COCAINE RECEPTOR BINDING LIGANDS

Abstract: The invention relates to novel compounds which show high affinity for cocaine receptors in the brain, particularly dopamine and serotonin transporter sites. The compounds may be used as imaging or pharmaceutical agents, in the diagnosis and treatment of drug addiction, depression, anorexia and neurodegenerative diseases.

Description: COCAINE RECEPTOR BINDING LIGANDS This application is a continuation- m-part application of U.S. Patent Application 08/506,541, filed July 24, 1995, which is a continuation-in-part of (1) U.S. Patent Application 07/972,472, filed March 23, 1993, which ..ssued May 9, 1995 as U.S. Patent 5,413,779; (2) U.S. Patent Application 08/164,576, filed December 10, 1993, which is in turn a contmuation-m-part of U.S. Patent Application 07/792,648, filed November 15, 1991, now U.S. Patent No. 5,380,848, which is in turn a contmuation- in-part of U.S. Patent Application 07/564,755, filed August 9, 1990, now U.S. Patent 5,128,118 and U.S. PCT Application PCT/US91/05553, filed August 9, 1991, filed in the U.S. PCT Receiving Office and designating the United States; and (3) U.S. Patent Application 08/436,970, filed May 8, 1995, all of which are incorporated herein by reference m their entirety. Field of the Invention: This invention is directed to a class of binding iigands for cocaine receptors and other receptors in the brain. Specifically, a novel family of compounds shows high binding specificity and activity, and, in a radiolabeled form, can be used to bind to these receptors, for biochemical assays and imaging techniques. Such imaging is useful for determining 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. DISCLOSURE OF PARENT APPLICATIONS: This application claims priority, inter alia, from of U.S. Patent Application 07/972,472 filed March 23, 1993, now U.S. Patent 5,413,779, the entirety of which is incorporated by reference. This application also claims priority from U.S. Patent Application 07/564,755, now U.S. Patent 5,128,1 18, and U.S. PCT Application PCT/US91/055 3 (the U.S. National Phase of which is U.S. 07/972,472), filed August 9, 1991 , both applications being incorporated herein by reference. In U.S. Application Serial No. 07/564,755, 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: Where the 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, , p_, or multisubstituted; Ri = CH 3 , CH 2 CH=CH 2 , (CH 2 ) n C 6 H 5 n = 1-4; R 2 = CH 3 , C 2 H S , CH 3 (CH 2 )j, (CH 3 ) 2 CH, C 6 H 5 , C 6 H 5 CH 2 , C 6 H 5 (CH 2 ) 2 ; X = pharmacologically acceptable anion Sites of specific interest included cocaine receptors associated with dopamine (DA) transporter sites. Subsequently, in the U.S. PCT Application from which priority is claimed, and which is incorporated herein by reference, the values for R : and R 2 were expanded, such that R j may be an alkyl of 1-7 carbon atoms, CH 2 CR 3 =CR < R S wherein R 3 -R 5 are each, independently Cj__ 6 alkyl, or phenyl compounds of the formula C 6 H ς (CH 2 ) y , wherein y = 1-6. The PCT filing also reveals the affinity cf r.ese compounds for cocaine receptors associated with serotonin ( 5-hydroxytryptamine, 5-HT) transporters, and confirms, for the first time, that the in vi tro binding reported in the earlier- filed application, is confirmed in in vivo testing. Specific disclosure for a variety of applications, including using the compounds in both PET and SPECT scanning, wherein either the iodine substituent, or one of the carbon groups is radioactive '1-123, 125 or 131 and Cll) thus providing methods 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 n 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 m 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 compounds, such as [ 3 H]WIN 35,428, the novel compounds of these applications exhibit extremely low IC 50 values for binding inhibition. In U.S. Patent Application 08/164,576, filed December 10, 1993, also incorporated herein by reference in its entirety, a family of compounds was disclosed, having the formula: Wherein Y is — C-O- R*, or Wherein R, is hydrogen, C,. 5 alkyl R, is phenyl, C t . 6 alkyl, C,^ alkyl-substituted phenyl R,, is C,. 6 alkyl, phenyl, C,^ alkyl substituted phenyl and Z is phenyl or naphtyi bearing 1-3 substituents selected from the 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 [ 3 H] 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 preferentially to the dopamine transporter. 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 the formula wherein R is CH 3 , C 2 H 5 , CH 2 CH 2 CH 3 , or CH(CH 3 ) 2 , R, is CH 3 , CH 2 C 6 H 5 , (CH 2 ) 2 C 6 H 5 , (CH 2 ) 3 C 6 H 5 , or wherein X is H, OCH 3 , or Cl and Y is H, OCH 3 , or Cl, and n= l-8. Another object of the invention is to provide compounds having the following formulas: wherein R, = hydrogen, C,. 5 alkyl, X = H, C,. 6 alkyl, C 3 . 8 cycloalkyl, C alkoxy, C j . 6 alkynyl, halogen, amino, acylamido, and Z=H, I, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , OR,, CONH 2 , CO 2 R„ C 1 6 alkyl, NR^, NHCORs, NHCO^, R b is C,. 6 alkyl, phenyl, C,. 6 alkyl substituted phenyl be 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. 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) -2- (substituted) tropane analog. Still another object of the invention s 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 that will become here m 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 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 carboxyhc acid (tropane acid) to 2-substιruted tetrazoles. oxazoies oxadiazoles, thiazoles, thiadiazoles and benzothiazole Figure 2 depicts the scheme m which the carboxamide obtained from the tropane acid was treated to obtain rutπles and tetrazoles Figure 3 depicts die scheme used to prepare 3-substιtuted isoxazoles DETAILED DESCRIPTION OF THE INVENTION The present invention includes novel compounds having the tollow g formula la, R = CH 3 b, R = CH,CH 3 CH 3 2a, R = CH,C 2 H 5 c, R=CH(CH 3 ) 3 3a. X = H, Y=CCH 3 b, R=(CH 2 ) 2 C 2 H 5 b, X = OCH 3 , Y = H c, R = (CH 2 ) 3 C j H 5 C X = OCH 3 , 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 synύiesis for related compounds will be apparent to those of ordinary skill in the art. Particular synthesis schemes are exemplified in U.S. Patent No. 5,444,070, which is incorporated herein in its entirety. Additional schemes follow hereinbelow. Preparation of 33- (Substituted phenyl) tropane-23-heterocyclic Analogues Chemistry The known 3/3- (substituted phenyl) -23-tropane carboxylic acid (tropane acid) (Carroll et al . , J. Med . Chem . 