AU4720499A

AU4720499A - 6-(4-arylalkylpiperazin-1-yl)benzodioxane and 6-(4-arylalkylpiperazin-1-yl)chromane derivatives: dopamine receptor subtype specific ligands

Info

Publication number: AU4720499A
Application number: AU47204/99A
Authority: AU
Inventors: Andrew Thurkauf; Jennifer N. Tran
Original assignee: Neurogen Corp
Current assignee: Neurogen Corp
Priority date: 1998-06-30
Filing date: 1999-06-25
Publication date: 2000-01-17
Also published as: EP1091949A2; WO2000000489A2; WO2000000489A3; JP2002519350A; CA2336089A1

Description

WO 00/00489 PCT/US99/14426 6-(4-Arylalkylpiperazin-1-yl)benzodioxane and 6-(4 Arylalkylpiperazin-1-yl)chromane Derivatives: Dopamine Receptor Subtype Specific Ligands 5 BACKGROUND OF THE INVENTION Field of the Invention This invention relates to 6-(4-arylalkylpiperazin-1 yl)benzodioxanes and 6-(4-arylalkylpiperazin-1-yl)chromanes and pharmaceutical compositions containing such compounds. It also 10 relates to the use of such compounds in the treatment or prevention of psychotic disorders such as schizophrenia and other central nervous system diseases. Description of the Related Art The therapeutic effect of conventional antipsychotics, 15 known as neuroleptics, is generally believed to be exerted through blockade of dopamine receptors. However, neuroleptics are frequently responsible for undesirable extrapyramidal side effects (EPS) and tardive dyskinesias, which are attributed to blockade of D2 receptors in the striatal region of the brain. 20 The dopamine D 4 receptor subtype has recently been identified (Nature, 350: 610 (Van Tol et al., 1991) ; Nature, 347: 146 (Sokolof f et al. , 1990) ) . Its unique localization in limbic brain areas and its differential recognition of various antipsychotics indicates that the D4 receptor plays a major 25 role in the etiology of schizophrenia. Selective D 4 antagonists are considered effective antipsychotics free from the -1- WO 00/00489 PCT/US99/14426 neurological side effects displayed by conventional neuroleptics. -2- WO 00/00489 PCTIUS99/14426 SUMMARY OF THE INVENTION This invention provides novel compounds-of Formula I which interact with dopamine subtypes. Accordingly, a broad embodiment of the invention is directed to a compound of 5 Formula I: R2 O0 N R6 R 7 R, R3 R4 X N N-A 4 R8 R9 I or pharmaceutically acceptable addition salts thereof wherein: A is C 1

-C

4 alkylene optionally substituted with C 1

-C

2 alkyl; 10 R 1 , R 2 , R 3 , R4 and R 5 independently represent hydrogen, halogen, Ci-C 6 alkyl, C 1

-C

6 alkoxy, C 1

-C

6 alkylthio, hydroxy, amino, mono- or di(C 1

-C

6 )alkylamino, cyano, nitro, perfluoroalkyl or perfluoroalkoxy; and

R

6 , R 7 , R 8 , and R 9 independently represent hydrogen or C1-C6 15 alkyl; and X is oxygen, a bond, C 1

