AU2001262931B2 - Method of promoting smoking cessation - Google Patents

Description

WO 01/89524 PCT/US01/10827 METHOD OF PROMOTING SMOKING CESSATION BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to methods and reagents for promoting smoking cessation. The present invention relates to methods and reagents for preventing smoking addiction. The present invention also relates to methods and reagents for treating nicotine addiction.

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.

Tobacco products, including cigarettes, cigars, pipes and smokeless tobacco, can cause a variety of well-recognized health problems. From a public health perspective, it is desirable to stop consuming tobacco products, especially in the form of smoking. However, some individuals cannot quit smoking tobacco products, in spite of focused attempts to succeed. One major factor in the difficulty of quitting smoking is the presence of nicotine in tobacco.

Nicotine can produce a myriad of behavioral effects and is unquestionably one of the most popular and powerful reinforcing agents. In addition, smoking, arguably the vehicle of choice for nicotine delivery, may cause a variety of well-recognized health problems. For these reasons it has sometimes been desirable to cease consumption of nicotine. However, for some, the termination of nicotine consumption can not be accomplished, in spite of focused attempts to succeed.

One method for assisting smoking cessation is to reduce consumption over time. For complex reasons, this method is not always entirely successful. One method for assisting smoking cessation is to provide an alternate delivery vehicle for nictone. Such delivery vehicles include oral preparations such as gums, and transdermal vehicles such as skin patches.

WO 01/89524 PCT/USU1/10827 Another method for assisting smoking cessation is to replace the nicotine signal from tobacco with a substitute reinforcer. Bupropion is used to promote smoking cessation and it may act as a substitute reinforcer.

Nicotine antagonists have been considered as an approach to smoking cessation. A nicotine antagonist would block the reinforcing signal from nicotine that creates and maintains the addiction to smoking. Over time, the smoker would dissociate the physical and psychological aspects of smoking. For example, mecamylamine has been used to promote smoking cessation, although it is generally ineffective alone. Another approach is to administer an antagonist, mecamylamine, together with nicotine replacement therapy.

Compounds which act as nicotine substitutes and block nicotine's effects would be preferred smoking cessation reagents.

Lemer-Mamarosh et al. Life Sci. 56:67-70 (1995) describe antagonism of nicotine's action by 3-phenyl-substituted tropane analogs of cocaine. The study demonstrated that the phenyltropanes blocked nicotine-induced seizures in mice. The authors also found that the analogs could compete with mecamylamine, an indirect nicotine antagonist, in vitro.

However, the results of this study do not suggest that the phenyltropane compounds could be used to treat nicotine addiction and provide a method of smoking cessation.

The phenyltropane analogs were well-known to inhibit the reuptake of dopamine, serotonin and norepinephrine. Lerner-Mamarosh et al. demonstrated that the anti-seizure activity of the phenyltropanes correlated with the ability of the analogs to inhibit the dopamine transporter. Therefore, it was highly likely that the anti-seizure activity was an indirect effect of the phenyltropanes on dopamine.

Lemer-Mamarosh et al. also found that the analogs could compete with mecamylamine, an indirect nicotine antagonist, in vitro. Therefore, the authors speculated that the anti-seizure activity could be due to the interaction of the phenyltropanes with a nicotinic acetylcholine receptor. Even if this speculation were true, this finding would not suggest that the phenyltropane compounds would be useful for smoking cessation. There are a large number (at least 1000) of different nicotinic acetylcholine receptors (nAChRs). The nAChRs are composed of various alpha(2-9) and beta(l-4) subunit combinations. Even now very little is known concerning the specific receptor involved in any particular pharmacological response. Some data suggest that nicotine-induced seizures appear to be WO 01/89524 PCT/US01/10827 mediated by the alpha-7 nicotinic receptors. Other data suggest that this class of receptors does not mediate nicotine reinforcement. Nicotine reinforcement is central to nicotine addiction. Therefore, these experiments do not suggest that these compounds would block nicotine and be useful smoking cessation reagents.

In spite of the known methods for treating smoking addiction, there remains a lack of generally effective means of treating and/or preventing smoking addiction. Accordingly, there remains a strong need for methods of treating smoking addiction.

SUMMARY OF THE INVENTION It is an object of the present invention to provide methods and reagents for smoking cessation.

It is another object of the present invention to provide methods and reagents for treating nicotine addiction.

It is another object of the present invention to provide methods and reagents for preventing smoking addiction.

The objects of the invention, and others, are accomplished with a method of training a smoker to quit smoking, comprising administering to a smoker in need thereof an effective amount of a tropane compound represented by the formula: R2,N

Y

wherein

R

1 is CO 2

R

3

CONR

4 R, R 6

CH

2 R6, WO 01/89524 WO 0189524PCT/1JS01/10827 x N N R(

A-N

x Y 7 R(7 A- A A\ -N or

N

R3 is I C 16 alkyl, C 3 .1 cycloalkyl or

R

4 and R(5 are each independently, C 1 6 alkyl, C 2 -6 alkene, C 26 alkyne, CH 2

-CO-

phenyl, phenyl, phenyl. substituted with 1-3 Of C 1 6 alk,-yl,C 26 alkene, C 26 alkyne or C 16 alkoxy, hydroxy, CH 2 OH-, CI-6 alkoxy, phenoxy, amino, amino substituted with 1 or 2 C 1 6 alkyl, C 26 alkene, C 2 6 alkyne, C 1 6 alkoxy, C 18 acyl, phenyl, or phenoxy, or R(4 and R, may combine to form, together with the nitrogen atom to which they are bonded, a cyclic structure selected from the group consisting of a pyrrolidinyl. group, morpholinyl group, piperidinyl group and a group represented by the formula WO 01/89524 WO 0189524PCT/1JS01/10827

R

6 is OH, H, C 1-6 alkyl, cycloalkyl, C 1 6 alkoxy, Cl, Br, 1, CN, NH 2

NHCI.

6 alkyl,

N(CL.

6 alkyl) 2

OCO-CI-

6 alkyl, OCO-CI- 3 alkylaryl, C0 2

-CI-

6 alkyl, C0 2

-C

14 3 alkylaryl, or substituted phenoxy;

R

7 is H, C 1 6 alkyl, C 3 .8 cycloalkyl, C 16 alkoxy, C 26 alkynyl, halogen, amino or; x

Y;,

A is S,0or NH;

R

2 is H, C 15 alkyl, halogenated C 1 6 alkyl, C 26 alkenyl. or (CH 2

),,CO

2 RX-, where n is an integer of 1 to 8 and R, is C,- 6 alkyl; each X is, independently, H, C 16 alkyl, C 3 8 cycloalkyl, C 1 6 alkoxy, C 2 6 alkynyl, phenyl C I 6 -phenYl, halogen, amino, or acylaniido, CRk=CRkR, CR.,R,-CH=CPRR, C -=CR, each R, is, independently, H, C 1 6 alkyl, phenyl, substituted phenyl, CH 2 OH, C 1 phenyl; each Y is, independently, H, 1, Br, Cl, F, CN, CF 3

NO

2

N

3

OR.

8

CO

2

NH

2 C0 2 R8,

C

16 alkyl, NR 9

R.

10

NHCOR

1 I or NHCO 2

R

2 R. is H or C 1 6 alkyl; and

R

9 RIO, RI, and R, 2 are each, independently, H or C 1 6 alkyl, or X and Y, taken together with the phenyl. group to which they are bonded, form a 2naplithyl group, the dotted line between C 2 and C 3 represents a single or double bond, or a pharmaceutically acceptable salt thereof.

WO 01/89524 PCT/USU1/10827 BRIEF DESCRIPTION OF THE FIGURES A more complete appreciation of the invention and many of the attendant advantages thereof will be readily obtained as the same becomes better understood by reference to the following Figures in conjunction with the detailed description below.

Figure 1: Comparison of cocaine and its analogs for blockade of antinociception induced by nicotine. Antagonists were administered i.p. 10 min before nicotine (2.5 mg/kg) was administered s.c, and mice were tested 5 min after nicotine injection in tail-flick test.

Each point represents mean S.E. of 8 to 12 mice.

Figure 2: Dose-response relationship of nicotine-induced antinociception and its antagonism by cocaine. Cocaine (5 mg/kg) was administered i.p. 10 min before nicotine, and mice were tested 5 min after nicotine injection in tail-flick test. Each point represents mean S.E. of 8 to 12 mice.

Figure 3: Correlation between dopamine norepinephrine and serotonin (C) transporter binding potencies (IC 50 expressed as nM) and nicotinic antagonistic potency

(AD

5 0 values expressed as umol/kg) for cocaine analogs in tail-flick test.

Figure 4: Blockade of nicotine-induced motor impairment by cocaine. Cocaine was administered i.p. 10 min before nicotine and mice were tested 20 min after nicotine mg/kg) injection. Effect of vehicle is also represented in graph. Each point represents mean S.E. of 8 to 12 mice. Statistically different from nicotine (alone) at P Figure 5: Failure of nicotine antagonists DHPE and mecamylamine in blocking cocaine-induced increase in locomotor activity in mice, antagonists were administered s.c. min before cocaine (15 mg/kg) i.p. injection. Ten minutes later, mice were placed into activity cages for 30 min. Each point represents mean S.E, of 8 to 12 mice. Coc, cocaine; Meca mecamylamine. *Statistically different from vehicle at P Figure 6: Lack of blockade of nicotine-induced antinociception by cocainemethiodide after i.p. administration in mice using tail-flick test. Cocaine-methiodide (at and 25 mg/kg) injection. Each point represents mean S.E. of 8 to 12 mice. Coc-I, cocainemethiodide; Nic, nicotine.

WO 01/89524 PCT/USU1/10827 Figure 7: Effect of different concentrations of cocaine on current activated by 1 /M nicotine applied in a 3 2 a-expressing oocytes and 10 pM nicotine applied in a 3

P,-

expressing oocytes. Nicotine or cocaine was applied as a 10-s pulse and changes in current from baseline values was measured for a total of 1 min. Oocytes were held at -70 mV.

DETAILED DESCRIPTION OF THE INVENTION The present invention is based, in part, on the recognition that phenyltropanes can be used to antagonize/block nicotine reinforcement. As one skilled in the art will readily appreciate, the act of smoking involves both physiological responses, nicotine-induced biochemical signals in the brain, and sensory and psychological signals, smell, taste, the ritualization of smoking. Over time, the reinforcing activity of nicotine becomes closely linked to the sensory and psychological responses associated with smoking. As a result, the design of methods of assisting smokers to cease smoking preferably allows nicotine reinforcement to be dissociated from the sensory and psychological aspects of smoking.

