PIPERIDINYL THIACYCLIC DERIVATIVES

Abstract: Piperidinyl thiacyclic derivatives useful in the treatment of allergic diseases and diseases responding to antagonism of 5HT2 receptors, pharmaceutical compositions and methods of treatment using these compounds.

Description: PIPERIDINYL THIACYCLIC DERIVATIVES Field of the Invention The present invention is directed to compounds, pharmaceutical compositions and methods of treatment using same. The compounds of the present invention are piperidinyl thiacyclic derivatives useful in the treatment of allergic diseases and the treatment of diseases responsive to serotonin 5HT 2 antagonists. Summary of the Invention The present invention comprises compounds of Formula I optical isomers or pharmaceutically acceptable salts thereof, wherein Y is -C(=0)-, -C(=CH 2 )-, -C(H)(OH)-, -C(OH) (phenyl)- or -C(B)(OH) wnerein B is Y is attached at the heterocycle positions 2 or 3, or Y is also attached at 2' or 3' wnen B is present. X and X' are the same or different and are carbon, CH or nitrogen, provided that when Y is attached at the 3 or 3' position, X and X' are each carbon, and when Y is attached at the 2 or 2 ■ position, X and X' are the same or different and are CH or nitrogen; R l is -(CH 2 ) n -Z-(CH 2 ) m COR 5 , -C(0)R 8 or ■& 2 r 3, R 2 ' and R3 ' are the same or different and are hydrogen or Cχ_ 4 alkyl, or when R 2 and R 3 , and R 2 ' and R 3 ' are respectively taken together, with the atoms to which R 2 and R 3 , and R 2 > and R3- are respectively attached, each form a phenyl moiety respectively substituted with R 4 or R ' ; Z is a bond, 0, or S; R 4 or R ' are the same or different and are hydrogen, chloro, fluoro, C 1 - 4 alkyl, or Cι_ 4 alkoxy; R 5 is OH, C 1 - 4 alkoxy or -NR6R7; Re and R 7 are the same or different and are H or Cι_ 4 alkyl; Rs is Cι_ 4 alkyl or Cι_ 4 alkoxy; Rg is H, Cι_ 4 alkyl, C 1 - 4 alkoxy, OH, chloro, bromo, fluoro, -CF3, -NHC(O)R 10 , or C0 2 Rn; Rio is Cι_ 4 alkyl or Cι_ alkoxy; R ll is hydrogen or C 1 - 4 alkyl; n is an integer from 0-3 provided that when Z is not a bond n is an integer from 2-3; m is an integer from 1 to 3; d is an integer from 1 to 5; and e is zero or 1, provided that when e is 1: d is an integer from 2 to 5; and X is N, or R 2 and R 3 , with the atoms to which R 2 and R 3 are attached, form a phenyl moiety; or X is N, and R 2 and R 3 , with the atoms to which R 2 and R 3 are attached, form a phenyl moiety. The present invention further comprises the use of these compounds in a pharmaceutical composition. These compounds are useful in the treatment of subjects having allergic diseases and diseases responsive to 5HT 2 antagonism. Detailed Description of the Present Invention Terms used herein have the following meanings: "Cι_ 4 alkyl" is a branched or straight chain alkyl having 1, 2 , 3 or 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc.; "C 1 -. 4 alkoxy" is a branched or straight chain alkoxy having 1, 2, 3 or 4 carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, etc.; and "pharmaceutically acceptable salt" is either an acid addition salt or a basic addition salt. The compound of Formula I comprises an optionally substituted heterocycle linked to an optionally substituted piperidinyl by a Y group. Tne Y group represents a carbonyl group (-C(=0)-) , an ethenylene group (-C(=CH )-) r a hydroxymethylene group (-C(H) (OH)-) , a methine group substituted with hydroxy and phenyl (-C(OH) (phenyl)-) or a methine group substituted witn hydroxy and an optionally substituted heterocycle represented by "E" (-C(B) (OH)-) . The Y as a carbonyl group is preferred. As shown in Formula I, Y can be linked to one heterocycle or two of the same or different types of heterocycles (the second heterocycle being B) . The heterocycles of the present invention are selected from thienyl (also known as thiophenyl) as in Example 1, thiazolyl as in Example 3, benzothiophenyl as in Example 5 and benzothiazolyl as in Example 8. The heterocycle benzothiazolyl is preferred, and, when two heterocycles are present, they are preferably both not simultaneously thiophenyl. As shown in formula I, the straight dotted line of 3 indicates attachment to the remainder of the compound of formula I via the line intersected by the dotted line, the intersected line being between positions 2' and 3' of the heterocycle. The curved dotted line between R 2 and R 3( , and the curved dotted line R 2 ' and 3 ' each represent a possible ring formation therebetween, as more fully described hereafter. The heterocycles are attached to Y via the available carbon atom at either the 2 or the 3 position of the heterocycle (see Formula I) or, in the heterocycle designated as "B", the 2' or 3' position, as represented by a line positioned therebetween, provided that when Y is attached at the 3 or 3' position, X and X' are each carbon, and when Y is attached at the 2 or 2 ' position X and X 1 are --- each independently CH or nitrogen. That is, when the heterocycle or heterocycles do not contain a nitrogen in the ring, Y may attach thereto at the 2 or 3 positions (2' or 3' positions in B), but when there is a nitrogen atom at position 3 of the heterocycle, Y will only attach at the 2 position (or the 2' position of B). The heterocycle or heterocycles attached to Y in Formula I may be optionally substituted. When the heterocycle contains one ring, i.e., a thiophenyl or thiazolyl ring, the substitutions are represented by R and R 3 , or, when the second heterocycle represented by B is present, the substituents are also represented by R ' and R 3 ' . When the heterocycle(s) contain(s) two rings, i.e., benzothiophenyl or benzothiazolyl, the substitution of the heterocycles is by R 4 or R 4 * at any position on the phenyl moiety except on the carbon atoms shared with the five membered ring moieties. R 4 and R 4 ' may be the same or different moieties. Each of R 2 , R 2 >, R 3 , or R 3 ' can be a hydrogen or C 1 - 4 alkyl. Preferably, R 2 , R 2 ', ^ 3 , or R 3 ' are each hydrogen. Each of R 4 or R 4 > can be hydrogen, chloro, fluoro, C 1 - 4 alkyl or Cι_ 4 alkoxy. Preferably, R 4 and R ' are hydrogen. Ri is attached to the nitrogen in the piperdinyl moiety and may be -(CH 2 ) n -Z-(CH 2 ) n *COR 5 , -C(0)Rβ or Z is a bond, oxygen atom (0) or sulfur atom (S). When Z is a bond, the subscript n represents the integers 0, 1, 2 or 3. When Z is other than a bond, n represents the integers 2 or 3. The subscript m represents the integer 1, 2 or 3. R 5 is -OH, C 1 - 4 alkoxy or -NR6R7. Rε and R 7 are each -o - independently hydrogen or Cι- 4 alkyl. The subscript d represents any of the integers 1, 2, 3, 4 or 5, and preferably the integers 1, 2 or 3. The subscript e represents the integers 0 or 1, and preferably 1, witn tne proviso that both d and e cannot simultaneously be 1. Wnen e is 1, d is greater than 1, i.e., 2, 3, 4 or 5. Also, when e is 1: (1) d is an integer from 2 to 5; and (2) (a) X is N, o_r R 2 and R 3 , with the atoms to which R 2 and R 3 are attacne , form a phenyl moiety; c_r_ (b) X is N, and R 2 and R 3 , with the atoms to which R 2 and R 3 are attached, form a phenyl moiety. In other words, when e is 1, d is always an integer from 2 to 5. Additionally, when e is 1, the heterocycle group shown in Formula I attached Y (not the "B" heterocycle) is not a thiophene radical, i.e., either N is present in the five membered ring and/or a phenyl group is fused to the five membered ring. R δ means C 1 - 4 alkyl or C 1 -4 alkoxy. Rg means H, Cι_ alkyl, C 1 - 4 alkoxy, OH, chloro, bromo, fluoro, -CF 3 , - NHC(0)Rιo, or CO 2 R 11 . Rg can substitute the phenyl moiety at any ortho, meta or para position, the para position being preferred. Rio is Cι_ alkyl or Cι_ alkoxy, and Rn is C 1 - 4 alkyl. Preferably Rg is an ester or an acid. "Pharmaceutically acceptable acid addition salts" applies to any non-toxic organic or inorganic acid addition salt of the base compounds of formula I or any of its intermediates. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric and phosphoric acid and acid metal salts such as sodium monohydrogen ortnophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono-, di- and t icarboxylic acids. Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicyclic, 2-phenyoxybenzoic, p-toluenesulfonic acid and sulfonic acids such as methanesulfonic acid and 2- hydroxyethane sulfonic acid. Either the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated or substantially anhydrous form. In general, the acid addition salts of these compounds show increased solubility in water and various hydrophilic organic solvents and, in comparison to their free base forms, generally demonstrate higher melting points. Some of the compounds of Formula I contain asymmetric centers. Any reference in this application, including the claims, to one of the compounds represented by Formula I is meant to encompass either a specific optical isomer or a mixture of enantiomers or diasteriomers. The specific optical isomers can be separated and recovered by techniques known in the art such as chromatography on chiral stationary phases or resolution via chiral salt formation and subsequent separation by selective crystallization. The piperidinyl thiacyclic derivatives of Formula I can be prepared by utilizing conventional procedures and techniques which are well known and appreciated in the art. The schemes show compounds having a connecting line through the heterocycle between positions 2 and 3 of the heterocycle (positions 2 and 3 being designated as in Formula I). This is to indicate attachment at the heterocycle at either position 2 or 3 with the caveat that when X is nitrogen, the heterocycle is always attached at Dosition 2. One general synthetic procedure for the preparation of the compounds of Formula I wherein Y is -C(=0)- is set forth in Scheme A. In Scheme A, ail substituents are as previously defined unless otherwise indicated. Scheme A (1) :2) (6) E = C1-C4 alkoxy αr N(OCH3)CH3 Hal = Cl, Br, or I Scheme A provides one general synthetic procedure for preparing the compounds of Formula I wherein Y is -C(=0)-. In step a, the appropriate lithio thiacyclic derivative of structure (1) is acylated with the piperidinyl derivative of structure (2) to give the corresponding piperidinyl thiacyclic derivative of structure (3). For example, a solution of the appropriate lithio thiacyclic derivative of structure (1) is contacted with the piperidinyl derivative of structure (2) at a temperature range of from about -90°C to about -50°C and more preferably about -78°C. The reaction is typically conducted under anhydrous conditions in a suitable aprotic organic solvent such as tetrahydrofuran. The piperidinyl derivative and the lithio thiacyclic derivative are preferably present in the reaction zone in an approximately equimolar quantity. A slight excess of either reactant is not deleterious to the reaction. The reaction is allowed to proceed for a period of time ranging from about 20 minutes to about 5 hours, and more preferably about 30 minutes. The reaction is then quenched with a proton source such as, for example, saturated aqueous ammonium chloride or methanol. The resulting reaction mixture is extracted with a suitable solvent, such as ethyl