WO2006023630A2 - The use of n-aryl diazaspiracyclic compounds in the treatment of addiction - Google Patents

Abstract

Compounds, compositions and methods for treating drug addiction, nicotine addiction, and/or obesity are disclosed. The compounds are N-aryl diazaspirocyclic compounds, bridged analogs of N-heteraryl diazaspirocyclic compounds, or prodrugs or metabolites of these compounds. The aryl group can be a five- or six-membered heterocyclic ring (heteroaryl). The compounds are effective at inhibiting dopamine production and/or secretion, and accordingly are effective at inhibiting the physiological 'reward' process that is associated with ingestion of nicotine and/or illicit drugs. The compounds and compositions can be administered in effective amounts to inhibit dopamine release, wihout resulting in appreciable adverse side effects (e.g., side effects such as significant increases in blood pressure and heart rate, significant negative effects upon the gastro-intestinal tract, and significant effects upon skeletal muscle).

Description

THE USE OF N-ARYL DIAZASPIRACYCLIC COMPOUNDS

IN THE TREATMENT OF ADDICTION

This application claims benefit of U.S. Provisional Patent Application

No. 60/603,479, filed August 20, 2004.

Field of the Invention

The present invention relates to nicotinic antagonists, particularly antagonists

and partial antagonists that have more potent antagonistic activity with respect to

dopamine release than at the α₄β₂ receptor, pharmaceutical compositions including

these compounds, and the use of these compounds in the treatment of addiction,

including smoking addiction, addiction to narcotics and other drugs, and obesity that

occurs following drug cessation.

Background of the Invention

Smoking addiction is a complex phenomenon believed to involve cognition

enhancement, psychological conditioning, stress adaptation, reinforcing properties and relief from withdrawal. Consequently, providing therapeutic treatment for smoking

addiction is an extremely difficult challenge.

The nicotine in tobacco may be partially responsible for the difficulty some

individuals face in overcoming smoking addiction. Numerous methods have been

developed to assist with smoking cessation, including reducing consumption over

time, and providing alternate delivery vehicles for nicotine, including gums and skin

patches.

Neuronal nicotinic acetylcholine receptors (nAChRs) are widely distributed

throughout the central and peripheral nervous systems including several regions of the

brain. The two most prominent CNS subtypes of nAChRs are α₄β₂ andα₇. However,

the predominance of a particular nicotinic receptor subtype in the brain does not necessarily reflect its functional importance. For example, although of lesser

prevalence in the brain, the α₃β₂-containing receptor subtypes are believed to be at

least partially responsible for mediating dopamine release, based on studies in which

antagonists of these receptors (i.e., bungarotoxin and α-conoxin partially inhibited

dopamine release (Dworsin et al, J. Pharm. Ex. Titer. 10(10):1561-1581 (2000)).

Accordingly, it is believed that there are multiple receptor subtypes involved in

nicotine-evoked dopamine release in striatum. Nicotine antagonists active against one

or more of these receptors one are well known in the art, and are described, for

example, in Dwoskin et al., J. Pharm. Ex. Titer. 298(2):395 (2001).

One pharmaceutical approach to causing smoking cessation involves blocking

the nicotine signal from tobacco with another agent, such as Bupropion. At low

micromolar concentrations, Buproprion non-competitively inhibits α₃β₂, α₄β₂ and α₇ nAChRs, and is now marketed as an aid to smoking cessation. Other non-competitive

nicotinic antagonists have also been considered as an approach to smoking cessation.

One theory is that the nicotine antagonists block the reinforcing signal from nicotine

associated with smoking addiction. Mecamylamine, an antagonist at both α₄β₂ and α₇

receptors, is an example of a nicotine antagonist that has been used, alone and in

combination with nicotine replacement therapy, to promote smoking cessation.

In spite of the known methods for treating smoking addiction, there remains an

interest in new methods and pharmaceutical compositions for treating smoking

addiction.

It is also difficult to overcome addiction to other compounds, including

opiates, cocaine, and other ilicit drugs. Mecamylamine and other nicotinic

compounds have been proposed for use in overcoming addiction to these illicit drugs

(see for example, Reid, Neuropsychopharmacology, 20(3):297-307 (1999); Campiani et al., J Med Chem, 46:3822-39 (2003) (discussing the role of dopamine

D3/D2 receptors), Chi and de Wit H , Alcoholism: Clinical and Experimental

Research, 27:780-786 (2003); PiUa et al., Nature, 400:371-5 (1999) (discussing the

role of partial dopamine D3 receptor agonists); Reid et al.,

Neuropsychopharmacology, 20:297-307 (1999); Slemmer et al., J. Pharmacol. Exp.

Ther. 295:321-327 (2000); Vorel et al., J. Neurosci., 22:9595-603 (2002) (discussing

how dopamine D3 receptor antagonism inhibits cocaine-seeking and cocaine-

enhanced brain reward in rats), and Zachariou et al., Neuropsychopharmacology,

24:576-589 (2001), the contents of each of which are hereby incorporated by reference

in their entirety) .

Weight gain is often associated with drug cessation (see, for example, Dwoskin et al., "Recent developments in neuronal nicotinic acetylcholine receptor antagonists," Exp. Opin. Ther. Patents 10:1561-1581 (2000). It would be desirable to provide methods and compositions for inhibiting this weight gain.

Dopamine release is believed to be associated with the physiological "reward" associated with consumption of these substances of addiction. Modulation of

dopamine release has been proposed for use in treating addiction. Modulation of the α₄β₂ receptor is one way to modulate dopamine release, and may be at least part of the

mechanism by which mecamylamine is effective at treating drug addiction. However, it may be desirable in some instances to modulate dopamine release without

antagonizing α₄β₂ activity. Thus, the availability of a variety of ligands that bind with

high affinity and selectivity for receptors other than α₄β₂, and that modulate dopamine

release, are of interest.

Further, a limitation of some nicotinic compounds is that they are associated

with various undesirable side effects, for example, by stimulating muscle and ganglionic receptors. It would be desirable to have compounds, compositions and

methods for preventing and/or treating drug addiction, promoting smoking cessation,

and inhibiting obesity associated with overcoming addiction, where the compounds

exhibit pharmacology with a beneficial effect (e.g., inhibition of dopamine secretion),

but without significant associated side effects.

The present invention provides such compounds, compositions and methods.

Summary of the Invention

Compounds, pharmaceutical compositions, and methods of treating nicotine

addiction, drug addiction, and/or obesity associated with drug and/or nicotine

cessation are disclosed. The compounds function by decreasing dopamine release,

without significantly affecting the α₄β₂ receptor. Decreased dopamine release results

in a decreased physiological "reward" associated with administration of nicotine or

illicit drugs, and thus helps overcome addiction.

The compounds are N-aryl diazaspirocyclic compounds, bridged analogs of N-

heteroaryl diazaspirocyclic compounds, or prodrugs or metabolites of these

compounds. The aryl group can be a five- or six-membered heterocyclic ring

(heteroaryl). Examples of the N-aryl diazaspiocyclic compounds include 7-(3-

pyridyl)-l,7-diazaspiro[4.4]nonane and l-(3-pyridyl)-l,7-diazaspiro[4.4]nonane.

Examples of bridged analogs of N-heteroaryl diazaspirocyclic compounds include 1'-

(3 -pyridyl)-spiro [ 1 -azabicyclo [2.2.1 ]heptane-2,3 '-pyrrolidine] .

The compounds and compositions can be used to treat and/or prevent a wide

variety of conditions or disorders, particularly those disorders characterized by

dysfunction of nicotinic cholinergic neurotransmission, including disorders involving

neuromodulation of neurotransmitter release, such as dopamine release. CNS

disorders, which are characterized by an alteration in normal neurotransmitter release, are another example of disorders that can be treated and/or prevented. The

compounds and compositions can also be used to alleviate pain. The methods involve

administering to a subject an effective amount of an N-aryl diazaspirocyclic compound, bridged analog of an N-heteroaryl diazaspirocyclic compound, or prodrug

or metabolite thereof to alleviate the particular disorder.

The pharmaceutical compositions include an effective amount of the

compounds described herein. When employed in effective amounts, the compounds

can cause a decrease in dopamine release in a subject, without demonstrating

stimulant sensitization properties. The pharmaceutical compositions provide therapeutic benefit to individuals

suffering from such disorders and exhibiting clinical manifestations of such disorders.

The pharmaceutical compositions are believed to be safe and effective with regards to

treating these 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

Compounds, pharmaceutical compositions including the compounds, and

methods of preparation and use thereof are disclosed.

The following definitions will be useful in understanding the metes and

bounds of the invention as described herein.

As used herein, "alkyl" refers to straight chain or branched alkyl radicals

including C₁-C₈, preferably C₁-C₅, such as methyl, ethyl, or isopropyl; "substituted

alkyl" refers to alkyl radicals further bearing one or more substituent groups such as

hydroxy, alkoxy, aryloxy, mercapto, aryl, heterocyclo, halo, amino, carboxyl,

carbamyl, cyano, and the like; "alkenyl" refers to straight chain or branched hydrocarbon radicals including C₁-C₈, preferably C₁-C₅ 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, non-aromatic, 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.

As used herein, an "agonist" is a substance that stimulates its binding partner,

typically a receptor. Stimulation is defined in the context of the particular assay, or

may be apparent in the literature from a discussion herein that makes a comparison to

a factor or substance that is accepted as an "agonist" or an "antagonist" of the

particular binding partner under substantially similar circumstances as appreciated by

those of skill in the art. Stimulation may be defined with respect to an increase in a

particular effect or function that is induced by interaction of the agonist or partial

agonist with a binding partner and can include allosteric effects. As used herein, an "antagonist" is a substance that inhibits its binding partner,

typically a receptor. Inhibition is defined in the context of the particular assay, or may

be apparent in the literature from a discussion herein that makes a comparison to a

factor or substance that is accepted as an "agonist" or an "antagonist" of the particular

binding partner under substantially similar circumstances as appreciated by those of

skill in the art. Inhibition may be defined with respect to a decrease in a particular

effect or function that is induced by interaction of the antagonist with a binding

partner, and can include allosteric effects.

As used herein, a "partial agonist" is a substance that provides a level of

stimulation to its binding partner that is intermediate between that of a full or

complete antagonist and an agonist defined by any accepted standard for agonist

activity.

As used herein, a "partial antagonist" is a substance that provides a level of

inhibition to its binding partner that is intermediate between that of a full or complete

antagonist and an inactive ligand.

It will be recognized that stimulation, and hence, inhibition is defined

intrinsically for any substance or category of substances to be defined as agonists,

antagonists, or partial agonists. As used herein, "intrinsic activity", or "efficacy,"

relates to some measure of biological effectiveness of the binding partner complex.

With regard to receptor pharmacology, the context in which intrinsic activity or

efficacy should be defined will depend on the context of the binding partner (e.g.,

receptor/ligand) complex and the consideration of an activity relevant to a particular

biological outcome. For example, in some circumstances, intrinsic activity may vary

depending on the particular second messenger system involved. See Hoyer, D. and

Boddeke, H., Trends Pharmacol Sd. 14(7):270-5 (1993). Where such contextually specific evaluations are relevant, and how they might be relevant in the context of the

present invention, will be apparent to one of ordinary skill in the art.

As used herein, neurotransmitters whose release is mediated by the compounds

described herein include, but are not limited to, acetylcholine, dopamine,

norepinephrine, serotonin, and glutamate, and the compounds described herein

function as agonists or partial agonists at one or more of the Central Nervous System

(CNS) nAChRs.

I. Compounds

The compounds are N-aryl diazaspirocyclic compounds, bridged analogs of N-

heteroaryl diazaspirocyclic compounds, prodrugs or metabolites of these compounds,

and pharmaceutically acceptable salts thereof.

The compounds can bind to, and modulate nicotinic acetylcholine receptors in

the patient's brain in the cortex, hippocampus, thalamus, basal ganglia, and spinal cord. When so bound, the compounds express nicotinic pharmacology and, in

particular, can antagonize the release of dopamine at effective concentrations that do

not significantly antagonize the α₄β₂ receptor.

Receptor binding constants provide a measure of the ability of the compound

to bind to half of the relevant receptor sites of certain brain cells of the patient. See,

for example, Cheng et al., Biochem. Pharmacol. 22:3099 (1973). The receptor

binding constants of the compounds described herein, at one or more receptors other

than the α₄β₂ receptor that mediate dopamine release, generally exceed about 0.1 nM,

often exceed about 1 nM, and frequently exceed about 10 nM, and are often less than

about 100 μM, often less than about 10 μM and frequently less than about 5 μM.

Preferred compounds generally have receptor binding constants less than about 2.5

μM, sometimes are less than about 1 μM, and can be less than about 100 nM. Preferably, the compounds can cross the blood-brain barrier, and thus enter the

central nervous system of the patient. Log P values provide a measure of the ability of

a compound to pass across a diffusion barrier, such as a biological membrane,

including the blood brain barrier. See, for example, Hansch et al., J. Med. Chem.llύ

(1968). Typical log P values for the compounds described herein are generally greater

than about -0.5, often are greater than about 0, and frequently are greater than about

0.5, and are typically less than about 3, often are less than about 2, and frequently are

less than about 1.

In one embodiment, the compounds have the structure represented by Formula

1 below:

Formula 1

In the formula, Q¹ is (CZ₂)_U, Q^π is (CZ₂)_V, Q^m is (CZ₂)_W, and Q^w is (CZ₂)_X

where u, v, w and x are individually 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3. R is

hydrogen, lower alkyl, acyl, alkoxycarbonyl or aryloxycarbonyl, preferably hydrogen

or lower alkyl. When the value of u is 0, the value of v must be greater than 0, and, in

the case of Formula 1, when the value of w is 0, the value of x must be greater than 0.

In addition, the values of u, v, w and x are selected such that the diazaspirocyclic ring

contains 7, 8, 9, 10 or 11 members, preferably 8, 9 or 10 members.

Formula 2

In another embodiment, the compounds are represented by Formula 2, above.

In Formula 2 Q¹ is (CZ₂)_U, Q^π is (CZ₂)_V, Q^m is (CZ₂)_W, Q^w is (CZ₂)_X, Q^v is(CZ₂)_y and

Q^VI is (CZ₂)_Z where u, v, w, x, y and z are individually 0, 1, 2, 3 or 4, preferably 0, 1

or 2. The values of u, v, w, x, y and z are selected such that the bridged diazaspirocyclic ring contains 8, 9, 10, 11, 12 or 13 members, preferably 9, 10, 11 or

12 members. In the case of Formula 2, the values w and x can be simultaneously 0.

In addition, R is hydrogen, lower alkyl, acyl, alkoxycarbonyl or aryloxycarbonyl,

preferably hydrogen or lower alkyl.

Each individual Z represents either hydrogen or a suitable non-hydrogen substituent species (e.g., alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,

heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, alkylaryl, substituted

alkylaryl, arylalkyl or substituted arylalkyl; but preferably lower alkyl or aryl).

In either formula, Cy represents a suitable five- or six-membered

heteroaromatic ring. In one embodiment, Cy is a six membered ring of the formula:

Each of X, X', X", X"' and X"" is individually nitrogen, nitrogen bonded to

oxygen (e.g., an N-oxide or N-O functionality) or carbon bonded to a substituent

species. No more than three of X, X', X", X"' and X"" are nitrogen or nitrogen bonded to oxygen, and it is preferred that only one or two of X, X', X", X'" and X"" be nitrogen

or nitrogen bonded to oxygen. In addition, it is highly preferred that not more than

one of X, X', 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'". Most

preferably, X'" is nitrogen. In certain preferred circumstances, both X' and X'" are

nitrogen. Typically, X, X" and X"" are carbon bonded to a substituent species, and it

is typical that the substituent species at X, X" and X"" are hydrogen. For certain other preferred compounds where X"¹ is carbon bonded to a substituent species such as

hydrogen, X and X" are both nitrogen. In certain other preferred compounds where X'

is carbon bonded to a substituent species such as hydrogen, X and X" are both

nitrogen.

In another embodiment, Cy is a five 5-membered heteroaromatic ring, such as pyrrole, furan, thiophene, isoxazole, isothiazole, oxazole, thiazole, pyrazole, 1,2,4-

oxadiazole, 1,3,4-oxadiazole and 1,2,4-triazole. Other examples of such rings are

described in U.S. Patent No. 6,022,868 to Olesen et al., the contents of which are

incorporated herein by reference in their entirety. One way of depicting Cy is as

follows:

where Y and Y" are individually nitrogen, nitrogen bonded to a substituent species,

oxygen, sulfur or carbon bonded to a substituent species, and Y' and Y¹" are nitrogen

or carbon bonded to a substituent species. The dashed lines indicate that the bonds

(between Y and Y' and between Y¹ and Y") can be either single or double bonds.

However, when the bond between Y and Y' is a single bond, the bond between Y' and Y" must be a double bond and vice versa. In cases in which Y or Y" is oxygen or

sulfur, only one of Y and Y" is either oxygen or sulfur. At least one of Y, Y', Y" and

Y'" must be oxygen, sulfur, nitrogen or nitrogen bonded to a substituent species. It is

preferred that no more than three of Y, Y', Y" and Y'" be oxygen, sulfur, nitrogen or

nitrogen bonded to a substituent species. It is further preferred that at least one, but no

more than three, of Y, Y', Y" and Y'" be nitrogen.

Substituent species associated with any of X, X, X", X¹", X^tm, Y, Y', Y" and

Y'" (when any is carbon bonded to a substituent species or nitrogen bonded to a

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; as determined in accordance with Hansch et

al, Chem. Rev. 91:165 (1991).

Examples of suitable substituent species associated with any of X, X, X", X'", X"", Y, Y', Y" and Y'" (when any is carbon bonded to a substituent species or nitrogen

bonded to a substituent species), include hydrogen, 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), -OR¹, -NR¹R", -CF₃, -CN, -NO₂, -C₂R¹, -SR¹, -N₃, -

C(=O)NR'R", -NR'C(=O) R", -C(=O)R', -CO=O)OR¹, -OC(^O)R¹, -O(CR'R")_rC(=O)R^!,

-O(CR¹R")_rNR"C(=O)R', -0(CR¹R¹O_rNR¹¹SO₂R, -OC(=O)NR'R", -NR'C(=O)O R", -

SO₂R¹, -SO₂NR¹R¹¹, and -NR¹SO₂R", where R and R" are individually hydrogen, lower

alkyl (e.g., straight chain or branched alkyl including C₁-C₈, preferably C₁-C₅, such as

methyl, ethyl, or isopropyl), cycloalkyl, heterocyclyl, aryl, or arylalkyl (such as

benzyl), and r is an integer from 1 to 6. R¹ and R" can combine to form a cyclic

functionality. The term "substituted" as applied to alkyl, aryl, cycloalkyl and the like refers to the substituents described above, starting with halo and ending with -

NR¹SO₂R".

Examples of suitable Cy groups include 3-pyridyl (unsubstituted or substituted

in the 5 and/or 6 position(s) with any of the aforementioned substituents), 5-

pyrimidinyl (unsubstituted or substituted in the 2 position with any of the

aforementioned substituents), 4 and 5-isoxazolyl, 4 and 5-isothiazolyl, 5-oxazolyl, 5-

thiazolyl, 5-(l,2,4-oxadiazolyl), 2-(l,3,4-oxadiazolyl) or 3-(l,2,4-triazolyl).

Representative aryl groups include phenyl, naphthyl, furanyl, thienyl,

pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, and indolyl. Other

representative aromatic ring systems are set forth in Gibson et al., J. Med. Chem.

39:4065 (1996). Any of these aromatic group containing species can be substituted

with at least one substituent group, such as those described above that are associated with x' and the like. Representative substitevely include alkyl, aryl, halo, hydroxy,

alkoxy, aryloxy or amino substituents.

Adjacent substituents of X, X¹, X", X^m, X"", Y, Y¹, Y" and Y¹" (when

substituents are present) 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 compounds can occur in stereoisomeric forms, including both single

enantiomers and racemic mixtures of such compounds, as well as mixtures of varying

degrees of enantiomeric excess.

The compounds can be 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 sulfate, phosphate, and nitrate; organic acid addition salts such as acetate, galactarate, propionate, succinate, lactate,

glycolate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-

toluenesulfonate, and ascorbate; salts with an acidic amino acid such as aspartate and

glutamate; alkali metal salts such as sodium and potassium; alkaline earth metal salts

such as magnesium and calcium; ammonium salt; organic basic salts such as

trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine, and N₅N'-

dibenzylethylenediamine; and salts with a basic amino acid such as lysine and

arginine. The salts can be in some cases hydrates or ethanol solvates. The

stoichiometry of the salt will vary with the nature of the components. 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.

