MXPA00008291A - Benzylpiperazinyl- and benzylpiperidinyl ethanone derivatives, their preparation and their use as dopamine d4 - Google Patents

Abstract

Disclosed are compounds of formula (I) or pharmaceutically acceptable addition salts thereof wherein:Y represents oxygen or sulfur;Z is nitrogen or CH;R1, R2 and R3represents hydrogen, halogen, hydroxy, alkoxy, alkyl, trifluoromethyl or trifluoromethoxy;R4 and R4'represent hydrogen, alkyl or form a ring with the atom to which they are attached;R5 represents hydrogen, alkyl, alkoxy, or alkylthio, and R6 represents hydrogen or alkyl;or R5 and R6 form a ring together with the atoms to which they are attached;and R7, R8, R9, R10 and R11 represent hydrogen or alkyl, which compounds are useful for the treatment and/or prevention of neuropsychological disorders including, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, Parkinson-like motor disorders and motion disorders related to the use of neuroleptic agents. Also encompassed within the scope of the invention are intermediates of formulae (VII-a) and (VII-b) wherein X represents oxygen, or sulfur, or CH2, m is zero or an integer of from 1-4, and L is a leaving group.

Description

DERIVATIVES OF BENC ILPIPERAZ INIL AND BENCILPIPERIDINIL ETANONA, ITS PREPARATION AND ITS USE AS ANTAGONISTS OF RECEPTOR D, OF DOPAMINE BACKGROUND OF THE INVENTION Field of the invention This invention describes 2- (4-benzylpiperiin-1-yl) and substituted 2- (1-benzylpiperidin-4-yl) ethanones and pharmaceutical compositions containing such compounds. It also describes the use of such compounds in the treatment or prevention of psychotic disorders such as schizophrenia and other diseases of the central nervous system.

DESCRIPTION OF THE RELATED TECHNIQUE The therapeutic effect of conventional antipsychotics, known as neurocephaly, is generally believed to exert a blockade on dopamine receptors. However, the REF .: 122589 Neuroleptics are frequently responsible for extrapyramidal side effects (EPS) and delayed dyskinesias, which are attributed to the blockade of D2 receptors in the striated region of the brain. The subtype of the dopamine receptor O4 has been identified (Nature, 347: 146 (So oloff et al., 1990)). Its unique location in the limbic brain area and its differential recognition of several antipsychotics suggests that the D receptor may play a greater role in the etiology of schizophrenia. Selective antagonists are considered effective antipsychotics free from the neurological side effects displayed by conventional neuroleptics.

Several 4-benzylpiperazines have been described. See for example, Arch. Med. Res., 25: 435-440 (Terrón et al., 1994) and Toxicol. Appl Pharmacol., 7_: 257-267 (Schmidt and Martin, nineteen ninety five) .

BRIEF DESCRIPTION OF THE INVENTION The invention provides novel compounds which interact with the subtypes of the dopamine receptor. In accordance, in a broad aspect, the present invention provides compounds of formula I: e n Where: Y represents oxygen or sulfur; Z in nitrogen or CH; Ri, R2 and R3 independently represent hydrogen, halogen, hydroxy, lower alkoxy, Ci-Cß alkyl, trifluoromethyl or trifluoromethoxy; R 4 and R 4 'independently represent hydrogen or C 1 -C 6 alkyl; or R4 and R4 'together with the atom to which they are attached form a ring having 3-7 mi. R5 represents hydrogen, C? -C6 alkyl, Ci-C? Alkoxy, or C? -C6 qulitium; R6 is hydrogen or C? -C6 alkyl; or R5 and R6 together represent C1-C5 alkylene, C1-C4 alkylenexy, C1-C4 alkyleneitium wherein the oxygen or sulfur atoms are immediately adjacent to the phenyl ring, and together with the atoms to which they are attached form a ring that has from 5 to 9 members; and R? , R8, R9, Rio, and Rn independently represent hydrogen or Ci-Ce alkyl.

The dopamma D receptors they are concentrated in the limbic system (Science, 265: 1034 (Taubes, 1994)) which controls knowledge and emotion. Therefore, compounds that interact with these receptors are useful in the treatment of cognitive disorders. Such disorders include cognitive deficits which are in a significant component of the negative symptoms (social isolation and insensibility) of schizophrenia. Other disorders include those that involve memory impairment or attention deficit disorders.

The compounds of the present invention demonstrate a high affinity and selectivity in binding to the D < . These compounds are therefore useful in the treatment of a variety of neurological disorders, such as, for example, schizophrenia, psychotic depression and mania. Other dopamine-mediated diseases such as Parkinson's and late dysmenias can also be treated directly or indirectly by the modulation of the D4 receptors.

The compounds of this invention are also useful in the treatment of depression, memory impairment or Alzheimer's disease by modulation of D4 receptors since they exist selectively in known areas to control emotion and cognitive functions.

Thus, in another aspect, the invention provides methods for the treatment and / or prevention of neuropsychological or effective disorders that include, for example, schizophrenia, mania, dementia, depression, anguish, compulsive behavior, substance abuse, memory impairment, cognitive deficits, motor disorders such as Parkinson's disease, for example, Parkinsonism and dystonia, and movement disorders related to the use of neuroleptic agents. In addition, the compounds of the invention are useful in the treatment of depression, memory impairment or Alzheimer disease. In addition, the compounds of the present invention are useful in the treatment of other disorders that respond to dopaminergic blockade, for example, the substance abuse disorder and the compulsive obsessive disorder. These compounds are also useful in the treatment of side effects associated with the use of conventional neurol optic agents.