acetate, washed with water, dried over either Na 2 S0 4 or MgS0 4 , filtered and the solvent evaporated in υacuo . Appropriate lithio thiacyclic derivatives of structure (1) are commercially available or prepared by techniσues and procedures well known in the art. For example, a solution of the appropriate starting thiacyclic derivative is contacted with an organolithium compound such as n-butyllithium or t-butyllithium, more preferably with t- butyllithiu , for a period of time ranging from about 5 minutes to about 30 minutes and more preferably about 15 minutes; at a temperature range of from about -90°C to about -50°C and more preferably about -78°C. The organolithium compound will be present in the quantity of from about 1.0 to about 1.1 equivalents for every mole of thiacyclic derivative utilized, and more preferably will be present in an approximately equimolar quantity with the lithio thiacyclic derivative. The reaction is typically conducted under anhydrous conditions in a suitable aprotic organic solvent such as tetrahydrofuran. Typically, when Y is to be attached at the 3 position of the lithio thiacyclic derivative of structure (1), an appropriate starting thiacyclic derivative is one wherein the 3 position is substituted with bromine or iodine. When Y is to be attached at the 2 position of the lithio thiacyclic derivative of structure (1), an appropriate starting heterocyclic derivative is one wherein the 2 position is substituted with hydrogen, bromine or iodine. Examples of appropriate starting heterocyclic derivatives are 3-bromobenzo[b]thiophene, benzo[b]thiophene, benzothiazole, 2-bromobenzothiazole, thiazole, and 3- bromothiophene. The piperidinyl heterocyclic derivative of structure (3) can be purified according to techniques known in the art. For example, one suitable technique is to subject the concentrate obtained above to chromatography on silica gel utilizing an appropriate organic solvent such as ethyl acetate as the eluting agent. The eluent can be evaporated and the resulting product can be recrystallized from a suitable solvent such as, for example, cyclohexane. Other suitable solvent systems will be readily apparent to those skilled in the art. In optional step b, the piperidine unctionality of the appropriate piperidinyl thiacyclic derivative of structure (3) is deprotected under acidic conditions to give the piperidinyl thiacyclic derivative of structure (4) using procedures and techniques well known in the art. For example, the t-butyloxycarbonyl group (t-Boc) can be cleaved with trifluoroacetic acid. In optional step c, the piperidine functionality of the appropriate piperidinyl thiacyclic derivative of structure (4) is N-alkylated under basic conditions with the appropriate alkyl halide of structure (5) to give the piperidinyl thiacyclic derivative of structure (6). For example, the piperidinyl thiacyclic derivative of structure (4) is reacted with the appropriate alkyl halide of structure (5) in the presence of a base such as K 2 C0 3 , KHCO 3 , Na 2 Cθ 3 , NaHC0 3 , triethylamine, or pyridine in a solvent such as dimethylformamide, dimethylsulfoxide, aqueous tetrahydrofuran or ethanol. Typically the reactants will be stirred together for a period of time ranging from about 30 minutes to about 48 hours, at a temperature range of from about 0°C to about 100°C. The non-reacting substituents appearing in the alkyl halide (Ri) correspond to those appearing in the product. The piperidinyl thiacyclic derivative of structure (6) can be recovered from the reaction zone by treatment with water and extraction with an organic solvent as is known in the art. It can be purified by techniques known in the art such as recrystallization or chromatography as described previously. Typically the piperidinyl thiacyclic derivative of structure (4), as its trifluoroacetic acid salt, is converted in situ to its free base during the alkylation and may be optionally converted to other acid addition salts as is known in the art. Alternativel , the piperidine functionality of the appropriate piperidinyl thiacyclic derivative of structure (4) can be N-alkylated with the appropriate alkyl halide of structure (5) under phase-transfer catalysis conditions as is known in the art. Alternatively, those piperidinyl thiacyclic derivatives of structure (6) wherein Ri is -(CH ) n -Z-(CH 2 ) m COR 5 wherein R5 is OH or wherein Rg is C0 2 Rn and Ru is H may be prepared from the appropriate piperidinyl thiacyclic derivatives of structure (6) wherein Ri is -(CH 2 ) n -Z-(CH 2 ) n .CORs wherein R 5 is C 1 - 4 alkoxy or wherein Rg is C0 2 Rn and Ru is C 1 - 4 alkyl via an ester hydrolysis reaction as is known in the art. Starting materials for use in Scheme A are readily available to one of ordinary skill in the art. For example, carbomethoxy methoxyethyl chloride is described in J. Org. Chem. 2_6 , 4325-7 1961. The following examples present typical syntheses as described in Scheme A. These examples are understood to be illustrative only and are not intended to limit the scope of the present invention in any way. As used herein, the following terms have the indicated meanings: "g" refers to grams; "mmol" refers to milli oleε; "mL" refers to miliiliters; "bp" refers to boiling point; " p" refers to melting point; "°C" refers to temperature in degrees Celsius; "mm Hg" refers to pressure in millimeters of mercury; "uL" refers to microliterε; "μg" refers to micrograms; and "μM" refers to πucromolar. Example I 4-[ (Thiophene-2-yl)carbonyl ]-i-pipericinecarboxylic acid, 1,1-dimethviethyl ester Mix 4-piperidinecarboxylic acid (107.5g, 832mmol), IN sodium hydroxide (40g in 900mL water) and tert-butanol (1800mL). Add, by portionwise addition, di-tert-butyl dicarbonate (200g, 916mmol). Stir overnight, evaporate the solvent in vacuo and acidify the aqueous phase with aqueous hydrochloric acid. Extract the acidic aσueous phase witr. ethyl ether (3X), combine the organic phases and wash with water and brine. Dry (MgS0 4 ), evaporate the solvent in vacuo and recrystallize (ethyl acetate/hexane) to give 1,4- piperidinedicarboxylic acid, 1-(1,1-dimethylethyl) ester as white needles, .p. 147-149°C. Dissolve 1,4-piperidinedicarboxylic acid, l-(l,i- dimethylethyl) ester (50. Oς, 218mmol) in anhydrous methylene chloride (500mL) and place under a nitrogen atmosphere. Add, by portionwise addition, 1,1'- carbonyldii idazoie (38.9g, 240mmol) and stir for 1 hour. Add, in one portion, N,0-dimethylhydroxylamine hydrochloride (23.4g, 240mmol) and stir overnight. Wash the solution with IN hydrochloric acid (2X), saturated sodium hydrogen carbonate and brine. Dry (MgSθ 4 ), evaporate the solvent in vacuo and purify by distillation to give 4- [ [ (N-methoxy-N-methyl)amino]carbonyl]-l- piperidinecarboxylic acid, 1,1-dimethylethyl ester as a clear oil, b.p. 120-140°C @ 0.8mm Hg. Mix 4-[[ (N-methoxy-N-methyl)amino]carbonyl]-l- piperidinecarboxylic acid, 1,1-dimethylethyl ester (3.0g, 11.02mmol) and anhydrous tetrahydrofuran (lOmL), cool to - 78°C and place under an argon atmosphere. Add 2- lithiothiophene (12.1mL of a IM solution in tetrahydrofuran, 12.1mmol). Stir the resulting brown . solution at -78°C for 1 hour, remove the ice bath and allow to warm for 15 minutes. Add saturated ammonium chloride (lOmL) and stir for 30 minutes. Partition between ethyl acetate and water, separate the organic phase and wash the aqueous phase with additional ethyl acetate. Wash the combined organic phases with saturated sodium chloride, dry (MgS0 4 ) and evaporate the solvent in vacuo . Purify by silica gel chromatography (20% ethyl acetate/hexane) and recrystallize (ethyl acetate/hexane) to give the title compound as pale yellow crystalline solid; mp 154-156°C. Anal. Calcd for C 15 H 21 NO 3 S: C, 60.99; H, * 7.17; N, 4.74. Found: C, 60.89; H, 7.26; N, 4.74. - b - Exa ple 2 ( Thi ophene- 2-yl ) ( -pipe idiny l ) me thanone » CF CO?H Mix 4-[(thiophene-2-yl)carbonyl]-l-piperidinecarboxylic acid, 1,1-dimethylethyl ester (12.9g, 43.67mmol) and trifluoroacetic acid (80mL) and stir at room temperature for 2 hours. Cool in an ice/water bath and dilute with ethyl ether. Collect the resulting solid by filtration, wash with ethyl acetate and recrystaliize (methanol/ethyl ether) to give the title compound as an off-white solid; mp 186-187°C. Anal. Calcd for Cι 0 Ki 3 NOS«CF 3 CO 2 K: C, 46.60; H, 4.56; N, 4.50. Found: C, 46.35; H, 4.56; N, 4.49. Example 3 4-[ (2-Thiazolyl)carbonyl j-i-pjperidinecarboxylic acid, 1,1- dimethylethyl ester Prepare according the the procedure described in Example using 2-lithiothiazole. Example 4 (2-Thiazolyl) (4-piperidinyl)methanone«CFτC07H Prepare according to the procedure described in Example 2 using 4-[ (2-thiazolyl)carbonyl]-l-piperidinecarboxylic acid, 1,1-dimethylethyl ester. Example 5 4-[ (Benzofblthiophene-3-yl)carbonyl j-1-piperidinecarboxylie acid, 1,1-dimethylethyl ester Dissolve benzo[b]thiophene (23g, 0.170mmol) in carbon tetrachloride (80mL). Add, by dropwise addition, a solution of bromine (26.85g, 0.168mmol) in carbon tetrachloride (30mL) and stir at room temperature for 2 days. Quench with a IM solution of sodium thiosulfate and separate the organic phase. Extract the aσueous phase with carbon tetrachloride, combine the organic phases and dry (MgS0 4 ). Evaporate the solvent in vacuo and purify by distillation to give 3-bromobenzo[b]thiophene as a pale yellow liquid (17.33g, 48%); bo 64-72°C @ 0.02mm Eg. Dissolve freshly distilled 3-bromoDenzo[ b] thiophene (2.47c, ii.59mmol ) in annydrous ethyl ether (50mL) , place under ar. argon atmosphere and cool to -78°C. Add, by dropwise addition, t-buty lithium (13.6mL cf a 1.7M solution pentane, 23.1mmol) and stir at -78°C for 20 minutes. Add, by dropwise addition, a solution cf 4-[[ (N-methoxy-N- methyl)amino]carbonyl ]-l-pipεridmecarDoxylic acid, 1,1- dimethylethyl ester (3.16g, il.59mmol) in anhydrous tetrahydrofuran (15mL). Stir at -78°C for 1 nour and quench with saturated ammonium chloride. Partition Detwee water and ethyl acetate, separate the organic phase and extract the aqueous phase with ethyl acetate. Wash the combined organic phases with saturated sodium chloride and dry (Na S0 ). Evaporate the solvent in vacuo and purify DV chromatography (20% ethyl acetate/hexane) to give the title compound as a colorless foam. Mass Spectrum: EI/70EV m/e 345 { VX" ) Example 6 (Benzofb ' Jthiophene-3-yl) ( -pipe idi yl )methanone»CF-.CQ?H Dissolve 4-[ (benzo[b]thiophene-3-yi )carbonyl ]-l- piperidinecarboxylic acid, 1,1-dimethylethyl ester (3.75g, 10.8mmol) in trifluoroacetic acid (30mL). Stir at room temperature for 30-40 minutes. Cool in an ice bath and dilute with ethyl ether (200mL) . Keep at 0°C for 1-2 hours, collect the solid by filtration and recrystaliize (methanol/ethyl ether) to give the title compound as small colorless plates; mp 195-197°C. Anal. Calcd for Cι 4 Hi 5 NOS«CF 3 C0 2 H: C, 53.48; H, 4.49; N, 3.90. Found: C, 53.14; H, 4.50; N, 3.90. Example 7 [Benzo[b]thiophene-3-yl] [1-f 2-( -methoxyphenyl)ethyl1-4- piperidinyl]methanone Mix (benzo[b]thiophene-3-yl) (4-piperidinyl)methanone»CF 3 C0 2 H (2.0g, 5.56mmol), 2-(4-methoxyphenyl)ethyl bromide (1.27g, 5.93mmol), potassium carbonate (1.95g, 1.41mmol) and anhydrous di