Representative compounds include the following:

7-(3-pyridyl)-l,7-diazaspiro[4.4]nonane

7-(5-pyrimidinyl)- 1 ,7-diazaspiro [4.4]nonane

7-(5-isoxazolyl)-l,7-diazaspiro[4.4]nonane

7-(5-isothiazolyl)- 1 ,7-diazaspiro[4.4]nonane

7-(5-(l ,2,4-oxadiazol)yl)- 1 ,7-diazaspiro[4.4]nonane

7-(2-(l ,3,4-oxadiazol)yl)-l ,7-diazaspiro[4.4]nonane

7-(2-pyrazinyl)- 1 ,7-diazaspiro [4.4]nonane

7-(3-pyridazinyl)-l,7-diazaspiro[4.4]nonane

7-(5-methoxy-3-pyridyl)-l,7-diazaspiro[4.4]nonane

7-(5-cyclopentyloxy-3-pyridyl)-l,7-diazaspiro[4.4]nonane

7-(5-phenoxy-3-pyridyl)-l,7-diazaspiro[4.4]nonane

7-(5-(4-hydroxyρhenoxy)-3-pyridyl)-l,7-diazaspiro[4.4]nonane 7-(5-ethynyl-3-pyridyl)-l,7-diazaspiro[4.4]nonane

7-(6-chloro-3-pyridyl)-l,7-diazaspiro[4.4]nonane

7-(6-methoxy-3-pyridazinyl)-l,7-diazaspiro[4.4]nonane

l-(3-pyridyl)-l,7-diazaspiro[4.4]nonane

1 -(5-pyrimidinyl)-l ,7-diazaspiro[4.4]nonane

1 -(5-isoxazolyl)-l ,7-diazaspiro[4.4]nonane

1 -(5-isothiazolyl)-l ,7-diazaspiro[4.4]nonane

l-(5-(l,2,4-oxadiazol)yl)-l,7-diazaspiro[4.4]nonane

l-(2-(l,3,4-oxadiazol)yl)-l,7-diazaspiro[4.4]nonane

1 -(2-pyrazinyl)- 1 ,7-diazaspiro[4.4]nonane

1 -(3 -pyridazinyl)- 1 ,7-diazaspiro [4.4]nonane

1 -methyl-7-(3-pyridyl)-l ,7-diazaspiro [4.4]nonane

1 -methyl-7-(5-pyrimidinyl)- 1 ,7-diazaspiro [4.4]nonane

1 -methyl-7-(5-isoxazolyl)- 1 ,7-diazaspiro [4.4]nonane

1 -methyl-7-(5-isothiazolyl)- 1 ,7-diazaspiro[4.4]nonane

1 -methyl-7-(5-(l ,2,4-oxadiazol)yl)- 1 ,7-diazaspiro [4.4]nonane

1 -methyl-7-(2-(l ,3,4-oxadiazol)yl)- 1 ,7-diazaspiro[4.4]nonane

1 -methyl-7-(2-pyrazinyl)-l ,7-diazaspiro[4.4]nonane

l-methyl-7-(3-pyridazinyl)-l,7-diazaspiro[4.4]nonane

l-methyl-7-(5-methoxy-3-pyridyl)-l,7-diazaspiro[4.4]nonane

1 -methyl-7-(5-cyclopentyloxy-3-pyridyl)- 1 ,7-diazaspiro[4.4]nonane

1 -methyl-7-(5-phenoxy-3-ρyridyl)-l ,7-diazasρiro[4.4]nonane

1 -methyl-7-(5 -(4-hydroxyphenoxy)-3 -pyridyl)- 1 ,7-diazaspiro [4.4]nonane

l-methyl-7-(5-ethynyl-3-pyridyl)-l,7-diazaspiro[4.4]nonane

1 -methyl-7-(6-chloro-3 -pyridyl)- 1 ,7-diazaspiro[4.4]nonane l-methyl-7-(6-methoxy-3-pyridazinyl)-l,7-diazaspiro[4.4]nonane

7-methyl-l-(3-pyridyl)-l,7-diazaspiro[4.4]nonane

7-methyl- 1 -(5-pyrimidinyl)- 1 ,7-diazaspiro[4.4]nonane

7-methyl-l-(5-isoxazolyl)-l,7-diazaspiro[4.4]nonane

7-methyl-l-(5-isothiazolyl)-l,7-diazaspiro[4.4]nonane

7-methyl- 1 -(5-( 1 ,2,4-oxadiazol)yl)- 1 ,7-diazaspiro[4.4]nonane

7-methyl-l-(2-(l,3,4-oxadiazol)yl)-l,7-diazaspiro[4.4]nonane

7-methyl-l-(2-pyrazinyl)-l,7-diazaspiro[4.4]nonane

7-methyl- 1 -(3 -pyridazinyl)- 1 ,7-diazaspiro[4.4]nonane

2-(3-pyridyl)-2,7-diazaspiro[4.4]nonane

2-(5-pyrimidinyl)-2,7-diazaspiro[4.4]nonane

2-(5-isoxazolyl)-2,7-diazaspiro[4.4]nonane

2-(5-isothiazolyl)-2,7-diazaspiro[4.4]nonane

2-(5-(l,2,4-oxadiazol)yl)-2,7-diazaspiro[4.4]nonane 2-(2-(l ,3,4-oxadiazol)yl)-2,7-diazaspiro[4.4]nonane

2-(2-pyrazinyl)-2,7-diazaspiro[4.4]nonane

2-(3-pyridazinyl)-2,7-diazaspiro[4.4]nonane

2-(5-methoxy-3-pyridyl)-2,7-diazaspiro[4.4]nonane

2-(5-cyclopentyloxy-3-pyridyl)-2,7-diazaspiro[4.4]nonane

2-(5-phenoxy-3-pyridyl)-2,7-diazaspiro[4.4]nonane

2-(5-(4-hydroxyphenoxy)-3-pyridyl)-2,7-diazaspiro[4.4]nonane

2-(5-ethynyl~3-pyridyl)-2,7-diazaspiro[4.4]nonane

2-(6-chloro-3-pyridyl)-2,7-diazaspiro[4.4]nonane

2-(6-methoxy-3-pyridazinyl)-2,7-diazaspiro[4.4]nonane

2-methyl-7-(3-pyridyl)-2,7-diazaspiro[4.4]nonane 2-methyl-7-(5-methoxy-3-pyridyl)-2,7-diazaspiro[4.4]nonane

2-methyl-7-(5-phenoxy-3-pyridyl)-2,7-diazaspiro[4.4]nonane

6-(3-pyridyl)- 1 ,6-diazaspiro[3.4] octane

1 -methyl-6-(3 -pyridyl)- 1 ,6-diazaspiro[3.4] octane

2-(3-pyridyl)-2,5-diazaspiro[3.4]octane

5-methyl-2-(3-pyridyl)-2,5-diazaspiro[3.4]octane

6-(3-pyridyl)-l,6-diazaspiro[3.5]nonane

1 -methyl-6-(3 -pyridyl)- 1 ,6-diazaspiro[3.5]nonane

2-(3-pyridyl)-2,5-diazaspiro[3.5]nonane

5-methyl-2-(3-pyridyl)-2,5-diazaspiro[3.5]nonane

2-(3-pyridyl)-2,6-diazaspiro[4.5]decane

6-methyl-2-(3-pyridyl)-2,6-diazaspiro[4.5]decane

7-(3-pyridyl)-l,7-diazaspiro[4.5]decane

1 -methyl-7-(3 -pyridyl)- 1 ,7-diazaspiro[4.5] decane 8-(3 -pyridyl)- 1 ,8-diazaspiro[5.5]undecane

l-methyl-8-(3-pyridyl)-l,8-diazaspiro[5.5]undecane

Other representative compounds of the present invention include the

following:

1 '-(3-pyridyl)-spiro[ 1 -azabicyclo[2.2.1 ]heptane-2,3 '-pyrrolidine]

1 '-(5-ethoxy-3-pyridyl)-spiro[ 1 -azabicyclo[2.2.1 ]heptane-2,3 '-pyrrolidine]

1 '-(5-cyclopentyloxy-3-pyridyl)-spiro[ 1 -azabicyclo[2.2.1 ]heptane-2,3 '-pyrrolidine]

r-(5-phenoxy-3-pyridyl)-spiro[l-azabicyclo[2.2.1]heptane-2,3'-pyrrolidine]

1 '-(5-(4-hydroxyphenoxy)-3-pyridyl)-spiro[ 1 -azabicyclo[2.2.1 ]heptane-2,3 '- pyrrolidine]

r-(5-pyrimidinyl)-spiro[l-azabicyclo[2.2.1]heptane-2,3'-pyrrolidine] 1 '-(5-isoxazolyl)-spiro[ 1 -azabicyclo[2.2.1 ]heptane-2,3 '-pyrrolidine]

l'-(5-isothiazolyl)-spiro[l-azabicyclo[2.2.1]heptane-2,3'-pyrrolidine]

1 '-(5-(1 ,2,4-oxadiazol)yl)-spiro[ l-azabicyclo[2.2.1 ]heptane-2,3 '-pyrrolidine]

r-(2-(l,3,4-oxadiazol)yl)-spiro[l-azabicyclo[2.2.1]heptane-2,3'-pyrrolidine]

1 '-(2-pyrazinyl)-spiro[ 1 -azabicyclo[2.2.1 ]heptane-2,3 '-pyrrolidine]

1 '-(3-pyridazinyl)-spiro[ 1 -azabicyclo[2.2.1 ]heptane-2, 3 '-pyrrolidine]

r-(5-ethynyl-3-pyridyl)-spiro[l-azabicyclo[2.2.1]heptane-2,3'-pyrrolidine]

r-(6-chloro-3-pyridyl)-spiro[l-azabicyclo[2.2.1]heptane-2,3'-pyrrolidine]

r-(6-methoxy-3-pyridazinyl)-spiro[l-azabicyclo[2.2.1]heptane-2,3'-pyrrolidme]

1 '-(3 -pyridyl)-spiro [ 1 -azabicyclo [2.2.2] octane-2,3 '-pyrrolidine] r-(5-methoxy-3-pyridyl)-spiro[l-azabicyclo[2.2.2]octane-2,3'-pyrrolidine]

r-(5-cyclopentyloxy-3-pyridyl)-spiro[l-azabicyclo[2.2.2]octane-2,3'-ρyrrolidine]

r-(5-phenoxy-3-pyridyl)-spiro[l-azabicyclo[2.2.2]octane-2,3 '-pyrrolidine]

1 '-(5-(4-hydroxyphenoxy)-3-pyridyl)-spiro[ 1 -azabicyclo[2.2.2]octane-2,3 '-pyrrolidine] l'-(5-ethynyl-3-pyridyl)-spiro[l-azabicyclo[2.2.2]octane-2,3'-pyrrolidine]

l'-(6-chloro-3-pyridyl)-spiro[l-azabicyclo[2.2.2]octane-2,3'-pyrrolidine]

l'-(5-pyrimidinyl)-spiro[l-azabicyclo[2.2.2]octane-2,3'-pyrrolidine]

1 '-(2-pyrazinyl)-spiro[ 1 -azabicyclo[2.2.2]octane-2,3 '-pyrrolidine]

1 '-(3-pyridazinyl)-spiro[ 1 -azabicyclo[2.2.2]octane-2,3 '-pyrrolidine]

1 '-(6-methoxy-3 -pyridazinyl)-spiro [ 1 -azabicyclo [2.2.2] octane-2,3 '-pyrrolidine]

l'-(5-isoxazolyl)-spiro[l-azabicyclo[2.2.2]octane-2,3'-pyrrolidine]

l'-(5-isothiazolyl)-spiro[l-azabicyclo[2.2.2]octane-2,3 '-pyrrolidine]

r-(5-(l,2,4-oxadiazol)yl)-spiro[l-azabicyclo[2.2.2]octane-2,3'-pyrrolidine]

r-(2-(l,3,4-oxadiazol)yl)-spiro[l-azabicyclo[2.2.2]octane-2,3'-pyrrolidine]

r-(3-pyridyl)-2'H-spiro[l-azabicyclo[2.2.1]heptane-7,3'-pyrrolidine] 1 '-(5-methoxy-3-pyridyl)-2'H-spiro[ 1 -azabicyclo[2.2.1 ]heptane-7,3 '-pyrrolidine]

1 '-(5-cyclopentyloxy-3-pyridyl)-2'H-spiro[ 1 -azabicyclo[2.2.1 ]heptane-7,3 '-

pyrrolidine]

r-(5-phenoxy-3-pyridyl)-2'H-spiro[l-azabicyclo[2.2.1]heptane-7,3'-pyrrolidine] 1 '-(5-(4-hydroxyphenoxy)-3-pyridyl)-2'H-spiro[l -azabicyclo[2.2.1 ]heptane-7,3 '-

pyrrolidine] r-(6-chloro-3-pyridyl)-2Η-spiro[l-azabicyclo[2.2.1]heptane-7,3'-pyrrolidine]

1 '-(5-pyrimidinyl)-2'H-spiro[ 1 -azabicyclo[2.2.1 ]heptane-7,3 '-pyrrolidine]

r-(2-pyrazinyl)-2'H-spiro[l-azabicyclo[2.2.1]heptane-7,3'-pyrrolidine]

r-(3-pyridazinyl)-2'H-spiro[l-azabicyclo[2.2.1]heptane-7,3'-pyrrolidine]

r-(6-methoxy-3-pyridazinyl)-2'H-spiro[l-azabicyclo[2.2.1]heptane-7,3'-pyrrolidine] 1 '-(5-isoxazolyl)-2'H-spiro[ 1 -azabicyclo[2.2.1 ]heptane-7,3 '-pyrrolidine]

r-(5-isothiazolyl)-2'H-spiro[l-azabicyclo[2.2.1]heptane-7,3 '-pyrrolidine]

r-(5-(l,2,4-oxadiazol)yl)-2'H-spiro[l-azabicyclo[2.2.1]heptane-7,3'-pyrrolidine]

r-(2-(l,3,4-oxadiazol)yl)-2'H-spiro[l-azabicyclo[2.2.1]heptane-7,3'-pyrrolidine]

II. Methods of Preparing the Compounds

Scheme 1

Reacrion 1

Reaction 2

H

Ar

The compounds of Formulas 1 and 2 can be prepared using a general method involving arylation of one amino group of an optionally protected diazaspiroalkane

(Scheme 1). Arylation at N with an appropriate aryl, or preferably heteroaryl, halide

or triflate can be performed according to methods known to those skilled in the art, for

example, employing metal (e.g., copper or palladium compounds) catalysis. The

preferred general method in the present invention utilizes the teachings of Buchwald

or Hartwig (Buchwald et al, J. Org. Chem., 61: 7240 (1996); Hartwig et al., J.

Org..Chem., 64: 5575 (1999); see also Old et al., J. Am. Chem. Soc. 120: 9722

(1998)), wherein an amine is treated with a palladium(O) catalyst, a phosphine ligand

and base. Thus, 1 -benzyl- l,7-diazaspiro[4.4]nonane is reacted with 3-bromopyridine

in the presence of tris(dibenzylideneacetone)dipalladium(0), 2,2'-

bis(diphenylphosphino)-l,l'-binaphthyl and sodium tert-butoxide in toluene, to give l-benzyl-7-(3-pyridyl)diazaspiro[4.4]nonane. Removal of the benzyl group by

hydrogenation, over 10% palladium on carbon, provides 7-(3-pyridyl)-

diazaspiro[4.4]nonane. Alternatively, one skilled in the art will recognize that various

protecting group strategies can be employed to provide products bearing an aryl group

on nitrogen N', as opposed to N (Reaction 1 , Scheme 1). A particularly useful

combination of protecting groups in the present invention is benzyl and a carbamate,

specifically, tert-butylcarbamate. Thus, 1 -benzyl- l,7-diazaspiro[4.4]nonane is

converted into l-benzyl-7-(tert-butoxycarbonyl)-l,7-diazaspiro[4.4]nonane by

treatment with di-tert-butyl dicarbonate. Subsequent hydrogenation and palladium-

catalyzed arylation, with 3-bromopyridine, gives 7-(tert-butoxycarbonyl)-l-(3- pyridyl)diazaspiro[4.4]nonane. Removal of the tert-butoxycarbonyl group, with

hydrochloric acid, provides l-(3-pyridyl)-diazaspiro[4.4]nonane. Finally, in many

cases where N and N' are sterically dissimilar, and whenever N is tertiary (as in

Reaction 2, Schemel), selective arylation of N can be accomplished without first protecting N'. Thus, reaction of l,7-diazaspiro[4.4]nonane with 3-bromopyridine,

under the palladium-catalyzed conditions reported previously, gives almost

exclusively 7-(3-pyridyl)-diazaspiro[4.4]nonane.

It will be obvious to those skilled in the art that incorporation of substituents

on the heteroaryl ring introduced onto the diazaspiroalkane can be readily realized.

Such substituents can provide useful properties in and of themselves or serve as a

handle for further synthetic elaboration. A suitably protected heteroaryl

diazaspiroalkane can be elaborated to give a number of useful compounds possessing

substituents on the heteroaryl ring. For example, l-benzyl-7-(5-bromo-3-pyridyl)-l,7-

diazaspiro[4.4]nonane can be made by reacting 3,5-dibromopyridine with 1-benzyl-

l,7-diazaspiro[4.4]nonane according to procedures described previously. The conversion of l-benzyl-7-(5-bromo-3-pyridyl)diazaspiro[4.4]nonane into the

corresponding 5-amino-substituted compound can be accomplished by the general

method of Zwart et al., Recueil Trav. Chim. Pays-Bas 74: 1062 (1955), in which the

bromo compound heated with aqueous ammonia in the presence of a copper catalyst.

5-Alkylamino substituted compounds can be prepared in a similar manner. 5-Ethynyl-

substituted compounds can be prepared from the 5-bromo compound by palladium

catalyzed coupling using 2-methyl-3-butyn-2-ol, followed by base- catalyzed (sodium hydride) removal of the acetone unit, according to the general techniques described in

Cosford et al., J Med. Chem. 39: 3235 (1996). The 5-ethynyl analogs can be

converted into the corresponding 5-ethenyl, and subsequently to the corresponding 5-

ethyl analogs by successive catalytic hydrogenation reactions. The 5-azido-substituted

analogs can be prepared from the 5-bromo compound by reaction with lithium azide in N,N-dimethylformamide. 5-Alkylthio-substituted analogs can be prepared from the

5-bromo compound by reaction with an appropriate sodium alkylmercaptide (sodium

alkanethiolate), using techniques known to those skilled in the art of organic synthesis.

A number of other analogs, bearing substituents in the 5 position of the pyridine ring, can be synthesized from the corresponding amino compounds, vide

supra, via a 5-diazonium salt intermediate. Examples of other 5-substituted analogs

that can be produced from 5-diazonium salt intermediates include, but are not limited

to: 5-hydroxy, 5-alkoxy, 5-fluoro, 5-chloro, 5-iodo, 5-cyano, and 5-mercapto. These

compounds can be synthesized using the general techniques set forth in Zwart et al.,

supra. For example, l-benzyl-7-(5-hydroxy-3-pyridyl)-l,7-diazaspiro[4.4]nonane can

be prepared from the reaction of the corresponding 5-diazonium salt intermediate with

water. Likewise, l-benzyl-7-(5-alkoxy-3-pyridyl)-l,7-diazaspiro[4.4]nonanes can be made from the reaction of the diazonium salt with alcohols. Appropriate 5-diazonium

salts can be used to synthesize cyano or halo compounds, as will be known to those

skilled in the art. 5-Mercapto substitutions can be obtained using techniques

described in Hoffman et al., J. Med. Chem. 36: 953 (1993). The 5-mercaptan so

generated can, in turn, be converted to a 5-alkylthio substitutuent by reaction with

sodium hydride and an appropriate alkyl bromide. Subsequent oxidation would then

provide a sulfone. 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. Likewise, the 5-hydroxy

compounds are precursors of both the 5-aryloxy and 5-heteroaryloxy via nucleophilic aromatic substitution at electron deficient aromatic rings (e.g., 4-fluorobenzonitrile

and 2,4-dichloropyrimidine). Such chemistry is well known to those skilled in the art

of organic synthesis. Ether derivatives can also be prepared from the 5-hydroxy

compounds by alkylation with alkyl halides and a suitable base or via Mitsunobu

chemistry, in which a trialkyl- or triarylphosphine and diethyl azodicarboxylate are

typically used. See Hughes, Org. React. (N. Y.) 42: 335 (1992) and Hughes, Org.

Prep. Proced. Int. 28: 127 (1996) for typical Mitsunobu conditions.

5-Cyano-substituted analogs of the aforementioned compounds can be

hydrolyzed to afford the corresponding 5-carboxarnido-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 analogs. 5-Acyl-

substituted analogs can be prepared from corresponding 5-carboxylic acid-substituted

analogs by reaction with an appropriate alkyllithium using techniques known to those

skilled in the art of organic synthesis.

5-Carboxylic acid-substituted analogs of the aforementioned compounds can

be converted to the corresponding esters by reaction with an appropriate alcohol and

acid catalyst. 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 analogs. 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 analogs. The 5-carboxylic acid-substituted

analogs can also be converted to the corresponding 5-alkylaminoacyl analogs by sequential treatment with thionyl chloride and an appropriate alkylamine. Certain of

these amides are known to readily undergo nucleophilic acyl substitution to produce ketones. Thus, the so-called Weinreb amides (N-methoxy-N-methylamides) react

with aryllithium reagents to produce the corresponding diaryl ketones. For example,

see Selnick et al, Tet. Lett. 34: 2043 (1993).

5-Tosyloxymethyl-substituted analogs of the aforementioned compounds can

be converted to the corresponding 5 -methyl-substituted compounds by reduction with

lithium aluminum hydride. 5-Tosyloxymethyl-substituted analogs of the

aforementioned compounds can also be used to produce 5-alkyl-substituted

compounds via reaction with an alkyllithium reagent. 5-Hydroxy-substituted analogs

of the aforementioned compounds can be used to prepare 5-N-alkyl- or 5-N- arylcarbamoyloxy-substituted compounds by reaction with N-alkyl- or N-

arylisocyanates. 5-Amino-substituted analogs of the aforementioned compounds can

be used to prepare 5-alkoxycarboxamido-substituted compounds and 5-urea

derivatives by reaction with alkyl chloroformate esters and N-alkyl- or N-

arylisocyanates, respectively, using techniques known to those skilled in the art of

organic synthesis.

Chemistries analogous to those described hereinbefore for the preparation of

5-substituted pyridine analogs of diazaspiro compounds can be devised for the synthesis of analogs bearing substituents in the 2, 4, and 6 positions of the pyridine

ring. For example, a number of 2-, 4-, and 6-aminopyridyldiazaspiroalkanes can be

converted to the corresponding diazonium salt intermediates, which can be

transformed to a variety of compounds with substituents at the 2, 4, and 6 positions of

the pyridine ring as was described for the 5-substituted analogs above. The requisite 2-, A-, and 6-aminopyridyl diazaspiroalkanes are available via the Chichibabin

reaction of unsubstituted pyridyl diazaspiroalkanes (e.g., l-benzyl-7-(3-pyridyi)-l,7-

diazaspiro[4.4]nonane, described previously) with sodium amide. Similar reactions

are described in Chemistry of Heterocyclic Compounds, Volume 14, part 3, pp.3-5

(Interscience Publishers, 1962) and by Lahti et al., J. Med. Chem. 42: 2227 (1999).

After the desired heteroaryl ring functional group manipulation has been

accomplished, the optional protecting group can be removed from the diazabicycle

using appropriate conditions. Thus, for example, hydrogenolysis of l-benzyl-7-(5-

alkoxy-3- pyridyl)-l,7-diazaspiro[4.4]nonane will generate 7-(5-alkoxy-3-pyridyl)-

l,7-diazaspiro[4.4]nonane. Those skilled in the art of organic chemistry will

appreciate the necessity of pairing protecting groups with the chemistries required to

generate particular functionalities. In some cases it can be necessary, to retain a particular functionality, to replace one protecting group with another.

In an alternative approach to the synthesis of pyridine-substituted pyridyl

diazaspiroalkanes, 3,5-dibromopyridine can be converted into the corresponding 5-

alkoxy-3-bromo- and 5-aryloxy-3-bromopyridines by the action of sodium alkoxides

or sodium aryloxides. Procedures such as those described by Comins et al., J. Org.