The present invention is based on the recognition that the phenyltropane compounds function as nicotine antagonists, but that this nicotine antagonism (antinociception) does not correlate with affinity for the dopamine, serotonin or norepinephrine transporters. In addition, this nicotine antagonism is highly relevant to smoking cessation. Not wishing to be bound by any particular theory, the experiments presented in the following Examples appear to suggest that the phenyltropanes interact with the a4P 2 nicotinic receptor subtype. The phenyltropanes blocked nicotine-induced antinociception, which is mediated by the c 4 2 nicotinic receptor subtype (Damaj et al., J. Pharmacol. Exp. Ther. 284: 1058-1065). It is recognized that the that the c 4

P

2 receptors are responsible for increased dopamine release in response to nicotine (see Sharples et al., J. Neuroscience 23:2783-2791, 2000). In addition, it is recognized that dopamine mediates nicotine reinforcement. Accordingly, antinociception can be used as a surrogate for nicotine reinforcement.

Without being limited to any theory, it is believed that the phenyltropane compounds of the present invention are useful in training a smoker to cease smoking. In the method of the present invention, the phenyltropanes satisfy the smoker's craving for nicotine, but also decouple the physiological effects from the act of smoking. Thus, the phenyltropanes of the present invention may have function as a nicotine substitute (nicotine agonist) and/or may WO 01/89524 PCT/USU1/10827 block reinforcement (nicotine antagonist). As a result, the smoker is able to reduce the amount of smoking, and may be able to quit smoking altogether.

The description above emphasizes the use of the phenyltropane compounds in relation to treating smoking addiction. The phenyltropane compounds may also be used to treat addiction to smokeless tobacco, chewing tobacco.

The method of the present invention comprises administering a tropane compound of amount of a tropane compound represented by the formula: R2,

N

wherein RI is COzR 3

CONR

4

R

5

R

6

CH

2

R

6

X

Y,

N

-N

A-N

R7 Ry

A\

r

N

o r

/N-

R7

A\

N

AN\

N

WO 01/89524 WO 0189524PCT/1JS01/10827 R(3 is H, C 16 alkyl, C 3 -8 cycloalkyl or

(CH

2 0 8 R(4 and R, are each independently, H, C,-6 alkyl, C 2 6 alkene, C 2 6 alkyne, CH 2

-CO-

phenyl, phenyl, phenyl substituted with 1-3 Of C 16 alkyl,C 26 alkene, C 2 6 alkyne or C 1 6 alkoxy, hydroxy, CH 2 OH, C 1 6 alkoxy, phenoxy, amino, amino substituted with 1 or 2 C 16 alkyl, C 26 alkene, C 26 alkyne, C 16 alkoxy, Cl.

8 acyl, phenyl, or phenoxy, or R, and R,5 may combine to form, together with the nitrogen atom to which they are bonded, a cyclic structure selected from the group consisting of a pyrrolidinyl. group, morpholinyl group, piperidinyl.

group and a group represented by the fonnula N' (CH 2 0 6

R

6 is OH, H, C 1 6 alkyl, C 3 .8 cycloalkyl, C 1 6 alkoxy, Cl, Br, 1, CN, NH 2

NHC

16 alkyl,

N(CI-

6 alkYl) 2 OCO-Cb- 6 alkyl, OCO-CQ 3 alkylaryl, C0 2

-C.

6 alkyl, C0 2

-C.

3 alkylaryl, or substituted phenoxy; R(7 is H, C 1 6 alkyl, cycloalkyl, C 1 6 alkoxy, C 2 6 alkynyl, halogen, amino or; x A is S,Oor NH; R2 is H, alkyl, halogenated C 1 6 alkyl, C 2 6 alkenyl or (CH 2 )nC 2 Rx, where n is an integer of 1 to 8 and is C 1 6 alkyl; each X is, independently, H, C,.

6 alkyl, cycloalkyl, C 1 alkoxy, C 2 6 alkynyl, phenyl, C 1 6 -phenyl, halogen, amino, or acylamido, CR -CRR 2

CR(-HC

2 2 C 1R WO 01/89524 PCT/USU1/10827

C(=RR)R,;

each RP is, independently, H, CI., alkyl, phenyl, substituted phenyl, CH 2 OH, Ci.

6 phenyl; each Y is, independently, H, I, Br, Cl, F, CN, CF 3

NO

2

N

3 ORg, CO 2

NH

2

CO

2 Rg,

C

16 alkyl, NR g

R

0 i, NHCOR, 1 or NHCO 2

R,

2 R, is H or C.6 alkyl; and

R

9

R

1 i, R, 1 and R 12 are each, independently, H or Ci 1 6 alkyl, or X and Y, taken together with the phenyl group to which they are bonded, form a 2naphthyl group, the dotted line between C 2 and C 3 represents a single or double bond, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, the compound used in the present method bears a group

R

2 of H. Compounds where R 2 is H may exhibit higher activity in treating nicotine addiction.

In another preferred embodiment, the compounds bear an R, group of CO 2

R

3 or

CONHR

4

R

5 an R 2 group of H or C1-5 alkyl, an X group of H, C 16 alkyl, halogen or amino, a Y group of H, C-.

6 alkyl or halogen. In this embodiment, R 3 is preferably H C 1 6 alkyl, C 38 cycloalkyl, or phenyl; R 4 and Rs are each independently, H or Ci., alkyl or combine to form the cyclic structure described above; and the halogen is I, Br or Cl. Especially preferred alkyl groups have 1 to 4 carbon atoms.

When a single bond connects the C 2 and C 3 positions of the tropane ring, the R, group and the phenyl substituent at the 3-position may have a or p stereochemistry. Preferably, the phenyl substituent has 33 stereochmeistry. In one particularly preferred embodiment, the R, group and the phenyl substituent at the 3-position are on the same face of the ring (cis). In another particularly preferred embodiment, the R, group at C 2 and the group and phenyl group at C 3 are on the same face of the ring, where the phenyl substituent has 3P stereochmeistry.

Compounds that may also be used in the present invention are those represented by the formula described above in which the phenyl group at the 3-position is linked to the tropane ring by one of-CH 2 -CO-O- or O-CO- moiety. Compounds that may also be used in the present invention are those represented by the formula described above in which the phenyl group at the 3-position is replaced with a pyridine group, a 3- or 4-pyridyl WO 01/89524 PCT/USU1/10827 group. The pyridyl group may be substituted by X and Y in the same manner as the phenyl group in the formula above.

The compounds are illustrated with the group R 2 of undefined stereochemistry, such that the R 2 group may be on the opposite or same side of the bridging nitrogen as the C, and

C

3 substitutions.

The compound depicted as above is shown as a single enantiomeric compound, however, both enantiomers are within the scope of the present invention, such as a racemic mixture. Moreover, it is within the specific scope of the present invention to administer compounds which are enantiomerically enriched in a single enantiomer. Within the context of the present invention enrichment in a single enantiomer may comprise an enantiomeric excess of 55%, even more preferably 70%, even more preferably 80%, even more preferably 90%, even more preferably 95%, even more preferably 98%.

An enantiomerically enriched composition may be prepared by conventional methods known to those of ordinary skill in the art, such as by using an enantiomerically enriched starting material or by resolution of a racemic mixture or a mixture of a lower enantiomeric purity. Resolution may be conducted by conventional methods known to those of skill in the art, such as by chiral chromatography, formation of diasteriomeric derivatives followed by separation, or enantioselective crystallization.

As described above, it is within the context of the present invention to administer a composition enriched in a single entantiomer. In one embodiment of the present invention, the composition is enriched in the enantiomer. In another embodiment of the present invention, the composition is enriched in the enantiomer. Administration of a composition enriched in a single enantiomer offers the advantage of maximizing the effect of treating nicotine addiction, while minimizing unwanted activities.

Preparation of Tropane Compounds The compounds used in the method of the present invention may be prepared by conventional methods known to those of ordinary skill in the art. For examples of compounds that may be used in the present invention, and methods of preparation thereof, see U.S. 5,128,118; 5,380,848; 5,413,779; 5,496,953; 5,736,123; WO 92/02260; U.S. Patent Application Serial No. 09/083,043, filed May 22, 1998; U.S. Patent Application Serial No.

WO 01/89524 PCT/USU1/10827 08/706,263, filed September 4, 1996; U.S. Patent Application Serial No. 08/506,541, filed July 24, 1995, the relevant portions of which, which describe specific compounds and the preparation thereof, are hereby incorporated by reference. Examples of compounds that may be used in the present invention are shown below.

The compounds may be used in the form of a pharmaceutically acceptable salt via protonation of the amine with a suitable acid. The acid may be an inorganic acid or an organic acid. Suitable acids include, for example, hydrochloric, hydroiodic, hydrobromic, sulfuric, phosphoric, citric, acetic and formic acids.

WO 01/89524 WO 0189524PCT/USOI/10827 Non-limiting examples of compounds which may be used in the present invention: CH3%,N

*C

4

H

6 0 6

NH

2 C02OCH3 I02

*H-C-OH

H-C-OH

C0 2

H

CH3,

CO

2

CH

3

*C

4

H

6 0 6 CH WO 01/89524 WO 0189524PCT/USOI/10827 CH3,N

N

C02 I-c

N

01-3 OH WO 01/89524 WO 0189524PCT/US01/10827

CH

C0 2

C

2

HS

00 WO 01/89524 WO 0189524PCT/US01/10827 -0*HCI

CO

2

CH(CH

3 2 0c

CH,

CH

2 0H 0 WO 01/89524 WO 0189524PCT/US01/10827

CH

3

O

2

C

0

CH

3 CH3020 CH302 oc-Qo 0

OH

3

H

0 I c WO 01/89524 WO 0189524PCT/US01/10827

CH,

C0 2

CH

3 0

OH

3

IHC

CH

3

N

0 WO 01/89524 WO 0189524PCT/US01/10827

CH

CO

2

CH

3 N0 2

CO

2

CH

3 CH3N, C0 2

CH

3 0'

CH

3 04,H,06 -0.5 H 2 0 WO 01/89524 WO 0189524PCT/US01/10827

N-

0 0 CH3.

