EP1240144A2 - Verbindungen zur förderung der neuronendifferenzierung - Google Patents

Verbindungen zur förderung der neuronendifferenzierung

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Publication number
EP1240144A2
EP1240144A2 EP00976295A EP00976295A EP1240144A2 EP 1240144 A2 EP1240144 A2 EP 1240144A2 EP 00976295 A EP00976295 A EP 00976295A EP 00976295 A EP00976295 A EP 00976295A EP 1240144 A2 EP1240144 A2 EP 1240144A2
Authority
EP
European Patent Office
Prior art keywords
compound
substituted
alkyl
aryl
heterocycle
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP00976295A
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English (en)
French (fr)
Inventor
Shripad Bhagwat
Moorthy Palanki
Paul Erdman
Mary Doubleday
Hiroshi Sato
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nippon Kayaku Co Ltd
Original Assignee
Nippon Kayaku Co Ltd
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Publication date
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Publication of EP1240144A2 publication Critical patent/EP1240144A2/de
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C07C323/59—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole 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
    • C07D277/24—Radicals substituted by oxygen atoms
    • 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
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • This invention is generally directed to neuroprotective agents, pharmaceutical compositions containing the same, as well as to methods related to the use of such neuroprotective agents.
  • Neurotrophic factors are a group of proteinaceous compounds that participate in differentiation induction of neurons to maintain the existence and survival of cells, of which nerve growth factors (NGFs) are a representative class. NGFs are involved in the differentiation, existence, maintenance and/or repair of neurons in both the central and peripheral nervous systems of animals and represent a series of proteins having molecular weights of approximately 50,000 daltons.
  • paphological symptoms In the central nervous system, such damage is found to cause, for example, Alzheimer's disease, dementia induced by cerebro-vascular disorders, disturbance of consciousness due to cerebral contusion, and tremor or muscle rigidity associated with Parkinson's disease.
  • damage to the peripheral nervous system is associated with a number of conditions, such as amyotropic lateral sclerosis, spinal muscle atrophy, motor function disturbances due to neuron damage, neuropathy induced by diabetes mellitus, uremia, vitamin B, or B 12 deficiency, chronic liver disease, sarcoidosis, amyloidosis, hypothyrea, cancer, angiopathy, Sjogren symptoms, immunopathy accompanied by infections, hereditary disease, physical compression, certain types of drugs (e.g.. carcinostatic. tuberculostatic and/or anti-epileptic agents), or upon exposure to. for example, arsenic, thallium or carbon disulfide.
  • drugs e.g. carcinostatic. tuberculostatic and/or anti-epileptic agents
  • NGF neurotrophic factor
  • the present invention is directed to compounds having activity as neuroprotective agents (also referred to herein as simply “compounds'), as well as to compositions and methods related thereto.
  • neuroprotective agent means a compound that prevents neuron cell death.
  • the compounds of the present invention have the following structure (I):
  • R quarantin R 2 , R 3 , R 4 and R 5 are as defined below, including stereoisomers and pharmaceutically acceptable salts thereof.
  • the present invention is also directed to methods for treating a variety of conditions by administering an effective amount of a neuroprotective agent of this invention to an animal or subject in need thereof (referred to herein as a "patient"), typically a warm-blooded animal (including a human).
  • a patient typically a warm-blooded animal (including a human).
  • the compounds of this invention are preferably formulated as a pharmaceutical composition which contains an effective dosage amount of one or more neuroprotective agents in combination with one (or more) pharmaceutically acceptable carrier(s).
  • Conditions that may be treated by the compounds of this invention, or a pharmaceutical composition containing the same, include any condition which may benefit from administration of neuroprotective agents generally, and are particularly useful for the prevention and/or treatment of various conditions including (but not limited to) increased intracraniel pressure and cerebral herniation, cerebral edema, hydrocephalus, meningintis, encephalitis, ischemic encephalopathy, cerebral infarction, intracranial hemorrhage, epidermal hematoma, subdural hematoma, parenchymal injuries, Alzheimer's deasease, Huntington's disease, Parkinsonism, amytrophic lateral sclerosis, multiple sclerosis, hepatic encephalopathy. leukodystrophy. acute idiopathic neuropathy, neurilemmoma, and/or neurofibroma.
  • Figure 1 shows the effect of a representative compound according to the present invention in a rat taxol-induced neuropathy model.