35:1313-1817 (1992)) served as the starting material for the synthesis of 2/3- substituted tetrazoles, oxazoies, oxadiazoles, thiazoles, thiadiazoles and benzothiazole as shown in Figure 1. The tropane acid was refiuxed w th N-acetyl and benzoic hydrazide m phosphorous oxychloride to obtain the corresponding 5 -substituted 1, 3 , 4 -oxadiazoles (Afanasiadi et al . , Chem. Heterocyclic Co pd. 397-400 (1995) ) . N-benzoyl hydrazide amide obtained by the reaction cf the acid cnloride of tropane acid with N-benzo c hydrazide was cyclized with Lawesson's reagent (El-Barbary et al . , Acta Chimica Scandinavi ca 597-601 (1980)) in refluxing THF to the 5-substιtuted 1, 3 , 4- thiadiazoles . The N- phenylacyl carboxamide obtained from tropane acid and 2- aminoacetophenone was cyclized by refluxing the amide in phosphorous oxychloride to obtain the required 5-suostιtuted oxazoies (Carroll et al., Med. Chem. Res . 3:468 (1993)). Cyclization of the same amide with Lawesson's reagent (El-Barbary et al., 1980) in refluxing THF gave the 5-substituted thiazoles respectively. The benzothiazole 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 tri ethylsilylazide to the nitrile afforded the corresponding tetrazoles (Saunders et al . , Med . Chem . 33:1128-1138 (1990)). 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 acetophenoneoxime with n-BuLi at 0°C. The corresponding addition product was cyclized without isolation using sulfuric acid at reflux temperature to furnish the recruired 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 vi tro and in vivo assay systems may be used for the screening of potential 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 th= 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 vi tro assays for binding are described in Boja et al Ann. NY Aca . Sci . 654:282-291 (1992), which is incorporated herein by reference in its entirety. A particularly preferred in vi tro assay involves the ability of a compound in question to displace the binding of a known labelled compound to 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 any of the currently available counting procedures, including the imaging procedures detailed m the disclosures of the parent applications. The preferred isotope may be selected from 3 H, C, 14 C, C, 32 P, 35 S, 36 C1, 51 Cr, 57 Co, 5β Co, 59 Fe, 90 Y, l "i, *"ι, and ιaβ Re.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) , autoradiogra , 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 displacement studies which determine in vivo ICSO's which in turn reflect doses that occupy receptors in vivo are described n Cline et al '(1992) Synapse 12:37-46). In addition to its uses m determining in vivo potency/occupancy, these same brain imaging methods can be used to determine rate of entry of compounds into the brain (Stathis et al (1995) Psychopharmacology 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 psychostimulant is 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 . 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. For 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 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 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 (i.e., 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 (199.) , 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 quantities of the compounds may vary in accordance with the binding properties of the compound (i.e., 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 longer duration of action than 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 {Stathis 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 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; i.e., 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 on the subject to be treated, the presence of other agonists and antagonises 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 1000, preferably about .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. However, the exact dosage must be determined by factoring m 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 subsequent infection or other administration. Alternatively, continuous intravenous infusion sufficient to maintain appropriate concentrations m the blood are contemplated. The compounds of the present invention may be administered 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 inhibiting the uptake of dopamine, norepmephnne , serotonin and other monoamines. The compounds of the present invention may find use as an ipsychotics , antidepressants , local anesthetics, anti-Parkinsonian agents, anti-obesity drugs, drugs useful in the treatment of bipolar disorder, eating disorders, obesity, attention deficit disorder, panic attacks and disorder, obsessive-compulsive disorder, sexual dysfunction, as anticholinergic agents and as sigma receptor drugs. The compounds of the invention may also be useful in trea t ing neurodegenerative disorders, in particular for treating 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 physical properties of some of these compounds are given in Table I. Table I Physical Properties of 2β-substituted Hetrocyclic Analogs of 3β-(4-Substituted-phenyl) Tropane and Cocaine Code Name Compound RTI-188 RTI-195 co c CD RTI-194 CO RTI-200 c H m RTI-199 co ro x RTI-189 m m RTM78 33 c RTI-219 m RTI-202 σ> RTI-161 RTI-158 RTI-163 RTI-157 RTI-165 RTI-171 RTI-180 O RTI-177 O RT1-176 O RTI-181 no ro RTI-184 o RTI-185 ) i. HCl Salt; b. Tartrate Salt; c. 0.25 mol water; d. 0.5 mol water; e. 0.75 mol water; f. 1 mol water. - Many of the preferred compounds of the invention fall within the broad class of compounds described by the formula: Rj Wherein R s = hydrogen, C s alkyl, R 2 = hydrogen, C,. 6 alkyl, C 3 . 8 cycloalkyl, C alkoxy, C^alkynyl, halogen, amine, CH 2 C 5 H 5 , (CH 2 ) 2 C 6 H 5 , (CH 2 ) 3 C 6 H 5 or R 3 =OH, hydrogen, C,. 6 alkyl, C 3 . 8 cycloalkyl, C M alkoxy, Cl, Br, I, CN, NH 2 , NHC,^ alkyl, NC 1 6 alkyl, OCOC,^ alkyl, OCOC,. 3 alkylaryl, A=S, O or N X=H, C,^ alkyl, C 3 _ 8 cycloalkyl, C alkoxy, C,. 6 alkynyl, halogen, amino, acylamido, C 2 H 5 , CH 2 CH 3 CH 3 , CH(CH 3 ) 2 , Z=H, I, Br, Cl, F, CN, CF 3 , N0 2 , N 3 , OR x , CONH 2 , C0 2 R,, C,. 