ethylformamide (20mL). Warm to approximately 90°C and stir overnight. Allow to cool to room temperature and partition between a 2:1 mixture of ethyl acetate:toluene and water. Separate the aqueous phase and wash the organic phase with water and saturated sodium chloride. Dry (Na 2 Sθ ) and evaporate the solvent in vacuo . Purify by chromatography (40% ethyl acetate/hexane) and recrystaliize (cyclohexane) to give the title compound as pale yellow plates; mp 114-116°C. Anal. Calcd for C 23 H 25 0 2 S: C, 72.79; H, 6.64; N, 3.69 Found: C, 72.58; H, 6.63; N, 3.66. Examole 8 4- [ (2-Benzothiazoiyi)carbonyl 1 -l-piperiάineca bo ylic aci , 1-dimethvlethvl ester Dissolve benzothiazole (2.0g, 14.79mmol) in anhydrous tetrahydrofuran (50mL), place under an argon atmosphere and cool to -78°C. Add, by dropwise addition, n-butyilithium (6.5mL of a 2.5M solution in hexane, 16.27mmol) and stir at -78°C for 30 minutes. Add, by dropwise addition, a solution of 4-[ [ (N-methoxy-N-methyl)amino]carbonyl ]-l- piperidinecarboxylic acid, 1,1-dimethylethyl ester (4»03g, 14.79mmol) in anhydrous tetrahydrofuran (50mL). Stir at - 78°C for 1.5 hours, remove the ice bath and allow to warm for 10 minutes, quench with saturated ammonium chloride (lOOmL) and stir for an additional hour. Separate the organic phase and extract the aqueous phase with ethyl acetate. Combine the organic phases, dry (MgS0 4 ) and evaporate the solvent in vacuo . Purify by chromatography (10% ethyl acetate/hexane) to give the title compound as pale yellow crystals; mp 94-95°C. Anal. Calcd for Ci 8 H 22 N 2 0 3 S: C, 62.40; K, 6.40; N, 8.09. Found: C, 62.20; E, 6.46; N, 7.94. Example 9 2-Benzothiazolyl ) ( 4-piperidinyl )methanone»CFgC0 7 H Mix 4- [ ( 2-benzothiazolyl)carbonyl ]-l-piperidinecarboxylic acid, 1,1-dimethylethyl ester (10.5g, 30.31mmol) and trifluoroacetic acid (75mL) and stir at room temperature for 2 hours. Cool in an ice/water bath and add ethyl ethe: until a solid begins to precipitate. Stir at 0°C for 30 minutes, collect the solid by filtration and wash with ethyl ether and recrystaliize (methanol/ethyl ether) to give the title compound as a white powder; mp 195-197°C. Anal. Calcd for Ci3Hi 4 2 OS«CF3C0 2 H: C, 50.00; H, 4.20; N, 7.77. Found: C, 50.12; H, 4.17; N, 7.79. Example 10 [2-Benzothiazolyl ] [ 1-[ 2-( 4-methoxyphenyl)ethyl ]-4- piperidinyllmethanone Mix (2-benzothiazolyl) ( -piperidinyl)methanone»CF 3 C0 2 H (331g, 9.19mmol), 2-(4-methoxyphenyl)ethyl bromide (2.07g, 9.64mmol), potassium carbonate (3.33g, 24.1mmol) and dimethylformamide (35mL) and heat at 90°C overnignt. Cool to room temperature and partition between a 2:1 mixture of ethyl acetate/toluene and water. Separate the aqueous phase and wash the organic phase with water and brine. Dry (MgS0 4 ) and evaporate the solvent in vacuo . Purify by chromatography (30% ethyl acetate/hexane) and recrystaliize (cyclohexane) to give the title compound as a tan powder; mp 119-120°C. Anal. Calcd for C 22 H 2 N 2 θ 2 S: C, 69.44; E, 6.36; N, 7.36 Found: C, 69.48; H, 6.52; N, 7.06. Example 44 gives an alternative method of making this compound. Example 11 [2-Benzothiazolyl] f1-f 2-( -fluorophenyl)ethyl1-4- piperidinylImethanone Mix (2-benzothiazolyl) (4-piperidinyl)methanone*CF 3 C0 2 H (1.95g, 5.43mmol), 2-(4-fluorophenyl)ethyl bromide (I.70g, 8.35mmol), benzyltriethylam onium bromide (149mg, 0.54mmol) , sodium hydroxide (5g), water (25mL) and methylene chloride (25mL). Stir at room temperature under an argon atmosphere overnight, then heat at reflux overnight. Cool the reaction to room temperature, separate the organic phase and extract the aqueous phase with methylene chloride (50mL). Combine the organic phases, dry (Na 2 S0 4 ) and evaporate the solvent in vacuo . Purify by chromatography (20% ethyl acetate/hexane with 2% triethylamine) and recrystaliize (hexane) to give the title compound as pale yellow needles; mp 97-98°C. Anal. Calcd for C 2 ιH 2 ιFN 2 OS: C, 68.45; H, 5.74; N, 7.60. Found: 68.26; H, 5.58; N, 7.29. Example 12 [2-Benzothiazolyl1 [l-(2-phenylethyl)-4- piperidinyl]methanone Mix (2-benzothiazolyl) ( -piperidinyl)methanone»CF 3 C0 H (2.56g, 7.13mmol), 2-phenylethyl bromide (1.45g, 7.84mmol), 18-Crown-6 (188mg, 0.71mmol), potassium carbonate (9.85g, 71.3mmol) and methylene chloride (lOO L). Stir at room temperature under an argon atmosphere for 2 hours, then add potassium iodide (200mg). Stir at room temperature for an additional 2 hours then heat at reflux overnight. Add additional 2-phenylethyl bromide (1.45g, 7.84mmol) and heat at reflux overnight. Add additional 2-phenylethyl bromide (1.45g, 7.84mmol) and heat at reflux overnight. Cool the reaction to room temperature and pour into water (150mL). Separate the organic phase, wash with water (lOOmL) and dry (Na 2 S0 ). Evaporate the solvent invacuo and purify by chromatography (20% ethyl acetate/hexane with 2% triethylamine) to give the title compound as a yellow solid; mp 108.5-109.5°C. 5 Anal. Calcd for C 2 ιH 22 N 2 OS: C, 71.97; E, 6.33; N, 8.00. Found: C, 71.94; E, 6.22; N, 7.74. Example 13 0 4-[ ( 2-Benzothiazolvi)carbonyl 1 -l-pjperidineacetic acid, methyl ester»HCl Mix (2-benzothiazolyl) (4-piperidinyl)methanone»CF 3 C0 2 H 20 (3.0g, 8.33mmol), methyl bromoacetate (1.34g, 8.74mmol), sodium bicarbonate (1.75g, 20.83mmol), tetrahydrofuran (120mL) and water (30mL). Heat at reflux for 4 hours, cool to room temperature and partition between ethyl acetate and water. Separate the organic phase and extract the aqueous _- phase with ethyl acetate. Combine the organic phases, wash with water and dry (MgS0 4 ). Evaporate the solvent invacuo to give a yellow oil. Dissolve the oil in ethanol/ethyl ether and treat with ethereal hydrogen chloride gas. Cool overnight, collect the resulting solid by filtration, wash 30 with ethyl ether and dry to give the title compound as a white crystalline solid; mp 177-178°C. Anal. Calcd for Cι 6 Hι 8 N 2 0 3 S»HCl : C, 54.16; E, 5.40; N, 7.89. Found: C, 53.87; H, 5.41; N, 8.06. 35 Example 14 4-[ 3-[ -[ (2-Benzothiazolyl)carbonyl 1-1- piperidinylIpropoxy1benzoic acid, methyl ester Dissolve 4-(3-chloropropoxy)benzoic acid, methyl ester (6.97g, 30.5mmol) in anhydrous acetone (lOOmL) and add powdered sodium iodide (16.0g, 107mmol). Heat at reflux under an argon atmosphere for 38 hours. Dilute with ethyl ether (lOOmL) and filter through Celite ® filter aid. Wash the filtrate with water and brine, then dry (MgS0 4 ). Evaporate the solvent in vacuo to give 4-(3- iodopropoxy)benzoic acid, methyl ester as a yellow oil. Mix (2-benzothiazolyl) (4-piperidinyl)methanone»CF 3 C0 2 H (7.08g, 19.7mmol), 4-(3-iodopropoxy)benzoic acid, methyl ester (6.50g, 20.3mmol), sodium hydrogen carbonate (3.41g, 40.6mmol), tetrahydrofuran (lOOmL) and water (20mL). Heat at reflux under an argon atmosphere overnight. Cool to room temperature, dilute with ethyl acetate (150mL), wash with 10% sodium hydrogen carbonate (50mL), water (2X50mL) and saturated sodium chloride (50mL). Dry (MgSθ 4 ), evaporate the solvent in vacuo and triturate with hexane. Collect the solid by filtration and recrystaliize (methanol) to give the title compound as a pale yellow solid; mp 108-109.5°C. Anal . Calcd f or C 24 H 26 N 2 0 4 S : C , 65 . 73 ; H , 5 . 98 ; N , 6 . 39 ^oun 65.44; H, 6.06; N , 6.34 example ID [ 2-Benzothiazolyl ] [ l-[ 3-( 4-methoxyphenyl . propoxy ]-4- piperidinyl jmethaπone Mix (2-benzothiazolyl) (4-piperidinyl)methanone»CF 3 C0 2 H (7.0g, 19.5mmol), 1-(3-chloropropoxy)-4-methoxybenzene (4.01g, 20.0mmol), sodium bicarbonate (3.36g, 40.0mmol), sodium iodide (3.04g, 20.3mmol), tetrahydrofuran (lOOmL) and water (20mL). Place under an argon atomsphere and heal at reflux for 24 hours. Dilute with ethyl acetate (lOOmL) and wash with water (50mL) and brine (50mL). Dry (MgΞ0 ), evaporate the solvent invacuo to give an yellow solid Purify by chromatography (ethyl acetate) and recrystaliize (ethanol) to give the title compound as a pale yellow solid; mp 114-115°C. Anal. Calcd for C 3 H 26 N 2 θ 3 S: C, 67.29; E, 6.38; N, 6.82 Found: C, 67.12; H, 6.44; N, 6.67. Example 16 4-f5-[4-[ (2-Benzothiazolyl)carbonyl]-l- piperidinylIpentoxyIbenzoic acid, methyl ester Prepare according to the procedure described in Example 15 using 4-(5-chloropentoxy)benzoic acid, methyl ester. 4-(5- Chloropentoxy)benzoic acid, methyl ester can be prepared from methyl 4-hydoxybenzoate and 1,3-dibromopropane according the the procedure described in J. Am. Chem. Soc. 44, 2645 1922. Example 17 [2-Benzothiazolyl] [1- 13-(4-hydroxyphenyl)propoxy]-4- piperidnyl]methanone Prepare according to the procedure described in Example 15 using l-(3-chloropropoxy)-4-hydroxybenzene. l-(3- Chloropropoxy)-4-hydroxybenzene can be prepared by treating l-(3-chloropropoxy)-4-methoxybenzene with trimethylsilyl iodide according the the procedure described in J. Org. Chem. 4_2. 3761 1977. Example 18 [ 2-Benzothiazolyl ] f1-f 3-(3-methyIphenyl)propoxy]-4- pjperidinyl1methanone Prepare according to the procedure described in Example 15 using 1-(3-chloropropoxy)-3-methylbenzene. l-(3- Chloropropoxy)-3-methylbenzene can be prepared from m- cresol and 1,3-dibromopropane according the the procedure described in . Am. Chem. Soc. 4_4, 2645 1922. Example 19 f2-Benzothiazolyl] [1—f3—(4-fluorophenyl)propox ]-4- piperidinvlImethanone Prepare according to the procedure described in Example 15 using l-(3-chloropropoxy)-4-fluorobenzene. Example 20 f2-Benzothiazolyl] f1-f3-f4-acetamidophenyl)propox ]-4- piperidinyljmethanone Mix (2-benzothiazolyl) (4-piperidinyl)methanone»CF 3 C0 2 H (3.45g, 9.6mmol), l-(3-chloropropoxy)-4-acetamidobenzene (2.20g, 9.66mmol), sodium bicarbonate (1.68g, 20.0mmol), sodium iodide (1.50g, lO.Ommol), tetrahydrofuran (lOOmL) and water (20mL). Place under an argon atomsphere and heat at reflux for 24 hours. Dilute with ethyl acetate (lOOmL) and wash with water (50mL) and brine (50mL). Dry (MgS0 4 ), evaporate the solvent in vacuo to give a pale yellow solid. Purify by recrystallization (ethanol) to give the title compound as a pale yellow solid; mp 171-172°C. Anal. Calcd for C 24 H 27 N 3 θ 3 S: C, 65.88; H, 6.22; N, 9.60. Found: C, 65.62; H, 6.22; N, 9.60. Example 21 f (2-( -Chlorobenzothi zolyl) )ca ponyl 1-1- piperidinecarboxyiic acid, 1,i-άimethyiethyl estei Slurry 2-amino-4-chlorobenzothiazole (0.255mol) in water (325mL), heat to reflux and add 48% hydrobromic acid (130mL). Maintain at reflux for 20 minutes, cool to 0°C and add a solution of sodium nitrite (17.56g, 0.255mol) in water (90mL), maintaining a temperature of 0°C. Stir at 0°C for 15 minutes and add by dropwise addition (while keeping cold) to a rapidly stirring mixture of copper (I) bromide (42.03g, 0.293mol) in 48% hydrobromic acid (86mL) and water (225mL). Stir at room temperature for 20 minutes and then heat on a steam bath for an additional 20 minutes. Allow to stand overnight, extract into methylene chloride and dry (MgS0 4 ). Evaporate the solvent in vacuo and purify by chromatography to give 2-bromo-4-chlorobenzothiazole. Dissolve 2-bromo-4-chlorobenzothiazole (14.79mmol) in anhydrous tetrahydrofuran (50mL), place under an argon atmosphere and cool to -78°C. Add, by dropwise addition, n-butyllithium (6.5mL of a 2.5M solution in hexane, 16.27mmol) and stir at -78°C for 