In yet another aspect, the present invention provides useful intermediates for preparing compounds of formula I.

Still further in another aspect, the present invention provides useful intermediates for preparing compounds of formula I.

DETAILED DESCRIPTION OF THE INVENTION As mentioned above, this invention includes the substituted 2- (4-benzyl) -piper azine-1 and piperidinyl-1-ethanones of formula I. Preferred compounds of the formula I are those wherein R2 and R3 are not both simultaneously hydrogen. Other preferred compounds of formula I are those wherein R7, R8, R9, and Rio are hydrogen. In the compounds of the invention, Rn is preferably hydrogen, methyl or ethyl; and more preferably hydrogen.

As can be noted, the present invention includes compounds wherein R 5 and Re together represent C 1 -C 5 alkylene, C 1 -C alkyleneoxy, and C 1 -C 4 alkylenethioxy. In these compounds, the hydrogen and sulfur atoms are immediately adjacent to the phenyl ring carried by the R5 group. In such cases, R5 and Re together with the atoms to which they are attached form a ring that It has 5-9 members. Examples of such rings include the following: i fc ^ '^ ¡"b? Ftr Among the preferred bicyclic ring systems are those compounds where n is 0 or an integer from 1 to 2.

In these compounds, R and R4 'independently represent hydrogen or C? -C6 alkyl, or R4 and R4' together with the atom to which they are attached form a ring having from 3 to 7 members. Representative spiro ring systems include the following: The compounds wherein R5 and Re together with the atoms to which they are attached form a ring having from 5 to 9 members as discussed above which are represented by formula II II ^ ms¿ ^ _ ^^ t¿¡s ^ wherein X represents oxygen, or sulfur, or CH; And it's oxygen or sulfur; Z is nitrogen or CH; n is zero or an integer of 1-4; Ri, 2 and R 3 independently represent hydrogen, halogen, hydroxy, lower alkoxy, C 1 -C 6 alkyl, trifluoromethyl or trifluoromethoxy; R 4 and R 4 'independently represent hydrogen or C 1 -C 6 alkyl; or R4 and R4 'together with the atom to which they are attached form a ring having from 3-7 i embro s; R-, Rβ, R9, Rio, and Rn independently represent hydrogen or Ci-Cß alkyl.

Preferred compounds of formula II are those wherein R2 and R3 are not simultaneously hydrogen. In the preferred compounds of Formula II R4 and R 'are independently hydrogen or C? -C4 alkyl. In other preferred compounds of formula II, H is 0 or 1, and more preferably 0.

A preferred group of compounds of formula II are those wherein Y is oxygen, X is CH2 and Z is CH. Such compounds are represented by 1 to formula lia: lia wherein n, Ra, R2, R3, R4, R4 ', R7, Rβ, s, Rio, and Rn are as defined above for formula II.

In the compounds of formula Ia, Rn is preferably hydrogen, methyl or ethyl. In the preferred compounds of formula Ia, Ri is hydrogen or halogen, and R2 and R3 are independently selected from hydrogen, Ci-Cß alkyl and halogen. More preferably such compounds of formula la are those wherein En is hydrogen or methyl, Ri is hydrogen or halogen, and not both R2 and R3 are hydrogen simultaneously. Particularly preferred compounds of formula Ia are those in which R n is hydrogen or methyl, R 2 is hydrogen R 3 is methyl, methoxy, chloro or fluoro, R 4 and R 4 'are independently hydrogen or lower alkyl, more preferably C 1 -C 2 alkyl, and Ri It is hydrogen or halogen.

Another preferred group of compounds of formula II are those wherein Z is nitrogen and X is CH2. Such compounds are generally represented by the formula Ilb.

Ilb wherein n, Y, Rl R2, R3, R, R4 ', R ?, Rs, R9, Rio, and R11 are as defined above for formula II.

In such compounds, Rn is preferably hydrogen, methyl or ethyl. In addition, in such preferred compounds, Y is oxygen, Ri is hydrogen or halogen, and R2 and R3 are independently selected from hydrogen, Ci-Cß alkyl and halogen. More preferred compounds of formula Ilb are those wherein Rn is hydrogen or methyl, Y is oxygen, Ri is hydrogen or halogen, and both R 'and R3 are not simultaneously hydrogen. Particularly preferred compounds of formula Ilb wherein Ru is hydrogen or methyl, Y is oxygen, R 2 is hydrogen R 3 is methyl, methoxy, chloro or fluoro, R 4 and R 'are independently hydrogen or lower alkyl, more preferably C 1 -C 2 alkyl , and Ri is hydrogen or halogen.

The compounds of formula I wherein R5 is hydrogen or lower alkyl and R6 is hydrogen are represented by formula III: where Y, Z, Ri, R2, R3, R4, R4 ', R5, RT, Rβ, R9, Rio, and Ru are as defined above for the formula I. In the compounds of formula III, R2 and 3 preferably are not both simultaneously hydrogen.

A preferred group of compounds of formula III, below formula Illa, are those wherein Y is oxygen, Z is nitrogen, Ri is hydrogen or halogen, and R 2 and R 3 are independently selected from hydrogen, Ci-Cß alkyl, and halogen. Continuing the most preferred compounds of the formula Illa are those where both R2 and R3 are not simultaneously hydrogen. Other preferred compounds of formula Illa are those wherein R 2 is hydrogen, R 3 is methyl, chloro or fluoro; and one or both of R 4 and R 4 'is lower alkyl, more preferably C 1 -C 2 alkyl, and Ri is hydrogen or halogen. Particularly the compounds of formula Illa are those in which R2 is hydrogen and R3 is a methyl, chloro or fluoro group in the 4-position on the phenyl ring.

