MXPA00006906A - Piperazino derivatives as neurokinin antagonists - Google Patents

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

DERIVATIVES OF PIPERACINO AS ANTAGONISTS OF THE NEUROQUININE BACKGROUND OF THE INVENTION The present invention relates to a genus of compounds useful as neurokinin receptor antagonists. In particular, these may be antagonists of the neurokinin-1 receptor (NKi). Some may also be antagonists of neurokinin receptor 1 (NKi) and neurokinin receptor 2 (NK2) antagonists, ie dual receptor antagonists (NK ^ / (NK2) .Some may also be antagonists of neurokinin receptor 2 (NK2). Some may also be antagonists of neurokinin 3 receptor (NK3) Neurokinin receptors are found in the nervous system and in the circulatory system and peripheral tissues of mammals and therefore are involved in a variety of biological procedures. considers, therefore, that neurokinin receptor antagonists are useful in the treatment or prevention of various conditions of mammalian diseases, for example, lung disorders such as asthma, cough, bronchospasm, chronic obstructive pulmonary diseases and pulmonary hyperreactivity; skin and itching, such as, for example, atopic dermatitis, and swelling and skin rashes; neurogenic inflammation, such as arthritis, migraine, nociception; CNS diseases such as anxiety, Parkinson's disease, movement disorders and psychosis; seizure disorders, kidney disorders, urinary incontinence, eye inflammation, pain with inflammation and eating disorders such as, for example, inhibition of food consumption; allergic rhinitis, neurodegenerative disorders, psoriasis, Huntington's disease, depression, emesis and various gastrointestinal disorders, such as Crohn's disease. In particular, NKi receptors have been reported to be involved in microvascular filtration and mucosal secretion and have been associated with NK2 receptors with muscle contraction, making the NK-i and NK2 receptor antagonists especially useful in the treatment and in the prevention of asthma. In addition, NK3 receptor antagonists are especially useful in the treatment and prevention of asthma, inflammatory diseases and conditions, such as eye inflammation, allergic rhinitis, skin swelling and hives, psoriasis, atopic dermatitis, CNS diseases such as anxiety. and Parkinson's disease.

BRIEF DESCRIPTION OF THE INVENTION The invention relates to compounds of the formula: each X is independently O, NRd or S; n is from 0 to 2; u is from 0 to 2; I is from 0 to 2; m is 1, and y is from 1 to 3; or m is 2, and y is 0; and with the proviso that only one Rc is different from H in the portion each Rc is independently H, Ci-Cß alkyl, - (CH2) n? -R4 where it is not from 1 to 6; Rd is independently selected from the group consisting of H, C 1 -C 2 alkyl, CN, ORa, phenyl, substituted phenyl, benzyl, substituted benzyl or allyl; -N A ° II ^ I a O R4 is -ORg, SRg, -CN, Rb -C- N- Rj, -ORa, , Rc 'is H, Ci-Cß alkyl or (CH 2) nORa, with the proviso that only one Rc' is different from H; each Ra and Rb is independently selected from the group consisting of H, C? -C6 alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, allyl; except that when R is, Ra is not H; or when Ra and Rb are joined to the same nitrogen, then Ra and Rb together with the nitrogen to which they are adhered form a ring of 4 to 7 members formed by 1 nitrogen atom and from 3 to 6 carbon atoms; where each Ri and R 2 is independently H, C 1 -C 6 alkyl, O 0 C 2 F 5, Cl, Br, I, F, NO 2 > ORg, CN, NRgRj ,, - C-Ra -O- C-Rg CF3 Rb and where Ra is not H in or when Ri and R2 are adjacent carbons in a ring, they can form where n 'is 1 or 2; II and each R3 is independently H, alkyl Ci-Ce, CF3, C2F5, - C- Rg, -O-, Cl, Br, I, F, ORa, OCF3, or phenyl; A is heteroaryl or substituted heteroaryl, Q is N or CH; Ar2 is heteroaryl or substituted heteroaryl, m? = 0-1; m2 = 1-2, n3 is 0-4; each Re and Rf is independently selected from the group consisting of H, Ci-Cß alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, allyl; or Re and Rf taken with the carbon to which they are attached can also form a carbonyl group with the proviso that only one carbonyl group is in the moiety n5 is from 1 to 2; each R5 is selected independently of the group formed Or by H, OH, i and! _ R r a, C? -C6 alkyl, (CH2) n? -R4, where ni is from 1 to 6 with the proviso that when it is not 1, R is not OH or NRaRb; further, with the proviso that when ns is 2, R5 is C-C alkyl, and two Rs can be attached to the nitrogen to form a quaternary salt; Re is H, Ci-Cß alkyl, C 3 -C β cycloalkyl, when X3 is (H, H), O, NRd, or S; or Re 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 n3 is 1, Re can also be -ORa where Ra is not H, or R6 is -NRa, Rb, -O- ( CR a, R b) n -heteroaryl, -O- (CR a, R) n 7 -substituted heteroaryl, -O- (CR a, R b) n 7 -heterocycloalkyl, -O- (CR a, R b) n 7 -substituted heterocycloalkyl, -O- ( CRa, Rb) n -aryl, -O- (CRa, Rb) n7-substituted aryl, -NRa- (CRa, R) n7-heteroaryl, -NRa- (CRa, Rb) n7-substituted heteroaryl, -NRa- ( CRa, R) n7-aryl, -NRa- (CRa, Rb) n7-substituted aryl, -NRa- (CRa, Rb) n7-heterocycloalkyl, -NRa- (CRa, Rb) n7-substituted heterocycloalkyl, where n is 0 to 4 and Ra and Rb are each independently selected from the group consisting of H and Ci-Cß alkyl; or an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