Chem. 55: 69 (1990) and Hertog et al., Recueil Trav. CUm. Pays-Bas 74: 1171 (1955)

are used. This is exemplified by the preparation 7-(5-(4-methoxyphenoxy)-3-pyridyi)-

l,7-diazaspiro[4.4]nonane. Reaction of 3,5-dibromopyridine with sodium 4-

methoxyphenoxide in N,N-dimethylformamide gives 3-bromo-5-(4-

methoxyphenoxy)pyridine. Coupling of 3-bromo-5-(4-methoxyphenoxy)pyridine with l-benzyl-7-(3-pyridyl)-l,7-diazaspiro[4.4]nonane in the presence of sodium tert-

butoxide, and a catalytic amount of tris(dibenzylideneacetone)dipalladium(0) and 2,2'-

bis(diphenylphosphino)-l,l'-binaphthyl, in toluene, followed by hydrogenolysis of the

benzyl protecting group, will provide 7-(5-(4-methoxyphenoxy)-3-pyridyi)-l,7-

diazaspiro[4.4]nonane.

Other aryl halides undergo the palladium-catalyzed coupling reaction

described previously. Thus 7-(5-pyrimidinyl)-l,7-diazaspiro[4.4]nonane is prepared

in a similar manner from 5-bromopyrimidine and optionally 1 -position protected 1,7-

diazaspiro[4.4]nonane followed by deprotection, if necessary. This technology is

especially applicable in cases, such as 3-bromopyridine, 3,5-dibromopyridine, and 5-

bromopyrimidine, where the aromatic ring is not activated toward nucleophilic

aromatic substitution.

In some cases, coupling of the heteroaromatic ring to the diazaspirocycle can

be accomplished without the use of palladium catalysis. Examples of both five- and

six-membered heteroaromatic ring compounds, which are activated toward nucleophilic aromatic substitution, are known by those skilled in the art of organic

synthesis. For example, 7-(6-chloro-3-pyridazinyl)-l,7-diazaspiro[4.4]nonane can be synthesized from 3,6-dichloropyridazine and 1 ,7-diazaspiro[4.4]nonane. Likewise,

2,6-dicloropyrazine, and 2-bromothiazole will react with l,7-diazaspiro[4.4]nonane to

give 7-(6-chloro-2-pyrazinyl)-l,7-diazaspiro[4.4]nonane and 7-(2-thiazoyl)-l,7- diazaspiro[4.4]nonane, respectively.

The coupling reactions described in this application, whether palladium catalyzed or not, are amenable to high through-put synthetic techniques. Thus a

library of compounds of the present invention can be produced by coupling, in a 96-

well plate format, for instance, various haloarenes with various diazaspiro

compounds.

Specific Diazaspiro Ring Systems

Optionally protected diazaspiroalkane intermediates used to prepare the

compounds of Formulas I and II can be prepared by numerous methods. Several of

these diazaspiroalkane intermediates are known and can be prepared using prior art

methods. However, the synthesis of the intermediates using palladium chemistry is

new to the art, and the pharmaceutical activity of the intermediates was not

appreciated in the prior art.

The compounds of Formula 1, where U=V=I, w=0 and x=3, possess a 2,5-

diazaspiro [3 ,4] octane core which can be prepared as depicted in Scheme 2.

Alkylation of N-benzyl-L-proline ethyl ester (Aldrich Chemical), using a

strong base such as lithium diisopropylamide (LDA) and the aminomethyl equivalent

cyanomethylbenzylamine, provides a beta-lactam, according to the procedure reported

by Overman, J. Am. Chem. Soc. 107:1698 (1985) and Tet. Lett. 25: 1635 (1985). This

can subsequently be reduced with lithium aluminum hydride to provide the 2,5- dibenzyl derivative of 2,5-diazaspiro[3,4]octane. Removal of the benzyl protecting

groups, by either hydrogenation or oxidative cleavage with, for example, eerie

ammonium nitrate, will produce 2,5-diazaspiro[3,4]octane. Alternatively, chemistry

similar to that described in EP patent application 90117078.7 (publication number EP

0 417 631) can be used to produce a geminal bis(hydroxymethyl) derivative and

subsequently convert it to the desired 2,5-diazaspiro[3,4]octane (Scheme 2). The

subsequent palladium-catalyzed arylation, as described previously, would be expected

to proceed with selectivity for the less sterically hindered azetidinyl nitrogen,

producing 2-aryl-2,5-diazaspiro[3,4]octanes. The isomeric 5-aryl-2,5-

diazspiro[3,4]octanes can be made by first protecting the azetidinyl nitrogen (with, for

instance, a carbamate) and then performing the arylation, followed by deprotection.

Scheme 2

The compounds of Formula 1, wherein u=2, v=l, w=0 and x=3, possess the

1 ,7-diazaspiro[4.4]nonane system which can be prepared according to numerous

methods, several of which are shown above in Scheme 3. In one embodiment

(Method A), a suitably protected proline ester, for example N-benzyl-L-proline ethyl ester, can be deprotonated with lithium diisopropylamide and allowed to react by

Michael addition to nitroethylene. This provides methyl 2-(2-nitroethyl)-l-

benzylpyrrolidine-2-carboxylate. Subsequent reduction of the nitro group using

Raney nickel, followed by lactamization by methods known to those skilled in the art

(for example, heating in a suitable solvent with or without an acidic or basic catalyst),

provides 1 -benzyl- l,7-diazaspiro[4.4]nonan-6-one.

The l,7-diazaspiro[4.4]nonane-6-one can alternatively be prepared according

to one of several other methods reported in the literature. Such teachings indicate that

a suitably protected proline ester can be deprotonated with lithium diisopropylamide

and allowed to react with an alkylating agent such as chloroacetonitrile, then subjected

to nitrile reduction and cyclization (Method B, Scheme 3) as reported by Culbertson et

al, J. Med Chem. 33:2270 (1990).

Other teachings indicate that a suitably protected proline ester can be

deprotonated with lithium diisopropylamide and allowed to react with an alkylating agent such as allyl bromide (Method C, Scheme 3). The resulting olefin can then be

oxidatively cleaved to an aldehyde, as reported by Genin et al., J. Org. Chem. 58:2334

(1993); Hinds et al., J. Med. Chem. 34:1777 (1991); Kim et al., J. Org. Chem.

61:3138 (1996); EP 0 360 390 and U.S. Patent No. 5,733,912. The aldehyde can then

be subjected to reductive animation with an ammonium salt or primary aliphatic or

aromatic amine, according to methods known to those skilled in the art. Alternatively,

the aldehyde can be reduced to the corresponding alcohol and the alcohol then

transformed to an amine by conversion to a leaving group, followed by displacement

with the appropriate amine. This can also be achieved by displacing the leaving group

with an azide ion and subsequently reduction to the primary amine using methods

known to those skilled in the art. The alcohol can be converted to an amine using Mitsunobu conditions, as discussed previously. The alkyl 2-aminoethyl pyrrolidine-2-

carboxylate, obtained according to one of the methods described above, can be

cyclized to a spirolactam by methods known to those skilled in the art, such as heating

in a suitable solvent with or without an acidic or basic catalyst.

The lactam obtained by any one of the above methods (Methods A, B or C)

can be treated with a suitable reducing agent, such as lithium aluminum hydride, to

provide the protected l,7-diazaspiro[4.4]nonane, in this example, 1 -benzyl- 1,7-

diazaspiro[4.4]nonane. The protecting group can be removed using methods known

those skilled in the art to provide the desired l,7-diazaspiro[4.4]nonane. Arylation at

either nitrogen can be accomplished using methods described herein.

Scheme 3

a) (i) LDA; (ii) nitroethylene (Method A) or CICH2CN (Method B); (iii) RaNi; (iv) PhCH3, heat b) (i) LDA; (ii) allyl bromide; (iii) O₃ or OsO₄, NaIO₄; (iv) NH₄CI, NaBH(OAc)₃ (Method C) c) (i) LiAIH₄ or BH₃; (ii) [-PG]

Alternatively, the l,7-diazaspiro[4.4]nonane core can also be prepared

according to Scheme 4. The conversion of l,4-dioxaspiro[4.5]decan-8-one to 4-

benzoyloxycyclohexanone can be readily achieved by those skilled in the art.

Subsequent transformation of 4-benzoyloxycyclohexanone to 1,7- diazaspiro[4.4]nonane (through the intermediacy of 4-oxocaprolactam, as shown) can

be performed according to the teachings of Majer et al., Coll. Czech. Chem. Comm.

47:950 (1982).

Scheme 4

The compounds of Formula 1, wherein u=2, V=I, w=l and x=2, possess the symmetrical 2,7-diazaspiro[4,4]nonane system which can be prepared according to

Scheme 5. This method is reported by Overman et al., J. Org. Chem. 46: 2757 (1981)

and Culbertson et al., J. Med. Chem. 33:2270 (1990).

Scheme 5

The compounds of Formula 1, wherein u=3, v=l, w=0 and x=3, possess the

l,7-diazaspiro[4.5]decane system which can be prepared according to Scheme 6. The

teachings of Kim et al., J. Org. Chem. 61:3138 (1996), patent EP360390 and US

patent 5,733,912 indicate that a suitably protected proline ester (e.g., N-benzyl-L-

proline ethyl ester) can be deprotonated with lithium diisopropylamide and allowed to react with an alkylating agent such as allyl bromide. US patent 5,733,912 also teaches

that hydroboration/oxidation of the allyl side chain can be performed to provide the 2-

(3-hydroxypropyl) group. Those skilled in the art will appreciate that the hydroxyl

group can then be converted to an amino group by a number of methods, for example

oxidation followed by reductive animation. Alternatively, a suitably protected proline

ester can be deprotonated with lithium diisopropylamide and allowed to react with an

alkylating agent such as diiodopropane. Conversion of the primary iodide to an amine

can then be performed according to known methods, for example treatment with

ammonia in the presence of a copper catalyst. The resulting amino ester can be

cyclized to afford a protected 1 ,7-diazaspiro[4.5]decan-6-one using any number of

known procedures, for example heating in a suitable solvent in the presence or

absence of an acidic or basic catalyst, as discussed previously. Alternatively, the known l,7-diaza-spiro[4.5]decan-6-one can be prepared according to the teachings of

Loefas et al, J. Het. Chem. 21:583 (1984), in which the ring contraction of 2,10-

diazabicyclo[4.4.0]dec-l-ene is used.

The l,7-diazaspiro[4.5]decan-6-one, obtained by any of the above methods,

can then be treated with a reducing agent, such as lithium aluminum hydride, followed

by removal of the protecting group, to provide the desired l,7-diazaspiro[4.5]decane.

Arylation can then be carried out at either nitrogen using methods described herein.

Scheme 6

a) X=OH: (i) LDA, allyl bromide; (ii) BH₃, H₂O₂ X=I: LDA, 1 ,3-diiodopropane b) X=OH: (i) PCC or Swern; (ii) NH₄CI, NaBH(OAc)₃; (iii) heat (÷catalyst?) X=I: (i) NH₃, CuI; (ii) heat (÷catalyst?) c) (i) BH₃ or LiAIH₄; (ii) [-PG]

The compounds of Formula 1, wherein u=2, v=l, w=0, and x=4, possess the

2,6-diazaspiro[4.5]decane core which can be prepared according to the method of

Ciblat, et al., Tet. Lett. 42: 4815 (2001). Thus, commercially available l-benzyl-3-

pyrrolidinone can be reacted with 2-methyl-2-(2-aminoethyl)-l,3-dioxolane (Islam

and Raphael, J. Chem. Soc. 3151 (1955)) in an intramolecular Mannich reaction. The product, the ethylene ketal of 2-benzyl-2,10-diazaspiro[4,5]decan-7-one, can then be

hydrolyzed to the ketone, using aqueous hydrochloric acid. Deoxygenation of the ketone can then be accomplished by standard methods, such as conversion to the

corresponding 1,3-dithiane, followed by treatment with Raney nickel. The 2-benzyl-

2,6-diazaspiro[4,5]decane thus produced can be directly arylated on the 6-position

nitrogen or converted into 6-(tert-butoxycarbonyl)-2,6-diazaspiro[4,5]decane by

treatment with di-tert-butyl dicarbonate, followed by hydrogenation. The latter

derivative can then be arylated at the 2-position nitrogen. Similar chemistry can be

used to convert other azacyclic ketones into the corresponding spirodiaza compounds.

Thus, reaction of any of various N-protected 3-azetidinones (the synthesis of which is described by LaIl, et al, J. Org. Chem. 67: 1536 (2002) and Marchand, et al,

Heterocycles 49: 149 (1998)) with 2-methyl-2-(2-aminoethyl)-l,3-dioxolane, followed

by deoxygenation (as described above), will produce the corresponding protected 2,5-

diazaspiro[3.5]nonane (Formula 1, wherein u=l, v=l, w=0, and x=4).

The compounds of Formula 1, wherein u=v=2, w=0, and x=3, possess the 1,8-

diazaspiro[4.5]decane core which can be prepared according to Scheme 7. According

to the teachings reported by Wittekind et al., J Het. Chem. 9:11 (1972), a protected A-

piperidone can be converted to the 4-nitropiperidine. Subsequent Michael addition

with ethyl acrylate, for example, followed by reduction of the nitro group with Raney

nickel, provides the l,8-diazaspiro[4.5]decan-2-one. This lactam can be reduced with

an appropriate reducing agent, such as lithium aluminum hydride, followed by removal of the protecting group, to provide the optionally substituted 1,8-

diazaspiro[4.5jdecane. Arylation on either nitrogen can be accomplished using

methods described herein.

Scheme 7

^{1 ■} ) ^L -^|A™^IH4

The compounds of Formula 1, wherein u=2, v=l, and w=x=2, possess the 2,8-

diazaspiro[4.5]decane core which can be prepared according to Scheme 8. According

to various teachings (HeIv. Chun. Acta 60: 1650 (1977); Smith et al., J. Med. Chem.

19:3772 (1995); Elliott et al., Biorg. Med. Chem. Lett. 8:1851 (1998)), a protected 4- piperidone can be converted to the 4-piperidinylidene acetic acid ester via Wittig

olefination. Subsequent Michael addition with the anion of nitromethane, followed by

reduction of the nitro group and spontaneous cyclization with Raney nickel, provides

the protected 2,8-diazaspiro[4.5]decan-3-one. Treatment of the protected 2,8-

diazaspiro[4.5]decan-3-one with a reducing agent, such as lithium aluminum hydride,

followed by removal of the protecting group, provides the 2,8-diazaspiro[4.5]decane.

Arylation can be accomplished on either nitrogen using the methods described herein.

Scheme 8

The compounds of Formula 1, wherein u=2, v=l, w=4 and x=0, possess the l,8-diazaspiro[5.5]decane core and can be prepared according to the procedures

utilized for the analogous l,7-diazaspiro[4.4]nonanes by substituting pipecolinate

ester for proline ester. Alternatively, the procedure reported in Zhu et al., J. Org.

Chem. 58:6451 (1993) can be employed.

The compounds of Formula 1 wherein u=3, v=l, w=l and x=3, possess the

symmetrical 2,8-diazaspiro[5.5]undecane core and can be prepared according to the

procedures reported in HeIv. Chim. Acta 36:1815 (1953), J. Org. Chem. 28:336 (1963)

or, preferably, Culbertson et al., J. Med. Chem. 33:2270 (1990).

The compounds of Formula 1, wherein u=v=2 and w=x=2, possess the

symmetrical 3,9-diazaspiro[5.5]undecane core and can be prepared according to

procedures reported in Rice et al., J. Het. Chem. 1:125 (1964), US patent 3,282,947, or J. Med. Chem. 8:62 (1965).

Single enantiomer compounds of the present invention can be made by various

methods. One method, well known to those skilled in the art of organic synthesis,

involves resolution using diastereomeric salts. Compounds of the present invention

contain basic nitrogen atoms and will react with acids to form crystalline salts.

Various acids, carboxylic and sulfonic, are commercially available in enantiomerically

pure form. Examples include tartaric, dibenzoyl- and di-p-toluoyltartaric, and

camphorsulfonic acids. When any one of these or other single enantiomer acids is

reacted with a racemic amine base, diastereomeric salts result. Fractional

crystallization of the salts, and subsequent regeneration of the bases, results in

enantiomeric resolution thereof.

Another means of separation of involves conversion of the enantiomeric mixture into diastereomeric amides or carbamates, using a chiral acid or

chloroformate. Thus, when racemic 7-(3-pyridyl)-l,7-diazaspiro[4.4]nonane is

coupled with N-(tert-butoxycarbonyl)-S-proline, using diphenyl chlorophosphate, and the protecting group removed (with trifluoroacetic acid), the resulting diastereomeric

proline amides of 7-(3-pyridyl)-l,7-diazaspiro[4.4]nonane are separable by liquid

chromatography. The separated amides are then transformed into (+) and (-) 7-(3- pyridyl)-l,7-diazaspiro[4.4]nonane by the Edman degradation.

Selective synthesis of single enantiomers can also be accomplished by

methods known to those skilled in the art. Such methods will vary as the chemistry

used for construction of the diazaspiro rings varies. For instance, for the syntheses in

which the alkylation of a proline derivative is used to form the diazaspiro system

(such as described for the l,7-diazaspiro[4.4]nonane system), the alkylation of proline

can be carried out in a stereospecific manner. Thus, methods such as those described by Beck et al., Org. Synth. 72: 62 (1993) or Wang and Germanas, Synlett : 33 (1999)

(and references therein) can be used to control the stereochemistry of the alkylation

step. When enantiomerically pure proline ester (commercially available from Aldrich)

is used as the starting material for such a process, the alkylation product is also a

single enantiomer. A variety of electrophiles can be used in such alkylations,

including allyl halides, which have been useful in assembling spiro systems related to

compounds of the present invention Genin and Johnson, J. Amer. Chem. Soc. 114:

8778 (1992).

Bridged Spiro Ring Systems The compounds of Formula 2, wherein u=l, v=2, w=0, x=0, y=2 and z=2,

possess the spiro[l-azabicyclo[2.2.1]heptane-7,3'-pyrrolidine] core and can be prepared according to Scheme 9. The anion of ethyl nitroacetate, formed in the

presence of an amine base, can be condensed with tetrahydropyran-4-one using the

procedure reported in Fornicola et al., J. Org. Chem. 63:3528 (1998). Simultaneous reduction of the nitro group and the olefin under catalytic hydrogenation conditions

provides the 2-(4-oxanyl)glycine ester. This compound can be treated with

hydrobromic acid to afford a dibromide, which is cyclized under basic conditions to

the azabicyclo[2.2.1]heptane-7-carboxylic acid. Treatment of the acid with ethanol

and sulfuric acid provides the ethyl azabicyclo[2.2.1]heptane-7-carboxylate. This

compound is then deprotonated with lithium diisopropylamide and reacted by

Michael addition with nitroethylene to give the ethyl aza-7-(2-

nitroethyl)bicyclo[2.2.1]heptane-7-carboxylate. Reduction of the nitro group with

Raney nickel, followed by spontaneous cyclization, affords the spirolactam.

Treatment of the lactam with lithium aluminum hydride affords the spiro[l-

azabicyclo[2.2.1]heptane-7,3'-pyrrolidine], which is subsequently arylated on the pyrrolidine nitrogen to produce compounds of the present invention.

Scheme 9

The compounds of Formula 2, wherein u=l, v=2, w=l, x=0, y=l and z=2, possess the spiro[l-azabicyclo[2.2.1]heptane-2,3 '-pyrrolidine] ring system and can be prepared according to Scheme 10. Conversion of tetrahydrofuran-3-ylmethanol

(Aldrich) to 3-(bromomethyl)tetrahydrofuran can be achieved through mesylation and subsequent treatment with lithium bromide. The reaction of ethyl glycinate with

benzophenone imine provides ethyl 3-aza-4,4-diphenyl-but-3-enoate which serves to

both protect the amine and activate the methylene carbon toward alkylation.

Alkylation of this imine can be performed, according to the method of Hansen, J. Org.

Chem. 63:775 (1998), by deprotonating with potassium tert-butoxide and reacting

with the 3-(bromomethyl)tetrahydrofuran. Deprotection under acidic conditions

gives the desired 2-amino-3-(tetrahydrofuran-3-yl) propionic ester. Ring opening of

the tetrahydrofuran can be achieved by treatment with hydrobromic acid to afford the

dibromoamino acid intermediate, which, upon heating under basic conditions, cyclizes

to the l-azabicyclo[2.2.1]heptane-2-carboxylic acid. This acid iscan subsequently converted to the ethyl ester, using ethanol and sulfuric acid. Alkylation iscan then

performed by deprotonation with lithium diisopropylamide and reaction with

nitroethylene. Subsequent reduction of the nitro group using Raney nickel, followed

by lactamization by methods known to those skilled in the art, gives the spiro[l-

azabicyclo[2.2.1]heptane-2,3'-pyrrolidine]-2'-one. Treatment of the lactam with

lithium aluminum hydride, gives the desired spiro[l-azabicyclo[2.2.1]heptane-2,3'- pyrrolidine], which is subsequently arylated on the pyrrolidine nitrogen to give

compounds of the present invention.

Scheme 10

ethyl glycinate

The compounds of Formula 2, wherein u=l ,v=2, w=l, X=O, y=2 and z=2,

possess the spiro[l-azabicyclo[2.2.2]octane-2,3'-pyrrolidine] core and can be prepared

in a manner similar to that for the corresponding spiro[l-azabicyclo[2.2.1]heptane-

2,3 '-pyrrolidine], as seen in Scheme 11. Ethyl quinuclidine-2-carboxylate can be generated from (4-bromomethyl)tetrahydropyran by the procedures discussed

previously for ethyl l-azabicyclo[2.2.1]heptane-2-carboxylate. The requisite 4-

(bromomethyl)tetrahydropyran can be prepared according to procedures found in

Burger, et al, J. Am. Chem. Soc. 72:5512 (1950), Thomas, et al., J. Pharm.

Pharmacol. 15:167 (1963) and J. Am. Chem. Soc. 115:8401 (1993). Ethyl

quinuclidine-2-carboxylate iscan then deprotonated with lithium diisopropylamide and

reacted with nitroethylene. Subsequent treatment with Raney nickel gives directly the

spirolactam, spiro[azabicyclo[2.2.2]octane-2,3'-pyrrolidine]-2'-one, by reduction of

the nitro group followed by spontaneous cyclization. This lactam iscan then reduced

with lithium aluminum hydride to provide the desired spiro[l-

azabicyclo[2.2.2]octane-2,3'-pyrrolidine], which is then arylated on the pyrrolidine nitrogen.

¹¹A"

ethyl glycinate

Alternate Synthetic Methods

The compounds can be produced using varying methods. Alternatives to the

palladium catalyzed coupling protocol described above can be used. For instance,

those skilled in the art of organic synthesis will recognize that one or more of the

nitrogen containing rings can be formed by any one of many common amine

syntheses. Thus, an arylamine can be reacted with a protected cyclic amine derivative

(see scheme 12), which contains two reactive electrophiles, to generate an N-

aryldiazaspiro compound. A variety of electrophiles participate in such chemistry (e.g., halides and sulfonates via nucleophilic displacement, aldehydes via reductive

animation, esters and other acid derivatives via acyl substitution, followed by

reduction).

