AU778629B2

AU778629B2 - Cocaine receptor binding ligands

Info

Publication number: AU778629B2
Application number: AU83629/01A
Authority: AU
Inventors: Philip Abraham; John W Boja; Frank I Carroll; Michael J Kuhar; Anita H Lewin
Original assignee: RTI International Inc
Current assignee: RTI International Inc
Priority date: 1996-08-22
Filing date: 2001-10-25
Publication date: 2004-12-16
Anticipated expiration: 2017-08-22
Also published as: AU8362901A

Description

WO 98/07427 WO 9807427PCTIUS97/14702 COCAINE RECEPTOR BIN~DING LIGANDS *:*Field of the invention: This invention is directed to a class of binding ligands for cocaine receptors and other receptors ~n !:he bDrain.

Spec :ical-y, a novel family of compounds shows high binding sneci: icity and activity, and, n a radiolabeled form, can be used :o bind to chese recentcors, for biochemical assays and mac echniaues. Such L7,-aa-na Is -,seful :'or ci-eern 29-10-04;12:32 ;PIZZEYS S61732218077 6/ 47 2 effective doses of new drug candidates in human populations. In addition, the high specificity, slow onset and long duration of the action of these compounds at the receptors makes them particularly well suited for therapeutic uses, for example as substitute medication for psychostimulant abuse. Some of these compounds may be useful in treating Parkinson's Disease or depression, by virtue of their inhibitory properties at monoamine transporters.

In U.S. Patent No. 5,128,818 there is disclosure of a family of compounds exhibiting particularly high specificity and affinity for cocaine receptors and other neurotransmitter receptors in the brain of the formula: H R, 'N C Xs b< /C02R3 2 2R3 4 4 \v^ a a a a.

a a.

a a a a a COMS ID No: SBMI-00976988 Received by IP Australia: Time 12:28 Date 2004-10-29 WO 98/07427 PCTIUS97/14702 Where !:he broken line represents an optional chemical bond and the substituents at 2 and 3 may be at any position; The iodo substituent may be at o, mn, 2, or multisubstituted; R, CH3, C:E 2

CH=C

2 1CAH n 1-4;

R

2

=CH

3 *-HS CH 3 3, (CE 3 2 CH, CH,, CsHsCH 2

C

6

H

5

(CE

2 2; X pharmaccologically acceptable anion Sites of Soecific interest included cocaine receptors associated with dopamine (DA) transporter sites.* Subsequently, in the U.S. PCT Application from which priori ty 4S claimed, and which is incorporated herein by reference, the values for R, and R. were expanded, such that R, may be an alkyl of 1-7 carbon atoms, C.H 2

CR

3 =CR,Rs wherein R 3 are each, independently alkyl, or phenyl compounds of the formula CH.i(CH,)Y, wherein y 1-6. The 2CT filing also reveals the af finicy z::.ese comiocunds focr co-caine receptors assoc-4ate6 wir:hserotonih 5-hydroxytryptamine, 5-UT) transporters, and confirms, for the first time, that the in vitro binding reported in the earlier -f iled application, is confirmed in in vivo testing.

Specific disclosure for a variety of applications, iricludina using the compounds n both PET and SPECT scanning, wiierei~n either :he iocdine substituent, or one of the carbon =rouus s radioactlve '-123, 125 or 131 and C1 1) thus orovi dino method4s 3 29-10-04;12:32 :PI ZZ-YS 61732218077 8/ 47 4 for scanning for the presence of specific cocaine receptors. Such scanning processes may be used to determine physiological conditions associated with dopamine and serotonin reuptabe inhibitors, which lead to behavioral and neurodegenerative disorders/diseases. Such disorders include depression, bipolar disorder, eating disorders, obesity, attention deficit disorder, panic attacks and disorders, obsessive-compulsive disorder, Parkinson's Disease, and cocaine, nicotine and alcohol addiction. These compounds, in addition to being used in treatment of these disorders, may be used to examine in general the density and distribution of specific cocaine receptors in various parts of the brain and/or body, to determine the efficacy of neurological treatments aimed at halting or reversing the degeneration of specific nerves in the brain, and for screening drugs, such as antidepressant drugs.

The affinity and specificity of these compounds, as reported in the applications incorporated, is surprisingly high, and compared with prior art 15 compounds, such as 3 H] WIN 35,428, the novel compounds of these applications exhibit extremely low IC50 values for binding inhibition.

In U.S. Patent No. 5,496,953, filed December 10, 1993, also Incorporated herein by reference In its entirety, a family of compounds was disclosed, having the formula: 0 0* 0* COMS ID No: SBMI-00976988 Received by IP Australia: Time 12:28 Date 2004-10-29 WO 98/07427 WO 9807427PCTIUS97/14702

N

11 WhereinYi s-C-O-Rb or 0-N Rb Where in R, is hydrogen, C,- 5 alkyl R. is phenyl, C 1 6 alkyl, alkyI- substituted phenyl is C,.

6 alkyl, phenyl, C1- alkyl substituted phenyl and Z is phenyl or naphtyl bearing 1-3 substiruents selected from the SUBSTITUTELL SHET(ULE 26) WO 98/07427 PCT/US97/14702 group consisting of F, Cl, I, and alkyl.

These compounds exhibit unusually high affinity and specificity for binding to receptors for the dopamine transporter site, as well as the serotonin transporter site, based on inhibition of [IH]paroxetine binding. This high affinity makes certain of these compounds particularly well suited for use as therapeutic agents, as well as for imaging agents for dopamine and serotonin transporters.

SUMMARY OF THE INVENTION Accordingly, one object of this invention is to provide novel compounds which bind to cocaine receptors.

Another object of the invention is to provide novel 3- (substituted phenyl)-2-(substituted)tropane analogs which bind to cocaine receptors.

Still another object of the invention is to provide 3- (substituted phenyl)-2-(substituted)tropane analogs which bind oreferentiaily to the dopamine transporrer.

Yet- another object of the invention is to provide 3- (substituted phenyl)-2-(substituted)tropane analogs which bind preferentially to the serotonin transporter.

Another object of the invention is to provide a compound of S* the formula WO 98/07427 WO 9807427PCTIUS97/14702 C0 2

R

1 wherein R is CH 3 CAH, CHCH,CH 3 or CH(CH,) 2 R, is CH 3 CH,6H 5 2 CAH, (CH 2 3

C

6

H

5 or wherein X is H, OCH 3 or ClI and Y is H, OCH 3 or Cl1, and n=l1-8.

Another object of the invention is to provide compounds having the following formulas: wherein R, =hydrogen, alkcyl, X=H, C,- 6 alkyl, CM. cycloalkyl, alkoxy, C 1 6 alkynyl, halogen, amino, acylamido, and Z=H, 1, Br, Cl, F, CN, CF 3

NO

2

N

3 OR,, CONH), C0 2

R

1

C,-

6 alkyfl,

NR.

4

R

5 NHCOR5, NHCO,R 6 R.t is C,- 6 alkyl, phenyl, C,.

6 alkyl substituted phenyl -7- SUBSTITUTE SHEET (RULE 26) WO 98/07427 PCT/US97/14702

RI\

N

YR, Y, and Z are as defined Z above and Z may additionally be RI R, C R2 R R I=C C-CH=C RI R3 R, R3

C=:CR

RI\ R, R 2

R

3 H or C 1 6 alkyl N X. Y, Z are defined above and M X= 1-8 -CH CHz -C C- A further object of the invention is to provide a method for treating psychostimulant abuse, by administering to a patient in need of such treatment a pharmaceutically effective amount of a 3-(substituted phenyl)-2-(substituted) tropane analog.

A still further object of the invention is to provide method for inhibiting the action of a psychostimulant, by administering to a patient in need of such treatment a psychostimulant-inhibiting amount of a 3-(substituted phenyl)-2-(substituted) tropane analog.

Still another object of the invention is to provide a method for inhibiting neurotransmitter re-uptake by administering to a patient in need of such treatment a neurotransmitter transporter-inhibiting amount of a 3-(substituted phenyl)-2- (substituted) tropane analog.

-8- SUBSTITUTE SHEET (RULE 26) WO 98/07427 PCT/US97/14702 Another object of the invention is to provide a method for treating neurodegenerative disorders, by administering to a patient in need of such treatment a pharmaceutically effective amount of a 3- (substituted phenyl) (substituted) tropane analog.

Still another object of the invention is to provide a method for treating depression, by administering to a patient in need of such treatment a pharmaceutically effective amount of a 3- (substituted phenyl)-2-(substituted)tropane analog.

Briefly, the invention pertains to the discovery that certain cocaine analogs are particularly well suited for therapeutic use as neurochemical agents. These particular cocaine analogs, in modulating neurotransmitter actions, may also be useful for modulating the actions of pyschostimulant drugs, for modulating endocrine function, for modulating motor function, and for modulating complex behaviors.

With the foregoing and other objects, advantages and features of the invention chat will become here in after apparent, the nature of the invention may be more clearly understood by reference to the following detailed description of the preferred embodiments of the invention and to the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS: A more complete appreciation of the invention and many of the attendant advantages thereof will be readily obtained as the 9 WO 98/07427 PCT/US97/14702 same becomes better understood by reference to the following detailed description when considered in connection with the accompanying drawings, wherein: Figure 1 depicts the scheme for convening 3-(substituted phenyl)-2-tropane carboxylic acid (tropane acid) to 2-substituted tetrazoles. oxazoles. oxadiazoles.

thiazoles, thiadiazoles and benzothiazole.

Figure 2 depicts the scheme in which the carboxamide obtained from the tropane acid was treated to obtain nitriles and tetrazoles.

Figure 3 depicts the scheme used to prepare 3-substituted isoxazoles.

DETAILED DESCRIPTION OF THE INVENTION The present invention includes novel compounds having the following formula: r .CO.CH -CO0zB la. R=C,H 3 b. R=CH,CH3CH 3 c, R=CH(CH 33 2a, R=CH,CHs b, R=(CH,),C,H c, R=(CH) 3

CH

5 3a. X=H. Y=CCH3 b, X=OCH,, Y=H c, X=OCH,,

Y=OCH

3 d, X=C. Y=H e, X= H, Y=C f, X=C, Y=C The compounds of this invention can be prepared according to the synthesis methods described in the parent applications. Alternative synthesis for related compounds will be apparent to SUBSTITUTE SHEET (RULE 26) WO 98/07427 PCT[US97/14702 those of ordinary skill in the art. Particular synthesis schemes are exetflD.if ied in U.S. Patent No.- 5,444,070, which i s incorporated herein in its entirety. Additional schemes follow hereinbelow.

Preparation of 3j6- (Substituted phenyl) tropane- 24-heterocyclic Analogues ChemisBtry The known 30- (substituted phenyl) -2 -tropane carboxylic acid (tropane acid) (Carroll et J. med. Chem. 35:"13_13-1817 (1992) served as the starting material for the synthesis of substituted tetrazoles, oxazoles, oxadiazoles, thiazoles, thiadiazoles and benzothiazole as shown in Figure 1.

The :ropane acid was refluxed with N-acetyl and benzoic hydrazide in phosphorous oxychioride to obtain the corresponding 1.,.4-oxadiazoleS (Afanasiadi et al., Chem.

Heterocyc..C Comnpd. 397-400 (199S)) N-benzoyl hydrazide amide obtained by- rthe reaction cf the acidc.:hloride of zroloane acid with N-b-enzoic hydrazide was cyclized with Lawesson's reagent (El-Barbary et al., Acta Chirnaca Scandiriavica 597-601 (1980)) i~n *ref luxing TI{F to the 5-substituted !,3,4-thiadiazoles. The Nphenylacyl carboxatnide obtained -from tropane acid and 2- *aminoacetophenole was cyclized by ref luxincr the amide J.n phosphorous oxychioride :to obtain :he required 5 -subs t m. ited oxazoles Carroll ec al., Med. Chem. Res. 3:468 (1993)).

11 WO 98/07427 PCTIUS97/14702 Cyciization of the same amide with Lawesson's reagent (El-Barbary et al., 1980) in refluxing THF gave the 5-substituted thiazoles respectively. The benzothiazcle was obtained without the cyclization step by the reaction of acid chloride obtained from the appropriate tropane acid with 2-aminothiophenol.

The previously reported carboxamide (Carroll et al., 1993) obtained from the tropane acid was dehydrated with trifluoroacetic acid and pyridine in THF to the nitriles (Campagna et al., Tet. Letts. 22:1813-1816 (1977)) as shown in Figure 2. Cycloaddition of trimethylsiiylazide to the nitrile afforded the corresponding cetrazoles (Saunders et al., Med.

Chem. 33:1128-1138 (1990)).

i Figure 3 outlines the route used to prepare 3-substituted isoxazole. The known tropane compounds (Carroll et al., J. Med.

Chem. 34:2719-2725 (1991)) were treated with dilithiated methyl or phenyl acetoneoximes, obtained by the treatment of acetone or S acetophenoneoxime with n-BuLi at 0DC. The corresponding addition S product was cyclized without isolation using sulfuric ac-l at reflux temperature to furnish the required isoxazoles (Saunders et al., 1990).

The therapeutic effects of the present cocaine analogs can be analyzed in various ways, many of which are well known to those of skill in the art. In particular, both in vitro and in vivo assay systems may be used for the screening of poten:ial WO 98/07427 PCT/US97/14702 drugs which act as agonists or antagonists at cocaine receptors, or drugs which are effective to modulate neurotransmitter level or activity, in particular by binding to a transporter of that neurotransmitter.

The compounds of the invention may be prepared and labeled with any detectable moiety, in particular a radioactive element, and may then be introduced into a tissue or cellular sample.