All variables of the formulas mentioned above, such as Z, R-i, R2 and R3 have the same meaning throughout the description 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. In addition, compounds of formula I where both X are O are preferably. In addition, the compounds are preferably of formula I where I is O, m is 1, and y is 1 -3. In addition, compounds of formula I are preferably those wherein n is 1 and u is 0. Further, compounds of formula I are preferably and n is 0 or 1. In addition, compounds of formula I are preferably Ar2 is In addition, compounds of formula I where both X are O are preferably; I is 0; m is 1; and it is 1 -3; n is 1; n is 1; u is 0; Rc is H or C -? - C6 alkyl; An is , where n4 is 0 or 1; Z is defined in formula I, where Re, Rf are H, alkyl C-i-Cß, n3 is 0-4 and Re is or Re and Rf taken together with the carbon to which they are attached form a carbonyl group, n3 is 1 and Rβ is In addition, the compounds of formula I are preferably those in which Ari and Ar2 are both The compounds of this invention are exemplified by the following formulas where Y represents the following groups: a compound of the formula where Y is H a compound of the formula where Y is phenyl; or any enantiomer thereof or a pharmaceutically acceptable salt thereof; or a compound of the formula: find their uyenes or, m, p, ci Cl where Ar1 is selected from the following groups: The preceding groups represent all possible stereoisomers, including enantiomers, diastereomers, the endo, exo, R and S forms. Preferred Y variables are: The preferred Ar1 variables are The invention further relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the 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 antagonism of the neurokinin. The invention also relates to the use of a compound of formula 1 for the preparation of a medicament for the treatment of chronic diseases of the respiratory tract, such as asthma and allergies; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrocytes, 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; autoimmune disorders; graft rejection; systemic lupus erythematosus; Gl disorders, such as Crohn's disease and ulcerative colitis; functional disorders of the bladder; circulatory disorders such as angina; Raynaud's disease; cough and pain. In particular, the invention further relates to a method of treating asthma comprising the administration to a mammal in need of said treatment of an anti-asthma effective amount of a compound of formula I for said purpose.

DETAILED DESCRIPTION OF THE INVENTION As used in the present invention, the term "alkyl" means a straight or branched chain saturated hydrocarbon having from 1 to 6 carbon atoms. The number of carbon atoms can be designated. For example, Ci-Cß alkyl represents a saturated, straight-chain or branched hydrocarbon having from 1 to 6 carbon atoms. The term "C3-C3-cycloalkyl" means a cycloalkyl having from 3 to 6 carbon atoms, which is cyclopropyl, cyclobutyl and cyclohexyl. The term "alkenyl" means a saturated straight-chain or branched alkenyl having 2 to 6 carbon atoms. The number of carbon atoms can be designated. For example, "C2-Ce alkenyl" represents a rectilinear or branched alkenyl having from 1 to 6 carbon atoms. The term "alkynyl" means a straight or branched chain alkynyl having from 2 to 6 carbon atoms. The number of carbon atoms can be designated. For example, "C2-C6 alkynyl" represents a rectilinear or branched alkenyl having from 2 to 6 carbon atoms. As used in the present invention, a dark thick line (- ^) denotes a chemical bond above the plane of the page.

A dotted line (? I ||) denotes a chemical link below the plane of the page.

As used in the example, it means that Ri R2 and R3 can be each of the rings of the preceding naphthyl portion. Asymmetric centers exist in the compounds of formula I of the invention. Accordingly, the compounds of the formula I include stereoisomers. All isomeric forms and mixtures thereof are within the scope of the present invention. Unless otherwise indicated, the methods of preparation disclosed in the present invention may result in product distribution including all possible structural isomers, although it is understood that the psychological response may vary according to the stereochemical structure . The isomers can be separated by conventional means, such as fractional crystallization, preparatory plate or column chromatography on silica, alumina, or reverse phase supports or HPLC analysis (high performance liquid chromatography). The 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, the enantiomers can be separated by chromatography on a chiral support. The compounds of formula I can exist in solvated as unsolvated forms, including hydrated forms, for example, the hemihydrate. In general, solvated forms, with pharmaceutically acceptable solvents, such as water, ethanol, and the like are equivalent to unsolvated forms for the purposes of the invention. Those compounds of formula I which contain a basic group such as -CH 2 NH 2, form pharmaceutically acceptable salts. Preferred pharmaceutically acceptable salts are non-toxic acid addition salts formed by adding to a suitable compound of the invention about a stoichiometric amount of a mineral acid, such as HCl, HBr, H2SO4 or H3PO4 or an organic acid, such as the acids acetic, propionic, valeric, oleic, palmitic, stearic, lauric, benzoic, lactic, paratoluenesulfonic, methanesulfonic, citric, maleic, fumaric, succinic and the like, respectively.

