MXPA06010720A - Process for preparing n-aryl-piperazine derivatives cross-reference to related applications - Google Patents

Abstract

Processes for preparing N-aryl -piperazine derivatives of formula I particularly (R)-4- cyano-N- [2-[4-(2, 3-dihydro-1, 4-benzodioxan -5-yl)-1-piperazinyi -propyl]-N-(2- pyridinyl) -benzamide, are disclosed. Compositions comprising N-aryl-piperazine derivatives and low levels of common impurities are also disclosed. In addition, products produced by the process are disclosed.

Description

PROCESS FOR PREPARING DERIVATIVES OF N-ARIL-PIPERAZINES FIELD OF THE INVENTION The present invention relates to processes for preparing N-aryl-piperazine derivatives, particularly to the large-scale production of N-aryl-piperazine-useful derivatives, among others, as modulators of the 5-H IA receptor. . BACKGROUND OF THE INVENTION Certain N-aryl-piperazine derivatives possess pharmaceutical activity. In particular, certain N-aryl-piperazine derivatives act on the central nervous system (CNS) by binding to the 5-HT receptors. In pharmacological trials, it has been shown that certain N-aryl-piperazine derivatives bind to the 5-HTIA type receptors. Many of the N-aryl-piperazine derivatives exhibit activity as 5-HTIA antagonists. See, for example, US-A-6,127,357, WO 97/03982, US-B-6,469,007, the disclosures of which are incorporated herein by reference. Certain N-aryl-piperazine derivatives are useful for treating a subject suffering from central nervous system (CNS) disorders such as schizophrenia (and other psychotic disorders such as paranoia and manic depressive illness), Parkinson's disease and other motor disorders, anxiety (for example, generalized anxiety disorders, panic attacks and obsessive disorders) REF: 175702 compulsive), depression (such as by potentiation of serotonin reuptake inhibitors and norepinephrine reuptake inhibitors), Tour.ette syndrome, migraine, autism, attention deficit disorders, and hyperactivity disorders. These compounds may also be useful for the treatment of sleep disorders, social phobias, pain, thermoregulatory disorders, endocrine disorders, urinary incontinence, vasospasm, stroke, eating disorders such as obesity, anorexia and bulimia, sexual dysfunction and the treatment of abstinence from alcohol, drugs and nicotine. In addition, these compounds are useful for the treatment of cognitive dysfunction and may be useful for the treatment of cognitive dysfunction associated with mild cognitive impairment (MCI), Alzheimer's disease and other dementias, including dementia of the body of Lewy Body, vascular and post-apoplectic dementias. Cognitive dysfunction associated with surgical procedures, brain injury or stroke may also be treated with such compounds. In addition, these compounds may be useful for the treatment of diseases in which cognitive dysfunction is a comorbidity eg, Parkinson's disease, autism and attention deficit disorders. In United States Published Application Na 20030204087 a multi-stage synthesis of certain N-aryl-piperazine derivatives of formula I is described: including (R) -4-cyano-N- [2- [4- (2, 3-dihydro-l, 4-benzodioxan-5-yl) -1-piperazinyl-propyl] -N- (2-pyridinyl) benzamide . The reaction reaction scheme for (R) -4-cyano-N- [2- [4- (2,3-dihydro-1,4-benzodioxan-5-yl) -1-piperazinyl-propyl] -N- (2-pyridinyl) benzamide is shown in Reaction Scheme 1, where the benzodioxanoaniline 2 is dialkylated with chloroethanol or ethyl bromoacetate. The diol intermediate 3 is directly prepared or reduced from the corresponding diester 4. The diol moiety is activated as dimesylate 5 followed by coupling with aminosulfonic acid 6. Hydrolysis of the sulfonic acid moiety of compound 7 gives. { 2- [4- (2,3-Dihydro-benzo [1,4] dioxin-5-yl) piperazin-1-yl] -propyl} -pyridin-2-yl-amine) 8. Acylation of compound 8 with p-cyanobenzoyl chloride gives the desired N-aryl-piperazine derivative, (R) -4-cyano-N- [2- [4- ( 2, 3-dihydro-l, 4-benzodioxan-5-yl) -1-piperazinyl-propyl] -N- (2-pyridinyl) -benzamide 1. Although they are useful for laboratory preparations, the above conditions of the (R ) -4-cyano-N- [2- [4- (2,3-dihydro-l, 4-benzodioxan-5-yl) -1-piperazinyl-propyl] -N- (2-pyridinyl) -benzamide are less suitable for a commercial-scale process. The disadvantages include the need for the purification of the intermediates and the difficult isolation of the final product. The polyalkylation by-products from the alkylation of the benzodioxanoaniline 2 and the by-products formed during the formation of piperazine from the dimesylate 5 and the aminosulfonic acid 6 accumulate and make the crystallization of the piperazine salt difficult. This consequently affects the yield and purity of the final product.

SUMMARY OF THE INVENTION The present invention relates to processes for preparing N-aryl-piperazine derivatives, to compositions comprising N-aryl-piperazine derivatives and to a low level of customary impurities and to products produced by improved processes. In one embodiment, the present invention relates to processes for preparing a compound of formula I: or a pharmaceutically acceptable salt thereof; wherein R is C? -C alkyl; Ar 1 is C 6 -C 2 aryl optionally substituted with up to three substituents independently selected from the group consisting of halo, alkyl, alkoxy, alkoxycarbonyl, nitro, amino, alkylamino, dialkylamino, haloalkyl, dihaloalkyl, trihaloalkyl, cyano and amido substituents, each having alkyl not more than six carbon atoms; and Ar 2 is dihydrobenzodioxinyl, benzodioxinyl or phenyl optionally substituted with up to three substituents independently selected from the group consisting of halo, methoxy, halomethyl, dihalomethyl and trihalomethyl; comprising the steps of: (a) dialkylating an amino-substituted aryl compound or an amino-substituted heteroaryl compound of the formula Ar 2 NH 2 wherein Ar 2 is as defined above, with 2-haloethanol to form a compound of the formula II : and forming a salt of the compound of formula II, (b) activating the salt of the compound of formula II to form a corresponding compound of formula III: where L is a leaving group; (c) coupling the compound of formula III with an aminoalkyl (pyridin-2-yl) sulfamic acid of formula wherein R is as defined above, to form a compound of formula IV: IV wherein R is C? -C4 alkyl and Ar2 is as defined above; (d). hydrolyzing the compound of formula IV to form a compound of formula V: and forming a salt of the compound of formula V; and (e) acylating the salt of the compound of formula V with a compound of formula VI: SAW wherein X is halo and Ar1 is as defined above; to form a compound of formula I as defined above. In another embodiment, the present invention relates to the product produced by the process described above.

