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WO2004009599A1 - Composes heteroaromatiques olefiniques azacycliques a cinq elements, compositions pharmaceutiques contenant lesdits composes et leur utilisation comme inhibiteurs des recepteurs nicotiniques cholinergiques - Google Patents

Composes heteroaromatiques olefiniques azacycliques a cinq elements, compositions pharmaceutiques contenant lesdits composes et leur utilisation comme inhibiteurs des recepteurs nicotiniques cholinergiques Download PDF

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Publication number
WO2004009599A1
WO2004009599A1 PCT/US2002/022997 US0222997W WO2004009599A1 WO 2004009599 A1 WO2004009599 A1 WO 2004009599A1 US 0222997 W US0222997 W US 0222997W WO 2004009599 A1 WO2004009599 A1 WO 2004009599A1
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Prior art keywords
isoxazole
azabicyclo
vinyl
hydrogen
carbon
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Thomas Jeffrey Clark
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Gyre Therapeutics Inc
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Targacept Inc
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Priority to AU2002313690A priority patent/AU2002313690A1/en
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    • 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
    • C07D413/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • 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
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to pharmaceutical compositions, particularly pharmaceutical compositions incorporating compounds that are capable of affecting nicotinic cholinergic receptors. More particularly, the present invention relates to compounds capable of affecting nicotinic cholinergic receptors, for example, as modulators of specific nicotinic receptor subtypes. The present invention also relates to methods for treating a wide variety of conditions and disorders, 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. 330:811 (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 CNS disorders. Indeed, a wide variety of compounds have been reported to have therapeutic properties. See, for example, U.S. Patent Nos. 5,1871,166 to Kikuchi et al., 5,672,601 to Cignarella, PCT WO 99/21834 and PCT WO 97/40049, UK Patent Application GB 2295387 and European Patent Application 297,858.
  • 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 deficiency of choline, dopamine, norepinephrine and/or serotonin.
  • Relatively common CNS disorders include pre-senile dementia (early-onset Alzheimer's disease), senile dementia (dementia of the Alzheimer's type), micro-infarct dementia, ATDS-related dementia, Creutzfeld- Jakob disease, Pick's disease, Parkinsonism including Parkinson's disease, progressive supranuclear palsy, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, attention deficit disorder, anxiety, dyslexia, schizophrenia, depression, obsessive-compulsive disorders and Tourette's syndrome.
  • CNS diseases e.g., CNS diseases
  • nicotinic receptors such as those which have the potential to effect the functioning of the CNS, but, 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 cardiovascular and skeletal muscle sites).
  • the present invention relates to aryl olefinic azacyclic compounds and aryl acetylenic azacylic compounds.
  • the present invention relates in particular to five-membered heteroaromatic olefinic azacyclic compounds and five-membered heteroaromatic acetylenic azacylic compounds, including isoxazolyl olefinic cycloalkylamines and isoxazolyl acetylenic cycloalkylamines.
  • the present invention also relates to prodrug derivatives of the compounds of the present invention.
  • Exemplary compounds of the present invention are 5-(2-(5-azabicyclo[3.3.0]octyl)vinyl) isoxazole and 5-(2-(5-azabicyclo[3.3.0]octyl)ethynyl)isoxazole.
  • the compounds of the present invention bind specifically to certain nicotinic receptors and modulate their function.
  • the present invention relates to methods for synthesizing these types of compounds.
  • 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 dysfunction 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 of 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/or (ii) modulate neurotransmitter secretion and thus prevent and suppress the symptoms associated with those diseases.
  • the compounds are expected to have the potential to fulfill the following results for the patient: (i) to alter the number of nicotinic cholinergic receptors of the brain of the patient, (ii) to exhibit neuroprotective effects and (iii) to result in no appreciable adverse side effects when administered in effective amounts—side effects such as significant increases in blood pressure and heart rate, significant negative effects upon the gastro-intestinal tract, and significant effects upon skeletal muscle.
