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  • 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
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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  • 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
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  • 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
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  • 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
  • C07D213/24—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
  • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
  • C07D213/32—Sulfur atoms
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  • 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
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  • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
  • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
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  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems

Definitions

• the present invention relates to pharmaceutical compositions, and particularly pharmaceutical compositions incorporating compounds that are capable of affecting nicotinic cholinergic receptors. More particularly, the present invention relates to compounds capable of activating nicotinic cholinergic receptors, for example, as agonists of specific nicotinic receptor subtypes. The present invention also relates to methods for treating a wide variety of conditions and disorders, and particularly conditions and disorders associated with dysfunction of the central and autonomic nervous systems.
• Nicotine has been proposed to have a number of pharmacological effects. See, for example, Pullan et al. N. Engl. J. Med. 330:81 1-815 (1994). Certain of those effects may be related to effects upon neurotransmitter release. See for example, Sjak-shie et al., Brain Res. 624:295 (1993), where neuroprotective effects of nicotine are proposed. Release of acetylcholine and dopamine by neurons upon administration of nicotine has been reported by Rowell et al., J. Neurochem. 43:1593 (1984); Rapier et al., J Neurochem. 50:1123 (1988); Sandor et al., Brain Res. 567:313 (1991) and Vizi, Br. J.
• Nicotinic compounds are reported as being particularly useful for treating a wide variety of Central Nervous System (CNS) disorders.
• CNS Central Nervous System
• CNS disorders are a type of neurological disorder.
• CNS disorders can be drug induced; can be attributed to genetic predisposition, infection or trauma; or can be of unknown etiology.
• CNS disorders comprise neuropsychiatric disorders, neurological diseases and mental illnesses; and include neurodegenerative diseases, behavioral disorders, cognitive disorders and cognitive affective disorders.
• CNS disorders whose clinical manifestations have been attributed to CNS dysfunction (i.e., disorders resulting from inappropriate levels of neurotransmitter release, inappropriate properties of neurotransmitter receptors, and/or inappropriate interaction between neurotransmitters and neurotransmitter receptors).
• CNS disorders can be attributed to a cholinergic deficiency, a dopaminergic deficiency, an adrenergic deficiency and or a serotonergic deficiency.
• CNS disorders of relatively common occurrence include presenile dementia (early onset Alzheimer's disease), senile dementia (dementia of the Alzheimer's type), Parkinsonism including Parkinson's disease, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, attention deficit disorder, anxiety, dyslexia, hypoxia, schizophrenia and Tourette's syndrome.
• CNS diseases e.g., CNS diseases
• a pharmaceutical composition incorporating a compound which interacts with nicotinic receptors, such as those which have the potential to effect the functioning of the CNS, but which compound when employed in an amount sufficient to effect the functioning of the CNS, does not significantly effect those receptor subtypes which have the potential to induce undesirable side effects (e.g., appreciable activity at skeletal muscle sites).
• the present invention relates to aryl olefinic azacyclic compounds and aryl acetylenic azacylic compounds, including pyridyl olefinic cycloalkylamines and pyridyl acetylenic cycloalkylamines.
• the present invention also relates to prodrug derivatives of the compounds of the present invention.
• Exemplary compounds of the present invention are (S)-(E)-3-(3-pyrrolidin-2-yl-prop-l-enyl)pyridine, (S)-(E)-3-(2- pyrrolidin-2-ylvinyl)pyridine, 3-(2-pyrrolidin-2-ylethenyl)pyridine, 3-(3-pyrrolidin-2- ylprop-1 -enyl)pyridine, 3-(2-(2-azetidinyl)ethenyl)pyridine, 3-(3-(2-azetidinyl)prop- 1 -enyl)pyridine, 2-(2-(3-pyridyl)ethenyl)-l-azabicyclo[3.3.0]octane, 2-(3-(3- pyridyl)prop-2-enyl)-l-azabicyclo[3.3.0]octane, 3-(2-(3-pyridyl)ethenyl)-2- aza
• the compounds of the present invention function as agonists, and bind specifically to certain nicotinic receptors.
• the present invention also relates to methods for the prevention or treatment of a wide variety of conditions or disorders, and particularly those disorders characterized by disfunction of nicotinic cholinergic neurotransmission including disorders involving neuromodulation of neurotransmitter release, such as dopamine release.
• the present invention also relates to methods for the prevention or treatment of disorders, such as central nervous system (CNS) disorders, which are characterized by an alteration in normal neurotransmitter release.
• CNS central nervous system
• the present invention also relates to methods for the treatment of certain conditions (e.g., a method for alleviating pain). The methods involve administering to a subject an effective amount of a compound of the present invention.
• the present invention relates to a method for using the compounds of the present invention for the manufacture of pharmaceutical compositions for the treatment of a wide variety of diseases and disorders.
• the present invention in another aspect, relates to a pharmaceutical composition
• a pharmaceutical composition comprising an effective amount of a compound of the present invention.
• a pharmaceutical composition incorporates a compound which, when employed in effective amounts, has the capability of interacting with relevant nicotinic receptor sites of a subject, and hence has the capability of acting as a therapeutic agent in the prevention or treatment of a wide variety of conditions and disorders, particularly those disorders characterized by an alteration in normal neurotransmitter release.
• Preferred pharmaceutical compositions comprise compounds of the present invention.
• compositions of the present invention are useful for the prevention and treatment of disorders, such as CNS disorders, which are characterized by an alteration in normal neurotransmitter release.
• the pharmaceutical compositions provide therapeutic benefit to individuals suffering from such disorders and exhibiting clinical manifestations of such disorders in that the compounds within those compositions, when employed in effective amounts, have the potential to (i) exhibit nicotinic pharmacology and affect relevant nicotinic receptors sites (e.g., act as a pharmacological agonist to activate nicotinic receptors), and (ii) elicit neurotransmitter secretion, and hence prevent and suppress the symptoms associated with those diseases.
• the compounds are expected to have the potential to (i) increase the number of nicotinic cholinergic receptors of the brain of the patient, (ii) exhibit neuroprotective effects and (iii) when employed in effective amounts do not cause appreciable adverse side effects (e.g., significant increases in blood pressure and heart rate, significant negative effects upon the gastro-intestinal tract, and
• compositions of the present invention are believed to be safe and effective with regards to prevention and treatment of a wide variety of conditions and disorders.
• the compounds of the present invention include compounds of the formula:
• each of X, X', X", Y' and Y" are individually nitrogen, nitrogen bonded to oxygen (e.g., an N-oxide or N-0 functionality) or carbon bonded to a substituent species characterized as having a sigma m value greater than 0, often greater than 0.1, and generally greater than 0.2, and even greater than 0.3; less than 0 and generally less than -0.1 ; or 0; as determined in accordance with Hansch et al., Chem. Rev. 91 :165 (1991).
• substituent species When any of X, X', X", Y' and Y" are carbon bonded to a substituent species, those substituent species typically have a sigma m value between about -0.3 and about 0.75, frequently between about -0.25 and about 0.6; and each sigma m value individually can be 0 or not equal to zero.
• sigma m value between about -0.3 and about 0.75, frequently between about -0.25 and about 0.6; and each sigma m value individually can be 0 or not equal to zero.
• X' is CH, CBr or COR', where R' preferably is benzyl, methyl, ethyl, isopropyl, isobutyl, tertiary butyl or cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl). Most preferably, X" is nitrogen.
• X is C-NR'R", C-OR' or C-NO 2 , typically C-NH 2 , C- NHCH 3 or C-N(CH 3 ) 2 , with C-NH being preferred.
• both X' and X" are nitrogen.
