sulfono (SO2) groups, more typically one sulfono group, and from 1 to about 8 carbon atoms, still more preferably 1 to about 6 carbon atoms, even more preferably 1 to about 3 carbon atoms. Methylsulfonyl (-S(O)2CH3) and ethylsulfonyl (-S(O)2CH2CH3) are
particularly preferred sulfonoalkyl ring substituents. Preferred substituted
alkylsulfonyl substituents include haloalkylsulfonyl groups that contain one or more F, Cl, Br or I atoms, preferably one or more F atoms, and preferably 1 to about 3 carbon atoms, more preferably one or two carbon atoms. Specifically preferred groups include fluoromethylsulfonyl, particularly trifluoromethylsulfonyl (-S(O)2CF3), and fluoroethylsulfonyl such as 2-trifluoroethylsulfonyl (-S(O)2CH2CF3) and
pentafluoroethylsulfonyl (-S(O)2CF2CF3) .
Without wishing to be bound by theory, compounds of the invention that contain an alkylsulfinyl and/or alkylsulfonyl group, may be, in effect, "pro-drugs" wherein after administration of the compound to a subject the sulfinyl or sulfonyl group(s) are metabolized (reduced) in vivo to the corresponding sulfide moiety.
Specifically preferred compounds of Formula I include the following: N-(4-benzyloxyphenyl)-1-indolinylcarboximidamide;
N-(4-methoxynaphthyl)-1-indoIinylcarboximidamide;
N-(1-naphthyl)-1-indolinylcarboximidamide;
N-(3,4-dimethoxynaphthyl)-1-indolinylcarboximidamide;
N-(3,4-dichlorophenyl)-1-indolinylcarboximidamide;
N-(1-naphthyl)-1-(7-ethyl)-indolinylcarboximidamide;
N-(2-naphthyl)-1-(7-ethyl)-indolinylcarboximidamide;
N-(4-sec-butylphenyl)-1-indolinylcarboximidamide;
N-(2,3-dichlorophenyl)-1-mdolmylcarboximidamide;
N-(2,3-dimethylphenyl)-1-indolinylcarboximidamide;
N-(5,6,7,8-tetrahydro-1-naphthyl)-1-indolinylcarboximidamide;
N-(2-biphenyl)-1-indolmylcarboximidamide;
N-(1-naphthyl)-N-methyl-1-indolinylcarboximidamide;
N-(2-naphthyl)-1-indolinylcarboximidamide;
N-phenyl-1-indolinylcarboximidamide ;
N-(2-chlorophenyl)-1-indolinylcarboximidamide;
N-(2-methylphenyl)-1-indolinylcarboximidamide;
N-(3-methylphenyl)-1-indolinylcarboximidamide;
N-(2,5-dimethylphenyl)-1-indolinylcarboximidamide ;
N-(2,5-dibromophenyl)-1-indolinylcarboximidamide;
N-(2,5-dichlorophenyl)-1-indolinylcarboximidamide;
N-(5-acenaphthyl)-1-(5-methoxy)-indolinylcarboximidamide ;
N-(5-acenaphthyl)-1-(5-bromo)-indolinylcarboximidamide;
N-(2,3-dimethoxyphenyl)-1-mdolinylcarboximidamide;
and pharmaceutically acceptable salts of said compounds.
N-(1-naphthyl)-1-indolinylcarboximidamide and pharmaceutically acceptable salts thereof are particularly preferred compounds of Formula I.
Additional preferred compounds of Formula I include the following where the compound is structurally depicted above the chemical name thereof, and
pharmaceutically acceptable salts of these depicted compounds.
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Specifically preferred compounds of Formula II include the following:
N-(1-naphthyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(1-naphthyl)-1-(7-trifluoromethyl)-(1,2,3,4-tetrahydroquinolinyl) carboximidamide;
N-(1-naphthyl)-1-(7-methyl)-(1,2,3,4-tetrahydroquinolinyl)
carboximidamide;
N-(2,5-dibromophenyl)-1-(7-trifluoromethyl)-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(1-naphthyl)-1-(2-trifluoromethyl)-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(4-benzyloxyphenyl)-1-(1 ,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(4-methoxynaphthyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(3,4-dichlorophenyl)-1-(1 ,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(5-acenaphthyl)-1-(5-methoxy)-(1 ,2,3,4-tetrahydroquinolinyl)
carboximidamide;
N-(5-acenaphthyl)-1-(5-bromo)-(1,2,3,4-tetrahydroquinolinyl)
carboximidamide;
N-(1-naphthyl)-1-(7-ethyl)-(1,2,3,4-tetrahydroquinolinyl)
carboximidamide;
N-(4-sec-butylphenyI)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2,3-dichlorophenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2,3-dimethylphenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(5,6,7,8-tetrahydro-1-naphthyl)-1-(1,2,3,4-tetrahydroquinolinyl)
carboximidamide;
N-(2-biphenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(3-biphenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(1-naphthyl)-1-(1 ,2,3,4-tetrahydroquinolinyl)carboximidamide; N-(2-ethylphenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(3-ethylphenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2,5-dimethylphenyl)-1-(1,2,3,4-tetrahydroquinoIinyl)carboximidamide;
N-(2-chloro-5-ethylphenyl)-1-(7-trifluoromethyl)-(1,2,3,4-tetrahydroquinolinyl) carboximidamide;
N-(2,5-dibromophenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2,5-dichlorophenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(3-methylthiophenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2,3-dichlorophenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2,3-difluorophenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
and pharmaceutically acceptable salts of said compounds.
N-(2,5-dibromophenyl)-1-(7-trifluoromethyl)-(1,2,3,4-tetrahydroquinolinyl) carboximidamide and pharmaceutically acceptable salts thereof are particularly preferred compounds of Formula II, i.e. the compound of the following structure and pharmaceutically acceptable salts thereof:
Figure imgf000036_0001
Additional preferred compounds of Formulae II and IF include the following where the compound is structurally depicted above the chemical name thereof, and pharmaceutically acceptable salts of these depicted compounds.
Figure imgf000036_0002
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Specifically preferred compounds of Formula III include the following: N-(1-naphthyl)-1-(1,2,3,4-tetrahydroisoqumolmyl)carboximidamide;
N-(1-naphthyl)-1-(7-trifluoromethyl)-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(1-naphthyl)-1-(7-methyl)-(1 ,2,3,4-tetrahydroisoquinolinyl)
carboximidamide;
N-(2,5-dibromophenyl)-1-(7-trifluoromethyl)-(1,2,3,4-tetrahydroisoquinolinyl) carboximidamide;
N-(1-naphthyl)-1-(2-trifluoromethyl)-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(4-benzyloxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide; N-(4-methoxynaphthyl)-1-(1 ,2,3,4-tetrahydroisoquinoIinyl)carboximidamide;
N-(3,4-dichlorophenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(5-acenaphthyl)-1-(5-methoxy)-(1,2,3,4-tetrahydroisoquinolinyl)
carboximidamide;
N-(5-acenaphthyl)-1-(5-bromo)-(1,2,3,4-tetrahydroisoquinolinyl)
carboximidamide;
N-(1-naphthyl)-1-(7-ethyl)-(1,2,3,4-tetrahydroisoquinolinyl)
carboximidamide; N-(4-sec-butylphenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(2,3-dichlorophenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(2,3-dimethylphenyl)-1-(1,2,3,4-tetrahydroisoquinoIinyl)carboximidamide;
N-(5,6,7,8-tetrahydro-1-naphthyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)
carboximidamide;
N-(2-biphenyl)-1-(1 ,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(3-biphenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(1-naphthyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(2-ethylphenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(3-ethylphenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(2,5-dimethylphenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(2-chloro-5-ethylphenyl)-1-(7-trifluoromethyl)-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(2,5-dibromophenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide; N-(2,5-dibromophenyl)-1-(1,2,3,4-tetrahydroisoquinolinyI)carboximidamide;
N-(3-methylthiophenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(2,3-dichlorophenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(2,3-difluorophenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide; and pharmaceutically acceptable salts of said compounds.
Specifically preferred compounds of Formula IV include the following:
N-(3-biphenyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(1-naphthyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(2-methylphenyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(2,3-dimethylphenyl)-1-(benzfcd]indolinyl)carboximidamide;
N-(2,5-dimethylphenyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(4-benzyloxyphenyl)-1-(benz[cd]indolinyl)carboximidamide ;
N-(4-methoxynaphthyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(3,4-dichlorophenyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(5-acenaphthyl)-1-(5-methoxy)-1-(benz[cd]indolinyl)carboximidamide;
N-(5-acenaphthyl)-1-(5-bromo)-(benz[cd]indolinyl)carboximidamide;
N-(1-mphthyl)-1-(7-ethyl)-(benz[cd]indolinyl)carboximidamide;
N-(4-sec-butylphenyl)-1-(benz[cd]indolinyl)carboximidamide; N-(2,3-diclnorophenyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(3-methylphenyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(5,6,7,8-tetrahydro-1-naphthyl)-1-(benz[cd]indolinyl)carboximidamide ;
N-(2-biphenyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(1-naphthyl)-1-(7-trifluoromethyl)-(benz[cd]indolinyl)carboximidamide ;
N-(3-ethylphenyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(2,5-dibromophenyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(2,5-dichlorophenyl)-1-(benz[cd]indolinyl)carboximidamide;
and pharmaceutically acceptable salts of said compounds.
N-(2-methylphenyl)-1-(benz[cd]indolinyl)carboximidamide is a particularly preferred compound of Formula IV.
Additional preferred compounds of Formula IV include the following where the compound is structurally depicted above the chemical name thereof, and pharmaceutically acceptable salts of these depicted compounds.
Figure imgf000044_0001
Figure imgf000045_0001
Specifically preferred compounds of Formula V include the following:
N-(1-naphthyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(4-benzyloxyphenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(4-methoxynaphthyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(3,4-dichlorophenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide; N-(5-acenaphthyl)-1-(5-methoxy)-1-(5,6-dihydrophenanthridinyl)
carboximidamide;
N-(5-acenaphthyl)-1-(5-bromo)-(5,6-dihydrophenanthridinyl)
carboximidamide;
N-(1-naphthyl)-1-(7-ethyl)-(5,6-dihydrophenanthridinyl)
carboximidamide;
N-(4-sec-butylphenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(2,3-dichlorophenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide; N-(2,3-dimethylphenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide ;
N-(5,6,7,8-tetrahydro-1-naphthyl)-1-(5,6-dihydrophenanthridinyl)
carboximidamide ;
N-(2-biphenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide ;
N-(3-biphenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide ;
N-(1-naphthyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide ;
N-(1-naphthyl)-1-(7-trifluoromethyl)-(5,6-dihydrophenanthridinyl)
carboximidamide ;
N-(2-methylphenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide ;
N-(3-ethylphenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide ;
N-(2,5-dimethylphenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide ;
N-(2-ethylphenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
and pharmaceutically acceptable salts of said compounds.
Specifically preferred compounds of Formula VI include the following where the where the compound is structurally depicted above the chemical name thereof, and pharmaceutically acceptable salts of these depicted compounds:
Figure imgf000046_0001
y [ p
yl]carboximidamide
Specifically preferred compounds of Formula VII include the following where the where the compound is structurally depicted above the chemical name thereof, and pharmaceutically acceptable salts of these depicted compounds:
Figure imgf000046_0002
Figure imgf000047_0001
Specifically preferred compounds of Formulae VIII and IX include the following where the where the compound is structurally depicted above the chemical name thereof, and pharmaceutically acceptable salts of these depicted compounds:
Figure imgf000047_0002
Excluded from certain aspects of the invention are N-(alkylphenyl)-1-indolinylcarboximidamide compounds (i.e. compounds of Formula I where X is CH2 and R is alkyl-substituted phenyl, particularly where R1 is H), specifically N-(monoalkylphenyl)-1-mdolinylcarboximidamide such as N-(m-ethylphenyl)-1-indolinyl carboximidamide; as well as compounds of the invention where R is acenaphthyl, particularly where R is unsubstituted acenaphthyl and/or ring substituents R2 and R3 are each only hydrogen, and/or where X is CH2 in the case of Formulae I and II, and/or one of R and R1 is hydrogen; as well as compounds of Formula III where R or R1 is aralkyl, particularly where ring substituents R2 and R3 are each only hydrogen, and/or R and R1 are each other than hydrogen.