In yet another embodiment, the present invention relates to compositions comprising: at least one compound of formula I: or a pharmaceutically acceptable salt thereof; wherein R is C? -C alkyl; Ar 1 is C 6 -C 2 aryl optionally substituted with up to three substituents independently selected from the group consisting of halo, alkyl, alkoxy, alkoxycarbonyl, nitro, amino, alkylamino, dialkylamino, haloalkyl, dihaloalkyl, trihaloalkyl, cyano and amido substituents, each having alkyl not more than six carbon atoms; and Ar 2 is dihydrobenzodioxinyl, benzodioxinyl or phenyl optionally substituted with up to three substituents independently selected from the group consisting of halo, methoxy, halomethyl, dihalomethyl and trihalomethyl; less than about 0.5% by weight, based on the weight of the composition, of a dimer of the compound of formula I; And less than about 0.5% by weight, based on the weight of the composition of a polyalkylation impurity. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to processes for preparing N-aryl-piperazine derivatives, to compositions comprising N-aryl-piperazine derivatives and to low levels of customary impurity and to products produced by improved processes. The following definitions are provided for a better understanding of the terms and abbreviations used in this specification.

As used herein and in the appended claims, the singular forms "a", "an", "the", and "the" include the plural reference unless the context clearly dictates otherwise. For example, a reference to "a compound" is a reference to one or more compounds and equivalents thereof known to those skilled in the art and so on. The abbreviations in the description correspond to units of measurement, techniques, properties or compounds as follows: "min" means minutes, "h" means time (s), "μl" means microliter (s), "ml" means milliliter (s), "mM" means millimolar, "M" means molar, "mmol" means millimeter (s), "cm" means centimeters, "SEM" means standard error of the mean and "IU" means international units. "? aC" and? "ED50 value" means a dose that results in 50% relief of the condition or effect observed (50% of the maximum endpoint mean). In the context of this description, numerous terms will be used. The term "treatment" as used herein includes preventive (eg, prophylactic), curative or palliative treatment and "treating" as used herein also includes preventive, curative and palliative treatment. The terms "component", "drug" or "pharmacologically active agent" or "active agent" or "medicament" are used interchangeably herein to refer to a compound or compounds or a composition of matter that, when administered to a an organism (human or animal) induces a pharmacological and / or psychological effect through local and / or systemic action. The term "modulation" refers to the ability to enhance or inhibit a functional property of a biological activity or process, for example, receptor binding activity or signaling activity. Said enhancement or inhibition may be representative of the occurrence of a specific event such as the activation of a signal transduction path and / or may manifest itself only in particular cell types. The modulator is intended to comprise any compound, for example, antibody, small molecule, peptide, oligopeptide, polypeptide or protein, preferably small molecules or peptides. As used herein, "amine substituted aryl compound" means a phenyl or naphthyl compound substituted with at least one amino substituent and optionally substituted with up to 3 substituents independently selected from the group consisting of halo, methoxy, halomethyl, dihalomethyl and trihalomethyl. Said amino-substituted aryl compounds include phenylamine (also known as aniline) and naphthalenylamine.

As used herein, "amino-substituted heteroaryl compound" means a dihydrobenzodioxinyl or benzodioxinyl compound substituted with at least one amino substituent and optionally substituted with up to three substituents independently selected from the group consisting of halo, methoxy, halomethyl, dihalomethyl and trihalomethyl. Said amino-substituted amino compounds include benzodioxanoaniline and dihydrobenzodioxanoaniniline, especially 2,3-dihydro-benzo [1,4] dioxin-5-ylamine. In the present invention, the compounds of formula I can be prepared in the form of pharmaceutically acceptable salts. As used herein, the term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic salts and organic salts. Suitable inorganic salts include inorganic and organic acids such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, malic, maleic, mandelic, ethanolsulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic and the like. Hydrochloric, hydrobromic, phosphoric and sulfuric acids are particularly preferred, and more preferably the hydrochloride salt.

The term "subject" or "patient" refers to an animal including the human species that can be treated with the compositions and / or methods of the present invention. "Alkyl" as used herein, refers to an aliphatic hydrocarbon chain and includes straight and branched chains such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and isohexyl. "Lower alkyl" refers to an alkyl having 1 to 3 carbon atoms.

