PIPERAZINO DERIVATIVES AS NEUROKININ ANTAGONISTS

Abstract: The invention relates to neurokinin antagonists of formula (I) wherein Z, Rc, y, m, u, Ar2, n, X, Rc', I and Ar2 are as described herein. These compounds are useful in the treatment of diseases such as asthma, anxiety, depression, emesis and nociception.

Description: PIPERAZINO DERIVATIVES AS NEUROKININ ANTAGONISTS BACKGROUND OF THE INVENTION The present invention relates to a genus of compounds useful as antagonists of neurokinin receptors. In particular, these can be neurokinin-1 receptor (NK-|) antagonists. Some can also be neurokinin- 1 receptor (NK-| antagonists and neurokinin-2 receptor (NK2) antagonists, that is, NK1 / NK2 dual receptor antagonists. Some can also be neurokinin-2 receptor (NK2) antagonists. Some can also be neurokinin-3 receptor (NK3) antagonists. Neurokinin receptors are found in the nervous system and the circulatory system and peripheral tissues of mammals, and therefore are involved in a variety of biological processes. Neurokinin receptor antagonists are consequently expected to be useful in the treatment or prevention of various mammalian disease states, for example pulmonary disorders like asthma, cough, bronchospasm, chronic obstructive pulmonary diseases, and airway hyperreactivity; skin disorders and itch, for example, atopic dermatitis, and cutaneous wheal and flare; neurogenic inflammation inflammatory diseases such as arthritis, migraine, nociception; CNS diseases such as anxiety, Parkinson's disease, movement disorders and psychosis; convulsive disorders, renal disorders, urinary incontinence, ocular inflammation, inflammatory pain, and eating disorders such as food intake inhibition; allergic rhinitis, neurodegenerative disorders, psoriasis, Huntington's disease, depression, emesis and various gastrointestinal disorders such as Crohn's disease. In particular, NK1 receptors have been reported to be involved in microvascular leakage and mucus secretion, and NK2 receptors have been associated with smooth muscle contraction, making NK1 and NK2 receptor antagonists especially useful in the treatment and prevention of asthma. Moreover, NK3 receptor antagonists are especially useful in the treatment and prevention of asthma, inflammatory diseases and conditions, such as ocular inflammation, allergic rhinitis, cutaneous wheal and flare, psoriasis, atopic dermatitis, CNS diseases such as anxiety and Parkinson's disease. Summary of the Invention The invention relates to compounds of the formula: each X is independently, O, NRrj, or S; n is 0 to 2; u is 0 to 2; I is 0 to 2; m is 1 , and y is 1 to 3; or m is 2, and y is 0; and with the further proviso that no more than one R c is other than H in the moiety; each R c is independently H, C1-C6 alkyl, where ni is 1 to 6; Rd is independently selected from the group consisting of H, C-i-Cβ alkyl, CN, OR a , phenyl, substituted phenyl, benzyl, substituted benzyl, or allyl; ■ N \ II I R 4 is -OR a , SR a , -CN, Rb — C — N-R b • OR a OR a R c ' is H, Ci-Cβ alkyl or (CH2) n OR a , with the proviso that no more than one R C ' is other than H; each R a and Rb is independently selected from the group consisting of H, C-i-Cβ alkyl, phenyl, substituted phenyl, benzyl, Rb O I II substituted benzyl, allyl; with the proviso that when R4 is — N-C-OR a , R a is not H; or when R a and Rb are attached to the same nitrogen, then R a and Rb together with the nitrogen to which they are attached, form a 4 to 7 member ring comprised of 1 nitrogen atom and 3 to 6 carbon atoms; - wherein each R1 and R2 is independently H, C-t-C-6 alkyl, CF3, o o II II C 2 F 5 , CI, Br, I, F, N0 2 , OR a> CN, NR a R , -C-Ra ■ o — C-Ra O Ra Rb O Ra O O O R a II I 1 If I II II — -O — C-N— Rb -N-C-OR a • N-C-R b — C-OR a — C — -R b O O. II .0 — s- ■ R a -s—? R a , -SR a , and -s /-/°NHR a . anc j wne re R a is not H o ° x n R b O II # I II i n -S — R a -S — R a or — N-C-OR a . or when R1 and R2 are on adjacent carbons on a ring, they can form wherein n' is 1 or 2; o II and each R3 is independently H, Ci-Cβ alkyl, CF3, C2F5, — C- Ra , o o R a II >■ > -o— C- Ra , -C— -R b CI, Br, I, F, OR a , OCF3, or phenyl; Ari is heteroaryl or substituted heteroaryl, Q is N or CH; Ar2 is heteroaryl or substituted heteroaryl; Z is mi = 0-1 ; nri 2 = 1 -2; n 3 is 0-4; each R e and Rf is independently selected from the group consisting of H, C-i-Cβ alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, allyl; or R e and Rf taken together with the carbon to which they are attached can also form a carbonyl group with the proviso that no more than one carbonyl group is in the moiety; ns is 1 to 2; each R5 is independently selected from the group consisting of H, o OH, — c-Ra , C-i-Cβ alkyl, (CH2)m-R 4 wherein ni is 1 to 6 with the proviso that when ni is 1 , R4 is not OH or NR a Rb; also with the proviso that when ns is 2, R5 is C-i-Cβ alkyl, and two R5 can be attached to the nitrogen to form a quaternary salt; R 6 is H, C-1-C6 alkyl, C3-C6 cycloalkyl, wherein X3 is (H,H), O, NRd, or S; or RQ is heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, when n3 is 0-4; when Re.Rf taken together with the carbon atom to which they are attached form a carbonyl group and n 3 is 1 , Re can also be -ORa wherein R a is not H, or R 6 is -NR a ,Rb> -0-(CRa,Rb)n 7 -heteroaryl, -0-(CR a ,Rb)n7- substituted heteroaryl, -0-(CR a ,Rb)n 7 -heterocycloalkyl, -0- ' (CR a ,Rb)n 7 - substituted heterocycloalkyl, -0-(CR a ,Rb)n 7 -aryl, -0-(CR a ,Rb)n 7 - substituted aryl, -NR a -(CRa,Rb)n 7 -heteroaryl, -NR a -(CRa,Rb)n 7 - substituted heteroaryl, -NR a -(CRa,Rb)n -aryl, -NR a -(CRa,Rb)n 7 - substituted aryl, -NR a -(CR a ,Rb)n7-heterocycloalkyl, -NR a -(CR a ,Rb)n 7 - substituted heterocycloalkyl, wherein j is 0 to 4 and R a and Rb are each independently selected from the group consisting of H and C-i-Cε alkyl; or an enantiomer thereof, or a pharmaceutically acceptable salt thereof. All of the variables in the above formulas such as Z, Ri , R2, and R3, have the same meaning throughout the specification unless otherwise specified. Preferred compounds of the invention