• X, Y 1 and Y" each are carbon s bonded to a substituent species, and it is typical that X, Y' and Y" each are carbon bonded to a substituent species such as hydrogen.
• the individual substituents of X, Y' and Y" (when X, Y' and Y" are carbon bonded to a substituent species) usually include hydrogen, halo (e.g., F, Cl, Br, or I), alkyl (e.g., lower straight chain or branched C )-8 alkyl, but preferably methyl or ethyl), or NR'R", where in such case R' and R" are individually hydrogen or lower alkyl, including C
• X is CH and Y' is CH.
• X and Y' both are CH, and Y" is carbon bonded to a non-hydrogen substituent species, such as -NR'R", -OR' or -NO 2 , such as -NHCH 3 or -N(CH 3 ) 2 , with -NH 2 being most preferred.
• a non-hydrogen substituent species such as -NR'R", -OR' or -NO 2 , such as -NHCH 3 or -N(CH 3 ) 2 , with -NH 2 being most preferred.
• Adjacent substituents of X, X', Y", X" and Y' can combine to form one or more saturated or unsaturated, substituted or unsubstituted carbocyclic or heterocyclic rings containing, but not limited to, ether, acetal, ketal, amine, ketone, lactone, lactam, carbamate, or urea functionalities.
• m is an integer and n is an integer such that the sum of m plus n is 0, 1, 2 or 3, preferably is lor 2, and more preferably is 1.
• the substituents of either X, X', X", Y' and Y" can include hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, heterocyclyl (e.g., beta-styryl), substituted heterocyclyl, cycloalkyl, substituted cycloalkyl. aryl, substituted aryl, alkylaryl, substituted alkylaryl. arylalkyl and substituted arylalkyl functionalities.
• the substituents of X, X', X", Y' and Y" individually usually include hydrogen, halo (e.g., F, Cl, Br, or I), alkyl (e.g., lower straight chain or branched C ⁇ -8 alkyl, but preferably methyl or ethyl), or NR'R", where in such case R' and R" are individually hydrogen or lower alkyl, including C C 8 , preferably C 1 -C 5 alkyl.
• halo e.g., F, Cl, Br, or I
• alkyl e.g., lower straight chain or branched C ⁇ -8 alkyl, but preferably methyl or ethyl
• NR'R where in such case R' and R" are individually hydrogen or lower alkyl, including C C 8 , preferably C 1 -C 5 alkyl.
• R' and R" can be straight chain or branched alkyl, or R' and R" can form a cycloalkyl funtionality (e.g., cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and quinuclidinyl).
• Representative aromatic group-containing species include pyridinyl, quinolinyl, pyrimidinyl, phenyl, and benzyl (where any of the foregoing can be suitably substituted with at least one substituent group, such as alkyl, halo, or amino substituents).
• Other representative aromatic ring systems are set forth in Gibson et al., J. Med.
• the two carbon bridging species is ethylenic, that species can have a trans(Z) or cis(E) form, but most preferably is trans(E).
• E, E 1 , E ' and E 111 individually represent hydrogen or a suitable non-hydrogen substituent (e.g., alkyl, substituted alkyl, halo substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl.
• a suitable non-hydrogen substituent e.g., alkyl, substituted alkyl, halo substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl.
• alkylaryl substituted alkylaryl, arylalkyl or substituted arylalkyl
• preferably lower alkyl e.g., straight chain or branched alkyl including C]-C 8 , preferably C 1 -C 5 , such as methyl, ethyl, or isopropyl
• halo substituted lower alkyl e.g., straight chain or branched alkyl including C ⁇ -C 8 , preferably C 1 -C 5 , such as trifluoromethyl or trichloromethyl.
• E, E 1 , E ⁇ and E 111 are hydrogen, or at least one of E, E 1 .
• E 11 and E 1 " is non-hydrogen and the remaining E, E 1 , E 11 and E 111 are hydrogen.
• E and E 1 each can be hydrogen, or E can be hydrogen and E 1 can be methyl; or when m is 1 and n is 1, E, E 1 , E ⁇ and E ⁇ all can be hydrogen, or E, E 1 and E can be hydrogen and E can be methyl, or E 1 , E ' and E 1 " can be hydrogen and E can be methyl.
• the selection of m, n, E, E 1 , E 11 and E 1 " is such that 0, 1 or 2, usually 0 or 1, and preferably 0, of the substituents designated as E, E 1 , E ⁇ and E IH are non-hydrogen (e.g., substituents such as alkyl or halo-substituted alkyl).
• substituents such as alkyl or halo-substituted alkyl.
• compounds of the present invention have chiral and geometric centers, and the present invention relates to racemic mixtures of such compounds as well as enamiomeric compounds.
• Z' and Z" individually represent hydrogen or lower alkyl (e.g., straight chain or branched alkyl including C]-C 8 , preferably C 1 -C 5 , such as methyl, ethyl, or isopropyl), substituted alkyl, acyl, alkoxycarbonyl, or aryloxycarbonyl; and preferably Z' is hydrogen or methyl, and Z" is hydrogen.
• alkyl e.g., straight chain or branched alkyl including C]-C 8 , preferably C 1 -C 5 , such as methyl, ethyl, or isopropyl
• Z' is hydrogen or methyl
• Z" is hydrogen.
• the associated carbon and nitrogen atoms can combine to form a monocyclic ring structure such as azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl (optionally substituted with pyridinyl, such as 3-pyridinyl, or pyrimidinyl, such 5-pyridinyl) or a bicyclic ring structure such as 3-(2- azabicyclo[4.2.0]octyl), 3-(2-azabicyclo[2.2.2]octyl), or 3-(2- azabicyclo[2.2.1]heptyl).
• a monocyclic ring structure such as azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl (optionally substituted with pyridinyl, such as 3-pyridinyl, or pyrimidinyl, such 5-pyridinyl) or a bicyclic ring structure such as 3-(2- azabicyclo[4.2.0]o
• neither E ⁇ nor E 1 are substituted or unsubstituted aryl, heteroaryl, benzhydryl or benzyl.
• the associated carbon and nitrogen atoms can combine to form a bicyclic ring structure such as l-(2-azabicyclo[2.2.1]heptyl), l-(2- azabicyclo[3.1.0]hexyl, 3-(8-azabicyclo[3.2.1]octyl), 2-(7-azabicyclo[3.1.1]heptyl), 3- (7-azabicyclo[2.2.1]heptyl or 6-(2-azabicyclo[2.2.1]octyl.
• the aromatic ring of the formula is substituted by at least least two positions with nitrogen.
• alkyl refers to straight chain or branched alkyl radicals including CpC 8 , preferably C ⁇ -C , such as methyl, ethyl, or isopropyl; "substituted alkyl” refers to alkyl radicals further bearing one or more substituent groups such as hydroxy, alkoxy, mercapto, aryl, heterocyclo, halo, amino, carboxyl, carbamyl, cyano, and the like; "alkenyl” refers to straight chain or branched hydrocarbon radicals including C ⁇ -C 8 , preferably C ⁇ -C 5 and having at least one carbon-carbon double bond; “substituted alkenyl” refers to alkenyl radicals further bearing one or more substituent groups as defined above; "cycloalkyl” refers to saturated or unsaturated cyclic ring- containing radicals containing three to eight carbon atoms, preferably three to six carbon atoms; "substitute
• B X, X', X", Y', Y", E, E', E", E'", Z', Z", Z"', m, n, j, R and R" are as defined hereinbefore.
• the compound prefereably is such that B is an ethylenic bridging species, and as such, the compound can have the cis (Z) or trans (E) form, but most preferably the trans (E) form.
• both R' and R" are hydrogen, but either or both of R' and R" can be methyl.