-C

2 alkylene, or methyleneoxy. Dopamine D 4 receptors are concentrated in the limbic system (Science, 265: 1034 (Taubes, 1994)) which controls cognition and emotion. Therefore, compounds that interact with 20 these receptors are useful in the treatment of cognitive disorders. Such disorders include cognitive deficits which are -3- WO 00/00489 PCTIUS99/14426 a significant component of the negative symptoms (social withdrawal and unresponsiveness) of schizophrenia. Other disorders include those involving memory impairment or attention deficit disorders. 5 Compounds of the present invention demonstrate high affinity and selectivity in binding to the D 4 receptor subtype. These compounds are therefore useful in treatment of a variety of neuropsychological disorders, such as, for example, schizophrenia, psychotic depression and mania. Other dopamine 10 mediated diseases such as Parkinsonism and tardive dyskinesias can also be treated directly or indirectly by modulation of D 4 receptors. Compounds of this invention are also useful in the treatment of depression, memory-impairment or Alzheimer's 15 disease by modulation of D 4 receptors since they exist selectively in areas known to control emotion and cognitive functions. Thus, in another aspect, the invention provides methods for treatment and/or prevention of neuropsychochological or 20 affective disorders including, for example, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, memory impairment, cognitive deficits, Parkinson-like motor disorders, e.g., Parkinsonism and dystonia, and motion disorders related to the use of 25 neuroleptic agents. In addition, the compounds of the -4- WO 00/00489 PCT/US99/14426 invention are useful in treatment of depression, memory impairment or Alzheimer's disease. Further, the compounds of the present invention are useful for the treatment of other disorders that respond to dopaminergic blockade, e.g., 5 substance abuse and obsessive compulsive disorder. These compounds are also useful in treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents. In yet another aspect, the invention provides 10 pharmaceutical compositions comprising compounds of Formula I. In another aspect, the invention provides intermediates useful in the preparation of compounds of Formula I. -5- WO 00/00489 PCTIUS99/14426 DETAILED DESCRIPTION OF THE INVENTION As mentioned above, the invention -encompasses 6-(4 Arylalkylpiperazin-1-yl) benzodioxane and 6- (4 Arylalkylpiperazin-1-yl)chromane derivatives of Formula I. 5 Preferred compounds of Formula I are those where X is oxygen or methylene. Still other preferred compounds of Formula I are those where R 1 , R 2 , and R. are hydrogen and R 3 and R 4 are independently hydrogen, halogen, CI-C 6 alkyl, or C 1

-C

6 alkoxy. Other preferred compounds of Formula I are those where R , R 7 , 10 R., and R 9 are independently hydrogen, methyl, or ethyl. Other preferred compounds of Formula I are those where A is methylene or ethylene, each of which is optionally substituted independently with a C 1

-C

2 group. More preferably, A is methylene. 15 Preferred compounds of the invention include those of Formula IA: R2 O R1 R3 X N N : 4 R5 IA wherein: 20 R 1 , R 2 , R 3 , R4 and R 5 independently represent hydrogen, halogen,

C

1

-C

6 alkyl, Ci-C 6 alkoxy, C 1

-C

4 alkylthio, hydroxy, amino, -6- WO 00/00489 PCT/US99/14426 mono- or di (C 1 -C) alkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy; and X is oxygen, a bond, methyleneoxy, or C 1

-C

2 alkylene. 5 Preferred compounds of Formula IA are those where R 1 , R 2 ,

R

3 , R 4 , and R 5 independently represent hydrogen, halogen, Ci-C 6 alkyl, or C 1

-C

6 alkoxy. Other preferred compounds of Formula IA are those where

R

1 , R 2 , and R 5 are hydrogen. 10 More preferred compounds of Formula IA are those where R 1 ,

R

2 , and R. are hydrogen and R 3 and R 4 independently represent hydrogen, halogen, C 1

-C

6 alkyl, or C 1

-C

4 alkoxy, where not both

R

3 and R 4 are hydrogen. Particularly preferred compounds of Formula IA are those 15 where R 3 and R 4 independently represent hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, or ethoxy, where not both R 3 and R 4 are hydrogen. Other particularly preferred compounds of Formula IA are those where X is a bond or methyleneoxy and R 3 and R 4 20 independently represent hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, or ethoxy. The present invention further encompasses compounds of Formula II: -7- WO 00/00489 PCT/US99/14426 R2 N R, R3 R5 II wherein R 1 , R 2 , R 3 , R4 and R 5 are defined as above for Formula I. 5 Preferred compounds of Formula II are those where R 1 , R 2 ,

R

3 , R 4 , and R. independently represent hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 alkoxy. Other preferred compounds of Formula II are those where

R

1 , R 2 , and R. are hydrogen. 10 More preferred compounds of Formula II are those where R 1 ,

R

2 , and R. are hydrogen and R 3 and R 4 independently represent hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 4 alkoxy, where not both