Scheme 12

_Dn PG

^Q-N reagents QU-Q ^IV

Q-¹ ]- Q^{ιv +} ArNH₂ (vary with E)

E = CH₂Z (where Z = X or sulfonate), CHO, CO₂R

The requisite bis-electophiles can be synthesized by many diverse methods.

Schemes 2, 3 and 6 all incorporate such intermediates (in reaction with benzylamine

or ammonia). Pedersen, et al., J. Org. Chem. 58: 6966 (1993) and Berkowitz, et al., J.

Org. Chem. 60: 1233 (1995) both report the alkylation of dianions of N-acyl α-

aminoesters. These alkylations also can be used for synthesis of N-aryldiazaspiro

compounds. Thus, dianion of commercially available (Acros) ethyl 2-pyrrolidone-5- carboxylate can be alkylated with ethyl bromoacetate to generate ethyl 5-

(carboethoxymethyl)-2-pyrrolidone-5-carboxylate. The second spiro ring can be

formed by reacting ethyl 5-(carboethoxymethyl)-2-pyrrolidone-5-carboxylate with an

arylamine. The resulting 2-aryl-2,6-diazspiro[4.4]nonane-l ,3,7-trione can be reduced

with diborane to give 7-aryl-l,7-diazaspiro[4.4]nonane. Depending on the nature of

the aryl group, the order of the synthetic steps can be changed. Likewise, it can be

necessary to incorporate protection/deprotection steps into particular methods.

A wide variety or arylamines are available for use in the approach outlined in

Scheme 12. Pn addition to aminopyridines and aminopyrimidines, 3-aminoisoxazole

is commercially available (Aldrich). This provides a means of synthesizing N-

isoxazolyldiazaspiro compounds. The isomeric 4-aminoisoxazole can be made by

reducing the corresponding nitro compound using the method described by Reiter, J.

Org. Chem. 52: 2714 (1987). Examples of other amino derivatives of 5-membered

aromatic rings include 3-aminoisothiazole, made according to Holland, et al., J. Chem. Soc, 7277 (1965), and 4-aminoisothiazole, made according to Avalos, et al.,

An. Quim. 72: 922 (1976). Thus, a variety of N-aryldiazaspiro compounds of the

present invention, in which the aryl group is a five-membered heterocycle, can be

produced.

III. Pharmaceutical Compositions The compounds described herein can be incorporated into pharmaceutical

compositions and used to bring about smoking cessation, treat drug addiction, or treat

or prevent obesity associated with drug cessattion. The pharmaceutical compositions

described herein include one or more compounds of Formulas 1 or 2 and/or

pharmaceutically acceptable salts thereof. Optically active compounds can be

employed as racemic mixtures or as pure enantiomers. The manner in which the compounds are administered can vary. The

compositions are preferably administered orally (e.g., in liquid form within a solvent

such as an aqueous or non-aqueous liquid, or within a solid carrier). Preferred

compositions for oral administration include pills, tablets, capsules, caplets, syrups,

and solutions, including hard gelatin capsules and time-release capsules.

Compositions may be formulated in unit dose form, or in multiple or subunit doses.

Preferred compositions are in liquid or semisolid form. Compositions including a

liquid pharmaceutically inert carrier such as water or other pharmaceutically compatible liquids or semisolids maybe used. The use of such liquids and semisolids

is well known to those of skill in the art.

The compositions can also be administered via injection, i.e., intraveneously,

intramuscularly, subcutaneously, intraperitoneally, intraarterially, intrathecally; and intracerebroventricularly. Intravenous administration is a preferred method of

injection. Suitable carriers for injection are well known to those of skill in the art, and

include 5% dextrose solutions, saline, and phosphate buffered saline. The compounds

can also be administered as an infusion or injection (e.g., as a suspension or as an

emulsion in a pharmaceutically acceptable liquid or mixture of liquids).

The formulations may also be administered using other means, for example,

transdermally (e.g., using a transdermal patch, using technology that is commercially

available from Novartis and Alza Corporation). Formulations useful for transdermal

administration are well known to those of skill in the art. The compounds can also 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); or rectally. 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. The usefulness of these formulations may depend on the particular

composition used and the particular subject receiving the treatment. These

formulations may contain a liquid carrier that may be oily, aqueous, emulsified or

contain certain solvents suitable to the mode of administration.

The compositions can be administered intermittently 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 are

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.

Preferably, upon administration, the active ingredients interact with receptor sites within the body of the subject, that control dopamine release. The compounds

may be antagonists at both the α4β2 subtype and those NNR subtypes affecting

dopamine release, as long as the effective concentration needed to effectively control

dopamine release is at least an order of magniture less than that necessary to

significantly affect the α4β2 receptor. In one embodiment, the compounds are partial

antagonists, and the partial antagonism permits the compounds to result in a preferred

side effect profile relative to full antagonists.

The ability of these compounds to partially inhibit the release of dopamine is

especially significant, as it indicates that the compounds can be useful in interrupting

the dopamine reward system, and thus in treating disorders that are mediated by it.

Such disorders include substance abuse, tobacco use and weight gain that

accompanies drug cessation. Thus, the compounds described herein are a useful alternative in treating

dependencies on drugs of abuse including alcohol, amphetamines, barbiturates,

benzodiazepines, caffeine, cannabinoids, cocaine, hallucinogens, opiates,

phencyclidine and tobacco and the treatment of eating disorders such as obesity that

occurs following drug cessation while reducing side effects associated with the use of

psychomotor stimulants (agitation, sleeplessness, addiction, etc.).

The compounds also advantageously affect the functioning of the CNS, in a

manner which is designed to optimize the effect upon those relevant receptor subtypes

that have an effect upon dopamine release, while minimizing the effects upon muscle-

type receptor subtypes.

Preferably, the compositions are administered such that active ingredients

interact with regions where dopamine production is affected or occurs. The

compounds described herein are very potent at affecting doamine production and/or secretion at very low concentrations, and are very efficacious (i.e., they inhibit

dopamine production and/or secretion to an effective degree).

In certain circumstances, the compounds described herein can be employed as

part of a pharmaceutical composition with other compounds intended to prevent or

treat drug addiction, nicotine addiction, and/or obesity. In addition to effective

amounts of the compounds described herein, the pharmaceutical compositions can

also include various other components as additives or adjuncts. Exemplary

pharmaceutically acceptable components or adjuncts which are employed in relevant

circumstances include antidepressants, 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 can be imposed as a result of administration of the pharmaceutical

composition.

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.

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., to antagonize or

partially antagonize dopamine production and/or secretion, thus resulting in effective prevention or treatment of the disorder). Prevention of the disorders is manifested by

delaying the onset of the symptoms of the disorder. Treatment of the disorder is

manifested by decreasing the symptoms associated with the disorder or an

amelioration of the recurrence of the symptoms of the disorder. Preferably, the

effective amount is sufficient to obtain the desired result, but insufficient to cause

appreciable side effects.

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 decrease 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 desired therapeutic effects occur (i.e., where

dopamine production and/or secretion is sufficiently lowered) but below the amount

where muscular effects are observed.

The compounds, when employed in effective amounts in accordance with the

method described herein, are selective to certain relevant nicotinic receptors, but do

not significantly activate receptors associated with undesirable side effects at

concentrations at least greater than those required for suppressing the release of

dopamine or other neurotransmitters. By this is meant that a particular dose of compound effective in preventing and/or treating drug addiction, nicotine addiction

and/or obesity (primarily but not necessarily the obesity associated drug or nicotine

cessation) is essentially ineffective in eliciting activation of certain ganglionic-type

nicotinic receptors at concentration higher than 5 times, preferably higher than 100 times, and more preferably higher than 1 ,000 times than those required for

suppression of dopamine production and/or release. This selectivity of certain

compounds described herein against those ganglionic-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 suppression of dopamine production and/or release.

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 μg/ 24 hr/ patient. The effective dose generally does

not exceed about 500, often does not exceed about 400, and frequently does not

exceed about 300 μg/ 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 described herein, when employed in effective amounts in

accordance with the methods described herein, can provide some degree of prevention

of the progression of CNS disorders, ameliorate symptoms of CNS disorders, and

ameliorate to some degree of the recurrence of CNS disorders. The effective amounts

of those compounds are typically below the threshold concentration required to elicit

any appreciable side effects, for example those effects relating to skeletal muscle. The compounds can be administered in a therapeutic window in which certain CNS

disorders are treated and certain side effects are avoided. Ideally, the effective dose of

the compounds described herein 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, the compounds are administered at a dosage effective for treating

the CNS disorders but less than 1/5, and often less than 1/10, the amount required to

elicit certain side effects to any significant degree.

Most preferably, effective doses are at very low concentrations, where

maximal effects are observed to occur, with a minimum of side effects.

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 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 μg/kg of patient

weight, but frequently between about 10 μg to less than 100 μg/kg of patient weight.

For compounds 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 50 μg to less than 5 mg/kg of

patient weight. The foregoing effective doses typically represent that amount

administered as a single dose, or as one or more doses administered over a 24-hour

period.

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 μg/ 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 μg/ 24 hr/ patient. In addition, the compositions are advantageously administered at an effective dose 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, the compounds are dose dependent, and, as such, inhibit cytokine production

and/or secretion when employed at low concentrations but do not exhibit those

inhibiting effects at higher concentrations. The compounds exhibit inhibitory effects

on dopamine production and/or secretion when employed in amounts less than those amounts necessary to elicit activation to any significant degree of nicotinic receptor

subtypes associated with side effects.

IV. Methods of Using the Compounds and/or Pharmaceutical Compositions

The compounds can be used to treat drug addiction, nicotine addiction and/or

obesity, such as the obesity associated with drug cessation. The compounds 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, it is

preferable to administer the active ingredients to in a manner that optimizes effects

upon dopamine production and/or secretion, while minimizing effects upon receptor

subtypes such as those that are associated with muscle and ganglia. This can be

accomplished by targeted drug delivery and/or by adjusting the dosage such that a

desired effect is obtained without meeting the threshold dosage required to achieve

significant side effects.

The compounds have the ability to bind to, and in most circumstances, antagonize or partially antagonize one or more nicotinic receptors of the brain of the

patient that modulate dopamine release, other than the α₄β₂ receptor, at concentrations

at which the α₄β₂ receptor is largely unaffected. As such, such compounds have the

ability to express nicotinic pharmacology, and in particular, to act as dopamine

antagonists. 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 such typical

compounds generally are less than about 1 μM, often are less than about 100 nM, and

frequently are less than about 50 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, when employed in effective amounts as described

herein, are selective to certain relevant nicotinic receptors, but do not significantly

activate receptors associated with undesirable side effects. By this is meant that a

particular dose of compound that is effective at suppressing dopamine production

and/or release is essentially ineffective in eliciting activation of certain ganglionic-

type nicotinic receptors. This selectivity of the compounds of the present invention against those 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.

The compounds demonstrate poor ability to cause isotopic rubidium ion flux

through nicotinic receptors in cell preparations expressing muscle-type nicotinic

acetylcholine receptors. Thus, the compounds exhibit receptor activation constants or

EC₅₀ values (i.e., which provide a measure of the concentration of compound needed

to activate half of the relevant receptor sites of the skeletal muscle of a patient) which

are extremely high (i.e., greater than about 100 μM). Generally, typical preferred

compounds useful in carrying the present invention activate isotopic rubidium ion flux

by less than 10 percent, often by less than 5 percent, of that maximally provided by S(-

) nicotine.

Accordingly, the compounds are effective at suppressing of dopamine

production and/or release, and can be used to treat drug addiction, nicotine addiction, and/or obesity at effective at concentrations that are not sufficient to elicit any

appreciable side effects, as is demonstrated by decreased effects on preparations

believed to reflect effects on the cardiovascular system, or effects to skeletal muscle.

As such, administration of the compounds provides a therapeutic window in which

treatment of drug addiction, nicotine addiction and/or obesity is effected, and side effects are avoided. That is, an effective dose of a compound of the present invention

is sufficient to provide the desired antagonistic effects on dopamine production and/or

secretion, but is insufficient (i.e., is not at a high enough level) to provide undesirable

side effects. Preferably, the compounds results in treatment of drug addiction, nicotine

addiction and/or obesity upon administration of less 1/3, frequently less than 1/5, and often less than 1/10, that amount sufficient to cause any side effects to a significant

degree.

The following examples are provided to illustrate the present invention, and

should not be construed as limiting thereof. In these examples, all parts and

percentages are by weight, unless otherwise noted. Reaction yields are reported in mole percentages. Several commercially available starting materials are used

throughout the following examples. 3-Bromopyridine, 3,5-dibromopyridine, 5- bromonicotinic acid, 5-bromopyrimidine, and 4-penten-2-ol were obtained from

Aldrich Chemical Company or Lancaster Synthesis Inc. 2-Amino-5-bromo-3- methylpyridine was purchased from Maybridge Chemical Company Ltd. (R)-(+)-

propylene oxide was obtained from Fluka Chemical Company, and (S)-(-)-propylene

oxide was obtained from Aldrich Chemical Company. Column chromatography was

done using either Merck silica gel 60 (70-230 mesh) or aluminum oxide (activated, neutral, Brockmann I, standard grade, about 150 mesh). Pressure reactions were done

in a heavy wall glass pressure tube (185 mL capacity), with Ace-Thread, and plunger

valve available from Ace Glass Inc. Reaction mixtures were typically heated using a

high-temperature silicon oil bath, and temperatures refer to those of the oil bath. The

following abbreviations are used in the following examples: CHCl₃ for chloroform,

CH₂Cl₂ for dichloromethane, CH₃OH for methanol, DMF for N₅N-

dimethylformamide, and EtOAc for ethyl acetate, THF for tetrahydrofuran, and Et₃N for triethylamine.

V. Assays

Binding Assay

The ability of the compounds to bind to relevant receptor sites was determined

in accordance with the techniques described in U.S. Patent No. 5,597,919 to Dull et al. Inhibition constants (Kj values) were calculated from the IC₅₀ values using the method

of Cheng et al., Biochem. Pharmacol. 22:3099 (1973). For the α4β2 subtype, the Ki

value for each of the examples in this application was less than 1 μM, indicating that

compounds of the present invention bind tightly to the receptor.

Determination of Log P Value

Log P values, which have been used to assess the relative abilities of

compounds to pass across the blood-brain barrier (Hansch, et al., J. Med. Chem. 11: 1

(1968)), were calculated using the Cerius software package Version 3.5 by Molecular

Simulations, hie. Determination of Dopamine Release

Dopamine release was measured using the techniques described in U.S. Pat. No. 5,597,919 to Dull et al. Release is expressed as a percentage of release obtained with a concentration of (S)-(-)-nicotine resulting in maximal effects. Reported EC₅₀ values are expressed in nM, and E_max values represent the amount released relative to (S)-(-)-nicotine on a percentage basis.

Antagonism of dopamine release can also be evaluated using the assays

described in Gradyet al., "Characterization of nicotinic receptor mediated

[3H]dopamine release from synaptosomes prepared from mouse striatum," J.

Neurochem. 59: 848-856 (1992) and Soliakov and Wonnacott, "Voltage-sensitive

Ca²⁺ channels involved in nicotinic receptor-mediated [3H]dopamine release from rat

striatal synaptosomes," J. Neurochem. 67:163-170 (1996).

Determination of Rubidium Ion Release

Rubidium release was measured using the techniques described in Bencherif et

al., JPET 279: 1413-1421 (1996). Reported EC₅₀ values are expressed in nM, and

E_max values represent the amount of rubidium ion released relative to 300μM tetramethylammonium ion, on a percentage basis.

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. Pat. No.

5,597,919 to Dull et al. The maximal activation for individual compounds (E_max) was

determined as a percentage of the maximal activation induced by (S)-(-)-nicotine.

Reported E_max values represent the amount released relative to (S)-(-)-nicotine on a percentage basis.

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. Pat. No. 5,597,919 to Dull et al. The maximal activation for individual compounds (E_max) was

determined as a percentage of the maximal activation induced by (S)-(-)-nicotine.

Reported E_max values represent the amount released relative to (S)-(-)-nicotine on a percentage basis.

Selectivity

The selectivity of the compounds for a given receptor can be evaluated by

comparing the binding of the compounds to different receptors using known

methodology.

VI. Synthetic Examples

The following synthetic 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 percentage. Example 1

Sample No. 1 is 7-(3-pyridyl)-l,7-diazaspiro[4.4]nonane dihydrochloride,

which was prepared according to the following techniques:

Nitroethylene

Nitroethylene was prepared accordingly to the procedure reported by

Ranganathan, et al., J. Org. Chem. 45: 1185 (1980).

Ethyl 2-(2-nitroethyl)-l-benzylpyrrolidine-2-carboxylate

Under a nitrogen atmosphere, a solution of diisopropylamine (4.34 g, 6.01 mL,

42.9 mmol) in dry THF (50 mL) was cooled in an ice bath as n-butyllithium (17.1 mL

of 2.5 M in hexane, 42.8 mmol) was added by syringe. The ice bath was removed and the solution of lithium diisopropylamide was first warmed to ambient temperature and

then transferred by cannula into a stirred solution of ethyl (S)-N-benzyl pyrrolidine-2-

carboxylate (10.0 g, 42.9 mmol) (Fluka) in dry THF (50 mL), held at -78°C under

nitrogen. The addition took 10 min. After stirring an additional 30 min at -78 "C, the enolate solution was treated (via cannula) with a solution of nitroethylene (3.13 g,

42.9 mmol) in dry THF (20 mL). The mixture was then stirred for 1 h at -78°C.

Saturated aqueous ammonium chloride solution was then added (at -78°C), and the

mixture was warmed to ambient temperature and extracted the ethyl acetate (4 x 30

mL). The extracts were dried (K₂CO₃) and concentrated by rotary evaporation. The

residue was purified by chromatography on a Merck silica gel 60 (70-230 mesh)

column with 9:1 (v/v) hexane/ethyl acetate. Concentration of selected fractions gave

10.0 g (76.3%) of viscous, tan oil.

6-Benzyl-2,6-diazaspiro[4.4]nonan-l-one

Raney nickel (~2 g) was added to a solution of ethyl 2-(2-nitroethyl)-l-

benzylpyrrolidine-2-carboxylate (6.00 g, 19.6 mmol) in absolute ethanol (200 mL) in a hydrogenation bottle. The mixture was shaken for 12 h under a hydrogen

atmosphere (50 psi) in a Parr hydrogenation apparatus, filtered through a Celite pad

and concentrated by rotary evaporation. GCMS analysis indicated that the

hydrogenation product was a mixture of the primary amine and the lactam resulting

from cyclization of the amine onto the ester. The mixture was dissolved in toluene

(150 mL). A catalytic amount of p-toluenesulfonic acid (~30 mg) was added and the

mixture was heated at reflux under a nitrogen atmosphere for 24 h. Upon evaporation

of the toluene, the residue (now entirely lactam, by GCMS) crystallized to give 4.20 g (93.1%) of tan solid (mp 152-153°C).

l-Benzyl-l,7-diazaspiro[4.4]nonane

Lithium aluminum hydride (1.98 g, 52.2 mmol) was added in portions, under

argon, to a ice bath cooled solution of 6-benzyl-2,6-diazaspiro[4.4]nonan-l-one (4.00

g, 17.4 mmol) in dry THF (100 mL). The addition funnel was replaced with a reflux condenser, and the mixture was heated at reflux for 24 h. The mixture was cooled to

0°C and treated drop-wise (caution: exothermic reaction) with 10 M aqueous sodium

hydroxide until hydrogen evolution ceased and the aluminate salts were granular. The

mixture was stirred 1 h at 0°C and filtered through Celite. The filtrate was dried

(K₂CO₃) and concentrated, leaving 3.60 g (95.7%) of viscous, colorless liquid.

l-Benzyl-7-(3-pyridyl)-l,7-diazaspiro[4.4]nonane A mixture of l-benzyl-l,7-diazaspiro[4.4]nonane (2.00 g, 9.26 mmol), 3-

bromopyridine (1.38 g, 8.73 mmol), potassium tert-butoxide (2.50 g, 22.3 mmol),

tris(dibenzylideneacetone)dipalladium(0) (0.318 g, 0.347 mmol), 2,2'-

bis(diphenylphosphino)-l,l'-binaphthyl (0.324 g, 0.520 mmol) and dry toluene (50

mL) was placed in a pressure tube under argon. The mixture was stirred and heated at

90°C (bath temperature) for 24 h and cooled. Water (20 mL) was added and the mixture was extracted with ethyl acetate (6 x 25 mL). The extracts were dried

(K₂CO₃) and concentrated. Column chromatography of the residue on Merck silica

gel 60 (70-230 mesh), with 6:4 (v/v) chloroform/acetone, gave 1.80 g (66.2%) of light

brown oil, after concentration of selected fractions.

7-(3-Pyridyl)-l,7-diazaspiro[4.4]nonane dihydrochloride

Aqueous hydrochloric acid (0.5 mL of 12 M) and 10% palladium on carbon

(0.100 g) were added to a solution of l-benzyl-7-(3-pyridyi)-l,7- diazaspiro[4.4]nonane (1.0 g, 3.41 mmol) in methanol (30 mL). The mixture was

shaken under a hydrogen atmosphere (50 psi) in a Parr hydrogenation apparatus for 24

h and filtered through Celite. The filtrate was concentrated by rotary evaporation and

column chromatographed on Merck silica gel 60 (70-230 mesh). Elution with

0.01:1:9 (v/v) aqueous ammonia/methanol/chloroform, and concentration of selected fractions, gave 0.650 g (93.8%) of viscous, brown oil. A portion (300 mg, 1.48

mmol) of this material was treated with aqueous hydrochloric acid (2 mL). The water

was azeotropically removed by repeated treatment with small volumes of ethanol (~ 5

mL) and rotary evaporation. The resulting solid was recrystallized from hot

isopropanol to give 360 mg (88.2%) of fine tan crystals.