"Alkoxy" as used herein, refers to the group R-O- where R is an alkyl group of 1 to 6 carbon atoms. "Alkoxycarbonyl" as used herein, refers to the group R-0-C (= 0) where R is an alkyl group of 1 to 6 carbon atoms. "Halogen" (or "halo") as used herein, refers to chlorine, bromine, fluorine and iodine. In one embodiment, the present invention relates to processes for preparing a compound of formula I: or a pharmaceutically acceptable salt thereof; wherein R is C? -C4 alkyl; Ar 1 is C 6 -C 2 aryl optionally substituted with up to three substituents independently selected from the group consisting of halo, alkyl, alkoxy, alkoxycarbonyl, nitro, amino, alkylamino, dialkylamino, haloalkyl, dihaloalkyl, trihaloalkyl, cyano and amido substituents, each having alkyl not more than six carbon atoms; and Ar 2 is dihydrobenzodioxinyl, benzodioxinyl or phenyl optionally substituted with up to three substituents independently selected from the group consisting of halo, methoxy, halomethyl, dihalomethyl and trihalomethyl; comprising the steps of: (a) dialkylating an amino-substituted aryl compound or an amino-substituted heteroaryl compound of the formula Ar 2 NH 2 wherein Ar 2 is as defined above, with 2-haloethanol to form a compound of the formula II : II and forming a salt of the compound of formula II, (b) activating the salt of the compound of formula II to form a corresponding compound of formula III: lll; where L is a leaving group; (c) coupling the compound of formula III with an aminoalkyl (pyridin-2-yl) sulfamic acid of formula wherein R is as defined above, to form a compound of formula IV: IV wherein R is C? -C alkyl and Ar2 is as defined above; (d) hydrolyzing the compound of formula IV to form a compound of formula V: and forming a salt of the compound of formula V; and (e) acylating the salt of the compound of formula V with a compound of formula VI: VI • »where X is halo and Ar1 is as defined above; to form a compound of formula I as defined above. In preferred embodiments, the aminoalkyl (pyridin-2-yl) sulfamic acid is 2-aminopropyl (pyridin-2-yl) sulfamic acid, more preferably, (2R) -2-aminopropyl (pyridin-2-yl) sulfamic acid. In certain preferred embodiments, 2-aminopropyl (pyridin-2-yl) sulfamic acid is formed from its precursor 2- (5-alkyl-2,2-dioxo-2? 6- [1,2,3] oxathiazolidin -3-yl) -pyridine, preferably the precursor 2- (5-methyl-2, 2-dioxo-2? 6- [1,2, 3] oxathiazolidin-3-yl) -pyridine. In certain preferred embodiments, R is methyl. In certain preferred embodiments Ar1 is a substituted phenyl, preferably a phenyl substituted with cyano, more preferably p-cyanophenyl. In certain preferred embodiments, Ar2 is dihydrobenzodioxinyl. In certain preferred embodiments, L is halo, tosylate, mesylate or p-bromophenylsulfonyloxy, preferably mesylate or halo (especially chlorine or bromine), more preferably mesylate. In certain preferred embodiments, X is chlorine. In certain preferred embodiments, the amino-substituted aryl compound is aniline or naphthalenylamine. In other preferred embodiments, the heteroaryl compound substituted with amino is benzodioxanoaniline or dihydrobenzodioxanoaniline, preferably dihydrobenzodioxanoaniline. In certain preferred embodiments, step (b) is carried out in the presence of a tertiary amine, preferably the tertiary amine is triethylamine. In certain preferred embodiments, the 2-haloethanol is 2-chloroethanol. In certain preferred embodiments, the dialkylation step is carried out in the presence of at least one inorganic base in an aprotic solvent. In certain preferred embodiments, the salt of the compound of formula II is an inorganic salt, preferably a hydrogen chloride salt. In certain preferred embodiments the salt of compound of formula V is an inorganic salt, preferably a hydrogen chloride salt. In certain preferred embodiments, the protection stage or the activation step is carried out at a temperature from about 0 ° C to about 25 ° C, preferably at a temperature from about 0 ° C to about 15 ° C, more preferably a temperature of about 0 ° C to about 10 ° C. The process of the invention is particularly useful for the preparation of compounds of formula I A: or a pharmaceutically acceptable salt thereof, The process of the invention is particularly useful for the preparation of 4-cyano-N-. { 2- [4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -propyl} -? - pyridin-2-yl-benzamide or a pharmaceutically acceptable salt thereof, especially including (R) -4-cyano-N- [2- [4- (2,3-dihydro-l, 4-benzodioxan-5 -yl) -1-piperazinyl-propyl] -? - (2-pyridinyl) -benzamide or a pharmaceutically acceptable salt thereof. The improved process of the invention is characterized by improved product purity, higher yields, lower costs and technical convenience with respect to the synthetic route described in US Published Application 2 200330204087. For example, with respect to the formation of cyano-N-. { 2- [4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -propyl YN-pyridin-2-yl-benzamide, the dialkylation of benzodioxanoaniline with 2- Chlorine ethanol is catalyzed with inorganic bases in an aprotic solvent. Polyalkylation is minimized under these conditions. In addition, simple filtration of the inorganic salt formed during the reaction avoids the need for multiple extractions of the highly water soluble diol. The subsequent formation of diol salt gives a stable solid which can be easily isolated with a high yield and purity. The yield and rate of formation of aminosulfonic acid from ammonia from sulfamate are improved using a higher concentration and molar equivalent of ammonia. A very pure crystalline product was isolated and purified simply by exchange of solvent with acetonitrile. The product solid aminosulfonic acid 6 is easily isolated by filtration. The diol salt can be transformed to the piperazine salt in high yield and purity. Activation of the diol can be achieved using methanolsulfonic anhydride (mesyl) or methanesulfonyl chloride (mesyl), preferably methanesulfonyl chloride. The dimesylate is formed directly from the diol salt. The reaction can be carried out at low temperatures, for example the range from about 0SC to about 252C, preferably from about 0aC to about 25SC, more preferably from about 0aC to about 10aC to avoid displacement of the mesylate chloride. The dimesylate formed is then added to a warm mixture of aminosulfonic acid and Hünig base in butyronitrile to give piperazinesulfonic acid. The sulfonic acid moiety of the piperazine is then hydrolysed using a 3N HCl solution. The piperazine is purified and isolated by filtration as the piperazine salt. The salts formed allow the easy isolation and purification of piperazine.