Other particularly preferred compounds of formula Illa are those wherein the phenyl substituted with R2 and R3 is 2-lcoxy-5-halo-phenyl-1. Representative of such particularly preferred compounds are those wherein the phenyl carrying R2 and R3 is 2 -alkoxy (C? -C2) -5-fluoro or 5-chlorophenyl.

Another preferred group of the compounds of formula III, below formula Illb, are those wherein Y is oxygen, Z is CH, Ri is hydrogen or halogen, and R2 and R3 are independently selected from Ci-Cß alkyl hydrogen, and halogen. Continuing with more preferred compounds of formula Illb are those where both R2 and R3 are not simultaneously hydrogen. Other preferred compounds of formula Illb are those wherein R 2 is hydrogen, R 3 is methyl, chloro, or fluoro, and one or both of R 4 and R 4 'are lower alkyl, more preferably C 1 -C 2 alkyl, and Ri is hydrogen or halogen. The compounds particularly • iri¡¡aíi ^ HÍ¡-_ preferred formula 11 Ib are those where R2 is hydrogen and R3 is a methyl, chloro or fluoro group at the 4-position of the phenyl ring. Other particularly preferred compounds of formula Illb are those wherein the phenyl substituted with R2 and R3 is 2-alkoxy-5-halophenol. Representative of such particularly preferred compounds are those wherein the phenyl carrying R2 and R3 is -alkoxy (C1-C2) -5-fluoro or 5-chloro-phenyl.

Illa Illb The substituents in the Illa and Illb formulas are as defined above for formula III.

Another preferred group of compounds of the invention are included by the formula IV i.e. where R5 and R6 together form a ring and R4 and R4 'also together form a ring.

IV wherein X, n, Y, Z, Ri, R2, R3, Rv, Re, Rg, Rio, and Ru are as defined above for formula I, and m is zero or an integer of 1-4. Preferably, R2 and R3 are not both simultaneously hydrogen in the compounds of formula IV.

Preferred compounds of formula IV are those wherein X is CH2, n is 0, R4 and R4 ' they form a five-membered carbocyclic ring with the atom to which they are attached (i.e., m is 2), and Rn is hydrogen. Where Z in formula IV is CH, the resulting compounds having m = 2 are designated by formula IVa. Where Z in formula IV is nitrogen, the resulting compounds having m = 2 are designated by formula IVb.

IVa IVb In the preferred compounds of each of the formulas IVa and IVb, X is CH2, Y is oxygen, and n is 0. The most preferred compounds are those wherein X is CH2, Y is oxygen, and n is 0, Ri is hydrogen or halogen, and R2 and R3 are - * "• - - independently selected from hydrogen, C 1 -C 6 alkyl, and halogen. Continuing with the most preferred compounds of these formulas are those wherein X is CH, Y is oxygen, and n is 0 and not both of R2 and R3 are simultaneously hydrogen. Other preferred compounds of formulas IVa and IVb are those wherein Z is CH, Y is oxygen, R2 is hydrogen, and R3 is a methyl, fluoro or chloro group at the 4-position on the phenyl ring. Other particularly preferred compounds of these formulas are those wherein the phenyl substituted with R2 and R3 is 2-alkoxy-5-halophenyl.

Also included within the scope of the invention are intermediates useful in the preparation of compounds of the present invention. In this way, the invention provides compounds of formula Vll-a; VH-a wherein X, n, Y and Ri are as defined above for formula I, m is zero or an integer of 1-4, and L is a leaving group such as, for example, halogen, sulfonyl methane, or to lueno sul foni lo. A preferred group of compounds of formula Vll-a are those wherein And it is oxygen, X is oxygen or, more preferably, methylene, m is 2, and Ri is hydrogen or halogen.

Another preferred group of intermediaries is included by the formula Vll-b: VII-b wherein Y, R1, R4, R4 ', Rs are as defined above for formula I, and L is a leaving group.

A preferred group of compounds of formula Vll-b are those wherein Y is oxygen or, more preferably, methylene, and Ri is hydrogen or halogen. Other preferred compounds of formula Vll-b are those wherein one or both of R4 and R4 'are lower alkyl, more preferably Ci-Cz alkyl, and Ri is hydrogen or halogen.

In certain situations, the compounds of formula I may contain one or more asymmetric carbon atoms, so that the compounds may exist in different stereo and someric forms. These compounds, for example, can be racemates or optically active forms. In these situations, the enantiomers alone, i.e. Optically active forms can be obtained by asymmetric synthesis or by the separation of the racemates. The separation of Racemates can be carried out, for example, by conventional methods such as crystallization, in the presence of a resolving agent, or by chromatography, using, for example, a chiral HPLC column.

Representative compounds of the present invention, which are included by the formula I include, but are not limited to, the compounds in Table I and their pharmaceutically acceptable acid addition salts. In addition, if the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Vice versa, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to the conventional procedures for preparing the acid addition salts of the base compounds.

The non-toxic pharmaceutical salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluene sulphonic, phonogenic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic, such as acetic, HOOC- (CH2) n-ACOOH where n is 0-4 and the like. Those skilled in the art recognize a wide variety of pharmaceutically acceptable non-toxic addition salts.

The present invention also includes the acylated pro-drugs of the compounds of formula I. Those skilled in the art will recognize various synthetic methodologies which can be employed to prepare pharmaceutically acceptable non-toxic addition salts and acylated pro-drugs of the included compounds by the formula I.