• Z" is hydrogen, and Z' is hydrogen or methyl.
• m is 1
• n is 0 or 1.
• each of E and E' is hydrogen, and preferably E' is hydrogen or methyl, but most preferably both of E and E' are hydrogen.
• each of E" and E'" is hydrogen, and preferably E'" is hydrogen or methyl, but most preferably both of E" and E'" are hydrogen.
• Y" is carbon bonded to a substituent species, and most preferably, that substituent species is hydrogen, halo, NR'R" or OR".
• X" is nitrogen or carbon bonded to a substituent species such as NR'R", NO or OR", but most preferably is nitrogen.
• X' is nitrogen, but also preferably is carbon bonded to a substituent species such as hydrogen, R', halo, OR', NR'R", CC, CN, C 2 R' or CHCHR'.
• X and Y' each are carbon bonded to a substituent species, such as hydrogen.
• j is 0 or 1
• Z" is lower alkyl
• Q is selected from the following:
• Representative compounds useful in carrying out the present invention include the following:
• certain compounds of the present invention can be prepared in either racemic form or in enantiomerically pure form.
• certain pyridyl olefinic pyrrolidine compounds can be prepared by using a palladium-catalyzed coupling reaction of a 3- bromopyridine or 3-iodopyridine with an olefin possessing a protected pyrrolidine functionally, such as (2S)-2-allyl-l-tert-butoxycarbonylpyrrolidine, also known as (2S)-N-(tert-butoxycarbonyl)-2-(3-prop-l -enyl)pyrrolidine.
• Reaction conditions employing palladium(II) acetate, tri-o-tolylphosphine, and triethylamine, similar to those described by Frank et. al., J. Org. Chem. 43 (15): 2947-2949 (1978) and Malek et. al., J. Org. Chem. 47: 5395 (1982) can be used.
• the tert-butoxycarbonyl protecting group of the resulting reaction product, (2S)-(2E)-N-(tert-butoxycarbonyl)- 2-(3-prop-l-(3-pyridyl)-l-enyl)pyrrolidine can then be removed by treatment with strong acid such as trifluoroacetic acid to produce (2S)-(2E)-2-(3-prop-l-(3-pyridyl)- 1 -enyl)pyrrolidine.
• the pyrrolidine ring can then be N-methylated using aqueous formaldehyde and sodium cyanoborohydride using methodology similar to that described by M.
• (2S)- (2E)-2-(3-(l-methylpyrrolidin-2-yl)prop-l-enyl)pyridine The requisite side chain, (2S)-2-allyl-l-tert-butoxycarbonylpyrrolidine can be prepared from commercially available (Aldrich Chemical Company) (2S)-2-pyrrolidinemethanol.
• the pyrrolidine nitrogen of the latter compound can be protected by treatment with di-tert-butyl dicarbonate in dichloromethane using triethylamine as a base to produce (2S)-N-(tert- butoxycarbonyl)-2-(hydroxymethyl)pyrrolidine.
• the latter compound can be treated with iodine, triphenylphosphine, and diethyl azodicarboxylate to give (2S)-N-(tert- butoxycarbonyl)-2-(iodomethyl)pyrrolidine.
• Treatment of the latter compound with vinylmagnesium bromide and copper(I) iodide produces the required olefinic pyrrolidine, (2S)-2-allyl-l-tert-butoxycarbonylpyrrolidine.
• (2R)-2- pyrrolidinemethanol is also commercially available (Aldrich Chemical Company)
• the corresponding enantiomeric synthetic intermediates and compounds of the present invention can be prepared in a similar fashion, namely (2R)-2-allyl-l-tert- butoxycarbonylpyrrolidine, (2R)-(2E)-N-(tert-butoxycarbony l)-2-(3 -prop- 1 -(3 - pyridyl)- 1 -enyl)pyrrolidine, (2R)-(2E)-2-(3-prop- 1 -(3 -pyridyl)- 1 -enyl)pyrrolidine and (2R)-(2E)-3 -(3 -( 1 -methylpyrrolidine-2-yl)prop- 1 -enyl)pyridine.
• f t enantiomerically pure 2-pyrrolidinemethanol can be synthetically elaborated to the required chiral olefinic pyrrolidine, 2-allyl-l-tert-butoxycarbonylpyrrolidine using the methodology of M. Ikeda et al., Heterocycles 50: 31-34 (1999).
• 5-substituted-pyridyl olefinic pyrrolidine compounds of the present invention can vary.
• a 5-substituted-3-halo-pyridine compound is subjected to a palladium- catalyzed reaction with an olefinic pyrrolidine compound such as (2S)-2-allyl-l-tert- butoxycarbonylpyrrolidine as described above.
• Certain compounds of the present invention possessing a shorter olefinic side chain can be prepared by a variety of methods.
• a 3-halopyridine such as a 3-bromopyridine or 3-iodopyridine is coupled with (2S)-2-vinyl-l-tert-butoxycarbonylpyrrolidine.
• (2S)-2-vinyl-l-tert-butoxycarbonylpyrrolidine is coupled with (2S)-2-vinyl-l-tert-butoxycarbonylpyrrolidine.
• the latter olefinic pyrrolidine compound can be prepared according to the techniques described by M. Ikeda et al., Heterocycles 50: 31-34 (1999), starting from commercially available (2S)-2-pyrrolidinemethanol.
• the protecting group can then be removed from the resulting reaction product, (2S)-(2E)-N-(tert-butoxycarbonyl)-3- (2-pyrrolidin-2ylvinyl)pyridine using trifluoroacetic acid to give (2S)-(2E)-3-(2- pyrrolidin-2-ylvinyl)pyridine.
• the latter compound can be N-methylated using the previously described methodology.
• (2R)-2-pyrrolidinemethanol the corresponding enantiomers of the above compounds can be prepared.
• 2-allylquinuclidine can be subjected to a palladium- catalyzed coupling reaction with a 3-halopyridine, such as 3-bromopyridine or 3- iodopyridine to afford 2-(l-(3-pyridyl)propen-3-yl)quinuclidine.
• a 3-halopyridine such as 3-bromopyridine or 3- iodopyridine
• 2-(l-(3-pyridyl)propen-3-yl)quinuclidine can be prepared from 3-quinuclidinone (commercially available from Aldrich Chemical Company) by alkylation and modified Wolff- ishner
• 3-quinuclidinone can be converted to the corresponding imine with isopropylamine and molecular sieves. Alkylation of the imine with lithium diisopropylamine and allyl bromide, followed by hydrolysis produces 2-allyl-3- quinuclidinone. Removal of the carbonyl-protecting group can then be effected by converting the ketone into the p-toluenesulfonyl hydrazone followed by reduction with sodium cyanoborohydride to afford 2-allylquinuclidine.
• pyridyl acetylenic pyrrolidine compounds of the present invention can vary.
• a palladium-catalyzed reaction can be used for the coupling of a 3-bromopyridine or a 3-iodopyridine with an alkyne possessing a protected pyrrolidine functionality, such as (2S)-N-(tert- butoxycarbonyl)-2-prop-2-ynylpyrrolidine.
• Reaction conditions employing tetrakis(triphenylphosphine)palladium(0), copper(I) iodide, and a base such as triethylamine and an appropriate solvent, such as 1 ,2-dimethoxyethane or N,N- dimethylformamide can be used.
• a base such as triethylamine
• an appropriate solvent such as 1 ,2-dimethoxyethane or N,N- dimethylformamide
• the resulting coupling reaction product, (2S)-N-(tert-butoxycarbonyl)-2-(3-(3-pyridyl)prop-2-ynyl)pyrrolidine can then be treated with a strong acid such as trifluoroacetic acid to remove the protecting group producing (2S)-3-(3-pyrrolidin-2-ylprop-l -ynyl)pyridine.
