CA2383307A1

CA2383307A1 - Arylalkyloxyalkylamines and arylalkylthioalkylamines, pharmaceutical compositions containing them and their use as inhibitors of nicotinic cholinergic receptors

Info

Publication number: CA2383307A1
Application number: CA002383307A
Authority: CA
Inventors: Jared Miller Wagner; Gary Maurice Dull
Original assignee: Targacept Inc
Current assignee: Individual
Priority date: 1999-08-31
Filing date: 2000-06-30
Publication date: 2001-03-08
Also published as: AU5900700A; EP1212301A1; WO2001016107A1

Abstract

Patients susceptible to or suffering from conditions and disorders, such as central nervous system disorders, are treated by administering to a patient in need arylalkyloxyalkylamine and arylalkylthioalkylamine compounds, including arylmethoxyalkylamines and arylmethylthioalkylamines, such as pyridylmethoxyalkylamines and pyridylmethylthio alkylamines. Exemplary compounds include methyl(3-(3-pyridylmethoxy)propyl)amine, 3- pyridyl(pyrrolidin-2-ylmethoxy)methane, methyl(1-methyl-2-(3- pyridylmethoxy)ethyl)amine, (3-((3-pyridyl)methoxy)propyl)dimethylamine, (2- ((5-bromo-3-pyridyl)methoxy)ethyl)methylamine, methyl(2-((5-methoxy-3- pyridyl)methoxy)ethyl)amine, (2-((3-quinolyl)methoxy)ehtyl)methylamine, methyl(2-(pyrimidin-5-ylmethoxy)ethyl)amine, 3-((3- pyridyl)methoxy)quinuclidine, (3-pyridyl)quinuclidin-2-ylmethoxy)methane, (3 - pyridyl)(pyrrolidin-2-ylmethylthio)methane and (2-((3- pyridyl)methylthio)ethyl)methylamine.

Description

ARYLALKYLOXYALKYLAMINES AND ARYLALKYLTHIOALKYLAMINES, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND THEIR
USE AS INHIBITORS OF NICOTINIC CHOLINERGIC RECEPTORS
Background of the Invention 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. 330:811-815 (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. Pharmacol. 47:765 (1973). Release of norepinephrine by neurons upon administration of nicotine has been reported by Hall et al., Biochem.
Pharmacol.
21:1829 (1972). Release of serotonin by neurons upon administration of nicotine has been reported by Hery et al., Arch. Int. Pharmacodyn. Ther. 296:91 (1977).
Release of glutamate by neurons upon administration of nicotine has been reported by Toth et al., Neurochem Res. 17:265 (1992). In addition, nicotine reportedly potentiates the pharmacological behavior of certain pharmaceutical compositions used for the treatment of certain disorders. See, Sanberg et al., Pharmacol. Biochem. &
Behavior 46:303 (1993); Harsing et al., J. Neurochem. 59:48 (1993) and Hughes, Proceedings from Intl. Symp. Nic. S40 (1994). Furthermore, various other beneficial pharmacological effects of nicotine have been proposed. See, Decina et al., Biol.
Psychiatry 28:502 (1990); Wagner et al., Pharmacopsychiatry 21:301 (1988);
Pomerleau et al., Addictive Behaviors 9:265 (1984); Onaivi et al., Life Sci.
54(3):193 (1994); Tripathi et al., JPET 221: 91-96 (1982) and Hamon, Trends in Pharmacol.
Res. 15:36.
Various nicotinic compounds have been reported as being useful for treating a wide variety of conditions and disorders. See, for example, Williams et al.
DN&P
7(4):205-227 (1994), Arneric et al., CNSDrug Rev. 1(1):1-26 (1995), Arneric et al., Exp. Opin. Invest. Drugs 5(1):79-100 (1996), Bencherif et al., JPET 279:1413 (1996), Lippiello et al., JPET 279:1422 (1996), Damaj et al., Neuroscience (1997), Holladay et al., J. Med. Chem 40(28): 4169-4194 (1997), Bannon et al., Science 279: 77-(1998), PCT WO 94/08992, PCT WO 96/31475, PCT WO 96/40682, and U.S. Patent Nos. 5,583,140 to Bencherif et al., 5,597,919 to Dull et al. 5,604,231 to Smith et al.
and 5,852,041 to Cosford et al. Nicotinic compounds are reported as being particularly useful for treating a wide variety of Central Nervous System (CNS) disorders.
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. There are several 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). Several 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, schizophrenia and Tourette's syndrome.
It would be desirable to provide a useful method for the prevention and treatment of a condition or disorder by administering a nicotinic compound to a patient susceptible to or suffering from such a condition or disorder. It would be highly beneficial to provide individuals suffering from certain disorders (e.g., CNS
diseases) with interruption of the symptoms of those disorders by the administration of a pharmaceutical composition containing an active ingredient having nicotinic pharmacology and which has a beneficial effect (e.g., upon the functioning of the CNS), but which does not provide any significant associated side effects. It would be highly desirable to provide 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).
Summary of the Invention The present invention relates to arylalkyloxyalkylamine and arylalkylthioalkylamine compounds. Of particular interest are arylmethoxyalkylamines and arylmethylthioalkylamines, such as pyridylmethoxyalkylamines and pyridylmethylthioalkylamines. The present invention also relates to prodrug derivatives of the compounds of the present invention. Exemplary compounds of the present invention include methyl(3-(3-pyridylmethoxy)propyl)amine, 3-pyridyl(pyrrolidin-2-ylmethoxy)methane, methyl(1-methyl-2-(3-pyridylmethoxy)ethyl)amine, (3-((3-pyridyl)methoxy) propyl) dimethylamine, (2-((5-bromo-3-pyridyl)methoxy)ethyl)methylamine, methyl(2-((5-methoxy-3-pyridyl)methoxy)ethyl)amine, (2-((3-quinolyl)methoxy)ethyl) methylamine, methyl(2-(pyrimidin-5-ylmethoxy)ethyl)amine, 3-((3-pyridyl) methoxy)quinuclidine, (3-pyridyl)quinuclidin-2-ylmethoxy)methane, (3-pyridyl)(pyrrolidin-2-ylmethylthio)methane and (2-((3-pyridyl)methylthio) ethyl)methylamine.