30 minutes. Add, by dropwise addition, a solution of 4-[ [ (N-methoxy-N- methyl)amino]carbonyl]-l-piperidinecarboxylic acid, 1,1- dimethylethyl ester (4.03g, 14.79mmol) in anhydrous tetrahydrofuran (50mL). Stir at -78°C for 1.5 hours, remove the ice bath and allow to warm for 10 minutes, quench with saturated ammonium chloride (lOOmL) and stir for an additional hour. Separate the organic phase and extract the aqueous phase with ethyl acetate. Combine the organic phases, dry (MgS0 4 ) and evaporate the solvent in vacua . Purify by chromatography to give the title compound. Example 22 f 2-( -Chiorobenzothiazolyl) ] ( -piperidinyl)methanone * »CF-*,CO?H Mix 4-[ (2-(4-chlorobenzothiazolyl) )carbonyl]-l- piperidinecarboxylic acid, 1,1-dimethylethyl ester (30.31mmol) and trifluoroacetic acid (75mL) and stir at room temperature for 2 hours. Cool in an ice/water bath and add ethyl ether until a solid begins to precipitate. Stir at 0°C for 30 minutes, collect the solid by filtration and wash with ethyl ether to give the title compound. Examoie 23 * 2-( -Chlorobenzothiazolyl) 1 [ —[2—(4-methoxypnenyl)ethyl 4-piperidinvlImethanone Mix f2-(4-chlorobenzothiazolyl) ] (4- piperidinyl)methanone»CF 3 C0 2 H (9.19mmol), 2-(4- methoxyphenyl)ethyl bromide (2.07g, 9.64mmol), potassium carbonate (3.33g, 24.1mmol) and dimethylforma ide (35mL) and heat at 90°C overnight. Cool to room temperature and partition between a 2:1 mixture of ethyl acetate/toluene and water. Separate the aqueous phase and wash the organic phase with water and brine. Dry (MgS0 4 ) and evaporate the solvent in vacuo . Purify by chromatography to give the title compound. Example 24 [ (2-(6-Methoxybenzothiazolyl) )carbonyl1-1- pjperidinecarboxylic acid, 1,1-dimethylethyl ester Slurry 2-amino-6-methoxybenzothiazole (0.255mol) in wate: (325mL), heat to reflux and add 48% hydrobromic acid (130mL). Maintain at reflux for 20 minutes, cool to 0°C and add a solution of sodium nitrite (17.56g, 0.255mol) in water (90mL), maintaining a temperature of 0°C. Stir at 0°C for 15 minutes and add by dropwise addition (while keeping cold) to a rapidly stirring mixture of copper (I) bromide (42.03g,0.293mol) in 48% hydrobromic acid (86mL) and water (225mL). Stir at room temperature for 20 minutes. Allow to stand overnight, extract into methylene chloride and dry (MgS0 4 ). Evaporate the solvent in vacuo and purify by chromatography to give 2-bromo-6- methoxybenzothiazole. Dissolve 2-bromo-6-methoxybenzothiazole (14.79mmol) in anhydrous tetrahydrofuran (50mL), place under an argon atmosphere and cool to -78°C. Add, by dropwise addition, n-butyllithium (6.5mL of a 2.5M solution in hexane, 16.27mmol) and stir at -78°C for 30 minutes. Add, by dropwise addition, a solution of 4-[[ (N-methoxy-N- methyl)amino]carbonyl]-l-piperidinecarboxylic acid, 1,1- dimethylethyl ester (4.03g, 14.79mmol) in anhydrous tetrahydrofuran (50mL). Stir at -78°C for 1.5 hours, remove the ice bath and allow to warm for 10 minutes, quench with saturated ammonium chloride (lOOmL) and stir for an additional hour. Separate the organic phase and extract the aqueous phase with ethyl acetate. Combine the organic phases, dry (MgS0 4 ) and evaporate the solvent in vacuo . Purify by chromatography to give the title compound. Examole 25 [ 2-(6-Methoxybenzothiazolyl ) ] f 4-pipericinyl ) • methanone»CF--;CO?H Mix 4-[ ( 2-( 6-methoxybenzothiazolyl ) )carbonyl1-1- piperidinecarboxylic acid, 1,1-dimethylethyl ester (30.31mmol) and trifluoroacetic acid (75mL) and stir at room temperature for 2 hours. Cool in an ice/water bath and add ethyl ether until a solid begins to precipitate. Stir at 0°C for 30 minutes, collect the solid by filtration and wash with ethyl ether to give the title compound. Example 26 4-f 3-f 4-[ f 2-f 6-Methoxybenzothiazolyl) 1carbonyl 1-1- pjperidinyl ]propoxyIbenzoic acid, methyl ester Mix [ 2-(6-methoxybenzothiazolyl) ] ( 4- piperidinyl)methanone»CF 3 C0 2 H (9.19mmol), 3-(4- methoxyphenyl )propyl bromide (9.64mmol), potassium carbonate (3.33g, 24.1mmol) and dimethylforma ide (35mL) and heat at 90°C overnight. Coci to room temperature and partition between a 2:1 mixture of ethyl acetate/toluene and water. Separate the aqueous phase and wash the organic phase with water and brine. Dry (MgS0 4 ) and evaporate the solvent in vacuo . Purify by chromatography to give the title compound. Example 27 4—[3—f4—T [2-(6-Methoxybenzothiazolyl) 1carbonyl1-1- piperidinyllpropoxyIbenzoic acid Dissolve 4-[3-[4-[ [2-(6-methoxybenzothiazolyl) ]carbony1]-1- piperidinyl]propoxyIbenzoic acid, methyl ester (0.233mmol) in ethanol (4mL) and treat with lithium hydroxide (42mg, lOmmol) and water (lmL). Stir under nitrogen atmosphere until hydrolysis is complete, evaporate the solvent, acidify with dilute hydrochloric acid and extract the aqueous phases with ethyl acetate (2X). Wash the combined organic phases with water, then with saturated sodium chloride. Dry (MgS0 4 ), evaporate the solvent in vacuo and purify by silica gel chromatography to give the title compound. Example 28 [ (2-(6-Fiuorobenzothiazoiyl) )carbonyl 1-1- piperidinecarboxylic acid, 1,1-dimethviethyl ester Slurry 2-amino-6-fluorobenzothiazole (0.255mol) in water (325mL), heat to reflux and add 48% hydrobromic acid (130mL). Maintain at reflux for 20 minutes, cool to 0°C and add a solution of sodium nitrite (17.56g, 0.255mol) in water (90mL), maintaining a temperature of 0°C. Stir at 0°C for 15 minutes and add by dropwise addition (while keeping cold) to a rapidly stirring mixture of copper (I) bromide (42.03g,0.293mol) in 48% hydrobromic acid (86mL) and water (225mL). Stir at room temperature for 20 minutes. Allow to stand overnight, extract into methylene chloride and dry (MgS0 4 ). Evaporate the solvent in vacuo and purify by chromatography to give 2-bromo-6- fluorobenzothiazole. Dissolve 2-bromo-6-fluorobenzothiazole (14.79mmol) in anhydrous tetrahydrofuran (50mL), place under an argon atmosphere and cool to -78°C. Add, by dropwise addition, n-butyllithium (6.5mL of a 2.5M solution in hexane, 16.27mmol) and stir at -78°C for 30 minutes. Add, by dropwise addition, a solution of 4-[[ (N-methoxy-N- methyl)aminojcarbonyl]-l-piperidinecarboxylic acid, 1,1- dimethylethyl ester (4.03c, 14.79mmol) in anhydrous tetrahydrofuran (50mL). Stir at -78°C for 1.5 hours, remove the ice bath and allow to warm for 10 minutes, quench with saturated ammonium chloride (lOOmL) and stir for an additional hour. Separate the organic phase and extract the aσueous phase with ethyl acetate. Combine the organic phases, dry (MgS0 4 ) and evaporate the solvent in vacuo . Purify by chromatography to give the title compound, Example 29 [ 2-(6-Fluorobenzothiazolyl) 1 (4-piperidinyl)- methanone->CF 3 C07H Mix 4-[ (2-(6-fluorobenzothiazolyl) )carbonyl]-l- piperidinecarboxylic acid, 1,1-dimethylethyl ester (30.31mmol) and trifluoroacetic acid (75mL) and stir at room temperature for 2 hours. Cool in an ice/water bath and add ethyl ether until a solid begins to precipitate. Stir at 0°C for 30 minutes, collect the solid by filtration and wash with ethyl ether to give the title compound. Example 30 2—[ — f2-(6-Fluorobenzothiazolyl) lcarbonyl1-1- pjperidinyllethoxylacetic acid, methyl ester Mix [2-(6-fluorobenzothiazolyl) ] (4- piperidinyl)methanone»CF 3 C0 2 H (9.19mmol), carbomethoxy methoxyethyl chloride (9.64mmol), potassium carbonate (3.33g, 24.1mmol) and dimethylformamide (35mL) and heat at 90°C overnight. Cool to room temperature and partition between a 2:1 mixture of ethyl acetate/toluene and water. Separate the aqueous phase and wash the organic phase with water and brine. Dry (MgS0 ) and evaporate the solvent in υacuo . Purify by chromatography to give the title compound, Example 31 2-f4-f [ 2-(6-Fluorobenzothiazolyl) jcarbonyl piperidinyllethoxylacetic acid Dissolve 2-[4-[ [ 2-(6-fluorobenzothiazolyl) jcarbonyl]-l- piperidinyllethoxyjacetic acid, methyl ester (0.233mmol) in ethanol (4mL) and treat with lithium hydroxide (42mg, lOmmol) and water (ImL). Stir under nitrogen atmosphere until hydrolysis is complete, evaporate the solvent, acidify with dilute hydrochloric acid and extract the aqueous phases with ethyl acetate (2X). Wash the combined organic phases with water, then with saturated sodium chloride. Dry (MgS0 4 ), evaporate the solvent in vacuo and purify by silica gel chromatography to give the title compound. The following compounds can be prepared according to the procedures described above in Examples 1-31: 2-[4-[ [2-(4-Chlorobenzothiazolyl) 1carbonyl1-1- piperidinylethoxy]acetic acid, methyl ester; 2—[4—[ [2-(4-Chlorobenzothiazolyl) ]carbony11-1- piperidinyl]ethoxyacetic acid; [2-(4-Chlorobenzothiazolyl1 [l-[2-(4-methoxyphenyl)ethyl]-4- piperidinyl]methanone; 4-[3-[4-[ [2-(4-Chlorobenzothiazolyl) 1carbonyl1-1- piperidinyl]propoxyIbenzoic acid, methyl ester; 4-[3-[4-[ [2-(4-Chlorobenzothiazolyl) 1carbonyl]-l- piperidinyljpropoxyIbenzoic acid; 2-[4-[ [2-(4-Methoxybenzothiazolyl) ]carbonyl]-l- piperidinyl]ethoxyacetic acid, methyl ester; 2-[ -[ [2-(4-Methoxybenzothiazolyl) ]carbonyl]-1- piperidinyl]ethoxyacetic acid; [2-(4-Methoxybenzothiazolyl] [1-[2-(4-methoxyphenyl)ethyl]- 4-piperidinylImethanone; 4-[3-[4-[ [2-(4-Methoxybenzothiazolyl) ]carbonyl]-1- piperidinyl]propoxyIbenzoic acid, methyl ester; 4-[3-[4-[ [2-(4-Methoxybenzothiazolyl) ]carbonyl]-1- piperidinyl]propoxyIbenzoic acid; 2-[4-[ [2-(6-Methoxybenzothiazolyl) ]carbonyl]-l- piperidinyl]ethoxyacetic acid, methyl ester; 2-[ 4-[ f2-(6-Methoxybenzothiazolyl) jcarbonyl]-l- piperidinyllethoxyacetic acid; [2-(6-Methoxybenzothiazolyl] [1-f2-(4-methoxyphenyl)ethyl]- -piperidinyljmethanone; 4-[3-[4-[ [2-(6-Methoxybenzothiazolyl) ]carbonyl1-1- piperidinylIpropoxyIbenzoic acid, methyl ester; 4—[3—t4—[ [2-(6-Methoxybenzothiazolyl) ]carbonyl]-l- piperidinylIpropoxyIbenzoic acid; 2-[ -f f2-( -Methylbenzothiazolyl) ]carbonyl]-I- piperidinyllethoxyacetic acid, methyl ester; 2-[ -[ f2-(4-Methylbenzothiazolyl) ]carbonyl]-l- piperidinyllethoxyacetic acid; [2-(4-Methylbenzothiazolyl1 [l-f2-(4-methoxyphenyl)ethyl1-4- piperidinylImethanone; 4—[3—[4—[ [2-(4-Methylbenzothiazolyl) 1carbonyl1-1- piperidinylIpropoxyIbenzoic acid, methyl ester; 4-f3-[4-[ f2-(4-Methylbenzothiazolyl) ]carbonyl1-1- piperidinylIpropoxyIbenzoic acid? 2-[ -[ [2-(6-Methylbenzothiazolyl) ]carbonyl1-1- piperidinyllethoxyacetic acid, methyl ester; 2-[4-f [2-(6-Methylbenzothiazolyl) ]carbonyl1-1- piperidinyllethoxyacetic acid; f2-(6-Methylbenzothiazolyl1 [1-[2—( -methoxyphenyl)ethyl1-4- piperidinylImethanone; 4—[3—[ —[ [2-(6-Methylbenzothiazolyl) ]carbonyl]-l- piperidinylIpropoxyIbenzoic acid, methyl ester; 4—[3—[4—[ [2-(6-Methylbenzothiazolyl) ]carbonyl]-1- piperidinylIpropoxyIbenzoic acid; 2-[4-[ t2-(6-Fluorobenzothiazolyl) ]carbonyl]-l- piperidinyllethoxyacetic acid, methyl ester; 2-[4-[ [2-(6-Fluorobenzothiazolyl) lcarbonyl1-1- piperidinyllethoxyacetic acid; [2-(6-Fluorobenzothiazolyl] [l-[2-(4-methoxyphenyl)ethyl]-4- piperidinyl]methanone; 4-[3-[4-[ [2-(6-Fluorobenzothiazolyl) lcarbonyl]-l- piperidinylIpropoxy]benzoic acid, methyl ester; 4-[3-[4-[ [2-(6-Fluorobenzothiazolyl) 1carbonyl]-1- piperidinylIpropoxyIbenzoic acid; 2-[4-[ [2-(6-Chlorobenzothiazolyl) lcarbonyl]-l- piperidinyllethoxyacetic acid, methyl ester; 2-[4-[ [2-(6-Chlorobenzothiazolyl) ]carbonyl}-l- piperidinyllethoxyacetic acid; f2-(6-Chlorobenzothiazolyl] f1-[2-(4-methoxyphenyl)ethyl1-4- piperidinylImethanone; 4—[3—[ —[ [2-(6-Chlorobenzothiazolyl) lcarbonyl1-1- piperidinyl]propoxy]benzoic acid, methyl ester; 4-f 3-[4-[ [ 2-(6-Chlorobenzothiazolyl) ]carbonyl ]-1- piperidinyl IpropoxyIbenzoic acid. A general synthetic procedure for the preparation of the compounds of Formula I wherein Y is -C(=CH 2 )-, -C(H)(OH)-, -C(OH) (phenyl)- or -C(B)(0H)- is set forth in Scheme B. In Scheme B, all substituents are as previously defined unless otherwise indicated. Scheme B (6] R 4 (8) Y 1 = phenyl or R 4 * Scheme B provides a general syntnetic procedure for preparing the compounds cf Formula I wnerein Y is -C(=CH 2 )-,-C(H) (OH)-, -C(OH) (pnenyl)- or -C(B)(OH)-. In step al, the carbonyl functionality of tne appropriate piperidinyl thiacyclic derivative of structure (6) is reduced to the corresponding hydroxymethylene group by techniques well known in the art. For example, one suitable technique is to react the piperidinyl thiacyclic derivative of structure (6) with a reducing agent, such as sodium borohydride, in a suitable solvent such as ethanol. The piperidinyl thiacyclic derivative of structure (6) and the reducing agent are preferably present in the reaction zone in an approximately equimolar quantity. A slight excess of either reactant is not deleterious to the reaction. The reaction is allowed to proceed for a period of time ranging from about 20 minutes to about 5 hours, and more preferably about 1.5 hours. The solvent is removed under vacuum and the piperidinyl thiacyclic derivative of structure (7) can be recovered from the reaction zone by treatment with water and extraction with an organic solvent as is known in the art. The piperidinyl thiacyclic derivative of structure (7) can be purified by techniσues known in the art such as recrystallization or chromatography as described previously in Scheme A, step a. In step a2, the carbonyl functionality of the appropriate piperidinyl thiacyclic derivative of structure (6) is converted to the corresponding ethenylene group by techniques well known in the art. For example, one suitable technique is to react the piperidinyl thiacyclic derivative of structure (6) with a suitable ylide such as triphenylphosphonium methylide, in a suitable solvent such as tetrahydrofuran. The piperidinyl thiacyclic derivative of structure (6) and the triphenylphosphonium methylide are preferably present in the reaction zone in an approximately equimolar quantity. A slight excess of either reactant is not deleterious to the reaction. The reaction is allowed to proceed for a period of time ranging from about 20 minutes to about 5 hours, and more preferably about 2 hours; at a temperature range of from about -40°C to room temperature, and more preferably about -10°C. The reaction is then quenched with a proton source such as, for example, water or saturated aqueous ammonium chloride. The resulting reaction mixture is extracted with a sutiable solvent, such as ethyl ether, dried over either Na 2 S0 4 or MgS0 , filtered and the solvent evaporated in vacuo . The piperidinyl thiacyclic derivative of structure (8) can be purified by techniques known in the art such as recrystallization or chromatography as described previously in Scheme A, step a. In step a3, the carbonyl functionality of the appropriate piperidinyl thiacyclic derivative of structure (6) is converted to the corresponding phenyl tertiary alcohol or thiacyclic tertiary alcohol group by techniques well known in the art. For example, one suitable technique is to react the piperidinyl thiacyclic derivative of structure (6) with a suitable lithio thiacyclic derivative of structure (1) or phenyllithium in a suitable solvent such as tetrahydrofuran. The piperidinyl thiacyclic derivative of structure (6) and the suitable lithio thiacyclic derivative of structure (1) or phenyllithium are preferably present in the reaction zone in an approximately equimolar quantity. A slight excess of either reactant is not deleterious to the reaction. The reaction is allowed to proceed for a period of time ranging from about 5 minutes to about 5 hours, and more preferably about 30 minutes; at a temperature range of from about -90°C to -40°C, and more preferably about -78°C. The reaction is then quenched with a proton source such as, for example, saturated aqueous ammonium chloride or methanol. The resulting reaction mixture is extracted with a suitable solvent, such as ethyl ether, dried over either Na 2 S0 or MgS0 , filtered and the solvent evaporated in vacuo . The piperidinyl thiacyclic derivative of structure (9) can be purified by techniσues known in the art such as recrystallization or chromatography as described previously in Scheme A, step a. Alternatively, those piperidinyl thiacyclic derivatives of structure (7), those piperidinyl thiacyclic derivatives of structure (8) and those piperidinyl thiacyclic derivatives of structure (9) wherein Ri is -(CH 2 ) n -Z- (CH 2 ) m COR 5 wherein R 5 is OH or wherein R 9 is C0 2 Rχι and Ru is H may be prepared from tne appropriate piperidinyl thiacyclic derivatives of structure (7), the piperidinyl thiacyclic derivatives of structure (8) and the piperidinyl thiacyclic derivatives of structure (9) wherein Ri is -(CE 2 ) n -Z-(CH 2 ) m CORs wherein R 5 is C 1 - 4 alkoxy or wherein Rg is C0 Rn and Ru is C 1 -4 alkyl via an ester hydrolysis reaction as is known in the art. Starting materials for use in Scheme B are readily avaiable to one of ordinary skill in the art. The following examples present typical syntheses as described in Scheme B. These examples are understood to be illustrative only and are not intended to limit the scope of the present invention in any way. Example 32 α- f l- [ 2- ( 4-Methoxyphenyl ) ethyl 1 -4-piperidinyl 1 -α-phenyl-2- benzothiazolemethanol Dissolve [2-benzothiazolyll [l-[2-(4-methoxyphenyl)ethyl1-4- piperidinylImethanone (2.0g, 5.26mmol) in anhydrous tetrahydrofuran (50mL), place under an argon atmosphere and cool to -78°C. Add, by dropwise addition, phenyllithium (3.16mL of a 2.0M solution in cyclohexane/ethyl ether, 6.31mmol). Stir at -78°C for 30 minutes, quench with saturated ammonium chloride (lOOmL), separate the organic phase and extract the aqueous phase with ethyl acetate. Combine the organic phases, dry (MgS0 4 ) and evaporate the solvent in vacuo . Purify by chromatography (75% ethyl acetate/hexane) to give a yellow oil. Dissolve the oil in methylene chloride and treat with activated charcoal. Filter and evaporate the solvent in vacuo to give the title compound as a white electrostatic powder; mp 67-70°C. Anal. Calcd for C 28 H 3 oN 2 0 2 S: C, 73.33; H, 6.59; N, 6.11. Found: C, 72.73; K, 6.64; N, 5.90. Example 33 α—[1—[2—(4-Methoxyphenyl)ethyl1-4-piperidinyl1-2- benzothiazolemethanol Dissolve [2-benzothiazolyll fl-f 2-(4-methoxyphenyl)ethyl1-4- piperidinylImethanone (3.0g, 7.88mmol) in methanol (ISOmL) and cool to 0°C. Add sodium borohydride (597mg, 15.77mmol) and stir for 1.5 hours, adding additional sodium borohydride after 30 minutes. Evaporate the solvent in vacuo and partition the residue between water and methylene chloride. Separate the organic phase, wash with saturated sodium chloride, dry (MgS0 4 ) and evaporate the solvent in vacuo . Purify by recrystallization (ethyl acetate) to give the title compound as white fluffy crystals; mp 127-129°C. Anal. Calcd for C 22 H 26 N 2 O 2 S»0.25H 2 0: C, 68.27; H, 6.90; N, 7.24. Found; C, 68.30; H, 6.89; N, 7.25 Example 34 2-[l-fl-f2-(4-Methoxyphenyl)ethyl1-4- piperidinyllethenylIbenzothiazole Dissolve methyltriphenylphosphonium bromide (2.50g, 6.99mmol) in anhydrous tetrahydrofuran (50mL). Add n- butyllithiu (2.8mL of a 2.5M solution in hexane, 6.99mmol) and cool to -10°C. Add, by dropwise addition, a solution of [2-benzothiazolyl] [l-[2-(4-methoxyphenyl)ethyl]-4- piperidinylImethanone (2.66g, 6.99mmol) in anhydrous tetrahydrofuran (50mL). Stir for 2 hours then quench with water. Separate the organic phase and extract the aqueous phase with ethyl ether. Combine the organic phases, dry (MgS0 ) and evaporate the solvent in vacuo . Purify by chromatography (50% ethyl ether/hexane) to give the title compound as a white powder; mp 84-85°C. Anal. Calcd for C 23 H 26 N 2 0S: C, 72.98; H, 6.92; N, 7.40. Found: C, 72.92; H, 7.01; N, 7.28. Another general synthetic procedure for the preparation of the compounds of Formula I wherein Y is -C(=0)- or -C(H)(OH)- is set forth in Scheme C. In Scheme C, all substituents are as previously defined unless otherwise indicated. Scheme C In step a, the appropriate lithio thiacyclic derivative of structure (1) is reacted with the piperidinyl derivative of structure (10) to give the corresponding piperidinyl thiacyclic derivative of structure (7). For example, a solution of the appropriate lithio thiacyclic derivative of structure (1) is contacted with the piperidinyl derivative of structure (10) at a temperature range of from about -90°C to about -50°C and more preferably about -78°C. The reaction is typically conducted under anhydrous conditions in a suitable aprotic organic solvent such as tetrahydrofuran. A slight excess of either reactant is not deleterious to the reaction. The piperidinyl derivative and the benzimidazole derivative are preferably present in the reaction zone in an approximately equimolar quantity. The reaction is allowed to proceed for 5 a period of time ranging from about 20 minutes to about 5 hours, and more preferably about 2 hours. The reaction is then quenched with a proton source such as, for example, saturated aqueous ammonium chloride or methanol. The resulting reaction mixture after dilution with water is 10 extracted with a suitable solvent, such as ethyl acetate, washed with water, dried over either Na S0 4 or MgS0 4 , filtered and the solvent evaporated in vacuo . The piperidinyl thiacyclic derivative of structure (7) can be purified by techniques known in the art such as 15. recrystallization or chromatography as described previously in Scheme A, step a. In optional step b, the hydroxy methylene functionality of the appropriate piperidinyl thiacyclic derivative of 20 structure (7) is oxidized to give the corresponding piperidinyl thiacyclic derivative of structure (6) by techniques well known in the art, such as Swern Oxidation using dimethylsulfoxide, oxalyl chloride and triethylamine. 25 The piperidinyl thiacyclic derivatives of structure (6) may be converted to the corresponding piperidinyl thiacyclic derivatives of structures (7), (8) and (9) as described previously in Scheme B. 30 Starting materials for use in Scheme C are readily available to one of ordinary skill in the art. For example, l-(2-phenylethyl)-4-piperidinecarboxyaldehyde is disclosed in United States Patent 5,021,428 which is hereby incorporated by reference. 