General Methods of Preparation The compounds of this invention can be prepared by methods known in the art, see for example WO 96/34864 and WO 97/08166 and the examples described below. Unless indicated otherwise, the variables in the structural formulas are as defined above. The reagents and starting materials used in the methods and examples below are known or can be prepared according to known methods. As used in the present invention the term "substituted phenyl" means where Ri R 2 and R 3, are as described in the present invention. "Substituted" means substituted by Ri R2 and / or R3, as described herein. "Aryl" means phenyl, naphthyl, indenyl, tetrahydronaphthyl, indanyl, anthracenyl or fluorenyl. "Halogen" refers to fluorine, chlorine, bromine or iodine atoms. "Heterocycloalkyl" refers to rings having from 4 to 6 members comprising from 1 to 3 heteroatoms selected independently from the group consisting of -O-, -S- and -N (R6) -, where the remaining ring members They are carbon. Examples of heterocycloalkyl rings are tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl. "Heteroaryl" refers to benzofused or unique aromatic rings of 5 to 10 members, comprising from 1 to 3 heteroatoms independently selected from the group consisting of -O-, -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 quinolyl, tianaphtenyl and benzofurazanyl. N-oxides of nitrogen-containing heteroaryl groups are also included. Furthermore, all positional isomers are contemplated, for example, 1-pyridyl, 2-pyridyl, 3-pyridyl and 4-pyridyl. When the substituents R2 and R3 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 thus formed are morpholinyl, piperazinyl and piperidinyl. As used in the present invention, each Rc and Rc- is independently selected from the group consisting of H, Ci-Cß alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, substituted or unsubstituted phenyl, and substituted or unsubstituted benzyl . As used in the present invention, the term "BOC" means t-butoxycarbonyl. As used in the present invention, the term "parallel synthesis" means the preparation of individual chemical compounds such as a batch, for example, 20, 30 or even 100 identical reactions generally on a single substrate but using a different reagent in each container. These reagents are always of the same general class, in this case, each carboxylic acid or organic amines in any set of parallel reactions. The conditions used for each reaction are identical to those described in the examples, unless a simplified absorption is employed, generally a simple wash with either an acid or a base, if appropriate, then water. The presence of the product is detected by thin layer chromatography (TLC), using products known as representative standards. Generally, an additional characterization is developed by combination of HPLC / MS analysis. Additional purification is not carried out on these materials before they are subjected to biological tests. The in vitro and in vivo activity of the compounds of formula I can be determined by various methods in the art, as a test of ability to inhibit the activity of the NKi agonist in substance P, a NK2 test of hamster trachea in isolated form, a test of the effect of NKi antagonists on substance P - induced microvascular airway filtration, measurement of NK2 activity in vivo in guinea pigs, measurement of bronchoconstriction due to NKA and neurokinin receptor binding assays. Typical procedures are published in WO96 / 34864. For all compounds of the invention, the NKi binding is on a scale of about 0-100% inhibition at a concentration of 1 μM. For all compounds of the invention, the NK2 binding is on a scale of about 0-100% inhibition at a concentration of 1 μM. It should be understood that while the NK bond for certain compounds of the invention, it is as low as 0% at a concentration of 1 μM, at higher concentrations these compounds will have an inhibition activity of NK binding. The K, of a compound is that concentration in which the compound caused 50% inhibition, both of KNi and NK2. For these compounds of the invention having a greater than 50% inhibition of NK-i, the Ks for NK are determined. For these compounds of this invention having a greater inhibition of 50% of NK2, Ks are determined. for NK2. The compounds of the formula I exhibit the antagonist activity of NKi and NK2 for various degrees, ie, certain compounds have a strong NK-i antagonist activity, but a weaker antagonist activity of NK2. Others have a stronger activated NK2 antagonist, but have a weaker antagonist activity of NK-i. Certain compounds have strong antagonistic activities of both NKi and NK2. Other compounds also have NK3 antagonists. Many compounds of formula I have an asymmetric center and therefore there are a pair of enantiomers. In such cases, one enantiomer may have different biological activity than the other. For example, one enantiomer may have a strong NKi activity and a weak NK2 activity, although the other enantiomer has a weak NKi activity and a strong NK2 activity. It has been found that certain compounds of formula I are antagonists of both N ^ and NK2 receptors and are therefore useful in the treatment of 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 an acceptable pharmaceutical carrier. The compounds of this invention can be administered in conventional oral dosage forms such as capsules, tablets, powders, wafers, 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. The pharmaceutically acceptable excipients and additives include fillers, binders, disintegrants, pH regulators, preservatives, antioxidants, lubricants, flavors, thickeners, coloring agents, non-toxic and chemically compatible emulsifiers and the like. The daily dose of a compound of formula I for the treatment of asthma, cough, bronchospasm, inflammatory disease, migraine, nociception and gastrointestinal disorders is from about 0.1 mg to about 20 mg / kg of body weight per day, preferably about 0.5 15 mg / kg, more preferably 0.5 to about 5 mg / kg. For an average body weight of 70 kg, the dosage scale 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 divided into 2-4 doses . The exact dose, however, is determined by the intervening clinician and this depends on the potency of the compound administered, the age, weight, condition and response of the patient. The present invention provides the following examples, which should not be construed as limiting the scope of the disclosure. Analogous structures and alternative mechanical paths, within the scope of the invention, will be obvious to those skilled in the art.

EXAMPLE 1 2- (3,4-dichloropheniDpiperazine) A. Synthesis of the 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 -Cl, H or other substituents, i.e., OCH 3, CF 3, Br, I, F, etc. R2 = CI, H or other substituents, that is, OCH3, CF3, Br, I, F, etc.

B. Resolution of (+, -) - 2- (3,4-dichloropheniDpiperazine 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 moles) and heated until all the material dissolved. EtOAc (2.2 I) was added to this solution and allowed to stand at room temperature overnight. The solvent phase was decanted from the precipitated salt and concentrated in vacuo. 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 (0.327 mol).

Step 2: The concentrated salts of both solvent phases in step 1 were combined and heated in methanol (550 ml) until the dissolution of all the material. EtOAc (2.75 I) was added to this solution and allowed to stand at room 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 of the solvent phase in step 2 was dissolved in a solution of H 2 O (800 ml) and aqueous ammonia (400 ml) and extracted with CH 2 Cl 2 (4 x 400 ml). The combined organic layers were dried with MgSO 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 the enantiomer TO). [a] D 4 c = -45.0 ° (MeOH).

Step 4: The precipitated salts from step 1 were combined and heated in CH3OH (220 ml) until all the materials dissolved. EtOAc (2.2 I) was added to this solution and allowed to stand at room temperature overnight. The solvent phase was decanted from the precipitated salt and concentrated in vacuo to give -43 g of piperazine salt (93% ee of enantiomer B).

Step 5: A portion of salt of 12.3 g (75% ee of enantiomer B) prepared by a procedure analogous to that of step 4 was dissolved in 0.5 M NaOH (400 ml) and extracted with CH 2 Cl 2 (4 x 155 ml). . The combined organic layers were dried with MgSO 4 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 the enantiomeric purity of piperazine The enantiomeric purity of the piperazine was measured by chiral HPLC analysis of the d-tert-butoxycarbonyl derivative. The di-tert-butoxycarbonyl derivative was prepared by adding a small sample of piperazine (free base or salt) (-0.2 mg) to di-tert-butyl dicarbonate (-1 mg) and methanol (0.5 ml) and heat at 80 ° C for 1 hour. If the piperazine sample is a salt, triethylamine (20μl) is also added. The derivative was analyzed by HPLC analysis using a ChiralPak AD column eluting with hexane-isopropyl alcohol, 95: 5.