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. 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, in another aspect, relates to a pharmaceutical composition comprising an effective amount of a compound of the present invention.
Such 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.
The pharmaceutical 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. In addition, 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 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 foregoing and other aspects of the present invention are explained in detail in the detailed description and examples set forth below.
Detailed Description of the Invention The compounds of the present invention include compounds of the formula:
X. %X ~B-(CEE~)m (CE~~En}~
Y,! Y.
X"
where B and Q are defined hereinafter; and each of X, X', X", Y' and Y" are individually nitrogen, nitrogen bonded to oxygen (e.g., an N-oxide or N-O
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). 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. Preferably, less than 4, more preferably less than 3, and most preferably 1 or 2 of X, X', X", Y' and Y" are nitrogen or nitrogen bonded to oxygen.
In addition, it is highly preferred that not more than one of X, X', X", Y' and Y" be nitrogen bonded to oxygen; and it is preferred that if one of those species is nitrogen bonded to oxygen, that species is X". Typically, 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. For certain other preferred compounds X" is C-NR'R", C-OR' or C-N02, typically C-NH2, C-NHCH3 or C-N(CH3)2, with C-NH2 being preferred. In certain preferred circumstances, both X' and X" are nitrogen.
Typically, X, Y' and Y" each are carbon 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" usually include hydrogen, halo (e.g., F, Cl, Br, or I), alkyl (e.g., lower straight chain or branched C1_g alkyl, but preferably methyl or ethyl), or NR'R", where in such case R' and R" are individually hydrogen or lower alkyl, including C1-Cg, preferably C~-C; alkyl. Typically, X is CH and Y' is CH.
However, in certain circumstances, it is desired that X and Y' both are CH, and Y" is carbon bonded to a non-hydrogen substituent species, such as -NR'R", -OR' or -N02, with -NHCH3 or -N(CH3)2 being preferred and with -NH2 being most preferred.
Adjacent substituents of X, X', Y", X" and Y' (when adjacent X, X', Y", X" and Y' each are carbon bonded to a respective substituent component) 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. In addition, m is an integer and n is an integer such that the sum of m plus n is 2, 3, 4 or 5, preferably is 2 or 3, and more preferably is 3.
The substituents of either X, X', X", Y' and Y" (when each respective X, X', X", Y' and Y" is carbon) 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, substituted arylalkyl, acyl, alkoxycarbonyl and aryloxycarbonyl 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 C1_g alkyl, but preferably methyl or ethyl), or NR'R", where in such case R' and R"
are individually hydrogen or lower alkyl, including C1-Cg, preferably C1-CS alkyl.
More specifically, X, X', X", Y' and Y", and most preferably X', can include N, N-O, C-H, C-F, C-Cl, C-Br, C-I, C-R', C-NR'R", C-CF3, C-OH, C-CN, C-N02, C-C2R', C-SH, C-SCH3, C-N3, C-S02CH3, C-OR', C-SR', C-C(=O)NR'R", C-NR'C(=O)R', C-C(=O)R', C-C(=O)OR', C(CH2)qOR', C-OC(=O)R', C-(CR'R")qOCH2C2R', C-(CR'R")qC(=O)R', C-O(CR'R")qC(=O)R', C(CR'R")qC(CHCH3)OR', C(CR'R")qNR'R", C-CH=CHR', COC(=O)NR'R" and C-NR'C(=O)OR' where R' and R" are individually hydrogen or lower alkyl (e.g., C1-Clo alkyl, preferably C~-CS
alkyl, and more preferably methyl, ethyl, isopropyl or isobutyl), an aromatic group-containing species or a substituted aromatic group-containing species, and q is an integer from 1 to 6. 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. Chem. 39:4065 (1996).
E, EI, EII and EII~ 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), preferably lower alkyl (e.g., straight chain or branched alkyl including C~-C8, preferably C1-C5, such as methyl, ethyl, or isopropyl) or halo substituted lower alkyl (e.g., straight chain or branched alkyl including C1-Cg, preferably C~-C5, such as trifluoromethyl or trichloromethyl).
Generally all of E, EI, Eti and EI~~ are hydrogen, or at least one of E, EI, EII and EIII is non-hydrogen and the remaining E, EI, EII and EIII are hydrogen. For example, when m is 2 and n is 0, E and EI each can be hydrogen; or when m is 2 and n is 1, E, EI, EI~
and EIn all can be hydrogen, or E, E' and EII can be hydrogen and Eiii can be methyl;
or when m is 1 and n is 2, EI, ELI and EII~ can be hydrogen and E can be methyl.
Typically, the selection of m, n, E, EI, EII and Ein is such that 0, 1 or 2, usually 0 or l, of the substituents designated as E, E', EII and EIU are non-hydrogen (e.g., substituents such as alkyl or halo-substituted alkyl). Depending upon the selection of E, EI, EIi arid EIIh compounds of the present invention have chiral centers, and the present invention relates to racemic mixtures of such compounds as well as enamiomeric compounds.
B is represented by the bridging species -(CEIVEv)~-BI-, where EIV and Ev individually represent those species previous described for E, EI, EII and Em;
j is 1 or 2, most preferably l; B is oxygen or sulfur, most preferably oxygen. EIV and Ev most preferably are hydrogen or lower alkyl, with at least one of Eiv and Ev being hydrogen, and most preferably all of EIV and Ev are hydrogen. Thus, for example, BI
can be -CH 2-O-.
Q is represented by N Z' Z"; where Z' and Z" individually represent hydrogen or lower alkyl (e.g., straight chain or branched alkyl including C1-C8, preferably C1-C5, such as methyl, ethyl, or isopropyl), substituted alkyl, acyl, alkoxycarbonyl, or aryloxycarbonyl; and preferably Z' is hydrogen or methyl, and Z" is hydrogen.
In addition, it is possible for 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).
As employed herein, "alkyl" refers to straight chain or branched alkyl radicals including C1-Cg, preferably C,-C5, 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 C1-Cg, preferably C~-CS 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 cycloalkyl" refers to cycloalkyl radicals further bearing one or more substituent groups as defined above; "aryl" refers to aromatic radicals having six to ten carbon atoms; "substituted aryl" refers to aryl radicals further bearing one or more substituent groups as defined above; "alkylaryl" refers to alkyl-substituted aryl radicals; "substituted alkylaryl" refers to alkylaryl radicals further bearing one or more substituent groups as defined above; "arylalkyl" refers to aryl-substituted alkyl radicals; "substituted arylalkyl" refers to arylalkyl radicals further bearing one or more substituent groups as defined above; "heterocyclyl" refers to saturated or unsaturated cyclic radicals containing one or more heteroatoms (e.g., O, N, S) as part of the ring structure and having two to seven carbon atoms in the ring;
"substituted heterocyclyl" refers to heterocyclyl radicals further bearing one or more substituent groups as defined above; "acyl" refers to straight chain or branched alkyl-or substituted alkyl-carbonyl radicals including C1-Cg, preferably C1-C5, such as formyl, acetyl, or propanoyl; "alkoxycarbonyl" refers to an alkyl or substituted alkyl radical attached to an O-carbonyl moiety; and "aryloxycarbonyl" refers to an aryl or substituted aryl radical attached to an O-carbonyl moiety.
Of particular interest are compounds of the formula set forth hereinbefore wherein preferably Z" is hydrogen, and Z' is hydrogen or methyl; preferably m is 1, 2 or 3, and n is 1; preferably each of E and E' is hydrogen, and preferably E' is hydrogen or methyl, but most preferably all of E and E' are hydrogen; preferably, each of E" and E"' is hydrogen, and preferably E"' is hydrogen or methyl; preferably Y" is carbon bonded to a substituent species, and most preferably, that substituent species is hydrogen, halo, NR'R" or OR"; preferably X" is nitrogen or carbon bonded to a substituent species such as NR'R", NOZ or OR", but most preferably is nitrogen;
preferably X' is nitrogen, but also preferably is carbon bonded to a substituent species such as hydrogen, R', halo, OR', NR'R", CN, CZR' or CHCHR'; preferably both R' and R" are hydrogen, but either or both of R' and R" can be methyl; preferably X and Y' each are carbon bonded to a substituent species, such as hydrogen; and preferably j is 0.
Representative compounds of the present invention include the following:
methyl(3-(phenylmethoxy)propyl)amine, methyl(3-((3-methoxyphenyl)methoxy)propyl)amine, methyl(3-((4-methoxyphenyl)methoxy)propyl)amine, 3-((3-(methylamine)propoxy)methyl)phenol, 4-((3-(methylamine)propoxy)methyl)phenol, methyl(3-(3-pyridylmethoxy)propyl)amine, methyl(2-(3-pyridylmethoxy)ethylamine, methyl( 1-methyl-3-(3-pyridylmethoxy)propyl)amine, methyl( 1-methyl-2-(3-pyridylmethoxy)ethyl)amine, (3-((5-bromo-3-pyridyl)methoxy)propyl)methylamine, methyl(3-((5-methoxy-3-pyridyl)methoxy)propyl)amine, (2-((5-bromo-3-pyridyl)methoxy)ethyl)methylamine, methyl(2-((5-methoxy-3-pyridyl)methoxy)ethyl)amine, (3-((5-bromo-3-pyridyl)methoxy)-1-methylpropyl)methylamine, methyl( 1-methyl-(3-((5-methoxy-3-pyridyl)methoxy)propyl)amine, (2-((5-bromo-3-pyridyl)methoxy)-isopropyl)methylamine, methyl(1-methyl-(2-((5-methoxy-3-pyridyl)methoxy)ethyl)amine, (2-((5-trifluoromethyl)-3-pyridyl)methoxy)ethyl)methylamine, (2-((5-trifluoromethoxy)-3-pyridyl)methoxy)ethyl)methylamine, (2-((5-difluoromethoxy)-3-pyridyl)methoxy)ethyl)methylamine, ( 1 R)-methyl( 1-methyl-3-(3-pyridylmethoxy)propyl)amine, (1 S)-methyl(1-methyl-3-(3-pyridylmethoxy)propyl)amine, ( 1 R)-methyl( 1-methyl-2-(3-pyridylmethoxy)ethyl)amine, (1 S)-methyl(1-methyl-2-(3-pyridylmethoxy)ethyl)amine, methyl((2-(2-methyl-3-pyridylmethoxy)ethyl)amine, methyl((2-(4-methyl-3-pyridylmethoxy)ethyl)amine, methyl((2-(6-methyl-3-pyridylmethoxy)ethyl)amine, methyl( 1-methyl-2-(2-methyl-3-pyridylmethoxy)ethyl)amine, methyl( 1-methyl-2-(4-methyl-3-pyridylmethoxy)ethyl)amine, methyl( 1-methyl-2-(6-methyl-3-pyridylmethoxy)ethyl)amine, (2-( 1-methylpyrrolidin-2-yl)ethoxy)-3-pyridylmethane, (2R)-(2-( 1-methylpyrrolidin-2-yl)ethoxy)-3-pyridylmethane, (2S)-(2-( 1-methylpyrrolidin-2-yl)ethoxy)-3-pyridylmethane, 3-pyridyl(pyrrolidin-2-ylmethoxy)methane, (2R)-3-pyridyl(pyrrolidin-2-ylmethoxy)methane, (2S)-3-pyridyl(pyrrolidin-2-ylmethoxy)methane, (( 1-(methylpyrrolidin-2-yl)methoxy)-3-pyridylmethane, (2R)-(( 1-(methylpyrrolidin-2-yl)methoxy)-3-pyridylmethane, (2S)-(( 1-(methylpyrrolidin-2-yl)methoxy)-3-pyridylmethane, ((2-azetidinyl)methoxy)(3-pyridyl)methane, (2R)-((2-azetidinyl)methoxy)(3-pyridyl)methane, (2S)-((2-azetidinyl)methoxy)(3-pyridyl)methane, N-methyl-((2-azetidinyl)methoxy)(3-pyridyl)methane, N-methyl-(2R)-((2-azetidinyl)methoxy)(3-pyridyl)methane, N-methyl-(2S)-((2-azetidinyl)methoxy)(3-pyridyl)methane, ((3-pyridyl)methoxy)pyrrolidine, (3R)-((3-pyridyl)methoxy)pyrrolidine, (3 S)-((3-pyridyl)methoxy)pyrrolidine, ((3-pyridyl)methoxy)-1-methylpyrrolidine, (3R)-((3-pyridyl)methoxy)-1-methylpyrrolidine, (3 S)-((3-pyridyl)methoxy)-1-methylpyrrolidine, (2-((3-quinolyl)methoxy)ethyl)methylamine, methyl(2-(pyrimidin-5-ylmethoxy)ethyl)amine, 3-((3-pyridyl)methoxy)quinuclidine, (3-pyridyl)quinuclidin-2-ylmethoxy)methane, to (3-((3-pyridyl)methoxy)propylamine, (2-((3-pyridyl)methoxy)ethylamine, (2-((5-methoxy-3-pyridyl)methoxy)ethylamine, 1-((3-pyridyl)methoxy)prop-2ylamine, 4-((3-pyridyl)methoxy)but-2-ylamine, 1-((3-pyridyl)methoxy)-2-methylprop-2-ylamine, (3-((3-pyridyl)methoxy)propyl)dimethylamine, (2-((3-pyridyl)methoxy)ethyl)dimethylamine, dimethyl(2-((5-methoxy-3-pyridyl)methoxy)ethyl)amine, (2-((3-pyridyl)methoxy)-isopropyl)dimethylamine, 3-((3-pyridyl)methoxy)-1-methylpropyl)dimethylamine, (2-((3-pyridyl)methoxy)-tert-butyl)methylamine, (2-((3-pyridyl)methoxy)-tent-butyl)dimethylamine, 4-((3-pyridyl)methoxy)piperidine, 4-((3-pyridyl)methoxy)-1-methylpiperidine, methyl(2-((6-methyl-3-pyridyl)methoxy)ethyl)amine, methyl(2-((6-methyl-5-methoxy-3-pyridyl)methoxy)ethyl)amine, (2-((3-pyridyl)methylthio)ethyl)methylamine, (3-pyridyl)(pyrrolidin-2-ylmethylthio)methane, (2R)-(3-pyridyl)(pyrrolidin-2-ylmethylthio)methane, (2S)-(3-pyridyl)(pyrrolidin-2-ylmethylthio)methane, (3-pyridyl)(( 1-methylpyrrolidin-2-yl)methylthio)methane, (2R)-(3-pyridyl)((1-methylpyrrolidin-2-yl)methylthio)methane, and (2S)-(3-pyridyl)(( 1-methylpyrrolidin-2-yl)methylthio)methane.
The manner in which certain arylmethoxyalkylamine compounds of the present invention are provided can vary. Certain phenylmethoxyalkylamine compounds can be prepared by the alkylation of certain phenylcarbinols (benzyl alcohols) with a 1,3-dihalopropane, such as 1,3-dichloropropane, 1,3-dibromopropane, 1,3-diiodopropane, or 1-chloro-3-iodopropane, which are commercially available from Aldrich Chemical Company, in the presence of a base (e.g., sodium hydride) in dry N,N-dimethylformamide. The resulting 3-halo-1-phenylmethoxypropane can be converted to a phenylmethoxyalkylamine, such as methyl(3-(phenylmethoxy)propyl)amine, by treatment with methylamine in a solvent, such as tetrahydrofuran or aqueous methanol. The manner in which certain 3-substituted-phenyl analogs of the present invention can be synthetically prepared is analogous to that described for the preparation of methyl(3-(phenylmethoxy)propyl)amine with the exception that 3-substituted-phenylcarbinols are employed rather than phenylcarbinol. For example, 3-methoxybenzyl alcohol (available from Aldrich Chemical Company) could be converted to methyl(3-((3-methoxyphenyl)methoxy)propyl)amine using the methodology described above.
Selective methyl ether cleavage could then be done to produce the phenolic compound, 3-((3-(methylamine)propoxy)methyl)phenol. The manner in which certain 4-substituted-phenyl analogs of the present invention can be synthetically prepared is analogous to that described for the preparation of methyl(3-((3-phenyl)methoxy)propyl)amine with the exception that 4-substituted-phenylcarbinols are employed rather than phenylcarbinol. For example, 4-methoxybenzyl alcohol (available from Aldrich Chemical Company) could be converted to methyl(3-((4-methoxyphenyl)methoxy)propyl)amine using the methodology described above.
Selective methyl ether cleavage could then be done to produce the phenolic compound, 4-((3-(methylamine)propoxy)methyl)phenol.
The manner in which compounds of the present invention are synthesized can vary. Certain pyridylmethoxyalkylamine compounds can be prepared by the alkylation of 3-pyridylcarbinol with a 1,3-dihalopropane such as 1,3-dichloropropane, 1,3-dibromopropane, 1,3-diiodopropane, or 1-chloro-3-iodopropane (commercially available from Aldrich Chemical Company) in the presence of a base, such as sodium hydride, in dry N,N-dimethylformamide. The resulting 3-halo-1-pyridylmethoxypropane, such as 3-chloro-1-(3-pyridylmethoxy)propane, can be converted to a pyridylmethoxyalkylamine, such as methyl(3-(3-pyridylmethoxy)propyl)amine by treatment with an excess of aqueous methylamine in a solvent such as tetrahydrofuran or methanol assisted by heating.
Alternatively, treatment of 3-chloro-1-(3-pyridylmethoxy)propane with an excess of aqueous ammonia in methanol, assisted by heating, affords the primary amine, 3-((3-pyridyl)methoxy)propylamine. Alternatively, treatment of 3-chloro-1-(3-pyridylmethoxy)propane with an excess of aqueous dimethylamine in methanol, assisted by heating, affords the tertiary amine, (3-((3-pyridyl)methoxy)propyl) dimethylamine.
Other compounds of the present invention such as methyl(2-(3-pyridylmethoxy)ethylamine can be provided in a similar manner. For example, 3-pyridylcarbinol can be alkylated with the p-toluenesulfonate ester of N-(tert-butoxycarbonyl)butoxycarbonyl-N-methylethanolamine using sodium hydride in N,N-dimethyformamide. The protecting group of the resulting N-butoxycarbonyl pyridylmethoxyethanolamine compound can be removed by treatment with a strong acid such as trifluoroacetic acid to produce methyl(2-(3-pyridylmethoxy)ethylamine.
The requisite side chain, the tosylate of N-butoxycarbonyl protected N-methylethanolamine can be prepared according to the procedures set forth in J.
Christoffers et al., Liebigs Ann.lRecl. (7):1353-1358(1997).
Certain pyridylmethoxyalkylamines that possess a branched side chain, such as methyl(1-methyl-3-(3-pyridylmethoxy)propyl)amine can be prepared by alkylating 3-pyridylcarbinol with a 1,3-dihalobutane, such as 1,3-dibromobutane, in the presence of a base such as sodium hydride in dry N,N-dimethylformamide. Treatment of the resulting monobromo intermediate with methylamine in tetrahydrofuran or aqueous methanol provides a compound having a methyl branched side chain--methyl(1-methyl-3-(3-pyridylmethoxy)propyl)amine. In a similar manner 3-pyridylcarbinol can be alkylated with 1,3-dibromopropane and the resulting intermediate can be aminated with methylamine to produce the shorter chain compound--methyl(1-methyl-2-(3-pyridylmethoxy)ethyl)amine.
Chiral starting materials are available for the synthesis of the pure enantiomers of the branched chain pyridylmethoxyalkylamines, such as (1R)- and (1S)-methyl(1-methyl-3-(3-pyridylmethoxy)propyl)amine. One approach can be carried out using either methyl (R)-(-)-3-hydroxybutyrate or the (+)-enantiomer, (S)-(+)-3-hydroxybutyrate, both of which are available from Aldrich Chemical Company.
For example, (R)-(-)-3-hydroxybutyrate can be converted to (R)-(-)-3-tetrahydropyranyloxybutyl bromide, using the procedures set forth in Yuasa et al., J.
Chem. Soc., Perk. Trans. 1(5): 465 (1996). Alkylation of 3-pyridylcarbinol with (R)-(-)-3-tetrahydropyranyloxybutyl bromide using sodium hydride in N,N-dimethylformamide produces the tetrahydropyranyl ether of 4-(3-pyridyloxy)butan-(2R)-ol. Removal of the tetrahydropyranyl protecting group of that compound using p-toluenesulfonic acid monohydrate in methanol affords 4-(3-pyridyloxy)butan-(2R)-ol. The resulting chiral alcohol can be elaborated to the chiral pyridymethoxyalkylamine, (1S)-methyl(1-methyl-3-(3-pyridylmethoxy)propyl)amine, using a two-step sequence involving tosylation and methylamine displacement of the intermediate tosylate. In a similar process, (S)-(+)-3-hydroxybutyrate can be converted to (S)-(+)-3-tetrahydropyranyloxybutyl bromide using the procedures set forth in Sakai et al., Agric. Biol. Chem. 50(6): 1621 (1986). This protected bromo alcohol can be converted to the corresponding chiral pyridylmethoxyalkylamine, (1R)-methyl(1-methyl-3-(3-pyridylmethoxy)propyl)amine, using a sequence involving alkylation of 3-pyridylcarbinol, removal of the tetrahydropyranyl group, tosylation, and methylamine displacement of the intermediate tosylate.
Other chiral starting materials are available for the synthesis of the pure enantiomers of the branched chain pyridylmethoxyalkylamines, such as ( 1 R)-and (1S)-methyl(1-methyl-2-(3-pyridylmethoxy)ethyl)amine. One approach can be performed using (2R)- and (2S)-1-p-toluenesulfonyloxy-N-methyl-N-(tert-butoxycarbonyl)-2-propanamine to alkylate 3-pyridylcarbinol using sodium hydride in N,N-dimethylformamide. The resulting butoxycarbonyl-protected amine can be deprotected using trifluoroacetic acid or hydrochloric acid to produce ( 1 R)-and ( 1 S)-methyl(1-methyl-2-(3-pyridylmethoxy)ethyl)amine. The requisite tosylate esters of the chiral aminopropanols can be prepared from either N-methyl-L-alanine or N-methyl-D-alanine (both available from Sigma Chemical Company) using methodology similar to that reported by Schlessinger et al., Tetrahedron Lett.
28:2083-2086 (1987). Thus, either N-methyl-L-alanine or N-methyl-D-alanine can be reacted sequentially with lithium aluminum hydride (to give the corresponding N-methyl aminopropanols) di-tert-butyl dicarbonate (to protect the amino group), and p-toluenesulfonyl chloride (to esterify the alcohol).
Certain pyridylmethoxyalklylamines that possess a branched side chain, such as methyl(1-methyl-3-(3-pyridylmethoxy)propyl)amine, can be prepared by alkylating 3-pyridylcarbinol with a protected 3-hydroxy-1-halobutane, such as 3-[(tert-butyl)dimethylsilyloxy]-1-bromobutane (prepared according to the procedures set forth in Gerlach et al., Helv. Chim. Acta. 60(8): 2860 (1977)), thereby producing a (tert-butyl)dimethylsilyl protected 4-(3-pyridylmethoxy)butan-2-ol. The (tert-butyl)dimethylsilyl group can be removed by treatment with ammonium fluoride or aqueous acetic acid to give 4-(3-pyridylmethoxy)butan-2-ol. Mesylation or tosylation of that compound with methanesulfonyl chloride in triethylamine or p-toluenesulfonyl chloride in pyridine, followed by treatment with methylamine in tetrahydrofuran or aqueous methanol, provides a compound having a methyl branched side chain (e.g., methyl( 1-methyl-3-(3-pyridylmethoxy)propyl)amine).