6 alkyl, NR 4 R 5 , NHCORj, NHC0 2 R 6 , and Q l and Q 2 may be the same or different and = H, OCH 3 , or Cl, wherein R 4 -R« are each C^ alkyl, R and R λ are independently H, C^ 6 alkyl, C 1-6 alkene, C 1-6 aikyne, phenyl, phenyl substituted with 1-3 of C l-6 alkyl, alkene, alkyl or alkoxy, C l-β alkoxy, phenoxy, amine, amine substituted with 1-2 of C 1-6 alkyl, alkene, aikyne, alkoxy or phenyl or phenoxy or R and R 1 may combine to form heterocyclic structure including pyrrolidinyl, piperidinyl and morpholino moieties, unsubstituted or substituted with 1-2 C l-β alkyl, alkene, aikyne 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 compounds of the RTI-4229 series include the following: RTI-4229-31, 32, 51, 55, 83, 96, 97, 98, 101, 105, 108, 110, 111, 112, 116, 121, 122, 127, 132, 139, 140, 142, 145, 146, 147 ~ 150, 153, 178, 138, 189, 190, 191, 193, 195, 199, 200, 203, 204, 205, 206, 219, 230, 239, 240, 241, 242, 251, 252, 274, 277, 278, 279, 280, 281, 282, 283, 286, 287, 296, 304, 305, 307, 309, 318, and 330. The chemical structures of these compounds, along with their IC 50 values for inhbition of radioligand binding are given below. DA is dopamine, 5-HT is 5-hydroxytryptamme (serotonin), and NE is norepinephrine, DA = [ 3 H]WIN 35,428; 5-HT = [ 3 H] paroxetine and NE N = [ 3 H] nisofetine: NE N 4,027.87 ±380.70 RTI-4229-98 NE N 129.3 ±15 NE N 5.45 ±0.21 NE N 967.55 ±26.25 NE N 3,791 ±149 NE N 3, 444 ±44 NE N 137.3 ±10.5 -28- NE N 56.9±2.6 NE N 144 ±3 NE N 122 ± 12 -30- SUBSπTUTE SHEET (RULE 26) NE N 644±27.7 .HCl NE N 141 ±16.1 NE,, 124±3.56 -34- NE N 4,095.01 ±413.45 -tartrate NE N 3921.58± 130 -36- SUBSTfTUTE SHEET (RULE 26) NE N 3125±333 NE 2799 ±300 -37- NE N 21.8±1.0 H RTI-4229-307 BIH-141-15 ,C0 2 CH 3 .3/4H,0 DA 6.11 ±0.67 + tartrate 5-HT 3.16±0.33 NE N 115.8±5.1 H NE N 14.9±1.18 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: Particularly preferred compounds include RTI-4229-77, 87, 113, 1 14, 1 17, 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: NE N 363 ±36 NE N 7,876±551 -41- NE N 245 ±13 NE N 835 ±7.5 NE N 402.8±29.5 -44- + (-)-tartrate ,0 NE N 954±97.3 -45- NE N 1714±38.5 NE N 6321 ±703 NE N 762.01 ±37.8 -46- NE N 918.4± 108.34 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 antidepressan , 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 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°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. X H NMR and 13 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 polari eter (1 dm cell) . Melting point was recorded on a Uni- melt 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 [μL thickness]) precoated TLC plates using the solvent systems indicated. Developed chromatograms were evaluated under 254 nm UV light or with iodine. ξjXAMP^E 1 General Procedure For the Preparation of Amides To a solution of 1 mmol of 33- (4-Chlorophenyl) -εropane-2 / S- carboxylic acid or 3β- (4-Methylphenyl) -tropane - 2β-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 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 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 °C, and 2.0 eq of the amine hydrochloride containing 4.0 eq of triethylamine, or 2.5 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 (Na 2 S0 4 ) , filtered and the solvent removed in vacuo to give crude product . The crude was purified by flash column chromatography or crystallization. EA P E 2 3/3- (4-Chlorophenyl) -2/3- (5-phenyl-1, 3, 4-oxadiasεol-2-yl) -tropane Hydrochloride (RTI-188) To a solution of 0.59 g (2 mmol) of 33- (4-Chlorophenyl) - tropane- 2 -carboxylic acid (chloro acid) in 2 ml Of POC1, was added 0.31 g (2.2 mmol) of N-benzoic hydrazide and refiuxed 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 [50V (ether/triethylamine 9:1) in hexane] gave 0.33 g (42%) of pure oxadiazole (RTI-188) which was recrystallized from ether/petroleum ether: l H NMR (CDCl j ) 1.81 (m, 3 H) , 2.18 (s, 3 H) , 2.26 (m, 2 H) , 2.66 (m, 1 H) , 3.33 (m, 2 H) , 3.51 (m, 2 H) , 7.16 (m, 4 H) 7.45 (m, 3 H) , 7.86 (m, 2 H) ; IR (CHC1 3 ) 2950, 1550, 1490, 1450, 1340, 1090 cm "1 ; [α] D -106.25° (c = 0.08, CHC1 3 ) . The oxadiazole was converted into hydrochloride sal : l H NMR (MeOD) 2.08 (m, 1 H) , 2.57 (m, 5 H) , 3.0 (s, 3 H) , 4.01 (m, 2 H) , 4.15 ( , 1 H) , 4.39 (m, 1 H) , 7.24 (m, 4 H) , 7.52 (m, 5 H) : mp 160-162°C; Anal calcd for C^H^Cl^O.0.75H 2 0; 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; [a] D +84.59° (c = 0.36, CH 3 OH) . Further elution gave as a second fraction 0.1 g (13%) of white solid which was characterized to be 3/3- (4-Chlorophenyl) -2α- (5-phenyl-l, 3, -oxadiazol-2-yl) -tropane: *H NMR (CDC1 3 ) 1.76 (m, 3 H) , 2.06 (s, 3 H) , 2.45 (s, 3 H) , 3.36 (m, 2 H) , 3.51 (m, 1 H) , 3.65 ( , 1 H) , 7.21 (m, 4 H) , 7.47 ( , 3 H) 7.91 (m, 2 H) ; mp 170-171°C; Anal calcd for C 22 H 22 CIN,0; 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; [α] D +33.06° (c = 0.18, CHC1 3 ) . EXAMPLE 3 30- ( 4 -Methylphenyl) - 2/3- ( 5-phenyl- l , 3 , -oxadiazol- 2 -yl) - tropane Hydrochloride (RTI - 195) Reaction of 0 . 65 g ( 2 . 5 mmol ) of 3/3- (4 -Methylphenyl) - tropane-2/3-carboxylic acid (Methyl acid) as described above for RTI-188 gave after work-up and purification by flash column chromatography [(50% ( ether/triethylamine 9 : 1 ) in hexane] 0.36 g (40%) of pure oxadiazole (RTI-195) which was recrystallized from ether/petroleum ether: X H NMR (CDC1 3 ) 1.83 (m, 3 H) , 2.18 (s, 3 H) , 2.21 (s, 3 H) , 2.3 (m, 2 H) , 2.67 ( , 1 H) , 3.33 (m, 1 H) , 3.41 (m, 1 H) , 3.53 (m, 1 H) , 3.61 (m, 1 H) 7.0 ( , 2 HJ.7.13 (m, 2 H) , 7.44 ( , 3 H) , 7.86 ( , 2 H) ; IR (CHCL 5 ) 2990, 1545, 1505, 1440, 1350. cm -1 ; [a] D -163.92° (c = 0.2, CHCl j ). The oxadiazole was converted into hydrochloride salt : ; H NMR (MeOD) 2.05 (m, 1 H) , 2.21 (s, 3 H) , 2.51 (m, 5 H) , 2.99 (s, 3 H) , 3.86 (m, 1 H) , 3.95 (m, 1 H) , 4.14 (m, 1 H) , 4.35 ( , 1 H) , 7.02 (m, 4 H) 7.53 (m, 5 H) ; mp 175-178°C; Anal calcd for C 23 H 26 CIN 3 O.0.75H 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; [α] D +97.22° (c = 0.25, CHjOH) . Further elution gave as a second fraction 0. I8g (20%) of solid which was characterized to be 33- (4-Methylphenyl) -2α- (5- phenyl-i, 3, 4 -oxadiazol-2 -yl) -tropane which was recrystallized from ether/ petroleum ether: l H NMR (CDC1,) 1.77 (m, 2 H) , 2.0 (m, 4 H) , 2.25 (s, 3 H) , 2.47 (a, 3 H) , 3.33 (m, 2 H) , 3.51 (m, 1 H) , 3.69 (d of d, J - 2.6, 12 Hz, 1 H) , 6.91 (m, 2 H) 7.03 (m, 2 H) .7.45 (m, 2 H) , 7.45 ( , 3 H) , 7.89 ( , 2 H) ; IR (CHCL 3 ) 3020, 1540, 1510, 1415, 1250, 1215. c . x ; Anal calcd for C 23 H 25 N,0; C = 76.85; H = 7.01, N = 11.69; found C = 76.60, H = 7.12, N = 11.55; [α] D +40.73° (c = 0.28, CHC1 3 ) . EXAMPLE 4 3/3- (4-Methγlphβnyl) -2β- (5-methyl-l, 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 gave after work-up and Purification by flash column chromatography [(75% (ether/triethylamine 9:1 ) in hexane] 0.29 g (39%) of pure oxadiazole (RTI-194) which was recrystallized from ether/petroleum ether: X H NMR (CDC1 3 ) 1.75 (m, 3 H) , 2.18 (s, 3 H) , 2.22 (s, 3 H} , 2.25 (m, 2 H) , 2.35 (s, 3 H) , 2.56 (m, 1 H) , 3.24 (m, 1 H) , 3.4 (m, 2 H) , 3.47 (m, 1 H) 7.0 ( , 4 H) ; 1 C NMR (CDC1 3 ) 11.06, 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 cm 1 ; [a] 0 - 108.47° ( c = 0.14, CHC1 3 ) . The-oxadiazole was converted into hydrochloride salt: X H NMR (MeOD) 1.99 (m, 1 H) , 2.23 (s, 3 H) , 2.27 (s, 3 H) , 2.47 m, 5 H) , 2.94 (s, 3 H) , 3.72 (m, 1 H) , 3.79 (m, 1 H) , 4.10 (m, 1 H) , 4.23 ( , 1 H) , 7.05 (m, 4 H) ; mp 146°C.