EXAMPLE 2 (+, -) - r3,5-D -methylbenzoic-3- (3,4-dichlorophenyl) piperazine To a cooled solution of CH2Cl2 (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, Et3N (4.2 ml, 30 mmol) and N, N-dimethylaminopropylethylcarbodimide (DEC) (5.86 g, 30 mmol) were added under an atmosphere of nitrogen. The reaction was maintained at -20 ° C for one hour and gradually warmed to room temperature overnight. After being stirred for 22 hours, the reaction was complete and CH2Cl2 (200 ml) was added. The organic solution was washed with brine (150 ml, 3 x), dried over MgSO 4, filtered and concentrated under vacuum to give 8.2 g of crude product. The product was crystallized from CH2Cl2 / hexane to give a mild yellow solid (6.3 g, 17.34 mmol, 57.8%); p.f. 139-141 ° C; FAB MS (Spectrum of mass by fast bombardment of atoms) [M + 1] +35 Cl 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 (1.5 g, 31.65 mmol) in CH2Cl2 (200 mL) at 0 ° C, was added Hünig 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 of the reaction, it was diluted with CH2Cl2 (400 ml) and washed with brine (300 ml, 2 x), dried over MgSO, filtered and concentrated. The crude material was purified by flash chromatography on silica gel, eluting with 2% [NH4OH / MeOH (1: 9)] /98% CH2CI2 to give the title compound as a light yellow solid (7.1 g, 47.3%); p.f. 77-79 ° C, FAB MS [M + 1] + 35Cl, 79Br 482.9, 484.9.

EXAMPLE 4 (+ - H3,5-Dimethylbenzop-3- (RM3,4-dichlorophenyl) piperazine (enantiomer 11 The titled compound was prepared by an analogous method to that described in Example 2, using -2- (R) - (3,4-dichlorophenyl) piperazine in place of (+, -) - 2- (3,4-dichlorophenyl) ) piperazine; p.f. 97-100 ° C; FAB MS [M + 1] + 35 Cl 363, 1; [a] D22-5 ° c = + 87.2 ° (MeOH).

EXAMPLE 5 (-) - Bromoacetyl-2- (R) - (3,4-dichlorophenip-4- (3,5-dimethy1-benzoyl) piperazine (enantiomer B) The titled compound was prepared by an analogous method to that described in Example 3 using (+) - [3,5-dimethylbenzoyl] -3- (R) - (3,4-dichlorophenyl) piperazine (Enantiomer B) (Example 4 ) instead of (+, -) - [3,5-dimethylbenzoyl] -3- (3,4-dichlorophenyl) piperazine; p.f. 68-71 ° C; FAB MS [M + 1] +35 CI79Br 482.9, 484.8; [] D21 9 ° c = -45.6 ° (MeOH).

EXAMPLE 6 (+, -) - 2- (3,4-Dichlorophenyl-4-r3,5-dimethylbenzoyl) -1-rrr3-methyl-1- (phenylmethyl-4-piperidinipaminolacetillpiperazine (diastereomers A v B) Step 1 To a solution of BOC glycine (0.979 g, 5.59 mmol) and Et3N (0.85 mL, 6.1 mmol) in CH2Cl2 (10 mL) was added the reagent BOP (benzotripazol-1-yloxy-tris (dimethylamino) Phosphine hexafluorophosphate) (2.46 g, 5.57 mmol). After stirring for 15 minutes, (+, -) - (3,5-dimethylbenzoyl-3- (3,4-dichlorophenyl) piperazine (1.83 g, 5.03 mmol) (prepared in Example 2) was added. After 5 hours, the reaction mixture was added to 0.2 N HCl (100 ml) and extracted with CH 2 Cl 2 (3 x 60 ml) The combined organic layers were washed with brine, dried with MgSO 4 and concentrated. crude was purified by flash chromatography on silica gel eluting with CH2Cl2-MeOH, 50: 1 to 30: 1, to give 2.15 g of compound 2 (indicated above) as a white foam (4.1 mmol, 82%).

Step 2 Compound 2 (1.32 g, 2.5 mmol.) Was treated with sat. MeOH. HCl (15 ml) for 2.5 h and concentrated. The resulting powder was dissolved in CH2CI2, washed with saturated NaHCO3, dried with MgSO4 and concentrated to give compound 3, in free base form.

Step 3 To a solution of -78 ° C 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 minutes and then cooled 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 hours when it was warmed to room temperature, overnight. The reaction mixture was cooled and concentrated. The residue was suspended in H2O and extracted with CH2Cl2. The combined organic layers were dried with MgSO, filtered and concentrated. The product was purified by flash chromatography on silica gel, eluting with hexane-EtOAc, 1: 1, to give the compound 4, 1-benzyl-3-methyl-4-piperidone, as a yellow oil (0.65, 30%).

Step 4 A mixture of ketone 4 (step 3) (70 mg, 0.13 mmol) was stirred and compound 3 (34 mg, 0.17 mmol) was stirred in titanium isopropoxide (45 mg, 0.16 mmol), for 1.5 hours. Ethanol (1.0 ml) and NaCNBH3 (5.4 mg, 8.6 mmol) were added to the mixture 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 MgSO4 and concentrated. The residue was chromatographed on silica gel, eluting with 5% sat. MeOH in CH 2 Cl 2 to give both pure diastereomers. Diastareomer A (15 mg) HRMS (High Res. Mass Spectrum) (FAB (Rapid Bombardment of Atoms), M + H +): m / e calculated for [C34H41N4CI2O2] + 607.2607; found 607.2597.

EXAMPLE 7 2- (3,4-Dichlorophenyl) -4- (3,5-dimethylbenzoyl) -1-rrr8- (phenylmethin-8-azabicyclo3.2.noct-3-ynamylnoacetylpiperazine) of Example 6, compound 3 By a method analogous to that described in Example 6, the product of 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 mmole) and Ti (O- / Pr) 4 (105 ml, 0.50 mmole) and stirred for one hour. To the thick reaction mixture was added NaBH3CN (59.5 mg, 0.95 mmol) and the mixture was stirred overnight. H2O (1 ml) was added to the reaction mixture and filtered. The filtrate was washed with EtOH, concentrated and purified by silica chromatography, eluting with aqueous CH2Cl2-MeOH-NH3, 30: 1: 0.1 to 15: 1: 0.1, to give the title product as a white foam. HRMS (FAB, M + H +); m / e calculated [C35H4? CI2N4? 2] +: 619.2607 found 619.2594.] EXAMPLE 8 2- (R) - (3,4-Dichlorophenyl- (3,5-dimethylbenzoyl) -1-rr8-metin-8-azabicyclo3.2.noct-3-ylamino-acetylpiperazine (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 the Step 1 and tropinone instead of 1-benzyl-3-methyl-4-piperidone. HRMS (FAB, M + H +); m / e calculated [C 29 H 37 Cl 2 N 4 O 2] +: 543.2294, found 543.2282.