  • the pharmaceutical 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:
  • Cy represents a 5-membered, preferably heteroaromatic ring, such as isoxazole, isothiazole, oxazole, thiazole, pyrazole, 1,2,4-oxadiazole and 1,2,4-triazole.
  • heteroaromatic ring such as isoxazole, isothiazole, oxazole, thiazole, pyrazole, 1,2,4-oxadiazole and 1,2,4-triazole.
  • Cy is attached to B' at any one of the various ring carbon atoms.
  • the 5-membered heteroaromatic ring may bear one or more additional (i.e., in addition to B') non-hydrogen substituent species.
  • X, X 1 , X 11 , X m and X N are individually nitrogen, nitrogen bonded to a substituent species (including oxygen, as in the case of an N-oxide), oxygen, sulfur or carbon bonded to a substituent species.
  • substituent species can individually be hydrogen or non-hydrogen.
  • R' and R" can together form a cycloalkyl functionality.
  • Representative aromatic group-containing species include phenyl, benzyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl and quinolinyl.
  • Other representative aromatic ring systems are set forth in Gibson et al., J. Med. Chem. 39:4065 (1996).
  • R' or R" is a non-hydrogen substituent species, it may be further substituted, one or more times, by non-hydrogen substituent species, as described hereinbefore.
  • B' is a substituted or unsubstituted two carbon bridging species; preferably can be acetylenic or ethylenic, and more preferably is ethylenic. That is, B' can be selected from - CC- or -CR -CR"-, wherein R' and R" are defined hereinbefore, but R' and R" preferably each are hydrogen.
  • the two carbon bridging species is ethylenic, that species can have a trans(E) or cis(Z) form, but most preferably is trans(E).
  • E, E', E" and E' 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, alkylaryl, substituted alkylaryl, arylalkyl or substituted arylalkyl).
  • 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.
  • E, E', E" and E"' are preferably lower alkyl (e.g., straight chain or branched alkyl including - , preferably C r C 5 , such as methyl, ethyl, or isopropyl) or halo substituted lower alkyl (e.g., straight chain or branched alkyl including C r C s , preferably - , such as trifluoromethyl or trichloromethyl).
  • halo substituted lower alkyl e.g., straight chain or branched alkyl including C r C s , preferably - , such as trifluoromethyl or trichloromethyl.
  • E, E', E" and E'" are hydrogen, or at least one E, E', E" and E'" is non-hydrogen and the remaining E, E', E” and E'" are hydrogen.
  • E and E' each can be hydrogen, or E can be hydrogen and E' can be methyl; or when m is 1 and n is 1, E, E', E" and E"' all can be hydrogen, or E, E' and E" can be hydrogen and E'" can be methyl, or E', E" and E'" can be hydrogen and E can be methyl.
  • the selection of m, n, E, E', E" and E'" is such that 0, 1 or 2, usually 0 or 1, and preferably 0, of the substituents designated as E, E', E" and E'" are non-hydrogen (e.g., substituents such as alkyl or halo-substituted alkyl).
  • Q is one of the following azacycles:
  • Z" j represents a suitable non-hydrogen substituent group (e.g., alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl or substituted arylalkyl), but preferably alkyl.
  • Z" represents either hydrogen or lower alkyl.
  • Z' represents hydrogen, lower alkyl, acyl, alkoxycarbonyl, or aryloxycarbonyl.
  • Z' is hydrogen or methyl and Z" is hydrogen.
  • the dotted line indicates that the bond between the two atoms can be either a single or a double bond.
  • Suitable Q's are disclosed in U.S. Serial No. 09/431,700 filed November 1, 1999, the disclosure of which is incorporated herein by reference in its entirety.
  • the azacycles identified above can optionally include one or more oxygen atoms in any position other than the bridgehead position.
  • the ring includes one oxygen and one nitrogen atom, with the proviso that at least two carbon atoms are between the oxygen and nitrogen atoms.