are compounds of formula I, wherein each X is O or at least one X is O. Also preferred are compounds of formula I wherein both X's are O. Also preferred are compounds of formula I wherein I is 0, m is 1 , and y is 1-3. Also preferred are compounds of formula I wherein n is 1 and u is 0. Also preferred are compounds of formula I wherein Aη is ferred are compounds of formula I wherein Ar2 is Also preferred are compounds of formula I wherein both X's are O; I is 0; m is 1 ; y is 1-3; n is 1 ; u is 0; R c is H or Ci-Cβ alkyl; Aη is Ar2 " is Z is defined in Formula I, when R e ,Rf are H, C1-C6 alkyl, n 3 is 0-4 and or Re and Rf taken together with the carbon to which they are attached form a carbonyl group, n 3 is 1 and RQ is Also preferred are compounds of formula I wherein An and Ar2 are both Compounds of this invention are exemplified by the following formulae wherein Y represents the following groups: compound of the formula v V\ o wherein Y is " " , o V or / N i ? = H a compound of the formula wherein Y is phenyl; or any enantiomer thereof, or a pharmaceutically acceptable salt thereof; or a compound of the formula: B A. O The above examples represent all the possible stereoisomers, including enantiomers, diastereomers, endo, exo, R and S forms. Preferred Y variables are Preferred Ar' variables are The invention also relates to a pharmaceutical composition comprising a thereapeutically effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier. The invention also relates to the use of a compound of claim 1 for the preparation of a medicament for inducing neurokinin antagonism. The invention also relates to the use of a compound of formula I for the preparation of a medicament for treating chronic airway diseases such as asthma and allergies; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositos, osteoarthritis, and rheumatoid arthritis; migraine; central nervous system disorders such as depression, psychosis, dementia, and Alzheimer's disease; Down's syndrome; neuropathy; multiple sclerosis; ophthalmic disorders; conjunctivitis; auto immune disorders; graft rejection; systemic lupus erythematosus; Gl disorders such as Crohn's disease and ulcerative colitis; disorders of bladder function; circulatory disorders such as angina; Raynaud's disease; coughing and pain. In particular, the invention also relates to a method of treating asthma which comprises administering to a mammal in need of such treatment an anti-asthma effective amount of a compound of formula I for such purpose. Detailed Description of the Invention As used herein the term alkyl means a straight or branched, saturated hydrocarbon chain having from 1 to 6 carbon atoms. The number of carbon atoms may be designated. For example, "C1-C6 alkyl" represents a straight or branched, saturated hydrocarbon having from 1 to 6 carbon atoms. The term C3-C6 cycloalkyl means a cycloalkyl having from 3 to 6 carbon atoms, that is cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term alkenyl means means a straight or branched, saturated alkenyl having from 2 to 6 carbon atoms. The number of carbon atoms may be designated. For example, "C2-C6 alkenyl" represents a straight or branched alkenyl having from 1 to 6 carbon atoms. The term alkynyl means a straight or branched alkynyl having from 2 to 6 carbon atoms. The number of carbon atoms may be designated. For example, "C2-C6 alkynyl" represents a straight or branched chain alkynyl having from 2 to 6 carbon atoms. As used herein, a heavy dark line ( — m ) denotes a chemical bond coming above the plane of the page. A dashed line ( ) denotes a chemical bond coming below the plane of the page. As used herein, , for example, means that Ri , R2, and R3 can be in either of the rings of the above naphthyl moiety. Asymmetric centers exist in compounds of formula I of the invention. Accordingly, compounds of formula I include stereoisomers. All such isomeric forms and mixtures thereof are within the scope of the present invention. Unless otherwise indicated, the methods of preparation disclosed herein may result in product distributions which include all possible structural isomers, although it is understood that physiological response may vary according to stereochemical structure. The- isomers may be separated by conventional means such as fractional crystallization, preparative plate or column chromatography on silica, alumina, or reversed phase supports or HPLC (high performance liquid chromatography). Enantiomers may be separated, where appropriate, by derivatization or salt formation with an optically pure reagent, followed by separation by one of the aforementioned methods. Alternatively, enantiomers may be separated by chromatography on a chiral support. The compounds of formula I can exist in unsolvated as well as solvated forms, including hydrated forms, e.g. the hemihydrate. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol, and the like are equivalent to the unsolvated forms for the purposes of the invention. Those compounds of formula I which contain a basic group such as -CH2NH2, form pharmaceutically acceptable salts. The preferred pharmaceutically acceptable salts are nontoxic acid addition salts formed by adding to a suitable compound of the invention about a stoichiometric amount of a mineral acid , such as HCI, HBr, H2S0 or H3P0 or of an organic acid such as acetic, propionic, valeric, oleic, palmitic, stearic, lauric, benzoic, lactic, para-toluenesulfonic, methanesulfonic, citric, maleic, fumaric, succinic and the like, respectively. General Methods of Preparation The compounds of this invention may be prepared by methods known in the art, see for example WO 96/34864 and WO 97/08166, and the examples described below. As used herein RT means room temperature. Unless otherwise indicated, variables in the structural formulas below are as defined above. Starting materials and reagents used in the methods and examples below are known or may be prepared according to known methods. As used herein the term "substituted phenyl" means wherein Ri , R2, and R3 are as described herein. "Substituted " means