EXAMPLE 9 2- (R) - (3,4-Dichlorophenyl) -4- (3,5-dimethylbenzoin-1 -r3-r5- (phenylmethyl) - (1S, 4S) -2,5-diazabicyclo2.2. pheptane-2-H-1-oxopropypyperazine (Enantiomer To a cooled solution of CH2Cl2 (10 ml) containing diisopropylethylamine (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), chloropropionyl chloride (0.075 ml, 0.8 mmol) was added. The reaction mixture was warmed to room temperature. After 20 minutes, (1S, 4S) -2-benzyl-2,5-diazabicyclo (2.2.1) heptane 2HBr (297 mg, 0.85 mmole) and diisopropylethylamine (0.275 ml, 2.0 mmole) were added and the mixture was left stand overnight, after which, the reaction mixture was concentrated. The product was purified by flash chromatography on silica gel, eluting with CH 2 Cl 2 / MeOH / NH 3, 30: 1: 0.1, to give a foamy solid (140 mg, 0.23 mmol, 29%), HRMS: calculated [C 34 H 39 Cl 2 N 4 O 2] +: 605.2450 found 605.2465.

EXAMPLE 10 (-1-1.1-dimethylethyl 2-r3-r2- (RH3,4-dichlorophenyl) -4- (dimethylbenzoyl) -1-piperazinip-3-oxoprop.p-1 (S) -4 (S) -2 , 5-diazabicyclo2.2.nheptan-5-carboxylate Part 1 To a solution of the compound obtained from example 4 (20.7 g, 57 mmol) in anhydrous CH 2 Cl 2 (320 ml) at -78 ° C, 3-bromopropionyl chloride (9.8 g, 57 mmol) and Et 3 N (5.76 g) were added. , 57 mmol). After stirring at -78 ° C for 4 hours, additional 3-bromopropionyl chloride (0.5 ml, 4.96 mmoles) and Et3N (0.5 ml, 4 mmoles) were added. A portion of the material (40 ml) was absorbed by diluting with CH2Cl2 and washing with water, as described in example 4, to give intermediate A of 3-bromopropionamide, as shown above. EM FAB [M + 1] + 498.9.

Part 2 The residue of the preceding reaction solution was evaporated without water washing to give a brown solid (25 g, 50.5 mmol), which was redissolved in absolute EtOH (200 ml) and cooled to 0 ° C. To this cooled solution was added (1S, 4S) -N-t-BOC-2,5-diazabicyclo [2.2.1] -heptane (9.0 g, 45.5 mmoles) and Et3N (4.1 g, 40.4 mmoles). The solution was stirred overnight at room temperature. After completion of the reaction, the EtOH was evaporated and the residue redissolved in CH2Cl2 (500 mL), washed with brine (300 mL, 3x), dried over (MgSO4), filtered and concentrated to give a product raw toasted color (30 g). The crude material was purified by flash chromatography on silica gel (400 g), eluting with 3% [(NH4OH: MeOH (1: 9)] /97% CH2CI2 to give the title compound as an off-white solid (15.5 g, 25.1 mmole, 55%), mp 78-82 ° C, FAB Mass [M + 1] + 35CI 615.1, [a] D22 ° c = 51.1 ° (MeOH).

EXAMPLE 11 -1-r3-r (1S), 4 (S) -2.5-diazabicyclo2.2.pheptan-2-yl) -1-oxopropip-2- (R) - (3,4-dichlorophenyl) -hydrochloride 4- (3,5-dimethylbenzoyl) piperazine To a solution of the compound obtained from Example 10 (14.5 g, 23.55 mmol) in CH2Cl2 (25 mL) at room temperature was added a solution of 4M HCl-dioxane (58.8 mL, 235.2 mmol). The mixture was stirred at room temperature for 2 hours and the excess of acid and solvents were evaporated to give the titled compound as a light yellow solid (15.5 g); p.f. 60-64 ° C; FAB MS [M + 1] +35 Cl 515.2, [a] D22 ° c = -34.3 ° (MeOH).

EXAMPLE 12 (-) - N-r4-rr5-r3-r2- (R) - (3,4-dichlorophenyl-4- (3,5-dimethylbenzoic-1-piperazinin-3-oxopropyl- (1S.4S) -2.5- diazabicyclo2.2.nheptan-2-inmethyl-2-thiazolyl-acetamide (enantiomer B) A solution of chiral intermediate 1 of Example 11 (200 mg, 0.34 mmol), 2-acetamido-4-chloromethyl thiazole (64.8 mg, 10.34 mmol) and Hünig's base (1.088 mmol) in CH2Cl2 (4 mL) should be stirred room temperature under N2 for 24 hours. It is then diluted with CH2Cl2 (200 ml), washed with brine, the organic layer is separated, dried over MgSO, filtered and evaporated. Purify by flash chromatography on silica gel to obtain the titled compound 2 as a white solid; p.f. 105-110 ° C; FAB MS [M + 1] +35 CI 669.0, [] D24 c = 23.4 ° (MeOH).

EXAMPLE 13 (-) - N-r4-r5-r3-r2- (R) - (3,4-dichlorophenyl-4- (3,5-dimethylbenzoin-1-piperazin-3-oxopropyl- (1S, 4S ) -2,5-diazabicycloi2.2.nheptan-2-ipmetipfenillacetamida (enantiomer B) By an analogous method to that described in Example 12, using the chiral intermediate of Example 11 and 4-acetamidobenzyl chloride, in the Hünig base present in CH 2 Cl 2, the title compound was obtained as a white solid, after purification by flash chromatography on silica gel; p.f. 101-106 ° C; FAB MS [M + 1] +35 Cl 662.1, [] D23-3 ° c = -27.3 ° (MeOH).