R

3 and R 4 are hydrogen. Particularly preferred compounds of Formula II are those 15 where R 3 and R 4 independently represent hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, or ethoxy, where not both R 3 and R 4 are hydrogen. The present invention further encompasses compounds of 20 Formula III: -8- WO 00/00489 PCTIUS99/14426 R2 O R1 R3 R5 N N4 III wherein R 1 , R 2 , R 3 , R4 and R 5 are defined as above for Formula I. 5 Preferred compounds of Formula III are those where R 1 , R 2 ,

R

3 , R 4 , and R 5 independently represent hydrogen, halogen, C 1

-C

6 alkyl, or C 1

-C

6 alkoxy. Other preferred compounds of Formula III are those where R1, R 2 , and R 5 are hydrogen. 10 More preferred compounds of Formula III are those where

R

1 , R 2 , and RS are hydrogen and R 3 and R 4 independently represent hydrogen, halogen, C 1

-C

6 alkyl, or Ci-C 4 alkoxy, where not both

R

3 and R 4 are hydrogen. Particularly preferred compounds of Formula III are those 15 where R 3 and R 4 independently represent hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, or ethoxy, where not both R 3 and R 4 are hydrogen. The invention also provides intermediates useful in 20 preparing compounds of Formula I. These intermediates have Formulae IV-A, IV-B, IV-C, IV-D, IV-E, and IV-F. -9- WO 00/00489 PCTIUS99/14426 0 N R NH Rg IV-A N 6 R 7 R8" NH Rg 5 IV-B O: N R R8- NH R TV- C 0 O N R NH 10 R 9 IV-D -10- WO 00/00489 PCT/US99/14426 0 N NH

R

9 IV-E In each of Formulae IV-A-F, R 6 , R 7 , R 8 , and R 9 independently represent hydrogen or Cl-C, alkyl. Particularly 5 preferred compounds of Formulae IV-A-F, are those where R 6 , R 7 , R., and R, are all hydrogen. In certain situations, the compounds of Formula I may contain one or more asymmetric carbon atoms, so that the 10 compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. In these situations, the single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates 15 can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column. Representative compounds of the present invention, which are encompassed by Formula I, include, but are not limited to 20 the compounds in Table 1 and their pharmaceutically acceptable acid addition salts. In addition, if the compound of the invention is obtained as an acid addition salt, the free base -11- WO 00/00489 PCT/US99/14426 can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic 5 solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Non-toxic pharmaceutical salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, 10 formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic,

HOOC-(CH

2 )n-COOH where n is 0-4, and the like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts. 15 The present invention also encompasses the acylated prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds 20 encompassed by Formula I. Where a compound exists in various tautomeric forms, the invention is not limited to any one of the specific tautomers. The invention includes all tautomeric forms of a compound. By "C 1

-C

6 alkyl" or "lower alkyl" in the present invention 25 is meant straight or branched chain alkyl groups having 1-6 -12- WO 00/00489 PCT/US99/14426 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, -pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3 methylpentyl. Preferred Cl-C6 alkyl groups are methyl, ethyl, 5 propyl, butyl, cyclopropyl and cyclopropylmethyl. By "C 1

-C

6 alkoxy" or "lower alkoxy" in the present invention is meant straight or branched chain alkoxy groups having 1-6 carbon atoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, 10 pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3 hexoxy, and 3-methylpentoxy. By the term "halogen" in the present invention is meant fluorine, bromine, chlorine, and iodine. Representative 6-(4-arylalkylpiperazin-1-yl)benzodioxane 15 and 6-(4-arylalkylpiperazin-1-yl)chromanes of the present invention are shown in Table 1. -13- WO 00/00489 PCT/US99/14426 Table 1 F O N N F Compound 1 \N N OMe Compound 2 (0:a