35 The following examples present typical syntheses as described in Scneme C. Tnese examples are understood to be illustrative only and are not intended to limit tne scope of tne present invention in any way. Example 35 α-f 1- ( 2-Phenylethyl )-4-piperidinyl 1-2- benzo[b] thiopheneπtethanol Dissolve benzofb]thiophene (2.21g, 16.38mmol) in anhydrous tetrahydrofuran (70mL), place under an argon atmosphere and cool to -78°C. Add, by dropwise addition, n-butyllithium (7.21mL of a 2.5M solution in hexane, 18.02mmol) and stir for 30 minutes at -78°C. Add, by dropwise addition, a solution of 1-( 2-phenylethyl)-4-piperidinecarboxyaldehyde (3.56g, 16.38mmol) in annydrous tetrahydrofuran (25mL). Stir at -78°C for 2 hours, remove the ice bath and allow tc warm over 1 hour. Quench with methanol (lOmL) and pour into aσueous saturated ammonium chloride (lOOmL). Separate the organic phase and extract the aqueous phase with ethyl acetate. Combine the organic phases, dry (MgS0 4 ) and evaporate the solvent in vacuo . Purify by crystallization (ethyl acetate/hexane) to give the title compound as a white crystalline solid; mp I78°C. Anal. Calcd for C 22 H 25 NOS: C, 75.17; H, 7.17; N, 3.94 Found: C, 75.08; H, 7.32; N, 4.23. Example 36 fBenzofb]thiophene-2-yl] fl-(2-phenylethyl)-4- piperidinylImethanone Dissolve oxalyl chloride (4.22g, 33.28mmol) in methylene chloride (200mL), place under an argon atmosphere and cool to -78°C. Add, by dropwise addition, dimethylsulfoxide (5.42g, 69.33mmol) and stir at -78°C for 15 minutes. Add, by dropwise addition, a solution of α-[l-(2-phenylethyl)-4- piperidinyl]-2-benzo[b]thiophenemethanol (9.75g, 27.73mmol) in dimethylsulfoxide (150mL). Stir at -78°C for 30 minutes, add triethylamine (15.18g, 0.150mol) and stir at -78°C for 1 hour. Remove the ice bath and stir for an additional 1.5 hours. Evaporate the solvent in vacuo and recrystaliize (isopropanol) to give the title compound as a fluffy white crystalline solid; mp 129-130°C. Anal. Calcd for C 22 H 23 NOS: C, 75.61; H, 6.63; N, 4.01. Found: C, 75.46; H, 6.63; N, 3.87. .4 - Examole 37 α-f1-(2-Phenylethyl )-4-pipe idinyl]-ct-phenyl-2- benzofb]thiophenemethanol Dissolve [benzofb]thiophene-2-yl] [l-(2-phenylethyl)-4- piperidinylImethanone (3.5g, lO.Olmmol) in anhydrous tetrahydrofuran (lOOmL), place under an argon atmosphere and cool to -78°C. Add, by dropwise addition, phenyllithium (6mL of a 2.0M solution in cyclohexane/ethyl ether, 12.0mmol) and stir at -78°C for 5 hours. Remove the ice bath and allow to warm to room temperature. Pour into saturated ammonium chloride (lOOmL) and stir for 20 minutes. Separate the organic phase and extract the aqueous phase with ethyl acetate. Combine the organic phases, wash with water, dry (MgS0 ) and evaporate the solvent in vacuo . Purify by chromatography (50% ethyl acetate/hexane) and recrystaliize (isopropanol) to give the title compound as a white solid; mp 144-146°C. Anal. Calcd for C 28 H 29 NOS: C, 78.65; H, 6.84; N, 3.28. Found: C, 78.55; H, 6.94; N, 3.20. Exa ple 38 α-fl-(2-Phenylethyl)-4-piperidinyl1-3- benzofb]thiophenemethanol Dissolve n-butyllithium (9.4mL of a 2.5M solution in hexane, 23.46mmol) in anhydrous ethyl ether (lOOmL), place under an argon atmosphere and cool to -78°C. Add, by dropwise addition, a solution of 3-bromobenzofb]thiophene (5.0g, 23.46mmol) in anhydrous ethyl ether (50mL). Stir at -78°C for 30 minutes then add, by dropwise addition, a solution of l-(2-phenylethyl)-4-piperidinecarboxaldehyde (5.10g, 23.46mmol) in anhydrous ethyl ether (50mL). Stir for 5 hours at -78°C, remove the ice bath and stir for an additional 1 hour. Quench with saturated ammonium chloride (150mL) and stir overnight. Separate the organic phase and extract the aσueous phase with ethyl ether and methylene chloride. Combine the organic phases, dry (MgS0 4 ) and evaporate the solvent in vacuo . Purify by recrystallization (isopropanol) to give the title compound as an off-white solid. Anal. Calcd for C 22 H 25 NOS: C, 75.17; H, 7.17; N, 3.98. Found: C, 75.10; H, 7.22; N, 4.16. Exampie 39 [Benzofb]thiophene-3-yl1 f1-(2-phenylethyl .-4* piperidinylIme hanone Dissolve oxalyl chloride (4.22g, 33.28mmol) in methylene chloride (200mL), place under an argon atmosphere and cool to -78°C. Add, by dropwise addition, dimethylsulfoxide (5.42g, 69.33mmol) and stir at -78°C for 15 minutes. Add, by dropwise addition, a solution of α-[l-(2-phenylethyl)-4- piperidinyl]-3-benzo[b]thiophenemethanol (9.75g, 27.73mmol) in dimethylsulfoxide (150mL). Stir at -78°C for 30 minutes, add triethylamine (15.18g, 0.150mol) and stir at -78°C for 1 hour. Remove the ice bath and stir for an additional 1.5 hours. Evaporate the solvent in vacuo and recrystaliize (isopropanol) to give the title compound as a tan powder; mp 110-112°C. Anal. Calcd for C 22 H 23 NOS: C, 75.61; H, 6.63; N, 4.01. Found: C, 75.66; H, 6.74; N, 3.98. Example 40 α-[l-(2-Phenylethyl)-4-piperidinyl1-2-thiophenemethanol Dissolve l-(2-phenylethyl)-4-piperidinecarboxaldehyde (10.Og, 46.02mmol) in anhydrous tetrahydrofuran (300mL), place under an argon atmosphere and cool to -78°C. Add, by dropwise addition, a solution of 2-lithiothiophene (46.02mL of a IM solution in tetrahydrofuran, 46.02mmol) and stir for 3 hours at -78°C. Quench with saturated ammonium chloride, separate the organic phase and extract the aqueous phase with ethyl acetate. Combine the organic phases, dry (MgS0 4 ) and evaporate the solvent in vacuo . Purify by chromatography (ethyl acetate) and recrystaliize (cyclohexane) to give the title compound as a white solid; mp 123-125°C. Anal. Calcd for Cι 8 H 23 NOS: C, 71.72; H, 7.69; N, 4.65. Found: C, 71.76; H, 7.88; N, 4.57. Examoie 41 ' Thiophene-2-yl ] [l-(2-phenylethyl)-4-piperidinylImethanone Dissolve oxalyl chloride (1.23g, 9.67mmol) in methylene chloride (lOOmL), place under an argon atmosphere and cool to -78°C. Add dimethylsulfoxide (1.43mL) and stir for 15 minutes. Add, by dropwise addition, a solution of α-[l-(2- phenylethyl)-4-piperidinyl1-2-thiophenemethanol (2.43g, 8.06mmol) in methylene chloride (lOOmL). Stir at -78°C for 30 minutes, then add triethylamine (6.07mL). Stir at - 78°C for 30 minutes, remove the ice bath and allow to warm to room temperature. Evaporate the solvent in vacuo and partition between methylene chloride and water. Separate the organic phase and extract the aσueous phase with methylene chloride. Combine the organic phases, wash with water and dry (MgS0 4 ). Evaporate the solvent in vacuo and recrystaliize (isopropanol) to give the title compound as a white crystalline solid; mp 77~79°C. Anal. Calcd for Cι 8 H 2 ιNOS: C, 72.20; H, 7.07; N, 4.68. Found: C, 72.13? H, 7.18; N, 4.61. Example 42 α-fl-(2-Phenylethyl)-4-piperidinyl]-2-thiazolemethanol Prepare according to the procedure described in Example 29 using 2-lithiothiazole. Example 43 f2-Thiazolyl] fl-(2-phenylethyl)-4-piperidinyl]methanone Prepare according to the procedure described in Example 30 using α-[l-(2-phenylethyl)-4-piperidinyl]-2- thiazolemethanol. Another general synthetic procedure for the preparation of the compounds of Formula I wherein Y is -C(=0)- is set forth in Scheme D. In Scheme D, all substituents are as previously defined unless otherwise indicated. Scheme D E = Cι-C alkoxy or N(0CH 3 )CH3 Scheme D provides a general synthetic procedure for preparing the comounds of Formula (I) wherein Y is -C(=0)-. For example, a solution of the appropriate lithio thiacyclic derivative of structure (1) is contacted with the piperidinyl derivative of structure (11) at a temperature range of from about -90°C to about -50°C and more preferably about -78°C. The reaction is typically conducted under anhydrous conditions in a suitable aprotic organic solvent such as tetrahydrofuran. A slight excess of either reactant is not deleterious to the reaction. The piperidinyl derivative and the benzimidazole derivative are preferably present in the reaction zone in an approximately equimolar quantity. The reaction is allowed to proceed for a period of time ranging from about 20 minutes to about 5 hours, and more preferably about 1 hour. The reaction is then quenched with a proton source such as, for example, saturated aqueous ammonium chloride or methanol. The resulting reaction mixture is extracted with a suitable solvent, such as ethyl acetate, washed with water, dried over either Na 2 S0 4 or MgS0 4 , filtered and the solvent evaporated in vacuo . The piperidinyl thiacyclic derivative of structure (6) can be purified by techniques known in the art such as recrystallization or chromatography as described previously in Scheme A, step a. The piperidinyl thiacyclic derivatives of structure (6) may be converted to the corresponding piperidinyl thiacyclic derivatives of structures (7), (8) and (9) as described previously in Scheme B. Starting materials for use in Scheme D are readily available to one of ordinary skill in the art. For example, 1-[2-(4-methoxyphenyl)ethyl]-4- piperidinecarboxylic acid, methyl ester is described in J. Org. Chem. , 5_5, 1399 1990. The following example presents a typical synthesis as described in Scheme D. This example is understood to be illustrative only and is not intended to limit the scope of the present invention in any way. Example 44 i 2-Benzothiazolyl 1 [ 1—[ 2—( 4-methoxyp ' nenyl )ethyl]-4- pjperidinyl Imethanone Dissolve freshly distilled benzothiazole (3.41g, 25.24mmcl) in anhydrous tetrahydrofuran (60mL), place under an argon atmosphere and cool to -78°C. Add, by dropwise addition, n-butyllithium (15.14mL of a 2.5M solution in hexane, 37.86mmol) and stir briefly at -78°C. Add, by dropwise addition, a solution of l-f 2- ( 4-methoxyphenyl)ethyl ]-4- piperidinecarboxylic acid, methyl ester (7.0g, 25.24mmol) in anhydrous tetrahydrofuran (40mL). Stir for 1 hour at - 78°C, quench with methanol (5mL) and pour into saturated ammonium chloride (lOOmL). Filter, separate the organic phase and extract the aqueous phase with ethyl acetate. Combine the organic phases and wash with water and brine. Dry (MgS0 4 ) and evaporate the solvent in vacuo . Purify by chromatography (ethyl acetate) and recrystaliize (cyclohexane) to give the title compound as a pale yellow powder; mp 118-120°C. Anal. Calcd for C 22 H 24 N 2 0 2 S: C, 69.44; 6.36; N, 7.36 Found: C, 69.65; E, 6.51; N, 7.21 Example 10 gives an alternative method of making this compound. A general synthetic procedure for the preparation of the compounds of Formula I wherein Y is -C(B)(OH)- wherein 3 and the thiacyclic portion of the compound of Formula I are identical is set forth in Scheme Ξ. In Scheme E, all substituents are as previously defined unless otherwise indicated. Scheme E (13) = C1-C4 alkoxy The appropriate lithio thiacyclic derivative of structure (1) is reacted with the piperidinyl derivative of structure (12) to give the corresponding bis(thiacyclic) tertiary alcohol derivative of structure (13). For example, a solution of the appropriate lithio thiacyclic derivative of structure (1) is contacted with, the piperidinyl derivative of structure (12) at a temperature range of from about -90°C to about -50°C and more preferably about -78°C. The reaction is typically conducted under anhydrous conditions in a suitable aprotic organic solvent such as tetrahydro uran. The piperidinyl derivative and the lithio thiacyclic derivative are preferably present in the reaction zone in an approximately a 1:2 ratio. The reaction is allowed to proceed for a period of time ranging from about 20 minutes to about 5 hours, and more preferably about 2 hours. The reaction is then quenched with a proton