(dec); Anal calcd for C ιa H 24 CIN 3 O.0.5H 2 O; C = 63.06; H = 7.35, N = 12.26; Cl = 10.34; found C = 63.21, H = 7.40, N = 12.07; Cl = 10.27; [a] 0 -43.05° (c = 0.15, CHjOH) . EXAMPLE 5 33- (4-Chlorophenyl) -2/3- (5-phenyl-l, 3 , 4- thiadiazol-2-yl) -tropane Hydrochloride (RTI-200) . Reaction of 0.59g ( 2 mmol ) of 3/3- (4-Chlorophenyl) tropane-2 / 3- 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 (66%) of pure N- [3/3- (4-Chlorophenyl) - tropane-23-carboxylic] -N' -benzoylhydrazide : : H NMR (CDC1 3 ) δ 1.76 (m, 3 H) , 2.24 (m, 2 H) , 2.41 (s, 3 H) , 2.51 (m, 1 H) , 2.68 (m, 1 H) , 3.18 (m, 1 H) , 3.44 (m, 2 H) , 7.22 (m, 4 H) , 7.46 (m, 3 H) , 7.78 (m, 2 H) , 9.02 (br s, 1 H) , 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 mmol) of N- [3/3- (4-Chlorophenyl) - tropane-2/3-carboxylic] -N' -benzoyl-hydrazide and 0.8g (2 mmol) of Lawesson's reagent in 10 ml toluene was refiuxed for 4 h under nitrogen. The reaction mixture was cooled and solvent removed in vacuo to give a yellow 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 [50% ether/triethylamine (9 : 1) in hexane] to obtain 0.23 g (58%) of pure thiadiazole (RTI-200) which was further purified by recrystallizing from ether: J H NMR ;CDC1 3 ) δ 1.75 tm, 3 H) , 2.20 (m, 3 H) , 2.32 (s, 3 H) , 3.30 (ra, 3 H) , 3.78 (m, 1 H) , 6.86 (m, 2 H) , 7.08 (m, 2 H) , 7.43 ( , 3 H) , 7.97 (m, 2 H) ; 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 (CC1 2940, 1490, 1460, 1340, 1245, 1100, 1010 cm '1 The thiadiazole was converted into hydrochloride salt : L H NMR (MeOD) δ 2.06 ( , 1 H) , 2.53 (ra, 5 H) , 2.97 (s, 3 H) , 3.92 (m, 1 H) , 4.17 (m, 2 H) , 4.39 (m, 1 H) , 7.11 (m, 2 H) , 7.26 (m, 2 H) , 7.51 (m, 3 H) , 7.79 (m, 2 H) ; mp 165-170°C; Anal calcd for C 22 H 23 C1 2 N 3 S.0.75H 2 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; [o] 0 -42.81° (c = 0.16, MeOH) . Further elution gave 0.08 g (21%) as a second fraction which was characterized to be 3/3- (4-chlorophenyl) -2α- (5-phenyl-i, 3 , 4- oxadiazol-2-yl) -tropane. EXAMPLE 6 30- (4-Methylphenyl) -23- (5-phenyl-l, 3, 4-thiadiazol-2-yl) -tropane Hydrochloride (RTI-199) Reaction of 0.65 g (2.5 mmol) of 3/3- (4-Methylphenyl) - tropane-2/3-carboxylic acid as described above for preparation of amides gave after work up and purification by flash column chromaJtography [(50% CMA-80 in methylene chloride)] 0.48 g (51%) pure N- [3/3- (4-Methylphenyl) Tropane-2/3-carboxylic] -N' -benzoyl - hydrazide which was further purified by recrystallizing from ether/pet ether: l H NMR (CDC1,) δ 1.75 (m, 3 H) , 2.20 (m, 2 H) , 2.27 (s, 3 H) , 2.42 (s, 3 H) , 2.51 (m, 1 H) , 2.67 (m, 1 H) , 3.18 (m, 1 H) , 3.47 (m, 2 H) , 7.11 ( , 4 H) , 7.48 (m, 3 H) , 7.81 (m, 2 H) , 9.06 (br s, 1 H) , 13.09 (br s, 1 H) ; IR (CHC1 3 ) 3385, 3045, 1625, 1570, 1460, 1420, 1100 cm "1 ; Reaction of 0.29 g (0.75 mmol) of N- [3 / 3- (4-Methylphenyl) - tropane-2/3-carboxylic] -N' -benzoyl-hydrazide as described above for RTI-200 gave after work and purification by flash chromatography [40% ether/triethylamine (9 1) in hexane] 0.16 g (58%) of pure thiadiazole (RTI-199) : : H NMR (CDC1 3 ) δ 1.70 (m, 1 H) , 1.88 (m, 2 H) , 2.20 (s, 3 H) , 2.23 (m, 2 H) , 2.21 (s, 3 H) , 2.38 (m, 1 H) , 3.21 (m, 1 H) , 3.32 (m, 1 H) , 3.39 (m, 1 H) , 3.78 (m, 1 H) , 6.81 ( , 2 H) , 6.92 (m, 2 H) , 7.43 (m,3 H) , 7.97 (m, 2 H) ; 13 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 2935, 1510, 1450, 1250, 1120, 1100, 1060 cπT 1 The thiadiazole was converted into hydrochloride salt; : H NMR (MeOD) δ 1.95 (m, 1 H) , 2.17 (s, 3 H) , 2.41 ( , 5 H) , 2.89 (s, 3 H) , 3.76 (m, 1 H) , 4.05 (m, 2 H) , 4.30 (m, 1 H) , 4.22 (m, 1 H) , 6.89 (m, 2 H) , 6.99 (m, 2 H) , 7.39 (m, 3 H) , 7.67 (m, 2 H) ; mp 180-185°C; Anal calcd for C 23 H 26 CIN 3 S .H 2 0; C = 65.62, H = 6.46, N = 9.98, Cl = 18.42; S = 7.62. found C = 65.57, H = 6.63, N = 9.91, Cl = 18.24; S = 7. 55; [α] „ -33.5° (c = 0.2, MeOH) Further elution gave 0.04 g (15%) of a second fraction which was characterized to be 3/3- (4-Methylphenyl ) -2α (5-phenyl-ι, 3 , 4- oxadiazol-2-yl) -tropane. EXAMPLE 7 3/3- (4-Chloroph.enyl) -2/3- (5-phenyl-oxazol-2-yl) -tropane Tartrate RTI-189) Reaction of 0.73 g (2.5 mmol) of 3/3- (4-Chlorophenyl) - tropane-2/3 carboxylic acid as described above for the preparation of amides gave after purification by flash column chromatography (15% CMA 80 in methylene chloride) 0.8 g (81%) of pure 3/3- (4- Chlorophenyl) -tropane-2/3-N- (phenyacyl) carboxamide : -H NMR (CDC1 3 ) δ 1.71 (m, 3 H) , 2.19 (m, 2 H) , 2.39 (s, 3 H) , 2.46 (m, 1 H) , 2.58 (m, 1 H) , 3.13 (m, 1 H) , 3.43 ( , 2 H) , 4.74 (m, 2 H) , 7.13 (m, 4 H) , 7.49 (m, 2 H) , 7.59 (m, 1 H) , 7.96 (m, 2 H) , 10.57 (br s, 1 H) ; IR (CHClj) 3135, 3010, 2930, 1695, 1650, 1590, 1530, 1485, 1450, 1355, 1220 cm "1 . A solution of 0.725 g (1.83 mmol) of 3/3- (4 -Chlorophenyl) - tropane-2/3-N (phenyacyl) carboxamide in 6 ml POCl, was heated at 125°C under nitrogen for 2 hours. The reaction mixture was cooled and poured into ice and rendered basic to pH 7-8 using concentrated NH Λ 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 0.63 g crude oxazole. Purification of the crude by flash column chromatography [(40% (ether/triethylamine 9 : l ) in hexane] gave 0.34 g (49%) of pure oxazole (RTI-189) which was further purified by recrystallizing from ether/petroleum ether: *H NMR (CDCl 3 ) 1.79 ( , 3 H) , 2.22 (s, 3 H) , 2.27 (m, 2 H) , 2.66 (m, 1 H) , 3.27 (m, 1 H) , 3.40 (m, 2 H) , 3.53 (m, 1 H) , 7.11 (s, 1 H) , 7.16 (s, 4 H) 7.31 (m, 5 H) ; IR (CHC13) 2950, 1540, 1490, 1445, 1350, 1120, 1090 CM "1 ; [ ] D - 70.37° (c = 0.19, CHC1 3 ) . The oxazole was converted into tartrate salt: X H NMR (MeOD) 2.14 ( , 1 H) , 2.54 (m, 5 H) , 2.96 (s, 3 H) , 3.75 (m, 2 H) , 4.12 (m, 1 H) , 4.25 (m, 1 H) , 4.41 (s, 2 H) , 7.05 (m, 2 H) , 7.29 (m, 7 H) , 7.45 (s, 1 H) , 7.43 (s, 1 H) ; mp 126°C (dec) ; Anal calcd for C 27 H 29 CIN 2 O 7 .0.75H 2 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; [a] D +101.43° (c = 0.21, CH 3 OH) . EXAMPLE 8 3/3- (4 -Methylphenyi) -23- (5-phenγl-oxazol-2 -yl) -tropane Tartrate (RTI-178) Reaction of 0.52 g (2 mmol) of 3/3- (4 -Methylphenyi) -tropane- 2/ -carboxylic acid as described above for preparation of amides gave after work up and purification by flash column chromatography (15% CMA in methylene chloride) 0.54 g (72%) of pure 3/3- ( -Methylphenyi) -tropane-2/3-N- (phenyacyl) carcoxamide : *H NMR (CDCl j ) δ 1.73 (m, 3 H) , 2.14 (m, 2 H) , 2.26 (s, 3 H) , 2.40 (s, 3 H) , 2.47 (m, 1 H) , 2.59 (m, 1 H) , 3.14 (ra, 1 H) , 3.42 (m, 2 H) , 4.74 (m, 2 H) , 7.05 (m, 4 H) , 7.48 (m, 2 H) , 7.59 (m, 2 H) , 7.97 (m, 2 H) , 10.62 (br s, 1 H) ; IR (CHC1 3 ) 3155, 3005, 2930, 1690, 1650, 1520, 1450, 1355, 1215 cπf 1 Reaction of 0.5 g (1.33 mmol) of 3/3- (4-Methylphenyi) - tropane- 2/3-N- (phenyacyl) carboxamide as described above for RTI- 189 gave after workup and purification by flash column chromatography [(40% (ether/triethylamine 9 : 1 ) in hexane] 0.1 g (31%) RTI-158 as a first fraction. Further elution gave 0.19 g (42%) of pure oxazole RTI-178: : H NMR (CDC1 1.8 (m, 3 H) , 2.18 (m, 2 H) , 2.21 (s, 3 H) , 2.22 (a, 3 H) , 2.67 (m, 1 H) , 3.28 (m, 1 H) , 3.42 (m, 2 H) , 3.53 (m, I H) , 6.98 (m, 2 H) , 7.11 (m, 3 H) , 7.30 (m, 5 H) . The oxazole was crystallized aa the tartrate salt : H NMR (MeOD) 1.99 (m, 1 H) , 2.19 (s, 3 H) , 2.54 (m, 5 H) , 2.95 (s, 3 H) , 3.74 (m, 2 H) , 4.13 (m, 1 H) , 4.26 (m, 1 H) , 4.4 (s, 2 H) , 6.91 (m, 2 H) , 7.0 (m, 2 H) , 7.25 (m, 2 H) , 7.33 (m, 3 H) , 7.43 (s, 1 H) ; mp 175-181 C; Anal calcd for C 2a H 32 N-0., .1H 2 0 ; C = 63.87; H = 6.51, N = 5.32; found C = 64.21, H = 6.40, N = 5.19; [a] 0 - 104.04° (C = 0.6, CH 3 OH) . EXAMPLE ? 