N

'00 2

CH

3 0 WO 01/89524 WO 0189524PCT/US01/10827

CH

C0OCH 3

S

CHS

WO 01/89524 WO 0189524PCT/US01/10827

HN

0 CH:3,

-C

4

HG

66

H

2 0 0 2 0H 3 HGC2H

CH,

C0 2

CH

3 -aN3 WO 01/89524 WO 0189524PCT/US01/10827 *HCIOO.25H20 CH S' 4 HA0 4 0 -C4HrOr ,CO 2 CHs C02H WO 01/89524 WO 0189524PCT/USOI/10827 CH, eC 4

H

4 0 4 0.-25H 2 0 C0 2

(CH

2 )p

H

3 C N

CO

2

CH-

3

CHWN

CO

2

CH

3 0 4

H

6 0 6

~~CO

2

CH,

CH3M ~O2CH2 WO 01/89524 WO 0189524PCT/US01/10827

CH,

C0CH

CH

2

COCH

CH HCI H 2 0

~~COCH

3

CH

3 WO 01/89524 WO 0189524PCT/US01/10827 -O-N3

CH

3 -0 O NH 2 WO 01/89524 WO 0189524PCT/US01/10827 HCI o 1.5 H 2 0 -cl HCI -O.75 H 2 0 *0.25 H

CI

C

4

H

6 0 6 -0.5 H 2 0 $co 2 Me C 4

H

6 0 6 a H 2 0 WO 01/89524 WO 0189524PCT/US01/10827

CC

2 Me *C 4

H

6 0 6 ~-1J *HCI *0.5 H 2 0

CH

3

CH

3 CH1

NH

2 2*HCI WO 01/89524 WO 0189524PCT/US01/10827 CH3-, QN3 *lHCI o 1.5 H 2 0

CH,

OCHs O .HCI 1.5 H 2 0

CH

3 N 0 HOt 0.25 H 2 0 OCHs HCIl 0.76 H 2 0 CH3N

ON

3 0 WO 01/89524 WO 0189524PCT/US01/10827

CH

3 1

C

4 HB0 6 a 0.5 H 2 0 (Tartrate) s HCI 0 0H

HCI

CH

3 a HCI e 0.75 H 2 0O WO 01/89524 WO 0189524PCT/US01/10827 OCH3 O 2HUI H 2 0

NH

2

N

C0 2 0H 3 Sn(CH 3 3 CH1N 0S0 2 0F 2

CH

3 1

CHN

OCH

3 L HCI *0.75 H 2 0 WO 01/89524 WO 0189524PCT/US01/10827 C H 3 ,N

CH

2 COCHS O

CH

3

OCH

2

SCH

3 0HCI

CH

3 .N.c

OCH

3 HOI 1.5 H 2 0

QF

CH

3 ~o 2HCI H 2 0 WO 01/89524 WO 0189524PCT/US01/10827

C

2

CH

3 CH3.

N

OH

CH-

WO 01/89524 WO 0189524PCT/USOI/10827

CHNN

C0 2

H

Qr

CH.

N

C0 2

H

QF

N HCI e 0.25 H 2 0

OAC

H

I OH 3 N HCI .0.75 H 2 0 Br HCI 0 WO 01/89524 WO 0189524PCT/US01/10827 *cI -*HCI N HOI 0.25 H 2 0 0

NH

COCH,

Qci.

N

C

2

CH

3

HCI

Qci cI 2

CHS.

*HCI

O cI CHaS WO 01/89524 WO 0189524PCT/US01/10827

-H

2 0 -HCI -r<coz CH3',

CO

2 CH(CHG)2

HCI

N C0 2

H

CO

2 Me *CHOH 1 .0.75 H 2 0

OHOH

Q OH C2 0 11 -1 IC-0 HCI CH., 3

!CH(CH

3 2

HCI

WO 01/89524 WO 0189524PCT/US01/10827 CH3' N 0

NH-

2 HCI cI

HCI

CH,

CH

3

O

2 CH(Ot-b)2

HCI

CH,,

N~

N 0 WO 01/89524 WO 0189524PCT/US01/10827 CHN .NY, CH3 N" N~AH3 N HO- H 2 0 Qc OCHCI4 CHt 2

CH

3 WO 01/89524 PCT/US01/10827 N 0 I HCI 9 0.25 H 2 0

NH

2 '0 nHCI H 2 0 HCI 1.5 H 2 0 NH 2 HCI H 2 0

CH

3

N//

N

CH

3 WO 01/89524 WO 0189524PCT/US01/10827 ,C30 CH 3 N 11 I ~L4 CO-CH

SHCI

OH

3 .H3 0 CH 3 N 11

CO-OH

OH3 /\Sn(CH) Sn(0H 33 WO 01/89524 WO 0189524PCT/US01/10827

N

HCI

CH

0 0 CHj

HCI

H *HCI

H

N 0

OH

3 *HOI *0.25

H

2 0 Qcl

H

N

CO

2

CH

3

F

WO 01/89524 WO 0189524PCT/USOI/10827 "I

N

AN

*HCI H 2 0 *HCI H 2 0 0 *HCI 1.H 2 0 L~Z\HI 2 H 2 0 WO 01/89524 WO 0189524PCT/US01/10827

-*HCI

oQ y 0

CH

3 -ci HCI

CH

3

CHS

HCI

HCI

WO 01/89524 WO 0189524PCT/US01/10827 /OH 3

-CH

C H 3 e HCI *1.25 H 2 0 cl HOI *1.5 H 2 0 -cl *HCI 1.5 WO 01/89524 PCT/US01/10827 N CH3

N

3

HCI

O CH 3 N HOI 0

Y

N 0 N HCI- 1.25 H 2 0 0

C=-N

Qc WO 01/89524 PCT/US01/10827 WO 01/89524 WO 0189524PCT/US01/10827 2HCI CHH3 N 11 ,,oool-

-NH-CH,-C-=CH

Qc N CH 3

O-NH-NH

2 .2 HOI Qc WO 01/89524 WO 0189524PCT/USOI/10827 *0 4

H

6 06 0 0 11 11

,C-NH-NH-C-CHS

-C 3*

HOI

CHC

-CH

3 110 WO 01/89524 WO 0189524PCT/US01/10827 N 0'CH WO 01/89524 WO 0189524PCT/US01/10827

N.CH,

11 "-OCHS

C-N

QC,

fumarate

HCI

0 N.C H 3 0 N1 CH.

C-N

*t CH umarate

OCH,

'CH

3 N 0

CH,-C

4

H

6 c4 WO 01/89524 WO 0189524PCT/US01/10827 N -CHs Tartrate Qci CH,

N

cc*

HCI

Qci CH,N 0 CON0

HCI

0N' OHS HCI WO 01/89524 WO 0189524PCT/US01/10827

NHSN

*HCI

O C H, ~CCHs N 0

CH

N,_H

HCI

~-cI WO 01/89524 WO 0189524PCT/US01/10827 O HCI of 0 CH3

N

N

~N -HCI O CH 3 ~CH 3

P

N s

'N

NW -HCI Qc

~CH

3 NH-N0 Ol HCI WO 01/89524 WO 0189524PCT/USOI/10827 0 0

HO

CH- NOH 3 CH HCI 0-H-C

HCI

WO 01/89524 WO 0189524PCT/US01/10827

-HCI

-HOI

-HG!

WO 01/89524 WO 0189524PCT/US01/10827

CHS.,

~:~~:72H3 HCI 1.5 H 2 0

N

OHH

NH *2HCI

H

0 0 N 3 ciQ N 0 NH N -9 HOI WO 01/89524 WO 0189524PCT/US01/10827 00 2

H

N CH s

O

~N HCI ~~cI NC *2

HCI

N 0

N

CH,

HCI

WO 01/89524 WO 0189524PCT/US01/10827 CHS

N

H4

HCI

CHsQ

HCI

-Tartrato N I-H3 N N *T artrate WO 01/89524 WO 0189524PCT/US01/10827 *Tartrate

HCI

00 0 N .CH, S02 -2 HCI

CH,

WO 01/89524 WO 0189524PCT/US01/10827 N0 2

N

*H HCI NH *N0HCI H H (9 O CH,

NO

*2 HCI

CH,

H

N

s )=o

N

H

NH

N

H

cH3 N*

HOI

N CHs WO 01/89524 WO 0189524PCT/US01/10827 N2 HOI O OH 3

N

HCI

N

~A~~OCHs

*HCI

HOI

WO 01/89524 WO 0189524PCT/US01/10827 L) HCI Oci

N

C N N CH9HN yNH

NO

2 CHS 0 NN

N

N-H

HCI

NO,

NN lN -'rN-H

-*HCI

,CCHs HCi 00H, WO 01/89524 WO 0189524PCT/US01/10827

-HCI

N0 2 N"~CH.8

HCI

~-cI

N

Snt 0 C0,C

HCI

~-cI 0 C0CH

HCI

O CI WO 01/89524 WO 0189524PCT/US01/10827 0 0 OF

C

4 HsD.

0 0 Q F C4 0.5 H 2 0 00 F C 4 Hsca WO 01/89524 WO 0189524PCT/US01/10827 L;H3 N HCI -H 2 0

CO

2

CH

3 /K COCH HCI 0.5 H 2 0 /CHa N *HCI 0.25 H 2 0 CO CH 3 Qci

CI

WO 01/89524 WO 0189524PCT/US01/10827 N0 2

N

CHCH

OHS 0 *HCI Q H 3 WO 01/89524 WO 0189524PCT/US01/10827

GIH

2 3, 0 C Hs0*

NO

2

CHHC

O CI WO 01/89524 WO 0189524PCT/US01/10827 CH9sN a 1

C

4 HG(:b 0.5

H

2 0

F

C

4

H

6

Q

CH,,

.N

H

2 0 WO 01/89524 WO 0189524PCT/US01/10827 4 6 0 6 '0.5 H 2 0 O CH, 002 Me O 3 (-)-tartrale

H

2 0

CO

2 CH (-)tartrata 0 p WO 01/89524 WO 0189524PCT/US01/10827 tartrate

CO

2 CH~ 1 H 2 0 CHa.,.N

CO

2

CH

3

*C

4

H

6 0 6 1.0 H 2 0

C(CH:

3 )3

CC(CH

3

)N

CO

2 CH3 *~4HO 4 6 0 0.2 0.20

CO(CCH

3

C

4

H

6 0 6 1.5 H 2 0

C

CH

2

CH

3 WO 01/89524 WO 0189524PCT/US01/10827

GH

3 ,0 2

CH

3

*C

4

HG

6

E

6 -0.75 H 2 0 C H 2 C HS

CHS-..

*C

4

H

6 0 6 0I

*C

4

HOOS

6 0.25 H 2 0 0 H3..N COC~ C 4 HG0 6 -0.25 H 2 0 CH32CH3

COC

3

C

4

HS

6 0 6 0.75 H 2 0 O C(CH3) 3 WO 01/89524 WO 0189524PCT/US01/10827

CH

3

-I

-C

4

H

6 0 6 CH

C

2

CH

2 S?

C

4

R

6 0 6 0.5 H 2 0 O CH 2 CH3 CH3,H 3 0 4

H

6 06 .0 CH 2

CH

3

N

C0 2

CH

3 -(-)-tartrate 0.5 H 2 0

N

00 2

CH.