By "alkyl" in the present invention it is understood that it is a C.sub.Cß alkyl, i.e. groups of straight or branched open chain alkyl having 1-6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3 -met i lpent i lo.

By "alkoxy" or "lower alkoxy" in the present invention it is understood that it is a C6-C6 alkoxy, i.e. straight or branched open chain alkoxy groups having from 1-6 carbon atoms, such as for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy , neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-me ti lpentoxy.

By the term "halogen" in the present invention it is understood that it is fluorine, bromine, chlorine, and iodine.

The representative compounds of the invention are shown below in Table 1.

Table 1 Composed Compound 2a Compound 3a Compound 4a Compound 5a Compound 6a Compue s to 7 Compound 10 The compounds of the invention are useful in the treatment of neuropsychological disorders; the pharmaceutical utility of the compounds of this invention is indicated by the assays by the affinity of the dopamine receptor subtype described below in the examples. The interaction of substituted 2- (4-phenylmethyl) -piperaz mo-1-ethanones of the invention with the dopamma receptor subtypes results in the pharmacological activity of these compounds.

The compounds of the general formula I can be administered orally, locally, parenterally, by inhalation or dew or rectally in unit dose formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intramuscular intramuscular injections, intrasternal injection or infusion techniques. In addition, there is the proportion of a pharmaceutical formulation comprising a compound of general formula I and a pharmaceutically acceptable carrier. One or more compounds of the general formula I can be presented in association with one or more pharmaceutically acceptable carriers and / or diluents and / or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of the general formula I can be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to any method known in the art of manufacturing pharmaceutical compositions and such compositions may contain one or more of the agents selected from the group consisting of sweetening agents, anti-aging agents, agents dyes and preserving agents in addition to provide pharmaceutically elegant and tasty preparations. Tablets containing the active ingredient in admixture with pharmaceutically non-toxic acceptable excipients are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, starch grain or alginic acid; binding agents, for example, starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets can be uncoated or they can to be coated by known techniques to retard disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules where the active ingredient is mixed with water or an oily medium, for example peanut oil, liquid parafma or olive oil.

Aqueous suspensions containing the active materials in admixture with excipients are suitable for the manufacture of aqueous suspensions. Such excipients are agents suspending agents, for example, carboxymethyl cellulose sodium, methoxy cellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum; Dispersing agents or wetting agents may be a naturally occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example poly (oxyethylene) stearate, or condensation products of sodium oxide. ethylene with long-chain aliphatic alcohols, for example hept adecaet and leneoxy ce t anol, or condensation products of ethylene oxide with partial fatty acid ester derivatives and a hexitol such as monooleate sorbitol of polyoxyethylene glycol, or products of condensation of ethylene oxide with pacliest ester derivatives of fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example, ethyl, or n-hydroxybenzoate. propyl, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide flavorful oral preparations. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water provides the active ingredient in the mixture with a dispersing or wetting agent, the suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those previously mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil, or arachis oil, or a mineral oil, for example a liquid paraffin or mixtures thereof. Suitable emulsifying agents can be naturally occurring gums, for example acacia gum or tragacanth gum, naturally occurring phosphatides, for example soy, lecithin, and jj ^ í ^ i ^^^^ - esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of said partial esters with ethylene oxides, for example the sorbitan monooleate of polyethylene glycol. The emulsions may also contain sweetening and anti-aging agents.

The syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a condom and savory agents and dyes. The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous solution. This suspension can be formulated according to the conicida technique using wetting agents and dispersing agents that have been mentioned above. The sterile injectable preparation can also be a solution sterile injectable or a suspension in a non-toxic parenterally acceptable diluent or a solvent, for example as a solution in 1,3-but anodium 1. Among the acceptable vehicles and solvents that may be employed are water, Rmger solution and a solution of isotonic sodium chloride. In addition fixed, sterile oils are conventionally employed as a solvent or a dispersing medium. For this purpose any soft fixed oil can be employed including synthetic mono or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compounds of general formula I can also be administered in the form of suppositories by rectal administration of the medicament. These compositions can be prepared by mixing the medicament with the suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the medication. Such materials are cocoa butter and po 1 i eti liclicol es.

The compounds of general formula I can be administered parenterally in a sterile medium. The medication, depending on the vehicle and concentration used, may be either suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffers can be dissolved in the vehicle.

The dose levels of the order of about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-mentioned conditions (about 0.5 mg per day of 7 g per patient per day). The amount of active ingredient that can be combined with the carrier materials for producing a single dosage form that will vary depending on the host treated and the particular mode of administration. Dosage unit forms will generally contain between about 1 mg to about 500 mg of an active ingredient.

It will be understandable, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed, age, body weight, general health, sex, diet, the time of administration, the mode of administration, and the proportion of the excretion, the combination of the drug and the severity of the particular disease that is submitted to the therapy.

Representative illustrations of suitable methods for the preparation of compounds of the present invention are shown in the following schemes, those with experience in The art will recognize that starting materials may be varied and additional steps may be employed to produce the compounds included by the present invention. For example, in certain situations, the protection of reactive radicals such as auno groups will be required.

A compound of 2 - (-benzylpiper azin-1-yl-1-ethanone of formula I can be prepared according to the reactions shown in the scheme 1.

E S BURN 1 wherein Ri, R2, R3, R4, R4 ', R5, Re and Y are as defined above for formula I.