The dilaquilación of benzodioxanoanilina. with chloroethanol is preferably carried out in an aprotic solvent, such as xylene, toluene, propionitrile and butyronitrile, preferably in a polar high-boiling aprotic solvent such as propionitrile and butyronitrile and more preferably butyronitrile at a temperature of about 45 ° C to about 120 ° C, preferably at about 50 ° C, under reflux in the presence of a base, preferably in an inorganic base such as potassium carbonate or sodium carbonate, by catalysts such as sodium iodide or t-butylammonium iodide. The use of an inorganic base gives a by-product of inorganic salt that can be easily removed by filtration. The product diol is very soluble in water and the use of an inorganic base avoids the need for an aqueous treatment. A salt, preferably the aniline diol hydrochloride, can be obtained to facilitate the isolation with high yield and purity. The yield and rate of conversion of the ammonia from sulfamate was improved with the increase of the molar equivalent of the ammonia used. This step is characterized by an easy isolation of the product from the exchange of solvent with CH3CN. The piperazine formulation step is carried out from the coupling of the activated diol and aminosulfonic acid. It is important that the piperazine can be prepared from the diol salt and aminosulfonic acid without isolation of intermediates, without changing the solvent (preferably butyronitrile) and with high yield and purity. In addition, modifications of the present process are less laborious and need less time than the synthetic route described in United States Published Application Na 20030204087. In other embodiments, the invention relates to "the products produced by the improved process containing lower levels. of usual impurities, including the dimer of the compound of formula I and the polyalkylation products The impurities of the dimer of formula I include the compounds of formula A: wherein Q is H, -CH3, -CH (CH3) 2, CH (CH2) 2CH3, or CH (CH2) 3CH3. In still other embodiments, the invention relates to compositions comprising: the product produced by the improved process; and at least one pharmaceutically acceptable carrier. In another embodiment, the invention relates to compositions comprising: at least one compound of formula I: or a pharmaceutically acceptable salt thereof; wherein R is C? -C alkyl; Ar1 is aryl C6-C? optionally substituted with up to three substituents independently selected from the group consisting of halo, alkyl, alkoxy, alkoxycarbonyl, nitro, amino, alkylamino, dialkylamino, haloalkyl, dihaloalkyl, trihaloalkyl, cyano, and amido substituents, each alkyl having no more than six carbon atoms; and Ar 2 is dihydrobenzodioxinyl, benzodioxinyl or phenyl optionally substituted with up to three substituents independently selected from the group consisting of halo, methoxy, halomethyl, dihalomethyl and trihalomethyl; less than about 0.5% by weight, based on the weight of the composition, of a dimer of the compound of formula I; And less than about 0.5% by weight, based on the weight of the composition of a polyalkylation impurity. In certain preferred embodiments, the composition additionally comprises at least one pharmaceutically acceptable carrier. In certain preferred embodiments, R is methyl. In certain preferred embodiments, Ar 1 is a substituted phenyl, preferably phenyl substituted with cyano, more preferably p-cyanophenyl. In certain preferred embodiments, Ar2 is dihydrobenzodioxinyl. In certain preferred embodiments, L is a mesylate or halo, especially chlorine or bromine, preferably mesylate. In certain preferred embodiments, the compound of formula I is a compound of formula IA: or a pharmaceutically acceptable salt thereof. In certain preferred embodiments, the compound of formula I is 4-cyano-N-. { 2- [4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -propyl} -N-pyridin-2-yl-benzamide or a pharmaceutically acceptable salt thereof, preferably (R) -4-cyano-N- [2- [4- (2,3-dihydro-l, 4-benzodioxan-5- il) -1-piperazinyl-propyl] -N- (2-pyridinyl) -benzamide or a pharmaceutically acceptable salt thereof. Some of the compounds of the present invention may contain chiral centers and said compounds may exist in the form of stereoisomers (i.e., enantiomers). The present invention includes all of these stereoisomers and mixtures thereof. including racemic mixtures. Racemic mixtures of stereoisomers as well as substantially pure stereoisomers are within the scope of the invention. The term "substantially pure" as used herein, means that at least about 90% by mole, more preferably at least about 95% by mole and more preferably at least about 98% by mole is present. of the desired stereoisomer with respect to other possible stereoisomers. Preferred enantiomers can be isolated from racemic mixtures by any method known to those skilled in the art, including high performance liquid chromatography (HPLC) and the formation and crystallization of chiral or prepared salts by the methods described herein. See, for example, Jacques, et al. , Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H. et al. , Tetrahedron, 33: 2725 (1997); Eliel, E.L. Stereochemistry of Carbon Compounds, (McGraw-Hill, Y, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions, p 286 (E.L. Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). The present invention includes prodrugs of the compounds of formula I. "Prodrug" as used herein means a compound that can be converted in vivo by metabolic means (for example by hydrolysis) into a compound of formula I. various forms of prodrugs, for example, as discussed in Bungaard, (ed), Design of Produgs, Elsevier (1985); Widder, et al. (ed), Methods in Enzymology, vol. 4, Academic Press (1985); Kroggaard-Larsen, et al. , (ed). "Design and Application of Produgs", Textbook of Drug Design and Development, Chapter 5, 113-191 (1191), Bundgaard, et al., Journal of Drug Deliver Reviews, 1992, 8: 1-38, Bundgaard, JX of Pharmaceutical Sciences, 1998, 77: 285 et seq .; and Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975). In addition, the compounds of formula I can exist in unsolvated forms as well as solvated with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, solvated forms are considered equivalent to unsolvated forms for the purpose of the present invention. The compounds can be synthesized, for example, by the methods described below, or variations thereof as will be appreciated by those skilled in the art. It is contemplated that all the processes described in conjunction with the present invention can be practiced at any scale, including 'milligrams, grams, multigrams, kilograms, multikilograms or commercial industrial scale. As will be easy to understand, the functional groups present may contain protecting groups during the course of the synthesis. Protecting groups are per se known as functional chemical groups that can be selectively linked and removed from functionalities such as hydroxyl groups and carboxyl groups. These groups are present in a chemical compound to render said functionality inert to the chemical reaction conditions to which the compound is exposed. Any variety of protecting groups can be employed with the present invention. Protecting groups that can be employed in accordance with the present invention can be described in Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis 2 - Ed. Wiley & Sons, 1991. The compounds of the present invention are suitably prepared according to the following general description and specific examples. The variables used are as defined for formula I, unless otherwise indicated. The reagents used in the preparation of the compounds of this invention can be obtained commercially or can be prepared by standard procedures described in the literature. The process described above can be carried out to give a compound of formula I in the form of a free base or as an acid addition salt. If the compound of formula I is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product of the process is a free base, an acid addition salt, particularly a pharmaceutically acceptable acid addition salt, can be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional methods for preparing acid addition salts from basic compounds. Examples of acid addition salts are those formed from inorganic and organic acids such as sulfuric, hydrochloric, hydrobromic, phosphoric, tartaric, fumaric, maleic, citric, acetic, formic, methanesulfonic, p-toluenesulfonic, oxalic and succinic acids. The compounds of formula I may contain one or more asymmetric carbon atoms so that the compounds may exist in different stereoisomeric forms. The compounds may be, for example, recemates or optically active forms. The optically active forms can be obtained by resolution of the recemates or by asymmetric synthesis.