3 0 OH HOI *0.5 H 2 0 WO 01/89524 WO 0189524PCT/US01/10827 1 .5 H 2 0

N

CO

2

CH

3 COC 3 (-)-tartrate O SiCHH)

N

C0 *H (-)-tartrate

H

2 0 WO 01/89524 WO 0189524PCT/USOI/10827 0 .25H 2 0 00 2

CH

3 *tartrate 5/4 H 2 0 0-H

CO

2 CH9 tartrate *5/4 H 2 0 tartrate 1/2 H 2 0 -1/4 HZ0 WO 01/89524 WO 0189524PCT/US01/10827

CO

2

CH

3 -3/4 H 2 0) -tartrate Q CH 3

CH

0C 3 *lartrate

-H

2 0 C 0 C t a r t r a t e

N

C0 2

CHS

*C

4 H606-1.SH 2 0 002~

*C

4

H

6 0r,-H 2 0 WO 01/89524 WO 0189524PCT/US01/10827

.H

6 0 6 -0.5H 2 0

CC

2

CH

3

*C

4

H

4 0 4 -0.75H 2 0

N

CO

2

CH

3 O Sn(CHS) 3 C0 2 0H 3 O Sn(CH:3):

&CCH,

O Si(CH 3 )s WO 01/89524 WO 0189524PCT/US01/10827

F.

CH3aN

N

C0 2

CH

3

C

4

H

6 06*O.SH 2 0 CHS%.

N

00 2

CHS

0 4 1H 6 0.5H 2 0 02 C0 2

CH

3 4

H

6 Os-i.25H 2 0 O E N WO 01/89524 WO 0189524PCT/US01/10827 2 0

-OCHS

-C

4

HG

6 0 6 .05H 2 0 Ca, z C 2

CH

3 0

C

4 HGOG .75

NH

2 WO 01/89524 WO 0189524PCT/US01/10827 I 02 H

C

4

H

6 0 6 -0.5

H

2 0

NH

2

CH-N

C'OZCH

3 0 4 H0 6 0.5 H 2 0

NH

2 1-12\ I-n~lw_ 4

H

6 0 6 -0.5 H 2 0 C0 2 0H 3 0 4

H

6 0s WO 01/89524 PCT/US01/10827 CH3aN C0 2

GH

3

.C

4 HG0 6

C

4 HsOs WO 01/89524 WO 0189524PCT/US01/10827

'(CH

3 3

-C

4

H

6 0 6 C4H 6 0 6 1 ,25H 2 0) Ph HCI 0.75 H 2 0 Ph

H

C02CH2 O Sn(CHs)a WO 01/89524 WO 0189524PCT/US01/10827

CO

2

CH

3 O Sn(C H 3 3 CH3.. Ph (A *HOI -O.75 H 2 0

.C

4 HGPQ 0.5 H 2 0 WO 01/89524 WO 0189524PCT/US01/10827 CH3-N G

*HCI

O CI HOI 0.5 H 2 0

-HCI

CH3-, N Q cI W(Ph) HCI 0.5 H 2 0

CH

3 W~ HOI 0.5 H 2 WO 01/89524 WO 0189524PCT/US01/10827

CH

3 0 2 0R 3

*CH

3

C

6

H

4

SO

3

H

i HCI CH3, CHsc 6

H

4 SO31- WO 01/89524 WO 0189524PCT/US01/10827 2

CH

3 4

H

6 0 6 0.5 H 2 0 0H

C

4

H

6 0 6 0.5 H 2 0

O

2

H*C

4

H

6 0 6 -0.5 H 2 0 ;0 2

CH

3 .C0 4

H

6 0 6

-H

2 0 WO 01/89524 WO 0189524PCT/US01/10827

H,.

HCI

OHs C0 4

H

6 0 6 0H O CH 3 WO 01/89524 WO 0189524PCT/US01/10827

O

2

~*C

4 H606 H 2 0 0 2 0H 3 C460 0.5 H 2 0 WO 01/89524 WO 0189524PCT/US01/10827

C

4

H

6 0 6

C)

2 0&H 3

C

4

H

6 0 6 0.75 H 2 0 ,,H3 2

H

O CH 3 C H3

CHSC

6

H

4

SO

3

H

WO 01/89524 WO 0189524PCT/US01/10827 *HCI -H 2 0 V

CH

V 2

CH

3 -HU CH3

C-

H. 0.33 H210 C0 2 CH3

CH

3 *Hl H 2 0

CH

2 0 -0.5 H 2 0 I C0 2 CHS 1- H 0 WO 01/89524 WO 0189524PCT/US01/10827 *HCI -0.75H 2 0 -2.25H 2 0 0 2

CH

3 0c-C 0 *HI O.5H 2 0

OH

3 WO 01/89524 WO 0189524PCT/US01/10827 K) UtH 2

LM

3 H, O2H 3

HCI

C 4

H

6 0 6 OH CH 3 ak j4[OH 3 0 6

H

4 00 2 0H(C0 2 H)71 2 WO 01/89524 WO 0189524PCT/US01/10827

CH

3 .C Ha 0 2 H(CH3) 2 02CH 0 2 H HCI -0.26 H 2 0

CH

3 HOI -O.5H 2 0 00 2

CH

3 0H 3

F

0 2 H HCI 0.5H 2 0 OHH3 WO 01/89524 WO 0189524PCT/US01/10827 *HCI -O.75H 2 0 Q 3

CO

2 CHs C Hs *H01 .75H 2 0 0 2

H

3 HCI -O.75IH 2

O

QH

H

2 CH 3 *HCI* .75H 2 0 *HC l5H 2 0 WO 01/89524 WO 0189524PCT/USOI/10827 '0 2

CH

3 0 2

CH

3 O Hs C0 2

CH

3 .HCI 0.75 H 2 0 WO 01/89524 WO 0189524PCT/US01/10827 HCI 0.5 H 2 0 2 CH3

QHCI

CH

3 -HCI 9 H 2 0

HCI

HOI H 2 0 WO 01/89524 WO 0189524PCT/US01/10827 *HCI 0.80 H 2 0

,CH

3 HOI 0.75 H 2 0

CH

3

CH

3

CH

3

C

6

H

4

SO

3

H

WO 01/89524 WO 0189524PCT/US01/10827

C

2

H

5

HCI

*HCI a 0.5 H 2 0 -HOI 0.25 H 2 0 WO 01/89524 WO 0189524PCT/US01/10827 -HOI 1.5 H 2 0 CHSa, aHOI o'0.25 H 2 0 CH31.

-HCI 1.0 H 2 0 -*HCI- 1.25 H 2 0 O F 3 *HlCI -H 2 0 O CH 3 WO 01/89524 WO 0189524PCT/US01/10827

-H

2 0 0 2 CHS a (D)Tartrate 0.25 H 2 0 -(D)Tartrate 0.25 H 2 0 *(D)Tartrate m 1 Hp0 WO 01/89524 WO 0189524PCT/US01/10827

OD

3 *(D)-Tartrate a 0.25H 2 0 *HCI *2H7O -10)0- WO 01/89524 WO 0189524PCT/US01/10827 *HCI *I .5H 2 0 *2H01 .C.25H 2 0*CH 3 0H H3 *2H01 -0.75H 2 0 CHH3 ONH(CHp 2

NH

2 *2HC1 0O.SH 2 0 -cNH-CH=CH2--Nl -2HCI -10)1- WO 01/89524 WO 0189524PCT/US01/10827 *2H01 9HOI 90.5H 2 0 a(D)tartrate 02CH3

-HCI

-10)2- WO 01/89524 WO 0189524PCT/US01/10827 *HCI -1.25H 2 0

CH

CH

*HCI

CH3a,

HCI

OH

3 -10)3- WO 01/89524 WO 0189524PCT/US01/10827

NQ

O CI ~K0 2

CH

3 HC -10)4- WO 01/89524 WO 0189524PCT/US01/10827 .2HCI.H 2 0

N

92HCIoO52 O CI CH~ N Q N H '02HCIO.75CH 3 0H O CI -10)5- WO 01/89524 WO 0189524PCT/US01/10827 1 9 rCHS, CH, 0 2

CH

3 10

,CC

6 Hs

CH,.

CO

2

CH

3

*HCI

NO

F

*HCI H 2 0

-CH

3 *HCI '1 .5H 2 0 *HCI -0.75H 2 0 -10)6- WO 01/89524 WO 0189524PCT/US01/10827 0H 3 *HCI .1 .5H 2 0 CH3 0 2

GH

3

QH

3 s *HCI.3H 2 0 HCI*1.5H 2 0 S*HCfr1.75H 2 0 QH3 -10)7- WO 01/89524 WO 0189524PCT/US01/10827

H

3

H

3 -CI 1.5 2

CH

3 N H3 -2HCI.75H 2

O

CH

3 N N Z CH 3 o2HCI.75H 2

O

C H3 *2HCI*1 .5H 2 0 -108- WO 01/89524 WO 0189524PCT/US01/10827 C H 3 -2HCI.O.25H 2 0

CH

3

CH

3 C H 3 NO N H Q O H 3

NH

2 -2HCI.2.75H 2 0

CH

3 I" *HCI

*HCI

-109- WO 01/89524 WO 0189524PCT/US01/10827

CHN

H

Ph

CH

3 I *HCI.H 2 0

H

0 c *HCI*1 .25Hg0 0

OH

3 C H 3 *HCloH 2 0

OCH

3

CH

3 N N

H

3 N 2H-ICH.75H 2 0 b CH 3 -110- WO 01/89524 WO 0189524PCT/US01/10827

CH

3 N N

CH

3 62HC2.75H 2 0

*HGI-H

2 0

-HCI.H

2 0

@HCI'H

2 0 N ,.CH 3 0-N N~CH3

*HCI

O cI

CH

3 -111- WO 01/89524 WO 0189524PCT/US01/10827

CO

2

CH

3

I

*HOC-C-C-C-OH

CH

3

*HCI

*C

4

H

4 0 4 .O.5H 2 0

*C

4

H

4 0 4 *0.5H 2 0) -112- WO 01/89524 WO 0189524PCT/US01/10827 CH3, N I *C 4

H

4 0 4 0.5H 2 0

H

o0 Ph

CH

3

~,N

I *C4H404-0.5H20 Ph o0

H

OH

3

N

OC

4

H

4 0 4 60.75H 2 0 o H 3

H

H 4

H

4 0 4 5H 2 0 0,

H

CH,

C

4

H

4 0 4 .O.25H 2 0 -113- WO 01/89524 WO 0189524PCT/US01/10827

-HCI

*0 4

H

6

Q

-C

4

H

6 ,0 6 *c 4

'C

4

H

6

Q)

-114- WO 01/89524 WO 0189524PCT/US01/10827

C

4 H6(Os

CH

3

N

H *0 4

H

4 0 4 0 c N0

CONH<>

ONH

2 *2HCI oI WICH3 C0 2

CH(CH

3 2

-HCI

CH3 O.IH 3 ~K .1 C02CH 3 -115- WO 01/89524 WO 0189524PCT/US01/10827

-HCI

CH

3 CH3

N

H N-OCH 3 *HCI 90.33 H 2 0 O cI cI

H

*HCI

H N -116- WO 01/89524 WO 0189524PCT/US01/10827

-HCI

NIO) HCI CH3...N

N--OCH

3

H

2

C

CH3,, H

N-OCH

3 Qci

OH

3 H CI 0 .5H 2 0 -117- WO 01/89524 WO 0189524PCT/US01/10827

HOI

N *HCI

HOI

N

8% -*HCI I-CH3 0 2

GH

3 430 O H 3

CH

3 -118- WO 01/89524 WO 0189524PCT/US01/10827 CHs.-N OH O

HCI

HC

N N C

H

Me -HCI-1.25H 2 0 H, -H OzCH3

C

7

H

7

SO

3

H

F

-119- WO 01/89524 WO 0189524PCT/US01/10827 0 2

CH

3 cr

F

F

-120- WO 01/89524 PCT/USU1/10827 Administration of the Tropane Compounds A variety of administration techniques may be utilized, among them oral, transdermal or parenteral techniques such as subcutaneous, intravenous, intraperitoneal, intracerebral and intracerebroventricular injections, catheterizations and the like. Such methods of administration are well-known to those skilled in the art. For a general discussion of drug delivery systems, see Kirk-Othmer Encyclopedia of Chemical Technology, Fourth Edition, Volume 8, pp. 445-475.