As shown in Scheme 1, an aniline of the general structure V having an appropriate secondary amino group is condensed with chloroacetyl chloride or an appropriate derivative thereof (VI). The resulting intermediary VII in turn, it reacts with a piperazine derivative of general structure VII to provide a derivative of 2- (4-benzylpiperazin-i1) -1-ethanone of formula I. The piperazine derivatives VIII are generally available as However, they can also be prepared using methods described in the literature.

The 2- (4-benzylpiper azin-1-yl) -1-ethanones of the invention can be prepared according to the reactions shown below in Scheme 2.

E SQUEMA 2 where the substituents carry the same definitions as stated above by formula I.

As shown in Scheme 2, an ester of pir idine-4-acetic acid (XI) can be reduced with hydrogen gas in the presence of a catalyst, for example, platinum, to provide an amino ester derivative of piperidine XII. The amino ester XII may be condensed with an appropriate benzylated alkylating agent containing a leaving group W, where it may be a halogen or a sulfonate ester or the like, to provide an N-benzylpiper idine of the general structure XIII. The ester group of XIII can be saponified in a base to provide an amino acid of general structure XIV which is subsequently condensed with a secondary amine to provide the desired compound of formula I wherein Z is carbon methine (Z = CH).

Those skilled in the art will recognize that the starting materials may be varied and that additional steps may be employed to produce compounds included by the present invention, as demonstrated in the following examples. In some cases, the Protection of certain reagent functionalities may be necessary to achieve some of the above transformations. In general, the need for such protecting groups will be apparent to those skilled in the art of organic synthesis as well as the conditions necessary to bind and remove such groups.

The invention is further illustrated with the following examples which are not construed as limiting the invention, in the field or the essence of the specific procedures described therein.

EXAMPLE 1 Preparation of starting materials and intermediaries. The starting materials and various intermediates can be obtained from commercial sources, prepared from commercially available organic compounds, or prepared using well-known synthetic methods.

A representative example of a method for preparing the ethanone intermediates of the invention are discussed below. 2-chloro-l-indolinyletan-l-one An amount of 2,3-dihydro-1 H-1-indo (also known as indoline, 2.1 g, 17.6 mmol) is dissolved in toluene (60 ml). To the solution of the amine in toluene is added acetyl chloride (2.0 g, 17.6 mmol) dissolved in 1,2-dichloroethane (20 ml). The reaction mixture turns brown with the addition of the acid chloride. The reaction is left to proceed at room temperature, with stirring, for about 3 hours, after the reaction mixture is diluted with ethyl acetate and washed with water solution: saturated NaCl 50:50 (v / v) (2 times) The organic phase is dried over anhydrous MgSO.sub.2 and concentrated to produce 2-chloro-1- (2,3-dihydro-1-yl-m-dolyl) -1-ethanone (can also be called 2-chloro-1-indole-1-inethane). -one) in 85% yield (2.92 g, 15 mmol) as a light brown solid.

EXAMPLE 2 2- (4- (4-chlorobenzyl) piperazinyl) -1-indolinyletan-1-one CQ r? 'Rxa To a solution of (4-chlorobenzyl) piperazine (1.5 g, 7.2 mmol) in acetonitrile (100 ml) is added 2-chloro-l- (2,3-dihydro-l-l-indolyl) -l-ethanone (1.4 g, 7.16 mmol) and K2CO3 (12 g, 87 mmol). The reaction mixture is left to proceed at room temperature for about 6 hours. The reaction mixture is then filtered and concentrated and the residue resuspended in ethyl acetate and extracted with HCl (3M). The aqueous phase is basified with NaOH (10 M) and then extracted with more ethyl acetate. The final ethyl acetate phase is washed with brine, dried over MgSO4 and concentrated. Thus the desired 2- (4- (4-chlorobenzyl) -piperazino-1- (2, 3-dihydro-lH-l-indo 1 i 1) - 1 -ethanone (alternatively called 2- (4- (4-chlorobenzyl ) piperazinyl) -1-indole ini-1-one) is obtained as a light pink solid (1.3 g, 3.5 mmol) in 50% yield Pf: 139.5 - 140 ° C 1 E NMR (400 MHz, CDC13 ) d 8.23 ppm (d., 1H, 8.8 Hz), 7.26 ppm (m., 4H), 7.24 ppm (m., 2H), 7.01 ppm (t., 1H, 7.2 Hz), 4.16 ppm (t., 2H, 8.4 Hz), 3.48 ppm (s, 2H), 3. 25 ppm (s., 2H), 3.19 ppm (br.t, 2H, 8.4 Hz), 2.64 ppm (brs, 4H), 2.51 ppm (brs., 4H) and MS (Cl) M + 369.

The HBr salt of the title compound (Compound 19) is prepared from a methanolic solution (using 48% aqueous HBr), and ethanol / acetone ratio to produce a white solid, Mp: 258-260 ° C.