Alternatively, pyridylmethoxyalkylamines possessing a branched side chain, such as ( 1-methyl-3-(3-pyridyloxy)propyl)methylamine, can be synthesized by alkylating 3-pyridylcarbinol with a protected 1-iodo-3-butanone, namely 2-methyl-2-(2-iodoethyl)-1,3-dioxolane, with is prepared according to the procedures set forth in Stowell et al., J. Org. Chem. 48: 5381 (1983). The resulting ketal can be deprotected by treatment with aqueous acetic acid or p-toluenesulfonic acid in methanol to yield 4-(3-pyridylmethoxy)butan-2-one. Reductive amination of the resulting ketone using methylamine and sodium cyanoborohydride according to the methodology set forth in Borch, Org. Syn. 52: 124 (1972) provides (1-methyl-3-(3-pyridylmethoxy)propyl) methylamine. Alternatively, the intermediate, 4-(3-pyridylmethoxy)butan-2-one, can be reduced with sodium borohydride to yield an alcohol, 4-(3-pyridylmethoxy)butan-2-0l. Mesylation or tosylation of that alcohol, followed by mesylation or tosylation displacement using methylamine, provides the branched chain pyridylmethoxyalkylamine, methyl(1-methyl-3-(3-pyridyloxy)propyl)amine.
The manner in which certain 5-substituted-3-pyridylmethoxyalkylamine compounds of the present invention can be synthetically produced can vary. For example, 5-bromo-3-pyridylmethoxy-containing compounds can be prepared using a combination of synthetic techniques known to those skilled in the art. Thus, 5-bromo-substituted analogs of methyl(3-(3-pyridylmethoxy)propyl)amine, methyl(2-(3-pyridylmethoxy)ethyl)amine, methyl(1-methyl-3-(3-pyridylmethoxy)propyl)amine, methyl(1-methyl-2-(3-pyridylmethoxy)ethyl)amine and other compounds of the present invention can all be prepared starting from 5-bromo-3-hydroxymethylpyridine, which in turn can be prepared from 5-bromonicotinic acid (available from Aldrich Chemical Company). Thus, 5-bromonicotinic acid is converted to the mixed anhydride with ethyl chloroformate and reduced with lithium aluminum hydride in tetrahydrofuran at -78°C to afford 5-bromo-3-hydroxymethylpyridine as reported by Ashimori et al., Chem. Pharm. Bull. 3 8:

(1990). Alternatively, 5-bromonicotinic acid is esterified in the presence of sulfuric acid and ethanol, and the intermediate ester is reduced with sodium borohydride to yield 5-bromo-3-hydroxymethylpyridine, according to the techniques reported in C. F.
Nutaitis et al., Org. Prep. And Proc. Int. 24: 143 (1992). The 5-bromo-3-hydroxymethylpyridine can then be reacted with a number of different alkylating agents such as the p-toluenesulfonate ester of N-(tert-butoxycarbonyl)-N-methylethanolamine and others as previously described to provide the 5-bromo-pyridylmethoxy compounds such as (3-((5-bromo-3-pyridyl)methoxy)propyl) methylamine, (2-((5-bromo-3-pyridyl)methoxy)ethyl)methylamine, (3-((5-bromo-3-pyridyl)methoxy)-1-methylpropyl)methylamine, and (2-((5-bromo-3-pyridyl) methoxy)-isopropyl)methylamine.
Certain C-S-substituted pyridyl compounds of the present invention bearing a trifluoromethy l functionality at the C-5-pyridyl position can be prepared by a variety of methods. In one approach 5-trifluoromethyl-3-pyridinemethanol can be alkylated with the p-toluenesulfonate ester of N-(tert-butoxycarbonyl)(butoxycarbonyl)-N-methylethanolamine using sodium hydride in N,N-dimethyformamide. The protecting group of the resulting N-butoxycarbonyl-pyridinylmethoxyethanolamine compound can be removed by treatment with a strong acid such as trifluoroacetic acid to produce (2-((5-trifluoromethyl)-3-pyridyl)methoxy)ethyl)methylamine. The requisite side chain, the tosylate of -butoxycarbonyl-protected N-methylethanolamine can be prepared according to the procedures set forth in J. Christoffers et al., Liebigs Ann.lRecl. (7):1353-1358 (1997). The required S-trifluoromethyl-3-pyridylcarbinol can be prepared from 5-trifluoromethyl-3-pyridinecarboxylic acid using methodology described by Ashimori et al., Chem. Pharm. Bull. 38: 2446 (1990).
A number of analogs substituted at C-5 of the pyridine ring in the aforementioned compounds can be prepared from the corresponding 5-bromo compound. For example, 5-amino substituted compounds and 5-alkylamino substituted compounds can be prepared from the corresponding 5-bromo compound using the general techniques described in C. Zwart, et al., Recueil Trav.
Chim. Pays-Bas 74:1062 (1955). 5-Alkoxy substituted analogs can be prepared from the corresponding 5-bromo compound using the general techniques described in D.L.
Comins, et al., J. Org. Chem. 55:69 (1990) and H.J. Den Hertog et al., Recl.
Trav.
Chim. Pays-Bas 74:1171 (1955). 5-Ethynyl-substituted compounds can be prepared from the appropriate 5-bromo compound using the general techniques described in N.D.P. Cosford et al., J. Med. Chem. 39:3235 (1996). The 5-ethynyl analogs can be converted into the corresponding 5-ethenyl, and subsequently the corresponding ethyl analogs by successive catalytic hydrogenation reactions using techniques known to those skilled in the art of organic synthesis. 5-Azido substituted analogs can be prepared from the corresponding 5-bromo compound by reaction with sodium azide in dimethylformamide. 5-Alkylthio substituted analogs can be prepared from the corresponding 5-bromo compound by reaction with an appropriate alkylmercaptan in the presence of sodium using techniques known to those skilled in the art of organic synthesis.
A number of 5-substituted analogs of the aforementioned compounds can be synthesized from the corresponding 5-amino compounds via the 5-diazonium intermediate. Among the other 5-substituted analogs that can be produced from diazonium intermediates are: 5-hydroxy analogs, 5-fluoro analogs, 5-chloro analogs, 5-bromo analogs, 5-iodo analogs, 5-cyano analogs, and 5-mercapto analogs.
These compounds can be synthesized using the general techniques set forth in Zwart et al., supra. For example, 5-hydroxy substituted analogs can be prepared from the reaction of the corresponding 5-diazonium intermediate with water. 5-Fluoro substituted analogs can be prepared from the reaction of the 5-diazonium intermediate with fluoroboric acid. 5-Chloro substituted analogs can be prepared from the reaction of the 5-amino compound with sodium nitrite and hydrochloric acid in the presence of copper chloride. 5-Cyano substituted analogs can be prepared from the reaction of the corresponding 5-diazonium intermediate with potassium copper cyanide. 5-Amino substituted analogs can also be converted to the corresponding 5-nitro analogs by reaction with fuming sulfuric acid and peroxide, according to the general techniques described in Y. Morisawa, J. Med. Chem. 20:129 (1977) for converting an aminopyridine to a nitropyridine. Appropriate 5-diazonium intermediates can also be used for the synthesis of mercapto-substituted analogs using the general techniques described in J.M. Hoffman et al., J. Med. Chem. 36:953 (1993). The 5-mercapto substituted analogs can in turn be converted to the 5-alkylthio substituted analogs by reaction with sodium hydride and an appropriate alkyl bromide. 5-Acylamido analogs of the aforementioned compounds can be prepared by reaction of the corresponding 5-amino compounds with an appropriate acid anhydride or acid chloride using techniques known to those skilled in the art of organic synthesis.
5-hydroxy substituted analogs of the aforementioned compounds can be used to prepare corresponding 5-alkanoyloxy substituted compounds by reaction with the appropriate acid, acid chloride, or acid anhydride.
5-cyano substituted analogs of the aforementioned compounds can be hydrolyzed using techniques known to those skilled in the art of organic synthesis to afford the corresponding 5-carboxamido substituted compounds. Further hydrolysis results in formation of the corresponding 5-carboxylic acid substituted analogs.