Average quantities of the compounds may vary in accordance with the binding properties of the compound affinity, onset and duration of binding) and in particular should be based upon the recommendations and prescription of a qualified physician.

The therapeutic compositions useful in practicing the therapeutic methods of this invention may include, in admixture, a pharmaceutically acceptable excipient (carrier) and one or more of the compounds of the invention, as described herein as an active ingredient.

The preparation of therapeutic compositions which contain such neuroactive compounds as active ingredients is well understood in the art. Such compositions may be prepared for oral administration, or as injectables, either as liquid solutions or suspensions, however, solid forms suitable for solution in, or suspension in, liquid prior to injection can also be prepared. The preparation can also be emulsified. The active therapeutic ingredient is often mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol, or the like and combinations thereof. In addition, if desired, the composition can contain minor amounts of auxiliary substances such as wetting or emulsifying agents, and pH buffering agents which enhance the effectiveness of the active ingredient. The compounds of the invention can be formulated into the therapeutic composition as neutralized pharmaceutically acceptable salt forms.

The therapeutic compositions are conventionally administered orally, by unit dose, for example. The term "unit dose" when used in reference to a therapeutic composition of the present invention refers to physically discrete units suitable as unitary dosage for humans, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required diluent; carrier, or vehicle.

The compositions are administered in a manner compatible with the dosage -121- WO 01/89524 PCT/US01/10827 formulation, and in a therapeutically effective amount. The quantity to be administered depends on the subject to be treated, the presence of other agonists and antagonists in the subject's system, and degree of binding or inhibition of binding desired. Precise amounts of active ingredient required to be administered depend on the judgment of the practitioner and are peculiar to each individual. However, suitable dosages may range from about 0.01 to about 1,000, preferably about 0.25 to about 500, and more preferably 10 to 50 milligrams of active ingredient per kilogram body weight of individual per day and depend on the route of administration. For oral administration, 1 to 100 milligrams of active ingredient per kilogram body weight of individual per day is a preferred dose. However, the exact dosage must be determined by factoring in rate of degradation in the stomach, absorption from the stomach, other medications administered, etc. Suitable regimes for administration are also variable, but are typified by an initial administration followed by repeated doses at one or more hour intervals by a subsequent injection or other administration. Alternatively, continuous intravenous infusion sufficient to maintain appropriate concentrations in the blood are contemplated.

The present invention is directed to a method of treating smoking addiction. This may be accomplished by administering to a patient in need of terminating a smoking addiction a phenyltropane compound. While not wishing to bound by any particular theory, it is believed that by smoking addiction may be successfully treated by blocking some of the pharmacological effects of nicotine, such as, but not limited to reinforcement, antinociception, hypothermia, drug discrimination and motor impairment, while also dissociating some of the reinforcing affects of smoking. Within the context of the present invention, a patient in need of terminating a smoking addiction is a person who smokes on a regular basis and is either unable or unwilling to terminate smoking on a regular basis. The method of treating a smoking addiction may be practiced, by administering a phenyltropane compound as described, preferably concurrent with or in advance of the act of smoking. In this fashion, the patient addicted to smoking will also be subject to the effects of the phenyltropane compounds while smoking, which can act to dissociate the reinforcing effects of smoking, from the act of smoking itself. The amount of phenyltropane compound administered to be effective to dissociate the reinforcing effects of smoking from the act of smoking may vary depending on the patient and the nature of the patients addiction to -122- WO 01/89524 PCT/US01/10827 smoking, however, determination of effective dosages and treatment schedules is within the level of skill of those of ordinary skill in the art, without undue experimentation.

The present invention is also directed to a method of preventing an addiction to smoking, by administering a phenyltropane compound. A person (patient) in need of preventing an addiction to smoking may be a non-smoker or an occasional smoker, who is concerned about developing an addiction to smoking. The method of preventing a smoking addiction may be practiced, by administering phenyltropane compounds as described, preferably in advance of the act of smoking. In this fashion, subject to the effects of the phenyltropane compounds, the patient will not develop a strong association of the act of smoking with the reinforcing effects of smoking. The amount of phenyltropane compound administered to be effective to prevent the association of the reinforcing effects of smoking from the act of smoking may vary depending on the patient and the nature of the patient.

However, determination of effective dosages and treatment schedules is within the level of skill of those of ordinary skill in the art, without undue experimentation.

The present invention is also directed to a method of treating nicotine addiction. This may be accomplished administering to a patient in need thereof, a phenyltropane compound.

Within the context of the present invention, a patient in need of terminating a nicotine addiction is a person who consumes nicotine on a regular basis and is either unable or unwilling to terminate nicotine consumption on a regular basis. The method of treating a nicotine addiction may be practiced, by administering phenyltropane compounds as described, preferably concurrent with or in advance of the act of nicotine consumption. In this fashion, the patient addicted to nicotine will also be subject to the effects of the phenyltropane compounds, which can act to dissociate the physiological effects of nicotine consumption from the act of consuming nicotine. The amount of phenyltropane compound administered to be effective to dissociate the physiological effects of nicotine from the act of nicotine consumption may vary depending on the patient and the nature of the patients addiction to nicotine. However, determination of effective dosages and treatment schedules is within the level of skill of those of ordinary skill in the art, without undue experimentation.

The method of the present invention may be practiced with compounds which exhibit a noncompetative nicotinic antagonist activity. Damaj et al. The Journal of Pharmacology and Experimental Therapeutics vol. 289, no.3 (1999) 1229-1236, provides a pharmacological WO 01/89524 PCT/USU1/10827 characterization of nicotine's interaction with cocaine and cocaine analogs, the entire contents of which are hereby incorporated by reference. The effectiveness of the present method is appreciated in the ability to block some but not all of the pharmacological effects of nicotine. In a preferred embodiment the present method blocks the pharmacological effects of antinociception, seizures, and motor impairment, while not effecting body temperature or drug discrimination.

According to another embodiment of the present invention, it is possible to prevent the development of an addiction to smoking, by administering to a humar, in need of preventing an addiction to smoking, a phenyltropane compound. In this embodiment, the compound can be administered prophylactically in order to prevent a subject from becoming addicted to smoking in the first place. Alternatively, the compound can be administered to a subject who is in the process of smoking cessation in order to prevent a relapse.

EXAMPLES

Having generally described this invention, a further understanding can be obtained by reference to certain specific examples which are provided herein for purposes of illustration only and are not intended to be limiting unless otherwise specified.

Materials and Methods Animals Male ICR mice (20-25 g) and male Sprague-Dawley rats (175-225 g) obtained from Harlan Laboratories (Indianapolis, IN) were used throughout the study. The mice were housed in groups of six and had free access to food and water. The rats were housed individually and had restricted access to food as described later.

Drugs (-)-Nicotine was obtained from Aldrich Chemical Company, Inc. (Milwaukee, WI) and converted to the ditartrate salt as described by Aceto et al. (1979). Dihydro-Perythroidine, fluoxetine, nomifensine, GBR 12909, lidocaine, amphetamine, caffeine, and nisoxetine were purchased from Research Biochemicals Inc. (Natick, MA). Mocamylamine hydrochloride was a gift from Merck, Sharp and Dohme Co. (West Point, PA). Procaine -124- WO 01/89524 PCT/USU1/10827 was purchased from Sigma Chemical Co. (St. Louis, MO). Cocaine HC1, cocaine methiodide methamphetamine, and methylphenidate were supplied by the National Institute on Drug Abuse (Washington, DC). The cocaine analogs used in the present study were various carboxylic acid esters of substituted phenyltropanes (Carroll et al., 1991, 1992; Lewin et al., 1992). All drugs were dissolved in physiological saline sodium chloride) and given in a total volume of 0.2 ml/100 g b.wt. in rats and 1 ml/100 g b.wt. in mice for a.c. and i.p.

injections. Cocaine HC1 and cocaine methiodide were administered i.p. to animals. All doses are expressed as the free base of the drug.

Behavioral and Pharmacological Assays in Mice Locomotor Activity. Mice were placed into individual Omnitech photocell activity cages (28 x 16.5 cm) 10 min after i.p. administration of either 0.9% saline or cocaine.

Interruptions of the photocell beams (two banks of eight cells each) were then recorded for the next 30 min. Data were expressed as number of photocell interruptions. For antagonism studies, the mice were pretreated s.c. with either saline, dihydro-P-erythroidine, or mecamylamine 10 min before cocaine.

Anitinociception. The tail-flick method ofD'Amour and Smith (1941) as modified by Dewey et al. (1970) was used. A control response (2-4 s) was determined for each animal before treatment, and a test latency was determined after drug administration. To minimize tissue damage, a maximum latency of 10 s was imposed. Antinociceptive response was calculated as percent maximum possible effect MPE), where %MPE [((testcontrol)/( 10-control)) x 100], Groups of 8 to 12 animals were used for each dose and for each treatment. Mice were tested 5 min after nicotine administration for the dose-response evaluation. Antagonism studies were carried out by pretreating the mice s.c. with either saline or various drugs at different times before nicotine. The animals were tested 5 min after administration of nicotine.

Body Temperature. Rectal temperature was measured by a thermistor probe (inserted 24 mm) and digital thermometer (Yellow Springs Instrument Co., Yellow Springs, OH).

Readings were taken just before and at 30 min after the s.c. injection of nicotine. For -125- WO 01/89524 PCT/US01/10827 antagonism studies, mice were pretreated with either saline or various drugs 10 min before nicotine. The difference in rectal temperature before and after treatment was calculated for each mouse. The ambient temperature of the laboratory varied from 21 to 24 C from day to day.