EXAMPLE 14 (-) - 2- (R) - (3,4-Dichlorophenyl-4- (3,5-dimethylbenzoyl) -1-ri-oxo-3-r5- (2-thienylmethyl) -1- (S) , 4 (S) -2,5-diazabicyclo2.2.nheptan-2-n-propinpperazine (enantiomer B) A mixture of the compound obtained from example 11, 0.206 g, 0.35 mmol) in CF3CH2OH (3 ml), Hünig's base (113 mg, 0.87 mmol) and 2-thiophene carboxaldehyde (44 mg, 0.39 mmol) was stirred at room temperature night under nitrogen atmosphere. After evaporation of CF3CH2OH, the residue was redissolved in CH2Cl2 (50 ml) and washed with saturated NaHCO3 solution (30 ml, 2x), dried (MgSO4), filtered and concentrated to give a soft brown solid. (0.26 g). The product was purified by flash chromatography on silica gel (50 g), eluting with 5% [NH 4 OH -MeOH) (1: 9)] / 95% CH 2 Cl 2 to give the title compound as a pale yellow solid (100 mg, 0.163 mmol, 47%); p.f. 70-72 ° C; HRMS calculated for [M + 1] + C 32 H 37 S N 4 O 2 Cl 2: 661.2014; found: 611.2011; [a] D225 ° c = -20.8 ° C (MeOH).

EXAMPLE 15 2- (R) - (3,4-Dichlorophenyl-4- (3,5-dimethylbenzoyl) -1-r3-r5- (1H-pyrrole-2-inmetn- (1S, 4S) -2.5- diazabicic! of2.2.pheptan-2-l1-1-oxopropippyperazine (enantiomer B) By an analogous method to that described in Example 14, using the chiral intermediate of Example 11, the titled compound 2 was obtained as a white solid after purification by flash chromatography on silica gel; mp 81-83 ° C; FAB MS [M + 1] * 35CI 594.1.

EXAMPLE 16 2- (R) - (3,4-dichlorophenyl) -4- (3,5-d.methylbenzoyl) -1 -M -oxo-3-r5- (3-thienylmethi) -1 - (S). 4 (S) -2,5-diazabicyclo2.2.nheptan-2-inpropylpiperazine (enantiomer 11 By an analogous method to that described in example 14, but using 3-thiophene carboxaldehyde instead of 2-thiophene carboxaldehyde, the titled compound was obtained as a white solid after purification by flash chromatography; p.f. 63-65 ° C; MS FAB [M + 1] +35 Cl 61 1.3.

EXAMPLE 17 Various salt derivatives of hydrochloride (-) - 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 (from example 11), were prepared as pure enantiomers, according to the methods described in example 12 or example 14, but using reagents appropriate instead of benzyl bromide.

H 81-83 594.1 calculated 595.2243 -ri 75-77 found 595.2234 calculated 606.2403 71-73 found 606.2396 calculated 662.2665 -car 101-106 662.1 found 662.2675 calculated 653.2298 58-61 found 653.2292 as calculated salt 625.2171 HCl 183 found 625.2165 \\ // decomposed as calculated salt 625.2171 HCl 179 found 625.2165 decomposed 56-60 626.2 calculated 626.2123 found 626.21 16 67-70 624.2 calculated 624.2508 found 624.2512 80-85 691.3 calculated 691.2566 found 691.2554 63-66 597.7 calculated 597.2148 found 597.2147 EXAMPLE 18 A series of hydrochloride salt derivatives of (-) - 1- [3 - [(1S), 4 (S) -2,5-diazabicyclo [2.2.1] heptan-2-yl) -1-oxopropyl was prepared ] -2- (R) - (3,4-dichlorophenyl) -4- (3,5-dimethylbenzoyl) piperazine (from example 11), via parallel synthesis (ie without purification), according to the methods described in example 12 or example 14, but using appropriate type Y reagents.

Reactive Y FAB MS [M + 1] + ^ 35 ° C, I EXAMPLE 19 1,1-dimethylethyl-3-oxo-8-azabicyclo3.2.11octan-8-carboxylate To a solution of N-benzyl-2- (S), 6 (S) -azabicyclo [3.2.1] hepta-3-one (10 g, 46.5 mmole) in EtOAc (120 ml) was added t-BOC anhydride (12.2 g, 56 mmol) and Pd (OH) 2 (2 g). The mixture was hydrogenated at 48.5 psi, at room temperature overnight. After completion of the reaction, the catalyst was filtered, the filtrate was washed with a saturated NaHCO3 solution (100 ml, 2x), dried over (Na2SO4), filtered and concentrated to give a crude material of the titled compound in the form of oil (12 g), FAB MS [M + 1] + 226.

EXAMPLE 20 1, 1-dimethylethyl 3 - [(phenylmethyl) amino-8-azabicyclo f3.2.p octan-8-carboxylate (exo and endo products) To a solution of the compound obtained in Example 19 (10 g, 44.4 mmol) in CF 3 CH 2 OH (50 mL) was added benzylamine (4.8 g, 44.4 mmol) and NaBH 3 CN (5.7 g, 62.84 mmol). The mixture was stirred at room temperature for 20 hours. After completing the reaction, the solvent was removed and the residue was redissolved in EtOAc (200 ml), washed with a saturated NaHCO3 solution (150 ml, 2x), dried (Na2SO), filtered and concentrated to give a oil. The crude material was purified by flash chromatography on silica gel (300 g), eluting with 2% [(NH OH: MeOH) (1: 9j798% CH2CI2 to give the endo product (3.6 g, 1.73 mmole, 25.6%) in the form of a white solid, FAB MS [M + 1] + 314.4 and exo product (3.6 g, 1.73 mmole, 25.6% as a light oil, FAB MS [M + 1] + 313.3.

EXAMPLE 21 1.1-dimethylethyl 3-endo-amino-8-azabicyclo3.2.noctan-8-carboxylate The endo compound (3.6 g, 1.3 mmol) of Example 20 was dissolved in MeOH (100 mL) and Pd (OH) 2-C (0.76 g) was added. The mixture was hydrogenated at 45 psi at room temperature for two days. Additional Pd (OH) 2-C (0.76 g) was added and hydrogenolysis was continued at 45 psi, for one more day. After the reaction was complete, the catalyst was filtered and the filtrate was concentrated to an oil which was purified on silica gel flash chromatography (150 g), with 5% [(NH4OH: MeOH) (1: 9)] / 95% CH2Cl2 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 -dimeti leti I -3-rr2- [2- (R) - (3,4-dichlorophenyl) -2-oxoethylene-amino-8-azabicyclo3.2.noctan-8-carboxylate Example 5 To a solution of the bromoacetyl derivative (1.33 g, 2.75 mmol) of Example 5 in CH 2 Cl 2 (2 mL) and of the endo compound of Example 21 (0.75 g, 3.3 mmol), Hünig's base (0.31 g. 2.75 mmoles). The mixture was stirred at room temperature overnight. The reaction was diluted with CH2Cl2 (100 mL) and washed with water (50 mL, 3x), dried (Na2SO4), 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% [(NH4OH: MeOH) (1: 9)] / 96.5% MeOH, to give the title compound as an off-white solid (1.5 g; 2.38 mmol), 87%); p.f. 98-100 ° C, FAB MS [M + 1] +35 Cl 629.3.