EXAMPLE 3 The following compounds are prepared essentially according to the procedures set forth above in Examples 1 and 2: (a) 2- (4- (4-chlorobenzyl) piperazine-1- (2-methyl-2,3-dihydro-1H-1-indole) -1-ethanone (Compound 3) (dihydr obr omuro salt : Compound 3a). (B) 2- (4- (4-chlorobenzyl) piperazine-1- (1, 2, 3, 4-tetrahydro-1 -quin 1 inyl) -1-ethanone (Compound 4) (dihydrobromide salt: Compound 4a). (c) 2- (4- (4-chlorobenzyl) piperazine-1 - (3,4-dihydro-2f-benzo [b] 1,4-oxazin-4-yl) -1-et-anone (Compound 5) (dihydrobr omuro salt: Compound 5a). (d) 2- (4- (4-chlorobenzyl) piperazino-l- (3,4-dihydro-2i? -benzo [b] 1,4-thiazin-4-yl) ) -1-ethanone (Compound 6) (dihydrobromide salt: Compound 6a). (E) 1- (2, 2- dimet i 1 indole inyl) -2- (4- (4-chlorobenzyl) -piperazinyl) ethan 1-one (Compound 7). (F) 1- (2, 2-dimethyl-indolinyl) -2- (4- (4-me ti lbenc1) -piper az ini 1) et an-1 -one (Compound (g) 1- (2-methylindolinyl) -2- (4- (4-methylbenzyl) -piperazinyl) ethan-1-one (Compound 9). (h) 2 - (4 - [- c) r obenci 11 piper a z ini 1) - 1 - spiro [cyclopentane - 2, 2 'indol in - l - yl] ethanone (Compound 10). (i) 2- (4- (4-chlorobenzyl) -piperazinyl) -1- (4-f luoroindo-1-in-1) e-t-1-one (Compound 11). (j) l- (5-chloro-2,2-dimime 111 indo 1 ini 1) -2- (4- (4-chlorobenzyl) piperazinyl) ethan-1-one (Compound 12). (k) 2- (4- (5-Chloro-2-methoxybenzyl) piperazine) -1- (2-met i 1 indolinyl) ethan-1-one (Compound 13). (1) 2- (4- (4-chlorobenzyl) piperazinyl) -l- (2-me t i 1 indole in i 1) e tan-1 -one (both resolved enantiomers).

. { C ompue s t o 14 * (+) -me ti l o). { Compound 14 b, (-) - met? Lo) (m) l-? ndolinyl-2- (4- (4-methylbenzyl) p? perazin?) propan-l-one (compound 15). (n) 1- (2, 2-dimethyl indol inyl) -2- (4- (4-fluorobenzyl) piperazinyl) ethan-1 -one (Compound 16). (o) 2- (4- (4-Chlorobenzyl) piperazinyl) -1- (7-met i lindolinyl) ethan-1-one (Compound 17). (p) 1- (6-Chloroindolinyl) -2- (4,4-chlorobenzylpiperazinyl) ethan-1-one (Compound 18). (q) N-Butyl-2- (4- (4-chlorobenzyl) piperazinyl) -N-phenylethanamide (Compound 2) dihydrobromide salt: Compound 2a).

EXAMPLE 4 Compound I The ethylene-4-pyridyl acetate (5 g) is dissolved in ethanol (30 ml), and treated with the catalyst platinum oxide (30 mg) and hydrogenated in a Parr apparatus for 4 hours. The catalyst is filtered and the ethyl acetate is isolated by removal of the solvent under vacuum. This material is then dissolved in acetonitrile (50 ml) and treated with 4-chlorobenzyl chloride (4.9 g) and sodium carbonate (10 g). The resulting mixture is heated in methanol (30 ml) and treated with a solution of lithium hydroxide (2 g) in water (10 ml). The mixture is to be overnight. The addition of 47.6 ml of an IN HCl solution followed by the concentration and extraction of the chloroform residue provides the acid 1- (4-chlorobenzyl) - 4-p? Pepd? 1 acet ico desired. A portion of this material (8 g) is dissolved in methylene chloride and treated with 1,1 '-carbonyldiimidazole (0.65 g) and allowed to stand overnight. This solution is then treated with 2 -met i 1 mdol ina (0.5 g). After 2 hours the resulting mixture is washed 3 times with water dried and concentrated. Purification by silica gel column chromatography affords 1.2 g of the desired 2- (1- (4-chlorobenzylpiperidin-4-yl) -1- (2-methylindolin-1-yl) -1-ethanone (Compound 1). The dihydrochloride salt is subsequently prepared (Compue s to la).

EXAMPLE 5 Assay for the binding activity of the D2 and D4 receptor. The pharmaceutical utility of the compounds of this invention is indicated by the assays for the affinity of the dopamine receptor subtypes described below.

The pellets of the CHO cells containing the D2 or D receptors cloned from the c-DNA are used for the assays (Tallman, J.F. et al., J. Ph.m. Exp. Th., 1997, 282, 1011).

The cloned membranes are homogenized in 100 volumes (P / vol) of the 0.05 M tps-HCl buffer at 4 ° C and with a pH of 7.4 containing 120 mM NaCl, 1 mM EDTA and 5 mM MgCl2. The samples are centrifuged at 48,000 X g then re suspended and rehomogenized. The final tissue sample is kept frozen until use. The tissue is resuspended 1:20 (w / vol) in the 0.05 M Tps-HCl buffer containing 120 mM NaCl before use.

The incubations are carried out at 48 ° C and contain 0.4 ml of the tissue sample, 0.5 nM 3H-YM 09151-2 (emonapri de, ci s- 5-chloro- 2 -me toxi -4- (methylamo) -N- (2-met? L-2- (phenylmethyl) -3-pi rro 1 idini 1) benz amide) and the compound of interest in a total incubation of 1.0 ml. A nonspecific ligature such as the ligature found in the presence of spiperone lmM; apart from the additions, the non-specific ligation is less than 20% of the total ligature. The characteristics of the ligation, for example, of the compounds included in formula I for the D2 and D4 receptor subtypes are shown in Table 2 for rat striatal homogenates.