source such as, for example, saturated aσueous ammonium chloride or methanol. Tne resulting reaction mixture is extracted with a suitable solvent, such as ethyl acetate, washed with water, dried over either Na 2 S0 or MgS0 4 , filtered and the solvent evaporated in vacuo . The bis(thiacyclic) tertiary alcohol derivative of structure (13) can be purified by techniques known in the art such as recrystallization or chromatography as described previously in Scheme A, step a. Alternatively, those bis( thiacyclic) tertiary alcohol derivatives of structure (13) wherein Ri is -(CH ) n -Σ- (CH ) m COR 5 wherein R 5 is OH or wherein Rg is C0 2 Rn and Ru is H may be prepared from the appropriate bis(thiacyclic) tertiary alcohol derivatives of structure (13) wherein Ri is -(CH 2 ) n -Z-(CH 2 ) ιr) COR 5 wherein R 5 is Cι~ alkoxy or wherein Rg is C0 Rn and Ru is Cι~ alkyl via an ester hydrolysis reaction as is known in the art. Starting materials for use in Scheme E are readily available to one of ordinary skill in the art. The following examples present typical syntheses as described in Scheme E. These examples are understood to be illustrative only and are not intended to limit the scope of the present invention in any way. Example 45 ct—C1—[2—(4-Methoxyphenyl)ethyl]-4-piperidinyl1-ot- (thiophene-2-yl)-2-thiophenemethanol Dissolve l-[2-(4-methoxyphenyl)ethyl1-4- piperidinecarboxylic acid, methyl ester (4.0g, 14.42mmol) in anhydrous tetrahydrofuran (lOOmL), place under an argon atmosphere and cool to -78°C. Add, by dropwise addition, 2-lithiothiophene (14.42mL of a IM solution in tetrahydrofuran, 14.42mmol) and stir at -78°C for 3 hours. Add additional 2-lithiothiophene (14.42mL of a IM solution in tetrahydrofuran, 14.42mmol) and stir at -78°C for 2 hours. Remove the ice bath and allow to warm to room temperature. Quench with saturated ammonium chloride (lOOmL), separate the organic phase and extract the aqueous phase with ethyl acetate. Combine the organic phases, dry (MgS0 4 ) and evaporate the solvent in vacuo . Purify by chromatography (ethyl acetate) and recrystaliize (ethyl acetate) to give the title compound as fluffy white crystals; mp 153-155°C. Anal. Calcd for C 23 H 27 N0 2 S 2 : C, 66.79; H, 6.58; N, 3.39 Found: C, 66.68; K, 6.40; N, 3.49. Example 46 α-[ 1- f 2-( 4-Methoxyphenyl)ethyl 1-4-pioeridinyl1-α-( 2- thiazolyll)-2-thiazolemethanol Prepare according to the procedure described in Example 34 using 2-lithiothiazole. Example 47 α—C1—[2—(4-Methoxyphenyl)ethyl }-4-piperidinyl]-α- (benzo[b1thiophene-2-yl)-2-benzofb1thiophenemethanol Dissolve benzofblthiophene (10.Og, 74.5mmol) in anhydrous tetrahydrofuran (lOOmL), place under an argon atmosphere and cool to -78°C. Add, by dropwise addition, n- butyllithium (32.79mL, 81.97mmol) and stir briefly. Add, by dropwise addition, a solution of l-[2-(4- methoxyphenyl)ethyl1-4-piperidinecarboxylic acid, methyl ester (20.67g, 74.52mmol) in anhydrous tetrahydrofuran (200mL) and stir at -78°C for 1.5 hours. Quench with saturated ammonium chloride, separate the organic phase and extract the aqueous phase with ethyl ether. Combine the organic phases, dry (MgS0 4 ) and evaporate the solvent in vacuo . Purify by chromatograpny (50% ethyl acetate/hexane) and recrystaliize (isopropanol) to give the title compound as a white solid; mp 168-179°C. Anal. Calcd for C 23 H 25 N0 2 S: C, 72.79; H, 6.64; N, 3.69. Found: C, 72.34; H, 6.15; N, 2.63. Another general synthetic procedure for the preparation of the compounds of Formula I wherein Y is -C(OH) (phenyl)- is set forth in Scheme F. In Scheme F, all substituents are as previously defined unless otherwise indicated. Scheme F For example, a solution of the appropriate lithio thiacyclic derivative of structure (1) is contacted with the piperidinyl derivative of structure (14) at a temperature range of from about -90°C to about -50°C and more preferably about -78°C. The reaction is typically conducted under anhydrous conditions in a suitable aprotic organic solvent such as tetrahydrofuran. The piperidinyl derivative and the lithio thiacyclic derivative are preferably present in the reaction zone in an approximately equimolar quantitiy. A slight excess of either reactant is not deleterious to the reaction. The reaction is allowed to proceed for a period of time ranging from about 20 minutes to about 5 hours, and more preferably about 2 hours. The reaction is then quenched with a proton source such as, for example, saturated aqueous ammonium chloride or methanol. The resulting reaction mixture is extracted with a suitable solvent, such as ethyl acetate, washed with water, dried over either Na 2 S0 4 or MgS0 4 , filtered and the solvent evaporated in vacuo . The piperidinyl thiacyclic derivative of structure (15) can be purified by techniques known in the art such as recrystallization or chromatography as described previously in Scheme A, step a. Alternatively, those piperidinyl thiacyclic derivatives of structure (15) wherein Ri is -(CH 2 ) n -Z-(CH ) m COR 5 wherein 5 is OH or wherein Rg is C0 2 Rn and Ru is H may be prepared from the appropriate piperidinyl thiacyclic derivatives of structure (15) wherein Ri is -(CH ) n -Z-(CH 2 ) π ,COR 5 wherein R 5 is C 1 - alkoxy or wherein Rg is C0 2 Rn and Ru is C 1 - 4 alkyl via an ester hydrolysis reaction as is known in the art. Starting materials for use in Scheme F are readily available to one or ordinary skill in the art. For example, phenylf1-(2-phenylethyl)-4- piperidinyl]methanone»HCl and α-fl-(2-phenylethyl)-4- piperidinyl]phenylmethanol-»HCl is disclosed in United States Patent 5,021,428 which is hereby incorporated by reference. The following example presents a typical synthesis as described in Scheme F. This example is understood to be illustrative only and is not intended to limit the scope of the present invention in any way. Example 48 α-fl-(2-Phenylethyl)-4-piperidinyll-a-phenyl-2- thiophenemethanol Mix phenyl[l-(2-phenylethyl)-4-piperidinylImethanone«HC1 (5.0g, 15.16mmol), IN sodium hydroxide (lOOmL) and methylene chloride (250mL) and stir overnight at room temperature. Separate the organic phase and extract the aqueous phase with methylene chloride. Combine the organic phases, dry (MgSθ 4 ) and evaporate the solvent in vacuo to give phenyl[l-(2-phenylethyl)-4-piperidinylImethanone. Dissolve phenyl[l-(2-phenylethyl)-4-piperidinylImethanone (4.45g, 15.16mmol) in anhydrous tetrahydrof ran (40mL), place under an argon atmosphere and cool to -78°C. Add, by dropwise addition, 2-lithiothiophene (15.16mL of a IM solution in tetrahydrofuran, 15.l6mmol) and stir at -78°C for 1.5 hours. Quench with saturated ammonium chloride, separate the organic phase and extract the aqueous phase with ethyl ether. Combine the organic phases, dry (MgS0 4 ) and evaporate the solvent in vacuo . Purify by chromatography (50% ethyl acetate/hexane) and recrystaliize (cyclohexane) to give the title compound as a white crystalline solid; mp 143-144°C. Anal. Calcd for C 24 H 27 NOS: C, 76.35; H, 7.21; N, 3.71. Found: C, 76.34; H, 7.32; N, 3.59. Example 49 α-fl-(2-Phenylethyl)- -piperidinyll-ot-phenyl-2- thiazolemethanol Prepare according to the procedure described in Example 37 using 2-lithiothiazole. The compounds of the present invention are useful as non-sedating Hi anti-histamineε and mediator release inhibitors and are thus useful in the treatment of a variety of allergic diseases such as allergic rhinitis, seasonal rhinitis, allergic dermatoses such as acute urticaria, atopic dermatitis, contact dermatitis, gastrointestinal allergies which can be caused by the ingeεtion of either food or drugs, allergic pulmonary disease, ophthalmic allergies, insect stings and anaphylaxis, including the inhibition of brochospasms. These conditions and diseases can be relieved by administering to the patient in need thereof the compounds of formula I in an amount sufficient to treat the disease or condition such as an anti-allergic disease amount. Since compounds of formula I are also seratonin 5HT 2 antagonists, they are useful in the treatment of a variety of disease states and conditions such as the treatment of anxiety, varxant angina, anorexia ή * phenomenon, intermittent claudication and coronary or peripheral vasoεpasms. Also, these compounds can be used to treat late restenosis and to inhibit the development of atherosclerosis. The compounds inhibit the development of vascular smooth muscle cell hyperplasia. They should be administered on a prophylactic basis to prevent the development of this condition. These conditions and diseases can be relieved by administering to the patient in need thereof the compounds of formula I in an amount sufficient to treat the disease or condition such as an anxiolytic amount, antianginal amount, anti-anorexic amount. This can also be defined as an amount effective in treating a patient having a disease which responds to antagonism of 5HT 2 receptors. This quantity will be within the dosage range at which the compound exhibits its serotonin 5HT 2 antagonistic properties. One method of demonstrating the utility of the compounds of Formula I as anti-allergic disease agents is the following test protocol. One group of 10 guinea pigs is dosed orally with from about O.lmg/kg to about lOOmg/kg of the test compound. A control group of 10 guinea pigs is dosed orally with a similar volume of a vehicle (a solution of 0.5% methylcellulose and 1% ethanol). Both groups should be anesthetized and their dorsal areas shaved. One hour later, both groups are given intravenous injections of 1% Evans Blue Dye (1ml) via the jugular vein. Immediately following the dye injection, both groups are injected intradermally in the dorsal area with histamine diphosphate injections (lμg/0.1 ml) to produce histamine wheals. Twenty minutes after injection of the histamine, the animals are sacrificed and the size of the wheal area is then calculated from the diameter of the exposed wheal. A compound is considered to possess antihistamine activity if the wheal area of the drug treated group is statistically smaller than that of the control group. Any other method for testing the compounds of Formula I for anti-allergic efficacy may be used. For example, see Van Rossum, J. M. , Arch, Int. Pharmacodyn. 143: 299 (1963); Chang, R. S. L, et al. and Histamine Hi Receptors in Brain Labeled with [3H] Mepyramine., Eur. J. Pharmacol . 48:463-464 (1978). Mediator release inhibition may be tested according to published methods, one of which is Yanagihara, Y., Abe, T., Kuroda, T. and Shida, T., Immunopharma- cological actions of the new antiallergic drug butyl 3'- flH-trtrazol-5-yl)oxamilate. Arzneim.-Forsch. 