Compounds of the invention can be prepared by the reaction of a suitable precursor compound, e.g. indolinyl (or derivative thereof) compound, 1,2,3,4-tetrahydroquinolinyl (or derivative thereof) compound, 1,2,3,4-tetrahydroisoquinolinyl compound, benz[cd]indolinyl compound, 5,6-dihydrophenanthridinyl compound, 2,3,4,5-tetrahydro-[1,5]-benzothiazepine compounds (or derviative thereof, e.g. where X is other atom), 2a,3,4,5-tetrabenz[cd]indoline compound, 5,6,11,12-tetrahydrodiben[b,f]azocine compound, etc. (depending on whether a compound of Formulae I, I", II, II", III, IV, V, VI, VII, VIII or IX respectively, is being prepared) with a preformed alkyl or aryl cyanamide (see S.R. Safer, et al., J. Org. Chem. , 13:924 (1948)) or the corresponding N-substituted alkyl or aryl cyanamide. Typically, a salt of the amine (e.g. an HCl salt) is reacted with the cyanamide.
More particularly, compounds the invention can be suitably prepared by reaction of an appropriate indolinyl (or derivative thereof) salt (to prepare compounds of Formulae I, I', I", la, Iaa or Ib), 1,2,3, 4-tetrahydroquinolinyl (or derivative thereof) salt (to prepare compounds of Formulae II, II", IIa, IIaa or lIb), 1,2,3,4-tetrahydroisoquinolinyl salt (to prepare compounds of Formulae III, IIIa, IIIaa or IIIb), benz[cd]indolinyl salt (to prepare compounds of Formulae IV, IVa, IVaa or IVb), or 5,6-dihydrophenanthridinyl salt (to prepare compounds of Formulae V, Va, Vaa or Vb) or other appropriate salt such as salts of above mentioned precursor compounds (to form compounds of Formulae VI-IX) with a substituted cyanamide in a suitable solvent such as toluene, chlorobenzene or the like under an inert
atmosphere such as argon or nitrogen as exemplified in the Scheme below. The reaction solution is then heated e.g. from about 110° to 120°C for 2 to about 16 hours until reaction completion, e.g. as indicated by thin layer chromatography. The reaction solution is then cooled to room temperature, and the solvent is then removed under reduced pressure to provide the desired compound of the invention. The crude product then can be purified by recrystallization and/or column chromatography, e.g. by elution one or more times on silica gel (e.g., 60-200 mesh, 50x w/w) with suitable solvents. See Example 2 which follows for exemplary conditions.
The indolinyl (or derivative thereof), 1,2,3,4-tetrahydroquinoline (or derivative thereof), 1,2,3,4-tetrahydroisoquinoline, benz[cd] indolinyl or 5,6-dihydrophenanthridinyl ot other presursor such as those mentioned above (for
Formulae VI-IX) and cyanamide reagents with appropriate substituents are
commercially available or can be readily prepared by known procedures. For example, the cyanamide starting material can be synthesized from the correspondingly substituted amine by treatment with cyanogen bromide (BrCN) in a suitable solvent such as dry ethyl ether or toluene at reduced temperatures (e.g. 0°C) or room temperature. As exemplified in the Scheme below, the amine to be reacted with cyanogen bromide is substituted with the R moiety as defined above for Formulae I, I" , II, II", III, IV, V, VI, VII, VIII or IX (in the Scheme, that R moiety is exemplified as phenyl which may be ring-substituted by groups R1 and R2). Thus, various R groups of compounds of Formula I through IX (Which includes Formulae I" and II") can be provided by use of suitable substituted amines that are reacted with BrCN, such as e.g. substituted and unsubstituted anilines as shown in the Scheme, substituted and unsubstituted 1-naphmylamine, 2-naphthylamine, acenaphthylamine, etc. R1 groups other than hydrogen of compounds of Formulae I through IX can be readily provided by reaction of a substituted cyanamide with a suitable nucleophile such as a halide reagent (e.g., a substituted or unsubstituted alkyl or alkenyl iodide or bromide). Thus, as exemplified in the Scheme below, the aryl cyanamide is reacted with NaH in a solvent of tetrahydrofuran and reacted with the iodide reagent RM, such as substituted or unsubstituted methyl, ethyl, propyl, butyl, etc. iodide, an alkenyl iodide, etc. Also, compounds of the invention having an R1 group of methyl can be prepared by reaction of a mono-substituted amine (e.g., an aniline,
naphthylamine or acenaphthylamine) with formic acid followed by treatment with lithium aluminum hydride to provide the corresponding methyl- substituted cyanamide (e.g., C6H5N(CH3)CN from unsubstituted aniline). Alkylsulfinyl-substituted or alkylsulfonyl-substituted reagents, that can provide correspondingly substituted compounds of the invention as described above, can be provided by oxidation (e.g. , H2O2) of alkylthio-substituted reagents. See for instance Example 46 which follows.
While the Scheme depicts preparation of compounds of Formula I, the same procedures can be employed to prepare compounds of Formulae I', II, II", III, IV, V, VI, VII, VIII or IX by use of a 1,2, 3, 4- tetrahydroquinolinyl (or derivative thereof) salt, 1,2,3,4-tetrahydroisoquinolinyl salt, benz[cd]indolinyl salt or 5,6-dihydrophenanthridinyl salt or other corresponding salt for compounds of Formulae VI through IX, respectively, in place of the indolinyl salt shown in the Scheme.
Figure imgf000050_0001
Compounds of Formula II where R and R1 are each hydrogen can be prepared by reaction of 1,2,3,4-tetrahydroquinoline compound with cyanamide. R2 substituents can be provided by reaction of a substituted or unsubstituted quinoline compound with a Grignard reagent followed by hydrogenation to provide the substituted 1,2,3,4-tetrahydroquinoline compound. See Example 3 which follows for an exemplary procedure. See also Examples 41 and 42 which follow. Compounds of Formulae I", H" and VI where X is -S(O)- or -S(O)2- can be prepared by oxidation (e.g. with H2O2 and/or with sodium periodate) of the corresponding preformed compounds where the ring member X is -S-. See for instance Example 47 which follows. The amine starting materials are commercially available and/or can be readily prepared. For example, benz[cd]indoline and 5,6-dihydrophenanthridine reagents can be prepared treatment of a benz[cd]indo-2(1H)-one compound or 5,6-dihydrophenanthridinone compound with a base such as diborane in a suitable solvent such as tetrahydrofuran. See Example 1 which follows for exemplary conditions. Chiral compounds of the invention may be used as optically enriched or racemic mixtures. An optically enriched mixture contains substantially more (e.g. about 60%, 70%, 80% or 90% or more) of one enantiomer or diastereoisomer than the other stereoisomers. Optically enriched mixtures can be obtained by known procedures, e.g. , column chromatography using an optically active binding material or formation of a salt using an optically active material, particularly an optically active acid.
Particularly preferred optically enriched mixtures include sulfinyl-containing compound of the invention, e.g. compounds of Formulae I", II" or VI where X is -S(O)-, or compounds having having an alkylsulfinyl or other sulfinyl substituent. Such optically active mxtures of sulfinyl-containing compounds can be readily prepared, e.g. by column chromatography using an optically active binding material.
As discussed above, the present invention includes methods for treating preventing certain neurological disorders, including the consequences of stroke, heart attack and traumatic head or brain injury, epilepsy or neurodegenerative diseases comprising the administration of an effective amount of one or more compounds of the invention to a subject including a mammal, particularly a human, in need of such treatment. In particular, the invention provides methods for treatment and/or prophylaxis of nerve cell death (degeneration) resulting e.g. from hypoxia,
hypoglycemia, brain or spinal cord ischemia, brain or spinal cord trauma, stroke, heart attack or drowning. Typical candidates for treatment include e.g. heart attack, stroke and/ or persons suffering from cardiac arrest neurological deficits, brain or spinal cord injury patients, patients undergoing major surgery such as heart surgery where brain ischemia is a potential complication and patients such as divers suffering from decompression sickness due to gas emboli in the blood stream. Candidates for treatment also will include those patients undergoing a surgical procedure involving extra- corporal circulation such as e.g. a bypass procedure. The invention in particular provides methods for treatment which comprise administration of one or more compounds of the invention to a patient that is undergoing surgery or other procedure where brain or spinal cord ischemia is a potential risk. For example, carotid endarterectomy is a surgical procedure employed to correct atherosclerosis of the carotid arteries. Major risks associated with the procedure include intraoperative embolization and the danger of hypertension in the brain following increased cerebral blood flow, which may result in aneurism or hemorrhage. Thus, an effective amount of one or more compounds of the present invention could be administered pre-operatively or peri-operatively to reduce such risks associated with carotid endarterectomy, or other post-surgical neuorological deficits.
The invention further includes methods for prophylaxis against neurological deficits resulting from e.g. coronary artery bypass graft surgery and aortic valve replacement surgery, or other procedure involving extra-corporal circulation. Those methods will comprise administering to a patient undergoing such surgical procedures an effective amount of one or more compounds of the invention, typically either pre- operatively or peri-operatively.
The invention also provides methods for prophylaxis and treatment against neurological injury for patients undergoing myocardial infarction, a procedure that can result in ischemic insult to the patient. Such methods will comprise administering to a patient undergoing such surgical procedure an effective amount of one or more compounds of the invention, typically either pre-operatively or peri-operatively.
Also provided are methods for treating or preventing neuropathic pain such as may experienced by cancer patients, persons having diabetes, amputees and other persons who may experience neuropathic pain. These methods for treatment comprise administration of an effective amount of one or more compounds of the invention to a patient in need of such treatment.
The invention also provides methods for treatment and prophylaxis against retinal ischemia or degeneration and resulting visual loss. For example, a compound of the invention can be administered parenterally or by other procedure as described herein to a subject a suffering from or susceptible to ischemic insult that may adversely affect retinal function, e.g. , significantly elevated intraocular pressures, diseases such as retinal artery or vein occlusion, diabetes or other ischemic ocularrelated diseases. Post- ischemic administration also may limit retinal damage. The invention also includes methods for treating and prophylaxis against decreased blood flow or nutrient supply to retinal tissue or optic nerve, or treatment or prophylaxis against retinal trauma or optic nerve injury. Subjects for treatment according to such therapeutic methods of the invention may be suffering or susceptible to retinal ischemia that is associated with atherosclerosis, venous capillary insufficiency, obstructive arterial or venous retinopthies, senile macular degeneration, cycstoid macular edema or glaucoma, or the retinal ischemia may be associated with a tumor or injury to the mammal. Intravitreal injection of a compound of the invention also may be a preferred administration route to provide more direct treatment to the ischemic retina.
The invention also provides methods for treatment of a subject suffering from shingles as well as treatment of a person suffering from or susceptible to migraines, particularly to alleviate the pain and discomfort associated with those disorders.
These methods comprise administration of an effective amount of one or more compounds of the invention to a patient in need of treatment.
The invention further provides a method of treating Korsakoff s disease, a chronic alcoholism-induced condition, comprising administering to a subject including a mammal, particularly a human, one or more compounds of the invention in an amount effective to treat the disease. Compounds of the invention are anticipated to have utility for the attenuation of cell loss, hemorrhages and/or amino acid changes associated with Korsakoff s disease.
As discussed above, the invention also includes methods for treating a person suffering from or susceptible to cerebral palsy, emesis, narcotic withdrawal symptoms and age-dependent dementia, comprising administering to a subject including a mammal, particularly a human, one or more compounds of the invention in an amount effective to treat the condition.
As discussed above, preferred compounds of the invention in a standard anticonvulsant in vivo audiogenic test, such as the audiogenic mouse assay of
