Pharmaceutical compositions and methods for use

#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., 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), Japan Patent 7061940 to Kozo et al., PCT WO 94/08992, PCT WO 96/31475, PCT WO 96/40682, PCT WO 97/11072, U.S. patent application Ser. No. 09/210,113, filed on Dec. 11, 1998 and Ser. No. 09/327,141, filed Jun. 7, 1999, and U.S. Pat. No. 5,583,140 to Bencherif et al., U.S. Pat. No. 5,597,919 to Dull et al. U.S. Pat. No. 5,604,231 to Smith et al., U.S. Pat. Nos. 5,817,679, 5,852,041 to Cosford et al. and U.S. Pat. No. 6,060,473 to Shen et al. Nicotinic compounds are reported as being particularly useful for treating a wide variety of Central Nervous System (CNS) disorders.

#The compounds of the present invention include compounds having the structure represented by the formula: In the structure, Cy represents a suitable 5 or 6 member aromatic ring, and exemplary ring systems are set forth hereinafter. B′ represents a suitable bridging moiety, such as a bridging moiety having a length of two carbon atoms (e.g., an ethylenic or acetylenic moiety). When the bridging moiety is ethylenic, the compound can have a Z (cis) or E (trans) form, but preferably the E (trans) form. Q is (CH2)m, Q′ is (CH2)p, and Q″ is (CH2)q where m is 1, 2, 3 or 4 (preferably 1, 2 or 3), p is 0,1, 2 or 3 (preferably 0, 1 or 2), and q is 0, 1 or 2 (preferably 0 or 1). In addition, the values of m, p and q are selected such that the azabicyclic ring contains 6 members, or 7 members, or 8 members, or 9 members. Zj represents a suitable non-hydrogen substituent group, and exemplary groups are set forth hereinafter. In addition, j is an integer from 0 to 5, preferably 0 or 1. At the point of attachment of B′ to the azabicyclic ring system, the stereochemistry of the compound can be either endo or exo. Z′ is either hydrogen or lower alkyl (C1-8), and Z′ can be positioned at any location within the azabicyclic ring.

#For representative compounds of the present invention, Cy includes the following: Cy can be a five member heteroaromatic ring, such as one of those described in U.S. Pat. No. 6,022,868 to Olesen et al., the disclosure of which is incorporated by reference in its entirety, which may bear suitable non-hydrogen substituent species as set forth hereinafter. Thus, as used herein, the terms “5 or 6 member aromatic ring” and “five or six member heteroaromatic ring” refer to aromatic ring systems wherein the structure of the ring is composed of either 5 or 6 members (e.g., carbon atoms, or carbon and nitrogen atoms); and those 5 or 6 member rings can possess suitable substituent moieties. Each of X, X′ and X″ 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′ and X″ 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. In addition, A and A′ individually are either hydrogen or suitable non-hydrogen substituent species; and typically those substituent species 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, 1 or 2 of X, X′ and X″ are nitrogen or nitrogen bonded to oxygen. In addition, it is highly preferred that not more than one of X, X′ and X″ 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, CR′, or COR′, where R′ (defined hereinafter) preferably is benzyl, methyl, ethyl, isopropyl, isobutyl, tertiary butyl, cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl), or an unsubstituted or substituted, five or six membered, aromatic or heteroaromatic ring. Most preferably, X″ is nitrogen. For certain other preferred compounds X″ is C—NR′R″, COR′ or CNO2, typically CNH2, CNHCH3 or CN(CH3)2, with CNH2 being preferred. In certain preferred circumstances, both X′ and X″ are nitrogen. Typically, X is carbon bonded to a substituent species, and it is typical that X is carbon bonded to a substituent species such as hydrogen. Adjacent substituents of X, X′, A′, X″ and A (when adjacent X, X′ and X″ 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.

#The substituents of either X, X′ or X″ (when each respective X, X′ and X″ is carbon), the substituents A, A′ and Z, and the substituents attached to five member heteroaromatic ring representatives of unit Cy can include alkyl, substituted alkyl, alkenyl, substituted alkenyl, heterocyclyl, substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, halo (e.g., F, Cl, Br, or I), —NR′R″, —CF3, —OH, —CN, —NO2, —C2R′, —SH, —SCH3, —N3, —SO2CH3, —OR′, —SR′, —C(═O)NR′R″, —NR′C(═O)R′, —C(═O)R′, —C(═O)OR′, —(CH2)xOR′, —OC(═O)R′, —(CR′R″)xOCH2C2R′, —(CR′R″)xC(═O)R′, —O(CR′R″)xC(═O)R′, —C2(CR′R″)xOR′, —(CR′R″)xNR′R″, —OC(═O)NR′R″ and —NR′C(═O)OR′ where R′ and R″ are individually hydrogen or lower alkyl (e.g., straight chain or branched alkyl including C1-C8, preferably C1-C5, such as methyl, ethyl, or isopropyl), an aromatic group-containing species or a substituted aromatic group-containing species, and x 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 functionality. 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, hydroxyl, alkoxy, halo, or amino substituents). Other representative aromatic ring systems are set forth in Gibson et al., J. Med. Chem. 39: 4065 (1996). The substituents of X, X′ and X″, the substituents A and A′, and the substituents attached to five member heteroaromatic ring representatives of unit Cy individually can include hydrogen.