  • Figure 2 shows the effects of representative compounds according to the present invention on a rat taxol-induced neuropathy model.
  • Figure 3 shows the effects of representative compounds according to the present invention on a rat taxol-induced neuropathy model.
  • the present invention is directed to compounds which have activity as neuroprotective agents, as well as to compositions and methods relating to the same.
  • the compounds of this invention have the following structure (I):
  • R is alkyl, substituted alkyl, aryl, substituted aryl, ar lalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl;
  • R 2 is -OR 2a or -NR 2b R 2c ;
  • R 2a is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, or substituted heterocyclealkyl;
  • R 2b and R 2c are the same or different and independently hydrogen, alkyl.
  • R 2d is alkyl, substituted alkyl, aryl or substituted aryl, or R 2b and R 2c taken together with the nitrogen atom to which they are attached from a heterocyclic ring or substituted heterocyclic ring;
  • R 3a , R b and R, c are the same or different and independently hydrogen, alkyl. substituted alkyl, aryl, substituted aryl, arylalkyl, substitued arylalkyl, heterocycle.
  • R 3d and R 3c are the same or different and independently hydrogen, amino, alkyl.
  • heterocyclealkyl or substituted heterocyclealkyl or R 4f and R g taken together with the nitrogen atom to which they are attached form a heterocycle or substituted heterocycle, or R 4c and R ⁇ taken together with the nitrogen atom to which they are attached from a heterocyclic ring or substituted heterocyclic ring.
  • Alkyl means a straight chain or branched, saturated or unsaturated alkyl, cyclic or non-cyclic hydrocarbon having from 1 to 10 carbon atoms.
  • Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and the like; while saturated branched alkyls include isopropyl, _>ec-butyl, isobutyl. tert- butyl, isopentyl, and the like.
  • Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (also referred to as an "alkenyl” or "alkynyl", respectively).
  • Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1 - butenyl, 2-butenyl, isobutylenyl, 1-pentenyl. 2-pentenyl, 3-methyl-l -butenyl. 2-methyl-2- butenyl, 2.3-dimethyl-2-butenyl, and the like; while representative straight chain and branched alkynyls include acetylenyl, propynyl, 1 -butynyl, 2-butynyl, 1 -pentynyl. 2- pentynyl, 3-methyl-l butynyl, and the like.
  • Representative saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like: while unsaturated cyclic alkyls include cyclopentenyl and cyclohexenyl, and the like.
  • Cycloalkyls are also referred to herein as "carbocyclic" rings systems, and include bi- and tri-cyclic ring systems having from 8 to 14 carbon atoms such as a cycloalkyl (such as cyclo pentane or cyclohexane) fused to one or more aromatic (such as phenyl) or non-aromatic (such as cyclohexane) carbocyclic rings. .
  • Alkanediyl means a divalent alkyl group having two hydrogen atoms taken from the same carbon atom or different carbon atoms of the alkyl, such as -CH 2 -, -CH(CH 3 )-, -CH(CH 3 )CH 2 -, -CH 2 CH 2 CH 2 -, CH 2 CH(CH 3 )CH 2 -, -(cyclohexyl)-. and the like.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • Aryl means an aromatic carbocyclic moiety such as phenyl or naphthyl.
  • Arylalkyl means an alkyl having at least one alkyl hydrogen atoms replaced with an aryl moiety, such as benzyl. -(CH 2 ) 2 phenyl, -(CH 2 ) 3 phenyl, -CH(phenyl) 2 , and the like.
  • Heteroaryl means an aromatic heterocycle ring of 5- to 10 members and having at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono- and bicyclic ring systems.
  • Representative heteroaryls are pyridyl, fiiryl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl.
  • Heteroarylalkyl means an alkyl having at least one alkyl hydrogen atom replaced with a heteroaryl moiety, such as -CH 2 pyridinyl, -CH 2 pyrimidinyl, and the like.
  • Heterocycle means a heterocyclic ring containing from 5 to 10 ring atoms
  • Heterocycle means a 5- to 7-membered monocyclic, or 7- to 10- membered bicyclic, heterocyclic ring which is either saturated, unsaturated, or aromatic, and which contains from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized, including bicyclic rings in which any of the above heterocycles are fused to a benzene ring.
  • the heterocycle may be attached via any heteroatom or carbon atom.
  • Heterocycles include heteroaryls as defined above.