The compounds of formula I possess pharmacological activity. In particular, they act on the central nervous system (CNS) by binding to 5-HT receptors. In pharmacological assays, compounds have been shown to bind particularly to 5-HT-type receptors. A- In general, compounds selectively bind to 5-HTIA-type receptors to a much greater extent than they bind to. other receptors, such as 0C receivers? and D2. Many have activity, 5-HT? A antagonists in the pharmacological trial. The compositions and products produced by the process of the present invention comprising compounds of formula I are useful for treating a subject suffering from central nervous system (CNS) disorders such as schizophrenia, (and other psychotic disorders such as paranoia and disease manic depressive), Parkinson's disease and other motor disorders, anxiety (for example, generalized anxiety disorders, panic attacks and obsessive-compulsive disorders), depression (such as by potentiation of serotonin reuptake inhibitors and reuptake inhibitors). norepinephrine), Tourette syndrome, migraine, autism, attention deficit disorders and hyperactivity disorders. These compositions and products produced by the process of the present invention may also be useful for the treatment of sleep disorders, social phobias, pain, thermoregulatory disorders, endocrine disorders, urinary incontinence, vasospasm, stroke, eating disorders such as for example obesity, anorexia and bulimia, sexual dysfunction and the treatment of abstinence from alcohol, drugs and nicotine. In addition, these compositions and products produced by the process of the present invention are useful for the treatment of cognitive dysfunction and may be useful for the treatment of cognitive dysfunction associated with mild cognitive impairment (MCI), Alzheimer's disease and others. dementias, including Lewy Body dementia, vascular and post-stroke dementia. Cognitive dysfunction associated with surgical procedures, brain injury or stroke may also be treated with said compositions and products produced by the process of the present invention. In addition, these compositions and products produced by the process of the present invention may be useful for the treatment of diseases in which cognitive dysfunction is a comorbidity eg, Parkinson's disease, autism and attention deficit disorders. In other embodiments, the invention relates to compositions comprising: a. at least one compound of formula I or a pharmaceutically acceptable salt thereof; b. less than about 0.5% by weight, based on the weight of the composition of a dimer of the compound of formula I; c. less than about 0.5% by weight, based on the weight of the composition of a polyalkylation impurity; d. optionally at least one pharmaceutically acceptable carrier. Generally, the compound of formula I or a pharmaceutically acceptable salt thereof will be present at a level of from about 0.1% by weight to about 90% by weight, based on the total weight of the composition. Preferably, the compound of formula I or a pharmaceutically acceptable salt thereof will be present at a level of at least about 1% by weight based on the total weight of the composition. More preferably, the compound of formula I or a pharmaceutically acceptable salt thereof will be present at a level of at least about 5% by weight, based on the total weight of the composition. Even more preferably, the compound of formula I or a pharmaceutically acceptable salt thereof will be present at a level of at least about 10% by weight based on the total weight of the composition. Even more preferably, the compound of formula I or a pharmaceutically acceptable salt thereof will be present at a level of at least about 25% by weight, based on the total weight of the composition. Preferably, the compositions of the invention comprise less than about 0.2% by weight of the dimer of the compound of formula I, based on the total weight of the composition. More preferably, the compositions of the invention comprise less than about 0.2% by weight of the dimer of the compound of formula I, based on the total weight of the composition. Even more preferably, the compositions of the invention are substantially free of the dimer of the compound of formula I. Preferably, the compositions of the invention comprise less than about 0.2% by weight of the polyalkylation impurity, based on the total weight of the composition. More preferably, the compositions of the invention comprise less than about 0.1% by weight of the polyalkylation impurity, based on the total weight of the composition. Even more preferably, the compositions of the invention are substantially free of the polyalkylation impurity. Said compositions are prepared according to acceptable pharmaceutical methods such as those described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, PA (1985). Pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and that are biologically acceptable. The compounds and compositions of this invention can be administered orally or parenterally, either pure or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances that can act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, emollients, compression aids, binders or tablet disintegrating agents or as an encapsulating material. In the powders, the carrier is a finely divided solid which is mixed with the finely divided active ingredient. In the tablets, the active ingredient is mixed with a carrier having the necessary compression properties in the proper proportions and compacted in the desired shape and size. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, low melting point waxes, and ion exchange resins. Liquid carriers can be used in the preparation of solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier may contain other pharmaceutically suitable additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, viscosity regulating dyes, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives such as the above, for example cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols for example glycols and their derivatives and oils). (for example coconut oil and fractionated peanut oil) For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration The liquid pharmaceutical compositions, which are sterile solutions or suspensions can be administered for example by intramuscular injection., intraperitoneal or subcutaneous. Sterile solutions can also be administered intravenously. Oral administration can be by a liquid or solid composition form. Preferably, the pharmaceutical composition is in unit dosage form, for example, tablets, capsules, powders, solutions, suspensions, emulsions, granules or suppositories. In such form the composition is subdivided into unit doses containing the appropriate amounts of active ingredient; the unit dosage forms may be packaged compositions, for example, powders, vials, ampoules, pre-filled syringes or packaged seals containing liquids. The unit dosage form may be, for example, the capsule itself or tablet or may be an appropriate number of any of said compositions in packaged form. In another embodiment of the present invention, the compositions and products produced by the process of the present invention can be administered to a mammal with one or more active pharmaceutical agents, such as those agents used to treat any other medical condition present in the mammal. Examples of such active pharmaceutical agents include pain relief agents, anti-angiogenic agents, antineoplastic agents, antidiabetic agents, anti-infective agents or gastrointestinal agents or combinations thereof. The one or more other active pharmaceutical agents can be administered in a therapeutically effective amount simultaneously (such as individually at the same time or together in a pharmaceutical composition) and / or successively with one or more compounds of the present invention. The term "combination therapy" refers to the administration of two or more therapeutic agents or compounds to treat a therapeutic condition or disorder described in the present disclosure, eg, depression, anxiety, hypotension, sleep disorders, eating disorders, dysfunction. sexual or other condition or disorder. Said administration includes the use of each type of therapeutic agent in a concurrent manner. In any case, the treatment regimen will provide beneficial effects of the combination of drugs in the treatment of the conditions or disorders described herein. The route of administration can be any route that efficiently transports the active compound of formula I to an appropriate or desired site of action such as the oral, nasal, pulmonary, transdermal, such as passive or iontophoretic, or parenteral, eg, rectal route. , by deposit, subcutaneous, intravenous, intraurethral, intramuscular, intranasal ophthalmic solution or an ointment. In addition, the administration of the compound of formula I with other active ingredients may be concurrent or simultaneous. EXAMPLES The present invention is further defined in the following examples, in which all parts and percentages are by weight and degrees by degrees centigrade unless otherwise indicated. It should be understood that these examples, while indicating preferred embodiments of the invention, will be given by way of illustration only. From the above analysis and from these examples, a person skilled in the art can deduce the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various uses and terms . The reagents and intermediates used in that document are available in the market or can be prepared according to standard bibliographic procedures. Reaction enzyme 2 shows the synthesis of (R) -4-cyano-N- [2- [4- (2,3-dihydro-l, 4-benzodioxan-5-yl) -1-piperazinyl-propyl ] -N- (2-pyridinyl) benzamide as described in more detail below. Reaction scheme 2 EXAMPLE 1 PREPARATION OF THE HYDROGEN CHLORIDE SALT OF 2 [- (2, 3-DIHYDRO-BENZO [1, 4JDI0XIN-5-IL) - (2-HYDROXY-ETHYL) -AMINO] -ETHANOL To a solution of benzodioxanoaniline (50 g, 0.331 mol) in butyronitrile (150 ml) at room temperature was added sodium carbonate (70.2 g, 0.662 mol), sodium iodide (5 g, 0.033 mol) and chloroethanol (160 g, 133 ml). The reaction mixture was heated to reflux (115 ± 5 ° C) After 16 hours, it was cooled to room temperature and then the suspension was filtered through a Büchner funnel. The solids were washed with ethyl acetate (2 x 100 ml). The combined filtrates were concentrated to 1/4 of their original volume. Toluene was added (150 ml) followed by the addition of 10 N HCl in EtOH (66 ml). The reaction mixture was stirred at 23-25 ° C overnight for 16 hours and then cooled to 0-5 ° C for 2 hours. The product was filtered through a Büchner funnel, washed with toluene (2 x 50 ml), dried in a vacuum oven to give 79 g (86%) of the diol HCl as a light purple solid. XH RM? (CDCl 3) d 6.83-6.70 (m, 3H), 4.29-4.20 (m, 4H), 3.54 (t, J = 5.1 Hz, 4H), 3.20 ( t, J = 5.1 Hz, 4H), 3.09 (br s, 2H) (free base). mp: 145-148 ° C Potassium carbonate has been replaced by sodium carbonate and t-butylammonium iodide has been replaced by sodium iodide.