• a strong acid such as trifluoroacetic acid
• the latter compound can be N-methylated by heating with formaldehyde and formic acid to afford (2S)-3- (3-(l-methylpyrrolidin-2-yl)prop-l-ynyl)pyridine.
• (2S)-N-(tert- butoxycarbonyl)-2-prop-2-ynylpyrrolidine can be prepared by treatment of (2S)-N- (tert-butoxycarbonyl)-2-(iodomethyl)pyrrolidine ⁇ the synthesis of which has been previously described above, with the lithium salt of trimethylsilylacetylene or with lithium acetylide, ethylenediamine complex (commercially available from Aldrich Chemical Company) followed by desilylation, if necessary, using potassium fluoride in acetonitrile.
• Certain compounds of the present invention possessing a shorter acetylenic side chain can be prepared by a variety of methods.
• a 3- halopyridine such as 3-bromopyridine can be coupled with an alkyne possessing a protected pyrrolidine functionality such as (2S)-N-(tert-butoxycarbonyl)-2- t f ethynylpyrrolidine.
• Reaction condition employing a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) copper(I) iodide, triethylamine and a solvent such as N,N-dimethylformamide can be used.
• the resulting reaction product, (2S)-N- (tert-butoxycarbonyl)-3-(2-pyrrolidin-2-ylethynyl)pyridine can be treated with a strong acid such as trifluoroacetic acid to afford (2S)-3-(2-pyrrolidin-2- ylethynyl)pyridine.
• a strong acid such as trifluoroacetic acid
• Treatment of the latter compound with formic acid and formaldehyde or formaldehyde and sodium cyanoborohydride affords the N-methyl analog, (2S)-3-(2-(l-methylpyrrolidin-2-yl)ethynyl)pyridine.
• the required alkyne (2S)-N-(tert-butoxycarbonyl)-2-ethynylpyrrolidine can be prepared from N-(tert- butoxycarbonyl)-(S)-proline according to the methods described in WO 97/05139 to R. L. Elliot et al.
• the enantiomeric alkyne, (2R)-N-(tert-butoxycarbonyl)-2- ethynylpyrrolidine, prepared from N-(tert-butoxycarbonyl)-(R)-proline the enantiomers of the above compounds of the present invention can be prepared.
• these Z-olefinic isomers can be prepared by the controlled hydrogenation of the corresponding alkynylcompunds (e.g., a 3-(3-pyrrolidin-2-ylprop-l-ynyl)pyridine- type compound) using commercially available Lindlar catalyst (Aldrich Chemical Company) using the methodology set forth in H. Lindlar et al., Org. Syn. 46: 89 (1966).
• alkynylcompunds e.g., a 3-(3-pyrrolidin-2-ylprop-l-ynyl)pyridine- type compound
• bromo-imidazopyridine, 6-bromo-2-methyl- lH-imidazo[4.5-b]pyridine can be prepared in 82% yield by heating 2.3-diamino-5- n bromopyridine with acetic acid in polyphosphoric acid according to the methods described by P. K. Dubey et al., Indian ! Chem. 16B(6):531-533 (1978).
• 2,3- Diamino-5-bromopyridine can be prepared in 97% yield by heating 2-amino-5- bromo-3-nitropyridine (commercially available from Aldrich Chemical Company and Lancaster Synthesis, Inc) with tin(II) chloride dihydrate in boiling ethanol according to the techniques described by S. X. Cai et al., J. Med. Chem. 40(22): 3679-3686 (1997).
• a bromo fused-ring heterocycle such as 6-bromo-l,3- dioxolo[4,5-bJpyridine can be coupled with the previously mentioned olefinic amine side chains, using the Heck reaction.
• the resulting Boc-protected intermediate can be deprotected with a strong acid such as trifluoroacetic acid.
• the requisite bromo compound, 6-bromo-l,3-dioxolo[4,5-b]pyridine can be synthesized from 5-bromo- 2,3-dihydroxypyridine, also known as 5-bromo-3-hydroxy-2(lH)-pyridinone, via a methylenation procedure using bromochloromethane, in the presence of potassium carbonate and N,N-dimethylformamide according to the methodology of F. Dallacker et al., Z. Naturforsch. 34 b:1729-1736 (1979).
• 5-Bromo-2,3-dihydroxypyridine can be prepared from furfural (2-furaldehyde, commercially available from Aldrich Chemical Company and Lancaster Synthesis, Inc) using the methods described in F.
• 5-bromo-2,3- dihydroxypyridine can be prepared according to the techniques described in EP 0081745 to D. Rose and N. Maak.
• the bromo compound, 7-bromo-2,3-dihydro-l,4-dioxino[2,3-bJpyridine (also known as 7-bromo-5-aza-4-oxachromane) can be condensed with the previously mentioned olefinic amine side chains.
• the resulting Boc-protected compound can be deprotected with strong acid such as trifluoroacetic acid.
• the required bromo compound, 7- bromo-2,3-dihydro-l,4-dioxino[2,3-bJpyridine can be prepared by treating 5-bromo- 2,3-dihydroxypyridine with 1 ,2-dibromoethane and potassium carbonate in N,N- dimethylformamide according to the methodology of F. Dallacker et al., Z Naturforsch. 34 b:1729-1736 (1979).
• 5-Bromo-2,3-dihydroxypyridine can be prepared from furfural as described above.
• polycyclic aromatic compounds of the present invention can be prepared by the Heck reaction.
• certain compounds can be synthesized by the palladium- catalyzed coupling of a bromo fused-ring heterocycle, such as 6-bromo-lH- 0 imidazo[4,5-bjpyridine-2-thiol with the previously mentioned olefinic amine side chains.
• the Boc-protected intermediate, resulting from the Heck reaction can be subjected to treatment with a strong acid, such as trifluoroacetic acid.
• 6-bromo-lH-imidazo[4,5-bjpyridine-2-thiol can be prepared by treating 6-bromo-lH-imidazo[4,5-b]pyridine with sulfur at 230-260°C according to the methods described in Y. M. Yutilov, Khim. Geterotsikl Doedin. 6: 799-804 (1988).
• 6-Bromo-lH-imidazo[4,5-b]pyridine can be obtained from Sigma- Aldrich Chemical Company.
• 6-bromo-lH-imidazo[4,5-b]pyridine can be prepared by treating 2,3-diamino-5-bromopyridine with formic acid in polyphosphoric acid using methodology similar to that described by P.
• 2,3-Diamino-5-bromopyridine can be prepared in 97% yield by heating 2-amino-5-bromo-3-nitropyridine (commercially available from Aldrich Chemical Company and Lancaster Synthesis, Inc) with tin(II) chloride dihydrate in boiling ethanol according to the techniques described by S. X. Cai et al., J Med. Chem. , 40(22): 3679-3686 (1997).
• 6-bromo-lH- imidazo[4,5-b]pyridine-2-thiol can be prepared by heating 2,3-diamino-5- bromopyridine with K + " SCSOEt in aqueous ethanol using methodology similar to that described by T. C. Kuhler et al., J. Med Chem. 38(25): 4906-4916 (1995).
• 2,3- Diamino-5-bromopyridine can be prepared from 2-amino-5-bromo-3-nitropyridine as described above.
• 6-bromo-2-phenylmethylthio-lH-imidazo[4,5-bJpyridine can be coupled via Heck reaction with the previously mentioned olefinic amine side chains.
• the resulting Boc-protected intermediate can be subjected to treatment with a strong acid, such as trifluoroacetic acid.