Table 2 Compue s to D4 K: D2 Ki (nM) No. 2"1 7 92 2 1 5 4 ND 3 0. 7 74 4 4 7 10, 000 5 4 2 9 2610 6 1 4. 2 10,000 'the numbers of compounds related to the compounds shown in Table 1.

The binding constants of the compounds of formula I for receptor D expressed in nM are generally in the range of about 0.1 nanomolar (nM) to about 500 nanomolar (nM). The referred compounds have restricted ligatures of about 0.1 to 100 nM.

Preferred compounds typically have binding constants for the D2 receptor of at least about 10-15 times that of the binding constant D4. In this manner, the compounds of the invention are generally at least about 10 times more selective for the D4 receptor than for the D2 receptor. Preferably, these compounds are at least 20, and more preferably at least 25-50, times more selective for the D4 receptor than the D2 receptor. More preferably, the compounds of formula I are at least 100 times more selective for the D4 receptor than the D2 receptor.

The invention and the manner and process of manufacturing and the use of it, are now described in complete, detailed, clear, concise and exact terms to enable any person with experience in the technique to which it belongs, produce it and make use of the same It is understandable that the aspects understood before of the present invention and that the Modifications can be made in that respect without leaving the essence and scope of the present invention as set forth in the claims. For the particularly distinct claim the subject matter is considered as the invention, claims conclude this specification.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims (38)