E0? MPLO 2 PREPARATION OF ACID (2R) -2-AMINOPROPIL (PYRIDIN-2-IL) SULFAMIC A mixture of sulfamate (25 g, 0.13 mol) in a 7.8 N ammonia solution in MeOH (270 ml, 2.1 mol) was stirred at room temperature under N2 atmosphere for one day. The resulting mixture was concentrated to 1/3 of its original volume and then acetonitrile (80 ml) was added. The mixture was concentrated to 1/3 of its original volume. Another portion of acetonitrile (80 ml) was added and the mixture was concentrated again to 1/3 of its original volume. The suspension was heated at 40-45 ° C for 10-15 minutes and then cooled to room temperature. The white solids were then filtered, washed with acetonitrile (50 ml) and dried in a vacuum oven to give 22 g (81%) of the sulfamic acid as an off white solid (98% area by LC / MS) . ^ • H RM? (DMSO) d 8, 17 (d, J = 3 Hz, ÍH), 7.5-7.9 (m, EH), 6/82 (t, J = 4.5 Hz, 1H), 4.03 (dd, J = 10.8 Hz, 3.6 Hz, 1H), 3.94 (ss, J = 10.8 Hz, 5.7 Hz, 1H), 3.4-3.6 (m, 1H). ) 1.18 (d, J = 5, 1 Hz, 3H); 13C RM? (DMSO) d 156.1, 146.8, 136.9, 115.7, 114.6, 50.1, 47.9, 16.7; IR (KBr):? Max 3426, 3137, 3073, 2980, 2518, 1629, 1588, 1520, 1465, 1432, 1366, 1286, 1234, 1197, 1146, 1117, 1063, 1042 cm "1; CH? (Calculated ) C 41.6 H 5.62 N 18.2, CH (observed) C 41.1 H 5.49 N 17.7, mp 175.5-179 ° C.

EXAMPLE 3 PREPARATION OF THE HYDROGEN CHLORIDE SALT. { 2- [4- (2,3-DIHYDROBENZO [1,4] DIOXY? -5-IL) -PIPERAZIN-1-IL] -PROPIL} -PIRIDI? -2-IL-AMINE) A mixture of diol-HCl (50.0 g, 0.18 mol) in butyronitrile (250 ml) was cooled to 8-9 ° C in an ice water bath. To this mixture, methanesulfonyl chloride (74 g, 0.64 mol) was added followed by the addition of triethylamine (TEA) (150 ml, 1.07 mol) for 30 minutes keeping the reaction temperature below about 25. ° C. After the addition, the reaction mixture was allowed to stir in an ice-water bath for an additional 30 minutes. At the end of this time, cold water (300 ml) was added. The two layers were separated. The aqueous layer was extracted with butyronitrile (100 ml). The combined butyronitrile layers were extracted with saturated NaHCO 3 (300 ml) and H 2 O (300 ml). This solution of dimesylate and butyronitrile was then added over 30 minutes to a mixture of aminosulfonic acid (37.4 g, 0.16 mol) and Hünig's base (127 ml, 0.727 mol) in butyronitrile (150 ml) heated to 60 ° C. 65 ° C. The mixture was heated for 3 hours.