substituted by Ri , R2, and/or R3 as described herein. "Aryl" means phenyl, naphthyl, indenyl, tetrahydronaphthyl, indanyl, anthracenyl or fluorenyl. "Halogeno" refers to fluoro, chloro, bromo or iodo atoms. "Heterocycloalkyl" refers to 4- to 6-membered rings comprising 1 to 3 heteroatoms independently selected from the group consisting of -O-, -S- and -N(R 6 )-, with the remaining ring members being carbon. Examples of heterocycloalkyl rings are tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl. "Heteroaryl" refers to 5- to 10-membered single or benzofused aromatic rings comprising 1 to 3 heteroatoms independently selected from the group consisting of -0-, -S- and -N=. Examples of single-ring heteroaryl groups are pyridyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, thiadiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazolyl. Examples of benzofused heteroaryl groups are quinolinyl, thianaphthenyl and benzofurazanyl. N-oxides of nitrogen-containing heteroaryl groups are also included. All positional isomers are contemplated, e.g., 1 -pyridyl, 2-pyridyl, 3-pyridyl and 4-pyridyl. Where R 2 and R 3 substituents form a ring and additional heteroatoms are present, the rings do not include adjacent oxygen and/or sulfur atoms or three adjacent heteroatoms. Typical rings so formed are morpholinyl, piperazinyl and piperidinyl. As used herein, each R c and R C ' is independently selected from the group consisting of H, Ci-Cβ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, unsubstituted or substituted phenyl, and unsubstituted or substituted benzyl. As used herein, the term "BOC" means t-butoxycarbonyl. As used herein, the term "Ph" means phenyl. As used herein, the term "RT" means room temperature. As used herein, the term "parallel synthesis" means the preparation of individual chemical compounds as one of a batch of, for instance, 20, 30, or even 100 identical reactions on usually a single substrate but using a different reagent in each vessel. Such reagents are always of the same general class- in this case, either carboxylic acids or organic amines in any set of parallel reactions. The conditions used for each reaction are identical to those described in the examples , except that a simplified work-up is employed, generally a simple wash either with acid or base if appropriate, then water. The presence of the product is detected by thin layer chromatography (TLC) using known products as representative standards. Further characterization by combination HPLC/MS is generally performed. No further, purification is performed on these materials before they are submitted to biological assays. The in vitro and in vivo activity of the compounds of formula I can be determined by various procedures known in the art, such as a test for their ability to inhibit the activity of the NKi agonist Substance P, an isolated hamster trachea NK2 assay, a test of the effect of NK1 antagonists on Substance P-induced airway microvascuiar leakage, measurement of NK2 activity in vivo in guinea pigs, measurement of bronchoconstriction due to NKA, and neurokinin receptor binding assay(s). Typical procedures are published in W096/34864. For all of the compounds of the invention, the NK1 binding is in a range of about 0-100 % inhibition at 1 μM concentration. For all of the compounds of the invention, the NK2 binding is in a range of about 0- 100 % inhibition at 1 μM concentration. It should be understood that while the NK binding for certain compounds of the invention is as low as 0% at 1 μM concentration, that at higher concentrations these compounds are expected to have NK binding inhibition activity. The Kj of a compound is that concentration at which the compound caused 50% inhibition of either NK1 or NK2. For those compounds of the invention having higher than 50% inhibition of NK1 , Kj 's for NK1 are determined. For those compounds of the invention having higher than 50% inhibition of NK2 , Kj 's for NK2 are determined. Compounds of formula I exhibit NKi and NK2 antagonist activity to varying degrees, i.e., certain compounds have strong NKi antagonist activity, but weaker NK2 antagonist activity. Others are strong NK2 antagonists, but weaker NK antagonists. Certain compounds have both strong NKi and NK2 antagonist activities. Some compounds can also be NK3 antagonists. Many compounds of formula I have an asymmetric center and therefore exist as a pair of enantiomers. In such cases, one enantiomer can have different biological activity than the other. For example, one enantiomer can have strong NK activity and weak NK2 activity while the other enantiomer has weak NKi activity and strong NK2 activity. Certain compounds of formula I have been found to be antagonists of both NKi and NK2 receptors, and are therefore useful in treating conditions caused or aggravated by the activity of NKi and NK2 receptors. The present invention also relates to a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier. Compounds of this invention can be administered in conventional oral dosage forms such as capsules, tablets, powders, cachets, suspensions or solutions, or in injectable dosage forms such as solutions, suspensions, or powders for reconstitution. The pharmaceutical compositions can be prepared with conventional excipients and additives, using well known formulation techniques. Pharmaceutically acceptable excipients and additives include nontoxic and chemically compatible fillers, binders, disintegrants, buffers, preservatives, anti-oxidants, lubricants, flavorings, thickeners, coloring agents, emulsifiers and the like. The daily dose of a compound of formula I for treating asthma, cough, bronchospasm, inflammatory disease, migraine, nociception and gastrointestinal disorders is about 0.1 mg to about 20 mg/kg of body weight per day, preferably about 0.5 to about 15 mg/kg, more preferably 0.5 to about 5 mg/kg. For an average body weight of 70 kg, the dosage range-is therefore from about 1 to about 1500 mg of drug per day, preferably about 50 to about 100 mg , given in a single dose or 2-4 divided doses. The exact dose , however is determined by the attending clinician , and is dependent on the potency of the compound administered, the age, weight, condition and response of the patient. The present invention is exemplified by the following examples, which should not be construed to limit the scope of the disclosure. 