Example 48 which follows, where DBA/2 mice about 20-23 days old are injected intraperitoneally with a test compound 30 minutes prior to being placed in a bell jar with exposure to auditory stimulus of 12KHz sine wave at 110-120 db. References herein in vivo "audiogenic assay" are intended to refer to that protocol. Generally preferred compounds exhibit 20% or more inhibition (relative to subjects treated with vehicle control only) at a dose of 20 mg/kg, more preferably about 50% or more or 70% or more inhibition at a dose of 20 mg/kg in such an in vivo audiogenic assay. As discussed above, activity in the audiogenic assay has been recognized as indicative that a test compound has neuroprotective properties. See, e.g. , M. Tricklebank et al., European Journal of Pharmacology, supra; T. Seyfried, Federation Proceedings, supra.
The invention also provides methods for determining binding activity of compounds of the invention as well as in vitro and in vivo binding activity diagnostic methods using one or more radiolabelled compounds of the invention, e.g., a compound of the invention that is labeled with 125I, tritium, 32P, 99Tc, or the like, preferably 125I. For instance, a compound of the invention having a phenyl or other aryl substituent that is ring substituted with one or more 125I groups can be
administered to a mammal and the subject then scanned for binding of the compound. Specifically, single photon emission computed tomography ("SPECT") can be employed to detect such binding. Such an analysis of the mammal could e.g. aid in the diagnosis and treatment of acute cerebral ischemia. That is, a labeled compound of the invention will selectively bind to ischemic tissue of e.g. a subject's brain to differentiate between ischemic and non- ischemic tissue and thereby assess trauma or other injury to the brain.
Accordingly, the invention includes compounds of the invention that contain a radiolabel such as 125I, tritium, 32P, 99Tc, or the like, preferably 125I. Such
radiolabelled compounds can be suitably prepared by procedures known in the synthesis art. For example, a compound of the invention having an aromatic group, such as phenyl, that has a bromo or chloro ring substituent can be employed in an exchange labeling reaction to provide the corresponding compound having an 125I ring substiment.
Compounds of the invention may be used in therapy in conjunction with other medicaments. For example, for treatment of a stroke victim or a person susceptible to stroke, one or more compounds of Formulae I, II, III, IV or V, or one or compounds of Formulae I", II", VI, VII, VIII or IX, may be suitably administered together with a pharmaceutical targeted for interaction in the blood clotting mechanism such as streptokinase, tPA, urokinase and other agents that lyse clots. Also, one or more compounds of the invention may be administered together with agents such as heparin and related heparin-based compounds, acenocoumarol or other known anticoagulants.
The compounds of this invention can be administered intranasally, orally or by injection, e.g. , intramuscular, intraperitoneal, subcutaneous or intravenous injection, or by transdermal, intraocular or enteral means. The optimal dose can be determined by conventional means. Compounds of the present invention are suitably
administered to a subject in the protonated and water-soluble form, e.g. , as a pharmaceutically acceptable salt of an organic or inorganic acid, e.g., hydrochloride, sulfate, hemi-sulfate, phosphate, nitrate, acetate, oxalate, citrate, maleate, mesylate, etc.
Compounds of the invention can be employed, either alone or in combination with one or more other therapeutic agents as discussed above, as a pharmaceutical composition in mixture with conventional excipient, i.e. , pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, enteral or intranasal application which do not deleteriously react with the active compounds and are not deleterious to the recipient thereof. Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, etc. The
pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously react with the active compounds.
For parenteral application, particularly suitable are solutions, preferably oily or aqueous solutions as well as suspensions, emulsions, or implants, including suppositories. Ampules are convenient unit dosages. For enteral application, particularly suitable are tablets, dragees or capsules having talc and/or carbohydrate carrier binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch. A syrup, elixir or the like can be used wherein a sweetened vehicle is employed. Sustained release compositions can be formulated including those wherein the active component is protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, etc.
Intravenous or parenteral administration, e.g., sub-cutaneous, intraperitoneal or intramuscular administration are preferred. The compounds of this invention are particularly valuable in the treatment of mammalian subjects, e.g. , humans, to provide neuroprotective therapy and/or prophylaxis. Typically, such subjects include those afflicted with neurodegenerative diseases such as Parkinson's disease,
Huntington's disease, Amyotrophic Lateral Sclerosis, Alzheimer's disease, Down's Syndrome and Korsakoff s disease. Also suitable for treatment are those subjects suffering from or likely to suffer from nervous system dysfunctions resulting from, for example, epilepsy or nerve cell degeneration which is the result of hypoxia, hypoglycemia, brain or spinal chord ischemia or brain or spinal chord trauma. As discussed above, typical candidates for treatment include heart attack, stroke, brain or spinal cord injury patients, patients undergoing major surgery where brain or spinal cord ischemia is a potential complication and patients such as divers suffering from decompression sickness due to gas emboli in the blood stream.
It will be appreciated that the actual preferred amounts of active compounds used in a given therapy will vary according to the specific compound being utilized, the particular compositions formulated, the mode of application, the particular site of administration, etc. Optimal administration rates for a given protocol of
administration can be readily ascertained by those skilled in the art using conventional dosage determination tests conducted with regard to the foregoing guidelines. In general, a suitable effective dose of one or more compounds of Formulae I, II, III, IV or V, or one or compounds of Formulae I", II", VI, VII, VIII or IX, particularly when using the more potent compound(s) of Formulae I, II, III, IV or V, or one or compounds of Formulae I", II", VI, VII, VIII or IX, will be in the range of from 0.01 to 100 milligrams per kilogram of bodyweight of recipient per day, preferably in the range of from 0.01 to 20 milligrams per kilogram bodyweight of recipient per day, more preferably in the range of 0.05 to 4 milligrams per kilogram bodyweight of recipient per day. The desired dose is suitably administered once daily, or several sub-doses, e.g. 2 to 4 sub-doses, are administered at appropriate intervals through the day, or other appropriate schedule. Such sub-doses may be administered as unit dosage forms, e.g. , containing from 0.05 to 10 milligrams of compound(s) of
Formulae I, II, III, IV or V, or one or compounds of Formulae I" , II", VI, VII, VIII or IX, per unit dosage, preferably from 0.2 to 2 milligrams per unit dosage.
Compounds of the invention also should be useful as rubber accelerators. See U.S. Patent No. 1,411,713 for a discussion of rubber accelerator applications.
The entire text of all documents cited herein are incorporated by reference herein. The following non-limiting examples are illustrative of the invention.
GENERAL COMMENTS
In the following examples, all percentages reported herein, unless otherwise specified, are percent by weight. All temperatures are expressed in degrees Celsius.
Melting points were determined in open capillary tubes on a Thomas-Hoover apparatus and are uncorrected. Thin-layer chromatography was performed on Bakerflex 1B2-F silica gel plates. Compounds were visualized on TLC with 254-nM UV light or as a blue spot with bromcresol spray reagent (Sigma Chemical Co.).
Preparative TLC was performed on Analtech GF precoated silica gel (1000 μm) glass-backed plates (20 × 20 cm). The IR, 1H and 13C NMR spectra of all compounds were consistent with their assigned structures. NMR spectra were recorded on Varian Gemini 300 and the chemical shifts were reported in ppm (δ) relative to the residual signal of the deuterated solvent (CDCl3, δ 7.26; CHD2OD, δ 3.30). Elemental analyses were performed by either Galbraith Laboratories (Knoxville, TN) or MHW Laboratories (Tuscon, AZ). High Resolution Mass spectra (HRMS) were recorded on a Finnegan MAT 90. HPLC were performed on a C18 reverse phase column using 50:50 water: acetonitrile with 0.1 % TFA as a mobile phase. BrCN was obtained from Aldrich Chemical Co., and was used as received. All starting amines were obtained from commercial sources and were purified by standard procedures before use, or they were prepared by published procedures. Chlorobenzene, ether (Et2O) and tetrahydrofuran (THF) were anhydrous quality solvents (Sure Seal) supplied by Aldrich. All other solvents were reagent grade. Alkyl- and
arylcyanamides were prepared as described above and according to published procedures (e.g. , PCT/US92/01050) by reaction of the amines with BrCN in ether. EXAMPLE 1
1(a). Preparation of Benz[cd]indoline HCl salt
Figure imgf000058_0001
To a cooled (ice bath) solution of Benz[cd]indo-2(1H)-one (9.0 g, 53.2 mmol) in tetrahydrofuran (50 ml) was added dropwise 100 ml of diborane 1M in
tetrahydrofuran (100 mmol) under argon. The resulting mixture was refluxed for 12 hours and quenched with aqueous HCl (1M) at 0-5°C. The solution was basified to pH 14 by adding NaOH 1N and the product extracted with chloroform. The combined organic layers were washed with brine and dried over MgSO4. Flash column chromatography (silica gel, 2:1 hexane/dichloromethane) afforded
Benz[cd]indoline (5.58 g, 67.6%). To form the HCl salt, Benz[cd]indoline (1.0g, 6.44 mmol) was then dissolved in a minimum amount of diethyl ether and 15 ml of 1M HCl diethyl ether solution was added. The precipitate was collected by filtration, washed with diethyl ether and dried to afford Benz[cd]indoline HCl (1.21 g, 98%) as a white solid. 1H-NMR (CD3OD): δ ppm 7.90-7.55 (m, ArH, 6H), 5.16 (s, ArCH2, 2H).
1(b). Preparation of 6-Dihydrophenanthridine HCl salt
Figure imgf000058_0002
The title compound was obtained as a white solid from 6(5H)-phenanthridinone by the method described in Example 1(a) above in 12% yleld. 1H-NMR (CD3OD): δ ppm 8.12-7.45 (m, ArH, 6H), 4.59 (s, ArCH2, 2H). EXAMPLE 2 Preparation of N-(1-Naphthyl)-1-indolinylcarboximidamide
(Formula I: R= 1-naphthyl, R1=hydrogen, m=n=0)
Part 1 : Preparation of 1-Naphthylcyanamide
Cyanogen bromide (4.4 gm, 41.9 mmol) was added in portions to the stirred and ice-bath cooled solution of 1-aminonaphthalene (10.0 gm, 69.8 mmol) in toluene
(100 mL). After 0.5 hour, the cooling bath was removed the reaction mixture was stirred at room temperature for 12 hours. The precipitate was filtered and the solid was triturated with water (150 mL) for 0.5 hour. The resulted solid was filtered and washed with water (4 × 20 mL) and the solid was dried in vacuum oven at 40 °C. This material (4.6 gm) was used as such without any further purification.
Part 2: Preparation of N-(1-Naphthyl)-1-indolinylcarboximidamide mesylate
A mixture of 1-naphthylcyanamide (610 mg, 3.63 mmol), indoline mesylate (663 mg, 3.09 mmol) and chlorobenzene (18 ml) in a round bottom flask were heated to reflux on an oil bath for 4 hours. The reaction was allowed to cool to room temperature, solvent was removed by rotavapor, and the residue was
chromatographed on silica gel using a mixture of hexanes: ethyl acetate (2: 1) followed by chloroform/methanol (10: 1) as eluents. The white foam-solid obtained upon concentration of fractions was treated with diethyl ether for overnight. White solid was filtered washed with diethyl ether to give the title product as free base as white solid; mp: 151-155°C; TLC (CHCl3:MeOH; 10: 1); Rf = 0.23; Η
NMR(CDCl3): 8.173-8.144 (m, ArH, 1H), 7.856-7.826 (m, ArH, 2H), 7.574-7.405 (m, ArH, 2H), 7.240-7.154 (m, ArH, 2H), 7.080-7.052 (m, ArH, 1H), 6.952-6.927 (m, ArH, 1H), 4.208-4.152 (t, J=8.45 Hz, CH2, 2H), 3.231-3.174 (t, J=8.45 Hz, CH2, 2H); Anal. Calcd. for C19H17N3 0.5H2O; C: 77.0, H: 6.07, N: 14.18; Found: C: 76.10, H: 5.78, N: 13.98. EXAMPLE 3 Preparation of (±) 2-(4-tert-butylphenyl)-6-isopropyl-1-(1,2,3,4- (tetrahydroquinolinylcarboximidamide) hydrochloride (Formula II: hydrochloride salt of R=R1=H, R2=2-(4-tert-butylphenyl), R3=6-isopropyl, X=CH2, m=n=1)
Part 1 : Preparation of 2-(4-tert-butylphenyl)-6-isopropylquinoline
Figure imgf000060_0001
To a cooled (ice bath) 2M diethyl ether solution of 4-tert-butylpheny .magnesium bromide (15 ml, 0.03 mol) was added dropwise under argon
15 ml of a tetrahydrofuran solution of 6-isopropylquinoline (5.13 g, 0.03 mol). The resulting mixture was refluxed for 5 hours, stirred at room temperature for 12 hours and quenched with water (80 ml). The yellow precipitate obtained was then filtered and washed with hexane. Crystallization in hexane: chloroform 40: 1 ylelded 3.7 g of pure (±)-2-(4-tert-butylphenyl)-6-isopropylquinoline (40% yleld). 1H NMR(CDCl3):