• the required bromo compound, 6-bromo-2- phenylmethylthio-lH-imidazo[4,5-b]pyridine can be prepared by alkylating the previously described 6-bromo-lH-imidazo[4,5-b]pyridine-2-thiol with benzyl bromide in the presence of potassium carbonate and N,N-dimethylformamide.
• 6-bromooxazolo[4,5-b]pyridine can be subjected to palladium catalyzed coupling and deprotection of the resulting intermediate with trifluoroacetic acid.
• the requisite 6-bromooxazolo[4,5-b]pyridine can be produced from 2-amino-5-bromo-3-pyridinol by condensation with formic acid or a trialkyl orthoformate, using methodology similar to that of M-C. Viaud et al., Heterocycles 41 : 2799-2809 (1995).
• the use of other carboxylic acids produces 2-substituted-6-
• 5-Bromooxazolo[5,4-b]pyridine isomeric by orientation of ring fusion to the previously described 6-bromooxazolo[4,5-b]pyridine, can also be used in the Heck coupling and subsequent deprotection.
• the required 5-bromooxazolo[5,4-b]pyridine is synthesized from 3-amino-5-bromo-2-pyridinol (3-amino-5-bromo-2-pyridone) by the condensation with formic acid (or a derivative thereof) as described above.
• 3- Amino-5-bromo-2-pyridinol can be made by bromination (using techniques described by T. Batkowski, Rocz. Chem.
• polycyclic aromatic compounds of the present invention can be prepared by the Heck reaction.
• both 5-bromofuro[2,3-b]pyridine and 5-bromo-lH- pyrrolo[2,3-b]pyridine can undergo palladium catalyzed coupling with the previously described olefinic amine side chains. Subsequent removal of the tert-butoxycarbonyl group with trifluoroacetic acid.
• the requisite 5-bromofuro[2,3-b]pyridine and 5- bromo-lH-pyrrolo[2,3-bjpyridine can be made from 2,3-dihydrofuro[2,3-b]pyridine and 2,3-dihydropyrrolo[2,3-b]pyridine respectively, by bromination (bromine and sodium bicarbonate in methanol) and dehydrogenation (2,3-dichloro-5,6-dicyano-l ,4- benzoquinone), using chemistry described by E. C. Taylor et al., Tetrahedron 43: 5145-5158 (1987).
• 2,3-Dihydrofuro[2,3-b]pyridine and 2,3-dihydropyrrolo[2.3- bjpyridine are, in turn, made from 2-chloropyrimidine (Aldrich Chemical Company), as described by A. E. Frissen et al., Tetrahedron 45: 803-812 (1989), by nucleophilic displacement of the chloride (with the sodium salt of 3-butyn-l-ol or with 4-amino-l- butyne) and subsequent intramolecular Diels-Alder reaction.
• 2,3-dihydrofuro[2,3-b]pyridine and 2,3-dihydropyrrolo[2,3-b]pyridine are also produced from 3-methylthio-l,2,4-triazene (E. C. Taylor et al., Tetrahedron 43: 5145- 5158 (1987)), which in turn is made from glyoxal and S-methylthiosemicarbazide (W. Paudler et al., J. Heterocyclic Chem. 7: 767-771 (1970)).
• Brominated dihydrofuropyridines, dihydropyrrolopyridines, and dihydropyranopyridines are also substrates for the palladium catalyzed coupling.
• both 5-bromo-2,3-dihydrofuro[2,3-b]pyridine and 5-bromo-2,3- dihydropyrrolo[2,3-b]pyridine can be coupled with the previously mentioned olefinic amine side chain in a Heck process and subsequent deprotection.
• 6-bromo-2,3-dihydrofuro[3,2-b]pyridine isomeric at the ring fusion with the [2,3-b] system
• 6- bromo-2,3-dihydrofuro[3,2-b]pyridine can be made from 5-bromo-2-methyl-3- pyridinol by sequential treatment with two equivalents of lithium diisopropylamide (to generate the 2-methylenyl, 3-oxy dianion) and one equivalent of dibromomethane.
• two equivalents of lithium diisopropylamide to generate the 2-methylenyl, 3-oxy dianion
• dibromomethane Alternatively, using chemistry similar to that described by M. U. Koller et al., Synth. Commun.
• silyl-protected pyridinol (5-bromo-2-methyl-3- trimethylsilyloxypyridine) can be treated sequentially with one equivalent of lithium diisopropylamide and an alkyl or aryl aldehyde to produce a 2-(2-(l -alkyl- or 1-aryl- l-hydroxy)ethyl)-5-bromo-3-(trimethylsilyloxy)pyridine.
• Such materials can be converted, by methods (such as acid catalyzed cyclization or the Williamson synthesis) known to those skilled in the art, into the corresponding cyclic ethers (2- alkyl- or 2-aryl-6-bromo-2,3-dihydrofuro[3,2-b]pyridines.
• Similar chemistry in which epoxides (instead of aldehydes) are used in reaction with the pyridylmethyl carbanion, leads to 2-alkyl- and 2-aryl-7-bromo-2,3-dihydropyrano[3.2-b]pyridines.
• These 2-substituted. brominated dihydrofuro- and dihydropyranopyridines are also substrates for the Heck reaction.
• 6-bromo-2,3-dihydro-2- phenylfuro[3.2-b]pyridine can be coupled, in a palladium catalyzed process, and the coupling product treated with trifluoroacetic acid.
• the 5-bromo-2-methyl-3 -pyridinol, required for the syntheses of the brominated dihydrofuro- and dihydropyranopyridines, is produced by standard transformations of commercially available materials.
• 2-methylnicotinic acid Aldrich Chemical Company
• thionyl chloride, bromine, and ammonia Methodology described by C. V. Greco et al., J. Heterocyclic Chem. 7: 761-766 (1970)
• 3-(2- (azetidinyl)vinyl)pyridine can be synthesized starting from commercially azetidine-4- carboxylic acid (Aldrich Chemical Company).
• Azetidine-4-carboxylic acid can be reduced by any of a number of methods common to the art, such as treatment with lithium aluminum hydride to give (2-azetidinyl)methan-l-ol.
• azetidinyl nitrogen of the latter compound can be accomplished by treatment with t- butylpyrocarbonate and base to give N-t-butyloxycarbonyl (N-t-BOC) protected (2- azetidinyl)methan-l-ol, using methodology similar to that described by Carpino et al., Acc. Chem. Res, 6:191 (1973).
• This alcohol can be converted to the alkyl iodide using diethyl azodicarboxylate. triphenylphosphine and iodine according to the procedure of Mitsunobu, see for example: Mitsunobu, Synthesis 1 :1-28, (1981).
• N-t- BOC-4-(iodomethyl)azetidine with magnesium under anhydrous conditions, followed by pyridine-3-carboxaldehyde can afford the Grignard product, N-t-BOC-2-(2- azetidinyl)-l-(3-pyridyl)ethan-l-ol.
• Treatment of the latter compound with methanesulfonyl chloride gives the O-mesylate which can in turn be eliminated to give N-t-BOC-3-(2-(azetidinyl)vinyl)pyridine using l ,8-diazabicyclo[5.4.0]undec-7- ene in accordance with the method described by Wolkoff J. Org.
• t-BOC protecting group can be removed under acidic conditions, such as treatment with trifluoroacetic acid, to give the desired product 3-(2- (azetidinyl)vinyl)pyridine.
• 2-(2-(3-Pyridyl)vinyl- 7-azabicyclo[2.2.1 jheptane can be synthesized starting with ethyl 7-aza-7- (ethoxycarbonyl)bicyclo[2.2.1]heptane-2-carboxylate which can be generated from commercially available tropinone (Lancaster Chemical Company) according to the method of Badio et al., Eur. J. Pharmacol, 321 :865 (1997).