Motor Coordination. To measure motor coordination, a wooden rod 6 cm in diameter was partitioned into three compartments by circular metal discs (28 cm in diameter) at 18-cm intervals. The rod was attached to a motor and rotated at a rate of 4 rpm. Naive mice were trained until they could remain on the rotarod for 3 min. Animals that failed to meet this criterion within 5 trials were discarded. This training took place no longer than 15 min before the s.c. administration of nicotine. Twenty minutes after the injection, mice were placed on the rotarod for 5 min. The amount of time the animals remained on the rotarod was recorded and percent impairment was calculated as Impairment time in s/300)) x 100]. An impairment value of 0% corresponds to the subjects that remained on the rotarod for 5 min (300 whereas 100% impairment corresponds to subjects, that fell off the rotarod immediately.

Seizure Activity. Following s.c. injection of nicotine at a dose of 9 mg/kg, each animal was placed in a 30 cm x 30 cm Plexiglass cage and observed for 5 min. Whether a clonic seizure occurred within a 5-min time period was noted for each animal after s.c.

administration of different drugs. This amount of time was chosen because seizures occur very quickly after nicotine administration. Results are expressed as percentage seizure.

Antagonism studies were carried out by pretreating the mice i.p. with either saline or cocaine 6 min before nicotine.

Nicotine Drug Discrimination in Rats Rats were individually housed in a temperature-controlled environment and were maintained on a diet (Agway Rodent Chow) that restricted their body weight to approximately 85% of their free feeding weight. Water was available ad libitum in the home cages. A two-lever operant drug nation paradigm (VI 15) was carried out in eight operant chambers (4 Lafayette model 80001 and 4 BRS/LVIE model s 002). Reinforcement was a -126- WO 01/89524 PCT/USU1/10827 Bioserv 45-mg precision dustless pellet. Data were collected automatically by two Commodore 64 microcomputers.

Rats were trained to respond on one lever after a s.c. injection of-(-)-nicotine (0.4 mg/kg) and another lever after a s.c. injection of saline. Rats were placed in an operant chamber 5 min after injections. The specific procedure for training rats to discriminate between nicotine and saline has been described previously (Rosecrans, 1989). Animals were required to meet a criterion of three successive days of 80% or greater correct-lever responding before testing was initiated. Injections were given 5 min before placing the animal in the operant chamber. The schedule of injections, was determined using a Latin Square design. Dose-response curves were determined for nicotine 5 min after s.c. injections.

For antagonism testing, animals were assessed for the behavioral effects of cocaine in conjunction with the training dose of nicotine. Cocaine war, administered 10 min before the injection of (-)-nicotine.

Oocyte Expression Studies Oocyte Preparation. Oocyte preparation was performed according to the method of Mirshahi and Woodward (1995) with minor modifications. Briefly, oocytes were isolated from female adult oocyte-positive Xenopus laevis frogs. Frogs were anesthetized in a 0.2% 3-aminobenzoic acid ethyl ester solution (Sigma Chemical Co.) for 30 min and a fraction of the ovarian lobes were removed. The eggs were rinsed in Ca 2 -free ND96 solution, treated with collagenase type IA (Sigma Chemical Co.) for 1 h to remove the follicle layer, and then rinsed again. Healthy stage V-VI oocytes were selected and maintained for up to 14 days after surgery in 0.5 x L-15 media.

mRNA Preparation and Microinjection. a 4 a 3 and P rat subunit cDNA contained within a pcDNAIneo vector were kindly supplied by Dr. James Patrick (Baylor College of Medicine, Houston, TX). The template was linearized downstream of the coding sequence and mRNA was synthetized using an in vitro transcription kit from Ambion (Austin, TX).

The quantity and quality of message were determined via optical density (spectrophotometer; Beckman Instruments Inc., Schaumburg, IL) and denaturing formaldehyde gel analysis.

Oocytes were injected with either 51 ng (41 nl) of a4 and P2 and a 3 and 12 mRNA mixed in a 1-1 ratio using a Variable Nanoject (Drummond Scientific Co., Broomall, PA). Oocytes -127- WO 01/89524 PCT/USU1/10827 were incubated in 0.5 x L-15 media IA (Sigma Chemical Co.) supplemented with penicillin, streptomycin, and gentimycin for 4 to 6 days at 19 C before recording.

Electrophvsiological Recordings. Oocytes were placed within a Plexiglas chamber (total volume 0.2 ml) and continually perfumed (10 ml/min) with buffer consisting of 116 mM NaC1, 1.8 mM CaCl 2 2.5 mM KC1, 1.0 tM atropine, and 10.0 mM HEPES at pH 7.2.

Oocytes were impaled with two microelectrodes containing 3 M KCL (0.3-3 MQ) and voltage-clamped at -70 rm using an Axon Geneclamp amplifier (Axon Instrunents Inc., Foster City, CA). Oocytes were stimulated for 10 s with various concentrations of acetylcholine and nicotine using a six-port injection valve. Except where noted, applications were separated by 5-min periods ofwashout. Currents were filtered at 10 Hz and collected by a Macintosh Centris 650 computer with a 16-bit analog digital interface board, and data were analyzed using Pulse Control voltage-clamp software running under the Igor Pro graphic platform (Wavemetrics, Lake Oswego, OR). Drugs were applied at different concentrations and concentration-response curves were normalized to the current induced by 1 (c4 2 receptors) or 10 pM (aP 2 receptors) of acetylcholine. The normalizing concentration of acetylcholine war, applied before and after drug application to each oocyte to check for desensitization. Data were rejected if responses to the normalizing dose fell below 75% of the original responses.

Statistical Analysis Data were analyzed statistically by an analysis of variance followed by the Fisher's P least-significant difference multiple comparison test. The null hypothesis was rejected at the 0.06 level. ED 5 o, ECs, and ADo (antagonist dose 50%) values with 95% CLs were calculated by unweighted least-squares linear regression as described by Tallarida and Murray (1987).

-128- WO 01/89524 PCT/USU1/10827 Results Effect of cocaine Analogs on Nicotine-induced Antinociception in Mice. Cocaine and its derivatives, the structures of which are described in Table 1, were evaluated for their ability to antagonize a 2.5 mg/kg dose of nicotine in the tail-flick procedure. Cocaine as well as all of its analogs, with the exception of RTI-70, produced dose dependent inhibition of nicotine's antinociceptive effect. Their antagonistic potencies are presented in Table 2, and dose-response curves of cocaine and selected analogs are shown in Fig. 1. The letter demonstrates that the antinociceptive effects of nicotine can be completely blocked by these agents. By themselves, these analogs did not produce significant effects on tail-flick latencies at any of the doses tested.

In regard to the structure activity relationship of the 3-phenyltropane analogs, the effects of substitution on the aromatic ring, of changes in the 23-substituent, and of removal of the N-methyl group were investigated. Because compounds RTI-29, -32, -51, -96, -111, and -112 differ only in their aromatic substituents, a comparison of the results from these compounds reveals the effect of these substituents. The 4-bromo analog (RTI-51) and the 3,4-dichloro analog (RTI-111) were approximately 3-fold and 2.5-fold, respectively, more potent than cocaine in blocking nicotine's antinociceptive effect. The 4-methyl analog (RTI- 32) was slightly more potent than cocaine, the 3-methyl-4-chloro analog (RTI-112) had approximately the same activity as cocaine, and the 4-amino analog (RTI-29) was one-half as potent as cocaine. RTI-120, which differs from RTI-32 by having a phenyl ester substituent in the 2-position, is only one-half as potent as RTI-32. The 2p-phenyl ester (RTI-113), which also has a 4-chloro substituent, was even less potent. In contrast, RTI-121, which is a 23isopropyl ester possessing a 4-iodo substituent, was 10-fold more potent than cocaine, The 2P-pyrrolidlinoamide analog (RTI-147), which has a 4-chloro substituent, was about one-half as potent as cocaine, whereas the 2P-pyrrolidinoamide (RTI-229), which has a 4-iodo substituent, possessed about the same potency as cocaine. The nortropane analog (RTI-110) was 3-fold more potent than cocaine. The 2-carboxy analog (RTI-70) and the 2a analog (RTI-268) were both much less potent than cocaine. WIN 36,065-2, which differs structurally from cocaine by having the aromatic ring connected directly to the 3-position of the tropane ring, was. 2.5-times less potent than cocaine. However, the addition of WO 01/89524 PCT/USU1/10827 substituents to the aromatic ring of WIN 35,065-2 led to compounds with increased potency.

A comparison of the potency of WIN 35,065-2 to those of R77-29, -32, -51, -55, -111, and -112, which differ only in their aromatic substituents, reveals the effect of these substituents.

The. 4-iodo analog (RTI-55), the 4-bromo analog (RTI-51), the 3,4-dichloro analog (RTI- 111), and the 4-methyl analog (RTI-32) were approximately 9- to 4-fold more potent than the unsubstituted analog WIN 35,065-2 in blocking nicotine's antinociceptive effect. The 3methyl-4-chloro analog (RTI-112) was approximately twice as potent as WIN 35,065-2, and the 4-amino analog (RTI-29) had approximately the same activity as WIN 35,065-2.

As mentioned above, cocaine dose-dependently blocked nicotine-induced antinociception with an ADs of 3.2 ,mol/kg (1 mg/kg). In addition, the dose-response curve of nicotine-induced antinociception was shifted to the right by cocaine (6 mg/kg) (Fig. 1), and the EDo 0 value of nicotine was increased from 1.5 mg/kg to 7.4 mg/kg (4.7- 12.0).

To determine whether these cocaine analogs could be blocking nicotine's effects through actions on neurotransporters, their potency to inhibit dopamine, norepinephrine, or serotonin transporters, was correlated with their antagonistic potency (Fig. The rankorder analysis did not show any significant correlation between the potency of 3 phenyltropane cocaine analogs in blocking nicotine's action and their affinity to the different transporters.

Pharmacological Interaction of Nicotine and Cocaine. To further characterize cocaine/nicotine interactions, additional experiments were conducted to determine whether cocaine would attenuate several of nicotine's effects in a dose-responsive manner.

Pretreatment with cocaine blocked the effect of a dose of 2.5 mg/kg of nicotine on the rotarod test in a dose-dependent manner (Fig. 4) with an AD 50 of 2 A/mol/kg (0.7 mg/kg). By itself, cocaine did not significantly alter performance on the rotarod test. Cocaine was moderately effective in antagonizing nicotine-induced seizures in mice with an estimated ADo of pmol/kg (Table 2, Seizure activity). However, cocaine failed to significantly block the discriminative stimulus effect of nicotine in rats (Table 2, Drug discrimination). Cocaine and a selected number of analogs were also evaluated for potential blockade of nicotine-induced hypothermia. Cocaine produced little antagonism of nicotine's hypothermic effects at doses -130- WO 01/89524 PCT/USU1/10827 that were 10-fold greater than those effective for antinociceptive blockade (Table 2, Body temperature). Among the cocaine analogs tested, RT1-31, -32, -55, -112, -121, and WIN 35,065-2 significantly blocked nicotine-induced hypothermia in mice, with RTI-31 being the most potent blocker (ADs 5 of 1.1 kimol/kg) (Table Interestingly, RTI-31 was more potent in blocking nicotine hypothermia than antinociception, whereas RTI-32 and RTI-121 were 15-fold and more than a 100-fold less potent, respectively.