5 Alternative mechanistic pathways and analogous structures within the scope of the invention will be apparent to those skilled in the art. EXAMPLE 1 2-(3,4-Dichlorophenyl)piperazine 0 A. Synthesis of racemic compound (+,-)-2-(3,4-Dichlorophenyl)piperazine was synthesized according to the method published in J.Med.Chem. 9,181 ,1966. A. General method for the synthesis of (+,-)-2-aryl-piperazine derivatives. R 1 = Cl, H or other substituents i.e. OCH 3 , CF 3 , Br, I, F, etc. ■ 5 R 2 = Cl, H or other substituents i.e. OCH 3 , CF 3l Br, I, F, etc. B. Resolution of (+,-)-2-(3,4-dichlorophenyl)piperazine Step 1 : A solution of (+,-)-2-(3,4-dichlorophenyl)piperazine (36.05 g, 0.156 mol) in CH3OH (200 ml_) was treated with a solution containing two equivalents of N-acetyl-L-leucine (54.02 g, 0.312 mol) and heated 20 until all of the material was dissolved. EtOAc (2.2 L) was added to this solution and allowed to stand at ambient temperature overnight. The solvent phase was decanted from the precipitated salt and concentrated in vaclio. This procedure was repeated using 37.88 g of (+,-)-2-(3,4- dichlorophenyl)piperazine (0.164 mol) and 56.68 g of N-acetyl-L-leucine 25 (0.327 mol). Step 2: The concentrated salts from both solvent phases in step 1 were combined and heated in methanol (550 mL) until all of the material dissolved. EtOAc (2.75 L) was added to this solution and allowed to stand at ambient temperature overnight. The solvent phase was decanted from the precipitated salt and concentrated in vacuo to give -95 g of piperazine salt (72% ee of enantiomer A). Step 3: The salt from the solvent phase in step 2 was dissolved in a solution of H2O (800 mL) and aq. ammonia (400 mL) and extracted with CH2CI2 (4 x 400 mL). The combined organic layers were dried with MgSθ4 and concentrated to give 37 g of the piperazine free base. The free base was recrystallized three times from hexane (890, 600 and 450 mL) to give 16 g of (-)-2-(R)-(3,4-dichlorophenyl)piperazine (>99.9% ee of enantiomer A). [α]D 4'7°C = -45.0° (MeOH) Step 4: The precipitated salts from step 1 were combined and heated in CH3OH (220 mL) until all of the material dissolved. EtOAc (2.2 L) was added to this solution and allowed to stand at ambient temperature overnight. The solvent phase was decanted from the precipitated salt and dried in vacuo to give -43 g of piperazine salt (93% ee of enantiomer B). Step 5: A 12.3 g portion of salt (75% ee of enantiomer B) prepared by an analogous procedure to that in step 4 was dissolved in 0.5 M NaOH (400 mL) and extracted with CH2CI2 (4 x 155 mL). The combined organic layers were dried with MgS0 and concentrated to give 3.72 g of the piperazine free base. The free base was recrystallized twice from hexane (90 and 70 mL) to give 2.1 g of piperazine (98% ee of enantiomer B). C. Analytical procedure for measuring piperazine enantiomeric purity. The enantiomeric purity of the piperazine was measured by chiral HPLC analysis of the di-tert-butoxycarbonyl piperazine derivative. The di-tert-butoxycarbonyl derivative was prepared by adding a small piperazine sample (free base or salt)(~ .2 mg) to di-tert-butyl dicarbonate (~ 1 mg) and methanol (0.5 mL) and heating at 80°C for 1 h. If the piperazine sample is a salt, triethylamine (20 μL) is also added. The derivative was analyzed by HPLC using a ChiralPak AD column eluting with 95:5 hexane-isopropyl alcohol. EXAMPLE 2 (+,-)-[3,5-Dimethylbenzoyl]-3-(3,4-dichlorophenyl)piperazine To a cooled solution of CH2CI2 (600 mL) containing (+,-)-2-(3,4- dichlorophenyl)piperazine (6.934 g, 30 mmol), 3,5-dimethylbenzoic acid (4.55 g, 30 mmol), and N-hydroxybenzotriazole monohydrate (4.05 g, 30 mmol) at -20 °C were added Et3N (4.2 mL, 30 mmol) and N,N- dimethylaminopropylethylcarbodimide (DEC) ( 5.86 g, 30 mmol) under nitrogen. The reaction was kept at -20 °C for an hour and gradually warmed to RT overnight. After stirring 22 hours, the reaction was complete and CH2CI2 (200 mL) was added. The organic solution was washed with brine (150 mL, 3x), dried over MgSθ4, filtered and concentrated under vacuum to give 8.2 g of crude product. The product was crystallized from CH2Cl2/Hexane to give a light yellow solid (6.3 g, 17.34 mmol, 57.8%), m.p.139-14l 0 C; FAB MS [M+1]+ 35 CI 363.1. EXAMPLE 3 (+,-)-Bromoacetyl-2-(3,4-dichlorophenyl)-4-(3,5- dimethylbenzoyl)piperazine To a cooled solution of (+,-)-[3,5-dimethylbenzoyl]-3-(3,4- dichlorophenyl)piperazine (11.5 g, 31.65 mmol) in CH2CI2 (200 mL) at 0 °C was added Hϋnig's base (4.5 g, 35 mmol) and bromoacetyl bromide (6.4 g, 31.65 mmol). The solution was stirred at 0 °C overnight under N2. After completion the reaction was diluted with CH2CI2 (400 mL) and washed with brine (300 mL, 2x), dried over MgSθ4, filtered and concentrated. The crude material was purified by flash grade silica gel chromatography, eluting with 2% [NH4θH/MeOH (1 :9)] / 98% CH2CI2 to give the title compound as a light yellow solid (7.1 g, 47.3%), m.p. 77-79 °C, FAB MS [M+1]+ 35C| 79B Γ 482.9, 484.9. EXAMPLE 4 (+)-[3,5-Dimethylbenzoyl]-3-(R)-(3,4-dichlorophenyl)piperazine (Enantiomer B) The title compound was prepared by an analogous method to that desecribed in Example 2 using (-)-2-(R)-(3,4- dichlorophenyl)piperazine in place of (+,-)-2-(3,4- dichlorophenyl)piperazine, m.p. 97-100 °C; FAB MS [M+1]+ 35 CI 363.1 ; [α] D 2'5 C = +87 - 2 ° (MθOH). EXAMPLE 5 (-)-Bromoacetyl-2-(R)-(3,4-dichlorophenyl)-4-(3,5-dimethyl- benzoyl)piperazine (Enantiomer B) The title compound was prepared by an analogous method to that desecribed in Example 3 using (+)-[3,5-dimethylbenzoyl]-3-(R)-(3,4- dichloro-phenyl)piperazine (Enantiomer B) (Example 4) in place of (+,-)- [3,5-dimethylbenzoyl]-3-(3,4-dichlorophenyl)piperazine, m.p. 68-71 °C, FAB MS [M+1]+ 35 CI 7 9 β r 482.9, 484.8; [α]D '9°C = -45.6° (MeOH). EXAMPLE 6 (+,-)-2-(3,4-Dichlorophenyl)-4-[3,5-dimethylbenzoyl]-1-[[[3-methyl-1- (phenylmethyl)-4-piperidinyl]amino]acetyl]piperazine (diastereomers A and B) Step 1 : To a solution of BOC glycine (0.979 g, 5.59 mmol) and Et3N (0.85 mL, 6.1 mmol) in CH CI (10 mL) was added BOP (benzotriazol-1- yloxy-tris(dimethyl-amino)phosphonium hexafluorophosphate) reagent (2.46 g, 5.57 mmol). After stirring for 15 min, (+,-)-(3,5-dimethylbenzoyl)- 3-(3,4-dichlorophenyl)piperazine (1.83 g, 5.03 mmol) (prepared in Example 2) was added. After 5 h, the reaction mixture was added to 0.2 N HCI (100 mL) and extracted with CH2CI2 (3 x 60 mL). The combined organic layers were washed with brine, dried with MgS0 4 and concentrated. The crude material was purified by flash chromatography on silica gel eluting with 50:1 to 30:1 CH2Cl2-MeOH to give 2.15 g of compound 2 (shown above) as a white foam (4.1 mmol, 82%). Step 2: Compound 2 (1.32 g, 2.5 mmol) was treated with MeOH saturated HCI (15 mL) for 2.5 h and concentrated. The resulting powder was dissolved in CH2CI2, washed with sat. NaHC03, dried with MgS0 4 and concentrated to give compound 3 as the free base. Step 3: To a -78°C solution of LDA (10.79 mmol) in THF (30 mL) was added 1-benzyl-4-piperidone (2.0 mL, 10.8 mmol). The reaction mixture was warmed to 0°C for 20 min and then cooled back to -78°C. Methyl iodide (0.67 mL, 10.8 mmol) was added to the enolate solution which was stirred at 0°C for 2 h then warmed to RT overnight. The reaction mixture was quenched with sat. NH 4 CI and concentrated. The residue was suspended in H2O and extracted with CH2CI2. The combined organic layers were dried with MgS0 , filtered and concentrated. The product was purified by flash chromatography on silica gel eluting with 1 :1 hexane-EtOAc to give the 1 -benzyl-3-methyl-4- piperidone 4 as a yellow oil (0.65 g, 30%). Step 4: A mixture of the ketone 4 (step 3) (70 mg, 0.13 mmol) and the compound 3 (34 mg, 0.17 mmol) was stirred in titanium isopropoxide (45 mg, 0.16 mmol) for 1.5 h. To the mixture were added ethanol (1.0 mL) and NaCNBH3 (5.4 mg, 8.6 mmol) and the mixture was stirred overnight. The reaction mixture was filtered and washed with EtOAc. The- filtrate was washed with H2O and brine, dried with MgS0 4 and concentrated. The residue was chromatographed on silica gel eluting with 5% NH3 sat. MeOH in CH2CI2 to give both diastereomers pure. Diastereomer A (15 mg) HRMS (FAB, M+H+): m/e calc'd for [C 34 H 4 ι N 4 CI 2 θ2] + 607.2607; found 607.2603. Diastereomer B (17 mg) HRMS (FAB, M+H+): m/e calc'd for [C 34 H 4 ι N 4 CI θ2] + 607.2607; found 607.2597. EXAMPLE 7 2-(3,4-Dichlorophenyl)-4-(3,5-dimethylbenzoyl)-1-[[[8-(phenylmethyl)-8- azabicyclo[3.2.1 ]oct-3-yl]amino]acetyl]piperazine compound 3 By an analogous method to that described in Example 6, the product from Example 6, compound 3 (185 mg, 0.44 mmol) was combined with 8-benzyl-8-azabicyclo[3.2.1]octan-3-one (97 mg, 0.45 mmol) and Ti(0- Pr) (105 mL, 0.50 mmol) and left stirring for 1 h. To the thick reaction mixture was added NaBHsCN (59.5 mg, 0.95 mmol) and the mixture was stirred overnight. To the reaction mixture was added H2O (1 mL) and it was filtered. The filtrate was washed with EtOH, concentrated and purified by silica gel chromatography, eluting with 30:1 :0.1 to 15:1 :0.1 CH Cl2-MeOH-NH3 aq. to give the title product as a white foam. HRMS (FAB, M+H + ); m/e calc'd [C3sH 4 ιCl2N 4 θ2] + : 619.2607, found 619.2594. EXAMPLE 8 2-(R)-(3,4-Dichlorophenyl)-4-(3,5-dimethylbenzoyl)-1 -[[[8-methyl-8- azabicyclo[3.2.1 ]oct-3-yl]amino]acetyl]piperazine (enantiomer B) This compound was prepared by a procedure analogous to Example 6 except for the use of (+)-[3,5-dimethylbenzoyl]-3-(R)-(3,4- dichlorophenyl)-piperazine (Enantiomer B) in stepl and tropinone in place of 1-benzyl-3-methyl-4-piperidone. HRMS (FAB, M+H+); m/e calc'd [C29H 3 7CI 2 N 4 θ2] + : 543.2294, found 543.2282. EXAMPLE 9 2-(R)-(3,4-Dichlorophenyl)-4-(3,5-dimethylbenzoyl)-1-[3-[5- (phenylmethyl)-(1 S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-1- oxopropyljpiperazine ( enantiomer B) To a cooled solution of CH2CI2 (10 mL) containing diisopropyl- ethylamine (0.275 mL, 2.0 mmol) and [3,5-dimethylbenzoyl]-3-(R)-(3,4- dichlorophenyl)piperazine (Enantiomer B) (Example 4) (305 mg, 0.84 mmol) was added chloropropionyl chloride (0.075 mL, 0.8 mmol). The reaction mixture was allowed to warm to RT. After 20 minutes, (1 S.4S)- 2-benzyl-2,5-diazabicyclo(2.2.1)heptane-2HBr (297 mg, 0.85 mmol) and diisopropylethylamine (0.275 mL, 2.0 mmol) were added and the mixture was left over night, after which the reaction mixture was concentrated. The product was purified by flash chromatography on flash grade silica gel, eluting with 30:1 :0.1 CH2Cl2/MeOH/NH3 to give a foamy solid (140 mg, 0.23 mmol, 29%), High Res. MS:[M+1]+ calcd. for C34H39CI N 4 O 605.2450; Found, 605.2465. EXAMPLE 10 (-)-1 ,1-Dimethylethyl 2-[3-[2-(R)-(3,4-dichlorophenyl)-4- (dimethylbenzoyl)-1-piperazinyl]-3-oxopropyl]-1 (S),4(S)-2,5- diazabicyclo[2.2.1 ]heptane-5-carboxylate chiral enantiomer B Part 1 : To a solution of the compound obtained from Example 4 (20.7 g, 57 mmol) in dry CH2CI2 (320 mL) at -78 °C was added 3-bromopropionyl chloride (9.8 g, 57 mmol) and EtβN (5.76 g, 57 mmole). After stirring at -78 °C for 4 h, additional 3-bromopropionyl chloride (0.5 ml, 4.96 mmol) and Et3N (0.5 ml, 4 mmol) were added. A portion of the material (40 mL) was worked up by diluting with CH2CI2 and washing with water, as described in Example 4, to give the 3-bromopropionamide intermediate A as shown above. FAB MS [M+1]+ 498.9. Part 2: The remainder of the above reaction solution was evaporated without water washing to give a brown solid (25 g, 50.5 mmole) which was redissloved in absolute EtOH (200 mL) and cooled to 0 °C. To this cooled solution was added (1 ,S,4S)-N-t-BOC-2,5-diazabicyclo[2.2.1]- heptane (9.0 g, 45.5 mmol) and Et3N (4.1 g, 40.4 mmol). The solution was stirred overnight at RT. After the reaction was complete, EtOH was evaporated and the residue was redissolved in CH2CI2 (500 mL), washed with brine (300 mL, 3x), dried (MgS0 4 ), filtered