  • alkyl refers to straight chain or branched alkyl radicals including Cj-C 8 , preferably C j - , 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 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; "substituted
  • Compounds of the present invention can occur as stereoisomeric structures, and the present invention relates to racemic mixtures of such compounds as well as single enantiomer compounds.
  • Representative compounds useful in carrying out the present invention include the following:
  • compounds of the present invention can be prepared in either racemic form or in enantiomerically pure form.
  • certain 5-membered heterocyclyl olefinic pyrrolidine compounds can be prepared by using a palladium-catalyzed coupling reaction of a 5-bromoisoxazole or 5-iodoisoxazole 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( ⁇ ) acetate, tri-o-tolylphosphine, and triethylamine, similar to those described by Frank et al., J Org. Chem. 43(15): 2947 (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- 1 -(5-isoxazolyl)- 1 -enyl)pyrrolidine can then be removed by treatment with a strong acid, such as trifluoroacetic acid, to produce (2S)-(2E)-5-(3-(pyrrolidin-2-yl)prop-l-enyl)isoxazole.
  • the pyrrolidine ring can then be N- methylated using aqueous formaldehyde and sodium cyanoborohydride using methodology similar to that described by Abreo et al, J. Med. Chem. 39: 817 (1996) to afford (2S)-(2E)-5- (3 -( 1 -methylpyrrolidin-2-yl)prop- 1 -enyl)isoxazole.
  • (2S)-2-allyl-N-(tert-butoxycarbonyl)pyrrolidine 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 desired olefinic pyrrolidine, (2S)-2-allyl-N-tert-butoxycarbonylpyrrolidine.
  • enantiomerically pure 2-pyrrolidinemethanol can be synthetically elaborated to the aforementioned chiral olefinic pyrrolidine, 2-allyl-N-tert-butoxycarbonylpyrrolidine, using the methodology of Ikeda et al., Heterocycles 50: 31 (1999).
  • Certain compounds of the present invention possessing an ethenyl or ethynyl linker between the heteroaromatic ring and the azacycle, can be prepared by a variety of methods.
  • a 5- haloisoxazole such as a 5-bromoisoxazole is coupled with (2S)- N-(tert-butoxycarbonyl)-2- vinylpyrrolidine or (2S)- N-(tert-butoxycarbonyl)-2-ethynylpyrrolidine, and the tert- butoxycarbonyl protecting groups subsequently removed.
  • (2S)-N- (tert-butoxycarbonyl)-2-ethynylpyrrolidine may be prepared by treatment of the aldehyde with carbon tetrabromide and triphenyl phosphine followed by n-butyllithium.
  • the products of such a sequence, (2S)-(2E)-5-(2-pyrrolidin-2-ylvinyl)isoxazole and (2S)-5-(2-pyrrolidin-2- ylethynyl)isoxazole can subsequently be methylated, as described previously, to produce the corresponding N-methyl derivatives.
  • 5-membered heteroaromatic olefinic azacyclic compounds, of the present invention can be synthesized.
  • Those examples possessing a 1- azabicyclo [3.3.0] octane moiety can be synthesized utilizing 5- azabicyclo[3.3.0]octanecarboxaldehyde as a key intermediate in the synthetic pathway.
  • Compounds of the present invention include those in which the isoxazole ring is substituted (e.g., on the 3 and 4 position) with moieties that are stable to the processes used in their generation. For instance, treatment of 5 -azabicyclo [3.3.0] octanecarboxaldehyde with the anion of 5-(diethylphosphonylmethyl)-3-methylisoxazole will provide (E)-5-(2-(5- azabicyclo[3.3.0]octyl)vinyl)-3-methylisoxazole in a similar manner to that described hereinbefore.
  • 5-Diethylphosphonylmethyl-3-methylisoxazole can be prepared as described in Lee et al., Syn.