After the labeled material or its binding partner(s) has had an opportunity to react with sites within thc sample, the location and concentration of binding of the compound may be examined by known techniques, which may vary with the nature of the label attached.

Illustrative in vitro assays for binding are described in Boja et al Ann. NY Acad. Sci. 654:282-291 (1992), which is incorporated herein by reference in its entirety. A particularly preferred in vitro assay involves the ability of a compound in question to displace the binding of a known labelled compound to S binding sites in a tissue sample, isolated membranes or synaptosomes. Alternatively, the compounds may be analyzed by their ability to inhibit reuptake of a labelled neurotransmitter in a sample, in particular, in synaptosomes.

The compound or its binding partner(s) can also be labeled with any detectable moiety, but are preferably labelled with a radioactive element. The radioactive label can be detected by WO 98/07427 PCT[US97/14702 any of the currently available ccunting procedures, including the imaging procedures detailed in the disclosures of the parent applications. The preferred isotope may be selected from 3 H, "C, 1C, 1C, 22p, 2SS, 36 C1, 5 Cr, 5"Co, 5sCo, 5 Fe, 90 Y, :2s, and a6Re. c, As noted in the parent disclosures, the binding of the labelled compounds may be analyzed by various imaging techniques, including positron emission tomography (PET), single photon emission computed tomography SPECT), autoradiogram, and the like. Such imaging techniques are useful for determining effective doses of new drug candidates. By performing in vivo competition studies, it is possible to use brain imaging studies to determine the oral doses of new drug candidates, which produce significant receptor occupancy in the brain. In vivo S displacement studies which determine in vivo ICSO's which in turn reflect doses that occupy receptors in vivo are described in Cline et al ':1992) Synapse 12:37-46). in addition to 1s uses in determining in vivo potency/occupancy, these same brain imaging methods can be used to determine rate of entry cf compounds into the brain (Stathis et al (1995) Psychopharmacclogy 119:376-384) and duration of action (Volkow et al (1995) Synapse 19:206-211) The binding of the compounds of the invention may be at any location where a receptor for a particular psychostim.uant is WO 98/07427 PCTIUS97/14702 present, and more specifically, any location where a dopamine or serotonin transporter is present. Such locations are in general any area comprising a part of the dopamine or serotonin pathway, in particular at synapses. Examples of locations known to be associated with dopamine transport include the cerebral cortex, hypothalamus, substantia nigra, nucleus accumbens, arcuate nucleus, anterior periventricular nuclei, median eminence and amygdala. Examples of locations known to be associated with serotonin include the striatum, cerebral cortex, hypothalamus, Raphe nuclei, pre-optic area and suprachiasmatic nucleus.

By "psychostimulant" is meant any compounds whose abuse is dependent upon mesolimbic and mesocortical dopaminergic pathways.

°*o In particular, psychostimulant relates to cocaine. However, the compounds of the invention may also be used to treat abuse of compounds not traditionally classified as "psychostimulants, but which act at a dopamine or serotonin transporter. Such abused compounds include ethanol and nicotine.

o SFor in vivo studies, the compounds of the invention may be prepared in pharmaceutical compositions, with a suitable carrier and at a strength effective for administration by various means

S

to a patient experiencing an adverse medical condition associated with cocaine receptor binding or neurotransmitter release and reuptake, for the treatment thereof. The action of the compounds may be analyzed by the imaging methods noted above, and also by WO 98/07427 PCT/US97/14702 behavioral studies. In particular, the pharmaceutical effects of the compounds of the invention may be reflected in locomotor activity, including the induction of ipsilateral rotation, stereotyped sniffing and the "swim test" in schedule-controlled operant behavior response for food or shock termination) or drug self-administration. In general, maximal behavioral effects are seen at near complete occupancy of transporter sites.

Such protocols are described in Boja et al (1992), Balster et al Drug and Alcohol Dependence 29:145-151 (1991) Cline et al Pharm.

Exp. Ther. 260:1174-1179 (1992), and Cline et al Behavioral Pharmacology 3:113-116 (1992), which are hereby incorporated herein by reference in their entireties.

A variety of administrative techniques may be utilized, among them oral or parenteral techniques such as subcutaneous, intravenous, intraperitoneal, intracerebral and intracerebroventricular injections, catheterizations and the like. Average quan:tites 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 or veterinarian.

The compounds of the invention preferably have a long duration of action, which is important to facilitate dosing schedules. In rats, the present compounds have a 7-10 fold WU 9/U74Z7 PCT/US97/14702 longer duration of action ncan cocaine (Fleckenstein et al, "Highly potent cocaine analogs cause long-lasting increases in locomotor activity," Eur. J. Pharmacol., in press, which is incorporated herein by reference in its entirety). In addition, the present compounds also preferably have a slow rate of entry into the brain, which is important in decreasing the potential for abuse (Stachis et al, supra, which is incorporated herein by reference in its entirety). The present compounds enter the brain more slowly than cocaine.

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 adminstration, 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 Spharmaceutically acceptable and compatible with the active ingredient. Suitable excipients are, for example, water, saline, WO98/07427 PCT/US97/14702 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 formulation, and in a therapeutically effective amount. The quantity to be administered depends cn 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 oeculiar to each individual. However, suitable dosages may range from about 0.01 zo about 1000, preferably about .25 to WO 98/07427 PCT/US97/14702 about 500, and more preferably 10 to 50 milligrams of active ingredient oer kilogram body weight of individual per day and depend on the route of administration. 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 and are also variable, but are typified by an initial administration followed by repeated doses at one or more hour intervals by a subsecuent injection cr other administration. Alternatively, continuous intravenous infusion sufficient to maintain appropriate concentrations in the blood are contemplated.

The compounds of the present invention may be administered S. for their activities as surrogate agonist medications for cocaine, nicotine, alcohol, amphetamine and other psychostimulant abuse. Because of their favorable binding characteristics to transporters of neurotransmitters, they may be used for inhibitin the uptake of dopamine, norepinephrine, serotonin and other monoamines. The compounds of the present invention may find use as antipsychotics, antidepressants, local anesthetics, anti-Parkinsonian agents, anti-obesity drugs, drugs useful in the treatment of bipolar disorder, eating disorders, obesity, S attention deficit disorder, panic attacks and disorder, obsessive-compulsive disorder, sexual dysfunction, as anticholinergic agents and as sigma receptor drugs.

*WO 98/07427 PCT/US97/14702 The compounds of the invention may also be useful in treating neurodegenerative disordiers, in parzti;cular ortreating Parkinson's Disease, but also may be useful in the treatment of cocaine, nicotine and alcohol addiction.

The preferred compounds of the present invention are derived from the series of compounds designated RTI-4229. The p~hysical properties of some of these compounds are given in Table7 C Table I Physical Properties of 41-substituted Hetrocyclic Analogs of 3p-(4-Substituted-phenyl) Tropane and Cocaine Code Name Compound Molecular Formulae' mp 0

C

RI-188 Ria1 -1j95 1 194 R1'1-200 RTl' 199 RI- 189 IZTI- 178 RTI-219 WII*202 W1(I-61 RI1-158 RTi- 163 RI 15 7 RH 16 5

C

22 11 2 3 C1 2

N

3 Oe

C

23 H1 26 C1N 3 0C C 1 811 2 4 Cl N 3 Od

C

22 l-1 2 3

C'ANS

C

2 3l1 26 ClN 3

S'

C

27

H

29 C1N 2

O

7 b~c

C

20 11 32

N

2

O

7 br

C

23 11 2 4

CIN

2

S'

C

21 11 22 Cl 2

N

2 Sc

C

15 11 1 8 C1 2

N

2 e C 16112 1 C1N 2

C,

5 18 C1N 5 e

C

1 I 1 23

CI

2

NS'

CIB 1 22 C1 2

N

2 0 160- 162 175- 178 146 (dcc) 165- 170 180-185 126 (dcc) 175-181 228-230 140-150 (dec) 220 (dcc) 270 (dec) 296-300 212 (dec) 235 (dec) [aXID(C)MeOH 84.59 (0.36) +97.22 (0.25) -43.05 (0.15) -42.81 (0.16) -33.50 (0.20) 101.43 (0.21) -104.04 (0.60 +27.43 (0.11) -172.49 (0.28) -71.00 (0.50) -76.40 (0.50) -124.94 (0.39) -110.97 (0.16) -102.89 (0.46) Yield% S* IZ I 17 1 ITIl 180 Rl177 RTI- 176 ITI- 181 P J1- 184 l&I- 185

C

19 11 2 5

CIN

2 0

C

18 11 22

CIN

2 0c

C.

2 3 11 2 4 Cl 2

N

2 0r

C

24 [127CI N 2 0

C

23 11 24 C11N 2 Od C1 9 1H 23

CIN

2

O

3 d

C,,H

25

CIN

2 0 3 277 235 (dec) 287 270-295 (dcc) 2679 (dec) 117-121 205 -107.28 (0.71) -94.57 (0.39) -97.50 (0.28) -102.22 (0.68) -91.11 (0.43) -53.60 (0.25) -56.71 (0.43) a. Ili Salt; b. Tartrate Salt; c. 0.25 miol water; d. 0.5 mol water; e. 0.75 inol water; f. 1 miol water.

*WO 98/07427 PCTIUS97/1 4702 Many of the preferred compounds of the invention fall within the broad class of compounds described by the formula:

N

Wherein Y =CH,R3

CONRR'

N R,0..N A-N

R

2 R hydrogen, alkcyl, R, =hydrogen, C,.

6 alkyl, C,- 8 cvcloalkyl, C, 4 alkoxy, C, allcynyI, halogen, amnine. CH,C 6

,H

5

(CH,)

2

C

6

H

5

(CH,)

3

C

6

H

5 or Q1

R

3 =OH, hydrogen, C,.6 alkcyl, C 3 cycloalicyl, alkoxy, Cl, Br, CN, NH 2

NHC,.

6 alkyl, NC, 4 6 alkyl, 0C0C 16 alkcyl, 0C0CI 1 3 alcylaryl, A=S,O0or N X=H, C, 4 6 alkyl, CM. cycloalkyl, C, 4 alkoxy, C,.

6 alkcynyl, halogen, amino, acylamido, C,11 5 CH,CH3CH 3

CH(CH

3 2 -23- SUBSTITUTE SHEET (RULE 26) WO 98/07427 PC~fUS97I147O2 Z=H, Cl, C73, N0 2 N3, OR,, CONII,, C0 2 alkyl, NRRs, N1HCOR,, N{C0 2

R

6 and Q' and Q' may be the same or dif ferent and OCH 3 or cl, wherein R,-Rs are each alkyl, R and R' are independently c,.

-alkyl, alkene, 01.6 a3.kyne, phenyl, phenyl substituted with 1-3 Of C,- 6 alkyl, alkene, alkyl or alkoxy, CI-6 alkoxy, phenoxy, amine, amine substizuted with i-2 of C 1 6 alkyl, alkene, alkyne, alkoxy or phenyl or phenoxy or R and RI may combine t~o form heterocyclic structure including pyrrolidinyl, piperi4dinyl and mornholiflo moieties, unsubstituted or substituted with 1-2 C,'6 alkyl, alkene, alkyne or alkoxy groups.

The present inventors have surprisingly found that certain of the RTI-4229 series of compounds are particularly potent .~.pharmaceutical agents in accordance with the present invention.

Preferred comounds of the RTI-4229 series include the following: RTI-4229-3-, 32, 51, 55, 83, 96, 97, 98, :01, 105, :91 08, ill 11, 112, -16, 121, 12Z2, !27, 132, 139, 140, 142, 145, 146, 147, 150, 153, 1-78, 188, 199, 190, 191, 193, 195, 199, 200 203, 204, 205, 206, 219, 230, 2-39, 240, 241, 242, 251, 252, 274 277, 278, 279, 280, 281, 282, 283, 286, 287, 296, 304, 305, 307, 309, 3-18, and 330. The chemical structures of these compoounds, along with their Co~ values for inhbition of radioligand binding are given below. DA is dopami-ne, 5-FIT is 5 -hydroxytrpt amilne WO 98/07427 (serotonin), and NE is norepinephrine. DA=[ 3 H]WIN 35,428; paroxetine and NE, nisofetine: PULI/US97/147U2 RTI-4229-3 1 DA 1.12±0.1 4.5±1.34 NE. 37±2.1 RTI-4229-32 DA 1.71±0.31 240±27 NEN 60±0.53 RTI-4229-5 1 DA 1.69±0.23 5-HT 10.6±0.24 NE,. 3 7.4 2 RTI-4229-5 D A 1.26±0.04 4.21±0.34 NEN 36±3 '02H3*C 4

H

5 06 '0 2

CH

3

CH-

3 :O 1 c1 3 ,0 2

CH-

3

C

4 H-506 I AYO 98/07427 W098(7427PCTIUS97/14702 RTI-4229-83 DA 55 ±2 28.4±3.83 NEN 4,027.87+380.70 CH3>,

C

4

H

5 ,0 6 0.5 H 2 0O (Tartrate)

-CH

2 CH-,1 HC1 1.5 H-,O

F

CH

3 N RTI-4229-96 DA 2.95 ±0.58 76±2.8 NEN4 520± 10.4

CH

3 *4 4.

C. *44* 4 4 4 4 444* RTI-4229-97 DA 3.91±0.59 5-HT 181±14 NEN 282 RTI-4229-98 DA 0.69±0.2 0.36±0.047 NEN 10.97 ±0.88 *2HC1 2H,)O

NH

2 CO,)Me 4.

4 444 4 4* 4t

CH

3 ,N.