Reduction of the 5-cyano substituted analogs with lithium aluminum hydride yields the corresponding 5-aminomethyl analog.
5-acyl substituted analogs can be prepared from corresponding 5-carboxylic acid substituted analogs by reaction with an appropriate alkyl lithium.
5-carboxylic acid substituted analogs of the aforementioned compounds can be converted to the corresponding ester by reaction with an appropriate alcohol.
Compounds with an ester group at the 5-pyridyl position can be reduced with sodium borohydride or lithium aluminum hydride to produce the corresponding 5-hydroxymethyl substituted analog. These analogs in turn can be converted to compounds bearing an ether moiety at the 5-pyridyl position by reaction with sodium hydride and an appropriate alkyl halide, using conventional techniques.
Alternatively, the 5-hydroxymethyl substituted analogs can be reacted with tosyl chloride to provide the corresponding 5-tosyloxymethyl analog. The 5-carboxylic acid substituted analogs can also be converted to the corresponding 5-alkylaminoacyl analog by reaction with an appropriate alkylamine and thionyl chloride, using techniques known to those skilled in the art. 5-Acyl substituted analogs of the aforementioned compounds can be prepared from the reaction of the appropriate S-carboxylic acid substituted compound with an appropriate alkyl lithium salt, using techniques known to those skilled in the art of organic synthesis.
5-tosyloxymethyl substituted analogs of the aforementioned compounds can be converted to the corresponding 5-methyl substituted compounds by reduction with lithium aluminum hydride. Tosyloxymethyl substituted analogs of the aforementioned compounds can also be used to produce 5-alkyl substituted compounds via reaction with an alkyl lithium salt using techniques known to those skilled in the art of organic synthesis.
5-hydroxy substituted analogs of the aforementioned compounds can be used to prepare 5-N-alkylcarbamoyloxy substituted compounds by reaction with N-alkylisocyanates. 5-Amino substituted analogs of the aforementioned compounds can be used to prepare 5-N-alkoxycarboxamido substituted compounds by reaction with alkyl chloroformate esters, using techniques known to those skilled in the art of organic synthesis.
Analogous chemistries to the ones described hereinbefore for the preparation of the 5-substituted analogs of the pyridylmethoxyalkylamine compounds can be devised for the synthesis of the 2-, 4-, and 6-substituted compounds utilizing the 1s appropriate 2-, 4-, and 6-substituted-3-hydroxymethylpyridine. For example, 2-methylnicotinic acid and 6-methylnicotinic acid (both commercially available from Aldrich Chemical Company) can be converted to the 2- and 6-methyl-3-hydroxymethylpyridines using the previously described methods of C. F.
Nutaitis et al., Org. Prep. And Proc. Int. 24: 143 ( 1992) and Ashimori et al., Chem.
Pharm. Bull.
38: 2446 (1990). These in turn can be used to prepare 2- and 6-methyl-3-pyridylmethoxyalkylamines such as methyl((2-(2-methyl-3-pyridylmethoxy)ethyl) amine and methyl((2-(6-methyl-3-pyridylmethoxy)ethyl)amine and methyl(1-methyl-2-(2-methyl-3-pyridylmethoxy)ethyl)amine and methyl(1-methyl-2-(6-methyl-3-pyridylmethoxy)ethyl)amine using the methodology previously described. The 4-substituted-3-pyridylmethoxyalkylamine-type compounds, such as methyl((2-(4-methyl-3-pyridylmethoxy)ethyl)amine and methyl(1-methyl-2-(4-methyl-3-pyridylmethoxy)ethyl)amine can be prepared starting from 4-methyl-3-hydroxymethylpyridine. The 4-methyl-3-hydroxymethylpyridine can be prepared starting from methyl 4-methylnicotinate using methods similar to that described by C.
F. Nutaitis et al., Org. Prep. And Proc. Int. 24: 143 (1992). The synthesis of methyl 4-methylnicotinate has been described by J. M. Bobbitt, et al., J. Org. Chem.
25:560 ( 1960).
Compounds of the present invention such as pyridylmethoxyalkyl-cycloalkylamines, such as (2-(1-methylpyrrolidin-2-yl)ethoxy)-3-pyridylmethane can be synthetically produced by a variety of methods. In one approach, 2-(2-chloroethyl)-1-methylpyrrolidine (available from Aldrich Chemical Company) can be used to alkylate 3-pyridylcarbinol using sodium hydride in tetrahydrofuran or N,N-dimethylformamide. In some cases it may be necessary to convert the commercially available chloro compound to the bromo or iodo compound using sodium bromide or sodium iodide in acetone or 2-butanone and using this intermediate immediately. The resulting racemic product, (2-( 1-methylpyrrolidin-2-yl)ethoxy)-3-pyridylmethane can then be resolved into the corresponding enantiomers using an optically active acid such as di-benzoyl-L-tartaric acid or di-p-toluoyl-L-tartaric acid or other chiral acids to give the (2R)- and (2S)- (2-(1-methylpyrrolidin-2-yl)ethoxy)-3-pyridylmethane compounds.
Compounds of the present invention which possess a pyridylmethoxy ether functionality linked to a chiral azacyclic fragment, such as (2R)- and (2S)-3-pyridyl(pyrrolidin-2-ylmethoxy)methane and (2R)- and (2S)-((1-(methylpyrrolidin-2-yl)methoxy)-3-pyridylmethane can be prepared by a number of synthetic methods.
By one approach, the p-toluenesulfonate ester of (2S)-1-(tert-butoxycarbonyl)-pyrrolidinemethanol can be used to alkylate 3-pyridylcarbinol using sodium hydride in tetrahydrofuran or N,N-dimethylformamide. The butoxylcarbonyl-protecting group can be removed with strong acid such as trifluoroacetic acid or aqueous hydrochloric acid to give (2S)-3-pyridyl(pyrrolidin-2-ylmethoxy)methane. The required p-toluenesulfonate ester of (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinemethanol can be prepared by treating (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinemethanol with p-toluenesulfonyl chloride in pyridine. (2S)-2-pyrrolidinemethanol is available from Aldrich Chemical Company and can be butoxycarbonyl-protected by treatment with di-tert-butyl dicarbonate in tetrahydrofuran, followed by treatment with p-toluenesulfonyl chloride. The corresponding enantiomer, (2R)-3-pyridyl(pyrrolidin-2-ylmethoxy)methane can be prepared in an analogous manner starting from the p-toluenesulfonate ester of (2R)-1-(tert-butoxycarbonyl)-2-pyrrolidinemethanol. (2R)-2-Pyrrolidinemethanol is available from Aldrich Chemical Company and can be butoxycarbonyl-protected by treatment with di-tert-butyl dicarbonate in tetrahydrofuran, followed by conversion to its tosylate. It should be mentioned that (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinemethanol and (2R)-1-(tert-butoxycarbonyl)-2-pyrrolidinemethanol can be prepared according to the methods of D. A. Evans et al., J. Am. Chem. Soc.
101: 371-378 (1979) and B. D. Harris et al., Heterocycles 24: 1045-1060 (1986) starting from commercially available (Aldrich Chemical Company) D-proline and L-proline.
(2R)-and (2S)-3-pyridyl(pyrrolidin-2-ylmethoxy)methane can be N-methylated.
Methylation methods similar to those described by M. A. Abreo et al., J. Med.
Chem.
39: 817-825 (1996), employing aqueous formaldehyde and sodium cyanoborohydride can be used to produce (2R)- and (2S)-((1-(methylpyrrolidin-2-yl)methoxy)-3-pyridylmethane.
Compounds of the present invention which possess an arylmethoxy ether functionality with a chiral azacyclic fragment, such as ((2-azetidinyl)methoxy)(3-pyridyl)methane-type compounds can be prepared by a variety of synthetic methods.
In one synthetic approach, the p-toluenesulfonate ester of a 3-pyridylcarbinol-type compound can be used to alkylate (2S)-1-(tert-butoxycarbonyl)-2-azetidinemethanol in the presence of a base such as sodium hydride in a solvent such as tetrahydrofuran or N,N-dimethylformamide. The tert-butoxycarbonyl group can be removed with a strong acid such as trifluoroacetic acid or hydrochloric acid affording (2S)-((2-azetidinyl)methoxy)(3-pyridyl)methane-type compounds. The requisite nonracemic compound, (2S)-1-tert-butoxycarbonyl)-2-azetidinemethanol can be prepared from (2S)-2-azetidinecarboxylic acid (commercially available from Aldrich Chemical Company) using the method of M. A. Abreo et al., J. Med. Chem. 39: 817-825 (1996).
The enantiomeric azetidinyl compound, (2R)-((2-azetidinyl)methoxy)(3-pyridyl)methane can be prepared in an analogous way by coupling the p-toluenesulfonate ester of a 3-pyridylcarbinol-type compound with (2R)-1-(benzyloxycarbonyl)-2-azetidinemethanol, followed by treatment with base, such as methanolic potassium hydroxide to remove the benzyloxycarbonyl protecting group.
The required (2R)-1-(benzyloxycarbonyl)-2-azetidinemethanol can be prepared from D-methionine using the methodology of M. A. Abreo et al., J. Med. Chem. 39:

825 (1996). Compounds of the present invention such as the N-methyl analogs of (2R)-((2-azetidinyl)methoxy)(3-pyridyl)methane and its enantiomeric compound, (2S)-((2-azetidinyl)methoxy)(3-pyridyl)methane can be N-methylated employing aqueous formaldehyde and sodium cyanoborohydride as described by M. A. Abreo et al., J. Med. Chem. 39: 817-825 (1996) to give N-methyl-(2R)-((2-azetidinyl) methoxy)(3-pyridyl)methane and N-methyl-(2S)-((2-azetidinyl)methoxy)(3-pyridyl)methane, respectively.
Compounds of the present invention that are arylmethoxyethers and possess a cyclic amine functionality can be prepared from an arylcarbinol, such as 3-pyridylcarbinol and hydroxylated cyclic amines using the general coupling method of O. Mitsunobu, Synthesis: 1 (1981). For example, (3S)-((3-pyridyl)methoxy) pyrrolidine can be synthesized by the coupling of 3-pyridylcarbinol and (3R)-N-(tert-butoxycarbonyl)-3-hydroxypyrrolidine in the presence of triphenylphosphine and diethyl azodicarboxylate in tetrahydrofuran. The resulting intermediate can then be treated with a strong acid such as trifluoroacetic acid to remove the tert-butoxycarbonyl protecting group to produce (3S)-((3-pyridyl)methoxy)pyrrolidine.
The latter compound can be N-methylated to afford (3S)-((3-pyridyl)methoxy)-1-methylpyrrolidine. Methylation methods employing aqueous formaldehyde and sodium cyanoborohydride as described by M. A. Abreo et al., J. Med. Chem. 39:

825 (1996) can be used. The N-protected starting material, (3R)-N-(tert-butoxycarbonyl)-3-hydroxypyrrolidine can be prepared from (R)-(+)-3-pyrrolidinol (commercially available from Aldrich Chemical Company) according to the general techniques described by P. G. Houghton et al., J. Chem. Soc. Perkin Trans I
(Issue 13): 1421-1424 (1993). The corresponding enantiomers, (3R)-((3-pyridyl)methoxy) pyrrolidine and (3R)-((3-pyridyl)methoxy)-1-methylpyrrolidine can be prepared in a similar manner starting from (S)-(-)-3-pyrrolidinol hydrochloride (commercially available from Aldrich Chemical Company).
Using this approach, other compounds containing arylmethoxy ether and azacyclic functionality can be prepared. Thus, commercially available 3-quinuclidinol (available from Aldrich Chemical Company) can be converted to its p-toluenesulfonate and used to alkylate 3-pyridylcarbinol in the presence of sodium hydride and N,N-dimethylformamide to afford 3-((3-pyridyl)methoxy)quinuclidine.
Certain fused polycyclic aromatics can be used as starting materials to prepare compounds of the present invention which possess fused rings. For example, 3-quinolinecarbinol can be alkylated with the p-toluenesulfonate ester of N-(tert-butoxycarbonyl)( butoxycarbonyl)-N-methylethanolamine using sodium hydride in N,N-dimethyformamide. The protecting group of the resulting N- butoxycarbonyl pyrimidinylmethoxyethanolamine compound can be removed by treatment with a strong acid such as trifluoroacetic acid to produce (2-((3-quinolyl)methoxy)ethyl) methylamine. The requisite side chain, the tosylate of N- Butoxycarbonyl -protected N-methylethanolamine can be prepared according to the procedures set forth in J.
Christoffers et al., LiebigsAnn.lRecl. (7):1353-1358(1997). The required 3-quinolinecarbinol can be prepared by the sodium borohydride reduction of 3-quinolinecarboxaldehyde (available from Aldrich Chemical Company).
Certain heteroaromatics can be used as starting materials to prepare compounds of the present invention. For example, 5-pyrimidinecarbinol can be alkylated with the p-toluenesulfonate ester of N-(tert-butoxycarbonyl) (butoxycarbonyl)-N-methylethanolamine using sodium hydride in N,N-dimethyformamide. The protecting group of the resulting N-butoxycarbonyl-pyrimidinylmethoxyethanolamine compound can be removed by treatment with a strong acid such as trifluoroacetic acid to produce methyl(2-(pyrimidin-5-ylmethoxy)ethyl)amine. The requisite side chain, the tosylate of N-butoxycarbonyl-protected N-methylethanolamine can be prepared according to the procedures set forth in J. Christoffers et al., Liebigs Ann.lRecl. (7):1353-1358 (1997). The required 5-pyrimidinecarbinol can be prepared from 5-pyrimidinecarboxylic acid using methodology similar to that described by C. F. Nutaitis et al., Org. Prep. And Proc.
Int., 24: 143 (1992) or from ethyl 5-pyrimidinecarboxylate using methodolgy similar to that described by Ashimori et al., Chem. Pharm. Bull. 3 8: 2446 ( 1990).
The 5-pyrimidinecarboxylic acid can be prepared from 5-bromopyrimidine by lithiation and treatment with carbon dioxide as described by W. S. Messer, Jr. et al., Bioorg. Med Chem. Lett. 2(8):781-786 (1992). The ethyl 5-pyrimidinecarboxylate can be prepared from 5-bromopyrimidine using a palladium-catalyzed alkoxycarbonylation as described by R. A. Head et al., Tetrahedron Lett. 25(15):5939-5942 (1984).
The manner in which compounds of the present invention are synthesized can vary. Certain pyridylmethylthioalkylamine compounds can be prepared by the alkylation of 3-pyridinemethanethiol with the p-toluenesulfonate ester of N-(tert-butoxycarbonyl)-N-methylethanolamine using sodium hydride in N,N-dimethyformamide. The protecting group of the resulting N-butoxycarbonyl-pyridylmethylthioethanolamine compound can be removed by treatment with a strong acid such as trifluoroacetic acid to produce (2-((3-pyridyl)methylthio)ethyl) methylamine. The requisite side chain, the tosylate of N-butoxycarbonyl -protected N-methylethanolamine can be prepared according to the procedures set forth in J.
Christoffers et al., Liebigs Ann.lRecl. (7):1353-1358 (1997). The 3-pyridinemethanethiol can be prepared from 3-(chloromethyl)pyridine hydrochloride (available from Aldrich Chemical Company) by heating with thiourea, followed by hydrolysis of the intermediate isothiourea with concentrated aqueous sodium hydroxide according to the methodology of T. J. Brown et al., J. Med. Chem.
35(20):3613-3624 (1992).
In a similar manner, compounds of the present invention which possess a pyridylmethylthio ether functionality linked to a chiral azacyclic fragment, such as (2R)- and (2S)-3-pyridyl(pyrrolidin-2-ylmethoxy)methane and (2R)- and (2S)-((1-(methylpyrrolidin-2-yl)methoxy)-3-pyridylmethane can be prepared by a number of synthetic methods. By one approach, the p-toluenesulfonate ester of (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinemethanol (the synthesis of which has been previously described) can be used to alkylate 3-pyridinemethanethiol using sodium hydride in tetrahydrofuran or N,N-dimethylformamide. The Butoxycarbonyl-protecting group can be removed with strong acid such as trifluoroacetic acid or aqueous hydrochloric acid to give (2S)-(3-pyridyl)(pyrrolidin-2-ylmethylthio)methane. The latter compound can be N-methylated employing aqueous formaldehyde and sodium cyanoborohydride as using methodology similar to that described by M.A. Abreo et al., J. Med. Chem. 39: 817-825 (1996) to produce (2S)-(3-pyridyl)((1-methylpyrrolidin-2-yl)methylthio)methane. In a similar manner, by using the p-toluenesulfonate ester of (2R)-1-(tert-butoxycarbonyl)-2-pyrrolidinemethanol (the synthesis of which has been previously described), 3-pyridinemethanethiol can be alklyated and further elaborated to give (2R)-(3-pyridyl)(pyrrolidin-2-ylmethylthio) methane and (2R)-(3-pyridyl)((1-methylpyrrolidin-2-yl)methylthio)methane.
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. For example, 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). Examples of 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 amino acid such as lysine salt and arginine salt. 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. DN&P 7(4):205-227 (1994), Arneric et al., CNS Drug Rev. 1 ( 1 ):1-26 (1995), Arneric et al., Exp. Opin.
Invest. Drugs 5(1):79-100 (1996), Bencherif et al., JPET 279:1413 (1996), Lippiello et al., JPET 279:1422 (1996), Damaj et al., Neuroscience (1997), Holladay et al., J.
Med. Chem 40(28): 4169-4194 (1997), Bannon et al., Science 279: 77-80 (1998), PCT
WO 94/08992, PCT WO 96/31475, and U.S. Patent Nos. 5,583,140 to Bencherif et al., 5,597,919 to Dull et al., and 5,604,231 to Smith et al the disclosures of which are incorporated herein by reference in their entirety. 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, 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 posed as a result of administration of the pharmaceutical composition. In certain circumstances, 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).
Although it is possible to administer the compounds in the form of a bulk active chemical, it is preferred to present 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.
For example, the compounds can be administered in the form of a tablet, a hard gelatin capsule or as a time release capsule. As another example, 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. In addition, 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, while minimizing the effects upon muscle-type receptor subtypes. Other suitable methods for administering the compounds of the present invention are described in U.S. Patent No. 5,604,231 to Smith et al.
The appropriate dose of the compound is that amount effective to prevent occurrence of the symptoms of the disorder or to treat some symptoms of the disorder from which the patient suffers. By "effective amount", "therapeutic amount" or "effective dose" is meant that amount sufficient to elicit the desired pharmacological or therapeutic effects, thus resulting in effective prevention or treatment of the disorder. Thus, when treating a CNS 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 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. For human patients, 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.
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 ug/kg of patient weight, but frequently between about 10 ug to less than 100 ug/kg of patient weight. For compounds of the present invention that do not induce effects on muscle type nicotinic receptors at low concentrations, the effective dose is less than 5 mg/kg of patient weight; and often such compounds are administered in an amount from ug to Iess 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.
For human patients, 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. For human patients, 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. In addition, 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.
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, such 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 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 2.5 uM, sometimes are less than about 1 uM, 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, 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 neurotransmitters. Generally, 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. By this is meant that a particular dose of compound resulting in prevention and/or treatment of a CNS disorder, is essentially ineffective in eliciting activation of certain ganglia-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. This selectivity of certain compounds of the present invention against those ganglia-type receptors responsible for cardiovascular side effects is demonstrated by a lack of the ability of those compounds to activate nicotinic function of adrenal chromaffin tissue at concentrations greater 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, an amelioration to some degree of the reoccurrence of CNS disorders. However, such effective amounts of those compounds are not sufficient to elicit any appreciable side effects, as demonstrated by increased effects relating to skeletal muscle. As such, 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. Preferably, 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. Exemplary of such 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. Thus, pharmaceutical 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.
In such situations, 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. For the treatment of such conditions or disorders, 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 1 Ou/kg of patient weight. 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.
For human patients, 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. For human patients, 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.
In addition, 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. 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.
The following examples are provided to illustrate the present invention, and should not be construed as limiting the scope thereof. In these examples, all parts and percentages are by weight, unless otherwise noted. Reaction yields are reported in mole percentages.
Examples Example 1 Synthesis of Methyl(3-(3-pyridylmethoxy)propyl)amine 3-Chloro-1-(3-pyridylmethoxy)propane Under a nitrogen atmosphere, a solution of 3-pyridylcarbinol (3.00 g, 27.5 mmol) in N, N-dimethylformamide (DMF) (10 mL) was added drop-wise over 5 min to a cold (0-5°C), stirring slurry of sodium hydride (0.99 g of an 80%
dispersion in mineral oil, 33.0 mmol) in DMF (15 mL). The mixture was allowed to stir and warm to ambient temperature over 1 h. Next, 1-chloro-3-iodopropane (6.732 g, 53.0 mmol) was added drop-wise over 5 min. The resulting dark-brown mixture was stirred at ambient temperature for 4 h. Water (30 mL) was added, followed by saturated NaCI

solution (25 mL), and the mixture was extracted with ether (4 x 50 mL). The combined ether extracts were dried (Na2S04), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 0.360 g (7.1 %) of an oil.
Methyl(3-(3-pyridylmethoxy)propyl)amine The 3-chloro-1-(3-pyridylmethoxy)propane (0.360 g, 1.96 mmol) was dissolved in methanol (25 mL) and added to a 40 wt% aqueous solution of methylamine (50 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100°C (oil bath temperature) for 4 h.
After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCI
solution (25 mL) was added to the residue, the pH was adjusted to 1 with 10%
HCl solution and the solution was extracted with CHCl3 (3 x 20 mL) to remove impurities.
The pH of the aqueous phase was adjusted to 6, and impurities were extracted with ether (3 x 15 mL). The aqueous layer was basified to pH 10 with 10% NaOH
solution and extracted with chloroform (4 x 15 mL). The combined chloroform extracts were dried (Na2S04), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 52.8 mg (15.0%) of a dark brown oil.
Example 2 Determination of Binding to Relevant Receptor Sites 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 ICSO 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. The compound of Example 1 exhibits a Ki of 2272 nM.