and concentrated to give a tan crude product (30 g). The crude material was purified by flash chromatography on silica gel (400 g), eluting with 3% [(1 :9) (NH4θH:MeOH)]/ 97% CH2CI2 to give the title compound as an off white solid (15.5g, 25.1 mmol, 55%), m.p. 78-82 °C; FAB Mass [M+1]+ 35d 615.1 , [α] 2 D 2°C = -51.1 ° (MeOH). EXAMPLE 11 (-)-1-[3-[(1 S),4(S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-1 -oxopropyl]-2- (R)-(3,4-dichlorophenyl)-4-(3,5-dimethylbenzoyl)piperazine hydrochloride To a solution of the compound obtained from Example 10 (14.5 g, 23.55 mmol) in CH2CI2 (25 mL) at RT was added 4M HCI-dioxane (58.8 mL, 235.2 mmol) solution. The mixture was stirred at RT for 2 h and excess acid and solvents were evaporated to give the title compound as g) , m.p.60-64 0 C; FAB MS [M+1]+ 35 CI 515.2; Example 12 (-)-N-[4-[[5-[3-[2-(R)-(3,4-Dichlorophenyl-4-(3,5-dimethylbenzoyl]-1- piperazinyl]-3-oxopropyl]-(1 S,4S)-2,5-diazabicyclo[2.2.1]heptan-2- yl]methyl-2-thiazoiyl]]acetamide (enantiomer B) Stir a solution of chiral intermediate 1 made in Example 11 (200 mg, 0.34 mmol), 2-acetamido-4-chloromethyl thiazole (64.8 mg, 10.34 mmol), and Hϋnig's base (1.088 mmol) in CH2CI2 (4 ml) at room temperature under N2 for 24 h. Dilute the reaction mixture with CH2CI2 (200ml), wash with brine, separate the organic layer, dry over MgS0 , filter and evaporate. Purifiy by flash grade silica gel chromatography, to obtain the title compound 2 as a white solid, m.p. 105-110 °C; FAB MS [M+1]+ 35 Cl 669.0; [OC]D 4'7 ° C = -23.4° (MeOH). EXAMPLE 13 (-)-N-[4-[[5-[3-[2-(R)-(3,4-Dichlorophenyl-4-(3,5-dimethylbenzoyl]-1- piperazinyl]-3-oxopropyl]-(1 S,4S)-2,5-diazabicyclo[2.2.1]heptan-2- l]methyl]phenyl]acetamide enantiomer B) By an analogous method to that described in Example 12, using the chiral intermediate made in Example 11 and 4-acetamido- benzyl chloride, in the present of Hϋnig's base in CH2CI2, the title compound 2 was obtained as a white solid after purification by flash grade silica gel chromatography, m.p. 101-106 °C; FAB MS [M+1] + 35ci 662.1 ; [α] D 3°C = -27.3° (MeOH). EXAMPLE 14 (-)-2-|R)-(3,4-Dichlorophenyl)-4-(3,5-dimethylbenzoyl)-1-[1 -oxo-3-[5-(2- thienylmethyl)-1-(S),4(S)-2,5-diazabicyclo[2.2.1]- heptan-2-yl]propyl]piperazine (enantiomer B) A mixture of the compound obtained from Example 11 (0.206 g, 0.35 mmol) in CF3CH2OH (3 mL), Hϋnig's base (113 mg, 0.87 mmol) and 2-thiophene carboxaldehyde (44 mg, 0.39 mmol) was stirred at RT overnight under nitrogen. After evaporation of CF3CH2OH, the residue was redissolved in CH2CI2 (50 mL) and washed with saturated NaHCθ3 solution (30 mL, 2x), dried (MgS04), filtered and concentrated to give a light brown solid (0.26 g). Product was purified by flash chromatography on silica gel (50 g), eluting with 5% [(1 :9) NH4θH-MeOH)] / 95% CH2CI2 to give the title compound as a pale yellow solid (100 mg, 0.163 mmol, 47%), m.p. 70-72 °C; HR MS, calc'd for [M+H]+ C 3 2H 3 7SN 4 0 2 Cl2: 611.2014; found: 611.2011 ; [α] D 2 5 ° C = -20.8° (MeOH). EXAMPLE 15 2-(R)-(3,4-Dichlorophenyl-4-(3,5-dimethylbenzoyl]-1-[3-[5-(1 H-pyrroll-2- yl)methyl]-(1 S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-1-oxopropyl] piperazine (enantiomer B) By an analogous method to that described in Example 14, using the chiral intermediate of Example 11 , the title compound 2 was obtained as a white solid after purification by flash grade silica gel chromatography, m.p. 81-83 O C; FAB MS [M+1]+ 35ci 594.1 EXAMPLE 16 2-(R)-(3,4-Dichlorophenyl)-4-(3,5-dimethylbenzoyl)-1 -[1-oxo-3-[5-(3- thienylmethyl)-1-(S),4(S)-2,5-diazabicyclo[2.2.1]- heptan-2-yl]propyl]piperazine (enantiomer B) By an analogous method to that described in Example 14, but using 3-thiophene carboxaldehyde in place of 2-thiophene-carbox- aldehyde, the title compound was obtained as a white solid after purification by flash chrmoatography, m.p. 63-65 °C; FAB MS [M+1 ]+ 35d 611.3. EXAMPLE 17 A series derivatives of (-)-1-[3-[(1S),4(S)-2,5-diazabicyclo[2.2.1j- heptan-2-yl)-1-oxopropyl]-2-(R)-(3,4-dichlorophenyl)-4-(3,5-dimethyl- benzoyl)piperazine hydrochloride salt (from Example 11) was prepared as pure enantiomers according to the methods described in Example 12 or Example 14, but using appropriate reagents in place of benzyl bromide. FAB MS HR MS m.p. o c [M+1] + 35 CI [M+1] + 35 CI H 81-83 594.1 calc'd i 595.2243 75-77 found 595.2234 calc'd 606.2403 71-73 found 606.2396 as HCI salt calc'd 625.2171 183 found 625.2165 decomposed as HCI salt calc'd 625.2171 179 found 625.2165 decomposed ft 102-104 648.2 H 2 N ^* ° 87-89 674.3 79-81 648.3 \ r O r N 78-80 676 EXAMPLE 18 A series derivatives of (-)-1-[3-[(1 S),4(S)-2,5-diazabicyclo[2.2.1]- heptan-2-yl)-1-oxopropyl]-2-(R)-(3,4-dichlorophenyl)-4-(3,5- dimethylbenzoyl)piperazine hydrochloride salt (from Example 11 ) was prepared via parallel synthesis (i.e. without purification) according to the methods described in Example 12 and Example 14, but using appropriate Y type reagents. Reagent Y FAB MS [M+1] + 35 CI .9,677.9 EXAMPLE 19 1 , 1 -Dimethylethyl 3-oxo-8-azabicyclo[3.2.1 ]octane-8-carboxylate To a soluton of N-benzyl-2(S),6(S)-azabicyclo[3.2.1]hepta-3-one (10 g, 46.5 mmol) in EtOAc (120 mL) was added t-BOC anhydride (12.2 g, 56 mmol) and Pd(OH)2 (2 g). The mixture was hydrogenolyzed at 48.5 psi at RT overnight. After reaction was complete, the catalyst was filtered off, the filtrate was washed with saturated NaHCθ3 solution (100 mL, 2x), dried (Na2Sθ4), filtered and concentrated to give a crude material of the title compound as an oil (12 g), FAB MS [M+1]+ 226. EXAMPLE 20 1 , 1 -Dimethylethyl 3-[(phenylmethyl)amino]-8-azabicyclo[3.2.1 ]octane-8- carboxylate (exo and endo products) To a solution of the compound obtained in Example 19 (10 g, 44.4 mmol) in CF3CH2OH (50 mL) was added benzylamine (4.8 g, 44.4 mmol) and NaBHsCN (5.7 g, 62.84 mmol). The mixture was stirred at RT for 20 h. After completion of the reaction, solvent was removed and the residue was redissolved in EtOAc (200 mL), washed with saturated NaHCU3 solution (150 mL, 2x), dried (Na2S0 4 ), filtered and concentrated to give an oil. The crude material was purified by flash chromatography on silica gel (300 g), eluting with 2% [(NH 4 OH:MeOH) (1 :9)] / 98% CH 2 CI 2 to give endo product (3.6 g, 11.73 mmol, 25.6%) as a white solid, FAB MS [M+1]+ 314.4 and exo product (3.6 g, 11.73 mmol, 25.6%) as a clear oil, FAB MS [M+11+ 313.3. EXAMPLE 21 1 ,1 -Dimethylethyl 3-endo-amino-8-azabicyclo[3.2.1]octane-8- carboxylate The endo compound (3.6 g, 11.3 mmol) from Example 20 was dissolved in MeOH (100 mL) and Pd(OH) -C (0.76g) was added. The mixture was hydrogenolyzed at 45 psi at RT for 2 days. Additional Pd(OH)2-C (0.76g) was added and hydrogenolysis was continued at 45 psi for one more day. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated to give an oil which was purified on flash grade silica gel (150 g), eluting with 5%. [(NH 4 OH:MeOH) (1 :9)] / 95% CH 2 CI to give the title compound as a solid (1.9 g, 8.39 mmol, 74%), FAB MS [M+1]+ 227.1. EXAMPLE 22 1 , 1 -Dimethylethyl 3-[[2-[2-(R)-(3,4-dichlorophenyl)-2-oxoethyl]endo- amino]-8-azabicyclo[3.2.1 ]octane-8-carboxylate To a solution of the bromoacetyl derivative (1.33 g, 2.75 mmol) from Example 5 in CH2CI2 (2 mL), and endo compound from Example 21 (0.75 g, 3.3 mmol) was added Hϋnig's base (0.13 g, 2.75 mmol). The mixture was stirred at RT overnight. The reaction was diluted with CH2CI2 (100 mL) and washed with water (50 mL, 3x), dried (Na2S04), filtered and concentrated to give a yellow solid (1.9 g). The crude material was purified by flash chromatography on silica gel (100 g), eluting with 3.5 % [(1 :9) (NH4θH:MeOH)] / 96.5% MeOH to give the title compound as an off-white solid (1.5 g, 2.38 mmol, 87%) , m.p 98-100 °C, FAB MS [M+1]+ 3 5CI 629.3. EXAMPLE 23 2-(R)-(3,4-Dichlorophenyl)-4-(3,5-dimethylbenzoyl)-1 -[[[8-azabicyclo- [3.2.1]octan-3-yl]endo-amino]acetyl]piperazine hydrochloride To a solution of the compound from Example 22 (1.46 g, 2.35 mol) in CH2CI2 (2 mL) was added 4M HCI/dioxane (10 ml, 40 mmol). The mixture was stirred at RT for 1h. Solvent and excess HCI were evaporated to give the title compound as a white solid in quantitatiive yield, FAB MS [M+1]+ 35 CI 529.4. EXAMPLE 24 2-(R)-(3,4-Dichlorophenyl)-4-(3,5-dimethylbenzoyl)-1-[[[8- (phenylmethyl)-8-azabicyclo[3.2.1 ]octan-3-yl]endo- amino]acetyl]piperazine By an analogous method to that described in Example 12, but using the compound prepared in Example 23 in place of the product from Example 11 , and benzyl bromide in place of 2-acetamido-4-chloro- methylthiazole, the title compound was obtained as a white solid after silica gel purification, m.p.82-84 °C; HR MS [M+H]+ calc'd for C35H41 N4O2CI2, 619.2607; Found: 619.2594. EXAMPLE 25 2-(R)-(3,4-Dichlorophenyl)-4-(3,5-dimethylbenzoyl)-1-[[[8-(2-thienyl- methyl)-8-azabicyclo[3.2.1]octan-3-yl]endo-amino]acetyl]piperazine By an analogous method to that described in Example 14, but using the compound prepared in Example 23 in place of the product from Example 11 , the title compound was obtained as a white solid after silica gel purification, m.p. 82-84 O C; FAB MS [M+1]+ 35 CI 625.3. EXAMPLE 26 2-(R)-(3,4-Dichlorophenyl)-4-(3,5-dimethylbenzoyl)-1-[[[8-(3-pyridinyl- methyl)-8-azabicyclo[3.2.1]octan-3-yl]endo-amino]acetyl]piperazine By an analogous method to that described in Example 12, but using the compound prepared in Example 23 in place of the product from Example 11 , and 3-picolyl chloride in place of 2-acetamido-4-chloro- methylthiazole, the title compound was obtained as a light brown solid after silica gel purification, m.p. 81-83 °C; FAB MS [M+1]+ 35 CI 620.5. EXAMPLE 27 1 ,1 -Dimethylethyl 3-exo-amino-8-azabicyclo[3.2.1 ]octane-8-carboxylate The title compound was prepared as its HCI salt according to the methods described in Example 21 , but using the exo product made from Example 20 in place of the endo product from Example 20 with addition of HCI (0.5 equivalent) during the hydrogenolysis. FAB MS [M+1]+ 227.0. EXAMPLE 28 1 , 1 -Dimethylethyl 3-[[2-[2-(R)-(3,4-dichlorophenyl)-2-oxoethyl]exo- amino]-8-azabicyclo[3.2.1]octane-8-carboxyiate xamp e The title compound was prepared by an analogous method to that described in Example 22, but using the compound obtained from Example 27 in place of the endo product made in Example 21. FAB MS [M+1]+ 35 CI 629.2. EXAMPLE 29 2-(R)-(3,4-Dichlorophenyl)-4-(3,5-dimethylbenzoyl)-1 -[[[8-azabicyclo- [3.2.1 ]octan-3-yl]exo-amino]acetyl]piperazine hydrochloride The title compound was prepared by an analogous method to that described in Example 23, but using compound obtained in Example 28 in place of the endo product from Example 22. FAB MS [M+1]+ 35 CI 529.3. EXAMPLE 30 2-(R)-(3,4-Dichlorophenyl)-4-(3,5-dimethylbenzoyl)-1-[[[8- (phenylmethyl)-8-azabicyclo[3.2.1]octan-3-yl]exo- amino]acetyl]piperazine The title compound was prepared by an analogous method to that described in Example 24, but using the exo compound made in Example 29 in place of the endo product from Example 23, m.p. 61-63 °C; FAB MS [M+1]+ 35 CI 619.5. EXAMPLE 31 2-(R)-(3,4-Dichlorophenyl)-4-(3,5-dimethylbenzoyl)-1-[[[8-(2- thienylmethyl)-8-azabicyclo[3.2.1]octan-3-yl]exo-amino]acetyl]piperazine The title compound was prepared by an analogous method to that described in Example 14, but using the exo compound prepared in Example 29 in place of the endo product from Example 23, m.p. 62-64 0 C; FAB MS [M+1]+ 35 CI 625.4. EXAMPLE 32 N-[4-[[Exo-3-[[2-[2-(R)-(3,4-dichlorophenyl)-4-(3,5-dimethylbenzoyl)-1- piperazinyl]-2-oxoethyl]amino]-8-aza[3.2.1 ]octan-8-yl]- methyl]phenyl]acetamide The title compound was prepared by an analogous method to that described in Example 24, but using 4-acetamidobenzylchloride in place of benzyl bromide and the exo compound made in Example 29 in place of the endo product from Example 23. m.p. 113-115 °C; FAB MS [M+1 ]+ 35 CI 676.4. EXAMPLE 33 N-[4-[[Endo-3-[[2-[2-(R)-(3,4-dichlorophenyl)-4-(3,5-dimethylbenzoyl)-1- piperazinyl]-2-oxoethyl]amino]-8-aza[3.2.1 ]octan-8-yl]- methyl]phenyl]acetamide The title compound was prepared by an analogous method to that described in Example 24, but using 4-acetamidobenzylchloride in place of benzyl bromide. M.p. 