RTI-4229- 101 DA 2.2±0.19 26±3.2 NEN

OH

-26- QI IPCTtTI ITC C~rlr:T 1011 r- f)Z W- I II w I L. Ul IL.L. I IWLSL I.WJ WO 98/07427 WO 9807427PCTIUS97/14702 RTI-4229- 105 DA 1.60±0.05 143±2f-15 NEN 127.2±5.9 RTI -4229-108 DA 2.64±0.31 98±8.7 NEN 129.3+±15 N HCI 0.25 H,0

OAC

O CI

*HCI

C

*8*C

C.

C C

C

C C

C.

RTI-4229-1 DA 0.62±0.09 5-UT 4.13±0.62 NEN 5.45 ±0.21

CO

2

CH

3 RTI-4229-1 11 DA 0.79±0.08 3.13 ±0.36 NEr4 17.96±0.85 Cl RTI-4229-1 12 DA 0.82±0.05 10.5 ±0.41 NEN 3 6.2-11. 02 HCI .2H 2 0O -27- CH 3 S UlB ST7 I JT"rE OfSM r EI R U LE f26) .WO 98/07427 PCT1US97/14702

CH

3 RTI-4229-1 16 DA 33 ±3.9 1,227± 176 NEN 967.55 ±26.25 HCl 0 c-0 CCOCH(CH3)2

.HCI

I

OSO*

9 S 9 @0 S 9* S 9* S S 0055 *5 a

S

*5 9*

S

9

*OSO

9

LOSS

0 9 55 9 0 .5 9 9.

0* RT1-4229-121 DA 0.43 ±0.05 66.84±6.53 NEN 285±7.6 RTI-42 29- 122 DA 1.50±0.35 5-HT 184.38±21.91 NEN 3,791±149 RTI-4229- 127 DA 19±1 5-UT 4,499±557 NEN 3,444±44

CH

3 ,N 0- CH3.

N

HCI CH3, 0 CHCH3

N

O-CH

I

CH-7CH3 j 2- HCl CH3

N

2, HCI CH3 RTI-4229- 132 DA 3.48±0.11 208±18 NE.. 137.3±10.5 -28- SUB~STIT UTE SHEET (RULE 26) WO 98/07427 PCTIUS97/14702 RTI-4229-139 N DA 1.67±0.13 H HC 85±9.3 c NE. 56.9+±2.6 RTI-4229- 140 N C2H DA 101±16H

C

5,701 ±721 NE,, 2,076±2850 RTI-4229- 142 H N 02H *DA 4.39±0.20 5-HT 68.59±2.02F :NEN 18.78 ±0.68 RTI-4229-145 DA 9.60±0.42 0 OH 5-HT 2,932± 181 .HCL NEN 1,478±96 -29- WO 98/07427 wb 9807427PCTIUS97/14702 RTI -4229-146 DA 2.05 ±0.23 98±10 NEN 144± 3 N OH

H

HCI 1.51-H20 RTI-4229- 147 DA 1.38±0.03 12,393.99± 1207.03 NEN 3,949+:72 HCI .22 120

CH

3 a. a a.

a a a a a a a a a.

RTI-4229- 150 DA 3.74 ±0.52 5-HT 2,019±133 NEN 4,738 ±322

CO

2

CH

3 HCI RTI-4229- 153 DA 1.06±0. 12 5-LIT 3.59±0.27 NEN 132± H \0 Cl- 3 N 11 co-C-

CH

3

I

RTI-4229- 173 DA 49.9+7.3 8.13 +'0.30 NEN 122±-112

NH

SUB-- 0%1 S'r-EET (RUl f6)m WO 98/07427 RTI-4229- 178 DA 35.4 ±1.74 1,698.7-/±166.68 NE,, 677 ±67.5 RTI-4229- 188 DA 12.56±1.03 3,303.76±195.85 NE,. 929±88.1 /C3

N

PCTIUS97/14702 Tartrate

-CH

3 o.

C

RTI-4229- 189 DA 19.71 ±1.98 1,116.18±107.148 NEN 496±42.1 RTI-4229- 190 DA 0.96±0.10 168±1.8 NEN 235±8.39 CHi, 0 .c0

.HCI

SUBSTITUTE SHEET (RULE 26) WO 98/07427 A I %J13 -I I I A i -A.

RTI-4229-191 DA 0.61±0.08 15.5 ±0.72 NEN 101.7±10.5 0

-HCI

CH

3 RTI-4229- 193 DA 1.68±0.14 1,066.38+109.12 NEN 644±27.7 0

HCI

RTI-4229- 195 DA 47.48 ±4.76 22,310.9±822.83 NEN 1,310±36.7 RTI -4229- 199 DA 35.88±3.40 51,459.7±4,513.10 NEN 24,320.8±-L-3,822.61

.CH

3 0

NI

*HC I 11 CH3 4.

*CH

3 f'I Inrc-i-,-rl ri-I- ruic-r 101 11 c a WO 98/07427 RTI-4229-200 DA 15.29±2.43 18,416.5±1,508.79 NEN 4,142.08+466.07 PCT[US97/14702

CH

3

'S

NI

HCI

RTI-4229-203

CH-

DA 9.37 ±0.52 5-1-T 2,153.39±143.18 NEN 2,743.73±140.92 RTI-4229-204 DA 3.91±10.23 3,772.17±383.64 NEN 4,782.70±487.10 RTI14229 -205 DA 8.19+0.90 5.237.30±453.397 NEN 2.136.62±208.5-2 N CH3 N0 o1 Q C' tl

CF-

Qc I Hc' /CH 3 *HCl

IC'

CH

3 N RTI-4229-206 DA 27.38 ±1.47 1,203.39±41.79 NE,. 1.277.60± 117.68

CH

3 0 Q0 CHi SUBSTITUTE SHEET (RULE 26) WO 98/07427 PCTUS97/14702 RTI-4 229-2 19 DA 5.71 ±0.36 N' CH 3

S

10,341.5±76.11 NEN 8,563 ±824 RTI-4229-230N DA 1.28±0.17 .HCl 57.41±5.04 c NE., 141±16.1 RTI-4229-239N l DA 0.61 ±0.07 114.3±3.69

H

NEN 35.6 ±2.57 RI-4229-240 DA 1.38 ±0.03 l 38.4±2.31 c N EN 84.5 ±3.09 RTI-4229-24 1 DA 1.02 ±0.06 618.5 ±28 NEN 124±3.56 -34- SUBSTITUTE SHEET (RULE 26) WO 98/07427 WO 9807427PCTIUS97/14702 RTI-4229-242 DA 7.67±0.31 226.54±27.37 NEN4 510.1±51.4 ,C0 2

CH

3 0.HC1I RTI-4229-25 1 DA 1.93±0.14 10.1±1.1 NEN 114±13.1 RTI-4229-252 DA 2.56±0.22 35.2±2.45 NEN 124.6±8.3 N ~~OEt HCl 0 N OCH 3 ,C0 2

CH

3

HCI

-cl 0 RTI-4229-274 DA 3.96±0.2 -HT 5.62±0.2 NEN 14.4±1.3

.C

4

H

5 0 6 a a a a a a.

RTI-4229-277 DA 5.94±0.61 !-.909.71 ±255.41 NE., 5.695.38±214.72 co,_ 2 NO SUBSTITUTE SHEET (RULE 26) WO 98/07427 PTU9140 PCTIUS97/14702 RTI-4229-278 DA 8.14±0.73 2,146.50±138.71 NEN 4,095.01 ±413.45 RTI-4229-279 DA 5.98±0.48 1.06±0.10 NEN 74.3 ±3.8

CO

2 CH,(CH3)2

HCI

KNIN) O 2

CO

2 -CF1

-C

4 H5106

CH

3 RTI-4229-280 DA 3.12±0.39 6.81±0.41 NEN 484.13 ±51.6 RTI-4229-28 1 BIH- 14 1-7 DA 2.37 ±0.28 15.69± 1.5 NE, 820.5 ±45.8

CO

2

)CH-

3

*C

4 H-506 0.5 H 2 0 O CH 3

'ICO

2 Me Q -CH 3 (-)-tartrate

H

2 0O RTI-4229-282 BIH- 141-2 DA 68.53 ±7.08 70.38±4.13 NE, 3921.58±130 ,.(-)-tartrate H,0 SUBSTITUTE SHEET (RULE 26) WO 98/07427 WO 9807427PCTfUS97/14702 RTTI-4229-283 BIH-141-12 DA 14.3 5 3 3.13+0.16 NEm 3125 ±333 -~tartrate C0 2 C14 3 SI H 2

O

RTI-4229-286 DA 20.7±0.57 5062 ±485 NEN 1231+±91

C

4 H-506 0.5 HP12 "C0)-CH 3

C

4

H-

5 06 1.25 H 2 0

CH

3 RTI-4229-287 DA 325 1686± 140 NEN 17,819 ±440 RTI-4229 -2 96 BIH- 141-1 DA 5.29 ±0.53 11.39±0.28 NEN 1592.23 ±93.4 ,C02CH3 (-)-tartrate .0.5

S.

S

S RTI-4229-304 BIH-141-1 1 DA 15.04±1.2 7.09±0.71 NEN 2799-±300 -5/4 H 2 0O -37- SUBSTITUTE SHEET (RULE 26) WO 98/07427 WO 9807427PCTIUS97/14702 RTI-4229-305 BIH- 141-18 DA 1.24±0.11 1.59±0.2 NEN 21.8 0

CO

2

CH

3 tarUate 1/2 H 2 0 (Th~H RTI-4229-307 BIH- 141-15 DA 6.11±0.67 S-HT 3.16±0.33 NEm 115.8±5.1

.CO

2

CH

3 3/4 HO tartrate

-CH

3

C

RTI-4229-309 BIHl-141-17 DA 1.73 ±0.05 2.25±0.17 NEN 14.9±1.18

N

CO

2

CH

3 tartrate I~ 1/2 H 2 0 RTI-4229-3 18 DA 0.51±0.03 0.80±0.06 NEN 21.1±1.0

CO

2

CH

3

C

4

H

5 O .0.5 H 2 0

-C

4

H

5 0 6 .0.5 H 2 0 RTI-4229-330 DA 310.2±21 15.1±0.97

NE,

-38- SUBSTITUTE SHEET (RULE 26) WO 98/07427 PCTIUS97/14702 Particul~arly preferred compounds include ?TT-4229-77, 87, 113, 1.14, 1177, 119, :120, 124, 125, 126, 1.30, '141, 143, 144, 151 152, 154, 165, 171, 173, 176, 177, 180, 181, 2.94, 202, 295, 298, 319, 334, 335, 336, 337, 338, 345, 346, 347, 348, 352 and 353.

The chemical str'uctures of these compounds are given below: WO 98/07427 PCTIUS97/14702 Particularly preferred compounds include RTI-4229-77, 87, 113, 114, 117, 119, 120, 124, 125, 126, 130, 141, 143, 144, 151, 152, 154. 165, 171, 173, 176, 177, 180, 181, 194, 202. 295, 298, 319, 334, 335, 336, 337, 338, 345, 346, 347, 348, 352 and 353. The chemical structures of these compounds are given below: RTI-4229-77

CH

3

I

N 0 DA 2.51+±0.25 QNH, NE, 2,246.86±238.99 2.-I RTI-4229-87 DA 204±29 S-HT 29,391 ±2,324 NEN 35.782±6,245

C

RTI-4229-1 13 DA 1.98±0.05 S-HT 2,336± 176 NE,~ 2.955 ±223 RTI-4229-1 14 DA 1.40±0.13 1,404±7.1 NEN, 778 ±21

CH

3 COICH(CH3)2

HCI

(h7 Lc I RTI-4229-1 17 DA 6.45 ±0.85 6.090±488 NE, 1,926+±38

CH

3 Co?,CH(CH3)2 SUBSTITUTE SHEET (RULE 26) WO98/07427 PCT1US97/14702

CH

3

NN

RTI-4229-1 19 0

HCI

DA 167±13 40,615±9,416 NE N 6,985 ±635 RTI-4229-.120 CH3... N 0 DA 3.26 ±0.06 0-Q 24,471±1,515 4 iI C-I NEI, 5,833 ±373 *RTI-4229-124 CH3, N N CH 3

H

DA 1,028±65 e 5-HT 33,085±5,434 NE N 70,993±3,563 RTI-4229- 125NN

H

DA 4.05±0.57 HI-H) 2,584±799 c NEN 363±36

CH

3 N N CH 3 RTI-4229- 126 /A DA 100±6.3 HCI. 3,824±418 NEN' 7,876+551 -1 SUBSTITUTE SHEET (RULE 26) WO 98/07427 WO 9807427PCTIUS97/14702 RTI-4229- 130 DA 1.62±0.02 195 ±4.8 NEN 245 ±13 0 -N

N

HCI 1.5 H 2 0 RTI-4229- 141 DA 1.81±0.19 337±43 NEN 835 HC1 120) S S

S

RTI-4229- 143 DA 4.1±0.22 404±56 NEN 4,069 177 RTI-4229- 144 DA 3.44±0.36 106± 10 NEN 1,825±166 0 cl L- 0' HCI 120) N 01N Br

N

0 HCl

HO

S S

S.