  • heterocycles also include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofiiranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
  • Heterocyclealkyl means an alkyl having at least one alkyl hydrogen atom replaced with a heterocycle, such as -CH 2 morpholinyl, and the like.
  • substituted means any of the above groups (i.e., alkyl, alkanediyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle and heterocyclealkyl) wherein at least one hydrogen atom is replaced with a substituent.
  • two hydrogen atoms are replaced.
  • Y is alkanediyl, substitute alkanediyl, or a direct bond
  • R a and R b are the same or different and independently hydrogen, amino. alkyl. substituted alkyl (including halogenated alkyl). aryl, substituted aryl.
  • R is pyridinyl.
  • R t is pyridin-3-yl, and compounds of this invention have the following structure:
  • R 2 is -NR 2b R 2c , and compounds of this invention have the following structure (III):
  • R 3 and R 5 are hydrogen, and compounds of this invention have the following structure (IV):
  • R 3 is, in one embodiment, alkyl or substituted alkyl.
  • R is heterocycle and, more specifically, an aromatic heterocycle (i.e., heteroaryl) such as pyridin-2-yl or pyridin-3-yl.
  • R is aryl such as phenyl, or alkyl (including cycloalkyl).
  • R is heteroaryl such as thiazolyl.
  • R 2a is aryl such as phenyl or substituted aryl such as 4-chlorophenyl, or arylalkyl. such as benzyl (i.e., -CH 2 phenyl) or -(CH 2 ) 2 phenyl.
  • R 2a is heterocyclealkyl, such as -(CH 2 ) 2 morpholinyl, -(CH 2 ) 2 indolyl, -(CH 2 ) 2 . 3 piperidinyl, -(CH,) 3 pyridinyl or -(CH 2 ) 2 thiophenyl.
  • R 2 is -NR 2b R 2c , wherein R 2b is hydrogen and R 2c is alkyl, substituted alkyl (e.g., (CH 2 ) 3 OCH 3 ), arylalkyl (e.g. benzyl) or heteroarylalkyl (e.g. -CH 2 pyridinyl or -CH 2 thiophenyl).
  • R 2c is -OR 2d or -SO 2 R 2d wherein R 2d is alkyl such as methyl, aryl such as phenyl or arylalkyl such as benzyl.
  • R 2b and R 2c are both alkyl such as methyl or ethyl.
  • cycloalkylamide
  • R 3b and R 3c taken together form a substituted heterocyclic ring such as the following structures (vi) through (x):
  • R 4 moieties of this invention include (but are not limited to) those listed in Table 1 of Example 45.
  • R 4 is hydrogen, alkyl such as methyl or ethyl, aryl such as phenyl or naphthyl, or arylalkyl such as benzyl.
  • representative embodiments representative of this invention.
  • R a groups include alkyl and substituted alkyl, as well as aryl, substituted aryl, arylalkyl and substituted arylalkyl. Further representative R 4 groups include heterocycle, substituted heterocycle, heterocyclealkyl and substituted heterocyclealkyl.
  • representative R b groups include alkyl. substituted alkyl, aryl and substituted aryl.
  • representative R 4c and R d groups include alkyl, substituted alkyl, aryl, and substituted aryl.
  • R 4 is -SO 2 R c .
  • representative R4e groups include alkyl, substituted alkyl. aryl, substituted aryl, arylalkyl, and substituted arylalkyl, as well as heterocycle and substituted heterocycle.
  • R and R 4 taken together form a substituted or unsubstituted heterocyclic ring of the following structure (xi):
  • ring A represents a heterocyclic ring as defined above.
  • Representative heterocyclic rings in this regard include pyrrolyl, imidazolyl, pyrazolyl. pyrrolidinyl, pyridinyl, pyrimidinyl, and the like, as well as keto-substituted heterocycles such as hydantinyl . ketopiperazinyl, diketopiperazinyl, and the like.
  • R, and R are taken together to form a substituted heterocyclic ring having the following structures (xii), (xiii) or (xiv):
  • R h and R j represents the same or difference substituents as defined above, such as hydrogen or alkyl.
  • R 5 is hydrogen. In another emobiment. R 5 is alkyl such as methyl, ethyl, n-propyl, n-butyl and cyclohexyl.
  • compositions of structure (1) are also within the scope of this invention.
  • the compound may generally be utilized as the free base.
  • the compounds may be used in the form of acid addition salts.
  • Acid addition salts of the free base amino compounds of the present invention may be prepared by methods well known in the art, and may be formed from organic and inorganic acids.