Example 2

Sample 2 is l-(3-pyridyl)-l,7-diaza-spiro[4.4]nonane dihydrochloride, which

was prepared according to the following techniques:

tert-Butyl 6-benzyl-2,6-diazaspiro [4.4]nonane-2-carboxylate

Di-t-butyl dicarbonate (1.45 g, 6.64 mmol) was added to a solution of 1-

benzyl-l,7-diazaspiro[4.4]nonane (1.30 g, 6.01 mmol) and triethylamine (1 mL) in

dichloromethane (25 mL), and the mixture was stirred at ambient temperature

overnight. The mixture was poured into saturated aqueous sodium bicarbonate (10 niL) and extracted with chloroform (4 x 25 niL). The extracts were dried (K₂CO₃)

and concentrated by rotary evaporation. The residue was column chromatographed on

Merck silica gel 60 (70-230 mesh), eluting with, to give 1.85 g (97.4%) of viscous,

colorless oil, after concentration of selected fractions.

tert-Butyl 2,6-diazaspiro[4.4]nonane-2-carboxyIate

A solution of t-butyl 6-benzyl-2,6-diazaspiro[4.4]nonane-2-carboxylate (1.70

g, 5.37 mmol) in methanol (30 mL) was mixed with 10% palladium on carbon (50

mg). The mixture was shaken under a hydrogen atmosphere (50 psi) in a Parr

hydrogenation apparatus for 8 h and filtered through Celite. The filtrate was

concentrated by rotary evaporation and high vacuum treatment, leaving 1.26 g of

viscous, light brown oil (>100%), which was of sufficient purity to be used in the subsequent reaction.

tert-Butyl 6-(3-pyridyl)-2,6-diazaspiro[4.4]nonane-2-carboxylate

A mixture of tert-butyl 2,6-diazaspiro[4.4]nonane-2-carboxylate (1.00 g, ~4.4 mmol), 3-bromopyridine (0.736 g, 4.66 mmol), potassium tert-butoxide (1.22 g, 10.9

mmol), tris(dibenzylideneacetone)dipalladium(0) (0.155 g, 0.169 mmol), 2,2'-

bis(diphenylphosphino)-l,r-bmaphthyl (0.158 g, 0.254 mmol) and dry toluene (25 mL) was placed in a pressure tube under argon. The mixture was stirred and heated at

180° C (bath temperature) for 8 h and cooled. Thin layer analysis indicated that very

little conversion had taken place. A second charge, equal in quantity to the first, of all

reagents except the tert-butyl 2,6-diazaspiro[4.4]nonane-2-carboxylate was added to

pressure tube and the tube was returned to the bath for another 8 h. Again relatively

little reaction seemed to have occurred, so a third charge of reagents was added and

heating (at 180°C) was continued for a third 8 h period. Water (20 mL) was added

and the mixture was extracted with ethyl acetate (6 x 25 mL). The extracts were dried (K₂CO₃) and concentrated. Column chromatography of the residue on Merck silica

gel 60 (70-230 mesh), with 6:4 (v/v) chloroform/acetone, gave 150 mg (-11%) of

light brown oil, after concentration of selected fractions.

l-(3-Pyridyl)-l,7-diazaspiro[4.4]nonane dihydrochloride

A solution of tert-butyl 6-(3-pyridyl)-2,6-diazaspiro[4.4]nonane-2-carboxylate

(100 mg, 0.330 mmol) in dichloromethane (5 mL) was rapidly stirred with 1 mL of 12 M hydrochloric acid at ambient temperature for Ih, during which time the biphasic

mixture became monophasic. The dichloromethane was evaporated, and the residue was dissolved in water (3 mL) and made strongly basic (pH 9) with potassium

carbonate. The mixture was saturated with sodium chloride and extracted with

chloroform (4 x 10 mL). The extracts were dried (K₂CO₃) and concentrated , first by rotary evaporation and then by high vacuum treatment. The viscous brown oil which

resulted was 98% pure by GCMS and weighed 50 mg (73%). A sample of this free base (40 mg, 020 mmol)was dissolved in 10 drops of 12 M hydrochloric acid. The

water was azeotropically removed by repeated treatment with small volumes of

ethanol (~ 5 mL) and rotary evaporation. The resulting solid was recrystallized from

hot isopropanol to give 40 mg (72%) of fine tan crystals (mp 170-175°C).

Example 3

Sample 3 is l-methyl-7-(3-pyridyl)-l,7-diazaspiro[4.4]nonane, which was

prepared according to the following techniques:

l-Methyl-7-(3-pyridyl)-l,7-diazaspiro[4.4]nonane

7-(3-Pyridyl)-l,7-diazaspiro[4.4]nonane (30 mg, 0.15 mmol) was dissolved in

98% formic acid (0.5 mL) and formaldehyde (1 mL, 28% aqueous solution). The

reaction mixture was heated to reflux for 8 h. The reaction mixture was cooled to

room temperature, basified with saturated aqueous sodium bicarbonate to pH 9-10 and extracted with chloroform (4 x 3mL). The combined chloroform extracts were dried

(K₂CO₃), filtered and concentrated on a rotary evaporator to afford 30 mg of the

desired compound (93.6%) as a light brown liquid.

Example 4

Sample 4 is l-methyl-7-(5-ethoxy-3-pyridyl)-l,7-diazaspiro[4.4]nonane, which

was prepared according to the following techniques:

5-bromo-3-ethoxypyridine

Under a nitrogen atmosphere, sodium (4.60 g, 200 mmol) was added to absolute ethanol (100 mL) at 0-5⁰C, and the stirring mixture was allowed to warm to

ambient temperature over 18 h. To the resulting solution was added 3,5-

dibromopyridine (31.5 g, 133 mmol), followed by DMF (100 mL). The mixture was

heated at 70°C for 48 h. The brown mixture was cooled, poured into water (600 mL), and extracted with ether (3 x 500 mL). The combined ether extracts were dried

(Na₂SO₄), filtered, and concentrated by rotary evaporation. Purification by vacuum

distillation afforded 22.85 g (85.0%) of an oil, bp 89-90°C at 2.8 mm Hg (lit. bp

11 TC at 5 mm Hg, see K. Clarke, et al., J. Chem. Soc. 1885 (I960)).

l-Benzyl-7-(5-ethoxy-3-pyridyl)-l,7-diazaspiro[4.4]nonane l-Benzyl-l,7-diazaspiro[4.4]nonane (500.0 mg, 2.4 mmol) was dissolved in

dry toluene (15 mL) in a 50 mL round bottom flask equipped with a magnetic stirring

bar. Nitrogen was bubbled through the solution in a slow stream. To the stirring

solution was added 3-bromo-5-ethoxypyridine (513.8 mg, 2.55 mmol), potassium tert-

butoxide (1039.0 mg, 9.26 mmol), rac-2,2'-bis(diphenylphosphino)-l,l'-binaphthyl (

86.4 mg, 0.14 mmol) and tris(dibenzylideneacetone)dϊpalladium(0) (63.6 mg, 0.06

mmol), while continuing to purge with nitrogen. Nitrogen flow was discontinued and

the flask was sealed and heated at 9O⁰C for 8 h. The reaction was cooled and the solvent was removed by rotary evaporation. The resulting residue was suspended in

saturated aqueous sodium bicarbonate (10 mL) and extracted with chloroform (4 x 25

mL). The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated

by rotary evaporation to a thick dark mass. Purification by column chromatography,

using methanol/chloroform (2:98, v/v) as the eluent, gave 0.54 g of the desired

compound as a light brown viscous liquid (69%).

7-(5-Ethoxy-3-pyridyl)- 1 ,7-diazaspiro [4.4] nonane

To a solution of l-benzyl-7-(5-ethoxy-3-pyridyl)-l,7-diazaspiro[4.4]nonane

(540 mg, 1.6 mmol) in ethanol (25 mL) in a pressure bottle was added concentrated

HCl (1 mL) and Pearlman's catalyst (Pd(OH)₂, 20% on carbon, 50 mg). The solution was shaken under 50 psi of hydrogen gas for 8 h. The catalyst was removed by

filtration through Celite, and the filter cake was washed with ethanol (20 mL). The

solvent was removed by rotary evaporation, and the residue was basified with saturated aqueous sodium bicarbonate to pH 8-9. Solid sodium chloride (2 g) was

added, and the mixture was extracted with chloroform (4 x 20 mL). The combined

chloroform extracts were dried (Na₂SO₄), filtered and concentrated by rotary

evaporation to afford 360.7 mg of the desired compound as a light brown viscous

liquid (91.1%).

l-Methyl-7-(5-ethoxy-3-pyridyl)-l,7-diazaspiro[4.4]nonane To a stirring solution of 7-(5-ethoxy-3-pyridyl)-l,7-diazaspiro[4.4]nonane

(360.4mg, 1.4 mmol) in 37% aqueous solution of formaldehyde (4 mL) was added

98% formic acid (2 mL) under nitrogen. The reaction mixture was heated to reflux

for 8 h. The reaction mixture was cooled to room temperature, then basified with

saturated aqueous sodium bicarbonate to pH 8-9 and extracted with chloroform (4 x

15mL). The combined chloroform extracts were dried (Na₂SO₄), filtered and concentrated by rotary evaporation to afford a viscous brown liquid. This was

distilled using a Kugelrohr apparatus (2mm, 18O⁰C) to give a very light cream-colored

syrup (340 mg, 89.3%).

Example 5

Sample 5 is l-methyl-7-(5-phenoxy-3-pyridyl)-l,7-diazaspiro[4.4]nonane,

which was prepared according to the following techniques:

3-Bromo-5-phenoxypyridine

Sodium hydride (1.35 g of 80% in mineral oil, 45.0 mmol) was added to a

stirred solution of phenol (4.26 g, 45.3 mmol) in DMF (30 mL) at 0°C, under

nitrogen. The mixture was stirred at room temperature for 3 h, treated with 3,5-

dibromopyridine (4.0 g, 16.9 mmol) and heated at 100°C for 48 h. The reaction

mixture was cooled to room temperature, poured into a mixture of water (100 mL)

and 5M sodium hydroxide (10 mL), and extracted with ether (3 x 60 mL). The

combined ether extracts were dried (Na₂SO₄), filtered, and rotary evaporated to a pale

yellow semi-solid (4.9 g). This was chromatographed on a silica gel (200 g) column

with hexane/ethyl acetate/chloroform (8:1:1, v/v) as eluant to give 2.86 g (68% yield) of a colorless oil.

l-Benzyl-7-(5-phenoxy-3-pyridyl)-l,7-diazaspiro[4.4]nonane l-Benzyl-l,7-diazaspiro[4.4]nonane (500.0 mg, 2.4 mmol) was dissolved in

dry toluene (15 mL) in a 50 mL round bottom flask equipped with a magnetic stirring

bar. Nitrogen was bubbled through the solution in a slow stream. To the stirring

solution was added 3-bromo-5-phenoxypyridine (636.8 mg, 2.55 mmol), potassium

tert-butoxide (1039.0 mg, 9.26 mmol), rac-2,2'-bis(diphenylphosphino)-l,l'-

binaphthyl (86.4 mg, 0.14 mmol) and tris(dibenzylideneacetone)dipalladium(0) (63.6

mg, 0.06 mmol), while continuing to purge with nitrogen. Nitrogen flow was discontinued and the flask was sealed and heated at 9O⁰C for 8 h. The reaction was

cooled and the solvent was removed by rotary evaporation. The resulting residue was

suspended in saturated aqueous sodium bicarbonate (10 mL) and extracted with

chloroform (4 x 25 mL). The combined organic extracts were dried (Na₂SO₄),

filtered, concentrated by rotary evaporation to a thick dark mass. This was purified by

column chromatography, using methanol/chloroform (2:98, v/v) as the eluent, to

afford 0.70 g of the desired compound as a light brown viscous liquid (78.6%).

7-(5-Phenoxy-3-pyridyl)-l,7-diazaspiro[4.4]nonane

To a solution of l-benzyl-7-(5-phenoxy-3-pyridyl)-l,7-diazaspiro[4.4]nonane

(690 mg, 1.79 mmol) in ethanol (25 mL) in a pressure bottle was added concentrated

HCl (1 mL) and Pearlman's catalyst (Pd(OH)₂, 20% on carbon, 50 mg). The solution was shaken under 50 psi of hydrogen gas for 8 h. The catalysts was removed by

filtration through Celite, and the filter cake was washed with ethanol (20 mL). The

solvent was removed by rotary evaporation, and the residue was basifϊed with

saturated aqueous sodium bicarbonate to pH 8-9. Solid sodium chloride (2 g) was

added, and the solution was extracted with chloroform (4 x 20 mL). The combined

chloroform extracts were dried (Na₂SO₄), filtered and concentrated by rotary

evaporation to afford 490 mg of the desired compound as a light brown viscous liquid

(92.7 %).

l-Methyl-7-(5-phenoxy-3-pyridyl)-l,7-diazaspiro[4.4]nonane

To a stirring solution of 7-(5-phenoxy-3-pyridyl)-l,7-diazaspiro[4.4]nonane

(420 mg, 1.42 mmol) in 37% aqueous solution of formaldehyde (5 mL) was added

98% formic acid (3 mL) under nitrogen. The reaction mixture was heated to reflux

for 8 h. The reaction mixture was cooled to room temperature, then basified with

saturated aqueous sodium bicarbonate to pH 8-9 and extracted with chloroform (4 x 15 mL). The combined chloroform extracts were dried (Na₂SO₄), filtered and

concentrated by rotary evaporation to afford a thick brown viscous liquid. This was

distilled using a Kugelrohr apparatus (2mm, 18O⁰C) to give a very pale cream-colored syrup (400 mg, 90.9 %).

l-Methyl-7-(5-phenoxy-3-pyridyl)-l,7-diazaspiro[4.4]nonane dihydrochloride l-Methyl-7-(5-phenoxy-3-pyridyl)-l,7-diazaspiro[4.4]nonane (200 mg, 0.65

mmol) was dissolved in concentrated HCl (1 mL) and sonicated for 5 min. The

excess acid and water were removed by repeated azeotropic evaporation with small portions of ethanol. A pale yellow solid was obtained. The solid was dissolved in the

minimum amount of absolute ethanol (~ 1 mL), and then ether was added drop-wise

until the solution became opaque. Cooling in the refrigerator overnight produced

cream-colored crystals, which were filtered, washed with ether and dried in a vacuum oven to yield 210 mg (85.4 %) of pure dihydrochloride salt, m.p. 180-191⁰C. Example 6

Sample 6 is r-(3-pyridyl)-spiro[l-azabicyclo[2.2.1]heptane-2,3'-pyrrolidine] dihydrochloride, which was prepared according to the following techniques:

(3-oxolanyl)methyl methanesulfonate

To a stirring solution of (3-oxolanyl)methan-l-ol (25 g, 245 mmol) and triethylamine (34.37 mL, 245 mmol) in dry dichloromethane (250 mL) at O⁰C under

N₂ atmosphere was added dropwise methanesulfonyl chloride (18.94 mL, 245 mmol).

The reaction mixture was stirred overnight after warming to room temperature, then a

saturated solution OfNaHCO₃ (100 mL) was added and the mixture stirred for another

30 min. The biphasic mixture was separated and the organic layer was discarded.

The aqueous layer was extracted with dichloromethane (3 x 25 mL) and the combined

dichloromethane extracts were dried (Na₂SO₄), filtered and concentrated by rotary evaporation to give 42.16 g of (3-oxolanyl)methyl methanesulfonate (99 %) as a light

brown liquid.

3-(Bromomethyl)oxolane

To a stirring solution of (3-oxolanyl)methyl methanesulfonate (42.16 g, 239.5

mmol) in dry acetone (600 mL) was added lithium bromide (101.7 g, 1198 mmol).

The reaction mixture was heated to reflux for 3 h, then it was cooled and the solvent

removed by rotary evaporation. The residue was dissolved in water (200 mL) and

extracted with dichloromethane (2 x 100 mL). The combined extracts were dried

(Na₂SO₄), filtered and concentrated by rotary evaporation to afford a light brown liquid. It was distilled at 70°C and lmm of pressure to give 33.00 g (86.77 %) of 3-

(bromomethyl)oxolane as a colorless liquid.

Methyl 3-aza-4,4-diphenyl-but-3-enoate

To a stirring solution of methyl glycine ester hydrochloride (17.49 g, 139 mmol) in dry dichloromethane (150 mL) under N₂ at room temperature was added

diphenylimine (25.00 g, 137 mmol) in one portion. The reaction mixture was stirred

for 24 h, during which time ammonium chloride precipitated. Water (20 mL) was

added and the layers were separated. The organic layer was washed with saturated

Na₂CO₃ solution (2 x 20 mL) and brine (20 mL). The organic layer was dried

(Na₂SO₄), filtered and concentrated by rotary evaporation to give ~35 g of a thick light

brown syrup (99% pure) in ~ 100% yield. This was taken on to the next reaction

without further purification.

Methyl 3-(3-oxolanyl)-2-aminopropanoate

To a stirring solution of methyl 3-aza-4,4-diphenyl-but-3-enoate (23.00 g, 90

mmol) under N₂ in dry DMF (25 mL) and toluene (25 mL) was added potassium tert-

butoxide (10.20 g, 90 mmol) in one portion. The reaction mixture was stirred for 15 min; it changed color from yellow to dark reddish-brown. Then, a solution of 3-

(bromomethyl)oxolane (15 g, 90 mmol) in DMF (20 mL) and dry toluene (20 mL)

was added via cannula over a period of 30 min. The reaction mixture was stirred for

an additional 16 h at ambient temperature. Then, IN HCl (100 mL) was added to the

reaction mixture and it was stirred for another 30 min. The mixture was extracted with

ethyl acetate (3 x 50 mL). The aqueous layer was basified with solid K₂CO₃ to pH 8-9,

then saturated with solid NaCl and extracted with ethyl acetate (4 x 50 mL). The

combined ethyl acetate extracts were dried (K₂CO₃), filtered and concentrated by

rotary evaporation to give methyl 3-(3-oxolanyl)-2-aminopropanoate (10 g, 59.37 %)

as a brown liquid.

Ethyl l-azabicyclo[2.2.1]heptane-2-carboxylate

Methyl 3-(3-oxolanyl)-2-aminopropanoate (6.00 g, 3.46 mmol) was placed in a

sealed pressure tube, then 48% aqueous HBr (20 mL) was added and the solution was saturated with HBr gas. The tube was sealed carefully and heated at 110°- 120° C for 8

h. The reaction was then cooled and the contents transferred to a 250 mL round

bottom flask with 20 mL of water. The excess acid was removed by rotary

evaporation to give a semi solid brown mass. Then 30% aqueous ammonium

hydroxide (150 mL) was added at O⁰C and the mixture was heated at gentle reflux for

4 h. The solvent was removed by rotary evaporation to give a brown solid, which then

was dissolved in absolute ethanol (50 mL). Concentrated H₂SO₄ (10 mL) was added

and the solution was refluxed for 8 h. The contents were cooled in an ice bath, and

then basified with concentrated NaHCO₃ solution to pH 8-9 and extracted with

chloroform (4 x 4OmL). The combined chloroform extracts were dried (K₂CO₃),

filtered and concentrated to give a brown-black liquid which was distilled using a

Kugelrohr apparatus (lmm, 14O⁰C) to afford a colorless liquid (4 g, 68.25%) as a mixture of the exo and endo isomers of ethyl l-azabicyclo[2.2.1]heptane-2- carboxylate.

Ethyl l-aza-2-(nitroethyl)bicyclo[2.2.1]heptane-2-carboxylate

Lithium diisopropylamide (LDA) was prepared at O⁰C from diisopropylamine

(2.078g, 20.53mmol) and n-butyllithium (8.2ImL, 20.53 mmol) in dry THF (20 mL)

under an N₂ atmosphere. To a stirring solution of a mixture of the exo and endo

isomers of ethyl l-azabicyclo[2.2.1]heptane-2-carboxylate (2.67g, 15.79 mmol) in dry THF (35 mL) at -78⁰C under N₂ atmosphere was added via cannula the LDA solution

over a period of 15 min. The reaction mixture was stirred for an additional 40

minutes. Then a solution of nitroethylene (1.45 g, 20.53 mmol) in dry THF (20 mL)

was added dropwise via cannula to the reaction mixture over a period of 15 min.

After stirring for 2 h at -78⁰C, the reaction was quenched by adding a saturated solution of ammonium chloride (20 mL). It was extracted with ethyl acetate (5 x 25

mL), dried (Na₂SO₄), filtered and concentrated by rotary evaporation to give 3.82 g of

the desired product (86% pure) as a light brown liquid, which was taken on to the next

^{■ ■} step without further purification.

2 Η-spiro[azabicyclo[2.2.1]heptane-2,3 ^f-pyrroIidin]-2 '-one

Ethyl l-aza-2-(nitroethyl)bicyclo[2.2.1]heptane-2-carboxylate (3.82 g, 86%

pure, 15.78 mmol) was dissolved in ethanol (50 mL) in a hydrogenolysis bottle. A

catalytic amount of Raney nickel was added and the mixture was subjected to

hydrogenolysis at 50 psi on a Parr apparatus for 16 h. The catalyst was removed by

filtration through a celite plug and washed with ethanol (20 mL). A catalytic amount

(5 mg) of p-toluenesulfonic acid was added and the reaction mixture was refluxed for

12 h. The solvent was removed by rotary evaporation to afford a light brown solid.

This was dissolved in cone. NaHCO₃ solution (10 mL), saturated with NaCl and extracted with chloroform (4 x 40 mL). The combined chloroform extracts were dried

(K₂CO₃), filtered and concentrated by rotary evaporation to give a light brown solid.

It was purified by column chromatography, using MeOH:CHCl₃:NH₄OH (9:1:0.01,

v/v) as the eluent, to afford 1.96 g (75%) of 2'H-spiro[azabicyclo[2.2.1]heptane-2,3'-

pyrrolidin]-2'-one as a cream-colored solid (m.p. 98⁰C).

Spiro[l-azabicyclo[2.2.1]heptane-2,3 '-pyrrolidine]

To a solution of 2Η-spiro[azabicyclo[2.2.1]heptane-2,3'-pyrrolidin]-2'-one (1.00 g, 6.02 mmol) in dry THF (20 mL) at O⁰C under N₂ atmosphere was added

lithium aluminum hydride (647 mg, 17.7 mmol) and the mixture was refluxed for 24

h. The reaction mixture was cooled in ice bath and then ether (20 mL) was added.

Excess hydride was quenched by the dropwise addition of 5 M solution of NaOH. The resulting solid aluminate salts were removed by filtration through a celite plug.

The filtrate was dried (Na₂SO₄), filtered and concentrated by rotary evaporation to

yield 800 mg of spiro[l-azabicyclo[2.2.1]heptane-2,3'-pyrrolidine] as a colorless

liquid (87.43%).

1 '-(3-Pyridyl)-spiro[l-azabicyclo[2.2.1]heptane-2,3 '-pyrrolidine] dihydrochloride A mixture of spiro[l-azabicyclo[2.2.1]heptane-2,3 '-pyrrolidine] (300 mg, 1.98

mmol), 3-bromopyridine (344 mg, 2.18 mmol),

tris(dibenzylideneacetone)dipalladium(0) (54.57mg, 0.0654 mmol), rac-2,2'-

bis(diphenylphosphino)- 1 , 1 '-binaphthyl (74.22 mg, 0.131 mmol) and potassium tert-

butoxide (668.8 mg, 5.96 mmol) in dry toluene (20 mL) was heated in a sealed tube

flushed with argon gas at 9O⁰C for 8 h. The reaction was cooled to O⁰C and the

contents transferred to a 10OmL round bottom flask. The solvent was removed by

rotary evaporation and the residue was dissolved in a saturated solution OfNaHCO₃

(10 mL) and extracted with chloroform (4 x 15mL). The combined chloroform extracts were dried (K₂CO₃), filtered and concentrated by rotary evaporation to give a

dark colored syrup. This was purified by column chromatography, using

MeOH:CHCl₃:NH₄OH (8:2:0.01, v/v) as the eluent, to afford 350 mg (79.0%) of 1'- (3-pyridyl)-spiro[l-azabicyclo[2.2.1]heptane-2,3'-pyrrolidine] as a light brown syrup.