RTI-4229- 151 DA 2.33 ±0.26 1,074±125 NEN 60+2 CH3li HCI 42 7 CH 3 SUBbI 1-1UTESHEET- (RULE 26) WO 98107427 WO 9807427PCTIUS97/14702 a

C

a a..

a a a. a a RTI-4229-152- DA 494±37 1,995±109 NENj 22,689±1,957 RTI-4229-154 DA '6.0±0.55 3,460±245 NENj 135 ±13 RTI14229- 165 DA 0.59±0.04 5-HT 572±58 NEN 161±12 RTI-4229-171 DA 0.93 ±0.09 5-HT 3),818.25±346.14 NEN 254±31 RTI-4229-176 DA 1.58±0.02 5.109.72±187.101 NE, 398±17.6

HCI.-

N 0 1

N

N'

IICH3 01H

HCI

Cl CH3....N 1\ CH 3

HCI

-CH

3 Hc' -43- SUBSTi1TUIL SHEET (RVULE 26) WO 98/07427 PTU9/40 PCT[US97/14702 RTI-4229- 177 DA 1.28±0-18 2,418.21 ±135.68 NEN4 504±29 RTI-4229- 180 DA 0.73 ±0.04 36.35 ±4.99 NEN 67.9±5.25 RTI-4229-181 DA 2.57±0.14 5-HT 100±9.0 NEN 868 RTI-4229- 194 DA 4.45±0.12 5-HT 4,884.47 ±155.42 NE,, 253 ±18.9

HCI

0-N c lI 0* a a a.a.

a a a a.

a a a. a a a.

CH

3 RTI-4229-202 DA 1.37±0.14 1,118.85±120.00 NE.. 402.8±29.5 N *HCI O C! -44- WO 98/07427 PTU9/40 PCTIUS97/14702

CH

3

N

RTI-4229-295 BIHI-141-14 DA '21.31±0.87 2.96±0.04 NEN 1349± 105 C0 2 )CH3

*CHCH

3 RTI-4229-298 BIN- 141-4 DA 3.7±0.16 46.8±5.8 NE, 346.6±25 .COld- 3 (-)-tartrate 1.5 1HL2O

S

S. 0* S

S

S.

S

SS 55 4

S

5* RTI-4229-3 19 DA 1.1±0.09 5-HT 11.4±1.3 NEN 70.2 ±6.28

-C

4

H

5 0 6 0.5 H 2 0O

S

S..

0 00 0 RTI-4229-334 DA 0.50 ±0.03 5-1-T 3086± 153 NEN 120± 10.4 RTI-4229-3 DA 1419±0.12 2318± 153 NEN 954+97.3

CH

3

CH

3 SubIIUIq,~ ir-rr i 11- WO 98/07427 WO 9807427PCT[US97/14702 C H 3 RTI-4229-3 36 DA 4.09±0.44 5741±421 NEN4 1714±38.5 I CH3 p uc

CH

3 RTI-4229-3 37 DA 7.31±0.61 36,842±3616 NEN 6321 ±703

H

N

5555 5e 55 4 *5 C p5 *5 5s as 5 @555 5* 5* S 5 5* 5 05 5 5 5S5@ 5 SOs.

RTI-4229-3 38 DA 1104.2±54.6 5-HT 7.41±0.55 NEN 3366±584

/C

2

CH

2

Q

.C

4

H

5 0 6 CH3, RTI-4229-345 DA 6.42 ±0.46 76.000± NEN 5290.4±448.99 es 605 55 0 5.

5 RTI-4229-346 DA 1.57+0.10 5880.4±179 NE, -762.01±37.8 -46- SUBSTITUTE SHEET (RULE 26) WO 98/07427 PCT/US97/14702

F

C H 3 RTI-4229-347 DA 1.86±0.09 7256.95±+210 NEN4 918.4±108.34 RTI-4229-348 DA 28.2±1.9 34,674±3954 NEN 2667.2 ±6267.3 H4 .HCI .0.5 H,0 Ph a a RTI-4229-352 DA 2.86±0.21 64.9±1.97 NEN 52.4±4.9 RTI-4229-353 DA 330.54 ±17.12 0.69 ±0.07 NEN 148.4±9.15

.CH-;C

5

H

4

SO

3

H

.COCHi -tartrate a a.

-47- SUBSTITUTE SHEET (RULE 26) WO 98/07427 PCT/US97/14702 It should be noted that compound RTI-353 is a highly potent compound at the serotonin site, and is selective relative to the dopamine and norepinephrine sites. This compound is particularly useful as an antidepressant, and as an imaging agent for serotonin transporters.

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.

EXAMPLES

All certified grade reagents or solvents were purchased from Aldrich Chemical Co. or Fluka Chemical Co. All reagents were normally used without further purification. When anhydrous conditions were required, solvents were distilled and dried by oo standard techniques immediately prior to use.

All air and moisture sensitive reactions were conducted under a prepurified nitrogen atmosphere in flame-dried glassware, previously dried at 150 0 C. Anhydrous solvents were transferred using conventional syringe or steel canula techniques under an inert atmosphere. Removal of solvents in vacuo was done on a Buchi rotavapor rotary evaporator operated at water aspirator pressure.

e• WO 98/07427 PCTIUS97/14702 'H NMR and 'C NMR spectra were recorded at 250 Mhz on a Bruker AM250 spectrometer. Optical rotations were recorded on at the Sodium D line on a Rudolph Research Autopol III colarimeter (1 dm cell). Melting point was recorded on a Unimelt Thomas Hoover capillary melting point apparatus in open capillary tubes and were uncorrected. Elemental analysis were performed by Atlantic Microlab, Inc., Norcross, Georgia.

Reaction products were purified by flash column chromatography using silica gel (mesh size 230-400) purchased from VWR Scientific. Thin layer chromatography (TLC) was performed on Whatman 254 nm fluorescent silica gel 60A (1 x 3 inches, 250 thickness)) precoated TLC plates using the solvent systems indicated. Developed chromatograms were evaluated under 254 nm UV light or with iodine.

EXAMPLE 1 General Procedure For the Preparation of Amides To a solution of 1 mmoi of 30-(4-Chlorophenyl) -ropane-2 carboxylic acidor 3- (4-Methylphenyl) -tropane-20-carboxylic acid in 5 ml of methylene chloride was added dropwise with stirring under nitrogen 2.0 eq oxalyl chloride (2 M solution in methylene S chloride). The resulting solution was stirred at room temperature for an hour after evolution of gas has ceased. The solvent was removed in vacuo at room temperature and then at high WO 98/07427 PCTIUS97/14702 vacuum to remove residual traces of oxalyl chloride. The resulting residue of acid chloride was suspended in 5 ml methylene chloride under nitrogen at 0 OC, and 2.0 eq of the amine hydrochloride containing 4.0 eq of triethylamine, or eq of the amine free base was added. The mixture was stirred at room temperature overnight. Aqueous 3N NaOH (5 ml) was added to basify the reaction mixture, the organic layer was separated and the aqueous layer extracted with 3 x 10 ml chloroform. The combined organic layers were dried (NaSO) filtered and the solvent removed in vacuo to give crude product. The crude was purified by flash column chromatography or crystallization.

EXAMPLE 2 3- (4-Chlorophenyl)-2(-(5-phenyl-1,3,4-oxadiazol-2-yl)-tropane Hydrochloride (RTI-188) S" To a solution of 0.59 g (2 mmol) of 30-(4-Chlorophenyl)tropane-2e-carboxylic acid (chloro acid) in 2 ml Of POC1, was Sadded 0.31 g (2.2 mmol) of N-benzoic hydrazide and refluxed under nitrogen- for 2 hours. The reaction mixture was cooled, poured into ice and rendered basic to pH 7-8 using concentrated NH,0H.

To the ice cold aqueous layer was added 10 ml brine and extracted thrice with 10 ml methylene chloride. The organic layers were combined dried (NaSO) filtered, and the solvent removed in vacuo to give 0.9 g of crude residue. Purification of the residue by flash column chromatography [50% (ether/triethylamine *o WO 98/07427 PCTIUS97/14702 9:1) Jrx hexane] gave 0.33 g of pure oxadiazole (RTI-188) which was recrystallized from ether/ petroleum ether: 1H NMR CCDC!,) 1. 81 (mn, 3 2.1 IS 3 H) 2.26 Cm, 2 H) 2. 66 1 H) 3 .3 3 Cm, 2 H) 3.5 1 (in, 2 H) 7 .16 (mn, 4 H) 7. 45 (in, 3 H), 7.86 Cm, 2 H) IR (CHC1 3 2950, 1550, 1490, 1450, 1340, 1090 cin'; (alt) -106.25o (c 0.08, CHCl 3 The oxadiazole was converted into hydrochloride salt: 'H NNR (MeOD) 2.08 Cm, 1 2.57 Cm, 5 3.0 3 4.01 2 H), 4. 15 (mn, I H) 4. 39 Cm, 1 H) 7. 24 Cm, 4 H) 7. 52 5 H) mp 160-I62 0 C; Anal calcd for C,,H 23 C1 2

N

3 0.0.75H2O; C 61.47; H 5.74, N 9.78; Cl 16.50; found C 61.47, H 5.73, N 9.76; Cl 16.56; [at] 0 +84.590 Cc 0.36, CH3OH).

Further elution gave as a second fraction 0.1 g C13%) of white solid which was characterized to be 30- (4-Chiorophelyl) -2a- (S-pheny1-1,3,4Oxadiazo-2-yl) tropane: 1H NMR CCDC1 3 1.76 (m, 3 2.06 Cs, 3 2.45 Cs, 3 3.36 Cm, 2 3.51 Cm, 1 H), 3.65 Cm, H) 7.-2 1 Cm, 4 H) 7. 47 (mn, 3 H) 7 .9 1 1i, 2 mD 170-!71 0 C; Anal calcd for C' 22

H

22 CINO; C =69.55; H 5.34, N 11.06; Cl 9.33; found C 69.49, H =5.85, N =11.01; Cl 9.41; [a]D +33.060 Cc 0 .18, CHC1 3 EXAMPLE 2 *3$-(4-MethyJ.phalyl) 2-Spey-134oaizl--l-rpn Hydrochloride (RTI-195) Reac,:.on of 0.65 2.5 mmci) of 30-(4-Methylpheiyl)- WO 98/07427 PCI'1US97/14702 acid (Methyl acid) as described above for RTI-188 gave after work-up and purification by flash column chromatography (ether/triethylamine 9 in hexane) 0.36 g (40!k) of pure oxadiazole (RTI-195) which was recrystallized from ether/petroleum ether: 'H NMR CCDC1 3 1.83 3 H) 2.18 3 H) 2.21 3 2.3 (in, 2 H) 2.67 Cm, 2. H) 3.33 (mn, 2. H) 3 .4 1 (in, 2. H) 3.5 3 (in, I H) 3 61 (Mn, 1 H) 7. 0 (mn, 2 H) .7.213 (mn, 2 H) 7 .44 3 H) 7 .86 Cm, 2 H) IR (CICL~, j2990, 1545, 1505, 1440, 1350. cm'; (ot] 0 -163.920 Cc 0.2, CHCI.

The oxadiazole was converted into hydrochloride salt: NMR (MeOD) 2. 05 Cm, 2. H) 2 221 Cs, 3 H) 2. 51 (in, 5 H) 2. 99 3 H) 3. 86 (in, 1 H) 3.9 5 Cm, 2. H) 4. 14 Cm, 2. H) 4.-3 5 (mn, H) 7.02 Cm, 4 H) 7.53 Cm, 5 H) mp 275-178OC; Anal calcd for

C

23

H

26 C1N 3 0.0.7SH 2 O; C 67.47; H 6.77, N 10.26; Cl 8.66; found C 67.58, H 6.79, N 10.34; Cl 8.78; [a] 0 +97.220 Cc 25, CH 3

OH)

Further elutiJon gave as a second fractilon, 0.18a of Soj~d which was characterized t~o be 3 -:4-Met!hyluhely1)-/2a-i5phenyl 3,4 -Cxadiazol 2- y) rropane which was recrysta.1 _zed from ether! petroleum ether: 'H NMR (CDC1 3 1.77 Cm, 2 H) Cm, 4 H) 2. 25 Cs, 3 H1), 2. 47 Cs, 3 H) 3 33 2 H) 2.S51 (M, 1 3. 69 Cd o f d, J 2. 6, 122Hz, 1 H) 6. 91 m,2 H) 0.23 (in, 2 H) 7. 45 (mn, 2 H) 7 .4 5 Cm, 3 H) 7. 89 m,2 H) I R *,HCL 3 3020, 1540, 1510, 1415, 1250, 1215. Anal calcd for C,2 2

NO

WO 98/07427 PCT1US97/14702 C =76.85; H 7.01, N 1.69; found C 76.60, H 7.12, N= 1-1.55; (a3 0 D +40.730 (C 0.28, CHC1 3 EXAMPLE 4 3p- (4-Mothyiphalyl) (5-methyl-1,3,4-oxadiazol- 2 -yl) -tropane Hydrochloride (RTI-194) Reaction of 0.65g (2.5 mmol) of methyl acid as described above for RTI-195 using 0.21 g (2.75 mmol) of N-acetic hydrazide ga ve after work-up and Purification by flash column chromatography [(751; (ether/ triethylamfine 9:1 in hexanel 0.29 g of pure oxadiazole (RTI-194) which was recrystallized from ether/petroleum ether: 'H NMR (CDC1 3 1.7S Cm, 3 H) 2.18 3 H) 2.22 3 H) 2.25 (in, 2 H) 2.35 Cs, 3 H) 2.56 Cm, 1 H) 3 24 1 H) 3 .4 (in, 2 H) 3 47 (in, 1 H) 7. 0 Cm, 4 H) 'JC NMR (CDCl 3 1.1.06, 20.9, 25.08, 26.32, 34.11, 34.6, 41.83, 45.73, 61.97, 66.21, 127.11, 128.85, 135.85, 138.19, 162.5, 167.44; IR (CHCL 3 2950, 1590, 1510, 1450, 1350, 1215 [Cf1D 108.470 fc 0.14, CHC1 3 The-oxadiazole was converted into hydrochloride salre: 'H NM~R (MeOD) 1.-99 Cm, I. H) 2 .23 Cs, 3 H) 2.27 Cs, 3 H) 2. 47 'iM, H) 2. 94 Cs, 3 H) 3. 72 Cm, 1 H) 3. 79 Cm, 1 H) 4. 10 Cm, I. H) 4.23 Cm, 1 H) 7.05 CM, 4 H) mp 1460C. dec); Anal caicd for

C,

8

H.