  • Suitable organic acids include aleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, 1,2-ethanedisulfonic, acetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, glycolic, glutamic, benzenesulfonic, p-tolyenesulfonic, hippuric, sebacic, 2-hydroxy-l-naphthoic and perchloric acids.
  • Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids.
  • the compounds of structure (I) may have chiral centers and may occur as recemates, reacemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof. Furthermore, some of the crystalline forms of the compounds of structure (I) may exist as polymo ⁇ hs, which are included in the present invention. In addition, some of the compounds of structure (I) may also form solvates with water or other organic solvents. Such solvates are similarly included within the scope of this invention.
  • compound 2 may be prepared by treating aldehyde 1 with an acrylate ester in the presence of sodium cyanide in dimethylformamide solvent.
  • compound 3 can be prepared from aldehyde 1 using the above conditions.
  • compound may be prepared from compound 2 by treating it with piperidine and aqueous formaldehyde in tetrahydrofuran.
  • the piperidyl adduct intermediate can be treated with hydrochloric acid to give compound 4.
  • Treatment of compound 4 with 2-aminoethanethiol in tetrahydrofuran will result in compound 5.
  • the amine group in compound 5 can be converted to amides (by treating with acid chloride), carbamates (by treating with chloroformates) and ureas (by treating with isocyanates) in dichloromethane or tetrahydrofuran. Once the amine group was converted to NHR .
  • ester group OR 2a can by hydrolyzed either under basic (using sodium hydroxide) or acidic (hydrochloric acid) to give compound 6.
  • the acid group in compound 6 can be functionalized to an amide by standard coupling conditions using a carbodiimide (such as ethyl diisopropyl carbodiimide) in a suitable solvent (such as tetrahydrofuran or dichloromethane).
  • a carbodiimide such as ethyl diisopropyl carbodiimide
  • suitable solvent such as tetrahydrofuran or dichloromethane
  • compound 8 can be prepared from compound 3 by treatment with piperidine and aqueous formaldehyde in tetrahydrofuran.
  • the intermediate piperidyl adduct can be treated with N-acetyl cysteine in tetrahydrofuran or ethanol to give compound 8.
  • the acid group in compound 8 can be further functionalized to an amide by treating with an amine and a suitable carbodiimide (such as ethyl diisopropyl carbodiimide) in dichloromethane or tetrahydrofuran.
  • the t-butyl ester in compound 9 can be hydrolyzed to an acid, as in compound 10, using an acid (such as hydrochloric acid).
  • compound 12 can be prepared from compound 3 by treating it with piperidine and aqueous formaldehyde in tetrahydrofuran.
  • the piperidyl adduct intermediate can be treated with a limited amount of hydrochloric acid to give compound 12.
  • Treatment of compound 12 with an appropriately substituted thiol in tetrahydrofuran resulted in compound 13.
  • the Fmoc group on compound 13 can be cleaved with piperidine in dimethylformamide to give the free amine.
  • the t-butyl ester in compound 14 can be cleaved to a free acid using hydrochloric acid in water-tetrahydrofuran solvent system to give compound 15.
  • the acid group in compound 15 can be functionalized to an amide by standard coupling conditions using a carbodiimide (such as ethyl diisopropyl carbodiimide) in a suitable solvent (such as tetrahydrofuran or dichloromethane), or to an ester by treating with an alkyl halide, triethylamine in dimethylformamide.
  • a carbodiimide such as ethyl diisopropyl carbodiimide
  • a suitable solvent such as tetrahydrofuran or dichloromethane
  • the acid 21 can be attached to a solid phase resin (such as 2-chlorotrityl resin) in the presence of diisopropylethylamine to give compound 22.
  • a solid phase resin such as 2-chlorotrityl resin
  • the FMOC group in compound 22 can be cleaved using piperidine in dimethylformamide to give free amine, which can be treated with either an acid chloride to give an amide, or a chloroformate to give a carbamate, or to an isocyanate to give a urea.
  • Compound 23 can be cleaved off the resin using trifluoroacetic acid in dichloromethane.
  • compositions containing one or more compounds of this invention are disclosed.
  • a compound of structure (I) is preferably formulated as a pharmaceutical composition.
  • Pharmaceutical compositions of the present invention comprise a compound of this invention and a pharmaceutically acceptable carrier, wherein the compound is present in the composition in an amount which is effective to treat the condition of interest.