30 - ( 4 - Chlorophenyl ) - 2 /3 - ( 5 - pheny 1 thiaz o l - 2 - yl ) - tropane Hydrochloride (RTI -219 ) To a solution of 0 . 74 g ( 1. 86 mmol) of 3/3- (4 -Chlorophenyl) - tropane- 2/3-N- (phenyacyl) carboxamide and 1.51 g (7.45 mmol) of Lawesson's reagent in 18 ml of toluene was refiuxed under N 2 for 5 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 [ (40% (ether/triethylamine 9 -. 1 ) in hexane] to give 0.21 g (30%) of pure thiazole RTI-219: ' * H NMR (CDC1 3 ) 1.61 (m, 1 H) , 1.82 (m, 2 H) , 2.22 (m, 2 H) , 2.34 (s, 3 H) , 2.39 (m, 1 H) , 3.28 (m, 2 H) , 3.39 (m, 1 H) , 3.49 (m, 1 H) , 6.8 (m, 2 H) 7.07 (m, 2 H) .7.32 (m, 3 H) , 7.57 (m, 2 H) , 7.60 (s, 1 H) ; 13 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 (CHC1 3 ) 2945, 1590, 1485, 1445, 1350, 1125, 1090. cm "1 . The thiazole was converted into hydrochloride sal : λ H NMR (MeOD) 1.99 (m, 1 H) , 2.51 (m, 5 H) , 2.93 (s, 3 H) , 3.79 (m, 2 H) , 4.15 " (m, 1 H) , 4.28 (m, 1 H) , 7.02 (d, J = 8.5 Hz, 2 H) 7.21 (d, J = 8.5 HZ, 2 H) , 7.39 (m, 5 H) , 8.06 (s, 1 H) ; mp 228 -230 °C; Anal calcd for C 23 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; [α] D +27.43° (c = 0.11, CH 3 OH) . EXAMPLE 10 30- (4-Chlorophenyl) -20- (benzothiazol-2-yl) - tropaneHydrochloride (RTI-202) Reaction of 0.59 g (2 mmol) of 3/3- (4-Chlorophenyl) - ropane- 2/ -carboxylic acid aa 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 from ether/hexane: l K NMR (CDC1 3 ) δ 1.65 (m, 1 H) , 1.87 (m, 2 H) , 2.24 (m, 2 H) , 2.34 (s, 3 H) , 2.41 (m, 1 H) , 3.28 (m, 2 H) , 3.40 (m, 1 H) , 3.62 (m, 1 H) , 6.8 (m, 2 H) , 6.81 (m, 2 H) , 7.29 (m, 2 H) , 7.70 (m, 1 H) , 7.84 (m, 1 H) ; 13 C NMR (CDCl 3 ) δ 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 (CHC1 3 ) 2940, 2795, 1495, 1445, 1305, 1130, 1105, 1015, 907 CM' 1 ; [a] D -233.89° (c = 0.09, CHC1 3 ) . The benzothiazole was converted into hydrochloride salt: : H NMR (MeOD) δ 2.02 (m, 1 H) , 2.43 (m, 4 H) , 2.89 (m, 1 H) , 2.98 (s, 3 H) .7 3.90 (m, 2 H) , 4.23 (m, 1 H) , 4.34 (m, 1 H) , 7.02 (m, 2 H) , 7.13 (m, 2 H) , 7.45 (m, 2 H) , 7.81 (m, 1 H) , 8.16 (m, 1 H) ; mp 140-150°C (dec); Anal calcd for C 21 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; [a] D -1 72.49° (c 0.28, MeOH) . EXAMPLE 11 30- (4-Chlorophenyl) -tropane-20-nitrile (RTI-161) To a solution of 0.95g (3.5 mmol) of 30- (4 -Chlorophenyl) - tropane-20-carboxamide 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 th≥ residue was taken in 10 ml saturated aqueous K 2 C0 3 and extracted thrice with 10 ml CHC1 3 . The organic layers were combined and washed with 20 ml brine dried (NaS0 4 ) , 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 (77%) of pure nitrile RTΣ-161 which was recrystallized from methylene chloride and hexane: l H NMR (CDC1 3 ) δ 1.70 (m, 3 H) , 2.22 (m, 3 H) , 2.35 (a, 3 H) , 2.80 (m, 1 H) , 3.04 (m, 1 H) , 3.34 (m, 1 H) , 3.43 (m, 1 H) , 7.26 <m, 4 H) ; IR iCHClj) 3700, 2950, 2225, 1490, 1470, 1090, 900 cm "'1 ; mp 167-173°C; Anal calcd for C 15 H lβ Cl 2 N 2 .0.75H-O; c = 57.98, H = 6.32 N = 9.02, Cl = 22.82; found C = 58.22, H = 6.12, N = 8.48, Cl = 22.89; [ ] D -73.33° (c = 0.48, MeOH) . EXAMPLE 12 30- (4-Methylphenyi) -tropane-20-nitrile Hydrochloride (RTI-158) Reaction of 0.26g (1 mmol) of 30- (4-Methylphenyi) -tropane- 2 -carboxamide as described above for RTI -161 gave after work up and purification 0.16 g (67%) of pure nitrile (RTI-158) : l H NMR (CDCl j ) δ 1.68 (m, 3 H) , 2.18 (m, 3 H) , 2.32 (s, 3 H) , 2.35 (s, 1 H) , 2.82 (m, 1 H) , 3.02 (m, 1 H) , 3.36 (m, 1 H) , 3.43 (m, 1 H) , 7.18 (m, 4 H) ; IR (CHC1 3 ) 3675, 3000, 2950, 2200, 1600, 1510, 1450, 1350, 1220, 1100 cm "1 . The crude product was crystallized as the HCl sal : λ H NMR (MeOH) δ 2.08 -2.58 (ra, 9 H) , 2.92 (s, 3 H) , 3.54 (m, 1 H) , 3.69 (br s, 1 H) , 4.12 (br s, 1 H) , 4.29 (m, 1 H) , 7.21 (ra, 4 H) ; mp 270°C (dec); Anal calcd for C 16 H 21 CIN 2 ; 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; [α] D -76.4° (c = 0.5, MeOH). EXAMPLE 13 30- (4-Chlorophenyl) - ropane-20-tetrazole (RTI-163) To " a solution of 0.13 g ( 0.5 mmol) of RTI-161 in 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 150°C for 24 hours in an oil bath. The reaction mixture was cooled and transferred using MeOH. The solvent was removed in vacuo to give a brownish residue. Purification of the crude by flash column chromatography (20% -50% CMA in methylene chloride) gave 0.05 g (33%) of pure tetrazole (RTI-163): : H NMR (CDC1 3 + 1 drop MeOD) δ 1.73 (m, 1 H) , 2.44 - 2.02 (m, 4 H) , 2.6 (m, 1 H) , 2.68 (s, 3 H) , 3.33 (ra, 1 H) , 3.65 (m, 1 H) , 3.73 (m, 1 H) , 3.97 (m, 1 H) , 6.68 (d, J = 8 Hz, 2 H) , 7.07 (d, J « 8 Hz, 2 H) ; mp 296-300°C; Anal calcd for C 1S H 18 CIN S .0.75H 2 0 ; C = 56.78, H = 6.19 N = 22.07, Cl = 11.17; found C = 56.69, H = 6.22, N = 22.09, Cl = 11.15; [θf] D -124.94° (c-0.39, MeOH). EXAMPLE 14 30- (4 -Methylphenyi) -tropane-20- etrazole 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 (88%) of pure tetrazole (RTI-157) : l K NMR (CDC1 3 + 1 drop MeOD) δ 1.8 (ra, 1 H) , 2.14 (s, 3 H) , 2.35 (m, 5 H) , 2.71 (a, 3 H) , 3.36 (m, 1 H) , 3.75 (m, 2 H) , 4.02 (m, 1 H) , 6.48 (d, J = 8 Hz, 2 H) , 6.82 (d, J = 8 Hz, 2 H) . The purified product was converted into HCl sal : *H NMR (MeOD) δ 2.01 (m, 1 H) , 2.27 (s, 3 H) , 2.69 (m, 5 H) , 2.97 (s, 3 H) , 3.81 (m, 2 H) , 4.18 (m, 2 H) , 5.5 (s, 1 H) , 6.76 (d, J = 8 Hz, 2 H) , 7.02 (d, J = 8 Hz, 2 H) ; mp 212**C (dec); Anal calcd for C 16 H 23 C1 2 N 5 .0.25H 2 0; C = 53.26, H = 6.56 N = 19.41; found C = 53.41, H = 6.50, N = 19.02; [α] D -110.97° (c = 0.16, MeOH). EXAMPLE 15 30- (4-Chlorophenyl) -20- ( 3 -methyliβoxazol - 5 - 1 ) tropane Hydrochloride (RTI-165) A solution of n-butyl lithium in hexane 5.9 ml (2.5 M. 14.6 mmol) was added to a stirred solution of acetone oxime 0.55 g (7.3 mmol) in dry THF (15 ml) at 0 °C under nitrogen. After l hour, a solution of 1.65 g (5.62 mmol) 30- (4 -Chlorophenyl) -20- (carbomethoxy) tropane in 10 ml dry was added dropwise with stirring at 0°C. The solution was allowed to warm to room temperature 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 C0 3 (10 ml) and extracted thrice with 10 ml methylene chloride. The combined organic layers were dried (Na 2 S0 4 ) , 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 (46%) of pure isoxazole RTI-165 which was further purified by crystallization from methylene chloride/hexane: *H NMR (CDC1 3 ) δ 1.71 (m, 3 H) , 2.10 (m, 3 H) , 2.18 (s, 3 H) , 2.24 (a, 3 