2 ,C1N 3 0.0.511H,O; C 63.06; 'H 7.35, N 12.26; Cl 10.34; found C 63.Z7-, 7.40, IN 12.07; CI 10.27; [aW 0 -43.050 Cc 15, CH 3

OH).

WO 98/07427 PCT1US97/14702 EXAM'PLE (4 -Chloropheny1) 2- (5 -phenyl 3, 4 -thiadiazol 2-yl) tropane Hydrochloride (RTI-200).

Reaction of 0.-5 9g (2 mmol) of 3 (C4 -Chlorophenyl) tropane 2 carboxylic acid as described above for the preparation of amides gave after purification of the crude by crystallizing from ethyl acetate/ether 0.52 g of pure N- (313-(4 -Chlorophenyl) trouane-2 -carboxylic] -benzoylhydraz4-de: 1H NMR (CDC1 3 6 1.76 (in, 3 2.24 (mn, 2 2.41 3 2.51 (mn, I. 2.68 (mn, L H) 3 .1S (mn, i H) 3 44 (mn, 2 H) 7 2 2 4 H) 7. 46 (in, 3 H), 7. 78 (mn, 2 H) 9.02 (br s, 1 12.97 (br s, 1 H) IR (CHC1 3 3385, 3035, 3000, 1620, 1570, 1485, 1450, 1215 cm- 1 A solution of 0.4 g (1 mmcl) of N-[30-(4-Chlorophenyl)- -benzoyl-hydrazide and 0. .8g (2 mmol) of Lawesson'S reagent in 10 ml toluene was ref luxed for 4 h under nitrogen. The reaction mixture was cooled and solvent removed n vacuc to give a yellow residue. To the residue was added 3 g or silica ael and 10 mi cf iethylene chloride, zhe resul:-ing slurry was mnixed properly and the solvent removed in vacuo. The crude compound impregnated on silica gel was loaded on a column *and purified by flash column chromatography ether/trieth2laiine( 9 :21) in hexanel t o obtain 0.23 g of pure thiadiazole (RT1-200) which was further puriffied by recrystallizing fromn ether: Ili NNR CDC-', 6 2.75 (mn, 2 H) 2.20 3 2-.32 3 3.30 (mn, 3 3.78 I. 86 (mn, WO 98/07427 PCTIUS97/14702 2 H) 7. 08 Cm, 2 H) 7.-4 3 3 H) 7. 97 (mn, 2 H) 1 3 C NMR 25.55, 25.88, 34.60, 36.09, 41.55, 49.73, 61.48, 65.33, 127.59, 128.28, 128.78, 128.88, 130.37, 130.88, 132.19, 139.27, 168-29, 169.56; IR (CCd 4 2940, 1490, 1460, 1340, 1245, 1100, 1010 cmn' The thiadiazole was converted into hydrochloride salt: 1H NMR (MeOD) 6 2.-0 6 (in, 1 H) 2 .5 3 5 H) 2.-9 7 3 H) 3 .9 2 (mn, 1 H) 4 .17 (mn, 2 H) 4 39 (mn, 1 H) 7. 11 (in, 2 H) 7.-2 6 Cm, 2 H) 7.51 3 H) 7.79 Cm, 2 H) mp 165-170 0 C; Anal calcd for

C,

2

H

2 3 C1 2

N

3 S.0.75H,0; C =59.26, H 5.54, N 9.42, Cl 15.90; S= 7.19. found C 59.27, H 5.52, N =9.40, Cl =15.99; S 7.09; Cot), -42.810 Cc 0.16, MeCH).

Further elution gave 0. 08 g as a second f raction which was characterized to be 303- (4-chiorophenyl) -2a- (5-phenyl-1, 3,4oxadiazol-2-yl) -cropane.

EXAMPLE 6 (4 -Hethyiphenyl) (S-phenyl-1, 3 ,4-thiadiazol-2 yl) -tropans Hydrochloride (RTI-199) *Reaction of 0.65 g (2.5 mmcl) of 3j3-(4-Methy1phenl)tropane-2g-carboxylic acid as described above for preparatiJon of amides gave after work up and puri4ficat-ion by flash column chromartography [(SO0% CMA-80 in methylene chloride)) 0.48 a (511k) pure N- (30- (4-Metbhylpheflyl) Tropane-'2&carboxylilc -NI -benzoylhydrazide which was further purlfied by recrystall-zirng _fromn ether/pet ether: 11 NMR (C-DCl 3 6 1. 75 (mn, 3 H) 2. 20 2 H), WO 98/07427 PCT/US97/14702 2.27 3 2.42 3 2.51 1 2.67 1 3.18 1 H) 3.47 2 7.11 4 7.48 3 7.81 (m, 2 9.06 (br s, I 13.09 (br s, 1 IR (CHC1 3 3385, 3045, 1625, 1570, 1460, 1420, 1100 cm'; Reaction of 0.29 g (0.75 mmol) of N-[30-(4-Methylphenyl)as described above for RTI-200 gave after work and purification by flash chromatography [40% ether/triethylamine(9 1) in hexane] 0.16 g of pure thiadiazole (RTI-199) H NMR (CDC1 3 6 1.70 (m, 1 1.88 2 2.20 3 2.23 2 H) 2.21 3 H), 2.38 1 3.21 1 3.32 1 3.39 1 3.78 1 6.81 2 6.92 2 7.43 (m,3 7.97 (m, 2 "C NMR 20.98, 25.65, 25.95, 34.79, 36.25, 41.65, 50.05, 61.68, 65.49, 127.32, 127.65, 128.89, 128.95, 130.29, 131.11, 135.94, 137.68, 168.83, 169.45; IR (CC1 4 2935, 1510, 1450, 1250, 1120, 1100, 1060 cm The thiadiazole was converted into hydrochloride salt; -H NMR :MeOD) 6 1.95 1 2.17 3 2.41 5 2.89 3 3.76 1 4.05 2 4.30 1 4.22 (m, H 1 6.89 2 6.99 2 7.39 3 7.67 2 H); mp 180-185C; Anal calcd for C 23

H

2

CIN

3

S.H

2 O; C 65.62, H 6.46, N 9.98, Cl 18.42; S 7.62. found C 65.57, H 6.63, N S 9.91, Cl 18.24; 5 7. 55; [a]D -33.50 (c 0.2, MeOH) Further elution gave 0.04 g of a second fraction which WO 98/07427 PCTIUS97/14702 was character ized to be Met hylphenylI) -2a(5-phenl -1,3,4axadiazol-2-yl) -tropane.

EXAMPLE 7 (4-Chlorophenyl) -20- (5-phenyl-oxazol-2-y.) -tropane Tartrate RTI-189) Reaction of 0.73 g (2.5 mmcl) of 30-(4-Chlorophenyl)carboxylic acid as described above for the preparation of amides gave after purification by flash column chromatography CMA 80 in methylene chlori.de) 0.8 g of pure 3-4 Chiorophenyl) tropane 2 a-N- (phenyacyl) carboxamide: '11 NMR CCDCl 3 6 1 .7 1 3 H) 2 .19 2 H) 2. 39 Cs, 3 H) 2. 46 1 H) 2.58 (mn, 1 3.13 1 3.43 (mn, 2 4.74 2 7.13 (mn, 4 7. 49 (in, 2 H) 7. 59 Cm, 1 H) 7.-9 6 (in, 2 H) 10.-5 7 (br s, 1 H) ;IR (CHCl 3 3135, 3010, 2930, 1695, 1650, 1590, 1530, 1485, 1450, 1355, 1220 cm.

A solution of 0.725 g (1.83 mmol) of 30- (4-Chloropheny1) in 6 ml POC, -was heated art 1250C under nitrogen for 2 hours. The reaction mixture was cooled and poured into ice and rendered basic to pH 7-8 using *concentrated NH,OH. To the ice cold aaueous layer was added ml brine and extracted thrice with 10 ml iethylene chloride. The organic layers were combined dried (NaSO,) filtered, and the solvent removed iLn vacuc to 0.63 g crude oxazole. Pur-, FiJc a c ion of the crude by f -lash column chroinatograpfly WO 98/07427 PCTUS97/14702 (ether/triethylamine 9 1 in hexane) gave 0.34 g of pure oxazole (RTI-189) which was further purified by recrystallizing from ether/petroleum ether: 'H NMR (CDC1 3 1.79 3 2.22 3 2.27 2 2.66 1 3.27 1 3.40 (m, 2 3.53 1 7.11 1 7.16 4 H) 7.31 5 H); IR (CHC13) 2950, 1540, 1490, 1445, 1350, 1120, 1090 CIM'; [ai 70.370 (c 0.19, CHC1 1 The oxazole was converted into tartrate salt: 'H NMR (MeOD) 2.14 1 2.54 5 2.96 3 3.75 2 4.12 1 4.25 1 4.41 2 7.05 2 7.29 (m, 7 7.45 1 7.43 1 mp 126 0 C (dec); Anal calcd for C 27

H

2 ,CINO,.0.75H,0; C 59.78; H 5.67, N 5.16; Cl 6.54; found C 59.78, H 5.58, N 4.93; Cl 6.31; [crI, +101.430 (c 0.21, CH 3

OH).

EXAMPLE 8 S34- (4-Methylphenyl)-2 (5-phenyl-oxazol-2-yl) -tropane Tartrate (RTI-178) Reaction of 0.52 g (2 mmol) of 30-(4-Methylpheny1)-tropane- 23-carboxylic acid as described above for preparation of amides cgave after work up and purification by flash column chromatography (15% CMA in methylene chloride) 0.54 g of cure 33 (4 Methylphenyl) cropane 2 (phenyacyl) carboxamide: H NMR 'CDC1 3 6 1.73 3 H) 2.14 2 H) 2.26 3 H) 2.40 WO 98/07427 PCT1UJS97/14702 Cs, 3 H) 2.-4 7 2. H) 2. 59 Cm, I. H) 3 .14 2. H) 3 .4 2 (m, 2 H) 4 74 2 H) 7. 05 4 7 48 Cm, 2 H) 7. 59 (in, 2 H) 7. 97 (mn, 2 H) 2.0.62 Cbr s, 2. IR (CC1 3 3155, 3005, 2930, 1690, 1650, 2.520, 1450, 1355, 1215 cm-1 React ion of 0.-5 ,g 33 minol) of 3 j6- (4 -Methylphenyl) (phelyacyl) carboxamide as described above for RTI- 189 gave after workup and purification by flash column chromatography (401; (ether/ triethylainine 9 1 in hexane) 0. 1 g RTI-158 as a first fraction. Further elution gave 0.19 g of pure oxazole RTI-178: "i NNR (CDC1.) 1.8 (In, 3 H), 2. 18 Cm, 2 H) 2. 21 3 H) 2. 22 3 H) 2. 67 1 3. 28 Cm, 1 H) 3 .4 2 Cm, 2 H) 3.-5 3 (in, I H) 6 .9 8 2 H) 7.1 Cm, 3 7.30 5 H).

The oxazole was crystallized as the tartrate salt: 'H NMR (MeOD) 1. 99 (mn, 1 H) 2. 19 3 H) 2.54 (mn, 5 H) 2.95 Cs, 3 3.74 Cm, 2 4.13 Cm, 1 4.26 Cm, 1 4.4 Cs, 2 H), 6.91 2 7.0 Cm, 2 7.25 (mn, 2 7.33 Cm, 2 H) 7.43 a a Cs, 1 H) io 175-181 C; Anal calcd for C.,H 3 2 NO,.1H 2 0; C 63.87; H 6.51, N =5.32; found C 64.22., H =6.40, N 5.19; jaIY] 104.040 Cc 0.6, CH 3

OH)

a 0 Hydrochloride (RTI-219) 4:To a solution of 0. 74 g 86 minol) of 30- (4 -Chloropleny!) WO 98/07427 PCTIUS97/14702 and 1.51 g (7.45 mmol) of Lawesson's reagent in 18 ml of toluene was refluxed under N, for hours. The reaction mixture was cooled and solvent removed in vacuo to give crude residue. To the residue was added 3 g of silica gel and 10 ml of methylene chloride, the resulting slurry was mixed properly and the solvent removed in vacuo. The crude compound impregnated on silica gel was loaded on a column and purified by flash column chromatography (ether/triethylamine 9 1 in hexane) to give 0.21 g of pure thiazole RTI-219: 'H NMR (CDC1,) 1.61 1 H) 1.82 2 H) 2.22 2 2.34 3 2.39 1 H) 3.28 2 H), 3.39 1 3.49 1 H) 6.8 2 H) 7.07 2 H).7.32 (m, 3 7.57 2 7.60 1 H) 3 C NMR (MeOD) 25.51, 25.99, 35.01, 36.92, 41.72, 52.97, 61.58, 65.70, 126.45, 127.60, 128.13, 128.89, 129.05, 131.91, 132.43, 136.11, 139.91, 140.27, 168.97; IR (CHC13) 2945, 1590, 1485, 1445, 1350, 1125, 1090. cm-.

The thiazole was converted into hydrochloride salt: 'H NMR o (MeOD) 1.99 1 H) 2.51 5 2.93 3 H) 3.79 2m, 2 H) 4.15 1 H) 4.28 I 7.02 J 8.5 Hz, 2 H) 7.21 oo• J 8.5 Hz, 2 H) 7.39 5 8.06 1 mp 228-230°C; Anal calcd for C,,H 24

CIN

2

S.H

2 0; C 61.47, H 5.83, N 6.23, S 7.13, Cl 15.78; found C 61.61, H 5.76, N 6.20, S 7.51, Cl 15.84; [a]o -27.43° (c 0.11, CH 3

OH).