114-116 °C; FAB MS [M+1]+ 3 5ci , 676.4. EXAMPLE 34 3-[[Endo-3-[[2-[2-(R)-(3,4-dichlorophenyl)-4-(3,5-dimethylbenzoyl)-1 - piperazinyl]-2-oxoethyl]amino]-8-aza[3.2.1]octan-8-yl]methyl]benzamide The title compound was prepared by an analogous method to that described in Example 24, but using 3-chloromethylphenylamide in place of benzyl bromide. M.p. 106-108 °C; FAB MS [M+1]+ 3 5d 662.0. EXAMPLE 35 A series derivatives of 2-(R)-(3,4-dichlorophenyl)-4-(3,5-dimethyl- benzoyl)-1 -[[[8-azabicyclo-[3.2.1 ]octan-3-yl]exo-amino]acetyl]piperazine hydrochloride salt (from Example 29) was prepared as pure enantiomers according to the methods described in Example 31 or Example 32 but using appropriate Y type reagents as follows. FABMS m-P- EXAMPLE 36 A series derivatives of 2-(R)-(3,4-dichlorophenyl)-4-(3,5-dimethyl- benzoyl)-1 -[[[8-azabicyclo-[3.2.1 ]octan-3-yl]endo- amino]acetyl]piperazine hydrochloride salt (from Example 23) was prepared as pure enantiomers according to the methods described in Example 31 or Example 32 but using appropriate Y type reagents as follows. _Y FABMS m.p. \ 107-109 NH 676.2 -ft O EXAMPLE 37 2(R)-(3,4-Dichlorophenyl)-4-[(4-fluoro-1 -naphthalenyl)carbonyl]- 1-[1-oxo-3-[5-(phenylmethyl)-1 (S),4(S)-2,5-diazabicyclo[2.2.1]- heptan-2-yl]propyl]piperazine Step 1 : 3-((1S,4S)-N-Benzyl-2,5-diazabicyclo[2.2.1]heptanyl)propionic acid (1 S,4S)-N-Benzyl-2,5-diazabicyclo[2.2.1]heptane-2HBr (5 g) was suspended in 25 ml of CH2CI2 with stirring under N2. A slight excess (5.53 g; 3 equivs.) of Hϋnig's Base was added. After a short time, the suspended solid dissolved. After about 0.25 h of stirring a ca. 10% excess of methyl 3-bromopropionate (2.7 g) was added dropwise over a period of ca. 10 min. The solution was stirred at RT overnight. The product was isolated by washing with H2O (2x) then with sat. aq. NaCI. The organic layer was separated, dried (Na2S0 4 ), filtered and evaporated to a pale yellow oil which was dissolved in 1 N HCI (ca. 50 ml) -and allowed to stand overnight. Little hydrolysis had occurred, so the solution was made more concentrated by evaporating off much of the water present under reduced pressure. The resulting solution was kept at RT for 2.5 days. The remainder of the water was removed under reduced pressure to produce the title compound of Step 1 as its 2HCI salt, a glass which was used directly in the next step. Steps 2-4: Step 2: To a coooled solution of (+,-)-2-(3,4-dichlorophenyl)piperazine (20 g,-86.53 mmol) in CH3OH (900 ml) at -78°C was added dropwise a solution of t-BOC anhydride (19.47 g, 86.53 mmol) in CH3OH (263 ml) over 3 h under N2. The solution was gradually warmed to RT overnight. After reaction was complete, the solvent was evaporated and the residue dried under high vacuum overnight to give (A) (28 g) as a white solid. FAB Mass [M+1]+ 35ci 331.2. The product from Step 1 (1 g) and (A) (1 g) were suspended in CH2CI2 (5 ml) to give a white slurry. Et 3 N (1 g; 3 equivs.) was added along with another 4 ml of CH2CI2. The mixture was stirred at RT under N2 for 1.75 h and then was cooled in an ice bath. After 2 h, a solution of BOP-CI (0.85 g) in CH2CI2 (3 ml) was added over a period of about 10 min. After 0.5 h of stirring, the ice bath was removed and the reaction was allowed to procede at RT. After 4 days, (B) was isolated and purified by flash chromatography on silica gel using CH2CI2 / 5% of 2M NH3 in CH3OH as eluent. FAB-MS showed the major peak at m/z = 573 or as expected for (M+1) + of the CI2 molecule. Step 3: (B) was dissolved in 5 mL of CH2CI2, the solution was cooled in an ice bath and 5 ml of 4M HCI in dioxane was added. After 10 min, the ice bath was removed and reaction was allowed to proceed at RT for 4 h. Reagents and solvents were evaporated off and the product was stored overnight under vacuum. Step 4: The product of Step 3 and 4-fluoro-1-naphthoic acid were reacted under essentially identical conditions to those described in Example 12 to produce the title compound, which was converted to its 2HCI salt using 4M HCI in dioxane and IPA as cosolvent. The product was a tan solid, m.p. 199 - 201 °C (dec); FAB-MS: m/z 645.2 correct for (M+1 ) + of C 3 6H35N4θ 2 35 CI 2 F. Using a similar procedure, the following compounds were also prepared: Ar. Data EXAMPLE 38 Using procedures similar to those described above in Examples 2-14 and 37, the following compounds were prepared:

Claims: WHAT IS CLAIMED IS: 1. A compound selected from the group consisting of wherein Y is selected from the group consisting of 3)2 a compound of the formula Cl Cl wherein Y is selected from the group consisting of and a compound of the formula wherein Y is phenyl; or an enantiomer, diastereomer, endo, exo R or S form thereof, or a pharmaceutically acceptable salt thereof. 2. A compound of claim 1 of the formula wherein Y is selected from the group consisting of όvy A. H JT. y ϊ «" ■ * ■ * or a a compound of the formula 3. A compound selected from the group consisting of wherein Ar' is selected from the group consisting of or any enantiomer, diastereomer, endo, exo R, or S form thereof, or a pharmaceutically acceptable salt thereof. 4. . A compound of claim 3 wherein Ar' is selected from the group consisting of 5. A compound of claim 1 selected from the group consisting of a compound of the formula wherein Y is selected from the group consisting of a compound of the formula wherein Y is selected from the group consisting of a compound of the formula roup consisting of and a compound of the formula the following table:

Inventors: BLYTHIN DAVID J, CHEN XIAO, MCCORMICK KEVIN D, PIWINSKI JOHN J, SHIH NENG-YANG, SHUE HO-JANE, BLYTHIN, DAVID, J., CHEN, XIAO, MCCORMICK, KEVIN, D., PIWINSKI, JOHN, J., SHIH, NENG-YANG, SHUE, HO-JANE
Applicants: BLYTHIN DAVID J, CHEN XIAO, MCCORMICK KEVIN D, PIWINSKI JOHN J, SCHERING CORP, SHIH NENG YANG, SHUE HO JANE, BLYTHIN, DAVID, J., CHEN, XIAO, MCCORMICK, KEVIN, D., PIWINSKI, JOHN, J., SCHERING CORPORATION, SHIH, NENG-YANG, SHUE, HO-JANE
Application year: 1999
Main classification: C07D487
IPC codes: A61K31, A61P11, A61P17, A61P25, A61P29, A61P43, C07D471, C07D487