• This compound can then be reduced to ethyl 7-aza-2-(hydroxymethyl)bicyclo[2.2.1]heptane-7-carboxylate using excess diisobutylaluminum hydride.
• This alcohol can then be converted to ethyl 7-aza-2-(iodomethyl)bicyclo[2.2. l]heptane-7-carboxylate using diethyl azodicarboxylate, triphenylphosphine and iodine according to the procedure of Mitsunobu, see for example: Mitsunobu, Synthesis 1:1-28, (1981). Conversion of ethyl 7-aza-2-(iodomethyl)bicyclo[2.2.1 ]heptane-7-carboxylate to the magnesium
• ethyl 3-aza-3-((4-toluenesulfonyl)bicyclo[2.2.1 ]hept-5-ene-2-carboxylate synthesized according to the method of Hamley et al., Synlett, 1 :29 (1991), can be reduced to 2- aza-3-(hydroxymethyl)-2-((4-toluenesulfonyl)bicyclo[2.2.1]hept-5-ene using an excess of diisobutyllithium hydride at 0°C. Reduction of the olefin can be accomplished by various methods known to the art.
• Mitsunobu see for example: Mitsunobu, Synthesis 1 :1-28, (1981). Conversion of the latter alkyl iodide to the Grignard reagent followed by reaction with pyridine 3- carboxaldehyde can afford 3-(2-(3-pyridyl)-2-hydroxyethyl)-2-aza-2-((4- toluenesulfonyl)bicyclo[2.2.1]heptane.
• the desired product 3-(2-(3- pyridyl)vinyl)-2-azabicyclo[2.2.1 jheptane can be obtained by treatment of the aforementioned N-tosylate with sodium naphthylide according to the procedure of Ji et al., J. Am. Chem. Soc. 89:531 1 (1967).
• cetian aryl substituted olefinic amine compounds possessing a l-azabicyclo[3.3.0]octane moiety can vary.
• 5- (2-(3-pyridyl)vinyl)-l-azabicyclo[3.3.0]octane can be synthesized by first reacting 1- azabicyclo[3.3.0]oct-l(5)-ene perchlorate (Miyano et al., Synthesis 1 :701 (1978)) with allylmagnesium bromide to give l-aza-5-prop-2-enylbicyclo[3.3.0]octane.
• the present invention relates to a method for providing prevention of a condition or disorder to a subject susceptible to such a condition or disorder, and for providing treatment to a subject suffering therefrom.
• the method comprises administering to a patient an amount of a compound effective for providing some degree of prevention of the progression of a CNS disorder (i.e., provide protective effects), amelioration of the symptoms of a CNS disorder, and amelioration of the recurrence of a CNS disorder.
• the method involves administering an effective amount of a compound selected from the general formulae which are set forth hereinbefore.
• the present invention relates to a pharmaceutical composition incorporating a compound selected from the general formulae which are set forth hereinbefore.
• Optically active compounds can be employed as racemic mixtures or as enantiomers.
• the compounds can be employed in a free base form or in a salt form (e.g., as pharmaceutically acceptable salts).
• suitable pharmaceutically acceptable salts include inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate, and nitrate; organic acid addition salts such as acetate, galactarate, propionate, succinate, lactate, glycolate, malate, tartrate, citrate.
• salts with acidic amino acid such as aspartate and glutamate
• alkali metal salts such as sodium salt and potassium salt
• alkaline earth metal salts such as magnesium salt and calcium salt
• ammonium salt organic basic salts such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, and N,N'- dibenzylethylenediamine salt
• salts with basic amino acid such as lysine salt and arginine salt.
• the salts may be in some cases hydrates or ethanol solvates.
• the present invention relates to a method for providing prevention of a condition or disorder to a subject susceptible to such a condition or disorder, and for providing treatment to a subject suffering therefrom.
• the method comprises administering to a patient an amount of a compound effective for providing some degree of prevention of the progression of a CNS disorder (i.e., provide protective effects), amelioration of the symptoms of a CNS disorder, and amelioration of the reoccurrence of a CNS disorder.
• the method involves administering an effective amount of a compound selected from the general formulae which are set forth hereinbefore.
• the present invention relates to a pharmaceutical composition incorporating a compound selected from the general formulae which are set forth hereinbefore.
• the present invention also relates to prodrug derivatives of the compounds of the present invention.
• the compounds normally are not optically active. However, certain compounds can possess substituent groups of a character so that those compounds possess optical activity. Optically active compounds can be employed as racemic mixtures or as enantiomers.
• the compounds can be employed in a free base form or in a salt form (e.g., as pharmaceutically acceptable salts).
• Suitable pharmaceutically acceptable salts include inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate, and nitrate; organic acid addition salts such as acetate, galactarate, propionate, succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p- toluenesulfonate, and ascorbate; salts with acidic amino acid such as aspartate and glutamate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; ammonium salt; organic basic salts such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, and N,N'-dibenzylethylenediamine salt; and salts with basic
• salts may be in some cases hydrates or ethanol solvates.
• Compounds of the present invention are useful for treating those types of conditions and disorders for which other types of nicotinic compounds have been proposed as therapeutics. See, for example, Williams et al. DN&P 7(4):205-227 (1994), Arneric et al., CNS Drug Rev. l(l):l-26 (1995), Arneric et al., Exp. Opin. Invest. Drugs 5(1):79-100 (1996), Bencherif et al., JPET279: ⁇ 413 (1996), Lippiello et al, JPET279-A422 (1996), Damaj et al., Neuroscience (1997), Holladay et al., J. Med.
• Compounds of the present invention can be used as analgesics, to treat ulcerative colitis, to treat a variety of neurodegenerative diseases, and to treat convulsions such as those that are symtematic of epilepsy.
• CNS disorders which can be treated in accordance with the present invention include presenile dementia (early onset Alzheimer's disease), senile dementia (dementia of the Alzheimer's type), HIV-dementia, multiple cerebral infarcts, Parkinsonism including Parkinson's disease, Pick's disease, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, attention deficit disorder, anxiety, depression, mild cognitive impairment, dyslexia, schizophrenia and Tourette's syndrome.
• Compounds of the present invention also can be used to treat conditions such as syphillis and Creutzfeld-Jakob disease.
• the pharmaceutical composition also can include various other components as additives or adjuncts.
• exemplary pharmaceutically acceptable components or adjuncts which are employed in relevant circumstances include antioxidants, free radical scavenging agents, peptides, growth factors, antibiotics, bacteriostatic agents, immunosuppressives, anticoagulants, buffering agents, anti-inflammatory agents, antipyretics, time release binders, anaesthetics, steroids and corticosteroids.
• Such components can provide additional therapeutic benefit, act to affect the therapeutic action of the pharmaceutical composition, or act towards preventing any potential side effects which may be posed as a result of administration of the pharmaceutical composition.
• a compound of the present invention can be employed as part of a pharmaceutical composition with other compounds intended to prevent or treat a particular disorder.
• the manner in which the compounds are administered can vary.
• the compounds can be administered by inhalation (e.g., in the form of an aerosol either nasally or using delivery articles of the type set forth in U.S. Patent No. 4,922,901 to Brooks et al., the disclosure of which is incorporated herein in its entirety); topically (e.g., in lotion form); orally (e.g., in liquid form within a solvent such as an aqueous or non-aqueous liquid, or within a solid carrier); intravenously (e.g., within a dextrose or saline solution); as an infusion or injection (e.g., as a suspension or as an emulsion in a pharmaceutically acceptable liquid or mixture of liquids); intrathecally; intracerebro ventricularly; or transdermally (e.g., using a transdermal patch).