8.2 (m, ArH, 4H), 7.84 (m, ArH, 1H), 7.60 (m, ArH, 4H), 3.12 (s, CH(Me)2, 1H),
1.4 (s, CH(Me)2 and C(Me)3, 15H); Mass/Cl-NH3: MH+ 304.
Part 2: Preparation of (±)-2-(4-tert-butylphenyl)-6-isopropyl-1,2,3,4- tetrahydroquinoline hydrochloride
Figure imgf000060_0002
2-(4-tert-butylphenyl)-6-isopropylquinoline (2.5g, 8.2 mmol) was dissolved in 100 ml of methanol; platinum (IV) oxide (300 mg, 1.3 mmol) was added and the suspension hydrogenated at 50 psi for 12 hours. The catalyst was filtered off on a bed of celite and 20 ml of 1N HCl in ethyl ether was added to the filtrate which was then concentrated to yleld crude (±)-2-(4-tert-butylphenyl)-6-isopropyl-1 ,2,3,4-tetrahydroquinoline hydrochloride. Mass/Cl-NH3: MH+ 308.
Part 3: Preparation of (±)-2-(4-tert-butylphenyl)-6-isopropyl-1-(1,2,3,4- tetrahydroquinolinecarboximidamide hydrochloride
Figure imgf000061_0001
The crude (4-)-2-(4-tert-butylphenyl)-6-isopropyl-1,2,3,4-tetrahydroquinoline hydrochloride (300 mg, approximately 0.8 mmol) obtained in Part 2 above and cyanamide (350 mg, 8 mmol) were dissolved in ethanol and the mixture heated to reflux for 2 days. The solvent was evaporated, water was added and the product extracted with ethyl acetate. The crude product was purified on silica gel with chloroformrmethanol 9: 1 as eluant. The obtgained solid was washed successively with water and ethyl ether to yleld (±) 2-(4-tert-butylphenyl)-6-isopropyl-1-(1,2,3,4-tetrahydroquinolinylcarboximidamide) hydrochloride (70 mg, 21 %). 1H
NMR(CD3OD): δ ppm 7.40 (m, ArH, 3H), 7.20 (m, ArH, 4H), 5.30 (M, CHN, 1H), 2.90 (s, CH(Me)2, 1H), 2.70 (m, CH2, 2H), 1.9 (m, CH2, 2H), 1.25 and 1.28 (s, CH(Me)2 and C(Me)3, 15H); Mass/Cl-NH3: MH+ 350.
EXAMPLES 4-47
By methods indicated above in Examples 1-3 and using appropriately substituted reagents, the following compounds were prepared having the specified physical characteristics. EXAMPLE 4 N-(4-Benzyloxyphenyl)-1-indolinylcarboximidamide•mesylate
(Formula I: mesylate salt of R=4-benzyloxyphenyl, R1 =H, m=n=0)
White solid; mp: 144-145°C; TLC (CHCl3:MeOH; 10: 1); Rf = 0.37; 1H NMR (CDCl3): 7.391-6.858 (m, ArH, 13H), 5.000 (s, CH2, 2H), 3.894-3.841 (t, J=7.97 Hz, CH2, 2H), 3.143-3.090 (t, J=7.97 Hz, CH2, 2H), 2.706 (s, CH3, 3H); Anal. Calcd. for C23H25N3SO4: C: 62.85, H: 5.74, N: 9.57; Found: C: 62.66, H: 5.50, N: 9.38. EXAMPLE 5 N-(4-Methoxynaphthyl)-1-indolinylcarboximidamide•mesylate
(Formula I: mesylate salt of R=4-methoxy naphthyl, R1 =H, m=n=0)
White solid; mp: 151-155°C; TLC (CHCl3:MeOH; 10: 1); Rf = 0.23; 1H NMR(CDCl3): 8.313-7.097 (m, ArH, 9H), 6.723-6.695 (d, J=8.24 Hz, ArH, 1H), 3.996 (s, OCH3, 3H), 3.497-3,469 (t, CH2, 2H), 2.971 (t, CH2, 2H), 2.733 (s, CH3, 3H); Anal. Calcd. for C21H23N3SO4: C: 61.00, H: 5.61, N: 10.17; Found: C: 61.15, H: 5.48, N: 10.08.
EXAMPLE 6 N-(3,4-Dichlorophenyl)-1-indolinylcarboximidamide
(Formula I: R=3,4-dichlorophenyl, R1=H, m=n=0)
White solid; mp: 133-134°C; TLC (CHCl3:MeOH; 10: 1): Rf = 0.29; 1H NMR(CDCl3): 7.697-7.670 (d, J=8.03 Hz, ArH, 1H), 7.370-7.342 (d, J=8.48 Hz, ArH, 1H), 7.208-7.090 (m, ArH, 3H), 6.939-6.811 (m, ArH, 2H), 4.097-4.040 (t, J=8.37 Hz, CH2, 2H), 3.828 (s, OCH3, 3H), 3.182-3.125 (t, J=8.37 Hz, CH2, 2H); Anal. Calcd. for C15N13N3Cl2: C: 58.84, H: 4.28, N: 13.72; Found: C: 59.00, H: 4.44, N: 13.51.
EXAMPLE 7 N-(5-Acenaphthyl)-1-(5-methoxy)-1-mdolinylcarboximidamide•HCl
(Formula I: hydrochloride salt of R=5-acenaphthyl, R1 =H, m=n=1 ,
R3= methoxy (at 5-indoline position))
Yellow solid; mp: 124-127°C; TLC (CHCl3:MeOH; 10: 1); Rf = 0.30; Η NMR(CDCl3): 7.744-6.674 (m, ArH, 8H), 3.982-3.971 (m, CH2, 2H), 3.777 (s, OCH3, 3H), 3.433-3.334 (m, CH2, 4H), 3.117-3.061 (t, J=8.31 Hz, CH2, 2H); Anal. Calcd. for C22H22N3ClO: C: 69.56, H: 5.84, N: 11.06; Found: C: 69.45, H: 5.98, N: 10.96. EXAMPLE 8 N-(5-Acenaphthyl)-1-(5-bromo)-indolinylcarboximidamide
(Formula I: R=5-acenaphthyl, R1 =H, m=0, n = 1, R3=bromo (at 5- indoline position))
Yellow foam; mp: 80-85°C; TLC (CHCl3:MeOH; 10: 1); Rf = 0.35; Η
NMR(CDCl3): 7.856-7.828 (d, J=8.52 Hz, ArH, 1H), 7.683-6.656 (d, J=8.24 Hz, ArH, 1H), 7.422-7.395 (t, ArH, 1H), 7.372-7.212 (m, ArH, 2H), 6.995-6.971 (d, ArH, J=7.21 Hz, 1H), 4.185-4.128 (t, J-8.51 Hz, CH2, 2H), 3.437-3.343 (m, CH2, 2H), 3.206-3.148 (t, J=8.73 Hz, CH2, 2H); Anal. Calcd. for C21H18N3Br: C: 64.30, H: 4.62, N: 10.71; Found: C: 64.56, H: 4.34, N: 10.25.
EXAMPLE 9 N-(1-Naphthyl)-1-(7-ethyl)-indolinylcarboximidamide
(Formula I: R=1-naphthyl, R1=H, m=0, n=1 , R3=ethyl (at 7- indoline position))
White solid; mp: 160-164°C; TLC (CHCl3:MeOH; 10:1); Rf = 0.40; 1H
NMR(CDCl3): 7.861-7.081 (m, ArH, 10H), 3.064-3.044 (br, CH2, 2H), 2.858-2.783
(q, CH2, 2H), 1.333-1.282 (t, J=7.54 Hz, CH3, 3H); Anal. Calcd. for C21H21N3: C:
79.97, H: 6.71, N: 13.32; Found: C: 79.90, H: 6.85,N: 13.33.
EXAMPLE 10 N-(4-sec-butylphenyl)-1-indolinylcarboximidamide•mesylate
(Formula I: mesylate salt of R=4-sec-butylphenyl, R1 =H, m=n=0)
White solid; TLC (CHCl3:MeOH; 10: 1); Rf=0.28; 1H NMR (CDCl3): 7.21- 6.93 (m, 3H, ArH), 4.00 (t, 2H, J=8 Hz, -Ar-CH2-), 3.13 (t, 2H, J=8 Hz, -NCH2- ), 2.68 (s, 3H, CH3SO3H), 2.55-2.45 (m, 1H, -CH-), 1.58-1.45 (m, 2H, -CH2-), 1.16
(d, 3H, J=7 Hz, -CH3), 0.74 (t, 3H, J=7.3, -CH3); HPLC: 98.6%; Rtn time: 18.6 minutes; MS: 294 (M+).
EXAMPLE 11 N-(2,3-dicWorophenyl)-1-indolinylcarboximidamide•HCl
(Formula I: hydrochloride salt of R=2,3-dichlorophenyl, R1=H, m=n=0)
Light gray powder; mp: 187-187°C; TLC (CH2Cl2:MeOH; 11 : 1); Rf = 0.35;
1H NMR(CD3OD): 7.621-7.589 (q, 1H, J=3.26 Hz, ArH), 7.479-7.136 (m, 6H, ArH), 4.247-4.194 (t, 2H, J=8.04 Hz, CH2), 3.301-3.247 (t, 2H, J=8.04 Hz, CH2); Anal. Calcd. for C15H13N3Cl2 HCl 0.5H2O (351.67): C: 51.23, H: 4.30, N: 11.94, Cl: 30.24; Found: C: 51.14, H: 4.48, N: 11.76, Cl: 30.20.
EXAMPLE 12 N-(2,3-dimethylphenyl)-1-indolmylcarboximidamide•HCl
(Formula I: hydrochloride salt of R=2,3-dimethylphenyl,
R1 =H, m=n=0)
White powder; purity: 99.2% (HPLC); mp: 192-194°C; TLC (CH2Cl2:MeOH; 11:1); Rf = 0.48; 1H NMR(CD3OD): 7.46-7.13 (m, 7H, ArH), 4.22-4.17 (t, 2H, J=8.14 Hz, CH2), 3.30-3.25 (t, 2H, J=8.14 Hz, CH2), 2.37 (s, 3H, CH3), 2.26 (s, 3H, CH3).
EXAMPLE 13 N-(5,6,7,8-tetrahydro-1-naphthyl)-1- indolinylcarboximidamide•HCl
(Formula I: hydrochloride salt of R=5,6,7,8-tetrahydro-1- naphthyl, R1 =H, m=n=0)
Light gray powder; purity: 97.5% (HPLC); mp: 175-177°C; TLC
(CH,Cl2:MeOH; 11 :1); Rf = 0.53; 1H NMR(CD3OD): 7.45-7.09 (m, 7H, ArH), 4.21-4.16 (t, 2H, J=8.15 Hz, CH2), 3.29-3.24 (t, 2H, J=8.15 Hz, CH2), 2.87-2.83 (t, 3H, J=5.88 Hz, CH3), 2.76-2.72 (t, 3H, J=5.88 Hz, CH3).
EXAMPLE 14 N-(2-biphenyl)-1-indolinylcarboximidamide•HCl
(Formula I: hydrochloride salt of R=2-biphenyl, R1=H, m=n=0)
Light gray powder; purity: 96.7% (HPLC); mp: 144-146°C; TLC
(CH2Cl2:MeOH; 11 : 1); Rf = 0.44; 1H NMR(CD3OD): 7.54-6.99 (m, 13H, ArH), 3.87-3.81 (t, 2H, J=8.11 Hz, CH2), 3.10-3.05 (t, 2H, J=7.97 Hz, CH2); Anal.
Calcd. for C21H20N3Cl 0.5H2O (349.86): C: 70.28, H: 5.89, N: 11.70, Cl: 30.24; Found: C: 70.50, H: 6.03, N: 11.64.
EXAMPLE 15 N-phenyl-1-indolinylcarboximidamide•HCl
(Formula I: hydrochloride salt of R=phenyl, R1=H, m=n=0)
White powder; purity: 99.0% (HPLC); mp: 222-224°C; TLC (CHCl3:MeOH; 10: 1): Rf=0.10; 1H NMR (CD3OD): 7.50-7.44 (m, 2H, Ar-H), 7.39-7.30 (m, 5H, Ar-H), 7.26-7.21 (m, 1H, Ar-H), 7.15-7.09 (m, 1H, Ar-H), 4.22-4.17 (t, 2H, J=8.20, CH2), 3.29-3.23 (t, 2H, J=8.20, CH2); Anal. Calcd. for C15H15N3•HCl (273.77): C: 65.81, H: 5.89, N: 15.35; Found: C: 65.70, H: 5.78, N: 15.52.
EXAMPLE 16 N-(2-chlorophenyl)-1-indolinylcarboximidamide•HCl
(Formula I: hydrochloride salt of R=2-chlorophenyl, R1 =H, m=n=0)
White powder; purity: 98.8% (HPLC); mp: 172-174°C; TLC (CHCl3:MeOH; 10: 1): Rf=0.19; 1H NMR (CD3OD): 7.63-7.60 (m, 1H, Ar-H), 7.47-7.35 (m, 5H, Ar-H), 7.28-7.23 (m, 1H, Ar-H), 7.16-7.11 (m, 1H, Ar-H), 4.24-4.19 (t, 2H,
J=8.10, CH2), 3.29-3.24 (t, 2H, J=8.10, CH2); Anal. Calcd. for C15H,5N3Cl•HCl (308.21): C: 58.46, H: 4.91, N: 13.63, Cl: 23.01; Found: C: 58.64, H: 5.10, N: 13.48, Cl: 22.88. EXAMPLE 17 N-(2-tolyl)-1-indolinylcarboximidamide•HCl
(Formula I: hydrochloride salt of R=2-methylphenyl, R1 =H, m=n=0)
Light gray powder; purity: 98.6% (HPLC); mp: 225-226°C; TLC
(CHCl3:MeOH; 10:1): Rf=0.36; 1H NMR (CD3OD): 7.46-7.13 (m, 8H, Ar-H), 4.23-4.17 (m, 2H, J=8.10, CH2), 3.29-3.23 (t, J=8.10, CH2); Anal. Calcd. for
C16H17N3Cl•HCl (287.79): C: 66.78, H: 6.30, N: 14.60; Found: C: 67.00, H: 6.41 ,
N: 14.77. EXAMPLE 18 N-(3-tolyl)-1-indolinylcarboximidamide•HCl
(Formula I: hydrochloride salt of R=3-methylphenyl, R1=H, m=n=0)
Light gray powder; purity: 99.0% (HPLC); mp: 122-124°C; TLC
(CHCl3:MeOH; 10: 1): Rf=0.17; 1H NMR (CD3OD): 7.39-7.09 (m, 8H, Ar-H), 4.22-4.17 (t, 2H, J=8.05, CH2), 3.28-3.23 (t, J=8.10, CH2); Anal. Calcd. for
C16H17N3Cl•HCl•0.2 ether (302.62): C: 66.68, H: 6.66, N: 13.89; Found: C: 66.90, H: 6.52, N: 13.71. EXAMPLE 19 N-(2-chloro-5-ethylphenyl)-[(7-trifluoromethyl)-1,2,3,4- tetrahydroquinolinyl]carboximidamide•HCl
(Formula II: R=2-chloro-5-ethylphenyl, R1=H, R3=7- trifluoromethyl, n= 1, m=0)
White solid; mp: 220°C; 'H NMR (300 MHz, CD3OD): δ 7.78 (s, 1H, Ar- H), 7.41-7.44 (m, 3H, Ar-H) 7.17-7.20 (br s, 1H, Ar-H), 3.89-3.93 (t, J=6.5Hz,
2H, N-CH2), 2.88-2.92 (t, 2H, J=6.5Hz, CH2), 2.59-2.67 (q, 2H, J=7.5Hz, CH2),
2.09-2.19 (dt, 2H, J=7.5Hz, CH2), 1.19-1.24 (t, 3H, CH3); MS (El): m/e 382 (M+ for free base); Anal. Calcd. for C19H19CIF3N3•HCl: C: 54.09, H: 4.87, N: 9.96;
Found: C: 54.05, H: 5.01, N: 10.00.
EXAMPLE 20 N-(1-naphthyl)-[(7-trifluoromethyl-1,2,3,4- tetrahydroquinolinyl]carboximidamide•HCl
(Formula II: R= 1-naphthyl, R1 =H, R3=7-trifluoromethyl, n= 1, m=0)
White solid; mp: 215-220°C; 1H NMR (300 MHz, CD3OD): δ 7.90-8.02 (m, 3H, Ar-H), 7.80 (br s, 1H, Ar-H), 7.52-7.68 (m, 4H, Ar-H), 7.37-7.41 (m, 2H, Ar-H), 3.94-3.98 (t, J=6.5Hz, 2H, N-CH2), 2.87-2.92 (t, 2H, ArCH2), 2.13-2.22 (q, J=6.5Hz, 2H, CH2); MS (El): m/e 371 (M+ for free base); Anal. Calcd. for
C21H19F3N3•HCl: C: 61.99, H: 4.96, N: 10.32; Found: C: 61.65, H: 4.63, N: 10.02.
EXAMPLE 21 N-(1-naphthyl)-(1,2,3,4- tetrahydroquinolinyl)carboximidamide•HCl
(Formula II: R= 1-naphthyl, R1=H, m=n=0)
White solid; mp: 244°C; 1H NMR (300 MHz, CD3OD): δ 7.92-8.03 (m, 3H, Ar-H), 7.49-7.68 (m, 5H, Ar-H), 7.12-7.27 (m, 3H, Ar-H), 3.89-3.93 (t, J=6.5Hz, 2H, N-CH2), 2.84-2.88 (t, J=6.5Hz, 2H, Ar-CH2), 2.11-2.19 (q, J=6.5Hz, 2H, CH2); MS (El): m/e 302 (M+ for free base); Anal. Calcd. for C20H19N3•HCl: C: 71.10, H: 5.97, N: 12.43; Found: C: 70.83, H: 5.82, N: 12.32.
EXAMPLE 22 N-(3-biphenyl)-1-(benz[cd]indolinyl)carboximidamide•HCl
(Formula IV: hydrochloride salt of R=3-biphenyl, R1 =H, m=n=0)
Light gray solid; purity: 98.9% (HPLC); mp: 222-224°C; TLC
(CH2Cl2:MeOH; 11: 1): Rf=0.58; 1H NMR (CD3OD): 7.78-7.30 (m, 15H, Ar-H), 5.60 (s, CH2); Anal. Calcd. for C24H19N3•ΗCl•1.3H2O: C: 70.42, H: 5.57, N:
10.26; Found: C: 70.70, H: 5.22, N: 9.96.
EXAMPLE 23 N-(2-tolyl)-1-(benz[cd]indolinyl)carboximidamide•HCl
(Formula IV: hydrochloride salt of R=2-methylphenyl, R1 =H, m=n=0)
Light gray powder; purity: 99.0% (HPLC); mp: 132-134°C; TLC
(CH2Cl2:MeOH; 11: 1): Rf=0.58; Η NMR (CD3OD): 7.78-7.37 (m, 10H, Ar-H), 5.58 (s, 2H, CH2), 2.41 (s, 3H, CH3).
EXAMPLE 24 N-(2,3-dimethylphenyl)-1- benzjcd] mdolinylcarboximidamide• HCl
(Formula IV: hydrochloride salt of R= 2,3-dimethylphenyl, R1=H, m=n=0)
Gray powder; purity: 97.6% (HPLC); mp: 236-238°C; TLC (CHCl3:MeOH; 10: 1): Rf=0.27; 1H NMR (CD3OD): 7.79-7.23 (m, 9H, Ar-H), 5.58 (s, 2H, CH2), 2.40 (s, 3H, CH3), 2.31 (s, 3H, CH3); Anal. Calcd. for C20H19N3•HCl (338.84): C: 71.10, H: 5.97, N: 12.44; Found: C: 71.16, H: 5.94, N: 12.22.
EXAMPLE 25 N-(2,5-dimefhylphenyl)-1- benz[cd]indolinylcarboximidamide•HCl
(Formula IV: hydrochloride salt of R=2,5-dimethylphenyl, R1=H, m=n=0)
White solid; purity: 97.4% (HPLC); mp: 132-134°C; TLC (CHCl3:MeOH; 10: 1): Rf=0.28; 1H NMR (CD3OD): 7.76-7.21 (m, 9H, Ar-H), 5.57 (s, 2H, CH2), 2.37 (s, 3H, CH3), 2.35 (s, 3H, CH3); Anal. Calcd. for C20H19N3•HCl•0.4H2O (345.06): C: 69.62, H: 6.08, N: 12.18; Found: C: 69.66, H: 5.70, N: 11.85.
EXAMPLE 26 N-(1-naphthyl)-1-benz[cd]indolinylcarboximidamide•HCl
(Formula IV: hydrochloride salt of R= 1-naphthyl, R1=H, m=n=0)
Light gray solid; purity: 98% (HPLC); mp: 250-251°C; Rf=0.43
(chloroform/methanol 20/1); Η NMR (CD3OD): 8.10-7.40 (m, 13H, Ar-H), 5.68 (s, 2H, ArCH2); HRMS: 323.1419 (cal: 323.1422 for C22H17N3). EXAMPLE 27 N-(3-ethylphenyl)-1-benz[cd]indolinylcarboximidamide•mesy late
(Formula IV: mesylate salt of R=3-ethylphenyl, R1 =H, m=n=0) Light gray solid; purity: 98% (HPLC); mp: 158-159°C; Rf=0.38
(chloroform/methanol 10/1); Η NMR (CD3OD): 7.76-7.25 (m, 10H, Ar-H), 5.56 (s, 2H, ArCH2), 2.68-2.74 (m, 5H, CH2 + CH3SO3H), 1.26 (t, 3H, CH3, J=7.45Hz); Anal. Calcd. for C20H19N3•CH3SO3H: C: 63.46, H: 5.83, N: 10.57; Found: C:
63.30, H: 5.74, N: 10.39.
EXAMPLE 28 N-(naphth-1-yl)-1-(6- hydro)phenant-uidinylcarboximidamide•HCl
(Formula V: hydrochloride salt of R = 1-naphthyl, R1 =H, m=n=0)
White solid; purity: 93.7% (HPLC); mp: 234-236°C; Rf=0.38