4* *0* WO 98/07427 PCT1US97/14702 EXAMPLE 3,6- (4-Chlorophfl) -2j6- (benzothiazol-2-yl) -tropanydrochloride (RTI -202) Reaction of 0. 59 g (2 mmol) of 30- (4 -Chlorophelyl) -tropaleacid as described above for preparation of amides gave after purification of the crude by flash column chromatography (50% CMA-80 in methylene chloride) 0.3 g (41 of pure RTI-202 which was further purified by recrystallizing f rom ether/hexaie: 'H NNR. CCDCl 3 6 1. 65 Cm, I H) 1.-87 2 H) 2.24 2 H) 2.34 3 H) 2.41 1 H) 3.28 (mn, 2 H) 3.40 (in, 1 H) 3. 62 2. H) 6. 8 2 H) 6. 81 (in, 2 H) 7. 29 (in, 2 H) 7.70 (mn, 1 H) 7. 84 (mn, 1 H) IIC NMR (CDCl 3 6 25.58, 26.07, 35.40, 36.95, 41.56, 53.09, 61.57, 65.47, 120.95, 122.42, :.124.11, 125.20, 128.05, 129.03, 131.87, 136.72, 139.91, 151.33, 171.11; IR (CHCl 3 2940, 2795, 1495, 1445, 1305, 1130, 1105, 1015, 90'7 CM' D 3.9 (C 0.09, CHC1 3 The benzothiazole was converted into hydrochloride salt: 'H NM~R (MeOD) 6 2. 02 Cm, IH) 2. 43 4 2. 89 (mn, 1 H) 2.9 8 3 W) 7 3. 90 Cm, 2 4 .23 Cm, 1 H) 4.34 in, I 7 .02 (m, 2 H) 7. 13 2 H) 7.4 5 2 H) 7. 81 1 H) 8.2.16 1 H); *mp 140-150-C (,dec) Anal calcd for C 2

,H

22 C1 2

,N

2 S.0.75H 2 0 C =60.21, H 5..65, N =6.69, Cl 16.93; S =7.65: found C 60.14,

H=

5.74, N =6.60, Cl 16.89; S 7.71; (alt 0 -1 72.490 (c 0.28, MeOH).

WO 98/07427 PCT/US97/14702 EXAMPLE 1I 30-(4-ChlorophenYl)-tropane-20-nitrile (RTI-1 6 1 To a solution of 0.95g (3.5 mmol) of 3P-(4-Chlorophenyl)in 20 ml dry THF was added 0.56 ml (7 mmol) pyridine. To the resulting solution at room temperature was added dropwise with stirring under nitrogen 0.35 ml (4.2 mmol) of trifluoroacetic anhydride. The reaction was stirred at room temperature for 30 minutes, and quenched with 10 ml water.

The solvent was removed under vacuo and the residue was taken in ml saturated aqueous

K

2 CO, and extracted thrice with 10 ml CHCl The organic layers were combined and washed with 20 ml brine dried (NaSO,), filtered, and the solvent removed in vacuo to give 0.26 g crude product. Purification of the crude by flash column chromatography (10% CMA in methylene chloride) gave 0.68 g of pure nitrile RTI-161 which was recrystallized from methylene chloride and hexane: 'H NMR (CDC13) 6 1.70 3 H), S2.22 3 2.35 3 2.80 (mn, 1 3.04 (mn, 1 3.34 (in, 3.43 1. 7.26 m, 4 7R (CHC13 700, 2950, 2225, 1490, 1470, 1090, 900 cm mp 167-173oC; Anal calcd for C,H,C1 2

,N

2 .C.7 5 HO; C 57.98, 6.32 N 9.02, Cl 22.82; found C 58.22, H 6.12, N 8.48, C1 22.89; [a 0 -73.330 (c S* 0.48, MeOH) WO 98/07427 PCT1US97/14702 EXAMPLE 12 30-(4-Methylphenyl)-tropane-24-nitrile Hydrochloride (RTI-158) Reaction of 0.26g (1 mmol) of 30-(4-Methylphenyl)-tropaneas described above for RTI-161 gave after work up and purification 0.26 g (671) of pure nitrile (RTI-158): 'H NMR (CDCl3) 6 1.68 3 2.18 3 2.32 3 2.35 (s, 1 2.82 1 3.02 1 3.36 1 3.43 1 H), 7.18 4 IR (CHC1 3 3675, 3000, 2950, 2200, 1600, 1510, 1450, 1350, 1220, 1100 cmrn.

The crude product was crystallized as the HC1 salt: IH NMR (MeOH) 6 2.08 -2.58 9 2.92 3 3.54 1 3.69 (br s, 1 4.12 (br s, 1 4.29 1 7.21 4 mp 270 0 C Anal calcd for C,,H 21 CIN,; C 69.42, H 7.65 N 10.12, Cl 12.81; found C 69.31, H 7.70, N 10.12, Cl 12.81; -76.40 (c 0.5, MeOH).

EXAMPLE 13 30-(4-Chlorophnyl)-tropane-20-tetrazole (RTI-163) To a solution of 0.13 g 0.5 mmol) of RTI-161 -n 5 ml dry THF was added 0.28 ml (5 mmol) azidotrimethylsilane and the mixture was placed in a PTFE-lined autoclave. The solution was heated to 150C for 24 hours in an oil bath. The reaction mixture was cooled and transferred using MeOH. The solvent was removed in vacuo to aive a brownish residue. Purification of the WO 98/07427 PCT1US97/14702 crude by flash column chromatography (2016-50% CMA in methylene chloride) gave 0.05 g of pure tetrazole (RTI163) H NMR (CDC1, 1 drop MeOD) 6 1.73 2. 2.44 2.02 4 2.6 1 2.68 3 3.33 (in, 1 3.65 1 3.73 (mn, 1 3.97 1 6.68 Cd, J 8 Hz, 2 7.07 J =8 Hz, 2 H) mp 296-300*C; Anal calcd for C,.sHeCIN5.0.75H 2 0; C =56.78, H 6.2.9 N =22.07, Cl 11.17; found C 56.69, H 6.22, N 22.09, Cl =11.15; [alo -124.940 (c=0.39, MeOH) EXAMPLE-14 (4-Mathyiphflyl) tropans-20-tetrazole Hydrochloride (RTI-157) Reaction of 0.12 g (0.5 mmol) of RTI-158 as described above for RTI-163 gave after workup and purification of the crude by flash column chromatography (100% CMA) 0.14 g of pure tetrazole (RTI-157) H NMR CCDC1 3 1 drop MeOD) 6 1.8 1 H), 2. 14 Cs, 3 H) 2. 35 Cm, 5 H) 2. 71 Cs, 3 H) 3. 36 Cm, 1 H) 3. Cm, 2 H) 4.02 Cm, I 6.48 Cd, J =8 Hz, 2Z 6.82 Cd, i 8 Hz, 2 H).

-,he purified product was converted i;nto HCJ. salt: 'H NMR (MeOD) 6 2.01 Cm, 1 2.27 3 2.69 (Im, 5 .97 Cs, 3 3.81 Cm, 2 4.18 Cm, 2 5.5 I. 6.76 Cd, J 8 Hz, 2 7.02 J 8 Hz, 2 mp 212**C- (dec); Anal calcd for C'SH 23 Cl 2 Ns.0.25H 2 0; C 53.26, H 6.56 N 19.41; found C 53.41. H 6.50, N 19.02; (OI -110-970 (c 0.16, MeCH.).

WO 98/07427 PCT/US97/14702 EXAMPLE 34 4Clr~~y)-0 3mtyioao--l rpn Hydrochloride (RTI-165) A solution of n-butyl 1.4thium in hexane 5.9 ml (2.5 M. 14.6 mmcl) was added to a stirred solution of acetone oxime 0.55 g (7.3 mmol) in dry THFf (15 ml) at 0 0 C under nitrogen. After 1 hour, a solution of 1. 65 g (5.62 mmcl) 30- (4-Chlorophenyl) -26 (carbomethoxy) tropane in !0 ml dry was added dropwise with stirring at Qoc. The solution was allowed to warm to room zemperature over 18 hours. The mixture was poured into a stirred solution of concentrated sulfuric acid (3.2 g) in THF (,15 ml) and water (4 ml) and was heated under reflux for 1 hour. The cooled solution was made basic using saturated aqueous

K

2 CO, (10 ml) and extracted thrice with 10 ml methylene chloride. The combined organic layers were dried (Na 2 SO.) I filtered and solvent removed in vacuo to give 1.8 g of crude isoxazole. Purification of the crude residue by flash column chromatography (10% CMA in methylene chloride) gave 0.74 g of pure isoxazole RTI-165 which was further purified by crystallization from methylene chloride /hexane: 1H NMR (CDC.

3 6 1.71 (in, 3 H) 2.-10 3 H), 2.18 3 2.24 3 3.20 (in, 2 3.32 (mn, 2 6.18 1 H) 6. 9 J 8 H.z, 2 H),7.14 J 8, Hz, 2 H) IR (CCd 4 2950, 1590, 1490, 1420, 1350, 1020, 910 cmn'; rnp 154-156aC; Anal calcd for C, 8

,H

2 ,N,0C2.; C =68.28, -H 6.68, N =3.84, Cl 1.9; found C 68.22, H =6.69, N =8.87, Cl1 11. 19; £a1 0 WO 98/07427 PCT/US97/14702 125.580 (C 0.43, MeOH).

The isoxazole was crystallized as the hydrochlorde salt: ~H NMRP. (MeOD) 6 2. 04 3 H) 2. 19 (mn, 1 H) 2. 30 Cm, IH) 2.4 8 2 H) 2. 60 Cm, I. H) 2. 70 2. H) 2. 90 3 3. 68 Cm, 1 H) 3. 82. (in, 1 H) 4 .04 Cm, 1 H) 4. 15 1 5. 55 1 H) 7. 04 Cd, J 8 Hz, 2 H) 7 .14 J 8 Hz, 2 H) mp, 23 5 0C (dec) Anal calcd f or CIH 22

C'

2

N

2 0; C 61.-19, H 6.28, N 7. 93, Cl 20.07; found C= 60.98, H =6.38, N 7.91, Cl 19.96; La] 0 -102.890 Cc =0.46, MeCH).

EXAMPLE 16 3#(-atyp~nl-0(-ohlsxzl5y~rpn Hydrochloride (RTI-171) Reaction of 1.09 g C4 inmol) of 303-(4-Methylphelyl) -29- Ccarbomethoxy)tropale as described above for RTI-1.65 gave after workup 1. 21 g crude isoxazole. Purif ication of the crude by f lash column chromatography C15!k CMA in methylene chloride) gave 0.73 a pure isoxazoi- (RTI-171) -L NMR :%CDC1,' 6 1.73 (Mn, 3 H) 2.11 Cm, 3 H) 2. 17 3 H) 2.23 Cs, 3 H) 2.25 3 H) 3. 2 C m, 2 H) 3. 32 Cm, 2 H) 6. 13 Cs, I H) 6. 97 (mn, 4 IR (CC1 4 2935, 2785, 1590, 1S10, 1460, 1421, 1350, 1125, 1010, 910 cm'1 The isoxazole was crystallized as the hydrochloride salt: NMR (MeOD) 6 2.01 (5 3 H) 2. 32 Cm, 2 H) 2 .4 2 4 H) 2 .81 Cs, 3 H) 2. 61 Cm, 1 H) 3. 78 Cm, 1 H) 4. 03 Cm, 66 WO 98/07427 CIIUW9iW14IU.

1 4.15 1 5.45 1 6.96 4 mp 277 0 C; Anal calcd for C,H, 2 5

CIN

2 0; C 68.55, H 7.57, N 8.42, Cl 10.65; found C 68.65, H 7.62, N 8.42, C1 10.56; [alo -107.280 (c 0.71, MEOH).

EXAMPLE 17 (4-Iodophenyl) (3-methy1isoxazol- 5-yl) tropane Hydrochloride (RTI-180) Reaction of 0.73 g (1.9 mmol) of 30-(4- (carbomehoxy)tropane as described above for RTI-165 gave after workup 0.77 g of crude isoxazole. Purification of the crude by flash column chromatography CMA80 in methylene chloride) gave 0.37 g of pure isoxazole RTI-180: 'H NMR (CDC1 3 6 1.71 (m, S 3 2.12 3 2.18 3 2.24 3 3.17 2 H), 3.33 2 6.18 1 6.74 2 7.49 2 IR (CHC1 3 2940, 1600, 1485, 1450, 1420, 1355 cm-1.

The isoxazole was crystallized as the hydrochloride salt: !H NMR (MeOD) 6 2.11 3 2.50 6 H) 2.89 H) 3.70 1 3.90 1 4.14 1 4.22 1 5.6 6 s, 1 6.96 2 7.56 2 mp >2350C (dec); Anal calcd for CSH, 22 C1IN 2 O.0.

2 5H0 C 48.12, H 5.05, N 6.24, Cl 15.79; I 56.50; found C 47.84, H 5.05, N 6.19, Cl 15.77; S 56.46; [au -94.570 (c 0.39, MeOH) WO 98107427 PCT[US97/14702 EXAMPLE-18 Hydrochloride (RTI-177) Reaction of 1.18 g (4 mmol) of 30-(4-%Chlorophenyl -2B.- (carbomethoxy)tropale as described above for RTI-165 gave after work up 1.46 g of crude isoxazole. Purification of the crude by flash column chromatography (20!r (ether/ triethylamine 9 in hexane] gave 0.75 g of pure isoxazole RTI-177 which was further purified by crystallizing from ether/petroleum echer: 'H NMR 1,ODC1 3 (5 1.-74 Cm, 3 H) 2. 22 (in, 3 H) 2. 27 3 F) 3.2 4 2 H) 3 36 2 H) 6. 80 i H) 6 94 2 H) 7. 12 2 7.40 3 H) 7.76 2 H) IR (CIC1 3 2940, 1600, -590, 1490, 1450, 1405, 1350 cm-1.