--

\ ICI O N N Cl Compound 3 0 Me N N Me Compound 4 The invention also pertains to the use of compounds of 5 general Formula I in the treatment of neuropsychological disorders. The interaction of compounds of the invention with dopamine receptors is shown in the examples. This interaction results in the pharmacological activity of these compounds. The compounds of general formula I may be administered 10 orally, topically, parenterally, by inhalation or spray or -14- WO 00/00489 PCT/US99/14426 rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, 5 intrasternal injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general formula I and a pharmaceutically acceptable carrier. One or more compounds of general formula I may be present in association with one or more non-toxic 10 pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, 15 dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain 20 one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically 25 acceptable excipients which are suitable for the manufacture of -15- WO 00/00489 PCT/US99/14426 tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding 5 agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action 10 over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium 15 phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of 20 aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for 25 example, lecithin, or condensation products of an alkylene -16- WO 00/00489 PCT/US99/14426 oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters 5 derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, 10 for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, 15 olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral 20 preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting 25 agent, suspending agent and one or more preservatives. -17- WO 00/00489 PCTIUS99/14426 Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. 5 Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, 10 for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for 15 example polyoxyethylene sorbitan monoleate. The emulsions may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a 20 preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents 25 which have been mentioned above. The sterile injectable -18- WO 00/00489 PCT/US99/14426 preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are 5 water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find 10 use in the preparation of injectables. The compounds of general formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient 15 which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. Compounds of general formula I may be administered 20 parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle. -19- WO 00/00489 PCT/US99/14426 Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day -are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active 5 ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient. 10 It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of 15 excretion, drug combination and the severity of the particular disease undergoing therapy. A representative synthesis of the 6-(4-arylalkylpiperazin 1-yl)benzodioxanes and 6-(4-arylalkylpiperazin-1-yl)chromanes of the invention is presented in Scheme I. Those having skill 20 in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention. -20- WO 00/00489 PCT/US99/14426 Scheme I

R

1 R2 R6 CO~ N Ry A-i R3 X N, IV RNH

R

5

R

4 8V Base RR i N R R1 R2 R3 R8-- N A:) R4 I R9 R5 In Scheme I, A, RiR, and X are as defined above for Formula I, and Z is a leaving group. 5 Thus, for example, a 5-piperazinyl-2,3 dihydrobenzo[b]furan (IV, X is a bond), a 1-(1,4-benzodioxan-6 yl)piperazine (IV, X = oxygen), a 1-(chroman-6-yl)piperazine (IV, X = -CH 2 -), or a 7-piperazinyl-2H,3H,4H,5H-benzo[f]oxepin (IV, X is -CH 2