  • Heteroaromtic olefinic azabicyclic compounds containing other five-membered heterocycles can be prepared using Homer- Wadsworth- Emmons reaction chemistry as described in US Patent No. 6,022,868 to Olesen et al.
  • condensation of 5-azabicyclo[3.3.0]octanecarboxaldehyde with a 5-membered (heterocyclyl)methyllithium followed by dehydration of the resulting alcohol will also provide the desired compounds.
  • Representative examples of 5-membered (heterocyclyl)methyllithium species are described by Micetich et al., Can. J. Chem. 48: 2006 (1970).
  • the azabicycle moiety in the present invention can vary as well.
  • (E)-5- (2-(6-azabicyclo[4.3.0]nonyl)vinyl)isoxazole and (E)-5-(2-(5- azabicyclo[3.2.0]heptyl)vinyl)isoxazole can be prepared in a similar manner as described.
  • N-(tert-butoxycarbonyl)-2-(methoxycarbonyl)pyrrolidine Treatment of N-(tert-butoxycarbonyl)-2-(methoxycarbonyl)pyrrolidine with lithium diisopropylamine, followed by reaction with 1,4-dibromobutane, can provide N-(tert- butoxycarbonyl)-2-(4-bromobutyl)-2-(methoxycarbonyl)pyrrolidine which, upon deprotection of the amine, followed by intramolecular nucleophilic substitution and diisobutylaluminum hydride reduction of the ester can provide 6-azabicyclo[4.3.0]nonanecarboxaldehyde.
  • azabicyclic compounds can be prepared from pipecolinic acid, in a manner similar to that just described.
  • conversion to the methyl ester and protection of the amine as its N-(tert-butoxycarbonyl) derivative gives a material, N-(tert-butoxycarbonyl)-2- (methoxycarbonyl)piperidine, which is homologous to the previously described N-(tert- butoxycarbonyl)-2-(methoxycarbonyl)pyrrolidine.
  • 5-membered heteroaromatic alkynyl azacyclic compounds are produced can vary. For example, treatment of 5-azabicyclo[3.3.0]octanecarboxaldehyde with carbon tetrabromide in carbon tetrachloride solution will provide l-aza-5-(2,2- dibromovinyl)bicyclo[3.3.0]octane which, upon treatment with n-butyllithium, will provide l-aza-5-ethynylbicyclo[3.3.0]octane.
  • mixtures of the (E) and (Z) olefinic compounds can be prepared by reaction of the aldyhydes with Wittig reagents. Subsequent chromatographic separation will provide samples of both geometric isomers.
  • Wittig reaction see House et al., J Org. Chem 29:3327 (1964).
  • 2-allylquinuclidine can be subjected to a palladium-catalyzed coupling reaction with a 5-haloisoxazole, such as 5-bromoisoxazole, to afford 2-(l-(5- isoxazolyl)propen-3-yl)quinuclidine.
  • the precursor 2-allylquinuclidine can be prepared from 3-quinuclidinone (commercially available from Aldrich Chemical Company) by alkylation and modified Wolff-Kishner reduction, as described in Forsyth et al., J Am. Chem. Soc. 109:7270 (1987).
  • 3-quinuclidinone can be converted to the corresponding imine with isopropylamine and molecular sieves.
  • Removal of the carbonyl-protecting group can then be effected by converting the ketone into the p- toluenesulfonylhydrazone, followed by reduction with sodium cyanoborohydri.de, to afford 2- allylquinuclidine.
  • 5-(2-(2-azetidinyl)vinyl)isoxazole can be synthesized starting from commercially azetidine-2-carboxylic acid (Aldrich Chemical Company).
  • Azetidine-2-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 azetidine-2-methanol.
  • azetidinyl nitrogen of the latter compound can be accomplished by treatment with tert-butylpyrocarbonate and base to give N-(tert-butyloxycarbonyl)-2-(hydroxymethyl)azetidine, using methodology similar to that described by Carpino et al., Ace. Chem. Res, 6:191 (1973).