During this time, the mixture became transparent. The mixture was cooled to room temperature and then 3N HCl was added (250 ml). This was stirred at room temperature for 2 hours and then two layers were separated. The aqueous layer was extracted with CH2C12 (2 X 250 ml) then cooled to 4-6 ° C before adding ethyl acetate (EtOAc) (400 ml) followed by the slow addition of 10 N NaOH (100 ml). (Note: the pH of the aqueous layer was -10-11). The two layers were separated. The aqueous layer was extracted with EtOAc (150 mL). The combined EtOAc layers were extracted with H20 (300 ml), then the solvent was changed with toluene (400 ml). To the toluene solution was added ethyl acetate (2B) (55 ml). This was heated to 60-65 ° C before slowly adding 9.54? in ethanol (68 ml). The mixture was cooled to room temperature and a solid formed. The mixture was stirred at room temperature overnight then cooled to 0-5 ° C for 2-3 hours before filtration, yielding 32.6 g, yield 43% of the title compound as an off-white solid. Rf = 0.28 (20: 1 CHCl3: CHC13: CH30H) (free base) 1HRM? (CDCl 3) d 8.37 (m, HH), 7.30-7.65 (m, 2H), 6.77 (t, J = 8, 1 Hz, HH), 6.40-6.60 ( m, 1H), 6.40 (d, J = 8.3 Hz, 1H) 5.37 (, ÍH), 4.15-4.40 (m, 4H), 3.30 (m, 1H), 2.90-3.20 (m, 4H), 2.82 (, ÍH), 2.62 (m, 1H), 1.10 (d, J = 6.4 Hz, 3H). EXAMPLE 4 PREPARATION OF THE HYDROGEN CHLORIDE SALT OF (R) -4-CYANO-N- [2- [4- (2,3-DIHYDRO-1, 4-BE? ZODIOXAN-5-IL) -1-PIPERAZINIL -PROPIL] -N- (2-PYRIDINYL) BENZAMIDE To a solution of potassium carbonate (125.1 g, 906 mmol) in H20 (159 mL), EtOAc (500 mL) was added. To the biphasic mixture, hydrogen chloride salt was added. { 2- [4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -propyl} pyridin-2-yl-amine (100 g, 216 mmol) in H20 (300 mL). The mixture was stirred and cooled to 0-5 ° C before adding a solution of 4-cyanobenzoyl chloride (42.8 g, 259 mmol) in EtOAc (200 mL) for 30 minutes. The reaction mixture was heated to 23-25 ° C and stirred for an additional 1 hour. H20 (300 ml) was added and the mixture was stirred for 5 minutes. The two layers were separated. The aqueous layer was extracted with EtOAc (150 mL). The combined organic layers were washed with brine (300 ml) and H20 (300 ml) then concentrated to about 1/3 of their original volume. Additional EtOAc (-300 ml) was added to the reaction mixture. The solution was heated to 63-67 ° C. HCl in EtOH (4.8 N, 50 ml) was added dropwise over 1 hour. It was stirred at 63-67 ° C for 10 minutes after it was cooled to 23-25 ° C. Whitish solids formed after the addition. After 1 hour of stirring at room temperature, the reaction mixture was cooled in an ice bath at 0-5 ° C and stirred for a further 1 hour. The solids were filtered, washed with EtOAc (2 x 100 ml) and dried in vacuo to give 90.4 g (80%) of the title compound (98.6% by HPLC) as an off-white solid. X H NMR (DMSO) d 8.45 (m, HH), 7.69-7.78 (m, 3H), 7.45 (d, J = 8.3 Hz, 2H), 7.28 (m, 1H), 7.20 (d, J = 8.0 Hz, 1H), 6.78 (t, J = 8, l Hz, IH), 6.58 (m, 2H), 4.41 (m, 2H), 4.25 (m, 4H), 3.50-3.90 (m, 8H), 3.39 (m, ÍH), 3.19 (m, lH), 1.40 (d, J = 6.7 Hz, 3H). The polyalkylation impurity and dimer impurity levels were measured by high performance liquid chromatography (HPLC) with a detection limit of 0.05% by weight, based on the weight of the total composition. For example 4, the percentage of HPLC showed no impurity of dimers or polyalkylation impurity. When ranges are used herein for physical properties such as molecular weight or chemical properties such as chemical formulas, it is intended to include all combinations and sub-combinations of ranges of specific embodiments thereof. The descriptions of each patent, patent application and publication cited or described in this document are incorporated herein by reference in their entirety. Those skilled in the art will appreciate that numerous changes and modifications can be made to the preferred embodiments of the invention and that such changes and modifications can be made without departing from the spirit of the invention. Therefore, it is intended that the appended claims cover all of these equivalent variations that are included within the true spirit and scope of the invention. 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.

Claims (49)