The isoxazole was crystallized as the hydrochloride salt: 'H NMR (MeOD) 6 2. 35 Cm, 6 H) 2. 84 Cs, 3 H) 3 .7 3 Cm, 1 H) 4.0 9 i,1 H) 4. 21 Cm, 1 H) 6. 12 Cs, 1 H) 7. 14 4 H) 7. 34 Cm, 3 H) 7. 57 Cm, 2 H) mp 287OC; Anal calcd f or C 2

,H

2 ,C1IN0- 0. 25H 2 0 C 65.79, H- 5.88, N 6.67, Cl =16.89; found C =6.4 5.79, N =6.68, Cl 17.00; [a]I -97.50 Cc 0.28, MeOH).

EXAMPLE 19 3p- (4-Methylpheflyl) 2#(3 pheflyliBoxazol.5.yl) tropane Hydrochloride (RTI-176) Reaction of 1.09 g (4 mmcl) of 30- (4-Methylphenyl','-20- (carbomethoxy) trcpane as described above for RTI-165 gave after WO 98/07427 PCTIUS97/14702 work up 1. 56 g of crude isoxazole. Purification of the crude by flash column chromatography [25% (ether/ triethYlamife 9 in hexane] gave 1.1 g (771) of pure isoxazole RTI-17G which was further purif ied by crystallizing from methylenie chloride/ hexane: 1H NNR (CDC1,) 6 1.76 (in, 3 H) 2.23 3 H) 2.24 3 H) 2.27 3 H) 3.23 2 H) 3.36 (in, 2 H) 6. 74 I 6.93 (mn, 4 H) 7.41 (m,3 H) 7.76 (in, 2 H) IR (CCd 4 2935, 1590, 1455, 1410, 1215 cm-' The isoxazole was crystallized as the hydrochloride salt: 'H NMR (MeOD) 6 2. 08 1 H) 2. 15 Cs, 3 H) 2. 45 5 2. 84 3 H) 3.68 (mn, 1 H) 3.88 (mn, 1 H) 4.07 Cm, 1 H) 4.22 Cm, 1 H) 5. 97 1 H) 7. 0 4 H) 7.33 Cm, 3 7.54 2 H); mp 270-295-C (dec); Anal calcd for C, 4

H.,CIN

2 0; C =72.99,

H

6.89, N 7.10, Cl 8.98; found C =72.91, H 6.91, N 7.15, Cl 8.98; [all) -102.22 Cc 0.68, MeOH).

EXAM~PLE 3g3- (4-Iodophenyl) -2p- (3-phenylisoxazol-5-yl) tropane Hydrochloride (RTI-181) Reaction of 0 .73 g 9 inmol) of 30- (4-Iodophel) -29- (carbomethoxy)"ropale as described above for RTI-181. gave after ~.:~:workup 1.46 g of crude isoxazole. Puri J:icat ion of the crude by flash columnn chromatography [20% (ether/ triethylainine 9 1) in hexane] gave 0.5 g of pure isoxazole RTI-181 which was further purified by crystalli-Lzing f rom mechylene chloride /hexale: 69 WO 98/07427 PCTIUS97/14702 'H NMR (CDC1 3 6 1. 72 Cm, 3 H) 2. 15 (i,2 H) 2. 28 Cs 3 H), 3.22 Cm, 2 H) 3.35 2 H) 6.74 2 H)0, 6.79 Cs, I 7.44 (mn, 5 H) 7.75 (mn, 2 H) IR .CEC1,) 2940, 1580, 1480, 1475, 1450, 1400, 1355, 1005 cm-1 The isoxazole was crystallized as the hydrochloride salt: 1 H NMR (MeOD) 6 2. 54 Cm, 6 H) 2.-9 2 (s 3 H) 3.-7 9 (mn, 1 H), 4. 05 Cm, I H) 4 .19 Cm, 1 H) 4 .33 Cm, 1, H) 6.1 C Ss, 1 7.02 2 H) 7. 43 Cm, 3 H) 7.-6 3 Cm, 4 H) mrp 2 67 1C Cdec); Anal calcd for C.,H,,ClIN 2 O-0.5HO C 53.55, H1 4.89, N =5.43, Cl 13.75; i 49.21: found C 53.75, IH 4.87, N =5.41, Cl= 13.68; 1 48.95; 106D -91-11o Cc =0.43, MeGH) EXAMPLE 21 Biochemistry of 31d- (Substituted phenyl) -20- (heterocyclic) tropanes inhibition of radioligand binding data at the dopamine, serotanin, and norepinephrine transporters are listed in Table II, and TV.

Table 11 b Table HI 3P-(Substituted-pheny)-2P-(eterocyclic tropafles

CH)N

J4n v

IC

50 (nM) Code Name RTI-163 RT1-157 1 DA 331ij NE 5-HT 'H-WIN 35,428 IH-nisoxetine 1311-paroxeine

NE/DA

Ratio Ratio

N-

II

CI 911±6.1 17.386±2050 5,456±64 19 6 C'1 3 1557±196 32,478±2078 43,574±5420 21 28 RTI- 165 RTI-171 RTu-180 RTI- 177 RHI-176 RTI-181

N

O-j'cN RI- 189CH, RTI-178

CI

CFI

3

CI

C1I

C

CH

3

CI

CH

3 Cl

CH

3 Cl RTI-188 RTI- 195

N-N

0.59±0.04 0.93 ±0.09 0.73 ±0.04 1.28 18 1.58±0.02 2.57±0.14 19.7±1.98 35.4±1.74 12.6±1.03 47.5 ±4.76 4.45±0.12 15.3 ±2.43 35.9 ±3.4 1.37±0. 14 5.71±0.36 181±12 254±31 67.9 5.25 504+29 398± 18 868 ±95 496±42 677 ±68 929±88 1310±37 253 19 4142 466 24,321 ±3822 403 ±30 572 ±58 3818 346 36.4±5.0 2418±136 5110±187 100±9.0 1116±107 1699±167 3304±196 23,310± 822 4885 155 18,417±1509 51,460±4513 1119±120 970 4105 498 1889 3234 39 57 48 262 491 1098 1203 1434 817 1811 0 YCf 11-194 N-N RTI-200 RTI-199

N-N

R1-202 RTI-2-19 c,11) 8563 J 824 10,342± 76 1500 WO 98/07427 WO 9807427PCT/US97/14702 TA-BLE III Comparison of Transporter Binding Pthencies

H

C0 2

)R

2 a

IC

5 o (nM) RTI 5H AN No. R, R7 ['H]Paroxetine 3 H] WIN 35,428 3 H]Nisoxerine 279 CH 3

CH

3 1.06±0.39 5.98±0.48 74.3 ±3.8 353 C 2 11 5

CH

3 0.69±0.07 331±17 148±9.2 Paroxetine* 0.28±0.02 623 ±25 313 a serotonin DA doparnine NE norepinephrine *Aropax; Seroxat; see Merck Index.

-72- SUBSTITUTE SHEET (RULE 26) WO 98/07427 WO 9807427PCT1US97/14702 3p~-(Substiruted phenyI)-2p-(substituted)tropanes C H 3

N

ICso (nM) Code DA NE Name R X jjH]-WIN 35,428 3 H]-nisoxetine 3 H]-paroxetine RTI-93 RTI-99 RTI-100 RTI- 101 RTI- 102 RTI-103 RTI-104 RTI- 105 RTI-108 RTI-123 RTI- 131 RTI- 132 RTI-139 RTI-145 RTI-158 RTI- 161 RTI-164 RTI-230 RTI-239 RTI-240 RTI-24 1

CH

2 0H

CH,OH

CH-,OH

CH

2 0H

CO

2

H

CO

2

H

CO

2

H

CH

2 OAc

CH

2

CI

CH

2

OCOC

6

H,

CH.,NH,

CH,N(CH

3 2

CM

3

CH

2

OCO

2

CH

3

CN

CH

2

NHCH

3

C(CH

3

=CH

2

CH(CH

3 2

CH(CH

3 2

CH

2

CO

2

CH

3 Cl Br

F

Br

F

Cl Cl Cl

CH

3

CH

3

CI

Cl

CH

3 Cl CH3

CI

CM

3

CI

CM

3 1.53±0.15 1.49+0.05 47 ±4.6 2.2 ±0.19 474 57 278 ±43 2744+141 1.60 ±0.05 2.64±0.31 1.78±0.09 10.5 ±1.7 3 .48 11 1.67 ±0.13 9.6±0.42 57 ±7.3 13.1 ±0.76 13 .6 ±2.03 1.28±0.17 0.61 ±0.07 1.38+±0.03 1.02-0.06 43.8 ±6.4 43,400±5500 17,400±1400 100,000 127 ±5 .9 129±15 393 30 120±20 137± 11 57 ±2..6 1478 ±96 1624±136 25 16 ±253 280 ±19 141± 16 35.6± 2.57 84.5 ±3.09 124±3.56 204±16 51 ±4.6 4741 ±335 26±3.2 1928± 120 3070±208 100.00 143 98 ±8.7 3.53 ±0.58 855 52 208 18 85 ±9.3 2930 181 5095 ±3 1887 +134 2246±94 57 ±5 .0 114±3.69 38.4 ±2.31 618 ±28 SUBSTITUTE SHEET (RULE 26) WO 98/07427 PCT/US97/14702 This invention has been described in both generic terms, and by reference to specific description. No specific description or example is considered binding, unless so identified.

Alternate forms and methods will occur to those of ordinary skill in the art, without the exercise of inventive faculty, and remain within the scope of this invention, save as limited by the claims set forth below.