CH

2 -) may be reacted with an appropriately 10 substituted alkylating agent (V), e.g., a benzylic alkylating agent, in the presence of a suitable base to afford a compound of Formula I. The leaving group (Z) on alkylating agent V may be a halide, sulphonate ester or the like. Where they are not 15 commercially available, the compounds of general structure V may be prepared by procedures analogous to those described in literature. The compounds of general structure V are either -21- WO 00/00489 PCT/US99/14426 known or capable of being prepared by the methods known in the art. Those having skill in the art will recognize that the starting material may be varied and additional steps employed to produce compounds encompassed by the present invention. The 5 base employed may be an inorganic base such as potassium carbonate, sodium hydroxide or the like; or an organic base such as triethylamine, pyridine or the like. The disclosures of all articles and references mentioned in this application, including patents, are incorporated herein 10 by reference. The preparation of the compounds of the present invention is illustrated further by the following examples which are not to be construed as limiting the invention in scope or spirit to the specific procedures and compounds described in them. 15 Example 1 1-(1,4-benzodioxan-6-vl)piverazine. A solution of 1,4-benzodioxan-6-amine (2.00 g, 13.2 mmol), bis-(2-choroethyl)amine hydrochloride (3.54 g, 19.8 mmol) and 20 potassium carbonate (1.83 g, 13.2 mmol) in of 20 mL chlorobenzene is heated to reflux for 24 hours. The dark brown reaction mixture is then partitioned between 3N NaOH and methylene chloride. The organic layer is separated, dried over Mg 2 SO4, filtered and concentrated. Purification by flash 25 column chromatography (8% methanol/methylene chloride on -22- WO 00/00489 PCT/US99/14426 silica) provides 0.88 g (30%) of the desired 1-(1,4 benzodioxan-6-yl)piperazine as a white solid (m.p. 138 0 C, TLC Rf 0.37 with 10% methanol/methylene chloride). 5 Example 2 1-(Chroman-6-vl)piperazine. 1. A solution of 4-chromanone (2.00 g, 13.50 mmol) in 20 mL acetic acid is added to a suspension of of zinc dust (20 g) in acetic acid (40 mL). The mixture is heated at 100 *C for 16 10 h. After cooling to room temperature, the excess zinc is filtered off and the solvent is evaporated. The residue was stirred is water (20 mL), basified with NaOH pellets and extracted with ethyl acetate (20 mL). The organic layer is dried over Mg 2 SO,, filtered and concentrated. Purification by 15 flash column chromatography (10% ethyl acetate-hexane) affords 1.63 g (91%) of 4-chroman as a yellow oil, TLC Rf 0.50 (10% ethyl acetate:hexane). 2. 4-chroman (1.63 g, 12.16 mmol) from part 1 of this 20 example is treated with 70% HNO 3 (6 mL) at 15-20 *C. The mixture is stirred at room temperature for 1 hr. The solution is cooled 0 OC with ice water, extracted with ethyl acetate, and concentrated. This crude material is then dissolved in ethanol (50 mL), treated with Raney Nickel (1 g) and 25 hydrogenated for 3h at room temperature. The resulting mixture -23- WO 00/00489 PCT/US99/14426 is filtered, concentrated, and purified by flash column chromatography (20% ethyl acetate-hexane) to afford 0.48 g (26%) of 6-aminochroman as a yellow oil. TLC Rf 0.28 (35% ethyl acetate:hexane). 5 3. A solution of 6-aminochroman from part 2 of this example (0.300 g, 2.013 mmol), bis-(2-choroethyl)amine hydrochloride (0.539 g, 3.020 mmol) and potassium carbonate (0.278 g, 2.013 mmol) in 10 mL chlorobenzene is heated at 10 reflux for 24 h . The dark brown reaction mixture is then partitioned between 3N NaOH and methylene chloride. The organic layer is separated, dried over Mg 2