  • the pharmaceutical compositions of the present invention include a compound of structure (I) in an amount from 0.1 mg to 250 mg per dosage depending upon the route of administration, and more typically from 1 mg to 60 mg. Appropriate concentrations and dosages can be readily determined by one skilled in the art.
  • compositions formulated as liquid solutions include saline and sterile water, and may optionally include antioxidants, buffers, bacterioslats and other common additives.
  • the compositions can also be formulated as pills, capsules, granules, or tablets which contain, in addition to a compound of this invention, diluents, dispersing and surface active agents, binders, and lubricants.
  • One skilled in this art may further formulate the compounds of this invention in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington's Pharmaceutical Sciences, Gennaro. Ed., Mack Publishing Co., Easton. PA 1990.
  • the present invention provides a method for treating a variety of conditions by administering an effective amount of a compound of structure (1) to a patient in need thereof.
  • treatment includes preventative administration, as well as "rescue” treatment when, for example, a patient has already developed neuropathy.
  • Conditions that may be treated by the compounds of this invention, or a pharmaceutical composition containing the same include any condition which is responsive to treatment by a neuroprotective agent generally and, more specifically, for treatment of central or peripheral nervous disorders, or for promoting nerve cell differentiation. Representative conditions in this regard include (but not limited to) increased intracraniel pressure and cerebral herniation, cerebral edema, hydrocephalus, meningintis.
  • encephalitis ischemic encephalopathy, cerebral infarction, intracranial hemorrhage, epidermal hematoma, subdural hematoma, parenchymal injuries, Alzheimer's deasease, Huntington ' s disease, Parkinsonism, amytrophic lateral sclerosis, multiple sclerosis, hepatic encephalopathy, leukodystrophy, acute idiopalhic neuropathy, diabetic neuropathy, chemotherapy-induced neuropathy, HIV-induced neuropathy, neurilemmoma, and/or neurofibroma.
  • the methods of this invention include systemic administration of a compound of this invention, preferably in the fo ⁇ n of a pharmaceutical composition.
  • systemic administration encompasses both oral and parenteral methods of administration.
  • suitable pharmaceutical compositions include powders, granules, pills, tablets, and capsules as well as liquids, syrups, suspensions, and emulsions. These compositions may also include flavorants, preservatives, suspending, thickening and emulsifying agents, and other pharmaceutically acceptable additives.
  • the compounds of the present invention can be prepared in aqueous injection solutions which may contain buffers, antioxidants, bacteriostats, and other additives commonly employed in such solutions.
  • Ethyl chloroformate (2.93 g) was added to a solution of 2-[(tert-butoxy)- carbonylaminojacetic acid (4.73 g) and triethylamine (4.09 g) in dichloromethane (150 mL) at 0 _C. The solution was stirred for 20 min. and 2-[(2-aminocthylthio)methyl]-4- piperidyl-l -(3-pyridyl)butane-l,4-dione (10 g), triethylamine (4.1 g) and dichloromethane (150 mL) were added to the reaction mixture and stirred at room temperature for lh.
  • the resin was treated with 10 eq of 4-chlorophenyl isocyanate in dichloromethane (6 mL) for two days. The resin was washed with washed with dimethyl formamide, isopropanol, dichloromethane and ether and dried. The resin was treated with 20% trifluoroacetic acid in dichloromethane (5 mL). The solution was filtered, concentrated and purified on HPLC (C-18 prep column, 10% to 90% acetonitrile in water both containing 0.1% TFA) to give 12% of the title compound; ESMS, (M+l) + 480.
  • the title compound was prepared from 3-( ⁇ (2R)-2-[(fluoren-9- ylmethoxy)carbonylamino]-2-(methoxycarbonyl)ethylthio ⁇ methyI)-4-oxo-4-(3- pyridyl)butanoic acid and 4-fluorophenyl isocyanate as described in Example 16 in a 5% yield; ESMS, (M+l) + 464.
  • the title compound was prepared from 3-( ⁇ (2R)-2-[(fluoren-9- ylmethoxy)carbonylamino]-2-(methoxycarbonyl)ethylthio ⁇ methyl)-4-oxo-4-(3- pyridyl)butanoic acid and 2-methoxyphenyl isocyanate as described in Example 16 in a 14% yield: ESMS, (M+l) + 476.