1. CLAIMS Having described the invention as above, the content is claimed as property < in the following claims: 1. A process for preparing a compound of formula I: or a pharmaceutically acceptable salt thereof; characterized in that R is C1-C4 alkyl; ? r1 is aryl C6-C? optionally substituted with up to three substituents independently selected from the group consisting of halo, alkyl, alkoxy, alkoxycarbonyl, nitro, amino, alkylamino, dialkylamino, haloalkyl, dihaloalkyl, trihaloalkyl, cyano, and amido substituents, each alkyl having no more than six carbon atoms; and Ar 2 is dihydrobenzodioxinyl, benzodioxinyl or phenyl optionally substituted with up to three substituents independently selected from the group consisting of halo, methoxy, halomethyl, dihalomethyl and trihalomethyl; comprising the steps of: (a) dialkylating an amino-substituted aryl compound or an amino-substituted heteroaryl compound of the formula Ar 2 NH 2 wherein Ar 2 is as defined above, with 2-haloethanol to form a compound of the formula II : and forming a salt of the compound of formula II, (b) activating the salt of the compound of formula II to form a corresponding compound of formula IIX: lll where L is a leaving group; (c) coupling the compound of formula III with an aminoalkyl (pyridin-2-yl) sulfamic acid of formula wherein R is as defined above, to form a compound of formula IV: IV wherein R is C1-C4 alkyl and Ar2 is as defined above; (d) hydrolyzing the compound of formula IV to form a compound of formula V: and forming a salt of the compound of formula V; and (e) acylating the salt of the compound of formula V with a compound of formula VI: VI - wherein X is halo and Ar1 is as defined above; to form a compound of formula I as defined above.
2. 2. A process according to claim 1, characterized in that the aminoalkyl (pyridine-2-yl) sulfamic acid is formed from its precursor 2- (5-alkyl-2, 2-dioxo-2? 6- [1 , 2, 3] oxathiazolidin-3-yl) -pyridine.
3. 3. A process according to claim 1 or claim 2, characterized in that the aminoalkyl (pyridine-2-yl) sulfamic acid is 2-aminopropyl (pyridin-2-yl) sulfamic acid.
4. 4. A process according to claim 3, characterized in that the aminoalkyl (pyridine-2-yl) sulfamic acid is (2R) -2-aminopropyl (pyridin-2-yl) sulfamic acid.
5. 5. A process according to claim 2 characterized in that the precursor 2- (5-alkyl-2, 2-dioxo-2? 6- [1,2,3] oxathiazolidin-3-yl) -pyridine is the precursor 2 - (5-methyl-2, 2-dioxo-2? 6- [1,2,3] oxathiazolidin-3-yl) -pyridine.
6. 6. A process according to claim 1, characterized in that R is methyl.
7. 7. A process according to any of claims 1 to 6, characterized in that? R1 is a substituted phenyl.
8. 8. A process according to claim 7, characterized in that Ar1 is a phenyl substituted with cyano.
9. 9. A process according to claim 7, characterized in that Ar1 is a p-cyanophenyl.
10. 10. A process according to any of claims 1 to 9, characterized in that Ar2 is dihydrobenzodioxinil.
11. 11. A process according to any of claims 1 to 9, characterized in that the heteroaryl compound substituted with amino is benzodioxanoanilina or dihidrobenzodioxanoanilina.
12. 12. A process according to claim 11, characterized in that the heteroaryl compound substituted with amino is 2,3-dihydro-benzo [1,4] dioxin-5-yl-amine.
13. 13. A process according to any of claims 1 to 9, characterized in that the amino-substituted aryl compound is aniline or naphthalenylamine.
14. 14. A process according to any of claims 1 to 13, characterized in that L is halo, tosylate, mesylate or p-bromophenylsulfonyloxy.
15. 15. A process according to claim 14, characterized in that L is mesylate.
16. 16. A process according to claim 14,. characterized in that L is halo.
17. 17. A process according to claim 16, characterized in that L is chlorine or bromine.
18. 18-. A process according to any of claims 1 to 17, characterized in that X is chlorine.
19. 19. A process according to any of claims 1 to 18, characterized in that step (b) is carried out in the presence of a tertiary amine.
20. 20. A process according to claim 19, characterized in that the tertiary amine is triethylamine.
21. 21. A process according to any of claims 1 to 20, characterized in that 2-haloethanol is 2-chloroethanol.
22. 22. A process according to any of claims 1 to 21, characterized in that the dialkylation step is carried out in the presence of at least one inorganic base in an aprotic solvent.
23. 23. A process according to any of claims 1 to 22, characterized in that the salt of the compound formula II is an inorganic salt.
24. 24. A process according to claim 23, characterized in that the salt of the compound of formula II is a hydrogen chloride salt.
25. 25. A process according to any of claims 1 to 24, characterized in that the salt of the compound of formula V is an inorganic salt.
26. 26. A process according to claim 25, characterized in that the salt of the compound of formula V is a hydrogen chloride salt.
27. 27. A process according to any of claims 1 to 26, characterized in that the activation step (b) is carried out at a temperature from about 0aC to about 252C.
28. 28. A process according to claim 27, characterized in that the activation step (b) is carried out at a temperature from about 0aC to about 15aC.
29. 29. A process according to claim 1, characterized in that the compound of formula I prepared is a compound of formula IA:
30. 30. A process according to claim 1, characterized in that the compound of formula I prepared is 4-cyano-N-. { 2- [4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) piperazin-1-yl] -propyl} -N-pyridin-2-yl-benzamide or a pharmaceutically acceptable salt thereof.
31. 31. A process according to claim 29, characterized in that the compound of formula I is (R) -4-cyano-N- [2- [4- (2,3-dihydro-l, -benzodioxan-5-yl. ) -1-piperazinyl-propyl] -N- (2-pyridinyl) benzamide or a pharmaceutically acceptable salt thereof.
32. 32. A product characterized in that it is produced by a process according to any of claims 1 to 31.
33. 33. A composition characterized in that it comprises: a product produced by the process according to any of claims 1 to 31; and at least one pharmaceutically acceptable carrier.
34. 34. A composition characterized in that it comprises: at least one compound of formula I: or a pharmaceutically acceptable salt thereof; wherein R is C? -C4 alkyl; Ar1 is aryl Cg-C? optionally substituted with up to three substituents independently selected from the group consisting of halo, alkyl, alkoxy, alkoxycarbonyl, nitro, amino, alkylamino, dialkylamino, haloalkyl, dihaloalkyl, trihaloalkyl, cyano, and amido substituents, each alkyl having no more than six carbon atoms; and Ar 2 is dihydrobenzodioxinyl, benzodioxinyl or phenyl optionally substituted with up to three substituents independently selected from the group consisting of halo, methoxy, halomethyl, dihalomethyl and trihalomethyl; less than about 0.5% by weight, based on the weight of the composition, of a dimer of the compound of formula i; and less than about 0.5% by weight, based on the weight of the composition of a polyalkylation impurity.
35. 35. A compound according to claim 34, characterized in that the dimer is a compound of formula wherein Q is H, -CH3, -CH (CH3) 2, CH (CH2) 2, CH3, or CH (CH2) 3CH3
36. 36. A compound according to claim 35, characterized in that Q is H.
37. 37. A compound according to claim 35, characterized in that Q is -CH3, -CH (CH3) 2, CH (CH2) 2CH3, or CH (CH2) 3CH3.
38. 38. A composition according to any of claims 34 to 37, characterized in that it additionally comprises at least one pharmaceutically acceptable carrier.
39. 39. A composition according to claim 34, characterized in that the compound of formula I is a compound of formula IA: or a pharmaceutically acceptable salt thereof.
40. 40. A composition according to any of claims 34 to 39, characterized in that R is methyl.
41. 41. A composition according to any of claims 34 to 40 characterized in that Ar1 is a substituted phenyl.
42. 42. A composition according to claim 41, characterized in that Ar1 is a phenyl substituted with cyano.
43. 43. A composition according to claim 42, characterized in that Ar1 is a p-cyanophenyl.
44. 44. A composition according to any of claims 34 to 43, characterized in that Ar2 is dihydrobenzodioxinyl.
45. 45. A composition according to claim 34, characterized in that the compound of formula I is 4-cyano- N-. { 2- [4- (2, 3-dihydro-benzo [l,] dioxin-5-yl) piperazin-1-yl] -propyl} -N-pyridin-2-yl-benzamide or a pharmaceutically acceptable salt thereof.
46. 46. A composition according to claim 34, characterized in that the compound of formula I is (R) -4-cyano-N- [2- [4- (2,3-dihydro-l, 4-benzodioxan-5- il) -1-piperazinyl-propyl] -N- (2-pyridinyl) benzamide or a pharmaceutically acceptable salt thereof.
47. 47. A composition according to any of claims 34 to 46, characterized in that the dimer is present at a level of less than about 0.2% by weight, based on the weight of the composition.
48. 48 A composition in accordance with the claim 47, characterized in that the dimer is present at a level of less than about 0.1% by weight, based on the weight of the composition.
49. 49. A composition according to any of claims 34 to 46, characterized in that the composition is substantially free of the dimer.