SO

4 , filtered and concentrated. Purification by flash column chromatography (5% methanol-methylene chloride) affords 0.157 g (36%) of 1 15 (chroman-6-yl)piperazine as a white solid, TLC Rf 0.35 (elution with 10% methanol-methylene chloride). Example 3 F 0 N N-/F 20 1-(1,4-benzodioxan-6-vl)-4-(4-fluorobenzvl)piperazine oxalate A solution of 1-(1,4-benzodioxan-6-yl)piperazine prepared as described in Example 1 (0.146 g, 0.663 mmol) in CH3CN (5 mL) is treated with potassium carbonate (0.458 g, 3.32 -24- WO 00/00489 PCT/US99/14426 mmol ) and 4-fluorobenzyl chloride (0.144 g, 0.995 mmol). The mixture is heated at reflux for 4 hours. The resulting mixture is then cooled to room temperature and washed successively with saturated aqueous NH4Cl (20 mL) and saturated aqueous NaCl (20 5 mL). The organic portion is dried over Mg2SO 4 , filtered and concentrated. Purification by flash column chromatography (30% ethyl acetate-hexane) gives 0.074 g (34%) of 1-(1,4 benzodioxan-6-yl)-4-(4-fluorobenzyl)piperazine as a white solid (TLC Rf 0.35; 30% ethyl acetate:hexane). A solution of this 10 material in 1 mL of ethanol is treated with oxalic acid (0.020 g, 0.225 mmol) and concentrated to give 1-(l-(1,4-benzodioxan 6-yl) -4- (4-fluorobenzyl)piperazine oxalic acid salt (Compound 1) 0.079 g (88%), m.p. 177-179 OC. 15 Example 4 0 Me 1-f\ -jc 1-(chroman-6-vl)-4-(4-methylbenzvl)piperazine oxalate A solution of 1-(chroman-6-yl)piperazine prepared as described in Example 2 (0.157 g, 0.723 mmol) in CH3CN (5 mL) is 20 treated with potassium carbonate (0.500 g, 3.615 mmol) and 4 methylbenzyl chloride (0.102 g, 0.723 mmol) . The mixture is heated at reflux for 4 hours, cooled to room temperature and diluted with CH 2 Cl 2 (20 mL). This mixture is washed -25- WO 00/00489 PCT/US99/14426 successively with saturated aqueous NH 4 Cl (20 mL) and saturated aqueous soduium chloride (20 mL). The organic phase is dried over MgSO 4 and concentrated. Purification by flash chromatography (30 % ethyl acetate-hexane) gives 40 mg (17 %) 5 of the desired 1-(chroman-6-yl)-4-(4-methylbenzyl)piperazine as a white solid, TLC Rf 0.35 (30% ethyl acetate-hexane). A solution of this material in 1 mL of ethanol is treated with oxalic acid (11 mg) and concentrated to give 1-(chroman-6-yl) 4-(4-methylbenzyl)piperazine oxalate (Compound 4) 51 mg, m.p. 10 199 *C. Example 5 The following compounds are prepared essentially according to the procedures set forth above in Examples 3 and 4. 15 (a) 1-(1,4-benzodioxan-6-yl)-4-(4-chlorobenzyl)piperazine oxalate (Compound 3, m.p. 213-215 *C) (b) 1- (1,4-benzodioxan-6-yl) -4- (4-methylbenzyl)piperazine 20 oxalate (Compound 5, m.p. 200-201 *C) (c) 1-(1,4-benzodioxan-6-yl)-4-(4 methoxybenzyl)piperazine oxalate (Compound 6, m.p. 193-195 *C) -26- WO 00/00489 PCTIUS99/14426 (d) 1-(1,4-benzodioxan-6-yl)-4-(3-chlorobenzyl)piperazine oxalate (Compound 7, m.p. 213-215 OC) (e) 1-(1,4-benzodioxan-6-yl)-4-(3 5 methoxybenzyl)piperazine oxalate (Compound 2, m.p. 213-215 *C) (f) 1-(1,4-benzodioxan-6-yl)-4-(2-chlorobenzyl)piperazine oxalate (Compound 8, m.p. 175 *C) 10 (g) 1-(1,4-benzodioxan-6-yl)-4-(2 methoxybenzyl)piperazine oxalate (Compound 9, m.p. 143 OC) (h) 1- (1, 4-benzodioxan-6-yl) -4-benzylpiperazine hydrochloride (Compound 10, m.p. 143-145 *C) 15 (i) 1-(chroman-6-yl)-4-(4-chlorobenzyl)piperazine oxalate (Compound 11). Example 6 20 Assays For D 2 , D 3 and D 4 Receptor Binding Activity The pharmaceutical utility of compounds of this invention is indicated by the assays for dopamine receptor subtype affinity described below. Pellets of COS cells containing recombinantly produced D 2 , 25 D 3 or D 4 receptors from human are used for the assays. The -27- WO 00/00489 PCT/US99/14426 sample is homogenized in 100 volumes (w/vol) of 0.05 M Tris HCl buffer at 40 C and pH 7.4. The sample is then centrifuged at 30,000 x g and resuspended and rehomogenized. The sample is then centrifuged as described and the final tissue sample is 5 frozen until use. The tissue is resuspended 1:20 (wt/vol) in 0.05 M Tris HCl buffer containing 100 mM NaCl. Incubations are carried out at 48 0 C and contain 0.4 ml of tissue sample, 0.5 nM 3 H-YM 09151-2 and the compound of interest in a total incubation of 1.0 ml. Nonspecific binding 10 is defined as that binding found in the presence of 1 mM spiperone; without further additions, nonspecific binding is less than 20% of total binding. Binding characteristics for representative compounds of the invention for the D 2 , D 3 and

D

4 receptor subtypes are shown in Table 2 for rat striatal 15 homogenates. TABLE 2 Compound Number 1