  • This alcohol can be oxidized by a Swern oxidation to the corresponding aldehyde.
  • a Homer- Wadsworth-Emmons reaction between the aldehyde and diethyl (5-isoxazolylmethyl)phosphonate, followed by deprotection, will provide compounds of the present invention.
  • l]heptane-2-carboxy late is, in turn, made from commercially available tetrahycfro-3-ft ⁇ ranmethanol and glycine methyl ester through the following sequence of reactions.
  • Tetrahydro-3-furanmethanol is converted first to the mesylate by treatment with methanesulfonyl chloride in dichloromethane and triethylamine, and then the mesylate is converted into 3-(bromomethyl)oxolane by treatment with lithium bromide in acetone.
  • This bromide is used to alkylate the anion, generated by reaction with potassium t-butoxide, of methyl 3-aza-4,4-diphenylbut-3-enoate, the product of reaction of glycine methyl ester and diphenylimine.
  • the alkylation product, methyl 3-(3- oxolanyl)-2-aminopropanoate, is then treated with fuming, refluxing hydrobromic acid, to close the azabicyclic system, and the resulting l-azabicyclo[2.2.1]heptane-2-carboxylic acid is then re-esterified with ethanol and sulfuric acid.
  • azabicyclic esters useful in the synthesis of compounds of the present invention, are similarly generated.
  • the use of tetrahydro-4-pyranmethanol, in place of tetrahydro-3-furanmethanol, in the sequence described above gives the corresponding ethyl quinuclidine-2-carboxylate.
  • Ethyl quinuclidine-2-carboxylate can also be made according to the method described by Ricciardi and Doukas, Heterocycles 24:971 (1986).
  • 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 pure 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 an acidic amino acid such as aspartate and glutamate; alkali metal salts such as sodium and potassium; alkaline earth metal salts such as magnesium and calcium; ammonium salt; organic basic salts such as trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine,
  • the salts may be in some cases hydrates or ethanol solvates.
  • Representative salts are provided as described in U.S. Patent Nos. 5,597,919 to Dull et al, 5,616,716 to Dull et al. and 5,663,356 to Ruecroft et al., the disclosures of which are incorporated herein by reference in their entirety.
  • 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., Drug News Perspec. 7(4):205 (1994), Arneric et al., CNS Drug Rev. 1(1): 1 (1995), Arneric et al, Exp. Opin. Invest. Drugs 5(1):79 (1996), Bencherif et al., J. Pharmacol. Exp. Ther. 279:1413 (1996), Lippiello et al., J. Pharmacol. Exp. Ther. 279:1422 (1996), Damaj et al., J. Pharmacol. Exp. Ther.
  • Compounds of the present invention can be used as analgesics, to treat ulcerative colitis, inflammatory and auto-immune diseases (e.g., arthritis, cholangitis, stomatitis, pouchitis, viral pneumonitis), to treat a variety of neurodegenerative diseases, and to treat convulsions such as those that are symptomatic of epilepsy.
  • inflammatory and auto-immune diseases e.g., arthritis, cholangitis, stomatitis, pouchitis, viral pneumonitis
  • convulsions such as those that are symptomatic of epilepsy.
  • CNS disorders which can be treated in accordance with the present invention include pre-senile dementia (early onset Alzheimer's disease), senile dementia (dementia of the Alzheimer's type), HlV-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 compounds of the present invention also can be appropriately synthesized and used as or within pharmaceutical compositions that are used as diagnostic probes.
  • 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, anti-pyretics, time-release binders, anaesthetics, steroids, vitamins, minerals 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 imposed 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 fonn 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; intracerebroventricularly; 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
  • each compound in the form of a pharmaceutical composition or formulation for efficient and effective administration.
  • exemplary 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 administered preferably 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.