A portion of the free base (200 mg) was converted to a hydrochloride salt, which was

crystallized from isopropanol and ethanol to yield 200 mg (76%) of a light brown

solid, (m.p. 232°-236°C).

Example 7

Sample 7 is l'-(5-ethoxy-3-pyridyl)-spiro[l-azabicyclo[2.2.1]heptane-2,3'- pyrrolidine], which was prepared according to the following techniques:

l'-(5-Ethoxy-3-pyridyl)-spiro[l-azabicyclo[2.2.1]heptane-2,3 '-pyrrolidine]

A mixture of spiro[l-azabicyclo[2.2.1]heptane-2,3'-pyrrolidine] (50 mg, 0.3 mmol) tris(dibenzylideneacetone)dipalladium(0) (9 mg, 0.009 mmol), rac-2,2'-

bis(diphenylphosphino)-l,l'-binaphthyl (12 mg, 0.018 mmol), potassium tert-butoxide

(147 mg, 1.2 mmol), and 5-bromo-3-ethoxypyridine (73 mg, 0.36 mmol) in dry

toluene (5 mL) was placed in a sealed tube under argon and heated at 160° C for 17 h.

The reaction was cooled to O⁰C and the contents transferred to a 10OmL round bottom

flask. The solvent was removed by rotary evaporation and the residue was dissolved

in a saturated solution OfNaHCO₃ (10 mL) and extracted with chloroform (4 x

15mL). The combined chloroform extracts were dried (K₂CO₃), filtered and

concentrated by rotary evaporation to give a dark colored syrup. This was purified by

column chromatography, using MeOH : CHCl₃ :NH₄OH (8:2:0.01, v/v) as the eluent, to

give 28 mg (27%) of l'-(5-ethoxy-3-pyridyl)-spiro[l-azabicyclo[2.2.1]heptane-2,3'-

pyrrolidine] as a viscous brown oil. Example 8

Sample 8 is l'-(5-phenoxy-3-pyridyl)-spiro[l-azabicyclo[2.2.1]heptane-2,3'-

pyrrolidine], which was prepared according to the following techniques:

l'-(5-Phenoxy-3-pyridyl)-spiro[l-azabicyclo[2.2.1]heptane-2,3 '-pyrrolidine] A mixture of spiro[ 1 -azabicyclo[2.2.1 ]heptane-2,3 '-pyrrolidine] (50 mg,

0.3mmol), tris(dibenzylideneacetone)dipalladium(0) (9mg, 0.009 mmol), rac-2,2'-

bis(diphenylphosphino)-l,l'-binaphthyl (12 mg, 0.018 mmol), potassium tert-butoxide

(147 mg, 1.3 mmol), and 5-bromo-3-phenoxypyridine (90 mg, 0.36 mmol) in dry

toluene (5 mL) was heated in a sealed tube under argon at 160° C for 17 h. The

reaction was cooled to O⁰C and the contents transferred to a 10OmL round bottom

flask. The solvent was removed by rotary evaporation and the residue was dissolved in a saturated solution OfNaHCO₃ (10 mL) and extracted with chloroform (4 x

15mL). The combined chloroform extracts were dried (K₂CO₃), filtered and

concentrated by rotary evaporation to give a dark colored syrup. This was purified by column chromatography, using MeOH: CHCl₃ :NH₄OH (8:2:0.01, v/v) as the eluent, to

afford 55.8 mg of l'-(5-phenoxy- 3-pyridyl)-spiro[l-azabicyclo[2.2.1]heptane-2,3'-

pyrrolidine] (52%) as a viscous tan oil.

Example 9

Sample 9 is r-(5-pyrimidinyl)-spiro[l-azabicyclo[2.2.1]heptane-2,3'-

pyrrolidine], which was prepared according to the following techniques:

l'-(5-Pyrimidinyl)-spiro[l-azabicyclo[2.2.1]heptane-2,3 '-pyrrolidine]

A mixture of spiro[l-azabicyclo[2.2.1]heptane-2,3 '-pyrrolidine] (100 mg, 0.06

mmol), tris(dibenzylideneacetone)dipalladium(0) (18mg, 0.0018 mmol), rac-2,2'-

bis(diphenylphosphino)-l,l'-binaphthyl (24 mg, 0.0036 mmol), potassium tert-

butoxide (300 mg, 2.6 mmol), and 5-bromopyrimidine (114 mg, 0.7 mmol) in dry toluene (10 niL) was placed in a sealed tube under argon and heated at 125° C for 17

h. The reaction was cooled to O⁰C and the contents transferred to a 10OmL round

bottom flask. The solvent was removed by rotary evaporation and the residue was

dissolved in a saturated solution OfNaHCO₃ (10 mL) and extracted with chloroform

(4 x 15mL). The combined chloroform extracts were dried (K₂CO₃), filtered and

concentrated by rotary evaporation to give a dark colored syrup. This was purified by

column chromatography, using MeOH : CHCl₃ :NH₄OH (8:2:0.01, v/v) as the eluent, to

afford 49.0 mg of r-(5-pyrimidinyl)-spiro[l-azabicyclo[2.2.1]heptane-2,3'- pyrrolidine] (32%) as a viscous brown oil.

Example 10

Sample 10 is r-(3-pyridyl)-spiro[l-azabicyclo[2.2.2]octane-2,3'-pyrrolidine], which was prepared according to the following techniques:

Ethyl quinuclidine-2-carboxylate

The ethyl quinuclidine-2-carboxylate for this synthesis was prepared according

to the method described by Ricciardi and Doukas (Heterocycles 24:971 (1986)). We have also prepared ethyl quinuclidine-2-carboxylate using chemistry analogous to that

used for the synthesis of ethyl l-azabicyclo[2.2.1]heptane-2-carboxylate, but using 4- (bromomethyl)oxane in place of 3-(bromomethyl)oxolane.

Ethyl 2-(2-nitroethyl)quinuclidine-2-carboxylate Lithium diisopropylamide was prepared at O⁰C from lithium diisopropylamine

(193.53mg, 1.91 mmol) and n-butyllithium (0.764mL, 1.91 mmol) under N₂. It was

added via cannula to a stirring solution of ethyl quinuclidine-2-carboxylate (320 mg,

1.74 mmol) in dry THF (10 mL) at -78⁰C. After Ih, a solution of nitroethylene

(140.41 mg, 1.91 mmol) in THF (5 mL) was added dropwise to the reaction mixture.

After stirring for 2 h at -78⁰C, the reaction was quenched by adding a saturated solution of ammonium chloride (20 mL). It was extracted with ethyl acetate (5 x 25

mL), dried (Na₂SO₄), filtered and concentrated by rotary evaporation to give 325 mg

(70% pure) ethyl 2-(2-nitroethyl)quinuclidine-2-carboxylate as a light brown liquid,

which was taken on to the next step without further purification.

2 Η-spiro[azabicyclo[2.2.2] octane-2,3 '-pyrrolidin]-2 '-one

A solution of ethyl 2-(2-nitroethyl)quinuclidine-2-carboxylate (320 mg, ) in

ethanol (10 mL) was subjected to hydrogenolysis at 50 psi on a Parr apparatus for 16 h

using Raney nickel as a catalyst. The catalyst was removed by filtration through a celite plug and washed with ethanol (20 mL). A catalytic amount (5 mg) of p-

toluenesulfonic acid was added and the reaction mixture was refluxed for 12 h. The

solvent was removed by rotary evaporation to afford a light brown solid. This was

dissolved in cone. NaHCO₃ solution (10 mL), saturated with NaCl and extracted with chloroform (4 x 40 mL). The combined chloroform extracts were dried (K₂CO₃),

filtered and concentrated by rotary evaporation to give a light brown solid. It was

purified by chromatography, using MeOH: CHCl₃ :NH₄OH (8:2:0.01, v/v) as the eluent, to give 120 mg (38.2%) of desired compound as light cream-colored solid

(m.p. 103°-105°C).

Spiro [1-azabicyclo [2.2.2] octane-2,3 '-pyrrolidine]

To a solution of 2Η-spiro[azabicyclo[2.2.2]octane-2,3'-pyrrolidin]-2'-one (100

mg, 0.55 mmol) in dry THF (10 mL) at O⁰C under N₂ atmosphere was added lithium

aluminum hydride (74 mg, 1.94 mmol) and the mixture was refluxed for 24 h. The

reaction mixture was cooled in ice bath and then ether (20 mL) was added. Excess

hydride was quenched by the dropwise addition of 5 M solution of NaOH. The

resulting solid aluminate salts were removed by filtration through a celite plug. The

filtrate was dried (Na₂SO₄), filtered and concentrated by rotary evaporation to yield 83 mg of spiro[l-azabicyclo[2.2.2]octane-2,3'-pyrrolidine] as a colorless liquid (90 %).

1 '-(3-Pyridyl)-spiro [1-azabicyclo [2.2.2] octane-2,3 '-pyrrolidine]

A stirring solution of spiro[l-azabicyclo[2.2.2]octane-2,3 '-pyrrolidine] (80 mg, 0.48 mmol), tris(dibenzylidineacetone)dipalladium(0) (26.47 mg, 0.024 mmol), rac-

2,2'-bis(diphenylphosphino)-l,r-binaphthyl (30 mg, 0.048 mmol) and potassium tert-

butoxide (215 mg, 1.92 mmol) in dry toluene (15 mL) was placed in a sealed tube

under argon and heated at 9O⁰C for 16 h. The reaction was cooled to O⁰C and the

contents transferred to a 10OmL round bottom flask. The solvent was removed by

rotary evaporation and the residue was dissolved in a saturated solution OfNaHCO₃

(10 mL) and extracted with chloroform (4 x 15mL). The combined chloroform

extracts were dried (K₂CO₃), filtered and concentrated by rotary evaporation to give a

dark colored syrup. This was purified by column chromatography, using MeOH:CHCl₃:NH₄OH (8:2:0.01, v/v) as the eluent, to give 102 mg (85.7 %) of l'-(3-

pyridyl)-spiro[l-azabicyclo[2.2.2]octane-2,3'-pyrrolidine] as a light brown syrup. Example 11

Sample 11 is l'-(3-pyridyl)-2'H-spiro[l-azabicyclo[2.2.1]heptane-7,3'-

pyrrolidine], which was prepared according to the following techniques:

Ethyl 2-(2H,3H,5H-4-oxinyl)-2-nitroacetate

A 2 M solution of titanium tetrachloride in THF was made by slow addition of

the titanium tetrachloride (7.59 g, 40 mmol) to dry THF (20 mL) at O⁰C under an

nitrogen, atmosphere. Ethyl nitroacetate (2.66 g, 20 mmol) was then added to the

stirring solution, and the mixture was stirred for 5 min. Next, tetrahydro-4-H- pyran-

4-one (2.00 g, 20 mmol) was added in one portion. Then, a 1.0 M solution of N-

methyl morpholine in THF (8.09 g, 80 mmol) was added dropwise over a period of 2

h at O⁰C. The mixture was then allowed to warm to room temperature and was stirred for 18 h. It was then poured into water (20 mL) and extracted with ethyl acetate (5 x

4OmL). The combined extracts were dried over Na₂SO₄, filtered and concentrated by

rotary evaporation. The thick brown syrup was purified by column chromatography,

using ethyl acetate :hexane (1 :9, v/v) as eluent, to afford 3.00 g of pure compound as a

light-brown syrup (70%).

Ethyl 2-(4-oxanyl)-2-aminoacetate

Raney nickel (~2 g) was added to a solution of ethyl 2-(2H,3H,5H-4-oxinyl)-2-

nitroacetate (2.50 g, 11.62 mmol) in ethanol (50 mL) and cone. HCl (1 mL). The

mixture was subjected to hydrogenolysis at 50 psi on a Parr apparatus for 18 h. The

catalyst was removed by careful filtration through a celite plug. The solvent was

removed by rotary evaporation. The residue was basifϊed with saturated aqueous

NaHCO₃ to pH 8-9, then saturated with NaCl and extracted with chloroform (4 x 25 mL). The combined extracts were dried over K₂CO₃, filtered and concentrated to yield

2.40 g (~ 100%) of desired compound as a tan liquid.

l-azabicyclo[2.2.1] heptane-7- carboxylic acid hydrochloride

Ethyl 2-(oxanyi)-2-aminoacetate (1.50 g, 8.02 mmol) was dissolved in 48%

HBr (10 mL) in a pressure tube and saturated with HBr gas. The tube was sealed

carefully and heated for 12 h at 120°- 13 O⁰C. The reaction was cooled to room

temperature, transferred to a 250 mL round bottom flask, and the acid was removed by

rotary evaporation. The dark colored residue was dissolved in 30% ammonia solution

(50 mL). This mixture was stirred for 5 h at room temperature, until cyclization to the

desired acid was complete. The ammonia solution was removed by rotary evaporation

to afford a light brown solid, which was redissolved in 5 mL of water and purified on

an ion exchange resin using water as the eluent and ammonia (30% aq.). Ammoniacal

fractions containing the desired acid were combined and concentrated to afford pure acid, which was converted to an HCl salt and crystallized from isopropanol and

diethyl ether to give 1.21 g (85%) of a cream-colored solid (m.p. 232° turns brown,

melts at 253°-254°C).

Ethyl l-azabicycIo[2.2.1]heptane-7-carboxylate

A solution of 1 -azabicyclo [2.2.1] heptane-7- carboxylic acid hydrochloride

(1.20 g, 6.76 mmol) in absolute ethanol (10 mL) and concentrated sulfuric acid (2 mL)

was refluxed for 8 h. The reaction mixture was cooled and then basified with

saturated aqueous NaHCO₃ to pH 8-9. The solution was saturated with solid NaCl

and extracted with chloroform (4 x 20 mL). The combined chloroform extracts were

dried over Na₂SO₄, filtered and concentrated by rotary evaporation to give a light

brown liquid. This was purified by Kugelrohr distillation at 12O⁰C and 2.5mm pressure to afford 1.00 g (90%) as a colorless liquid.

Ethyl l-aza-7-(2-nitroethyl)bicyclo[2.2.1]heptane-7-carboxylate

Lithium diisopropylamide was prepared by the addition of n-butyllithium (1.70

mL, 6.26 mmol) to diisopropylamine (431.1 mg, 6.26 mmol) in dry THF (5 mL) at 0° under a N₂ atmosphere. The reaction was stirred at room temperature for 15 min and

then transferred via cannula to a stirring solution of ethyl l-azabicyclo[2.2.1]heptane-

7-carboxylate (600 mg, 3.55 mmol) in THF (2OmL) at -78° C under a N₂ atmosphere.

The reaction mixture was stirred for 30 min at -78°C, then a solution of nitroethylene

(285.3 mg, 3.91 mmol) in THF (10 mL) was added via cannula and the reaction was

stirred for additional 2 h at -78°C. Then the reaction was quenched with saturated

NH₄Cl solution (10 mL). The reaction mixture was allowed to warm to room

temperature and then was extracted with ethyl acetate (4 x 20 mL). The combined

fractions were dried (K₂CO₃), filtered and concentrated by rotary evaporation to give

650 mg of a light-brown liquid. It was purified by column chromatography, using ethyl acetate:dichloromethane (8:2, v/v), to give 600 mg (85%) of tan liquid.

2Η-Spiro[l-azabicyclo[2.2.1]heptane-7,3'-pyrrolidin]-2'-one

Ethyl l-aza-7-(2-nitroethyl)bicyclo[2.2.1]heptane-7-carboxylate (550 mg, 2.27

mmol) was dissolved in ethanol (25 mL) and subjected to hydrogenolysis at 50 psi for

18 h, using Raney nickel as a catalyst. The catalyst was removed by filtration through

a celite plug. The solvent was removed by rotary evaporation. The resultant residue

was dissolved in toluene (50 mL) and a catalytic amount of p-toluenesulfonic acid (10

mg) was added. The solution was refluxed for 12 h and then the solvent was removed

by rotary evaporation. The residue was added to saturated NaHCO₃ (10 mL) solution

and extracted with chloroform (5 x 15 mL). The combined chloroform extracts were

dried (K₂CO₃), filtered, and concentrated. The residue was purified by column chromatography, using CHCl₃: MeOH :NH₄OH (9:1:0.01, v/v) as the eluent, to afford

320 mg (85%) of pure compound as a cream-colored thick syrup.

2 Η-Spiro[l-azabicyclo[2.2.1]heptane-7,3 '-pyrrolidine] To a stirring solution of 2'H-spiro[l-azabicyclo[2.2.1]heptane-7,3'-pyrrolidin]-

2'-one (300 mg, 1.80 mmol) in dry THF (30 mL) at 0° under N₂ was added LiAlH₄

(274.33 mg, 7.22 mmol). The ice bath was removed and the reaction mixture was

refluxed for 24 h. The reaction mixture was cooled to O⁰C, diethyl ether (20 mL) was

added and 5M NaOH was added dropwise with constant stirring until all unreacted

LiAlH₄ solidified. The reaction mixture was filtered through celite and then the

filtrate was dried (K₂CO₃), filtered and concentrated by rotary evaporation to yield

250 mg (70 %) of a colorless syrup.

l'-(3-Pyridyl)-2'H-spiro[l-azabicyclo[2.2.1]heptane-7;,3'-pyrrolidine]

2Η-Spiro[l-azabicyclo[2.2.1]heptane-7,3'-pyrrolidine] (100 mg, 0.66 mmol),

tris(dibenzylideneacetone)dipalladium(0) (30mg, 0.020 mmol), rac-2,2'- bis(diphenylphosphino)-l,r-binaphthyl (45mg, 0.040 mmol), potassium tert-butoxide

(369mg, 3.3mmol) and 3-bromopyridine (114mg, 0.72 mmol) and dry toluene (10

niL) were placed in a pressure tube which was flushed with argon. The tube was

carefully sealed and heated for 8 h at 9O⁰C. The reaction mixture was cooled,

transferred to a round bottom flask and the solvent removed by rotary evaporation.

The residue was poured into saturated NaHCO₃ solution (5 mL) and extracted with

chloroform (4 x 15 mL). The combined chloroform extracts were dried over K₂CO₃,

filtered and concentrated by rotary evaporation. The residue was purified by column

chromatography, using CHCl₃ :MeOH:NH₄OH (8:2:0.01, v/v) as eluent, to afford 130

mg (86.7%) of a light brown syrup. The product turns dark brown on exposure to

light and air. Examples 12 and 13

Samples 12 and 13 are (+) and (-) 7-(3-pyridyl)-l,7-diazaspiro[4.4]nonane

respectively, which were prepared according to the following techniques:

Diastereomeric 7-(3-pyridyl)-l,7-diazaspiro[4.4]nonane S-proline amides

Triethylamine (6.0 mL, 43 mmol) and diphenyl chlorophosphate (4.0 mL, 19

mmol) were added, in that order, to a stirred suspension of N-(tert-butoxycarbonyl)-S-

proline (4.67 g, 21.7 mmol) in dichloromethane (100 mL) under a nitrogen

atmosphere. After stirring for 1.5 h at ambient temperature, the reaction mixture was

treated with a solution of 7-(3-pyridyl)-l ,7-diazaspiro[4.4]nonane (4.40 g, 21.6 mmol)

in dichloromethane (10 mL). The mixture was stirred 3 days at ambient temperature.

Sodium hydroxide solution (30 mL of 5 M) was then added. After stirring an

additional hour, the mixture was poured into a separatory funnel with chloroform (30

mL) and water (30 mL). The mixture was shaken vigorously, and the layers were

separated. The organic layer and a 30 mL chloroform extract of the aqueous layer were combined, dried (MgSO₄) and concentrated by rotrary evaporation. The residue

(7.2 g) was dissolved in dichloromethane (100 mL) and conbined with trifluroacetic

acid (50 mL). The mixture was stirred at ambient temperature for 1 h. The volatiles

were evaporated, first by rotary evaporation and then on the vacuum pump. The

residue was purified by preparative HLPC, using 10% acetonitrile, 0.1%

trifluoroacetic acid in water as eluent. Selected fractions were combined and

concentrated, leaving 3.13 g (79% yield) of the diastereomer which elutes at 11.4 min and 2.90 g (74% yield) of the diastereomer that elutes at 13.2 min, both as white

foams (presumably mono trifluoroacetate salts).

(+) and (-) 7-(3-pyridyl)-l,7-diazaspiro[4.4]nonane

Each of the two diastereomeric S-proline amides was dissolved in

dichloromethane (50 mL) and triethylamine (2-3 mL), and then combined with

phenylisothiocyanate (1.73 g, 12.8 mmol for the earlier eluting diastereomer and 1.57 g, 11.6 mmol for the later eluting diastereomer). The two reactions were stirred at

ambient temperature for 16 h, at which point thin layer chromatography indicated that

the reactions were complete. The mixtures were concentrated by rotary evaporation,

and each of the residues was taken up in dichloromethane (10 mL) and treated with

trifluoroacetic acid (10 mL). These reactions were held at 50°C for 16 h and

concentrated to dryness. Column chromatography on silica gel with 80:20:2

chlorform/methanol/ammonia gave 620 mg (derived from the earlier eluting

diastereomer, 40.5% yield) and 720 mg (derived from the later eluting diastereomer,

50.7% yield), as light brown oils. Chiral HPLC analysis was perormed on a Chiralcel

OD ® column, using 7:3 heaxane/ethanol. The isomer derived from the earlier eluting

diastereomer had the longer retention time on the chiral column (10.9 min); that

derived from the later eluting isomer exhibited a retention time of 8.7 min on the chiral column. The samples were enantiomerically pure within the limits of detection

(-2%).

Example 14

The study of the in vitro pharmacology of 7-(3-pyridyl)-l,7-

diazaspiro[4.4]nonane showed it to be an antagonist at both the α4β2 subtype (IC50 =

193 μM; Imax = 50%) and those NNR subtypes affecting dopamine release (IC50 =

901 nM; Imax = 67%). The ability of this compound to partially inhibit the release of

dopamine is especially significant, as it indicates that this compound (and others in the

N-arylspirodiazaalkane genus) may be useful in interrupting the dopamine reward

system, and thus treating disorders that are mediated by it. Such disorders include

substance abuse, tobacco use and weight gain that accompanies drug cessation.