.5

S

Claims

01.6 alkyl, 'NR 4 R 5 NHCOR 5 or NHCO 2 R 6 and Re is C 1 6 alkyl, phenyl, or C 1 e alkyl substituted phenyl.
2. A compound of the formula: 0@9 0@ 0 *00 00 *00. *0 0 0e wherein Ri-hydrogen or C1,5 alkyl,. COMS ID No: SBMI-00976988 Received by IP Australia: Time 12:28 Date 2004-10-29 2 9 -10 04 :12 37 P IZ Z Y 617 3 2 8 7 3 2/ 4 7 Y=H, OCH3 or Cl, and Z=H, 1, Br, Cl, F, CN, CF, N02, N3, OR1, CONI-12 C02111, CI-8 lkyl, NHCOR, NHC02R6, or t kCl C Rt R1, Rz2,R 3 Hor C I4 alky'
3. A compound of the formula: e r r r r rr r r r r r r r r r I wherein' 10 R, =hyd roge n or C 1 6 a lkyl, X=H, C1.6 alkyl. C3-a cycloalkyl, C1.4 alkoxy, C1-alkynyl, halogen, amino or acylamido, Y=H, OCH3 or CI Z=H, 1, Br, C, F, CN, CF, N02, N3, OR,, CONH2, C02RI, C-6 alkyl, NR4R5, NHCOR, NHC02zRs, or COMS ID No: SBM-00976988 Received by IP Australia: ime 12:28 Date 2004-10-29 2 9- 10 04 :12:'3 7 P1I Z ZE 713217 Y S3 4 6 17 3 2 2 18 0 7 7 3 3/ 4 7 C=C C-CHC R 3 -C=C-Ri Rl, R 2 R 3 =Hor C 1 4 ajfl and M=(CH 2 wherein x-1 -CH=CH-or-C!nC-,
4. A method for treating psychostimulant abuse, by administering to a patient in need of such treatment a psychostimu la nt-i nh ibiting amount of a compound of formula: RNb wherein 10 Rj~hydrogen or CI- 5 alkyl, X=H, C 14 6 alkyl, C 38 cycloalkyl, C 1 .4 alkoxy, C1.6 alkynyl, halogen, amino or acylamido, Z=H, 1, Br, Cl, F, CN, CF3, NO 2 N 3 OR,, CONH 2 C0 2 Rj, C 14 salkyl, NR4R 5 s, NHCOR 5 or NHCO 2 R6, and 15 Rb is C 1 -6 alkyl, phenyl or C 14 6 alkyl substituted phenyl; COMS ID No: SBMI-00976988 Received by IP Australia: Time 12:28 Date 2004-10-29
29-10-04: 12:371 P I Z Z YS :61732218077 #34/ 47 78 wherein Ri= hydrogen or 0145 alkyl, Y=H, OCH 3 or CI, and Z=H, 1. Br, CI, F. CN, CF 3 NO 2 N 3 OR,, CONH 2 C0 2 RI, C 14 alkyl, NR 4 R 5 NHCOR 5 NHC0 2 R 6 or R2 RI ~R 2 R, C=C C-CH=C" R2, R 3 =H or C 1 4 alkyl o-0 wherein hydrogen or CI-6 alkyl, X=H, C 14 ealkyl, C3-8 cycloalkyI, C 1 4 alkoxy, C 1 .6alkynyI, halogen, amino or acylamido, OCH 3 or CI, Z=H, 1, Br, CI, F, CN, CF 3 NO?, N 3 OR,, CONH 2 CO 2 R1, 014 alkyl, NR 4 R 5 NHCOR 5 NHCO 2 RG, or COMS ID No: SBMI-00976988 Received by IP Australia: Time 12:28 Date 2004-10-29 29-10-04:12*37 :P1ZZEYS:63217 #3/4 :61732218077 35/ 47 R 2 R-R 2 -C=C-R! RI, R 2 R 3 =H or C 1 4 alkcyl and M=(CH 2 wherein x=1 -CH=CH- or -CeC-. 5. A method for inhibiting the action of a psychostimulant, by administering to a patient in need of such treatment a psychostimulant- inhibiting amount of a compound of formula: wherein 10 R, =hydrogen or Ci. 5 j alkyl, X=H, C 1 -6alkyl, C" cycloalkyI, CI-4alkoxy, C 1 -6alkynyl, halogen, amino or acylamido, Z=H. 1, Br, Cl, F, CN, CF 3 NO 2 N 3 ORi, CONH 2 CO 2 Ri, Cl. 6 alkyl, NR 4 R 5 NHCOR5, NHCO 2 RB, and 15 Rb is C1.6 alkyl, phenyl or C alkyl substituted phenyl; COMS ID No: SBMI-00976988 Received by IP Australia: Time 12:28 Date 2004-10-29 2 9- 10 04; 12:'3?7 PI Z Z -Y S :8617 322 1 80 77 36/ 47 N y z OT wherein R 1 4oydrogen or C1.6 alkyl, Y=H, OCH 3 or CI, and Z=H, I, Br, Cl,F. CN, CE 3 NO 2 N 3 OR 1 CONH 2 C0 2 Rl, C 1 ealkyl, NR 4 R 5 NHGOR5, NHCO 2 Rs, or c 'R II R 1 C 2 1 R. C==C-Ri RI, R2.R 3 =H OrC 1 4 aklyl '-or RI\ 0 ~0 *0 0 0 0 0 0 0 00 00 *0*0 0**0 0 0 0*0* 0000 0 0*00 0. ~0 0* 00 0* 00 0 wherein 10 R, =hydrogen or C I.. 5 alkyl, 014 alkyl, C 3 8 cycloalkyl, 01.4 alkoxy. C 1 .6 alkynyl, halogen. amino or acylamido, OCH 3 or CI, COMS ID No: SBMI-00976988 Received by IP Australia: Time 12:28 Date 2004-10-29 2 9- 10 -0 4 :12 :37 :P I ZZ E YS :6 17 3 221 80 77 #3/4 37/ 47 81 Z=H, 1, Br, CI, F, ON, OF 3 NO 2 N 3 ORI, CONH 2 C0 2 R 1 C.. 6 alkyl, NR 4 Rs, NHCOR 5 NHO 2 Rr 6 or CC C-CH=C R3 I R -CC- 1 RI. R 2 R 3 ~for C 4 alkyl and M=(CH 2 wherein x 1-8, -CH=CH- or -C C-. 6. A method for inhibiting neurotransmitter re-uptake by administering to a patient in need of such treatment a neurotransmitter transporter-inhibiting amount of a compoun d of formula: Rj,, 000 *0 0V 00 00 0 p0 *0 0 OS 0 0 .0 0 0000 00 S 0 0 00 0 0 .0 *0*0 00*S *905 C 0005 005 090500 S 0~00 0~ 00 .0 S. 00 0, wherein R,=hydrogen or C1. 5 alkyl, X=H, C 16 alkyl, C 3 -8CYCloalkyl, C 1 -4alkoxy, Cl 1 .,alkynyI, halogen, amino or acylamido, 15 Z=H, 1, Br, CI, F, ON, OF 3 NO 2 N 3 OR 1 CONH 2 C0 2 Ri, C 14 alkyl, NR 4 R 5 NHCOR 5 or NHCQ 2 R 6 and Rb is C 1 .6 alkyl, phanyl or C 15 alkyl substituted phenyl; COMS ID No: SBMI-00976988 Received by IP Australia: Time 12:28 Date 2004-10-29 2 9- 10- 04 :1 2:'38 :P I Z Z~ :6:22 7 Y 3S 4 6 17 3 2 2 18 0 7 7 3 S/ 4 7 N y wherein Rlhydrogen or C 1 .5 alkyl. Y=H, OCH 3 or CI, and Z=H, 1, Br, CI, F, ON, CF 3 NO 2 N 3 ORI, CONH2, CO 2 R 1 CI- 4 alkyl, NR 4 Rs, NHCQR 5 NHCO 2 Rs, or c==c R Cf=C. R 1 R 3 1R 2 R 3 Rj, R 2 R 3 !.IHor CII 4 alkyl S a wherein Rj~hydrogen or C 1 5 alkyl, X=H, C 14 6alkyl, C~cycloalkyI, C 1 -4alkoxy, CI 14 alkynyl, halogen, amino or acylamido, Y=H, OCH 3 or CI, COMS ID No: SBMI-00976988 Received by IP Australia: 'rime 12:28 Date 2004-10-29 2 9- 10 -04 :12 :3 8 :Pi IEY Z6122 7 Z E9 Y4S 6 17 3 2 2 1 0 7 7 39/ 47 83 Z=H, 1, Br, Cl, F, CN, CF 3 NO 2 N 3 ORi, CONH- 2 CO 2 C 14 alkyl, NR 4 R 5 NHCOR?., NHCO 2 R 6 or *R R2R R LC-CH=C 4 I R3R R, R C=C-R 1 Rl, R 2 ,R 3 i= Hor C 4 alky and M =(CH 2 wherein x=1-8, -CH=CH- or-CEC-. 7. A method for treating neurodegenerative disorders, by administering to a patient in need of such treatment a pharmaceutically effective amount of a compound of formula: S wherein Rl~hydrogen or 01.5 alkyl, X=H, 01-6 alkyl, C 3 8 cycloalkyl, C1-4 alkoxy, C1-6 alkynyl, halogen, amino or acylamido, Z=H, 1, Br, CI, F, CN, OF 3 NO 2 N 3 OR 1 CONH 2 C0 2 R 1 C1.6 alkyl, NR 4 R 5 NHCORs, NHCO 2 R 6 and Rb IS C 1 6 alkyl, phenyl or Cl-ealkyl substituted phenyl; COMS ID No: SBMI-00976988 Received by IP Australia: Time 12:28 Date 2004-10-29 2 9- 10 -0 4 :1 2'38 P I Z~ Z13287 E Y0 41 6 17 3 2 2 18 0 7 7 40/ 47 wherein R, =hydrogen or C 1 5 alkyl, Y=H, OCH 3 or Cl, and Z=H, I, Br, Cl,F, CN, CF 3 NO 2 N 3 OR 1 CONH 2 CO 2 Ri. Cl4 alkyl, NR 4 Rs, NHCORs, NHCO 2 R 6 RI R C-CH=C I R 3 -c=C-R, RR 3 HorCI.4 alkyl wherein 10 R 1 =hydrogen or Ci-. 5 alkyl, X C 1 .6 alkyl, C3-acycloalkyl, C 1 .4 alkoxy, C 1 .6alkynyl, halogen, amino or acylamido, Y=H, OCH 3 or CI, COMS IDNo. SBMI-00976988 Received by IP Australia: Time 12:28 Date 2004-10-29 910 04:12 :3 8 :P I Z EYS 617 3 22 1 80 77 41/4 7 Z=H, 1, Br, Cl, F, CN, CF%3, NO 2 N 3 OR,, CONH 2 C0 2 Ri, Cie salkyl NR 4 R 5 NHCQR 5 NHC0 2 R6, or C=CII C-CH=C\ I P3 I R KI R 2 -C=C-R, R 1 R 2 P 3 -H orC,. 4 alkyl and M=(CH2Ax, wherein x -CH =CH- or -C=RC-. 8. A method for treating depression, by administering to a patient in need of such treatment a pharmaceutically effective amount of a compound of formnula: *j :10 wherein RI hydrogen or CI-6alkyl, X=H, C1.6 alkyl, C3. cycloalkyl, C 14 alkoxy, C 1 alkynyl, halogen, amino or acylamido, Z=H, 1, Br, Cl, F, CN, OF 3 NO 2 N 3 OR,, CONH 2 CO 2 R 1 014 alkyl, NR 4 R 5 NHCOR 5 or NHCO 2 Rr 6 and Rb is 01.6 alkyl, phenyl or C 1 -6 alkyl substituted phenyl; COMS IDNo: SBMI-00976988 Received by IP Australia: Time 12:28 Date 2004-10-29 2 9- 10- 0 4: 12 :3 8 :P1I Z Z EYS 12107#4/4 6 17 3 2 2 1 8 0 7 7 42/ 47 wherein hydrogen or C 1 -5 alkyl, Y=H, OCH 3 or CI, and Z=H, I, Br, C1,F, CN, CF 3 NO 2 N 3 ORI, CONH 2 C0 2 R,Cl 4 alkyl, NR 4 R 5 NHCOR 5 NHC0 2 RS, or -C=C-R, Ri, R 2 R 3 or C 1 4 alky[ S S S *SSS S S*. *5**9S S S. 5* ozx 10 R, hydrogen or Ci-alkyl, X=H, C 14 6alkyl, C3.8cycloalkyI, C 1 4 alkoxy, C 1 .6alkynyI, halogen, amino or acylamido, Y=H, OCH 3 or CI, Z=H, 1, Br, CI, F, CN, CF 3 NO 2 N 3 OR,, CONH 2 C0 2 RI, C 14 alkyl, COMS ID No: SBMI-00976988 Received by IP Australia: Time 12:28 Date 2004-10-29 2 9- 10 -0 4 :12 '38 P1I Z Z EYS:132107#4/ 7 6 17 3 2 2 1 8 0 7 7 43/ 47 NR 4 Rs, NHCORs, NHCO 2 Rr 6 or *R1 -C=C-R 1 R 1 R 2 R 3 HorC1- 4 alkyl M=(CH 2 wherein x=1-8, -CH=CH- or 9. A method for treating anorexia, by administering to a patient in need of such treatment a pharmaceutically effective amount of a compound of formula: 10 wherein hydrogen or C1. 5 alkyl, X=H, Cj- alkyl, C 3 8 cycloalkyl, C 1 -4 alkoxy, Cl- 4 alkynyl, halogen, amino or acylamido, Z=H, 1, Br, Cl, F, CN, CF 3 NO 2 N 3 OR,, CONH- 2 C0 2 Rj. C 14 alkyl, NR 4 Rs, NHCORs, NHCO 2 Ro, and Rb IS C 1 .6 alkyl, phenyl or C 1 .6 alkyl substituted p~henyl; COMS ID No: SBMI-00976988 Received by IP Australia: Time 12:28 Date 2004-10-29 2 9- 10 -04 :12 :3 8 :P IEY Z6722 7 Z 44 41S 6 17 3 2 2 18 0 7 7 44/ 47 N Yt z wherein R 1 ~hydrogen or 01-4 alkyl, Y=H, OCH-3 or Cl, and Z=H, I, Br, Ci,F, CN, CF 3 NO 2 N 3 ORi,CONH 2 C0 2 R 1 Cl 4 alkyl, NR 4 R 6 NHCORs, NHCO 2 R 6 or C=C -CH~ Ri 2 -C=C-R, RipR,,vR 3 H or C 1 4 aOCyI C *C C C C. C C C M-Ozx R, hydrogen or C 1 5 alkyl, X=H, C 1 .6 alkyl, C3.acycloalkyI, C 1 -4alkoxy, C 1 .6 alkynyl, halogen, amino or acylamido, Y=H, OCH~3 or CI, Z=H. I, Br, Cl, F, CN, CF 3 NO 2 N 3 ORi, CONH 2 C0 2 R 1 CI-ealkyl, COMS ID No: SBMI-00976988 Received by IP Australia: Time 12:28 Date 2004-10-29 01-11-04:14:23 P IZZEYS :61732218077 4/ NR 4 Rs, NHCORs, NHCO2Re, or R t ,R2 .I ,Rz C=C\ C-CH=C R R3 R R3 -C=C-RI R, R2, R3 H or C 14 aikyl and M=(CH 2 wherein x=1-8, -CH=CH- or -CsC-. A compound selected from the group consisting of RTI-4229-139, 178, 189, 195, 199, 200, 219, 230, 239, 240, 242, 251, 252, 274, 165, 171, 176, 177,180, 181,194, 202, 334, 335, 336, 337, 345, 346, 347 and 348. 0*0* 0@ @0* S S 0 0 0 S 00 0 0 S 0 0050 0000 0 0*00 0009 oo oo o oo oooo oooo *oe oooo** o*ooo *oo o* *ooo *o 10 11. A method for treating psychostimulant abuse, by administering to a patient in need of such treatment a psychostimulant-inhibiting amount of compound of Claim 12. A method for inhibiting the action of a psychostimulant, by 15 administering to a patient in need of such treatment a psychostimulant- inhibiting amount of a compound of Claim 13. A method for inhibiting neurotransmitter re-uptake by administering to a patient in need of such treatment such treatment a neurotransmitter transporter-inhibiting amount of a compound of Claim COMS ID No: SBMI-00979271 Received by IP Australia: Time 15:12 Date 2004-11-01 29-10-04:12:39 :PI ZZEYS 61732218077 46/ 47 14. A method for treating neurodegenerative disorders, by administering to a patient in need of such treatment a pharmaceutically effective amount of a compound of Claim A method for treating depression, by administering to a patient in need of such treatment a pharmaceutically effective amount of a compound of Claim 16. A method for treating anorexia, by administering to a patient in need of such treatment a pharmaceutically effective amount of a compound of Claim 17. A pharmaceutical composition comprising a compound of any one of claims 1 to 3 and 10 and a pharmaceutically acceptable excipient, carrier, diluent and/or adjuvant DATED THIS TWENTY-NINTH DAY OF OCTOBER 2004 RESEARCH TRIANGLE INSTITUTE BY PIZZEYS PATENT AND TRADEMARK ATTORNEYS *•o •0 COMS ID No: SBMI-00976988 Received by IP Australia: Time 12:28 Date 2004-10-29