  • Preferable administration is such that the active ingredients of the pharmaceutical formulation interact with receptor sites within the body of the subject that affect the functioning of the CNS. More specifically, in treating a CNS disorder, preferable administration is designed to optimize the effect upon those relevant receptor subtypes that have an effect upon the functioning of the CNS, while minimizing the effects upon muscle-type receptor subtypes.
  • Other suitable methods for administering the compounds of the present invention are described in U.
  • 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 activate relevant nicotinic receptor subtypes (e.g., provide neurotransmitter secretion, thus resulting in effective prevention or treatment of the disorder).
  • 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 activate 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 recurrence 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 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 these 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, including the blood brain barrier. See, for example, Hansch et al., J. Med. Chem. 11:1 (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. As such, these compounds have the ability to express nicotinic pharmacology and, in particular, to act as nicotinic agonists.
  • 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 ⁇ M, often are less than about 10 ⁇ M and frequently are less than about 5 ⁇ M; and of preferred compounds generally are less than about 2.5 ⁇ M, sometimes are less than about 1 ⁇ M, and can be less than about 100 nM.
  • 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, for example, 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, these compounds have the ability to activate relevant neurons to release or secrete acetylcholine, dopamine, and other neurotransmitters.
  • 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 ganglionic-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.
  • Compounds of the present invention when employed in effective amounts in accordance with the method of the present invention, are effective towards providing some degree of prevention of the progression of CNS disorders, amelioration of the symptoms of CNS disorders, and amelioration to some degree of the recurrence of CNS disorders.
  • effective amounts of those compounds are not sufficient to elicit any appreciable side effects, as demonstrated by increased effects relating to skeletal muscle.
  • administration of certain compounds of the present invention 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, poucbitis, acute cholangitis, aphthous stomatitis, arthritis (e.g., rheumatoid arthritis and osteoarthritis), 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 many 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 auto-immune disorders such as lupus, as anti-infectious agents (e.g., for treating bacterial, fungal and viral infections, as well as the effects, such as sepsis, of other types of toxins), as anti-inflammatory agents (e.g., for treating acute cholangitis, aphthous stomatitis, asthma, and ulcerative colitis), and as inhibitors of cytokine release (e.g., as is desirable in the treatment of cachexia, inflammation, neurodegenerative diseases, viral infection, and neoplasia).
  • auto-immune disorders such as lupus
  • anti-infectious agents e.g., for treating bacterial, fungal and viral infections, as well as the effects, such as sepsis, of other types of toxins
  • anti-inflammatory agents e.g., for treating acute cholangitis, aphthous stomatitis, asthma
  • 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.
  • preferable administration 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.
  • Preferable administration 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 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 compounds generally requires administering the compound in an amount of less than 5 mg/kg of patient weight. Often, 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 ⁇ g/kg of patient weight, but frequently between about 10 ⁇ g to less than 100 ⁇ g/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 ⁇ g 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 ⁇ g/ 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 ⁇ g/ 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 (Kj 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. All final compounds of the present invention reported herein have acceptable binding to the relevant receptor sites.
  • Sample No. 1 is (E)-5-(2-(5-azabicyclo[3.3.0]octyl)vinyl)isoxazole, which was prepared in accordance with the following techniques:
  • N-bromosuccinimide (21.4 g, 120 mmole), 5-methylisoxazole (9.97g, 120 mmole) and benzoylperoxide (2.41 g, 12.0 mmole) in carbon tetrachloride (250 mL) were heated while stirring at 80°C for 6 h.
  • the reaction mixture was filtered and then concentrated by rotary evarporation. Distillation at reduced pressure (bp 54-57 °C, 0.5 mm Hg) provided pure product as a colorless oil (14.00 g, 72% yield).
  • Sample No. 1 exhibits a K; of 140 nM.
  • the low binding constant indicates that the compound exhibits good high-affinity binding to certain CNS nicotinic receptors.