  • the title compound was prepared from 3-( ⁇ (2R)-2-[(fluoren-9- ylmethoxy)carbonylamino]-2-(methoxycarbonyl)ethylthio ⁇ methyl)-4-oxo-4-(3- pyridyl )butanoic acid and 3,4,5-trimethoxyphenyl isocyanate as described in Example 16 in a 7.2% yield: ESMS. (M+l) * 536.
  • the title compound was prepared from 3-( ⁇ (2R)-2-[(fluoren-9- ylmethoxy)carbonylamino]-2-(methoxycarbonyl)ethylthio ⁇ methyl)-4-oxo-4-(3- pyridyl)butanoic acid and 1 -naphthyl isocyanate as described in Example 16 in a 12% yield: ESMS. (M+l ) + 496.
  • the title compound was prepared from 3-( ⁇ (2R)-2-[(fluoren-9- ylmethoxy)carbonylamino]-2-( methoxycarbonyl )ethylthio ⁇ methyl )-4-oxo-4-(3- pyridyl)butanoic acid and benzyl chloroformate as described in Example 16 at 12% yield; ESMS, (M+l ) + 460.
  • the title compound was prepared from 3-( ⁇ (2R)-2-[(fluoren-9- ylmethoxy)carbonylamino]-2-(methoxycarbonyl)ethylthio ⁇ methyl)-4-oxo-4-(3- pyridyl)butanoic acid and allyl isocyanate as described in Example 23 to provide the desired compound in a 10.4% yield; ESMS, (M+l ) + 410.
  • the title compound was prepared from 3-( ⁇ (2R)-2-[(fluoren-9- ylmethoxy)carbonylamino]-2-(methoxycarbonyl)ethylthio ⁇ methyl)-4-oxo-4-(3- pyridyl)butanoic acid and cyclohexyl isocyanate as described in Example 16 in a 6% yield; ESMS, (M+l ) + 452.
  • Triethylamine (14.7 ⁇ L) was added to a solution of 3- ⁇ [2-(N- cyclohexylacetylamino)ethylthio]methyl ⁇ -4-oxo-4-(3-pyridyl)butanoic acid (44.6 mg) in dichloromethane (1.1 mL) and stirred for 30 min. The solution was cooled to 0 °C and ethyl chloroformate (10.5 ⁇ L) was added and stirred for 10 minutes. Dimethylamine in tetrahydrofuran (2M, 53 ⁇ L) was added and stirred at room temperature overnight. The solution was concentrated and purified on preparative HPLC (C-18 prep column, 10% to 90% acetronitrile in water both containing 0.1% TFA) to give 6.8 mg of the title compound; ESMS (M+l) + 420.
  • Differentiated PC 12 (rat pheochromocytoma) cells are utilized to model taxol-damaged neurons. Differentiated PC 12 have nerve-like morphology which is disrupted by administration of taxol. Quantification of damage to differentiated PC12 cells by taxol is measured by the release of LDH that occurs upon cell necrosis.
  • PC 12 cells are differentiated with NGF (100 mg/ml) for 29 hours. Compounds are added for 19 hours (pre-treatment), then taxol (0.24 mM) is added. 72 hours (3 days) after taxol addition, cell survival is assayed by LDH release. Complete cellular protection (100%) is defined as the protection derived from 30 mM NK5805. NK5805 is a reference compound for neuronal protection. It was originally identified by Nippon Kayaku Co. Ltd. in published PCT WO99/05091 and has the following structure:
  • LDH values were quantified by calculating the following % survival, relative to 30 mM NK5805, according to Equation (1):
  • a 100% protection level is equivalent to the group given no taxol.
  • results Table 2 identifies preferred compounds with significant protection of differentiated PC 12 from taxol damage.
  • preferred compounds (from Table 1 above) having a protection level of at least 50% at 10 ⁇ M concentration in this assay are as follows: 5, 8, 24, 32, 58, 60, 61, 74, 81. 90-92, 94, 95, 97-102, 105, 106, 1 10-1 13, 115-1 17, 121-123, 125-129, 132, 136, 140, 164, 169, 170, 174-184, 187-189, 195, 196, 198, 202, 204-208. 214-226, 240. 244, 246. 249. 251-253, 257. 259. 260. 263, 264, 268-273. 275. 277-282, 285, 335, 337-345, 355, 357-375, 378-388, 420-426, 432-435 and 444.