H) , 3.20 (m, 2 H) , 3.32 (m, 2 H) , 6.18 (S, 1 H) , 6.9 (d, J = 8 Hz, 2 H),7.14 (d, J = 8, Hz , 2 H) ; IR (CC1 4 ) 2950, 1590, 1490, 1420, 1350, 1020, 910 cm "1 ; mp 154-156°C; Anal calcd for C, β H 21 N 2 0Cl ; C = 68.28, H = 6.68, N = 8.84, Cl = 11.19; found C = 68.22, H = 6.69, N = 8.87, Cl = 11.19; [α] D - 125.58° (C = 0.43, MeOH) . The isoxazole was crystallized as the hydrochloride salt: : H NMR (MeOD) δ 2.04 (s, 3 H) , 2.19 (m, 1 H) , 2.30 (m, 1 H) , 2.48 (m, 2 H) , 2.60 (m, 1 H) , 2.70 (m, 1 H) , 2.90 (s, 3 H) , 3.68 (m, 1 H) , 3.81 (m, 1 H) , 4.04 (m, 1 H) , 4.15 (m, 1 H) , 5.55 (s, 1 H) , 7.04 (d, J = 8 Hz, 2 H) , 7.14 (d, J = 8 Hz, 2 H) ; mp >235°C (dec); Anal calcd for C H 22 C1 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; [a] D -102.89° (c = 0.46, MeOH) . EXAMPLE 16 30- ( -Methylphenyi) -20- (3-mβthyliaoxazol-5-yl) tropane Hydrochloride (RTI-171) Reaction of 1.09 g (4 mmol) of 30- (4 -Methylphenyi) -20- (carbomethoxy) tropane as described above for RTI-165 gave after workup 1.21 g crude isoxazole. Purification of the crude by flash column chromatography (15% CMA in methylene chloride) gave 0.73 g (62%) pure isoxazole (RTI-171): -H NMR (CDCl,) δ 1.73 (m, 3 H) , 2.11 (m, 3 H) , 2.17 (s, 3 H) , 2.23 (s, 3 H) , 2.25 is, 3 H) , 3.2Q (m, 2 H) , 3.32 (m, 2 H) , 6.13 (s, 1 H) , 6.97 (m, 4 H) ; IR (CC1 4 ) 2935, 2785, 1590, 1510, 1460, 1421, 1350, 1125,1010, 910 cm "1 . The isoxazole was crystallized as the hydrochloride salt: : H NMR (MeOD) δ 2.01 (a, 3 H) , 2.24 (a, 3 H) , 2.32 (m, 2 H) , 2.42 (m, 4 H) , 2.81 (s, 3 H) , 3.61 (m, 1 H) , 3.78 (m, 1 H) , 4.03 (ra, 1 H) , 4.15 (m, 1 H) , 5.45 (s, 1 H) , 6.96 (m, 4 H) ; mp 277°C; Anal calcd for C 19 H 25 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, Cl = 10.56; [α] 0 -107.28° (c = 0.71, MEOH) . EXAMPLE 17 30- (4-Iodophenyl) -20- (3-methyliaoxazol-5-yl) tropane Hydrochloride (RTI-180) Reaction of 0.73 g (1.9 mmol) of 30- (4-Iodophenyl) -20- (carbomethoxy) tropane as described above for RTI-165 gave after workup 0.77 g of crude isoxazole. Purification of the crude by flash column chromatography (5% CMA80 in methylene chloride) gave 0.37 g (49%) of pure isoxazole RTI-180: 'H NMR (CDC1 3 ) δ 1.71 (m, 3 H) , 2.12 (m, 3 H) , 2.18 (a, 3 H) , 2.24 (s, 3 H) , 3.17 (m, 2 H) , 3.33 (m, 2 H) , 6.18 (a, 1 H) , 6.74 (m, 2 H) , 7.49 (m, 2 H) ; IR (CHCl j ) 2940, 1600, 1485, 1450, 1420, 1355 cm -1 . The isoxazole was crystallized as the hydrochloride salt: -H NMR (MeOD) δ 2.11 (s, 3 H), 2.50 (m, 6 H), 2.89 (s, 3 H) , 3.70 (m, 1 H) , 3.90 (m, 1 H) , 4.14 (m, 1 H) , 4.22 (m, 1 H) , 5.66 (s, 1 H) , 6.96 (m, 2 H) , 7.56 (ra, 2 H) ; mp >235°C (dec); Anal calcd for C 1B H 22 ClIN 2 O-0.25H 2 0 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; I = 56.46; [αr] D -94.57° (c = 0.39, MeOH). EXAMPLE 18 30- ( -Chlorophenyl) -20- ( 3 -phenyliβoxazol - 5 - yl ) tropane Hydrochloride (RTI-177) Reaction of 1.18 g (4 mmol) of 30- (4 -Chlorophenyl) -20- (carbomethoxy) tropane 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% (ether/triethylamine 9 : l) in hexane] gave 0.75 g (50%) of pure isoxazole RTI-177 which was further purified by crystallizing from ether/petroleum ether: l U NMR (CDClj) δ 1.74 (m, 3 H) , 2.22 (m, 3 H) , 2.27 (s, 3 H) , 3.24 (m, 2 H) , 3.36 (m, 2 H) , 6.80 (s, 1 H) , 6.94 (m, 2 H) , 7.12 (m,2 H) , 7.40 (m, 3 H) , 7.76 (m, 2 H) ; IR (CHC1 3 ) 2940, 1600, 1590, 1490, 1450, 1405, 1350 cm "1 . The isoxazole was crystallized as the hydrochloride salt: L H NMR (MeOD) δ 2.35 (m, 6 H) , 2.84 (s, 3 H) , 3.73 (m, 1 H) , 4.09 (m, 1 H) , 4.21 (m, 1 H) , 6.12 (a, 1 H) , 7.14 (m, 4 H) , 7.34 (m, 3 H) , 7.57 (m, 2 H) ; mp 287°C; Anal calcd for C 23 H 2« C1 2 IN 2 0- 0.25H 2 0 C = 65.79, H = 5.88, N 6.67, Cl = 16.89; found C = 65.94, H = 5.79, N = 6.68, Cl = 17.00; [a] 0 -97.5° (c = 0.28, MeOH). E MPLE 19 30- (4-Methylphenyl) -20- ( 3 -phβnylisoxazol - 5 -yl ) tropane Hydrochloride (RTI -176) Reaction of 1.09 g (4 mmol) of 30- (4 -Methylphenyi) -20- (carbomethoxy) tropane as described above for RTI-165 gave after work up 1.56 g of crude isoxazole. Purification of the crude by flash column chromatography [25% (ether/triethylamine 9 : l) in hexane] gave 1.1 g (77%) of pure isoxazole RTI -176 which was further purified by crystallizing from methylene chloride/hexane: X H NMR (CDC1 3 ) δ 1.76 (m, 3 H) , 2.23 (m, 3 H) , 2.24 (s, 3 H) , 2.27 (s, 3 H) , 3.23 (m, 2 H) , 3.36 (m, 2 H) , 6.74 (s, 1 H) , 6.93 (m, 4 H) , 7.41 (m,3 H) , 7.76 (m, 2 H) ; IR (CC1 « ) 2935, 1590, 1455, 1410, 1215 cm "1 The isoxazole was crystallized as the hydrochloride salt: X H NMR (MeOD) δ 2.08 (m, 1 H) , 2.15 (s, 3 H) , 2.45 (m, 5 H) , 2.84 (s, 3 H) , 3.68 (m, 1 H) , 3.88 (m, 1 H) , 4.07 (m, 1 H) , 4.22 (m, 1 H) , 5.97 (s, 1 H) , 7.0 (m, 4 H) , 7.33 (m, 3 H) , 7.54 (m, 2 H) ; mp 270-295°C (dec); Anal calcd for C 24 H 27 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; [α] D -102.22 (c = 0.68, MeOH). EXAMPLE 20 30- (4-Iodophenyl) -20- (3-phenylisoxazol-5-yl) tropane Hydrochloride (RTI-181) Reaction of 0.73 g (1.9 mmol) of 30- (4- Iodophenyl) -20- (carbomethoxy) tropane as described above for RTI-181 gave after workup 1.46 g of crude isoxazole. Purification of the crude by flash column chromatography [20% (ether/triethylamine 9 : 1) in hexane] gave 0.5 g (56%) of pure isoxazole RTI-181 which was further purified by crystallizing from methylene chloride/hexane: l H NMR (CDClj) δ 1.72 (m, 3 H) , 2.15 (m, 2 H) , 2.28 (s, 3 H) , 3.22 (m, 2 H) , 3.35 (m, 2 H) , 6.74 (m, 2 H) , 6.79 (s, 1 H) , 7.44 (m, 5 H) , 7.75 (m, 2 H) ; IR (CHC1 3 ) 2940, 1580, 1480, 1475, 1 450, 1400, 1355, 1005 cm "1 The isoxazole was crystallized as the hydrochloride salt: 1 H NMR (MeOD) ό 2.54 (m, 6 H) , 2.92 (a, 3 H) , 3.79 (m, 1 H) , 4.05 (m, 1 H) , 4.19 (m, 1 H) , 4.33 (m, 1 H) , 6.18 (s, 1 H) , 7.02 (m, 2 H) , 7.43 (m, 3 H) , 7.63 (m, 4 H) ; mp >267°C (dec); Anal calcd for C 23 H 24 C1IN 2 0 • 0.5H 2 0 C = 53.55, H = 4.89, N = 5.43, Cl = 13.75; I = 49.21: found C = 53.75, H = 4.87, N = 5.41, Cl = 13.68; I = 48.95; [ot] D -91.11° (c = 0.43, MeOH). SXAMPLg 2 Biochemistry of 30- (Substituted phenyl) -20- (heterocyclic) tropanβθ Inhibition of radioligand binding data at the dopamine, serotonin, and norepinephrine transporters are listed in Table II, III and IV. Table II 3β-(Substituted-phenyl)-2β-(heterocyclic)tropanes 1C S0 (nM) Code J2Δ_ _UE_ 5 HT NE/DA 5-HT/D Name Het [ 3 H]-WIN 35,428 [ 3 H]-nisoxetine 3 H]-paroxetine Ratio Ratio RTI-200 Cl 15.3 ±2.43 4142 ±466 18.417±1509 271 1203 RTI- 199 X N-XN Λ CH 3 35.9±3.4 24.321 ±3822 51,460±4513 677 1434 RTI-202 Cl 1.37 ±0.14 403 ±30 1119±120 294 817 RTi-219 Cl 5.71 ±0.36 8563 ±824 10,342±76 1500 1811 TABLE III Comparison of Transporter Binding Potencies 5-H = serotonin DA = dopamine NE = norepinephrine *Aropax; Seroxat; see Merck Index. 3β-(Substituted pheny l)-2β-(substituted)tropanes C 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.