D

4 Ki (nM) D 3 Ki (nM) D 2 Ki (nM) 1 11 3662 >4000 2 37 2569 2587 3 25 2625 >4000 4 35 2992 2309 1 Compound numbers relate to compounds shown in Figure 1. -28- WO 00/00489 PCT/US99/14426 The above data are representative of -the Ki values for compounds of the invention; all compounds of the invention are active in the above assay. The binding constants of compounds 5 of Formula I for the D 4 receptor, expressed in nM, generally range from about 0.5 nanomolar (nM) to about 100 nanomolar (nM). These compounds typically have binding constants for the

D

2 receptor of at least about 1000 nM. Thus, the compounds of the invention are generally at least about 10 time more 10 selective for the D 4 receptor than the D 2 receptor. Preferably, these compounds are at least 20, and more preferably at least 25-50, times more selective for the D 4 receptor than the D 2 receptor. Most preferably, these compounds are at least about 100 times more selective for the 15 D 4 receptor than the D 2 receptor. Similarly, the compounds of the invention are generally at least about 10 time more selective for the D 4 receptor than the D, receptor. The invention and the manner and process of making and using it, are now described in such full, clear, concise and 20 exact terms as to enable any person skilled in the art to which it pertains, to make and use the same. It is to be understood that the foregoing describes preferred embodiments of the present invention and that modifications may be made therein without departing from the spirit or scope of the present 25 invention as set forth in the claims. To particularly point -29- WO 00/00489 PCT/US99/14426 out and distinctly claim the subject matter regarded as invention, the following claims conclude this specification. -30-

Claims

1. A compound of the formula: R2 0 R6 Ry R R3 7 R4 X a N N-A 4 R 8 R 9 or the pharmaceutically acceptable acid addition salts thereof 5 wherein: A is C 1 -C 4 alkylene optionally substituted with C 1 -C 2 alkyl; R 1 , R

2 , R 3 , R4 and R 5 are the same or different and represent hydrogen, halogen, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 4 alkylthio, hydroxy, amino, mono- or di(C 1 -C)alkylamino, 10 cyano, nitro, trifluoromethyl or trifluoromethoxy; and R 6 , R 7 , R. and R. are the same or different and are hydrogen or C 1 -C 6 alkyl. X is oxygen, a bond, C 1 -C 2 alkylene, or methyleneoxy. 15 2. A compound according to claim 1, wherein A is methylene.

3. A compound according to claim 2 wherein R 1 , R 2 , R 3 , R 4 , and R. independently represent hydrogen, halogen, Ci-C 6 20 alkyl, or Ci-C 6 alkoxy. -31- WO 00/00489 PCT/US99/14426

4. A compound according to claim 3, wherein R 1 , R 2 , and R. are hydrogen.

5. A compound according to claim 3, wherein R 1 , R 2 , and 5 R 5 are hydrogen and R 3 and R 4 independently represent hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 4 alkoxy, where not both R 3 and R4 are hydrogen.

6. A compound according to claim 5, wherein R 3 and R 4 10 independently represent hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, or ethoxy, where not both R 3 and R 4 are hydrogen.

7. A compound according to claim 2, wherein X is oxygen. 15

8. A compound according to claim 7, wherein R 1 , R 2 , R 3 , R 4 , and R 5 independently represent hydrogen, halogen, C 1 -C 6 alkyl, or Ci-C 6 alkoxy. 20

9. A compound according to claim 8, wherein R 1 , R 2 , and R 5 are hydrogen.

10. A compound according to claim 8, wherein R 1 , R 2 , and R 5 are hydrogen and R 3 and R 4 independently represent hydrogen, -32- WO 00/00489 PCT/US99/14426 halogen, Cl-CE alkyl, or Ci-C 4 alkoxy, where not both R 3 and R 4 are hydrogen.

11. A compound according to claim 10, wherein R 3 and R 4 5 independently represent hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, or ethoxy, where not both R 3 and R 4 are hydrogen.