The in vivo evidence that N-arylspirodiazaalkanes can be useful in this manner

was derived from a fourteen-day preclinical safety pharmacology study, in which 7-(3-

pyridyl)-l,7-diazaspiro[4.4]nonane reduced weight gain in rats, without demonstrating stimulant sensitization properties.

Based on this data, it is anticipated that compounds of the N-

arylspirodiazaalkane genus described herein present a useful alternative in treating

dependencies on drugs of abuse including alcohol, amphetamines, barbiturates,

benzodiazepines, caffeine, cannabinoids, cocaine, hallucinogens, opiates,

phencyclidine and tobacco and in treating eating disorders such as obesity that occurs

following drug cessation while reducing side effects associated with the use of

psychomotor stimulants (agitation, sleeplessness, addiction, etc.).

Having hereby disclosed the subject matter of the present invention, it should

be apparent that many modifications, substitutions, and variations of the present

invention are possible in light thereof. It is to be understood that the present invention can be practiced other than as specifically described. Such modifications,

substitutions and variations are intended to be within the scope of the present application.

Claims

Claims:

1. A method for treating drug addiction, nicotine addiction, and/or obesity,

comprising administering an effective amount of a compound sufficient to decrease

production and/or secretion of dopamine of a compound having the following

formula:

Cy

Formula 1 and pharmaceutically acceptable salts thereof,

wherein Q¹ is (CZ₂)_U, Q^π is (CZ₂)_V, Q^m is (CZ₂)_W, and Q^w is (CZ₂)_X, u, v, w and x are individually 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3,

R is hydrogen, lower alkyl, acyl, alkoxycarbonyl or aryloxycarbonyl,

Z is, individually, selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted

heterocyclyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl and

substituted arylalkyl;

Cy is a six membered ring of the formula:

where each of X, X', X", X'" and X"" is individually nitrogen, nitrogen bonded

to oxygen or carbon bonded to a substituent species, wherein no more than three of X,

X', X", X'" and X"" are nitrogen or nitrogen bonded to oxygen,

or Cy is a five 5-membered heteroaromatic ring of the formula:

where Y and Y" are individually nitrogen, nitrogen bonded to a substituent

species, oxygen, sulfur or carbon bonded to a substituent species, and Y' and Y'" are

nitrogen or carbon bonded to a substituent species, wherein "substituent species" are, individually, selected from the group

consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, heterocyclyl, substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, aryl,

substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, halo, - OR', -NR'R", -CF₃, -CN, -NO₂, -C₂R', -SR', -N₃, -C(=O)NR'R", -NR'C(-O) R", -

C(=O)R', -C(=O)OR^!, -OC(=O)R', -O(CR'R")_rC(=O)R', -O(CR'R")_rNR"C(=O)R', -

O(CR'R")_rNR"SO₂R', -OC(=O)NR'R", -NR'C(=O)O R", -SO₂R', -SO₂NRR", and -

NR¹SO₂R",

where R' and R" are individually hydrogen, C₁-C₈ alkyl, cycloalkyl,

heterocyclyl, aryl, or arylalkyl, and r is an integer from 1 to 6, or R' and R" can

combine to form a cyclic functionality,

wherein the term "substituted" as applied to alkyl, aryl, cycloalkyl and the like

refers to the substituents described above, starting with halo and ending with - NR¹SO₂R", and

wherein the dashed lines indicate that the bonds (between Y and Y¹ and

between Y' and Y") can be either single or double bonds, with the proviso that when

the bond between Y and Y' is a single bond, the bond between Y' and Y" must be a

double bond and vice versa, where Y or Y" is oxygen or sulfur, only one of Y and Y"

is either oxygen or sulfur, and at least one of Y, Y', Y" and Y'" must be oxygen, sulfur,

nitrogen or nitrogen bonded to a substituent species.

2. The method of claim 1, wherein only one or two of X, X', X", X'" and X""

are nitrogen or nitrogen bonded to oxygen.

3. The method of claim 1 , wherein not more than one of X, X', X", X'" and X""

are nitrogen bonded to oxygen.

4. The method of claim 1, wherein X'" is nitrogen or nitrogen bonded to

oxygen.

5. The method of claim 1, wherein both X' and X'" are nitrogen.

6. The method of claim 1 , wherein X, X" and X"" are carbon bonded to a

substituent species.

7. The method of claim 6, where the substituent species at X, X" and X"" are hydrogen.

8. The method of claim 1, wherein X'" is carbon bonded to a substituent

species and X and X' are both nitrogen, or X' is carbon bonded to a substituent species

and X and X"¹ are both nitrogen.

9. The method of claim 1, wherein no more than three of Y, Y', Y" and Y'" are

oxygen, sulfur, nitrogen or nitrogen bonded to a substituent species.

10. The method of claim 1, wherein between one and three of Y, Y', Y" and Y"¹ are nitrogen. 11. A method for treating drug addiction, nicotine addiction, and/or obesity,

comprising administering an effective amount of a compound sufficient to decrease

production and/or secretion of dopamine of a compound having the following

formula:

Formula 2

and pharmaceutically acceptable salts thereof,

wherein Q¹ is (CZ₂)_U, Q^π is (CZ₂)_V, Q^ffl is (CZ₂)_W, Q^w is (CZ₂)_X, Q^v is(CZ₂)_y

and Q^VI is (CZ₂)_Z where u, v, w, x, y and z are individually 0, 1, 2, 3 or 4, and the values of u, v, w, x, y and z are selected such that the bridged diazaspirocyclic ring

contains 8, 9, 10,

11, 12 or 13 members,

R is hydrogen, lower alkyl, acyl, alkoxycarbonyl or aryloxycarbonyl,

Z is, individually, selected from the group consisting of hydrogen, alkyl,

substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted

heterocyclyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl and

substituted arylalkyl;

Cy is a six membered ring of the formula:

where each of X, X', X", X'" and X"" is individually nitrogen, nitrogen bonded

to oxygen or carbon bonded to a substituent species, wherein no more than three of X,

X', X", X" and X"" are nitrogen or nitrogen bonded to oxygen,

or Cy is a five 5-membered heteroaromatic ring of the formula:

where Y and Y" are individually nitrogen, nitrogen bonded to a substituent

species, oxygen, sulfur or carbon bonded to a substituent species, and Y' and Y'" are

nitrogen or carbon bonded to a substituent species,

wherein "substituent species" are, individually, selected from the group

consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, heterocyclyl, substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, aryl,

substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, halo, -

OR¹, -NR¹R", -CF₃, -CN, -NO₂, -C₂R¹, -SR¹, -N₃, -Q=O)NR¹R", -NR'C(=0) R", - C(=O)R', -C(=O)OR', -OC(=O)R', -0(CR¹R¹¹XCC=O)R¹, -O(CR¹R")_rNR"C(=O)R¹, -

0(CR¹R¹O₁NR¹¹SO₂R¹, -0C(=0)NR'R", -NR¹C(=O)O R", -SO₂R¹, -SO₂NR¹R", and -

NR¹SO₂R", where R¹ and R" are individually hydrogen, C₁-C₈ alkyl, cycloalkyl,

heterocyclyl, aryl, or arylalkyl, and r is an integer from 1 to 6, or R¹ and R" can

combine to form a cyclic functionality,

wherein the term "substituted" as applied to alkyl, aryl, cycloalkyl and the like

refers to the substituents described above, starting with halo and ending with -

NR¹SO₂R", and wherein the dashed lines indicate that the bonds (between Y and Y¹ and between Y' and Y") can be either single or double bonds, with the proviso that when

the bond between Y and Y' is a single bond, the bond between Y' and Y" must be a

double bond and vice versa, where Y or Y" is oxygen or sulfur, only one of Y and Y"

is either oxygen or sulfur, and at least one of Y, Y', Y" and Y'" must be oxygen, sulfur, nitrogen or nitrogen bonded to a substituent species.

12. The method of claim 11, wherein only one or two of X, X', X", X'" and

X"" are nitrogen or nitrogen bonded to oxygen.

13. The method of claim 11, wherein not more than one of X, X', X", X™ and

X"" are nitrogen bonded to oxygen.

14. The method of claim 11 , wherein X'" is nitrogen or nitrogen bonded to oxygen.

15. The method of claim 11, wherein both X and X" are nitrogen.

16. The method of claim 11, wherein X, X" and X"" are carbon bonded to a substituent species.

17. The method of claim 16, where the substituent species at X, X" and X"" are hydrogen.

18. The method of claim 11, wherein X'" is carbon bonded to a substituent

species and X and X are both nitrogen, or X' is carbon bonded to a substituent species

and X and X'" are both nitrogen.

19. The method of claim 11, wherein no more than three of Y, Y^?, Y" and Y"'

be oxygen, sulfur, nitrogen or nitrogen bonded to a substituent species.

20. The method of claim 11, wherein between one and three of Y, Y', Y" and

Y'" are nitrogen.

21. A method for treating drug addiction, nicotine addiction, and/or obesity,

comprising administering an effective amount of a compound selected from the group consisting of:

7-(3-pyridyl)-l,7-diazaspiro[4.4]nonane;

7-(5-pyrimidinyl)- 1 ,7-diazaspiro[4.4]nonane;

7-(5-isoxazolyl)-l,7-diazaspiro[4.4]nonane;

7-(5-isothiazolyl)-l,7-diazaspiro[4.4]nonane;

7-(5-(l ,2,4-oxadiazol)yl)-l ,7-diazaspiro[4.4]nonane;

7-(2-(l ,3,4-oxadiazol)yl)-l ,7-diazaspiro[4.4]nonane;

7-(2-pyrazinyl)- 1 ,7-diazaspiro[4.4]nonane;

7-(3-pyridazinyl)- 1 ,7-diazaspiro[4.4]nonane;

7-(5-methoxy-3-pyridyl)-l ,7-diazaspiro[4.4]nonane;

7-(5-cyclopentyloxy-3-pyridyl)-l,7-diazaspiro[4.4]nonane;

7-(5-phenoxy-3-pyridyl)-l,7-diazaspiro[4.4]nonane;

7-(5-(4-hydroxyphenoxy)-3-pyridyl)-l,7-diazaspiro[4.4]nonane;

7-(5-ethynyl-3-pyridyl)-l,7-diazaspiro[4.4]nonane;

7-(6-chloro-3-pyridyl)-l ,7-diazaspiro[4.4]nonane;

7-(6-methoxy-3-pyridazinyl)-l,7-diazaspiro[4.4]nonane;

l-(3-pyridyl)-l,7-diazaspiro[4.4]nonane;

1 -(5-pyrimidinyl)- 1 ,7-diazaspiro[4.4]nonane;

1 -(5-isoxazolyl)- 1 ,7-diazaspiro [4.4]nonane; l-(5-isothiazolyl)-l,7-diazaspiro[4.4]nonane;

l-(5-(l,2,4-oxadiazol)yl)-l,7-diazaspiro[4.4]nonane;

1 -(2-(1 ,3 ,4-oxadiazol)yl)- 1 ,7-diazaspiro [4.4]nonane;

l-(2-pyrazinyl)-l,7-diazaspiro[4.4]nonane;

l-(3-pyridazinyl)-l,7-diazaspiro[4.4]nonane;

l-methyl-7-(3-pyridyl)-l ,7-diazaspiro[4.4]nonane; 1 -methyl-7-(5-pyrimidinyl)- 1 ,7-diazaspiro[4.4]nonane;

1 -methyl-7-(5-isoxazolyl)- 1 ,7-diazaspiro[4.4]nonane;

1 -methyl-7-(5-isothiazolyl)- 1 ,7-diazaspiro[4.4]nonane;

1 -methyl-7-(5-(l ,2,4-oxadiazol)yl)- 1 ,7-diazaspiro[4.4]nonane;

l-methyl-7-(2-(l,3,4-oxadiazol)yl)-l,7-diazaspiro[4.4]nonane;

l-methyl-7-(2-pyrazinyl)-l,7-diazaspiro[4.4]nonane;

l-methyl-7-(3-pyridazinyl)-l,7-diazaspiro[4.4]nonane;

1 -methyl-7-(5-methoxy-3-pyridyl)-l ,7-diazaspiro[4.4]nonane;

l-methyl-7-(5-cyclopentyloxy-3-pyridyl)-l,7-diazaspiro[4.4]nonane; 1 -methyl-7-(5-phenoxy-3-pyridyl)-l ,7-diazaspiro[4.4]nonane;

l-methyl-7-(5-(4-hydroxyphenoxy)-3-pyridyl)-l,7-diazaspiro[4.4]nonane;

1 -methyl-7-(5-ethynyl-3-pyridyl)-l ,7-diazaspiro[4.4]nonane;

l-methyl-7-(6-chloro-3-pyridyl)-l,7-diazaspiro[4.4]nonane;

l-methyl-7-(6-methoxy-3-pyridazinyl)-l,7-diazaspiro[4.4]nonane; 7-methyl- 1 -(3 -pyridyl)- 1 ,7-diazaspiro[4.4]nonane;

7-methyl-l-(5-pyrimidinyl)-l,7-diazaspiro[4.4]nonane;

7-methyl- 1 -(5-isoxazolyl)- 1 ,7-diazaspiro[4.4]nonane;

7-methyl-l-(5-isothiazolyl)-l,7-diazaspiro[4.4]nonane;

7-methyl-l-(5-(l,2,4-oxadiazol)yl)-l,7-diazaspiro[4.4]nonane;

7-methyl-l-(2-(l,3,4-oxadiazol)yl)-l,7-diazaspiro[4.4]nonane;

7-methyl- 1 -(2-pyrazinyl)- 1 ,7-diazaspiro [4.4]nonane;

7-methyl-l-(3-pyridazinyl)-l,7-diazaspiro[4.4]nonane;

2-(3-pyridyl)-2,7-diazaspiro[4.4]nonane;

2-(5-pyrimidinyl)-2,7-diazaspiro[4.4]nonane;

2-(5-isoxazolyl)-2,7-diazaspiro[4.4]nonane; 2-(5-isothiazolyl)-2,7-diazaspiro[4.4]nonane;

2-(5-(l,2,4-oxadiazol)yl)-2,7-diazaspiro[4.4]nonane;

2-(2-(l,3,4-oxadiazol)yl)-2,7-diazaspiro[4.4]nonane;

2-(2-pyrazinyl)-2,7-diazaspiro[4.4]nonane;

2-(3-pyridazinyl)-2,7-diazaspiro[4.4]nonane;

2-(5-methoxy-3-pyridyl)-2,7-diazaspiro[4.4]nonane;

2-(5-cyclopentyloxy-3-pyridyl)-2,7-diazaspiro[4.4]nonane;

2-(5-phenoxy-3-pyridyl)-2,7-diazaspiro[4.4]nonane;

2-(5-(4-hydroxyphenoxy)-3-pyridyl)-2,7-diazaspiro[4.4]nonane; 2-(5-ethynyl-3-pyridyl)-2,7-diazaspiro[4.4]nonane;

2-(6-chloro-3-pyridyl)-2,7-diazaspiro[4.4]nonane;

2-(6-methoxy-3-pyridazinyl)-2,7-diazaspiro[4.4]nonane;

2-methyl-7-(3-pyridyl)-2,7-diazaspiro[4.4]nonane;

2-methyl-7-(5-methoxy-3-pyridyl)-2,7-diazaspiro[4.4]nonane;

2-methyl-7-(5-phenoxy-3-pyridyl)-2,7-diazaspiro[4.4]nonane;

6-(3-pyridyl)-l,6-diazaspiro[3.4]octane;

1 -methyl-6-(3 -pyridyl)- 1 ,6-diazaspiro[3.4] octane;

2-(3-pyridyl)-2,5-diazaspiro[3.4]octane;

5-methyl-2-(3-pyridyl)-2,5-diazaspiro[3.4]octane;

6-(3-pyridyl)-l,6-diazaspiro[3.5]nonane;

l-methyl-6-(3-pyridyl)-l,6-diazaspiro[3.5]nonane;

2-(3-pyridyl)-2,5-diazaspiro[3.5]nonane;

5-methyl-2-(3-pyridyl)-2,5-diazaspiro[3.5]nonane;

2-(3-pyridyl)-2,6-diazaspiro[4.5]decane;

6-methyl-2-(3-pyridyl)-2,6-diazaspiro[4.5]decane; 7-(3-pyridyl)-l,7-diazaspiro[4.5]decane;

1 -methyl-7-(3-pyridyl)-l ,7-diazaspiro[4.5]decane;

8-(3-pyridyl)-l,8-diazaspiro[5.5]undecane;

1 -methyl- 8 -(3 -pyridyl)- 1 , 8 -diazaspiro [5.5 ]undecane; and

pharmaceutically acceptable salts thereof.

22. A method for treating drug addiction, nicotine addiction, and/or obesity,

comprising administering an effective amount of a compound selected from the group

consisting of:

1 '-(3 -pyridyl)-spiro[ 1 -azabicyclo [2.2.1 ]heptane-2,3 '-pyrrolidine] ;

r-(5-ethoxy-3-pyridyl)-spiro[l-azabicyclo[2.2.1]heptane-2,3'-pyπOlidine];

1 '-(5-cyclopentyloxy-3-pyridyl)-spiro[ 1 -azabicyclo[2.2.1 ]heptane-2,3 '-pyrrolidine] ; r-(5-phenoxy-3-pyridyl)-spiro[l-azabicyclo[2.2.1]heptane-2,3'-pyrrolidine];

1 '-(5-(4-hydroxyphenoxy)-3-pyridyl)-spiro[ 1 -azabicyclo[2.2.1 ]heptane-2,3 '-

pyrrolidine];

r-(5-pyrimidinyl)-spiro[l-azabicyclo[2.2.1]heptane-2,3'-pyrrolidine];

1 '-(5-isoxazolyl)-spiro[ 1 -azabicyclo[2.2.1 ]heptane-2,3 '-pyrrolidine];

r-(5-isothiazolyl)-spiro[l-azabicyclo[2.2.1]heptane-2,3'-pyrrolidine]; r-(5-(l,2,4-oxadiazol)yl)-spiro[l-azabicyclo[2.2.1]heptane-2,3'-pyrrolidine];

r-(2-(l,3,4-oxadiazol)yl)-spiro[l-azabicyclo[2.2.1]heptane-2,3'-pyrrolidine];

r-(2-pyrazinyl)-spiro[l-azabicyclo[2.2.1]heptane-2,3'-pyrrolidine];

r-(3-pyridazinyl)-sρiro[l-azabicyclo[2.2.1]heptane-2,3'-ρyrrolidine];

1 '-(5-ethynyl-3-pyridyl)-spiro[ 1 -azabicyclo[2.2.1 ]heptane-2,3 '-pyrrolidine] ;

r-(6-chloro-3-pyridyl)-spiro[l-azabicyclo[2.2.1]heptane-2,3 '-pyrrolidine];

1 '-(6-methoxy-3-pyridazinyl)-spiro[l -azabicyclo[2.2.1 ]heptane-2,3 '-pyrrolidine] ;

r-(3-pyridyl)-spiro[l-azabicyclo[2.2.2]octane-2,3'-pyrrolidine]; r-(5-methoxy-3-pyridyl)-spiro[l-azabicyclo[2.2.2]octane-2,3'-pyrrolidine];

r-(5-cyclopentyloxy-3-pyridyl)-spiro[l-azabicyclo[2.2.2]octane-2,3'-pyrrolidine];

l'-(5-phenoxy-3-pyridyl)-spiro[l-azabicyclo[2.2.2]octane-2,3 '-pyrrolidine];

1 '-(5-(4-hydroxyphenoxy)-3 -pyridyl)-spiro[ 1 -azabicyclo [2.2.2] octane-2,3 '-

pyrrolidine];

1 '-(5-ethynyl-3-pyridyl)-spiro[ 1 -azabicyclo[2.2.2]octane-2,3 '-pyrrolidine] ;

r-(6-chloro-3-pyridyl)-spiro[l-azabicyclo[2.2.2]octane-2,3'-pyrrolidine];

1 '-(5-pyrimidinyl)-spiro[ 1 -azabicyclo[2.2.2]octane-2,3 '-pyrrolidine] ;

r-(2-pyrazinyl)-spiro[l-azabicyclo[2.2.2]octane-2,3'-pyrrolidine]; 1 '-(3 -pyridazinyl)-spiro [ 1 -azabicyclo [2.2.2] octane-2,3 '-pyrrolidine] ;

r-(6-methoxy-3-pyridazinyl)-spiro[l-azabicyclo[2.2.2]octane-2,3 '-pyrrolidine];

l'-(5-isoxazolyl)-spiro[l-azabicyclo[2.2.2]octane-2,3'-pyrrolidine]; r-(5-isothiazolyl)-spiro[l-azabicyclo[2.2.2]octane-2,3'-pyrrolidine];

1 '-(5-(1 ,2,4-oxadiazol)yl)-spiro[ 1 -azabicyclo[2.2.2]octane-2,3 '-pyrrolidine] ;

1 '-(2-(1 ,3,4-oxadiazol)yl)-spiro[ 1 -azabicyclo[2.2.2]octane-2,3 '-pyrrolidine] ;

1 '-(3-pyridyl)-2'H-spiro[l -azabicyclo[2.2. l]heptane-7,3 '-pyrrolidine];

r-(5-methoxy-3-pyridyl)-2'H-spiro[l-azabicyclo[2.2.1]heptane-7,3'-pyrrolidine];

1 '-(5-cycloρentyloxy-3-pyridyl)-2'H-spiro[ 1 -azabicyclo [2.2.1 ]heptane-7,3 '-

pyrrolidine];

r-(5-phenoxy-3-pyridyl)-2'H-spiro[l-azabicyclo[2.2.1]heptane-7,3'-pyrrolidine];

r-(5-(4-hydroxyphenoxy)-3-pyridyl)-2'H-spiro[l-azabicyclo[2.2.1]heptane-7,3'-

pyrrolidine];

1 '-(6-chloro-3 -pyridyl)-2 Η-spiro [ 1 -azabicyclo [2.2.1 ]heptane-7,3 '-pyrrolidine] ;

1 '-(5-pyrimidinyl)-2'H-spiro[ 1 -azabicyclo[2.2.1 ]heptane-7,3 '-pyrrolidine] ;

1 '-(2-pyrazinyl)-2'H-spiro[l -azabicyclo[2.2.1 ]heptane-7,3 '-pyrrolidine] ; r-(3-ρyridazinyl)-2'H-spiro[l-azabicyclo[2.2.1]heptane-7,3'-pyrrolidine];

r-(6-methoxy-3-pyridazinyl)-2'H-spiro[l-azabicyclo[2.2.1]heptane-7,3'-pyrrolidine]; 1 '-(5-isoxazolyl)-2'H-spiro[ 1 -azabicyclo[2.2.1 ]heptane-7,3 '-pyrrolidine] ;

r-(5-isothiazolyl)-2'H-spiro[l-azabicyclo[2.2.1]heptane-7,3'-pyrrolidine];

r-(5-(l,2,4-oxadiazol)yl)-2'H-spiro[l-azabicyclo[2.2.1]heptane-7,3'-pyrrolidine] ;

1 '-(2-(1 ,3,4-oxadiazol)yl)-2'H-spiro[ 1 -azabicyclo[2.2.1 ]heptane-7,3 '-pyrrolidine] ; and pharmaceutically acceptable salts thereof.