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Abstract

L'invention concerne des composés hétéroaromatiques oléfiniques azacycliques à cinq éléments et des composés hétéroaromatiques acétyléniques azacycliques à cinq éléments représentés par la formule (I). Dans cette formule, le noyau comprenant X, XI, XII, XIII et X IV est hétéroaromatique, B représente une espèce de pontage à deux atomes de carbone et Q, E, EI, EII, EIII, m et n sont tels que définis dans les spécifications. L'invention concerne également des compositions pharmaceutiques contenant lesdits composés capables d'affecter les récepteurs nicotiniques cholinergiques.
PCT/US2002/022997 2002-07-19 2002-07-19 Composes heteroaromatiques olefiniques azacycliques a cinq elements, compositions pharmaceutiques contenant lesdits composes et leur utilisation comme inhibiteurs des recepteurs nicotiniques cholinergiques Ceased WO2004009599A1 (fr)

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AU2002313690A AU2002313690A1 (en) 2002-07-19 2002-07-19 Five-membered heteroaromatic olefinic azacyclic compounds, pharmaceutical compositions containing them and their use as inhibitors of ncotinic cholinergic receptors

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US8772326B2 (en) 2008-07-10 2014-07-08 Anigion Biomedica Corp. Methods and compositions of small molecule modulators of hepatocyte growth factor (scatter factor) activity
US10875849B2 (en) 2019-04-11 2020-12-29 Angion Biomedica Corp. Solid forms of (E)-3-[2-(2-thienyl)vinyl]-1H-pyrazole
CN116178287A (zh) * 2023-02-21 2023-05-30 宁夏大学 3-苯乙炔基-1,2,4-三唑类衍生物及其制备方法

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Cited By (12)

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Publication number Priority date Publication date Assignee Title
WO2004058721A3 (fr) * 2002-12-21 2004-10-28 Angion Biomedica Corp Modulateurs a petites molecules de l'activite du facteur de croissance d'hepatocyte (facteur de dispersion)
US7192976B2 (en) 2002-12-21 2007-03-20 Angion Biomedica Corporation Small molecule modulators of hepatocyte growth factor (scatter factor) activity
US7250437B2 (en) 2002-12-21 2007-07-31 Angion Biomedica Corp. Small molecule modulators of hepatocyte growth factor (scatter factor) activity
US7265112B2 (en) 2002-12-21 2007-09-04 Angion Biomedica Corp. Small molecule modulators of hepatocyte growth factor (scatter factor) activity
EP2292227A3 (fr) * 2002-12-21 2011-05-25 Angion Biomedica Corp. Derivés de pyrazole comme modulateurs de l'activité du facteur de croissance hépatocytaire ( facteur de dispersion)
US8580834B2 (en) 2002-12-21 2013-11-12 Angion Biomedica Corp. Small molecule modulators of hepatocyte growth factor (scatter factor) activity
US9663471B2 (en) 2002-12-21 2017-05-30 Angion Biomedica Corporation Pyrazole derivatives as modulators of hepatocyte growth factor (scatter factor) activity
US8772326B2 (en) 2008-07-10 2014-07-08 Anigion Biomedica Corp. Methods and compositions of small molecule modulators of hepatocyte growth factor (scatter factor) activity
US10899750B2 (en) 2008-07-10 2021-01-26 Angion Biomedica Corp. Methods and compositions of small molecule modulators of hepatocyte growth factor (scatter factor) activity
US10875849B2 (en) 2019-04-11 2020-12-29 Angion Biomedica Corp. Solid forms of (E)-3-[2-(2-thienyl)vinyl]-1H-pyrazole
US11370783B2 (en) 2019-04-11 2022-06-28 Angion Biomedica Corp. Solid forms of (E)-3-[2-(2-thienyl)vinyl]-1H-pyrazole
CN116178287A (zh) * 2023-02-21 2023-05-30 宁夏大学 3-苯乙炔基-1,2,4-三唑类衍生物及其制备方法

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