(chloroform/methanol 10/1); 1H NMR (CD3OD): d ppm 7.92-7.32 (m, 15H, Ar-H), 4.97 (s, 2H, ArCH2); Anal. Calcd. for C24H19N3•HCl: C: 74.70, H: 5.22, N: 10.88; Found: C: 74.86, H: 5.40, N: 10.82.
EXAMPLE 29: N-(2-naphthyl)-1-indolinyl-carboximidamide•hydrochloride
(Formula I: hydrochloride salt of R=2-naphthyl,
R1=H,m=n=0) White plate; purity: 99.6% (HPLC); mp: 256-258°C; TLC (CH2Cl2:MeOH;
10: 1): Rf=0.19; 1H NMR (CD3OD): 8.00-7.97 (d, 1H, J=8.8Hz, Ar-H), 7.92-7.81 (m,3H, Ar-H), 7.55-7.36 (m, 5H, Ar-H), 7.24-7.12 (m, 2H, Ar-H), 4.27-4.22 (t, 2H, J=8.1Hz, CH2), 3.30-3.25 (t, 2H, J=8.1Hz, CH2). Anal. Calcd. for
CI9H17N3•HCl (323.83): C, 70.47, H, 5.60, N, 12.98; Found: C, 70.26, H, 5.76, N, 12.76.
EXAMPLE 30: N-(3-biphenyl)-1-indolinyl-carboximidamide
(Formula I: R=3-biphenyl, R1 =H, m=n=0) White powder; purity: 97.1 % (HPLC); mp: 148-150°; TLC (CH2Cl2:MeOH;
10:1): Rf=0.18; 1H NMR (CD3OD): 7.63-7.59 (m, 2H, Ar-H), 7.53-7.24 (m, 8H, Ar-H), 7.16-7.10 (m, 2H, Ar-H), 6.99-6.94 (m, 1H, Ar-H), 4.15-4.10 (t, 2H, J=8.2Hz, CH2), 3.20-3.15 (t, 2H, J=8.2Hz, CH2). Anal. Calcd. for
C21H19N3•0.2EtOAc (331.03): C, 79.10, H, 6.27, N, 12.69; Found: C, 78.92, H, 6.02, N, 12.96. EXAMPLE 31: N-(5-methoxynaphthyl)-1-indolinyl-carboximidamide•hydrochloride
(Formula I: HCl salt of R=5-methoxynaphthyl, R1 =H,m=n=0)
White solid; purity: 97.8% (HPLC); TLC (CHCl3: MeOH; 10: 1): Rf=0.15; mp: 236-239°C; 1H NMR (CD3OD): 8.38-8.34 (d, 1H, J=7.3Hz, Ar-H), 7.59-7.50 (m, 5H, Ar-H), 7.40-7.38 (d, 1H, J=6.8Hz, Ar-H), 7.29-7.24 (td, 1H, J=8, 1.4Hz,
Ar-H), 7.17-7.11 (td, 1H, J=7.4,1.0Hz, Ar-H), 7.06-7.03 (dd, 1H, J=6.4,1.3Hz,
Ar-H), 4.30-4.25 (t, 2H, J=8.0Hz, CH2), 4.04 (s, 3H, OCH3), 3.34-3.29 (t, 2H,
J=8.0Hz, CH2). Annal. Calcd. for C20H19N3O•HCl (353.86): C, 67.89, H, 5.70, N,
11.88; Found: C, 67.65, H, 5.61, N, 11.63.
EXAMPLE 32: N-(2-methylsulfinylphenyl)-1-indolinylcarboximidamide•hydrochloride
(Formula I: HCl salt of R=2-(CH3SO)phenyl, R1=H, m=n=0) Light yellow powder; purity: 99.6% (HPLC); TLC (CHCl3: MeOH; 10: 1):
Rf=0.5; 1H NMR (CD3OD): 8.01-7.98 (dd, 1H, J=2.7,7.7Hz, Ar-H), 7.76-7.67 (m, 2H, Ar-H), 7.57-7.54 (m, 1H, Ar-H), 7.48-7.45 (d, 1H, J=7.7Hz, Ar-H), 7.41-7.38 (d, 1H, J=6.6Hz, Ar-H), 7.32-7.26 (t, 3H, J=8.2Hz, Ar-H), 7.19-7.14 (m, 1H, Ar-H), 4.27-4.19 (m, 2H, CH2), 3.33-3.27 (t, 2H, J=8.4Hz, CH2), 2.92 (s, 3H, CH3).
EXAMPLE 33: N-(1-naphthyl)-(6-methyl-1,2,3,4- tetrahydroquinolinyl)carboximidamide hydrochloride
(Formula II: HCl salt of R=1-naphthyl, R1=H, X=CH2, R3=CH3, n=1, m=0)
Light purple solid: mp 205-206°C; Rf=0.364 (9:2 CHCl3/MeOH); 1H NMR (300 MHz, CD3OD) δ 7.92-8.0 (m, 3H, Ar-H), 7.51-7.68 (m, 4H, Ar-H), 7.37-7.40 (d, 1H, J=8.25Hz, Ar-H), 7.02-7.08 (m, 2H, Ar-H), 3.87-3.91 (t, 2H, J= 12.94Hz, CH2), 2.80-2.84 (t, 2H, J= 12.91Hz, CH2), 2.29 (s, 3H, CH3), 2.11-2.17 (m, 2H, CH2). MS(Cl): m/e 316 (M + for free base). Anal. Calcd. for C21H21N3•HCl: C, 71.68, H, 6.30, N, 11.94. Found: C, 71.73, H, 6.51, N, 12.07. EXAMPLE 34: N-(1-naphthyl)-N'-(2,3-dihydro-[1,4]- benzothiazinyl)carboximidamide hydrochloride
(Formula II: HCl salt of R = 1-naphthyl, R1 =H, X=S, m=n=0)
White solid: mp 245-246°C; Rf=0.13 (10: 1 CHCl3/MeOH); 1H NMR (300 MHz, CD3OD) δ 7.92-8.20 (m, 3H, Ar-H), 7.48-7.71 (m, 5H, Ar-H), 7.28-7.35 (m, 1H, Ar-H), 7.12-7.20 (m, 2H, Ar-H), 4.16-4.22 (m, 2H, CH2), 3.40-3.47 (m, 2H, CH2). MS(Cl): m/e 320 (M+ for free base). Anal. Calcd. for C19H17N3S•HCl: c, 64.12, H, 5.10, N, 11.81. Found: C, 64.28, H, 5.20, N, 11.69.
EXAMPLE 35: N-(2,5-dibromophenyl)-(7-trifluoromethyl-1,2,3,4- tetrahydroqumolinyl)carboximidamide hydrochloride
(Formula II: HCl salt of R=2,5-dibromophenyl, R1=H,
X=CH2, R3=CF3, n= 1, m=0)
Cream colored solid: mp 201-202°C; Rf=0.354 (Eth. Ac); 1H NMR (300 MHz, CD3OD) δ 7.79 (s, 1H, Ar-H), 7.45-7.48 (m, 1H, Ar-H), 7.25-7.28 (d, 1H, J=7.97Hz, Ar-H), 7.12-7.15 (m, 2H, Ar-H), 7.03-7.07 (m, 1H, Ar-H), 3.78-3.82 (t, 2H, J = 11.96Hz, CH2), 2.84-2.89 (t, 2H, J= 13.19Hz, CH2), 2.01-2.08 (m, 2H, CH2). MS(Cl): m/e 478 (M+ for free base). Anal. Calcd. for C17H14Br2F3N3•HCl: C, 39.76, H, 2.94, N, 8.18. Found: C, 39.57, H, 2.96, N, 7.98. EXAMPLE 36: N-(2,3-difluorophenyl)-(1,2,3,4- tetrahydroquinolinyl)carboximidamide hydrochloride
(Formula II: HCl salt of R= 2, 3 -fluorophenyl, R1 =H, X=CH2, m=n=0) White solid: mp 194-195°C; Rf=0.135 (10:2 CHCl3/MeOH); 1H NMR (300
MHz, CD3OD) δ 7.34-7.37 (m, 1H, Ar-H), 7.12-7.27 (m, 6H, Ar-H), 3.83-3.87 (t, 2H, J= 13.0Hz, CH2), 2.82-2.86 (t, 2H, J= 13.19Hz, CH2), 2.06-2.15 (m, 2H, CH2). MS(Cl): m/e 288 (M+ for free base). Anal. Calcd. for C16H15F2N3•HCl: c, 59.36, H, 4.98, N, 12.98. Found: C, 59.44, H, 4.97, N, 12.74. EXAMPLE 37: N-(2-trifluoromethoxyphenyl)-(1,2,3,4- tetrahydroquinolinyl)carboximidamide hydrochloride
(Formula II: HCl salt of R=2-trifluromethoxyphenyl, R1=H, X=CH2, m=n=0)
White solid: mp 80-82°C; Rf=0.115 (10: 1 CHCl3/MeOH); 1H NMR
(300MHz, CD3OD) δ 7.46-7.52 (t, 1H, J= 16.42Hz, Ar-H), 7.15-7.35 (m, 7H, Ar- H), 3.82-3.86 (t, 2H, J= 12.98Hz, CH2), 2.82-2.86 (t, 2H, J= 12.91Hz, CH2), 2.11- 2.17 (m, 2H, CH2). MS(C1): m/e 336 (M+ for free base). Anal. Calcd. for
C17H16F3N3O•HCl: C, 54.92, H, 4.61, N, 11.30. Found: C, 55.10, H, 4.78, N,
11.44.
EXAMPLE 38: N-(2-biphenyl)-1-benz[cd]indolinylcarboximidamide•hydrochloride
(Formula IV: HCl salt of R=2-biphenyl, R1=H, m=n=0)
Light grey powder; purity: 94.0% (HPLC); TLC (CHCl3:MeOH; 10: 1):
Rf=0.25; mp: 143-145°C; Η NMR (CD3OD): 7.73-7.70 (d, 1H, J=8.2Hz, Ar-H), 7.61-7.32 (m, 13H, Ar-H), 7.08-7.06 (d, 1H, J=7.1Hz, Ar-H), 5.19 (s, 2H, CH2). Anal. Calcd. for C24H19N3•HCl (385.89): c, 74.70, H, 5.22, N, 10.89; Found: C, 74.60, H, 5.40, N, 10.61.
EXAMPLE 39: N-(3,5-dichlorophenyl)-1-tetrahydrobenz[cd]indolinylcarboximidamide•hydrochloride
(Formula VII: HCl salt of R=3,5-dichlorophenyl, R1 =H, m=n=0) White solid; purity: 98.7% (HPLC); TLC (CHCl3: MeOH; 10: 1): Rf=0.28;
1H NMR (CD3OD): 7.39-7.35 (m, 3H, Ar-H), 7.19-7.14 (t, 1H, J=7.3Hz, Ar-H), 7.11-7.08 (d, 1H, J=7.4Hz, Ar-H), 6.95-6.93 (d, 1H, J=6.9HZ, Ar-H), 4.44-4.38 (dd, 1H, J=8.1,9.9Hz, NCH), 3.44-3.40 (dd, 1H, J=8.1 ,9.9Hz, NCH), 2.94-2.85 (m, 1H, CH), 2.75-2.69 (m, 1H, CH), 2.27-2.12 (m, 2H, CH2), 1.86-1.80 (m, 1H, CH), 1.41-1.29 (m, 1H, CH). Calcd. for C18H17N3Cl2•HCl (382.73): C, 56.49, H, 4.74, N, 11.98, Cl, 27.79; Found: C, 56.44, H, 5.00, N, 10.99, Cl, 27.61. EXAMPLE 40: N-(2,5-dibromophenyl)-(2,3,4,5-tetrahydro-[1,5]-benzothiazin-5- yl)carboximidamide hydrochloride
(Formula VI: HCl salt of R=2,5-dibromophenyl, R1 =H, X=S, m=n=0)
Whitish solid: mp 216-217°C; 1H NMR (300 MHz, CD3OD) δ 7.4-7.8 (m,
7H, Ar-H), 4.3-4.65 (brs, 1H, CH2), 3.2-3.4 (brs, 1H, CH2), 2.7-3.1 (m, 2H, CH2),
2.1-2.4 (m, 2H, CH2). MS(Cl): m/e 442 (M+ + H for free base). Anal. Calcd. for
C16H15Br2N3S•HCl: C, 40.23, H, 3.38, N, 8.80; Found: C, 40.08, H, 3.10, N, 8.73.
EXAMPLE 41 : Synthesis of 5,6,11,12-tetrahydrodibenz[b,f]azocincarboximidamide• hydrochloride
Figure imgf000072_0001
By method indicated above in Example 3, part 3 using 5,6, 11,12-tetrahydrodibenz[b,f]azocine•HCl
White solid: mp: 238-240°C, TLC (CHCl3:MeOH; 10: 1); Rf=0.25; 1H NMR (CD3OD) δ ppm 7.1 (m, Ar-H, 8H), 5.28 (d, CHN, 1H), 4.58 (d, CHN, 1H), 3.20 (m, CH2, 1H), 3.0 (m, CH2, 1H); Mass /CI-NH3: MH+ 252; Anal. Calcd. for
C16H18N3Cl•0.25H2O: C, 65.75, H, 6.38, N, 14.38; Found: C, 65.55, H, 6.37, N, 14.94.
EXAMPLE 42: Synthesis of N-(4'-sec-butylphenyl)-1-(5,6,11,12- tetrahydrodibenz[b,f]azocin)-carboximidamide•hydrochloride
Part A: Preparation of 5,6,11,12-tetrahydrodibenz[b,f]azocin-cyanamide
By method indicated in Example 2, part 1 above using 5,6,11,12-tetrahydrodibenz[b,f]azocine
Figure imgf000073_0001
Part B: Preparation of N-(4'-sec-butylphenyl)-1-(5,6,11,12- tetrahydrodibenz[b,f]azocin)-carboximidamide• hydrochloride
Figure imgf000073_0002
By method indicated in Example 2, part 2 above using 5,6,11,12-tetrahydrodibenz[b,f]azocin-cyanamide, sec-butylaniline and one equivalent of aluminum chloride.
Oil, TLC (CHCl3:MeOH; 10:0.5); Rf=0.25; 1H NMR (CDCl3) δ ppm 7.1 (m, Ar-H, 12H), 5.4 (br, CHN, 1H), 4.6 (br, CHN, 1H), 3.25 (br, CH2, 2H), 3.0 (br, CH2, 2H), 2.55 (m, CH, 1H), 1.60 (m, CH2, 2H), 1.2 (d, CH3CH2, 3H), 0.8 (t, CH3CH, 3H); Mass /CI-NH3: MH+ 384.
EXAMPLE 43: 10,11-dihydro-[5H]-dibenz[b,f]-tzepinylcarboximidamide
hydrochloride
White solid: mp 120-121 °C; 1H NMR (300 MHz, CD3OD) δ 7.31-7.46 (m, 8H, Ar-H), 3.23-3.36 (brs, 2H, Ar-CH2), 2.80-2.93 (brs, 1H, Ar-CH2); MS(Cl): m/e 238 (M+ for free base); Anal. Calcd. for C15H15N3•HCl: C, 60,99, H, 6.28, N, 14.22; Found: C, 60.91, H, 6.17, N, 14.29. EXAMPLE 44: N-(1-naphthyl)-dibenzo[b,f]azepinylcarboximidamide hydrochloride
White solid; mp 230°C; 1H NMR (300 MHz, CD3OD) δ 7.94-7.99 (m, 2H, Ar-H), 7.79-7.87 (m, 2H, Ar-H), 7.62-7.69 (m, 5H, Ar-H), 7.51-7.61 (m, 5H, Ar-H), 7.44-7.47 (m, 1H, Ar-H), 7.33-7.36 (brs, 2H, CH=CH); MS(Cl): m/e 262 (M+ + H for free base); Anal. Calcd. for C25H19N3•HCl: C, 75.46, H, 5.07, N, 10.56; Found: C, 75.59, H, 5.03, N, 10.55. EXAMPLE 45: N-(4-butoxyphenyl)-dibenzo[b,f]azepinylcarboximidamide
hydrochloride
White solid: mp 190-192°C; Rf =0.269 (10:2 CHCl3/MeOH); 1H NMR (300 MHz, CD3OD) δ 7.49-7.73 (m, 8H, Ar-H), 7.19 (s, 2H, Ar-H), 7.07-7.10 (m, 2H, Ar-H), 6.92-6.95 (m, 2H, Ar-H), 3.93-3.97 (t, 2H, J=13Hz, 2H, CH2), 1.68-1.78 (m, 2H, CH2), 1.40-1.52 (m, 2H, CH2), 0.928-0.977 (t, 3H, J= 14.71Hz, CH3); MS(C1): m/e 384 (M+ for free base); Anal. Calcd. for C25H25N3O•CH3SO3H: C, 65.11 , H, 6.09, N, 8.76; Found: C, 61.16, H, 6.45, N, 8.20. EXAMPLE 46: N-(2-chloro-5-methylsulfinylphenyl)-1-(6-trifluoromethyl- 1,2,3,4-tetrahydroquinolinyl)carboximidamide hydrochloride (Formula II: HCl salt of R=2-chloro-5-methylsulfinylphenyl, R1 =H, X=CH2, R3= 6- trifluoromethyl, n= 1, m=0) The title compound was prepared by oxidiation of the corresponding sulfide precursor (i.e. (N-(2-chloro-5-methylthiophenyl)-1-(6-trifluoromethyl-1,2,3,4-tetrahydroqumolinyl)-carboximidamide) with 30% hydrogen peroxide in methanol at reflux for 24 hours, followed by column chromatography over silica gel.
White solid: mp 188-190°C; Rf=0.12 (10: 1 CHCl3/MeOH); 1H NMR (300 MHz, CD3OD) δ 7.476-7.743 (m, 7H, Ar-H), 3.904-3.946 (t, J=6Hz, 2H, CH), 2.799 (s, 3H, CH3), 2.100-2.186 (m, 2H, CH2); MS(Cl): m/e 417 (M + for free base); Anal. Calcd. for C18H17ClF3N3OS•HCl: C, 47.80, H, 4.01, N, 9.29; Found: C, 47.86, H, 4.25, N, 9.16. EXAMPLE 47: N-(1-naphthyl)-1-(2,3-dihydro-1-oxo-6- trifluoromethylbenzo[1,4]thiazin-4-yl)carboximidamide mesylate (Formula II": mesylate salt of R= 1-naphthyl, R1 =H, X=-S(O)- R3=6-trifluoromethyl, n=1, m=0)
The title compound was prepared by oxidiation of the corresponding sulfide precursor (i.e. N-(1-naphthyl)-1-(2,3-dihydro-6-trifluoromethylbenzo[1,4]thiazin-4-yl)carboximidamide) with sodium periodate in acetonitrile: water (1: 1) at room
temperature for 24 hours, then conversion to free base with 1N NaOH followed by column chromatography over silica gel and conversion to the mesylate salt with methane sulfonic acid.
White solid: mp 231-234°C; Rf=0.45 (9: 1 CHCl3/MeOH); 1H NMR (300 MHz, CD3OD) δ 7.96-8.03 (m, 3H, Ar-H), 7.58-7.63 (m, 1H, Ar-H), 7.40-7.52 (m, 3H, Ar-H), 7.28-7.39 (d, J=6Hz, 1H, Ar-H), 7.02-7.11 (d, J=6Hz, 1H, Ar-H), 4.44-4.52 (brs, 1H, CH2), 4.02-4.20 (brs, 1H, CH2), 3.19-3.40 (brs, 1H, CH2); MS(C1): m/e 404 (M+ for free base); Anal. Calcd. for C20H16F3N3OS•HCl: C, 45.41, H, 4.76, N, 7.57; Found: C, 45.09, H, 4.40, N, 7.29.
EXAMPLE 48: In vivo Anticonvulsant activity in the DBA/2 mouse model
(Mouse audiogenic assay)
The in vivo potency of compounds of the invention is exemplified by data summarized in the Table I below and obtained pursuant to the following protocol.
Compounds were tested for their effectiveness in preventing seizures in DBA/2 mice which have a unique sensitivity to auditory stimulation. Exposure to loud high-frequency sounds can trigger seizure activity in these -tnimals. This sensitivity develops from postnatal day 12 and peaks around day 21 and slowly diminishes as the animals mature. The unusual response to auditory stimulation in this strain of mouse is believed to be due to a combination of early myelination (causing an unusually low excitatory threshold) and delayed development of inhibitory mechanisms.
Mice were injected intraperitoneally with the compound specified in Table I below or with vehicle control, 30 minutes prior to being placed in a bell jar and turning on the auditory stimulus (12 KHz sine wave at 110-120 db). Administered doses are specified in Table I as milligram of compound per kilogram bodyweight of mouse. The auditory stimulus was left on for 60 seconds and mice reactions were timed and recorded. Percentage inhibition was determined with reference to vehicle controls. Results are shown in the Table I below. "FB" refers to free base.
Figure imgf000076_0001
Figure imgf000077_0001
This invention has been described in detail with reference to preferred embodiments thereof. However, it will be appreciated that those skilled in the art, upon consideration of this disclosure, may make modifications and improvements within the spirit and scope of the invention.