23. Use of a compound having the following formula:

Formula 1

and pharmaceutically acceptable salts thereof,

wherein Q¹ is (CZ₂)_U, Q^π is (CZ₂)_V, Q^m is (CZ₂)_W, and Q^w is (CZ₂)_X u, v, w and x are individually 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3,

R is hydrogen, lower alkyl, acyl, alkoxycarbonyl or aryloxycarbonyl,

Z is, individually, selected from the group consisting of hydrogen, alkyl,

substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted

heterocyclyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl and

substituted arylalkyl;

Cy is a six membered ring of the formula: x I-i V I *

X" \_χ,,r X""

where each of X, X', X", X'" and X"" is individually nitrogen, nitrogen bonded

to oxygen or carbon bonded to a substituent species, wherein no more than three of X,

X', X", X'" and X"" are nitrogen or nitrogen bonded to oxygen,

or Cy is a five 5-membered heteroaromatic ring of the formula:

where Y and Y" are individually nitrogen, nitrogen bonded to a substituent

species, oxygen, sulfur or carbon bonded to a substituent species, and Y' and Y"¹ are

nitrogen or carbon bonded to a substituent species,

wherein "substituent species" are, individually, selected from the group

consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, heterocyclyl, substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, aryl,

substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, halo,

OR', -NR¹R", -CF₃, -CN, -NO₂, -C₂R¹, -SR', -N₃, -C(=O)NR'R", -NR'C(=O) R", -

C(=O)R', -C(=O)OR', -OC(=O)R', -O(CR'R")_rC(=O)R', -O(CR'R")_rNR"C(=O)R', -

O(CR'R")_rNR"SO₂R', -OC(=O)NR'R", -NR'C(=O)O R", -SO₂R¹, -SO₂NR¹R", and -

NR¹SO₂R", where R' and R" are individually hydrogen, C₁-C₈ alkyl, cycloalkyl, heterocyclyl, aryl, or arylalkyl, and r is an integer from 1 to 6, or R' and R" can

combine to form a cyclic functionality,

wherein the term ''substituted" as applied to alkyl, aryl, cycloalkyl and the like

refers to the substituents described above, starting with halo and ending with -

NR¹SO₂R", and

wherein the dashed lines indicate that the bonds (between Y and Y' and

between Y' and Y") can be either single or double bonds, with the proviso that when

the bond between Y and Y' is a single bond, the bond between Y' and Y" must be a

double bond and vice versa, where Y or Y" is oxygen or sulfur, only one of Y and Y"

is either oxygen or sulfur, and at least one of Y, Y', Y" and Y'" must be oxygen, sulfur,

nitrogen or nitrogen bonded to a substituent species, in the manufacture of a medicament for use in treating drug addiction, nicotine

addiction, and/or obesity.

24. The use of claim 23, wherein only one or two of X, X', X", X'" and X"" are nitrogen or nitrogen bonded to oxygen.

25. The use of claim 23, wherein not more than one of X, X', X", X"¹ and X""

are nitrogen bonded to oxygen.

26. The use of claim 23, wherein X"' is nitrogen or nitrogen bonded to

oxygen.

27. The use of claim 23 , wherein both X' and X^m are nitrogen.

28. The use of claim 23, wherein X, X" and X"" are carbon bonded to a

substituent species.

29. The use of claim 28, where the substituent species at X, X" and X"" are

hydrogen.

30. The use of claim 23, wherein X'" is carbon bonded to a substituent species and X and X' are both nitrogen, or X' is carbon bonded to a substituent species and X

and X'" are both nitrogen.

31. The use of claim 23, wherein no more than three of Y, Y', Y" and Y'" are

oxygen, sulfur, nitrogen or nitrogen bonded to a substituent species.

32. The use of claim 23, wherein between one and three of Y, Y', Y" and Y'" are nitrogen.

33. Use of a compound having the following formula:

Formula 2 and pharmaceutically acceptable salts thereof,

wherein Q¹ is (CZ₂)_U, Q^π is (CZ₂)_V, Q^m is (CZ₂)_W, Q^W is (CZ₂)_X, Q^v is(CZ₂)_y and Q^VI is (CZ₂)_Z where u, v, w, x, y and z are individually 0, 1, 2, 3 or 4, and the

values of u, v, w, x, y and z are selected such that the bridged diazaspirocyclic ring contains 8, 9, 10, 11, 12 or 13 members,

R is hydrogen, lower alkyl, acyl, alkoxycarbonyl or aryloxycarbonyl,

Z is, individually, selected from the group consisting of hydrogen, alkyl,

substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted

heterocyclyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl and

substituted arylalkyl;

Cy is a six membered ring of the formula:

where each of X, X', X", X'" and X"" is individually nitrogen, nitrogen bonded

to oxygen or carbon bonded to a substituent species, wherein no more than three of X,

X', X", X'" and X"" are nitrogen or nitrogen bonded to oxygen,

or Cy is a five 5-membered heteroaromatic ring of the formula:

where Y and Y" are individually nitrogen, nitrogen bonded to a substituent

species, oxygen, sulfur or carbon bonded to a substituent species, and Y' and Y'" are nitrogen or carbon bonded to a substituent species,

wherein "substituent species" are, individually, selected from the group

consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,

heterocyclyl, substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, aryl,

substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, halo, -

OR', -NR¹R", -CF₃, -CN, -NO₂, -C₂R', -SR', -N₃, -C(=O)NR'R", -NR'C(=O) R", -

C(=O)R', -C(=O)OR', -OC(=O)R', -O(CR'R")_rC(=O)R', -O(CR'R")_rNR"C(=O)R', -

O(CR'R")_rNR"SO₂R', -OC(=O)NR'R", -NR'C(=O)O R", -SO₂R', -SO₂NR¹R", and -

NR¹SO₂R",

where R' and R" are individually hydrogen, C₁-C₈ alkyl, cycloalkyl,

heterocyclyl, aryl, or arylalkyl, and r is an integer from 1 to 6, or R' and R" can

combine to form a cyclic functionality, wherein the term "substituted" as applied to alkyl, aryl, cycloalkyl and the like

refers to the substituents described above, starting with halo and ending with -

NR¹SO₂R", and wherein the dashed lines indicate that the bonds (between Y and Y' and

between Y' and Y") can be either single or double bonds, with the proviso that when

the bond between Y and Y' is a single bond, the bond between Y' and Y" must be a

double bond and vice versa, where Y or Y" is oxygen or sulfur, only one of Y and Y"

is either oxygen or sulfur, and at least one of Y, Y¹, Y" and Y'" must be oxygen, sulfur,

nitrogen or nitrogen bonded to a substituent species,

in the manufacture of a medicament for use in treating drug addiction, nicotine addiction, and/or obesity.

34. The use of claim 33, wherein only one or two of X, X', X", X^m and X"" are

nitrogen or nitrogen bonded to oxygen.

35. The use of claim 33, wherein not more than one of X, X', X", X'" and X""

are nitrogen bonded to oxygen.

36. The use of claim 33, wherein X'" is nitrogen or nitrogen bonded to

oxygen.

37. The use of claim 33, wherein both X' and X'" are nitrogen.

38. The use of claim 33, wherein X, X" and X"" are carbon bonded to a

substituent species.

39. The use of claim 38, where the substituent species at X, X" and X"" are

hydrogen.

40. The use of claim 33, wherein X'" is carbon bonded to a substituent species

and X and X' are both nitrogen, or X' is carbon bonded to a substituent species and X

and X'" are both nitrogen.

41. The use of claim 33, wherein no more than three of Y, Y', Y" and Y'" be

oxygen, sulfur, nitrogen or nitrogen bonded to a substituent species.

42. The use of claim 33, wherein between one and three of Y, Y', Y" and Y'"

are nitrogen.

43. Use of a compound selected from the group consisting of:

7-(3 -pyridyl)- 1 ,7-diazaspiro[4.4]nonane;

7-(5-pyrimidinyl)- 1 ,7-diazaspiro[4.4]nonane;

7-(5-isoxazolyl)-l,7-diazaspiro[4.4]nonane;

7-(5-isothiazolyl)- 1 ,7-diazaspiro[4.4]nonane;

7-(5-(l ,2,4-oxadiazol)yl)-l ,7-diazaspiro[4.4]nonane;

7-(2-(l ,3,4-oxadiazol)yl)-l ,7-diazaspiro[4.4]nonane;

7-(2-pyrazinyl)-l,7-diazaspiro[4.4]nonane;

7-(3-pyridazinyl)-l,7-diazaspiro[4.4]nonane;

7-(5-methoxy-3-pyridyl)-l,7-diazaspiro[4.4]nonane;

7-(5-cyclopentyloxy-3-pyridyl)- 1 ,7-diazaspiro[4.4]nonane;

7-(5-phenoxy-3-pyridyl)-l,7-diazaspiro[4.4]nonane;

7-(5-(4-hydroxyphenoxy)-3-pyridyl)-l,7-diazaspiro[4.4]nonane;

7-(5-ethynyl-3-pyridyl)- 1 ,7-diazaspiro[4.4]nonane;

7-(6-chloro-3-pyridyl)- 1 ,7-diazaspiro[4.4]nonane;

7-(6-methoxy-3-pyridazinyl)-l,7-diazaspiro[4.4]nonane;

l-(3-pyridyl)-l,7-diazaspiro[4.4]nonane;

1 -(5-pyrimidinyl)- 1 ,7-diazaspiro[4.4]nonane;

l-(5-isoxazolyl)-l,7-diazaspiro[4.4]nonane;

l-(5-isothiazolyl)-l,7-diazaspiro[4.4]nonane;

l-(5-(l,2,4-oxadiazol)yl)-l,7-diazaspiro[4.4]nonane; 1 -(2-(1 ,3,4-oxadiazol)yl)-l ,7-diazaspiro[4.4]nonane;

1 -(2-pyrazinyl)- 1 ,7-diazaspiro[4.4]nonane;

l-(3-pyridazinyl)-l,7-diazaspiro[4.4]nonane;

1 -methyl-7-(3 -pyridyl)- 1 ,7-diazaspiro [4.4]nonane;

l-methyl-7-(5-pyrimidinyl)-l ,7-diazaspiro[4.4]nonane;

l-methyl-7-(5-isoxazolyl)-l,7-diazaspiro[4.4]nonane;

1 -methyl-7-(5-isothiazolyl)-l ,7-diazaspiro [4.4]nonane;

1 -methyl-7-(5-( 1 ,2,4-oxadiazol)yl)- 1 ,7-diazaspiro [4.4]nonane;

1 -methyl-7-(2-(l ,3,4-oxadiazol)yl)-l ,7-diazaspiro[4.4]nonane;

1 -methyl-7-(2-pyrazinyl)-l ,7-diazaspiro[4.4]nonane; l-methyl-7-(3-pyridazinyl)-l,7-diazaspiro[4.4]nonane; l-methyl-7-(5-methoxy-3-pyridyl)-l,7-diazaspiro[4.4]nonane;

1 -methyl-7-(5-cyclopentyloxy-3 -pyridyl)- 1 ,7-diazaspiro[4.4]nonane;

l-methyl-7-(5-phenoxy-3-pyridyl)-l,7-diazaspiro[4.4]nonane; 1 -methyl-7-(5-(4-hydroxyphenoxy)-3-pyridyl)- 1 ,7-diazaspiro[4.4]nonane;

1 -methyl-7-(5-ethynyl-3 -pyridyl)- 1 ,7-diazaspiro[4.4]nonane; l-methyl-7-(6-chloro-3-pyridyl)-l,7-diazaspiro[4.4]nonane; l-methyl-7-(6-methoxy-3-pyridazinyl)-l,7-diazaspiro[4.4]nonane;

7-methyl-l -(3 -pyridyl)- 1 ,7-diazaspiro [4.4]nonane;

7-methyl-l-(5-pyrimidmyl)-l,7-diazaspiro[4.4]nonane;

7-methyl-l-(5-isoxazolyl)-l,7-diazaspiro[4.4]nonane;

7-methyl- 1 -(5-isothiazolyl)- 1 ,7-diazaspiro[4.4]nonane;

7-methyl- 1 -(5-( 1 ,2,4-oxadiazol)yl)- 1 ,7-diazaspiro[4.4]nonane;

7-methyl- 1 -(2-(1 ,3 ,4-oxadiazol)yl)- 1 ,7-diazaspiro [4.4]nonane;

7-methyl-l -(2 -pyrazinyl)-l ,7-diazaspiro[4.4]nonane; 7-methyl- 1 -(3 -pyridazinyl)- 1 ,7-diazaspiro [4.4]nonane;

2-(3-pyridyl)-2,7-diazaspiro[4.4]nonane;

2-(5-pyrimidinyl)-2,7-diazaspiro[4.4]nonane;

2-(5-isoxazolyl)-2,7-diazaspiro[4.4]nonane;

2-(5-isothiazolyl)-2,7-diazaspiro[4.4]nonane;

2-(5-(l,2,4-oxadiazol)yl)-2,7-diazaspiro[4.4]nonane;

2-(2-(l ,3 ,4-oxadiazol)yl)-2,7-diazaspiro[4.4]nonane;

2-(2-pyrazinyl)-2,7-diazaspiro[4.4]nonane;

2-(3-pyridazinyl)-2,7-diazaspiro[4.4]nonane; 2-(5-methoxy-3-pyridyl)-2,7-diazaspiro[4.4]nonane;

2-(5-cyclopentyloxy-3-pyridyl)-2,7-diazaspiro[4.4]nonane;

2-(5-phenoxy-3-pyridyl)-2,7-diazaspiro[4.4]nonane;

2-(5-(4-hydroxyphenoxy)-3-pyridyl)-2,7-diazaspiro[4.4]nonane;

2-(5-ethynyl-3-pyridyl)-2,7-diazaspiro[4.4]nonane; 2-(6-chloro-3-pyridyl)-2,7-diazaspiro[4.4]nonane;

2-(6-methoxy-3-pyridazinyl)-2,7-diazaspiro[4.4]nonane;

2-methyl-7-(3-pyridyl)-2,7-diazaspiro[4.4]nonane;

2-methyl-7-(5-methoxy-3-pyridyl)-2,7-diazaspiro[4.4]nonane;

2-methyl-7-(5-phenoxy-3-pyridyl)-2,7-diazaspiro[4.4]nonane;

6-(3 -pyridyl)- 1 ,6-diazaspiro[3.4] octane;

l~methyl-6-(3-pyridyl)-l,6~diazaspiro[3.4]octane;

2-(3-pyridyl)-2,5-diazaspiro[3.4]octane;

5-methyl-2-(3-pyridyl)-2,5-diazaspiro[3.4]octane;

6-(3-pyridyl)-l,6-diazaspiro[3.5]nonane;

l-methyl-6-(3-pyridyl)-l,6-diazaspiro[3.5Jnonane; 2-(3-pyridyl)-2,5-diazaspiro[3.5]nonane;

5-methyl-2-(3-pyridyl)-2,5-diazaspiro[3.5]nonane;

2-(3-pyridyl)-2,6-diazaspiro[4.5]decane;

6-methyl-2-(3-pyridyl)-2,6-diazaspiro[4.5]decane;

7-(3-pyridyl)-l ,7-diazaspiro[4.5]decane;

1 -methyl-7-(3 -pyridyl)- 1 ,7-diazaspiro [4.5] decane;

8-(3-pyridyl)-l,8-diazaspiro[5.5]undecane;

l-methyl-8-(3-pyridyl)-l,8-diazaspiro[5.5]undecane; and

pharmaceutically acceptable salts thereof, in the manufacture of a medicament for use in treating drug addiction, nicotine addiction, and/or obesity.

44. Use of a compound selected from the group consisting of: r-(3-pyridyl)-spiro[l-azabicyclo[2.2.1]heptane-2,3'-pyrrolidine];

r-(5-ethoxy-3-pyridyl)-spiro[l-azabicyclo[2.2.1]heptane-2,3 '-pyrrolidine];

1 '-(5-cyclopentyloxy-3 -pyridyl)-spiro[ 1 -azabicyclo[2.2.1 ]heptane-2,3 '-pyrrolidine] ;

1 '-(5-phenoxy-3-pyridyl)-spiro[ 1 -azabicyclo[2.2.1 ]heptane-2,3 '-pyrrolidine] ;

1 '-(5-(4-hydroxyphenoxy)-3-pyridyl)-spiro[ 1 -azabicyclo[2.2.1 ]heptane-2,3 '- pyrrolidine];

1 '-(5-pyrimidinyl)-spiro [ 1 -azabicyclo [2.2.1 ]heptane-2,3 '-pyrrolidine] ;

1 '-(5-isoxazolyl)-spiro[ 1 -azabicyclo [2.2.1 ]heptane-2,3 '-pyrrolidine];

1 '-(5-isothiazolyl)-spiro[ 1 -azabicyclo[2.2.1 ]heptane-2,3 '-pyrrolidine] ;

r-(5-(l,2,4-oxadiazol)yl)-spiro[l-azabicyclo[2.2.1]heptane-2,3'-pyrrolidine];

1 '-(2-(1 ,3,4-oxadiazol)yl)-spiro[l -azabicyclo[2.2.1 ]heptane-2,3 '-pyrrolidine] ;

r-(2-pyrazinyl)-spiro[l-azabicyclo[2.2.1]heptane-2,3'-pyrrolidine];

r-(3-pyridazinyl)-spiro[l-azabicyclo[2.2.1]heptane-2,3 '-pyrrolidine]; 1 '-(5-ethynyl-3 -pyridyl)-spiro[ 1 -azabicyclo[2.2.1 ]heptane-2,3 '-pyrrolidine] ;

r-(6-chloro-3-pyridyl)-spiro[l-azabicyclo[2.2.1]heptane-2,3'-pyrrolidine];

1 '-(6-methoxy-3-pyridazinyl)-spiro[ 1 -azabicyclo[2.2.1 ]heptane-2, 3 '-pyrrolidine] ;

1 '-(3 -pyridyl)-spiro [ 1 -azabicyclo [2.2.2] octane-2,3 '-pyrrolidine] ;

r-(5-methoxy-3-pyridyl)-spiro[l-azabicyclo[2.2.2]octane-2,3'-pyrrolidine];

r-(5-cyclopentyloxy-3-pyridyl)-spiro[l-azabicyclo[2.2.2]octane-2,3'-pyrrolidine];

r-(5-phenoxy-3-pyridyl)-spiro[l-azabicyclo[2.2.2]octane-2,3'-pyrrolidine];

r-(5-(4-hydroxyphenoxy)-3-pyridyl)-spiro[l-azabicyclo[2.2.2]octane-2,3'-

pyrrolidine]; r-(5-ethynyl-3-pyridyl)-spiro[l-azabicyclo[2.2.2]octane-2,3'-pyrrolidine];

r-(6-chloro-3-pyridyl)-spiro[l-azabicyclo[2.2.2]octane-2,3'-pyrrolidine];

r-(5-pyrimidinyl)-spiro[l-azabicyclo[2.2.2]octane-2,3'-pyrrolidme];

1 '-(2-pyrazinyl)-spiro[ 1 -azabicyclo[2.2.2]octane-2,3 '-pyrrolidine] ;

r-(3-pyridazinyl)-spiro[l-azabicyclo[2.2.2]octane-2,3'-pyrrolidine];

r-(6-methoxy-3-pyridazinyl)-spiro[l-azabicyclo[2.2.2]octane-2,3'-pyrrolidine];

r-(5-isoxazolyl)-spiro[l-azabicyclo[2.2.2]octane-2,3'-pyrrolidine];

r-(5-isothiazolyl)-spiro[l-azabicyclo[2.2.2]octane-2,3'-pyrrolidine];

l'-(5-(l,2,4-oxadiazol)yl)-spiro[l-azabicyclo[2.2.2]octane-2,3 '-pyrrolidine];

l'-(2-(l,3,4-oxadiazol)yl)-spiro[l-azabicyclo[2.2.2]octane-2,3'-pyrrolidine];

1 '-(3-pyridyl)-2'H-spiro[ 1 -azabicyclo[2.2.1 ]heptane-7,3 '-pyrrolidine] ;

r-(5-methoxy-3-pyridyl)-2'H-spiro[l-azabicyclo[2.2.1]heptane-7,3'-pyrrolidine];

r-(5-cyclopentyloxy-3-pyridyl)-2'H-spiro[l-azabicyclo[2.2.1]heptane-7,3'-

pyrrolidine];

1 '-(5-phenoxy-3-pyridyl)-2'H~spiro[ 1 -azabicyclo[2.2.1 ]heptane-7,3 '-pyrrolidine] ;

1 '-(5-(4-hydroxyphenoxy)-3-pyridyl)-2'H-spiro[ 1 -azabicyclo [2.2.1 ]heptane-7,3 '- pyrrolidine];

r-(6-chloro-3-pyridyl)-2'H-spiro[l-azabicyclo[2.2.1]heptane-7,3'-pyπOlidine];

1 '-(5-pyrimidinyl)-2'H-spiro[l -azabicyclo[2.2. l]heptane-7,3 '-pyrrolidine] ;

r-(2-pyrazinyl)-2'H-spiro[l-azabicyclo[2.2.1]heptane-7,3'-pyrrolidme];

r-(3-pyridazinyl)-2'H-spiiO[l-azabicyclo[2.2.1]heptane-7,3'-pyrrolidine];

1 '-(6-methoxy-3 -pyridazinyl)-2'H-spiro [ 1 -azabicyclo[2.2.1 ]heptane-7,3 '-pyrrolidine] ;

1 '-(5-isoxazolyl)-2'H-spiro[ 1 -azabicyclo[2.2. l]heptane-7,3 '-pyrrolidine] ;

l'-(5-isothiazolyl)-2'H-spiro[l-azabicyclo[2.2.1]heptane-7,3'-pyrrolidine];

l'-(5-(l,2,4-oxadiazol)yl)-2'H-spiro[l-azabicyclo[2.2.1]heptane-7,3'-pyrrolidine] ; 1 '-(2-(1 ,3,4-oxadiazol)yl)-2'H-spiro[l -azabicyclo[2.2.1 ]heptane-7,3 '-pyrrolidine]; and pharmaceutically acceptable salts thereof, in the manufacture of a medicament for use in treating drug addiction, nicotine addiction, and/or obesity.