Example 3 Neurotransmitter Release From Brain Synaptosomes Neurotransmitter release was measured using techniques similar to those previously published (Bencherif M, et al.:. JPET 279: 1413-1421, 1996).
Rat brain synaptosomes were prepared as follows: Female Sprague Dawley rats (100-200 g) were killed by decapitation after anesthesia with 70% COZ.
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 NaCI, 1.2 mM KH2P04, 2.4 mM KCI, 3.2 mM CaCl2, 1.2 mM MgS04, 25 mM HEPES,1 mM Ascorbic acid, 0.01 mM
pargyline HCl 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 3H
DA, 20 L
3H NE, 10 uL 3H 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 11-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 re-establish 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. The compound of Example 1 exhibits an Emu of 42 percent.
Example 4 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 (Emu) was determined as a percentage of the maximal activation induced by (S)-(-)-nicotine.

Reported Em~ values represent the amount released relative to (S)-(-)-nicotine on a percentage basis. Low Emu 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. Thus, there is provided 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 compound of Example 1 exhibits an Emu of 21 percent.
Example 5 Determination of Interaction with Ganglion Receptors The determination of the interaction of the compounds with ganglionic 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 (Emu) was determined as a percentage of the maximal activation induced by (S)-(-)-nicotine.
Reported Em~ values represent the amount released relative to (S)-(-)-nicotine on a percentage basis. Low Em~ 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.
Thus, there is provided 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 certain undesirable side effects to any significant degree. The compound of Example 1 exhibits an Em~ of 2 percent.

Claims

That Which Is Claimed Is:

1. A compound of the formula:
where each of X, X', X", Y' and Y" are individually nitrogen, nitrogen bonded to oxygen or carbon bonded to a substituent species characterized as having a sigma m value between about -0.3 and about 0.75; 1 or 2 of X, X', X", Y' and Y" are nitrogen or nitrogen bonded to oxygen; not more than 1 of X, X', X", Y' and Y" is nitrogen bonded to oxygen; m is an integer and n is an integer such that the sum of m plus n is 2, 3, 4 or 5; E, E I, E II and E III individually represent hydrogen, lower alkyl or halo substituted lower alkyl; B is a bridging species-(CE IV E V)j-BI-, where E IV
and E V
individually represent hydrogen, lower alkyl or halo substituted lower alkyl, j is 1 or 2, and B is oxygen or sulfur; and Q is N Z' Z", where Z' and Z" individually represent hydrogen or lower alkyl, or associated carbon and nitrogen atoms of Q combine to form a monocyclic ring structure.

2. The compound of Claim 1 wherein X" is represented by nitrogen bonded to oxygen.

3. The compound of Claim 1 wherein X' is CH, CBr or COR', where R' are benzyl, methyl, ethyl, isopropyl, isobutyl, tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

4. The compound of Claim 1 wherein X" is nitrogen.

5. The compound of Claim 1 wherein X" is C-NR'R", C-OR' or C-NO2, where R' and R" are benzyl, methyl, ethyl, isopropyl, isobutyl, tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

6. The compound of Claim 1 wherein X" is C-NH2, C-NHCH3 or C-N(CH3)2.

7. The compound of Claim 1 wherein both X' and X" are nitrogen.

8. The compound of Claim 1 wherein X, Y' and Y" each are carbon bonded to hydrogen.

9. The compound of Claim 1 wherein X, Y' and Y" each are carbon bonded to halo, lower alkyl or NR'R", where R' and R" are individually hydrogen or lower alkyl.

10. The compound of Claim 1 wherein X" is nitrogen; and X, X', Y' and Y" are carbon bonded to a substitutent species.

11. The compound of Claim 1 wherein B is oxygen.

12. The compound of Claim 1 wherein j is 1.

13. The compound of Claim 1 wherein B I is -CH2-O-.

14. The compound of Claim 1 wherein E IV and E V each are hydrogen or lower alkyl.

15. The compound of Claim 1 wherein all of E IV and E V is hydrogen.

16. The compound of Claim 1 wherein at least one of E, E I, E II and E III is non-hydrogen and the remaining E, E I, E II and E III are hydrogen.

17. The compound of Claim 1 wherein all of E, E I, E II and E III are hydrogen.

18. The compound of Claim 1 wherein m is 2 and n is 1, and E, E I and E II
are hydrogen and E III is methyl.

19. The compound of Claim 1 wherein Q is NHCH3.

20. The compound of Claim 1 wherein Q is N(CH3)2.

21. A pharmaceutical composition comprising a compound of the formula:

where each of X, X', X", Y' and Y" are individually nitrogen, nitrogen bonded to oxygen or carbon bonded to a substituent species characterized as having a sigma m value between about -0.3 and about 0.75; 1 or 2 of X, X', X", Y' and Y" are nitrogen or nitrogen bonded to oxygen; not more than 1 of X, X', X", Y' and Y" is nitrogen bonded to oxygen; m is an integer and n is an integer such that the sum of m plus n is 2, 3, 4 or 5; E, E I, E II and E III individually represent hydrogen, lower alkyl or halo substituted lower alkyl; B is a bridging species -(CE IV E V)j-B I-, where E
IV and E V
individually represent hydrogen, lower alkyl or halo substituted lower alkyl, j is 1 or 2, and B is oxygen or sulfur; and Q is N Z' Z", where Z' and Z" individually represent hydrogen or lower alkyl, or associated carbon and nitrogen atoms of Q combine to form a monocyclic ring structure.

22. The pharmaceutical compound according to Claim 21, wherein X' is CH, CBr or COR', where R' are benzyl, methyl, ethyl, isopropyl, isobutyl, tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

23. The pharmaceutical compound according to Claim 21, wherein X" is C-NR'R", C-OR' or C-NO2, where R' and R" are benzyl, methyl, ethyl, isopropyl, isobutyl, tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

24. The pharmaceutical compound according to Claim 21, wherein X" is C-NH2, C-NHCH3 or C-N(CH3)2.

25. The pharmaceutical compound according to Claim 21, wherein B I is -CH2-O-.

26. The pharmaceutical compound according to Claim 21, wherein Q is NHCH3.

27. The pharmaceutical compound according to Claim 21, wherein Q is N(CH3)2.

28. A method for treating a central nervous system disorder, said method comprising administering an effective amount of a compound having the formula:
where each of X, X', X", Y' and Y" are individually nitrogen, nitrogen bonded to oxygen or carbon bonded to a substituent species characterized as having a sigma m value between about -0.3 and about 0.75; 1 or 2 of X, X', X", Y' and Y" are nitrogen or nitrogen bonded to oxygen; not more than 1 of X, X', X", Y' and Y" is nitrogen bonded to oxygen; m is an integer and n is an integer such that the sum of m plus n is 2, 3, 4 or 5; E, E I, E II and E III individually represent hydrogen, lower alkyl or halo substituted lower alkyl; B is a bridging species -(CE IV E V)j-B I-, where E
IV and E V
individually represent hydrogen, lower alkyl or halo substituted lower alkyl, j is 1 or 2, and B is oxygen or sulfur; and Q is N Z' Z", where Z' and Z" individually represent hydrogen or lower alkyl, or associated carbon and nitrogen atoms of Q combine to form a monocyclic ring structure.

29. The method according to Claim 28, wherein X' is CH, CBr or COR', where R' are benzyl, methyl, ethyl, isopropyl, isobutyl, tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

30. The method according to Claim 28, wherein X" is C-NR'R", C-OR' or C-NO2, where R' and R" are benzyl, methyl, ethyl, isopropyl, isobutyl, tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

31. The method according to Claim 28, wherein X" is C-NH2, C-NHCH3 or C-N(CH3)2.

32. The method according to Claim 28, wherein B I is -CH2-O-.

33. The method according to Claim 28, wherein Q is NHCH3.

34. The method according to Claim 28, wherein Q is N(CH3)2.