EXAMPLE 23 2- (R H3,4-Dichlorophenyl) -4- (3,5-dimethylbenzoyl) -1-pT-8-azabicyclo3.2.poctan-3-yldole-aminolacetlyperazine hydrochloride To a solution of the compound of Example 22 (1.46 g, 2.35 mol) in CH 2 Cl 2 (2 mL) was added 4 M HCl / dioxane (10 mL, 40 mmol). The mixture was stirred at room temperature for one hour. The solvent and excess HCl were evaporated to give the titled compound as a white solid in quantitative yield, FAB MS [M + 1] + 35 Cl 529.4.

EXAMPLE 24 2- (R) - (3,4-d8-chlorophenyl) -4- (3,5-dimethylbenzoyl) -1 -rrr8- (phenylmethyl) -8- azabicyclo3.2.noctan-3-inendo-amino-1-acetylpiperazine By an analogous method to that described in example 12, but using the compound prepared in example 23, instead of the product of example 1 1 and benzyl bromide instead of 2-acetamido-4-chloro-methylthiazole, the compound titrated as a white solid after purification of silica gel; p.f. 82-84 ° C; HRMS calculated for [M + 1] + C 35 H 41 N 4 O 2 Cl 2: 619.2607; found: 619.2594.

EXAMPLE 25 2- (R) - (3,4-Dichlorophenin-4- (3,5-dimethylbenzoin-1-rrr8- (2-thienylmethyl) -8- azabicyclo3.2.1loctan-3-iriendo-arnino1acetillpiperazine By an analogous method to that described in example 14, but using the compound prepared in example 23, instead of the product of example 11, the titled compound was obtained as a solid bank after purification of silica gel; p.f. 82-84 ° C; FAB MS [M + 1] +35 Cl 625. 3.

EXAMPLE 26 2- (R) - (3,4-Dichlorophenyl) -4- (3,5-dimethylbenzoyl) -1 -rrr8- (3-pyridinyl-methyl) -8- azabicycloi3.2.noctan-3-enedo-aminolacet Npiperazine By an analogous method to that described in example 12, but using the compound prepared in example 23, instead of the product of example 11 and 3-picolyl chloride instead of 2-acetamido-4-chloro-methylthiazole, the compound titrated as a soft brown solid, after purification of silica gel; p.f. 81-83 ° C; FAB MS [M + 1] +35 Cl 620.5.

EXAMPLE 27 1,1-Dimethylethyl 3-exo-amino-8-azabicyclo3.2.poctan-8-carboxylate The titled compound was prepared as an HCl salt, according to the methods described in Example 21, but using the exo product of Example 20, instead of the endo product of Example 20, with the addition of HCl (0.5 equivalent), during the hydrogenolysis. FAB MS [M + 1] + 227.0.

EXAMPLE 28 1, 1 -dimethylethyl 3-rr 2 -r 2 - (R) - (3,4-dichlorophenyl) -2-oxoetpex-amino-8-azabicyl-3 -3-octane-8-carboxylate The titled compound was prepared by analogous method to that described in Example 22, but using the compound obtained from Example 27, instead of the endo product of Example 21, FAB MS [M + 1] +35 Cl 629.2.

EXAMPLE 29 2- (RH3.4-dic! Orophenyl) -4- (3,5-dimethylbenzoyl) -1-frr-8-azabicylchlor3.2.1loctan-3-aminodoxypiperazine hydrochloride The titled compound was prepared by analogous method to that described in Example 23, but using the compound obtained in Example 28 instead of the endo product of Example 22, FAB MS [M + 1] + 35 Cl 529.3.

EXAMPLE 30 2- (R) - (3,4-dichlorophenyl) -4-. { 3.5-d.methylbenzoyl) -1-rrr-8- (phenylmethyl) -8- azabicyclo3.2.1] octan-3-i! 1exo-aminolacetylpperaperazine The titled compound was prepared by analogous method to that described in Example 24, but using the exo compound obtained in Example 29 instead of the endo product of Example 23; p.f. 61-63 ° C; FAB MS [M + 1] +35 CI 619.5.

EXAMPLE 31 2- (R) - (3,4-Dichlorophenyl) -4- (3,5-dimethylbenzoyl) -1-rrr-8- (2-thienylmethyl) -8- azabicycloi3.2.poctan-3-ipexo-amino1acet ppiperazine The titled compound was prepared by an analogous method to that described in Example 14, but using the exo compound prepared in Example 29, instead of the endo product of Example 23; p.f. 62-64 ° C; FAB MS [M + 1P + 35 ° CI 625.4 EXAMPLE 32 Nr4-rrExo-3-rr2-r2- (R) - (3,4-dichlorophenyl) -4- (3,5-dimethylbenzoyl) -1-piperazinyl-2-oxoetyl-aminol-8-azai3.2.noctan-8- illmet¡nfenipacetamida The titled compound was prepared by analogous method to that described in Example 24, but using 4-acetamidobenzylchloride instead of benzyl bromide and the exo compound obtained in Example 29 instead of the endo product of Example 23; p.f. 113-115 ° C; FAB MS [M + 1] +35 Cl 676.4.

EXAMPLE 33 Nr4-rrEndo-3-rr2-r2- (R) - (3,4-dichlorophenyl) -4- (3,5-dimethylbenzoyl) -1- piperazinyl-2-oxoetin-amino-8-azar3.2.noctan-8- ipmet¡pfen¡pacetamide The titled compound was prepared by a method analogous to that described in Example 24, but using 4-acetamidobenzyl chloride in place of benzyl bromide. P.f. 114-116 ° C; FAB MS [M + 1] +35 Cl 676.4.