To assess a bidirectional cross-reactivity between cocaine and nicotine, dihydro-Perythroidine (DHPE) and mecamylamine were evaluated for their ability to influence cocaine-induced hyperactivity in mice. Indeed, pretreatment with DHpE and mecamylamine at 1 mg/kg administered s.c. 10 min before the injection of cocaine (15 mg/kg, did not significantly reduced the hypermotility induced by cocaine (Fig. Higher doses ofDHpE and mecamylarnine could not be tested because they significantly decreased mouse spontaneous activity.

Mechanisms of Antagonistic Effect of Cocaine in Tail-Flick Test. To ascertain that the cocaine/nicotine interaction was taking place centrally, cocaine methiodide was evaluated as a potential nicotinic antagonist. As seen in Fig. 6 cocaine methiodide given at doses and 25 times higher than the ADo 0 dose of cocaine (1.1 mg/kg) failed to significantly block nicotine-induced antinociception in mice.

The most prominent central nervous system effects of cocaine are thought to be mediated through blockade of neurotransmitter transporters. Nomifensine, GBR 12909, and bupropion, which are monoamine uptake inhibitors with different affinity and selectivity to the different transporters, dose-dependently blocked nicotine's antinociceptive effect in mice (Table However, their potency of blockade did not correlate well with dopamine uptake inhibition. Although nomifensine and GBR 12909 inhibit dopamine uptake with similar affinity, nomifensine was five times more potent than GBR 12909 as a blocker. In addition, bupropion, a nonselective weak dopamine uptake inhibitor (micromolar range) was as potent as GBR 12909 in blocking nicotine's action. In contrast, methylphenidate, a nonselective monoamine uptake inhibitor, failed to block nicotine's effect. Furthermore, dopaminergic and nondopaminergic central stimulants, such as amphetamine and caffeine, blocked -131- WO 01/89524 PCT/USU1/10827 nicotine-induced antinociception (Table 4).

Fluoxetine, a selective serotonin uptake inhibitor, failed to significantly block (Table 4) or enhance the effects of nicotine in the tail-flick test. However, nisoxetine, a selective inhibitor of the norepinephrine transporter, antagonized nicotine-induced antinociception in a dose-related manner, with an AD 0 value of 7.4 umol/kg (2.3 mg/kg).

Finally, because cocaine is known to possess local anesthetic properties, lidocaine and procaine, two local anesthetics, were evaluated as nicotinic antagonist. However, they failed to significantly block (Table 3) or enhance the effects of nicotine, when injected at high doses (up to 75 umol/kg) into mice.

Sand a3, Expressed Receptor in Oocytes. Cocaine at 100 PM elicited little current when applied for 10 s to oocytes expressing the a4P 2 and a(X 2 subunit combination.

Although it did not activate a 4 1 2 and czP 2 -expressed receptors, cocaine antagonized the effects of nicotine in a concentration-related manner. Indeed, the current induced by nicotine was blocked by coapplication of cocaine at different concentrations (Fig. The concentration of cocaine that blocked 50% of the nicotinic current was determined to be AM (range, 4.4-6.9) and 30.5 AM (range, 22-42.3) for a 4 1 2 and a 3, receptors, respectively.

-132- WO 01/89524 WO 0189524PCT/1JS01/10827 Table 1: Structure of cocaine analogs tested as nicotinic antagonists R2 a The COXCH 3 group has a 2a orientation.

-133- TABLE 2 Comparison of pharmacological potencies of tropane analogs in blocking nicotine-induced antinociception (tail-flick test) and hypothermis after systemic administration to their binding affinities to 3 Hlmonoamine transporters in brain Analog AID~ Tail-Flick AD 50 Hypothermia Dopamine Serotonin Norepinephrine WIN 35,4281IC 50 3 HParoxetine IC 50 r 3 H]Nisoxetime IC 50 /tmollhg Iptmollhg nM nM\ nM\ Cocaine 3.2 20% @32 102 1060 3830 RTI-29 6.8 NTb 9.8 5110 151 RTI-31 7.2 1.1 1.12 44.5 37 RTI-32 2.0 31.7 1.7 240 RTI-51 1.0 NTa 1.69 10.6 37.4 0.9 1.2 1.26 4.2 63 0% 90 40% 90 2070 59,500 >200,000 RTI-1 10 1.0 NTb 0.62 4.1 5.45 RTI-I11 1.3 NTb 0.79 3.1 17.9 RTI- 112 3.5 1.5 0.8 10.5 36.2 RTI- 113 5.6 NTb 1.98 2340 2926 RTI- 114 5.3 9 1.4 1404 778 RTI-120 4.0 NTb 3.2 6 24,500 5830 RTI-121 0.3 49 0.4 66.8 285 RTI-147 5.7 NTb 1.38 12,400 3950 RTI-229 3.6 NTb 0.37 1790 990 RTI-258 19.1 NTb 22.7 66.3 760 WIN 3 5,065-2 18.0 16.7 123 11962 920 a(Carolet al. 1991, 1992, 1995; Lewin et al., 1992).

bNT, not tested.

WO 01/89524 PCT/USU1/10827 TABLE 3 Effect of cocaine pretreatment on different pharmacological actions of nicotine after a.c.

administration mice and rats Pretreatment Dosea Challenge Dosea Responseb Body temperatureb t°C (Mean SE) Saline Saline -0.3 0.2 Saline Nicotine -5.2 0.2 Cocaine (10) Saline 0.5 0.1 Cocaine (10) Nicotine -4.1 0.6 Seizure activity Seizures (Mean) Saline Nicotine 100 Saline Cocaine (20) 0 Cocaine (10) Nicotine 83.3 Cocaine (20) Nicotine Cocaine (30) Nicotine 16c Drug discrimination Test (Mean SE) Saline Nicotine 87 8 Saline Cocaine (10) 17 7 Cocaine (10) Nicotine 69 8 a Doses are expressed in mg/kg in parenthesis.

b Mice were challenged with nicotine 10 min after i.p. administration of cocaine.

SP .05 from saline/nicotine -135- WO 01/89524 PCT/USU1/10827 TABLE 4 Effect of various neurotransmitter uptake inhibitors, stimulants, and NA' channel blockers on nicotine-induced antinociception in tail-flick test after s.c. administration Drug ADs 0 gmol/hg Bupropion 8 GBR 12909 8.4 Nomifensine 1.7 Amphetamine 36.9 Methylphenidate 5% 74 Caffeine 32.4 Nisoxetine 7.4 Fluoxetine 15% 86.7 Lidocaine 7% Procaine 5% Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.

-136- WO 01/89524 PCT/USU1/10827

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Claims (20)

1. A method of training a smoker to cease smoking, comprising administering to the smoker an effective amount of a tropane compound represented by the formula: wherein Ri is CO 2 R 3 CONR 4 R 5 R 6 CH 2 R 6 X Y, N A-N A-N X N "I-N Y R7 A 'N R7 SN or N -142- Rk 3 is H, C 1 6 alkyl, C 38 s cycloalkyl or R 4 and R(6 arc each independently, H, C 16 ailcyl, C 26 alkene, C 2 alkyne, CH 2 -CO- phienyl, phenyl, phenyl substituted with 1-3 of Cl-6alkl,C2- 6 alkene, C 26 alkyne orC. ailcoxy, hydroxy, CH 9 OH, C- 6 alkoxy, phenoxy, amino, amino substituted with 1 or 2C 1 6 alkyl, C 2 6 alkene,C- 6 alikyne, C 1 6 atkoxy, C 1 acyl, phenyl, or phenoxy, or R4 and R5 may combine to form, together wit the nitrogen atom to which they are bonded, a cyclic structure selected from the group consisting of a pyrrolidinyl group, morpholinyl group, piperidinyl group and a group represented by the formula -N R6 is OH, H, C 14 alkyt, C3 8 cycloalkyl, C 1 6 atkoxy, Cl, Br, 1, CN, NH 2 NC- 6 akyl, N(C 1 6 alkYl) 2 OCO-C 1 6 alkyl, OCO-C, 3 ailkylaryl, CQ 2 -CI-6 alkyl, CO 2 -C 1 -3 ailkyl, or substituted phenoxy; 1(6is H, CI-6 alkyl, C3-8 cycloallcyl, C- 6 alkoxy, C 2 6 alkynyl, halogen, amino or;, x /Y A is S, 0 or NY; R 2 is H, C 1 alkyl, halogenated C- 6 ailyl, C 2 6 aikenyl or (CH 2 0 C0 2 where n is an integer of 1 to 8 and is C 1 6 ailyl;- each X is, independently, H. alkyl, C,_8 cycloalkyl, C- 6 alkoxy, C 2 6 alkynyl, phenyl, C 1 -phenyl, halogen, amino, or acylamido, CRZ=CRZRV CRk-CH=CkR, C-Ck,. -143- WO 01/89524 PCT/USU1/10827 C(=RzRz)R,; each R, is, independently, H, C- 6 alkyl, phenyl, substituted phenyl, CH 2 OH, Ct. 6 phenyl; each Y is, independently, H, I, Br, Cl, F, CN, CF 3 NO 2 N 3 OR 8 CO 2 NH 2 CO 2 R 8 C, 1 alkyl, NRgRio, NHCORt or NHCO 2 R, 2 R 8 is H or CI. 6 alkyl; and R 10 RI and R 12 are each, independently, H or C 1 alkyl, or X and Y, taken together with the phenyl group to which they are bonded, form a 2- naphthyl group, the dotted line between C 2 and C 3 represents a single or double bond, or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein R 2 is H.

3. The method of claim 1, wherein R 1 is CO 2 R 3 or CONHR 4 Rs; R z is H or C 1 .5 alkyl; X is H, C 1 .6 alkyl, halogen or amino; and Y is H, CI., alkyl or halogen.

4. The method of claim 3, wherein R 3 is H, C 1 6 alkyl, C 3 8 cycloalkyl or phenyl; R 4 and R 5 are each, independently, H or C1-6 alkyl, or combine to form a cyclic structure selected from the group consisting of pyrrolidinyl, morpholinyl and piperidinyl moieties; and said halogen is I, Br or Cl. The method of claim 4, wherein R 3 is H, C 1 6 alkyl or phenyl; and R 4 and R, combine to form a cyclic structure selected from the group consisting of pyrrolidinyl, morpholinyl and piperidinyl moieties.

6. The method of claim 1, wherein said tropane compound is administered transdermally or orally to said smoker.

7. The method of claim 1, wherein R 1 and the C 3 phenyl group are cis oriented.

8. The method of claim 1, wherein said tropane compound is enriched in the entantiomer.

9. The method of claim I, wherein said tropane compound is enriched in the entantiomer. The method of claim 1, wherein said tropane compound is administered concurrent with an act of smoking.