Claims

What is claimed is:
1. A compound of the following Formula I:
Figure imgf000078_0001
wherein R and R1 are each independently hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alky Is ulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted carbocyclic aryl, or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms, with at least one of R and R1 being other than hydrogen;
each R2 and each R3 are each independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, or substituted or unsubstituted aralkyl;
X is substituted or substituted methylene, -S-, -O- or substituted or
unsubstituted -N-;
m is 0, 1 or 2; and n is 0, 1, 2, 3 or 4; with the exclusion of N-(m-ethylphenyl)-1-indolinylcarboximidamide; and pharmaceutically acceptable salts thereof.
2. A compound of claim 1 where X is substituted or unsubstituted methylene.
3. A compound of claim 1 that is:
N-(4-benzyloxyphenyl)-1-indolinylcarboximidamide;
N-(4-methoxynaphthyl)-1-indolinylcarboximidamide;
N-(1-naphthyl)-1-indolinyIcarboximidamide;
N-(3,4-dimethoxynaphthyl)-1-indolinylcarboximidamide;
N-(3,4-dichlorophenyl)-1-indolinylcarboximidamide;
N-(1-naphthyl)-1-(7-ethyl)-indolinylcarboximidamide;
N-(2-naphthyl)-1-(7-ethyl)-indolinylcarboximidamide ;
N-(4-sec-butylphenyl)-1-indolinylcarboximidamide;
N-(2,3-dichlorophenyl)-1-indolinylcarboximidamide;
N-(2,3-dimethylphenyl)-1-indolinylcarboximidamide;
N-(5,6,7,8-tetrahydro-1-naphthyl)-1-indolinylcarboximidamide; N-(2-biphenyl)-1-indolinylcarboximidamide;
N-(1-naphthyl)-N-methyl-1-indolinylcarboximidamide;
N-(2-naphthyl)-1-indoIinylcarboximidamide;
N-phenyl-1-indolinylcarboximidamide ;
N-(2-chlorophenyl)-1-indolinyIcarboximidamide;
N-(2-methylphenyl)-1-indolinylcarboximidamide;
N-(3 -methyIphenyl)-1-indolinylcarboximidamide ;
N-(2,5-dimethylphenyl)-1-indolinylcarboximidamide;
N-(2,5-dibromophenyl)-1-indolinylcarboximidamide;
N-(2,5-dichlorophenyl)-1-indolinylcarboximidamide;
N-(5-acenaphthyl)-1-(5-methoxy)-indolinylcarboximidamide; N-(5-acenaphthyl)-1-(5-bromo)-indolinylcarboximidamide; N-(2,3-dimethoxyphenyl)-1-indolinylcarboximidamide;
N-methyl-N-(4-sec-butylphenyl)-1-indolinyl-carboximidamide; N-(2-tolyl)-1-(3-benzothiazolinyl)-carboximidamide;
N-5-indanyl-1-indolinyl-carboximidamide;
N-(3,4-dimethylphenyl)-1-indolinyl-carboximidamide;
N-(2,3,4-trichlorophenyl)-1-indolinyl-carboximidamide ;
N-(2-naphthyl)-1-indolinyl-carboximidamide;
N-(3-biphenyl)-1-indolinyl-carboximidamide; N-(8-quinolinyl)-1-indolinyl-carboximidamide;
N-(2-tolyl)-1-(4-methoxylindolinyl)-carboximidamide;
N-(2-tolyl)-1-(3-methylindolinyl)-carboximidamide;
N-(2,4-dichlorophenyl)-1-indolinyl-carboximidamide;
N-(2-methoxylphenyl)-1-indolinyl-carboximidamide;
N-(2-trifluoromethyl)-1-indolinyl-carboximidamide;
N-(4-methoxynaphthyl)-1-(4-methoxylndolinyl)-carboximidamide;
N-(4-methoxynaphthyl)-1-(4-chloroindolinyl)-carboximidamide;
N-(2,4-dimethoxyphenyl)-1-indolinyl-carboximidamide;
N-(2,4-dimethyIphenyl)-1-indolinyl-carboximidamide;
N-(2,4-difluorophenyl)-1-indolinyl-carboximidamide;
N-(4-methoxy-2-nitrophenyl)-1-indolinyl-carboximidamide;
N-(4-methoxyphenyl)-1-indolinyl-carboximidamide;
N-(2,5-dichlorophenyl)-1-indolinyl-carboximidamide;
N-(4-chlorophenyl)-1-indolinyl-carboximidamide;
N-(1-naphthyl)-1-(5-fluoroindolinyl)-carboximidamide ;
N-(4,5-dimethylnaphthyl)-1-indolinyl-carboximidamide;
N-(5-acenaphthyl)-1-(4-methoxylndolinyl)-carboximidamide;
N-6-(benz[cd]indol-2(1H)-one)-1-indoIinyl-carboximidamide;
N-(2,3-difluorophenyl)-1-indolinyl-carboximidamide;
N-(2-(4'-methoxy)biphenyl)-1-indolinyl-carboximidamide;
N-(2-tert-butylphenyl)-1-indolinyl-carboximidamide;
N-(3,5-dichlorophenyl)-1-indolinyl-carboximidamide;
N-(2-pyrrolylphenyl)-1-indolinyl-carboximidamide;
N-(4-fluorenyl)-1-indolinyl-carboximidamide;
N-(6-coumarinyl)-1-indolinyl-carboximidamide;
N-(3-isopropylphenyl)-1-indolinyl-carboximidamide;
N-(5-methoxynaphthyl)-1-indolinyl-carboximidamide;
N-(3-(1H-imidazol-1-yl)-1-indolinyl-carboximidamide;
N-(3-quinolinyl)-1-indolinyl-carboximidamide;
N-(6-indazole)-1-indolinyl-carboximidamide;
N-(2-piperidinylphenyl)-1-indolinyl-carboximidamide; N-(2-methylmercapto)phenyl-1-mdolmyl-carboximidamide;
N-(1-methylsulfoxyphenyl)-1-indolinyl-carboximidamide ; or
N-(2-naphthyI)-1-(5-fluoroindolinyl)-carboximidamide;
or pharmaceutically acceptable salts of said compounds.
4. A compound of the following Formula I":
Figure imgf000081_0001
wherein R and R1 are each independently hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alky Is ulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted carbocyclic aryl, or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms, with at least one of R and R1 being other than hydrogen;
each R2 and each R3 are each independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, or substituted or unsubstituted aralkyl;
X is -SO- or -SO2-;
m is 0, 1 or 2; and n is 0, 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
5. A compound of the following Formula II:
Figure imgf000082_0001
wherein R and R1 are each independently hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkylsulfinyl or substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted carbocyclic aryl, substituted or unsubstituted aralkyl, or a substituted or unsubstituted
heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms;
each R2 and each R3 are each independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, or substituted or unsubstituted aralkyl having at least about 6 ring carbon atoms;
X is -O-, -S-, substituted or unsubstituted -N-, or substituted or unsubstituted methylene;
m and n are each independently 0, 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
6. A compound of claim 5 that is:
N-(1-naphthyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(1-naphthyl)-1-(7-trifluoromethyl)-(1,2,3,4-tetrahydroquinolinyl)
carboximidamide;
N-(1-naphthyl)-1-(7-methyl)-(1,2,3,4-tetrahydroquinolinyl) carboximidamide ;
N-(2,5-dibromophenyl)-1-(7-trifluoromethyl)-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(1-naphthyl)-1-(2-trifluoromethyl)-(1,2,3,4-tetrahydroquinolinyl)
carboximidamide;
N-(4-benzyloxyphenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(4-methoxynaphthyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(3,4-dichlorophenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(5-acenaphthyl)-1-(5-methoxy)-(1,2,3,4-tetrahydroquinolinyl)
carboximidamide;
N-(5-acenaphthyl)-1-(5-bromo)-(1,2,3,4-tetrahydroquinolinyl)
carboximidamide;
N-(1-naphthyl)-1-(7-ethyl)-(1,2,3,4-tetrahydroquinolinyl)
carboximidamide;
N-(4-sec-butylphenyl)-1-(1 ,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2,3-dichlorophenyl)-1-(1,2,3,4-tetrahydroquinolmyl)carboximidamide;
N-(2,3-dimethylphenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(5,6,7,8-tetrahydro-1-naphthyl)-1-(1,2,3,4-tetrahydroquinolinyl)
carboximidamide;
N-(2-biphenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(3-biphenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(1-naphthyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2-ethylphenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(3-ethylphenyl)-1-(1,2,3,4-tetrahydroqumolmyl)carboximidamide;
N-(2,5-dimethylphenyl)-1-(1,2,3,4-tetrahydroqumolmyl)carboximidamide;
N-(2-chloro-5-ethylphenyl)-1-(7-trifluoromethyl)-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2,5-dibromophenyl)-1-(1,2,3,4-tetrahydroquinolmyl)carboximidamide;
N-(2,5-dichlorophenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(3-methylthiophenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2,3-dichlorophenyl)-1-(1,2,3,4-tetrahydroquinolmyl)carboximidamide;
N-(2,3-difluorophenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide; N-(1-naphthyl)-1-(6-methyl-1 ,2,3,4-tetrahydroquinoline)carboximidamide;
N-(1-naphthyl)-4-(2,3-dihydro-[1,4]-benzomiazmyl)carboximidamide ;
N-(1-naphthyl)-4-(2,3-dihydro-[1,4]-benzoxazinyl)carboximidamide;
N-(2,5-dibromophenyl)-1-[7-[trifluoromethyl)-1,2,3,4-tetrahydroquinolinejcarboximidamide;
N-(1-naphthyl)-1-(2-methyl-1,2,3,4-tetrahydroquinolin-1-yl)carboximidamide;
N-(3-methylthiophenyl)-1-(1 ,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2,3-dichlorophenyl)-1-(1,2,3,4-tetrahydroqumolmyl)carboximidamide;
N-(2,3-difluorophenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-[2-chloro-5-(trifluoromethyl)phenyl]-1-(7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2-fluorophenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(3,4-difluorophenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2,4,5-trichlorophenyl)-1-(7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(3,4-dichlorophenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide ;
N-(2-trifluoromethoxyphenyl)-1-(1,2,3,4-tetrahydroqumolinyl)carboximidamide;
N-(2-chlorophenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2,5-dibromophenyl)-4-(2,3-dihydro-6-trifluoromethyl-[1,4]-benzothiazinyl)carboximidamide;
N-(2-chloro-5-thiomethylphenyl)-1-(7-trifluoromethyl-1 ,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2-chloro-5-miomethylphenyl)-1-(6-trifluoromethyl-1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2-chloro-5-sulfinylmethylphenyl)-1-(6-trifluoromethyl-1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2-chloro-5-sulfonylmethylphenyl)-1-(6-trifluoromethyl-1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2,5-dibromophenyl)-1-[6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolinyl]carboximidamide;
N-(2,5-dimethylphenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2,5-dibromophenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide; N-(2,5-dichlorophenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide ;
N-(3,5-dichlorophenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2-chloro-5-miomethylphenyl)-1-(1,2,3,4-tetrahydroquinoline)carboximidamide;
N-(2-methylthiophenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2-ethoxyphenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2-fluoro-5-trifluoromethylphenyl)-4-(6-chloro-[1,4]-benzothiazinyl)-carboximidamide;
N-(2-biphenyl)-1-(1,2,3,4-tetrahydroqumolmyl)carboximidamide;
N-(2-ethylphenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(8-quinolinyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2-methylsulfonylphenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide ;
N-(2,5-dibromophenyl)-4-(6-chloro-f1,4]-benzothiazinyl)carboximidamide;
N-phenyl-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2-chloro-5-methylthiophenyl)-1-(7-trifluoromethyl-1,2,3,4-tetrahydroquinolinyl)-carboximidamide ;
N-(3-trifluoromethoxyphenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2-trifluoromethoxyphenyl)-N-methyl-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2,3-difluorophenyl)-N-methyl-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2-trifluoromethoxyphenyl)-1-(6-trifluoromethyl-1 ,2,3,4-tetrahydroquinolinyl)-carboximidamide;
N-(1-naphthyl)-4-(6-chloro-2,3-dihydro-[1,4]-benzothiazinyl)carboximidamide;
N-(5-acenaphthyl)-4-(2,3-dihydro-[1,4]-benzothiazinyl)carboximidamide;
N-(2,3-difluorophenyl)-N-methyl-4-(2,3-dihydro-[1,4]-benzothiazinyl)
carboximidamide;
N-(1-naphthyl)-4-(6-trifluoromethyl-2,3-dihydro-[1,4]-benzothiazinyl)
carboximidamide;
N-(5,6,7,8-tetrahydro-1-naphthyl)-4-(2,3-dihydrobenzo-[1,4]-thiazinyl)
carboximidamide;
N-(3-biphenyl)-4-(2,3-dihydrobenzo-[1,4]-thiazinyl)carboximidamide;
N-(2-naphthyl)-4-(2,3-dihydrobenzo-[1 ,4]-thiazinyl)carboximidamide;
N-(3,5-dichlorophenyl)-4-(2,3-dihydro-[1,4]-benzothiazinyl)carboximidamide; N-(2,3-difluorophenyl)-4-(2,3-dihydro-[1,4]-benzothiazinyl)carboximidamide; or or a pharmaceutically acceptable salt of said compounds.
7. A compound of claim 6 that is N-(2,5-dibromophenyl)-1-(7-trifluoromethyl)-(1,2,3,4-tetrahydroquinolinyl)carboximidamide, or a pharmaceutically acceptable salt thereof.
8. A compound of the following Formula II" :
Figure imgf000086_0001
wherein R and R1 are each independently hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkylsulfinyl or substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted carbocyclic aryl, substituted or unsubstituted aralkyl, or a substituted or unsubstituted
heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms;
each R2 and each R3 are each independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, or substituted or unsubstituted aralkyl having at least about 6 ring carbon atoms;
X is sulfinyl (-S(O)-) or sulfonyl (-S(O2)-); m and n are each independently 0, 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
9. A compoud of claim 8 that is N-(2,5-dibromophenyl)-4-(2,3-dihydro-4-oxo-6-trifluoromethyl-[1,4]-benzothiazinyl)-carboximidamide ;
N-(2,5-dibromophenyl)-4-(2,3-dihydro-1-dioxo-6-trifluoromethyl)-([1,4]-bezothiazinyl)carboximidamide; or
N-(1-naphthyl)-4-(2,3-dihydro-6-trifluoromethylbenzo[1,4]-1-oxo-thiazinyl)carboximidamide;
or a pharmaceutically acceptable salt of said compounds.
10. A compound of the following Formula III:
Figure imgf000087_0001
wherein R and R1 are each independently hydrogen; substituted or
unsubstituted alkyl having from 1 to about 20 carbon atoms; substituted or
unsubstituted alkenyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms; substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfinyl having 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfonyl having 1 to about 20 carbon atoms; substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms; or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms; each R2 and each R3 are each independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms, or substituted or unsubstituted aralkyl having at least about 6 ring carbon atoms;
m is 0, 1, 2, 3, 4, 5 or 6; n is 0, 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
11. A compound of claim 10 wherein the compound is:
N-(1-naphthyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(1-naphthyl)-1-(7-trifluoromethyl)-(1,2,3,4-tetrahydroisoquinolinyl)
carboximidamide ;
N-(1-naphthyl)-1-(7-methyl)-(1,2,3,4-tetrahydroisoquinolinyl)
carboximidamide;
N-(2,5-dibromophenyl)-1-(7-trifluoromethyl)-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide ;
N-(1-naphthyl)-1-(2-trifluoromethyl)-(1,2,3,4-tetrahydroisoquinolinyl)
carboximidamide;
N-(4-benzyloxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(4-methoxynaphthyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(3,4-dichlorophenyI)-1-(1,2,3,4-tetrahydroisoqumolinyl)carboximidamide;
N-(5-acenaphthyl)-1-(5-methoxy)-(1,2,3,4-tetrahydroisoquinolinyl)
carboximidamide;
N-(5-acenaphthyl)-1-(5-bromo)-(1,2,3,4-tetrahydroisoquinolinyl)
carboximidamide;
N-(1-naphthyl)-1-(7-ethyl)-(1,2,3,4-tetrahydroisoquinolinyl) carboximidamide;
N-(4-sec-butylphenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(2,3-dichlorophenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(2,3-dimethylphenyl)-1-(1,2,3,4-tetrahydroisoqumolmyl)carboximidamide;
N-(5,6,7,8-tetrahydro-1-naphthyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)
carboximidamide;
N-(2-biphenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(3-biphenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(1-naphthyl)-1-(1,2,3,4-tetrahydroisoqumolinyl)carboximidamide;
N-(2-ethylphenyl)-1-(1 ,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(3-ethylphenyl)-1-(1 ,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(2,5-dimethylphenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(2-chloro-5-ethylphenyl)-1-(7-trifluoromethyl)-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(2,5-dibromophenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(2,5-dichlorophenyl)-1-(1,2,3,4-tetrahydroisoqumolmyl)carboximidamide;