Claims: CLAIMS : A compound of the formula wherein R s CH 3 , C 2 H 5 , CH 2 CH 3 CH 3 , or CH(CH 3 ) 2 , CH=CH 2 , CH 3 -C=CH 2 , CH 2 CH=CH 2 , CH=CHCH 3 , R t is CH 3 , CH 2 C 6 H S , (CH 2 ) 2 C 6 H 5 , (CH 2 ) 3 C 6 H 5 , or wherein X s H, 0CH 3 , or Cl and Y is H, OCH 3 , or Cl, and n= l-θ The compound of Claim 1, wherein R x is CH 3 The compound of Claim 2, wherein R is C 2 H 5 The compound of Claim 2, wherein R is CH 2 CH 3 CH 3 , The compound of Claim 2, wherein R is CH(CH 3 ] 6. The compound of Claim 1, wherein R is C 2 H 5 . 7. The compound of Claim 6 , wherein R j, is CH 2 C 6 H 5 . 8. The compound of Claim 6, wherein R : is (CH 2 ) 2 C 6 H 5 9. The compound of Claim 6, wherein R t is (CH 2 ) 3 C 6 H 5 10. The compound of Claim 6, wherein R is 11. The compound of Claim 10, wherein X is H and Y is 0CH 3 . 12. The compound of Claim 10, wherein X is OCH 3 and Y is H. 13. The compound of Claim 10, wherein X is OCH, and Y is OCH 3 . 14. The compound of Claim 10, wherein X is Cl and Y is H. 15. The compound of Claim 10, wherein X is H and Y is Cl . 16. The compound of Claim 10, wherein X is Cl and Y s Cl . 17. A method for treating psychostimulant abuse, by administering to a patient in need of such treatment a pharmaceutically effective amount of the compound of Claim 1. 18. A method for inhibiting the action of a psychostimulant, by administering to a patient in need of such treatment a psychostimulant-inhibiting amount of the compound of Claim 1. 19. A method for inhibiting neurotransmitter re-uptake by administering to a patient n need of such treatment a neurotransmitter transporter- inhibiting amount of the compound of Claim 1. 20. A method for treating neurodegenerative disorders, by administering to a patient in need of such treatment a pharmaceutically effective amount of the compound of Claim l. 21,- A method for treating depression, by administering to a patient in need of such treatment a pharmaceutically effective amount of the compound of Claim 1. 22. A method for treating anorexia, by administering to a patient m need of such treatment a pharmaceutically effective amount of the compound of Claim 1. 23. The method of Claim 17, wherein the compound is RTI- 4229-31, 32, 51, 55, 83, 96, 97, 98, 101, 105, 108, 110, 111, 112, 116, 121, 122, 127, 132, 139, 140, 142, 145, 146, 147, 150, 153, 178, 188, 189, 190, 191, 193, 195, 199, 200, 203, 204, 205, 206, 219, 230, 239, 240, 241, 242, 251, 252, 274, 277, 278, 279, 280, 281, 282, 283, 286, 287, 296, 304, 305, 307, 309, 318, or 330. 24. The method of Claim 17, wherein the compound is 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 or 353. 25. The method of Claim 18, wherein the compound is RTI- 4229-31, 32, 51, 55, 83, 96, 97, 98, 101, 105, 108, 110, 111, 112, 116, 121, 122, 127, 132, 139, 140, 142, 145, 146, 147, 150, 153, 178, 188, 189, 190, 191, 193, 195, 199, 200, 203, 204, 205, 206, 219 r 230, 239, 240, 241, 242, 251, 252, 274, 277, 278, 279, 280, 281, 282, 283, 286, 287, 296, 304, 305, 307, 309, 318, or 330. 26. The method of Claim 18, wherein the compound is 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 or 353 . 27. The method of Claim 19, wherein the compound is RTI- 4229-31, 32, 51, 55, 83, 96, 97, 98, 101, 105, 108, 110, 111, 112, 116, 121, 122, 127, 132, 139, 140, 142, 145, 146, 147, 150, 153, 178, 188, 189, 190, 191, 193, 195, 199, 200, 203, 204, 205, 206, 219, 230, 239, 240, 241, 242, 251, 252, 274, 277, 278, 279, 280, 281, 282, 283, 286, 287, 296, 304, 305, 307, 309, 318, or 330. 28. The method of Claim 19, wherein the compound is 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 or 353. 29. The method of Claim 20, wherein the compound is RTI - 4229-31,. 32, 51, 55, 83, 96, 97, 98, 101, 105, 108, 110, 11, 112, 116, 121, 122, 127, 132, 139, 140, 142, 145, 146, 147, 150, 153, 178, 188, 189, 190, 191, 193, 195, 199, 200, 203, 204, 205, 206, 219, 230, 239, 240, 241, 242, 251, 252, 274, 277, 278, 279, 280, 281, 282, 283, 286, 287, 296, 304, 305, 307, 309, 318, or 330. 30. The method of Claim 20, wherein the compound is 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 or 353. 31. The method of Claim 21, wherein the compound is RTI- 4229-31, 32, 51, 55, 83, 96, 97, 98, 101, 105, 108, 110, 111, 112, 116, 121, 122, 127, 132, 139, 140, 142, 145, 146, 147, 150, 153, 178, 188, 189, 190, 191, 193, 195, 199, 200, 203, 204, 205, 206, 219, 230, 239, 240, 241, 242, 251, 252, 274, 277, 278, 279, 280, 281, 282, 283, 286, 287, 296, 304, 305, 307, 309, 318, or 330. 32. The method of Claim 21, wherein the compound is 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 or 353. 33. The method of Claim 32, wherein the compound s RTI' 353. 34 . A compound of the formula : wherein R, =hydrogen, C[. 5 alkyl, X=H, C,. 6 alkyl, C 3 . g cycloalkyl, C alkoxy, C,^ alkynyl, halogen, amino or acylamido Z=H, I, Br, Cl , F, CN, CF 3 , NO,, N 3 , OR,, CONH,, C0 2 R,, C,. 6 alkyl, NR 4 5 , NHCOR,, or NHCC R^, and R,, is C 1-6 alkyl, phenyl, or C,. 6 alkyl substituted phenyl. 35. A compound of the formula: wherein R, = hydrogen or C,. 5 alkyl, Y=H, OCH 3 or Cl, and Z=H, I, Br, Cl, F, CN, CF 3 , N0 2 , N 3 , OR,, CONH,, CO,R,, C,^ alkyl, NR 4 R j , NHCOR,, NHCCRs, or — C=C-R, 36. A compound of the formula: R,, R 2 , R 3 = H or C, ;4 alkyl -81- wherein R, = hydrogen or C,. 5 alkyl, X=H, C,. 6 alkyl, C 3 . 8 cycloalkyl, C M alkoxy, C,_ 6 alkynyl, halogen, amino or acylamido, Y = H, OCH 3 orCl, Z = H, I, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , OR,, CONH 2 , CO,R,, C 16 alkyl, NR 4 R 5 , NHCORs, NHCO^, or ,R2 C=C C-CH=C Ri R 3 R 2 ' R 3 — C=C — R| R,,R 2 , R 3 = HorC 14 aflcyl and M=(CH 2 )., wherein x=l-8, -CH=CH- or -C≡C-. 