1. CLAIMS A compound of the formula or a pharmaceutically acceptable addition salt thereof characterized in that: Y represents oxygen or sulfur; Z in nitrogen or CH; Ri, R2 and R3 independently represent hydrogen, halogen, hydroxy, C6-C6 alkoxy, Ci-Ce alkyl, trifluoromethyl or trifluoromethoxy; R4 and R4 'independently represent hydrogen or Ci-C6 alkyl; or u ^^ a_? R4 and R4 'together with the atom to which they are attached form a ring having 3-7 mi embryos; R5 represents hydrogen, C? -C6 alkyl, C? -C6 alkoxy, or C? -C6 qulitium; R6 is hydrogen or C6-C6 alkyl; or Rs and R6 together represent C1-C5 alkylene, Ci-C4 alkyleneoxy, C? -C4 alkyleneitium wherein the oxygen or sulfur atoms are immediately adjacent to the phenyl ring, and together with the atoms to which they are attached form a ring which has from 5 to 9 members; and R7, R1, R9, Rio, and R11 independently represent hydrogen or Ci-Ce alkyl.
2. 2. A compound according to claim 1, characterized in that only one of R2 and R3 is hydrogen.
3. 3. A compound according to claim 1, characterized in that it has the fo rmul a: II e n do nde: X represents oxygen, or sulfur, or CH; And it's oxygen or sulfur; Z is nitrogen or CH; n is zero or an integer of 1-4; Ri, R2 and R3 independently represent hydrogen, halogen, hydroxy, C6-C6 alkoxy, C6-C6 alkyl, trifluoromethyl or trifluoromethoxy; R 4 and R 4 'independently represent hydrogen or C 1 -C 6 alkyl; or R4 and R 'together with the atom to which they are attached form a ring having 3-7 mi embro s; 1 RT, R ?, Rg, Rio, and Rii independently represent hydrogen or Ci-Ce alkyl.
4. 4. A compound according to claim 1, characterized in that it has the formula: wherein n, R1 (R2, R3, R4, R4 ', RT, Rβ, R9, Rio, and R11 are as defined above in claim 1.
5. 5. A compound according to claim 1, characterized in that it has the formula: wherein n, Ri, R2, R3, R4, R4 ', RT, Re, R », Rio, and Ru are as defined above in claim 1.
6. 6. A compound according to claim 1, characterized in that it has the formula: wherein n, R2, R2, R3, R4, R ', R5, Ri / Re, R9, Rio, and Ru are as defined above in rei indication 1.
7. 7. A compound according to claim 1, characterized in that it has the formula: wherein X, n, Ri, R2, R3, R7, R8, R9, Rio, and Ru are as defined above in claim 1.
8. 8. A compound according to claim 7, ac acylate because Y is oxygen, Ri is hydrogen or halogen, and R2 and R3 are 4 independently selected from hydrogen, C? -C6 alkyl, and halogen.
9. 9. A compound according to claim 8, characterized in that not both R2 and R3 are simultaneously hydrogen.
10. 10. A compound according to claim 8, characterized in that R2 is hydrogen and R3 is methyl, chloro or fluoro.
11. 11. A compound according to claim 10, characterized in that R3 is a methyl, chloro or fluoro group in the 4-position on the phenyl ring.
12. 12. A compound according to claim 11, characterized in that n is 0.
13. 13. A compound according to claim 6, characterized in that Y is oxygen, Ri is hydrogen or halogen, and R2 and R3 are independently selected from hydrogen, C? -C6 alkyl, and halogen.
14. 14. A compound according to claim 1, characterized in that it is 2- (4- (4-chlorobenzyl) piperazinyl) -1-indolinietan-one.
15. 15. A compound according to claim 1, characterized in that it is 2- (4- (4-chlorobenzyl) piperaz ino- 1- (2-met i 1-2, 3-dihydro-lH-1-indolyl) -1-ethanone .
16. 16. A compound according to claim 1, characterized in that it is 2- (4- (4-chlorobenzyl) piperazine-1- (1,2,3,4-tetrahydro-1-qumol? N? L) -1-ethanone.
17. 17. A compound according to the rei indication 1, characterized in that it is 2- (4- (4-chlorobenzyl) piperazmo-l- (3,4-dihydro-2 H -benzo [b] 1,4-oxazin-4-yl) ) -1-ethanone.
18. 18. A compound according to claim 1, characterized in that it is 2- (4- (4-chlorobenzyl (piperazinno- (3,4-dihydro-2 H -benzo [b] -1,4-thiazin-4-yl) -l-ethanone.
19. 19. A compound according to claim 1, characterized in that it is l- (2,2-dimethyl-indolinyl) -2- (4- (4-chlorobenzyl) -piperazinyl) ethan-1-one.
20. 20. A compound according to claim 1, characterized in that it is l- (2,2-dimethylindolyl) -2- (4- (4-methylbenzyl) -piperazinyl) ethan-1-one.
21. 21. A compound according to claim 1, characterized in that it is l- (2-methylindolinyl) -2- (4- (4-methylbenzyl) -piperazinyl) ethan-1-one.
22. 22. A compound according to claim 1, characterized in that it is 2- (4- (4-chlorobenzyl) piperazinyl) -1-spiro [c-clopentane-2, 2'-mdol? N-1? L] ethanone.
23. 23. A compound according to claim 1, characterized in that it is 2- (4- (4-chlorobenzyl) -piperazyl) -1- (4-fluoromdolinyl) ethan-1-one.
24. 24. A compound according to claim 1, characterized in that it is l- (5-chloro-2, 2-d? Met? Lmdolm? L) -2- (4- (4-chlorobenzyl) piperazine) ethan- 1 - ona
25. 25. A compound according to claim 1, characterized in that it is 2- (4- (5-chloro-2-methoxy-benzyl) piperazyl) -1- (2-methyl-ethyl-1-yl) -ethan-1-one.
26. 26. A compound according to claim 1, ac acterized because it is
27. 27. A compound according to claim 1, characterized in that it is
28. 28. A compound according to claim 1, characterized in that it is 1-indolinyl-2- (4- (4-methyl-benzyl) piperazine) propan-1-one.
29. 29. A compound according to claim 1, characterized in that it is l- (2,2- dimethyl indolinyl) -2- (4- (4-fluorobenzyl) piperazinyl) ethane-1 -one.
30. 30. A compound according to claim 1, characterized in that it is 2- (4- (4-chlorobenzyl) piperazinyl) -1- (7-methylindolinyl) ethan-1-one.
31. 31. A compound according to claim 1, characterized in that it is l- (6-chloroindolinyl) -2- (4- (4-chlorobenzyl) piperazinyl) ethan-1-one.
32. 32. A compound according to claim 1, characterized in that it is 1- (4- (4-chlorobenzyl) -piperazinyl) -2-indolinyletan-l-one.
33. 33. A compound according to claim 1, characterized in that it is N-butyl-2- (4- (4-chlorobenzyl) piperazinyl) -N-phenylethanamide.
34. 34. A compound of the formula ac acted because: X is oxygen sulfur, or methylene; And it represents oxygen, sulfur; Ri, R2 and R3 is hydrogen, halogen, hydroxy, Ci-C alco alkoxy, C?-C6 alkyl, tr i f luoromet i lo or tpfluoromethoxy; m is an integer from 1 to 4 and; L is a leaving group.
35. 35. A compound according to claim 34, characterized in that Y is oxygen, X is methylene, m is 2, and Ri is hydrogen or halogen.
36. 36. A compound of formula: characterized in that Y represents oxygen or sulfur; R 1 represents hydrogen, halogen, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, t-butyl omethyl or tr lf luoromethoxy; R4 and R4 'independently represent hydrogen or C i -C C alkyl; or R4 and R4 'together with the atom to which they are attached form a ring having 3-7 members; Rs represents hydrogen, C? -C6 alkyl, C? -C6 alkoxy, or C? -C6 alkylthio; Re is hydrogen or Ci-Ce alkyl, - or Rs and Re together represent C 1 -C 5 alkylene, C 1 -C 4 alkyleneoxy, C 1 -C 4 alkyleneitium wherein the oxygen or sulfur atoms are immediately adjacent to the phenyl ring, and together with the atoms to which they are attached form a ring that has from 5 to 9 members; Y L is a leaving group.
37. 37. A compound according to claim 36, characterized in that Y is oxygen or methylene, Rs is hydrogen or Ci-Cß alkyl, and Ri is hydrogen or halogen.
38. 38. A compound according to claim 37, characterized in that one or both of R and R4 'are C? -C6 alkyl, and Ri is halogen. SUMMARY OF THE INVENTION The invention describes the compounds of formula (I) or pharmaceutically acceptable addition salts thereof wherein: Y represents oxygen or sulfur; Z is nitrogen or CH; Ri and R2 represent hydrogen, halogen, hydroxy, alkoxy, alkyl, trifluoromethyl or trifluoromethoxy; R4 and R4 'represent hydrogen, alkyl or form a ring with the atom to which they are attached; R5 represents hydrogen, alkyl, alkoxy, or alkylthio, and R6 represents hydrogen or alkyl; Rs and Re form a ring together with the atoms to which they are attached; RT, R8, R9, Rio and R11 represent hydrogen or alkyl, the compounds are useful for the treatment and / or prevention of neuropsychotics disorders including schizophrenia, mania, dementia, depression, Anxiety, compulsive behavior, substance abuse, motor disorders such as Parkinson's disease and movement disorders related to the use of neuroleptic agents. It also includes from the field of the invention the intermediates of formulas (Vll-a) and (Vll-b) wherein X represents oxygen, or sulfur, or CH2, m is zero or an integer of 1-4, and L is a outgoing group. (Vll-b)