N-(3-methylthiophenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(2,3-dichlorophenyl)-1-(1,2,3,4-tetrahydroisoqumolmyl)carboximidamide; or
N-(2,3-difluorophenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide; and pharmaceutically acceptable salts of said compounds.
12. A compound of the following Formula IV:
Figure imgf000089_0001
wherein R and R1 are each independently hydrogen; substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms; substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfinyl having 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfonyl having 1 to about 20 carbon atoms; substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms; or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms, with at least one of R and R1 being other than hydrogen;
each R2 and each R3 are each independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms, or substituted or unsubstituted aralkyl having at least about 6 ring carbon atoms;
m is 0, 1 or 2; and n is an integer of 0-6; and pharmaceutically acceptable salts thereof.
13. A compound of claim 12 that is:
N-(3-biphenyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(1-naphthyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(2-methylphenyl)-1-(benz[cd]indolinyl)carboximidamide ;
N-(2,3-dimethylphenyl)-1-(benz[cd]indolinylcarboximidamide;
N-(2,5-dimethylphenyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(4-benzyloxyphenyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(4-methoxynaphthyl)-1-(benz[cd]indolinyl)carboximidamide; N-(3,4-dichlorophenyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(5-acenaphthyl)-1-(5-methoxy)-1-(benz[cd]indolinyl)carboximidamide;
N-(5-acenaphthyl)-1-(5-bromo)-(benz[cd]indolinyl)carboximidamide;
N-(1-naphthyl)-1-(7-ethyl)-(benz[cd]indolinylcarboximidamide;
N-(4-sec-butylphenyl)-1-(benz[cd]indolinylcarboximidamide;
N-(2,3-dichlorophenyl)-1-(benz[cd]indolinylcarboximidamide;
N-(3-methylphenyl)-1-(benz[cd]mdolmyl)carboximidamide;
N-(5,6,7,8-tetrahydro-1-naphthyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(2-biphenyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(1-naphthyl)-1-(7-trifluoromethyl)-(benz[cd]indolinyl)carboximidamide;
N-(3-ethylphenyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(2-ethylphenyl)-1-(benz[cd]indolinylcarboximidamide;
N-(2,5-dibromophenyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(2,5-dichlorophenyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(2-ethylphenyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(2-methoxyphenyl)-(1-benz[cd]mdolinyl)carboximidamide;
N-(2-biphenyl)-(1-benz[cd]indolinyl)carboximidamide;
N-(2-chlorophenyl)-(4-benz[cd]mdolmyl)carboximidamide;
N-(2,4-dimethoxyphenyl)-(1-benz[cd]indolinyl)carboximidamide;
N-(2,4-dichlorophenyl)-(1-benz[cd]indolinyl)carboximidamide;
N-(4-fluoro-2-methylphenyl)-(1-benz[cd]indolinyl)carboximidamide;
N-(2,3-dichlorophenyl)-(1-benz[cd]indolinyl)carboximidamide;
N-(3-methylmercaptophenyl)-(1-benz[cd]indolinyl)carboximidamide;
N-(3-bromophenyl)-(1-benz[cd]indolinylcarboximidamide; or
N-(3-methylcarboxylphenyl)-(1-benz[cd]indolinyl)carboximidamide;
or a pharmaceutically acceptable salt of said compounds.
14. A compound of the following Formula V:
Figure imgf000092_0001
wherein R and R1 are each independently hydrogen; substituted or
unsubstituted alkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms; substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfinyl having 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfonyl having 1 to about 20 carbon atoms; substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms; or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms, with at least one of R and R1 being other than hydrogen;
each R2, each R3 and each R4 are each independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms, or substituted or unsubstituted aralkyl having at least about 6 ring carbon atoms; m is 0, 1 or 2; and n and r are each independently 0, 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
15. A compound of claim 14 that is
N-(1-naphthyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(4-benzyloxyphenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(4-methoxynaphmyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(3,4-dichlorophenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(5-acenaphthyl)-1-(5-methoxy)-1-(5,6-dihydrophenanthridinyl)
carboximidamide;
N-(5-acenaphthyl)-1-(5-bromo)-(5,6-dihydrophenanthridinyl)
carboximidamide;
N-(1-naphthyl)-1-(7-ethyl)-(5,6-dihydrophenanthridinyl)
carboximidamide;
N-(4-sec-butylphenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(2,3-dichlorophenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(2,3-dimethylphenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(5,6,7,8-tetrahydro-1-naphthyl)-1-(5,6-dihydrophenanthridinyl)
carboximidamide;
N-(2-biphenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(3-biphenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(1-naphmyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(1-naphthyl)-1-(7-trifluoromethyl)-(5,6-dihydrophenanthridinyl)
carboximidamide;
N-(2-methylphenyl)-1-(5,6-dihydrophermnthridinyl)carboximidamide;
N-(3-ethylphenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(2,5-dimethylphenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide ; or
N-(2-ethylphenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
and pharmaceutically acceptable salts of said compounds.
16. A compound of the following Formula VI:
Figure imgf000094_0001
wherein R and R1 are each independently hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkylsulfinyl or substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted carbocyclic aryl, substituted or unsubstituted aralkyl, or a substituted or unsubstituted
heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms;
each R2 and each R3 are each independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, or substituted or unsubstituted aralkyl having at least about 6 ring carbon atoms;
X is -O-, -S-, sulfinyl (-S(O)-), sulfonyl (-S(O2)-), substituted or unsubstituted -N-, or substituted or unsubstituted methylene;
m is 0, 1, 2, 3, 4, 5 or 6; n is 0, 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
17. A compound of claim 16 that is
(2,5-dibromophenyl)-2,3,4,5-tetrahydro-[1,5]-benzothiazepin-5-yl)carboximidamide; or N-(2,5-dibromophenyl)-(1-oxo-2,3,4,5-tetrahydro-[1,5]-benzothiazepin-5-yl]carboximide; or
a pharmaceutically acceptable salt of said compounds.
18. A compound of the following Formula VU:
Figure imgf000095_0001
wherein R and R1 are each independently hydrogen; substituted or
unsubstituted alkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms; substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfinyl having 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfonyl having 1 to about 20 carbon atoms; substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms; or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms, with at least one of R and R1 being other than hydrogen;
each R2 and each R3 are each independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms, or substituted or unsubstituted aralkyl having at least about 6 ring carbon atoms; m is 0, 1 or 2; and n is an integer of 0-9; and pharmaceutically acceptable salts thereof.
19. A compound claim 18 that is
N-(4-methoxynaphmyl)-1-(2a,3,4,5-tetrahydrobenz[cd]indolmyl)-carboximidamide; N-(5-acenaphthyl)-1-(2a,3,4,5-tetrahydrobenz[cd]indolinyl)-carboximidamide;
N-(4,5-dimethylnaphthyl)-1-(2a,3,4,5-tetrahydrobenz[cd]indolinyl)-carboximidamide; or
N-(3,5-dichlorophenyl)-1-(2a,3,4,5-tetrahydrobenz[cd]indolinyl)-carboximidamide ; or pharmaceutically acceptable salts of said compounds.
20. A compound having the following Formula VIII:
Figure imgf000096_0001
wherein R and R1 are each independently hydrogen; substituted or
unsubstituted alkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms; substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfinyl having 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfonyl having 1 to about 20 carbon atoms; substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms; or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms, preferably with at least one of R and R1 being other than hydrogen;
each R2, each R3 and each R4 are each independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms, or substituted or unsubstituted aralkyl having at least about 6 ring carbon atoms;
m is 0, 1, 2, 3 or 4; n and r are each independently 0, 1, 2, 3 or 4; the dotted line represents an optional carbon-carbon endocyclic double bond; and
pharmaceutically acceptable salts thereof.
21. A compound of the following Formula IX:
Figure imgf000097_0001
wherein R and R1 are each independently hydrogen; substituted or
unsubstituted alkyl having from 1 to about 20 carbon atoms; substituted or
unsubstituted alkenyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms; substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfinyl having 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfonyl having 1 to about 20 carbon atoms; substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms; or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms, preferably with at least one of R and R1 being other than hydrogen;
each R2, each R3 and each R4 are each independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms, or substituted or unsubstituted aralkyl having at least about 6 ring carbon atoms;
m is 0, 1, 2, 3, 4, 5 or 6; and n and r are each independently 0, 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
22. A compound of any one of claims 1, 2, 4, 5, 8, 10, 12, 14, 16, 18, 20 or 21 wherein R is substituted or unsubstituted carbocyclic aryl, substituted or unsubstituted aralkyl, or a substituted or unsubstituted heteroaromatic or
heteroalicyclic group.
23. A compound of any one of claims 1, 2, 4, 5, 8, 10, 12, 14, 16, 18, 20 or 21 wherein R is substituted or unsubstituted carbocyclic aryl.
24. A compound of any one claims 1, 2, 4, 5, 8, 10, 12, 14, 16, 18, 20 or 21 wherein R is substituted or unsubstituted phenyl or napthyl.
25. A compound of any one claims 1, 2, 4, 5, 8, 10, 12, 14, 16, 18, 20 or 21 wherein R is phenyl or napthyl substituted at one or more ring positions by halogen, hydroxyl, azido, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted
alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, or substituted or
unsubstituted aralkyl.
26. A compound of any one claims 1, 2, 4, 5, 8, 10, 12, 14, 16, 18, 20 or 21 wherein R is phenyl or napthyl substituted at one or more ring positions by halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, aminoalkyl, or carbocyclic aryl preferably phenyl.
27. A compound of any one of claims 1, 2, 4, 5, 8, 10, 12, 14, 16, 18, 20, 21, 22, 23, 24, 25 or 26 wherein R1 is hydrogen or substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkylsulfinyl, or substituted or unsubstituted alkylsulfonyl.
28. A compound of any one of claims 1, 2, 4, 5, 8, 10, 12, 14, 16, 18, 20, 21 , 22, 23, 24, 25 or 26 wherein R1 is hydrogen or substituted or unsubstituted alkyl.
29. A compound of any one of claims 1, 2, 4 or 19-24 wherein in
Formulae I or I" at least one R2 or R3 substiment is a halogen, alkyl or alkoxy.
30. A compound of any of the preceding claims that is optically active.
31. A compound of claim 30 where the compound contains an optically active -S(O)- group.
32. A method of treating a nerve degeneration disease comprising administering to a mammal suffering from or susceptible to said disease a
therapeutically effective amount of a compound of any of claims 1-31.
33. A method of treating a neurodegenerative disease comprising administering to a mammal suffering from or susceptible to said disease a
therapeutically effective amount of a compound of any of claims 1-31.
34. A method of treating Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, Down's Syndrome or
Korsakoff s disease, Cerebral Palsy, or epilepsy, comprising administering to a mammal suffering from or susceptible to said disease a therapeutically effective amount of a compound of any of claims 1-31.
35. A method of treating or preventing nerve cell death or degeneration comprising administering to a mammal suffering from or susceptible to nerve cell death or degeneration a therapeutically effective amount of a compound of any one of claims 1-31.
36. The method of claim 35 wherein the nerve cell death or degeneration is caused by hypoxia, hypoglycemia, brain or spinal cord ischemia, retinal ischemia or brain or spinal cord trauma.
37. A method of treating a mammal suffering from or susceptible to stroke or heart attack comprising administering to the mammal a therapeutically effective amount of a compound of any one of claims 1-31.
38. A method of treating a mammal suffering from or susceptible to brain or spinal cord trauma comprising administering to the mammal a therapeutically effective amount of a compound of any one of claims 1-31.
39. A method of treating a mammal suffering from or susceptible to neuropathic pain, migraines, shingles, emesis, narcotic withdrawal symptoms or age-dependent dementia, comprising administering to the mammal a therapeutically effective amount of a compound of any one of claims 1-31.
40. A method of treating a mammal suffering from or susceptible decreased blood flow or nutrient supply to retinal tissue or optic nerve, or retinal ischemia or trauma, or optic nerve injury, comprising administering to the mammal a
therapeutically effective amount of a compound of any one of claims 1-31.
41. A method of treating a mammal suffering from or susceptible to post-surgical neurological deficits or neurological deficits associated with cardiac arrest, comprising administering to the mammal a therapeutically effective amount of a compound of any one of claims 1-31.
42. A method of treating a mammal suffering from or suceptible to a disorder of claims 39-41 comprising administering to the mammal a therapeutically effective amount of N-(m-ethylphenyl)-1-indolinylcarboximidamide.
43. A method of any one of claims 32-42 wherein the mammal is a human.
44. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of any one of claims 1-31 and a pharmaceutically acceptable carrier.
45. A compound of any one of claims 1-31 that is radiolabelled.
PCT/US1997/002678 1996-02-15 1997-02-14 Pharmaceutically active compounds and methods of use WO1997030054A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
JP9529602A JP2000504730A (en) 1996-02-15 1997-02-14 Pharmaceutical active substances and methods of use
EP97906923A EP0925300A1 (en) 1996-02-15 1997-02-14 Pharmaceutically active compounds and methods of use
AU22780/97A AU733475B2 (en) 1996-02-15 1997-02-14 Pharmaceutically active compounds containing 5-8 member N-hetero rings incorporating the linking group carboximidamide
US09/425,582 US6358993B1 (en) 1996-02-15 1999-10-22 Pharmaceutically active nitrogen ring compounds and methods of use thereof
US10/038,178 US6514990B2 (en) 1996-02-15 2001-11-09 Pharmaceutically active compounds and methods of use
US10/321,402 US6770668B2 (en) 1996-02-15 2002-12-17 Pharmaceutically active compounds and methods of use