• inhalation e.g., in the form of an aerosol either nasally or using delivery articles of the type set forth in U.
• each compound in the form of a pharmaceutical composition or formulation for efficient and effective administration.
• Exemplar ⁇ ' methods for administering such compounds will be apparent to the skilled artisan.
• the compounds can be administered in the form of a tablet, a hard gelatin capsule or as a time release capsule.
• the compounds can be delivered transdermally using the types of patch technologies available from Novartis and Alza Corporation.
• the administration of the pharmaceutical compositions of the present invention can be intermittent, or at a gradual, continuous, constant or controlled rate to a warm-blooded animal, (e.g., a mammal such as a mouse, rat, cat, rabbit, dog, pig, cow, or monkey); but advantageously is preferably administered to a human being.
• a warm-blooded animal e.g., a mammal such as a mouse, rat, cat, rabbit, dog, pig, cow, or monkey
• the time of day and the number of times per day that the pharmaceutical formulation is administered can vary.
• Administration preferably is such that the active ingredients of the pharmaceutical formulation interact with receptor sites within the body of the subject that effect the functioning of the CNS. More specifically, in treating a CNS disorder administration preferably is such so as to optimize the effect upon those relevant receptor subtypes which have an effect upon the functioning of the CNS.
• an effective amount of compound is an amount sufficient to pass across the blood-brain barrier of the subject, to bind to relevant receptor sites in the brain of the subject, and to activatie relevant nicotinic receptor subtypes (e.g., provide neurotransmitter secretion, thus resulting in effective prevention or treatment of the disorder).
• Prevention of the disorder is manifested by delaying the onset of the symptoms of the disorder.
• Treatment of the disorder is manifested by a decrease in the symptoms associated with the disorder or an amelioration of the reoccurrence of the symptoms of the disorder.
• the effective dose can vary, depending upon factors such as the condition of the patient, the severity of the symptoms of the disorder, and the manner in which the pharmaceutical composition is administered.
• the effective dose of typical compounds generally requires administering the compound in an amount sufficient to activate relevant receptors to effect neurotransmitter (e.g., dopamine) release but the amount should be insufficient to induce effects on skeletal muscles and ganglia to any significant degree.
• the effective dose of compounds will of course differ from patient to patient but in general includes amounts starting where CNS effects or other desired therapeutic effects occur, but below the amount where muscular effects are observed.
• the effective dose of compounds generally requires administering the compound in an amount of less than 5 mg/kg of patient weight.
• the compounds of the present invention are administered in an amount from less than about 1 mg/kg patent weight, and usually less than about 100 ug/kg of patient weight, but frequently between about 10 ug to less than 100 ug/kg of patient weight.
• the effective dose is less than 5 mg/kg of patient weight; and often such compounds are administered in an amount from 50 ug to less than 5 mg/kg of patient weight.
• the foregoing effective doses typically represent that amount administered as a single dose, or as one or more doses administered over a 24 hour period.
• the effective dose of typical compounds generally requires administering the compound in an amount of at least about 1 , often at least about 10, and frequently at least about 25 ug/ 24 hr./ patient.
• the effective dose of typical compounds requires administering the compound which generally does not exceed about 500, often does not exceed about 400, and frequently does not exceed about 300 ug/ 24 hr./ patient.
• administration of the effective dose is such that the concentration of the compound within the plasma of the patient normally does not exceed 500 ng/ml, and frequently does not exceed 100 ng/ml.
• the compounds useful according to the method of the present invention have the ability to pass across the blood-brain barrier of the patient. As such, such compounds have the ability to enter the central nervous system of the patient.
• the log P values of typical compounds, which are useful in carrying out the present invention are generally greater than about -0.5, often are greater than about 0, and frequently are greater than about 0.5.
• the log P values of such typical compounds generally are less than about 3, often are less than about 2, and frequently are less than about 1.
• Log P values provide a measure of the ability of a compound to pass across a diffusion barrier, such as a biological membrane. See, Hansch, et al., J. Med. Chem. 1 1 : 1 (1968).
• the compounds useful according to the method of the present invention have the ability to bind to, and in most circumstances, cause activation of, nicotinic dopaminergic receptors of the brain of the patient.
• the receptor binding constants of typical compounds useful in carrying out the present invention generally exceed about 0.1 nM, often exceed about 1 nM, and frequently exceed about 10 nM.
• the receptor binding constants of certain compounds are less than about 100 uM, often are less than about 10 uM and frequently are less than about 5 uM; and of preferred compounds generally are less than about 1 uM, often are less than about 100 nM, and frequently are less than about 50 nM.
• certain compounds possess receptor binding constants of less than 10 uM, and even less than 100 uM.
• Receptor binding constants provide a measure of the ability of the compound to bind to half of the relevant receptor sites of certain brain cells of the patient. See, Cheng, et al., Biochem. Pharmacol. 22:3099 (1973).
• the compounds useful according to the method of the present invention have the ability to demonstrate a nicotinic function by effectively activating neurotransmitter secretion from nerve ending preparations (i.e., synaptosomes). As such, such compounds have the ability to activate relevant neurons to release or secrete acetylcholine, dopamine, and other neuro transmitters.
• typical compounds useful in carrying out the present invention provide for the activation of dopamine secretion in amounts of at least one third, typically at least about 10 times less, frequently at least about 100 times less, and sometimes at least about 1,000 times less, than those required for activation of muscle-type nicotinic receptors.
• Certain compounds of the present invention can provide secretion of dopamine in an amount which is comparable to that elicited by an equal molar amount of (S)-(-)-nicotine.
• the compounds of the present invention when employed in effective amounts in accordance with the method of the present invention, are selective to certain relevant nicotinic receptors, but do not cause significant activation of receptors associated with undesirable side effects at concentrations at least greater than those required for activation of dopamine release.
• a particular dose of compound resulting in prevention and/or treatment of a CNS disorder is essentially ineffective in eliciting activation of certain muscle-type nicotinic receptors at concentration higher than 5 times, preferably higher than 100 times, and more preferably higher than 1 ,000 times, than those required for activation of dopamine release.
• administering provides a therapeutic window in which treatment of certain CNS disorders is provided, and certain side effects are avoided. That is, an effective dose of a compound of the present invention is sufficient to provide the desired effects upon the CNS, but is insufficient (i.e., is not at a high enough level) to provide undesirable side effects.
• effective administration of a compound of the present invention resulting in treatment of CNS disorders occurs upon administration of less than 1/5, and often less than 1/10 that amount sufficient to cause certain side effects to any significant degree.
• the pharmaceutical compositions of the present invention can be employed to prevent or treat certain other conditions, diseases and disorders.
• diseases and disorders include inflammatory bowel disease, acute cholangitis, aphteous stomatitis, arthritis (e.g., rheumatoid arthritis and ostearthritis), neurodegenerative diseases, cachexia secondary to infection (e.g., as occurs in AIDS, AIDS related complex and neoplasia), as well as those indications set forth in PCT WO 98/25619.
• the pharmaceutical compositions of the present invention can be employed in order to ameliorate may of the symptoms associated with those conditions, diseases and disorders.
• compositions of the present invention can be used in treating genetic diseases and disorders, in treating autoimmune disorders such as lupus, as anti-infectious agents (e.g, for treating bacterial, fungal and viral infections, as well as the effects of other types of toxins such as sepsis), as anti-inflammatory agents (e.g., for treating acute cholangitis, aphteous stomatitis, asthma, and ulcerative colitis), and as inhibitors of cytokines release (e.g., as is desirable in the treatment of cachexia, inflammation, neurodegenerative diseases, viral infection, and neoplasia),
• the compounds of the present invention can also be used as adjunct therapy in combination with existing therapies in the management of the aforementioned types of diseases and disorders.