12. A compound according to claim 2, wherein X is 10 methylene.

13. A compound according to claim 12, wherein R 1 , R 2 , R 3 , R 4 , and R 5 independently represent hydrogen, halogen, Cl-C6 alkyl, or C 1 -C 6 alkoxy. 15

14. A compound according to claim 13, wherein R 1 , R 2 , and R. are hydrogen.

15. A compound according to claim 13, wherein R 1 , R 2 , and 20 R. are hydrogen and R 3 and R 4 independently represent hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 4 alkoxy, where not both R 3 and R 4 are hydrogen.

16. A compound according to claim 15, wherein R 3 and R4 25 independently represent hydrogen, fluoro, chloro, bromo, -33- WO 00/00489 PCT/US99/14426 methyl, ethyl, methoxy, or ethoxy, where not both R 3 and R 4 are hydrogen.

17. A compound according to claim 2, wherein X is a bond. 5

18. A compound according to claim 2, wherein X is ethylene.

19. A compound according to claim 17, wherein 10 X is a bond; R 1 , R 2 , and R. are hydrogen; and R 3 and R 4 independently represent hydrogen, halogen, Ci-C 6 alkyl, or C 1 -C 4 alkoxy, where not both R 3 and R 4 are hydrogen. 15

20. A compound according to claim 18, wherein X is ethylene; R 1 , R 2 , and R 5 are hydrogen; and R 3 and R 4 independently represent hydrogen, halogen, Ci-Cs 20 alkyl, or C 1 -C 4 alkoxy, where not both R 3 and R 4 are hydrogen.

21. A compound according to claim 2, which is 1-(1,4 benzodioxan-6-yl)-4-(4-fluorobenzyl)piperazine. -34- WO 00/00489 PCT/US99/14426

22. A compound according to claim 2, which is 1-(1,4 benzodioxan-6-yl)-4-(4-chlorobenzyl)piperazine.

23. A compound according to claim 2, which is 1-(1,4 5 benzodioxan-6-yl)-4-(4-methylbenzyl)piperazine.

24. A compound according to claim 2, which is 1-(1,4 benzodioxan-6-yl) -4- (4-methoxybenzyl)piperazine. 10

25. A compound according to claim 2, which is 1-(1,4 benzodioxan-6-yl)-4-(3-chlorobenzyl)piperazine.

26. A compound according to claim 2, which is 1-(1,4 benzodioxan-6-yl) -4- (3-methoxybenzyl)piperazine. 15

27. A compound according to claim 2, which is 1-(1,4 benzodioxan-6-yl)-4-(2-chlorobenzyl)piperazine.

28. A compound according to claim 2, which is 1-(1,4 20 benzodioxan-6-yl) -4- (2-methoxybenzyl)piperazine.

29. A compound according to claim 2, which is 1-(1,4 benzodioxan-6-yl)-4-benzylpiperazine hydrochloride. -35- WO 00/00489 PCT/US99/14426

30. A compound according to claim 2, which is 1-(chroman 6-yl) -4- (4-methylbenzyl) piperazine.

31. A compound according to claim 2, which is 1-(chroman 5 6-yl) -4- (4-chlorobenzyl)piperazine

32. A compound of the formula: 0 N R 6 NH RR wherein R 6 , R 7 , R. and R 9 are the same or different and are 10 hydrogen or C 1 -C 6 alkyl.

33. A compound of the formula: N -- 1yR 7 N R R8' NH R9 wherein R 6 , R 7 , R. and R 9 are the same or different and are 15 hydrogen or Cl-CE alkyl.

34. A compound of the formula: -36- WO 00/00489 PCT/US99/14426 O N R R N NH R 9 wherein R 6 , R 7 , R. and R 9 are the same or different and are hydrogen or C 1 -C 6 alkyl. 5

35. A compound of the formula: o N R7 R8' NH RR wherein R 6 , R 7 , R. and R 9 are the same or different and are hydrogen or C 1 -C 6 alkyl. 10

36. A compound of the formula: 0 N R 7 NH R9 wherein R 6 , R 7 , R. and R 9 are the same or different and are hydrogen or Cl-C, alkyl.

-37-