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US60199296A 1996-02-15 1996-02-15
US08/601,992 1996-02-15

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US60199296A Continuation-In-Part 1996-02-15 1996-02-15

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US08/858,399 Continuation US6025355A (en) 1996-02-15 1997-05-19 Pharmaceutically active compounds and methods of use

Publications (1)

Publication Number Publication Date
WO1997030054A1 true WO1997030054A1 (en) 1997-08-21

Family

ID=24409543

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/002678 WO1997030054A1 (en) 1996-02-15 1997-02-14 Pharmaceutically active compounds and methods of use

Country Status (5)

Country Link
EP (1) EP0925300A1 (en)
JP (1) JP2000504730A (en)
KR (1) KR19990082494A (en)
AU (1) AU733475B2 (en)
WO (1) WO1997030054A1 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1041986A1 (en) * 1997-10-10 2000-10-11 Cambridge Neuroscience, Inc. Pharmaceutically active compound and methods of use
WO2003084938A2 (en) * 2002-04-10 2003-10-16 Orchid Chemicals & Pharmaceuticals Limited Pyrimidone derivatives useful for the treatment of inflammatin and immunological diseases
US6774263B1 (en) 1997-10-10 2004-08-10 Cambridge Neuroscience, Inc. Pharmaceutically active compound and methods of use
WO2006133821A1 (en) * 2005-06-13 2006-12-21 Merck Patent Gmbh Tetrahydroquinolines used in the form of modulators of mitotic motor-proteins eg5
US7417040B2 (en) 2004-03-01 2008-08-26 Bristol-Myers Squibb Company Fused tricyclic compounds as inhibitors of 17β-hydroxysteroid dehydrogenase 3

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4504482A (en) * 1983-07-28 1985-03-12 Sterling Drug Inc. [5(or 4)-(Pyridinyl)-2-pyrimidinyl]ureas and cardiotonic use thereof
US5507974A (en) * 1992-12-11 1996-04-16 Hoechst Aktiengesellschaft Aromatic, substituted pyrimidine compounds, methods for the preparation thereof, and use thereof

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3314963A (en) * 1962-07-23 1967-04-18 Pfizer & Co C Azabenzocycloalkane-n-carboxamidines
US3291799A (en) * 1964-09-21 1966-12-13 Hoffmann La Roche Isoquinoline carboxamidine
FR1473839A (en) * 1965-04-02 1967-03-24 Alphachimie New derivatives of 2, 3, 4, 5-tetrahydro- (1h) -1-benzazepine and their manufacturing processes
US3679692A (en) * 1969-10-01 1972-07-25 Mead Johnson & Co Iminomethylindolines
CA2182302A1 (en) * 1994-02-03 1995-08-10 Stanley M. Goldin Therapeutic guanidines

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4504482A (en) * 1983-07-28 1985-03-12 Sterling Drug Inc. [5(or 4)-(Pyridinyl)-2-pyrimidinyl]ureas and cardiotonic use thereof
US5507974A (en) * 1992-12-11 1996-04-16 Hoechst Aktiengesellschaft Aromatic, substituted pyrimidine compounds, methods for the preparation thereof, and use thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0925300A4 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1041986A1 (en) * 1997-10-10 2000-10-11 Cambridge Neuroscience, Inc. Pharmaceutically active compound and methods of use
EP1041986A4 (en) * 1997-10-10 2001-03-21 Cambridge Neuroscience Inc Pharmaceutically active compound and methods of use
US6774263B1 (en) 1997-10-10 2004-08-10 Cambridge Neuroscience, Inc. Pharmaceutically active compound and methods of use
KR100761451B1 (en) * 1997-10-10 2007-09-27 케임브리지 뉴로사이언스, 인코포레이티드 Pharmaceutically active compound and methods of use
WO2003084938A2 (en) * 2002-04-10 2003-10-16 Orchid Chemicals & Pharmaceuticals Limited Pyrimidone derivatives useful for the treatment of inflammatin and immunological diseases
WO2003084938A3 (en) * 2002-04-10 2004-02-05 Orchid Chemicals & Pharm Ltd Pyrimidone derivatives useful for the treatment of inflammatin and immunological diseases
US7417040B2 (en) 2004-03-01 2008-08-26 Bristol-Myers Squibb Company Fused tricyclic compounds as inhibitors of 17β-hydroxysteroid dehydrogenase 3
WO2006133821A1 (en) * 2005-06-13 2006-12-21 Merck Patent Gmbh Tetrahydroquinolines used in the form of modulators of mitotic motor-proteins eg5
AU2006257414B2 (en) * 2005-06-13 2011-08-25 Merck Patent Gmbh Tetrahydroquinolines used in the form of modulators of mitotic motor-proteins Eg5
US8207345B2 (en) 2005-06-13 2012-06-26 Merck Patent Gmbh Tetrahydroquinolines for use as modulators of the mitotic motor protein Eg5

Also Published As

Publication number Publication date
KR19990082494A (en) 1999-11-25
EP0925300A1 (en) 1999-06-30
EP0925300A4 (en) 1999-06-30
AU733475B2 (en) 2001-05-17
JP2000504730A (en) 2000-04-18
AU2278097A (en) 1997-09-02

Similar Documents

Publication Publication Date Title
JP2963107B2 (en) Substituted aminomethyltetralins and their heterocyclic analogs
CS201040B2 (en) Method of producing etherified hydroxy-benzo-diheterocyclic compounds
GB2042535A (en) 1-acylated-1,2,3,4-tetrahydroquinoline-2-carboxylic acids
US6514990B2 (en) Pharmaceutically active compounds and methods of use
LV12792A (en) Formyl- or cyano- indole derivatives having dopaminergic activity
NL7908031A (en) NEW QUINOLINE DERIVATIVES AND PHARMACEUTICAL PREPARATIONS CONTAINING SUCH A COMPOUND AND METHOD FOR PREPARING THESE COMPOUNDS.
JPH0717633B2 (en) Heteroaryl piperazine antipsychotics
NZ243783A (en) 5-aminosulphonylisoquinoline derivatives and pharmaceutical compositions
CN114031518B (en) Benzylamine or benzyl alcohol derivative and application thereof
JP2015157836A (en) Quinolone compound and pharmaceutical composition
FI90979C (en) Process for the preparation of therapeutically useful substituted 3,4-dihydro-2H-benzopyrans
CZ224098A3 (en) Quinolin-2-(1h)-one derivative, process of its preparation and pharmaceutical composition containing thereof
US4767756A (en) 3-substituted benzazepines
SK10002003A3 (en) 4-Aminobenzopyran derivatives
AU733475B2 (en) Pharmaceutically active compounds containing 5-8 member N-hetero rings incorporating the linking group carboximidamide
AU609169B2 (en) Benzazepines derivatives
US4771047A (en) Benzazepine derivatives
US6756389B2 (en) Pharmaceutically active compounds and methods of use
NO173988B (en) ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PYRROLIDE INGREDIENTS
CA2084162A1 (en) Quinolylmethoxyphenyl-acetamides
KR100254106B1 (en) 4-quinolinine derivative or salt thereof
AU766646B2 (en) Pharmaceutically active compounds and methods of use
NL7908030A (en) N-substd. kinicine analogues - useful as cardiovascular medicaments
JP5247667B2 (en) Medicine
CA2090635A1 (en) Substituted phenylquinazoline derivatives

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 08858399

Country of ref document: US

ENP Entry into the national phase

Ref country code: US

Ref document number: 1997 858399

Date of ref document: 19970520

Kind code of ref document: A

Format of ref document f/p: F

AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE HU IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TR TT UA UG US UZ VN YU AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE LS MW SD SZ UG AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF

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

Ref document number: 1019980706227

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 1997906923

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 1997906923

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1019980706227

Country of ref document: KR

WWR Wipo information: refused in national office

Ref document number: 1019980706227

Country of ref document: KR

WWW Wipo information: withdrawn in national office

Ref document number: 1997906923

Country of ref document: EP