38: 80-83 (1988) . Likewise, the compounds of Formula I can be tested by any appropriate method for 5HT 2 antagonism. The ability of the compounds to antagonize the effects of serotonin at the 5HT 2 receptor can be demonstrated by the spiroperidol binding test as described by Peroutka et al., in Mol. Pharmacol. , Vol. 16, pages 687-699 (1979). In this test, 5HT receptors are exposed to both [3H] spiroperidol, (a substance known to have a specific affinity for the receptor) and the test compound. The extent to which there is a decrease in binding of the [3H] spiroperidol to the receptor is indicative of the affinity of the test compound for the 5HT 2 receptor. The ability of the compounds to antagonize the 5HT receptors in vivo in the brain can be demonstrated via the 5- DMT head twitch test as described by Friedman et al . in Commun. Psychopharmacol. , Vol. 3, pages 89-92, (1979). The administration of 5-methoxy-N,N-dimethyltryptamine (DMT) to mice typically produces a characteristic head twitch in the mice. In this test, the mice are administered 5-DMT and a test compound. An absence of head twitches in the mice is considered to be predictive of the ability of the test compound to antagonize the 5HT receptor in vivo . An anti-allergic disease amount of the compounds of Formula I will vary with the disease being treated, the severity of the disease, the condition of the patient, the route of administration and a number of other conditions well known to those skilled in the art. Typically, an anti-allergic amount of the compounds of Formula I is about 0. Olmg/kg/day to about 120 mg/kg/day. This dose may be divided into a number of doses per day depending upon the result desired. This is also the dose for use separately as an antihistamine and the dose for use separately as a mediator release inhibitor. Likewise, the dosage range at which these compounds exhibit their ability to block the effects of serotonin at the 5HT 2 receptor can vary depending upon the particular compound being administered, the particular disease or condition being treated and its severity, the patient, other underlying disease states the patient is suffering from, and other medications that may be concurrently administered to the patient. Generally though, these compounds will exhibit their serotonin 5HT 2 antagonist properties at a dosage range of from about 0.001 mg/kg of - patient body weight/day to about 4.0 mg/kg of patient body weight/day. The compounds can be administered orally or parenterally to achieve these effects. "Treatment" means the ability of the compound to reduce the severity of or alleviate the symptoms related to the disease or be used prophylactically. The compounds of the present invention are administered to a patient in need of such therapy. "Patient" means a mammal such as a guinea pig or other rodent, dog, cat, or human. The route of administration may be by any appropriate method known to those skilled in the art such as oral, buccal, sublingual, parenteral, topical, opthalmical or by inhalation. Pharmaceutical compositions can be manufactured utilizing techniques known in the art. Typically an effective amount of the compound to treat a specified disease will be admixed with a pharmaceutically acceptable carrier. For oral administration, the compounds can be formulated into solid or liquid preparation such as capsules, tablets, lozenges, powders, suspensions or emulsions. Solid unit dosage forms can be capsules of the ordinary gelatin type containing, for example, surfactants, lubricants and inert fillers such as lactose, sucrose, and cornstarch or they can be sustained release preparations. In another embodiment, the compounds of Formula I can be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders, such as acacia, cornstarch, or gelatin, disintegrating agents such as potato starch or alginic acid, and a lubricant such as stearic acid or magnesium stearate. Liquid preparations are prepared by dissolving the active ingredient in an aqueous or non-aqueous pharmaceutically acceptable solvent which may also contain suspending agents, sweetening agents, flavoring agents and preservative agents as are known in the art. For parenteral administration the compounds may be dissolved in a physiologically acceptable carrier and administered as either a solution or a suspension. Illustrative of suitable pharmaceutical carriers are water, saline, dextrose solutions, fructose solutions, ethanol or oils of animal, vegetable or synthetic original. The pharmaceutical carrier may also contain preservatives, buffers, etc., as are known in the art. For nasal administration, the compounds may be dissolved in a physiologically acceptable pharmaceutical carrier and administered as a solution. Illustrative of suitable pharmaceutical carriers are water, saline, and aσueous alcoholic solutions. The pharmaceutical carrier may also contain preservatives, buffers, etc., as are known in the art. For topical administration, the compounds can be incorporated into a suitable topical carrier using techniques well known in the art. Examples of suitable topical carriers include oleaginous bases such as white - i i - petrolatum, absorption bases such as hydrophilic petrolatum, emulsion bases such as lanolin, and water soluble bases such as polyethylene glycol ointment. The topical carrier may also contain preservatives, buffers, etc., as are known in the art. For inhalation therapy, the compounds can be incorporated into an aqueous alcoholic solution containing a fluorinated hydrocarbon propellant and packaged into a suitable administration device as known in the art.

Claims: WHAT IS CLAIMED IS: 1. A compound of the formula; optical isomers or pharmaceutically acceptable salts thereof, wherein Y is -C(=0)-, -C(=CH 2 )-, -C(H)(OH)-, -C (OH) (phenyl )- or -C(B)(OH) wherein B is Y is attached at the heterocycle position 2 or 3, and when Y is -C(B)(OH), B is attached at heterocycle positions 2 ' or 3 ' ; X and X' are the same or different and are carbon, CH or nitrogen, provided that when Y is attached at the 3 or 3 ' position X and X' are each carbon, and when Y is attached at the 2 or 2' position X and X' are the same or different and are CH or nitrogen; Rl is -(CH 2 ) n -Z-(CH 2 ) rn COR 5 , -C(0)R 8 or R 2, R3, R2' and R3' are the same or different and are hydrogen or C 1 - 4 alkyl, or when R 2 and R 3f and R 2 ' and R 3 ' are respectively taken together, with the atoms to which R 2 and R 3( and R 2 > and R 3 ■ are respectively attached, each form a phenyl moiety respectively substituted with R or R 4 ' ; Z is a bond, 0, or S; R 4 or R 4 ' are the same or different and are hydrogen, chloro, fluoro, Cι_ 4 alkyl, or C 1 - 4 alkoxy; R5 is OH, Cι_ alkoxy or -NR 6 R 7 Re and R 7 are the same or different and are H or C 1 - 4 alkyl; R 8 is C 1 - 4 alkyl, C 1 - 4 alkoxy; 9 is H, C 1 - 4 alkyl, C 1 - 4 alkoxy, OH, chloro, bromo, fluoro, -CF 3/ -NHC(O)R 10 , or C0 2 Rn; Rio is C 1 - 4 alkyl or C 1 - 4 alkoxy; Ru is hydrogen or Cι- 4 _alkyl; n is an integer from 0-3 provided that when Z is not a bond, n is an integer from 2-3; m is an integer from 1 to 3; d is an integer from 1-5; and e is zero or 1, provided that when e is 1: d is an integer from 2 to 5; and X is N, or R 2 and R 3 , with the atoms to which R 2 and R 3 are attached, form a phenyl moiety; or X is N, and R 2 and R 3 , with the atoms to which R and R 3 are attached, form a phenyl moiety. 2. The compound of claim 1 wherein R 2 and R 3 together, with the atoms to which R and R 3 are attached, form a phenyl moiety. 3. The compound of claim 1 wherein X is nitrogen. 4. The compound of claim 1 wherein Ri is 5. The compound of claim 4 wherein d is 2, e is 0 and R 9 is C0 2 Rn. 6. The compound of claim 1 wherein R 2 and R 3 together, with the atoms to which R 2 and R 3 are attached, form a phenyl moiety and X is nitrogen. 7. The compound of claim 1 wherein R 2 and R 3 together, with the atoms to which R 2 and R 3 are attached, form a phenyl moiety and X is CH or carbon. 8. The compound of claim 1 wherein X is CH or carbon. 9. The compound of claim 1 wherein Y is -C(=0)-. 10. The compound of claim 1 wherein Y is -C(H)(OH)-. 11. The compound of claim 1 which is [2- Benzothiazolyl] fl-f 2-( -methoxyphenyl)ethyl]-4- piperidinyl]methanone or any pharmaceutically acceptable addition salt thereof. 12. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier . 13. Use of a compound according to any of claims 1-11 in the preparation of a medicine for the treatment of allergic disease. 14. Use of a compound according to any of claims 1-11 in the preparation of a medicine for treating a disease responsive to antagonism of the 5HT 2 receptor. 15. Use of a compound according to any of claims 1-11 as a medicine. 16. A method of using a compound of formula (3): (3) to make a compound of Formula I optical isomers or pharmaceutically acceptable addition salts thereof, wherein is -C(=0)-, -C(=CH 2 )-, -C(H)(OH -C(OH) (phenyl )- or -C(B) (OH) wherein B is d Y is attached at the heterocycle position 2 or 3, and when Y is -C(B) (OH), Y is also attached at heterocycle positions 2' or 3' ; X and X' are the same or different and are carbon, CH or nitrogen, provided that when Y is attached at the 3 or 3 ' position X and X 1 are each carbon, and when Y is attached at the 2 or 2 ' position X and X' are the same or different and are CH or nitrogen; Rl is -(CH 2 ) n -Z-(CH 2 )„COR 5 , -C(0)R 8 or 2 r 3, 2 ' and R3 ' are the same or different and are hydrogen or Cι_ 4 alkyl, or when R and Rs f and R 2 ' and R3 ' are respectively taken together, with the atoms to which R 2 and ^ , and R 2 * and R3- are respectively attached, each form a phenyl moiety substituted with R 4 or R 4 ' ; Z is a bond, 0, or S; R 4 or R 4 ' are the same or different and are hydrogen, chloro, fluoro, C1-. 4 alkyl, or C1- 4 alkoxy; R 5 is OH, Cι_ 4 alkoxy or -NR 6 R 7 . Rε and R are the same or different and are H or Cι_ 4 alkyl; R 8 is Cι_ 4 alkyl, Cι_ 4 alkoxy; Rg is H, Cι- 4 alkyl, Cι_ 4 alkoxy, OH, chloro, bromo, fluoro, -CF 3 , -NHC(O)R 10f or C0 2 Rn; Rio is Cι_ 4 alkyl or Cι- 4 alkoxy; Ru is hydrogen or Cι- 4 _alkyl; n is an integer from 0-3 provided that when Z is not a bond, n is an integer from 2-3; m is an integer from 1 to 3; d is an integer from 1-5; and e is zero or 1, provided that when e is 1: d is an integer from 2 to 5; and X is N, or R 2 and R 3 , with the atoms to which R and R 3 are attached, form a phenyl moiety; or X is N, and R 2 and R 3 , with the atoms to which R 2 and R 3 are attached, form a phenyl moiety; (a) by deprotecting the compound of formula (3) to produce compound (4): (4) reviously defined; (b) optionally reacting compound (4) with R x ' -Hal in the presence of an appropriate base to form compound ( 6 ) : (6) eviously defined and wherein Hal is Cl , Br or I; (c) optionally reducing the carbonyl functionality oi co pound (4) with a reducing agent to produce compound ( 7 ) : !7) eviously defined; (d) optionally converting the carbonyl functionality of compound (4) to an ethenylene group by reacting compound (7) with a suitable ylid to produce compound ( 8 ) : 8) eviously defined; (e) optionally converting the carbonyl functionality of compound (6) to a phenyl teriary alcohol or thiacyclic tertiary alcohol by reacting phenyllithium or R 4 to produce compound (9): eviously defined, and wherein Y' is phenyl or (9) eviously defined; or (f) optionally preparing pharmaceutically acceptable additon salts of Formula I.

Inventors: CARR ALBERT A, CHENG HSIEN C, DUDLEY MARK W, KANE JOHN M, MAYNARD GEORGE D, CARR, ALBERT, A., CHENG, HSIEN, C., DUDLEY, MARK, W., KANE, JOHN, M., MAYNARD, GEORGE, D.
Applicants: MERRELL DOW PHARMA, MERRELL DOW PHARMACEUTICALS INC.
Application year: 1993
Main classification: C07D417
IPC codes: A61K31, A61P37, C07D409, C07D417