  • Rat superior cervical ganglion (SCG) neurons have been used extensively to model neuronal systems. This assay utilizes SCG neurons to identify potential protective agents against taxol-induced neuropathy.
  • Neonatal rat SCG neurons are cultured with 2.5 ng/ml NFG and the test compounds. After 36 hours 1 mM taxol is added. 72 hours (3 days) after taxol addition, cell survival is assayed by LDH release. Complete cellular protection (100%) is defined as the protection derived from 30 mM. LDH values were quantified by calculating the following % survival, relative to 30 mM NK5805 as noted in Equation (1) above.
  • Table 3 identifies preferred compounds with significant protection of rat SCG from taxol damage.
  • preferred compounds from Table 1 above having a protection level of at least 50% at 10 ⁇ M concentration in this assay are as follows: 1, 2, 8, 25, 30, 32, 59-61, 74, 77, 120, 129, 130. 132-135, 139, 140, 143-146, 148. 152, 153, 159, 162-164, 168, 169, 175, 187-189, 194, 196, 197, 206, 218, 223, 226, 258, 259, 263, 356, 370, 378-388, 395, 396, 407, 410, 413, 416, 421, 422 and 435-442.
  • Sprague-Dawley female rats (215-225g) were used. One week prior to the initiation of dosing with test compounds, base line electrophysiological recording were obtained. Dosing of the test compounds was initiated one day prior to the first injection of taxol (A.G. Scientific). Beginning on Day 2 animals were injected with total of two doses of 15 mg/kg paclitaxel giving 3 days apart, for a cumulative dose of 30 mg/ml.
  • Test compounds were administered by intraperitoneal (i.p.) injection or by post orum (p.o.) gavage in conscious once daily.
  • Paclitaxel was administered on Day 2 and 5 by tail vein injection at 6 mg/ml in 50% saline /25%Cremophore /25% ethanol.
  • One group was given the paclitaxel vehicle alone in an equivalent volume.
  • Test compounds were formulated for dosing daily, immediately prior to dosing. The compounds were formulated by adding 15% of the final volume of pure PEG400 to the compounds and mixed on an orbital shaker for 40 minutes.
  • Taxol (A.G. Scientific) is solvated with Cremophore-ethanol vehicle at 12 mg/ml and then diluted 50/50 with saline. The test compounds are solvated with saline at appropriate concentration.
  • Sensory and motor nerve conduction velocities were evaluated using a method based in the protocol described by De Koning and Gispen (Peptides 5:415-422, 1987). Electrophysiological evaluation was carried out as a double blind study. Animals were anesthetized with isofluorane. In order to maintain body temperature, anesthetized animals were placed on DeltaphaseTM Isothermal Pads and rectal temperatures were monitored. Stimulating needle electrodes were inserted close to the sciatic nerve at the sciatic notch and the tibial nerve near the ankle. Subcutaneous recording electrodes were placed over the distal lumbricales foot muscles.
  • Stimuli were supramaximal square-waves of 0.1 msec duration generated with a Grass S88 Stimulator through a Grass stimulation isolation unit.
  • An ETH-260 Bride/Bio Amplifier (CB Sciences Inc), computer (Macintosh Iici), and data acquisition system (MacLab/200) were used for the recordings.
  • the motor and sensor ' nerve conduction velocities were calculated by measuring the distance between the sciatic notch and ankle sites, and the latency between the M-wave and the H- reflex.
  • the electrophysiological evaluations were conducted 2 weeks later. Statistical analysis was carried out using unpaired t-tests and repeated measures of analysis of variance (ANOVA) using Statview. In all cases 5% was chosen as the level of statistical significance in two-tailed tests.
  • Compound No. 60 was active to ameliorate the taxol-induced retardation of sensory nerve conduction velocity by i.p. administration at 10 mg/kg (see Figure 1, 3).
  • Compound No.188 (40 mg/kg), compound No. 440 and compound No. 438 (20 mg/kg) were active to ameliorate the taxol-induced retardation of sensory nerve conduction velocity by p.o. administration (see Figure 2, 3).
  • Compound No. 189 was active to ameliorate the taxol-induced retardation of sensory nerve conduction velocity by i.p. administration at 2.5 mg/kg (see Figure 2) and p.o. administration at 20 mg/kg (see Figure 3).
  • representative compounds of this invention such as compound No. 60, compound No. 188, compound No. 440, compound No. 438 and compound No. 189, are effective in this in vivo rat neuropathy model.

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