EXAMPLE 34 3-rrEndo-3-rr2-r2- (R) - (3,4-dichlorophenyl) -4- (3,5-dimethylbenzoin-1-piperazinyl) 2-oxoetyl-amino-8-azar3.2.1loctan-8-n-methyllmethylbenzamide The titled compound was prepared by a method analogous to that described in Example 24, but using 3-chloromethylphenylamide, instead of benzyl bromide. P.f. 106-108 ° C; FAB MS [M + 1] +35 Cl 662.0.

EXAMPLE 35 A series of salt derivatives of 2- (R) - (3,4-dichlorophenyl) -4- (3,5-dimethylbenzoyl) -1 - [[[8-azabicyclo] [3.2.1] octane hydrochloride was prepared. 3-yl] exo-amino] acetyl] piperazine (from Example 29), in the form of pure enantiomers, according to the methods described in example 31 or example 32, but using appropriate Y-type reagents.

AND FABMS _P 638. 2 85-87 EXAMPLE 36 A series of salt derivatives of 2- (R) - (3,4-dichlorophenyl) -4- (3,5-dimethylbenzoyl) -1 - [[[8-azabicyclo] [3.2.1] octane hydrochloride was prepared. 3-yl] endo-aminojacetyl piperazine (from example 23), in the form of pure enantiomers, according to the methods described in example 31 or example 32, but using appropriate Y-type reagents, as follows.

AND FABMS A 09 EXAMPLE 37 2- (R) - (3,4-Dichlorophenyl) -4-r (fluoro-1-naphthaleniDcarbonyl-1 -M -oxo-3-r5- (phenylmethyl-1 - (S) .4 (S) -2.5- diazabicyclo2.2.1 lheptan-2-ippropillpiperazine Step 1: Acid 3 - ((1 S, 4S) -N-benzyl-2,5-diazabicyclo [2.2.1] heptanil) propionic (1S, 4S) -N-benzyl-2,5-diazabicyclo [2.2.1] heptan-2HBr (5 g) was suspended in 25 ml of CH2Cl2 with stirring under N2 atmosphere. A slight excess of Hünig's base (5.53 g, 3 equiv.) Was added. After a brief lapse, the suspended solid dissolved. After about 0.25 hours of agitation of about 10% of an excess of methyl 3-bromopropionate (2.7 g) was added dropwise over a period of about 10 min. The solution was stirred at room temperature overnight. The product was isolated by washing with H2O (2x) then with saturated aqueous NaCl. The organic layer was separated, dried over (Na2SO), filtered and evaporated to a pale yellow oil which was dissolved in 1 N HCl (approximately 50 ml) and kept overnight. There was little hydrolysis, therefore, the solution was carried out in a more concentrated form by evaporation of the water present under reduced pressure. The resulting solution was kept at room temperature for 2.5 days. The water residue was extracted under reduced pressure to yield the compound titled in step 1 as a 2HCl salt, a crystal used directly in the next step.

Step 2-4 Step 2: To a cooled solution of (+, -) - 2- (3,4-dichlorophenyl) piperazine (20 g, 86.53 mmol) in CH3OH (900 mL) at -78 ° C, a solution of t-BOC anhydride (19.47 g; 86.53 mmoles) in CH3OH (263 ml) for 3 hours under N. The solution was gradually warmed to room temperature overnight. After completing the reaction, the solvent was evaporated and the residue was dried under high vacuum overnight to give (A) (28 g) as a white solid. Mass FAB [M + 1] +35 Cl 331.2. The product from step 1 (1 g) and (A) (1 g) was suspended in CH 2 Cl 2 (5 ml) to give a white suspension. Et3N (1 g, 3 equiv.) Was added along with another 4 ml of CH2CI2. The mixture was stirred at room temperature under N2 atmosphere for 1.75 h and then cooled in an ice bath. After two hours, a solution of BOP-CI (0.85 g) in CH2Cl2 (3 ml) was added over a period of about 10 min. After 0.5 hours of stirring, the ice bath was removed and the reaction was able to act at room temperature. After four days, it was isolated (B) and purified by flash chromatography on silica gel, using CH2Cl2 / 5% 2M NH3 in CH3OH as eluent. FAB-MS showed the highest peak at m / z = 573 as expected for (M + 1) + of the 35CI2 molecule.

Step 3: Dissolve (B) in 5 mL of CH2Cl2, cool the solution in an ice bath and add 5 mL of 4M HCl in dioxane. After 10 minutes, the ice bath was removed and the reaction was able to act at room temperature for 4 hours. The reagents and solvents were evaporated and the product was stored overnight under a vacuum atmosphere.

Step 4: The product from step 3 and 4-fluoro-1-naphthoic acid reacted under conditions essentially identical to those described in example 12 to produce the titled compound, which was converted to its 2HCl salt, using 4M HCl in dioxane and IPA as a cosolvent. The product was a brown solid. P.f. 199-201 ° C (dea); FAB-MS: m / z 645.2 corr. for (M + 1) + of Using a similar procedure, the following compounds were also prepared: An HR-MS data: PM (M + 1) + 645.1348 calculated for C32H33N O2CI4: 645.1358 HR-MS: MW (M + 1) + 646.1314 calculated for C3? H32N5? 2CI4: 646.1310 2 35CI2 x 79 Br EXAMPLE 38 The following compounds were prepared using procedures similar to those described above in Examples 12-14 and 37:

Claims (5)

1. NOVELTY OF THE INVENTION CLAIMS 1.- A compound selected from the group formed by where Y is selected from the group formed by omitted from the formula where Y is selected from the group formed by and a compound of the formula where Y is phenyl; or an enantiomer, diastereomer, endo form, exo R or S thereof, or a pharmaceutically acceptable salt thereof.
2. 2. A compound according to claim 1 of the formula where Y is selected from the group formed by or a compound of formula where Y is selected from the group formed by
3. 3.- A compound selected from the group formed by where Ar 'is selected from the group formed by or any enantiomer, diastereomer, endo, exo R or S forms thereof, or a pharmaceutically acceptable salt thereof.
4. 4. A compound according to claim 3, further characterized in that Ar1 is selected from the group formed by
5. 5. - A compound according to claim 1, further characterized in that it is selected from the group formed by a compound of the formula where Y is selected from the group formed by a compound of the formula where Y is selected from the group consisting of a compound of formula where Ar "is selected from the group formed by and a compound of the formula wherein A, and, Re > Rf, n3 and R5 are as defined in the following table