• administration preferably is such that the active ingredients of the pharmaceutical formulation act to optimize effects upon abnormal cytokine production, while minimizing effects upon receptor subtypes such as those that are associated with muscle and ganglia.
• Administration preferably is such that active ingredients interact with regions where cytokine production is affected or occurs.
• compounds of the present invention are very potent (i.e., affect cytokine production and/or secretion at very low concentrations), and are very efficacious (i.e., significantly inhibit cytokine production and/or secretion to a relatively high degree).
• Effective doses are most preferably at very low concentrations, where maximal effects are observed to occur. Concentrations, determined as the amount of compound per volume of relevant tissue, typically provide a measure of the degree to which that compound affects cytokine production. Typically, the effective dose of such compounds generally requires administering the compound in an amount of much less than 100 ug/kg of patient weight, and even less than 10u/kg of patient
• the foregoing effective doses typically represent the amount administered as a single dose, or as one or more doses administered over a 24 hour period.
• the effective dose of typical compounds generally requires administering the compound in an amount of at least about 1 , often at least about 10, and frequently at least about 25 ug / 24 hr. / patient.
• the effective dose of typical compounds requires administering the compound which generally does not exceed about 1, often does not exceed about 0.75, often does not exceed about 0.5, frequently does not exceed about 0.25 mg / 24 hr. / patient.
• administration of the effective dose is such that the concentration of the compound within the plasma of the patient normally does not exceed 500 pg/ml, often does not exceed 300 pg/ml, and frequently does not exceed 100 pg/ml.
• compounds of the present invention When employed in such a manner, compounds of the present invention are dose dependent, and as such, cause inhibition of cytokine production and/or secretion when employed at low concentrations but do not exhibit those inhibiting effects at higher concentrations. Compounds of the present invention exhibit inhibitory effects upon cytokine production and/or secretion when employed in amounts less than those amounts necessary to elicit activation of relevant nicotinic receptor subtypes to any significant degree.
• Binding of the compounds to relevant receptor sites was determined in accordance with the techniques described in U.S. Patent No. 5,597,919 to Dull et al. Inhibition constants (Ki values), reported in nM, were calculated from the IC 50 values using the method of Cheng et al., Biochem, Pharmacol. 22:3099 (1973). Low binding constants indicate that the compounds of the present invention exhibit good high affinity binding to certain CNS nicotinic receptors.
• Rat brain synaptosomes were prepared as follows: Female Sprague Dawley rats (100-200 g) were killed by decapitation after anesthesia with 70% C0 2 . Brains are dissected, and hippocampus, striatum, and thalamus isolated, and homogenized in 0.32 M sucrose containing 5 mM HEPES pH 7.4 using a glass/glass homogenizer. The tissue was then centrifuged for 1000 x g for 10 minutes and the pellet discarded. The supernatant was centrifuged at 12000 x g for 20 minutes.
• the resultant pellet was re-suspended in perfusion buffer (128 mM NaCl, 1.2 mM KH2PO4, 2.4 mM KCl, 3.2 mM CaCl 2 , 1.2 mM MgSO 4 , 25 mM HEPES, 1 mM Ascorbic acid, 0.01 mM pargyline HC1 and 10 mM glucose pH 7.4) and centrifuged for 15 minutes at 25000 x g. The final pellet was resuspended in perfusion buffer and placed in a water bath (37°C) for 10 minutes.
• Radiolabeled neurotransmitter is added (30 uL 3 H DA, 20 L 3 H NE, 10 uL 3 H glutamate) to achieve a final concentration of 100 nM, vortexed and placed in a water bath for additional 10 minutes. Tissue-loaded filters is placed onto 1 1-mm diameter Gelman A/E filters on an open-air support. After a 10-minute wash period, fractions are collected to establish the basal release and agonist applied in the perfusion stream. Further fractions were collected after agonist application to reestablish the baseline. The perfusate was collected directly into scintillation vials and released radioactivity was quantified using conventional liquid scintillation techniques.
• Release of neurotransmitter was determined in the presence of 10 uM of various ligands and was expressed as a percentage of release obtained with a concentration of 10 uM (S)-(-)-nicotine or 300 uM TMA resulting in maximal effects.
• Example 3 Determination of Interaction with Muscle Receptors The determination of the interaction of the compounds with muscle receptors was carried out in accordance with the techniques described in U.S. Patent No. 5,597,919 to Dull et al. The maximal activation for individual compounds (E max ) was determined as a percentage of the maximal activation induced by (S)-(-)-nicotine.
• 3S ⁇ Reported E max values represent the amount released relative to (S)-(-)-nicotine on a percentage basis.
• Low E max values at muscle-type receptors indicate that the compounds of the present invention do not induce activation of muscle-type receptors.
• Such preferable compounds have the capability to activate human CNS receptors without activating muscle-type nicotinic acetylcholine receptors.
• a therapeutic window for utilization in the treatment of CNS disorders That is, at certain levels the compounds show CNS effects to a significant degree but do not show undesirable muscle effects to any significant degree. The compounds begin to cause muscle effects only when employed in amounts of many times those required to activate dopamine release.
• E max The maximal activation for individual compounds (E max ) was determined as a percentage of the maximal activation induced by (S)-(-)-nicotine.
• Reported E max values represent the amount released relative to (S)-(-)-nicotine on a percentage basis.
• Low E max values at ganglia-type receptors indicate that the compounds of the present invention do not induce activation of ganglia-type receptors.
• Such preferable compounds have the capability to activate human CNS receptors without activating ganglia-type nicotinic acetylcholine receptors.
• a thick-walled glass pressure tube was charged with (2S)-N-(tert- butoxycarbonyl)-2-(3-prop-l-enyl)pyrrolidine (100.0 mg, 0.47 mmol), 3- bromopyridine (112.3 mg, 0.71 mmol), palladium(II) acetate (10.63 mg, 0.047 mmol), tri-o-tolylphosphine (14.42 mg, 0.074 mmol), triethylamine (1 mL, 7.17 mmol) and acetonitrile (10 mL). The tube was sealed, and the reaction mixture was stirred and heated at 110-120°C for 8 h.
• the product was purified by column chromatography on silica gel, eluting with a gradient of CHCl 3 -CH 3 OH ( ⁇ 9:1), containing 1% Et 3 N. Selected fractions were combined and concentrated under vacuum to give 20.0 mg (61.3%) of a pale, light-yellow oil.
• Galactaric acid (10.0 mg, 0.048 mmol) was added to a solution of (2S)-(2E)-2- (3-prop-l-(3-pyridyl)-l-enyl)pyrrolidine (18.0 mg, 0.096 mmol) in absolute ethanol (1 mL). The mixture was heated at 60°C and sonicated. Water (2-3 drops) was added, and the process was repeated 3-4 times producing a clear solution. The solution was filtered and concentrated; ethanol (2 mL) was added to the residue and removed by rotary evaporation. The resulting solid was dissolved in a minimum amount of ethanol and dry diethyl ether was added, producing a cloudy solution. After standing 2 days at ambient temperature, the resulting solid was filtered and washed with ether to give 16.6 mg (59.1%) of a pale, light-yellow solid, mp 138- 14PC.
• the compound exhibits a Ki of 472 nM, neurotransmittor release of 1 1%, and binding to muscle of 0% and binding to ganglia of 0%.
• the compound exhibits a Ki of 306 nM and a neurotransmitter release of 48%).

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