37. The method of Claim 17, wherein the compound is: wherein R,=hydrogen or Cj. 5 alkyl, X=H, C,. 6 alkyl, C 3 . g cycloalkyl, C alkoxy, C, .6 alkynyl, halogen, amino or acylamido, Z=H, I, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , OR,, CONH 2 , CO 2 R„ C, 6 alkyl, NR t,, NHCORj, or NHCO 2 R^, and R b is C,. 6 alkyl, phenyl or C,^ alkyl substituted phenyl; R,= hydrogen or C,. 5 alkyl, Y=H, OCH 3 orCl, and Z=H, I, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , OR,, CONH 2 , CO 2 R„ C, .6 alkyl, NR.R J , NHCOR,, NHCO^, or wherein R, = hydrogen or C,. 5 alkyl, X = H, C alkyl, C 3 . g cycloalkyl, C alkoxy, C,. 6 alkynyl, halogen, amino or acylamido, Y=H, OCH 3 orCl, Z = H, I, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , OR,, CONH,, CO,R,, C I6 alkyl, NR.R,, NHCOR 5 , NHCO^, or — C=C— Ri R,,R 2 , R 3 = HorC, 4 alkyl and M = (CH 2 )., wherein x= l-8, -CH=CH- or -C≡C-. 38. The method of Claim 18, wherein the compound is: wherein R, = hydrogen or C,. 5 alkyl, X = H, C,^ alkyl, C 3.g cycloalkyl, C alkoxy, C,. 6 alkynyl, halogen, amino or acylamido, Z = H, I, Br, Cl, F, CN, CF 3 , N0 2 , N 3 , OR,, CONH 2 , CO 2 R,, C 1 b alkyl, NR^, NHCOR,, NHCO^, and R b is C,. 6 alkyl, phenyl or C,^ alkyl substituted phenyl; wherein R, = hydrogen or C,_ 5 alkyl, Z=H, I, Br, Cl, F, CN, CF 3 , NO 2 , N 3> OR,, CONH 2 , CO 2 R„ C w alkyl, NR^, NHCOR,, NHCOA, or where R, =hydrogen or C,., alkyl, X = H, C,^ alkyl, C 3 . 8 cycloalkyl, C alkoxy, C,^ alkynyl, halogen, amino or acylamido, Y=H, OCH j or Cl, Z=H, I, Br, Cl, F, CN, CF 3 , NO,, N 3 , OR,, CONH,, C0 2 R„ C w alkyl, NR.R,, NHCOR,, NHCO,^, or — C=C— R, and R,, R 2) R 3 = H or C 1 . 4 aD yl M = (CH 2 )„ wherein x= l-8, -CH=CH- or -C=C-. 39. The method of Claim 19, wherein the compound is: wherein R,=hydrogen or Cι_ 5 alkyl, X=H, C,. 6 alkyl, Cj -g cycloalkyl, C alkoxy, C,. 6 alkynyl, halogen, amino or acylamido. Z=H, I, Br, Cl, F, CN, CF 3 , N0 2 , N 3 , OR,, CONH,, CO,R, , C, 6 alkyl, N^R,, NHCOR, or NHCO^, and R b is C,. 6 alkyl, phenyl or C,^ alkyl substituted phenyl; wherein R, = hydrogen or C,. 5 alkyl, Z = H, I, Br, Cl , F, CN, CF 3 , NO,, N 3 , OR,, CONH,, CO,R„ C, 6 alkyl, NR 4 R„ NHCOR,, NHCO,^, or — C=C-R, R|, R 2 , R 3 = H or C| 4 alkyl or wherein R ( = hydrogen or C x . $ alkyl, X=H, C,_ 6 alkyl, Cj. g cycloalkyl, C alkoxy, C,. 6 alkynyl, halogen, amino or acylamido, Z=H, I, Br, Cl , F, CN, CF 3 , NO,, N 3 , OR,, CONH,, CO 2 R,, C,. 6 alkyl, NR 4 Rs, NHCOR,, NHCO^, or — C=C — R, R,, R 2 , R 3 = H or C 1 4 alkyl and M = (CH 2 )„ wherein x= l-8, -CH=CH- or -C≡C-. 40. The method of Claim 20, wherein the compound is: wherein R, =hydrogen or C,. 5 alkyl, X=H, C,. 6 alkyl, C 3 . g cycloalkyl, C alkoxy, C,^ alkynyl, halogen, amino or acylamido, Z=H, I, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , OR,, CONH 2 , CO 2 R,, C w alkyl, NR 4 R„ NHCOR,, NHCO^, and R b is C alkyl, phenyl or C,^ alkyl substituted phenyl; wherein R, =hydrogen or C,., alkyl, Y=H, OCH 3 or Cl, and -87- SUBSηTUTE SHEET (RULE 26) Z = H, I, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , OR,, CONH,, C0 2 R,, C, .6 alkyl, NR 4 R„ NHCOR,, NHCO^, or - R,, wherein R, =hyd X = H, C,. 6 alkyl, C 3 . g cycloalkyl, C alkoxy, C,. 6 alkynyl, halogen, amino or acylamido, Y = H, OCH 3 or Cl, Z=H, I, Br, Cl, F, CN, CF 3 , NO,, N 3 , OR,, CONH 2 , CO 2 R,, C^ alkyl, NR 4 R„ NHCOR,, NHCO^, or — C=C-R, R,, R 2 , R 3 = H or C 1 4 alkyl and M = (CH 2 ) X , wherein x= 1-8, -CH=CH- or -C≡C-. 41. The method of Claim 21 , wherein the compound is: wherein R, = hydrogen or C,., alkyl, X=H, C,. 6 alkyl, C 3 . 8 cycloalkyl, C alkoxy, C,. 6 alkynyl, halogen, amino or acylamido, Z = H, I, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , OR,, CONH,, CO,R,, C, .6 alkyl, NR 4 R„ NHCOR, or NHCO.R*, and R b is C,. 6 alkyl, phenyl or C,. 6 alkyl substituted phenyl; wherein R, = hydrogen or C,. 5 alkyl, Y = H, OCH 3 or Cl, and Z =H, I, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , OR,, CONH 2 , CO 2 R,, C,^ alkyl, NR.R,, NHCOR,, NHCOjR,, or X=H, C,. 6 alkyl, C 3 . g cycloalkyl, C M alkoxy, C, 6 alkynyl, halogen, amino or acylamido, Y=H, OCH j OrCl, Z = H, I, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , OR,, CONH 2 , CO,R,, C, 6 alkyl, NR 4 R„ NHCOR,, — C=C— R, and Rι,R 2 , R 3 = HorC 14 alkyl M = (CH 2 )„ wherein x=l-8, -CH=CH- or -C^C-. 42. The method of Claim 22, wherein the compound is: wherein R,=hydrogen or C,. s alkyl, X = H, C,^ alkyl, C 3 . g cycloalkyl, C alkoxy, C,^ alkynyl, halogen, amino or acylamido, Z=H, I, Br, Cl, F, CN, CF 3 , NO 2 , N 3> OR,, CONH 2 , CO 2 R„ C,. 6 alkyl, NR 4 R„ NHCOR,, NHCOjR,;, and R b is C,^ alkyl, phenyl or C, 6 alkyl substituted phenyl; wherein R,=hydrogen or C,. 5 alkyl, Y=H, OCH 3 orCl, and Z = H, I, Br, Cl, F, CN, NR 4 R„ NHCOR,, wherein R, = hydrogen or C,., alkyl, X=H, C, 6 alkyl, C 3.g cycloalkyl, C alkoxy, C,. 6 alkynyl, halogen, amino or acylamido, Y = H, OCH 3 orCl, Z=H, I, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , OR,, CONH,, CO 2 R,, C, .6 alkyl, NR 4 R„ NHCOR,, NHCO^, or — C=C— R, R,,R 2 ,R 3 = HorC 14 alkyl and M=(CH 2 )„ wherein x = l-8, -CH=CH- or -C≡C-.

Inventors: ABRAHAM PHILIP, BOJA JOHN W, CARROLL FRANK I, KUHAR MICHAEL J, LEWIN ANITA H, ABRAHAM, PHILIP, BOJA, JOHN, W., CARROLL, FRANK, I., KUHAR, MICHAEL, J., LEWIN, ANITA, H.
Applicants: RES TRIANGLE INST, RESEARCH TRIANGLE INSTITUTE
Application year: 1997
Main classification: A61K31
IPC codes: A61K31, A61P25, A61P43, C07D451