11. The method of claim 1, wherein said tropane compound is administered prior to smoking.

12. A method of preventing an addition to smoking in an occasional smoker, comprising: administering to the occasional smoker an effective amount of a tropane compound represented by the formula: R2, N R1 X Y -145- WO 01/89524 WO 0189524PCT/1JS01/10827 wherein R, is C0 2 R 3 CONR 4 R(6, CH 2 R., -a~x N N R(7 R 17 0-' A-N x A AN orN R 3 is H, C -6 alkyl, C 3 -8 cycloalkyl or R 4 and F-5 are each independently, 1H, C 1 -6 alkyl, C 2 6 alkene, C 26 alkyne, CH 2 -CO- phenyl, phenyl, phenyl substituted with 1-3 of C 6 alkylC 2 6 alkene, C 2 6 alkcyne or C 1 6 alkoxy, hydroxy, CH 2 OH, C 1 6 alkoxy, phenoxy, amino, amino substituted with 1 or 2 C 1 6 alkyl, C 2 6 alkene, C 2 6 alkyne, CI. 6 alkoxy, C 1 .8 acyl, phenyl, or phenoxy, or R(4 and R(5 may combine to form, together with the nitrogen atom to which they are bonded, a cyclic structure selected from the group consisting of a pyrrolidinyl. group, morpholinyl group, piperidinyl group and a group represented by the formula -146- 0 -N (CH2)0-6 R 6 is OH, H, C 1 6 alkyl, C3- cycloakyl, C. 6 alkoxy, Cl, Br, I, CN, NH,, NHCI. 6 alkyl, N(C, 6 alkyl) 2 OCO-C, 6 alkyl, OCO-C, 3 alkylaryl, CO,-C., 6 alkyl, C0 2 -Ci-3 alkylaryl, or substituted phenoxy; R, is H, C.-6 alkyl, C 3 8 cycloalkyl, C-6 alkoxy, C2-6 alkynyl, halogen, amino or; X x Y; A is S, O or NH; R 2 is H, C 1 5 alkyl, halogenated C,- 6 alkyl, C 2 6 alkenyl or (CH 2 ),CO 2 RX, where n is an integer of 1 to 8 and R, is C, alkyl; each X is, independently, H, C, 1 6 alkyl, C, 3 cycloalkyl, C., 6 alkoxy, C, 6 alkynyl, phenyl, C, 6 -phenyl, halogen, amino, or acylamido, CIR=CRzR, CRzR-CH=CR&, C-CRI, C R 1 each R. is, independently, H, C, 1 6 alkyl, phenyl, substituted phenyl, CH20H, C1.- phenyl; each Y is, independently, H, I, Br, Cl, F, CN, CF 3 NO 2 N 3 ORa, C0 2 N 2 C 2 O,R,, C -6 alkyl, NRRRo, NHCORI or NH1CO0R, 2 R, is H or C 1 6 alkyl; and R9, RIO, and R, 12 are each, independently, H or Cj, alkyl, or X and Y, taken together with the phenyl group to which they are bonded, form a 2- naphthyl group, the dotted line between C 2 and C 3 represents an optional double bond, or a pharmaceutically acceptable salt thereof.

13. The method of claim 12, wherein said tropane -147- WO 01/89524 PCT/USU1/10827 compound is administered prior to smoking.

14. A method of treating nicotine addiction, comprising administering to a patient in need thereof an effective amount of a tropane compound represented by the formula:: R2, N RI X wherein R, is CO 2 R 3 CONR 4 R, R 6 CH 2 6 X Y, N A-N N 0' R7 N AN or A or N R 3 is H, CI. 6 alkyl, C 38 cycloalkyl or -148- WO 01/89524 WO 0189524PCT/1JS01/10827 (CH 2 0 8 R 4 and R. are each independently, alkyl, C 2 6 alkene, C 2 6 alkyne, CH 2 -CO- phenyl, phenyl, phenyl substituted with 1-3 of C 1 6 alkyl,C 2 6 alkene, C 2 alkyne or C 1 6 alkoxy, hydroxy, CH 2 OH, C 1 6 alkoxy, phenoxy, amino, amino substituted with 1 or 2 C 1 6 alkcyl, C 2 6 alkene, C 2 6 alkyne, C 1 6 alkoxy, C 1 8 acyl, phenyl, or phenoxy, or R 4 and R 5 may combine to form, together with the nitrogen atom to which they are bonded, a cyclic structure selected from the group consisting of a pyrrolidinyl. group, morpholinyl group, piperidinyl. group and a group represented by the formrula -j R 6 is OH, H, C 1 6 alkyl, C 3 -8 1 cycloalkyl, C 1 6 alkoxy, Cl, Br, I, CN, NH1 2 NHC. 6 alkyl, N(Cj- 6 alkyl) 2 OCO-C.. 6 alkyl, OCO-C.. 3 alkylaryl, C0 2 -CI-. 6 alkyl, C0 2 -Cl-. 3 alkylaryl, or substituted phenoxy; R 7 is H, C 1 6 alkyl, C 3 .8 6 cycloalkyl, C 16 alkoxy, C 2 6 alkynyl, halogen, amino or: x -cc Y; A is S, 0 or NH; R 2 is H, C 1 5 alkyl, halogenated C 1 6 alkyl, C 2 6 alkenyl or (CH 2 ),,C0 2 where n is an integer of 1 to 8 and k~ is C 1 6 alkyl; each X is, independently, H, C 1 6 alkyl, C 3 8 cycloalkyl, C 1 6 alkoxy, C 2 6 alkynyl, phenyl, C 1 6 -phenyl, halogen, amino, or acylamido, CR,=CR 2 R 2 CPRR-CH=CRZRZ, CE=CR., each R, is, independently, H, C 1 6 alkyl, phenyl, substituted phenyl, CH 2 OH, C 1 6 phenyl; -149- each Y is, independently, H, I, Br, Cl, F, CN, CF3, NOz, N 3 ORs, CO 2 NH 2 C0 2 R 8 C1- 6 alkyl, NR 9 Rio, NHCOR 1 or NHCO 2 RI 2 Rg is H or C 1 .6 alkyl; and R 9 Rio, R 1 and R 12 are each, independently, H or CI- 6 alkyl, or X and Y, taken together with the phenyl group to which they are bonded, form a 2-naphthyl group, the dotted line between C 2 and C 3 represents an optional double bond, or a pharmaceutically acceptable salt thereof.

15. A method of training a tobacco user to cease using tobacco, comprising administering to the tobacco user an effective amount ofa tropane compound represented by the formula: N X Y wherein RI is COzR 3 CONR 4 Rs, R 6 CH 2 R 6 -150- WO 01/89524 WO 0189524PCT/USOI/10827 N- R 7 0' R A-N x Y R(7 R(7 N' N or N/ R(3 is H, C 16 alkyl, C 3 cycloalkyl or -(CH 2 0 8 R 4 and R. are each independently, H, Cj-, alkyl, C 26 alkene, C 2 6 alkyne, CH 2 -CO- phenyl, phenyl, phenyl substituted with 1-3 of C 1 alkyl,C 26 alkene, C 26 alkyne or C 16 alkoxy, hydroxy, CH 2 OH, C 16 alkoxy, phenoxy, amino, amino substituted with 1 or 2 C 1 6 alkyl, C 2 6 alkene, C 26 alkyne, C 16 alkoxy, C 1 8 acyl, phenyl, or phenoxy, or R(4 and R(5 may combine to form, together with the nitrogen atom to which they are bonded, a cyclic structure selected from the group consisting of a pyrrolidinyl group, morpholinyl. group, piperidiny] group and a group represented by the formula 1- O -N N (CH 2 0 -6 \-j R% is OH, H, C, 6 alkyl, C 3 cycloalkyl, C 1 6 alkoxy, Cl, Br, I, CN, NH 2 NHC, alkyl, N(C,_ 6 alkyl),, OCO-C., 6 ailcyl, OCO-C 1 3 alkylaryl, C0 2 -C. 6 alkyl, C0 2 -C 1 -3 alkylaryl, or substituted phenoxy; R, is H, C-6 alkyl, C, cycloalkyl, C., 6 alkoxy, C, 6 alkynyl, halogen, amino or; X x Y; A is S, O or NH; R, is H, CI, alkyl, halogenated C,_ 6 alkyl, C2-6 alkenyl or (CH 2 ),COR, where n is an integer of 1 to 8 and Rx is alkyl; each X is, independently, H, C, 6 alkcyl, C 3 8 cycloalkyl, C-6 alkoxy, C2-6 alkynyl, phenyl, C 16 -phenyl, halogen, amino, or acylamido, CR=CRR,, CRR-CH=CR 2 R, C CR, C(=RzRR,&; each R, is, independently, H, C, 1 6 alkyl, phenyl, substituted phenyl, CH20H, C 1 phenyl; each Y is, independently, H, I, Br, Cl, F, CN, CF,, NO 2 N 3 OR,, CONH2, C0 2 Rs, alkyl, NR 9 NHCOR,, 1 or NHCO,R 12 R, is H or C 1 -6 alkyl; and R, RR, R, 1 and R 12 are each, independently, H or C,- 6 allyl, or X and Y, taken together with the phenyl group to which they are bonded, form a 2- naphthyl group, the dotted line between C, and C 3 represents an optional double bond or a pharmaceutically acceptable salt thereof

16. The method of claim 15, wherein said tobacco user is a smokeless tobacco user. -152-

17. The method of claim 1, wherein R, is C02CH 3 R 2 is CH 3 X is chloro; Y is methyl; and the dotted line between C 2 and C 3 represents an optional double bond.

18. The method of claim 17, wherein the compound is represented by the formula: N CO2CH3 CI. ^lO- CH3

19. The method of claim 12, wherein R 1 is C02CH 3 R 2 is CH 3 X is chloro; Y is methyl; and the dotted line between C 2 and C 3 represents an optional double bond. The method of claim 19, wherein the compound is represented by the formula: N C02C H3 C.H, -153- I 2.1. The method of claim 14, wherein RI is CO 2 CH 3 R 2 is CH 3 X is chloro; Y is methyl; and the dotted line between C 2 and C 3 represents an optional double bond.

22. The method of claim 21, wherein the compound is represented by the formula: CO2CH3 Ct. CH3

23. The method of claim 15, wherein Ri is CO 2 CH 3 R2 is CH 3 X is chloro Y is methyl; and the dotted line between C 2 and C 3 represents an optional double bond.

24. The method of claim 23, wherein the compound is represented by the formula: N l C 0 2 CH 3 C1. CH3 DATED THIS TWENTY-FOURTH DAY OF FEBRUARY 2004 RESEARCH TRIANGLE INSTITUTE BY PIZZEYS PATENT AND TRADE MARK ATTORNEYS -154-